AU640171B2

AU640171B2 - Cyclic peroxyacetal lactone, lactol and ether compounds

Info

Publication number: AU640171B2
Application number: AU64475/90A
Authority: AU
Inventors: Richard Kingston Haynes; Simone Charlotte Vonwiller
Original assignee: Rhone Poulenc Rorer SA
Current assignee: Aventis Pharma SA
Priority date: 1989-09-27
Filing date: 1990-09-27
Publication date: 1993-08-19
Anticipated expiration: 2010-09-27
Also published as: AU6447590A

Description

WO 91/04970 PCT/AU90/00456 CYCLIC PEROXYACETAL LACTONE, LACTOL AND ETHER COMPOUNDS Technical Field This invention relates to a new process for preparing cyclic peroxyacetal lactone, lactol or ether compounds.

Background of the Invention The present invention is particularly important in its application to the preparation of biologically active compounds comprising the cyclic peroxyacetal lactone or lactol functionalities.

One such biologically active compound is qinghaosu (Artemisinin) which has the following formula: o-o H H 0 0 Qinghaosu is a potent antimalarial which has been successfully used to treat patients suffering from malaria.

The reemergence of strains of malaria resistant to conventional (chloroquine) therapy is posing a worldwide problem, and indeed, there is no universally acceptable cure at the present time. Qinghaosu occurs to the extent of about 0.1 (dry weight) in an annual shrub, qinghao or (Artemisia annua) which grows in most provinces of China.

Unfortunately, the world demand for qinghaosu far exceeds the supply, and there is considerable pressure to develop bioactive analogues, or to develop alternative sources for the compound. The compound has been prepared by total synthesis in the laboratory, but the structural complexity is such that no total laboratory synthesis has been economically feasible.

WO 91/04970 In preparing a) b) c) 2 PCT/AU90/00456 The Disclosure of the Invention one aspect, the invention provides a process for a compound containing: peroxyacetal lactone peroxyacetal lactol or peroxyacetal ether functionality comprising oxygenating a compound containing: i) ii) iii) iv) v) hydroperoxy alkene carboxylic acid hydroperoxy alkene aldehyde hydroperoxy alkene keto or hydroperoxy alkene alcohol functionality dialkyl acetals of compounds in ii) and iii) above in the presence of one or more oxidizing metal catalysts.

The process of the present invention can be carried out as a "one-pot" reaction, referred to as the direct method or by a series of steps, referred to as the indirect method.

In particular, the direct method involves oxygenation of a compound of formula (CH2)m (Y)p HOO O (X)n

R

in the presence of one or more oxidizing metal catalysts to give a compound of formula (CH,)m (o-oN O (X)n R7 3 wherein n 1, 2 or 3 m 0, 1 or 2 p 0, 1, 2 or 3

OR

1

R

5 -COOH, -CROH, -C-R \0R 1 where R is H, alkyl, aryl or arylalkyl

R

1 are independently alkyl, aryl or arylalkyl or each R 1 together with the group to which they are attached form a cyclic acetal X CR 2

R

3

C=CR

2

R

3 S SO or SO2 where R 2 and R 3 are independently selected from H, optionally substituted alkyl, optionally substituted aryl, the optional substituents being selected from alkyl, aryl, halogen, OR, CF 3

NO

2 COR, NRR', SR, COOR, CONRR', S0 3 R, SO 2 NRR', SR, SOR and SO 2 R, where R and R' are as defined for R above; SR", SOR", S02R" where R" is alkyl or aryl optionally substituted by one or more substitutents selected from alkyl, aryl, halogen, OR, CF 3

NO

2 COR, NRR', SR, COOR, CONRR', SO 3

R,

SO

2 NRR', SR, SOR and SO 2 R, where R and R' are as defined for R above; and wherein when n>l, X is independently selected and can be branched or straight chain and X together with a substituent Y can also form a ring; Y is a substituent selected from H; alkyl or aryl optionally substituted by one or more sustituents selected from alkyl, aryl, halogen, OR, CF 3

NO

2 COR, NRR', SR, COOR, CONRR', SO 3 R, S02NRR', SR, SOR and SO 2 R, where R and R' are as defined for R above; 04828-TQ/3.2.93 4 Y can be on the same C atom as the hydroperoxy group and any C atom may be disubstituted by Y and includes replacement of H atom(s) in "(CH2)m" by Y;

R

6 or R 7 is as defined for R above, H, OH, OR 1 or together with the carbon atom to which they are attached form a keto group.

The direct method involves oxygenation of the hydroperoxy compound in the presence of one or more catalysts to undergo a new oxygenation-cleavagecyclization reaction to give a cyclic peroxyacetal lactone, lactol or ether compound. Optionally, a protic acid or lewis acid catalyst may be added.

According to IUPAC nomenclature, acetals derived from acids, ketones, aldehydes are all called "acetals".

However, it is common to name an acetal derived from a ketone, a "ketal". Thus, it is to be understood that the term "acetal" also includes within its scope acetals derived from ketones ie. ketals.

The skilled addressee would understand that the process of the invention may result in one or more stereogenic (chiral) centres being formed resulting in stereoisomers.

Thus, it is to be understood that the present invention includes within its scope the preparation of stereoisomerg. The present invention also encompasses any isomers or mixtures thereof when prepared according to the present invention.

The Schematic Diagram illustrates the process for the direct method, starting from a cyclic hydroperoxy alkene carboxylic acid, aldehyde, ketone, alcohol, aldehyde acetal and ketone acetal respectively.

04828-TQ/3.2.93 I

S

DIRECr MMTOD

HOG

HO

0 Oxygenation- Cleavage- Cyclization

HO

0

HO

Oxygenation- Cleavage- Cyclization Oxygenation- Cleavage- Cyclization '0-0.

0 H o R OH 0-0, 0 HO0

HOG

RI

,Zo Oxygenation- Cleavage- Pycizaticrn R H, Akyl -V Alk~yl NB: In tis Scheme, one enantiomer only of each chiral compound is depicted. There is also produced an equal amonowt of the other enandomer in each case.

SCHEMATIC DIAGRAM (A) The indirect method involves an esterif ication of the hydroperoxide to give a new intermediate hydroperoxide followed by treatment with one or more cata)osts in the presence of oxygen to undergo a new oxygenat. .n-cleavage reaction and subsequent cyclization to give a cyclic peroxyacetal lactone.

Thus, in another aspect of the invention there is provided a process for preparing a peroxyacetal lactorie compound of ?.formula 6- INO 91/04970 PCT/NU90/00456 (Y)P (CH 2

)M

0 (X)n

R

comprising; esterifying a compound of formula (Y)p/(C 2 HOO (X)n

COOH

to give aL compound of f ormula.

(CH

2

)M

HOO X)n

COOCN

3 ii) oxygenation in the presence of one or more oxidizinig metal citalysts to give compounds of formula (Y)py (CH )m 0Xn-CH HO Xn-fOH H

L

00H 3 0 -7 WO 9 1/04970 PC1'/AU9O/00Q456 f ollowed by iii) treatment with a protic acid or lewis acid to give the desired cyclic peroxy acetal lactone conrpound; where m,n,p,X,Y,R 6and R 7are as defined above.

The following Schematic Diagram illustrates the proces for the indirect mnethod, starting from a cyclic hydropero :y alkens carboxylic acid.

INDRECT METHOD

HOO

HO

Methylation HcO Oxygenation-Cleavage 0 0 0 cid-Catalyzed Cyclization NB: In this Scheme one enantiomer only of each chiral compo';ad is depicted. There is also produced an equal )Vnount of the other en~niomer in ezach case.

