AU633671B2

AU633671B2 - Process for the preparation of glycosylanthracyclinones

Info

Publication number: AU633671B2
Application number: AU68406/90A
Authority: AU
Inventors: Cenek Kolar
Original assignee: Behringwerke AG
Current assignee: Siemens Healthcare Diagnostics GmbH Germany
Priority date: 1989-12-27
Filing date: 1990-12-24
Publication date: 1993-02-04
Anticipated expiration: 2010-12-24
Also published as: KR910011879A; IE904681A1; CA2032974A1; DE3943029A1; JPH05345794A; PT96358A; EP0437820A3; EP0437820A2; AU6840690A

Description

!r _IIL-i i 63 367 1., COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: r ,,Complete Specification Lodged: Accepted: o* Published: .4 J iorit o e* Related Art 4o,* W dame of Applicant Address of Applicant 4 t Actual inventor: Address for Service Address for Service BEHRINGWERKE AKTIENGESELLSCHAFT D-3550 Marburg, Federal Republic of Germany CENEK KOLAR WATERMARK PATENT TRADEMARK ATTORNEYS.

LOCKED BAG NO. 5, HAWTHORN, VICTORIA 3122, AUSTRALIA Complete Specification for the invention entitled: PROCESS FOR THE PREPARATION OF GLYCOSYLANTHRACYCLINONES The following statement is a full description of this invention, including the best method of performing it known to us BEHRINGWERKE AKTIENGESELLSCHA2T HOE 89/B 050 Ma 812 Dr. Ha/Sd Description PROCESS FOR THE PREPARATION OF GLYCOSYLANTHRACYCLINONES 5 I The present invention relates to a process, particularly t. a glycosylation process, for the preparation of glycosylanthracyclinones which, owing to their cytostatic activity, are suitable for the treatment of carcinoses.

I ,10 The anthracycline class of substance is described in depth in the technical literature. Doxorubicin and its 14-desoxy analog daunorubicin are named here as the most successful representatives of this class of substance, which can be employed in the clinic for the treatment of ''15 a large number of solid tumors and leukemias. Other analogs which have been modified both in the aglycone moiety and in the carbohydrate unit have recently been introduced in the clinic or are in clinical testing.

The chemical preparation of anthracyclines is carried out, starting from a functionalized carbohydrate building block as a donor and an anthracyclinone as an acceptor, S. in the presence of a promoter. In this case, the hydroxyl glycosylated with a carbohydrate building block with the .:25 formation of an a-0-glycosidic linkage.

The following functionalized carbohydrate building blocks are used for the glycosylation of anthracyclinones: 1) Glycosyl halides using silver salts as promoters (F.

Arcamone in "Doxorubicin", Academic Press, 1981, pp.

82-92 and pp. 194-258).

2 -2- 2) Glycosyl halides using mercury salts as promoters Smith et al., J. Org. Chem. 42, 3653 (1977), F.

Arcamone et al., Cancer Treat Rep. 60, 829 (1976)).

3) Glycals using acid as a promoter Umezawa et al., J. Antibiotics 33, 1581 (1980)).

4) Glycals using N-iodosuccinimide Horton et al. in "Anthracycline Antibiotics", Editor H.S. El Khadem, Academic Press, 1982, pp. 197 224).

1-0-Acyl-carbohydrate donors using trimethylsilyl '10 triflate as a promoter (EP-O 143,323/1988).

a-Glycosides can be prepared selectively by methods 1 and 2, but as the glycosyl halides are very unstable, their use in glycoside synthesis, above all on the industrial scale, is very problematical. Moreover, expensive silver salts or toxic mercury salts are used in this case.

I a-Glycosides can only be prepared as a mixture of the aand p-products by method 3. Only 2'-haloanthracyclines can be prepared by method 4.

a-Glycosides can be prepared selectively by method 5, but 20 as the glycosyl donor is present as a mixture of the aand p-0-acyl derivatives, the p-0-acyl derivatives preferably reacting to completion in the glycosylation, 4 the a-O-acyl component usually remains unreacted during the reaction. Expensive chromatography is necessary in the purification of the desired a-glycosides.

