AU716772B2

AU716772B2 - Novel heterocyclic derivatives as intermediates for 2-thiosubstituted carbapenems

Info

Publication number: AU716772B2
Application number: AU28338/97A
Authority: AU
Inventors: Panayota Bitha; Karen Bush; Yang-I Lin; Subas Sakya; Timothy W. Strohmeyer
Original assignee: American Cyanamid Co
Current assignee: Wyeth Holdings LLC
Priority date: 1993-03-16
Filing date: 1997-06-27
Publication date: 2000-03-09
Anticipated expiration: 2014-03-15
Also published as: AU2833897A

Description

S F Ref: 264554D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name and Address Name and Address of Applicant: Actual Inventor(s): American Cyanamid Company One Cyanamid Plaza Wayne New Jersey 07470 UNITED STATES OF AMERICA Yang-I Lin, Panayota Bitha, Strohmeyer and Karen Bush Subas Sakya, Timothy W.

Address for Service: Invention Title: Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Novel Heterocyclic Derivatives as Intermediates for 2-Thiosubstituted Carbapenems The following statement is a full description of this invention, best method of performing It known to me/us:including the 5845 1 Novel Heterocyclic Derivatives as Intermediates for 2- Thiosubsituted Carbapenems Field of the Invention This invention relates to novel intermediate compounds for the production of novel carbapenem antibiotics and non-toxic pharmaceutically acceptable salts thereof, which have antimicrobial activity. Therefore, the present carbapenem antibiotics and pharmaceutical compositions thereof are useful in the treatment of bacterial infections in humans and animal, either alone or in combination with other anitibiotics. The present invention also provides processes for the preparation of the novel intermediates.

Summary of the Invention This invention is concerned with novel intermediate compounds and stereoselective processes for the production of compounds of formula IV.

According to an embodiment of this invention there is provided a compound selected from those of formula IV and IX:

HS

(CH

2 )nR 2

Z

HS (CH 2 )nR 2 IV (4-6) 9 9 9 9 0 999 *99** 9*9* 9 9*9* 9999 9**9 IV (1-3) wherein: Y is selected form chloro, bromo, iodo, methane-sulfonate and trifluoromethanesulfonate; n is an integer from 0-4; 2o Z is selected from oxygen, sulfur, sulfoxide and sulfone; R? is selected from: methyl, hydrogen, fluorine, chlorine, bromine, iodine, -OCOCH 3

-OCOCF

3

-OSO

2

CH

3

-OSO

2 Ph, azido, (ii) a moiety of the formula: wherein n" is an integer from 0-2; and R" is hydrogen or an organic group bonded via a carbon atom selected from substituted or unsubstituted (Ci-C 4 )alkyl, substituted or unsubstituted (C3-C)cycloalkyl, .III.XIO2219 doc.K\VW substituted or unsubstituted

(C

2

-C

4 )alkenyl, substituted or unsubstituted (C 2 -c 4 )alkynyl, substituted or unsubstituted aryl, substituted or unSubStituted heteroaryl, substituted or unsubstituted aryl(C 1

-C

6 alkyl, substituted or unsubstituted heterocyclyl, any of such groups being optionally Substituted; said substitution is selected from

(C

1

-C

4 )alkyl, hydroxy

(C

1

-C

4 )alkoxy, phenyl, heterocyclyl, amino, amidino, guanidino, carboxamido, carbamoyl, and quaternary ammonio; or R2 is hydroxy, -OR a -OC(O)Ra -OC(O)OR -OC(O)NRaa or 0Ra -oc( 0)-c NH 2 wherein R is independently selected V*00: and is as hereinabove defined or 0 0 P 0 CH2 CH2R 13 0 iwherein R1 is a moiety selected from those of the formulae: B_ B_

B

_N

-NH3 -N(CH3)3 and (iv) or R 2 is an organic residue bonded via a nitrogen atom, selected from NO, NO 2 NOV, NC, NCO, NHCN, anid NRhR- wherein Rh and eare independently selected from hydrogen; amino; substituted or unsubstituted amino; substituted or unsubstituted (C 1

-C

4 )alkyl and

(C

3 -C 6 cycloalkyl (C 1 -C 4 alkyl, aryl, aralkyl, heterocyclyl, heterocyclyl (C 1 -C 4 alkyl, heteroaryl and heteroaryl (C 1 -C 4 )alkyl wherein the heteroatom or heteroatoms are selected from oxygen, nitrogen and sulfur, and a cyclic group wherein R hand R taken together with the associated nitrogen is an unsubstituted or substituted mono- or bicyclic heterocyclic ring having up to four heteroatoms in each ring independently selected from oxygen, nitrogen and sulfur wherein the substituents in the afore mentioned substituted alkyl, amino and heterocyclic group consist of amino, mono-, di- and tri (C 1 -C 4 )alkylamino, hydroxyl, oxo, carboxyl, alkoxyl, chloro, fluoro, bromo, nitro,-s2NHF phenyl, berizyl, acyloxy, alkoxylcarbonyl, alkoxycarbonyloxy, cycloalkoxycarbonyloxy and carboxamido; or R2is a hydroxylamino, hydrazinyl, iminyl and hydroxamic 9 9* 9 9 .9 9e :25 9 .9 9 9 9 99 *9 9 *99* 30 *.99 9 9 9 9 *99.

9 9999 *999 35 9*9* acid derivative selected from those of the formulae: -N Rh) OR Rk)NRhIi

R

Rh0 N-and

R

respectively; wherein R and R are as hereinabove defined; moieties of the formulae: Rh N -N-

RI

t-N I h -iI Rh N-R~ a n d 44 4 4 .0 4 04 .4 44 0 4 4 4 4. .4 :25 44 44 04 4 44 4*4* 4 **44 4 4 4 4 *44* 4*44*4 4 40*4 4 4 44** 44 4 4 4 4 *440 35 4**4 4 4 4 4 4444 N Rh N h

~R

Rh wherein R hand R are as hereinabove defined; acylaijno moieties of the formulae: R

-N-

0 R~ wherein R hand R are as hereinabove defined; moieties represented by the formulae: Id Rh

R

P R

P

11 II N-C -NH- and RhO-C-NH-

R

J

wherein

R

h and R J are as hereinabove defined and R P is selected from oxygen and sulfur; moieties of the formula: Rk-C-C-NH- 11 11 N 0 1 ORk wherein

R

k represents hydrogen, substituted or unsubstituted

(C

1

-C

3 )alkyl*,

(C

2 -c 4 )alkenyl*,

(C

2

-C

4 )alkynyl*, heterocyclyl* and heteroaryi* wherein the heteroatom and heteroatoms are selected from 1-4 5 oxygen, nitrogen or sulfur and the cyclic portion has 5 or 6 ring atoms; wherein the aforesaid groups marked with an asterisk are optionally substituted by a substituent described hereinabove for R and R; moieties of the formula: R S(O) ,,NHn Swherein n" and Ra are as hereinabove defined; moieties represented by the oo ~formulae: 0

\II

P-NH-

EJ/

0 :0>11P-NH 0J 0 j and 0 FI-NH-

EJ

30 35 wheeinR hand Rj are as hereinabove defined; an amino moiety containing an acyl residue of an amino acid or peptide represented by the formula:

-N-C-CH-N\

h ItR h R R wherein R h is as hereinabove defined; Rm is hydrogen or an acyl residue of an amino acid or peptide; and R t is hydrogen, benzyl, straight or branched (C 1 -C 6 )alkyl optionally substituted with halo, hydroxy, amino, guanidinyl, carboxy, phenyl, aminocarbonyl, alkylthio, hydroxyphenyl or heterocyclyl; an acyclic quaternary ammonio moiety of the formula: B- R.R 8 R 9 wherein R 7 R 8 and R 9 are the same or different and are selected from hydrogen, a straight or branched (C 1 -C 4 )alkyl, (C 2

-C

4 )alkenyl and substituted (C 1 -C 4 )alkyl, wherein the substitution is selected from hydroxy, (c 1

-C

4 )alkyl, wherein the substitution is selected from (C 1 -C 4 )alkoxy, azido, amino, (C 1 -C 4 )alkylamino, di (C 1 -C 4 )alkylamino, guanidino, nitrile, carboxy, formimidoyl and phenyl; alternatively, 7 and R 8 taken together are -(CH X(CH .2X22-' wherein x is (C (w is an integer from 0 to oxygen, sulfur, NH NRhN OH and NOR h and B is a physiologically acceptable anion; or R 2is a moiety bonded via carbon atom; selected from the following groups; a nitrile moiety an acetylenic group, or a moiety of the formulae: -C

C-R

0 whjerein a is as hereinabove defined; so a moiety selected from those of the formulae: 39 s.e.

0 11 -C NR Rh

S

I h IJi R R C NO0RJ R

R

0@ 0 0

S.

6S *s 0 0

S

00 ge 0 0 *0 0 0 S 0S S S S d 0 055.

0

OSSS

S

0 0000 S. '000 000.

0 0 a.

0 S S 0 *OOS 00e0 0

S

0 11I 0h -C -N 0 c-I N R sIR h -C -N

RJ

1I

C-H

N-Ri -GzN-N- Rh R Ih

N"

R R

R

Rh '-Rh

N-R

R a wherein R, and Rj are as hereinabove defined; a m-oiety selected from -CHF 2

CE

3

-CF

2

CF

3

-CH(OCH

3 2 -CHC1 2 and CHR"Rj, with the proviso that excluded are the compound of Formula IV (4-6) *whereini Z=S, ni is 0 and R2 is hydrogen and comp11ounids ofFrml IV (4-6) whierei Z=O and represents the moiety CHRhRJ and R" and R" are both selected from hydrogen and unsubstituted alkyl.

1 Disclosed are novel carbapenemns represented by lbormula I and the production of compounds of formulae I.

R,

Ro-.

*6 E7

S

0

S...R

A1.111XXI02219.doc KWW -2wherein the moiety -S Cz is a 4,5 or 6 membered mono-, di- or tni-substituted oxygen or sulfur containing ring.

For example, the moiety -S z may be a 5 membered ring of the formula -S

(CH

2 )nR 2 In such an instance, the following isomers are included: R

R

1 z

C

2

R

3

(CH

2 )nR 2 z 0 N S

(CH

2 )nR 2 CO2R3 z 02 R 3

(CH

2 )nR 2 to Ri(CH 2 )nR 2 S 1 j C2R3 CO 2

R

3

(CH

2 )nR 2 -3and the stereochemical assignment of each residue

R,

R

and -(cH2)R 2

CO

2

R,

on the 4, 5 or 6-membered ring (containing the Z substituent) can be either R or S.

DETAILED DESCRIPTION As stated, the invention relates to novel intermediates for preparing compounds of Formula I: 4 1 o• 0010 represents a 4,5 or 6 membered mono, di-or tri-substituted ring and Z is selected from oxygen, sulfur, sulfoxide and sulfone; when Z is sulfoxide, the relative stereochemistry between the substituent and the sulfoxide can be cis or trans; Ro is hydrogen,

(C

1

-C

2 )alkyl, CH 2

OR

4

CH

2

NHR

5

CH(OR

4

)CH

3

CHFCH

3 or CH(NHR 5

)CH

3 wherein

R

4 is selected from hydrogen, and moieties of the formulae: -4- 0 0 0 0 0 0 II II II II II II

-CH

2 OCR I -CH 2 OCORg -C RI 0 -CORI,-COC 2 C O 0 0 0 II II II

II

-COCH

2 0 CORI -SORI and -PORg 0OR (ii) R 5 is selected from hydrogen, and moieties of the formulae: 1c 11 11 11 11 11 CR, CORI COCH 2 OCRI 0i 1 0 I~ '9POR 6 SOR and I 1*

OR

6 (iii) R 6 is selected from a straight, branched or substituted

(C

1

C

1 alkyl,

(C

2

-C

18 alkenyl, unsubstituted or substituted (C -C 7 )monocyclo(C 1

-C

1 0 )alkyl, unsubstituted or substituted

(C

5

-C

10 )bicyclo(C 1

-C

10 alkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl; the substitution for the alkyl, monocycloalkyl ard bicycloalkyl moieties are selected from trifluorop methyl, pentafluoroethyl, amino, mono(c 1

-C

6 alkylanino, di (C 1

-C

6 )alkylamino, hydroxy,

(C

1 -C alkoxy, (C 3 -c,)cycloalkoxy, carboxy,

(C

2 -Cl)dcarboalkoxy, cyano and (C 1

-C

1 0 carboxamido; the substitution for the aryl, heteroaryl and heterocyclyl moieties is selected from (C 1 -C )alkyl

(C

1

-C

6 )mono-, dior polyfluoroalcyl, hydroxy, (C 1 -C )alkoxy, (C 3 -C 8 )cycloalkoxy, amino, mono(C 1 -C 6 )alkylanino, di (C 1 -C 6 )alkylanino, carboxy, (C 2

-C,

0 )carboalkoxy, cyano, and (C 1 -C 10 )carboxamido;

R

1 is straight or branched (C 1

-C

8 )alkyl, straight or branched (C 2 -C 8 )alkenyl, (C 3

-C

8 )cycloalkyl, or wherein n' is an integer of from 1-6 and R is selected from CF 3 1 C 2 F 5 fluorine, chlorine, bromine, hydroxy, alkoxy, nitrile, azido, a quaternary ammonic group, amidino, formamidino, guanidino and wherein R' and are independently selected from hydrogen, straight or branched (C 1 -C 6 )alkyl, straight or branched (C 1 -C 6 )alkoxy, 2-hydroxyethyl, 2-azidoethyl and .2-aminoethyl; 20 (ii) and when R' is hydrogen or straight or *branched (C 1 -C 6 )alkyl, may also be selected from amino, hydroxy, :mono(C 1 -C 6 )alkylamino, di (C 1 dalkylamino, acyl, benzoyl, dihydroxybenzoyl, an acyl 25 residue of an amino acid or peptide, and straight or branched substituted (C 1 -C 6 alkyl wherein said alkyl suibstituent is selected from hydroxy, (C 1 -C 6 )alkoxy, azido, amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, guanidino, nitrile, carboxy, formimidoyl and phenyl; or (iii)RI and taken together with the associated nitrogen may also be an unsubstituted or substituted monocyclic or bicyclic heterocyclic ring having up to four (4) heteroatoms in each ring independently selected from oxygen, nitrogen and sulfur, wherein said substituent is selected from -6- 9* a. straight or branched (C 1

-C

6 )alkyl, straight or branched (C 1

-C

6 )alkoxy, (C 3

-C

8 )cycloalkyl,

(C

3

-C

8 )cycloalkoxy, trifluoromethyl, hydroxy, halogen (selected from bromine, chlorine, fluorine and iodine), amino, nitrile, carboxy, carbamido, carbamoyl, straight or branched mono(C 1

-C

6 )alkylamino, straight or branched di(C 1

-C

6 )alkylamino, and amino(C 1

-C

6 )alkyl.

The term "acyl residue of an amino acid or peptide" as used herein means the acyl residue of a naturally occurring amino acid, a racemic amino acid or a peptide derived therefrom. Suitable amino acids are those described herein and other known amino acids such as alanine, glycine, arginine, cysteine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, aminopimelic acid, threonine and the like.

The substituent or substituents on the -Sz-C ring are independently selected from moieties of the formula -(CH 2 nR 2 wherein: n is an integer from 0-4 and

R

2 is: methyl, fluorine, or any suitable leaving group such as but not limited to chlorine, bromine, iodine,

OCOCH

3

OCOCF

3

OSO

2

CH

3

OSO

2 Ph, NO 2 cyano or azido; (ii) R 2 may also be a moiety of the formula: -S(O)n,,Ra wherein n" is an integer from 0-2; and R a is hydrogen or an organic group bonded via a carbon atom selected from (C 1

-C

6 )alkyl, -7- (C 3 -C 7 cycloalkyl, (C 2

-C

6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, heteroaryl, aryl (C 1

-C

6 alkyl, heteroaryl (Cl-C 6 )alkyl, (C 1

-C

6 alkanoyl, arylcarbonyl, heteroarylcarbonyl,' heterocyclyl, heterocyclyl (C 1

-C

6 alkyl, heterocyclyl(C 1 -C 6 thioalkyl, any of such groups being optionally substituted.

Preferably, the heteroatom or heteroatoms in the above-named heterocyclyl and heteroaryl moieties are nitrogen atoms and may be quaternized and carry a positive charge and be associated with a physiologically acceptable counterion. As used herein, a physiologically acceptable counterion is selected from anions such as Cl-, OH-, HCO 3 CH 3 CO 2 Br I H 2 P 4 carboxylate and the like.

Optional substituents on the group R a include

(C

1 -C 6 )alkyl, hydroxy, (C 1 -C 6 alkoxy, phenyl, heterocyclyl, amino, amidino, gjuanidino, carboxamido, carbamoyl, (c 1 -C 6 )alkanoylamino, mono- and di(C 1 -C 6 )alkylamino, an acyclic quaternary ammonio moiety of the formula: 2 5 R R R wherein R 7 R. and R 9 are the same or different and are selected from hydrogen, a straight or branched (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl and substituted (C 1

-C

6 alkyl, wherein the substitution is selected from :30 hydroxy, (C -c 6 alkoxy, azido, amino, (C 1 alkylamino, di (C 1 -C 6 alkylanino, gjuanidino, nitrile, carboxy, formimidoyl, phenyl, an aniidino or guanidino moiety of the formula: -N=CR 1 0 -NR 11R1 wherein R 0is hydrogen, straight oit branched (C 1 -C 6 alkyl, amino, (C 1 -C 6 )alkylamino or di(C 1 -C 6 )alkylamino; and R 1.and R 12are independently -8- Sselected from hydrogen and straight or branched

(C

1

-C

6 )alkyl.

Suitably, Ra is (C 1

-C

6 )alkyl for example methyl, ethyl or isopropyl, optionally substituted by amino,

(C

1

-C

6 )alkanoylamino, carboxy, mono- and di(C 1

-C

6 )alkylamino, hydroxy, amidino or (C 1

-C

6 )alkoxy.

Preferably, Ra is ethyl substituted by

(C

1

-C

6 )alkanoylamino, for example Ra is acetamidoethyl.

Suitably, Ra is (C 2

-C

6 )alkenyl and, in particular, optionally substituted vinyl wherein the substituents are selected from those described hereinabove.

Preference for substituents is given to

(C

1

-C

6 )alkanoylamino such as acetamido; carbamoyl groups including mono- and di(C 1

-C

6 )alkylcarbamoyl, such as phenylcarbamoyl and NH 2 CO-; a carboxy group where the carboxy group is esterified with an alkyl ester such as methyl or as its aralkyl ester such as 4-nitrobenzyl ester or the carboxy group is salified as 20 its sodium or potassium salt.

Suitably, Ra is aryl such as phenyl; aralkyl wherein the aryl moiety is phenyl and the alkyl moiety is 1 to 6 carbon atoms such as benzyl or phenethyl. In So 25 particular R a may be optionally substituted aralkyl 25 wherein the substituents for the (Cl-C 6 )alkyl portion is as hereinabove defined and optional substitution for the phenyl ring consists of one or more of the following substituents: amino, (C 1

-C

6 )alkanoylamino, monoand di(C -C 6 )alkylamino, hydroxy, amidino, 30 (C -C 6 )alkoxy, sulphanoyl, carbamoyl, nitro, chloro, fluoro, bromo, carboxy and salts and esters thereof.

Suitable examples of the above-named list are: -9-

-CH

2 CH

-CH

2

-CH

C02H O1

NHCO-CH

2 M0 2

WN

2 -CHI -CH q or

NHIH

2 N

OCH

3 Suitably, Ra is a heteroaryl wherein the heteroatom or heteroatoms of the heteroaryl ring are selected from 1-4 oxygen, nitrogen or sulfur atoms such as 1,2-dihydro-2-methyl-5,6-dioxo-l,2,4-triazin-3-yl, thienyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, benzothienyl, furanyl, imidazolyl, thiazolyl, triazolyl; a heteroaryl(c1-C 6' S.i alkyl such as: -CHICH or -CHCH, wherein the alkyl portion is optionally Substituted as hereinabove described and the heteroaryl portion is 30 optionally substituted with substituents hereinabove 3defined. Suitable examples are: -CCH n -C-CH NCOCH

COCMH

I

C

-CHCH-f- CON r -CHC N10 HCOCHN On H Suitably, Ra is a bicyclic fused heteroaryl wherein the heteroatoms or heteroatoms of the heteroaryl ring are selected from 1-4 oxygen, nitrogen or sulfur atoms and optionally substituted as hereinabove defined. Preferably, examples are the and fused bicyclic heteroaryl ring system generically shown: Rb S* Hot A r y l 25 wherein the definitions of R b and R c may be selected ."Suitably, R a is a quaternized fused heteroaryl wherein the heteroatoms of the heteroaryl ring are selected from 1 to 4 nitrogens and optionally substituted as hereinabove defined. Preferably, examples are the and [4.4.0] quaternized fused heteroaryl rings, optionally substituted with an acidic substituent. Suitable examples are shown: -11-

IN

-B-

~I N 0 2

C

0 2 C N~~

-B-

"N

02 C

N

/ff 0 2 c

N;

0 2 c I N -ifN4 0 2 C I N I N C0 2 C0 2

N~~

IN

C0 2 (i) -12-

N

(7 0 2 c C 0) .i C 2 C 0/) w h isre R~ s1 hearei 1n aftfer d eIf Ine*d an d B- is a physiologically acceptable a n IJon -13- Suitably R a is a quaternized heteroaryl-

(C

1

-C

6 )alkyl group of the formula:

B-

CH

2

CH

2 wherein the definition of the heteroaryl moiety:

B-

+0 is as referenced above. Contemplated equivalents are disclosed in U.S. Patent 4,952,397.

Suitably Ra is a quaternized heteroaryl- (Cl-C 6 )thioalkyl group such as:

B-

S- 0 CHCH S Rd 20 2 wherein R is (C 1

-C

6 )alkyl and the definition of the heteroaryl ring:

B-

is as defined above. Contemplated equivalents of the S. heteroaryl ring and the alkyl group R d are disclosed in U.S. Patent 4,880,922.

30 Suitably, R a is a heterocyclyl wherein the heteroatom or heteroatoms in the heterocycle are selected from 1 to 4 oxygen, nitrogen or sulfur atoms.

Additionally, the above mentioned heterocyclyl moiety is optionally substituted with one or more of the substituents hereinabove defined. Preferred examples of the above-mentioned list are substituted pyrrolidinyl groups of the formula: -14- R f wherein the definitions of R e above referenced substituents equivalents are found in U.S.

Patent 4,963,543; U.S. Patent 4,740,507; sistet or pyrazolidinyl sbttet and Rfare any of the for Ra Contemplated Patent 4,921,852; U.S.

4,463,544 and U.S. Patent preferably: N R 9 -CN Rg a nd qe .4 4 .4 4. 444* 4 4 4 *4 4 .4 wherein Rg is hydrogen, tert-butyldimethylsily. or other suitable tni-substituted silyl groups, -CO 2CH 2-(4-nitrophenyl), or -CO2 CH 2CH=CH.2 (iii) R 2 may also be hydroxy, -OR a, -OC(O)Ra -OC(O)OR a, -OC(O)NR aRaI -c 0 )-c I-,'Ra

K

N

H

2 wherein Ra is independently selected and is as hereinabove defined or 0 -0 -P -OCH CH R 1 wheei R13 isamoiety selected from those of the formulae: Be B- B' -NH, -(CH) 3 and wherein B is a physiologically acceptable anion; (iv) R 2 may also be an organic residue bonded via a nitrogen atom, such as: NO, NO 2

NO

3 NC, NCO, NHCN, NRhR J wherein Rh and R are independently selected from hydrogen; substituted or unsubstituted amino, substituted or unsubstituted (C 1

-C

8 )alkyl and

(C

3

-C

8 )cycloalkyl(C 1

-C

8 )alkyl, aryl, aralkyl, heterocyclyl, heterocyclyl(C 1

-C

4 )alkyl, heteroaryl and heteroaryl(C 1

-C

4 )alkyl wherein the heteroatom or heteroatoms are selected from oxygen, nitrogen and sulfur, and a 15 cyclic group wherein R and R taken together with the associated nitrogen is an unsubstituted or substituted mono- or bicyclic heterocyclic ring having up to four (4) heteroatoms in each ring independently selected from oxygen, nitrogen and sulfur wherein the substituents in the aforementioned substituted alkyl, amino and heterocyclic groups consist of amino, mono-, di- and tri(C 1

-C

6 )alkylamino, hydroxyl, oxo, 25 carboxyl, alkoxyl, chloro, fluoro, bromo, nitro, -SO 2

NH

2 phenyl, benzyl, acyloxy, alkoxylcarbonyl, alkoxycarbonyloxy cycloalkoxycarbonyloxy and carboxamido.

Relative to the above defined NRhRJ, representative examples are: -16- -NH 2 IiHC3' -NH CH3' -NHCH(C3) 2' -N(CH3 2' N(CH 2 CH 3 2 1 -N[CH (CH 3)2]~2f NHCH 2 CH 2 OH, -NHCH 2 CH 2 CH 2

OH,

-N(CH 2 CH 2 OH) 2 -N[CH(l 3C 2 oHJ 2

I{(CH

2 Co 2

CH

3 -NH (CH 2 CH 2 oC~H 3 -NHCH 2 CF 3 NHCH 2 CH2 NHCO 2 C (CH 3 3 1 -NHCH(CH 3 )CH 2

CO

2

C(CH

3 3

-NHCH

2 CH 2 NH 2 -NHCH CH N(CH), -NHCH(CH )HN (CH) -11HCN 1

CN

1 432 N~CN 2

;CH

2

-NH(CN

2 2 t -N 0 a.

S

C. a

C.

-NH(CH

1 2 -M S

N

-NH(CH2).

(E)

-NN(CH

1

N

-NN(CH

2

-NN(CH

2 0

-NN(CN

1 2) 2 -N NH E-CHS. OCH, CI,3r. F. I.K0 1

.ON

SO 1

N

1 COIN, COH 2 n-1.2 n'-1.2 E-soem an obey.

11-1.1 E COIN, CONN 2 CON

CHN

2 D-N, COIN,

COH

*too 4 .a -N 0 N N. -N N-Cit 2 -17- R2',a an organic residue bonded through nitrogen, may also be; hydroxylamino, hydrazinyl, iminyl and hydroxamic acid derivatives of the formulae: N-and -~N(CRh)ORJ -N(R')OR',-N(R')NRhll'.

respectively; wherein Rhand Rj are as herei'nabove defined; moieties of the formulae: RhR Rh=N R-M-an Nh RhN R ~Rj Rh J wherein Rhand Rj are as hereinabove defined; (d) acylamino moieties of the formulae: *f 6 0 00 0 of too.

to 0e to 0.: R -C-N- 0 R~

R

N-

Rh- C 11I 0

II

R J

R

wherein R hand Rj are as hereinabove defined; (e) moieties represented by the formulae: R h N'I

I

N -C NH and h IRIp RI-C NH -18- Swherein R h and R are as hereinabove defined and R P is selected from oxygen and sulfur; moieties of the formulae: Rk-C-C-NH- II II N 0

OR

k k 10 wherein R represents hydrogen, substituted or unsubstituted (C 1

-C

3 )alkyl* (in the description of respective groups in the present specification, moieties marked with an asterisk may have a substituent as assigned hereinabove for R h and R 1 5

(C

2 -C )alkenyl*,

(C

2

-C

6 )alkynyl*, heterocyclyl* and heteroaryl* wherein the heteroatom or heteroatoms are selected from 1-4 oxygen, nitrogen or sulfur and the cyclic portion has or 6 ring atoms; moieties of the formulae: 20 RaS(O) ,NHn wherein n'and R a are as hereinabove defined; (h) moieties represented by the formulae: h 0 Rh 0 R h -H-P-NH- and P-NH-

R

J

R O wherein R h and R are as hereinabove defined.

R2, as an organic residue bonded through nitrogen, may also be an amino moiety containing an acyl residue of an amino acid or peptide represented by the formula: -19- -N-C-CH -N Rh R R wherein R h is as hereinabove defined; Rm is hydrogen or an acyl residue of an amino acid or peptide; and Rt is hydrogen, benzyl, straight or branched (C 1 -C 6 )alkyl optionally'substituted with halo, hydroxy, amino, guanidinyl, carboxy, phenyl, aminocarbonyl, alkylthio, hydroxyphenyl or heterocyclyl.

Representative examples of an acylamino moiety of *the formulae: Rh~C 0R from the above-mentioned groups are formylamino, acetylamino, isobutyryl amino, benzyl oxycarbonyl amino, l-aminocyclohexylcarbonylamino, 2- (2-amino-4-thiazolyl) -2-ethylideneacetylamino, 4 -bromobenzoylamino, nicotinoylamino, 25 3 -phenyl-5-methylisoxazol-4-yl-carbonylamino, pyrrolidinone, succinimidoyl and maleimidoyl.

Representative examples of a moiety of the formulae: RR R R N-C -N H and R 0-C -NHfrom the above-mentioned groups are:

H

1

N-C(O)NH-

CH

3

NHC(O)NN-.

H

2 N-C(S)N14- CH3NH-C(S) NH- 0 N-C(O)NH- HN N-C(O)NH-

NH

2

N-(S)-NH-

_NCH

H

3 0-()NH- ElM A C()H- 0 E t N KC(O)NH- HO cNC(O)NH-

I

C14 3 Nz- C(O)

-NH-

CO

2

H

0 11

CH

5

OCNH-

CH

3 -C-0-C HO-C-NH-

IH

Representative examples of an acylamino moiety of the formulae: 0 11 R -C-C-NH- 11 from the above-mentioned groups are: -21-

CH

3

-C-C-NH-

1i1i NO0

S

H

2

C-C-NH-

N

OCH

3

CH

3

-C-C-NH-

111 1 NO0

OCH

3

C-C-NH-

H2N N H1 11 NO0

OCH

2

CH-CH

2

CH

3

-C-C-NH-

1II11 NO0

S

H

2 N C-C-NH- NO0

OCH

2

CO

2

H

an 00 \/C-C-NH NO0

OCH

3 Representative examples of moieties of the formulae: R a S(O) from the above-mentioned listings are: -22- CI1 3 S0 2

NH-

C6H 5

SO

2

NH-

0 2 N S-NH-

SONH-

SO

2

NH-

9 *9 9 9 *9 9* a 9 a .9 HO \0 S0 2

-NH-

B r

SO

2

NH-

S02_NH-

CCH

3 2 CH-SO 2 NH- -/1ZSNH 0, SO0 2 N H- SO0 2 NH SO CF 3 SO NH- 0 C6H 5 CH 2 0C-CH 2 -S0 2 -NH- a nd C6H 5

-CH

2

-SO

2

NH-

Representative examples of moieties of the f ormulae: Rh o from the above-mentioned listings are (dimethoxyphosphinyl) amino, (diethoxyphosphinyl) -23amino, (diisopropoxyphosphinyl) amino, (diphenoxyphosphinyl) amino, and bis (phenylmethoxy) phosphinylamino, Representative examples of the formulae: Rho \I R J from the above-mentioned listings are: 9* *9 a

P-_NH-

C H30 C 0 01-NH- L 0 0 >NH 0

CH

3

\I

CH

3 ,N 0 /P-W a a.

Representative examples of the formulae: from the above-mentioned listings are: C H30"1 0 1 CH

/PNH-

0\I 5:2

NH.-

N.H

0 0PNH- 0

.CH

3

CH

3 Representative examples of moieties the formulae: -24-

N-

from the above-mentioned listings are: i C H,

CH

3 P h c H 3 P h

CH

3

S-CH

1 2

CH

3

N-

H 2 MR

N-

CH

3 H 2 C H-N N- 3 C

=N-

CH,

CIH

5 cH 2 00C

H

a nd Representative examples of moieties with the formulae: 0 _N(R )OR' and -N(CRh)R from the above-mentioned listings are: -NHOH, -N(CH 3 OH I -N (CH 3 OCH 3

-N(CH

2 CH 3

)OH,

-N (CH 2 CH 3 )OCH 3 -N (CH 3 OCH 2

CO

2 H, -N (CH 3 OCH 2 C0 2 CH 2

C

6

H

5 -N (C 0C 6

HS,

S. .5

S

S. S 4

-N(CH

3 )o -a Ir

-N(CH

2 CH-CH2)OCH, -K(CH3)O _G COK(CH3)2

-(D

0 -M

D

I

-MNa C0 2

CHICIRS

0 NH2

II

0

NHCO

1

CH

1

C

6

H*

ON

II

0

OCHJ

II

0 -MN1C-CHI and -N---Hi 0 0 Representative examples of moieties with the formulae: -N(R h )NRh RJ from the above-mentioned listings are:

-NKH

2 1 -N(CH 3

)NH

2 -N(CH 3 NHCH 3 1 -NHN(CH 3 2 -N(CH 3 )N(CH 3 2

-NHNHCO

2 CH 2

C

6

H

5

-NHNHC

6 H -NHNHCH 2C6 -26- -NHN S H ~CO0N CH 3 2

-NHNH

-NHNH -a C0 1

CHICGH

-N-NH

4

C

a. eq 9

C

-N-NH

-N-NH -N-N-CO 2 CH 2 a M0 N 2

<NQ)

C

C. C C~ a N-N .1H N NN N a nd Representative examples of moieties with the formulae: RhI

R

from the above-mentioned listings are: -27- M 0

H

3

C

CH

3 NN

CH

3 .9 .9 9.

9** 9 9. 9 9.

and Representative examples of moieties with the formulae: Rh

N

Rh N R from the above-mentioned listings are: I N-CHSNH NH

CHS

N CONH

CH

3

CH

3 and _N CH3

CON

IN

-28- Representative listings of moieties with the formulae: from the above -N NH 2

NH

2 N 'R h

-NR

N Rh ~-mentioned listings are: .i NH CH NH

N:

NHCOC

N C H -N

NCH

3 an d Representative listings of moieties with the formulae: 0

R

N- C C H-N Ihi I R R from the above-mentioned listings are: -29- 0 0 II

II

-N-C-CH2NCH

-NHCCH-NH

2 H

I

(C H 2 4

COOH

0 0 AWN a 0 -NHCC2N 2

CCHNHCH

3

-NHCCHCH

2 C I -C-Cn-nH-C-CHCH 1

CI

CH I

CH

2 CI MHz a..

a a 0 0 II II -MRHC-CH--HCCH( CHI) 4 C00H cH,)COaH MN 0 0 1I II

-N-C-CH-HC-CHNHI

H I

CH

2

OH

0 CC 2 NH

H

0 0 II II

-NC-CH

2

-NHC-CH-CH

1 NH2

-NC-CH

2 -NH-C-C1 2

-CH

2

OH

H I I CHI kHz H 0 NHI

_NCC

M \Wz 0

CHJ

N-C-C

CH

3 R2 ,as an organic residue bonded through nitrogen, may also be an acyclic quaternary ammonia moiety of the formula:

B

4

R

7

R

8

R

9 wherein R 7

R

8 and R 9are the same or different and are selected from hydrogen, a straight or branched

(C

1

-C

6 )alkyl, (C 2

-C

6 )alkenyl and substituted

(C

1

-C

6 )alkyl, wherein the substitution is selected from Is hydroxy,

(C

1

-C

6 )alkoxy, azido, amino,

(C

1

-C

6 alkylamino, di(C 1 -C 6 )alkylamino, guanidino, nitrile, carboxy, formimidoyl and phenyl. Alternatively, R and R 8 taken together may be -(CH2)2X(CH2)2-, wherein X is (CH 2 w (w is an integer from 0 to oxygen, sulfur, NH, NR NOH and NOR h Suitable examples are:

-NH,,

B

-N

OH

2

OH

B-

CH-

CH3

B

-NH

2

CH,,

B-

H

2 B- B- B -NH(CH3,), -(CH3 )3' B- B- H(Et. -NH2H -NH(Et) 2

-NH

2

C

6

H

B

B COOCHz

-NH

N3 2 N N

COOCH

B-

and

-NO

Et where B- Is a physiologically acceptable anion.

R2, as an organic residue bonded through nitrogen, may also be a quaternized heteroaryl wherein the heteroatoms are selected from 1-4 oxygen, nitrogen and sulfur atoms and must contain at least one positively charged nitrogen atom in association with a physiologically acceptable anion wherein the quaternized heteroaryl is optionally substituted by R a as hereinabove defined; preferably, the quarternized heteroaryl moiety is a quarternized bicyclic heteroaryl ring. Representative examples of quaternized heteroaryl groups are: -31ca -cx NKI-co;.

-Nr 9. 9* 9 *9 4. 9 ii i 9.

9.

9 9* 4 9 b.

*9 3- N' -s

I

U-

-N

1

NI

014 coI -32- 9-

CON

N (CH 5 2

H

S.

S S S. *S 5 0

S

S. 0

OS

8- N Z

I

9- S S

S

5.55 55.5

S

OS S Si 0e

S

N

-N

NF

c -33- 4.

4 o.

4 4*

I

9 44 4 4 49 4.

49 44 44 4 49 f 449* .4.

4

R

2 may also be an organic residue bonded via a carbon atom. Suitably, the organic residue is bonded to either a sp-, sp 2 or sp 3-hybridized carbon as follows: Suitably, an organic residue bonded via an sp-hybridized carbon can be a nitrile, -C=N or acetylenic, -C-C-Ra wherein R a is as hereinabove defined.

An organic residue bonded via an sp2-hybridized carbon can be moieties of the formulae: 0 Imino, C-N--R carbonyl, -C-Re Rh

S

-IC-RI

-C -R e thlocarbonyl olafinlc, -C C-R e Rh

R

oxlmlno, C-NOR Ih R Rh hydrazonyl, -C -N-N

RR

J

0 0 II II -C-OH eslter -C-OR ac I d, amide 0II

R

-C -N

KR

0 N NRh thl mde, -C

J

-34- I 1II1 C S R formyl -CH t h jog as e r, fu n ct laona I g ro u p. of th e f o rm uIaa:

SS

S

@0 S. 00 0 0 0 0O OS 0 0 0 *5 5 0 0@ 60 0 0

SS

S.

5005

I

*0@0 @0 00 0 @0

S

*OeS 0 0@Se 00 0050 0 *0 0 0@

SO

N-Rd N R- h- RRK R h a cylI i m ino -R h s u bzt itu tead a r yl s u b st It utad h st roca r y

/R

aN wherein Ra, Rhand R are as hereinabove def ined.

an organic residue bonded via an sp -_hybridized carbon can be -CHF, -CHCl -CH(OCH 2 CF 3 'C 2 CF3 o Representative examples of an organic residue bonded via an sp-hybridized carbon are: -C-C H C

H

2

N

0 C C Z C E E C H_ -H c __CCH 3

-C=C-CH

2

OH

-C=C-CH

2

NHCO

2 C C H 3 3 C -C H2 CH2NH CO C H

CN

4N H 2 +0B_ C C -K\

J

I

XN

N O H Representative examples of an organic residue bonded via an sp 2-hybridized carbon are: -36-

CH

3

OH

-CH =N-NH 2

.OCH

2

CO

2

H

CH3 C H N-

-CNH

\rN

NH

2

-C=NCH

3

N

CH

2 -S

\I

,-c=O

CH

2 SCH3 CH 2

CI

CH

2

NHCOCH,

QNH

2 -CH =N-CH 3 0 -CH=:N

N-CO

2

CH

2

CH

C H C 6

H

5

CH

3

HCOCH

3 -c=O O bI XOCH3

C

1 1 CH4 3

H

>OH

CON (Cu 5 2 0 11

NH

2 -37- CH3) 2 -H

NH'

-CH N- I NH 2 CH3 0 C02H

NH

0 0 -C-N NC0 2

CH

2 Ph. N N CH 3, C- N NCH 2 Ph.

a n d -C-N 0 R 3 is selected from hydrogen; a straight or branched (C 1 -C 4 )alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; a (C 1 -C 4 )alkoxymethyl group such as methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl or isobutoxymethyl; a straight or branched l-(C 1 -C 5 )aliphatic acyloxy-ethyl or methyl group such as acetoxymethyl, l-propionyloxyethyl, n-butyryloxymethyl, isobutyryloxymethyl or pivaloyloxymethyl; a straight, branched or cyclic 1- (C 1 -C 6 )alkoxycarbonyloxy-ethyl or methyl group such as ethoxycarbonyloxymethyl, l-isopropoxycarbonyloxyethyl, l-n-butoxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl or l-isobutoxycarbonyloxyethyl; a phthalidyl group; -38and water soluble cations such as lithium, sodium, potassium, ammonium or tetra(C 1 -C 4 )alkyl ammonium.

Preferred compounds are those of formula I wherein: Z is selected from oxygen; and R 0 is -CH(0R 4 )CH 3 wherein Ris selected from hydrogen and groups of formulae: 0 0 0 0 0 0

-CH

2 OCR* I -CH 2 OCORS -C RG -CORS ,-COCH2O C R a .0 0 0 0 *CC OS -SOR a nd -PORI 10 2CC4OO 6 11 61

OR$

wherein Ris selected from a straight, branched 6 *or substituted (C 1 -C 1 8 )alkyl, (C 2 -C is)alkenyl, unsubstituted or substituted (C 3 -C 7 )monocyclo-

(C

1 -Cl 0 alkyl, unsubstituted or substituted C 5

-C

0 )bicyclo(C 1

-C

1 0 )alkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl; wherein the substitution for the alkyl, monocycloalkyl- and bicycloalkyl moieties are selected from trifluoromethyl, pentafluoroethyl, amino, *mono(C 1 -C 6 alkylamino, di (C 1 -C 6 )alkylamino, hydroxy, (C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkoxy, carboxy, (C 2 -C 10 )carboalkoxy, cyano, and (C 1 -C 10 )carboxamido; and the substitution f or the aryl, heteroaryl and heterocyclyl is selected f rom.

(C 1 -C 6 )alkyl, (C 1 -C 6 mono-, di- or polyfluoroalkyl, hydroxy, (C 1 -C 6 alkoxy, (C 3 -C 8 )cycloalkoxy, amino, mono(C 1 -C 6 )alkylamino, -39- W di(C 1

-C

6 )alkylamino, carboxy, (C 2

-C

10 )carboalkoxy, cyano and (C 1

-C

10 )carboxamido;

R

1 is straight or branched (C 1

-C

4 )alkyl, straight or branched (C 2

-C

4 )alkenyl, (C 3

-C

6 )cycloalkyl, or

(CH

2 wherein n' is an integer of from 1-4; R is selected from CF3, C2F5, fluorine, chlorine, bromine, hydroxy, alkoxy, nitrile, azido, a quaternary ammonio group, amidino, formamidino, guanidino and NR'R''; wherein R' and are independently selected from hydrogen, straight or branched (C 1

-C

4 )alkyl, and straight or branched (C 1

-C

4 )alkoxy; (ii) when R' is hydrogen or straight or branched

(C

1

-C

4 )alkyl, R" may also be selected from amino, hydroxy, mono(C 1

-C

4 )alkylamino, di(C 1

-C

4 )alkylamino, acyl, benzoyl, dihydroxybenzoyl, and an acyl residue of an amino acid or peptide, or ~(iii) R' and R' taken together with the associated nitrogen is an unsubstituted or substituted monocyclic or bicyclic heterocyclic ring ~having up to four heteroatoms in each ring independently selected from oxygen, nitrogen and sulfur, wherein said substituent is selected from straight or branched (C 1

-C

4 )alkyl, straight or branched

(C

1

-C

4 )alkoxy, (C 3

-C

6 )cycloalkyl,

(C

3

-C

6 )cycloalkoxy, trifluoromethyl, hydroxy, halogen (selected from bromine, chlorine, fluorine and iodine), amino, nitrile, carboxy, carbamido, carbamoyl, straight or branched mono(C 1

-C

4 )alkylamino, straight or branched di(C 1

-C

4 )alkylamino, and amino(C 1

-C

4 )alkyl; n is an integer from 0-4; .0 0 ~0 *0 R 2 is: methyl, fluorine, chlorine, bromine, iodine, -OCOCH 3 1 -OCOCF 3

-OSO

2

CH

3

-OSO

2 Ph azido, (ii) a moiety of the formula: WR a wherein n"is an integer from 0-2; and Rais hydrogen or an organic group bonded via a carbon atom selected from substituted or unsubstituted (C 1 -C 4 )alkyl, substituted or unsubstituted (C 3 -C 6 )cycloalkyl, substituted or unsubstituted (C 2 -C 4 )alkenyl, substituted or unsubstituted (C 2 -C 4 )alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl (C 1 -C 6 alkyl, substituted or unsubstituted heterocyclyl; said substitution is selected from (C 1 -C 4 )alkyl, hydroxy, (C 1 -C 4 )alkoxy, phenyl, heterocyclyl, amino, amidino, guanidino, carboxamido, carbamoyl and quaternary ammonio.

Preferably, the above referenced heteroaryl or heterocyclyl moiety is monocyclic or bicyclic and each ring is comprised of 5 or 6 atoms. Preferably, at least one of the heteroatoms is nitrogen and is quarternized.

(ii) o R2 ishydroxy, -OR a, -OC(O)R a, -OC(O)ORaI -OC(O)NR aR aor -OC(O)-C(NI{ 2 )R awherein R ais independently selected and is as hereinabove defined or -41- O- P- OCH 2

CHR

1 3

I_

0 wherein R.

3 is a moiety selected from those of the formulae:

B-

H -N(CH 3 3 and (iv) or R 2 is an organic residue bonded via a nitrogen atom, selected from NO, NO 2

NO

3 NC, NCO, NHCN, and NRhRJ 2 h J wherein R and R are independently selected from hydrogen; substituted or unsubstituted S 20 amino, substituted or unsubstituted

(C

1

-C

4 )alkyl and

(C

3

-C

6 )cycloalkyl(C 1

-C

4 alkyl, aryl, aralkyl, heterocyclyl, heterocyclyl(C -C 4 )alkyl, heteroaryl and heteroaryl(C 1 alkyl wherein the heteroatom or heteroatoms are selected from oxygen, nitrogen and sulfur, and a oee* cyclic group wherein R h and R taken together with the associated nitrogen is an unsubstituted or substituted mono- or bicyclic heterocyclic ring having up to four heteroatoms in each ring independently selected from oxygen, nitrogen and sulfur wherein the substituents in the aforementioned substituted alkyl, amino and heterocyclic groups consist of amino, mono-, di- and tri(C 1

-C

4 )alkylamino, hydroxyl, oxo, carboxyl, alkoxyl, chloro, fluoro, bromo, nitro, -SO 2

NH

2 phenyl, benzyl, acyloxy, -42- 9 alkoxylcarbonyl, cycloalkoxycarbonyloxy alkoxycarbonyloxy, and carboxamido; or R 2 as an organic residue bonded through nitrogen, is a hydroxylamino, hydrazinyl, and hydroxamic acid derivative: 0 N(R)OR,--N(Rh)NRhRJ and N(CR )ORJ respectively; wherein R and R are as hereinabove defined; moieties of the formulae: *R Rh N -N/ R h -N-11 R I I R Rh R N--R and -N R R h wherein R and R are as hereinabove defined; acylamino moiety of the formula: R -C-N-

II

0 R' wherein Rh and R are as hereinabove defined; moieties represented by the formulae:

R

P

R

P

SII II N-C -NH- and Rh0-C-NH-

R

J

-43wherein R h and R are as hereinabove defined and R is oxygen or sulfur; moieties of the formula: 0 I I R k-c-C-NH-

II

N

I

ORk wherein Rk represents hydrogen, substituted or unsubstituted (C 1

-C

3 )alkyl* (in the description of respective groups in the present specification, groups marked with an asterisk may have a substituent as assigned hereinabove for R h and R

(C

2

-C

4 )alkenyl*,

(C

2

-C

4 )alkynyl*, heterocyclyl* and 20 heteroaryl* wherein the heteroatom or heteroatoms are selected from 1-4 oxygen, nitrogen or sulfur and the cyclic portion has 5 or 6 ring atoms; moieties of the formula: :25 RaS NHwherein n" and R are as hereinabove defined; or R 2 as an organic residue bonded through nitrogen, is an amino moiety containing an acyl residue of an amino acid or peptide represented by the formula: 0 R m I -N--C-CH

-N

Rh t

R

h -44wherein Rh is as hereinabove defined; Rm is hydrogen or an acyl residue of an amino acid or peptide; and Rt is hydrogen, benzyl, straight or branched (C 1

-C

4 )alkyl optionally substituted with halo, hydroxy, amino, guanidinyl, carboxy, phenyl, aminocarbonyl, alkylthio, hydroxyphenyl or heterocyclyl; R2, as an organic residue bonded through nitrogen, may also be an acyclic quaternary ammonio moiety of the formula:

B

-1R 7 R R 9 wherein B is a physiologically acceptable anion and R7, R and R 9 are the same or *7 8 9 different and are selected from hydrogen, a straight or branched (C 1

-C

4 )alkyl,

(C

2

-C

4 )alkenyl and substituted (C 1

-C

4 )alkyl, 20 wherein the substitution is selected from hydroxy, (C-C 4)alkoxy, azido, amino,

(C

1

-C

4 )alkyl- amino, di(C 1

-C

4 )alkylamino, guanidino, nitrile, carboxy, formimidoyl and phenyl; alternatively, R 7 and R 8 taken together are -(CH 2 2

X(CH

2 2 wherein X is (CH2)w (w is an integer from 0 to oxygen, sulfur, NH, NR NOH and NORh; or R 2 as an organic residue bonded through nitrogen, is a quaternized heteroaryl wherein the heteroatoms are selected from 1-4 oxygen, nitrogen and sulfur atoms with the proviso that the heteroaryl moiety must contain at least one positively charged nitrogen atom in association with a physiologically acceptable anion wherein the quaternized heteroaryl is optionally substituted by R a as hereinabove defined; quaternized fused bicyclic heteroaryl rings wherein the heteroatom or heteroatoms of the quaternized fused heteroaryl ring are selected from 1-3 oxygens, nitrogens and sulfurs; wherein the quaternized fused heteroaryl is optionally substituted by R a as hereinabove defined; or R 2 is an organic residue bonded via a carbon atom; suitably, the organic residue is 2 bonded to either a sp-, sp or sp3-hybridized carbon; wherein an organic residue bonded via an sp-hybridized carbon is a nitrile, or ocetylenic, S* wherein R is as hereinabove defined; an organic residue bonded via an sp 2 -hybridized carbon is selected from those of the formulae: -46- 0 11 -C=N -Ri Rh -C =c-Re Ih R R~

-C=NORJ

R h qq..

U U

U

U.

RR

0 0 -C-OH aster. C ORO -C N\

R

0 11

-C-SRO

-C-N NRh ISI _Rh -C-N 0 11

-C-H

0R -47an organic residue bonded via an sp -_hybridized carbon is -CHF 2 1 CF 3 1 -CF 2 CF 3 1 -CH(OCH 3 2 -CHCl2 or R 3 is hydrogen; a straight or branched (C 1 -C 4 )alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; a (C 1 -C 4 )alkoxymethyl group such as methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl or isobutoxymethyl; a straight or branched l-(C 1 -C 5 )aliphatic acyloxy-ethyl or methyl group such as acetoxymethyl, 1-propionyloxyethyl, n-butyryloxymethyl, isobutyryloxymethyl or pivaloyloxymethyl; a straight, branched or cyclic 1 -C 6 )alkoxycarbonyloxy-ethyl or methyl group such as, ethoxycarbonyloxymethyl, 5: l-isopropoxycarbonyloxyethyl, l-n-butoxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl or 5: l-isobutoxycarbonyloxyethyl; a phthalidyl group; or water soluble cations selected from lithium, sodium, potassium, ammoniumn or tetra(C 1 -C 4 )alkyl .ammonium.

Most preferred compounds are those of formula 0 1 wherein: is an integer from 0-4; Z is selected from oxygen; R 0is -CH(0R 4 )CH 3 R4is selected from hydrogen, -48o 0 0 0 0 0

-CH

2 OCRI I -CH 1 OCORI I -Cm Re -CORI ,-COC4 2 O CRe* 0 0 0

-COCH

2 OCORGI and-PR

OR$

R 6 is selected from a straight, branched or substituted (C 1 -C 18 )alkyl, (C 2 -C 18 alkenyl, unsubstituted or substituted (C 3 -C 7 )monocyclo(C 1

-C

1 0 alkyl, unsubstituted. or substituted,(C 5 -C 10 )bicyclo (C 1

-C,

0 alkyl, phenyl or substituted phenyl; the substitution for the alkyl, monocycloalkyl and bicycloalkyl are selected from trifluoromethyl, pentafluoroethyl, *amino, mono(C -C alkylamino, di(C -C alkylamino, **hydroxy, (C 1 -c 6 )alkoxy, (C 3 cycloalkoxy, carboxy, (C 1 )carboalkoxy, cyano, and

(C

1 -C 10 )carboxamido; the substitution f or the phenyl group is selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )mono-, di- or polyfluoroalkyl, hydroxy, 1 -C 6 )alkoxy, (C 3

-C,

8 )cycloalkoxy,.amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, carboxy, (C 2 -C 10 )carboalkoxy, cyano and (C 1 -C 10 )carboxamido; R 1is straight or branched (C1C4)lystraight or branched (C 2 -C 4 )alkenyl, or (CH 2 )nR; n' is an integer of from 1-4; R is selected from CF 3

C

2 F 5 fluorine, chlorine, bromine, hydroxy, alkoxy, nitrile, azido, a quaternary ammonio group, amidino, formamidino, guanidino and NR'R''; wherein R1 and are independently selected from hydrogen, straight or branched (C 1 -C 4 )alkyl, and straight or branched (C -C )alkoxy; and when R1 is hydrogen or straight or branched

(C

1

-C

4 )alkyl, R" may also be selected from amino, hydroxy, mono (C 1 -C 4 )alkylamino, -49- Wdi (C 1

-C

4 )alkylamino, acyl, benzoyl and dihydroxybenzoyl; Ris selected from methyl, fluorine, chlorine, bromine, iodine, -OCOCH 3 -OCOCF 3 -0S0 2

CH

3 -050 Ph, azido, a moiety of the formula: wherein n" is -an integer from 0-2; and R a is hydrogen, substituted or unsubstituted

C

1 -C 4 alkyl, substituted or unsubstituted (C 3 -C 6 cycloalkyl, substituted or unsubstituted (C 2 -C 4 alkenyl, substituted or unsubstituted (C 2 -C 4 alkynyl, substituted or unsubstituted phenyl; said substitution is selected f rom, (C 1 -C 4 )alkyl, hydroxy, (C 1 -C 4 )alkoxy, phenyl, amino, amidino, quanidino, carboxamido, carbamoyl V and quaternary-ammonio; oR sa a a or 2s hydroxy, -OR -OC (0)R -OC (0)OR 20 **OC(O)NRa R a, -OC(0)-C(H 2 )R a wherein R a.i independently selected and is as hereinabove defined or -0 -P-0 CH 2 CH 2 R 13 0 V wherein R is a moiety selected from those of the 13 formulae:

+N

_NH

3 I -N(CH 3 3 and where B -is a physiologically acceptable anion, or R 2 is an organic residue bonded via a nitrogen atom, selected from NVI I R R J R h jRh -N(CRh)OR -N -N= N-R P

R

P

N-C-NH- R oC-NH- R R N-C--NH- R C-NH 0 Rm hII R N-C-CH

-N

0 R R R -NRyR R 5 wherein R h and R are independently selected from hydrogen; substituted or unsubstituted

(C

1

-C

4 )alkyl and (C 3

-C

6 )cycloalkyl(C 1

-C

4 )alkyl, and substituted or unsubstituted phenyl, and with respect to the NRR moiety, R h and R taken together with the associated nitrogen may be unsubstituted or substituted mono- or bicyclic heterocyclic ring having from 5-7 atoms in each ring and up to four heteroatoms in each ring independently selected from oxygen, nitrogen and sulfur wherein the substituents consist of amino, mono-, di- and tri(C 1

-C

4 )alkylamino, hydroxyl, oxo, carboxyl, alkoxyl, chloro, fluoro, bromo, nitro, -SO2NH2, phenyl, benzyl, acyloxy, alkoxycarbonyloxy, cycloalkoxycarbonyloxy, alkoxylcarbonyl and carboxamido; R P is oxygen or sulfur; R m is hydrogen or an acyl residue of an amino acid or peptide; and Rt is hydrogen, benzyl, -51- W straight or branched (C 1

-C

4 )alkyl optionally substituted with halo, hydroxy, amino, guanidinyl, carboxy, phenyl, aminocarbonyl, alkylthio or hydroxyphenyl; and R 7

R

8 and R 9 are the same or different and are selected from hydrogen, a straight or branched

(C

1

-C

4 )alkyl, (C 2

-C

4 )alkenyl and substituted

(C

1

-C

4 )alkyl, wherein the substitution is selected from hydroxy, (C 1 -C )alkoxy, azido, amino,

(C

1

-C

4 )alkylamino, di(Cl-C 4 )alkylamino, guanidino, nitrile, carboxy, formimidoyl and phenyl; alternatively, R 7 and R taken together are -(CH2)2X(CH2)2-, wherein X is (CH 2 )w (w is an integer from 0 to oxygen, sulfur, NH, NR, NOH and NORh; e or R is an organic residue bonded via a carbon atom; suitably, the organic residue is bonded to *2 3 Seither an sp-, sp or sp -hybridized carbon; "wherein an sp-hybridized carbon is a nitrile moiety, an acetylene moiety or a moiety of the formula: C- R wherein R a is as hereinabove defined; an sp2-hybridized carbon is, -52- -C -19

-CNOEJ

c M 0 0 -C-O

C-R

0 3 R C N

""R

*9 0 -CH ;3 9 5 3k 44 xmehl 9t oy ehl -p ooy eh l ian sp-hyridized carnisgh, ched -CF cFci

-(OCH

3 )aloyaroyox-ty oCHr 2 orhy groupR suchC 4 aslkyl group suchoasmethyl, ehl -53l-isopropoxycarbonyloxyethyl, 1-n-butoxycarbonyloxyethyl, l-cyclohexyloxycarbonyloxyethyl or l-isobutoxycarbonyloxyethyl; a phthalidyl group; or water soluble cations such as lithium, sodium, potassium ammonium or tetra(C 1 -C 4 )alkyl ammonium.

Most particularly preferred compounds are those selected from formula I wherein: n is an integer from 0-4; Z is selected from oxygen; R is

-CH(OR

4

)CH

3 R is selected from hydrogen,

V

:0 0 0 0 0 0 V II II II II II II -CH OCR -CH OCOR 6 -c R 6 -COR ,-COCH 2 0 CR 6 2 1 V.V K I I II I I 3' -COCH 2

OCOR

6 and -POR 6

TT:'?OR

15 R is selected from a straight, branched or substituted

(C

1

-C

18 )alkyl, (C 2

-C

18 )alkenyl, unsubstituted or substituted (C 3

-C

7 monocyclo(C 1

-C

1 0 )alkyl, unsubstituted or substituted (C 5

-C

10 )bicyclo(C 1 -c 10 ))alkyl, phenyl and substituted phenyl; the substitution for the alkyl, monocycloalkyl and bicycloalkyl are selected from trifluoromethyl, pentafluoroethyl, amino, mono(C 1 -C alkylamino, di(C 1

-C

6 )alkylamino, hydroxy,

(C

1

-C

6 )alkoxy, (C 3 -C)cycloalkoxy, carboxy,

(C

2 -Clo)carboalkoxy, cyano and (C 1

C

10 )carboxamido; the substitution for the phenyl group is selected from

(C

1

-C

6 )alkyl, (C 1

-C

6 )mono-, di- or polyfluoroalkyl, hydroxy, (C 1 -C alkoxy, (C 3 -C cycloalkoxy, amino, -54mono (c 1 -c 6 alkylamino, di (C 1

-C

6 alkylanino, carboxy,

(C

2

-C,

0 carboalkoxy, cyano and (C 1

-C

1 0 carboxamido; *1is straight (C 1 -C 3 )alkyl, CH 2

CF

3 and CH 2 CF 2 CF 3 R is selected from: methyl, fluorine, chlorine, bromine, iodine, -OCOCH 3

-OCOCF

3

-OSO

2 CH 3 1 -OSO, Ph, azido; a moiety of the formula: -SO "Ra wherein is an integer from 0-2; and R a is hydrogen, substituted or unsubstituted (C 1 -C 4 alkyl, substituted or unsubstituted phenyl wherein the substituents are selected from (C 1- 4)akylhyroxy 1C )lkx amino, amidino, guanidino, carboxamido, carbamoyl and quaternary animonio; (c r s yroy a a a r ishydrxy,-OR -OC(O)NR R or

OC(O)-C(NH

2 )Ra whereinRa independently selected and is as hereinabove defined or 00 0000 300

B-

-NH

3 (CH 3 3 a nd or R 2is an organic residue bonded via a nitrogen atom, selected from -NRh Rj, 0 -N(CR')oR's N h

RP

N-C-NH-

B-

-NR7R8R9

RJ

N R h R

P

h I I R O-C-NHa a a.

a a.

aa

-N-C-CH-N

Ih I R R

R

m

/RR

wherein Rh and Rj are independently selected from hydrogen; substituted or unsubstituted

(C

1 -C alkyl and

(C

3

-C

6 cycloalkyl(C 1

-C

4 alkyl, and substituted or unsubstituted phenyl, wherein the substituents consist of amino, mono-, di- and tri(C 1

-C

4 alkylamino, hydroxyl, oxo, carboxyl, alkoxyl, chioro, fluoro, bromo, nitro, -So 2 NH phenyl, benzyl, acyloxy, alkoxylcarbonyloxy, cycloalkoxycarbonyl.

oxy and carboxamido; RP is oxygen or sulfur; Rm is hydrogen or an acyl residue of an amino acid or peptide, Rt is hydrogen or (C 1

-C

4 )alkyl, and R 7 R 8 and R 9 are the same or different and are selected from -56hydrogen, a straight or branched (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl and substituted (C 1 -C 4 )alkyl, wherein the substitution is selected from hydroxy, (C 1 -C 4 )alkoxy, azido, amino, (C 1 -c 4 )alkylamino, dic 1 -C 4 )alkylamino, guanidino, nitrile, carboxy, formimidoyl and phenyl; alternatively,

R

7 andR taken together are-(H22XC221 wherein X is (CH 2 )w (w is an integer, from 0 to oxygen, sulfur, NH, NRh NOH and NOR h; or R 2 is an organic residue bonded via a carbon atom; suitably, the organic residue is bonded to either an sp-,2 or sp -_hybridized carbon; wherein an sp-hybridized carbon is a nitrile,

-C-N;

an sp -_hybridized carbon is a moiety of the formulae: 0~R h C C-N

XR

C- NR h 2. F -C 8 R 3.s h d o e a st a g t o r n he c*C4) l y group~C su h a e h l t y n-R op so r p l -57n-butyl, isobutyl, or tert-butyl; a (C 1

-C

4 )alkoxymethyl group such as methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl or isobutoxymethyl; a straight or branched l-(C 1

-C

5 )aliphatic acyloxy-ethyl or methyl group such as acetoxymethyl, l-propionyloxyethyl, n-butyryloxymethyl, isobutyryloxymethyl or pivaloyloxymethyl; a straight, branched or cyclic l-(C 1

-C

6 )alkoxycarbonyloxy-ethyl or methyl group such as ethoxycarbonyloxymethyl, 1-isopropoxycarbonyloxyethyl, l-n-butoxycarbonyloxyethyl, 1-cyclohexyloxy carbonyloxyethyl, or l-isobutoxycarbonyloxyethyl; a phthalidyl group; or water soluble cations such as lithium, sodium, potassium ammonium or tetra(C 1

-C

4 alkyl ammonium.