SCHEMATIC DIAGRAM (B) 8- WO 91/04970 PCI/A U90/00456 Preferably, the starting hydroperoxide compound is obtained by oxygenation of the corresponding alkene compounds as follows: (CH 2

)M

(Y)p I tzN, (X)n

OH

0 0 Oxygenation Oxygenation (Y)p 1 (X)n

HOO

HO 0 R H. Alkyl IZ 'OH

OR,

OR'

Oxygenation Oxygenation Oxygenation

R

HOO

HOC

RO

R

R' =Alkyl NB: In this Scheme, one enantiomer only of each chiral compound is depicted. There is aio produced an equal amount of the other enantiomer in each case.

9 WO 91/04970 PCT/AU90/00456 Preferably, the alkene carboxylic acid has an alkyl" or other substituent on the double bond and an optionally substituted alkyl chain between the alkene group and the carboxyl group. The alkyl chain preferably contains two, four or more carbon atoms and may also contain one or more heteroatoms such as oxygen. The alkene carboxylic acid may be cyclic or acyclic. The process is preferably carried out as a "one-pot" reaction.

The present invention is particularly suitable for preparing qinghaosu.

According to the process of the invention, the starting material for preparing qinghaosu, comprising the alkene carboxylic acid functionalities is preferably qinghao acid (artemisinic acid or arteannuic acid) of the following formula: Hi Qinghao Acid H

OH

0 Qinghao acid occurs to the extent of 1 3 (dry weight) in Arcemisia annua, which is much greater than the natural occurrence of qinghaosu and is easily extracted from the plant. There have been several attempts carried out elsewhere to convert this compound into qinghaosu, but none is preparatively useful.

Thus, in another aspect of the invention there is provided a process for converting qinghao acid into qinghaosu comprising 10 i) reducing qinghao acid to give d'hydroqinghao acid of formula

H

HO

0 Dihydroqinghao acid ii) oxygenating dihydroqinghao acid to give the corresponding hydroperoxides and without isolation iii) oxgenating in the presence of one or more oxidising metal catalysts to give qinghaosu.

Optionally, a protic acid or lewis acid catalyst may be added following step iii).

In a further aspect of the invention there is provided a process for converting qinghao acid into qinghaosu comprising i) reducing qinghao acid to give dihydroqinghao acid; ii) oxygenating dihydroqinghao acid followed by methylation to give the methyl ester hydroperoxide of formula

H

HHO

CHOO

0 Methyl Ester Hydroperoxide iii) oxygenation in the presence of one or more oxidizing metal catalysts to give intermediate products of formulae 11 WO 91/04970 PCT/AU90/00456 and with or without isolation iv) treatment with protic or Lewis acid catalyst to give qinghaosu.

The process of the invention will now be described in more detail in relation to the preparation of qinghaosu.

However, it will be understood, that the invention is not limited to this preparation.

Best Mode of Carrying out the Invention In detail, the process of the invention can be applied to conversion of qinghao acid into qinghaosu according to the direct method as illustrated in the following Schematic Diagram Direct Method for Conversion of Qinghao Acid into Qinghaosu (Artemisinin) H

H

Reduction H 1) Oxygenation H 2) Oxygenation- H OH HO Cleavage- Cyclization

S

Qinghao Acid Dihydroqinghao acid

H

0- 0 0 Qinghaosu SCHEMATIC DIAGRAM (C) 12 WO 91/04970 PCT/AU90/00456 Firstly, qinghao acid is reduced by known methods to give dihydroqinghao acid. This acid is then converted by oxygenation into the new hydroperoxides. Without isolation, the mixture is treated with one or more metal complex catalysts under an oxygen atmosphere and undergoes the new oxygenation-cleavage-cyclization reaction to give qinghaosu.

The preparation of qinghaosu can be carried out according to the indirect method as illustrated in Schematic Diagram Indirect Method for Conversion of Qing ao Acid into Qinghaosu.

Reduction

-OH

H

1) Oxygenation 2) Methylation HOO CH

O

0 Methyl Ester Hyroeroie Methyl Ester Hydroperoxide

O

Qinghao Acid Dihydroqinghao acid Oxygenation-Cleavage H 0 H H H HO 0 CH O 0 CH30 i 0 O Peroxyhemiacetal Dicarbonyl Hydroperoxide Acid-catalyzed Cyclization V cdcaaye Qinghaosu SCHEMATIC DIAGRAM (D) WO 91/04970 3 PCT/AU90/00456 Firstly, qiaghao acid is reduced by known methods to give dihydroqinghao acid. This acid is than converted by oxygenation into the corresponding carboxylic acid hydroperoxides which are then methylated to give the corresponding tertiary hydroperoxide and its regioisomer.

The major tertiary hydroperoxide is than treated with one or more metal complex catalysts under an oxygen atmosphere and undergoes the new oxygen-cleavage reaction to give the corresponding peroxyhemiacetal and the hydroperoxide. These compounds are then cyclized through acid catalysis to give qinghaosu.

Alternatively, the above process can be carried out without first reducing qinghao acid into dihydroqinghao acid, in which case, a compound known as dehydroqin-haosu (artemisitene) is produced.

Without the reduction step, the direct method results in a "one-pot" reaction as illustrated in Schematic Diagram Direct Method for the Conversion of Qinghao Acid into Dehydroqinghaosu (Artemisitene).

H H 1) Oxygenation H 2) Oxygeantion-Cleavage-Cyclzation OH HO oo Qinghao Acid Dehydroqinghaosu SCHEMATIC DIAGRAM (E) Qinghao acid is converted by oxygenation into the hydroperoxides and without isolation, the mixture is treated as described above from the direct method to give dehydroqinghaosu.

14 WO 91/04970 PCT/AU90/00456 By-products of this reaction, not formed in the reaction of the indirect method are new keto-aldehydes of formulae Keto-aldehydes 0 H:

HH

H

0 OH 0 The indirect method for the preparation of dehydroqinghaosu is illustrated in Schematic Diagram Firstly, qinghao acid is converted by oxygenation into the corresponding carboxylic acid hydroperoxides which are then methylated to give the corresponding new tertiary methyl ester hydroperoxide and the mixture of regioisomeric hydroperoxides.

The major, tertiary methyl ester hydroperoxide is then treated with one or more metal complex catalysts under an oxygen atmosphere and undergoes the new oxygenation-cleavage reaction to give a mixture of the peroxyhemiacetal and dicarbonyl hydroperoxide. The peroxyhemiacetal and dicarbonyl hydroperoxide are then cyclized through acid catalysis to give dehydroqinghaosu.

15 WO 91/04970 PCT/A U90/00456 indirect Method for the Conbversion of Qinghao Acid into Dehydroqinghaosu.

H

H 01 0 Qinghao Acid 1) Oxygenation 2) Methylation

H

HOO OCH3 0 Regioisomeric Hydroperoxides Tertiary Hydroperoxide Oxygenation- SCleavage H: 0 H: 1 H00.1 H H I

HO

0OCH 3 0 OCH 2 0 0 Peroxyhemiaceral Dicarbonyl Hydroperoxide Acid-catalyzed Cyckization .0-0) 0, H 0 0 Dehydroqinghaosu SCHEMATIC DIAGRAM (F) WO 91/04970 16 PCT/AU90/00456 A new methyl peroxyacetal whose formula is given below, also forms as a result of the reaction of the peroxyhemiacetal and hydroperoxide with methanol liberated during the ring closure reaction leading to dehydroqinghaosu.