Surprisingly, it has been shown in the glycosylation of 1 equivalent of e-rhodomycinone with one eq. of 1- O-tert.-butyldimethylEilyldaunosamine derivative as donor that a-daunosaminylrhodomycinones are selectively formed in high yield. In this synthesis of the a-glycosylanthracyclinones, 3 eq. of glycosylation component, nitrobenzoyl-3-N-trifluoroacetyl-a-L-daunosaminyl r_ C^Y I 3 chloride) were formerly required.

Building on this knowledge, the aim has been set for the present invention of developing a novel process for the glycosylation of anthracyclinones using sugars.

This aim is achieved according to the invention by the process for the preparation of an anthracycline of the formula I RI 0 OH R3

S***H

0o 4 S0 OH I I 9 9 0* 10 in which

R

1 is H or OH 0 l4

R

2 is H, OH or OCH, R3 is H, COOCH 3 OH or an O--acyl protecting group

R

4 is CH 2

CH

3

COCH

3

COCH

2 OH or a CO-CH 2 O-acyl protecting 0* 15 group

R

s is NH 2 an NH-acyl protecting group, OH or an O-acyl protecting group

R

6 is H, OH, an O-acyl protecting group, NH 2 or an NHacyl protecting group

R

7 is H, OH or an O-acyl protecting group.

An acyl protecting group is understood as meaning an acyl group customary in carbohydrate chemistry, which is derived from a C 1

-C

4 -alkanoic acid, mono-, di- or trihaloacetic acid or benzoic acid.

-4 An acyl protecting group is preferably acetyl, mono-, dior trihaloacetyl where halogen fluorine or chlorine, or benzoyl or p-nitrobenzoyl.

Preferred compounds of the formula I are those in which

R

1

R

2

R

3

R

6 and R 7 retain their above-defined meaning, an acyl protecting group being acetyl, chloroacetyl, trifluoroacetyl or p-nitrobenzoyl.

The compounds of the formula I may optionally be present as ammonium salts.

1 '10 i t a 1 The process according to tion of a compound of the anthracyclinone compound the invention for the preparaformula I comprises reacting an of the formula II I i I I t it a tat' I t 4a i* 4 t ta tat a cal 0 4 a a1 in which 15 R 1 is H or OH

R

2 is H, OH or OCH 3

R

3 is H, COOCH 3 or an O-acyl protecting group and

R

4 is CHCH 3 COCHa, or a CO-CH 2 -O-acyl protecting group, with a functionalized carbohydrate building block of the formula III 3C 0 O-Si-R 9 Rio R6

R

III

5 in which

R

5 is an NH-acyl protecting group or an 0-acyl protecting group

R

6 is H, an NH-acyl protecting group or an O-acyl protecting group

R

7 is H or an O-acyl protecting group and

R

8 ,R and R 10 are (Ci-C 4 )-alkyl, an acyl protecting group for amino groupe preferably -eing trifluoroacetyl and for hydroxyl groups preferably being acetyl, trifluoroacetyl, chloroacetyl or p-nitrobenzoyl, in the presence of a promoter such as a trifluoromethanesulfonic acid tri-(Ci-C 4 )-alkylsilyl ester or anhydride or BF 3 .ether, in an anhydrous organic solvent, if desired in the presence of a base or of an acid entrainer and a drying agent at -50 0 C to 25 0 C to give a 1 2 compound of the formula I in which the radicals R R 2

R

3

R

4

R

5

R

6 and R 7 retain the meaning defined above and S" if appropriate deacylating these compounds preferably by means of an alkali liquor or an alcoholate to give cytostatically active compounds of the formula I in which R is H or OH

R

2 is H, OH or OCH 3

R

3 is H, COOCH 3 or OH 25 R 4 is CH 2

CH

3

COCH

3 or COCHzOH R is NH 2 or OH

R

6 is H, OH or NH, and o R 7 is H or OH.

