A fragmentation approach to a maytansine synthon: lithium dimethylcuprate-opening of substituted cyclohexene epoxides. X-Ray structure determination of ethyl t-2,3-epoxy-c-6-p-methoxybenzoyloxy-1-methylcyclohexane-r-1-carboxylate

Abstract

A scheme for the synthesis of maytansine synthons (3) is proposed. As background to this work, the stereoselective synthesis of several cyclohexene epoxides and their reactions with lithium dimethylcuprate are described. The sterically hindered cyclohexadiene monoepoxide (10) and the hydroxycyclohexene epoxide (13) were unreactive towards the cuprate reagent. However, epoxidation of the c-6-hydroxy-1-methylcyclohex-2-ene-r-1-carboxylate derivatives (18)–(23) gave, selectively, the trans-epoxides (24)–(29) which reacted regioselectively with lithium dimethylcuprate to give the alcohols (37)–(39). Epoxidations of the c-6-acyloxy-t-2-hydroxy-1-methylcyclohex-3-ene-r-1-carboxylates (44)–(46) were not stereoselective, whereas methyl c-6-benzyloxy-c-4-methoxy-1-methylcyclohex-2-ene-r-1-carboxylate (55) gave the trans-epoxide (56) which was converted into the alcohol (57) on treatment with lithium dimethylcuprate. Sodium borohydride reduction of the ketone (58) gave the cis-alcohol (59) which, on epoxidation and treatment with lithium dimethylcuprate, gave the lactone (61).

The structure of the major epoxide (28) obtained on epoxidation of ethyl c-6-p-methoxybenzoyloxy-1-methylcyclohex-2-ene-r-1-carboxylate (22) was confirmed by an X-ray structure determination.