H:

CHO Methyl Peroxyaceta

CH

3 O 0k OCH 0 OCH3 0 The dehydroqinghaosu can be converted according to known methods to give qinghaosu or other active antimalarial compounds.

There are many advantages in using the direct method.

Firstly, the direct method involves a "one-pot" reaction and therefore various isolation and/or purification steps are eliminated.

Secondly, the initial methylation step is eliminated.

The free acid then acts as an internal acid catalyst in the new oxygenation-cleavage-cyclization process. Thus, the need for an external acid catalyst to effect the final ring closure is not essential, but its presence speeds up the cyclization step and improves the overall yield.

The direct method may also be used to p:epare a compound like qinghaosu, but lacking the carbonyl group, and known as deoxoqinghaosu or deoxoartemisinin. The preparation is illustrated in the following Schematic Diagram 17 WO91/04970 PCT/AU90/00456 Direct Method for Conversion of Dihydroqinghao Alcohol into Deoxoqinghaosu (Deoxoarteisinin) H H

H

H Reduction 1) Oxygenation 4 H RedutiH H 0 H 2) Oxygenation- 0

CH

3 O HO H Cleavage- H 0 0 Cyclization Dihydroqinghao Acid Dihydroqinghao Alcohol Deoxoqinghaosu Methyl Ester SCHEMATIC DIAGRAM (G) The qinghao acid is first reduced to dihydroqinghao acid, and then this compound is converted by reduction into the known alkene alcohol we name "dihydroqinghao alcohol" via the dihydroqinghao acid methyl ester. The dihydroqinghao alcohol is then converted by oxygenation into the hydroperoxide mixture, which is treated with one or more complex catalysts under an oxygen atmosphere to give deoxoqinghaosu.

Deoxoqinghaosu is twice as active as qinghaosu as an antimalarial agent.

The oxygenation step of the present invention is preferably photosensitized oxygenation carried out by treating with singlet oxygen in the presence of Rose Bengal.

Preferably, the reaction is carried out in a solvent such as acetonitrile.

Methylation is preferably carried out by treating with diazomethane. This may be prepared from N-nitroso-N-methylurea. The diazomethane is preferably added dropwise in a solution of diethyl ether.

WO 91/04970 18 PCT/AU90/00456 The new oxygenation-cleavage-cyclization and oxygenation-cleavage reactions are typically carried out by treating with one or more oxidizing transition metal complex catalysts such as Cu(OSO2CF 2 Cu(II) propionate, copper(II)2-ethylhexanoate, other copper(II) carboxylate salts, and various iron (TII) salts such as Fe(phenanthroline) 3

(PF

6 3 Other catalysts that may be used are cobalt(II) and cobalt(III) salts. Preferably, this reaction is carried out in a solvent such as acetonitrile and by treating with any one of the above mentioned catalysts, or with a conbination of the copper and iron catalysts. Other suitable solvents include dichloromethane, hexane, ethyl acetate and the like. If the iron catalyst is omitted, then the overall conversion may be somewhat slower. The formation of the cleavage by-products may also be significantly decreased. This results in an increase in the yield of the final product. The new reaction is preferably carried out at a temperature in the range of -300 to -100C and preferably allowed to proceed to completion at room temperature.

The acid-catalysed ring closure is generally carried out in the presence of p-toluenesulfonic acid.

These reactions overall constitute the only known synthesis of dehydroqinghaosu, and provide a convenient means of obtaining this potentially commercially valuable compound in large amounts. The only known source of qinghaosu is the annual shrub Artemisia annua. Because of the large amount of qinghao acid present is Arcemisia annua (up to relative to qinghaosu (up to the above methods will substantially increase the availability of qinghaosu. Moreover, the methods have the potential of providing access to antimalarial agents structurally related to qinghaosu, but possessing enhanced activities.

Specific embodiments of the present invention are illustrated by the following preparative examples. It will be understood, however, that the invention is not confined to the specific limitations set forth in the individual examples.

WO 91/04970 19 PCT/AU90/00456 Example 1 Preparation of Qinghiaosu (Artemisinin) from Qinghao Acid Method 1. Direct Conversion H HI

H

NaBH 4 NiCl 2 I 1) 02, Rose Bengal H

H

H CH 3 OH, 0 °C 2) CH 3 CN, -30 C HOO OH" HOOHN h HO O 0 Qinghao Acid Dihydroqinghao acid Hydroperoxide H 02, Cu(OS0 2

CF

3 2 0.1 eq. 0- O H 0 Qinghaosu

CH

3 CN CH 2 C1 2 -20 OC room H O temperature, 3 h Optically-pure qinghao acid (arteannuic or artemisinic acid), obtained from Artemisia annua, was reduced with sodium borohydride in methanol according to a literature procedure (Xu, Zhu, Huang, Zhou, W.S. Tetrahedron 1986, 42, 819) to dihydroqinghao acid. This was converted into the hydroperoxide in the following way. A suspension of the acid (289 mg, 1.22 x 10 3 mol) in acetonitrile (5 ml) containing Rose Bengal (6 mg) was stirred vigorously under an oxygen balloon at OC whilst under irradiation from a tungsten lamp (500 After 4h a clear solution resulted and the oxygenation was complete. In addition to the tertiary hydroperoxide, the photooxygenation also produces a small amount (ca. 18%) of an allylic regioisomer, which does not undergo the subsequent reactions. Without isolation, the mixture was diluted with dichloromethane (20 mL) and the resulting so!utitn was cooled to -20 OC. A solution containing Cu(OSO 2

CF

3 2 (44 mg, eq.) in acetonitrile (0.5 mL) was added dropwise with stirring. The temperature was held at OC for 1 h and thereafter allowed to rise to room temperature, when the mixture was stirred for a further 2 h. The reaction mixture was poured into water (20 mL) and extracted with ether (2 x 25 mL). The combined extracts were washed with water mL) and brine (10 mL), and then dried (MgSO 4 Evaporation of the solvents left a 20 WO 91/04970 PCT/AU90/00456 viscous oil which after flash chromatography on silica gel with ether-light petroleum (1 1) gave crystalline qinghaosu (arternisinin) (165 mg, lH NMR spectrum (400 MHz, CDC1 3 'H NMP speQ-trum (400 MHz, CDCI 3 5 1.002 (3H, d, Jme-,6 6 Hz, 6.GH 3 1.03-1.12 (2H, in), 1.209 (3H, d, JM, 9 g 7.2 Hz, 9-CH 3 1.33-1.53 (311, mn), 1.446 s, 3-CH 3 1.73-1.81 mn), 1.86-1.93 (lH, in), 1.96-2.09 mn), 2.39-2.48 (Ilh, in), 3.398 (1H, dddd, J8,,8, 7.3, Jsa,8P 7.3, J 8 8 9 J8a,7a, Hz, 118a), 5.862 (1H, s, H1-12).

Addi.-.'n of 0.1 eq. of p-toluenesulfonic acid to the reaction mixture 0.5 h atter addit.zn of the metal catalyst resulted in a more rapid reaction, and formation of the qinghaosu in higher yield.

Example 2 Method 2. Indirect Conversion

HE

H

H.