SIn detail, the procedure in this case is as follows: A glycosyl donor of the formula III is prepared starting from a carbohydrate precursor, which contains one free hydroxyl group on the C1 atom, and a tri-(Ci-C 4 )-alkylsilyl halide in the presence of an organic base such as pyridine or imidazole and an organic solvent such as dichloromethane or dichloroethane at 20"-60 C.

I_ _I_ _Y~1_ 6 i The preparation of trimethylsilyl and tert.butyl(dimethyl)silyl derivatives of the formula III is particularly preferred in this case.

1 eq. to 1.5 eq. of glycosyl donor of the formula III are i 5 as a rule required for the glycosylation of 1 eq. of fi anthracyclinone. Trifluoromethanesulfonic acid tri-(Ci-

SC

4 )-alkylsilyl ester, preferably trimethylsilyl trifluoromethanesulfonate or tert.butyl(dimethyl)silyl trifiuoromethanesulfonate, or BF 3 -ether is preferably employed as the promoter. The glycosylation is carried Sout in an anhydrous organic solvent such as dichloro- S; methane, dichloroethane, ether, toluene, acetonitrile or mixtures thereof with acetone or ethyl acetate, as a rule in the presence of a drying agent such as a molecular i 15 sieve or barium sulfate at -70 0 C to 25"C, preferably at 50 0 C to -20"C. When using trifluoromethanesulfonic anhydride as the promoter, an organic base such as triethylamine or dimethylaminopyridine may be added.

The deacylation of the glycoside products is carried out S° 20 by means of an alkali metal base such as NaOH or an alcoholate such as sodium methylate.

The following examples illustrate the process according to the invention without the latter being restricted to the compounds mentioned in the examples.

C

7

EXAMPLES

EXAMPLE 1 Preparation of ,hcarhydrat. building blocks Methyl 4-O-p-nitrobenzoyl-2,3,6-tridesoxy-3-trifluoroacetamido-a-L-lyxohexopyranoside (Compound 1) 61 g (237 mmol) of methyl 3-N-trifluoroacetyldaunossminide were dissolved in 840 ml of dichloromethane/pyridine and 33 g (177 mmol) of p-nitrobenzoyl chloride were added. The reaction mixture was stirred at 35 0 C for 3 h, 10 then evaporated in vacuo and redistilled with toluene.

The residue dissolved in 600 ml of dichloromethane was ooo washed with 0.1 N HC1, then with water. The organic phase 0 was dried over sodium sulfate and evaporated. The crude product was purified by column chromatography on 600 g of 0o 15 silica gel (eluent: chloroform/ethyl acetate 15:1).

Yield: 92 g (95 Rf 0.76 (6:1 CHC1,/EtOAc; melting point: 65-67 0 C; -183C (c 1.03, chloroform).

4-0-p-Nitrobenzoyl-2,3,6-tridesoxy-3-trifluoroacetamido- L-lyxohexopyranose (Compound 2) 25 g (61.5 mmol) of methyl 4-0-p-nitrobenzoyl-3-N-tri- .o fluoroacetyl-a-L-daunosaminide were suspended in 250 ml of 30 strength trifluoroacetic acid. The reaction mixture was kept under reflux for 10 min. The cooled .reaction solution was extracted twice with ethyl acetate.

25 The organic phase was washed with phosphate buffer (0.1 mol of KH 2

PO

4 adjusted to pH 7.5 with 0.1 mol of NaOH), then with water and dried over sodium sulphate.

After evaporating the filtrate, the residue (21 g) was crystallized from ether. The mother liquor (6 g) was purified by column chromatography on 100 g of silica gel (eluent: chloroform/ethyl acetate Yield: 17.4 g (72.4 Rf 0.21 (9:1 CHCl 3 /EtOAc); melting point: 213°C; -1920 (c 0.86, EtOAc).