Unless otherwise specified herein, the particulars of the various definitions mentioned above and specific examples falling within such definitions are as follows: the aryl group is an aromatic monocyclic or bicyclic hydrocarbon group having from 6 to 15 carbon atoms such as a phenyl group, a biphenyl group, a l-naphthyl group or a 2-naphthyl group; the aralkyl or arylalkyl group is an S. 25 aromatically substituted alkyl group having from 7 to 15 carbon atoms such as a benzyl group, a l-naphthylmethyl group, a 2-naphthylmethyl group, a 5,6,7,8-tetrahydro-l-naphthyl group, a 5,6,7,8-tetrahydro-2-naphthyl group, a phenylethyl group, a 3-phenylpropyl group or a 4-phenylpropyl group; the heteroaryl group is an aromatic monocyclic or bicyclic heterocyclic group of 5 to 12 atoms wherein each ring is comprised of 5 to 6 atoms wherein the heteroatom or heteroatoms are selected -58from 1-4 oxygen, nitrogen or sulfur atoms such as thienyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, triazinyl, furanyl, imidazolyl, thiazolyl and triazolyl; the heterocyclyl group is a monocyclic or bicyclic heterocyclic group having from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur atoms and each ring of the heterocycle is comprised of 4 to 7 atoms, preferably 5 to 6 atoms such as pyrrPlidinyl group, a pyrazolidinyl group, an imidazolidinyl group, a 15 Piperidinyl group, a piperazinyl group or a morpholinyl group.

It is understood that any quarternized, positively charged nitrogen containing moiety used herein such as Strialkylamino, will be associated with a physioloically 20 acceptable counterion as previously defined.

Pharmaceutically suitable salts include both the metallic (inorganic) salts and organic salts; a list of which is given in Remington's Pharmaceutical Sciences, *17th Edit .17th Edition, page 1418 (1985). It is well known to one skilled in the art that an appropriate salt form is chosen based on physical and chemical stability, flowability, hygroscopicity and solubility. Preferred salts of this invention for the reasons cited above include potassium, sodium, calcium, magnesium and ammonium salts.

The present invention provides compounds that are useful as intermediates for making the above compounds of formula I. Such intermediate compounds are of formula IV(1-6) and IX(1-6): -59- (cH 2 )nR 2 HS

(CH

2 )nR 2 IV IV (4-6) z z Y9P

(CH

2 )nR 2 (CH 2 )nR 2 IX(1-3) IX (4-6) wherein: Y is selected from chioro, bromo, iodo, methane- 5 sulfonate and trifluoromethanesulfonate; and n, Z, and Rare as hereinabove described.

Preferrred intermediate compounds are those chosen from formula IV(l-6) or IX(l-6) wherein: R 2is methyl, fluorine, chlorine, bromine, iodine, -OCOCH 3 -OCOCF 3 -0S0 2 CH 3

-OSO

2 Ph, azido, a moiety of the formula: n,'R a wherein n''is an integer from 0-2.; and R a is hydrogen or an organic group bonded via a carbon atom selected from substituted or unsubstituted

(C

1

-C

4 )alkyl, substituted or unsubstituted

(C

3

-C

6 )cycloalkyl, substituted or unsubstituted

(C

2

-C

4 )alkenyl, substituted or unsubstituted

(C

2

-C

4 )alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl(C 1 -Cg)alkyl, substituted or unsubstituted heterocyclyl, any of such groups being optionally substituted; said substitution is selected from (C 1

-C

4 )alkyl, hydroxy, (C 1

-C

4 )alkoxy, phenyl, heterocyclyl, amino, amidino, guanidino, carboxamido, carbamoyl and quaternary ammonio; or R 2 is hydroxy, -OR a

-OC(O)R

a

-OC(O)OR

a -OC(O)NRaR a or Ra S: -oc( 0)-c

*N

N H 2 2 wherein Ra is independently selected and is as hereinabove defined or 0 i0 P-

CH

2 CH 2

R

1 0 wherein R3 is a moiety selected from those of the formulae: B- B

B"

NH

N(CH)

3 and -61or R 2 is an organic residue bonded via a nitrogen atom, selected from NO, NO 2

NO

3 NC, NCO, NHCN, and NRRJ wherein Rh and R J are independently selected from hydrogen; substituted or unsubstituted amino, substituted or unsubstituted (C 1

-C

4 )alkyl and

(C

3

-C

6 cycloalkyl(C 1

-C

4 )alkyl, aryl, aralkyl, heterocyclyl, heterocyclyl(C 1

-C

4 )alkyl, heteroaryl and heteroaryl(C 1

-C

4 )alkyl wherein the heteroatom or heteroatoms are selected from oxygen, nitrogen and sulfur, and a cyclic group wherein R h and R J taken together with the associated nitrogen is an unsubstituted or substituted mono- or bicyclic heterocyclic ring having up to four heteroatoms in each ring independently selected from oxygen, nitrogen and sulfur wherein the substituents in the aforementioned substituted alkyl, amino and heterocyclic groups consist of amino, mono-, di- and tri(C -C )alkylamino, hydroxyl, oxo, Scarboxyl, alkoxyl, chloro, fluoro, bromo, nitro, -SO2NH 2 phenyl, benzyl, acyloxy, alkoxylcarbonyl, o2 2 1 20 alkoxycarbonyloxy, cycloalkoxycarbonyloxy and carboxamido; or R2, as an organic residue bonded through nitrogen, is a hydroxylamino, hydrazinyl, and hydroxamic acid derivatives: 0

I

25 N(R)OR, -N(Rh)NRhRJ, and N(CRh)OR

J

respectively; wherein R h and R are as hereinabove defined; moieties of the formulae: -62- Rh R h

I

R I I Rh R N-R and

R

J

<RI h Rh wherein

R

h and R are as hereinabove defined; acylamino moieties of the formula: Rh C-N- *II

I

20 R' .0 R h J wherein R and R are as hereinabove defined; moieties represented by the formulae: h R II

II

N-C-NH- and Rh 0-C-NHwherein R h and R J are as hereinabove defined and R e is oxygen and sulfur; moieties of the formulae: 0 Rk-C-C-NH-

N

I

ORk -63b wherein R k represents hydrogen, substituted or unsubstituted (C 1

-C

3 )alkyl* (in the description of respective groups in the present specification, groups marked with an asterisk may have a substituent as assigned hereinabove for R and R (C2-C4)alkenyl*,

(C

2

-C

4 )alkynyl*, heterocyclyl* and heteroaryl* wherein the heteroatom or heteroatoms are selected from 1-4 oxygen, nitrogen or sulfur and the cyclic portion has or 6 ring atoms; moieties of the formula: RaS'(O) ,,NHwherein n" and R a are as hereinbefore defined; or R may be a moiety of the formula: 0 m II -N-C-CH -N I I Rh Rt Rh r R 15 wherein R is as hereinabove defined; R m is hydrogen or an acyl residue of an amino acid or peptide; and Rt is hydrogen, benzyl, straight or branched (C 1

-C

6 )alkyl optionally substituted with halo, hydroxy, amino, guanidinyl, carboxy, phenyl, aminocarbonyl, alkylthio, 20 hydroxyphenyl or heterocyclyl; or R is an organic residue bonded via a carbon atom; 2 suitably, the organic residue is bonded to either a 2 3 sp-, sp- or or -hybridized carbon; an sp-hybridized carbon is a nitrile, -C N wherein R a is as hereinabove defined; an sp2-hybridized carbon is, -64- 0 11 -C -its

-C=NEJ

-C =C-RI, Rh

NJ

-CNOEJ

-N 0 0 11 11 -C-OH; aateor -C-OR'; 9.

9* *e S S

S

5 5 0e

S.

S

S. *5

S

.9.

S

S.

5505

S

55 0

S

55 0

-C-

0 -C-N -C-N

-I

0 11

-C-SRO

0 11

-C-H

Rh _~wKRJ an sp -hybridized carbon is -CHF 2

CF

3

-CF

2

CF

3

-CH(OCH

3 2 -CHC1 2 or -CHRhRJ.

Most particularly preferred intermediate compounds are those chosen from formula IV(1-6) or IX(1-6) wherein:

R

2 is hydrogen, fluorine, chlorine, bromine, iodine, -OCOCH 3

-OCOCF

3

-OSO

2

CH

3

-OSO

2 Ph, azido, a moiety of the formula: Ra wherein n" is an integer from 0-2; and Ra is hydrogen or an organic group bonded via a carbon atom selected from substituted or unsubstituted

(C

1

-C

4 )alkyl, substituted or unsubstituted phenyl, any of such groups being optionally substituted; said substitution is selected from (C 1

-C

4 )alkyl, hydroxy, (C -C )alkoxy, amino, amidino, guanidino, carboxamido, carbamoyl and quaternary ammonio; or R2 is hydroxy, -OR a or -OC(O)NRaR a wherein R a is S* independently selected and is as hereinabove defined or 0 2 0

OCH

2

CH

2 R 3 he n i aN(C~z)

I-

or wherein R is a moiety selected from those of the formulae: 9

B-

S. B B

-NH

3 N(CH 3 3 and or R2 is an organic residue bonded via a nitrogen atom, selected from -NR RJ, -66- I I Rh 00 -N(CRh)0RJ. N~ -N= Rh N-RRN R h RF

R

I Rh0 I I

-MR

7 R8R 9 wherein Rh and Rj are independently selected from hydrogen; amino (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl(C 1 -C4)alkyl, and phenyl; R is oxygen or sulfur; **and R. R. and Rare the same or different and are 7 R selected from hydrogen, a straight or branched (C 1 -c 4 alkyl, (C 2 -c 4 )alkenyl and substituted (C 1 -C 4 )alkyl, wherein the substitution is selected from hydroxy,

(C

1 -C )alkoxy, azido, amino, (C -C )alkyl- 1. 4.

amino, di (C 1 -C 4 )alkylamino, guanidino, nitrile, carboxy, formimidoyl and phenyl; alternatively, R 7 and R.taken together are -(CH 2 2

X(CH

2 2 wherein X is (CH 2 )w (w is an integer from 0 to oxygen, sulfur, h h NH, NRh, NOH and NOR; or Ris a moiety of the formula: 0

R

-N-C-CH

-N

R R wherein Rhis as hereinabove defined; Rm is hydrogen or an acyl residue of an amaino acid or peptide; and Rt is hydrogen, benzyl, straight or branched (C 1 -C )alkyl optionally substituted with halo, hydroxy, amino, -67guanidinyl, carboxy, phenyl, aminocarbonyl, alkylthio, hydroxyphenyl or heterocyclyl; or R 2 is an organic residue bonded via a carbon atom; suitably, the organic residue is bonded to either 2 3 an sp-, sp or sp -hybridized carbon; wherein an sp-hybridized carbon is a nitrile, an sp2-hybridized carbon is 0 h IC R h 0 -C-N NRh h 10 wherein, R and R are as hereinabove defined; and an sp -hybridized carbon is -CHF 2 CF -CF 2 CF3 S*

-CH(OCH

3 2 CHRhRJ or -CHC12.

It will be appreciated that certain products within the scope of Formula I:

R

4

S

S.

7 0

COOR,

may be formed as optical isomers as well as epimeric mixtures thereof. It is intended that Formula I include within its scope all such optical isomers and epimeric mixtures. For example, when the 6 -substituent in I is l-hydroxyethyl, such substituents R may be either R or S configuration with the R con- Sfiguration being preferred. Likewise, the con- -68figuration of the carbapenem nucleus may be 5R or and 6R or 6S with 5R, 6S being the preferred configuration.

BIOLOGICAL ACTIVITY Method for in vitro Antibacterial Evaluations (Table 1) The minimal inhibitory concentration (MIC), the lowest concentration of the antibiotic which inhibits growth of the test organism, is determined by the agar dilution method using Mueller Hinton II agar following the recommendations of the National Commitee for Clinical Laboratory Standards [Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard M7-A2. National Committee for Clinical Laboratory Standards, Villanova, Pa.].

An inoculum of 107 cfu/ml is applied using a Steers replicator, yielding a final density of 104 cfu/spot, to the surface of the agar containing two fold serial dilutions of the antibacterial agent. The 20 plates are incubated at 35 C for 18 hours.

The organisms tested for susceptibility to the antibacterial agents comprise a spectrum of Grampositive and Gram-negative, recent clinical isolates, S" including those sensitive to various f-lactam antibiotics as well as those producing specific f-lactamases and thereby resistant to many f-lactams.

In Vivo Antibacterial Evaluation Determination of Effective Therapeutic Dose (ED 50 (Table 2 30 In Vivo Antibacterial Evaluation The therapeutic effects of the carbapenems are determined against various models of acute lethal infections coli #311, S. aureus Smith, P.

aeruginosa PA-7). Female mice, strain CD-1 (Charles River Laboratories), 20+ 2 grams, are challenged by an intraperitoneal injection of a bacterial suspension in broth or hog mucin at a bacterial density to kill -69non-treated controls within 24-48 hours. The antibacterial agent(s) [carbapenem contained in ml of 0.2% aqueous agar is administered subcutaneously, intravenously or orally 30 minutes after infection. When an oral dosing schedule is used, the animals are deprived of food for 5 hours before and 2 hours after infection. Five mice are treated at each dose level. The 7 day survival ratios from three separate tests are pooled for calculation of the median effective dose Penicill'in-Binding Protein Assay (Table 3 and 4) Binding of the test compounds to penicillin-binding proteins (PBPs) is determined using methods described by B.G. Spratt, Properties of the penicillin-binding proteins of Escherichia coli K12, Eur. J. Biochem., 72:341-352(1977) and N.H.

Georgopapadakou, S.A. Smith, C.M. Cimarusti, and R.B.Sykes, Binding of monobactams to penicillin-binding proteins of Escherichia coli and Staphvlococcus aureus: 20 Relation to antibacterial activity, Antimicrob. Agents Chemother., 23:98-104(1983). Membranes containing the PBPs are prepared from E. coli ATCC 25922 and S. aureus ATCC 29213. These membranes are incubated with the test compound at selected concentrations and are then challenged with 1C-benzylpenicillin. Following polyacryamide gel electrophoresis and fluorography,

IC

50 values are estimated using densitometry.

Stability to Hydrolysis by Renal Dehydropeptidase

(DHP)

(Table 30 Compounds are also tested for stability to renal dehydropeptidase (DHP) prepared from mouse and hog kidneys using butanol extraction procedures similar to those described by B.J. Campbell et al., 0-Lactamase Activity of Purified and Partially Characterized Human Renal Dipeptidase, J.Bio. Chem., 259:14586-14590(1984).

Assays are performed spectrophotometrically at C in 10mM HEPES buffer, pH 7.2 at a wavelength of I 295 nm. Extinction coefficients were determined for the carbapenems using a metallo--lactamase. Hydrolysis rates are obtained using a stock concentration of pl/ml of the antibiotic and 10-50 pl DHP in a volume of 1.0 ml. At least two concentrations of DHP are used for hydrolysis. The rate of hydrolysis (n moles/min) is determined per pl DHP added to the reaction.

Relative hydrolysis rates are calculated by setting the rate of hydrolysis of imipenem as 100 and normalizing the carbapenems to imipenem.

Testing Results Compounds of formula exhibit activity against a spectrum of Gram-positive and Gram-negative bacteria, including those producing specific f-lactamases.

1 5 Potent activity comparable to that noted with imipenem, biapenem and meropenem is noted with Examples 18, 21, 46, 47, 48, 49, 52, 54A, 64, 65, 79, 114, 120, 129, 162, 192 and 193 against strains of E. coli, Klebsiella, Enterobacter and most other Gram-negative 20 bacteria. Examples 46, 47, 48, 49, 52, 54A, 64, 114, 120, 129, 136, 161, 162, 174, 192 and 193 are also i active against Pseudomonas aeruqinosa but at a higher concentration than imipenem, biapenem and meropenem.

None of the carbapenems is active against the Xanthomonas maltophilia isolate tested. All of these compounds exhibit potent activity against the methicillin-sensitive Staphlococcus aureus isolates and the Enterococcus faecalis isolate at a comparable concentration as the reference carbapenems. None of the carbapenems exhibited good activity against the methicillin-resistant S. aureus (MRSA) or the Enterococcus faecium isolates. Examples 46, 47, 48, 49, 64, 65, 129, 136 and 161 are a mixture of two diastereoisomers. Example 114, Example 120 and Example 162, are optically pure compounds and have similar potency as their corresponding mixtures of -71diastereoisomers, Example 46 and Example 64, against all of the organisms.

Example 51A, Example 52 and Example 54A, acyl derivatives of amino acids of Example 46, also exhibit potent activity against both Gram-negative and Gram-positive bacteria but slightly less than Example 46, especially against Pseudomonas aeruqinosa. Example 51B and Example 54B, the di-amino acid analogues are less active than the corresponding mono-amino acid analogues against the organisms tested.

Example 59, which contains a methyl group in place of the aminomethyl group of Example 46, while active against a variety of organisms, demonstrates no activity against Pseudomonas aeruainosa and exhibits less activity against Gram-negative and Gram-positive bacteria than Example 46.

Example 174, the tetrahydrothiophene analogue, is S• slightly less active than the corresponding tetrahydrofuran analogue, Example 46.

20 Example 186, an isobutyl carbonate prodrug of S' Example 46, exhibited very poor activity on its own.

However, when incubated for 1 hour in the presence of mouse serum the antibacterial activity is partially restored to that of Example 46. A similar response is obtained with Example 195, the isobutyl carbonate prodrug of Example 64, after incubation in the presence of mouse serum.

Example 160, exhibits activity against the spectrum of organisms tested but is less active than Example 46.

Example 79 and Example 18, containing a cis configuration, and Example 21, containing a trans configuration, have similar potent activity against the majority of the isolates tested. These compounds are all less active against Pseudomonas aeruainosa than Example 64.

-72- Example 26, Example 42, Example 69, Example 34 and Example 38 are less active against the Gram-negative bacteria but have similar activity as the reference carbapenems against the Gram-positive bacteria.

Example 144, Example 148A and Example 148B are active against Gram-positive and most Gram-negative bacteria, except P. aeruainosa and X. maltophilia.

Example 144 is less active than Example 148A and Example 148B against the Gram-negative bacteria tested, but have comparable activity against the Gram-positive bacteria.

Example 87, a triazine thio analogue, is slightly less active than Example 46 and is especially poor against P. aeruginosa.

Comparable activity against Gram-negative and Gram-positive bacteria is obtained with optically pure positional isomers depicted by Example 192 (1,2-positional isomer) and Example 120 (1,3-positional isomer). The substitution of a formamidine moiety 20 Example 193, in place of the amino group Example 192, results in a slight decrease in activity against some organisms.

Example 46, Example 114, Example 120 and Example 162 have a similar binding profile to the essential penicillin binding proteins (PBPs) of E. coli and S.

aureus (Table 3 and E. coli PBP 2, as noted with the reference carbapenems, is the primary target for these compounds. Tight binding to PBP 4 is also observed for all of the carbapenems. In S. aureus, PBP 1 is the major target for Example 46, Example 114, Example 120, Example 162 and meropenem. Imipenem and biapenem bind tighter to the other PBPs as well.

However, all of the compounds have very low MICs for this strain.

Example 46 and Example 64 exhibit increased stability to mammalian dehydropeptidase than imipenem and meropenem. (Table -73- SThe potent ji vitro antibacterial activity of Example 46, 64 and 192 is also demonstrated by their in vivo efficacy against an acute lethal infection of 1.

aureus Smith and E. gcli 311 in mice when dosed by the subcutaneous route (Table These compounds show good efficacy relative to the reference carbapenems: meropenem, biapenem and imipenem. These compound also demonstrate good oral activity against both organism: S. aureus Smith and E. coli 311. L-amino acid derivatives of Example 192 as examplified by Example 261, 391, 265, 266, 257, 344 and 345 demonstrate substantially improved oral activity based on their and comparative SOD/SSC ratios (SOD single oral dose; SSC single subcutaneous dose). In particular, the improved oral activity is seen in Examples 261, 344 and 345.

S: o 12 i 3 0* Table I: Antibacterial Activity, MIC (pg/mi) Coiiirols Eumple No.

ORGANISM Pipera~c illinf Imipercm IBiapenem Meropcnerm E.coli(25922) E.coli(1 YES 912) E.col i(300) E.coli(352 18) E.coli(MEDEIROS 4) E.coli(MEDEIROS 14) E.coli(BUSH 9 1-39) K.pneumo(1 YES 688) K.oxytoca(CUHN 88-1 I) E.aerogenes(IVES 15(N;, E.cloacae(Richmond 1) C.diversus(IVES 1680) C.freundii(IVES 953) S.marcescens(1 YES 306~2) M.morganii(1 YES 335) Salmonella sp(CI-BM 88-58) P.stiuarii(CUFHN 88-7) 1 P.aerug.(27853) P.aerug.(IVES 5250) P.aenug.(MEDEIROS-7) P.aerug.(BUSH- 91-73) X.mailto.(NEMC 87-2 10) A.calco.(BMMR 88-2) S.aureus(292 13) S.aureus(25923) S.aureus(IVES 1097) S.aureus(I YES 1545) S.aureus(IVES 2837) CNS(IVES 191) CNS(IVES 1754) E.faecalis(CHBM 88-6() E.faecium-(DLMC 89- 1) 2.00 128.00 0.06 128.00 128.00 64.00 128.00 128.00 128.00 128.00 128.00 16.00 128.00 32.00 128.00 128.00 128.00 2.00 2.00 128.00 4.00 128.00 128.00 0.25 0.25 2.00 64.00 128.00 0.50 128.00 4.00 128.00 0.06 0.06 0.06 0.06 0.06 0.06 0.06 12.00 12.00 12.00 0.06 0.06 0.25 0.25 1.00 0.06 0.50) 1.00 0.25 0.50) 16.00 12 8.0() 0.25 0.06 0.06 0.06 006 1.00 0.06 64.00 0.50 .128.00 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.12 0.06 0.06 0.06 0.06 0.06 0.50 0.50 0.06 0.50 0.50 0.06 0.25 8.00 128.00 0.25 0.06 0.06 0.06 0.06 4.00 0.06 64.00 2.00 128.00 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.25 0.12 0.50 4.00 128.00 0.50 0.06 0.06 0.12 0.12 8.00 0.12 64.00 4.00 128.00 0.06 0.06 0.06 0.06 0.06 0.06 0.12 0.06 0.06 0.25 0.50 0.06 1.00 0.25 0.25 0.50 128.00 128.00 128.00 128.00 128.00 4.00 0.06 0.06 0.12 0.25 32.00 0.25 128.00 4.00 128.00 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.12 0.50 0.06 1.00 0.12 0.12 0.25 64.00 64.00 128.00 128.00 128.00 4.00 0.06 0.06 0.12 0.25 16.00 0.25 128.00 4.00 128.00 2.00 2.00 0.50 4.00 8.00 8.00 8.00 8.00 9.00 1.00 8.00 16.00 16.00 2.00 2.00 8.00, 128.00 128.00 128.00 128.00 128.00 8.00 0.06 0.06 0.06 <0.06 4.00 0.06 64.00 2.00 128.00 i Table I (Coniinued) Examnle No.

ORGANISM

E.coli(25922) E.coli(IVES 912) E.coii(300) E.coli(352 18) E.coli(MEDEIROS 4) E.coli(MEDE[ROS 14) E.coli(BUSH 91-39) K.pneumo(IVES 688) K.oxytoca(CUHN 88-11) E.aerogenes(IVES 1500) E.cloacae(Richmond 1) C.diversus(IVES 1680) C.freundii(IVES 953) S.marcescens(JVES 3062) M.morganii(IVES 335) Salmonella sp(CHBM 88-58)' P.stuartii(CUHN 88-7) P.aerug.(27853) P.aerug.(IVES 5250) P.aerug.(MEDEIROS.7) P.aerug.(BUSH 9 1-73) X.malbo.(NEMC 87-2 10) A.calco.(BMMR 88-2) S.aureus(292 13) S.aureus(25923) S.aureus(IVES 1097) S.aureus(IVES 1545) S.aureus(IVES 2837) CNS(IVES 191) CNS(IVES 1754) E.faecalis(CHBM 88-6(0) E.faecium(DLMC 89-1) 2.00 2.00 0.06 4.00 4.00 4.00 4.00 4.00 4.00 4.00 2.00 4.00 8.00 16.00 2.00 2.00 8.00 128.00 128.00 128' 00 128.00 128.00 16.00 0.06 0.06 0.06 0.25 16.00 0.06 128.00 4.00 128.00 4.00) 2.0) 0.06 4.00) 4.00) 4.00 4.00 4.10 8.0X) 8.00 8.(X0 16.00 16.00 2.0) 2.00 81)0 128.00 128.00 128.00 128.00 128.00 4.00 0.06 0.06 006 1.0o 0.06 32.00 0.50 64.00 8.00 4.00 0.06 2.00 16.00 16.00 16.00 32.00 16.00 8.00 2.00 32.00 32.00 16.00 4.00 4.00 16.00 128.00 128.00 128.00 128.00 128.00 8.00 0.06 0.06 0.06 0.06 4.00 0.06 64.00) 2.00 12800 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.12 0.25 0.06 0.50 4.00 4.00 4.00 8.00 128.00 1.00 0.06 0.06 0.06 0.12 8.00 0.06 64.00 2.00 128.00 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.12 0.50 0.06 0.50 8.00 2.00 8.00 16.00 128.00 2= .00 0.06 0.06 0.12 8.00 0.06 64.00 2.00 128.00 0.06 0.06 0.12 0.06 0.06 0.06 0.06 0.12 0.12 0.06 0.06 0.06 0.12 0.12 0.05 0.06 0.25 8.00 4.00 8.00 16.00 128.00 2.00 0.06 0.06 0.12 0.12 8.00 0.06 64.00 4.00 128.00 0.06 0.06 0.12 0.06 0.06 0.06 0.06 0 .06 0.06 0.06 0.06 0.06 0.12 0.25 0.50 0.06 0.50 16.00 8.00 8.00 32.00 128.00 2.00 0.06 0.06 0.12 0.25 16.00 0.12 64.00 4.00 128.00 0 0 0 *00 0 *0 *0 ~0* 0** *0* 0 0 0* 0 9 0 0 ow Table I (Continued) Eiamnple No.

0 ORGANISM 51A 51 ls 54A 54B E.coli(25922) E.coli(IVES 912) E.coli(300) E.coli(352 18) Ecoli(MEDEIROS 4) E.coli(MEDEIROS 14) E.coli(BUSH 91-39) K.pneumo(IVES 688) K.oxytoca(CUHN 88-11I) E.aerogenes(IVES 1500) E.cI oacae(Richmond 1) C.diversus(IVES 1680) C.freundii(IVES 953) S.marcescens(IVES 3062) M.morganii(IVES 335) Salmonella sp(CHBM 88I-58) P.stuartii(CUHN 88-7) P. aerug. (27853) P.aerug.(IVES 5250) P.aerug.(MEDEIROS-7) P.aerug.(BUSH 9 1-73) X.mahto.(NEMC 87-2 10) A.calco.(BMMR 88-2) S.aureus(292 13) S.aureus(25923) S.aureus(IVES 1097) S.aureus(IVES 1545) S aureus(IVES 2837) CNS(IVES 191) CNS(IVES 1754) E.faecalis(CHBM 88-60) E.faecium(DLMC 89-1) 0.06 0.06 0.06 0.06 0.12 0.25 0.50 0.06 0.25 1.00 0.50 0.06 2.00 0.50 0.50 0.06 1.00 128.00 128.00 128.00 128.00 128.00 16.00 0.12 0.50 1.00 1.00 128.00 2.00 128.00 8.00 128.00 0.50 1.00 2.00 1.00 4.00 4.00 8.00 2.00 8.00 16.(X) 1.00 32.00) 16.00 16.00 1.00X 16.00 128.00) 128.00 128.00 128.00 128.00 128.00 2.00 4.00 8.00 8.00 128.00 32.00 128.00 128.00 128.00 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.25 0.12 0.25 0.06 0.25 32.00 32.00 32.00 32.00 128.00 2.00 0.06 0.06 0.12 0.25 16.00 0.12 64.00 4.00 128.00 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.12 0.12 0.06 0.06 0.25 0.25 0.25 0.06 0.25 16.00 16.00 32.00 32.00 128.00 2.00 0.06 0.06 0.12 0.25 16.00 0.12 64.00 2.00 128.00 0.06 0.06 0.06 0.06 0.12 0.25 0.25 0.12 0.25 1.00 1.00 0.06 4.00 1.00 1.00 0.06 1.00 128.00 128.00 128.00 128.00 128.00 16.00 0.06 0.25 0.50 1.00 64.00 1.00 128.00 16.00 128.00 0.12 0.12 0.06 0.06 0.25 0.50 0.50 0.25 0.50 0.50 0.50 0.25 4.00 2.00 0.25 0.06 1.00 128.00 128.00 128.00 128.00 128.00 16.00 0.06 0.12 0.25 1.00 16.00 0.25 128.00 8.00 128.00 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.25 0.50 0.06 0.25 8.00 2.00 2.00 16.00 128.00 2.00 0.06 0.06 0.06 0.12 4.00 0.06 64.00 2.00 128.00 0 9 *9 9 9 See see a 9. Table I (Continued) Example No.

ORGANISM 65 69 E.coli(25922) E.coli(IVES 912) E.coli(300) E.coli(35218) E.coli(MEDEIROS 4) E.coli(MEDEIROS 14) E.coli(BUSH 91-39) K.pneumo(IVES 688) K.oxytoca(CUHN 88-1 I E.aerogenes(IVES 1500) E.cloacae(Richmond 1) C.diversus(lVES 1680) C.freundii(IVES 953) S.marcescens(lVES 3062) M.morganii(IVES 335) Salmonella sp(CHBM 88-5,) P.stuartii(CUHN 88-7) P.aerug.(27853) P.aerug.(IVES 5250) P.aerug.(MEDEIROS-7) P.aerug.(BUSH 91-73) X.malto.(NEMC 87-210) A.calco.(BMMR 88-2) S.aureus(29213) S.aureus(25923) S.aureus(lVES 1097) S.aureus(IVES 1545) S aureus(IVES 2837) CNS(IVES 191) CNS(IVES 1754) E.faecalis(CHBM 88-60) E.faecium(DJ..MC 89-1) 0.06 0.06 0.12 0.06 0.06 0.06 0.06 0.12 0.12 0.06 0.06 0.06 0.12 0.50 0.50 0.06 0.50 16.00 16.00 16.00 32.00 128.00 4.00 0.06 0.06 0.06 0.12 4.00 0.06 32.00 2.00 128.00 32.00 16.0(X 0.06 4.00 32.00 32.0() 64.00 64.0() 64.(x 32.00 8.00 64.(X00 128.00 64.00 32.00 32.00 64.00 128.00 128.00 128.00 128.00 128.00 16.00 0.06 0.06 0.06 0.06 2.00 0.06 128.00 2.00 128.00 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.25 0.12 0.06 0.06 64.00 64.00 64.00 64.00 128.00 2.00 0.06 0.06 0.12 0.25 128.00 0.25 64.00 4.00 12.00 0.06 0.06 0.06 0.06 0.12 0.25 0.25 0.12 0.12 1.00 0.12 0.06 4.00 1.00 0.50 0.06 0.12 128.00 128.00 128.00 128.00 128.00 16.00 0.06 0.12 0.25 0.50 32.00 0.50, 128.00 8.00 128.00 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.25 0.06 0.25 2.00 2.00 4.00 8.00 128.00 1.00 0.06 0.06 0.06 0.12 8.00 0.06 64.00 2.00 128.00 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.12 0.12 0.50 0.06 0.25 16.00 8.00 8.00 32.00 128.00 2.00 0.06 0.06 0.06 0.12 8.00 0.06 64.00 4.00 128.00 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.25 1.00 0.06 0.25 16.00 8.00 8.00 32.00 128.00 2.00 S0.06 0.06 0.06 0.06 4.00 0.06 64.00 4.00 128.00 0 0 0 *0 0~ 0 00 0** 0 0 0. Table I (Continued) Example No.

ORGANISM 148A 148B 160 E.coli(25922) Ecoli(IVES 912) E.col i(300) E.coii(352 18) E.coli(MEDEIROS 4) E.coli(MEDEIROS 14) E.coli(BUSH 9 1-39) K.pneumo(IVES 688) K.oxytoca(CUHN 88-1l) E.aerogenes(IVES 15(-X)) E.cloacae(Richmond 1) C.diversus(IVES 1680) C.freundii(1 YES 953) S.marcescens(IVES 3002) M.morganii(IVES 335) Salmonella sp(CHBM 88-58) P.stuartii(CUHN 88-7) P.aerug.(27853) P.aerug.(IVES 5250) P.aerug.(MEDEIROS-7) P.aerug.(BUSH 9 1-73) X.mahto.(NEMC 87-2 10) A.calco.(BMMR 88-2) S.aureus(292 13) S.aureus(25923) S.aureus(1 YES 1097) S.aureus(IVES 1545) S aureus(IVES 2837) CNS(IVES 191) CNS(IVES 1754) E.faecalis(CHBM 88-601) E.faecium(DLMC 89-I1) 0.12 0.06 0.25 0.06 o.06 0.12 0.12 0.12 0.25 0.12 0.12 0.06 0.25 0.25 1.00 0.06 1.00 16.00 8.00 16.00 128.00 4.00 0.06 0.12 0.25 0.50 8.00 0.25 128.00 8.00 128.00 2.(X) 0.01, 0.5t i 2.(X 2.00) 2.00 2.00 2.00 4.00 1.00 8.00 4.00 4.00 2.00 8.00 18.00) 128.00 >128.00 *128.00 >128.00 32.00 0.06 0.06 0.25 0.25 16.00 0.25 0.06 4.00 128.00 0.06 0.06 0.06 0.12 0.25 0.25 0.12 0.12 0.50 1.00 0.06 0.06 1.00 0.50 1.00 0.06 0.50 64.00 128.00 128.00 128.00 128.00 4.00 0.06 0.06 0.12 0.25 32.00 0.25 128.00 4.00 128.00 0.06 0.06 0.06 0.06 0.12 0.25 0.25 0.12 0.12 0.50 1.00 0.12 1.00 0.50 0.50 0.06 0.50 64.00 128.00 128.00 128.00 128.00 8.00 0.06 0.06 0.12 0.25 32.00 0.25 128.00 8.00 128.00 0.25 0.25 0.50 0.25 0.50 0.50 0.50 0.50 1.00 0.50 0.50 0.12 2.00 1.00 2.00 0.50 2.00 128.00 64.00 64.00 128.00 128.00 32.00 0.50 1.00 2.00 2.00 64.00 2.00 128.00 32.00 128.00 0.25 0.06 0.12 0.50 0.12 0.25 0.25 0.25 0.25 0.25 0.25 0.12 0.06 0.50 1.00 1.00 0.12 2.00 32.00 16.00 16.00 64.00 128.00 8.00 0.12 0.12 0.50 1.00 32.00 0.50 128.00 8.00 128.00 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.12 0.12 0.50 *=0.06 0.25 16.00 8.00 8.00 32.00 128.00 2.00 0.06 0.06 0.06 0.12 8.00 0.06 64.00 2.00 128.00 *1 p S p p p 4i 0 io* p. p p 0* p p p 5 P pp p p p p i p p p p p Table I (Continued) Example No.

ORGANISM

I 86* 193 195* E.coli(25922) Ecoli(IVES 912) E.coli(300) E.coli(352 18) Ecoli(MEDEIROS 4) Ecoli(MEDEIROS 14) Ecoli(BUSH 9 1-39) K.pneumo(IVES 688) K.oxytoca(CUH-N 88-11) E.aerogenes(IVES 1500) E.cloacae(Richmond 1) C.diversus(IVES 1680) C.freundii(IVES 953) S.marcescens(IVES 3062) M.morganii(IVES 335) Salmonella sp(CHBM 88-58) P.stuartii(CUHN 88-7) P.aerug.(27853) P.aerug.(IVES 5250) P.aerug.(MEDEIROS-7) P.aerug.(BUSH 9 1-73) X.malto.(NEMC 87-2 10) A.calco.(BMMR 88-2) S.aureus(292 13) S.aureus(25923) S.aureus(IVES 1097) S.aureus(IVES 1545) S aureus(IVES 2837) CNS(IVES 191) CNS(IVES 1754) E.faecalis(CHBM 88-60) E.faecium(DLMC 89- 1) 0.12 0.12 0.25 0.25 0.12 0.12 0.25 0.25 0.50 0.25 0.12 0.12 0.25 0.50 2.00 0.25 1.00 16.00 8.00 16.00 32.00 128.00 4.00 0.06 0.06 0.12 0.25 16.00 0.25 64.00 4.00 128.00 32.00 32.00 4.00 32.00 32.00 64.00 64.00 64.00 128.00 64.00 32.00 32.00 64.00 128.00 128.00 32.00 128.00 128.00 128.00 128.00 128.00 128.00 128.00 0.50 2.00 4.00 4.00 128.00 2.00 128.00 64.00 128.00 0.25 0.12 0.50 0.25 0.25 0.25 0.25 1.00 1.00 0.50 0.12 0.12 0.50 2.00 4.00 0.50 2.00 32.00 32.00 32.00 64.00 128.00 8.00 0.12 0.25 1.00 1.00 32.00 0.50 128.00 32.00 128.00 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.12 0.50 0.50 0.06 0.50 8.00 4.00 8.00 16.00 128.00 2.00 0.06 0.06 0.12 2.00 0.06 64.00 0.50 64.00, 0.06 0.06 0.12 0.06 0.06 0.06 0.06 0.06 0.12 0.06 0.06 0.50 1.00 1.00 0.06 1.00 16.00 8.00 16.00 32.00 128.00 8.00 0.06 0.06 0.25 4.00 0.12 128.00 2.00 128.00 64.00 64.00 2.00 64.00 128.00 128.00 128.00 128.00 128.00 128.00 64.00 64.00 128.00 128.00 128.00 128.00 128.00 128.00 128.00 128.00 128.00 128.00 128.00 0.25 0.50 4.00 4.00 128.00 1.00 128.00 64.00 128.00 0.50 0.50 1.00 0.50 0.50 0.50 1.00 2.00 1.00 1.00 1.00 0.25 2.00 4.00 8.00 1.00 4.00 128.00 128.00 128.00 128.00 128.00 32.00 0.12 0.25 1.00 1.00 32.00 0.50 128.00 64.00 128.00 *Preincubated' for one hour iii the presence of serum.

ii-,pe.

C

eec e e C b eec cc.

C

Ce C* C c c ae Table 2: In Vivo Efficacy of Carbapenems in Mice Subcutaneous Routes When Dosed by Oral and S. auireus Smith E. coli311 EDgi &kgl ED fmIgLkg CompSmnd SC SQODSSC SID SSC SOD/SSC Example 46 1.8 0.11 16 1.7 0.68 Example 64 1.3 0.05 26 1.1 0.42 2.6 Example 192 0.85 0.05 17 3.8 0.34 11 Example 261 0.21 0.06 3.5 0.95 0.54 1.8 Example 391 030 0.06 5 1.10 0.74 1.4 Example 265(A) 0.40 0.08 5 1.59 0.67 2.4 Example 265(B) 0.61 0.10 6 5.10 0.86 5.9 Example 266(A) 0.67 0.08 8.4 Example 266(B) 1.00 0.11 9.1 Examp'e 257 0.48 0.18 3.3 1.6 0.66 2.4 Examp'e344 0.25 0.19 1.3 0.79 0.80 0.99 Examp'e 345 0.28 0.30 0.93 0.77 1.4 0.55 Blapen:.m 1.4 0.04 35 8.6 0.58 Primaxin 3.30 0.03 110 ND 1.1 Meropenem 19.90 0.52 38.3 ND 0.30 0 S

S.

5@ S .5 CS S S S

C

5*5 9* S

C

C C *5 S DO. :0 *0 0S Co Table 3 Bindincr to Penicillin BindingT Proteins of E.coli ATCC 25922 Approximate 1C50 (ug/ml) Contros Examle No.

PBP IMIPENEM BIAPENEM 46 114 120 162 la/lb <0.1/0.47 <0.1/0.55 >1 >1 >1 2 <0.1 <0.1 0.04 0.05 0.05 0.05 3 1.8 0.32 0.6 3 2 2 4 <0.1 0.03 0.05 0.09 0.09 0.08 5/6 >100 >100 >100 >100 >100 >100

HIC

E.coli <0.06 <0.06 <0.06 <0.06 <0.06 <0.06 Table 4 Bincdincg to Penicillin Bindingi Proteins of S, aureus ATCC 29213 Approximate 1C50 (ug/mi) ControlsExmlNo PEP IHIPENEM MEROPENEM BIAPENEM 46 114 120 162 1 0.01 0.04 0.01 0.03 0.03 0.06 <0.01 2 0.05 0.18 0.02 0.58 0.55 0.35 0.50 3 O*A 0.35 0.02 1.2 0.80 0.65 0.55 4 ND ND ND 0.56 0.78 <1 <0.01 MIC <0.06 <0.06 <0.06 <0.06 <0.06 <0.06 <0.06 a PBP 4 not detect~ed in these assays.

-83- Table Hydrolysis of Carbapenems Sby Dehydropeptidases Antibiotic Relative Hydrolysis Rates Mouse Swine Imipenem 100 100 Meropenem 320+5 28+6 Biapenem <1 <1 Example 46 107 19 Example 64 30 o When the compounds are employed as antibacterials, 5 they can be combined with one or more pharmaceutically acceptable carriers, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing for example, from about 20 to ethanol and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.

An effective amount of compound from 2.0 mg/kg of body weight to 100.0 mg/kg of body weight should be administered one to five times per day via any typical route of administration including but not limited to oral, parenteral (including subcutaneous, intravenous, -84- Sintramuscular, intrasternal injection or infusion techniques), topical or rectal, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.

It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition of the host undergoing therapy.

These active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the o.

active ingredient and the particular form of administration desired. Adjuvants customarily employed in 25. the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.

These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.

The invention will be more fully described in conjunction with the following specific examples which are not to be construed as limiting the scope of the invention.

The active compounds of formula may be administered in combination with a substance capable of inhibiting the p-lactam hydrolase enzyme, dehydropeptidase. Such dipeptidase inhibitors are known in the art, as disclosed for example in U.S. Patent 4,539,208 and European Patent Application 0497353, and include such compounds as cilastatin, glutathione and N-acetyl-L-cysteine. The dipeptidase inhibitor may be used to inhibit the renal or gastrointestinal metabolism of the carbapenems of the present invention and may be used to enhance the gastrointestinal absorption of the active carbapenem compounds. When combined in such a manner, the carbapenem antibiotic and the peptidase inhibitor can be administered either in a pharmaceutical composition containing the two substances in combination or can be separately administered.

20 Administration separately or combined can be oral, intramuscularly or intravenously.

o* a [N:\LIBZ]00751:SAK I' i -86- PREPARATION OF THE COMPOUNDS Three distinct processes for producing carbapenems of formula I utilising intermediates according to the present invention are described.

R

o Ri z 15 N S

(CH

2 )nR 2

COOR,

3 S One method of preparation utilizes an addition-elimination reaction sequence by contacting 25 the carbapenem of formula III with the appropriate thiol IV and base, Step 1 Scheme I, in an inert solvent and atmosphere at low temperature. Suitable solvents include dioxane, tetrahydrofuran, dimethylformamide, acetonitrile and mixtures thereof; 30 with acetonitrile and dimethylformamide being preferred. Suitable bases include, but are not limited to, sodium or potassium carbonate, triethylamine, diisopropylethylamine, 4-(dimethylamino)pyridine and 2,6-1utidine; with diisopropylethylamine being preferred. A suitable temperature ranges from -40°C to SOne m ethod of preparation utilizes anrgon as the Saddition-elimination reaction sequence by contactingsphere.

2 the carbapenem of formula III with the appropriate thiol IV and base, Step 1 Scheme I, in an inert solvent and atmosphere at low temperature. Suitable solvents include dioxane, tetrahydrofuran, dimethylformamide, acetonitrile and mixtures thereof; with acetonitrile and dimethylformamide being preferred. Suitable bases include, but are not limited to, sodium or potassium carbonate, triethylamine, diisopropylethylamine, 4-(dimethylamino)pyridine and 2,6-lutidine; with diisopropylethylamine being preferred. A suitable temperature ranges from -40 0 c to C; with -5°C being used most often with argon as the inert atmosphere.

-87- It is understood that the thiol of formula IV is a representation of the regioisomeric possibilities Iv-.

to IV-6.

a.

q.

a.

a. a

S

q. a.

R

2

CH

2 IV- I

CH

2 n R 2 CH 2 )n R 2 I V-2 I V-3

R

2

CH

2 )n- Sz-:r CH 2 ,R 2 HS H 2 n RZ I V-6 1 V-4 1IY-5 -88- In addition, the asymmetric ring carbons bearing the thiol fragment, -511 and the alkyl fragment (CH 2 nR 2 may independently have the R or S stereochemical assignment. The nature of R 0

R

1 R 2

R

3

R

1 5 1 Z and n are as defined hereiribefore.

-89- SCHEME I

R

0 1

R,

N ,~OP(01, C00R 1

HS

T-(C H,)f)

IV

Step I i-Pr 2 NEt

R

0 1

-(CH

2 )nR, IStep 2 Pd/C

H

2 l:N /C2

R

COOR

3 Following the formation of the desired carbapenems of general formula II, the carboxyl protecting group

R

15 of these intermediates may be optionally removed in Step 2 by conventional procedures such as solvolysis, chemical reduction or hydrogenation. Protecting groups such as p-nitrobenzyl, benzyl or benzhydryl can be removed by catalytic hydrogenation. Intermediates II, in a suitable solvent mixture such as dioxane-water-ethanol, tetrahydrofuran-diethyl ether-buffer, tetrahydrofuran-aqueous dipotassium hydrogen phosphate-isopropanol or the like, may be treated under a hydrogen pressure of from 1 to 4 atmospheres in the presence of hydrogenation catalyst such as palladium on charcoal, palladium hydroxide, platinum oxide or the like, at a temperature from 200 to 40 C, for 0.2 to 4 hours. Protecting groups such as 2,2,2-trichloroethyl may be removed by mild zinc reduction. The allyl protecting group may be removed by using a catalyst comprising a mixture of a zero valent palladium compound and triarylphosphine in a suitable aprotic solvent such as tetrahydrofuran, methylene chloride or diethyl ether. Similarly, other conventional carboxyl protecting groups may be removed by methods known to those skilled in the art.

Thus, in Step 2, carbapenem esters of general formula II are deblocked according to the nature and chemical reactivity of their ester group to form the carbapenem of general formula I, wherein Ro, R 1 R2,

R

3 Z and n are as defined hereinbefore. The method of product isolation in Step 2 will vary on the method of deblocking used. But all methods used in the transformation follow conventional techniques in the art including chromatography and lyophilization.

It is usual to isolate carbapenems of general formula I as an alkali metal salt wherein R 3 is a lithium, sodium or a potassium ion or as a water soluble zwitterionic species, whereby R 3 represents a -91- W proton or the cationic component of an internal salt pair dependent on the nature of the R 2 substituent.

Compounds of formula I wherein R 3 is a physiologically hydrolyzable ester such as acetoxymethyl, pivaloyloxymethyl, methoxymethyl, etc., may be administered directly to the host without deblocking since these esters are hydrolyzed in vivo under physiological conditions.

A second method of producing carbapenems of formula I utilizes an acid mediated ring closure as the key step in the sequence outlined in Scheme II.

In Step 1 Scheme II, the 3-bromo-2-ketoester of Sformula V is contacted with the thiol IV in a suitable solvent and temperature range (as described in (U.S.

15 Patent 5,189,158). The product azetidinone of formula S'VI thus formed is a result of a nucleophilic displacement of the bromide of formula V by the conjugate base (thiolate species) of the thiol IV that is formed in situ, wherein R R 1

R

2

R

15 Z and n are as defined hereinbefore. Suitable solvents are anhydrous and include tetrahydrofuran, dimethoxyethane, acetonitrile, dimethylformamide and methylene chloride.

The following bases are representative: triethylamine, diisopropylethylamine, lithium bis(trimethylsilyl)amide or 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction temperature for transformation can range from -70o to In Step 2 Scheme II, the preferred l-(tert-butyldimethyl)siloxyethyl group of R and the o tert-butyldimethylsilyl protecting group for the azetidinone nitrogen of the compound of formula VI are hydrolyzed to the l-hydroxyethyl and N-H respectively via standard procedures in the art. A representative procedure entails contacting keto ester VI with hydrogen fluoride in acetonitrile-water solvent according to R.F.Newton et al, Tetrahedron Letters (1979), No. 41, pp 4381-82.

-92- RO Br

N

B

s v a.

a a a a a a a.

a a a a at..

a 'a a .a z 2

)R

2 Iv Step 1

TEA

s Oz

(CH-

2 )nR 00OR 1 Step 2 HF/MeCN z

(CH

2 nR 2 Step 3 "4 TiC1 4

ITHF

01 N O S((C 2 )R2 TBS t-butyldimethylsilyl continued 4, -93-

SCEEI

Step 4 Pd/c

H

2 9. COOR 3 -94- In Step 3 Scheme II, the compounds of formula VII are contacted with an appropriate acid in a suitable solvent at temperatures in the range of to +20 0 C. Suitable acids that can be employed for this step include, but are not limited to, titanium tetrachloride or hydrochloric acid. Suitable solvents and solvent combinations can be anhydrous or at least in part, aqueous ones. Tetrahydrofuran (THF), THF/water, dimethoxyethane (DME), DME/water, dioxane, acetonitrile, acetonitrile/water and dimethylforamide all serve as suitable solvents with THF being preferred. The product carbapenem II is isolated after S* a sequence of quenching the reaction with excess base such as aqueous sodium bicarbonate followed by 15 conventional techniques in the art including dissolution in an organic solvent, aqueous washing and chromatography.

Following formation of the carbapenem of formula o II the carboxyl protecting group, R 15 of these intermediates may be optionally removed in Step 4 by conventional procedures such as solvolysis, chemical *eg reduction or hydrogenation. Protecting groups such as p-nitrobenzyl, benzyl, or benzhydryl can be removed by catalytic hydrogenation. In the catalytic hydrogenation procedure intermediates II, in a suitable solvent mixture such as dioxane-water-ethanol, tetrahydrofuran-diethyl ether-buffer, tetrahydrofuran-aqueous dipotassium hydrogen phosphate-isopropanol or the like are treated under a hydrogen pressure of from 1 to 4 atmospheres in the presence of a hydrogenation catalyst such as palladium on charcoal, palladium hydroxide, platinum oxide or the like, at a temperature from 20° to 40°C, for 0.2 to 4 hours. Protecting groups such as 2,2,2-trichloroethyl may be removed by mild zinc reduction. The allyl protecting group may be removed by using a catalyst comprising a mixture of a zero valent palladium compound and triarylphosphine in a suitable aprotic solvent such as tetrahydrofuran, methylene chloride or diethyl ether. Similarly, other conventional carboxyl protecting groups may be removed by method known to those skilled in the art.

Thus, in Step 4, carbapenem esters of general formula II are deblocked according to the nature and chemical reactivity of their ester group to form the carbapenem of general formula I, wherein R R R2

R

3 Z and n are as defined hereinbefore. The method of product isolation in Step 4 will vary on the method of deblocking used. But all methods used in the transformation follow conventional techniques in the art including chromatography and lyophilization.

15 It is usual to isolate carbapenem I as an alkali metal salt wherein R is a lithium, sodium or potassium ion or as a water soluble zwitterionic species, whereby R 3 represents a proton or the cationic component of an internal salt pair dependent on the 20 nature of the R substituent.

Compounds of formula I wherein R is a physiologically hydrolyzable ester such as

S

acetoxymethyl, pivaloyloxymethyl, methoxymethyl, etc., may be administered directly to the host without deblocking since such esters are hydrolyzed in vivo 0 under physiological conditions.

A third method of producing carbapenems of formula I utilizes the synthetic route of Scheme III.

In Step 1 Scheme III, carbapenems of formula

II

are formed by the nucleophilic substitution of the silver thiolate carbapenem of formula VIII with the requisite halo-substituted heterocycle of formula

IX.

In this transformation Ro, R 1

R

2

R

1 5 Z and n are as defined hereinbefore and Y is chloro, bromo, iodo, Smethanesulfonate or trifluoromethanesulfonate.

-96- SCHEME III

R,

SAg z 4.

LK

DMNF/base/0' Step I 9* 9 9 a *a

R

0

R.

z 11N -t (CH)IR 2 AgY 0 Step 2 deblock

R

1 z

COOR

3 -97- It is understood that the halo-substituted heterocycle of formula IX is a representation of the regioisomeric possibilities IX-1 to IX-6 with IX-l to IX-3 being the preferred entities for use as reactant in Step 1 Scheme III.

z

R

2

CH

2

)YQ

I X-I

R

2 CH 2

Y

1 X-4

(CH

2 )f R I X-2 S (CH 2

)R

i X-5 C H 2

)*R

1 I X-3 z (CH 2 ).R2 I X-6 In addition, the asymmetric ring carbons bearing the halide Y, and the alkyl fragment, -(CH 2

)-R

2 may independently have the R or S stereochemical assignment.

The transformation in Step 1 Scheme III is usually conducted by contacting the carbapenem silver thiolate VIII with the halo-substituted heterocycle IX in a suitable solvent such as dimethylformamide or acetonitrile and an iodide source such as lithium iodide or equivalent metal iodide in a temperature range of 0 -60 C. The carbapenem product of formula II -98o is isolated after a sequence of dissolution in an organic solvent such as ethyl acetate, washing with water and chromatography.

Following formation of the carbapenem of formula II the carboxyl protecting group, R 15 of these intermediates may be optionally removed in Step 2 by conventional procedures such as solvolysis, chemical reduction or hydrogenation. Protecting groups such as p-nitrobenzyl, benzyl, or benhydryl can be removed by catalytic hydrogenation. In this procedure intermediates II, in a suitable solvent such as dioxane-water-ethanol, tetrahydrofuran-diethyl ether-buffer, tetrahydrofuran-aqueous dipotassium hydrogen phosphate-isopropanol or the like, are treated 1 5 under a hydrogen pressure of from 1 to 4 atmospheres in the presence of hydrogenation catalyst such as palladium on charcoal, palladium hydroxide, platinum oxide or the like, at a temperature from 200 to for 0.2 to 4 hours. Protecting groups such as 20 2 ,2,2-trichloroethyl may be removed by mild zinc reduction. The allyl protecting group may be removed by using a catalyst comprising a mixture of a zero S. valent palladium compound and triarylphosphine in a suitable aprotic solvent such as tetrahydrofuran, 25 methylene chloride or diethyl ether. Similarly, other conventional carboxyl protecting groups may be removed by methods known to those skilled in the art.

R

-99- It is usual to isolate carbapenems of formula I as an alkali metal salt wherein R 3 is a lithium, sodium or potassium ion or as a water soluble zwitterionic species, whereby R 3 represents a proton or the cationic component of an internal salt pair dependent on the nature of the R 2 substituent.

Compounds of formula I wherein R 3 is a physiologically hydrolyzable ester such as acetoxymethyl, pivaloyloxymethyl, methoxymethyl, etc., may be administered directly to the host without deblocking since such esters are hydrolyzed in vivo under physiological conditions.

Several synthetic routes are employed to prepare the various isomeric thiol entities of general formula 15 IV and halo-substituted heterocycles of general formula IX which are utilized in Step 1 of Schemes I, II, and III. The following synthetic schemes demonstrate preferred synthesis of compounds IV and IX.

'a Sn n.j 100 SCHEME IV BnOCH 2 CH(OEt) 2 2N H 2 S0 4 Reflux BnOCH 2

CHO

vi 1 ~MgBr Ph~ 0 O H ViI Br 2 /CCI4 S. S 9*

S

S..

5*5 S S

S.

Ph 0 Br OH Br.

Ca(OI-) 2 CaBr 2

H

2 0/MeOH/Reflux II2 Ph OCH 2 Ph KSAc/CH 3

CN

OCH

2 Ph ix I I KSAc/CH 3

CN

v

OCH

2 Ph SAc Me 3 SiI 0

OH

SII

Me 3 SiI SAc XIv [N:\LIBZ]0075 1:SAK -101- In accordance with Scheme IV, benzyloxyacetaldehyde diethyl acetal is hydrolyzed with dilute sulfuric acid giving benzyloxyacetaldehyde, which is then reacted with allyl magnesium bromide to give l-phenylmethoxy-4-penten-2-ol. This alcohol, is brominated with bromine in carbon tetrachloride or dichloromethane at -200C to 0°C to give 4,5-dibromo-l-(phenylmethoxy)-2-pentanol. This dibromo alcohol, in aqueous methanol, is cyclized with calcium hydroxide in the presence of calcium bromide, to give a racemic mixture of trans and cis-4-bromo-2- [(phenylmethoxy)methyl]tetrahydrofuran, IX and X respectively, which is separated by flash column S: chromatography using silica gel. The trans bromide, 15 IX, is reacted with potassium thioacetate, in a dipolar aprotic solvent, to give methyl]-3-tetrahydrofuranyl]ethanethioate, XI. The thioacetate, XI, is reacted with iodotrimethylsilane to give cis-[5-(hydroxymethyl)-3-tetrahydrofuranyl]ethane- 20 thioate, XIII. In the same manner, the cis bromide, X, is converted to the trans-[5-(hydroxymethyl)-3-tetrahydrofuranyl]ethanethioate, XIV.

In accordance with Scheme V, the cyclization of 1-phenylmethoxy-4-penten-2-ol with iodine in the presence of sodium bicarbonate gives a racemic mixture of cis and trans-5-(iodomethyl)-3-tetrahydrofuranols, XV and XVI, which is separated by flash column chromatography using silica gel.

The optically active tetrahydrofuran derivatives are prepared according to Scheme V.

Benzyloxyacetaldehyde is reacted with optically active 2-allyl-l,3,2-dioxaborolane-4,5-dicarboxylic acid ester, XVII, to give optically pure (S)-l-phenylmethoxy-4-penten-2-ol, XVIII. Cyclization of alcohol, XVIII, with iodine in the presence of sodium bicarbonate gives a mixture of optically pure 3-dideoxy-l-iodo-D-threopentitol,

XIX,

-102- 1 2 /NaHCO 3 Ph y 0OH di-XV

OH

dl-XVI N.MgI~r BnOCH 2

CHO

U.

a..

a U U*UU 0~ Ph ll,* 0

OH

CO

2

R

"ICO

2

R

0l

I

2 INaHCO 3 O Z-I 6H xIx

OH

win 103 and 2,5-anhydro-1 ,3-dideoxy-1-iodo-D-erythro-pentitol, XX, which is separated by flash chromatography using silica gel.

SCHEME VI

OCH

2 Ph Br X-trans 0H Br Me 3 Sil Jones reag._ Acetone, O'-RT

XXI

-N NC0 2

CH

2 Ph r-\ HN\_,NC0 2

CI

2 Ph

DCC

CH

2 C1 2

/DMF

XXII'

*4

S

S S

S.

S S C C S S 4

O

4 -N

NCO

2

CH

2 Ph KSAc cat 1 8Crown- 6 MeCN

XXIV

[N:\LEBZ]00751:SAK -104- In accordance with Scheme VI, the bromide, X-trans, is reacted with iodotrimethylsilane to give -4-bromo-2-tetrahydrofuranmethanol, XXI, which is oxidized with Jones reagent to give 2,5-anhydro-4bromo-3, 4-dideoxy-D-erythro-pentonic acid, XXII. The bromide, XXII, is reacted with phenylmethyl 1-piperazinecarboxylate, in the presence of 1,3 -dicyclohexylcarbodiimide, to give phenylmethyl 4- 5-anhydro-4-bromo-3, 4-dideoxy-D-erythro-pentonoyl)-1-piperazinecarboxylic acid ester, XXIII, which is then'reacted with potassium thioacetate, in a dipolar aprotic solvent, to give phenylmethyl 4 (4 -S-acetyl-2, 5-anhydro-3 -deoxy-4 -thio-L-threo-pentonoyl)-1-piperazinecarboxylic acid ester, XXIV.

SCHEME VII *e U.

U U 9* *U U U

U

U.

U U

U.

U. 9

U.

9 U U 9. U 'U U U9UU

U

9 *0U* U. *e

U.

1. Tf 2

O

PhCH 2 O Br pyr/CH 2

CI

2 hH

B

OH Br 2. AcSH SAc Br iPr 2 EtN THtF

XXV

NaO.Mc (I c() NcIC0 0 0

T

Q.s, CH 2 Ph

PI

KSAc. cai 18-Cr-6 C1 1 3 CN. 80 0

C

S -OCH 2 -Ph SAc

XXVII

XXVI

TMS I

CHCI

3 0 0

C

SAc SAc XXvnI xi

XXIX

-105- In accordance with Scheme VII, phenylmethoxy-2-pentanol is reacted with triflic anhydride, in the presence of pyridine, to give the desired triflate which is then reacted with thio acetic acid, in the presence of diisopropylethylamnine, to give S-(3 ,4-dibromo-l-[((phenylmethoxy) methyl) butyl Jethanethioic acid ester, XXV. The dibromo thioacetate,

XXV,

is treated with one equivalent of sodium methoxide, in methyl alcohol, to give 4-bromotetrahydro-2-[((phenylmethoxy)methyljthiophene, XXVI, which is reacted with potassium thioacetate, in a dipolar aprotic solvent, to give tetrahydro-5- ((phenylmethoxy) methyl) -3-thienyl

J-

ethanethioic acid ester, XXVII. The thioacetate, 15 XXVII, is reacted with iodotrimethylsilane, in chloroform, to give a mixture of ***methyl)-3-thienyl ethanethioic acid ester, XXVIII, and tetrahydro-5-(hydroxymethyl) -3-thienyl ethanethioic acid ester, XXIX, which is separated by flash column chromatography using silica gel.

In Scheme VIII, the thioacetate, XIII from Scheme IV, and the alcohol, XVI from Scheme V, are converted to the azido derivative,

XXXIII.

-106- SCHEME VIII OlOH S Ac X19 T r0 'p y ,IorOTf SAc nIBU 4 NN 3 9.

*9 4 .9 9 9 9 9 9 9.

9* 9 9* 9.

9 9* 9 9 9 **99 9999 9 99 9 99 .9 NaOMC/NICOH 0jN.1 0OH Xv' n.fBU 4 NN3 2. Tf 2 o/py SAc tKSA ~yN 3 OTf

C/CH-

3

CN

SHJ

-107- The thi oacetate, XIII, is reacted with triflic anhydride, in the presence of pyridine,, to give the desired trif late, XXX, which is then reacted with tetrabutylainmonium azide to give methyl) -3-tetrahydrofuranyl]ethanethioic acid ester,

XXXI.