HO

0 1) 02, Rose Bengal, hu, CH 3 CN, -30 0 C, 4 h' 2) CHAN, ether

H

HOO

CH

3 O0 0 Methyl Ester Hycfroperoxide Dihydroqinghao acid

HE

1) 02, Fe(phen) 3

(PF

6 3 0.03 eq., Cu(OSO 2

CF

3 2 0.1 eq., CH- 3 CN, 0 Oc O O H I 2) p-Toluenesulfonic Acid, 0.3 eq., CH 2 Cl:4, 4 h H Qinghaosu o The dihlydroqingh ao acid (103.1 mg, 4.a6 x 10-4 mol) was photooxygenated as describeu above. The solvent was removed uni vacuum from the reaction mixture to leav the crude mixture of the carboxylic acid hydroperoxide and its regioisomer in a ratio of 4.5: 1, according to lH NMR analysis. The ibture was dissolved in diethyl ether (17.5 mL), and treated dropwise with a solution cr diazoinethane, prepared form N-nitroso-N-inethylurea (350 ing) in diethyl ether (17.5 mL) at 0 OC. Addition of the diazoinethane solution was continued until TLC analysis indicated complete WO 91/04970 21 PCT/AU90/00456 conversion of the free carboxylic acid hydroperoxide into the methyl esters. The mixture was treated with 5% aqueous acetic acid to decompose excess diazomethane.

The resulting mixture was washed with water, aqueous sodium hydrogen carbonate and then brine. The ether solution was dried (MgSO 4 and then evaporated to dryness to give a viscous oil. The major (tertiary) hydroperoxide, a known compound (Jung, El Sohly, HN.; Groom. E.M. J. Org. Chem. 1986, 51, 819) was isolated by flash chromatography on silica gel with diethyl ether light petroleum as the second fraction (72.2 mg, 70%) The hydroperoxide (72.2 mg. 2.55 x 10- mol) in acetonitrile (4 mL) was treated with Fe(phenanthroline) 3

(PF

6 3 (0.03 sq.) in acetonitrile (0.9 mL) followed by Cu(OSO 2

CF

3 2 (0.1 eq.) in acetonitril (0.5 mL) at 0 OC. After 30 min. the reaction r'xture was worked up as described previously to give a crude product, which was dissolved in dichloromethane (20 mL). p-Toluenesulfonic acid monohydrate (15 mg, 7.65 x 10 5 mol) was added, and the resulting mixture was stirred at room temperature for 4h. It was then poured onto an ether-water mixture. The ether layer was separated, and the aqueous layer was extracted with ether. The combined ether layers were proce'sed in the usual way to give the crude product, which was submitted to flash chromatography on silica gel with ether-light petroleum to give qinghaosu as fine needles (20.1 mg, 28% from the hydroperoxide).

Ex.nple 3 Preparation of Dehydroqinghaosu (Arremisitene) from Qinghao Acid Method 1. Direct Conversion H

H

1) 02, Rose Bengal, CH 3 CN, .30 OC. 2 h

H

H 2)02. Fe(phen) 3

(PF

6 3 0.002 eq., Cu(OSO 2

CF

3 2 0.1 eq. 0 H OH HO

SCH

3 CN. 20 OC room temperature, 3 h 0 0 Qinghao Acid Dehydroqinghaosu Qinghao acid (32 mg, 1.37 x 10 4 mol) in acetonitrile (1.5 mL) containing Rose Bengal (ca. 0.5 mg) at -30 DC under oxygen was converted into the free carboxylic acid hydroperoxides corresponding to the methyl ester hydroperoxides described WO l /n-7n0 22 ^vv. ,7| L w u PCT/AU90/00456 below. Without isolation, the mixture was diluted with dichloromethane (5.4 mL) and the resulting solution was cooled to -20 OC. A solution containing Fe(phenanthroline) 3

(PF

6 3 (0.002 eq.) and Cu(OSOICF 3 2 (0.1 eq.) in acetonitrile (0.6 mL) was added dropwise with stirring. The temperature was held at -20 OC for lh and. thereafter allowed to rise to room temperature, when the mixture was stirred for a further two hours. By-products of the reaction, not formed in method 2 below, as detected by thin-layer chromatography of the reaction mixture, were the keto-aldehydes. The 0 H O H H J Keto-aldehydes H H H SOH OH 0 0 reaction mixture was poured into water (10 mL) and extracted with ether (2 x 25 mL).

The combined extracts were washed with water (10 mL) and brine (10 mL), and then dried (MgSO 4 Evaporation of the solvents left a viscous oil which was submitted to flash chromatography on silica gel with ether-light petroleum to give crystalline dehydroqinghaosu (artemisitene) 5 (14.4 mg, 38%).

Example 4 Method 2. Indirect Conversion a) Oxygenation of Qinghao Acid.

H H H 1) 0 2 Rose Bengal, hu h

CH

3 CN, -30 4 h C H

H

OC

H

OH 2) CH 2

N

2 ether OCH 3 HOO OCH 0 0 0 O O O Qinghao Acid Tertiary Hydroperoxide Regioisomeric Hydroperoxides A suspension of qinghao acid (arteannuic or artemisinic acid) (338.2 nig, 1.44 x 10-3 mol) in acetonitrile (35 mL) containing Rose Bengal (6 mg) was stirred vigorously under an oxygen balloon at -30 OC whilst under irradiation from a tungsten lamp (500 After 4h a clear solution resulted and the oxygenation was complete. The 23 WO 91/04970 PCI/A U90/00456 solvent was removed under vacuum to leave the crude mixture of the carboxylic acid hydroperoxides in a ratio of 4.5:1, according to IH NMR analysis. The mixture was dissolved in diethyl ether (17.5 mL), and treated dropwise with a solution of diazomethane, prepared form N-nitroso-N-methyl-urea (350 mg) in diethyl ether (17.5 mnl.) at 0 0 C. Addition of the diazomethane solution was continued until TLC analysis indicated complete conversion of the free cauboxylic acid hydN.operoxides into the methyl esters. The mixture was treated with 5% aqueous acetic acid to decompose excess diazomethane. The resulting mixture was washed with water, aqueous sodium hydrogen carbonate and then brine. The ether solution was dried NMgOW, and then evaporated to dryness to give a viscous oil. The major (tertiary) hydroperoxide, a new compound, was isolated by flash chromato-graphy on silica gel with diethyl ether Ii,,ht petroleum as the second fraction (287.4 mg, 7 'H NMR spectrum (400 M4Hz, CDC1 3 5 0.981 (3H, d, JMe,6 6.4 Hz, 6-CH 3 1.18-1.27 (1Hi, m, H6), 1.209 (3H, s, 3-CH 3 1.27-1.38 1.514 (1H, dddd,ge= 12.5, 12.5, 3.5 Hz, H813), 1.527 (1H, dddd, J =13.0, J 7.3, J 3.0, J 0.8 Hz, 1.72-1.79 B, mn), 1.804 (1H, dddd, 12.3, J& Sa 3.5 =35 J8(, 7 0 Hz, Hga), 1I .134 (1H, dddd, J 12.6. J 3.3, J 3.3 1.971 (1Hi, ddd, J =13. 1, J 10.8. J 3.5 Hz), 2.048 (1H, dddd, J 13.1, J 7.5, J 5.8 Hz), 3.141 (1H, br d, J8,p= 12.6 Hz, H8a), 3.74 1 (3H, s, OCH 3 4.979 (IH, ddd, J12.8a 1.6, J 1.6, J= 1.6, J 0.8 Hz, H12), 5.581 (IH,dd, igem l 1 methiylidene,8a 1.1 Hz, H methylidene), 6.362 (1H, d, 'gem 1. 1 Hz, H methylidene),. 7.575 (1H, br s, W/h/ Hz, OOH).

b) Cleavage-oxygenation to give the peroxyhemiacetal and dicarbonyl hydroperoxide H: 0 H: H 02 ~Fe(phen) 3

(PF

6 3 0.03 eq. HO H H HOCuCOSO 2

CF

3 2 0.1 eq. HO '0 0OH 0 OCH3

OCH

3 ClI 3 CN, 0 Ct I

I

0 30 mm~ 0 Dicarbonyl 0 Terdaqi Hydroperoxide Peroxyhemiacetal Hydroperoxide The tertiar); hydroperoxide (106.3 mng, 3.78 x 10-4 mol) in acetonit-ile (5 mL) was treated with Fe(phenanthroline) 3

(PF

6 3 (0.03 eq. in 0.6 mL. acetonitrile) and then with Cu(OS0 2

CF

3 2 (0.1 eq. in 0.5 mL. acetonitrile) at 0 'C under an oxygen atmosphere.

