Methods and compositions for the manufacture of C-3′ and C-4′ anthracycline antibiotics

A substituted anthracycline having the formula:

• wherein, R1 denotes an alkyl chain, a (—COCH2R13) group or a (C(OH)—CH2R13);
• wherein, R13 is a hydrogen (—H) group, a hydroxyl group (—OH);
• a methoxy group (—OCH3), an alkoxy group having 1-20 carbon atoms, an alkyl group having 1-20 carbon atoms, an aryl group having 1-20 carbon atoms, a fatty acyl group having the general structure —O—CO(CH2)nCH3, wherein n=an integer from 1 to about 20, a fatty acyl group having the general structure —O—CO(CH2)l(CH═CH)m(CH2)nCH3, wherein 1 is an integer between 1 to 3, m is an integer between 1 and 6, and n is an integer between 1 and 9, —OCO—(CH2)n—CH2NH2, or OCO—(CH2)n—CO2H;
• each of R2 and R3 is, independently of the other, a hydrogen (—H), a hydroxyl group (—OH) or a methoxy group (—OCH3);
• R4 is a hydrogen (—H) group, a methoxy group (—OCH3), a hydroxyl group (—OH) or a halide;
• each of Y1 and Y2 is, independently of the other, a double bonded oxygen, sulphur, or nitrogen atom;
• Z is a —H, —OH, a —CO2H group or a —CO2R group;
• R5, R6, are, independently, —H, —OH, a halide, —OR19, —SH, —SR19, —NH2, —NHR19, —N(R19)2 or —CH3, and R can additionally be a an alkylating moiety, wherein R19 an alkyl chain, an alkylating moiety, a cycloalkyl chain, a cyclic ring, or a hydrogen;
• R9 is an —H, —CH3, alkyl, aryl, CH2OH, or a CH2F group;
• R10, R11 and R12 are, independently, —H, —OH, a halide, —OR, —SH, —SR, —NH2, —NHR, —N(R)2, or —CH3;
• one of R7 and R8 is a —H;
• one of R7 and R8 is a X-alkyl-aromatic-ring (—XAAR) substituent, wherein, A is an alkyl group and wherein, AR is an unsubstituted phenyl ring, substituted phenyl ring, a substituted five-member ring or a heteroatomic five-member ring, of the general form;
• wherein, R14-R18 are independently a (—H) group, a hydroxyl group (—OH), a methoxy group (—OCH3), a nitro group (—NO2), an amine group (—NH2), a halide, an alkoxy group having 1-20 carbon atoms, an alkyl group having 1-20 carbon atoms, an aryl group having 1-20 carbon atoms, an alkyl-amino group, an alkyl-thio group, a cyano group (CN, SCN), an —CO2H group or an —CO2R group;
• and
• the aromatic ring may be disubstituted, trisubstituted, tetrasubstituted or pentasubstituted;
• and
• X is a —O, —N, —S, —SO or —SO2 group;
• and
• A is (CH2)n where n=0-10;
• wherein, if R7 is a XAAR substituent R8 is not and if R8 is a XAAR substituent R7 is not.

A method for the synthesis of a 4′—O—benzylated sugar comprising:

• (a) obtaining a C4 acetylated sugar;
• and
• (b) directly benzylating the acetylated sugar at C4 with a benzyl group;
• wherein the benzylation of the acetylated sugar at C4 with a benzyl group produces a 4′—O—benzylated sugar.

A method for the synthesis of amine containing anthracyclines comprising:

• (a) obtaining a substituted sugar azide, wherein the azido substitution is at the 1′, 2′, 3′, 4′ or 5′ position on the sugar, said azide serving as a masked and neutral form of amine substituent;
• (b) subjecting said azide to a coupling reaction with an anthracyclinone;
• and
• (c) subjecting said azide to a reduction reaction;
• wherein an amine containing anthracycline is produced.