Alternatively, the alcohol, XVI, is reacted with tetrabutylanonium azide to give the desired azide which is then reacted with triflic anhydride, in the presence of pyridine, to give the desired triflate, XXXII. The trif late, XXXII, is reacted with potassium thioacetate in acetonitrile to give the thioacetate, XXXI. The thioacetate, XXXI, is then reacted with sodium methoxide, in a mixture of methanol and tetrahydrofuran, to give cis- -5-azidomethyl) -3tetrahydrofuranthiol,

XXXIII.

-108- 9f SCHEME

IX

R

2 (CH2pn Lra Step i

DIBAL-H

0 *0 0* .0 S 0 0* 00 0 0 0 0* *0 0 ~0 00 000.

6) 4-O 2

NC

6

H

4

CO'

7) HCI(gas) Z

R

2 (CH2pn- 1 ZZJS teps 2-4 Step 6-7 2) CAHCH 2 S H/f4 Step 6-7 13) CH 3

SO

2 CI/Et 3

N

j4) BaCO 3 /Nal/I600

R

2

(CH

2 )n 2

R

2

(CH

2 )n -2 xxxvui

~X)O

Steps 8-9 8) KSAc 9) NaOMe 00 0 0000 0 0000 0000

S

05 0 00 00 Step Br 2 /CCI 4

R

2 (CH2 11 Ur

XXXVI

-109- O Scheme IX outlines synthetic methods common in the art that ensure access to other thiol congeners with the general formula IV-l to IV-3 and halo-substituted heterocycles of general formula IX-1 to IX-3.

The mono-substituted lactone, XXXIV, serves as the starting point for the above-mentioned compound classes. It will be appreciated that XXXIV is a representation of the following regioisomers: S v C Z(OCHO$R1(C(HI)) 5 oo XXXIV-1 XXXIV-2 XXXIV-3 oS 10 In addition, the asymmetric ring carbon bearing the

R

2

-(CH

2 n fragment may have the ,R or S stereochemistry, wherein n and R 2 are as defined hereinbefore. The preparation of lactones with general formula XXXIV utilizes basic synthetic techniques that 15 are common in the art.

In Step 1 Scheme IX, the lactone, XXXIV, is reduced via a standard diisobutylaluminum hydride or equivalent reduction in the art to the corresponding lactol, XXXV. This lactol, in turn can be treated with the sequence of reagents in Steps 2-4 as per the example of M.R.Dyson et al., Carbohydrate Research, Vol. 216, pp237-48 (1991) to form the dithioglycoside XXXVI. In Step 5, this dithioglycoside is converted to the 2-bromo-thioglycoside, XXXVII by bromine and carbon tetrachloride according to the method of M. R. Dyson et al, Med. Chem., Vol 34, pp2782-86 (1991). The 2-bromo-thioglycoside, XXXVII, thus formed (representative of the halo-substituted heterocycles of general formula IX-1 to IX-3) can be utilized in the carbapenem synthesis outlined in Scheme III.

-110- In steps 6 and 7 of Scheme IX, the lactol of general formula XXXV is converted to the 2-chlorotetrahydrofuranyl derivative of formula XXXVIII by stepwise treatment with 4-nitrobenzoyl chloride and hydrogen chloride gas. Both procedures are common in the art and are described in detail by Baker and Fletcher in J.Ora.Chem., Vol. 24, 4605 (1961) and Stevens, Ness and Fletcher in J.Ora.Chem., Vol 33, 1806-09 (1968) respectively. The 2-chlorotetrahydrofuran of formula XXXVIII is sequentially treated with potassium thioacetate and then by sodium methoxide in steps 8 and 9. The tetrahydrofuran thiol product XXXIX, representative of 15 the thiols of general formula IV-1 to IV-3, can be utilized in the carbapenem synthesis outlined in Schemes I and II.

-111- HOi ,0

OH

Mso isCi/PY LiN 3 leq.)/DNMI1 700

XI'.

C.

KS Ac/DMF/toluene 650 OMs

'U

SAc SUc l,2-Dideoxy-D-ribose, XL, is prepared according to M. Takeshita et al, J.Biol.Chem. (1987), 262(21), 10171.

In accordance with Scheme X, l, 2 -dideoxy-D-ribose is reacted with excess metharlesulfonyl chloride in pyridine to give dimesylate XLI, which is reacted with one equivalent of lithium azide in dimethylformamide 'to give azido derivative XLII. The azido derivative

XLII

is then reacted with potassium thioacetate in a mixture of dimethylformamide and toluene to give the desired thioacetate

XLIII.

-112-

SCHMEXI

0

MCPBA/CH

2

CI

2 0 Et 2 AICN/tol uene XcIIV MsC1/NEt 3 r.t.- 0 OMs CN

XLVI

4-MeOC 6

H

4

CH

2 S HI NaH/THF

XNLV

B

2

H

6 /THF <CIO 2 PNB/i-Pr 2

NEL/

r~t.

THF

4 -McOC(H 4

CH

2 S CH 2

NH

2

XLVII

4 -MeOCAHCH 2 S Ef

XLVII

0 1 .(CF 3

CO

2 2 Hg/ 0 2. H 2 S t 4 -MeOC 6

H

4 CH 2 S CH 2

NHCO

2 PNB HS CH 2

NHCO

2

PNB

xju(

L

-113- In accordance with Scheme XI, 2,5-dihydrofuran is reacted with m-chloroperbenzoic acid in methylene chloride to give epoxide XLIV, which is then reacted with diethylaluminium cyanide in toluene to give the cyanoalcohol XLV. The cyanoalcohol XLV is mesylated with methanesulfonyl chloride in the presence of triethylamine to give cyanomesylate XLVI, which is then reacted with 4-methoxybenzyl mercaptan and sodium hydride in tetrahydrofuran to give the cyanothioether XLVII. Reduction of the cyanothioether with diborane in tetrahydrofuran gives aminomethylthioether

XLVIII,

which is then reacted with 4-nitrobenzyl chloroformate in the presence of diisopropylethylamine in 15 tetrahydrofuran to give protected aminomethylthioether XLIX. Treatment of the protected aminomethylthioether XLIX with mercuric trifluoroacetate and anisole in aqueous acetic acid, followed by treatment with hydrogen sulfide gives the desired thiol L.

114 SCHEME XII 0 0

XXXIV

Step 3 Lawessons reagent Step 1 J. Med. Chem., 533(1992) 0

SH

XNXIX

0

OH

LI

i C S c

LII

[N:\LIBZ]00751:SAK -115- As an alternate synthetic route to Scheme IX, Scheme XII outlines complimentary methods common in the art to access thiol congeners with general formula IV-1 to IV-3 and halo-substituted heterocycles of general formula IX-1 to IX-3. In step 1 of Scheme XII, the thiolactol LI is prepared from the lactone XXXIV using the synthetic sequence of J. A. Secrist et al. in J.

Med. Chem., Vol 35, pp 533-538 (1992). Treatment of the thiolactol LI with anhydrous hydrochloric acid in step 2 represents one way to access the requisite 2-chlorotetrahydrothiophene LII, representative of the halo-substituted heterocycles of general formula IX-1 to IX-3, which can, in turn, be utilized in the carbapenem synthesis outlined in Scheme III.

The lactone XXXIV can also be converted to the thiolactone LIII using Lawessons' reagent in step 3 of Scheme XII. The procedure found to be most useful in this step is that of S. Scheibye et al., Tetrahedron, Vol 35, pp 1339-43 (1979). In step 4 of Scheme XII, 20 the thiolactone LIII is reduced with lithium triethylborohydride using the procedure of A. G. M.

Barrett et al, Or. Chem., Vol 54, pp 2275-2277 (1989). The thiolactol LIV thus formed representative of the thiols of general formula IV-1 to IV-3, can be utilized in the carbapenem syntheses outlined in Schemes I and II.

116 SCHEME XI1I

HO-

Hk o00

LV

Tso.

TsCVDMAPPy 0

LVI

3%HCIIMeOH reflux o0Me LiEt 3 BiF Dowex resin

H

2 0 LVII LVIII

S

5

S

*5 S

S

we

SS

S S S

S

.OH

LIX

[N:\LIBZ]00751 :SAK -117- In accordance with Scheme XIII, 1,2-0-isopropylidene-D-xylofuranose LV is reacted with excess p-toluenesulfonyl chloride in the presence of a catalytic amount of 4-dimethylaminopyridine in pyridine to give ditosylate LVI, which is treated with 3% hydrochloric acid in methanol under reflux to give p-toluenesulfonyl dimethyl acetal LVII. The p-toluenesulfonyl dimethyl acetal LVII is reduced with equivalent of lithium triethylborohydride in tetrahydrofuran to give dimethyl acetal LVIII, which is hydrolyzed with Dowex resin in water to give aldehyde hydrate LIX.

In the foregoing word description of the above schematic reaction diagrams for the synthesis of 15 3 -tetrahydrofuranyl)carbapenem and (3-tetrahydrothienyl)carbapenem antibacterials, it is understood that there is latitude in selection of precise reaction parameters. Suggestion of this latitude and its breadth is generally indicated by the enumeration of 20 equivalent solvent systems, temperature ranges, protecting groups, bases (organic and inorganic), and range of identities of involved reagents.

0** -118- Example 1 (Phenvlmethoxv)acetaldehyde A stirring mixture of 100 g of benzyloxyacetaldehyde diethyl acetal, 500 ml of tetrahydrofuran and 400 ml of 2N sulfuric acid is heated at reflux temperature for 45 minutes. The resulting solution is cooled to room temperature, concentrated in vacuo to 400 ml volume and diluted with 1000 ml of chloroform. The organic layer is washed with water, cold saturated sodium bicarbonate, saturated sodium chloride and dried. The filtrate is evaporated in vacuo to give the product as an oil. The crude oil is purified by Kugelrohr distillation (bath temperature 100°C) to give 59.0 g of the desired 15 product as a colorless oil.

H NMR(CDCl 3 9.73(t,lH); 7.36(m,5H); 4.63(s,2H); 4.11(d,2H).

1 IR(neat): 1736 cm 1 Example 2 20 l-(Phenylmethoxy)-4-penten-2-ol To a stirring 0 C solution of 59.0 g of product from Example 1 in 375 ml of diethyl ether is added, dropwise, 432.24 ml of 1M allylmagnesium bromide in ether. The reaction is stirred at 0°C for 1 hour, followed by overnight stirring at room temperature.

The reaction is cooled to 0°C, hydrolyzed with saturated ammonium chloride, and the layers are separated. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo to give the product as an oil. The crude oil is purified by Kugelrohr distillation (bath temperature 100°C) to give 61.5 g of the desired product as a colorless oil.

1 H NMR(CDCl 3 7.34(m,5H); 5.82(m,lH); 5.08(m,2H); 4.56(s,2H); 3.88(m,lH); 3.44(ABq,2H); 2.27(t,2H); 1.7(bs,lH).

-119- Examnle 3 4. 5-Dibromo-l- (nhenvlmethoxy) -2-Dentanol Using anhydrous conditions, 28.0 g of product from Example 2 in 40 ml of carbon tetrachloride, is cooled to -20 0 C. A solution of 7.88 ml of bromine in ml of carbon tetrachloride is added, dropwise, over minutes while maintaining the temperature at -20 0

C.

Vigorous stirring is required through out the addition to avoid local overheating of the reaction mixture. At the end of the addition, the reaction mixture turns red and the reaction is complete. The mixture is 00 concentrated in vacuo to give an oily residue. The oil is purified by chromatography (icaGel: 10% thy acetate/hexane to 20 ethyl acetate/hexane) to give 31 g of the desired product as a light yellow oil, which O is a mixture of 2 isomers.

HNMR(CDC1 )3 Isomer 1:6 7.35(m,5H) 4.55(s,2H); 4.1(m,lH); 3.88(dd,lH); 3.65(dd,lH); 3.38(dd,lH); 2.6(bs,1H, OH); 2.25(m,lH); 1.7(m,1H); Isomer 11: 6 7. 4(m, 5H) 4. 52 2. 5H) 4. 2 6(m, 0. 4.05(m,lH); 3.7(m,2H); 3.5(dd,1H); 3.38(dd,1H); 2.75(s,lH,oH); 2.22(m,lH); 2.1(m,lH).

:Examnle 4 Trans- -4-Bromotetrahydro-2- r (phenvlmethoxv) methyll1furan and c-is 4 Bromot et rahvdro- 2- r Uph env lmethoxy) methvl11 furan A solution of 10.0 g of product from Example 3 in 25 ml of methyl alcohol is diluted with 50 ml of distilled water. To this heterogeneous mixture is added 1.6 g of calcium hydroxide followed by 16.95 g of calcium bromide. The reaction is stirred vigorously -120while heating in an oil bath, at 100 0C, for 24 hours.

The internal temperature is maintained at 85 0 C. The reaction is cooled, extracted with methylene chloride, filtered thru diatomaceous earth and the layers partitioned. The organic layer is washed with water and saturated sodium chloride, dried and concentrated inf vacuo to give 7.18 g of an oil. The oil is purified by chromatography (Silica Gel: 5 ethyl acetate/hexane) to give 2.82 g of the trans-isomer and 2.89 g of the cis-isomer.

Hi NMR(CDCl 3 trans-Isomer:6 7.35(s,5H);I 4.6(s,2H); 4.48(m,2H); 4.3(dd,lH); 4.04-4.1(dd,1H); 6S 3.6-3.65(dd,lH); 3.5-3.57(dd,1H); 2.3(m,2H); ::'cis-Isomer:6 7.36(m,5H); 4.6(d,2H); 4.3-4.42(m,lH); 4.12-4.25(m,lH); 4.O-4.12(m,2i); 3.55-3.7(m,2H); 2 .55-2.7(m,lH); 2.08-2.2(m,lH).

Example Ethanethiojc acid trans- -S-rtetrahvdro-5-r (Phenvlmethoxv) methyl 1- 3-furanvi lester To an argon purged solution of 2.17 g of the cis-isomer from Example 4 in 25 ml of dry acetonitrile S. is added 0.96 g of potassium thioacetate. The reaction is heated at reflux temperature for 16 hours, cooled, filtered and diluted with ethyl acetate. The solution is washed with saturated sodium chloride, dried and concentrated in vacuo to give 2.16 g of a yellow oil.

The crude oil is purified by chromatography (Silica Gel: 5-10% ethyl acetate/hexane) to give 1.72 g of the desired product.

1H NMR(CDCl 3 :6 7.35(s,5H); 4.6(s,2H); 4 .28-4.32(dd,lH); 4.18-4.25(m,lH); 3 98 -4.O8(m,lH); 3 6 -3.68(dd,lH); 3.52(m,3H); 2.32(s,3H,Ac); 2 .l 6 2 .27(m,lH); 1.89-1.98(m,lH).

-121- Example 6 Ethanethioic acid trans-(+/-)-S-[tetrahvdro-5-(hydroxvmethyl)-3-furanyllester Using anhydrous conditions and under an argon flush, 0.80 g of product from Example 5 is dissolved in 11 ml of chloroform. The reaction mixture is cooled to 2°C and 0.47 ml of iodotrimethylsilane is added, via syringe. The reaction is stirred overnight at 2 C.

Upon completion of the reaction, 0.49 ml of methyl alcohol is added, the reaction is stirred for minutes longer and concentrated in vacuo. The residue is purified by chromatography (Silica Gel: 20-50% ethyl acetate/hexane) to give 0.406 g of the desired product 15 as a colorless oil.

H NMR(CDCl 3 4.26-4.31(dd,lH); 4.15(m,lH); 3.7-3.78(dd,lH); 3.6-3.68(dd,lH); 3.5-3.58(dd,lH); 2.32(s,3H,Ac); 2.19-2.29(m,lH); 1.86-1.96(m,lH); 1.75(bs,lH,OH).

Example 7 Ethanethioic acid hydro-3-furanvllester To a -20°C solution, under argon, of 0.406 g .25 of product from Example 6 in 30 ml of methylene chloride is added 0.3 ml of trichloroacetyl isocyanate.

The reaction is followed by thin layer chromatography (tlc). When reaction is complete, 1.16 ml of acetic acid, 0.54 ml of water and 9.84 ml of IM tetrabutylammonium fluoride in tetrahydrofuran is added. The mixture is stirred at room temperature overnight followed by concentration in vacuo. The residue is purified by chromatography (Silica Gel: 50% ethyl acetate/hexane) to give 0.430 g of the desired product.

-122- Hi NMR(CDCl 3 4.B(bs,2H,NH 2 4.2-4.32 3H); 4.05(m,2H); 3.62(dd,lH); 2.32(s,3H,Ac); 2.25(m,lH); lH).

Ref.: Journal of Labelled Compounds and Radiopharinaceuticals, Vol. XXIV, No. 1, p. 41, 1987.

IR(KBR); 1686 cm- 1 (broad).

Ethanethioic acid -S-tetrahvdro-5- r (phenvlzaethoxy) methyl 1-3 furanvi lester The title compound is prepared by the procedure of Example 5 using 2.17 g of trans-isomer product from Example 4, 0.96 g of potassium thioacetate and ml of acetonitrile to give 1.86 g of the desired product.

H i NMR(CDC 3 7.38(s,5H); 4.6(s,2H); 4.15(m,2H); 4.O(in,l); 3.74(dd,IH); 3.53(d,2H), 2.45(m,lH); 2.32(s,3H,Ac); Examvle 9 **20 Ethanethioic acid cis Ftetrahvdro-5- (hydroxymethvl) -3-furanyl 1ester The title compound is prepared by the procedure of Example 6 using 0.600 g of product from Example 8, 0.35 g of iodotrimethylsilane, 8 ml of chloroform and 0.37 ml of methyl alcohol to give 0.310 g of the desired product.

1 H NMR(CDCl 3 :6 4.13-4.2(dd,lH);* 3.98-4.12(n,2H); 3 3.52-3.6l(dd,lH); 2 .38-2.48(m,lH); 2.38(s,3H,Ac); l.9(bs,lH,OH); 1.65-1.78(m,1H).

-123- 1W Example Ethanethioic acid cis- rS- F (aminocarbonyi) oxvlmethvll1tetrahydro- 3-furanvi 1ester The title compound is prepared by the procedure of Example 7 using 0.28 g of product from Example 9 in 20 ml of methylene chloride, 0.208 ml of trichloroacetyl isocyanate, 0.80 ml of acetic acid, 6.79 ml of IM tetrabutylannonium fluoride in tetrahydrofuran and 0.37 ml of water to give 0.320 g of the desired product.

1 H NM(CDCl 3 :6 4.6-4.85(bs,2H,NH 2 4.12-4.28(=,3H); 3.98-4.l(m,2H); 3.7-3.8(dd,lH); 2.43-2.56(m,lH); 2.32(s,3H,Ac); 1.55-l.7(m,lH).

Ref.: Journal of Labelled Compounds and Radiopharmaceuticals, Vol. XXIV, No. 1, p. 41, 1987.

Example 11 r2R-F2alpha(R I .3beta(R 11-3-ri-Frr(,-ieh~ty dimethylsilylloxylethyll -camma-methyl-beta. 4-dioxo-2azetidinebutanoic acid (4-nitrophenyl)methyl es-ter Nine grams of [2S-[2alpha(S*),3beta(S*)) l-dimethylethyl)dimethylsilyl)oxyethyl.alpha.

methyl-4-oxo-2-azetidineacetic acid is suspended at room temperature, under argon flush, in 266 ml of dry acetonitrile. To this suspension is added 5.79 g of carbonyldiimidazole and the resulting clear solution is stirred for 30 minutes. Twenty-eight grams of p-nitrobenzylmalonate magnesium salt (dried in vacuo over P 2 0 5 for 1 week) is added and the reaction is heated at 65 0 C for 3 hours. The reaction is concentrated inj vacuo, diluted with methylene chloride and filtered. The filtrate is washed with saturated sodium chloride, dried and concentrated i~n vau to give 9.7 g of a yellow oil. The residue is purified by chromatography (Silica Gel: 25-45% ethyl acetate/hexane) to give 5.2 g of a crystalline solid.

1NMR indicates 35% in the enol form.

-124- 1H NMR(CDC1 3 11.93(d,minor isomer); 8.24(d,2H); 7.53(d,2H); 5.97(d,1H); 5.27(s,2H); 3.7-4.25(m,2H); 3.64(s,ca. 2H major isomer); 2.95(m,1H); 1.13-1.28(m,6H); 0.87(d,9H); 0.06(m,6H).

Example 12 r2R-r2alDhafR*).3betaR 11 -3-(l-Hydroxvethvl)-cammamethvl-beta.4-dioxo-2-azetidinebutanoic acid (4-nitrophenvl)methyl ester To a stirring 0°C solution, under argon, of 3.7 g of product from Example 11 in 40 ml of methyl alcohol is added 2.5 ml of concentrated hydrochloric acid. The reaction is stirred for 3 hours as the temperature rises to room temperature. The mixture is concentrated to 1/3 volume, diluted with ethyl acetate, 15 poured into cold saturated sodium bicarbonate solution and extracted. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo to give 2.61 g of a sticky solid. The residue is purified by chromatography (Silica Gel: ethyl acetate) 20 to give 1.91 g of the desired product as a colorless oil which solidifies on standing.

H NMR(CDCl 3 8.25(d,2H); 7.55(d,2H); 5.88(bs,1H); 5.28(s,2H); 4.15(m,lH); 3.81(m,lH); 3.65(d,2H); 2.90(m,2H); 1.31(d,3H); 1.26(d,3H).

Example 13 4-Dodecylbenzenesulfonyl azide To a stirring solution of 0.38 g of 4-docecylbenzenesulfonyl chloride in 1.9 ml of acetone is added 0.09 g of sodium azide. The resulting suspension is stirred at room temperature for 2 hours, followed by carefully concentrating the mixture in vacuo. The resulting orange oil is purified by chromatography (Silica Gel: hexane-20% methylene chloride/hexane) to give 0.22 g of pure product as a colorless oil.

Ref.: Synthetic Comm., 11(12), 947 (1981).

-125- 1 H NMR(CDC1 3 :6 7.87(dr2H); 7.56(d,2H); 0. 6-1. 7(m, 25H) IR(neat): 2125 cm'1.

Example 14 [2R-r2alpha(R .3beta(.R_ I 1 I -alpha-Diazo-3 (-hvdroXyethyl)-gamma-methyl-beta .4-dioxo-2-azetidinebutanoic acid (4-nitrophenylimethyl ester To a stirring room temperature solution, under argon, of 0.270 g of product from Example 12 in 3.2 ml of dry acetonitrile is added 0.327 g of triethylamine and 0.427 g of product from Example 13.

The reaction is stirred for 45 minutes, diluted with ethyl acetate, -washed with water, saturated sodium chloride, dried and filtered to give an oil. The oil is purified by chromatography (Silica Gel: 5-10% acetone/chloroform) to give 0.230 g of the desired product.

1 H NMR(CDCl 3 :6 8.26(d,2H); 7.55(d,2H); 5.95(bs,lH); 5.37(s,2H); 4.14(m,lH); 3.55-3.9(m,2H); 2.91(m,lH); 2.45(bs,lH); l.31(d,3H); l.22(d,3H).

Examvle f 4R- r4 alpha, 5beta. 6beta 1-3 f(Diphenoxvphosphinyl) oxy 1-6 (hvdroxvethvl)- 4-methvl-7-oxo-l-azabicvclor3. 2. Olhept-2-ene-2-carboxvlic acid (4-nitrophenv~methyl ester For 10 minutes, argon is bubbled through a suspension of 0. 10 g of product from. Example 14, 6 ml of dry cyclohexane and a catalytic amount of rhodium diacetate. The reaction is then heated at 80 0 C, under argon for 30 minutes, 1 ml of ethyl acetate is added and the heating continued for an additional hour. The suspension is cooled to room temperature, diluted with ethyl acetate and filtered through a pad of hydrous magnesium silicate. The filtrate is concentrated in -126vacuo and the residue is dissolved in 1 ml of dry acetonitrile and is called intermediate 15A. The solution (15A), under argon, is cooled to 0 0 C and 51 microliter of diphenylphosphoric chloride and 43 microliter of N,N-diisopropylethylamine, herein after called Hunig's base, is added. The reaction is stirred at 0 0Cfor 1 hour and then concentrated in vacuo to give 0.185 g of the product as an orange oil. The residue is purified by chromatography (Silica Gel: 5-10% acetone/chloroform) to give 0.045 g of the desired product as a white solid.

1 H NIAR(CDCl 3 8.lB(d,2H); 7.58(d,2H); 7.29(m,loH); 5.2 and 4.I-4.Afm,2H; 3.3(m,lH); l.34(d,3H); 1.24(d,3H).

C 15 Example 16 C cis- -Tetrahvdro-4-mercarto-2-furamethanoI 2-carbamate Under anhydrous conditions, 0.109 g of product C from Example 10 dissolved in 1.75 ml of tetrahydrofuran, cooled in an ice -bath, is treated, via syringe, C. with 120 microliter of sodium methoxide/methanol wt% in methanol). The progress of the reaction is monitored by thin layer chromatography. After minutes, 280 microliter of 1.86N hydrochloric C 25 acid/isopropyl alcohol is added and the reaction is stirred for 5 minutes. The reaction is concentrated in2 vacuo to give the desired product as a white solid which is used as is in the following reaction.

Example 17 r4R-r3-(3R .5R and 3S*.5S*)4alpha,5beta.6beta(R )11- 3-r rsrr Aminocarbonyl) oxylmethlltetrahdro3-furanyll-.

thiol (1-hvdroxyethyl) 4 -methvl-7-oxo-l-pzabicvclor3 Ohept-2-ene-2-carboxylic acid (4-nitrophenyl) methyl ester To a -20 0C solution, under argon, of 0.297 g of Product from Example 15 in 2.5 ml of acetonitrile, is added 61 microliter of Hunig's base, and 0.089 g of -127product from Example 16 suspended in 2.5 ml of acetonitrile. The reaction is stirred overnight and allowed to warm to room temperature. The mixture is concentrated in vacuo and purified by chromatography (Silica Gel: 80% ethyl acetate/acetone) to give 0.135 g of the desired product.

1HNMR (CDCl,) :6 8. 3(d, 2H); 7. 7(d, 2H) 5. 5(d, 1H); 5.25(d,lH); 5.l(bs,2H,NH 2 4.0-4.5(m,7H); 3.8(m,2H); 3.3(m,lH); 2.5(m,lH); 2.4(bs,lH,OH); l.8(m,0.5H); 1.7(m,0.5H); l.38(d,3HHe); l.25(d,3H,Me).

Example 18 r4R-r3(3R .5R and 3S .5S )4alpha.5beta.6beta(R )11- 3-r rs- r r(Aminocarbonvl oxvlmethyll1tetrahvdro-3furani thiol (l-hvdroxvethvl) -4-methvl-7-oxo- I-azabicvclor3 .2.0-lhent-2-ene-2-carboxylic acid monosodium salt A mixture of 0.181 g of product from Example V 17, 0.032 g of sodium bicarbonate, 2 ml of water, 11 ml of dioxane and 0.100 g of 10 palladium/carbon is reduced in a Parr apparatus at 42 psi of hydrogen for 3 hours. The reaction mixture is filtered through a pad of diatomaceous earth, washed with water and concentrated to 1/2 volume. The solution is extracted V....with ethyl acetate and the aqueous layer is :25 freeze-dried. The product is purified using C 8 reverse phase chromatography (95/5 water/ethyl alcohol) to give 0.095 g of the desired product as a yellow solid.

1 H NM.R(CDCl 3 :6 3.45-4.15(m,9H); 3.2-3.3(m,2H); 2.32-2.48(m,lH); l.57-l.64(m,0.5H); l.4-l.5(m,0.5H); l.l(d,3H,Me); l.03(dd,3H,Me).

IR(KBr): 1729 and 1606 cm-1 -128- Example 19 trans- -Tetrahvdro-4 -merca~to-2 -furanniethanol The title compound is prepared by the procedure of Example 16 using 0. 109 g of product from Example 7, 120 microliter of 25% methoxide/methyl alcohol, 1.75 ml of tetrahydrofuran, 280 microliter of 1.86N hydrochloric acid/isopropyl alcohol to give the desired product as a white solid.

Eane2 r4R-r3(3R .5S and 3S*.5R*)4alpha.5beta.6beta(R 111r 3-r 5- r (Aminocarbonvl) oxvl methyl 1 tetrahvdro-3furanvl 1thiol (1-hvdroxvethvll -4-methvl-7-oxo-lazabicyclorF3.2.01 hept-2-ene-2-carboxylic acid (4-nitrophenvl)methvl ester The title compound is prepared by the procedure of Example 17 using 0.089 g of product from Example 19 in 2.5 ml of acetonitrile, 0.297 g of product from Example 15 in 2.5 ml of acetonitrile, and 61 microliter of Hunig's base to give 0.126 g of the :0:::.desired product as a white solid.

Hi NMR(CDCl 3 :6 8.3(d,2H); 7.7(d,2H); 5.5(d,1H); 5.25(d,lH); 5.1(bs,2H,NH 2 4.0-4.3(m,7H); 3.8(m,2H); 3. 3(m,l1H) 2. 5(m,l1H) 2. 4(bs,l1H, OH) 1. 8(m, 0. 1.7(m,0.5H); l.38(d,3H,Me); 1.25(d,3H,He).

Examp~le 21 f4R-r3(3R .5S and 3S .5R )4al]Rha.5beta.6beta(R*)11oxvlmethvlltetrahvdro-3furanvi 1thiol (1-hydroxyethvfl)-4-methvl-7-oxo- 1-azabicycloF 3.2. Olhept-2-ene-2-carbo .xvlic acid monosodium salt The title compound is prepared by the procedure of Example 18 using 0.126 g of product from Example 20, 0.0223 g of sodium bicarbonate, 1.4 ml of water, 7.8 ml of dioxane, and 0.070 g of palladium/carbon to give 0.055 g of the desired product as a yellow solid.

-129- 1 H NMR(CDCl 3 :6 3.9-4.2(m,6H); 3.6-3.8(m,2H);' 3.25(m,2H); 2.35-2.49(m,lH); l.59-l.69(m,0.5H); l.42-l.52(m,0.5H); l.l2(d,3H,Me); 1.04(dd,3H,Me).

~Ethanethioic acid trans(+/-)-S-rtetrahvdro-5-:rr trifluoromethvl) sulfonyi 1oxvlmethvl 1-3-furanvi lester To a 0 0 C solution of 0.535 ml of trifluoromethanesulfonic anhydride in 3.75 ml of methylene chloride is added, via a syringe, a 0 0

C

solution of 0.529 g of product from Example 6 in 0.75 ml of methylene chloride and 0.243 ml of pyridine. The reaction is stirred in an ice bath for 4t minutes; during which time the progress of reaction is checked by thin layer chromatography. The mixture is 15 concentrated inl vacuo, slurried with ethyl acetate and ~filtered. The filtrate is purified by chromatography (Silica Gel: 50% ethyl acetate/hexane) to give 0.799 g of the desired product.

1 H NMR(CDCl 3 4.54-4.61(dd,lH); 4.41-4.49(dd,1H); 4.32-4.4(m,lH); 4.26-4.31(dd,lH); 4.0-4.1(m,lH); 3.67-3.75(dd,lH); 2.35(s,311); 2.l8-2.32(m,1H); 2. 03-2. 12 (in, H) Examp~le 23 Ethanethioic acid 25 -S-rtetrahvdro-5- (rhenoxvmethvl) 3-furanvll-ester To a 0 C solution of 0.326 g of phenol, 1.8 ml of Hunig's base, and 2.5 ml of methylene chloride is added, via syringe, 1.07 g of product from Example 22 in 0.50 ml of methylene chloride. The reaction is stirred in an ice bath for 50 minutes; during which time the progress of reaction is checked by thin layer chromatography. The mixture is concentrated in vacuo, dissolved in ethyl acetate and washed with sodium bicarbonate. The o rganic layer is dried, concentrated in vauo and purified by chromatography (Silica Gel: -130ethyl acetate/hexane) to give 0.532 g of the desired product.

1 H NNR(CDC 3 7.25(m,2H); 6.9(m,3H); 4.4(ma,lH); 4.35(dd,1H); 4.1(m,1H); 3.95(dd,2H); 3.7(dd,lH); 2.33(s,3H,Ac); 2.25(m,lH); 2.O(m,lH).

Example 24 trans- -Tetrahvdro-5- (ohenoxvmethvl) -3-furanthiol The title compound is prepared by the procedure of Example 16 using 0.532 g of product from Example 23, 506 microliter of 25% sodium methoxidd/methyl alcohol, 7.5 ml of tetrahydrofuran, and 1.18 ml of 1.86N hydrochloric acid/isopropyl, alcohol to give 0.311 g of the desired product.

H NMR (CDCl 3 :6 7.2 5(m, 2H) 6. 9(m, 3H) 4. 5(m, 1H); to 4.2(dd,1H); 3.95(m,2H); 3.6(dd,lH); 2.3(m,lH); l.95(m,lH); 1.75(d,1H,SH).

too.. Example r4R-r3(3R*5* and 3S *.5R *)4alpha.5beta.6beta(R*)Mj- 6- (l-Hydroxvyethvl) -4-methvl-7-oxo-3- (thenoxMethyl)-3-furanvllthiol-l-azabicyclor3.2.01hept-2-ene-2-carboxvlic acid (4-nitrophenvi) methyl ester The title compound is prepared by the proce-.

dure of Example 17 using 0.311 g of product from Example 24 in 7.5 ml of acetonitrile, 0.879 g of product from Example 15 in 7.5 ml of acetonitrile and 0.18 ml of Hunig's base to give 0.349 g of the desired product.

1 H NI4R(CDCl 3 :6 8.23(d,2H); 7.65(d,2H); 7.3(m,2H); 6.92(m,3H); 5.5(d,lH); 5.26(d,1H); 4.5(m,1H); 4.3(m,3H); 4.06(m,2H); 3.9(m,1H); 3.72(m,1H); 3.4(m,lH); 3 -3(dd,lH); 2.38(m,lH); 2.09(m,1H); 1.32 (d,3H,Me) l.29(t,3H,Me).

-131- Examiple 26 r4R-r3(3R*.S and 3S*.5R*)4aliDha.5beta,6beta(R )11- 6- (l-Hvdroxvethvl)-4-methvl-7-oxo-3- r (phenoxvmethvyi -3-furanvllthiol-l-azabicvclor3.2.01 hept-2-ene-2-carboxylic acid monosodium salt The title compound is prepared by the procedure of Example 18 using 0.320 g of product from Example 25, 0.054 g of sodium bicarbonate, 3.5 ml of water, 8.3 ml of dioxane and 0.166 g of palladium/carbon to give 0.052 g of the desired product.

1 HNMR (CDC1 :6 7. 3 9(m, 2H) 7. 07 3H) 4. 6(m, 2H); 4.25(m,4H); 4.20(m,lH); 4.0(m,lH); 3.8(m,lH); 3.43(m,lH); 2.25(m,lH); 2.l8(m,lH); l.3(d,3H,Me); 1.23(m,3H,Me).

Example- 27 cis- -4 -Bromnotetrahvdro-2-furarnmethanol The title compound is prepared by the procedure of Example 6 using 5.42 g of product from Example 4, 3.13 ml of iodotrimethylsilane, 117 ml of chloroform and 5.3 ml of methyl alcohol to give 3.17 g of the desired product.

1 H NMR(CDCl 3 4.3-4.5(m,lH); 4.0-4.2(m,3H); 3.6-3.8(m,2H); 2.l-2.2(m,lH); l.94(br s,1H).

Example 28 Trifluoromethanesulfonic acid cis- (4-bromotetrahydro-2-furanvlhnethvl ester The title compound is prepared by the procedure of Example 22 using 3.1 g of product from Example 27 in 4.5 ml of methylene chloride, 3.05 ml of trifluoromethanesulfonic anhydride in 21.5 ml of methylene chloride, and 1.38 ml of pyridine to give 4.76 g of the desired product.

1 H NMR(CDCl 3 :6 4.55-4.7(M,2H); 4.35-4.46(m.2H); 4.05-4.2(m,2H);2.7-2.8(m,lH); 2.1-2.2(m,lH).

-132- Exmpe2 cis-(+/-1-4-Bromo-2-r r(4-fluoronhenvl~thiolmethj.1tetrahvdrofuran The title compound is prepared by the procedure of Example 23 using 4.7 g of product from Example 28 in 15 ml of methylene chloride, 1.61 ml of 4-fluorothiophenol in 15 ml of methylene chloride, and 2.61 ml of Hunig's base to give 3.96 g of the desired product as a light yellow oil.

1 H NMR(CDC.

3 :6 7.35-7.48(m,2H); 6.9-7.l(m,2H); 4.32-4.5(m,lH); 4.0-4.15(m,3H); 3.2-3.32(m,1H); *0 3.05-3.15(m,lH); 2.62-2.78(m,1H); 2.l-2.25(m,lH).

cis-+/-)Examule ci-+--4-Bromo-2-r r(4-fluorophenvl) sulfonvll C. methyll1tetrahvdrofuran mixture of 3.3 g of product from Example 29, 174 ml of glacial acetic acid and 46.5 ml of hydrogen peroxide is heated at 100 C for 0.5 hour. The reaction mixture is concentrated in vacuo and purified by chromatography -(Silica Gel: 50% ethyl acetate/hexane) to give 3.4 g of the desired product as a white solid.

1 H NMR(CDCl 3 7.93-8.0(m,2H); 7.21-7.28(m,2H); 4.42-4.56(m,lH); 4.37-4.41(m,lH); 3.97-4.05(m, 2H); S 3.64-3.71(dd,1H); 3.41-3.47(dd,1H); 2.75-2.85(m,1H); 2.20-2.3(m,lH).

Example 31 Ethanethioic acid -S-r5-rrF(4-fluoronhenyl)sulfonvllmethvlltetrahvdro-3-furanvl lester The title compound is prepared by the procedure of Example 5 using 0.969 g of product from Example 0.360 q of potassium thioacetate, and 9 ml of acetonitrile to give 0.533 g of the desired product.

1 H NMR(CDCl 3 :6 7.93-8.0(m,2H); 7-2-7.3(m,2H); 4 .38-4.5(m,lH); 4.3.3-4.2l(dd,3.H)"; 3 .9-4.Ol(m,1H); 3.5-3.56(dd,lH); 3.4-3.48(dd,1H); 3.2-3.3(dd,1H); -133- 2.33(s,3H); 2.16-2.22(m,2H).

Examnle 32 trans- F F(4-Fluoro~henvi) sulfonvi imethyl 1tetrahydro-3 -furanth iol The title compound is prepared by the procedure of Example 16 using 0.955 g of product from Example 31, 0.72 ml of 25% sodium methoxide/methyl alcohol and 10 al of tetrahydrofuran to give 0.523 g of the desired product.

1H NMR(CDC 3 :6 S. 0(m, 2H) 7. 4(m, 2H) 4. 3-4. 6(m, 1H); 3.9-4.2(m,lH); 3.2-3.6(m,4H); 2.6(m,0.5H); 2.2(m,1H); 1.75(d,lH,SH); Example 33 r4R-r3(3R *5S *and 3S *.5R )4aliDha.5beta.6beta(R*)1]- 3-r r F5-r r (4-Fluoro~henyl) sulfonvllziethyli1tetrahvdro-3- ~furani thiol (l-hvdroxvethvl) -4-methyl-7-oxo-lazabicvcloF3 olher~t-2-ene-2-carboxylic acid (4 -nitrophenvi )zmethyl ester The title compound is prepared by the procedure of Example 17 using 0.523 g of product from Example 32 in 12 ml of acetonitrile, 1.13 g of product from Example 15 in 12 ml of acetonitrile and 0.23 ml of Hunig's base to give 0.726 g of the desired product.

1 H NMR(CDCl 3 8.23(m,2H); 7.95(ma,2H); 7.65(m,2H); 7.25(m,2H); 5.48-5.53(m,1H); 5.2-5.28(m,lH); 3.2-4.5(m,lOH); 2.58(m,lH); 2.2(m,0.5H); 1.37(m,3H,Me); l.27(m,3H,Me).

Example 34 r4R-F3(3R 5S *and 3S *R .5*4alvha.5beta.6beta(R*)11- (4-Fluorophenvl) sulfonvi lmethvll1tetrahvdro-3furanylithiol (l-hvdroxvethvl) -4-methvl-7-oxo-lazabicvclor3 01heRt-2-ene-2-carboxylic acid monosodium salt The title compound is prepared by the procedure of Example 18 using 0.821 g of product from Example 33, 0.124 g of sodium bicarbonate, 8 ml of water, 20 ml of dioxane, and 0.380 g of -134palladium/carbon to give 0.135 g of the desired product.

1H NMR(D 2 O 7.96-8.06(m,2H); 7 3 7-7.47(m,2H); 3 2 -4.65(m,1OH); 2.55(m,1H); 2.1(m,0.5H); l.

6 (m,0.SH); 1.25(d,3H,Me); 1.15(t,3H,Me).

MS(FAB):m/z 530(M+Na) and 508(M+H).

Example Ethanethiojc acid trans- r 5- r (4 -fluorohenoxvi methyl itetrahdro o3-furanyll ester The title compound is prepared by the procedure of Example 23 using 1.49 g of product from Example 22 in 1 ml of methylene chloride, 0.542 g of 4 -fluorophenol, 2.5 ml of Hunig's base and 3 ml of methylene chloride to give 0.963 g of the desired compound.

H NMR(CDCl 3 6.74-7.O(m,4H); 4 2 6 4 .47-(m,2H); 4

.O

5 -413(m,lH); 3.96-4.00(dd,2H); 3 67 -3.72(m,H); 2 .35(s,3H,Ac); 2.24(m,1H); 2 .O-2.l(m,lH).

Example 36 (4-Florophenox methyl 1 tetrahvdro-3-furanthio1 The title compound is prepared by the procedure of Example 16 using 0.943 g of product from Example 35, 0.86 ml of 25% sodium methoxide/methyl alcohol and 12 ml of tetrahydrofuran to give 0.417 g of the desired product.

1H NMR(CDC3):6 6 .75-7.05(m,4H); 4.3(dd,lH); 3.95(m,2H); 3.6(dd,lH); 2 2.05(m,1H); -135- Example 37 r4R-r3(3R S5S and 3S*.5R l4alDha-5beta.6betacR 111- 3-r r 5-r r (4-Fluoroiphenoxv) methyl ltetrahvdro-3furanvi 1thiol (1-hvdroxvethyl) -4-methyl -7-oxo_-lazabicyclo 01hept-2-ene-2-carboxylic acid (4-nitrophenvi) methyl ester The title compound is prepared by the procedure of Example 17 using 0.417 g of product from Example 36 in 9 ml of acetonitrile, 1.09 g of product from Example 15 in 9 ml of acetonitrile, and 220 microliter of Hunig's base to give 0.473 g of the desired product.

1 1 H NHR(CDCl 8.22(d,2H); 7.65(d,2H); 6.95(m,2H); 6.85(m,2H); 5.5(d,lH); 5.25(d,lH); 4.48(m,lH); 4.2-4.4(m,3H); 3.8-4.08(m,3H); 3.72(m,lH); 3.4(m,lH); 3.3(m,lH); 2.3-2.43(m,lH); 2.0-2.20(m,lH); l.37(d,3H,Me); l.31(t,3H,Me).

*Examr~le 38 [-4R-r3(3R .5S and 3S .5R )4alDha, 5beta. 6beta-(R*)1 F (4-Fluorophenoxv) methvlltetrahydro-3furanvllthiol-6- (l-hydroxyethvl) -4-methvl-7-oxo-lazabicyclo[3 Olhept-2-ene-2-carboxylic acid monosodium salt The title compound is prepared by the procedure of Example 18 using .0.450 g of product from Example 37, 0.074 g of sodium bicarbonate, 5 ml of water, 12 ml of dioxane and 0.226 g of palladium/carbon to give 0.147 g of the desired compound.

1 H NMR(D 2 0):S 7.0-7.1(m,4H); 4.6(m,2H); 4.l0-4.3(m,3.5H); 3.9-4.1(m,2H); 3.78(m,1H); 3.3-3.43(m,l.5H); 2.22-2.39(m,lH); 2.05-2.2(m,lH); l.29-l..31(d,3H,Me); l.20-l.23(dd,3H,Me).

-136- Example 22 Ethanethioic acid trans-(+/-)-S-rS-rr(4-fluorolhenvl thiolmethyl1tetrahvdro-3-furanvl lester The title compound is prepared by the procedure of Example 23 using 0.308 g of product from Example 22 in 1 ml of methylene chloride, 107 microliter of 4-fluorothiophenol, and 174 microliter of Hunig's base to give 0.236 g of the desired product.

1 H NMR(CDCl 3 7.4(m,2H); 7.0(m,2H); 4.3(dd,1H); 4.l-4.2(t,lH); 3.98-4.08(mlH); 3.6-3.65(dd,lH); 3.O8-3.15(m,1H); 2.98-3.05(dd,1H); 2.32(s,3H,Ac); 2.1-2.23(m,lH); 1.98-2.08(m,1H).

i' ":Example trans-(+/-)-5-rr4-(Fluorohenylmthiolmethvlltetrahvdro-3-furanethiol The title compound is-prepared by the procedure of Example 16 using 0.206 g of product from Example 39, 173 microliter of 25% sodium methoxide/methyl alcohol, 2.5 ml of tetrahydrofuran, and 403 microliter of 1.86N hydrochloric acid/isopropyl alcohol to give 0.0405 g of the desired product.

1H NMR(CDC1 3 7.4(m,2H); 7.O(m,2H); 4.3(m,2H); S3.55(m,lH); 3.48(m,lH); 3.1(m,1H); 2.9(m,1H); 25 2.2(m,1H); 2.0(m,1H); 1.78(d,lH,SH).

Example 41 F4R-r3(3R .5S and 3S *5R *5beta,6beta(R *l- 3-F F5-r(4-Fluorophenvl)thiolmethylltetrahvdro-3furanyl1thiol-6-( -hdroxvethvl -4-methyl-7-oxo-lazabicvclor3.2.Olhept-2-ene-2-carbovlic acid (4-nitrophenvl)methyl ester The title compound is prepared by the procedure of Example 17 using 0.110 g of product from Example 40 in 2 ml of acetonitrile, 0.268 g of product, from Example 15 in 2 ml of acetonitrile and microliter of Hunig's base to give 0.230 g of the desired product.

-137- 1 H NHR(CDCl 3 :6 8.3(d,2H); 7.7(d,2H); 7.4(m,2H); 5.5(d,21H); 5.25(d,lH); 4.3(m,4H); 3.85(m,lH); 3.7(m,1H); 3.4(n,111); 3.3(d,1H); 3.1(M,2H); 2.4(bs,1H,OH); 2.2(m,2H); 1.4(d,3H,Me); 1.3(m,3H,Me).

~Examnple 42 r4R-r3(3R 5S *and 3S*.5R*)5beta.6beta(B*I)11- 3-r r r r(4-Fluorophenvl~ thioimethvll tetrahvdro-3furanvi ithiol (l-hvdroxvethvl) -4-methvl-7-oxo-1azabicvclor3.2. Olheipt-2-ene-2-carboXvlic acid monosodium salt The title compound is prepared by the procedure of Example 18 using 0.230 g of product from Example 41, 0.118 g of 10% palladium/carbon, 0.038 g of sodium bicarbonate, 2.5 ml of water and 6.0 ml of dioxane to give 0.062 g of the desired product.

H NMR(D 0):6 7.25(bs,2H); 6.8(bs,2H); 2.35-4.4(m,10 2.88(M,2H); l.1(bs,3H,Me);-0.96(bs,3H,Me).

Ethanethioic acid S-r5- (azidomethyl)tetrahvdro-3-furanyl1 ester To a 0-0C solution of 5.768 g of product from Example 22 in 16 ml of methylene chloride, under argon, is added, via syringe, a 0 0 solution of 5.86 g of tetrabutylammonium azide in 16 ml of methylene chloride. The reaction is stirred in an ice bath for minutes and then concentrated in vacuo. The residue is purified by chromatography (Silica Gel: 50% ethyl acetate/ hexane) to give 3.418 g of the desired product.

1 H NMR(CDCl 3 :6 4.28-4.33(dd,lH, CH 4.15-4.17(m,lH,CHO): 4.0-4.12(m,lH,CHS); 3o63-3.38(dd,lH,CHN); 3.4-3.49(dd,1H,CHN); 3.24-3.68(dd,1H,CH 2 O0); 2.34-(s,3H,Ac); 2.16-2.26(m,lH); 1. 93-2.*01 (in,lH).

IR(neat): 2101 and 1693 cm -138- Examnle 44 5-(Azidomethvyltetrahvdro-3-furanthiol The title compound is prepared by the procedure of Example 16 using 3.35 g of product from Example 43, 3.8 ml of 25% sodium methoxide/methyl alcohol and 59 ml of tetrahydrofuran to give 1.995 g of the desired product.

1 H NMR(CDC 3 4.3-4.4(m,lH); 4.2-4.26(m,lH); 3.8-3.86(m,0.5H); 3.56-3.65(m,lH); 3.43-3.52(m,1.5H); 3.2-3.3(m,1H); 2.14-2.31(m,lH); l.9-1.98(m,lH); 1.78(d,lH,SH).

IR(neat): 2099 cm 1 Example r4R-r3(3R .5S and 3S .5R )4alpha.5beta.6beta(R )11- 3-rr5-(Azidomethvl)tetrahvdro-3-furanvllthiol- 6-(1-hvdroxvethvl)-4-methl-7-oxo-lazabicvclo[3.2.Olhept-2-ene-2-carboxlic acid S(4-nitrophenvl Imethyl ester The title compound is prepared by the procedure of Example 17 using 1.995 g of product from Example 44 in 35 ml of acetonitrile, 7.45 g of product from Example 15, and 1.7 ml of Hunig's base to give 2.83 g of the desired product.

H NR(CDC 3 8.3(d,2H) 7.7(d,2H); 5.5(d,1H); 5.25(d,lH) 4.35(m,4H) 3.8(m,lH) 3.7(m,H); 3.5(m,1H) 3.4(m,1H) 3.3(m,2H) 2.3(m,1H) 1.98(m,H); l.4(d,3H,Me); l.3(m,3H,Me).

IR(neat): 2101 and 1769 cm 1 Example 46 F4R-r3(3R .5S and 3S*.5R I4alpha.5beta6beta(R* Il- 3-F 5-(Aminomethvlltetrahvdro-3-furanvllthiol- 6-(l-hvdroxvethvl)-4-methvl-7-oxo-lazabicvclor3 01hett-2-ene-2-carboxvlic acid The title compound is prepared by the procedure of Example 18 using 2.8 g of product from Example 45, 0.60 g of 10% palladium/carbon, 27 ml of sodium phosphate buffer (pH 7) and 82 ml of dioxane to give -139- 0.562 g of the desired product.

1 H NMR(D 2 0) :6 4. 4(m,1IH) 4. 2(in,2. 5H) 3. 9 3.75(m,l.5H); 3.4(m,2H); 3.2(m,lH); 3.l(m,1H); 2.2(m,2H); l.35(d,3H,Me); l.30(d,3HIMe).

ExaMle 47 r4R-[3(3R .5S and 3S 5R )4al~ha,5beta.6beta(R )11- 6- (l-Hvdroxvethvl) rrtetrahvdro-5- (iminomethyl iamino Inmethyl 1 3 -furanvi 1 th io1 -4-methvi -7 -oxo-1I-a za bicvclor3 0]-hent-2-ene-2-carboxvlic-acid Five ml of phosphate buffer (pH is cooled to 0O and the pH is adjusted with 1N sodium hydroxide to pH 8.5. This solution is added to 0.052 g of product from Example 46, followed by the addition of 0.0832 g of ethyl methanimidate hydrochloride. The pH is maintained at pH 8.5 and the temperature at0 during the reaction. After 35 minutes, the pH is adjusted to pH 7 with 5% hydrochloric acid and the mixture is concentrated in vacuo. The residue is 20 purified by chromatography (C 1 8 reverse phase plates: aqueous ethyl alcohol) to give 0.038 g of the desired product.

1H NMR(D 2 0):6 7.68(t,lH,CH=N); 4.27(m,lH); 4.05(m,3H); 3.79(m,lH); 3.6(m,1H); 3.38(m,lH); 3.28(m,3H); 1.97(m,2H); 1.12(d,3H,Me); l.03(d,3H,Me).

Reference: The Journal of Antibiotics, 36, No. 8, p1034, 1983.

Example 48 r4R-r3(3R .5S and 3S .5R )4a1Pha.5beta.6beta(R fli1 6- (1-Hvdroxvethvl)-4-methvl-7-oxo-3- rrtetrahvdror (-iminoethvl)aminolmethvll-3-furanvllthiol- 1-azabicyclor3 01-hept-2-ene-2-carboxvlic acid The title compound is prepared by the procedure of Example 47 using 0.052 g of product from Example 46, 5 ml of sodium phosphate buffer (pH 7) adjusted to pH 8.5 and 0.097 g of ethyl acetimidate hydrochloride to give 0.045 g of the desired product.

1 H NMR(D 2 0):6 4.24(m,1H); 4.04(m,3H); 3.8(m,1H); -140- 3.58(m,1H); 3.25(m,4H); l.96(d,3H,Me-C--); 1.93(mn,2H); l.l1(d,3H,Me); l.02(d,3H,Me).

r4R-r3(2R .4S and 2S .4R )_4Aaa5beta.6beta(R III1- 4- r r2-Carboxv-6- (l-hydroxveth1l1-4-methvl-7-oxo-lazabicyclo r 01helpt-2-en-3-yll1thiol tetrahvdro-N .N .Ntrimethl-2-furanmethanaiium hydroxide. inner salt The title -compound is prepared by the procedure of Example 47 using 0.0514 g of product from Example 46, 3 ml of sodium phosphate buffer (pH 8.6), 0.26 ml of dimethyl sulfate, 1.5 ml of acetonitrile and 1.9 ml of dioxane to give 0.0073 g of the desired 1 H NMR(D 0) :6 4. 08 3H) 3.6-3.89 3H); 3.2-3.4(m,4H); 3.02(s,9H,3-Me); 2.05(m,lH); 1.96(m,lH); l.12(d,3H,Me); l.04(d,3H,He).

-Example 2. 5-Dioxo-4-oxazolidilepefltanoic ac id A suspension of 1.752 g of DL-2-aminopimelic acid, 55 -ml of tetrahydrofuran and 16 ml of 1.93M phosgene in toluene is heated, in an oil bath, at 500 for 1 hour. Argon is bubbled through the reaction to remove the excess phosgene and the solvents are removed under house vacuum. The resulting oil is dissolved in ml of ethyl alcohol, diluted with 14 ml of petroleum ether and the solution stored overnight at room temperature. The formed crystals are collected and dried to give 1.6 g of the desired product.

mp 102-104 0

C.

1 HNMR(DMSO-d 12.l(bs,lH); 9.14(s,lH); 4.44(t,lH); 2.21(t,2H); l.68(m,2H); l.5(m,2H); l.34(m,2H).

Reference: J. Med. Chem., (1986), 22,89-95.

-141r4R-r3(3R *.5S and 3S *SR*14Al=ha.Bbeta.6beta(Rf- 3-r r5-r r c2Amino-6-carboXV-l-oxohexyli aminolmethvll 5tetrahvdro-3-fU-rall thiol (1-hvdroxyethyl-4-fethvl- 7-oxo-l-azabicVclo r3.2. Olhept-2-efle-2-carboxgylic acid monosodium salt (AY The title compound is prepared by the procedure of Example 47 using 0.0514 g of product from Example 46 in 1.5 ml of sodium phosphate buffer (pH 0.0302 g of product from Example 50 in 0.5 ml of dioxane, adjusting reaction pH to 9, to give 0.0173 g 9 Tf the desired product.

H NMR(D 0):6 4.06(m,3H); 3.78(m,2H) F 3.57(m,lH); 3.25(m,4H); 2.02(t,3H); l.92(m,2H); l.68(m,2H); l.42(m,2H); l.20(m,2H); l.12(d,3H,Me); l.03(d,3H,Me).

MS(FAB): m/z 544(M+Na), 522(M+H).* [4R-[3(3R 5S *and 3S *,5R *)4alpha,5beta,6beta(R (2-Amino-6-carboxy1l-oxohexyl)aminoJ- 6 20 carboxy-l-oxohexyl] amino]methyl) tetrahydro-3-furanylthio-6- (l-hydroxyethyl) -4-methyl-7-oxo-l-azabicyclo- 0]hept-2-ene-2-carboxylic acid disodium salt (B) (0.0263 g) is also isolated from the reaction as a by-product.

925 H NMR (D 2 0) 3. 2-4. 2 5(10 H in 4 multiplets); :1.02-2.06(26H, 2-Me, CCH 2 C from THF ring and 18H from side chain in 2 doublets and many multiplets).

MS(FAB): m/z 723(M+Na), 701(M+H).

Example 52 r4R-r3(3R 5S *and 3S*,5R*)4alPha.5beta.6beta(R 11i- 6- (1-HvdroxvethylI -4-methvl-7-oxo-3- r F F (methylamino) acetvllamifomethll3furanyllthiol 1-azabicyclo 13.2. Olhept-2-efle-2-carboxylic acid The title compound is prepared by the procedure of Example 47 using 0.068 g of product from Example 46 in 2.0 ml of sodium phosphate buffer (pH and 0.029 g of 3-methyl-2,5-oxazolidiediole, prepared by the procedure described in J. Chm -142- No. 1, 243(1969), in 1 ml of dioxane to give 0.036 g of the desired product.

1 HNMR(D 2 0) :6 3. 1-4. 2(12H in multiplet); 2.58(s,3H,Me); 1.82(m,2H); 1.12(d,3H,Me); l.05(dd,3H,Me).

4- (Chloromethyll The title compound is prepared by the proce dure of Example 50 using 1.24 g of 2-chloro-L-alanile, 16 ml of 1.93M phosgene in toluene and 55 ml of tetrahydrofuran to give 0.150 g of the desired product.

H NMR(DMSO-d): 9.26(br s,1H,NH); 4.97(t,1H,CH); 3.99(dd,lH,CH 2 3.87(dd,lH,

CH

2 r4R-r3(3R .5S and 3S S5R )4alDha.5beta,6beta(R *I11- 3-r r5-r r(2-Aino"3-chloro-l-oxo~rORV1lam-inlmethVlltetrahvdro-3-furanvll1thiol (1-hvdroxyethvl) -4-methyl- 7-oxo-l-azabicvclor 3.2. Olhe~t-2-efle-2-carboxylic acid The title compound is prepared by the procedure of Example 47 using 0.0685 g of product from Example 46 in 1.5 ml of sodium phosphate buffer (pH 25 8.5) and 0.0299 g of product from Example 53 to give *9 9 0.0347 g of the desired product.

1 H NMR(D 2 0) :6 2. 8-4. 4(13H in multiplets) 1. 96 2H); 1.12(d,3H,Me); l.04(d,3H,14e).

[4R-[3(2R*,4S* and 2S*,4R*)4alpha,5beta,6beta(R 3-chloro-L-alanyl-N- 4- 2-carboxy-6- (l-hydroxyethyl) tetrahydro-2-furanyl Imethyl-3-chloro-Lalaliamide

(B)

(0.0152 g) is isolated as a by-product.

1 H NMR(D 2 0) :6 3. 2-4. 7(16H in multiplets) 1. 93 2H); 1.12(d,3H,Me); 1.05(d,311,Me).

-143- Wx trans- -Tetrahvdro-4 -mercapto-2 -furanmethanol The title compound is prepared by the procedure of Example 16 using 1.06 g of product from Example 6, 20 ml of tetrahydrofuran, 1.43 ml of 25% sodium methoxide/methyl alcohol, and 3.35 ml of 1.86N hydrochloric acid/isopropanol to give 0.687 g of the desired product.

1 H NMR(CDCl 3 :6 4. 25 (m,l H) 4. 2(dd, 1H) 3. 74 (dd,l1H); 3.4-3.6(m,3H); 2.98(s,lH,OH); 2.2(m,lH); 1.9(m,lH); 1.78 lH,SH).

ExaMle 56 r4R-r3(3R 5S *and 3S*.5R*)4alpha.5beta.6beta(R*111- 6- (1-Hydroxvethv1) -4-methvl-7-oxo-3- r ~(hydroxvmethvl) -3-furanyllthiol-azabicyclor 3.2.01hep-2-ne--caboxlicaci (4nitO~hnylmethyl ester The title compound is prepared by the procedure of Example 17 using 3.55 g of product from Example 15 in 25 ml of acetonitrile, 0.687 g of product from Example 55 in 25 ml of acetonitrile and 0.625 g of too. Hunig's base to give 1.66 g of the desired product.

90409 1 H NMR(CDCl 3 8.22(d,2H); 7.67(d,2H); to: 5.22(d,lH); 4.28(m,4H); 3.8(m,2H); 3.7(m,lH); 3.55(m,lH); 3.32-4.l(m,lH); 3.3(m,1H); 2.3(m,lH); 2.18(bs,2H,OH); l.98(m,lH); l.36(d,3H,Me); 1.28 (d,3H,Me).

Example 57 r4R-r3(3R .5S and 3S*.5R*)4al~ha.5beta.6beta(R *11- 6- (l-Hvdroxvethvl) -4-methyl-7-oxo-3-r[rtetrahydro-5- Fr(methylsulfonvl)oxylmethvl]-3-furanyllthiol-lazabicyclor3.2. 01hept-2-ene-2-carboxylic acid (4-nitroiphenvfl methyl ester To a 0 0 C solution, under argon, of 0.821 g of product from Example 56 and 3.4 ml of pyridine is added 148 microliter of methanesulfonyl chloride. The reaction is stirred at 00% for 2 hours, diluted with -144water and extracted with chloroform. The organic layer washed with water and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by chromatography (Silica Gel; 80% ethyl acetate/hexane) to give 0.632 g of the desired product.

1 NMR(CDC 3 8.22(d,2H); 7.64(d,2H); 5.53(d,lH); 5.25(d,lH); 4.2-4.45(m,6H); 3.78-3.88(m,1H); 3.72(dd,lH); 3.32-3.48(m,1H); 3.3(m,1H); 3.07(s,3H,Me); 2.28(m,1H); 2.08(m,1H); 1.7(bs,1H,OH); l.38(d,3H,Me); l.29(m,3H,He).

Example 58 so r4R-r3(3R .5S and 3S .5R 14al~ha.5beta.6beta(R*I31- 6- (l-Hydroxvethvl) -4-methvl-7-oxo-3- 0. 00 w (iodomethyl) -3-furanvllthiol-l-azabicvclor3 Olhep~t-2ene-2-carboXylic acid (4-nitrophenv1lmethyl ester A mixture of 0.80 g of product from Example 57, 0.431 g of sodium iodide and 20 ml of acetone is *heated at reflux temperature for 5 days. The reaction is concentrated ijn vacuo and the residue purified by chromatography (silica Gel: 80% ethyl acetate/hexane) to give 0,472 g of the desired product.

1 H NMR(CDC1 3 8.22(d,2H); 7.68(d,2H); 5.49(d,1H); 5.25(d,lH); 3.28-4.4(m,lOH); 2.14(m,2H); 1.38(m,3H,Me), *00 26 3H, Me) Example 59 r4R-r3-(3R*,5S* and 3S*.5R*)4alpha.5beta.6beta(R *)11- 6- (1-Hvdroxvethvl) -4-methyl-7-oxo-3- methyl-3-furanvl)thiol-l-azabicvclor3.2-.Olheipt-2ene-2-carboxcylic acid monosodium salt The title compound is prepared by the procedure of Example 18 using 0.450 g of product from Example 58, 0.230 g of 10% palladium/carbon, 0.161 g of sodium bicarbonate, 5 ml of water, and 12 ml of dioxane to give 0.0967 g of the desired product.