8 't4" *I I., 3,4-Bis-(trifluoroacetylamino)-2,3,4,6-tetradeboxy-Llyxohexopyranose (Compound 3) Benzyl 3,4-bis-(trifluoroacetylamino)-2,3,4,6-tetradesoxy-a-L-lyxohexopyranoside (6.5 g) was dissolved in glacial acetic acid and hydrogenated in the presence of strength Pd/C (6.5 g) for 48 hours. The mixture was then filtered and the filtrate was evaporated in vacuo.

The residue was redistilled with 2:1 methanol/toluene.

The resulting product was purified by column chromatography on silica gel (120 g) using 3:1 dichloromethanemethanol. Yield: 4.39 g; [a]D -63.3° (c 1, EtOAc).

2,6-Didesoxy-3,4-di-O-p-nitiobenzoyl-L-lyxohexopyranose (Compound 4) 2,3-Didesoxy-1,3,4-tri-O-p-nitrobenzoyl-a and P-L-lyxohexopyranose (2.5 g, 4.2 mmol) was dissolved in methanol ml) and aminated silica gel (Merck, 3 g) was added.

The reaction mixture was stirred at room temperature for 3 hours and then filtered. After evaporating the filtrate, the residue was dissolved in dichloromethane 20 (120 ml) and washed with phosphate buffer (pH 8, 60 ml x then with water. The organic phase was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (130 g) using 7:1 dichloromethane-acetone Yield: 1.42 g (76

IJ

i:, j j: i -i I i j a ;c" -q &r Example 2 Preparation of 1-0-trialkylsilylcarbohydrate derivatives 4-O-p-Nitrobenzoyl-2,3,6-tridesoxy-3-trifluoroacetamido- (compound 4.6 g (11.7 mmol) of 4-O-p-Nitrobenzoyl-2,3,6-tridesoxy- 3-trifluoroacetamido-L-lyxohexopyranose were dissolved in ml of pyridine/dichloromethane and 4.46 ml (35.1 mmol) of trimethylsilyl chloride were added at O0C.

After 16 h, 100 ml of dichloromethane were added to the reaction mixture, which was washed twice with 200 ml of 94 phosphate buffer (pH 7.5) each time. The organic phase was dried over sodium sulfate and evaporated in vacuo.

The residue was additionally redistilled with toluene.

The crude product, dried in a high vacuum, was purified by column chromatography on 100 g of silica gel (eluent: dichloromethane/petroleum ether/acetone Yield: 5.07 g (93.3 1-0-t-Butyl-dimethylsilyl-4-0-p-nitrobenzoyl-2,3,6tridesoxy-3-trifluoroacetamido-p-L-lyxohexopyranose (Compound 6) 4.05 g (10.3 mmol) of 4-O-p-Nitrobenzoyl-3-N-trifluoroacetyl-L-daunosamine were dissolved in 160 ml of pyridine/1,2-dichloroethane and 7.7 g (51.5 mmol) of t-butyl- 0000 dimethylsilyl chloride were added. After stirring at 15 for 16 h, the reaction mixture was diluted with 200 ml of 9000 dichloromethane and washed twice with phosphate buffer mol of KH 2

PO

4 adjusted to pH 7.5 with 0.1 mol of NaOH) with re-extraction of the aqueous phase. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was redistilled several times with toluene until pyridine was no longer present, then 00 purified by column chromatography on 150 g of silica gel 00 0 (eluent:petroleumether/dichloromethane/acetone 10:10:1).

Yield: 4.7 g (90.3 Rf 0.43 (10:10:1 chloroform/pet- 25 roleum ether/acetone); inclting point: 72-74C; -91o 000000 S0 (c 1, chloroform).

OV

3,4-Bis-(trifluoroacetylamino)-1-0-tert.-butyl(dimethyl)- '**silyl-2,3,4,6-tetra-desoxy-L-lyxohexopyranose (Compound 7) Starting from 3,4-bis-(trifluoroacetylamino)-2,3,4,6tetradesoxy-I-lyxohexopyranose and tert. -butyl (diemthyl) silyl chloride, the title compound was synthesized by the procedure for the preparation of compound 6.