24 WO 91/04970 PCT/AU90/00456 The reaction mixture was stirred for 30 min with slow warming toward room temperture, and then poured onto a mixture of ether and water. The aqueous phase was extracted with ether and the combined extracts were washed with water until colourless, and then with brine. The organic phase was dried (MgSO 4 and the solvent was removed under reduced pressure to leave a viscous oil, analysis of which by'H NMR spectroscopy indicated that it consisted of predominantly the oxygenaton products. This was isolated by flash chromatography on silica gel with ether-light petroleum as an unstable viscous oil (62.5 mg, Prolonged exposure of the mixture of oxygenation products to silica gel resulted in .'.ecomposition to a more polar product. The oxygenation products were an equilibrium mixture of the peroxyhemiacetal and the free dicarbonyl hydroperoxide. Both are new compounds. IR vm (CHCl 3 3580-3450 (br 3450-3130 (br 3001 2956 2940 2872 2854 1732 1714 (vs) 1627 1443 1285 1167 1100 961 909 cm- 1 1H NMR (400 MHz, CDC1 3 peroxyhemiacetal 6 0.933 (3H, d, JMe, 6 6.4 Hz, 6-CH 3 0.96-1.20 (2H, 1.217 (3H, s, 3-CH 3 1.26-1.39 (3H, 1.56-2.24 (4H, 2.32-2.45 (1H, m, H6), 2.94-3.01 (1H, dd, Jgasp 9.6, JSaBa 7.1 Hz, H8a), 3.804 (3H, s, OCH 3 5.468 (1H, s, methylidene), 6.260 (1H, s, methylidene), 9.617 (11, d, J12, 5 a 2.5 Hz, H12); dicarbonyl hydroperoxide 8 0.991 (3H, d, JMe.6 6.4 Hz, 6-CH). 0.96-1.20 (2H, 1.26-1.39 (3H, 1.56-2.24 (4H, 2.141 (3H, s, 3-CH 3 2.585 (1H, ddd, Jgem 17.6, J4,5 9.3, .4, 5 6.1 Hz, H4), 2.713 (1H, ddd, Jgem 17.6, J4, 5 9.3, J4, 5 6.1 Hz, H4), 3.197 (1H, dd, Jsa,8p 13.3 Jsa,8 3.5 Hz, H8a), 3.840 (3H, s, OCH 3 5.597 (1H, s, methylidene), 6.383 (1H, s, methylidene), 9.340 (1H, dd, J 1.5, J 1.5 Hz, H12), 10399 (1H, s, OOH).

Preirradiation at 6 9.6 (H12, peroxyhemiacetal) resulted in enhancements at 6 5.47 (methylidene, peroxyhemiacetal) of 1% and at 5 3.80 (OCH 3 of 1 3 C NMR spectrum (100 MHz, CDC13), 6 20.049, 20.369, 20.568, 22.070, 22.515, 23.513, 26.986, 27.256, 27.790, 29.644, 29.644, 29.886, 32.078, 33.777, 34.672, 35.144, 40.701, 41.657, 43.407, 43.862, 46.348, 52.278 (OCH 3 peroxyhemiacetal), 52.933

(OCH

3 dicarbonyl hydroperoxide), 58.546, 92.29 (C12a, dicarbonyl hydroperoxide), 92.31 (C12a, peroxyhemiacetal), 105.90 (C3, dicarbonyl hydroperoxide), 125.02 (methylidene C, peroxyhemiacetal), 129.01 (methylidene C, dicarbonyl hydroperoxide), 139.55 (C9, dicarbonyl hydroperoxide), 139.70 (C9, peroxyhemiacetal), 166.20 (C10, peroxyhemiacetal), 170.41 (C10, dicarbonyl hydroperoxide), 201.39 (C12, peroxyhemiacetal), 203.14 (C12, dicarbonyl hydroperoxide), 209.14 (C3, dicarbonyl hydroperoxide).

WO 91/04970 2SPCT/A U90/00456 c) Tandem cyclization of peroxyhemiaceral and dicarbonyl hydro peroxide to deh~ydroqinghaosu (arremisitene).

H0 H.H 0 o HODp-Tcluenesulfoa'ic Acid, 0.3 eq.

HO 0- 0HOH OR CH 2

C

2 4h

H

0 Dicarbonyi 0 Peroxyhemiacetal Hydroperoxide Dehydroqinghaosu The mixture of the peroxyhemiacetal and dicarbonyl hydroperoxide was prepared as described above from the tertiary hyclroperoxide (110.3 mg, 3.92 x 10, mul). The mixture of products was immediately dissolved in dichloromethane (5 m L) and treated with p-toluenesulfonic acid monohydrate (0.3 The resulting mixture was stirred for 4 h at room temperature, and then poured onto an ether-water mixture. The ether layer was separated, and the aqueous layer was extracted with ether. The combined ether layers were processed as described above to give a viscous oil, which upon flash chromatagraphy on silica gel with ether-light petroleum gave dehydroqinghaosu (artemisitine) as fine needles (47.9 mg, 43% from the tertiary hydroperoxide, or 30% from qinghao acid), m.p. 164-166 OC, a known compound. 1H NMR spectrum (400 MvHz, CDC1 3 8 1.017 (3H, d, JMe,6= 5 9 Hz, 6-CH 3 1.15-1.27 1.42-1.63 (3H, m, including H8), 1.43-1.48 (1H, m, H6), 1.459 (3H, s, 3-CH 3 1.72-1.80 (2H, m, including H8), 1.94-2.01 (1H, in), 2.04-2.10 (lH,m), 2.37-2.45 2.550 (1H, dcl, J8,8 13.6, J8,8 4.5 Hz, H8a), 5.672 (1H, dcl, g~em =11 mechylidene,8a 1.1 Hz, methylidene;., 5.995 (1K, s, H12), 6.570 (1H, dd, 1 gem Jmetiylidene,8a 0.5 Hz, H methylidene).

Also formed was the methyl peroxyacetal (17.8 mg, 14%) from the reaction of the peroxyhemniacetal and dicarbonyl hydroperoxide with the methanol formed during the ring closure reaction leading to dehydroqinghaosu.

H:

Methyl Peroxyacetal 0

OCH

3 WO 91/04970 26 PCT/AU90/00456 Example Conversion of Dihydroqinghao Alcohol into Deoxoqinghaosu H H H H LiAlH 4 ether 1; 02. Rose Bengal CH H HO H2) CH 3 CN, -30 OC HO0 cH 3 HO

HO

I hu 0 Dihydroqinghao Acid Dihydroqinghao Alcohol Alcohol Hydroperoxide Methyl Ester

H

02, Cu(OSO 2

CF

3 2 0.2 eq. O-O H Deoxoqinghaosu

CH

3 CN CH 2 Cl2, -20 OC room H O temperature, 2 h Dihydroqinghao alcohol (arteannuinol) was obtained by the reduction of dihydroqinghao acid methyl ester with lithium aluminium hydride in ether according to a literature procedure (Ye, B; Wu, Y. Tetrahedron 1989, 45, 7287).

