Protected 3,-5-dihydroxy-2,2-dimethyl-valeronitriles for the synthesis of epothilones and epothilone derivatives and process for the production

Compounds of general formula Ia

• 48
• in which
• R1, R2 can be the same or different and, independently of one another, stand for an alcohol protective group, such as, e.g., benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, THP, TBDMS, TMS, TES, TIP, TBDPS, MEM, MOM, allyl, trityl,
• or, in the case when R1 and R2 are bridged, stand for a ketal protective group, such as, e.g.,
• 49

Compounds of general formula Ib

• 50
• in which
• R1, R2 can be the same or different and, independently of one another, stand for an alcohol protective group, such as, e.g., benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, THP, TBDMS, TMS, TES, TIP, TBDPS, MEM, MOM, allyl, trityl,
• or, in the case when R1 and R2 are bridged, stand for a ketal protective group, such as, e.g.,
• 51

Process for the production of optically active compounds of general formula IIIa,

• 55
• wherein a racemic ester of general formula VI
• 56
• in which
• R1 stands for an alcohol protective group, such as, e.g., benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, THP, TBDMS, TMS, TES, TIP, TBDPS, MEM, MOM, allyl, trityl, and
• R3 stands for a C1-C6 alkyl group or an allyl, phenyl or benzyl group, is enantioselectively saponified by means of enzymatic saponification.

Process for the production of optically active compounds of general formula IIIa

• 57
• in which
• R1 stands for an alcohol protective group, such as, e.g., benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, THP, TBDMS, TMS, TES, TIP, TBDPS, MEM, MOM, allyl, trityl, wherein starting from the compounds of formula VII
• 58
• a chiral reduction of the keto group is made.

Process for the production of the compounds of general formula XIII

• 59
• in which
• R4 stands for a C1-C6 alkyl, methyl, ethyl, tert-butyl, phenyl or benzyl group, wherein compounds of general formula XIV
• 60
• in which
• R4 stands for a C1-C6 alkyl, methyl, ethyl, tert-butyl, phenyl or benzyl group,
• Nu stands for a leaving group, such as Cl, Br, imidazole, —OPh, —O—C6H4NO2, —O—C1-C4 alkyl,
• are reacted with a compound of formula V
• 61

Process for the production of ketones of general formula A

• 69
• in which R1, R2
• can be the same or different and, independently of one another, stand for an alcohol protective group, such as, e.g., benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, THP, TBDMS, TMS, TES, TIP, TBDPS, MEM, MOM, allyl, trityl,
• or, in the case when R1 and R2 are bridged, stand for a ketal protective group, such as, e.g.,
• 70
• V stands for a C1-C5 alkyl or alkenyl radical,
• wherein compounds of general formula Ia
• 71
• are reacted with compounds of general formula B
• M-V (B)
• in which M stands for Li or MgCl, MgBr, or MgI,
• and then are worked up under aqueous hydrolysis.