2,6-Didesoxy-3,4-di-O-p-nitrobenzoyl-1-0-tert.-butyl(dimethyl)silyl-L-lyxohexopyranose (Compound 8) The title compound was prepared by the procedure for the I- c- l -i~ 10 synthesis of compound 6 starting from 2,6-didesoxy-3,4di-O-p-nitrobenzoyl-L-lyxohexopyranose and tert.-butyl- (dimethyl)silyl chloride.

Example 3 Preparation of 7-O-trimethylsilyl-e-(iso)rhodomycincnes 7-O-Trimethylsilyl-e-rhodomycinone (Compound 9) 200 mg (0.429 mmol) of e-rhodomycinone (92 by HPLC) were dissolved in 10 ml of pyridine/dichloromethane and 0.180 ml (1.40 mmol) of trimethylsilyl chloride was added at 0°C. After stirring for 30 min, the reaction mixture was diluted with 20 ml of dichloromethane and washed twice with phosphate buffer (pH The trganic phase was dried over sodium sulfate and then evaporated, and the residue was redistilled with toluene to remove 15 pyridine residues. The acid-sensitive product was purified by column chromatography on 20 g of silica gel (eluent: chloroform/triethylamine 200:1). Yield: 180.6 mg (84 [a]D +2790 (c 0.037, chloroform).

I 7-O-Trimethylsilyl- -isorhodomycinone (Compound 200 mg (0.45 mmol) of e-isorhodomycinone were dissolved in 10 ml of pyridine/dichloromethane and 0.180 ml i,(1.398 mmol) of trimethylsilyl chloride was added at 0°C.

After stirring for 30 min, the reaction mixture was diluted with 20 ml of dichloromethane and washed twice 25 with phosphate buffer (pH The organic phase was dried over sodium sulfate, then evaporated in vacuo. The residue was redistilled with toluene to remove pyridine residues. The acid-sensitive product was purified by column chromatography on 20 g of silica gel (eluent: chloroform/triethylamine (200:1). Yield: 180 mg (82 [a]D +326' (c 0.0061, chloroform).

Example 4 Glycosylation of anthracyclinones with functionalized

R

2 is H, OH or OCH 3

R

3 is H, COOCH 3 OH or an O-acyl protecting group

R

4 is CH 2

CH

3

COCH

3

COCH

2 0H or a COCH20-acyl protecting group R is NH 2 an NH-acyl protecting group, OH or an Oacyl protecting group ./2

S

11 4* '4 44s 4l~ carbohydrate building blocks 7-0-(4-O-p-Nitrobenzoyl-2,3,6-tridesoxy-3-trifluoroacetylamino-a-L-lyxohexopyranosyl)-e-isorhodomycinone (Compound 11) e-Isorhodomycinone (6.0 g, 11.2 mmol), daunosamine donor (compound 6, 8.51 g, 16.8 mmol) and molecular sieve 4 A g) were suspended in L.1 dichloromethane-ethyl acetate (700 ml) under protective gas. After the addition of trimethylsilyl trifluoromethanesulfonate (4.97 g, 22.4 mmol) at -35 0 C, the reaction mixture was stirred for hours. Triethylamine (10 il) was added to the cooled mixture, which was filtered. The filtrate was washed twice with citrate buffer (0.1 molar citric acid solution adjusted to pH 5 with 0.1 molar NaOH), then with icewater. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue (12.6 g) was purified by column chromatography on silica gel (450 g) using 200:10:1 chloroform-ethyl acetate-formic acid. Yield: 7.15 g (78 Rf 0.33 (solvent see above).

I S 55 t C I zz I I t 1 5 S I t f e i t 7-0-(4-O-p-Nitrobenzoyl-2,3,6-tridesoxy-3-trifluoroacetylamino-a-L-lyxohexopyranosyl)-e-rhodomycinone (Compound 12) The title compound 12 was synthesized by the procedure for the preparation c compound 11 starting from 25 e-rhodomycinone and daunosamine donor (compound 6).

7-O-(4-0-p-Nitrobenzoyl-2,3,6-tridesoxy-3-trifluoroacetylamino-a-L-lyxohexopyranosyl)-daunomycinone (Compound 13) The title compound 13 was prepared by the procedure for the synthesis of compound 11 starting from daunomyrinone and daunosamine donor (compound 6).