Dihydroqinghao alcohol (43.9 mg, 1.97 x 10 mol) in acetonitrile (2.5 ml) containing Rose Bengal (ca. 0.5 mg) was then irradiated under oxygen at -30 OC for 2 h to give a hydroperoxide mixture containing predominantly the tertiary hydroperoxide. The mixture was diluted with dichloromethane, cooled to -15 OC and then treated with Cu(OS02CF 3 2 (0.2 eq) in acetonitrile (0.4 ml) for 1 h 45 min, with gradual warming to room temperature. The reaction mixture was quenched with water and then worked up as previously described to give a viscous oil. This was submitted to flash chromatography on silica gel with ether-light petroleum to give deoxoqinghaosu as a white solid (19 mg, 36% from dihydroqinghao alcohol). Spectroscopic data is in agreement with that reported in the literature (Jung, Li., Bustos, D. A.; ElSohly, H. McChesney, J. Tetrahedron Lett. 1989, 30, 5973) 27 WO 91/04970 PCT/AU90/00456 Example 6 Conversion of Model Compound into Peroxyacetal Lactone Method 1. Direct Conversion 0 2 Rose Bengal, hv, CH 3 CN, -40 OC

HOO

HO

OH

0 0 a b 02, Cu(OSO 2

CF

3 2 0.1 eq.

0

CH

3

CN-CH

2 C1 2 0 OC room temp., 4 h. O

HO

C

0 The compound a, a new compound, was obtained from a known mixture of the corresponding methyl ester and a double bond regioisomer of the ester (Claus, P. K.; Vierhapper, F. Wilier, R. L. J. Org. Chem., 1977, 42, 4016), through hydrolysis of the mixture with lithium hydroxide in aqueous dimethoxyethane, and separation of the resulting .'xture of carboxylic acids through an iodolactonization procedure (Corey, E. Wight, S. J. Org. Chem., 1988, 53, 5980). The acid a (134 mg, 7.97 x 10 mol) in acetonitrile (4 mL) containing Rose Bengal (3 mg) under oxygen was irradiated as described below for qinghao acid to give the racemic hydroperoxide b and double bond regioisomers in a ratio of 1:1. The mixture was diluted with dichloromethane (16 mL) and then treated with Cu(OSO 2

CF

3 2 (0.1 eq.) in acetonitrile (0.2 mL) under oxygen at 0 OC. This resulted in the immediate conversion of compound b into a polar intermediate. The other regioisomers of compound b did not appear to react under these conditions. The reaction mixture was allowed to warm to room temperature and was stirred for 4 h. The mixture was poured onto water and extracted with ether as described below for the preparation of qinghaosu to give a viscous oil. This was submitted to flash chromatography with ether-light petroleum 7:3 to give the racemic compound c as a colourless gum (51 mg, 28 WO 91/04970 PCT/AU90/00456 Example 7.

Method 2. Indirect Conversion

OH

1)02, Rose Bengal, hv. CH 3 CN, -40 2) CH 2

N

2 ether

C

HOO

CH O 0 1) 02, Fe(phen)3(PF 6 3 0.03 eq., Cu(OS0 2

CF

3 2 0.1 eq., CH 3

CN

2) p-TsOH, CH 2 C1 2 4 room temperature c 0 The acid a (110 mg, 6.54 x 10 4 mol) was converted into the racemic hydroperoxide b and its mixture of regioisomers as described above. The crude mixture of hydroperoxides was dissolved in ether and treated with an excess of diazomethane at 0 OC.

The racemic ester hydroperoxide d (96 mg, 45%) was isolated by flash chromatography with ether-light petroleum 3:7 of the mixture of ester hydroperoxides obtained after methylation. The hydroperoxide d (96 mg, 4.48 x 10 mol) in acetonitrile mL) under oxygen was treated with Fe(phen) 3

(PF

6 3 (0.03 eq.) in acetonitrile (1 mL) followed by Cu(OSO 2

CF

3 2 (0.1 eq.) in acetonitrile (0.5 mL) at 0 After 30 min, the reaction mixture was worked up to leave the crude product mixture consisting of a peroxy hemiacetal and hydroperoxide analogous to those described for the indirect conversion of qinghao acid into dehydroqinghaosu (artemisitene) described below. A solution of the mixture in dichloromethane (20 mL) containing p-toluenesulfonic acid (26 mg, 1.34 x 10 4 mol) was stirred for 4 h at room temperature. Workup as previously described gave a viscous oil which after purification by flash chromatography with ether-light petroleum 7:3 gave the racemic peroxyacetal lactone c (48 mg, 50% from a).

29 -Characterising data for compound c in examples 6 and 7 4 C 0 IR Vma (CEC1 3 2936 in, 2869 w, 1770 vs, 1451 w, 1295 w, 1239 mn, 1211 mn, 1193 mn, 1l 6 4 m, 1099 w, 962 w, 941 w, 914 wcm-1. 1 F NMR 5 1.5 1.7(mi, s, CE 3 1.7 -2.0 (in, H4 and H6), 2.1 (2H, t, J 4 ,3 8.2 Hz, 2.6 (2H, t, JT' 8.2 Hiz, H3T), 5.4 (lE, s, 13 C NMIRa 19.6, C5; 2j.6, CE- 3 29.0, CE 2 29.7, 2 X CH 2 34.4, C3T; 84.7, C7; 123. 1, C6'; 141.3, C3; 176.5, CT'.

Mass spectrum m/z: 219 213 185 181 167 (100), 153 149 121 (17), 83 71 61 (41).

Example 8 Conversion of the dimethyl acetal into artemether For Scheme see next page The dimethyl acetal of dihydroqinghao aldehyde was obtained by oxidising dihydroqinghao alcohol under Swern conditions and then stirring the resulting aldehyde in methanol in the presence of Dowex acidic resin. The dimethyl. acetal (49 mg;, 0.18 inmol) was irradiated in the presence of Rose Bengal in a mixture of acetonitrile (1.5 ml) and dichloromethane (0.5 ml) under an oxygen atmosphere at below -300. After 2 h when the conversion into the hydroperoxides was complete the reaction mixture was diluted with dichioromethane (7 ml) and then copper(LE) tifluoromethanesulfonate (0.018 minol; 0.18 ml, 0.1 M in acetohifrile) was added at -200. Stirring was continued at this temperature for 1 h before the reaction mixture was allowed to warm to room temperature and quenched by pouring onto ether/water. The usual workup afforded a viscous oil which was purified by flash chromatography on silica gel with ether-light petroleum 15:85 to'give l3-arteinether as the first fraction and as a crystalline solid (6.2 mg; 11%) and a mixture containing cc-artemether and its rearrangement producL, the peroxyacetal, in a ratio of 1: 1 (7 mg, Spectroscopic data obtained for bo th epirners of artemether were in agreement with that reported in the literature (1i, Yu, P. Chen, Y. Li, L.

Gal, Y. Wang, D. Zheng, Y. Kexue Ton gbao 1979, 24, 667).