1 HNMR(CDCl 3 3.3-4.6(m,8H); 2.0(m,2H); 1.2(m,9H,3x(e).

-145- Example 0 Ethanethioic acid ~cis- rtetrahydro-5- r r r (trifluoromethyl) sulfonvil oxylmethvll-3-furanvll ester The title compound is prepared by the procedure of Example 22 using 0.529.g of product from Example 9 in 0.75 ml of ziethylene chloride, 0.54 ml of trifluoromethanesulfonic anhydride in 3.75 ml of methylene chloride, and 0.243 ml of pyridine to give 0.560 g of the desired product.

I H NMR(CDCl 3 :6 4.55(m,2H); 4.35(m,lH); 4.2(dd,1H); 4.05(m,1H); 3.75(dd,1H); 2.65(m,lH); 2.35(s,3H,He); l.7(m,1H). ~ai ~cis- -s-F5-(Azidomethvl) tetrahvdro-3-furanvl lester The title compound is prepared by the procedure of Example 43 using 0.560 g of product from 20 Example 60 in 2 ml of methylene chloride, 0.569 g of tetrabutylammonium azide in 2 ml of methylene chloride to give 0.321 g of the desired product.

1 HNMR(CDCl 3 4.15(m,2H); 4.05(m,1H); 3.75(dd,lH); 3.45(dd,1H); 3.3(dd,1H); 2.49(,m,lH); 2.34(s,3HMe): 1.7(m,1H).

IR(NEAT): 2100 and 1692 cm-1 Example 62 cis- (Azidomethyl) tetrahvdro-3-furanthiol The title compound is prepared by the procedure of Example 16 using 0.310 g of product from Example 61 in 4.5 ml of tetrahydrofuran and 0.30 ml of sodium methoxide/methyl alcohol to give 0.159 g of the desired product.

1 H NMR(CDCl 3 :6 3.3-3.5(m,3H)j l.8(d,1H,SH); l.7(m,1H).

IR(neat): 2099 cm- 1 -146r4R-r3 OR .5S and 3S S5R )4alpDha.5beta,6beta(R*)1i- 3-rr 5- (Az idomethyll tetrahydro-3-furanyl ithiol -6- (1-hydroxyethyl -4 -methvl-7 -oxo-l-azabicvclo r3 *2 0hept-2-ene-2-carboxylic acid (4-nitro~henyli~methyl The title compound is prepared by the procedure of Example 17 using 0. 159 g of product f rom Example 62 in 3.5 ml of acetonitrile, 0.693 g of product from Example 15 in 3. 5 ml of acetonitrile and 134 microliter of Hunig's base to give 0.340 g of the desired product.

H NMR(CDCl 3 8.23(d,2H); 7.66(d,2H); 5.24(d,1H); 4.1-4.3(m,4H); 3.82(m,2H); 3.28-3.38(m,4H); 2.5(m,1H); l.85(m,1H); 1.73(bs,lH,OH); 1.37(d,3H,Me); l.29(m,3H,Me).

Example'64 r~4R-r3(3R 5S* and 3S*.5R* )4lha beta6bt(R*fli- 15- (Aminornethvl) tetrahydro-3-furanvllthiol -6- (1-hydroxvethvl) -4 -methvl-7-oxo-1-azabicyclo r3. 01 hept-2-ene-2-carboxylic acid The title compound is prepared by the procedure of Example 18 using 0.320 g of product from 63, 0.220 g of 10% palladium/carbon, 12 ml of 0.05M4 sodium phosphate buffer (pH 7) and 32 ml of dioxane to give 0.112 g of the desired product.

1H NMR(D 2 0):S 4.2(m,4H); 3.8(m,3H); 3.4(m,3H); 3.2(m,2H); 2.78(m,lH); 1.8(m,0.5H); l.6(m,0.5H); 1.25 (d,3H,Me); 1.20(m,3H,He).

Examnle r4R-r3(3R and 3S*.5R*)4alp2ha.5beta-6beta(R*111- 6- (1-Hydroxvethyl) r r 5- (iminomethyl I amino Imethyl I1tetrahydro-3-furanvll1thiol -4-methvl-7-oxo-l-azabicvclor3.*2.01 -hept-2-ene-2-carboxylic acid The title compound is prepared by the procedure of Example 47 using 0 .0615'g of product from Example 64, 0.0984 g of ethyl methanimidate -147- V hydrochloride, and 4 ml of sodium phosphate buffer (pH 7) to give 0.0379 g of the desired product.

1 H NMR (D 2 0):6 7.B(m,1H,CH=); 4.25(m,3H); 4.l(m,lH); 3.8(m,2H); 3.6(m,2H); 3.4(m,2H); 2.1(m,lH); l.7(m,0.5H); l.52(m,0.5H); 1.3(d,3H,Me); l.2(d,3H,Me).

Example 66 Ethanethioic acid trans- rtetrahvdro-5- r (2-naphthalenvloxvl methyl I 3-furanvi lester The title compound is prepared by the procedure of Example 23 using 0.813 g of product from Example 22 in 2 ml of methylene chloride, 0.380 g of :4.2-naphthol in 2 ml of methylene chloride, and 1. 38 ml of Hunig's base to give 0.673 g of the desired product.

1 ~H NMR(CDCl 7.05-7.75(m,7H); 4.35-4.45(m,lH); 4.28-4.35(dd,lH); 4.05-4.15(m,lH); 4.02(ma,2H); 3.65-3.75(dd,lH); 2.28(s,3H,Me) 2.24-2.34(m,lH); 1.95-2.05(m,1H).

Example 67 trans- -Tetrahydro-5- r (2 -naphtha 1enyl oxv)methyl 1 3-furanthiol The title compound is prepared by the procedure of Example 16 using 0.673 g of product from Example 66, 0.53 ml of 25% sodium methoxide/methyl alcohol and 8 ml of tetrahydrofuran to give 0. 099 g of the desired product.

1 H NMR(CDCl 3 7.05-7.75(m,7H); 4.55(m,lH); 4. 2 5(dd,l1H); 4. 02 2H) 3. 6(dd,l1H) 3. 5(m,l1H); 2. 3 5(m,l1H); 2. 0(m,IH) 1. 78 (d,l1H, SH) Example 68 r4R-r3(3R* 5S~ and 3S .5R )4alpha. 5beta. 6beta 11 6- (l-Hydroxvethvl) -4-methvl-7-oxo-3- r (2-naphthalenvloxv)methyl13-furanvllthiol-lazabicvclor3.2. Olhept-2-ene-2-carboxylic acid (4-nitrolphenyllmethyl ester The title compound is prepared by the procedure of Example 17 using 0. 099 g of the product f rom -148- Example 67 in 2 ml of acetonitrile, 0.226 g of product from Example 15 in 2 al of acetonitrile and 93 microliter of Hunig's base to give 0.158 g of the desired product.

1 H NMR(CDC1 3 :6 7. 05-8. 2(4m' and 2d, 11H) 5. 5(d, 1H); 5.2 (d,l1H) 3.3-4.6 (8m, 10 H) 2.5(m, 1H) ;2.2 1H); 1.4(d,3H,Me); 1.3(d,3H,Me).

Example 69 r4R-r3(3R S5S and 39*.5R )4alpha.5beta.6beta.(R Ill- 6- (1-Hvdroxyethyl)-4-methv-7-oxo- 3 -r r (2 -naphtha lenyloXV) methyl I 3-furanyl 1 thiol -Iazabjcyclor3 lhept-2-ene-2-carboXylic acid monosodium salt .The title compound is prepared by the procedure of Example 18 using 0.158 g of product from Example 68, 0.075 g of 10% palladium/carbon, 0.025 g of sodium bicarbonate, 1.5 ml of water, and 3.8 ml of dioxane to give 0.0307 g of the desired product.

1 ~H NMR(CDCl 3 6.4-7.4(m,7H); 3.0-4.5(m,lOH); 2.0(m,2H); l.4(m,3H,Me); 1.l(m,3H,Me).

Example (Phenvlmethoxv) carbamic acid 2.2. 2-trichloroethyl ester Under anhydrous conditions, 50 g of O-benzylhydroxylamine hydrochloride is suspended in 783 ml of acetonitrile. To the suspension is added 50.6 ml of pyridine followed by dropwise addition of 43.15 ml trichloroethyl chloroformate in 235 ml of acetonitrile.

The reaction is allowed to stir overnight at room temperature. The mixture is concentrated in~ vacuo and diluted with ethyl acetate. The organic layer is washed with 0.5M citric acid, water, saturated sodium bicarbonate, saturated sodium chloride, dried and concentrated in~ vacuo. The residue is purified by Kugelrohr distillation (bp 150 0 C at 0.5 mmHg.) to give g of the desired product.

-149- 1H NMR(CDC1 3 :6 7.52(s,1H); 7.4(m,5H); 4.93(s,2H); 4.80(s,2H).

CI-MS:m/z 315(H+NH 4 Exainple-71 ~Ethanethioic- acid trans- -S-[rtetrahvdro-5- r r fyhenvlmethoMv) U 2. 2.2 trichloroethoxvy) carbonyl I amino Imethyl 1 -3 -furanvi I ester To a OOC solution, under argon, of 1.0 g of product from Example 6, 1.69 g of product from Example 70, 1.49 g of triphenyiphosphine and 5.4 ml of tetrahydrofuran is added 0.988 g of diethyl azodicarboxylate in 1.4 ml of tetrahydrofuran. The reaction is stirred at room temperature for 48 hours, filtered and the filtrate concentrated in vacuo to give 5. 18 g of thick oil. The oil is purif ied by chromatography (Silica Gel: 15-25% ethyl acetate/ hexane) to give 0.805 g of the desired product.

Hi NHR(CDCl 3 :6 7.4(m,5H); 4.8-5.05(m,4H); 4.29(m,2H); 4.03(m,lH); 3.5-3.75(m,3H); 2.32(s,3H); 2.l(m,lH); 1.95 (i,M1).

IR(neat): 1719 and 1693 cm1 Examptle 72 Ethanethioic acid trans- -S-f 5-r r Acetyl (Dhenylinethoxy) amino inethyl 1 tetrahvdro-3 -furanvi 1 ester To a room temperature solution, under argon, of 0.188 g of product from Example 71 in 2.3 ml of glacial acetic acid is added 0.269 g of zinc dust. The reaction is stirred 10 minutes and 155 mnicroliter of acetic anhydride is added. The reaction is stirred at r -oom temperature overnight, diluted with ethyl acetate and filtered. The filtrate is concentrated in vacuo to give 0.110 g of the desired product.

H NMR(CDCl 3 7.39(s,5H); 4.89(d,2H); 4.31(m,2H); 4.05(m,lH); 3.78(m,1H); 3.64(m,lH); 2.32(s,3H); 2.13(s,31); 2.1(in,1H); IR(neat): 1684 and 1667 cm- 1 -150- CI-MS: m/z 324(MH+), 341(M+NH 4 Example 73 trans- r (Tetrahvdro-4-mercao-2-furanl i methvl (OhenylmethoXy) acetamide The title compound is prepared by the procedure of Example 16 using 0.390 g of product from Example 72, 0.580 ml of 25% sodium methoxide/methyl alcohol, 0.850 ml of tetrahydrofuran and 1.26 ml of 2N hydrochloric acid/isopropyl alcohol to give 0.205 g of the desired product.

1 H NMR(CDCl 3 :6 7.38(s,5H); 4.88(s,2H); 4.42(m,1H); 4.2 (m,lIH) 3.74 2H) 3.58 (m,l1H) 3.48 1H); 2.11(m,4H); l.98(m,1H); 1.73(d,lH).

***IR(neat): 1664 cm :15 CI-MS:m/z 282 Example 7.4 r4R-r3(3R*.5S* and 3S* SR*)4aloha.5beta.6beta(R*)11i.3 r r 5- [r rAcetyl (phenvlmethoxv) amino Imethyl 1 tetrahvdro- 3-furanvllthiol-6- (l-hvdroxvethvl) -4-methyl-7-oxo- 1-azabicyclor3 Olhept-2-ene-2-carboxylic acid (4-nitrophenyl~ methyl ester The title compound is prepared by the procedure of Example 17 using 0.190 g of product from Example 73, 0.401 g of product from Example 15, 5 ml of acetonitrile and 117.6 microliter of Hunig's base to give 0.286 g of the desired product.

1 H NMR(CDCl 3 8.22(d,2H); 7.65(d,2H); 7.38(s,5H); 5.22(m,lH); 4.87(d,2H); 4.2-4.45(m,4H); 3.62-3.88(m,5H); 3.28(m,2H); 1.95-2.15(m,5H); l.37(m,3H); 1.26(d-,3H).

IR(KBr): 3444, 1769 and 1706 cm-1 -151- Example 14R-[3(3R .5S and 3S .5R 14alpha.5beta.6beta(R I11- 3- r 5- Acetvl (PhenylmethoxV) aminolmethvl tetrahydro- 3-furanvy 1 thiol -6-(1-hdroxvethvl) -4-methyl-7-oxo- 1-azabicyclo[3.2.0olhept-2-ene-2-carboylic acid monosodium salt The title compound is prepared by the procedure of Example 18 using 0.272 g of product from Example 74, 0.0402 g of sodium bicarbonate, 2 ml of water, 11.3 ml of dioxane, and 0.110 g of palladium/carbon to give 0.059 g of the desired product.

1H NMR(D 2 0):6 7.34(d,5H); 4.85(m,2H); 4.15-3.3(m,2H); 3.35-3.83(m,10 2.95-3.25(m,3H); 1.72-1.92(m,6H); 15 1.04(d,3H); 0.9(d,3H).

Example 76 r4R-r3(3R 5S and 3S .5R )4alpha.Sbeta.6beta(R )11- 3- (Acetvlhvdroxyamino) methyl 1 tetrahvdro- 3-furanvllthiol-6-(l-hdroxvethvl)-4-methyl-7-oxol-azabicvcloF3.2.0lhept-2-ene-2-carboxylic acid monosodium salt A mixture of 0.010 g of product from Example 0.014 g of 10% palladium/carbon, and 1 ml of deuterium oxide is reduced in a Parr apparatus for 2 hours at 30 psi. The reaction solution is filtered and lyophilyzed to give 0.007 g of the desired product.

1H NMR(D 2 0):6 4.0-4.2(m,3H); 3.08-3.84(m,13H); 1.9-2.04(m,6H); 1.07(d,3H); 1.02(d,3H).

Example 77 cis-(+/-)-Tetrahvdro-4-mercapto-2-furamethanol The title compound is prepared by the procedure of Example 16 using 0.370 g of product from Example 9, 505 microliter of 25% sodium methoxide/methyl alcohol, 850 microliter of tetrahydrofuran and 1.1 ml of 2N hydrochloric acid/ isopropanol to give 0.209 g of the desired product.

-152- Hi NMR(CDCl 3 :6 3.55-4.1(m,5H); 3.23(m,lH); 2.23(m,lH); 1.64(m,lH); l.3(m,lH); 0.9(d,lH).

Example 78 r4R-r3(3R*.5R* and 3S .5S )4al~ha,5beta.6beta(R jj1- 6- (1-Hvdroxvethvl I-4-methyl-7-oxo-3- (hydroxmethyll -3-furanvllthiol-l-azabicvclor3 .2.01 hept-2-ene-2-carboxylic acid (4 -nitrophenvi Imethyl ester The title compound is prepared by the procedure of Example 17 using 0.080 g of the product from Example 77, 0.355 g of product from Example 15, 5 ml of acetonitrile and 7.3 microliter of Hunig's base to give 0.180 g of the desired product.

1 H NMR(CDCl 3 8.23(d,2H); 7.66(d,2H); 5.51(d,lH); 5.24(d,2H); 4.37(m,2H); 4.13(m,2H); 3.75(m,3H); 3.6(m,2H);_3.29(m,2H); 2.44(m,2H); 2.17(m,lH); .26-1.4(m,6H).* Exml 79 [r4R-r3(3R .5S- and 3S .5R )4alj~ha.5beta.6beta(R Ill- 206- (1-Hvdroxvethvl) -4-methivl-7-"cxo-3-F (hydroxymethyll -3-furanvllthiol-l-azabicyclor3.2 hept-2-ene-2-carboXylic acid monosodium salt The title compound is prepared by the procedure of Example 18 using 0.170 g of product from Example 78, 0.0328 g of sodium bicarbonate, 2 ml of water, 11.3 ml of dioxane, and 0.070 g of palladium/carbon to give 0.060 g of the desired compound.

1 H NMR(D 2 0):6 3.3-4.0(m,llH); 3.l8(m,1H); 2.25(m,lH); 1.22-l.5(m,1H); 0.94(m,6H).

cis -Tetrahvdro-5-rF(Rhenvlmethoxv) methyl- 3-furanthiol The title compound is prepared by the p rocedure of Example 16 using 1.89 g of product of Example 8, 0.392 g of sodium methoxide, 38.7 ml of methyl -153alcohol, and 38.7 ml of tetrahydrofuran to give 1.03 g of the desired product.

1H NMR(CDCl 3 7.28(m,5H); 4.55(m,2H); 4.12(m,lH); 4.02(m,H); 3.59(m,lH); 3.51(d2H); 3.31(m,1H); 1.74(d,H); l.59(m,lH).

IR(neat): 2859, 1496 and 1452 cm- Example 81 r4R-r3(3R .5S and 3S .5R )4alpha.5beta.6beta(R *11- 6-(l-Hvdroxvethvl)-4-methl-7-oxo-3-[rtetrahvdro-5r(Dhenlmethoxv)methvll-3-furanllthiol-1-azabicvclor3.2. Olhept-2-ene-2-carboxvlic acid (4-nitrophenyll methyl ester The title compound is prepared by the procedure of Example 17 using 0.921 g of product from Example 15, 0.347 g of product from Example 80, 271 microliter of Hunig's base and 200 microliter of acetonitrile to give 0.340 g of the desired product.

1 HNMR(CDCl 3 8.2(m,2H); 7.62(d,2H); 725(m,5H); 5.2-5.5(m,2H); 2.58(m,2H); 4.2(m,4H); 3.84(s,1H); 3.78(m,2H); 3.55(m,2H); 3.24-3.42(m,2H); 2.62(s,1H); 2.43-2.58(m,2H); l.6-1.85(m,2H); l.26(m,6H).

Example 82 [4R-[3(3R* 5S* and 3S .5R )4alpha5beta.6beta(R* 1- 6-(1-Hvdroxvethvl)-4-methvl-7-oxo-3-[ U(Dhenvlmethoxvmethv11-3-furanvllthio1-1-azabicvclo- [3.2.01hept-2-ene-2-carboxvlic acid monosodium salt The title compound is prepared by the procedure of Example 18 using 0.170 g of product from Example 81, 0.0277 g of sodium bicarbonate, 1.2 ml of water, 6.8 ml of dioxane, and 0.055 g of palladium/carbon to give 0.045 g of desired product.

1

HNMR(D

2 0):6 7.28(m,5H); 4.95(s,2H); 3.49-4.15(m,7H); 3.45(m,2H); 1.4-1.55(m,lH); 1.l(m,6H).

-154- Example 83 1.2.3.4-Tetrahvdro-2-methyl-3-thioxo-l.2.4-triazine- 5,6-dione Under anhydrous condition, 35 g of diethyloxalate is added, dropwise, to a vigorously stirred solution of 21 g of 2-methyl-3-thiosemicarbazide, 32.4 g of fresh sodium methoxide, and 750 ml of methyl alcohol. The resulting suspension is heated at 600C for 4 hours, stirred overnight at room teperature, and heated at 70°C for 15 hours. The white suspension is cooled to room temperature, 200 ml of ice water is added and the reaction concentrated in vacuo. The residue is cooled to 0°C and made acidic with 2N hydrochloric acid. The reaction mixture is 15 concentrated, ethyl alcohol is added and the suspension is heated to boiling. The white precipitate is collected, washed with hexane and dried to give 11 g of the crude product. Eight grams of the crude product is heated in methylene chloride and filtered while hot.

20 The collected solid is resuspended in methyl alcohol and a solution of 4N potassium-2-ethyl hexanoate is added. The mixture is cooled to 0°C and the precipitate collected. The solid is dissolvd in water, filtered, and 2N hydrochloric acid is added to the clear 0 C solution. The resulting precipitate is collected and dried to give 4.1 g of the pure product.

C3 NMR(CDCl 3 44.145, 150.115, 152.559, 169.786.

1H NMR(CDC1 3 13.11(s,1H); 12.5(br s,1H); 3.66(s,3H).

CI-MS:m/z 160(MH+).

Example 84 Ethanethioic acid trans-(+/-)-S-r5-r[(hexahvdro-2-methvl-5,6-dioxo-1.2.4triazin-3-vl thiolmethv11tetrahydro-3-furanyl1ester The title compound is prepared by the procedure of Example 23 using 0.551 g of product from Example 83 in 1 ml of tetrahydrofuran, 1.07 g of -155- W product from Example 22 in 1 ml of tetrahydrofuran, 3 ml of dimethylformamide, and 605 microliter of Hunig's base to give 0.357 g of the desired product.

1 H NMR(CDC 3 13.17(s,1II); 3.98-4.33(m,8H); 3.69(s,3H); 3.55(m,1H); 2.33(s,3H); 2.22(m,1H); 1.96 (t,1H).

IR(KBr): 1721 and 1672 cm- 1 Example trans- -Tetrahvdro-2-methyl-3 r r(tetrahvdro-4mercapto-2-furanvl)methvllthiol-1 .2.4-triazine- 5.6-dione The title compound is prepared'by the procedure of Example 16 using 0.357 g of product from Example 84,,281 microliter of 25% sodium methoxide/methyl alcohol and 500 microliter of tetrahydrofuran to give 0.148 g of the desired product.

1 H NMR(CDCl 3 9.37(bs,1H); 4. 55(s,lH); 4.26(m,3H); 3.83(s,3H); 3.6(m,2H); 2.34(m,2H); 2.06(m,2H); l.76(d,1H).

IR(KBr): 1722 and 1604 cm-1 Example 86 r4R-r3(3R .5S and 3S*.5R )4alPha.5beta,6beta(R V1- 3-r F5-Frr(Hexahvdro-2-methl-5.6-dioxo-1.2 .4-triazin- 3-vi) thiolmethvlltetrahvdro-3-furanvllthiol -6- (1-hvdroxvyethvl) -4-methyl-7-oxo-l-azabicyclor3 .2.01hent-2-ene-2-carboXylic acid (4-nitrorhenyl) methyl ester The title compound is prepared by the procedure of Example 17 using 0.207 g of product from Example 85, 0.0965 g of product from Example 15, 0.045 g of Hunig's base and 500 microliter of dimethylformamide to give 0.109 g of the desired product.

1 H NMR(CDC1 3 l0.3(bs,lH); 8.21(d,2H); 7.65(d,2H) 5.36(dd,2H); 4.47(m,lH); 4.2-4.4(m,4H); 4.15(m,lH); 3.99(m,1H); 3.81(s,3H); 3.71(m,1H); 3.48(m,lH); 3.35(m,1H); 2.6(bs,lH); 2.38(m,1H); 2.13(M,lH); 1.3(m,7H); 0.86(m,lH).

-156- Exam~le 87 r4R-r3(3R 5S* and 3S.5R*) 4alvha.5beta.6beta(R 1_11f(Hexahvdro-2-methl-5.6-dioxo-1.2 4-triazin- 3-vi)thiolmethvl1tetrahdro-3-furanvllthiol-6- (1-hvdroxvethvl)-4-methvl-7-oxo-1-azabicyclor3.2*01hept-2-ene-2-carboxvlic acid monosodium salt The title compound is prepared by the procedure of Example 18 using 0.10 g of product from Example 86, 0.0135 g of sodium bicarbonate, 2 ml of water, ml of dioxane, and 0.030 g of 10% palladium/carbon to t 0give 0.038 g of the desired product.

1 *H NMR(D 2 0):6 3.85-4.5(m,8H); 3.75(m,1H); 3.6(s,3H); 3.2(m,2H); l.8-2.2(m,3H); l.0(m,7H).

15 Example 88 F4R-[4alPha.5beta.6beta(R 11- 6-(l-Hydroxvethvl)-4-methvl-7-oxo-3-rFtetrahvdro-5- (hvdroxvmethvl)-3-furanvllthiol-l-azabicvclor3 .2.01hept-2-ene-2-carboxvlic acid monosodium salt 4444 20 The title compound is prepared by the procedure of Example 18 using 0.050 g of product from Example 56, 0.0096 g of sodium bicarbonate, 600 microliter of water, 3.4 ml of dioxane, and 0.030 g of palladium/carbon to give 0.028 g of the desired product.

1 H NMR(D 2 0):6 3.3-4.3(m,12H); 2.ll(m,2H); l.24(d,3H); 1.16(d,3H).

Example 89 Ethanethioic acid (C3R-cis) -S-F 5- rF r(2-bromoethoxvyhvdroxvhoshinvlloxyy1methylltetrahvdro-3-furanvllester A 0 C solution, under argon, of 0.520 g of product from Example 9, 0.53 ml of triethylamine, and ml of carbon tetrachloride is treated with 0.50 ml of 2-bromoethylphosphorodichloridate. The reaction is stirred at room temperature for 1.hour, filtered, and concentrated ijn vacuo. The residue is slurried in -157sodium acetate and tetrahydrofuran at room temperature for 4 hours.* The mixture is concentrated inf vacuo, the aqueous layer is acidified and extracted with 30% isopropyl alcohol and chloroform. The organic layers are combined, dried, concentrated in vacuo, and chromatographed (Silica Gel: ethyl acetate, 5-30% methyl alcohol/chloroform) to give 0.617 g of the desired product..

1 H NMR(MeOH-d 4 4.26(m,lH); 4.21-3.96(m,6H); 3.67(dd,lH,J=5.8Hz); 3.61(t,2H,J=5.BHz); 2.51(m,1H); .31(s,3H,COCH 3 l.72(m,lH).

MS (FAB) m/ z 3 63 (M 321(M+H-COCH 3 15.Example (2R-cis)-2-[r r F(4-Acetvlthio~tetrahvdro-2-furanv11methoxvl hvdroxyrhosphinvll1oxvl N. N-trimaethvlethanaminium hydroxide inner salt To a 0 0 C solution, under argon, of 0.508 g of product Example 89 in 15 ml of acetonitrile and 15 ml of chloroform is added 20 ml of anhydrous trimethylamine. The mixture is warmed at 70 C for 2.5 hours, under dry ice/acetone condenser, concentrated ijn vacuc, and slurried in 20 ml of methyl alcohol and 2.0 g of **Amberlyst A-2l for 0.5 hour. The suspension is 25filtered and the filtrate concentrated in vacuo. The residue is purified by chromatography (Silica Gel: 15-80% methyl alcohol/chloroform; 7:3:1 to 2:8:2 chloroform:methyl alcohol:water) to give 0.260 g of the desired product.

1 H NMR(MeOH-d 4 :6 4.28(br s,2H); 4.12(m,2H); 4.00-3.8(m,3H); 3.65(m,3H); 3.22(s,9H,CH 2 N(CH 3

Y

3 2.46(m,1H); 2.3(s,3H,COCH 3 l.7(m,1H).

HS(FAB):m/z 364(M+Na-H), 342(M+), 332(M+Na-HCOCH 3 -158- Examle- 91 r4R-r3(2R .4R *4alha.5beta.6beta( *IIl- 2-r rHvdroxvr r4-r r6-(l-hvdroxvethvli -4-methvl-2rr(4-nitrophenvi)methoxvlcarbonvi1-7-oxo-1-azabicvclor3.2.Olhelt-2-en-3-vlltioltetrahydro-2furanlllmethoxvlDhosphinvl1oxv-N.N.N-trimethvlethanaminium hydroxide. inner salt A solution of 0.190 g of Example 90 dissolved in 1.8 ml of anhydrous methyl alcohol at 0 0 C is treated with 130 microliters of 4.37M solution of 0 sodium methoxide. The reaction is stirred at 0 0 C for 1 hour and then concentrated in vacuo to give the crude thiol which is used in the next step.

The crude thiol is mixed at -300C with 0.393 g of product from Example 15A, dissolved in a 1:1 mixture of acetonitrile:dimethylformamide, and microliters of Hunig's base. The resulting solution is stirred at room temperature for 6 hours. The reaction solution is diluted with ethyl acetate to provide a foamy precipitate which is collected after trituration with ethyl acetate to give 0.387 g of the product mixture. A portion is purified to analytical purity using C reverse-phase chromatography.

.i 1 H NMR(MeOH-d 8.21(d,2H); 7.70(d,2H); 5.40(d,lH,J=13.9Hz) ;5.28(dlH,J=13.9Hz); 4.4-3.6(m,15H); 3.21(s,9H,N(CH 3 3 2.54(m,lH); l.90-l.65(m,lH); 1.30(m,6H).

Examile 92 r4R-r3(2R .4R )4alpha.5beta.6beta(R T11- 2-rrr r4-r r2-Carbox-6-(l-hydroxvethvl-4-methvl- 7-oxo-l-azabicvclor3.2.Olhent-2en-3-llthioltetrahydro-2-furanvllmethoxvlhvdroxyUhosphinl oxvl-N. N Ntrimethvlethanaminium hydroxide inner salt monosodium salt The title compound is prepared by the procedure of Example 18 using 0.387 g of product from Example 91, 0.046 g of sodium bicarbonate, 4 ml of -159water, 19 ml of dioxane, and 0.050 g of palladium/carbon to give 0.031 g of the desired product.

1 NNR(D 2 0):6 4.35-3.75(m,13H); 3.63(br s,2H); 3.39(ma,1H); 3.19(d,9H,N(CH 3 3 2.52(m,1H); 1.8-1.52(m,lH); 1.25(d,3H,CH 3 l.18(t,3H,CH 3 MS (FAB) :mi/z 5 5 3(M+Na) 5 31 Examiple 93 Ethanethioic acid (3S-trans) -S-r5-ir r(2-bromoethoxv~hvdroxv=hosphinyl i oxvlmethvll1-tetrahydro-3-furanyl lester The title compound is prepared by the procedure of Example 89 using 1.0 g of product from Example 6, 19 ml of carbon tetrachloride, 1.03 ml of triethyl- 15 amine, and 0.97 ml of 2-bromoethylphosphorodichlori- 0 to date to give 0.896 g of the desired product.

1 H NMR(CDCl 3 4.35(m,4H); 4.2-4.O(m,4H); 3.7(m,1H); 3.58(m,2H); 2.35(s,3H,COCH 3 2.28(m,lH); 2.O(m,1H).

NS(FAB):m/z 363(M+).

Example 94 (2R-trans) -l-r2-r ri r4-(Acetvlthiotetrahvdro-2furanyl Imethoxvl hvdroxvthosrhinvl 1 oXyj ethyl 1 pyridinium hydroxide inner salt of The title compound is prepared by the proce- 0. to: 25 dure ofExample 90 using 0.50 g of product from Example 93, 3 ml of pyridine, 4 g of Amberlyst-21, and 10 ml of methyl alcohol to give 0.233 g of the desired product.

1H NMR(DMSO-d 6 8 .l8(dd,2H,J=6.7 and 1.2Hz); 7.80(tt,lHJ=6.7 and 1.2Hz); 7.31(t,2H,J=6.7Hz); 3.78(br s,2H); 3.5(m,2H); 3.3B(dd,lH,J=9.l and 6.2Hz); 3.30(m,lH); 3.17(m,lH); 2.93(m,2H); 2.74(dd,1H,J=g.1 and 6.2Hz); l.5(s,3H,COCH 3 l.40(m,1H); l.l0(m,lH).

MS(FAB): 362(M+H).

-160r4R-r(2R *Example r4Rr32RAS )4aljha.5beta.6beta(R*)II- 1-rF2-rF HvdroxvF Ftetrahvdro-4- FF6- (l-hvdroxvethvl 54-methyl-2-rr(4-nitro~henyl~methoxv1 carbonvi 1-7-oxo-1azabicyclor3.2.0]he~t-2-en-3-yllthiol-2-furanvl]methoxv 1 Dhos~hinyll1oxv 1ethyll1 Dridinium hydroxide inner salt The title compound is prepared by the procedure of Example 91 using 0.209 g of product from Example 94, 130 microliter of 4.37M sodium methoxide, 2.06 ml of methyl alcohol, 0.406 g of product from Example 15A, 0.10 ml of Hunig's base to give 0.150 g of **.the desired product.

15 1 H NMR(MeOH-d 6 9.0(d,2H); B.60(t,1H); 8.24(d,2H); 8.l1(t,2H); 7.69(d,2H); 5.38(g,2H,CH Ar); 4.30(br 3.20(m,lH);. 2.95(m,lH); 2.18(m,1H); l.19(d,3H); 1.12(in, 3H).

20 Example 96 r4R-r3(2R*,4S*)4alr~ha.5beta.6beta(R*fll- Il- r2 rr F4 -r r2 -C arbov- 6 1-hvdroxveth 1) 4 -ethy 1-7 **oxo a zab icvclo r3. 0 1het 2 -en- 3 -y11 th io 1tetra hydro 2-furanyl lmethoxvlhvdroxyphosphinyll1oxyl ethyl 1 125 pyridinium hydroxide .inner salt monosodium salt .:The title compound is prepared by the procedure of Example 18 using 0.150 g of product from Example 95, 0.025 g of sodium bicarbonate, 3 ml of water, 9 ml of dioxane and 0.030 g of palladium/carbon to give 0.0786'g of the desired product.

1 H NMR(D 2 0) :6 8.98(d,2H,J=5.6Hz); 8.69(m,lh); 8.2(t,2H,J=6.5Hz); 4.42(br s,2H); 4.37-4.22(m,5H); 4. 00 (m,l1H) 3.82-3.7 (m,4H) 3.53 (br m,lIH) 3.45 (t,l1H) 2.19(m,lH); 2.05(m,lH), 1.38(d,3H); l.29(d,3H).

MS(FAB): 551(M+H).

-161- (tDimethoXyohos~hinvli hvdroxvacetic Acid (4-nitro~henvi methyl ester To a mixture of 4.32 g of p-nitrobenzyi glyoxalate and 2.0 ml of dimethyiphosphite in 25 ml of benzene is added a catalytic amount of p-toluenesulfonic acid. The reaction is heated at reflux temperature for 1.5 hours. The formed water is removed using a Dean-Stark trap. After cooling, the solvent is removed in~ vacuo and the resulting crystals are slurried in ethyl acetate and collected to give 3.48 g ~of the desired product.

1 H NMR(CDCl 3 :6 8. 3(d, 2H) 7.73 2H) 5.42 (AB q, 2H); 4.91(d,lH); 3.75(dd,6H).

Ref.: E. Nakamnura, Tet. Let., vol. 22. p 663 (1981).

Example 98 (Dimethoxyphosphinyl) r r(1.1-dimethvlethyl) dimethylsilylioxvi acetic acid (4-nitrophenvl)methyl ester To a mixture of 3.48 g of product from Example 97 and 12 ml of dimethylformamide is added 1.86 g of t-butyldimethylsilyl chloride and 1.86 g of imidazole. After stirring the reaction at room temperature for 2 hours, the mixture is diluted with .25 50% ethyl acetate/diethyl ether, washed 5 times with water, once with saturated sodium bicarbonate and once with saturated sodium chloride. The organic layer is dried, filtered and concentrated in vacuo to give 3.90 g of the desired silylated product.

1H NMR(CDCl 3 :6 8.23(d,2H); 7.59(d,2H); 5.35(AB q,2H);4.71(d,lH); 3.84(d,3H); 3.61(d,3H); O.91(s,9H); 0.ll(s,3H); 0.09(s,3H).

-162- IF Example 99 ethyll1-a-methvl-4-oxo-2-azetidineacetic- acid Ten grams of (3S,4S)-3[(R)-2.-(t-butylciimethylsilyloxy) ethylJ -l-carboxyethylj -2-azetidinone is dissolved, under argon, in 100 ml of anhydrous dimethylacetanide and treated with 10.46 g of t-butyldinethylsily. chloride and 14.14 g of triethylamine. The reaction is stirred overnight at room temperature followed by dilution with hexane. The organic layer is washed with water and saturated sodium chloride, dried and concentrated in vacuo. The residue is treated with 100 ml of tetrahydrofuran andlOO0 ml of 15 saturated sodium bicarbonate. The mixture is stirred at room temperature for 2.5 hours, diluted with 200 ml of diethyl ether and the layers separated. The organic layer is washed with saturated sodium chloride, dried .and concentrated in vacuo to give 19 g of product as a yellow oil.

H1 M(Dl3: 6. 62 (bs,l1H) 4. 0(m,l1H) 3. 54 (t,l1H); 3.27(dd,lH); 2.83(m,lH); l.18(d,3H); 1.14(d,3H); O.85(m,18H); O.09(m,12H).

xamrple 100 r 3S- r 3a* S. S1 i- r -Dimethylethl) dimethlsilvl 1-3-r I- r F -dimethylethvl) dimethylsilyl oLcI ethyl 1 (2 -Hvdroxy- 1-methvl ethyl) -2-azetidinone To a 0 C solution, under argon, of 25 g of product from Example 99 dissolved in 150 ml of anhydrous tetrahydrofuran is added 6.31 ml of borane-methyl sulfide complex. The reaction mixture is heated at reflux temperature for 1 hour, cooled to room temperature and concentrated inf vacuo. The residue is purified by chromatography (silica gel: 20% ethyl acetate/hexane) to give 20.45 g of the desired product as a colorless oil.

-163l H NMR(CDCl 3 3.05(m,1H); 3.75(m,1H); 3.55(mlH); 3.46(m,lH); 3.06(dd,lH); 1.99(m,1H); 1.85(m,lH); 1.27(d,3H); 0.95(d,3H); 0.88(m,18H); 0.097(m,12H).

Example 101 r2R-[2a(R .3B(R* 1-l-r(l.1-Dimethylethvl dimethvlsilyll-3-rl-r (1.1-dimethlethvl)dimethvlsilvlloXvI ethyll-a-methyl-4-oxo-2-azetidineacetaldehyde A mixture of 14.3 g of product from Example 100 dissolved in 75 ml of methylene chloride is treated with 8.47 g of pyridinium chlorochromate, 3.5 g of sodium acetate and 5 g of diatomaceous earth. The reaction is heated at reflux for 30 minutes, diluted with 400 ml of diethyl ether and filtered through a pad of hydrous magnesium silicate. The solid residue is triturated with diethyl ether and diethyl ether passed through a pad of hydrous magnesium silicate. The combined filtrates are concentrated in vacuo. the residue is purified by chromatography (silica gel: to 25% ethyl acetate/hexane) to give 8.95 g of the desired product as a tan solid.

1 H NMR(CDCl 3 9.88(s,1H); 4.09(m,lH); 3.82(t,lH); 2.96(m,LH); 2.79(m,1H); 1.25(d,3H); 1.14(d,3H); O.91(s,9H); 0.89(s,9H); O.09(d,12H).

Example 102 r2S-[2a(S*-E).38(S* 1 4-ri-F(l.1-Dimethlethvl)dimethlsilll-3-ri-rr(1.1dimethylethvl)dimethvlsiivlloxvlethvll-4-oxo-2azetidinll-rr(l.1-dimethvlethvl)dimethvlsilvjloxvl-2pentenoic acid (4-nitr~henvl)methl ester and r2S-r2a(S -Z)-38(S 11- 4-rl-rUl,1-Dimethvlethvl)dimethvlsilvll-3-rl-rr(l.idimethvlethvl) dimethylsili 1 oxl ethyl 1 -4-oxo-2azetidinvl-rr(.l-dimethvlethvldimethvlsilvloXyl-2- Dentenoic acid (4-nitrophenjAmethyl ester A mixture of 4.76 g of product from Example 98 in 30 ml of dry tetrahydrofuran, cooled to -400C, -164under argon, is treated with 12 al of 1M solution of lithium bis(trimethylsilyl)amuide. After 5 minutes, 4.08 g of product from Example 101 in 5 ml of tetrahydrofuran is added dropwise and the temperature of the cooling bath is allowed to warm gradually minutes) to 0 0 C. The reaction is diluted with diethyl ether and quenched with water. The organic layer is washed with water and saturated sodium chloride, dried and concentrated in~ vacuo. The residue is purified by filtration through silica gel eluting with 10% ethyl acetate/hexane to give 3.97 g of the product as a 88:12 mixture of E:Z isomers.

1 H NR(CDCl 3 isomer 6 8.2(d,2H); 7.6(d,2H); 5.27(s,211); 4.07(m,lH); 3.64(m,lH); 3.52(m,lH); 2.88(m,lH); l.27(d,3H); 1.06(cl,3H); .92(s,9H); O.91(s,9H); 0.89(s,9H); 0.21(s,3H); O.1(s,3H); 0.09(s,3H); O.0B7(s,3H); O.07(s,3H); a O.06(s,3H).

Z isomer 8 8.2(d,2H); 7.49(d,2H); 6.07(d,lH); 5.28(4,2H); 4.09(m,1H); 3.56(m,1H); 3.18(za,1H); *2.93(dd,lH); 2.5(d,3H); l.08(d,3H); O.95(s,9H); 0.92(s,9H); 0.89(s,9H); O.17(s,3H): 0.165(s,3H); O.16(s,3H); O.14(s,3H); O.09(s,3H); 0.06(s,3H).

12S-r2arS (R I and S*(S*113B(S*VI1- B-Bromo-l-r (1.1-Dimethylethvl) dimethvlsilvll-3ri-rrF(l.l-dimethlethy)dinethlsivlyloxv1ethl..

aamma-methvl-a. 4-dioxo-2--azetidinebutpnoic acid (4 -nitrophenyllnethyl ester To a cooled solution, under argon, of 0.0381 g of product from Example 102 in 0.5 ml of tetrahydrofuran is added 0.004 ml of bromine. The reaction is stirred for 15 minutes, quenched with sodium thiosulf ate and diluted with ethyl acetate. The organic layer is washed with saturated sodium chloride, dried and concentrated J 11 vau The residue is purified by flash chromatography (silica gel: 20% ethyl -165- I acetate/hexane). The pure bromide, as a mixture of diastereomers, 4:1, is obtained in quantitative yield.

lH NMR(CDC13):6 8.26(d,2H); 7.59(d,2H); 5.48-5.36(AB q and d,3H); 5.05(d, minor isomer); 4.12-4.02(m,1H); 3.67(t,1H); 3.43(m,1H); 2.87(m, minor isomer); 2.58(m,1H); 1.25(d,3H); 1.18(d,3H); 1.08(d, minor isomer); 0.98(s, minor isomer); 0.91(s,9H); 0.89(s,9H); 0.88(s, minor isomer); 0.33, 0.26, 0.07(3s, minor isomer); 0.21(s,3H); 0.13(s,3H); 0.1(s,3H); 0.06(s,3H).

Example 104 (also Example 56) [r4R-r3(3R.5S* and 3S* 5R )4a.58.6f(R 6-(l-Hvdroxvethyl)-4-methyl-7-oxo-3-rrtetrahydro-5- (hvdroxvmethvl)-3-furanvl1thiol-l-azabicclor3 .2.01- 15 hept-2-ene-2-carboxvlic acid (4-nitrophenvl)methyl ester A solution, under argon, of 0.5 g of product from Example 103, 0.119 g of product from Example and 7 ml of dry tetrahydrofuran is treated with 0.124 ml of triethylamine. The reaction is stirred for minutes, quenched and diluted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride, dried and concentrated in vacuo. The residue is dissolved in 5 ml of acetonitrile and treated with 25 10 ml of 10% aqueous hydrofluoric acid. After minutes, the reaction is quenched by pouring into rapidly stirring saturated sodium bicarbonate/ethyl acetate. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo to give the crude deprotected P-lactam, which is used in the cyclization step without further purification.

The crude P-lactam, under argon, is dissolved in 5 ml of dry tetrahydrofuran amd treated with 4.46 ml of 1M solution in methylene chloride of titanium tetrachloride. The reaction is stirred at room temperature for 2 hours and poured into rapidly stirring saturated sodium bicarbonate/ethyl acetate.

-166- W The organic layers is washed once with water and twice with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel: 20% ethyl acetate/hexane) to give 0.142 g of the desired product as a white solid.

1 H NMR(CDCl 3 :6 8.22(d,2H); 7.67(d,2H); 5.22(d,1H); 4.28(m,4H); 3.8(m,2H); 3.7(m,1H); 3.55(m,1H); 3.32-4.1(m,1H); 3.3(m,1H); 2.3(m,lH); 2.18(bs,2H); l.98(m,1H); 1.36(d,3H); l.28(d,3H).

Example 105 (also Example 78) r4R-r3(3R .5R and 3S*.5S 1_4a.5B.68l(R )11- 6- (1-Hvdroxvethvl)-4-methyl-7-oxo-3- r (hvdroxymethyl) -3-furanyllthiol-l-azabicyclor3 .2.01 hept-2-ene-2-carboxvlic acid (4-nitrophenyl) methyl -ester The title compound is prepared by the procedure of Example 104 using 0.166 g of product from Example 103, 0.0396 g of product from Example 77, 2.3 ml of dry tetrahydrofuran and 0.0413 ml of triethyl- .amine to obtain the crude P-lactam. The subsequent cyclization uses the above product, 1.48 ml of lM solution in methylene chloride of titanium tetrachloride and 1.6 ml of dry tetrahydrofuran to give 0.053 g of the desired product as a white solid.

1H NMR(CDCl 3 :6 8.23 2H) 7.66 2H) 5.51 1H); 5.24(d,lH); 4.37(m,2H); 4.13(m,2H); 3.75(m,3H); 3.6(m,2H); 3.29(m,2H); 2.44(m,2H); 2.17(m,lH); 1. 2-1. 4(m, 6H) Example 106 (4R-trans) (2-Prolpenyl) 3. 2-dioxoaborolane-4 dicarboxyl ic acid b is (I -methyl ethyl) ester To 400 ml of diethyl ether, under anhydrous conditions at -78 0 C, is added simultaneously, with vigorous stirring, 475 ml of 1M4 in diethyl ether allylmagnesium bromide and 60 ml of triethyl borate in 400 ml of diethyl ether. The reaction is stirred at -167- S-78OC for 3 hours; followed by the removal of the cooling bath and dropwise addition (over 2.5 hours) of 450 ml of 2N hydrochloric acid. The layers are separated and the aqueous layer is extracted 4 times with a mixture of diethyl ether:methylene chloride The organic layers are combined, dried and concentrated in vacuo to approximately 100 ml. The residue is redissolved in 400 ml of diethyl ether, treated with 77.8 g of (-)-diisopropyl L-tartrate, and stirred overnight at room temperature under argon. Ten grams of magnesium sulfate is added and the mixture stirred for 20 minutes. The reaction is concentrated in o vacuo to give 90 g of crude product. The residue is purified by Kugelrohr distillation (100 C to 110oC) to 15 give 39.35 g of product.

IH NMR(CDCl3) :6 5.82-5.96(m,1H); 4 97 -5.16(m,4H); 4.78(s,2H); 1.92(d,2H); 1.3(d,12H).

Example 107 SS)-l-Phenylmethoxv-4-penten-2-ol To a mixture of 40.0 g of product from Example 106 in 560 ml of dry methylene chloride with g of 4A molecular sieves, under anhydrous conditions at -78°C, is added 11.2 g of product from Example 1 in 9.6 ml of methylene chloride. The reaction is stirred vigorously while maintaining the temperature at -780C for 16 hours. The reaction is filtered, the molecular sieves are washed with methylene chloride and the aqueous layer is extracted with methylene chloride.

The combined organic layers are concentrated in vacuo and the residue dissolved in 400 ml of diethyl ether.

The diethyl ether layer is stirred for 24 hours with 600 ml of 1M potassium hydroxide. The aqueous layer is extracted with diethyl ether. The combined organic layers are washed with saturated sodium bicarbonate and concentrated in vacuo. The crude residue is purified by Kugelrohr distillation (100°C to 1100C) to give 13.4 g of the desired product.

-168- 1 H NMR(CDC1 3 :6 7.35(s,5H); 5.8(m,lH); 5.l(m,2H); 4.55(s,2H); 3.85(m,lH); 3.48(dd,1H); 3.35(dd,lH);.

2.68(bs,lH); 2.25(t,2H).

Examl 2. 5-Anhvdro-1 .3-dideoxv-l-iodo-D-threo-Rentitol and 2. 5-Anhydro- 1.3-dideoxv-l-iodo-D-ervthro-Rentitol To a 3 0 C vigorously stirring solution of 13.4 g of product from Example 107 dissolved in 262 ml of diethyl ether and 89 ml of water is added, in one portion, 8.73 g of sodium bicarbonate followed by 26.21 g of iodine. The reaction is stirred at room temperature for 1.5 hours. Saturated sodium sulfite is added slowly with vigorous stirring. The layers are separated and the organic layer is dried and ~.:concentrated in vacuo. The residue is purified by chromatography (silica gel: 20-to 50% ethyl acetate/hexane) to give 1.3 g of the cis-isomer(A) and 4.7 g of the trans-isomer(B).

1 HNMR(CDCl 3 cis-isomer 6 4.51-4.55(m,lH); 4.04-4.13(m,lH); 3.91-3.96(dd,IH); 3.78-3.83(dd,lH); 3.33-3.43(m,2H); 3.05(bs,lH,OH); 2.3-2.39(m,lH); l.89(m,0.5H); 1.79(m,0.5H).

1 H NMR(CDC1 3 trans-isomer 6 4. 54 57 (m,l1H); a 4.17-4.26(m,1H); 4.04-4.0B(m,lH); 3.80-3.85(m,1H); 3.27-3.31(m,2H); 2.68(bs,1H,OH); 2.21-2.2(m,1H); l.74-l.84(m,1H).

Example 109 2. 5-Anhdro-l-azido-1. 3-dideoxv-D-threo-r~entitoI To a mixture of 1.25 g of product from Example 108(cis-isomer) in 5 ml of dry dimethylformamide is added 0.537 g of lithium azide. The reaction is heated at 70 0Cfor 2 hours and then concentrated in vacuo. The residue is purified by chromatography (silica gel: diethyl ether) to give 0.642 g of the desired product.

IR(neat): 2100 c -169- 1 H NMR(CDCl 3 :6 4.4-4.5(bs,1H); 4.l-4.2(m,lH); S 3.73-3.91(m,3H); 3.45(m,2H); 2.23-2.36(m,1H); 1.71-1.76(m,O.5H); 1.66-1.71(m,0.5H).

Example 110 2. 5-Anhydro-l-azido-1. 3-dideoxv-D-threo-RentitoI 4- (tri fluoromethanesul fonate I The title compound is prepared by the procedure of Example 22 using 0.642 g of product from Example 109, 0.8 ml of trifluoromethanesulfonic anhydride and 0. 38 ml of pyridine to give 0. 890 g of pure product after chromatography (silica gel: diethyl ether).

IR(neat): 2104 cm 1 1 H NMR (CDCl 3 5. 5(m,l1H) 4.3 2H); 3. 9(m,1IH); 4* 3) 3.4(m,2H); 2.6(m,1H); 2.2(m,lH).

to Example 111 1. 4-Anhvdro-5-az ido-3 .5-dideox-2-thio-D-ervthropentitol 2-acetate *To an argon purged solution, cooled to 0 0C., of 0.89 g of product from Example 110 dissolved in ml of acetonitrile is added, in one portion, 0.406 g of potassium thioacetate. The reaction is. stirred at 0 C for 10 minutes and then allowed to warm to room temperature, slowly over 1.5 hours. The mixture is S..25 concentrated in vacuo and the residue purified by chromatography (silica gel: 30% ethyl acetate/hexane) to'give 0.422 g of the desired product.

1 H NMR(CDC1 3 :6 4.25-4.35(dd,1H); 4.35-4.25(m,lH); 4.0-4.07(m,lH); 3.6-3.69(dd,lH) 3.47-3.40(dd.,l); 3.30-3.22(dd,lH); 2.34(s,3H,Me); 2.25-2.15(m,lH); 2.l-1.92(m,lH).

IR(neat): 2100(N 3 and 1692(SAc)cm-1 Example. 112 1. 4-Anhvdro-5-azido-3 .5-dideoxv-2-thio-D-erythro- Reni The title compound is prepared by the procedure of Example 16 using 0.420 g of product from -170- W Example ill, 0.48 ml of 25 wt sodium methoxide/methyl alcohol to give 0.216 g of the desired product after chromatography (silica gel: 30% ethyl acetate/hexane).

1 Hi NMR(CDCl 3 4.25-4.4(m,1H); 4.18-4.24(dd,lH); 3.78-3.86(dd,O.5H); 3.54-3..66(m,lH); 3.4-3.54(m,1.5H);- 3.18-3.29(m,IH); 2.15-2.25(m,1.H); l.88-l.98(m,lH); 1.78 lH,SH).

Example 113 2-r4R-r4a.5B.6B(R 1. 4-Anhvdro-5-azido-3 .5-dideoxv-2-S- r6- (l-hvdroxvethyl) -4-methvl-2- r (4-nitronhenvl) methoXvl carbonyl 1- 7-oxo-l-azabicvclo[3.2. 01-hexpt-2-en-3 -vll-2-thio- D-e hro-iRentitol 15 The title compound is prepared by the proce- *dure of Example 17 using 0.215 g of product from Example 112, 0.883 g of product from Example 15 and 198 microliter of Hunig's base to give 0.288 g of the desired product after chromatography (silica gel: 20 ethyl acetate/hexane).

IR(neat): 2101, 1769 and 1709 cm 1 1H NMR (CDCl 3 1 8. 25 2H) 7. 7(d, 2H) 5. 5(d, 1H); 5.3(d,lH); 4.15-4.3(m,4H); 3.7-3.85(m,lH); V~too 253.57-3.66(m,1H); 3.26-3.5(m,2H); 3.15-3.26(m,2H); 2.57(bs,lH,OH); 2.08-2.25(m,1H); l.85-2.05(m,lH); l.28(d,3H,Me);. 1.21(d,3H,Me).

Example 114 2-r4R-r4a.5B,6fi(R )11- 5-Amino-1, 4-anhvdro-2-S- (2-carboxv-6- (1-hvdroxvethvl) 4-methl-7-oxo-l-azabicyclo[r3. 2. Olheyt-2-en-3-vl) dideoxv- 2-thio-D-erthro-pentitoI The title compound is prepared by the procedure of Example 18 using 0.288 g of product from Example 113, 0.198 g of 10% palladium/carbon, 12 ml of phosphate buffer (pH and 35 ml of dioxane to give 0.070 g of the desired product after chromatography (C 1 8 reverse phase silica gel plates: 95/5 water/ethyl alcohol).

-171- 1 ~H NMR (D 2 0):6 4.45-4.59(m#lH); 4.22-4.38(m,3H); 3.98-4.11(m,1H); 3.82-3.9(m,lH); 3.4-3.58(m,2H); 3.2-3.3(m,lH); 3.08-3.18(m,lH); 2.12-2.35(m,2H); l.36(d,3H,Me); 1.27(d,3H,Me).

Example 115 2. 5-Anhvdro-1-azido-1. 3-dideoxv-D-erythro-Dpentitol The title compound is prepared by the procedure of Example .109 using 2.3 g of product from Example 108 (trans-isomer), 0.988 g of lithium azide and 4 ml of dimethylformanide to give 1.42 g of the desired Soo.%product after chromatography (silica gel: diethyl ether).

0 :-1 IR(neat): 2100 cm.

Hi NMR(CDCl 4.56(m,lH); 4.35-4.45(m,1H); 6*3 3.98-4.12(dd,lH); 3.78-3.87(dd,1H); 3o47-3.55(dd,1H); 3.2-3.3(dd,lH); 2.65(bs,lH,OH.); 1.95-2.05(m,lH); .83-1.95(m,1H).

Examp~le 116 2. 5-Anhvdro-l-azido-1. 3-dideoxv-D-ervthro-pentitol 6e~ 4- (trifluoromethanesulfonate 6646The title compound is prepared by the procedure of Example 22 using 1.42 g of product from Example 115, 1.8 ml of trifluoromethanesulfonic anhydride and S2 0.85 ml of pyridine to give 2.22 g of the desired product after chromatography (silica gel: 75% ethyl acetate/hexane).

IR(neat): 2104 cm-1 1 H NMR(CDC 3 4.38-4.48(m,H); 4.1-4.27(m,2H); 3.58-3.68(dd,lH); 3.22-3.32(dd,lH); 2.3-2.4(m,lH); 2.16-2.26(m,2H).

Example 117 2 .5-Anhvdro-l-azido-1. 3 -dideo-xv-4-thio-L-threo-D~entitoI The title compound is prepared by the procedure of Example 111 using 2.22 g of product from Example 116, 1.01 g of potassium thioacetate and 25 ml of acetonitrile to give 0.90 g of the desired produc .t -172after chromatography (silica gel: 30% ethyl acetate/hexane).

IR(neat): 2100 and 1692 cm-1 1liH NMR(CDC 3 4.1-4.2(m,2HI); 3.95-4.08(m,lH); 3.7-3.78(dd,lH); 3.4-3.50(dd,lH); 3.25-3.35(dd,lH); 2.42-2.53(m,lH); 2.34(s,3H,Me); l.63-l.74(m,1H).

Exmpl 1 2. 5-Anhydro7I-azido-l 3-dideoxy-4-thio-L-threo-Dentitol The title compound is prepared by the procedure of Example 16 using 0.90 g of product from Example 117, 1.1 ml of 25 wt. sodium methoxide/methy. alcohol and 15 ml of tetrahydrofuran to give 0.441 g of the desired product after chromatography (silica gel: 15ethyl acetate/hexane).

IR(neat): 2570 and 2099 cm 1 H NMR(CDCl 3 4.O-4.25(m,2H); 3.57-3.67(m,1H); 3. 25-3. 5(m, 3H) 2.4-2.55(m,1H); l.82(d,lH,SH); 6-1. 7 5 (in, 1H).

Examiple 119 2-f4R-r4a.5B.66(,R )11- 2.5-Anhvdro-1-azido-.3-dideox-4-Sr6(..hvdroxy.

ethyl) -4-methvl-2-r r (4-nitrophenvlimethoxvlcprbonyl 1- 7-oxo-1-azabicvclor3 01hept-2-en-3-vll-4-thio-L- 25 threo-Pent itol The title compound is prepared by the procedure of Example 17 using 0.441 g of product from Example 118 in 10 ml of acetonitrile, 1.8 g of product from Example 15 in 10 ml of acetonitrile and 0.41 ml of Hunig's base to give 0.747 g of the desired product after chromatography (silica gel: 75% ethyl acetate/hexane).

IR(KBr): 2101, 1769 and 1708 cm- 1 1 H NMR(CDCl 3 8.25(d,2H); 7.7(d,2H); 5.55(d,lH); 5.28(d,1H); 4.12-4.4(m,4H); 3.8-3.95(m,2H); 3 .32-3.58(m,4H); 3.03(bs,lH,OH); 2 4 8 -2.65(m,1H); l.85-l.96(m,0.5H); l.68-1.78(m,0.5H); l.42(d,3H,Me); 1.35 3H,Me).

-173- Example 120 2- 4R-r4a. .5.68(R* 1 1l-Amino-2.5-anhvdro-4-S-(2-carboxv-6-(l-hydroxvethyl) 4-methvl-7-oxo-l-azabicvclor3.2.01 hept-2-en-3-vl) 3dideoxv-4-thio-L-threo-pentitol The title compound is prepared by the procedure of Example 18 using 0.747 g of product from Example 119, 0.513 g of 10% palladium/carbon, 30 ml of sodium phosphate buffer (pH 7) and 90 ml of dioxane to give 0.153 g of the desired product after chromatography (C 18 reverse phase silica gel plates: aqueous ethyl alcohol).

IH NMR(D 2 0):6 4.02-4.35(m,4H); 3.72-3.94(m,2H); 3.26-3.43(m,2H); 3.05-3.94(m,2H); 2.5-2.7(m,lH); 1.7-1.8(m,0.5H); 1.5-1.6(m,0.5H); 1.2-1.25(d,3H,Me); 1.10-1.17(q,3H,Me).

Example 121 cis and Tetrahvdro-5-(iodomethvl)-3-furanol The title compound is prepared by the proce- S'dure of Example 108 using 19.2 g of product from Example 2 in 385 ml of diethyl ether and 128 ml of water, 12.52 g of sodium bicarbonate and 37.56 g of 25 iodine to give 13.16 g of the product as a mixture of isomers.

Example 122 cis- -Tetrahvdro-5-(iodomethyl) -3-furanol trans-(+/-)-Tetrahvdro5-(iodomethvl)-3-furanol A 1.6 g portion of the mixed isomer product of Example 121 is purified by chromatography (silica gel: 30% ethyl acetate/hexane) to give 0.341 g of Isomer A and 0.994 g of Isomer B.

Isomer A(cis) CI-MS: m/z 246 (M+NH 4 Isomer B(trans) CI-MS: m/z 246 (M+NH 4 -174- Examnle 123 trans- r (Ethvlaraino) methyl I tetrAhvdro,-3--furanol A solution of 4.0 g of product from Example ~121, Isomer B, and 20 al of 70% aque ous, ethylazine is stirred at room temperature, in a pressure bottle, for hours. The reaction is concentrated in Yfluo and the residue purified by chromatography (silica gel: methyl alcohol/chloroform) to give 3.2 g of the desired product.

1H NMR(CDCl 3 5.1(bs,H 2 0,NH+OH); 4.58-4.75(m,2H); 4.2-4.26(dd,lH); 3.39-3.99(m,lH); 3.l-3.5(m,4H); 2.25-2.35(m,1H); 2.O-2.l(m,1H); 1.55(3H,Me).

5CI-MS: m/z 146 Example 124 trans- -Ethyl r (tetrahvdro-4-hydroxv-2-furanvl methyllcarbamic acid (4-nitrophenvlmethyl ester :Under anhydrous conditions with an argon purge, a solution of 3.2 g of product from Example 123 in 10 ml of dry tetrahydrofuran and 2.7 ml of Huning's base is cooled to -5 0C. The mixture is treated with 4.75 g of 4-nitrobenzyl chioroformate in 20 ml of methylene chloride while maintaining the temperature at 25-50C. The reaction is stirred at -5 C f or 2 hours; followed by concentration in vacuo. The residue is purified by chromatography (silica gel: 75% ethyl acetate/hexane) to give 2.63 g of the desired product.

1 H NMR(CDCl 3 :6 8. 2(d, 2H) 7. 6(d, 2H) 5.o3 2H); 4.6(m,lH); 4.28-4.42(m,lH); 3.92-4.02(dd,lH); 3.7-3.78(d,lH); 3.5-3.6(dd,1H); 3.38-3.49(m,2H); 3.2-3.3(dd,1H); 2.08(bs,lH,OH); l.92-2.05(m,lH); l.6-l.77(m,1H); 1.16(t,3H).

