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

Compounds of general formula Ia

• 49
• 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.,
• 50
• Y stands for a group —NA1A2,
• whereby A1 and A2, independently of one another, stand for the radicals C1-C6 alkyl, such as methyl, ethyl, propyl, or aryl or aralkyl, such as phenyl, benzyl or —OH, —OMe, —O-benzyl or for a radical
• 51

Compounds of general formula Ib

• 52
• 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.,
• 53
• Y stands for a group —NA1A2,
• whereby A1 and A2, independently of one another, stand for the radicals C1-C6 alkyl, such as methyl, ethyl, propyl, or aryl or aralkyl, such as phenyl, benzyl or —OH, —OMe, —O-benzyl or for a radical
• 54

Compounds of general formula II,

• 55
• in which
• Y stands for a group —NA1A2,
• whereby A1 and A2, independently of one another, stand for the radicals C1-C6 alkyl, such as methyl, ethyl, propyl, or aryl or aralkyl, such as phenyl, benzyl or —OH, —OMe, —O-benzyl or for a radical
• 56

Compounds of general formula III

• 57
• in which
• R1 stands for an alcohol protective group, for example benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, THP, TBDMS, TMS, TES, TIP, TBDPS, MEM, MOM, allyl, trityl,
• Y stands for a group —NA 1A2,
• whereby A1 and A2, independently of one another, stand for the radicals C1-C6 alkyl, such as methyl, ethyl, propyl, or aryl or aralkyl, such as phenyl, benzyl or —OH, —OMe, —O-benzyl or for a radical
• 58

Compounds of general formula XII

• 59
• in which
• Y stands for a group —NA1A2,
• whereby A1 and A2, independently of one another, stand for the radicals C1-C6 alkyl, such as methyl, ethyl, propyl, or aryl or aralkyl, such as phenyl, benzyl or —OH, —OMe, —O-benzyl or for a radical
• 60
• and
• R4 stands for a C1-C6 alkyl, methyl, ethyl, tert-butyl, phenyl or benzyl group.

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

• 61
• wherein a racemic ester of general formula VI
• 62
• 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,
• Y stands for a group —NA1A2,
• whereby A1 and A2, independently of one another, stand for the radicals C1-C6 alkyl, such as methyl, ethyl, propyl, or aryl or aralkyl, such as phenyl, benzyl or —OH, —OMe, —O-benzyl or for a radical
• 63
• R3 stands for a C1-C6 alkyl group or an allyl, phenyl or benzyl group, is enantioselectively saponified by means of enzymatic reaction.

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

• 64
• 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,
• Y stands for a group —NA1A2,
• whereby A1 and A2, independently of one another, stand for the radicals C1-C6 alkyl, such as methyl, ethyl, propyl, or aryl or aralkyl, such as phenyl, benzyl or —OH, —OMe, —O-benzyl or for a radical
• 65
• wherein starting from the compounds of general formula VII, whereby radicals R1 and Y have the above meaning,
• 66
• a chiral reduction of the keto group is made.

Process for the production of the compounds of general formula XIII

• 67
• in which
• Y stands for a group —NA1A2,
• whereby A1 and A2, independently of one another, stand for the radicals C1-C6 alkyl, such as methyl, ethyl, propyl, or aryl or aralkyl, such as phenyl, benzyl or —OH, —OMe, —O-benzyl or for a radical
• 68
• and
• R4 stands for a C1-C6 alkyl, methyl, ethyl, tert-butyl, phenyl or benzyl group, wherein compounds of general formula XIV
• 69
• 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 compounds of general formula V
• 70
• in which
• Y stands for a group —NA1A2,
• whereby A1 and A2, independently of one another, stand for the radicals C1-C6 alkyl, such as methyl, ethyl, propyl, or aryl or aralkyl, such as phenyl, benzyl or —OH, —OMe, —O-benzyl or for a radical
• 71
• and
• L stands for a silyl protective group.

Process for the production of ketones of general formula A

• 81
• 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.,
• 82
• V stands for a C1-C5 alkyl or alkenyl radical,
• wherein compounds of general formula Ia
• 83
• 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.