30 DOWEX SOW methanol dihydroqinghao aidehyde .dimethyl acetal 0,Rose Benigal, hv, H E CH 3 CN, -Sao H acetal hydroperoxide HO00

CH

3 0 CICHa 02, Cu(OSO 2

CF

3 )q 2 0.1 eq. CH- 3 CN CH 2 01 2 -200 room temperature HE HE

OCH

3 P-artemether OCH3 a-artemether peroxyacetal 31 Example 9 Conversion of the diethyl acetal into arteether diethyl acetal OEt r3-arteether OEt c-arteether peroxyacetal The diethyl acetal of dihydroqinghao aldehyde (23.6 mg; 0.083 mmol), prepared in an analogous manner to that of the dimethyl. acetal, was treated as described for the dimethyl acetal to give farteether (2 mg; as a crystalline solid and a mixture containing Cc-arteether and its rearrangemer' product, the peroxyacetal in a ratio of 18:82 (5.6 mg; Spectroscopic data obtained for both epimers of arte ether were in agreement with that reported in the literature (Li, Yu, P. Chen, Y.

X; Li, L. Gai, Y. Wang, D. Zheng, Y. Acta. P harm. Sinica 1981, 16, 429).

Claims

1. A process of preparing a compound of formula I(CH 2 )m 0-0 (X)n 0'--77R6 R wherein n 1, 2 or 3 m 0, 1 or 2 p 0, 1, 2 or 3 X CR

2 R

3 CCR 2 R 3 S, SO or SO 2 where R 2 and R 3 are independently selected from H, optionally substituted alkyl, optionally substituted aryl, the optional substituents being selected from alkyl, aryl, halogen, OR, CF 3 NO 2 COR, NRR', SR, COOR, CONRR', SO 3 R, S02NRR', SR, SOR and SO 2 R, where R and R' are H, alkyl, aryl or arylalkyl; SR", SOR", SO 2 R" where R" is alkyl or aryl optionally substituted by one or more substituents selected from alkyl, aryl, halogen, OR, CF 3 NO 2 COR, NRR', SR, COOR, CONRR', SO 3 R, SO 2 NRR', SR, SOR and SO 2 R, where R and R' are as defined above; and wherein when n>l, X is independently selected and can be branched or straight chain and X together with a substituent Y can also form a ring; Y is a substituent selected from H; alkyl or aryl optionally substituted by one or more substituents selected from alkyl, aryl, halogen, OR, CF 3 NO 2 COR, NRR', SR, COOR, CONRR', S03R, SO 2 NRR', SR, SOR and SO 2 R, where R and R' are as defined above;

04828-TQ/31.5.93 33 Y can be on the same C atom as the hydroperoxy group and any C atom may be disubstituted by Y and includes replacement of H atom(s) in "(CH 2 by Y; R 6 or R 7 is as defined for R above, H, OH, OR 1 or together with the carbon atom to which they are attached form a keto group, where.R 1 is alkyl, aryl or aralalkyl; which comprises oxygenating a compound of formula (CH,)m I HQ O O (X)n R in the presence of one or more oxidizing metal catalysts where OR 1 R 5 -COOH, -CROH, -C-R \OR1 where R is H, alkyl, aryl or arylalkyl R 1 are independently alkyl, aryl, arylalkyl or each R 1 together with the group to which they are attached form a cyclic acetal. 2. A process according to claim 1 wherein the catalyst is selected from one or more oxidizing transition metal complex salts of Copper(II), Iron(III), Cobalt(II) and Cobalt(III). 3. A process according claim 1 or 2 wherein the catalyst is one or more transition metal complex catalysts selected from Cu(OSO 2 CF 3 Cu(II)propionate, Cu(II) 2-ethylhexanoate, other Cu(II)carboxylate salts, Fe(phenanthroline) 3 (PF 6 3 and other iron(III) salts.

4. A process according to any one of the preceding claims further comprising the addition of a protic acid or lewis 04828-TQ/31.5.93 S34 acid catalyst. A process according to any one of the preceding claims wherein the startiag hydroperoxy functionality containing compound is derived by oxygenation of the corresponding compound containing alkene carboxylic acid, alkene aldehyde, alkene ketone, alkene alcohol functionality or dialkyl acetals of the aldehyde and ketone compounds. 6. A process according to claim 5, wherein the starting compound is deived by oxygenation of a compound of formula (CH )m O (X)n I- R where.in m, n, p, X, Y and R 5 are as defined above. 7. A process for preparing a peroxyacetal lactone compound of formula (Y)p (cH) -O R 7 wherein m,n,p,X,Y,R 6 and R 7 are as defined above; comprising; i) esterifying a compound of formula (CH 2 )m H o (X)n COOH 04828-TQ/31.5.23 to give a compound of formula (CH 2 )m HO (X)n C000H 3 followed by ii) oxygenating in the presence of one or more oxidizing metal catalysts to give compounds of formula (H )m (Yp(CHj 2 )m XnOCH 3 a 4 HOO (XnOH HOX Xn rOH 0 0 0 iii) treating with protic acid or Lewis acid catalyst to give the desired cyclic peroxy acetal lactone compound. 8. A process according to~ claim 7 wherein the metal catalyst is one or more transition metal complex catalysts selected from Cu(0S0 2 CF 3 2 1 Cu(II)propionate, Cu(II) 2-ethylhexanoate, other C-u(II)carboxylate salts, Fe (phenanthroline3) 3 (PF6) and other iron (III) salts. 9. A process f or converting ginghao acid into qinhaosu compris in~g i) reducing qinghao acid to give dihydroqinghao acid of f or- mul1a H H H HO 0 Dihydroqinghao' acid 048 28-TQ/3 1.5,93 36 ii) oxygenating dihydroqinghao acid to give the corresponding hydroperoxi-es and without isolation iii)oxgenating in the presence of one or more oxidising metal catalysts to give qinghaosu. 10. A process according claim 9 wherein the catalyst is one or more transition metal complex catalysts selected from Cu(OSO 2 CF 3 2 Cu(II) propionate, Cu(II) 2-ethylhexanoate, other Cu(II) carboxylate salts, Fe(phenanthroline) 3 (PFg) 3 and other iron (III) salts. 11. A process according to claim 9 or 10 further comprising the addition of a protic acid or lewis acid catalyst following step iii). 12. A process for converting qinghao acid into qinghaosu comprising i) reducing qinghao acid to give dihydroqinghao acid; ii) oxygenation of dihydroqinghao acid followed by methylation to give the methylester hydroperoxide of the formula H H H HOO CZ'O:i cH, 3 0 0 iii) oxyqenation in the presence of one or more oxidizin. metal catalysts to give intermediate products of formulae H O H i o.00 H HOO H H H Ho 0 CH.O CHO 0 0 'eroxyheTiacea Dicarbonyl Hydroperoxide 04828-TQ!31.5.93 37 and with or without isolation iv) treatment with protic or Lewis acid catalyst to give qinghaosu. 13. A process according to claim 12 wherein the metal catalyst is one or more transition metal complex catalysts selected from Cu(OSO 2 CF 3 2 Cu(II) propionate, Cu(II) 2-ethylhexanoate, other Cu(II) carboxylate salts, Fe(phenanthroline)3 (PF 6 3 and other iron (III) salts. 14. A process for converting qinghao acid into dehydroqinghaosu comprising i) oxygenation to give the intermediate hydroperoxide ii) oxygenation in the presence of one or more metal catalysts to give the desired product of formula Hi o A process according to claim 14 wherein the catalyst is one or more transition metal complex catalysts selected from >I.(OS0 2 CF 3 2 Cu(II) propionate, Cu(II) 2-ethylhexanoate, other Cu(II) carboxylate salts, Fe(phenanthroline)3(PF6)3 and other iron (III) salts. 16. A process according to claim 14 or 15 further comprising the addition of a protic acid or Lewis acid catalyst following step ii). 17. A process for converting qinghao acid into dehydroqinghaosu comprising 04828-TQ/31.6.93 38 i) oxygenation of qinghao acid into the hydroperoxides followed by methylation to give a compound of formula H HOO OCH 3 0 Tertiary Hydroperoxide ii) oxygenation in the presence of one or more oxidizing metal catalysts to give intermediate products of formulae Hi 0 H HOO H H HO 0 OCH 0 OCH3 0 0 and with or without isolation iii)treatment with protic or Lewis acid catalyst to give dehydroqinghaosu. 18. A process according to claim 17 wherein the metal catalyst is one or more transition metal complex catalysts selected from Cu(OSO 2 CF 3 2 Cu(II) propionate, Cu(II) 2-ethylhexanoate, other Cu(II) carboxylate salts, Fe(phenanthroline) 3 (PF 6 3 and other iron (III) salts. 19. A compound of formula o H HCO H 0 OCH, 04828-TQ/31.5.93 39 A compound of formula H H H 0 OCHO OHO 0 21. A compound of formula 0-0 0 HO o 0 22. A process of preparing deoxoqinghaosu comprising i) oxygenation of dihydroqinghao alcohol to give the intermediate hydroperoxides followed by ii) oxygenation in the presence of one or more metal catalysts to give the desired product of formula H 0-0, Deoxoqinghaosu 0- H 0 23. A process according to claim 25 wherein the metal catalyst is one or more transition metal complex catalysts selected from Cu(OSO 2 CF 3 2 Cu(II) propionate, Cu(II) 2-ethylhexanoate, other Cu(II) carboxylate salts, Fe(phenanthroline) 3 (PF6) 3 and other iron (III) salts. 24. Qinghaosu when prepared by a process according to any one of claims 1-8. 25. Qinghaosu when prepared by a process according to any one of claims 9-13. 04828-TQ/31.5.93 40 26. Deoxoqinghaosu when prepared by a process according to claim 22 or 23. 27. Dehydroqinghaosu prepared by a process according to any one of claims 14-18. 28. A process of preparing a compound comprising a peroxyacetal lactone functionality from a compound comprising hydroperoxy alkene carboxylic acid functionalities substantially as described with reference to any one of examples 1 4, 6 or 7. 29. A process of preparing a compound comprising a peroxyacetal ether functionality from a compound comprising hydroperoxy alkene alcohol functionalities substantially as described with reference to example A process of preparing qinghaosu substantially as described with reference to example 1 or 2. 31. A process of preparing dehydroqinghaosu substantially as described with reference to example 3 or 4. 32. A process of preparing deoxoqinghaosu substantially as described with reference to example Dated this 31 May 1993 RHONE-POULENC RORER S.A. By their Patent Attorney Griffith Hack Co. 04828-TQ/31.5.93 XNTERNAI'XONAX SUA1rCI Rer International Application No. PCT/AU 90/00456 I. CLASSIFICATION OF SUBJECT MATTER (if several classification symbols apply, indicate all) 6 According to International Patent Classification (IPC) or to both National Classification and IPC 5 Int. C1.