-175- Exml 2 trans- -Methanesulfonic acid 5-rFrEthvl r[r( 4 -nitro- Rhenvl methoxyl1carboni aminol1methyll1tetrahvdro-3 furanvi ester To a -5 0 C solution, under argon, of 2.63 g of product from Example. 124, 1.7 al of triethylamine and 18 ml of methylene chloride is added, dropwise, 0.94 ml of methanesulfonyl chloride. The reaction is stirred at -5 0 C for one hour, washed successively with saturated sodium chloride, 5% sodium bicarbonate and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel: 75% ethyl acetate/hexane) to give 3.18 g of the desired product.

1 5.25(s,2H); 4.23-4.40(m,lH); 4.08-4.19(m,lH); 3.34-4.02(m,lH); 3.22-3.62(ma,4H); 3.05(s,3H,Me); 2.28-2.38(dd,1H); 1.75-l.95(m,lH); 1.16(t,3H,Me).

Example 126 S 20 cis-(+/-)-Ethanethioic acid rethvlrr(4-nitrorhenyl)methoxvlcarbonvllaminolmethyll tetrahvdro-3-furaivl ester A solution of 3.18 g of product from Example 125 in 10 ml of toluene and 10 ml of dimethylformamide is purged with argon. To this solution is added 1.36 g of potassium thioacetate and the reaction mixture is heaedovernight at 650 C in an oil bath with continuous stirring. The reaction mixture is cooled and diluted with 70 ml of water and 80 ml of toluene. The organic phase is washed w ith water, dried and concentrated in vacuo to give a dark yellow oil. The residue is purified by chromatography (silica gel: 50% ethyl acetate/he xane) to give 2.283 g of the desired product.

IR(neat): 1698 cm 1 1H NMR(CDC1 3 8.2(d,2H); 7.6(d,2H); 5.25(s,2H); 4.02-4.l8(m,2H); 3.9-4.02(m,1H) 3.65-3.75(m,1H); 3.5-3.6(dd,lH); 3.38-3.5(m,4H); 3.2-3.3(dd,lH); -176- 2.37-2.52(m,lH); 2.32(s,3H,He); l.45-l.6(m,1H); 1. 16 3H, Me) Examiple 127 c-is- -Ethvl r tetrahydro-4-mercaipto-2-furanvl lmethvllcarbamic acid (4-nitronhenyllmethyl ester A 0-5 0 C solution, purged with argon, of 0.737 g of product from Example 126 in 5 ml of methyl alcohol is treated with 0.525 ml of 4N sodium hydroxide. The reaction is stirred for 10 minutes, acidified with 2.17 ml of 0.968N hydrochloric acid and diluted with 20 ml of ethyl acetate. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel: 50% ethyl acetate/hexane) to give 0.483 g of the desired product.

1 H NMR(CDCl 3 8.2(d,2H); 7.6(d,2H); 5.3(s,2H); 3): 4.02-4.23(m,2H); 3.25-3.65(m,6H); 2.4-2.55(m,lH); 1.75-l.8(d,lH); l.45-l.6(m,lH); l.16(t,3H).

Example 128 0 LLR-r(3R.5R and 3S .5S ),4a,58.686(R )11- 3-F F5-rr Ethyl rr(4-nitrophenvl)methoxylcarbonvllaminol methyll1tetrahydro-3-furanvll1thiol (l-hvdroxvethyl) 4 -methvl-7-oxo-l-azabicyclor3 .2.Olhept-2-ene-carboxylic acid (4-nitrophenyl)methyl ester The title compound is prepared by the proce- VO...dure of Example 17 using 0.483 g of product from ~.:Example 127 in 5 ml of acetonitrile, 0.923 g of product from Example 15 in 5 ml of acetonitrile and 0.21 ml of Hunig's base to give 0.63 g of the desired product after chromatography (silica gel: 75% to 80% ethyl acetate/hexane).

1H NMR(CDCl 3 8.2(d,4H); 7.68(d,2H); 7.52(dd,2H); 5.3(dd+s,3H); 4.0-4.35(m,4H); 3 7 3 .85(m,2H); 3.25-3.65(m,6H); 2.4-2.55(m,1H); 1.5-l.8(m,lH+l OH); l.37(d,3H,Me); l.27(t,3H,Me); l.6(t,3H,Me of Et).

-177- *Example 129 c.5,6(R*I]I r4R-r3(3R .5R and 3S*.5S*1.4c~5.8R)1 3-r (5-r rEthvlaminohllethvlltetrahdro-3-furanlthiol 6 (1-hvdroxvethvl) -4-methvl-7-oxo-3.-azabicyclor3 .2.01hept-2-ene-carboxylic acid The title compound is prepared by the procedure of Example 18 using 0.755 g of product from Example 128, 0.345 g of 10% palladium/carbon, 11 ml of sodium phosphate buffer (pH 7) and 33 ml of dioxane to give 0.118 g of the desired product after chromatography (C 18 reverse phase silica gel plates: acetonitrile/water).

1 H NMR(D 2 0):6 4.3-6.O(m,4H); 4.0-4.2(m,2H); 3.3-3.7(m,6H); 2.8-2.95(m,lH); 1.95-2.05(m,o.5H); l.75-l.85(m,O.5H); 1.4-l.6(m,9H,3Me).

*MS (FAB) m/ z 3 71 3 93 (M+Na) 7 41 (2M+H).

Example 130 .:cis- -5-r (Ethyvlamino) methyl tetrahvdro- 3 -furpnol The title compound is prepared by the proce- V 20 dure of Example 123 using 5.0 g of product from Example 122 Isomer A and 25 ml of 70% aqueous ethylamine to give 4.6 g of the product after chromatography (silica gel: 30% methyl alcohol/chloroform).

Example 131 cis- -Ethyl- r (tetrahvdro-4-hydroxy-2-furanvl) methyll carbamic-acid (4-nitroiphenyl)methyl. ester :The title compound is prepared by the procedure of Example 124 using 4.6 g of product from Example 130, 4.73 g of 4-nitrobenzyl chioroformate, 2.7 ml of Hunig's base, 25 ml of methylene chloride and 7 ml of tetrahydrofuran to give 2.035 g of the desired product after chromatography (silica gel: 75% ethyl acetate/hexane).

-178- Exml 3 cis- -Ethyl r rTetrahvdro-4- I (methvlsulfonvl) oXyl -2furanvilmethyl carbamic acid (4-nitrophenvl)methvl ester The title compound is prepared by the procedure of Example 125 using 2.035 g of product from Example 131, 1.31 g of triethylamine, 0.73 g of methanesulfonyl chloride and 14 ml of methylene chloride to give 3.18 g of the desired product after chromatography (silica gel: 75% ethyl acetate/hexane).

ExaMne 133 trans- -Ethanethioic acid rethvl rr (4-nitro~henvllmethoxylcarbonvll aminol methltetrahvdro-3-furanyl 1 ester The title compound is prepared by the procedure of Example 126 using 3.1 g of product from Example 132, 1.05 g of potassium thioacetate, 10 ml of dimethylformamide and 10 ml of toluene to give 1.9 g of the desired product after chromatography (silica gel: 75% ethyl acetate/hexane).

1 H NMR(CDCl): 8.23(d,2H); 7.52(d,2H); 5.25(s,2H); 4.1-4.32(m,2H); 3.92-4.02(m,lH); 3.18-3.65(m,5H); 2.32(s,3H,Me); 1.0-2.12(m,2H); l.l8(t,3H,Me).

Example 134 trans- -Ethyl r (tetrahvdro-4-mercapto-2-furanvl) methyllcarbamic acid (4-nitrophenvllmethyl ester The title compound is prepared by the procedure of Example 127 using 0.573 g of product from Example 133, 0.39 ml of 4N sodium hydroxide, 1.52 ml of 0.968N hydrochloric acid and 3.75 ml of methyl alcohol to give 0.382 g of the desired product after chromatography (silica gel: 50% ethyl acetate/hexane).

1 H NXMR(CDC 3 8.2(d,2H);-7.49(d,2H); 5.2(s,2H); 4.18-4.30(m,1H); 4.02-4.15(m,1H); 3.1-3.5(m,6H), 1.92-2.1(m,1H); 1.75-1.9(mH); l.69(d,1H,SH); 1.08 (t,3H,Me).

-179- Example 135 r4Rr30R .5S and 3S .5R 1.4a.SB.6B(R 111- 3-r r5-rEthvl[r(4-nitrohenvllmethoxvlcarbonllaminolmethylltetrahvdro-3-furanvl1thiol-6-(1-hvdroXvethvl)- 4-methvl-7-oxo-l-azabicvcloT3.2.Olhet-2-ene-2carboxylic acid (4-nitro~henl)methyl ester The title compound is prepared by the procedure of Example 17 using 0.382 g of product from Example 134 in 4 ml of acetonitrile, 0.723 g of product from Example 15 in 4 ml of acetonitrile and 170 microliters of Hunig's base to give 0.527 g of the desired product after chromatography (silica gel: ethyl acetate/hexane).

Hi NMR(CDC1 3 8.2(dd,4H); 7.65(d,2H); 7.52(d,2H); 5.52(d,2H); 5.23(s,4H); 5.22(d,2H); 4.2-4.35(m,4H); 3.2-3.85(m,BH); l.7-2.2(m,2H+OH); 1.37(dd,3H,Me); l.27(dd,3H,Me); 1.15(t,3H,Me of Et).

Exami~le 136 *I2~ F4R-F3(3R .5R and 3S*.5S*).4a.5.68l(R )11- 3-F (5-r rEthvlaminolmethylltetrahvdro-3-furanvllthiol-6- (1-hdroxvethvl)-4-methvl-7-oxo-1-azabicycloF3.2.01hept-2-ene-carboxlic acid The title compound is prepared by the procedure of Example 18 using 0.510 g of product from Example 135, 0.239 g of 10% palladium/carbon, 7.5 ml of sodium phosphate buffer (pH 7) and 22 ml of dioxane to give 0.040 g of the desired product after chromatography (C reverse phase silica gel plates: acetonitrile/water).

-180- O Example 137 Ethanethioic Acid S-f3.4-dibromo-1- (Dhenvlmethoxvmethyl 1butvl ester To a 0°C solution, under argon, of 1.44 ml of triflic anhydride in 20 ml of methylene chloride is added, sequentially, 0.69 ml of pyridine and 2.51 g of product from Example 3 in 5 ml of methylene chloride.

The reaction is stirred for 15 minutes, followed by dilution with diethyl ether. The mixture is filtered and concentrated in vacuo to give the desired triflate.

To the triflate, at 0°C, is added, sequentially, 0.8657 g of thiolacetic acid and 0.61 ml of triethylamine. The reaction is warmed to room temperature and stirred for 6 hours. The reaction 15 mixture is washed with water and extracted with diethyl ether. The diethyl ether extract is washed with sodium bicarbonate, water, dried and concentrated in vacuo.

The residue is purified by chromatography (silica gel: S" 50 100% methylene chloride/hexane) to give 0.638 g of 20 the desired product.

H NMR(CDCl 3 :6 7.35(m,10H); 4.56(m,5H); 4 .34-3.82(m,6H); 3.72-3.51(m,5H).

IR(neat): 2920, 1693, 699 and 629 cm 1 CI-MS: m/z 411(M++H).

Example 138 4-Bromotetrahydro-2- r (henvlmethoxy)methyl 1 thiophene 0diastereomers A 0 C solution, under argon, of 0.638 g of product from Example 137 in 16 ml of dry methyl alcohol is treated with 0.39 ml of 4.37M sodium methoxide. The reaction is stirred for 2 hours at 0°C followed by 2 hours at room temperature. The reaction mixture is concentrated in vacuo and the residue is purified by chromatography (silica gel: 0 20% ethyl acetate/hexane) to give 0.413 g of the product as a mixture of diastereomers.

-181- 1 H NMR(CDC1 3 7.34(m,1oH); 4.55(m,5H); 4.22(m,lH); 3.79(m,1H); 3.5(m,6H); 3.21(m,1H); 3.10(M,1H); 2.75(m,lH); 2.34(m,2H); 1.90(m,lH).

IR(neat): 2930 cm-1 Cl-MB: m/z 287(M+H) and 207(M+H-PhCH 2).

Example 139 Ethanethioic acid S- Itetrahvdro-5- r (henvlmethoxv) methyll1-3-thienvlI1 ester diastereomers A mixture, under argon, of 0.384 g of product from Example 138, 0.353 g of 1B-crown-6, 0.183 g of potassium thioacetate and 2 ml of acetonitrile is heated under reflux temperature for 1.*5 hours and stirred at room temperature overnight. The reaction 15 mixture is diluted with water, extracted with ethyl 0 acetate, the organic layer washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel: 5 ethyl acetate/hexane) to give 0.0803 g of the product.

1 H NMR(ICDCl 3 :6 7.33(m,5H); 4.55(s,2H); 4.10(m,lH); 3.64(m,lH); 3.50(m,2H); 3.22(m,lH); 2.75(m,lH); 2.30(s,3H); 2.20(m,lH); 2.05(m,lH).

IR(neat): 2924, 1692 and 1028 cm- 1 *000 Cl-MS: m/z 283(M Example 140 Ethanethicic acid *0 S-tetrahvdro-5- (iodomethvl) -3 -thienyll1ester A 0 0C mixture, under argon, of 0.44 g of product from Example 139 in 5 ml of dry chloroform is treated with O.55m1l of trimethylsilyl iodide. The reaction is stirred, in the dark, for 2 hours. The reaction is quenched with 100 ml of saturated sodium sulfite, extracted with methylene chloride and the layers separated. -The organic layer is dried, filtered and concentratedinJ vacuo. The residue is purified by chromtatography (silica gel: 0 -100% methylene chloride/ hexane) to give 0. 31 g of the product.

-182- 3.40(m,1H); 3.30-3.O(m,6H); 2.85(m,1H); 2.75(m,lH); 2.60-2.40(m,2H); 2.6(s,2SH); 2.21(m,1H).

IR(neat): 2916 and 1687 cm 1 CI-MS: m/z 303 and 175 base).

Examnile 141 Ethanethioic acid s- r5- (az idomethyl) tetrahvdro-3 -thienvi 1ester A solution, under argon, of 0. 183' g of product from Example 140 in 1.0 ml of dry methylene chloride is treated with 0.689 g of tetra-n-butylammonitum azide. The reaction mixture is stirred vigorously overnight at room temperature. The reaction is concentrated in vacuo and the residue purified by chromatography (silica gel: 0 10% diethyl ether/hexane) to give 0.061 g of the desired product.

H 1 NMR(CDCl 3 4.35-4.1O(m,3H) 3.85(m,1H); 3.6(m,1H); 3.34(d,2H,J=6.7Hz); 3.32(dd,1H,J=11.0 and 3 .0Hz) 2. 94 (dd, 1H, J=11. 0 and 6. 04Hz) 2. 80 2H); 2.6(m,2H). IR(neat) 2099 and 1690 cm CI-MS: m/z 188(M -N 2 Example 142 (Az idomethvl tetrahydro-3-thionhenethiol A 0 0 solution, under argon, of 0.279 g of product from Example 141 in 3 ml of dry methyl alcohol is treated with 0.35 ml of 4.35M sodium methoxide.

After 2 hours, the reaction mixture is concentrated in vacuo and the residue purified by chromatography (silica gel: 0 5% diethyl ether/hexane) to give 0.0465 g of the desired product.

1 H NMR(CDCl 3 :6 4.05(m,1H); 3.45-3.40(m,4H); 3o27(m,1H); 3.0-2.78(m,4H); 2.60(m,2H); 2.22-2.0(m,3H); 1.93(d,1H,J=2.5Hz,SH); 1.85(m,1H).

IR(neat): 2917 and 2104 cm- 1 CI-MS: m/z 176(14++H).

-183- 4-r4R-r4c!.58T6p(R 11 1-l-AZido-1,2 .3,5-tetradeoxv-2.5e~ithio-4-s- r6- (1-hydroxvethvl) -4-methvl-2- rr 4 -nitro- Dhenvl methoxvl carbonvi 1-7-oxo-l-azabicvclo r3.2 *01hept-2-en-3-vll1-4-thio-D-e =thro-Rentitol A mixture of 0.070 g of product from Example 142, 0.237 g of product from Example 15 and 1.3 ml of acetonitrile is treated, at 0 0 C, with 69.6 microliter of Hunig's base. The reaction mixture is stirred at room temperature overnight; followed by concentration inl vacuo. The residue is purified by chromatography (silica gel: 0 60% ethyl acetate/hexane) to give 0.034 g of the desired product.

1 H NNR(CDCl 3 8.23(d,2H,J=3Hz); 7.66(d,2H,J=3Hz); 5.51(d,1H,J=13.7Hz); 5.23(d,lH,J=13.7Hz); 4.30(m,2H) 4.19(m,lH); 3.65(m,1H); 3.45(m,lH); 3.32(dd,1H); 2.92(dd,1H); 2.70(m,3H); 2.20(dt,1H); l.99(br s,lH,OH); o. .72(td,lH); l.37(d,3H); 1.30(d,3H).

IR(neat): 3468, 2104, 1769 and 1709 cm 1 MS(FAB): m/z 520(M Example 144 9. 4-r4R-r4a.58Ti6B(R 11--Azido-4-S-2-carboxv-6-(l.

hydroxyethyl) -4-methyl-7-oxo-1-azabicyclor3 .2.101heipt-2-en-3-yl1-123 5-tetrpdeoxv-2 .5-eiho4 thio-D-erythro-pentitol The title compound is prepared by the procedure of Example 18 using 0.030 g of product from 0 Example 143, 0.013 g of 10% palladium/carbon, 10 ml of dioxane and 5 ml of potassium phosphate buffer (pH to give 0.012 g of the desired product after chromatography (C isreverse phase silica gel plates: ethyl alcohol/water).

1H NMR(CDC 3 :6 4.18(m,3H); 3.50(m,2H); 3.40(m,2H); 2.94(dd,lH); 2.70(m,2H); 2.12(dt,1H); 1.73(dd,lH); l.23(d,3H); l.16(d,3H).

IR(neat): 3535, 3410, 2104 and 1745 cm- 1 MS(FAB): m/z 359(M -184wExamle 145 Ethanethioic acid S-rtetrahvdro-5-(hdroxvmethvl)-3-thienv lestater A 0 C solution, under argon, of 0.123 g of product from Example 139 in 1.0 ml of dry chloroform is treated with 51.1 microliter of boron trifluoride etherate and 0.193 g of tetra n-butylammonium iodide.

the reaction mixture is stirred at room temperature overnight and concentrated ji vacuo. The residue is purified by chromatography (silica gel: 0 100% ethyl acetate/hexane) to give 0.079 g of the desired product.

1 H NMR(CDCl 3 4.15(m,1H); 3.95(m,1H); 3.80-3.60(m,4H); 3.30(m,1H); 3.19(m,1H); 2.77(t,lH); 2.48(m,1H); 2.34(s,3H,SAc); 2.27(m,1H); 2.08(m,1H); 1.73(m,1H).

Example 146 Tetrahydro-4-mercapto-2-thiophenemethanol The title compound is prepared by the procedure of Example 138 using 0.079 g of product from 20 Example 146, 0.11 ml of 4.37M sodium methoxide and 1 ml of methyl alcohol to give 0.040 g of the desired product after chromatography (silica gel: 20 -30% ethyl .acetate/hexane).

1 H NMR(CDCl 3 3.83(m,1H); 3.60(m,4H); 3.35(m,1H); 3.10(m,LH); 2.79(m,H); 2.50-2.20(m,2H); 1.80(d,lH); 1.65(m,lH).

Example 147 14R-r4q58,,6l(R 11-6-(1-Hdroxethyl)-4-methyl-7 -oxo- 3-rrtetrahvdro-5-(hdroxvmethyl1)-3-thienvlthiol-1azabicyclor3.2.0lhept-2-ene-2-carboylic acid (4-nitrophenyllmethyl ester The title compound is prepared by the procedure of Example 143 using 0.040 g of product from Example 146, 0.154 g of product from Example 15, 46.4 microliter of Hunig's base and 1 ml of acetonitrile to give 0.071 g of the desired product after chromatography (silica gel: 20 100% ethyl -185acetate/hexane).

1 NMR(CDC 3 8.25(d,2H,J=8.8Hz); 7.66(d,2H,a=8.8Hz); 5.52(d,1H,J=13.7Hz); 5.22(d,1H,J=13.7Hz); 4.28(m,2H); 3.80-3.6(m,3H); 3.45(m,1H); 3.3(m,1H); 2.87(t,lH,J=6.7Hz); 2.5(in,1); 2.00(br s,1H,OH); 1.78(m,1H).

IR(neat): 3412, 1767 and 1708.cm-1 MS(FAB): m/z 495 Example 148 r 4R- r 4a.5B. 6B (R 1 r 2-carboxv-6- (l-hvdroxyethvl) 4 -methyl -7-oxo-l-azabicyclo r3. 2. 0 1hent-2 -en-3 -yl I- 2. 3. 5 -trideoXy-2 5-epithio-4 -thio-D-erythro-pentitol monosodium salt (AI and r 4R- r 4a~. 5, B(R 11-2-S- r 2-carboMv-6- (1-hvaro~rethv1) 4-methvl-7-oxo-1-azabicvclor3.2. Olhe~t-2-en-3-vll- S1. 3, 4 -tr ideoxy- 1 4 -e i th io- 2-th io -L-threo-pent itol1 monosodium salt MB The title compound is prepared by the procedure of Example 18 using 0.0715 g of product from *Example 147, 0.0125 g of sodium bicarbonate, 0. 021 g of 10% palladium/carbon, 11.5 ml of 8:2 dioxane:water to give 0.012 g of the trans isomer and 0.016 g of the cis isomer after chromatography (Preparative thin *fee 25 layer silica gel plate: 5% ethyl alcohol).

Isomer B (cis) 1H NMR(CDCl 3 4.19(m,2H); 3 .75-336(m,6H); 2.80(,1H); 2.50(m,lH); IR(neat): 3405 and 1742 cm-1 MS (FAB) m/ z 4 04 (M+Na) and 3 8 3(M+H).

-186- 3) Example 149 trans-(+/-)-4-Bromotetrahvdro-2-furanmethanol Under anhydrous conditions at -5 C, with an argon flush, 1.05 g of product from Example 4 in 32 ml of dry chloroform is treated, dropwise, with 200.1 ml of trimethylsilyl iodide. The reaction mixture is stirred at -5 C for 2.5 hours and then stored in a chill room overnight. The reaction is cooled to and 630 ml of methyl alcohol is added. The mixture is stirred for 10 minutes and concentrated in vacuo.

The residue is purified by chromatography (silica gel: 200 ml aliquots of 15%, 25%, 35% and 50% ethyl acetate/hexane) to give 0.559 g of the desired product.

Calculated for CgH BrO 2 1 5 Theory C 33.17, H 5.01, Br 44.14 Found C 33.07, H 5.13, Br 43.80 CI-MS: m/z 278(MH Example 150 2.5-Anhvdro-4-bromo-3,4-dideoxv-D-erythro-pentonic acid 20 A 0 C solution of 6.05 g of product from Example 149 in 120 ml of acetone is treated, dropwise, with 37.5 ml of 0.9M Jones reagent in 50 ml of acetone.

The reaction is warmed to room temperature and stirred for 45 additional minutes. The reaction is quenched with isopropyl alcohol and acetone, filtered through diatomaceous earth and concentrated in vacuo to 200 ml volume. The concentrate is mixed with 200 ml of saturated sodium chloride and and reconcentrated in vacuo. The aqueous layer is extracted with isopropyl alcohol/chloroform, dried and concentrated in vacuo to give 5.6 of the acid as a light brown oil.

1 H NMR(CDC1 3 4.84(t,1H,J=7.9Hz); 4.55(br s,1H); 4.38(dd,lH,J=6.0 and 4.4Hz); 4.19(dd,1H,J=8.7 and 1.6Hz); 2.73(m,lH); 2.57(m,H).

IR(neat): 3084 and 1737 cm 1 CI-MS: m/z 197(M+H).

-187- Example 151 4-(2.5-Anhvdro-4-broo-3.4-dideox-D-erthro- Rentonovl )-l-Rierazinecarboxvlic acid Rhenvlmethvl ester A mixture of 0.941 g of product from Example 150, 0.652 g of 1-hydroxybenzotriazole, 1.17 g of l-benzyloxycarbonyl piperazine, 1.39 g of dicyclohexylcarbodiimide and 8 ml of dry methylene chloride is stirred at room temperature for 1 hour.

Five ml of dimethylformamide is added and the stirring continued overnight at room temperature. The reaction mixture is diluted with water and extracted with chloroform. The organic layer is dried, concentrated in vacuo and the residue purified by chromatography Is (silica gel: 10 80% ethyl acetate/hexane) to give 1.1 g of the desired product.

1H NMR(CDCl 3 7.3.6(s,5HPh); 5.16(s,2H,PhCH 2 4.92(t,1H,J=7.2Hz); 4.58(m,1H); 4.23(dd,lH,J=10.4 and 4.3Hz); 4.14(dd,lH,J=2.l and 0.5Hz); 3.76(m,2H); 3.64(m,2H); 3.44(m,4H); 3.O0(m,1H); 2.40(m,lH).

IR(neat): 1702 cm CI-MS: m/z 398(M+H).

S. Example 152 4-(4-S-Acetl -2.5-anhvdro-3-deoXy-4-thio-L-threo- Dentonoyl)-l-Diperazinecarboxylic acid Dhenvlmethyl ester The title compound is prepared by the procedure of Example 139 using 1.14 g of product from Example 151, 0.393 g of potassium thioacetate, 0.1517 g of 18-crown-6 and 10 ml of acetonitrile to give 0.928 g of the desired product after chromatography (silica gel: 10 60% ethyl acetate/hexane).

1H NMR(CDCl 3 7.36(s,5H, Ph) 'S 15(s, 2H, PhCH 2); 4.64(t,1H,J=6.9Hz); 4.22(t,1H,J6.8Hz); 4.03(m,1H); 3 7 4-3.61(m,5H); 3.60-3.40(m,4H); 2.5(m,2H); 2.32(s,3H).

-1 IR(neat): 1698 and 1653 cm- -188- MS(FAB): m/z 393(M4+11).

4- (2 .5-Anhydro-3-deoxv-4-thio-L-threo-,Dentonoyl Riverazinecarboxylic acid Dhenvlmethvl ester A 0 0 C solution, under argon, of 0.20 g of product from Example 152 in 1.5 ml of dry methyl alcohol is treated with 0.25 ml of sodium hydroxide.

The reaction is monitored by thin layer chromatography.

After 1 hour an additional 0.17 ml of 4N? sodium hydroxide is added and the reaction stirred 1 hour.

The reaction mixture is quenched with 1.86N? hydrochloric acid/isopropyl alcohol, concentrated ijn vacuo and chromatographed (silica gel: 20 80% ethyl acetate/hexane) to give 0.116 g of the desired product.

V~~i 15 H NMR(CDCl 3 :6 7. 3 6(s, 5H, Ph) 5. 5(s, 2H, PhCH 2 4.64(t,lH,J=7.4Hz); 4.13(dd,1H,J=8.6 and 6.9Hz); 3.8-3.6(m,5H); 3.5-3.3(m,4H); 2.55(m,1H); 2.40(m,lH); l.82(d,lH,J=8.4Hz

SH).

Examiple 154 r 4R- r4q, 586 0(R *)jj-4-r2.5-Anhvdro-3-deoXy-4-S- 16 (I-hydroxvethy 1 -4-methyl- 2 r (4 -n itroph eniv1) methoxylcarbonvll-7-oxo-l-pzabicvclor3 olhept-2-en-3yll1-4-thio-L-threo-pentonoyll1-l-piperazinecarboxylic acid phenvlmethyl ester The title compound is prepared by the procedure of Example 143 using 0.112 g of product from Example 153, 0.190 g of product from Example 15, 55.7 microliter of Hunigs base and 1.1 ml of acetonitrile to give 0.189 g of the desired product after chromatography (silica gel: 10 100% ethyl acetate/hexane).

1 H NMR(CDCl 3 8.22(dd,2H,J=8.8 and 1.8Hz); 7.65(d,2H,J=8.BHz); 7.36(s,5H,Ph); 5.48(d,lH,J=13.8H2); 5.23(d,lH,J=13.8Hz); 5.15(s,2H,PhCH 2 4.63(m,lH); 4.27(m,2H);, 4.15(m,lH); 3.8-3.60(m,5H); 3 .50-3.35(m,4H); 3.27(dd,lH,J=6.9 and 2.6Hz); -189- 2.53(m,2H); 1.37(dd,3H,J=6.3 and 1.3Hz); 1.28(t,3H,J=8.OHz).

IR(neat): 1771 and 1702 cm1 MS(FAB): m/z 717(M+Na) and 695(M+H).

Example 155 r4R-r4a.5B.6B(R 11-4-r2.5-Anhvdro-4-Sr2-carboxv-6- (-hydroxvethvl)-4-methvl-7-oxo-lazabicyclor3.2.01hent-2-en-3-vl1 -3-deox-4-thjo-Lthreo-Dentonovll-l--iperazinecarboxlic acid Phenvlmethvl ester The title compound is prepared by the procedure of Example 18 using 0.170 g of product from Example 154, 0.034 g of 10% palladium/carbon, 15 ml of dioxane ard 10 ml of potassium phosphate buffer (pH 7.0)to give after chromatography

(C

18 reverse phase silica gel plates: 5% ethyl alcohol/water) 0.067 g of S.i the desired product.

liH NMR(D 2 0):6 7.40(s,5H); 5.16(s,2H,PhCH 2 4.44(m,1H); 4.3(m,2H); 4.10(m,lH); 3.7-3.38(m,6H); 3.5-3.30(m,5H); 3.29(m,lH); 2.50(m,2H); 1.28(d,3H); 1.18(d,3H).

MS(FAB): m/z 581(M +Na).

Example 156 l-4-S-Acetyl-2.5-anhdro-3-deoxv-4-thio-L-threopentonovl)piperazine x:The title compound is prepared by the procedure of Example 140 using 0.766 g of product from Example 152, 0.430 g of trimethylsilyl iodide and 4 ml of chloroform to give 0.504 g of the desired product after chromatography (silica gel: 15 20% ethyl acetate/hexane).

1 H NMR(MeOH-d 4 4.94(tlH,J=7.4Hz); 4.24(dd,1H,J=8.6 and 6.9Hz); 4.10-3.70(m,5H); 3.40-3.20(m,4H); 2.76(m,1H); 2.34(s,3H,SAc); 2.10(m,H).

-190- SExample 157 4- (4-S-Acetvl-2.5-anhvdro-3-deoxv-4-thio-L-threopentonol) -1-Dinerazinecarboxvlic acid (4-nitronhenvl)methyl ester A 0 C solution, under argon, of 0.300 g of product from Example 156 in 2.3 ml of dry tetrahydrofuran is treated with 0.150 g of Hunigs base and 0.250 g of nitrobenzyl chloroformate. The reaction mixture is stirred at 0°C and allowed to warm to room temperature (6 hours). The reaction is diluted with water and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo to give 0.251 g of the desired product after chromatography (silica gel: 0 15 100% ethyl acetate/hexane).

H NMR(MeOH-d 4 8.23(d,2H,J=8.8Hz); 7.52(d,2H,J=8.8Hz); 5.25(s,2H,PhCH2) 4 .64(t,lH,J=7.4Hz); 4.22(dd,lH,J=8.96 and 6.8Hz); 4.02(m,lH); 3.90-3.60(m,6H); 3 .50-3.40(m,4H); 20 2.48(m,2H); 2.33(s,3H,SAc).

IR(neat): 1702 cm 1 CI-MS: m/z 438(M+H).

Example 158 4- (2.5-Anhydro-3-deoxY-4-thio-L-threo-entonoyl) 25 1-piperazinecarboxylic acid (4-nitrophenvl)methyl ester The title compound is prepared by the procedure of Example 153 using 0.230 g of product from Example 157, 0.29 ml of 4N sodium hydroxide and 1.7 ml of methyl alcohol to give 0.086 g of the desired product after chromatography (silica gel: 10 -100% ethyl acetate/hexane).

H NMR(MeOH-d4):6 8.24(d,2H,J=8.8Hz); 7 .52(d,2H,J=8.8Hz); 5.24(s,2H,PhCH 2 4 .64(t,1H,J=7.3Hz); 4.13(dd,1H,J=8.6 and 6.9Hz); 3 9 0-3.30(m,10H); 2.55(m,lH); 2.42(m,lH); 1.82(d,lH,J=8.3Hz,SH).

-191w Examole 159 r4R-r4cf.5B.6BO(R 114-25-Anhvdro-3-deo r6-(l-hvdroxvethv1) -4-methvl-2-r r(4-nitro~henvl) mnethoxv carbonvi 1-7-oxo- l-azabjcyclo r3 01hent-2 en- 3-vi 1 4 -thio-L-threo-entonoy. 1-l-iperazinecarboxy ic acid (4-nitr-ophenvllmethvl ester The title compound is prepared by the procedure of Example 143 using 0.085 g of product from Example 158m 0.128 g of product from Example 15, 37.4 microliter of Hunigs base and 1.0 ml of acetonitrile to give 0.135 g of the desired product after chromatography (silica gel: 20, 40, 80 and 100% ethyl acetate/hexane followed by 2-4% methyl alcohol/ethyl :1:1:.acetate).

H NMR(CHCl): 8.24(d,2H,J=8.8Hz); 3) 8.23 (d,2H,J=8.BHz) 7.65(d,211,J=8.8Hz); 7 .52(d,2H,J=8.8Hz); 5.49(d,lH,J=13.8Hz); 5.22(d,lH,J=13.8Hz); 5.25(s,2H); 4.64(m,lh); 4.25(m,2H); 3 .84-3.83(m,6H); 3 .52-3.32(m,4H); 3 .27(m,1H); 2.54(m,2H); 1.37(d,3H,J=6.3Hz); 1. 26 3H,J=6. 4HZ).

IRZ(neat): 1772 and 1705 cm-1 Example 160 r4R-r4_C.5B,66(R -l-F 2 .5-Ahdro-4-S-2.carb..

6 -(l-hydroxvethvl) 4 -maethv1-7-oxo-l-azabicvc o[3 .2.01het-2)-en-3-vl l- 3 -deoxv--4-thio-threo-rentonov1 1- Diiperazine henlmethvl ester The title compound is prepared by the procedure of Example 18 using 0.120 g of product from Example 159, 0.030 g of 10% pall adium/ carbon, 5 ml of dioxane and 1.5 ml of potassium phosphate buffer (pH1 7) to give 0.053 g of the desired product after chromatography (preparative silica gel plate: 5% ethyl alcohol/water).

1 HNMR(CHCl 3 :6 4.90(m,lH); 4 .30-4.10(ma,3H); 4

.O-

3 .60(M,8H); 3.40(m,luH); 3.3(m,3H); 2 .80(m,11); l.28(d,3H); 1.20(t,3H).

-192- IR(KBr): 3545, 3408, 1770 arnd 1622 cm 1 MS (FAB): M/ z 4 26(14++H) Example 161 rU4R- r3 (3R* 5SS and 3S* .5R* JC*. 5B. 6B (B ill 3- rr 5-r [rr(Dimethvlamino~ methylenel aminolmethyl 1 tetrahvdro-3-furanvll1thiol (l-hvdroxvethvl j -4-methyl- 7 -oxo-1-azabicvclo r3.2.0 1heot-2-ene-2--carbo~,ljc acid Three ml of sodium phosphate buffer, pH 7, is cooled to 0 0 C and 0.052 g of product from Example 46 is added. To this cooled solution is added, dropwise, 159 ml of N,N-dimethylformamide diisopropyi acetal, while maintaining the pH below 8.5. The reaction mixture is stirred at 0 C for 35 minutes, pH adjusted to 7.0 and freeze-dried. The residue is purified by chromato- graphy (C 8 reverse phase tlc plates: *aqueous ethyl alcohol) to give 0.031 g of the desired product.

1H NMR (D 0) :6 7. 8(s, 1H) 4. 3(m, 1H) 49(,3H S 2 20 3.94(m,lH); 3.75(m,lH); 3.54(m,lH); 3.42(m,3H); 3 2 1(s,2H,N-Me); 3.01(s,3H,N-Me); 2.08(m,2H,SCCH4cc); l.26(d,2H,Me); 1.18(d,3H,Me).

Exampie -162 2 r4R- r4a,58, 68R )11-2.5-Anhdro-.3-dideo-...l.

(dimethvlamino) F2-carboxy-6- (l-hvdroxe l I- 4 -methyv1-7-oxo-l-azabicyclo r3.2. Olheyt-2-en-3-vl 1- 4-thio-L-threo-ventitol A mixture of 0.0342 g of product from Example 120, 80 Al of 37% aqueous formaldehyde, 4 ml of water and 0.030 g of platinum oxide is reduced in a Parr apparatus under 40 p si of hydrogen for 4 hours. The reaction mixture is filtered through a pad of diatomaceous earth, washed with a small volume of water and concentrated to a small volume (pH of the filtrate The residue is. purified by chromatography (C 1 reverse phase tlc plate: 95% aqueous ethyl alcohol) to give 0.015 g of the desired product.

-193- H NMR(D 2 0):6 4.4(m,1H); 4.00-4.25(m,3H); 3.95-3.80(m,2H); 3.5-3.2(m,4H); 2.88(d,6H,2N-Me); 2.70-2.55(m,lH); 1.8-1.7(m,0.5H); 1.6-1.5(m,0.5H(m,0.5H); 1.25(d,3H,Me); 1.18(d,3H,Me).

Example 163 2.4-Difluoro-alDha-2-DroDenvlbenenemethanol Under anhydrous condition at 0°C, a mixture of 18.0 g of freshly distilled 2,4-difluorobenzaldehyde and 120 ml of diethyl ether is treated, dropwise, with 139 ml of 1M allyl magnesium bromide. The reaction is stirred at 0°C for 1 hour then slowly allowed to warm to room temperature. After 5 hours, thin layer chromatography indicates complete reaction. The mixture is cooled to 0°C and quenched by the dropwise addition of 100 ml of ice cold saturated ammonium chloride. Two hundred ml of diethyl ether is added and the layers are separated. The aqueous layer is extracted with diethyl ether. The organic layers are combined, washed twice with saturated sodium chloride, dried filtered and concentrated in vacuo. The residue is purified by Kugelrohr distillation (1000C) to give 19.9 g of the desired product as a mixture of isomers.

1 H NMR(CDC1 3 7.45(m,lH); 6.88(m, 6.78(m,1H); 25 5.82(m,lH); 5.16(dd,2H); 5.03(q,1H); 2.53(m,2H); 1.89(bs,lH).

Example 164 alpha-(2,3-Dibromopropyl)-2.4-difluorobenzenemethanol Under anhydrous condition at 0°C, 3.0 g of product from Example 163 and 12 ml of anhydrous methylene chloride is treated, dropwise over minutes, with a solution of 2.5 g of bromine in 3 ml of methylene chloride. The reaction is quenched with cold saturated sodium sulfite solution and the layers separated. The organic layer is washed with saturated sodium chloride, dried, filtered and concentrated in vacuo. The residue is purified by chromatography -194- (silica gel: 5-10% ethyl acetate/hexane) to give 4.7 g of the desired product as a mixture of isomers.

I H NMR(CDCl 3 :6 7.53-7.41(m,1H); 6.95-6.77(m,2H); 5.28(m,1H); 4.61-3.63(m,3H); 2.69-l.95(m,3H).

Example 165 (cis and trans)- -4-Bromo-2-(2 .4-difluorophenyl jtetrahydrofuran A mixture of 4.5 g of product from Example 164, 1.67 g of calcium hydroxide, 7.5 g of calcium bromide, 25 ml of water and 12 ml of methyl alcohol is stirred and heated at 85 0 C overnight. The reaction mixture is cooled, diluted with ethyl acetate and filtered through diatomaceous earth. The layers are separated and the organic layer is washed with saturated sodium chloride, dried, filtered and concentrated in vacuo. The residue is purified by chromatography (silica gel: 3-5% ethyl acetate/hexane) to give 1.96 g of the desired product as a mixture of isomers.

1H NMR(CDCl 3 :6 7.65-7.57(m,1H); 7.46-7.38(m,lH); 6.93-6.74(m,4H); 5.43(q,lH); 5.16(t,lH); 4.59-4.57(m,lH); 4.53-4.47(m,2H); 4.25-4.21(m,3H); 3.05(m,lH); 2.89(q,lH); 2.36-2.lB(m,2H).

Example 166 (cis and trans)-(+/-)-Ethanethioic acid 4-difluorophenyl) tetrahvdro-3-furanyll ester The title compound is prepared by the procedure of Example 5 using 1.9 g of product from Example 165, 0.866 g of potassium thioacetate and 30 ml of acetonitrile to give, after chromatography (silica gel: ethyl acetate/hexane), 1.43 g of the desired product, as a mixture of isomers.

1 H NMR(CDCl 3 :6 7.44 2H) 6.87 2H) 6.78 2H); 5.14(m,2H); 4.50(m,2H); 4.26(m,2H); 4.ll(m,2H); 3.90(q,lH); 3.77(g,lH); 3.04(m,lh); 2.87(m,lH); 2.35(s,31); 2.32(s,3H).

-195- Example 167 4-Difluorophenvi tetrahydro-3-furanthiol stereoisomers The title compound is prepared by the procedure of Example 16 using 0.250 g of product from Example 166, 243 p1 of 25% sodium methoxide/methyl alcohol, 4.5 ml of tetrahydrofuran and 530 p1 of 2N hydrochloric acid/isopropyl alcohol to give, after chromatography (silica gel: 5-10% ethyl acetate/hexane), 0.180 g of the desired product, as a mixture of isomers.

1 H NMR (CDCl 3 7. 52 (q,l1H) 7. 41 (q,l1H) 6. 80 2H); 6.78(m,2H); 5.32(t,lH); 5.12(q,lH); 4.41(q,1H); 4.24(q,lH); 3.81(q,1H); 3.72(q,lH); 3.54(m,2H); 2.89(m,1H); 2.29(m,2H); l.79(d,lH) l.73(d,H) l.72(m,lH).

Examtrle 168 r R a 1- r5 2 D urpey)tta hvdro-3-furanyllthiol (l-hvdroxyethvl) -4-methvl-7oxo-l-azabjcyclor 3.2. 11hept-2-ene-2-carboXvlic acid *~~*(4-nitrophenyl) methyl ester The title compound is prepared by the procedure of Example 17 using 0.169 g of product from Example 167, 0.300 g of product from Example 15, 87 p1 of Hunig's base and 3 ml of acetonitrile to give, after chromatography (preparative silica gel plates: acetone/chloroform), 0.080 g of the desired product, as a mixture of isomers.

1 H NMR(CDCl 3 8.23(d,2H); 7.68(d,2H); 7.41(q,lH); 6.83(m,2H); 5.53(d,lH); 5.25(d,1H); 4-47(m,lH); 4.27(m,2H); 3.94(m,1H); 3.8(d,lH); 3.48(m,1H); 3.38(d,lH); 2*.44(m,lH); 2.24(m,1H); 2.17(d,lH); 1.37(d,3H); 1.29(d,3H).

-196- Example 169 r4R-r4a.5fi.6B(R 11-3-r r5-(2,4-DifluorOphenfltetrahvdro-3-furanvl Ithiol (1-hvdroxvethv1) -4-methyl-7oxo-l-azabicvclo r3.2. Olhept-2-ene-2-carboxvlic acid monosodium salt isomer 1 nd r4R-r4a.5B.6i(R~ 11-3-r r5-(2.4-Difluorophenv]A tetrahvdro-3-furanvll1thiol (1-hydroxvethvl l-4-methvl-7oxo-l-azabicvclor3 Olhept-2-ene-2-carboXylic acid monosodium salt isomer 2 The title compound is prepared by the procedure of Example 18 using 0.80 g of product from Example 168, 0.0117 g of sodium bicarbonate, 2 ml of water, 7: ml of dioxane and 0.030 g of palladium on carbon to 15 give, after chromatography (C 1 reverse phase plates: 18 ethyl alcohol/water), 0.020 g of isomer 1 and 0.040 g of isomer 2.

Isomer 1: 4. 2(m, 2H) 3. 9 5(m, 2H) 2. 6(m,l1H) 3. 2(bs, 2H); 8 3(m, 1H) 2. 3 5(m, 1H) 2. 0(m, 1H) 1. 22 3H); 1.19(d,3H).

Isomer 2: 1 H NMR(D 2 0):6 7.44(m,1H); 6.9(m,2H); 4.18(m,2H); 25 3.91(m,2H) 3.6(m,1H) 3.18(m,2H) 2.8(m,lH); 2.37(m,1H); 1.8(m,1H); l.22(d,3H); l.19(d,3H).

Example 170 1. 2-0- (1 -Methyl ethyl idene) -alnha-D-xvlofuranose bis (4-methylbenzenesulfonate) Under anhydrous condition, 50.0 g of l,2-isopropylidene-D-xylofuranose, 250 ml of dry pyridine and 0.200 g of dimethylaminopyridine is cooled to 0 0 C. To this mixture is. added, in portions, 110.26 g of p-toluenesulfonyl chloride. The reaction mixture is stirred and allowed to warm to room temperature overnight. The mixture is cooled to 0 0 C, quenched with water, extracted with ethyl acetate and the layers are -197- 9p separated. The organic layer is washed with water, saturated sodium chloride, dried, filtered and concentrated in vacuo. The residue is recrystallized from diethyl ether/hexane to give 116.6 g of the desired product.

1H NMR(CHC13):6 7.79(m,4H); 7.33(m,4H); 5.86(d,lH); 4.72(q,2H); 4.33(m,lH); 4.0(m,2H); 2.48(s,3H); 2.45(s,3H); 1.42(s,3H); 1.27(s,3H).

Example 171 2.5-Anhvdro-D-xvlose dimethyl acetal 3-(4-methylbenzenesulfonate) Under anhydrous condition at 0°C, hydrogen chloride gas is bubbled through 166 ml of dry methyl Salcohol. Five g of product from Example 170 is added S 15 and the reaction is stirred for 10 minutes at 0 C; followed by heating at reflux temperature for 15 hours.

The reaction mixture is cooled to 0 C and neutralized with solid sodium carbonate. The mixture is stirred for 15 minutes, filtered and concentrated in vacuo.

The residue is dissolved in 50 ml of acetone, filtered and concentrated in vacuo. The residue is purified by chromatography (silica gel: 40-50% ethyl acetate/hexane) to give 2.89 g of the desired product as a white solid.

H NMR(CHC1 7.82(d,2H); 7.37(d,2H); 4.81(d,lH); 4.53(m,1H); 4.41(d,lH); 4.22(m,1H); 4.11(m,1H); 3.73(dd,lH); 3.38(s,3H); 3.11(s,3H); 2.46(s,3H); 2.37(bs,lH).

Example 172 2.5-Anhydro-4-deoxy-D-erythro-Dentose dimethyl acetal Under anhydrous conditions at room temperature, 0.90 g of product from Example 171 and 25 ml of dry tetrahydrofuran is treated, via a syringe, with ml of M lithium triethylborohydride(Super-Hydride).

The reaction is stirred overnight at room temperature.

The mixture is cooled to 0°C, quenched carefully with ice, diluted with 75 ml of ethyl acetate and the layers -198are separated. The organic layer is washed with water, saturated sodium chloride, dried, filtered and concentrated in vacuo. The residue is purified by chromatography (silica gel: 40-60% ethyl acetate/hexane) to give 0.235 g of the desired product.

1 H NM:R(CHC1 3 :6 4.34(m,1H); 4.26(m,1H); 3.97(m,2H); 3.76(ml2H); 3.44(m,6H); 2.72(m,1H);* 2.15(m,lH); 1.92(m,lH).

Examvle 173 trans-Tetrahvdro-3-hvdroxv-2-furanvlmethanediol A mixture of 9.25 g of product from Example 172, 15 ml of water and 1.5 g of DOWEX-50W-XB (100-200 mesh, hydrogen form) is heated at 95 C for 4 hours.

9 The reaction mixture is cooled to room temperature, filtered and the residue washed with water. The filtrate is treated with toluene and concentrated in vacuo to give 1.1 g of the desired product as a sticky yellow oil.

1 HNMR(D 0):6 4.75(d,lH) 4.27(m,lH); 3.91-3.76(m,2H); 3.55(m,lH); 2.o0(m,1H); 1.78(m,lH).

*Example 174 r4R-r4cr.5f.6fi(R 11-1-Amino-4-S-r2-carboXy-6- (1-hvdroxvethvl) -4-methvl-7-oxo-l-azabicvclor3 .2.01 V-0.hep~t-2-en-2-vll-1,2 .3.4 .5-DentadeoXy-2 .5-e~ithio-4th io-D-erythro-lpentitol To a solution of 0.024 g of product from Example 144 in 1 ml of acetonitrile:water is added 17 p1 of tributylphosphine. The reaction mixture is stirred at room temperature for 24 hours followed by concentration in 1 vacuo. The residue is purified by chromaogra1h (Ci eerse phase preparative plates: ethyl alcohol:water) to give 0.014 g of the desired product.

I H NMR(CDCl 3 :6 4.20(m,2H); 4.05(t,lH); 3.80(m,2H); 3.45-3.20(m,3H); 3.l0.(dd,lH); 2.89(dd,lH); 2.26(m,lH); 2.O1(m,lH); 1.25(d,3H,J=6.2Hz); 1.15(d,3H,J=7.2Hz).

IR(KBr): 3400 and 1765 cm- 1 -199- MS(FAB): M/Z 359 Example 175 4-Bromotetrahvdro-2- r (nhenvlmethoxv~ methyll1thionhene 1.1-dioxide To a 0 0 C solution, under argon, of 5.65 g of product from Example 138 in 45 ml of dry methylene chloride is added, slowly, 7.8 g of m-chloroperbenzoic acid. The-reaction is stirred at 0 0 C for 2 hours, diluted with 100 ml of water and extracted with methylene chloride. The organic layer is washed with saturated sodium b icarbonate, dried, filtered and concentrated i:n vacuo. The residue is redissolved in *0 methylene chloride, passed through a short column of %0 silica gel, concentrated jjj vacuo to give 5.87 g of the desired sulfone (60:40 mixture of isomers).

1 H NMR(CDCl 3 :6 7.34(m,5H,Ph); 4.67(m,lH); 4.59(t,2H,CH 2 Ph); 4.36(m,lH); 3.77-3.58(m,4H); 3.50(dd,lH); 3.30(dd,lH); 2.90(m,lH); 2.70(mlH); 2.55(m,lH); 2.33(m,lH).

IR(neat): 2945,1320,1127,910 and 734 cm CI-MS: m/z 320(M H).

Example 176 4-Bromo-2-thionhenemethanol 1. 1-dioxide To a -780C solution, under argon, of 4.23 g of product from Example 175 in 28 ml of dry methylene chloride is added, dropwise, 17.2 ml of 1M boron trichloride. The reaction mixture is warmed to 0 0 C and stirred for 1 hour. The reaction is quenched with methyl alcohol, concentrated ini vacuo and chromatographed (silica gel: 0-30% ethyl acetate/hexane) to give 2.57 g of the desired product (1:1 mixture of isomers).

mp 56-57 C(ethyl acetate and hexane).

1 H NMR(CDCl 3 :6 4.75 (m,l1H) 4.42 (m,l1H) 4.12 2H); 3.94(m,lH); 3.65(m,2H); 3.53(dd,lH); 3 4 5-3.25(m,2H); 2.98(br s,lH,OH); 2.90(m,lH); 2.70(m,2H); 2.43(m,1H).

IR(KBr): 3461, 1314, 1284 and 1123 cm-1 -200- Example177Z Tetrahvdro4- r r (4--metho2vThenvl) methyl 1 thiol -2-thio- Rhenemethanol-1. 1-dioxide To a 0 C slurry, under argon, of 0.502 g of sodium hydride (60% oil dispersion) in 9 ml of dry tetrahydrofuran is added, dropwise over 5 minutes, 1.69 ml of p-methoxy--toluenethiol in 9 ml of dry tetrahydrofuran. The reaction is warmed to room temperature for 30 minutes, recooled to 0 0Cand a solution of 2.31 g of product from Example 176 in 10 ml of dry tetrahydrofuran is added. The reaction mixture is allowed to warm to room temperature and stirred overnight. The mixture is diluted with 100 ml of water 0 and extracted with diethyl ether. The organic layer is S 15 washed with saturated sodium chloride, dried and concentrated in vacuo to give an oil. The oil is purified by chromatography (silica gel: 0-90% ethyl acetate/hexane) to give 3.0 g of the desired product 0 (1:1 mixture of isomers).

1 H INU((C.l 3 7.23(dd,2H,J=l.7 and 6.86(d,2H,J=8.5Hz); 4.05(dt,lH); 3.81(s,3H,ArOMe); 3.77(s,2H,CH Ar); 3.45(m,lH); 3.4(,2HJIJ S...2.96(dd,lH,J=8.74 and 13.34 Hz) 2.81(t,lH,J=14.6Hz); 2.58(brs,1H,OH); 2.45(m,2H); 2.22(dt,1H,J=8.78 and *.25 13.82 Hz); l.97(dt,lH,J=11.0g and 13.34 Hz).

IR(neat): 3503, 1610 and 1512 cm.

ExamDle 178 Tetrahydro-4 r r (4 -methoyphenyl) methyl 1 thio 1 2 -thionhenemethanol methanesulfonate 1. 1-dioxide A 0 0C solution, under argon, of 2.53 g of product from Example 177 in 27 ml of dry methylene chloride is treated, sequerqtially, with 1.4 ml of triethylamine and 0.77 ml of methanesulfonyl chloridei.

The reaction is allowed to warm to room temperature over 1.5 hours. Th e mixture is diluted with diethyl ether, filtered through a short column of silica gel (diethyl ether and 50% methylene chloride/ethyl -201acetate) to give 3.087 g of the desired product (mixture of isomers).

1 H NMR(CDC1 3 7.22(d,2H,J=8.7 Hz); 6.87(d,2H,J=.8.7 Hz); 4.45(m,2H); 3.81(s,3H,ArOMe); 3.77(s,2H,CH 2 Ar); 3.50-3.20(m,4H); 3.10(s,3H,OSO 2 HMe); 2.85 1H); 2.56(m,1H); 2.27(m,1H); 1.80(m,1H).

IR(neat): 2837, 2107, 1610 and 1584 cm-1 Example 179 2- (Az idomethv1l tetrahvdro-4- r r(4-methoxy~henvi) methyl 1thiolthio~hene 1.1-dioxide A mixture, under argon, of 2.94 g of product from Example 178, 0.757 g of lithium azide and 8 m1 of dry dimethylformamide is stirred vigorously at 65 0Cfor 4 hours. The reaction mixture is diluted with 60 ml of water and extracted with diethyl ether and ethyl acetate. The combined organic layers are washed with *.saturated sodium chloride, dried and concentrated in ~.:vacuo. The residue is purified by chromatography (silica gel: 0-50% ethyl acetate/hexane) to give 1.89 g V 20 of the desired product (mixture of isomers).

H NMR(CDC1 3 :6 7.22(dd,2H,J=2.os and 8.6Hz); 6.87(d,2H,J=8.6); 3.81(s,3H,ArOMe); 3.77(d,2H,CH 2 Ar); 3.58(dd,1H,J=5.77 and 13.19Hz); 3.35-3.20(m,2H); 2.88(m,2H); 2.60(m,2H); 1.75(m,1H).

IR(neat): 2837, 2107, 1610 and 1584 cm- Exa ple 180 *..Tetrahvdro-4 -r r (4 -methoxvphenyl Imethyl 1thio -2 -thionhenemethanamine 1.1I-dioxide (stereoisomers) A 0 0C solution, under argon, of 1.4 g of product from Example 179 in 14 ml of dry methylene chloride is treated with 1.19 ml of triethylanine.

Hydrogen sulfide gas is slowly bubbled through the cold solution for 20 minutes (the excess gas is trapped in a flask containing an aqueous solutin of 5.25% sodium hypochlorite). The mixture is stirred at 0 0 C for 2 hours, the flask flushed for 20 minutes with argon and the reaction is concentrated in~ vacuo. The residue is -202purifiled by chromatography (silica gel: 10-100% ethyl acetate/hexane, 5% =ethyl alcohol/ethyl acetate) to give 0.757 g of the desired product (mixture of isomers).

1 H NMR(CDCl 3 7.22(d,2H,J=8.5lHz); 6.85(d,2H,J=8.5OHz); 4.26(br s,l1H); 3.82(s,3H,ArOMe); 3.77(s,2H,CH 2 Ar); 3.40(m,lH); 3.3-3.l0(m,3H); 3.9(dd,lH); 2.50(m,lH); 2.35(br s,2H,NH 2 2.33(t,lH,J=7.l6Hz); l.82(m,lH).

CI-MS: m/z 302 (M Example 181 cis (and trans) -rTetrahvdro-4- rrF(4-methoxy~henvl) methyl ithiol -2-thienylicarbamic acid (4-nitrop~henyl) methyl-ester S. S-dioxide A 0 C solution, under argon, of 0.757 g of *product from Example 180 in 8 =1 of dry methylene is treated with 0.812 g of p-nitrobenzyl chloroformate and 525 pl of triethylamine. The reaction is stirred overnight, diluted with water, extracted with methylene chloride, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel: 10-100% ethyl .acetate/hexane) to give 0.756 g of the desired product (mixture of isomers).

1 H NMR(CDCl 8.21(d,2H,J=8.74Hz); 7.50(d,2H,J=8.74Hz); 72(,HJ86H) 6.19(d,2H,J=.3H) ArNO lN) 5.19s,2,CH2 AO2) 3.81(s,3H,ArOMe); 3 75 (s,2H,CH 2 ArOMe); 3.69(m,1H); 3.49(m,lH); 3 3 8-3.15(m,3H); 2.82(m,lH); 2.53(m,1H); 2.20(m,lH); IR(KBr): 3389 and 1706 cm- 1 -203- 0 Examiple-182 r (Tetrahvdro-4-mercalto-2-thienyl methyl I carbamic_ acid (4-nitrophenvl) methyl ester thionhene-1. 1-dioxide stereoisomers A solution of 0.756 g of product from Example 181 in 31 ml of 80% acetic acid/water is treated with 0.35 ml of anisole and 0.805 g of mercuric trifluoroacetate. The reaction is stirred for 2 hours, diluted with water and hydrogen sulfide gas is bubbled through the solution for 5 minutes. The mixture is filtered, washed with a minimum of water and the filtrate concentrated in vacuo. The black precipitate is washed with ethyl acetate and concentrated in vacuo. The two extracts (water and ethyl acetate) appear to be identical by thin layer chromatography. The extracts combined and purified by chromatography (silica gel: 15-80% ethyl acetate/hexane) to give 0.44 g of the **desired product (3:2 mixture of isomers).

1 H NMR(CDC1 3 :6 8.23 (d,2H,J=8.7OHz); 7.50(d,2H,J=8.7OHz); 5.55(t,lH,NH); 5.21(s,2H, CH 2 ArNO 2 3.82-3.40(m,5H); 3.l1(m,lH); 2.94(dd,lH,J=ll.54 and 12.50Hz); 2.70(m,lH); 2.33(m,lH); 2.l0(d,lH,J=7.2Hz, SH of minor isomer); l.98(d,1H,J=7.2Hz, SH of major isomer); l.78(m,lH).

CI-MS: m/z 361 (MH Example 183 r4R-r4a. 5,86B6(R*) 11-6-(1-Hvdroxyethyl)-4-methvl-7-oxo- 3 -r r tetrahvdro-5- r r r r (4 -nitro~henyl) methoxy 1carbonyl I amino 1methy1-3 -thieny 1 thio az abicclo r 3 2. 0 hept- 2-ene-2-carboxvlic acid (4-nitrophenvl)methvl ester thiophene-S .S-dioxide The title compound is prepared by the procedure of Example 143 using 0.44 g of product from Example 182, 0.659 g of Example 15, 4 ml of dry acetonitrile and 0.143 g of Hunig's base to give, after chromatography (silica gel:l0-100% ethyl -204- W acetate/hexane), 0.*742 g of the desired product (mixture of isomers and trans isomer pure).

1 H NMR(CDC1 3 8.22(d,2H,J=8.5Hz) 8.21(d,2H,J=..5Hz); 7.64(d,2H,J=8.5Hz); 7.49(d,2H,J=8.5Hz); 5.66(brt,lH,NH); 5.49(d,lH,J=13.7Hz); 5.21(d,lH,J=13.7Hz); 5.2(d,2H,J=6.31Hz); 4.28(m,2H); 4.13(m,1H); 3.8-3.45 4H) .3.31 1H) 3.13 1H); 2. 3 5(t, 2H, J=6. 5Hz) 2. 0O0(br s, 1H) 1. 3 5(d, 3H, J=6. 24Hz); 1.26 (d,3H,J=6.2Hz).

IR(KBr): 3419, 3079, 1772 and 1719 cm MS(FAB): m/z 705(M r 4R-r 4a. 5B.68 (R 11-5-Amino-2-S-r2-carboXy-6- 15 (1-hvdroxvethyl) -4-methvl-7-oxo-1-azabicvclor3 .2.01 hept-2-en-3-vl 1-1.2.3.4. 5-Dentadeoxv-1. 4-epithio-2thio-L-threo-pentitol S 1 S -dioxide (Cis) .:rR-r4a,5fl.68(R 111-1-Amino-4-S-r2-carboXy-6- (1-hvdroxvethyl) -4-methvl-7-oxo-l-azabicyclo r3.2.01 hept-2-en-3-vll-1. 2.3.4. 5-tentadeoxy-2 2 2_ 4-thio-D-erythro-pentitol S S -dioxide (trans) r 4R- r 4r.5B, 6,6(R 11-3-r5-(Aminomethl)tetrahvdro-3thienyll-6-(1-hvdroxyethyl) -4-methvl-7-oxo-1-azabicyclor3.2. Olhept-2-ene-2-carboxylic acid thiorphene-SS-dioxide (mixture) dreThe title compound is prepared by the procedur of Example 18 using 0.502 g of product from Example 183, 0.205 g of 10% palladiumr on carbon, 24 ml of dioxane: 0.1M phosphate buffer to give, after chromatography (C is reverse phase chromatography plates: 5% ethyl alcohol/water), 0.014 g of the cis isomer, 0. 013 g of -the trans isomer and 0. 024 g of mixture of cis and trans isomers.

Cis Isomer: 1 NMR(D 2 0):6 4 .18(m,2H), 3.95-3.50(m,6H); 3.48-3.20(m,5H); 2.B2(m,lH); 1.90(m,lH); l.23(d,3H,J=6.2Hz); 1.16(d,3H,J=6.2Hz).

-205- V IR(KBr): 3538, 3410, 1748 and 1622cm- 1 Example 185 3 r r 5- (Az idomethyl) tetrahvdro-3 -furanyl 1 thio -4 -methyl 6-r I- r r (2-methylpropoxv) carbonyl 1 oxyl ethyl 1 -7-oxo-jazabicyclor3 Olhe~t-2-ene-2-carboxvlic acid (4-nitrophenvi) methyl ester diatereomers Using anhydrous conditions, 1.25 g of product from Example 45 in 27 ml of anhydrous tetrahydrofuran, is cooled to -78 0 C under argon. 0.325 ml of isobutyl chioroformate is added, followed by 2.7 ml of lithium bis(trimethylsilyl)amide. The reaction mixture is stirred at -78 0Cfor 1 hour, followed by stirring at -55 0Cfor another hour and then concentrated in vacuo. The residue is purified by 15 chromatography (Silica Gel: 50% ethyl acetate/hexane) to give 1.22 g of the desired product.