7-0-(3,4-Bis-(trifluoroacetylamino)-2,3,4,6-tetra-desoxya-L-lyxohexopyranosyl)-4-0-methyl-10-O-p-nitrobenzoyl-prhodomycinone (Compound 14) 4-0-Methyl-10-O-p-nitrobenzoyl- -rhodomycinone (2.64 g, 4.80 mmol), 3,4-bis-trifluoroacetylamino sugar (compound protecting group

R

7 is H or an O-acyl protecting group and

R

8

R

9 and R 10 are (C,-C 4 )-alkyl, in the presence of a promoter in an anhydrous organic solvent, if desired in the presence of a base or of an acid entrainer and a drying agent at -50C to 25°C to 3 12 7, 2.17 g, 4.80 mmol) and 4 A molecular sieve (3.0 g) were dissolved in dichloromethane (220 ml) and. trimethylsilyl triflate (1.2 ml) were added at -35 0 C. The reaction mixture was stirred at -35°C for 3 hours, then triethylamine (2.5 ml) was added and the mixture was filtered.

The filtrate was washed with phosphate buffer (pH 7, ml x then with water, dried (sodium sulfate) and evaporated in vacuo. The residue was purified by column chromatography on silica gel (220 g) using 15:1 chloroform-acetone. Yield: 3.38 g (81 Rf 0.37 (15:1 chloroform-acetone); melting point: 222"C; alpha D 250" (c 0.05, chloroform).

a 7-0-(3,4-Bis-0-p-nitrobenzoyl-2, 6-didesoxy-alpha-L-olyxo- .hexopyranosyl)-4-0-methyl-1-0-0--nitrobenzoyl-p-rhodomycinone (Compound The title compound was synthesized by the procedure for the preparation of compound 14 starting from 2-desoxyfucose donor (compound 8) and 4-O-methyl-10-O-p-nitrobenzoyl-A-rhodomycinone.

20 Example Deblocking of anthracyclines The anthracycline derivatives described in Example 4 were deblocked by known processes, as described in the following general procedure: Protected anthracycline compound was dissolved in methanol or chloroform-methanol and 1 N NaOH was added at 0°C.

After the reaction had taken place, the reaction mixture was neutralized with 1 N HC1. After the customary workup, the deblocked compound was purified on RP-18 silica gel or amino silica gel.

The following compounds were prepared by this procedure: -13- (3-Amino-2, 3, 6-tridesoxy-alpha-L-lyxohexopyranosyl) c-isorhodomycinone (Compound 16) (3-Amino-2, 3, 6-tridesoxy-alpha-L-lyxohexopyranosyl) V c-rhodomycinone (Compound 17) 7-0- (3-Amino-2 ,3,6-tridesoxy-a-L-1yxchexopyranosy1)daunomycinone (Compound 18) 4-Diamino-2, 3,4, 6-t etra-desoxy-cr-L-lyxo~hexopyranosyl) -4-0-methy1-p-rhodomycinone (Compound 19) 6-Didesoxy-a-L-lyxohexopyranosy1) ,I slt10 rhodomycinone (Compound aIt a I'll