5 C7D 321/10, 493/18, 497/18; C07C 409/14 II. FIELDS SEARCHED Minimum Documentation Searched 7 CLassification System Classification Symbols IPC C07D 321/10, 493/18, 497/18; C07C 409/14 IPC C07C 179/053 PC-3 C07C 179/02 IP C07C 73/06 Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included in the Fields Searched 8 I AU IPC as above; Australian Classification 09.33, 09.353 III. DOCUMENTS CONSIDERED TO BE RELEVANT 9 Category* I Citation of Document, with indication, where appropriate, Relevant to Sof the relevant passages 12 CLaim No 13 P,X Journal of the Chemical. Society; Chemical Cammnications, 1990, (1,3 to 5,10 to 23, No.6, issued 15 March 1990 (Cambridge, R.K. Haynes, 27,28,30 to 32) S.C. Vonwiller, 'Catalysed Oxygenation of Allylic Hydroperoxides a, Derived from Qinghao (Artemisinic) Acid. Conversion of Qinghao Acid into Dehydroqinghaosu (Artemisitene) and Qinghaosu (Artemisinin)', see pages 451 to 453, particularly page 452, compounds 4 to 6,8 P,X Tetrahedron Letters, Volume 30, No. 44, issued November 1989, (1,5,21) (Oxford, 'A Short and Stereospecific Synthesis of Deoxoartemisinin and (-)-deaodesoxyartemisinin', see pages 5973 to 5976, especially page 5974, cmpound 8 (ccntinued) Special categories of cited documents: 10 later document published after the international filing date or priority date document defining the general state of the and not in conflict with the application but art which is not considered to be of cited to understand the principle or theory particular relevance underlying the invention earlier document but published on or document of particular relevance; the after the international filing date claimed invention cannot be considered novel document which may throw doubts on priority or cannot be considered to involve an claim(s) or which is cited to establish the inventive step publication date of another citation or document of particular relevance; the other special reason (as specified) claimed invention cannot be considered to document referring to an oral disclosure, involve an inventive step when the document use, exhibition or other means is combined with one or more other such document published prior to the documents, such combination being obvious to international filing date but later than a person skilled in the art. the priority date claimed document member of the same patent family IV. CERTFICATION Date of the Actual Completion of the Dte of Mailing of this International International Search Search Report I Zl ,h mbr o199 International Searching Authority Signature of Authorized Officer Australian Patent Office A. PECK Form PCT/ISA/210 (second sheet) (January 1985) International Ap( ation No, PCT/A 90/00156 SURToER INFRMAITION CO UED FROM HE SECND SEET A Journal of Organic Chemistry, Volume 51, No.26, issued December (1) 1985 (Columbus Ohio, M. Jung et al., 'Practical Conversion of Artemisinic Acid into Desaoyartemisinin', see pages 5417 to 5419 A Pure Applied Chemistry, Volume 58, No.5, issued 1986, (Oxford, (1,20) W.S. Zhou, 'Total Synthesis of Arteanuuin (Qinghaosu) and SRelated Compounds', whole document (review article), pages 817 to S824, especially page 823, Scheme 8, compound A II V. OBSERVATIONS HERE CERTAIN CLAIMS WERE FOUND UNSEARMHABLE 1 This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: claim numbers because they relate to subject matter not required to be searched by this Authority, namely: Claim numbers because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically: Claim numbers because they are dependent claims and are not drafted in accordance with the second and third sentences of PCT Rule 6.4 VI. OBSERVATIONS WHERE UNITY OF ~WENTION IS LAKING 2 This International Searching Authority found multiple inventions in this international application as follows: The application claims two distinct inventions distinguished by the structural differences betWeen the heterocyclic lactone and ether compounds (claims 1 to 19,22 to 35), and the alicyclic cyciohexane and hydrogenated naphthalene derivatives (claims 20,21). As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims of the international application. 3 As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims of the international application for which fees were paid, specifically claims: No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claim numbers: 4. As all searchable claims could be searched without effort justifying an additional fee, the International Searching Authority did not invite payment of any additional fee. Remark on Protest The additional search fees were accompanied by applicant's protest. No protest accompanied the payment of additional search fees. Form PCT/ISA/210 (supplemental sheet (January 1985)