1 H NMR(CDCl :6 8.21 2H) 7.67 2H) 5.50 (d,lIH); 5.25(d,lHM); 5.15(t,lH,HCOCO); 4.27-4.33(m,3H); 3.8l-3.95(m,3H); 3.68-3.73(m,lH); 3.31-3.55(m,3H); 3.22-3.31(m,lH); 2.2-2.3(m,lH,CH(CH 2 *3 2); 1. 41 3H,CH 3 1.32(m,3H,CH 3 .4d6,C32) IR(neat): 2101, 1777, 1741 'and 1716 cm- 1 Examiple 186 3-r r5-(Amninomethyl) tetrahvdro-3-furanyllthiol-4methvl-6-r i-r r (2-methypropoxy) carbonyl loxylethvl-7oxo-1-azabicvclor3. 2. Olhept-2-ene-2-carboxylic acid diastereomers The title compound is prepared by the procedure of Example 18, using 1.22 g of product from Example 185, 0.764 g of 10% palladium on carbon, 21 ml of 0.lM sodium phosphate buffer (pH 7.0) and 78 ml of dioxane to give 0.122 g of the desired product.

-206- Ex*mle 187 1.4-Anhvdro-2-deoxv-D-ervthro-entitoi dimethanesulfonate The title compound is prepared by the procedure of Example 178 using 0.173 g of 1,2-dideoxy-Dribose prepared by the method of M. Takeshita et at., J.Bio.Chem., (1987), 262(21), 10171, 249 p1 of methanesulfonyl chloride and 3 ml of pyridine to give 0.310 g of the desired product after chromatography.

1H NMR(CDCl 3 5.l8-5.15(m,H); 4.4-4.31(m,2H); 4.3-4.25(m,H): 4.15-4.06(m,lH); 4.0-4.9(m,H); 3.1(s,3H,CH 3 3.09(s,3H,CH 3 2.3-2.2(m,2H).

Example 188 1.4-Anhvdro-5-azido-2.5-dideoxv-D-erythro-Dentitol 3 -methanesul fonate :The title compound is prepared by the procedure of Example 43 using 3.57 g of product from Example *:187, 0.726 g of lithium azide and 58 ml of dimethylformamide to give 2.12 g of the desired product after chromatcgraphy.

1 1H NMR(CDCl 3 5.08-5.04(m,lH); 4.2-4.09(m,2H); 3 .98-3.89(m,lH); 3.56-3.38(dd,2H); 3.06(s,3H,C 3 2.34-2.22(m,2H).

Example 189 2.5-Anhvdro-1-azido-1.4-dideoxv-3-thio-D-threo-pentitoI 3-acetate The title compound is prepared by the procedure of Example 5 using 1.57 g of product from Example 188, 0.892 g of potassium thioacetate, 10 ml of dimethylformamide and 10 ml of toluene to give 0.30 g of the desired product after chromatography.

1 H NMR(CDCl 3 4.28-4.2(m,lH); 4.2-4.1(dd,lH); 4 .08-3.98(m,lH); 3.89-3.79(dd,lH); 3.4-3.3(m,2H); 2 .5-2.35(m,lH); 2.36(s,3H,Ac); 2.05-1.9(m,lH).

-207- 0 Example-190 2. 5-Anhydro-l-azido- 4-dideoxv-3-thio-D-threo-Deititol The title compound is prepared by the procedure of Example 16 using 0.30 g of product from Example 189, 0.35 ml of sodium methoxide/methyl alcohol (25 wt and 5 ml of tetrahydrofuran to give 0.219 g of the desired product after chromatography.

1 H NMR(CDCl 3 :6 4.1-4.0(m,2H); 3.9-3.8(m,lH); 3.55-3.43(m,3H); 2.55-2.4(m,1H); 2.06-2.94(m,lH); l.65-l.62(d,lH,SH).

Example 191 r4R-r4ck.5B.6Bi(R 2. 5-Anhvdro-1-azido-1,.4-dideoxv-3-S-rF6-C 1-hvdroXyethyl)~-4-methvl-2- r[r4-nitro~henvi ~methoxvl carbonyl 1-7oxo-l-azabicyclor3.2.Olhet-en-3-vll-3-thio-D-threooentitol ***The title compound is prepared by the procedure of Example 17 using 0.219 g of product from Example 190 in 3 ml of acetonitrile, 0.818 g of product 20 from Example 15 in 4 ml of acetonitrile, and 186 p1 of *:Hunig's base to give 0.436 g of the desired product after chromatography.

H NMR(CDCl 3 :6 8.20(d,2H); 7.65(d,2H); 5.51(d,lH); 5.21(d,lH); 4.3-4.2(m,3H); 4.17-4.09(m,lH); 3.94-3.8(m,2H); 3.6-3.4(m,3H); 3.37-3.30(mlH); 2.67(bs,lHOH); 2.5-2.4(m,lH); 2.2-2.05(m,lH); .35(d,3H,CH 3 l.28(d,3H,CH 3 Example 192 r4R-r4a.58.68(R )I1l-Amino-2,.5-arhvdro-3-S-r2-carboxy-6- (l-hydroxvethvJA 4-methvl-7-oxo-1-azabicVclor3.2. Olheipt-2-en-3-vll-1 .4dideoXy-3 -thio-D-threo-pentitol The title compound is prepared by the procedure of Exa mple 18 using 0.436 g of product from Example 191, 0.150 g of palladium on carbon, 9 ml of 0.lM sodium phosphate buffer (pH 7.0) and 13 ml of -208- IW dioxane to give 0. 122 g of the desired product after chromatography.

1 H NMR(D 2 0):6 4.29-4.18(m,2H); 4.12-4.02(m,1H); 4.O-3.85(m,2H); 3.5-3.4(m,2H); 3.35-3.25(m,1H); 3.2-3.1(m,1H); 2.5-2.4(m,1H); 1.27(d,3H,CH 3 1.17(d,3H,CH 3 Exan~le 193_ r 4R- r4a. 5B. 68(R I1 2. 5-Anhvdro-3-s- r2-carboxy-6- (1-hydroxvethvl 1-4-methyl 7-oxo-1-azabicyclor3.2. Olhent-2-en-3-vll-1.4-dideoxy-.

I- r (iminomethyl I aminol -3-thio-D-threo-nentitol To 4 ml of a 5%C phosphate buffer (ph solution is added 0.052 g of product from Example 192 *and 0.832 g of ethyl formimidate hydrochloride, in portions. The pH is maintained at 8.5 with lN sodium hydroxide. The solution is stirred at 50C and pH for 5 minutes, then the pH is adjusted to pH 7.0 with hydrochloric acid and the reaction mixture is concentrated in vacuo with no heat. The residue is S 20 purified on a C 18reverse phase chromatography plate aqueous ethyl alcohol) to give 0. 055 g of the desired product.

1 NMR(D 2 0) :6 7.75-7.6(t,lH,CH=); 4.5-3.2(m,llH); 2-25m,1H;1.(m,1);l.l(d,3H,CH 3 0.99(d,3H,CH 3 Examp~le 194 3-rr-(Aidmthtetrahvdro-3-furanlthiol4methl- 6- r I- r r (2-methylpropoxv) carbonyl 1oxvl ethyl I -7-oxo-1azabicvclor3.2 .Olhelpt-2-ene-2-carboxylic acid (4 -nitrophenyl) methyl ester diastereomers The title compound is prepared by the procedure of Example 185 using 1.00 g of product from Exmaple 63 in 20 ml of tetrahydrofuran, 0.26 ml of isobutyl chloroformate and-2.2 ml of 0.lM lithium bis(trimethylsilyl)amide to give 0.636 g of the desired product after chromatography.

1 H NMR(CDC1 3 8.23(d,2H); 7.66(d,2H); 5.49(d,lH); 5.26(d,lH); 4 2 2-4.16(m,3H); 3.93(m,2H); 3.84(m,2H); -209- 3.47-3.36(m,4H); 2.5(m,-HjcHCH 3 1.97(m,1H); 1.7(m,0.5H); 1.85(m,.0.5H); 1.49(d,3H,CH 3 1.29(t,3H,CH 3 0.94(d,6H,2CH 3 -1 IR(neat): 2100, 1777, 1741 and 1707cm Examiple 195 3- r r5-Aminomethvl) tetrahvdro-3-furanyll1thiol -4methvl-6- r1- r r(2-methyi~ropoxy) carbonyi 1oxvl ethyl 1-7oxo-1-azabicyclor3 0]heipt-2-ene-2-carboxvlic acid diastereomers The title compound is prepared by the procedure of Example 18 using 0.764 g of product from Example 194, 0.478 g of palladium on carbon, 13 ml Of sodium phosphate buffer (pH 7.0) and 49 ml of dioxane to give after chromatography 0.0668 g of the desired product.

H NMR (D 2 0) :6 4. 2(m, 2H); 4.l1(m, 1H) 3. 95 2H); 3.8(m,3H); 3.65(m,lH); 3.35(m,1H); 3.13(m,2H); 2.6(m,lH); l.92(m,lH); l.6(m,lH); 1.35(d,3H,CH 3 l.18(dd,3H,CH 3 O.88(d,6H,2CH 3 Example 196 3. 6-Dioxabicyclo r3.*1401 hexane A 0 0 C solution, under argon, of 5 g of in 85 ml of methylene chloride is treated with 13.54 g of 85% n-chloroperbenzoic acid.

The reaction mixture-is allowed to warm to room temperature overnight. The reaction mixture is filtered and the filtrate stirred for 10 minutes with saturated sodium carbonate and the two layers separated. The organic layer is dried and concentrated in vacuo to give an oil. The oil is distilled under vacuum (water' aspirator) to give 3.93 g of the desired epoxide.

1 H NMR(CDCl 3 4.03(d,2H,J=lo.5Hz); 3.81(s,2H); 3.66 HS(CI):mx/z 87 (M -210- V Example 197 Tetrahvdro-4-hvdroxv-3-furancarbonitrile To 5.0 g of product from Example 196 is added 29 ml of 1M diethylaluminum cyanide at room temperature. The reaction is exothermic. The mixture is stirred for 3 hours, quenched very carefully with ethyl alcohol, as the evolved gas is hydrogen cyanide, cooled to 0 C and stirred until the reaction warms up to room temperature. The reaction is then flushed with argon for 10 minutes, concentrated in vacuo to about 15 ml, and filtered through a pad of diatomaceous earth. The pad is washed with methyl alcohol and diethyl ether.

The combined organic layers are refiltered and 15 concentrated in vacuo to give 0.383 g of the desired product.

NMR(CDC1 3 4.69(m,lH); 4.22(dd,1H,J=7.3 and 9.12Hz); 4.05(m,2H); 3.8(dd,lH,J=2.71 and 10.11Hz); 3.06(m,1H); 2.83(br s,lH,OH).

20 MS(CI): m/z 114 Example 198 (3R-trans)-Tetrahvdro-4-r(methylsulfonyl)oxyl- 3-furancarbonitrile The title compound is prepared by the procedure of Example 178 using 0.367 g of product from Example 197, 0.394 g of triethylamine, and 0.446 g of methanesulfonyl chloride to give 0.554 g of the desired product.

1 H NMR(CDCl 3 5.41(m,lH); 4.24(dd,1H,J=7.16 and 9.13Hz); 4.18-3.98(m,3H); 3.41(m,1H); 3.19(s,3H,SO 2

CH

3 MS(CI): m/z 192 Example 199 (3R-cis)-Tetrahvdro-4-r r [4-methoxvphenvl)methvl1thiol- 3-furancarbonitrile A 0 C slurry, under argon, of 0.14 g of sodium hydride in tetrahydrofuran is treated dropwise -211- 4 with 0.47 ml of 4-methoxytoluenethiol. The reaction mixture is allowed to warm to room temperature over minutes, followed by the dropwise addition of 0.539 g of product from Example 198 in 3 ml of tetrahydrofuran.

The reaction is stirred for 45 minutes and then cooled to o0C. The mixture is diluted, carefully, with water and extracted with diethyl ether. The organic layers are washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by chromatography (Silica gel: 5-40% ethyl acetate/hexane) to give 0.583 g of the desired product as an oil.

1 H NMR(CDC1 3 7.26(d,2H,J=8.7Hz); 6.87(d,2H,J=8.7Hz); 4.05(m,3H); 3.82(s,2H,ArCH 2 S. 3.81(s,3H,CH30Ar); 3.46(m,2H); 2.91(m,lH).

15 MS(CI): m/z 250 Example 200 cis-(+/-)-Tetrahydro-4-rr(4-methoxvphenyv)methyllthiol- 3- furanmethanamine A room temperature solution, under argon, of 20 4.22 ml of 1.OM lithium aluminum hydride in tetrahydrofuran is treated, dropwise, with 0.876 g of product from Example 199 in 3 ml of diethyl ether; during which time the reaction refluxes gently. After complete addition, the reaction is stirred at room temperature for 2 hour. The reaction mixture is quenched with 1 ml of water, 10.5 ml of 1.ON sodium hydroxide and 2.0 ml of water. The solid white precipitate formed is collected and washed with large volumes of diethyl ether. The diethyl ether layer is concentrated in vacuo to give 0.889 g of the desired product.

1H NMR(CDC 3 :6 7.23(d,2H,J=8.61Hz); 6.87(d,2H,J=8.61Hz); 3.95(m,2H); 3.81(s,3H,OCH 3 3.73(s,2H,ArCH 2 3.47(m,2H); 2.82(m,3H); 2.31(m,lH).

MS(CI): m/z 254(M++H).

-212- Example 201 cis -Tetrahvdro-4-f r (4-methoxvDhenvl) methyl 1 thiol 3-furanvY methyl carbamic acid (4-nitrophenvl)methyl ester A 0 C mixture of 0.889 g of product from Example 200, 0.534 g of potassium carbonate, 0.832 g of p-nitrobenzyl chloroformate and 7 ml of dry tetrahydrofuran is stirred for two hours, while warming to room temperature. The solution is diluted with 50 ml of water and extracted with ethyl acetate. The ethyl acetate layers are washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel: 10-100% ethyl acetate/hexane) to give 0.931 g of the desired 15 product as a colorless oil.

1H NMR(CDC13): 6 8.17(d,2H,J=8.7Hz); 7.48(d,2H,J=8.7Hz); 7.22(d,2H,J=8.6Hz); 6.83(d,2H,J=8.6Hz) 5.17(s,3H,ArCH 2 and NH); 4.02(t,1H,J=7.2Hz); 3.92(t,1H,J=7.4Hz); 20 3.77(s,3H,OC.

3 3.69(s,2H,ArCH 2 3.52(m,2H); 3.22(t,2H,J=6.4Hz); 2.89(m,1H); 2.27(m,H).

MS(CI): m/z 432(M Example 202 S -fTetrahydro-4-mercapto-3-furanvl)methyl carbamic acid (4-nitrophenyl)methvl ester A room temperature solution, under argon, of 0.905 g of product from Example 201 in 30 ml of acetic acid is treated with 0.45 ml of anisole and 1.07 g of mercuric trifluoroacetate. The reaction mixture is stirred for 2.5 hours, diluted with 30 ml of water, hydrogen sulfide gas is bubbled through for minutes and the argon for 10 minutes. The black precipitate is collected, washed with water and ethyl acetate and the combined filtrate is concentrated in vacuo. The residue is purified by chromatography (silica gel: 10-60% ethyl acetate/hexane) to give 0.545 g of the desired product.

-213- 0 1 H MM (CDCl1 3 8.21(d,2H,J=8.7Hz); 7.51(d,2H,J=8.7Hz); 5.21(s,2H,ArCH 2 5.20(brs,lH,NH); 4.20(dd,1H,J=7.1 and 9.0Hz); 4.03(dd,lH,J=7.8 and 8.9Hz); 3.58(m,2H); 3.37(m,2H); 3.06(m,lH); 2.29(m,lH); 1.73(d,1H,J=7.74Hz,

SH).

MS(CI): m/z 313(M H).

Examnle 203 r 4R- r3 (3R* 4R *or 3S*.4S*),4cz.58.68(R fli- 6- (1-Hvdroxvethvl) -4-met]3yl-7-oxo-3-r Itetrahvdro-4- ITr r r (14-nitrophenvl) methoxy I carbonyl 1 amino Imethyl 1 -3 furanvlithio-l-azabicvclor3 Olhent-2-ene-2-carboxylic acid (4-nitronhenvl~methyl ester The title compound is prepared by the procedure of Example 17 using 0.49 g of product from Example 202, 0.933 g of product from Example 15, 0.202 g of Hunig's base and 8 ml of acetonitrile to give after 999 chromatography 0.771 g of the desired product.

1 H NMR(CDCl 3 8.21(d,2HJ=8.7Hz); :9 8.19(d,2H,J=8.7Hz); 7.61(d,2H,J=8.7Hz); 7.49(d,2H,J=8.7Hz); 5.49(d,1H,J=13.8Hz); .95.24(d,1HJ=13.8Hz); 5.19(s,3H,NH and ArCH 2 4.24(m,3H); 4.20(t,lH,J=8.9Hz); 3.68(m,2H); 3.53(m,lH); 3.39(m,1H); 3.26(m,2H); 2.36(m,lH); 2.0(brs,2H); 1.35(d,3HJ=6.3Hz); 1.21(d,3H,J=7.2Hz).

Example 204 9f4R-r3(3R .4R or 3S .4S*),4a,5(3,6P(R 3-r r4-(Aminomethv~tetrahdro-3-furanlthiol-6- (1-hydroxvethvl) -4 -methvl-7-oxo-1-azabicvclo r3.2.01hent-2 -ene-2 -carboxvl ic acid The title compound is prepared by the procedure of Example 18 using 0.136 g of product from Example 203, *0.041 g of 10% palladium on carbon and 8 ml of dioxane: 0.2M phosphate buffer (pH 7) to give, after chromatography (C 18 reverse phase plates: 5% ethyl alcohol/water), 0.007 g of the desired product.

-214- Hi NMR (D 2 0) :6 4.19 3.75(m,lH); 3.58(m,3H); 3.42(m,lH); 3.25(m,2H); 3.l0(m,lH); 2.43(m,1H); 1.26(d,3H,J=5.7Hz); 1..l8(d,3H,J=6.7Hz).

Exml 0 Tetrahvdro-4 -merca]nto-2 -thionhenemethanol 1.1-dioxide stereoisomers The title compound is prepared by the procedure of Example 202 using 0.615 g of product from Example 177, 1.04 g of mercuric trifluoroacetate, 0.440 g of anisole and 31 ml of S0% acetic acid to give, after chromatography (Silica gel: 10-100% ethyl acetate/hexane), 0.322 g of the desired product.

1 H NMR(CDCl 3 :6 4.12(m,2H); 3.90(m,2H); 3.75(m,1H); 3.50(m,3H); 3.32(m,lH); 3.l0(dd,lH,J=8.5 and 13.4Hz); 2.93(t,lH,J=ll.5Hz); 2.75-2.58(m,2H); 2.38-2.20(m,3H); 2.10(d,1H,J=7.4Hz minor isomer SH); l.98(d,lH,J=7.4Hz major isomer SH) .MS(CI): m/z 183(M+H) Example 206 r 4R- r4a. 5,8,6,8(R 6- (1-Hvdroxvethvl) -4-methvl-7-oxo-3-rF (hvdroxvmethvl)-3-thienlithiol-.1..azabicclor3 2 .0 hept-2-ene-2-carboxylic acid 14-nitrophenvl) methyl ester stereoisomers The title compound is prepared by the procedure of Example 17 using 0.995 g of product from a. Example 15, 0.305 g of product from Example 205, 0.216 g of Hunig's base and 5 ml of acetonitrile to give, after chromatography (Silica gel: 20-100% ethyl acetate/hexane), 0.789 g of the desired product.

1H NMR(CDCl 3 8.22(d,2H,J=8.8Hz); 7.65(d,2H,J=8.8Hz); 5.51(d,lH,J=13.8Hz); 5.23(d,lH,J=l3.8Hz); 4.08(m,lH); 3.85(m,2H), 3 o6-3.3(m,4H), 3.02(t,lH,J=6.7Hz); 2.63(m,1H), 2.35(brs,21); 1.37(d,3H,J=7.2Hz); l.29(d,3H,J=7.2Hz).

HS(CI): m/z 527 (H -215- O Example 207 r4R-r4a. 58, 68 (R 1- 6- (-Hvdroxvethyl) -4-methvl-7-OX-3-r (hvdroxvmethvl -3-thienvl1thiol-1-azabicvclor3.2.0 heDt-2-ene-2-carboxylic acid thiophene-1.1-dioxide stereoisomers The title compound is prepared by the procedure of Example 18 using 0.208 g of product from Example 206, 0.033 g of sodium bicarbonate, 0.066 g of 10% palladium on carbon and 10 ml of dioxane/water to give, after chromatography (C18 reverse phase plates: 4% ethyl alcohol/water), 0.140 g of the desired product.

1 H NMR(CDCl 3 4.22(m,2H); 4.07-3.20(m,8H); 2.70(m,lH): 1.88(m,lH); 1.25(d,3H,J=6.4Hz), e 1.17(brs,3H).

MS(FAB): m/z 414 Example 208 (R)-l-Phenoxv-5-hexen-2-ol 20 Under anhydrous conditions at -78°C, 475 ml of 1M solution of allylmagnesium bromide in diethyl S: ether and 60 ml of triethyl borate in 400 ml of diethyl ether are added simultaneously, but separately, to 400 ml of diethyl ether. The reaction is stirred at -78°C for 3 hours, warmed to 0°C, 450 ml of 2N hydrochloric acid is added carefully and stirred at room temperature for 2 hours. The layers are separated and the organic layer is dried over magnesium sulfate. The diethyl ether layer is filtered and concentrated in vacuo to 100 ml. The residue is dissolved in 400 ml of diethyl ether and treated with 77.8 g of (-)-diisopropyl D-tartrate. The reaction is stirred overnight at room temperature under argon. Ten grams of magnesium sulfate is added and the mixture stirred for 20 minutes, filtered and concentrated in vacuo. The residue is purified by Kugelrohr distillation (at 0.15mm Hg, bp 100-130 C) to give 72.30 g of the desired borate ester.

-216- Under anhydrous conditions (argon) at -78 0 c, 20.24 g of (phenylmethoxy)acetaldehyde in 17.35 ml of toluene is added to a mixture of 72.3 g of borate ester in 1000 ml of toluene and 54.22 g of 4A 0 molecular sieves. The mixture is stirred at -78 0 C for 16 hours.

The reaction is filtered, the sieves washed with toluene and the filtrate is poured into 800 ml of water. The layers are separated, the organic layer dried and concentrated in vacuo. The residue is redissolved in 725 ml of diethyl ether and treated with IM potassium hydroxide for 24 hours at room temperature. The layers are separated, the organic layer is washed with saturated sodium bicarbonate, dried and concentrated in vacuo. The residue is purified by Kugelrohr distillation (1-2mm Hg, bp 9 100-110 C) to give 10.44 g of the desired product.

Calcd. C 12H 160 2 C: 74.69; H: 8.39 C: 74.69; H: 8.42 (a2 6 =_30 +1 in CHCl 3 20 Example 209 2.5-Anhydro-l, 3-dideoxy-l-iodo-L-threo-pentitol and 1. 4-Anhydro-3. To a vigorously stirred 3 C solution of 10.44 g of product from Example 208 in 200 ml of diethyl ether and 68 ml of water is added 6.76 g of 9. solid sodium bicarbonate, in one portion, followed by 20.33 g of iodine. The reaction mixture is stirred at room temperature for 1 1/2 hours and a saturated sodium sulfite solution is added slowly until the yellow color disappears. The layers are separated, the organic layer is dried ani concentrated in vacuo to give 11.8 g of a light yellow oil. The residue is purified by chromatography (Silica gel: 20-50% ethyl acetate/hexane) to give 2.14 g of the cis isomer and 3.6 g of trans isomer.

trans isomer: -217- 1 H NMR(CDCl 3 4.59(t,lH); 4.25-4.12(m,lH); 4.41-4.02(m,1H); 3.8(d,lH); 3.2(d,2H); 2.7(s,lH); 2.2-2.l(m,lH); 1.82-1.75(m,lH).

cis isomer: 1 H NMR(CDCl 3 :6 4.5(m,lH); 4.18-4.O(m,lH); 4.0-3.9(M,lH); 3.82-3.78(m,1H); 3.42-3.3(m,2H); 3.82(bs,lH,OH); 2.4-2.3(m,1H); 1.82-l.75(m,lH).

Examp~le 210 1. 4-Anhvdro-5-azido-3.5-dideoxv-D-erthro-Dentitol A mixture of 3.6 g of the trans isomer from Example 209, 1.54 g of lithium azide and 6 ml of dimethylformamide is heated in a 70 0 C oil bath for 3 hours. The reaction mixture is concentrated in vacuo.

The residue is purified by chromatography (Silica gel: 75% ethyl acetate/hexane) to give 1.88 g of the desired product.

H 1 NMR (CDCl 3 :6 4.56 1H) 4.4 1H) 4.l1(d, 1H); 3 -8 (m,l1H) 3. 51 (m,l1H) 3. 25 (dd, 1H) 2. 3(bs,1H, OH); 2.08-1.85(m,2H).

20 Example 211 1. 4 -Anhvdro- 5 -a z ido 3 5 -dideox D- e rth ro-Rent ito 1 2- (trifluoromethanesulfonate) Thetilecompound is prepared by the prce dure of Example 22 using 0.716 g of product from Example 210 in 4 ml of =ethylene chloride, 0.925 ml of trifluoromethanesulfonic anhydride in 7 ml of methylene chloride and 0.445 ml of pyridine to give, after chromatography (Silica gel: 75% ethyl acetate/hexane), 0.985 g of the desired product.

1H NMR(CDCl 3 5'.57(m,lH); 4.42(m,lH); 4.3-4.l(m,2H); 3.6(dd,1H); 3.3(dd,1H); 2.4-2.3(m,1H); 2.3-2.18(m,lH).

-218- W Example 212 2. 5-Anhydro-l-azido-1. 3-dideoxy-4-thio-D-threo-nentitol 4-acetate The title compound is prepared by the procedure of Example 5 using 0.985 g of product from Example 211, 0.450 g of potassium thioacetate and 10 ml of acetonitrile to give,- after chromatography (Silica gel: ethyl acetate/hexane), 0.510 g of the desired product.

1 H NMR(CDCl 3 4.2-4.1(m,2H); 4.08-3.98(m,1H); 3.8-3.7(m,1H); 3.5-3.4(dd,1H); 3.38-3.28(dd,1H); 2.52-2.42(m,1H); 3.34(s,3H,CH 3 l.75-1.65(m,1H).

Example 213 2. 5-Anhvdro-l-azido-1. 3-dideoxv-4-thio-D-threo-Dentitol 15 The title compound is prepared by the procedure of Example 16 using 0.510 g of product from Example 212, 0.6 ml of 25wt% sodium methoxide/methyl alcohol and 10 ml of tetrahydrofuran to give, after chromatography (Silica gel: 30% ethyl acetate/hexane), 20 0.318 g of the desired product.

1 H NMR(CDCl 3 6 4.2-4.05(m,2H); 3.65-3.60(m,lH); 3 .5-3.25(m,3H); 2.55-.2.4(m,1H); l.8(d,1H,SH); l.

7 5-l.6(m,1H).

Example 214 2 .5-Anhdro--azido-1didideox....s..r6.(.hydro.y ethyl) -4-methvl-2-rrF(4-nitrophenvl)methoxv1 carbonyl 1- 7 -oxo-l-azabicyclo r3.*2.01 hept-2-en-3-vl 1-4- D-threo-pentitol The title compound is prepared by the procedure of Example 17 using 0.318 g of product from Example 213 in 4 ml of acetonitrile, 1.18 g of product from Example 15 in 6 ml of acetonitrile and 0.27 ml of Hunig's base to give, after chromatography (Silica gel: ethyl acetate/hexane), 0.720 g of the desired Rroduct.

H NMR(CDCl 3 :6 8.24(d,2H); 7.67-7o65(d,2H); 5.53-5.48(d,1H); 5.26-5.22(d,lH); 4 29 -4.08(m,4H); -219- 3.79-3.74(m,2H); 3.46(3.27(mi4H); 2.52-2.45(m,lH); l.75-1.6(m,lH +1 OH); l.37(d,3H); 1.3(d,3H).

Examnile 215 r 4R- r 4a.5B. 68(R I 1-Amino-2 .5-anhvdro-4-S- r2-carboxv-6- -hvdroXvethvl i- 4-methvl-7-oxo-1-azabicyclo[3 Olhe~t-2-en-3-vll- 1.3 -dideoxv-4 -thio-D-threo-nent itol The title compound is prepared by the procedure of Example 18 using 0.720 g of product from Example 213, 0.496 gof 10% palladium on carbon, 15 ml of 0.1M sodium-phosphate buffer (pH 7) and 30 ml of dioxane to give, after chromatography (Reverse Phase Plates: 5% aqueous ethyl alcohol), 0.233 g of the desired product.

1H NMR(D 0):6 4.4-4.12(m,4H); 4.05-3.8(m,2H); .3.58-3.2(m,4H); 2.8-2.65(m,1H); l.8-l.6(m,1H); .35(d,3H); l.27(d,3H).' Example 216-253 Example 216 to 253 exemplify compounds of formula I obtained by the methods described hereinabove.

R

0 z S nR 2 0 C0 2

R

3 -220- (a Example Ro R 1 n ZR 2 R3 216 217 218 219 220 221 222 223 224 225 226 227 228 229 CH 3 CH(OH) CH 3

CH(OH)-

CH 3

CH(OH)-

CH 3 CH(OH) CH 3 CH(OH) CH 3 CH(OH) CH 3 CH(OH) CH 3 CH(OH) CH 3 CH(OH)

CH

3 CH(OH) CH 3 CH(OH) CH 3

CH(OH)-

CH 3 CH(OH) CH 3 C(OH) CM 3

CHM

3 CM 3 CH 3 CM 3

CHM

3

CHM

3

CHM

3

CHM

3

CHM

3

CHM

3

CHM

3 CH 3

CHM

3

H

OH

0CM C 2652 2652 NHCM 3 NHC 3 0CH 3 0CM 3 OCONH 2 OCONH 2 a *a a a a a 9 a a a.

a. a a.

'a a *aa.

a 4 9~~a a. a a.

.a -221to Example R, R1 N z R2

R

3 a a a a..

*0 a..

a a. a a 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249

CH

3 CH(OH)

CH

3 CH (OH)- CH 3

CH(OH)-

CH

3

CH(OH)-

CH

3 CH (OH)-

CH

3

CH(OH)-

CH

3

CH(OH)-

CH

3

CH(OH)-

CH

3

CH(OH)-

CH

3 CH (OH)-

CH

3

CH(OH)-

CH

3 CH(OH)

CH

3

CH(OH)-

CH

3

CH(OH)-

CH

3 CH (OH)-

CH

3

CH(OH)-

CH

3 CH (OH)-

CH

3

CH(OH)-

CH

3

CH(OH)-

CH

3

CH(OH)-

CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CR 3

CHR

3 CH 3 CH 3 CH 3 CH 3

CHR

3

CM

3 CH 3

CHR

3

CHR

3 CH 3

NHCH=NH

N=CHN(CH 3 2

N=CHN(CH

3 2 N'

(CH

3 3 N'(CH3)3

CONH

2

CONH

2 CON

(C

3 2

CON(CH

3 2 1-Pyridinium 1-Pyridinium

NH

2

NH

N

(CH

3 3 N+

(CR

3 3

NHCR=NH

NHCH=NH

N=CHN(CR

3 2

N=CHN(CH

3 2 -222-

S

Example N Z 2 as oo 0 250 HCton) CH, I a Ia U a UHC N Nit 0 251 CH 3 CH(OH) CH 1 0 II 252 CH 3 CH(OH)- CH 1 0 NC N aH 0 253 Cn 1 CH(OH)- CM 3 1 0 11

RCM

1 O N ExamDle 254 Carbonic acid 4-Nitrophenyl (4-Nitrophenyl)methyl Ester 5 To an ice cooled solution, under argon, of 7.3 g of p-nitrophenol and 7.5 ml of triethylamine in 36 ml of dry tetrahydrofuran, is added, dropwise, a solution of 10.78 g of p-nitrobenzyl chloroformate in 18 ml of dry tetrahydrofuran. The reaction mixture, a suspension, is stirrred at room temperature overnight.

The formed solid is collected, washed with water and dried to give 5.9 g of the desired product.

1 H NMR(CDCl 3 8.3(d,2H, J=3.OHz); 8.27(d,2H,J=3.OHz); 7.63(d,2H,J=8.7Hz); 7.40(d,2H,J=9.2); 5.41(s,2H).

.9 15__ Example 255 N-F[(4-Nitrophenyl)methoxvlcarbonyllalycine One and one half grams of glycine is slurried in 235 ml of a 80/20 mixture of ethyl alcohol/water.

To this is added 5.6 ml of triethylamine, solution occurs, followed by 6.36 g of product from Example 254.

A precipitate forms and the.reaction is stirred overnight at room temperature. The reaction mixture is concentrated in vacuo. The resulting oil is dissolved in water and ethyl alcohol, the pH is adjusted to with concentrated hydrochloric acid and the volume is -223- 3 reduced. The reaction mixture is extracted with methylene chloride, the organic layer is washed with water and concentrated in vacuo. The residue is purified by chromatography (Silica gel: ethyl acetate) to give 2.83 g of the desired product.

Example 256 r2-r(2.5-Dioxo-l-pvrrolidinvl)oxvY- 2 -oxoethyllcarbamic acid (4-Nitrophenvl)methyl Ester To a solution of 2.83 g of product from Example 255 in 43 ml of dioxane is added 1.28 g of N-hydroxysuccinimide and 2.30 g of 1,3-dicyclohexylcarbodiimide, hereinafter called DCC, in 13 ml of dioxane.

The formed suspension is stirred at room temperature overnight. The urea by-product is collected and the 15 filtrate is concentrated in vacuo to give an oil. The oil is dissolved in methylene chloride, washed with water, the layers are separated and the organic phase is cooled. The formed crystals are collected and dried to give 1.87 g of the desired product.

20 H NMR(CDC13):6 8.09(d,2H,J=8.7Hz); 7.21(d,2H, J=8.7Hz); 6.8(t,lH,NH); 5.13(s,2H); 4.19(d,2H); 2.74(s,4H).

Example 257 F3-S-r4R-r4a.58 .66(R 111-1-r (Aminoacetyl)aminol- 2.5-anhvdro-3-S-r2-carboxy-6-(l-hydroxethyl)-4remm methvl-7-oxo-l-azabicvclof3.2.0.1heDt-2-en-3-yl1-1,4dideoxy-3-thio-D-threo-pentitol To a 0-2 0 C solution of 5 ml of 0.M sodium dihydrogen phosphate buffer, pH 7.0, is added 0.171 g of product from Example 192 followed by the adjustment of the pH to 8.5 with lN sodium hydroxide. A solution of 0.175 g of product from Example 256 in 3.5 ml of dioxane is added while maintaining the pH at 8.5 with lN sodium hydroxide. After 5 minutes of stirring, a tlc sample shows no starting material present. The pH is adjusted to 7.0 and 0.055 g of 10% palladium on carbon is added. The reaction mixture is reduced in a -224- Parr apparatus, at 44 psi of hydrogen for 3. hours. The mixture is filtered, the filtrate concentrated ini vacuo to a small volume, and extracted with ethyl acetate. The aqueous phase is further concentrated and purified by reverse phase chromatography aqueous ethyl alcohol) to give 0.065 g of the desired product.

1 H NMR(D 2 0):S 4.4-4.15(m,3H); 4.15-4.02(m,lH); 4.02-3-65(M,4H); 3.65-3.35(m,4H); l.30(d,3H,Me, J=6. 5Hz); l.20(d,3H,Me,J=7.OHz).

Example 258 N- r r(4-Nitronhenyl )methvlcarbonvl]1-L-alanine The title compound is prepared by the procedure of Example 255 using 5.3 g of product from Example 254, 1.48 g of L-alanine, 4.6 ml of triethylamine, and 15 200 ml of 80/20 ethyl alcohol/water. The resulting oil .is purified by chromatography (3X, silica gel: ethyl acetate/hexane)'to give 3.A9 g of the desired product.

1H NI4R(CDCl 3 11. 0(s,l1H, COOH); S.04 2H, J=S.6Hz); 7.4 2H, J=8. 6Hz) 5. 9(d,l1H,KH); 5. 1(s, 2H) 4. 3(t,l1H, CH); l.36(d,3H,Me,J=7.2Hz).

Example 259 -r2-r (2.5-Dioxo-1-pyrrolidinyl) oxv1 -1-methvl-2oxoethyllcarbamic Acid (4-Nitrophenvl)methyl Ester The title compound is prepared by the procedure of Example 256 using 11.85 g of product from Example 258 in 170 ml of dioxane, 5.08 g of N-hydroxysuccinimide and 9.12 g of DCC in 46 ml of dioxane to give 9.8 g of the desired product.

1H NMR(CDCl 3 8.21(d,2H,J=8.5Hz); 7.51(d,2H,J=8.5); 5.55(d,lH); 5.23(s,2H); 2.86(s,4H); 1.61 (d,3H,J=7.3Hz).

-225- Sa Examp~le 260 r3-S-r4R-r a.58,68(R 1111-2.5-Anhvdro-3-Sr 2-carboxvl-6- (1-hvdroxvethv1l -4-methvl-7-oxo-1azabicyclo 13.2. olhe~t-2-en-3-vll- 1.4-dideoxv-lr r 2- r r- r (4 -nitro~henvflmethoxvl1carbonyl ]amino I-l3.- Ooorolpyl 1 amino I -3-thio-D-threo-veltitol monosodium salt Ten ml of 0.1M, pH 7, sodium dihydrogen phosphate buffer is cooled to 2 0 C. To the solution is added 0.342 g of product from Example 192 and the pH is adjusted to 8.5 with 1N sodium hydroxide. A solution of 0.401 g of product from Example 259 in 7 ml of dioxane is added while maintaining the pH at 8.5 with 1N sodium hydroxide. The reaction is monitored by tlc.

After 5 minutes there is no starting material present.

The pH is adjusted to pH 7.0 and the mixture is concentrated in vacuo. The residue is purified by 0 chromatography (Reverse Phase Plates: acetonitrile/water) to give 0.316 g of the desired product.

1 H NMR(CDC1 3 :6 8.26(d,2H) 7.57(d,2H) 5.3(d,2H)J- 4.20-3.25(m,11H);2.4(m,lH); 2.05(m,M)I; 1.36(d,3H, Example 261 r 3-S- r4R- r 4a.5B. 6,6(R )111 r(2-Amino-1oxopropvi) aminol 5-anhvdro-3-S- r 2-carboxv-6- (1hvdroxvethvl) -4-m~th 1 -7-oxo-1-azabicyclorF3.2.01 hert- 2-en-3-vll 4 1 dideoMv-3-thio-D-threO-Rentitol A mixture of 0.316 g of product from Example 260, 5.2 ml of 0.1M sodium dihydrogen phosphate buffer, 7 ml of dioxane and 0.090 g of 10% palladium on carbon is reduced in a Parr apparatus to give, after chromatography (Reverse Phase Plates: 5% aqueous ethyl alcohol) 0.041 g of the desired product.

1H NMR(CDCl 3 :6 4.35-4.15(=,3H); 4.l0-3.90(m,5H); 3.6-3.35(d,4H); 2.48(m,lH); 2.07(m,1H); l.49(d,3H, l.28(d,3H,J=6o0); l.19(d,3H,J=6.75).

-226- W ExamRle 262 (SI (Phenvlmethvl) A mixture of 8.9 g of L-phenylalanine, 4.8 ml of trichioromethyichioroformate (Diphosgene), 70 ml of dry tetrahydrofuran and 0.135 g of activated carbon is heated in an oil bath at 55 0Cfor 2 hours, until the L-phenylalanine is in solution. The reaction is filtered through diatomaceous earth. The filtrate is concentrated in vacuo, treated with diethyl ether and hexane, and the resulting crystals are collected to give 1.04 g of the desired product.

1 H NMR(CDCl 3 :6 7.19-7.17(m,2H); 7.38-7.31(m,3H); 6.31(s,lH,NI); 4.56-4.52(m,lH,cH); 3.30-3.29(m,lH); 3. 04-2 .97 (in, H) ExamDle 263 (SI i2-Methvlrorvyl The title compound is prepared by the procedure of Example 262 using.3.93 g of L-leucine, 2.7 ml of diphosgene, 0.075 g of activated carbon, and 40 ml 20 of dry tetrahydrofuran to give 2.74 g of the desired product.

1 HNMR(CDCl 3 7.l(s,1H,NH); 4.38-4.34(m,lH,CH-N); 1 85 -1.72(in,3H,CH 2and C-CH); 0.99,7(t,6H,2-Me).

see. Example 264 (SI -4-Methyl-2 .~The title compound is prepared by the procedure of Example 262 using 8.91 g of L-alanine, 9.0 ml of diphosgene, 0.250 g of activated carbon, and 150 ml of dry tetrahydrofuran to give 7.4 g of the desired product.

1NMR(DlMSO):6 9.0(bs,lH,NI); 1.33 3H) ,Me).

-227- Examiple 265 [3-S-r4R-r1-(S* .4eg.58.68(R*)111-1-r(2-Am-ino-l-oxo- 3 -phenvi~ropvi Iamino 1-2. 5-anhydro-3 r2 -carboxy-6- (l-hvdroxvethvl) -4-methvl-7-oxo-l-azabicvclo r3.2.*01hent-2-en-3-yl 1.4-dideoxv-3-thio-D-threo-Dentitol

(A)

To 3 ml of 0.1M, pH 7, sodium dihydrogen phosphate buffer cooled to 2 0 is added 0.308 g of product from Example 192 and the pH is adjusted to with 1N sodium hydroxide. A solution of 0.172 g of product from Example 262 in 3 ml of dioxane and 3 ml of sodium dihydrogen phosphate buffer is added while maintaining the pH at 8.5 with 1N sodium hydroxide.

The reaction is monitored by tlc. After there is no material present, the pH is adjusted to pH and the mixture is concentrated in vacuo. The residue is purified by chromatography (Reverse Phase Plates: acetonitrile/water) to give 0.162 g of the product 9. 4A and 0.073 g of [3-S-[4R-[4a,5fi,6fl(R 3-S- (2-carboxy-6- (l-hydroxyethyl) -4-methyl-7-oxo-lazbcco320]hp--n3y phenylalanyl-L-phenylalanyl) amino-3-thio-D-threopentitol as product B.

9OSSS Product A: 1 H NMR(D 2 0):6 7.4(t,3H); 7.3(d,2H); 4.4-4.2(m,2H); 4.05-3.9(m,2H); 3.9-3.8(m,2H); 4.59-3.0(=,7H) 2.4-2.2(m,lH); 2.02-1.95(m,lH); 1.29(d,3H,Me,J=7.oHz); so 1.11(d,3H,Me,J=7.OHz).

Product B: 1 NMR(D 2 0):6 7.4-7.3(m,6H); 7.25-7.15(m,4H); 4.5(t,lH); 4.3-4.3(m,2H); 4.05-3.2(m,5H); 3.45-2.9(m,8H); 2.0-1.9(m,lH); l.29(d,3H,Me,J=7.OHz); 1.09(d,3H,Me,J=7.OHz).

-228- 0 ExaLmle 266 r3-S-E4R-rl(S* .4alpha.5beta.6beta(R*)111-1-r(2-Amino- 4-methvl-l-oxopentyll~amino 1-2 .5-anhydro-3-S- r2-carboxv 6-(l-hvdroxvethvyl) -4-methvl-7-oxo-l-azabicvclor3 .2.01 he~t-2 -en- 3-vi 1-1.4 -dideoxv-3 -thio-D-threo-Rentjtol

(A)

The title compound is prepared by the procedure of Example 265 using 0.308 g of product from Example 192, 0.141 g of product from Example 263, 9 ml of 0.1M sodium dihydrogen phosphate buffer, pH 7.0, and 3 m1 of dioxane to give 0.135 g of product A and 0.051 g of [3-S-[4R-[4a,5p,6p(R*)JJJ-2,5-anhydro-3-S- [2 -carboxy-6- (1-hydroxyethyl) -4 -methyl-7 -oxo-lazabicyclo -hept-2-en-3-yl) -l,4-dideoxy-l- [N-Lleucyl-L-leucyl) amino-3 -thio-D-threo-pentitol 15 as product B.

~.:Product A: 1 1 HNMR(D 2 0):6 4.3-4.1(m,3H); 4.i-4.0(q,1H); 3.95-3.8(m,3H); 3.6-3.4(m,4H); 2.5-2.38(m,1H); 1.27(d,3H,Me,J=7.0).

*..*Product B: H NMR (D 0) :6 4. 4 2-4. 3(m, 1H) 4.3(m,3H); 4.15-4.0(m,lH); 4.0-3.8(m,3H); 3.6-3.4(m,4H); 2.5-2.4(m,lH); 2.1-2.0(m,lH); l.8-1.5(m,6H); 1.27(d,3H,Me,J=7.oHz); 1.18(d,3H,M3,J=7.0); l.0-O.B(m,12H,4Me).

An alternative method f or making the Product of Example 192, [4R-(4ca,5#,6,6(R )]-1-Amino-2,5-anhydro-3-S-[2carboxy-6- (1-hydroxyethyl) -4-methyl-7-oxo-l-azabicyclo[3 0]hept-2-en-3-ylJ 4-dideoxy-3-thio-D-threopentitol is described in Examples 267 to 272.

Examrle 267 2 -Deox-D-erythro-pentitol Under anhydrous conditions and an argon purge, 30.0 g of 2-deoxy-D-ribose is dissolved in 1 L of ethyl alcohol. Seven grams of sodium borohydride is added in portions at room temperature. The reaction -229mixture is stirred for 1-2 hours, until all bubbles disappear. The mixture is acidified with 25 ml of glacial acetic acid and the stirring continued for an additional 30 minutes. The solution is chromatographed using 180 ml of Dowex 50W-X8(H form) Resin (50-100 mesh) and ethyl alcohol. The filtrate is concentrated in vacuo to give 40.0 g of a thick oil.

MS(EI):m/z 119(M -OH).

Example 268 1.

4 -Anhvdro-2-deox-D-ervthro-pentitol To 40.0 g of product from Example 267 is added 500 ml of 2N hydrochloric acid. The mixture is heated, in an oil bath, at 95°C for 72 hours. The reaction is filtered and the filtrate concentrated in 15 vacuo to give 23.4 g of an oil. The oil is purified by Kugelrohr distillation to give 14.05 g (110-120°C at 0.4-0.3 mmHg) of the desired product.

IH NMR(CDC13):6 4.25(m,1H); 4.0(m,2H); 3.8(m,lH); 3.7(bs,lH,OH); 3.6(m,2H); 3.5(bs,1H,OH); 2.1(m,lH); 1.9(m,lH).

Example 269 S. 1.4-Anhvdro-2-deoxy-D-erythro-pentitol To a -20°C solution, under argon, of 8.4 ml 25 of trifluoromethanesulfonic anhydride in 75 ml of methylene chloride is added, dropwise, a solution of 5.9 g of product from Example 268 and 4.05 ml of pyridine in 25 ml of methylene chloride. The temperature is maintained below -10°C during the addition. The progress of the reaction is monitored by tlc. The reaction is filtered and the filtrate concentrated in vacuo to an oily residue. The residue is purified by chromatography (silica gel: 50% ethyl acetate/hexane) to give 7.03 g of the desired product.

1 H NMR(CDCl 3 4.8(bs,lH); 4.48-4.6(m,2H); 4.3-4.4(m,lH); 3.95-4.1(m,3H); 2 .1- 2 .21(m,lH); 1.

9 2 2 .02(m,1H).

-230- 0 Example 270 1. 4-Anhvdro-5-azido-2 A mixture of 7.0 g of product from Examnple 269 in 53 ml of methylene chloride and 8.75 g of n-tetrabutylanimonium azide is stirred at -20 0 C, 'under argon, for 2 hours. The reaction mixture is concentrated in vacuo and purified by chromatography (silica gel: 50% ethyl acetate/hexane) to give 3.22 g of the desired product.

1H NMR(CDCl 3 :6 4.22-4.3(m,1H); 3.92-4.l(m,2H); 3.85-3.9(m,lH); 3.3-3.5(m,2H); 2.l-2.25(m,2H); 1.0-2.0(m,lH).

Example 271 1. 4-Anhydro-5-azido-2. 3-(Trifluoromethanesulfonate) The title compound is prepared by the procedure of Example 269 using 3.2 g of product from Example 270 dissolved in 28 ml of methylene chloride, 4.14 m1 of trifluoromethanesulfonic anhydride dissolved in 57 ml of methylene chloride and 2.0 ml of pyridine to give after chromatography (silica gel: 50% ethyl acetate/hexane) 4.84 g of the desired product.

1H NMR(CDCl 3 5.25(m,lH); 4.12-4.20(m,2H); 3 .85-3.93(m,lH); 3.40-3.51(m,1H); 3.29-3.4(m,lH); Example 272 2. 5-Anhvdro-l-azido-1 .4-dideoxy-3-thio-Dthreo-Pentitol 3-Acetate To a 0 0C solution of 4.84 g of product from Example 271 in 120 ml of acetonitrile is added, in one portion, 2.21 g potassium thioacetate. The reaction is stirred at 0 0C for 35 minutes, concentrated _in vacuo and purified by chromatography (silica gel: 30% ethyl acetate/hexane) to give 2.63 g of the desired product.

1H NMR(CDCl 3 :6 4o2-4o3(m,lH); 4.l-4.19(q,lH); 4.0-4.08(m,1H); 3 o8-3.88(q,lH);'3o3-3.4(m,2H); 2o35-2o25(m,1H); 2 .36(s,3H,SAc); 1.

9 -2o05(m,1H).

-231- The procedure for making Example 192, [4R- (4a, 5p, 68 -l-amino-2,5-anhydro-3-S- 2-carboxy- 6-(1-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-en-3-yl]-1,4-dideoxy-3-thio-D-threo-pentitol from this point on is identical to the experimental described in Examples 190-192.

Example 273 rR- R -5-Hexene-1 2.3-triol A solution of 11 g of dimethyl-alpha-2-propenyl-1,3-dioxolane-4-methanol, prepared by the procedure described in J. Am. Chem.

Soc., 1985, 107(26), 8186-8190, in 300 ml of 1:1 tetrahydrofuran: 2N hydrochloric acid is heated at the reflux temperature of the solvents for 2 hours.

15 Chloroform is added and the layers are separated. The aqueous layer is re-extracted 2X with chloroform.

The aqueous layer is neutralized with potassium carbonate and exhaustively extracted with chloroform/iso-propanol. The combined organic layers are concentrated in vacuo to give 7.51 g of the desired product.

1 1 H NMR(CDC1 3 5.89(m,lH); 5.18(m,2H); 3.76(m,3H); 3.60(m,lH); 2.40(m,5H,3(OH) 2H).

Example 274 25 rR-(R R )-l-[[(1.1-dimethylethyl)diphenvlsilyloxy 5-hexene-2,3-diol A 0 C solution of 7.33 g of product from Example 273 in 120 ml of 5:1 dry methylene chloride/ N,N-dimethylformamide is treated with 5.29 g of imidazole and 16.77 g of t-butyl diphenylsilyl chloride. The reaction mixture is warmed to room temperature and stirred vigorously for 16 hours, diluted with diethyl ether and filtered. The filtrate is concentrated and purified by chromatography (Silica Gel: 0-50% ethyl acetate/hexane) to give 15 g of the desired product.

-232liH NMM(CDC1 3 7.67(m,4H) 7.42(m,6H); 5.82(m,1H); 5.10(m,2H); 3.84-3.70(m,3H); 3.58(m,1H); 2.29(t,lH,J=7.1Hz); 1.07(s,9H,t-bu).

IR(neat): 3430, 3072, 2957, 1650, 1595, 1472, 1428 cm- 1 Example 275 2. 5-Anhydro-4 .6-dideoxy-1-0-rf(. 1-dimethylethyl) diiphenylsilyll1-6-iodo- D-arabino-hexitol A 00 C solution of 14.67 g of product from Example 274 in 200 ml of 3:1 diethyl ether/water is treated with 4.99 g of sodium bicarbonate and 15.07 g of iodine. The reaction mixture is stirred vigorously for 24 hours at room temperature, quenched with 15 ml of saturated sodium sulfite, and diluted with 100 ml of water, the reaction mixture is extracted with diethyl :ether, dried, concentrated in vacuo, and purified by chromatography (silica gel: 0-10% ethyl acetate/hexane) to give 15.0 g of the desired product.

H NMR(CDCl 3 7. 74 64 4H) 7 46-7. 3 6(m, 6H) 4.62(t,lH,J=4Hz); 4.32(m,1H),4.lo(m,lH); 3.98(m,2H); .3.29(dd,2H,J=5.7, 1.4Hz); 2.25(M,lH); l.83(dt,lH); 1. 12 9H, t-Bu).

IR(neat): 3458, 3071, 2956, 1472, 1428 cm.

MS m/z 514 (M+NH Exam~le 276 2 .5-Anhvdro-6-azido-4 .6-dideoxv-1-O- r f1. 1-dimethylethyl) diphenylsilyll1-D-arabino-hexitol A solution, under argon, of 5. 0 g of product from Example 275 in 10 ml of dry N,N-dimethylformamide is treated with 0.986 g of lithium azide. The mixture is stirred at 80 0 C for 1 hour followed by room temperature for 18 hours. The reaction is diluted with water, extracted with. diethyl ether, concentrated in~ vacuo, purified by chromatography (silica gel: 5-50% ethyl acetate/hexane) to give 4.0 g of the desired product.

-233- *1H1 NMR(CDC1 3 :6 7.70(m,4H); 7.42(m,6H); .2MH; 4.50(m,1H); 4.02(m,3H); 3.80-3.50(m,2H); 3.22(dd,1H); 2.09 (in,1H) 1. 94(m, 1H) 1. 50 9H, t-Bu) IR(neat): 2956, 2101 cm-1 MS (CI) m/z 429 (H+NH 4

)X.

Examp~le 277 2. 5-Anhvdro-6-azido-4,.6-dideoxv-1-0-r(1. 1-dimethylethyl) diphenvisilyll1-D-arabino-hexitol 3-Methane sul fonate To a 0 0 C solution, under argon, of 3.78 g of product from Example 276 in 20 ml of dry methylene chloride is added, dropwise, 1.02 g of triethylamine and 1.16 g methanesulfonylchloride. The reaction mixture is stirred for 3 hours, diluted with water, 15 extracted with diethyl ether, concentrated in vacuo, :and purified by chromatography (silica gel: 0-50% ethyl acetate/hexane) to give 4.30 g of the desired product.

Hi NMR(CDCl 3 :6 7.68(m,4H); 7.41(m,6H); 5.36(m,lH); 4.43(m,1H); 4.18(m,1H); 3.88(m,2H); 3.54(dd,1H,J=13., 3. 5Hz) 3. 19 (dd, 1H, J=1 3. 0, 4. 5Hz) 2. 73 3H, OSO 2 Me); 2.48(m,1H), 2.18(m,1H); 1.0B(s,9H,t-Bu).

IR(neat): 2956, 2101 cm MS(CI): 430(M +H-N 2 Example 278 2 .5-Anhvdro-1-azido-1,3-dideoxy-6-0-r (1.1-dimethylethyl) diphenvisilvl 1-4-thio-D-arabino-hexitol 4-Acetate A solution of 3.78 g of product from Example 277, 1.76 g of potassiuim thioacetate, 6.12 g of 18-crown-6 and 25 ml of acetonitrile is heated at the reflux temperature of the solvents for 3 hours. The reaction is diluted with water, extracted with diethyl ether, concentrated in vacuo and purified by chromatography to give 2.209 g of the desired product.

1 H NMR(CDCl 3 :6 7.70(m,4H); 7.40(m,6H); 4.33(m,lH); 4 .13(m,lH); 4.0(m,1H); 3.83-3.70(m,2H), -234- 1W 3.45-3.25(m,3H); 2.60(m,lH); 2.32(s,3H,SAc); 1.77(m,1H); 1.05(s,9H,t-Bu).

IR(neat): 2957, 2100, 1696, 1113 cm- 1 NS(CI): m/z 48B(MINH 4 Examiple 279 2. 5-Anhydro-l-azido-1. 3-dideoXv-4-thio-D-arabino hexitol A 0 0 C mixture, under argon, of 2.21 g of product from Example 278 in 20 ml of 1:3.3 49% aqueous hydrogen fluoride/acetonitrile is stirred vigorously and allowed to warm slowly to room temperature over 6 hours. The reaction mixture is added slowly to 100 ml of saturated sodium bicarbonate. After the bubbling ceased, ethyl acetate is added and the layers are 15 separated. The organic layer is concentrated in vacuo :and purified by chromatography (silica gel: 5-50% ethyl acetate/hexane) to give 0. 664 g of the desired product.

NMR(CDCl 3 4.40(m,1H); 3.92(m,2H); 3.80(m,1H); 3.62(m,lH); 3.45(m,1H); 3.30(m,1H); 2.50(m,lH); 2.35(s,3H,COCH 3 2.OO(br s, lH, OH); IR(neat): 3471, 2925, 2101, 1693 cm- .MS(CI): 249(H+NH 4 Example 280 2. 5-Anhvdro-l-azido-1. 3-dideoxvy-4-thio-Darabino-hexitol 0 To a 0 C solution, under argon, of 1. 1 g of product from Example 279 in 5 ml of dry tetrahydrofuran is added, dropwise, 1.3 ml of 4.37M solution of sodium methoxide. The reaction is stirred for 1 hour, quenched with saturated ammonium chloride and concentrated in vacuo. The residue is purified by chromatography (silica gel: 10-100% ethyl acetate/hexane) to give 0. 752 g of the desired prod uct.

1 H NMR(CDCl 3 :6 4.24 1H) 3.90 (dd,lH,J=12 and 3Hz); 3.80-3.70(m,2H); 3.46(dd,lH,J=l3, 3.7Hz); 3.3(m,2H); 2.52(m,1H); 1.97(br s,lH,OH); l.80(m,1H); 1.66(d,1H,SH,J=8.1Hz).

-235- MSp(CI): m,/z 207(M+NH 4 Examiple 281 4-r4R-r4alDha. Sbeta. 6beta (R*111-2. 5-Anhvdro-1-azido- 1. 3-dideoxv-4-S- (l-hydroxyethvl I-4-methvl-2- I [(4-nitro~henyi Imethoxvl carbonvi 1-7-oxo-1aZabicvclo-r3 Olhe~t-2-ene-3-yll -4-thio-Darab ino-hexitol A 0 0 C mixture, under argon, of 0.752 g of product from Examnple 280, 2.10 g of product from Example 15 and 13 ml of dry acetonitrile is treated, dropwise, with 0.462 g of Hunig's base. The reaction, which is allowed to warm to room temperature, is stirred for 5 hours. The reaction is concentrated in vacuo and purified by chromatography to give 0.752 g of the desired product.

H NMR(CDCl 3 8.25 (d,2H,J=8.7Hz) 7.65(d,2H,J=8.7Hz);-5.51(d,1H); 5.22(d,1H); 4.27(m,3H); 4.0-3.70(m,3H); 3.60(m,1H); 3.45(m,lH); 3.30(m,2H); .2.70(br s,lH); 2.50(m,2H); 2.05(m,lH); 1.35(d,3H); 1.28(d,3H).

IR(KBr): 3449, 2971, 2102, 1767, 1709 cm1 MS (FAB) m/ z 5 3 4(M H).

Example 282 4 -r4R-r4aljpha,5beta.6beta(R I 11-2.5-Anhvdro-l-azido- 25 4-S-r2-carboxy-6-(l-hvdroxyethvll -4-methyl- 7 -oxo-l-azabiccor3.2.Ohet-2ene-3-vll1..13d ideoxy-D-arabino-hexitol A slurry of 0.20 g of product from Example 281 in 10 ml of dioxane: 0.1M4 sodium dihydrogen phosphate buffer pH 7.0 and 0.060 g of palladium on carbon is -hydrogenated in a Parr apparatus at 42 psi of hydrogen for 3 hours. The mixture is filtered, concentrated in 2 vacuo and purified by chromatography (Reverse Phase Plates:5% ethyl alcohol/water) to give 0.123 g of the desired product.

1H NMR (D 2 0):6 4.35(m,lH); 4.19(m,2H); 3.95(m,lH); 3.70(dd,1H); 3 6 5 -3.50(m,3H); 3 4 8 -3.32(m,2H); -236- V 3.15(m,1H): 2.68(m,1H); 1.74(m,1H); 1.24(d,3H); 1. 15Cd, 3H).

IR(KBr): 3403, 3027, 2969, 2104, 1751, 1598 cm- 1 MS(FAB): 373(k Exau~le 283 1-Amjio-2 .5-anhydro-1. 3-dideoxv-6-O- r 1-dimethylethyl) di~henylsilyll1-D-arabino-hexitol A slurry of 3.78 g of product from Example 276, 0.562 g of 10% palladium on carbon and 50 ml of tetrahydrofuran is hydrogenated under a balloon of hydrogen for 1 hour. The reaction mixture is filtered and the filtrate is concentrated in vacuo to give 3.4 of the desired product.

1 H NMR(CDCl 3 :6 7.72(m,4H); 7.45(m,6H); 4.58(br s,lH); 4.27(m,lH); 4.13(m,1H); 3.97(s,24); 2.82(dd,lH, J=13, 3.7Hz); 2.64(dd,lH,J=13, 6.8Hz); 2.05(m,lH); l.80(m,lH); l.08(s,9H,t-Bu).

IR(neat): 3366, 2955, 1589, 1472, 1112 cm 1 MS(CI): ma/z 386.6(M Example 284 2. 5-Anhydro-1. 3-dideoxv-6-O- r 1-dimethvl ethyl) dirhenylsilyll -l-F r F (4ntopev 1toycab laminol1-D-arabino-hexitol A slurry of 3.15 g of product from Example 25 283 and 1.35 g of potassium carbonate in 15 ml of tetrahydrofuran at 0 0C, under argon, is treated with 2.11 g of p-nitrobenzyl chloroformate and the reaction is stirred vigorously at 0 C for 4 hours. The reaction mixture is diluted with 100 ml of water, extracted with 3 X 100 ml of ethyl acetate, dried, concentrated ±n vacuo and purified by chromatography (Silica Gel: 5-50% ethyl acetate,/hexane) to give 3.49 g of the desired product.

1HNCC13)68..20(d,2H,J=8.7Hz); 7 .68(m,4H); 7.50(d,2H,J=8 .7Hz) 7. 4 2(m, 6H) 5. 62(br s,1IH, NH); 5.20(s,2H); 4.60(m,lH); 4.15(m,1H); 3 9 6(m,2H); -237- 3.50(m,lH); 3.30(m,lH); '3.12(M,1H); 2.l0(m,1H); l.80(m,1H); l.08(S,9H,t-Bu).

MS(CI): m/z 565(kM+H).