Claims

1. A process for the formula I the preparation of an anthracycline of R 0 OH R3 OH I I in which R 1 is H or OH R 2 is H, OH or OCH 3 R 3 is H, COOCH 3 OH or an O-acyl protecting group R 4 is CH 2 CHa, COCHa, COCH20H or a COCH 2 O-acyl protect- ing group R 5 is NH 2 an NH-acyl protecting group, OH or an 0- acyl protecting group R 6 is H, OH, an O-acyl protecting group, NH 2 or an NH-acyl protecting group R 7 is H, OH or an O-acyl protecting group, which comprises reacting an anthracyclinone compound S. of the formula II e in which R is H or OH R 2 is H, OH or OCH 3 R is H, COOCH 3 or an O-acyl protecting group and R is CH 2 CH 3 COCH 3 or a COCH 2 -O-acyl protecting I group, with a functionalized carbohydrate building block of the formula III H O-Si--R 9 H3O 9I i Ro 1 0 Rs i 6 in which R 5 is an NH-acyl protecting group or an O-acyl protecting group 4 R 6 is H, an NH-acyl protecting group or an O-acyl protecting group R 7 is H or an 0-acyl protecting group and R 8 R 9 and R 10 are (C-C 4 )-alkyl, in the presence of a promoter in an anhydrous organic solvent, if desired in the presence of a base or of an Sacid entrainer and a drying agent at -50 0 C to 25°C to give a compound of the formula I in which the radicals R 1 R R 3 R 4 R s R 6 and R 7 retain the meaning defined above for the formulae II and III and if appropriate deacylating these compounds to give cytostatically iactive compounds of the formula I in which R 1 is H or OH R 2 is H, OH or OCH 3 R 3 is H, COOCH 3 or OH R 4 is CH 2 CH 3 COCH 3 or COCH 2 0H R 5 is NH 2 or OH R 6 is H, OH or NH 2 and R 7 is H or OH. 1 equivalent of e-rhodomycinone with one eq. of 1- 0-tert.-butyldimethylsilyldaunosamine derivative as donor that a-daunosaminylrhodomycinones are selectively formed in high yield. In this synthesis of the a-glycosylanthra- cyclinones, 3 eq. of glycosylation component, nitrobenzoyl-3-N-trifluoroacetyl-a-L-daunosaminyl 16 16

2. The process as claimed in claim 1, wherein a compound of the formula I, in which R 1 is H or OH R 2 is H, OH or OCH 3 R 3 is H, COOCH 3 OH or an O-acyl protecting group R 4 is CH 2 CH 3 COCH 3 or a COCH-acyl protecting group R 5 is an NH-acyl protecting group or an 0-acyl protecting group R 6 is H,an O-acyl protecting group or an NH-acyl So protecting group v o o R 7 is H or an O-acyl protecting group is prepared.

3. The process as claimed in at least one of claims 1 and 2, wherein an acyl protecting yroup is an acetyl, mono-, di- or trihaloacetyl group where halogen fluorine or chlorine, or a benzoyl or p-nitrobenzoyl group. $tit

4. The process as claimed in at least one of claims 1 and 2, wherein a trifluoroacetyl group is used as an acyl protecting group for amino groups and an acetyl, r. chloroacetyl, trifluoroacetyl, benzoyl or p-nitro- benzoyl group is used as a protect,ng group for hydroxyl groups.

The process as claimed in claim 1, wherein trifluoro- methanesulfonic acid tri-(Ci-C 4 )-alkylsilyl ester or anhydride or BF 3 -ether is used as the promoter.

6. The process as claimed in claim 1, wherein trimethyl- silyl or tert.butyl(dimethyl)silyl trifluoromethane- sulfonate is used as the promoter.

7. The process as claimed in claim 1, wherein dichloro- methane, dichloroethane, ether, toluene, acetonitrile or one of their mixtures with acetone or ethyl acetate r 1. 17 is used as the organic solvent.

8. The process as claimed in claim 1, wherein deacylation is carried out by means of an alkali liquor or an alcoholate.

9. Functionalized carbohydrate building blocks of the formula III in which R 5 is an NH-acyl protecting group or an O-acyl protecting group R e is H, an NH-acyl protecting group or an 0-acyl protecting group R is H or an O-acyl protecting group and R 8 R 9 and R 10 are (Ci-C,)-alkyl, an acyl protecting group for amino groups being tri- fluoroacetyl and for hydroxyl groups being acetyl, chloroacetyl, trifluoroacetyl, benzoyl or p-nitro- benzoyl. I DATED this 21st day of December 1990. BEHRINGWERKE AKTIENGESELLSCHAFT WATERMARK PATENT TRADEMARK ATTORNEYS I "THE ATRIUM" 1 290 BURWOOD ROAD HAWTHORN. VIC. 3122. I