2. 5-Anhydro-1. 3-dideoxv-6-O- r(1. 1-dimethylethyli dighenvisilyli-I-Cr r(4-nitro~henvi methoxvl carbonvi 1aminol1-D-arabino-hexitol 4-Methanesulfonate The title compound is prepared by the procedure of Example 277 using 3.39 g of product from Example 284, 0.57 ml of methanesulfonyl chloride, 1.03 ml of triethylanine, and 30 ml of methylene chloride to give, after chromatography, 3.0 g of the desired product.

1 H NMR(CDCl 3 8.21(d,2H,J=8.7Hz); 7.66(m,4H); 7.50(d,2H,J=8.7Hz); 7.42((m,6H); 5.32(m,1H); 5.20(s,2H); 5.l0(m,lH); 4.33(m,1H); 4.13(m,lH); 3.85(dd,lH,J=6.7, 3.3Hz); 3.43(m,3.H); 3.20(m,lH); 2.93(s,3H,OSO 2 Me); 2.47(m,lH); 1.95(m,lH); 1. 08 9H, t-Bu) IR(neat): 3413, 3342, 2933, 1726, 1522 cm- 1 MS (CI) m/z 548 (M +H SO Me).

2 Calcid for C 31H 380 9N 2SSi C 57.31; H 5.77; N 4.46; S 5.10 Found: C 57.45; H 5.91; N 4.11; S 4.88 25 Example 286 2. 5-Anhvdro-1. 3-dideoxv-6-0- F 1 -d imethyl ethyl) dinhenylsilvll-1-r r r (4-nitrohenl)methovlcarbonl..aminol1-4-thio-D-arabino-hexitol 4-Acetat e The title compound is prepared by the procedure of Example 278 using 3.0 g of product from Example 285, 1.07 g of potassium thioacetate, 2.5 g of 18-Crown-6 and 15 ml of acetonitrile to give, after chromatography, 2.61 g of the desired product.

1 H NMR(CDCl 3 :6 8.22 (d,2H,J=8.7Hz); 7.70(m,4H); 7.50(d,2H,J=8.7HZ); 7.40(m,6H); 5.22(s,2H); 5.17(br s, 1H); 4.19(m,1H); 4.08(m,1H); 3.95(m,1H); 3.75(m,2H); -238m,2H); 3.45(m,1H); 3.24(m,l'H); 2.55(m,1H); 2.4l(s,3H,SAc); l.64(m,lH); l.06(s,9H,t-Bu).

MS(CI): M/z 566(k4+H C(CH 3 3 Example 287 2 .5-Anhvdro-1 .3-dideoxv-l1-r rrF(4-nitrophenvl~methoxv1 carboni aminol1-4-thio-D -arabino-hexitol 4-Acetate The title compound is prepared by the procedure of Example 279 using 2.51 g of product from Example 322, and 20 ml of 3:1 acetonitrile:48% aqueous hydrogen fluoride to give,-after chromatography, 1.35 g of the desired product.

'H NMR(CDCl 3 :6 8.22(d,2H,J=8.7Hz); 7.53(d,2H,J=8.7Hz); 5.30(br t,1H,NH); 5.20(s,2H); 4.22(m,1H); 3.86(m,2H); 3.76(dd,lH,J=13, 3.60(dd,1H,J=l2, 4.0Hz); 3.46(m,lH), 3.38(m,lH); 3.24(m,1H); 2.50(m,1H); 2.35(s,3H,SAc); 2.16(br s, lH,OH); 1.68(m,1H).

IR(KBr): 3340, 2935, 1722, 1696, 1607, 1521 cm'.

MS(CI): m/z 385.5(14 Example 288 2. 5-Anhvdro-1. 3-dideoxv-1-Fr rr(4-nitrophenvl)methoxvl carbonyl 1aminol -4-thio-D-arabino-hexitol The title compound is prepared by the procedure of Example 127 using 0.625 g of product from 25 Example 278, 0.85 ml of 4N sodium hydroxide and 3 ml of tetrahydrofuran to give, after chromatography, 0.440 g of the desired product.

1 H NMR(CDC 3 8.21(d,2H,J=8.7Hz) 7.50(d,2HJ=8.7Hz); 5.54 (br t,lIH,NH) 5.20 2H) 4.13 (m,l1H) 3.85(dd,lH,J=12 and 2Hz): 3.78-3.65(M,2H); 3.50(m,1H); 3.27(m,2H); 2.53(p,lH,J=6.OHz); l.63(m,lH); 1.62 1H,SH,J=2.OHz).

-1 IR(KBr): 3460, 3315, 2922,-*2553, 1700, 1607, 1554 cm- -239- Examle 289 r4-r4R-r4alpha.5beta.6beta(R

)III-

2. 5-Anhydro-1. 3-dideoxv-4-S-r6-(l-hvdroxyethvl) -4methyl-2- rr (4-nitrophenvl methoxvl carboxnvl 1-7-oxo- I-azabicvclor3.2.Olhept-2-en-3-vll-l-r r r(4-nitro- Rhenvl ~methoxvl carbonvi 1amino]1-4-thio-D-arabinohex itol The title compound is prepared by the procedure of Example 17 using 0.440 g of product from Example 324, 0.764 g of product from Example 15, 0.22 ml of Hunig's base and 4.3 ml of acetonitrile to give, after chromatography, 0.593 g of the desired product.

1 H NMR(CDCl 3 8.23(d,2H,J=8.7Hz); 8.22(d,2H,J=8.7Hz); 7.66(d,2H,J=8.7Hz); 7.52(d,2H,J=8.7Hz); 5.52(d,lH,J=13.8Hz); 5.22(d,1H,J=13.BHz); 5.21(s,2H); 4.25(m,3H); 3.84(m,2H); 3.67-3.40(m,4H); 3.30-3.20(m,2H); 1.7(m,1H); l.34(d,3H,J=7.3Hz); 1.25 (d,3H,J=7.3Hz).

MS(FAB): m/z 687(M Example29 r4-r4R-r4alipha.5beta.6beta(R 111- 1-Amino-2 5-anhvdro-4-S-r2-carboxy-6- (1-hvdroxvethvl) 4-methvl-7-oxo-l-azabicvclor 3.2. Olheipt-2-en-3-vll- 4-thio-D-arabino-hexitol The title compound is prepared by the procedure of Example 192 using 0.563 g of product from Example 325, 0.140 g of 10% palladium on carbon, and dioxane:o.i M sodium dihydrogen phosphate buffer pH (15 ml:5m1) to give, after chromatography, 0.050 g of the desired product.

11H NMR(D 2 0):6 4.36(m,1H); 4.21(m, 2H) 3.95 1H); 3 .78-3.50(m,3H); 3.40(m,2H); 3.l8(m,2H); 2.68(m,lH); 1.72(m,lH); l.24(d,3H,J=6.4Hz); 1.60(d,3H,J=7.2Hz).

IR(KBr): 3408, 3347, 2967, 1752, 1622, 1586, 1147cm 1 MS(FAB):m/z (M'B+NaCl) 395(M+Na) and 417(M+2Na-H).

-240- Example 291 13S-r3alDha,3 .4alRhal 1-rl-Methvl-2-oxo-2-r rrtetrahvdro-4- r r (4-methoxv~henv1) methyll1thiol -3-furanvi 1methyl 1 amino 1 ethyl 1 carbamic Acid (4-Nitrophenyl)~methyl Ester A room temperature mixture, under argon, of 0.455 g of product from Example 200, 0.578 g of product from Example 258., 0.516 g of 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDCI) and 4 ml of methylene chloride is stirred vigorously for 6 hours.

The reaction mixture is diluted with water, extracted with methylene chloride, dried, and concentrated in vacuo to give 0.90 g of the desired product.

1 H NMR(CDCl): 8.20(d,2H,J=S.7Hz); 7.50(d,2H,J=8.7Hz); 7.20(d,2H,J=8.7Hz); .:6.8(d,2H,J=8.7Hz); 6.45(br s, 1H, NH); 5.60(br s, 1H,NH); 5.25(s,2H,CH 2 ArNO 2 4.20(m,lH); 4.OO(t,1H); 3.90(t,1H); 3.80(s,3H,ArOMe); 3.68(s,2H,CH 2 ArOMe); 3.50(ma,2H); 3.26(m,2H); 2.80(m,1H); 2.25(m,1H); l.40(m,3H,CH 3 Example 292 r3S-r3alp-ha.3(R ).4alpha 11- r -Methl-2-oxo-2-r r rtetrahydro-4-mercato-3.f uranyl 1methyl 1 amino 1 ethyl 1 carbamic Acid (4Ntohnlmty Ester 25 The title compound is prepared by the procedure of Example 202 using 0.90 g of product from Example 291, 0.915 g of mercuric trifluoroacetate, 0_.386 g of anisole and 27 ml of 80% acetic acidi to give 0.60 g of the desired product.

1H NMR(CDCl 3 :6 6. 3 8(br s 1H,KH) 5.4 5(br s,l1H, NH); 5.20(s,2H,CH ArNo 4.20(m,2H); 4.00(dd,1H, J=8.8, 7.9Hz); 3.60-3.40(m,4H); 3.03(t,lH,J=7.4Hz); 2.28(m,lH); l.73(d,lH,SH); 1.41(d,3H,J=7.OHz).

IR(KBr): 3298, 2975, 2544, 1690, 1651, 1540 cm 1 MS(CI): m/Z 384(M -241- ExaMle 293 r4R-3E3S*.4S* 1.4alpha.5beta.6beta( i 6- (1-Hvdroxvethvl) -4-methyl-7-oxo-3- rrtetrahvdro-4r rr2-Err r(4-nitrophenvllmethoxvlcarboxnyllaminol-l.aminolmethvl-3-furanvllthiol -l-azabicvclo- [3.2 .01he~t-2-ene-2-carboxylic Acid (4-Nitrophenvi) methyl Ester The title -compound is prepared by the procedure of Example 17 using 0.576 g of product from Example 292, 0.893 g of product from Example 15, 0.194 g of Hunig's base and 5 ml of acetonitrile to give 0.950 g of the desired product.

1 H NMR(CDCl 3 8.21(d,2H,J=8.7Hz) 8.20(d,2H, as .J=8.7Hz); 7.65(d,2H,J=8.7Hz); 7.49(d,2H,J=8.7Hz); 6. 5 5(br s,lIH, NH) 4 4(br s, 1H, NH) 5. 5 0(dd,l1H); *5.22ddM);~ 5.19(sACH ArNO 4.35-4.2(m,3H); 3.95(m,1H); 3.70-3.40(m,6H); 3.29(m,1H); a 2.42-2.26(m,2H); 1.39(t,6H,2xCH 3; 1.26(d,3H,CH3)' as 0IR(Kr):2973, 2935, 2873, 1770, 1716, 1670, 1521 cm MS (FAB) m/ z (MB-INaCl) 7 2 8(M 7 5 0(M +Na.

Example 294 r4R.-F3r3S* 4S(S I .4alpha, 5beta. 6beta (R)11~ 3- r r4 r r 2-Amino- I-oxopropyl) aminolmethyl ltetrahydro-3furanyl 1 thiol (1-hvdroxvethvl) -4-methyl-7-oxo-l- 25 azabicyclor3.2.olhept-2-ene.2-.carboxylic Acid (A) and r 4R- r3U3R*, 4E* 1 4alpha, 5beta, 6beta 11 rr4 rF [2-Amino-lI-oxopropyl) aminolmethvl ]tetrahvdro-3furanvilI thiol (1-hydroxyethyll -4-methyl-7-oxo-lazabicyclor3 .2.Olhept-2-ene-2-carboxvlic Acid (B) The title compounds are prepared by the procedure of Example 192 using 0.90 g of product from Example 293, 0.270 g of 10% palladium on carbon and ml of 4:1 dioxane:O.lM sodium dihydrogen phosphate buffer at 42 psi of hydrogen to give a crude mixture which was purified by chromatography to give 0.074 g of product A and 0.095g of product B.

-242- Product A: 1 H NMR(D 2 0):S 4.24(m,3H); 4.00(2,2H); 3.66(m,1H); 3.60(m,2H); 3.41(m,1H); 3.31(m,3H); 2.40(m,1H); 1.43(d,3H); 1.25(d,3H); 1.15(d,3H).

IR(KBr): 3350, 3260, 3087,. 2965, 1750, 1677, 1584 cm- 1 MS(FAB): m/z (MB+NaC1) 414(!! 436(M +Na).

Product B: 1 H NMR (D 0) :6 4. 20 3H) 4. 10 1H) 3. 90 1H); 3.75(m,1H); 3.55(m,2H); 3.40-3.25(m4H); 2.35(m,1H); l.46(m,3H); 1.25(d,3H); 1.17(d,3H).

IR(KBr): 3374, 3089, 2967, 1750, 1677, 1583 cm-1 MS(FAB): m/z (M.B+NaCl) 414(M H) 4 3 6 (H +Na) Example 295 F F(4-Nitrophenvi ethoxvl carbonvi 1-L-valine The title compound is prepared by the proce- 5.54dure of Example 255 using 14.73 g of product from Example 254, 5.42 g of L-valine, 12.75 ml of triethylamine and 556 ml of 4:1 ethyl alcohol:water to give 4.89 g of the desired product after chromatography.

I0 H NMR(CDCl 3 8.22(d,2H); 7.51(d,2H); 5.32(d,lH); 5.22(d,2H); 4.4-4.3(m,lH); 2.35-2.15(m,lH); 1.02 3H,Me); O.95(d,3H,Me).

*Calculated for C 13H 16NO20* C=52.70; H=5.44; N=9.46 Found: C=52.44; H=5.64; N=9.18 ExaMle 296 -ri-r r 5-Dioxo-1-Dvrrolidinv]Aoxylcarbonvl-2methvlpropvllcarbamic Acid (4-Nitrophenvlhuaethyl Ester Using the procedure of Example 256, a room temperature solution, under argon, of 4.89 g of product from Example 295 and 72 ml of dioxane is added 2.09g of N-hydroxysuccinimide and 3.76 g of 1,3-dicyclohexylcarbodiimide in 19 ml of dioxane. A suspension is formed and the mixture is stirred overnight. The reaction is filtered and the filtrated is concentrated -243in vacuo to a thick oil. Crystallization from 75% ethyl acetate/hexane gives 4.*88 g of the desired product.

1 H NMR(CDCl 3 8.21(d,2H); 7.52(d,2H); 5.38(d,lH); 5.23(d,2H); 4.7-4.6(m,lH); 2.86(sl4H); 2.4-2.3(m,lH); l.l(d,3H,Me); 1.06(d,3H,Me).

Calculated for C 17

H

20

N

3 0 a C--51.78; H=5.11; N=10.66 Found: C--51.99; N=4.94; N=10.66.

10Exml29 N- F F(4-Nitrophenyl) methoxyl carbonvi 1-L-isoleucine The title compound is prepared by the procedure of Example 255 using 14.73 g of product from Example 254, 6.07 g of L-isoleucine, 12.73 ml of triethylamine and 556 ml of 4:1 ethyl alcohol:water to give 3.52 g of the desired product.

Calculated for C 1 H 8 2 0: C=54.19; H=5.85; N=9.03 Found: 20 C=54.27; H=5.85; N=8.81 1 H NMR(CDCl 3 :6 8.22(d,2H); 7.51(d,2H); 5.31(d,lH); 5.21(d,2H); 4.45-4.35(m,lH); 2.O-i.9(m,1H); l.55-1.4(m,1H); l.3-1.15(m,lH); 0.99(d,3H,He); 0.95 (t,3H,Me).

Examp~le 298 TS-(R .R n-ri-Frr(2.5-Dioxo-1-ipvrrolidinvl~oxylcarbonvll-2-methylbutyllcarbamic Acid (4 -Nitrophenvl) methyl Ester The title compound is prepared by the procedure of Example 256 using 3.52 g of product from Example 297, 1.50 g of N-hydroxysiccinimide, 2.70 g of 1,3-dicyclohexylcarbodiimide and 14 ml of dioxane to give 1.75 g of the desired product.

Calculated for C 18H 21N 308 C-53.07; H=5.20; N=l0.31 Found: C--53.66; H=5.26; N=10.20 -244- 1 H NMR(CDCl 3 :6 8.23(d,2H); 7.52(d,2H); 5.4-5.2(ma,3H); 4.74-4.68(m,lH); 2.86(s,4H); 2.l-2.0(m,lH); l.4-l.2(m,1H); l.07(d,3H,Me); 0.98 3H,Me).

~Examiple 299 2.5:3. 4-dianhvdro-D-ribose Dimethvlacetal A solution of 50.0 g of product from Example 170, 500 ml of anhydrous methyl alcohol, 20 ml of trifluoroacetic acid is heated at reflux temperature for 36 hours. The progress of the reaction is monitored by thin layer chromatography. The reaction mixture is cooled, with stirring, to 5-10 0 C and 50-g of sodium carbonate is added in portions. The reaction is heated at 60 0 C for 5 hours, filtered and the filtrate is concentrated in vacuo. The residue is extracted with =ethylene chloride and concentrated in vacuo to give 14 g of a yellow oil. The oil is purified by distillation (74-750C, at 2.5 torr) to give 9.7 g of the desired product.

1 20 H NMR(CDCl 3 4.31(d,lH); 4.l0(d,lH); 3.87-3.79(m,3H); 3.48(s,3H); 3.46(s,3H).

Exam le 300 -Anhvdro-4 -deoxv-D-ervthropentose Dimethyl Aceta 1 To a 0OC solution of 16.9 g of product from Example 299 in 55 ml of anhydrous tetrahydrofuran is added, dropwise over 30 minutes, 110.0 ml of 1.OH lithium aluminum hydride in tetrahydrofuran. The reaction mixture is heated in an 800C oil bath for 1 hour, cooled in an ice bath, and 18.37 g of sodium sulfate decahydrate is added in portions over an hour.

The mixture is filtered through diatomaceous earth and the filtrated is concentrated in vacuo to give 13.05 g of the desired product as an oil, which solidified when cooled.

.1H NMR(CDCl 3 4.25(d,lH); 3.9B(dd,2H); 3.75(m,1H); 3.44(s,3H,OMe); 3.42(s,3H,OMe); 2.4(brs,lH,OH); 2.2-2.1(m,lH); 2.0-l.8(m,1H).

-245- O Example 301 2.5-Anhvdro-4-deoxv-D-ervthro-Dentitol To a room temperature mixture of 12.0 g of product from Example 300 in 180 ml of acetonitrile is added, dropwise, a mixture of 12 ml of water and 48 ml of trifluoroacetic acid. The mixture is stirred overnight at room temperature and concentrated in vacuo to about 20 g. Two hundred and forty ml of tetrahydrofuran is added and the reaction mixture is neutralized with sodium bicarbonate solution. The solution-is filtered, dried and concentrated to give g of an aldehyde which was used immediately.

The above aldehyde, 12.0 g, is dissolved in 450 ml of ethyl alcohol and the mixture is purged with argon. Sodium borohydride, 2.79 g, is added in portions and the reaction is stirred at room temperature for 2 hours. Five ml of water is added o.

dropwise and the stirring is continued for 1 hour. The reaction mixture is concentrated in vacuo to an oil.

20 The oil is purified by Silica Gel flash column chromatography (10% methyl alcohol/ethyl acetate) to .o give 3.40 g of the desired product.

H NMR(CDC1 3 4.34-4.29(m,lH); 4.02-3.97(m,2H); 3.84-3.8(m,lH); 3.76-3.6(m,2H); 2.2-2.1(m,1H); 25 2.0-1.9(m,1H); 1.86(brs,2H,OH).

Example 302 r (4-Nitrophenvlmethoxv]carbonyllaminolbutanoic Acid The title compound is prepared by the procedure of Example 255 using 29.46 g of product from Example 254, 9.5 g of L-2-aminobutyric acid, 25.5 ml of triethylamine and 1112 ml of 4:1 ethyl alcohol/water to give 21.2 g of the desired product after chromatography.

1H NMR(CDCl 3 8.22(d,2H, J=8.5Hz); 7.52(d,2H, 5.35(d,1H); 5.25(s,2H); 4.7(m,1H); 2.1-2.0(m,lH); 2.0-1.9(m,lH); l.l(t,lH,Me).

-246- Example 303 r 1- r E 5-Dioxo-1-pvrrol idinvfl ovC~arbonyl I Ropvl 1 carbamic Acid (4-Nitropheftvllmethl Ester The title compound is prepared by the procedure of Example 256 using 21.2 g of product from Example 302 in 314 ml of dioxane, 9. 10 g of N-hydroxysucciniimide, 16.3 g of 1,3-dicyclohexycarbodiimide in 83 ml of dioxane, to give, 17.5 g of the desired product.

1 H NMR(CDCl 3 8.2(d,2H,J=8.5Hz); 7.52(d,2H,J=8.5Hz); 5.3 5(d, 1H, NH); 5. 24 2H,J=4. 7Hz); 4. 7(m,IH, CH); 2.l-1.9(m,2H); l.l(t,3H,Me).

Example 304 [4R-r3(2S I .4alnha .Sbeta.6beta(R* I- I- r (2 -Amino-lI-oxobutvl) aminol 5-anhydro-3-Sr 2 -carboxv- 6- 1- (hvdroxvethyl1 -4 -methyl -7 -oxo- Iazabicvclor3 Olhent-2-en-3-ll-1.4-dideoXv-3-thio- D-threo-pentitol Using the procedure of Example 257, a solu- *tion of 0.342 g of product from Example 192 in 10 ml of pH 7, 0.lM sodium dihydrogen phosphate buffer, is added 1N sodium hydroxide to bring the pH to 8.5. To this mixture is added 0.379 g of product from Example 303 dissolved in dioxane; the pH is maintained at pH With 1N sodium hydroxide. The reaction mixture is stirred at room temperature for 1 hour. 0.120 g of palladium on carbon is added and the reaction is reduced in a Parr apparatus at 48 psi of hydrogen for 3 hours. The mixture is filtered and the filtrate concentrated in~ vacuo to a small volume. The residue is extracted with ethyl acetate and purified by chromatography (Reverse phase plates: 5% aqueous ethyl alcohol) to give 0.109 g of the desired product.

11H NMR(D 2 0):6 4.3-4.l(m,3H); 4.15-4.02(m,lH); 4.0-3.7(M,3H); 3.6-3.4(m,4H); 2.55-2.4(m,1H); 2.15-2.0(m,lH); l.98-1.8(m,2H); 1.28(d,3H,Me,J=5.95Hz); 1.19(d,3H,Me,J=6.94Hz); 0.96(t,3H.Me,J=7.2Hz).

-247- Example 305 a r 3-S r 4R-l(S .4alha5beta.6beta(R I111- I-r(2-Amino-3-methl-1-oxopentylaminol-2.5-anhydro-3- S-r2-carboxv-6-(1-hdroxvethyl-4-methyl-7-oxoazabicvclor3.2 .0lhept-2-en-3-vll-1.4-dideoxy-3-thio-Dthreo-pentitol The title compound is prepared by the procedure of Example 257-using 0.20 g of product from Example 192 in 6 ml of pH 7.0 0.1M sodium dihydrogen phosphate buffer, 0.253 g of product from Example 296 in 6 ml of dioxane and 0.060 g of 10% palladium on carbon. The reaction is cooled to 0-4oC and the pH is adjusted to pH 7.4 before the addition of the palladium catalyst. the residue is purified by chromatography (Reverse phase plates: 20% acetonitrile/water) to give 0.045 g of the desired product.

H NMR(D 2 0):6 4.3-4.2(m,3H); 4.1-4.0(m,1H); 3.95-3.8(m,2H); 3.65(d,1H); 3.58-3.4(m,4H); 2.5-2.4(m,1H); 2.2-2.0(m,2H); 1.27(d,3H,Me); 1.18(d,3H,Me); 0.99(d,6H,2Me).

Example 306 r3-Sr4R- 1(S .S ).4alpha.5beta,6beta(R )11- 1-F (2-Amino-3-methl-1-oxoentyl) aminol 5-anhYdro-3- .S-F2-carboxv-6-(1-hdroxethylv-4-methl-7-oxo-l-aza- 25 bicyclof-3.2.0]hept-2-en-3-yll-1 4-dideoxy-3-thio-D- *sea threo-pentitol The title compound is prepared by the procedure of Example 257 using 0.342 g of product from Example 192 in 10 ml of pH 7 0.11M sodium dihydrogen phosphate buffer, 0.407 g of product from Example 299 in 7 ml of dioxane to give after chromatography (Reverse Phase plates: 25% acetonitrile/water) an oil.

The oil is mixed with 0.10 g of 10% palladium on carbon, 10 ml of pH 7 0.1M sodium dihydrogen phosphate buffer and 5 ml of dioxane. The solution is reduced in a Parr apparatus at 47 psi of hydrogen for 3 hours.

The reaction mixture is filtered, the filtrate is -248concentrated in vacuo to a small volume and purified by chromatography (Reverse phase plates: acetonitrile/water). to give 0.090 g of the desired product.

1 H NMR(D 2 0):6 4.25(m,3H); 4.O8(q,lIH); 3.9(m,2H); 3.65(d,lH); 3.6-3.4(m,4H); 3.32(s,1K); 2.45(m,lH); 2.05(m,1H); l.88(m,lH); 1.5(m,lH); l.29(d,3H,Me); l.,18(d,3H,Me); O.98(d,3H,Me); O.90(t,3H,Me).

ExaMle 307 2. 5-Anhdro-4-deox-D-e hro-pentitol I-Trifluoromethanesul fonate 0 To a -20 C solution, under argon, of 1.68 ml of trifluoromethanesulfonic anhydride in 15 ml of anhydrous methylene chloride is added, dropwise, a solution of 1.18 g of product from Example 301 in 5 ml of anhydrous methylene chloride and 0.81 ml of .::~pyridine. The temperature is maintained at -20 0

C

during the addition of the alcohol. No starting material is visible by tlc after the completion of the addition. The mixture is concentrated in vacuo and purified by chromatography (silica gel: 75% ethyl acetate/hexane) to give 0.693 g of the ditriflate and 1.64 g of the desired monotriflate.

1 H NMR(CDC1 3 :6 4.5(m,2H); 4.3(m,2H); 3.95(m,3H); 2.98(brs,lH,OH); 2.1-2.0(m,lH); l.95-1.85(m,lH).

Example 308 2. 5-Anhdro-l-azido- 4-dideoxv-D-erythro-Dentitol To a 0 0 solution of 1.64 g of product from Example 307 in 12 ml of =ethylene chloride is added a solution of 2.11 g of tetrabutylammonium azide in 12 ml of methylene chloride. The reaction is stirred overnight at room temperature. The mixture is concentrated in~ vacuo and-purified by chromatography- (Silica gel: 50% ethyl acetate/hexane) to give 0.611 g of the desired product.' -249- 1 NMR(CDC1 3 4.18(m,1H); 4.0-3.85(m,2H); 3.85-3.8(m,1H); 3.75-3.6(brs,H); 3.4-3.2(m,2H); 2.2-2.05(m,1H); 1.95-1.8(m,1H).

Example 309 2.5-Anhdro-1-azido-1.4-dideoxvy-D-erythro-petitol 3-Trifluoromethanesulfonate The title compound is prepared by the procedure of Example 307 using 0.6115 g of product from Example 308 in 6 ml of methylene chloride, 0.79 ml plus 0.50 ml for a total of 1.29 ml of trifluoromethanesulfonic anhydride in 11 ml of methylene chloride and 0.38 ml of pyridine to give after chromatography (Silica gel: 50% ethyl acetate/hexane) 0.952 g of the desired product.

1H NMR(CDC1 3 5.3(m,1H); 4.3-4.0(m,2H); 4.0-3.8(m,1H); 3.6-3.15(m,2H); 2.4-2.2(m,2H).

*Example 310 2. 5-Anhvdro--azido-1 4-dideoxv-3-thio-L-threo-pentitol 3-Acetate 20 To an ice cooled solution, under argon, of 0.952 g of product from Example 309 in 25 ml of acetonitrile is added 0.435 g of potassium thioacetate.

The cooled reaction is stirred for 1 hour, concentrated in vacuo, and purified by chromatography (Silica gel: 25 30% ethyl acetate/hexane) to give 0.465 g of the S. desired product.

1 H NMR(CDCl 3 4.2-4.12(m,lH); 4.1-4.05(m,lH); 4.0-3.9(m,1H); 3.8-3.7(1,1H); 3.3-3.2(m,2H); 2.45-2.3(m,l1H); 2.29(s,3H,Me); 1.95-1.85(m,1H).

Example 311 2. 5-Anhydro-1-azido-1. 4-dideoxv-3-thio-L-threo-pentitol The title compound is prepared by the procedure of Example 16 using 0.465 g of product from Example 310, 0.56 ml of 25% (by wt.) sodium methoxide/methyl alcohol and 7 ml of tetrahydrofuran to give after chromatography (Silica gel: ethyl acetate) 0.319 g of the desired product.

-250- Hi NMR(CDCl 3 :6 4.O(M,2H); 3.78(m,lH); 3.42(m,3H); 2.4(mn,lH); l.95(M,1lH); 1.58(d,lH,SH).

Exampile 312 r3-r4R-r4alipha.5beta.6beta(R )111- 2 .5-Anhydro-l-azido-1 .4-dideoxv-3-S- r6- (l-hvdroxvethl) -4-methv-2- r r(4-nitroiphenvl) methoxyl carbonvi 7-oxo-1-azabicyclor3 Olheipt-2-en-3-yll -3-thio-Lthreo-Pent itol The title compound is prepared by the procedure of Example 17 using 0. 319 g of product from Example 311 in 5 nil of acetonitrile, 0.954 g of product from Example 15 in 10 ml of acetonitrile, and 0. 3 ml of Hunig's base to give after chromatography (Silica gel: ethyl acetate) 0.486 g of the desired product.

1H NMR(CDCl 3 8.12(d,2H,ArHJ=8.7Hz); 7.57(d,2H,ArH,J=8.7Hz); 5.43(d,1H,benzylic H,J=13.7Hz); 5.14(d,lH,benzylic H,J=13.7Hz) 4.25-4.1(m,2H); 4.l-3.95(m,2H); 3.8-3.7(m,2H); 3.5-3.2(m,4H); 2.78(brs,lH,OH); 2.48-2.35(m,1H); 2.0-l.88(m,lH); l.26(d,3H,Me,J=6.2Hz); l.2(d,3H,Me,J=7.lHz).

Examiple 313 r3-r4R-r4alpha.5beta,6beta(R )]Hi- 1-Amino-2.5-anhvdro-3-S- r2-carboxvy-6- (l-hvdroxvethyl)- 4-methyl-7-oxo-l-azabicyclor3.2.Olhert-2-em-3-yl]-1 .4dideoxy-3-thio-L-threo-pentitol *The title compound is prepared by the procedure of Example 192 'using 0.486 g of product from Example 312, 0.167 g of 10% palladium on carbon, 9.8 ml :of 0.1M sodium dihydrogen phosphate buffer and 13 ml of dioxane to give after chromatography (Reverse phase plates: 5% aqueous ethyl alcohol) 0F.140 g of the desired product.

1 H NMR(CDCl 3 :6 4.4-4.3(m,IH);,4.3-4.2(m,2H); 4.l-3.9(m,2H); 3.9-3.8(m,lH); 3.5-3.4(m,2H); 3.2-3.l(m,2H); 2.6-2.4(m,lH); 2.0-1.9(m,1H); l.28(d,3H,Me,J=7.2Hz); 1.22(m,3H,MeJ=7.2Hz).

-251- Exainle 314 r3-r4R-rI(S. .4alpha.5beta.6beta(R V 111- 1- r(2-Amino-l-oxongrgpvl) aminol 5-anhvdro-3-S- r2carboxv-6-(:l-hydroxvethyll -4-methvl-7-oxo-l-azabicvclo- -r3.2. Olhept-2-en-3-vl1-l. 4-dideoXv-3-thio-L-threo- Rentitol The title compound is prepared by the procedure of Example 257 using 0.330 g of product from Example 313, 0.352 g of product from Example 259, 9.6 ml of O.1M PH 7.0 sodium dihydrogen phosphate buffer, 7 ml of dioxane and 0.110 g of 10% palladium on carbon to give after chromatography (Reverse phase plates: ethyl alcohol in water, 2X) 0.069 g of the desired product.

3.85-3.7(m,lH); 3.6-3.3(m,4H); 2.6-2.4(m,lH); 2.0-1.85(m,lH); 1.44(d,3H,Me,J=6.BHz); l.27(d,3H,Me,J=6.8Hz); l.21(d,3H,Me,J=7.OHz).

Example 315 20 1-Chloroethyl Cvclohexvl Carbonate To twenty grams of cyclohexanol dissolved in 500 ml of anhydrous methylene chloride is added 18.4 ml of pyridine. The solution is cooled to -78 0 C under an argon flush, 24.2 ml of 1-chloroethyl chloroformate in 25 160 ml of anhydrous methylene chloride is added dropwise. After the addition the milky reaction mixture is allowed to warm to room temperature. The now clear solution is stirred at room temperature for two hours, poured into a mixture of 100 ml of ice/l00 ml of saturated sodium chloride, the layers are separated and the organic layer is dried and concentrated in vacuo to give 41.03 g of an oily yellow product. The yellow oil is purified by distillation (2.1mm Hg at 82'DC to give 38.54 g of a colorless oil.

351HNMR(CDCl 3 6.5-6.4(qj,lH,Cl-CH); 4.75-4.64(m,lH, C(=0)-O-CH in ring); 1.83(d,3H,J=5.8,Me); 1.l23-2.02 (in, lH)o -252- Example 316 1-Bromoethvl Cvclohexvl Carbonate A mixture of 10.33 g of product from Example 315, 0.20 g of tetrabutylammonium bromide and 7.9 ml of trimethylsilyl bromide is heated in an oil bath for 24 hours at 90°C. The reaction flask is fitted with a 22 cm Vigreux column and the produced trimethylsilyl chloride is distilled and collected at atmospheric pressure as it is formed. After 24 hours, a slight vacuum is applied to remove any residual trimethylsilyl bromide or trimethylsilyl chloride from the reaction.

The formed oil is purified by distillation (87°C at mm Hg) to give 9.87 g of the desired product.

1 H NMR(CDC1 3 6.61(q,lH,BrCH); 4.69(m,lH); 2.03(d,3H,Me); 2.0-1.2(m,10H).

Example 317 I-Chloroethvl p-Nitrophenvl Carbonate The title compound is prepared by the procedure described in J. Med. Chem., 1988, Vol. 31, No. 2, 20 p.321.

To a ice cooled mixture of 27.8 g of p-nitrophenol, 16.0 g of pyridine and 1 L of chloroform is added, dropwise, 34 g of alpha-chloroethyl chloroformate. After 1 hour, the ice bath is removed 25 and the reaction is stirred for 16 hours at room temperature. The mixture is washed with water, sodium hydroxide and water. The organic layer is dried and concentrated in vacuo to give 47.85 g of the desired product.

H NMR(D 2 0):6 8.26(d,2H,ArH); 7.40(d,2H,ArH); 6.53(q,lH,CHCl); 1.93(d,3H,ArH).

Calculated for C C=44.00; H=3.30; N=5.70; C1=14.45 Found: C=44.04; H=3.40; N=5.80; Cl=14.45 -253- Example 318 I-Acetoxyethyl R-Nitrophenvl Carbonate STo a solution of 10.0 g of product from Example 317 in 250 ml of acetic acid is added 15.0 g mercuric acetate. The mixture is stirred at room temperature for 22 hours, concentrated in~ vacuo, and purified by chromatography (Silica gel: methylene chloride 5% methyl alcohol/methylene chloride) to give 7.5 g of the desired product.

1 H NI4R(D 2 0) :6 1. 62 (d,3H,CHMe) 2.13 3H, OAc); 6.86(q,lH,CHoAc); 7.41(d,2H,ArH); B.28(d,2H,ArH).

Examp~le 319 r3-r4R-r4alyha.5beta.6beta(R *)IIIi-r r r1-tAcetvloxv) ethoxvlcarbonvllaminol-2 3 r 2-carboxv-6- (1-hvdroxvethvl) -4-methvl-7-oxo-1azabicvclo r3. 2. 0 1heipt-2-en-3-vl 1 4-dideoxcy-3 -thio- D-threo-Dentitol ~:The pH of a solution of 0.342 g of product from Example 192 in 10 ml of 0.lM sodium dihydrogen phosphate buffer, pH 7.0, is adjusted to 8.5. To this is added a solution of 0.269 g of product from Example 318 in 7 ml of dioxane, maintaining the pH at 8.5 with *1N sodium hydroxide. The mixture is stirred at room temperature for 30 minutes, concentrated in vacuo and purified by chromatography (Reverse Phase Plates: acetonitrile/water) to give 0. 081 g of the desired product.

1 H NMR(D 0):6 6.76-6.73(m,lH); 4.3-4.2(m,3H); 4.15-4.05(q,lH); 4.0-3.B8(m,2H); 3.55-3.35(m,4H); 2.55-2.4(m,lH); 2.15-2.05(m,lH); 2.l1(s,3H,Ac); l.49(d,3H,Me,J=5.4Hz); 1.3(d,3H,Me,J=6.2Hz); 1.21(d,3H,Me,J=5.8Hz).

-254r3-r4R-r4alpha.5beta.6beta(R*I]11- 1- r r r1-(Acetvloxv) ethoxvl carbonvi lamninol 3-S-r2-r ri-Er (cclohexvloXv)carbonlloxylethoxvicarbonvl-6- (l-hvdroxvethvl -4-methvl-7-oxo-1azabicvclor3 Olhe~t-2-en-3-vll-l.4-dideoxv-3-thio- D-threo-Rentitol A 0 0 C solution, under argon, of 0.20 g of product from Example 319 in 10 ml of N,N-dimethylformamide, 0. 152 g of product from Example 316 in 5 ml of N,N-dimethylformamide and 0.110 g of sodium bicarbonate is stirred for 3.5 h ours. The reaction mixture is concentrated in vacua, extracted with ethyl acetate and water, and the organic layer is concentrated i±n vacua, to give after chromatography (Silica gel: ethyl acetate) 0.077g of the desired product.

1 H NMR (D 0) :6 6. 8(q, 1H, J=5. 4Hz) 6. 74(q,l1H, J=5. 3Hz); 2.5-1.1(27H1) 5Me: 1.17(d), 1.27(d), 1.42(d), 1.53(t), 20 198(s andin multiplets.

Example 321 2, 5 -Anhvdro-4 r (4 -methoxyiohenv1) methyl 1 -4 -thia- L-lyXose Dimethyl Acetal To 3.5 ml of tetrahydrofuran, at 0 0 C under argon, is added 0.168 g of sodium hydride, followed by the dropwise addition of 0.626 g of 4-methoxy-alphatoluenethiol. The thick mixture is stirred for minutes, during which time the temperature increased to room temperature. The solution is recooled to 0 C and a solution of 0.50 g of product from Example 299 in 2 ml of tetrahydrofuran is added. The reaction is stirred overnight at room temperatue. The mixture is cooled to 0 0C, quenched with ice water, and extracted with diethyl ether. The organic layer is washed with Water and saturated sodium chloride, dried and concentrated in~ vacuo to give after chromatography -255- (Silica gel: 25-50% ethyl acetate/hexane) 0.89 g of the desire product.

1 H NMR(CDCl 3 :6 7.25(d,2H); 6.85(d,2H); 4.38(d,lH); 4.13(m,lH); 4.03(m,lH); 3.79(m,4H); 3.72-3.61(mn,2H); 3.46(s,3H); 3.42(s,3H); 3.21-3.12(m,1H); 2.26(d,lH).

Example 322 2. 5-Anhydro-4-S- r (4-methoxyohenvl methylI1-4-thia- L-lygose To a 0 0 C solution of 0.340 g of product from' Example 321 in 4 ml of methylene chloride is added a solution of 1 ml of trifluoroacetic acid and 0.266 ml of water. The reaction is stirred at room temperature for 1 hour, concentrated in~ vacuo, extracted with methylene chloride, neutralized with 1 g of sodium bicarbonate, filtered and concentrated in vacuo to give after chromatography (Silica gel: 50-60% ethyl ~:acetate/hexane) 0.222 g of the desired product.

Hi NMR(CDCl 9.67(d,1H); 7.21(d,2H); 6.86(d,2H); 4.36(t,lH); 4.34-4.28(m,1H); 4.2(d,lH); 3.89-3.84(m,lH); 3.80(s,3H); 3.67(s,2H); 3.12(m,lH); Examrple 323 1. 4-Anhvdro-2-S-rF(4-methoxvphenvl )methyl 1-2-thio- L-arab initol 25 To a room temperature solution, under argon, of *10.9 g of product from Example 322 in 115 ml of absolute ethyl alcohol is added 1.57 g of sodium borohydride. The reaction is stirred at room :temperature for 1 hour. Water is added dropwise with stirring and the mixture is concentrated in vacuo. The residue is extracted with methylene chloride, washed with water, dried and concentrated jM vacuo to give after chromatography (Silica gel: 50-75% ethyl acetate/hexane) 7.68 g of the desired product.

1 H NMR(CDC 3 7.25(d,2H); 6.86(d,2H); 4.06(m,2H); 3.82-3.65(m,9H); 3.ll(m,1H); 2.0(brs,lH); 1.93(brs,1H).

-256- Exaniple- 324 1. 4-And~ro-2-S- r (4-methoxvphenvl methyl J-2-thio-Larabinitol 5- (4-Methvlbenzenesulfonate) To a 0 0 C solution, under argon, Of 0.580 g of product from Example 323 in 10 al of pyridine is added 0.430 g of p-toluenesulfonyl chloride. The reaction is stirred at room temperature overnight. The mixture is quenched with water, extracted with diethyl ether, washed with water and saturated sodium chloride, dried and concentrated in~ vacuo. The residue is purified by chromatography (Silica gel: 50% ethyl acetate/hexane) to give 0.520 g of the desired product.

1 H NMR(CDCl 3 :6 7.79(d,2H); 7.34(d,2H); 7.20(d,2H); 7.87(d,2H); 4.18(m,2H); 3.98(m,2H); 3.85(m,lH); 3.78(s,3H); 3.7(s,2H); 3.58(m,1H); 3.1(m,lH); 2.87(brs,lH); 2.43(s,3H).

Example 325 *0 1.4 -Anhvdro-5 -az ido-5-deoxy-2 r(4 -methoxvphenvl)methyll1-2-thio-L-arabinitol 20 A mixture of 2.0 g of product from Example 324, 0.460 g of lithium azide and 2 ml of N,N-dimethylformamide is stirred at 70 0 C for 65 hours. The reaction mixture is concentrated in vacuo. The residue is purified by chromatography (Silica gel: 30% ethyl 25 acetate/hexane) to give 0.454 g-of the desired product.

1 H NMR(CDCl 3 :6 7.25(d,2H); 6.86(d,2H); 4.09-4.03(m,lH); 3.96(t,lH); 3.83-3.66(m,7H); 3.52-3.33(m,2H); 3.11(1,1H); l.7(brs,lH).

Example 326 1. 4-Anhvdro-5-deoXy-2-S- r(4-methoxvphenvl) methyl 1r Er (4 -nitrophenvl) methoxy Icarbonyl Iaminol]-2 -thio- L-arabinitol To a0 0 C solution, under argon, of 0.269 g of product from Example 325 in 4.2 ml of methylene chloride is added 0.171 g of triethylamine followed by 0.308 g of p-nitrobenzylchloroformate. The reaction is stirred at 0 0 C for 2 hours, diluted with diethyl ether, -257filtered and the filtrate is concentrated in vacuo.

The residue is purified by chromatography (Silica gel: ethyl acetate/hexane) to give 0.425 g of the desired product.

1 H NMR(CDCl 3 8.21(d,2H)*; .7.49(d,2H) 7.23(d,2H); 6.85(d,2H); 5.24(rn,1H); 5.20(s,21); 4.06-4.O1(q,lH); 3.85-3.79(q,lH); 3.78(s,3i); 3.78-3.62(m,4H); 3.45(m,lH); 2.05(brs,lH).

Example 327 1. 4-Anhydro-5-deoxv-5-r r r(4-nitrophenvl) methoxvl carbonvl 1amino-2-thio-L-arabinitol The title compound is prepared by the procedure of Example 202 using 0.462 g of product from Example 326, 12 ml of 80% aqueous acetic acid, 0.187 g of anisole, and 0.443 g of mercuric trifluoroacetate to give after chromatography (Silica gel: 50-80% ethyl acetate/hexane) 0.248 g of the desired product.

5.21(s,2H); 4.23(q,lH); 3.83-3.67(m,3H); 3.49(m,2H); 3.31(m,lH); 2.39(brs,lH); l.76(d,lH).

Example 328 r2-r4R-r4alrha.5beta.6beta(R*)11- 1. 4-Anhvdro-5-deoxv-2-S- r6- (l-hvdroxyethvl) -4-methyl- 2- r r (4-nitrophenvl)xntethoXylcarbonvll-7-oxo-l-azabicyclor3.2.01heipt-2 -en-3-vl 1-5- rr r (4-nitrophenyl) methoxvl carbonvll1amino-2-thio-L-arabinitoI The title compound is prepared by the procedure of Example 17 using 0.210 g of product from :Example 327, 0.380 g of product from Example 15, 3 ml of acetonitrile, and 0.163 g of Hunig's base to give after chromatography (Silica gel: 5% methyl alcohol/chloroform) 0.249 g of the desired product.

1 H NMR(CDCl 3 8.24-8.19(m,4H); 7.65(d,2H); 7.49(d,2H); 5.52-5.18(m,6H); 4.29-4.24(m,2H); 3.95(t,lH); 3.79-3.70(m,4H); 3.49-3.4(m,3H); 3.28(dd,lH); 2.05(brs, 1Hi); l.36(d,3H); 1.28-.22(m,3H).

-258r2-r4R-E4albhla.bta6bta (R 111- 4-anhvdro-2-S- r 2-carboxv-6- fl-hvdroxvethyl I 4-methvl-7-oxo-1-azabicvclor3 Oht-2-en-3 -vi deox-2-thio-L-arabinitol The title compound is prepared by the procedure of Example 192 using 0.240 g of product from Example 328, 0.072 g of 10% palladium on carbon, 2.5 ml of 0.114 pH 7 sodium dihydrogen phosphate buffer and 7.5 ml of dioxane to give after chromatography (Reverse phase plates: 5% ethyl alcohol/water) 0.028 g of the desire product.

1 H NMR(D 2 0):6 4.38-4.3(m,lH); 4.25-4.2(m,2H); 4.l(m,lH); 4.05(m,lH); 3.94(m,lH); 3.75-3.6(m,2H); 3.48-3.4(m,2H); 3.28(djlH); 1.25(d,3H); l.19(d,3H).

Exam~le 330 (RI 2-Dimethvl-1. 3-dioxolane-4-carboxaldehyde A 0 0C mixture, under argon, of 13.7 g of 1,2,5, 6-di-O-isopropylidene-D-mannitol, 200 ml of methylene chloride, 72.3 g of potassium carbonate and 24.3 g of lead tetraacetate is stirred for 1 1/2 hours.

The suspension is filtered through diatomaceous earth and concentrated i~n vacuo. The oil is purified by distillation at water aspirator pressure to give 10.0 g (boiling point 62-66 0C) of the desired product.

1 H NMR(CDC1 3 9.73(d,lH); 4.4 (m,lH); 4.22-4.07(m,2H); 1.5(s,3H); 1.43(s,3H).

Example 331 Iand R-(R*.S*)1-2.2-Dimethvl-alpha-2- D2ropenyl-1. 3 -dioxolane-4 -methanol To a stirring -78 0C solution, under argon, of 556.ml of 1M4 allylmagnesium bromide is added, dropwise over 20 minutes, a solution of 36.4 g of product fro' Example 330 in 17 ml of tetrahydrofuran. The reaction Mixture is stirred at -78 0C for 2 hours. Thin layer chromatography indicates the presence of starting material. An additional 280 ml of 114 allylmag-nesium -259bromide is added and the reaction is stirred overnight at -78°C. The reaction is quenched with dropwise addition of saturated ammonium chloride, filtered through diatomaceous earth and washed with diethyl ether, ethyl acetate and 20% isopropyl alcohol/chloroform. The combined extracts are washed with saturated sodium chloride, dried and concentrated in vacuo to give, after Kugelrohr distillation at 38.25 g of the desired product.

1 H NMR(CDC13):6 5.83(m,lH); 5.15(q,2H); 4.05-3.57(m,4H); 2.39-2.12(m,3H); 1.43(d,3H); 1.38(d,3H).

Example 332 FR-(R* -2.2-Dimethvl-4- r1-(Dhenlmethoxy 3-butenvll-1.3-dioxolane (A) Sand FR-(R .R -2.2-Dimethvl-4-[1-fphenylmethoxy)- 3-butenvll-1.3-dioxolane (B) Under anhydrous conditions, a flask is S 20 charged with 10.7 g of sodium hydride and 35 ml of anhydrous tetrahydrofuran. This slurry is stirred for 10 minutes at 0°C followed by the dropwise addition of 38.25 g of product from Example 331 in 50 ml of anhydrous tetrahydrofuran. The ice bath is removed and 25 the reaction is stirred for 30 minutes at room temperature. The reaction mixture is recooled to 0°C and 20 ml of benzyl bromide is added dropwise followed by 0.150 g of tetrabutylammonium iodide. The reaction is allowed to warm to room temperature and the stirring is continued for 60 hours. The mixture is recooled to 0 C, quenched with ice cold saturated ammonium chloride, extracted with diethyl ether and washed with sodium bicarbonate and saturated sodium chloride. The organic layer is dried, concentrated in vacuo to give after chromatography (Silica gel: 5% diethyl ether/hexane) 5.7 g of compound A and 6.1 g of compound

B.

-260- Compound A: lB NMR(CDCl 3 :6 7.34-7.28(M,5SH); 5.89(m,lH): 5.18-5.08(2,2H); 4.62(q,2H); 4.11-4.01(=,2H); 3.89(m,lH); 3.57(q,lH); 2.42-2.39(m,2H); l.42(s,3H); l.35(st31).

Compound B: 1 H NMR(CDCl 3 :6 7.38-7.27(m,5H); 5.89(m,lH); 5.14-5.05(m,2H); 4.69(q,1H); 4.21(q,2H); 3.98(q,lH); 3.71(t,lH); 3.52(M,1H); 2.37-2.i8(m,2H); L.43(s,3H); 1.37(s,31).

Example 333 rs-(R S 11-3-(Phenvlmethoxv-5-hexene-1 .2-diol A mixture of 26.2 g of product from Example 332, 140 ml of 2N hydrochloric acid and 140 ml of tetrahydrofuran is heated at reflux temperature for 1 hour. The reaction mixture is cooled to 0 0 C, quenched with solid sodium bicarbonate, and extracted with chloroform. The organic layer is washed with saturated sodium chloride and water, dried and concentrated -in vacuo to give 11.0 g of the desired product.

*H1 NMR(CDCl 3 :6 7.36-7.30(m,5H); 5.87(m,lH); 5.19-5.09(m,2H); 4.6(q,2H); 3.79-3.63(m,4H); 2.53-2.37(m,2H); 2.13(brs,2H).

Example 334 25 2. 5-Anhvdro-l. 3-dideoXv-l-iodo-4-.o-(phenvlmethvl) D-ribo-hexitol (A) and 2. 5-Anhvdro-1. 3-dideoxv-l-iodo-4-0- (nhenvlmethvl to* D-arabino-hexitol (B) A 0 0 C solution of 4.5 g of product from Example 333 in 77.8 ml of diethyl ether and 25.5 ml of water is treated with 2.58 g of solid sodium bicarbonate followed by 7.6 g of iodine. The reaction is stirred for 3 hours at 0 0 then at room temperature ov ernight. The mixture is cooled to 0 0 C and sodium sulfite is added until the reaction is colorless. The solution is extracted with diethyl ether, dried and -261concentrated vacuo to give 7.0 g of an oil. The oil is purified by chromatography (Silica gel: 5% diethyl ether/hexane) to give 2.8 g of Isomer A and 1.86 g of Isomer B.

Isomer A: 1H NMR(CDCl 3 :6 7.37-7.28(m,5H); 4.51(q,2H); 4.12(ml2H); 3.97(m,lH);. 3.68(q,2H); 3.36(m,2H); 2.15(ml2H). 1.78(m,lH).

Isomer B: 1 H NMR(CDCl 3 :6 7.36-7.3(m,5H); 4.52(q,2H); 4.31(m,lH); 4.19-4.07(m,2H); 3.72-3.67(m,lH); 3.58-3.56(m,1H); 3.35(m,2H); 2.34(mllH); 2.07(m,lH); 1.96 (brs,lH).

ExaMle 335 2 5-Anhvdro-1. 3 -dideoxv-4 (phenvlmethl) -Dribo-hexitol A mixture of 6. 0 g of product from Example 334, Isomer A, 34 ml of ethyl alcohol, 17.2 ml of iN sodium hydroxide and 7.8 g of 10% palladium on carbon 20 is hydrogenated in a Parr apparatus at 45 psi of hydrogen for 15 hours. The reaction mixture is filtered, diluted with ethyl acetate, washed with saturated sodium chloride, dried and concentrated in vacuo to give 2.9 g of the desired product.

1 NMR(CDCl 3 :6 7.37-7.27(m,5H); 4.51(q,2H); 4.0l-3.97(m,2H); 3.77-3.58(m,2H); 2.15-2.08(m,lH); 1.83(brs,lH); l.58(brs,1H); l.58-l.48(m,lH); 1.28-(d,3H).

2 .~Example 336 2. 5-Anhydro-1. 3-dideoxv-]D-hexitol A mixture of 1.-1 g of product from Example 335 in 44 ml of ethyl alcohol and 22 ml of cyclohexane is treated with 0.250 g of, palladium hydroxide on carbon (Pearlman's catalyst). The resulting black suspension is heated at reflux temperature for 3 hours, filtered and concentrated in vacuo. The residue is purified by chromatography (Silica gel: 3% methyl -262alcohol/chloroform) to give 0.570 g of the desired product.

1 H NMR(CDCl 3 4.3-4.32(m,2H); 3.8(q,lH); 3.65-3.58(m,2H); 3.57-3.54(m,lH); 3.29(m,lH); l.99-l.93(m,lH); l.65(m,lH); l.26(d,3H).

Example 337 2. 5-Anhvdro-l. 3-dideoxv-D-ribo-hexitol 6- (4-Methylbenzenesulfonate) The title compound is prepared by the procedure of Example 307 using 0.290 g of product from 336, 0.440 g of p-toluenesulfonyl chloride and 8 al of pyridine to give after chromatography (Silica gel: 2% methyl alcohol/chloroform) 0.407 g of the desired product.

1 H NMR(CDCl 3 :6 7.89(d,2H); 7.35(d,2H); 4.31(m,lH); 4.27(m,lH); 4.08(m,lH); 3.94(m,lH); 3.8(m,lH); 2.45(s,3H); 2.34(brs,lH); l.93-l.91(m,lH); 1.20(d,-3H).

Example 338 2. 5-Anhydro-6-azido-l. 3. 6-trideoxy-D-ribo-hexitol A mixture, under argon, of 0.560 g of product from Example 337, 2 ml of N,N-dimethylformamide and 0.250 g of sodium azide is stirred at 75 0 for 12 hours. The reaction mixture is diluted with diethyl 25 ether, washed with water and saturated sodium chloride, dried and concentrated in vacuo to give 0.238 g of the desired product.

1 H NMR(CDCl 3 :6 4. -27 2H) 3.9 1H) 3.49 (m,lIH); 3.33-3.27(m,lH); 2.0l-l.94(m,lH); l.74(brs,lH); l.64(m,lH); l.26(d,3H).

Exaz~le 339 2. 5-Anhdro-6-azido-1. 3. 6-trideoXv-D-ribo-hexito1 4 -Methanesul fonate The title compound is prepared by the procedure of Example 277 using 0. 192 g of product f rom Example 338, 0.316 g of Huriig's'base, 0.280 g of methanesulfonyl chloride and.0.35 ml of methylene -263chloride to give after chromatography (Silica gel: ethyl acetate/hexane) 0.*140 g of the desired product.

1 H NMR(CDCl 3 5.08-5.05(m,1H); 4.26-4.l8(m,2H); 3.6-3.54(m,1H); 3.41-3.35(m,1H); 3.05(sl3H); 2.30-2.27(m,1H); l.8B-1.78(m,1lH); 1.34(d,3H).

Examp~le 340 2. 5-Anhydro-6-azido-1 6-trideoxv-4-thio- D-xvlo-hexitol 4-Acetate A mixture of 0.133 g of product from Example 339, 0.083 g of potassium thioacetate, 500 microliter of dimethylformamide and 500 microliter of toluene is 0 stirred, under argon, at 70 C overnight. The progress of the reaction is monitored by tic. An additional 0.050 g of potassium thioacetate is added and the reaction is stirred at 70 0 C for 5 more hours. The mixture is filtered through a thin pad of Silica gel, washed with diethyl ether and the filtrate is concentrated in vacuo. The residue is purified by chromatography (Silica gel: 20% diethyl ether/hexane) to give 0.043 g of the desired product.

H NMR(CDCl 3 :6 4.29-4.21(mlIH); 4.21-4.16(M,lH); 4.08-4.03(m,lH); 3.44-3.39(m,lH); 3.30-3.25(m,lH); 2.46(m,lH); 2.35(s,3H); 1.59(m,1H); 1.33(d,3H).

Example 341 2 .5-Anhydro-6-azido-1.3. 6-trideoXy-4-thio- D-xvl o-hexitol The title compound is prepared by the procedure of Example 16 using 0.040 g of product from :Example 340, 52 microliter of 25% (by wt) sodium methoxide/methyl alcohol and 0.50 ml of tetrahydrofuran to give 0.030 g of the desired product.

1 H NMR(CDCl 3 :6 4.l-3.96(m,2H); 3.55-3.43(m,3H); 2.61-2.47(m,lH); 1.7(d,1H); l.48(m,1H); 1.34(d,3H).

-264- 2. 5-Anhy-dro-6-azido-1 6-trideoxv-4-S-r6- (1-hydroxvethyl) -4-methyl-2-rrF(4-nitroiphenvllmethovl carbonyl 1- 7-oxo-1-azabicvclor3 Olhebt-2-en-3-yll -4-thio- D-Xylo-hexitol The title compound is prepared by the procedure of Example 17 using 0.030 g of product from Example 341, 0.103 g of product from Example 0.022 g of Hunig's base and 0.50 ml of acetonitrile to give after chromatography (Silica gel: acetone/chloroform) 0.062 g of the desired product.

1 H NMR(CDCl 3 .8.22(d,2H); 7.66(d,2H); 5.52(d,lH); 5.23(d,lH); 4.26(m,2H); 4.06(m,lH); 3.83(q,lH); 3.52(t,lH); 3.4(m,lH); 3.3(m,lH); 21.5(m,lH); l.84(brs, 1H); l.76(m,1H); l.38-l.25(m,9H); 0.88(m,2H).

4-r4R-r4alpha.5beta.6betafR*1-111- 6-Amino-2 .5-anhvdro-4-S-rF2-carboxv-6- (1-hvdroxvethyl) 4-methvl-7-oxo-l-azabicvclor3 Olhept-2-en-3-vll 20 1.3. 6-trideo-4 -thio-D-xyo-h~eiton The title compound is prepared by the procedure of Example 192 using 0.060 g of product from Example 342, 0.045 g of 10% palladium on carbon, 2.35 ml of 0.1M pH 7 sodium dihydrogei phosphate buffer, and 7.05 ml of dioxane to give after chromatography (Reverse phase plates: 5% ethyl alcohol/water) 0.012 g of the desired product.

1 H INMR(D 2 0):6 4.04(m,lH); 3.93-3.85(m,3H); 3.69(q,lH); 3.13-2.97(m,3H); 2.87-2.79(m,lH); 2.33-2o23(m,lH); l.44-l.36(m,1H); lo.0.95(m,6H); 0.86-0.84(m,3H).

Example 344 1, 4 -Anhvdro-2 5-dideoxv-5- (methvlamino) D-erthro-Rentitol To a 0 0 C solution of 15 ml of 40% methylamine is added 0.921 g of product from Example 269 in 2 ml of dioxane. The reaction mixture is. maintained and stirred at 0 0C for 50 minutes, tic indicates the -265absence of starting material. The reaction is concentrated Ji y-cu and the residue is chromatographed (Silica gel: 30% methyl alcohol/chloroform) 0.749 g of an oil containing the desired product and salts. The sample is redissolved in ethyl acetate; potassium carbonate is added and the, mixture is stirred for 2 hours at room temperature. The suspension is filtered, concentrated jja vau and rechromatographed (Silical gel: methyl alcohol) to give 0.102 g of the desired product.

1 H NMR(CDCl 3 :6 4.O-3.9(m,1H); 3.88-3.75(m,2H); 3.75-3.65(m,lH); 2.6-2.35(m,2H); 2.29(s,3H,N-Me); 2.05-l.92(m,lH); l.8-l.7(m,1H).

Example 345 1.4-Arihvdro-2 .5-dideoxy-5-rmethyl r r(4nitrophenvi lmethoxvl carbonvi 1amino 1- D-erthro-Rentitol A -50C mixture, under argon, of 4.35 g of product from Example 344 in 30 ml of methylene chloride 20 is treated with 5.8 ml of Huriig's base followed by dropwise addition of 7.15 ml of p-nitrobenzyl chloroformate in 20 ml of methylene chloride. The reaction mixture is stirred at -5 0 C for 2 1/2 hours.

The mixture is concentrated in vacuo and the residue is 25 purified by chromatography (Silica gel: 75% ethyl acetate/hexane) to give 6.75 g of the desired product.

1 H NNR(CDCl 3 8.22(d,2H,Arom,J=8.6Hz); V 7.56 (d,2H,Arom,J=8. 5Hz) 5.23 (s,2Hbenzylic H); 4.16-4.08(q,2H); 3.97-3.92(t,2H); 3.53(dd,lH); 3.39-3.31(dd,lH); 3.06(s,3HNMe); 2.2-2.l(m,lH); 2. 0-1. 85 (in, H) 1.4-Anhvdro-2.*5-dideoxv-5-rmethylr[m(4nitroiphenyl) metho2M 1 carbonyl 1 amino 1 -D-erthro- Rentitol -3-methanesulfonate The title compound is prepared by the procedure of Example 277 using 0.310 g of product from -266- Example 345, 93 microliters Of methanesulfonyl chloride and 167 microliters of triethylazine to give, after chromatography (Silica gel: ethyl acetate), 0.388 g of the desired product.

H NMR(CDCl 3 B.1(d,2H,J=8.7Hz); 7.47(d,2H,J=6.9Hz); 5.16(s,2H,benzylic 5.05(m,lH,S-0-CH); 4.2-4.l(m,lH); 4.05-3.9(m,lH); 3.88-3.78(q,1H); 3.55-3.4(m,lH); 3.35-3.2(m,lH); 2.97(s,6H,2Me); 2. 16-2. 12 2H) Example 347 2. 5-Anhvdro-l 4-dideoxv-I-EmethYl r r4-nitrophenyll methoxvl carbonvll1aminol1-3-thio-D-threo-Rentitol 3-Acetate The title compound is prepared by the procedure of Example 278 using 3.9 g of product from Example 346, 1.7 g of potassium thioacetate, 20 ml of dimethylformamide and 20 ml of toluene to give, after chromatography (Silica gel: 50% ethyl acetate/hexane) 2.*13 g of the desired product.

1H N)M(CDCl 3 8.22(d,2H.,J=8.OHz); 7.53(t,2H); 2.25(s,2H); 4.25-4.0(m,2H); 3.9(m,lH); 3.8(m,lH); 3.6(m,lH); 3.25(m,lH); 3.03(s,3H,N-He); 2.35(s,3H,SAc); l.98(m,lH).

Example 348 2. 5-Anhydro-1, 4-dideoxy-l- rmethyl r r 4-nitroiphenvl) methoxvl carbonvll1aminol -3-thio-D-threo-Rentitol To an ice cooled solution of 2.13 g of product from Example 347 in 15 ml of methyl alcohol is :.:added, dropwise maintaining the temperature below 1.52 ml of 4N sodium hydroxide. The reaction is stirred for 10 minutes. The reaction is monitored by tlc. To the cooled solution is added 2.17 xl of 0z.97N hydrochloric acid and the reaction mixture is diluted with ethyl acetate, washed with saturated sodium chloride, and the organic phase is dried. The solution is concentrated in vacuo arnd the residue is purified by -267chromatography (Silica gel: 50% ethyl acetate/hexane) to give 1.15 g of the desired product.

1 H NMR(CDCl 3 8.22(d,2H,J=8.OHz) 7. 5(d,2H,8. OHz); 5.21(s,2H); 4.l(m,2H); 3.8(m,2H); 3.5-3.25(m,2H); 3.07(s,3H,N-Me); 2.5(m,lH); 2.O(m,1H); l.66(SH).

Example 349 r3-r4R-r4alDha.5beta.6beta(R* 311- 2. 5=Anhvydro-1 4-dideoXy-3-S- r6- (1-hdroxethyllh 4-methyl-2- r r(4-nitrophenyl) methoxyl carbonvi 1- 7-oxo-l-azabicyclor 3.2. Olhent-2-en-3-vl I 1- rmethyl r r(4-nitro~henvi) methoxvl carbonvi 1amino 1- 3 -thio-D-threo-Dentitol The title compound is prepared by the procedure of Example 17 using 1.15 g of product from Example 348 in 15 ml of acetonitrile, 1.68 g of product from Example 15 in 15 ml of acetonitrile and 0.54 ml of Hunig's base to give, after chromatography (Silica gel: ethyl acetate/acetone) 1.52 g of the desired 1 20 H NMR(CDCl): 8. 2 2(d, 4H, Arom, J=8. 6Hz); 7.66(d,2H,Arom,J=8.6Hz) 7.52(d,2H,Arom,J=8.6); 5.52(d,1H,benzylic H, J=13.8Hz); 5.23(d,3H,benzylic H,J=10.3Hz); 4.35-4.2(m,3H); 4.2-4.0(m,1H); 3.95-3.75(m,3H); 3.7-3.l(m,3H); 3.07(s,3H,N-Me): 2.5-2.35(m,IH); 2.l-2.O(m,lH); 1.95-l.8(brs,1H,OH); 1.37(d,3H,,Ie,J=6.2Hz); l.28(d,3H,J=7.3Hz).

Example 350 r3-r4R-r4alhha.5beta.6beta(R )1]11- 2. 5-Anhvdro-3-S- r2-carboxv-6- (1-hvdroxvethyl) -4methyl-7-oxo-1-azabicvclof3.2.Olhent-2-en-3-vlu-1,4dideoxy-l- (methylamino) -3-thio-D-threo-pentitol The title compound is prepared by the procedure of Example 192 using 1.52 g of product from Example 349, 25 ml of 0.1M pH 7.0 sodium dihydrogen phosphate buffer, 0.70 g of 10% palladium on carbon and ml of dioxane to give, after chromatography -268- (Reverse Phase plates: 5% aqueous ethyl alcohol), 0.225 g of the desired product.

1 H NMR(D 2 0):6 4.6-3.8(m,6H); 3.6-3.2(m,4H); 2.76(s,3H,N-Me); 2.6-2.4(mjlH); 2.2-2.0(m,lH); 1.27 (d,3H,Me,J=5.5Hz); l.17(d,3H,Me,J=6.3).

Example 351 r3-E4R-r3(2S 1.4alha.5beta.6beta(R )III- 1-F (2-Alnino-l-Oxopro~vll methylaminol -2 3-S-F 2-carboxv-6- (l-hvdroXyethyl) -4-methvl-7-oxo- 1-azabicyclor3.2 .Olhe~t-2-en-3-vll-l .4-dideoxv- 3- thio-D-threo-Dentitol The title compound is prepared by the procedure of Example 304 using 0.173 g of product from Examiple 350, 0.177 g of product from Example 259, 5 ml of O.1M pH 7.0 sodium dihydrogen phosphate buffer, 4 ml of dioxane and 0.10 g of 10% palladium on carbon to give, after chromatography (Reverse Phase Plates: aqueous ethyl alcohol),0.0386 g of the desired product.

Example 352 .2-DeoXy-3 .5-bis-O-F (1.1-dimethylethyl) dimethylsilyll D-erythro -pentonoic Acid crainma-Lactone To a stirring solution, under argon, of *1.*18 g of 2-deoxy-D-erythro-pentonoic acid gamma-lactone, prepared by the procedure described in 25 Carbohydrate Research, Vol. 90, 1981, p 17-26, in 11 ml of dimethylformanide containing 3 ml of triethylamine is added dropwise a solution of 2.95 g of tert-butyldimethylsilyl chloride in 9 ml of dimethylformamide. The reaction mixture is stirred overnight at room temperature, poured into a mixture of 110 ml of hexane and 110 ml of water, the layers partitioned. The organic layer is washed with water, dried and concentrated to give 2.64 g of the desired product.

mp 77-78 0

C.

1 H NMR(CDC1 3 :6 4.45(m,lH); 4.34(m,1H); 3 .78(m,2H); 2.83(dd,lH); 2.38(d,1LH); 0.9(s,181).

-269- Example 353 2-Deoxv-3.5-bis-O-r (1.-dimethethvthvldimethvlsill 1-thio-D-erythro-pentonoic Acid aamma-Lactone To a solution, under argon, of 1.24 g of product from Example 352 in 16 ml of dry toluene is added 0.973 g of Lawesson's Reagent. The reaction mixture is heated at reflux temperature for 3 hours (the reaction is monitored by thin layer chromatography, tlc). Tlc indicates the presence of starting material. An additional 0.138 g of Lawesson's reagent is added and the reaction is heated at reflux temperature for an additional 1 1/2 hours. The mixture is cooled to room temperature, the solids are collected and washed with toluene. The mother liquor is concentrated to dryness and purified by chromatography (Silica gel: hexane/ethyl acetate) to give 0.960 g of the desired product.

Calcd for C H 360SSi C 54.20; H 9.63; S 8.51 20 Found: C 53.91; H 9.73; S 8.51.

H NMR(CDC1 3 4.65(m,1H); 4.55(m,lH); 3.85(q,2H); 3.25(dd,1H); 2.98(d,lH); 0.87(s,18H).

mp 90-91°C.

25 Example 354 2-Deoxv-3 5-bis-O-r(1l.1-dimethvlethyl)dimethylsilyl 1-thio-D-ervthro-pentofuranose To a -78 0 C solution, under argon, of 0.420 g of product from Example 353 in 8.4 ml of dry tetrahydrofuran is added dropwise 2.8 ml of Super Hydride (1M in tetrahydrofuran). After 1 hour an additional 1.4 ml of Super Hydride is added and the stirring continued at -78 C for 30 minutes. The reaction is quenched by the addition of 5 ml of 1N hydrochloric acid. Ethyl acetate and water are added and the layers are partitioned. The organic layer is washed with -270water, saturated sodium chloride, dried and concentrated to give 0.412 g of an oil.

Calcd for C 17

H

38 0 3 SSi 2 C 53.92; H 10.11; S 8.46 Found: C 54.62; H 9.94; S 8.23.

1HNMR (CDCl..):6 5. 5(m,l1H); 4. 37 (m,1IH); 4. 15 1H); 3.74-3.5(m,2H) 2.95(d,H); 2.54(m,1H); 2.06(m,1H); 0. 87 (2s, 18H) Example 355 Dimethylethyl I dimethvlsilyl 1-3- r1- r r (I.1Idimethylethyl) dinethvlsilvl Ioxvi ethyl 1 -4oxo-2-azatidinvll ethyI]-3-r (4nitrophenvi) methvoxvl 3-dioxopropyl 2-deoxy- 3. 5-bis-O-r (1.1-dimethvlethyl)dimethvlsilyll- I-th jo-alpha (and beta) -D-erthro-Rentofuranos ide 0 To a 0 C solution, under argon, of 0. 638 g of product from Example 103 in 5.3 ml of dry tetra- 20 hydrofuran is added 0.30 g of product from Example 354 in 4 ml of tetrahydrofuran. 0.133 ml of triethylamine is added and the reaction is stirred for 30 minutes at 00 C. The mixture is allowed to come to room temperature over 30 minutes, diluted with ethyl 25 acetate, washed with saturated sodium bicarbonate, saturated sodium chloride, dried and filtered. The filtrate is purified by chromatography (Silica gel: 98% hexane/ethyl acetate) to give 0.660 g of an impure solid. The solid is rechromatographed (Silica gel: hexane/ethyl acetate) to give 0.294 g of the desired product as a yellow oil.

1 H NMR(CDCl 3 8.23(d,2H); 7.57(d,2H); 5.36(m,2H).; 5.25(m,lH); 4.4-3.25(m,6H); 2.4-1.67(m,2H)OI l.22-1.0(4d.,6H).

-271- S Example 356 r2S-r2alipha(s .3beta(S*)311-rl-r3-(l-Hvdroxvethyl)- 4-oxo-2-azetjdinvll1ethvll -3-I (4-nitrophenvi) methoxvl 2. 3-dioxopropyl 2-deoxy-1-thio-alipha (and beta) -Derythro-Dentofuranoside To a room temperature solution, under argon, of 0.294 g of product from Example 355 in 3 m1 of dry tetrahydrofuran is added 3 ml of triethylainmonium trihydrofluoride. After 20 minutes, no starting o material was present (by tic). Stirred in an oil bath at 500 C for 1 hour and 40 minutes. Only polar spot visible by tic The -reaction mixture is, cooled, cold ethyl acetate is added, the layers are partitioned and the organic layer is washed with cold water, cold sodium bicarbonate, cold saturated sodium chloride, dried and concentrated to give 0.105 g of a glass.

The product is used immediately in following Example.

Example 357 r4R-r4al~ha.5beta. 6beta(R*) 11-6-(l-Hvdroxvet .hvl)-4- 20 methvl-2- f r (4-nitroi~henyU-methoxvl carbonyl 1 -7-oxo- -1-azabicvclor3 Olhert-2-en-3-vl 2-deoxv-1-thioalpha (and beta) -L-erthro-pentofuranoside ~*To a room temperature solution, under argon, of 0.105 g of product from Example 356 in 2 ml of dry tetrahydrofuran is added 0.82 ml of titanium tetrachloride (lM in methylene chloride). The reaction is stirred for 10 minutes and poured into a rapidly stirred mixture of ethyl acetate and saturated sodium bicarbonate. The layers are separated, the organic layer is washed with saturated sodium chloride, dried and concentrated to a glass. The glass is purified by chromatography (Silica Gel: 5% methyl alcohol/methylene chloride) -to give 0.026 g of the desired product.

1 H NMfR(acetone-d 6 :6 8.25(d,2H); 7.84(d,2H); 5.85(m,lH); 5.57(d,lH); 5.3(d,lH); 4.5-3.53(m,6H); 3.34(brs,lH); 2.75(m,lH); 2.45-1.93(m,2H); 1.25 (brs,6H).

-272- Example 358 r4R-r4al~ha,5beta,6bet&(R11 2-CarboXy-6- (1-hvdroxvethy.) -4-maethvl-7-oxo-l-azabicvclo r3.*2. Olheyt-2-en-3-vl 2-deoMv-I-thio-alpha land beta) -D-ervthro-Rentofuranoside To a solution of 0.026 g of product from Example 357 in 0.3 ml of water (degassed) and 0.3 al of dioxane is added 0.0053 g of potassium bicarbonate.

The mixture is transferred to a Parr apparatus with 0.2 ml of water and 0.2 ml of dioxane. 0.026 g of palladium on carbon is added and the reaction mixture is hydrogenolysed at room temperature, 35 psi, for 1 1/2 hours. The reaction is filtered and washed with water and ethyl acetate. The organic layer is dried and lyophilized to give 0.016 g of the desired product.

Hi NMR(D 2 0):6 5.8(m,lH); 4.54-3.95(m,4H); 3.9-3.45(m,6H); 2.78(m,lH); 2.49-2.2(m,lH); 2.05(m,1H); l.33(d,3H); 1.25(d,3H).

V, Example 359 20 rrIl.1-Dimethylethvl)dimethysilyloxvlmethll-.

-furanone The title compound is prepared by the procedure of Example 352 using 0.65 g of S-(+)-dihydro- 5.-I1yuoxymeyl)--(H)-furanone in 9 ml o dimethylformamide, 1.6 3 g of tert-butyldimethylsilyl chloride, and 1.63 ml of triethylamine to give 0.868 g of the desired product as a colorless oil.

1 H N(CDCl 3 :6 4.6(m,lH); 3.77(ABq,2H); 2.7-2.4(m,2H); 2.34-2.l(m,2H); 0.9(2s,9H); 0.l(2s,6H).

Exam~le 360 -5-F r(l1 -Dimethylethvl~dimethvlsilvlox,1methvl1 dihvdro-2 (3H) -furanthione The title compound is prepared by the procedure of Example 353 using 0.868 g of product from Example 359, 10 ml of toluene and 0.763 g of Lawesson's Reagent to give 0.530 g of the desired product.

-273- 1H1 MMR(CDCl 3 :6 4.99(m,lH); 3.86(ABq,2H); 3.27-2.99(M,2H); 2.4-2.l8(n,2H); 0.9(s,9H); O.1(2s,6H).

Example 361 (2S-cis) and (2g-trans) 5-r r r(1. -DilnethylethvlidizmethvlsillloXvlmethll..

tetrahvdro-2 (3H) -furanthiol The title compound is prepared by the procedure of Example 354 using 0.0445 g of product from Example 360, 0.9 ml of dry tetrahydrofuran and 0.362 ml of Super Hydride to give a mixture of anomers.

1 H NMR(CDCl 3 5.64, 5.46(m,lH); 4.31,4.13(2m,1H); 3.8-3.6(m,2H); 2.44-2.75(n,4H); 2.29,2.2(2d,lH); 0.9(2s,9H); 0.l(2s,6H).

ExaM~le 362 r2S-r2alDha.2rgamaS* beta(5R *)1.3beta-(S i1-i 1-F -Dimethlethldimethlsilyll3rl.rrF(1.1dimethlethyl dimethlsily Ioxyh ethl 13-r C 5-F r r 1dimethylethyl) dimethylsilvi 1 oxvlmethyl 1 tetrahvdro-2 *furanvi 1 thiol] -gamma -methy lpha. 4 -d ioxo- 2 20 azetidinebutanoic Acid (4-Nitrophenvl)methyl Ester The title compound is prepared by the procedure of Example 355 using 0.334 g of product from Example 103 in 2.8 ml of tetrahydrofuran 0.148 g of product from Example 361 in 2 ml of tetrahydrofuran, and 0.83 ml of triethylamine to give, after chromatography, 0.272 g of the major isomer and 0.128 g of the minor isomer.

Major Isomer: IH NM(D18.25(d,2H); 7.6(d,2H); 5.39(s,2H);

NMRCDC

3 )"a 5.18(m,lH); 4.43(d,1H); 3.98(m,2h); ABq,2H); 2.8(m,lH); 2.5(m,1H); 2.34-1.82(m,4H); l.25(d,3H); l.05(d,3H); l.0-0.9(4s,3H); 0.25(2s,6H); 0. 04 (4s, 12H) Minor Isomer: 351 NMR(CDCl 3 :6 8 .2 5(d, 2H) .763 2H) 5. 3 7(m, lh); 5.34(AIBg,2H); 4.45(d,1H); 4.03(m,2H); 3 .68-3.5(m,3H);- -274- 3 .16(im,lH); 2.65(mn,1H); 2.33-l.88(m,4H); l.3(d,3H); 1.l8(d,3H); O.9(48,27H); O.1-0(6s,18H).

ExaMile 363 r4R-r3 (5S ~4al]2ha. 5beta. 6beta 111- 6- (1-Hydroxyethvl) -4-methvl-7-oxo-3- r r (hvdroxm~ethvfl)-2-furanyllthiol -1-azabicyclo r 3.2.o 0hent-2-ene-2-carboXyljc Acid (4-Nitro~henvi) methyl Ester The title compound is prepared by the procedure of Example 356 using 0.271 g of product from Example 362 in 0.8 ml of tetrahydrofuran, 0.8 ml of triethylammonium trihydrofluoride to give 0.152 g of [2S-[2alpha,2ganmaS ,beta(5R )],3beta(S )JJ-3-(lhydroxyethyl) -gamma-methyl-alpha, 4 -dioxo-beta- [(tetra- (hydroxymethyl) -2-furanyl~thioJ -2-azetidinebutanoic. The above recovered product is reacted according to the procedure of Example 356 with 1.2 ml of titanium tetrachloride to give 0.046 g of the desired title product.

1 H NMR(CDCl 3 8.24(d,2H); 7.67(d,2H); 5.73(m,lH); 5.38(ABg,2H); 4.3(m,3H); 3.84-3.53(m,2H); 3'.3(m,lH); 2.43(m,lH); 2.35-l.6(m,4H); l.38(d,3H); 1.3(d,3H).

Examn1e 364 r4R-r3(5S *)4al~ha,5beta,6beta(R*)11- 6- (l-Hydro-xvethyl)-4-methyl-7-oxo-3- r (hvdroxymethvl)-2-furanvllthiol-l-azabicyclor3.2.olhexpt-2-ene-2-carboxylic Acid Monogotassium Salt The title compound is prepared by the procedure of Example 358 using 0.046 g of product from Example 363 in 700 microliters of dioxane, 700 microliters water containing 0.0096 g of potassium bicarbonate and 0.046 g of 10t palladium on carbon, at 38 psi, to give 0. 009 g of the desired product.

1 H NMR(D 2 0):S 5.73(m,lH); 4.25(m,1H); 3.8B-3.35(M,5H); 2.39(m,lH); 2.22-l.73(m,4H); l.33(d,3H); 1.24(d,3H).

-275i Example 365 3.5-Bis-O-r1. 1-Dimethvlethyl)dimethylsilvl1- D-ribonic Acid gamma-Lactone To three grams of gamma-lactone D-(+)-ribonic acid in 25 ml of dry dimethylformamide, under argon and cooled in an ice bath, is added, dropwise over minutes, 7.0 g of tert-butyldimethylsilyl chloride and 8.47 ml of triethylamine in 5 ml of dimethylformamide.

The reaction mixture is allowed to stir at room temperature for 2 hours then is diluted with diethyl ether. The mixture is washed with saturated sodium bicarbonate, water, and saturated sodium chloride; dried, filtered and concentrated in vacuo. The crystalline residue is purified by chromatography (Silica gel: 10% ethyl acetate/hexane) to give 5.74 g of a mixture of products.

"H NMR(CDC1 3 4.59(d,1H); 4.27(br s,2H) 3.82(q,2H); 0.9(3s,18H).

Example 366 20 2.5-Bis-O-r(1.1-Dimethvlethvlldimethylsilvll- D-ribonic Acid gamma-Lactone Methanesulfonate (A) 3.5-Bis-O-r(1.1-Dimethvlethyvldimethvlsilyll- D-ribonic Acid gamma-Lactone Methanesulfonate (B) To an ice cooled, under argon, solution of 2.0 g of product from Example 365 in 12 ml of pyridine is added 1.65 ml of methanesulfonyl chloride. The reaction is stirred at room temperature for 1 hour and then stored in a refrigerator for 2 days. The mixture is poured into cold water, extracted with diethyl ether and the layers are separated. The organic layer is washed with IN hydrochloric acid, saturated sodium bicarbonate, saturated copper sulfate and water; dried and concentrated in vacuo. The crystalline residue is purified by chromatography (Silica gel: 10% ethyl acetate/hexane) to give 1.46 g of the desired product and 0.79 g of product Product A: -276- 1 HI NHR(CDCl 3 5.17(m,lH); 4.75(m,1H); 4.59(br s, 1H); 3.85(br s,2H); 3.05(s,3H); 0.91(s,9H); 0.84(s,9H).

Example 367 (S)-3-rr(1,.1-Dimethlethvfldimethylsilvi1oxV-5rrr(1.1--dimethvylevldimethvldilvl1oxv1methl11 2(5H1)-furanone To 0.73 g of product from Example 366 in 8 ml of dry methylene chloride is added, dropwise, 0.288 ml of 1,8-dizabicyclo[5.4.0]Oundec-7-ene. After 30 minutes the reaction is diluted with diethy ether, washed with lN hydrochloric acid followed by saturated sodium chloride, dried and concentrated in vacuo to give 0.535 g of the desired product.

1 H NMR(CDCl 3 6.16(s,1H); 4.84(m,IH); 3.74(m,2H); 0.91(s,9H); 0.83(s,9H).

Example 368 3-Deox-25-bis-O-f(1,1-dimethylethYl)dimethylsilvll- D-threo-pentonic Acid gamma-Lactone To 0.535 g of product from Example 367 in 20 ml of ethyl alcohol is added 0.50 g of 10% palladium on carbon. The mixture is hydrogenated in a Parr apparatus at 34 psi of hydrogen. The reaction mixture is filtered, rinsed with ethyl acetate and concentrated in vacuo to give 0.417 g of the desired product.

H NMR(CDC13):6 4.51(m,1H); 4.3(m,1H); 3 .93-3.65(m,2H); 2.49(m,1H); 2.l(m,lH); 0.93(s,9H); 0.84(s,9H).

Example 369 3-Deoxv-2 5-bis--r) 1. 1-dimethylethYl)dimethylsilyl1- 1-thio-D-threo-Rentonic Acid gamma-Lactone To 0.416 g of product from Example 368 in 7.4 ml of toluene is added 0.562 g of Lawesson's reagent. The reaction is heated at reflux temperature for 3.5 hours, while monotoring by t1c. An additional 0.20 g of Lawesson's reagent is added and the reaction is refluxed and additional 1 1/2 hours. The solution is cooled overnight, concentrated in vacuo, and -277purified by chromaotgraphy (Silica gel: 10% ethyl acetate/hexane) to give 0. 184 g of the desired product.

1H NMR(CDCl 3 4.73(m,1H); 4.57(dd,lH); 3.86(m,2H); 2.52(rn,l); 2.1(m,1H); O.93(s,9H); 0.90(s,91).

Example 370 3-Deoxv-2 .5-bis-o-r (1.1-dimethylethvl)dimethvlsilvll- 1-thio-alpha (and beta) -D-threO-Rentofuranose To a -78 0 C solution, under argon, of 0.39 g of product from Example 369 in 5.17 ml of dry tetrahydrofuran is added, dropwise, 2.07 ml of Super Hydride. After 30 minutes, an additional 1 ml of Super Hydride is added. The reaction is stirred for minutes, quenched with 3.5 ml of-iN hydrochloric acid, and diluted with ethyl acetate and water. The layers are separated, the organic layer is washed with water and saturated sodium chloride, dried and concentrated in vacuo to give 0.377 g of the desired product.

1 H NMR(CDCl 3 5.27(m,lH); 4.34(m,lH); 4.05(m,1H); 8 3(dd,l1H) 3. 6 5(dd,l1H) 2. 2 5(d,l1H) 2. 2(m, 1H); l.93(m,lH); 0.93(s,9H); 0.89(s,9H).

Example 371 r2S-r2alpha(S ).3beta(S*)11- 1-r-r-r (1.1-Dimethvlethvldiethlsilll-3-r-r ri...

dimethylethvl) dimethylsilvi 1oxylehl4oo2 azetidinvllethvll-3-r (4-(nitroDhenyl)methoxLcy-2,3dioxo]propv1 3-deoXy-2.5-bis-O-r (1.1-dimethylethyl) dimethylsilyl 1-l-thio-allha (and beta) -D-threO-Rentofuranoside :To an ice cold solution, under argon, of 0.377 g of product from Example 370 in 3.3 ml of dry tetrahydrofuran is added 0.558 g of product from Example 103 in 4.7 ml of dry tetrahydrofuran. To this mixture is added, dropwise, 0.*139 ml of triethylamine and the reaction is stirred cold for 30 minutes. The cold bath is removed and the reaction is allowed to reach room temperature. The reaction is diluted with ethyl acetate, washed with saturated sodium bicarbonate -278- 0arnd saturated sodium chloride, dried and concentrated ivacuo. The residue is purified by chromatography (Silica gel: 20% ethyl acetate/hexane) to give 0.450 g of a major isomer and 0.118 g of a minor isomer Major isomer 1 RNNR(CDCl 3 8.25(d,2H); 7.59(d,2H); 5.38(s,2H); 5.03(s,lH); 4.3(m,lH); 4.2-3.96(m,3H); 3 7 9 -3.59(m,3H); 3.03(m,nI); 2.67(m,1H); 2.26(m,2H); 1.21(d,3H); l0 l.06(d,3H).

Minor Isomer 1 H NMR(CDCL 3 8.24e(a,2k); 7.6(,2nH; 5.36(ABq,2H); 5.03(d,1H); 4.4(d,1H); 4.37(m,lH);* 4.14(m,2H); 3.93(m,lH); 3.56(dd,1H); 3.54(dd,1H); 2.78(m,1H); 1.06 (d,3H).

Example 372 L 2s- r2alpha(S* ).3beta 11 20 r 4 -nitrophenvlimethoxvl-.3-dioxopropvl 3-ex--hoa ha (and beta) -threo-ipentofuranos ide The title compound is prepared by the procedure of Example 356 using 0.450 g of the major isomer from Example 371, 1.3 ml of tetrahydrofuran and 1.3 ml of triethylammonium trihydrogenfluoride to give 0.186 g of the desired product. The product is used immediately in following Example.

Examnle 373 r. 4 R- r4alpha -5beta,6beta (R 111 6- (l-Hvdroxvet vl) -4-methvl-2- r r( 4 -nitrophenvyl) methoxvl* carbonyLL[?-oxo-1-azabicvclo r 3. 2 0 01 hept-2 -en-3 -vl 3 -deoxv-1-thio-alipha (and beta) -threo-Dentofuranoside The title compound is prepared by the procedure of Example 357 using 0.186 g of product from Example 372, 2.3 ml of dry tetrahydrofuran, 1.45 al of IM titanium tetrachloride solution (methylene chloride) -279to give, after chromatography, 0.90 g of the desired product.

H1 NIAR(CDCL 3 8.23(d,2H); 7.65(d,2H); 5.57(s,111); 5.5(d,1H); 5.24(d,1H); 4.53(br d,1lH); 4.35(d,1H); 4.26(m,2H) 3.94(br d,1IH); 3.65(br d,mH); 3.3(m,1H); 2.55(m,1H); 2.17-1.52(m,4H); 1.37(d,3H); l.3(d,3H).

Example 374 1 4R-[4aloha.5beta.6beta(R)

III-

2-Carboxy-6- (l-hvdroxyethvl) -4-methvl-7-oxo-1-azabivclor3 .2.olhent-2-en-3-vl 3-deoxv-1I-thioalpha (and beta) -threo-nentofuranoside Potassium Salt The title compound is prepared by the procedure of Example 358 using 0.90 g product from Example 373, 1.4 ml of dioxane, 1.4 mal of water containing 0.0182 g of of potassium bicarbonate, and 0.90 g of palladium on carbon at 36 psi of hydrogen to give 0.053 g of the desired product.

H NM:R(D 0) :6 5. 53 1H); 4.38-3. 44 (m,B8H) 2. 56 1H); 1. 75 (m,l1H) 1. 35 3H) 1. 2 8(d, 31) Example 375 r4S-r3(2S or 2R .5R ).4alp3ha.5beta.6beta(R )11-, 6- (l-Hvdroxvethvl) -4-methvl-7-oxo-3- hydroxymethyll 2 -thienvllthjo]l-azabicvclor3 Olhept- 2-ene-2-carboxylic Acid (4-Nitrophenyl)methyl Ester A solution containing 0.396 g of [4R[4alpha, 6beta JJ-6- (l-hydroxyethyl) -3 -mercapto-4methy1-7-oxo-l-azabicyclo[3 O]hept-2-ene-2-carboxylic acid (4-nitrophenyl) methyl ester monosilver salt (prepared by the procedure of European Patent Appl.

EPO4Bl5llA2), 0.41 g of Phfflylsilyl) 3 -dideoxy-4-thioribofuranose (prepare6d by the procedure of J.A. Seprist et al., J. Med. Chem., 1992, 32, 533), and 16 ml of acetonitrile is stirred at 0 C under argon. To this. is addd dropwise, 0.98 mmol of a lM solution in hexane of diethylaluminum chloride.

After 1/2 hour the reaction is poured into saturated -280- 0 sodium bicarbonate and methylene chloride. The aqueous portion is washed with additional methylene chloride.

The organic layers are combined, dried and concentrated in vacuo. The residue is purified by chromatography (Silica gel: 40-60% ethyl acetate/hexane gradient) to give 0.98 g of product as a mixture of 2 isomers.

The above 0.98 g of product is dissolved in 4 ml of tetrahydrofuran and 0.15 ml of acetic acid. To this is added 1.*6 mmol of tetrabutylammoniun fluoride as a 1M tetrahydrofuran solution. The resulting solution is stirred for 6 hours at 20 0 C. Water and ethyl acetate are added and the reaction' is given an aqueous workup. Purification by chromatography gives 0.033 g of a major isomer and 0.008 g of a minor isomer.

Major Isomer: 1 H NMR(CDCl 3 1 8.2(d,2H,Ar); 7.65(d,2H,Ar); 5.38(dd,2H,CH Ar); 4.82(t,lH,CHS 2 3.75(mH 5 3.45fu,1H); .3(dI 2.4(m,2H,CH);2lmHH; 2) l.(,HCH2 .38(d,3H,CH 3 28 2H,C 3)M Minor Isomer: H NMRCDC1 8.2(d,2H,Ar); 7.63(d,2H,Ar);

NR(CD~

3 ):6 S5.18(dd,2H,CH Ar); 4.92(dd,CHS 4.3(m,2H,CH o); 2 .8(it2W 3.5(p,CHO); 3.42(t,lH); 32(dI, 2.2(m,3H); 1. 38 3H,CH 3 ;l.24(d,3H,CH 3 Examrnle 376 r4S-r3(2R* or 2S* .5R ).4alDha.5beta.6beta(R*f11 Vs.. 6- (l-HydroXvethvl) -4-methyl-7-oxo-3- hvdroxvmethvl) 2 -thienyllthio1llazabicyclor3 .2.01lheipt- 2-ene-2-carboxylic acid Mono~otassium Salt -The title compound is prepared by the procedure of Example 18 using 0.014 g of the major isomer from Example 375, 5 ml of 1:1 ethyl acetate:water, 0.0033 g of potassium bicarbonate and 0.015s g of palladium on carbon to give, after purification, 0.008 g of the desired compound.

-281- H1 NMR (D 2 0) :6 4. 95 (dd,lIH, CHS 2 4.2(dd,2H,CE 2

OH);

3.8-3.2(mr3H,CHjOH,H 5 and CHS) 6 and allylic CHi); 2.38(m,lH); 2.18(mr2H); 2.0(m,lH); 1.25(d,3H,CH 3 1.18(d,3H,CH 3 xml 7 f4S-r3(2R or 2S .5R ).4aliDha.5beta.6betg'R*)11- 6- (l-Hvdroxyethyl) -4-methvl1-7-oxo-3- r hydroxymethyl) -2-thienvllthjol-1-azabicyclor3 olheift- 2-ene-2-carbo2Mlic Acid Monosodium Salt The title compound is prepared by the procedure of Example 18 using 0.043 g of the minor isomer from Example 375, 6 ml of 1:1 ethyl acetate:water, 0.008 g of sodium bicarbonate and 0.043 g of palladium on carbon to give, after purification, 0.025 g of the desired product.

H NMR(D 2 0) :6 4. 88 CHS 2 4.2(m,2H,CH 2

OH);

68(m, H 5 3.6(m,1lH,CHOH); 3.42(m,3H,H 6 ,CHS and allylic CH); 2.3(m,2H); 2.l(m,lH); 1.95(m,lH); 1. 25 3H, CH 1.2(d,3H,CH 3 Example 378 1-S-Acetvl-5-0- (tert-butvldiphenvlsilvl)-2 *3-dideoxv- 4 -thioribofuranose Two grams of 5-0- (tert-butyldiphenylsilyl) 2, 3 -dideoxy-4-thioribofuranose (prepared according to J.A. Secrist et al., J. Med. Chem., 1992,35,533) is stirred with 0.456 g of thioacetic acid in '25 ml of methylene chloride and 0.0.025 g of toluenesulfonic acid for 68 hours. On workup the reactiion is adsorbed onto magnesium silicate and then flash chromatographed on silica gel to give 1.5 g of the desired product.

1 H NMR(CDCl 3 :6 7.65(m,4H,Ar); 7.4(m,6H,Ar); 2 3.63(m,3H,CH 2 2.3(d,3H,CH 3 2 4 -2.2(m,4H,2C 2 1. 03(s, 9H1, 3CH 3 -282- EXamI~qle 379 Ethanethioja Acid S- r 5-711 (Aminocarbonfl) oXyl methyl ]tetrahvrdro-2thienvil Ester A solution containing 0.817 g of product from Example 378, 15 ml of tetrahydrofuran, 1 ml of acetic acid and 8. 5 mmol of n-tetrabutylammonium fluoride 1M solution is stirred for 2 hours. The reaction progress is monitored by tlc. Following an aqueous woricup (ethyl acetate, 0. 5M potassium phosphate, saturated sodium chloride) and silica gel chromatography 0.252 g of the desired alcohol is isolated.

1 HNMR(CDCl 3 5.2(t,lH,CHS 2 3.7(m,3H,CH 2 0 and CBS); 2.4(s,311,CH 3 2.5-l.8(m,4H,2CH 2 The alcohol, 0.247 g, prepared above, 0.67 g of trichloroacetyl isocyanate and 17 ml of methylene chloride are reacted at -20 0C as described in Example 7. The intermediate thus formed is hydrolyzed with 650 .microliters of acetic acid, 5.Smmol of IM n-tetrabutyl- 20 ammonium fluoride and 1 ml of water as also described in Example 7 to yield, after woricup and purification, 0.276 g of the desired product.

Anal. Calcd for C 8 H 3

N

3

S

2 C 40.83; H 5.57; N 5.95 Found: C =40.88; H 5.33; N 5.72.

-283- Examle 380 T4R-r4alpha.Sbeta.6betafR) I1- 3-rs- rF(Aminocarbonvl) oxvlme lltetrahydro-2thienvi 1 thio (1-hvdroxvethvl 1-4 -methvl-7 -oxo-1azabicvclor3.2.01hept-2-ene-2-carboxlic Acid -(4-Nitrophenylmethvl Ester (A) and r4R-r4alvha.beta6beta(R*

III

oxvlmethvl1tetrahvdro-2thienvllthio]-6-(1-hdroxethvl)-4-methvl-7-oxo-iazabicvclo F 3 2. Olhent-2-ene-2-carboxulic Acid (4-Nitrohenvllmethvl Ester (B) The product, 0.256 g, from Example 379 and 1.2 mmol of sodium methoxide (as a 4.4M solution in methyl alcohol) is hydrolyzed in 8 ml of tetrahydrofuran as described in Example 16. The thiol product obtained in this reaction is immediately reacted with 0.476 g of product from Example 15, 0.155 g of diisopropylethyl amine, in 7 ml of acetonitrile at 00 under argon for a total of 18 hours as described in Example 17. The standard workup and purification yields two diastereomeric products. The least polar product carbapenem 0.156 g, has a tic Rf 0.36 and the more polar product carbapenem 0.142g, has a tlc Rf 0.28.

Example 381 4R-r3(5R*) .4alDha. Sbeta,6betaLR*) 11 3-Fr 5-Fr (Aminocarbonyl1 oxvlmethvll tetrahvdro- 2-thienyl 1thio-6- (l-hvdroxvethvl) -4-methvl-7-oxo- I-azabiccloF3.2.ol0hient-2-ene-2-carbovlic Acid Mononotassium Salt The title compound is prepared by the procedure of Example 18 using 0.116 g of product from Example 380, 20 ml of 1:1 dioxane:water, 0.030 g of potassium bicarbonate and 0.045 g of 10% palladium on carbon to give, after chromatography, 0.026 g of the desired product.

-284- 1 H NMR(CDC1 3 5.0O(t,1H,CHS 2 4.2(m,3H,CH 2 0CO and CHS); 4.0(,1H,CHOH); 3.8(m,1H,H 5 3.4(m,2H,H 6 and allylic CH); 2.5-1.8(m,4H2CH 2 1.22(d,3H,CH 3 1.18(d,3H,CH 3 Examile 382 r4R-r4alDha.5beta.6beta(R 11oxrmethvl1tet rahydro-2thienvyllthiol-6-(l-hydroxvethyl)-4-methl-7-oxo-lazabicyclor32.ol1hept-2-ene-2-carboxylic Acid Monopotassium Salt The title compound is prepared by the procedure of Example 18 using 0.137 g of product from Example 380, 15 ml of ethyl acetate, 9 ml of water, 0.029 g of potassium bicarbonate and 0.085 g of palladium on carbon to give, after chromatography, 0.031 g of the desired product.

IR(KBr): 4371, 33,97, 2963, 1713, 1613 cm 1 Example 383 Ethanethioic Acid S-(Tetrahvdro-5-(hdroxvmethyl)-2-thienlv) Ester A solution containing 2.19 g of product from Example 378, 20 ml of tetrahydrofuran, 5.3 g of acetic acid and 25 mmol of 3M solution of n-tetrabutylammonium fluoride is stirred for 18 hours or until all starting 25 material is consumed by t1c. The reaction is diluted with ethyl acetate, washed with aqueous 0.5M potassium dihydrogen phosphate and saturated sodium chloride, dried and concentrated 1 vacuo. The residue is purified by chromatography to give 0.876 g of the desired product.

1 H NMR(CDC1 3 5.08(t,lH,CHS 2 3.8-3.5(m,3H,CH 2 0 and CHS); 2.3(s,3H,CH 3 2.5-2.8(m,4H,2CH 2 -285- Examble 384 SRI-Ethanethioic Acic methyllettrahydro- 2-thienyll Ester To a 0 0 C mixture of 0.165 g of product from Example 383 in 4 ml of tetrahydrofuran and 0.222 g of, diisopropylethyl amine is added 0.122 g of chioromethylethyl ether. The reaction is stirred for minutes at 0 C and then 23 hours at 20 C. The mixture is given an aqueous worcup (ethyl acetate, potassium dihydrogen phosphate, saturated sodium chloride) and the purified by chromatography to give 0.100 g of the desired product.

1H NMR(CDC1 3 5.08(t,H,CHS 2 4.7(d,2H,CH 2 0 2 3 .B-3.4(m,5H2cH 2 oCHS); 2.3(s,3H,CH 3 2 .5-1.75(m,4H,2CH 2 l.2(t,3H,CH 3 Example 385 r4R-r3(5R 4alDha.5beta.6beta(R *)11- 3-F5- r Ethometoxv)methv I hitetrahdro-2-thieny thiol -6-(l-hydroxvethvl)-4-methl-7-oxo--azabicyclor32.01 he*t-2-ene-2-carboxlic acid (4-Nitrophenvl)methyl Ester The product, 0.096 g, of Example 384 is dissolved in 4 ml of tetrahydrofuran and is hydrolyzed and worked up in a similar fashion to that described in Example .16 using 0.35mmol of a 4.4M sodium methoxide solution to give the crude thiol product. The thiol product is reacted directly with 0.185 g of product from Example 15, 0.074 g of diisopropylethyl amine and 3 ml of acetonitrile as described in Example 17. The product of this reaction is a mixture of two diastereomers. The more polar of the two, 0.070 g, is isolated and characterized, 1H NMR(CDCl 3 8.22(d,2H,Ar); 7.65(d,2H,Ar); 5.38(ABq,2H,CH 2 Ar); 4.85(t,lH,cHS 2 5.18(s,2H,CH 2 0 2 4.25(m,2H,CH 2 3.78(m,lH,H 5 3.6(q,2H,CH 2 o); 3 .55-3.4(m, 2H,allylic H and CHS); 3.28(dd,lH,H 6 -286- 2.4-1.9(m,4H12CH 2 l.48(d,3H,CH 3 1. 3(d, 3H, CH 3 1.22(t,3H,CH 3 Examiple 386 r 4R- r3 .4aloha .5beta. 6beta fII- 3 r r 5- (Etho2Znkethoxy) methyl I tetrahydro-2 -thienvl1 hioli (1-hvdroxyethyl) -4-methvl-7-oxo-l-azabicvclor3. 01 he~t-2 -ene-2 -carboxyl ic acid Mononotass jum Salt The title. compound is prepared by the procedure of Example 18 using 0. 065 g of product from Example 385, 10 ml of 1:1 dioxane:water, 0.017 g potassium carbonate, and 0.033 g of 10% palladium on carbon to give, after purification, 0.019 g of the desired product.

I1 NMR(D 2 0) :6 4. 85 (m,l1H,CHS 2 4.7(s,2H,CH 2 0 2 4.2(m,2H); 3.8(m,2H); 3.64(m,4H); 3.45(m,2H,CHS, allylic CH); 3.4(dd,1H,H 2.35-l.85(m,4H,2CH{) @1.25(d,3H,CH 11);,HC ExaM~le 387 (2R) (Acetvloxv) tetrahydro-2-thiophenemethanol S 20 To a mixture of 0.54 g of 1-O-acetyl-5-0- (tert-butyldiphenylsilyl) 3-dideoxy-4thioribofuranose (prepared by the procedure of J.A.Secrist et al., J.

0 Med. Chem.,l992, 35, 533) in 8 ml of tetrahydrofuran And 0. 6 g of acetic acid is added 4 mmol of 1M n-tetrabutyl ammonium fluoride solution. The reaction is stirred for 5 hours and then another portion of 0.10 g of acetic acid and 1 mmol of n-tetrabutylammonium fluoride is added and the reaction is stirred for 1 hour. Cold potassium dihydrogen phosphate and ethyl acetate are added to the reaction mixture, followed by an aqueous workup. Purification by chromatography gives 0.164 g of the desired product.

1 NMR(D 2 0):6 6.15(t,lH,CHS(OAc)); 3.68(m,2H,CH 2 o); 3.58(dd,1H,ClHs); 2..2(m,5H,2CH 21 0H) 2.0(s,3H,CH 3 -287- (SR) -5-Az idomethyl)I tetrahvdro-2 -thio~heneol Acetate (ester) To a 00 C solution of 5 ml of methylene chloride and 0.439 g of product from Example 387 is added 0.303 g of triethylaniine followed by 0.341 g of methanesulfonyl chloride. The reaction is warmed to 2 09C with stirring for 2 hours. The reaction is concentrated in vacuo and the residue is purified by chromatography to give 0. 150 g of material which is dissolved in 1 ml of dimethylformainide. To this solution is added 0.338 g of n-tetrabutylannonium azide and the reaction solution is stirred at 20 0 C for 4 hours. The azido product is isolated following an aqueous workup and purification by chromatography to give 0.082 g of pure azide.

H NMR(D 0):6 6.l8(t,1H,CH(OAC)S); 3.7-3.2(m,3H,CH

N

3 CHS); 2.05(s,3H,CH 3 Examvle 389 20 r4R-r3(5R 4 a lha. 5beta. 6beta (R 11- 3 -Frr 5-Az idomethyl)-tetrahvdro-2 -thienvI 1 thio 1 -6- (1-nvaroxvety. -4-methy-1-7-oxo-1aaicyclCo i. 2. Olhept-2-ene-2-carboxylic ai (4-Nitroiphenyl) methyl Ester To a solution, under argon, of 0.080 g of product from Example 388, 4 ml of acetonitrile and 4 R[4alpha,Sbeta,6beta(R -6-(1-hydroxyethyl) -3mecpo4mty--oolaaiyl O]hept-2-ene- 2-carboxylic acid (4-nitrophenyl)methyl ester mono silver(+) salt (prepared by the procedure of European Patent Appl. EP0481511A2) is added O.6umol of 1IM diethylaluminum. chloride. The reaction is stirred for an hour followed by aqueous workup and chromatography to give 0.016 g of the desired product.

-288- 1 H NMR(CDC1 8.2(d,2HAr); 7.65 2H, Ar); 5.35(q,2H,CH 2 Ar);4.9(t,1LH,CHS 2 .8ml~H) 4.23(d,H 5 3.73(t,lH,alilylic 3.35(d,2H,C 2 N 3 3.3(dd,H 6 2.38(M,2H,CH 2 2.25(Z,1H); 1.95(d,3H,CH 3 1.3(d,3H,CH 3 Examiple 390 r4R-r4al~hasbeta,6beta(R*I1 3-r1r5- (Aminomethyl) tetrahvdro-2-thienvl ithiol -6- (1-hydroxvethyfl -4-methvl-7-oxo-l-azabicvclor 3.2.*01hept-2-ene-2-carboxylic Acid The title compound is prepared by the procedure of Example 192 using 0.010 g of Example 389, 3 ml of dioxane and O.lM pH 7.0 sodium dihydrogen phosphate buffer and 0.010 g of 10% palladium on carbon to give, after chromatography, 0.006 g of the desired product.

~H NMR(D 0):6 4.9(m,CHS 2 3.9(m,2H,CH N); 3.55(m,1H,CHOH); 34(~HH) 3.4-.15(,3HH alylicH);2.9-2.7(m,2H); 2.2(m,lH); 1.7(m,1H); l.22(d,3H,CH 3 l.18(d,3H,CH 3 Example 391 r3-S-r4R-r4alrha.5beta.6beta(R )111fN1.T 1.1y anaminol -2_5-anhydro-3-S-r2 carboxv-6- (1-hvdroxyeth.) -4-methvl-7-oxo-l-azabicycler 3.2.01 hept-2-en-3-vl 1-1. 4-dideoxv-3-thio-D-threo- Dentitol The title compound is prepared by the procedure of Example 257 using 0.494 g of product from Example 261, 0.437 g of product from Example 259, 6 ml of 0.1M pH 7.0 sodium dihydrogen phosphate buffer, 12 ml of dioxane and 0.13 g of 10% palladium on carbon to give, after chromatography (C ,-Reverse Phase Plates: ethyl alcohol/water), 0.*12 g of the desired product.

1 H NMR(D 2 0):6 4.25(m,4H); 4.05(m,2H); 3.9(m,2H); 3.6-3.4(m,4H); 2.5-2.4(m,lH); 2.l-2.0(m,lH); 1.50(d,3H,He, J=7Hz); 1.38(d,3H,Me, J=7.1Hz); l.27(d,3H,Me, J=6.3Hz); 1.19(d,3H,Me, J=7.lHz).

-289- Example 392 1.4-Dioxa-8-thiasDiro r4.51decane A mixture of 5.0 g of tetrahydrothiopyran-4one, 2.5 ml of ethylene glycol, 0.230 g of p-toluenesulfonic acid and 125 ml of benzene is stirred at reflux temperature for 2.5 hours. The water formed is removed using a Dean-Stark trap. The reaction is treated with saturated sodium bicarbonate, water, saturated sodium chloride, dried and concentrated in vacuo to give 6.52 g of the desired product as an oil.

Example 393 1.4-Dioxa-8-thiaspiror4.51decane 8-oxide A room temperature mixture of 13.8 g of product from Example 392 dissolved in 100 ml of acetic acid is treated, dropwise over 20 minutes, with 9.0 ml of 30% hydrogen peroxide. The reaction mixture is .stirred at room temperature for 1 hour, concentrated in •vacuo at 50°C, and extracted with ethyl acetate. The organic layer is washed 2 X with saturated sodium S" 20 bicarbonate, water and saturated sodium chloride, dried and concentrated in vacuo. The aqueous washes are combined and concentrated in vacuo to about 25 ml. The residue is saturated with solid potassium carbonate and extracted 2 X with 200 ml of ethyl acetate. The 25 organic phase is concentrated in vacuo to a solid which is triturated with hexane and collected to give 13.1 g of the desired product.

Example 394 1.4-Dioxa-8-thiasDiror4.51decan-7-ol A mixture of 0.88 g of product from Example 393, 5.0 ml of acetic anhydride and 2.0 ml of lutidine is heated at 110°-115°C for 2.5 hours, followed by increasing the temperature to 150°C and then heated for 3 hours. The reaction mixture is diluted with ethyl acetate, washed 2 X with 1N hydrochloric acid, water, saturated sodium chloride, dried and concentrated in vacuo. The residue is dissolved in methylene chloride, -290filtered through a pad of hydrous magnesium silicate and reconcentrated in vacuo to give 0.569 g of the desired product.

Example 395 Ethanethioic Acid S-(1.4-Dioxa-8-thiaspiror4.51decan-7-vl) Ester A mixture of 0.545 g of product from Example 394, 0.23 ml of thioacetic acid, 0.16 g of p-toluenesulfonic acid and 8 ml of carbon tetrachloride is stirred at room temperature for 1 hour. After work up concentration in vacuo gives 0.556 g of the desired product.

Example 396 1.

4 -Dioxa-8-thiaspiror4.5]decane-7-thiol A mixture of 0.56 g of product from Example 395, 0.60 ml of 4.37M sodium methoxide and 10 ml of tetrahydrofuran is stirred in an ice bath for minutes. Ethyl acetate is added followed by 20 potassium phosphate monobasic. The organic layer is dried and concentrated in vacuo to give 0.37 g of the desired product as a yellow oil.

Example 397 S. 4R-r4alpha.5ebeta.6beta(R*)]-3-1.4-Dioxa-8thiaspiror4.51dec-7-vlthio)6-(1-hvdroxvethvl)-4-methyl- 7-oxo-l-azabicvclor3.2.01hept-2-ene-2-carboxylic Acid (4-Nitrophenvl)methyl Ester The title compound is prepared by the procedure Example 17 using 0.335 g of product from Example 15, 0.121 g of product from Example 396, 0.11 ml of diisopropylethylamine and 5 ml of acetonitrile to give 0.080 g of the desired product after chromatography.

-291- 6 Example 398 r4R-r4alyha,5beta.6beta(R )I-3-1.4-Dioxa-8thias~iror-4. 5]dec-7-oxol 6- (1-hvdroxvyethv1) -4-methyl- 7-oxo-1-aZabicyclor3 Olhe~t-2-ene-2-carboxylic Acid Monosodium Salt The title compound is prepared by the procedure of Example 18 using 0.80 g of product from Example 397, 0.0125 g of sodium bicarbonate, 0.080 g of palladium on carbon, 4 ml of ethyl acetate and 2 ml of water to give 0.032 g of the desired product after chromatography.

Examiple 399 r 3- r4R- r 4alpha. 5beta. 6beta. 11 2 .6-Arihvdro-4 .5-dideoXy-3-S-6- (hvdroxvethvl) -4-methyl- 2- r[ (4-nitrophenyl) methoxy] carbony1 -7-oxo-l-azabicyclo r3.2 01hert-2-en-3-vl 1-1-0- (methoxMethyl) 3 -thio-D-threo-hexitol The title compound is prepared by the procedure of Example 17 using 0.375 g of (2R,3R)-2-methoxy- 20 methoxymethyl tetrahydropyran-3-thiol (prepared according to the procedure of Miyazaki,H. et al. in .e.Chem. Pharm. Bull., Vol 37, pp 2391-2397(198 in 5 ml of acetonitrile, 0.954 g of product from Example 15 in ml of acetonitrile and 0.3 ml of diisopropylethyl amine to give, after chromatography (Silica gel), the desired compound.

Exam~le 400 r3-r4R-r4alpha.5beta.6beta(R*nill- 2. 6-Anhvdro-3-S- r2-carboxv-6- (1-hvdroxvethvl) -4-methyl- 7-oxo-i-azabicyclor3 .2.-Olhert-2-en-3-vll -4 0- (methoxvmethyl) -3 -thio-D-threo-hexitol M~nosodium Salt The title compound is prepared by the procedure of Example 192 using 0.243 g of product from Example 399, 0.084 g of 10% palladium on carbon, 5 ml of 0.lM pH 7.0 sodium dihydrogen phosphate buffer and 7 ml of dioxane to give, after chromatography (Reverse -292- Phase Plates: 5% aqueous ethyl alcohol), to give the desired product.

2.4-Anhvdro-D-lyxonic Acid Methyl Ester A slurry of 1.01 g of 2,4-anhydro-3,5-bis-o- (phenylmethyl) -D-lyxonic acid methyl ester (prepared by the procedure in Tetrahedron Letters, Vol 31, No. 33, p4787, 1990), 0.253 g of palladium hydroxide on carbon, and 30 ml of methyl alcohol is hydrogenated under a balloon of hydrogen (1 atm.) for 2.5 hours. The mixture is filtered through diatomaceous earth, washed with ethyl acetate and ethyl alcohol, and concentrated in vacuo to give 0.460 g of the desired product.

1 H NMR(CDCl 3 5.07(d,1H, J 4.9Hz); 4.85(m,2H); 4.28(br d,1H); 4.1o(m~j2H); 3.83(s,3H,OMe); 2.65(br s, 1H).

IR(neat): 3400, 295.7, 1739, 1441, 1226, 1020 cm1 MS(CI):m/z 163(M++11).

Example 402 o oo 20 4-Anhvdro-D-lvxonicacdMtyEse (4-Methvlbenzenesulfonate) To a 0 0C solution, under argon, of 0.435 g of product from Example 401 in 9 ml of pyridine is added 0-614 g of p-toluenesulfonyl chloride and the reaction is stirred overnight. The reaction mixture is diluted with 50 ml of 10% hydrochloric acid and extracted with diethyl ether and ethyl acetate. The organic layers are combined, dried and purified by chromatography to give 0.517 g of the desired product.

1 NMR(CDCl 3 7.8l(d,2H,J 8.3Hz); 7.36(d,2H,J= 8.3Hz); 4.93(m,3H); 4.54(dd,1H,j 11.3 and 4.9Hz); 4.30(dd,1H,J dd,lH,J 11.3 and 3.75Hz);- 3.81(s,3HOMe); 2.92(d,1H,J 2.46(s,3HSO 2 ArMe).

IR(KBr): 3361, 2936, 1749, 1355, 1174 cm- 1 MS(CI):m/z 317(M -293e Example 403 2,4-Anhvdro-3-thio-D-arabinonic Acid Methyl Ester 3-Acetate 5-(4-Methvlbenzenesulfonate) A 0 0 C solution, under argon, of 0.111 g of product from Example 402 in 3 ml of dry methylene chloride is treated, sequentially, with 0.03 ml of pyridine and 0.07 ml of triflic anhydride. After the addition, the reaction is stirred for 30-45 minutes, until consumption of the starting material. The mixture is diluted with diethyl ether, filtered to remove salts, and the filtrate is concentrated in vacuo.

The residue, under argon at room temperature, is dissolved in 1.0 ml of dry acetonitrile, treated with 2 equivalents of potassium thioacetate and stirred for 2 hours. The mixture is diluted with water, extracted with ethyl acetate, dried, concentrated and "purified by chromatography to give 0.092 g of the desired product.

1 H NMR(CDCl 3 7.83(d,2H,J 8.3Hz); 7.35(d,2H,J 20 8.3Hz); 5.17(d,1H,J 8.17Hz); 4.90(m,2H); 4.27(m,2H); 3 .80(s,3H,OMe); 2.45(s,3H,SO 2 ArMe); 2.31(s,3H,SAc).

S .IR(neat): 2851, 1755, 1703, 1598, 1438, 1362, 1129 -1 cm MS(CI):m/z 375(M++H).

25 Example 404 2 4 -Anhvdro-3-thio-D-arabinonic Acid Methyl Ester 5-(4-Methvlbenzenesulfonate) To a 0 C solution, under argon, of 0.618 g of product from Example 403 in 4 ml of dry tetrahydrofuran is added, dropwise, 0.45 ml of 4.37M sodium methoxide.

The reaction is stirred at 0°C for 45 minutes, quenched with 1-2 ml of 10% hydrochloric acid and the mixture is concentrated in vacuo. The residue is purified by chromatography (Silica gel: 5-50% ethyl acetate/hexane) to give 0.285 g of the desired product as a colorless oil.

-294- H1 NNR(CDC1 3 :6 7.82 (d,'2H,J 8.3Hz); 7.36(d,2H,j 8.3Hz); 5.13(d,1lH,J 4.78(m,1H); 4.21(d,2H,J= 2.4Hz); 3.85(s,3H,OMe); 2.45(s,3H,ArCH 3 1.97(d,1H,J= 9Hz,SH).

IR(neat): 2850, 2566, 1751, 1598, 1438, 1361, 1178 c-1 MS(CI) :m/z 161(14 4H-oTs).

Examiple 405 r3-r4R-r4alpha.5beta.6beta(R *flu- 2 .4-Anhydro-3-s-r6-(1-hydroxv-ethvl) -4-methvl-2-r r (4nitrophenyl) methoxvl carbonyi 1-7-oxo-1-azabicyclo- 13 Olhept-2-en-3-y11-3-thjo-D-arabinonic Acid Methyl Ester 5- (4-Methylbenzenesulfonate) To a 0 0C solution, under argon, of 0.273 g of p -roduct from Example 404, 0.439 g of product from Example 15, in 3.8 ml of acetonitrile is added, dropwise, 0.13 ml of Hunig's base. After addition the reaction is warmed to room temperature for 2 hours.

mixture is concentrated in vacuo and purified by (Silica gel: 10-100% ethyl acetate/hexane) to give 0.49 g of the desired product.

1i H NMR(CC1 8.2(d,2H, 8.7Hz);.7.8(d,2k1,J= *o 3Hz orz; 7. 65(d, 2H, J 8. Hz) 7. 37 2H, J 8. 3Hz); 4 9(d, 1H,Ji 13.8BHz) 5. 24 (d,l1H, J= 13. 8Hz) 5. 2 0(d,l1H, J 8. 5Hz) 4. 96 (m,l1H) 4. 7 9(dd,l1H); 4.35-4.l0(m,4H);* 3, 83(s,3H,CO 2 Me); 3.5(m,1H); 3. 31 (dd, 2H); 2.4 6 (1,3H, ArOMe) 1. 3 7(d, 3H, J 6. 3Hz); 1.22(d,3H,J =7.4H4).

IR(KBr) 3527, 3111, 2877, 1772, 1522, 1347, 1212, '1177, 1140cm- 1 MS (FAB) z 6 7 7 -295- Example 406 r3-r4R-[4alhpa.5beta.6beta(R*fLu- 2.4-Anhdro-3-S-r2-carboxv-6-( -hdroxvethvl -4methvl-7-oxo-1-azabjcclor3 .2.Ohet-2-en-3-vl1-3thio-D-arabinonic Acid 1-Methyl Ester (4-Methvlbenzenesulfonate Monosodium Salt The title compound is prepared by the procedure of Example 192 using 0.150 g of product from Example 405, 0.046 g of 10% palladium on carbon, 0.028 g of sodium bicarbonate, 7.25 ml of dioxane:sodium dihydrogen phosphate buffer, pH 7.0 in a Parr apparatus to give after chromatography 0.011 g of the desired product.

1 H NMR(CDC1 3 7.87(d,2HJ 8.3Hz); 7.51(d,2HJ 8.3Hz); 4.5-4.3(m,5H); 3.34(s,3H,CO 2 Me); 3.3-3.1(m,4H); 2.48(s,3H,ArMe); l.13(d,3H); 1.1(d,3H).

IR(KBr): 3538, 3409, 2923, 1745, 1624, 1141, 1119 cm- 4Examle 407 43-r4R-r4alpha.5beta.6beta(R*1111- 1-F F Fl-(Acetyloxv) ethoxvlcarbonvllaminol-2 1.4-dideoxv-3-S-r2-Fr(2.2-dimethl-l-oxopropoxv)methoxvlcarbonvll-6-(1-hvdroxvethvl)-4-methvl-7-oxo-lazabicyclo r 3.2.01 he~t-2-en-3-vl 1 -thio-D-threo-pentitol A 0 0 C mixture of 0.557 g of product from 4 .4 04 25 Example 319, 0.24 ml of chloromethyl pivalate. 0.189 g of sodium bicarbonate and 0.252 g of sodium iodide is stirred for 5 hours. The reaction is monitored by tlc.

The solution is concentrated in vacuo, the residue is slurried with ethyl acetate, filtered, concentrated in vacuo and purified by chromatography (Silica Gel: ethyl acetate) to give 0.249 g of the desired product.

1 -NI (CDCl 6.7(mlHC); 5.82(ABq,2HOCH 0); 5.36(m,lHNH); 4.3-4.l(m,3H); 4.0-3.9(m,1H); 3.78(m,2H); 3.55(m,lH); 3.38(m,lIH); 3.21(m,3H); 2.45-2.3(m,1H); l.99(s,3H,Ac); 2.05-l.9(m,1H); 1.38(d,3H,Me,J 5.1Hz); 1.25(d,3H,Me,J 6.1Hz); 1.19(d,3H,Me,J 7.0Hz); 1.49(s,9H,3Me,t-Bu).

-296- Example 408 r4R-r3(3R 5R and 3S*.S ).4alnha.5beta.6beta(R*11i- 3- r r 5-[r(Aiiinocarbonyl Aoxvlmethyll1tetrahvdro-3furanvil1thiol (1-hydroxvethy) -4-methvl-7-oxo-iazabicyclorF3.2. olhent-2-ene-2-carboxylic acid (2 .2-Dimethyl-1-oxonronoxvl methyl Ester The title compound is prepared by the procedure of Example .407 using 0.460 g of product from Example 18, 0.24 ml of chioromethyl pivalate, 0.189 of sodium bicarbonate and 0.252 g of sodium iodide to give after chromatography 0.3 g of the desired product.

ExaMne 409 14R-r3(3R*.5S* and- 3S*.5R*L.4alha.5beta.6beta(R* ill- 3- Frr5- F (Aminocarbonyl) oxylmethvl 1tetrahydro-3furanli thiol (l-hydroxvethv) -4-methvl-7oxo-1-azabicvclor3 Olhent-2-ene-2cabxvi acid (2..2-Dinethvl-ioxolproRoxy) methyl Ester The title compound is prepared by the proce- 20 dure of Example 407 using 0.460 g of product from .Example 21, 0.*24 ml of chioromethyl pivalate, 0.189 g of sodium bicarbonate and 0.252 g of sodium iodide to give after chromatograph 0.32 g of the desired product.

0:.

Claims

2. A compound selected from those of formula IV as defined in claim 1 substantially as herein described with reference to any example thereof. A process for preparing a compound of formula IV as defined in claim 1 which too. 1process is substantially as herein described with reference to the examples.
4. A compound of formula IV as defined in claim 1 when prepared by the process 20 ol claim 3. Dated 6 January, 2000 American Cyanamid Company Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON .IlXX]02219 .doc KWW