Synthesis of cyclo-bis[7α, 12α-diacetoxy-3β-dicyanomethyl-3α-(4-methylenephenyl)cholanamide]; a cholaphane with reduced flexibility and externally-directed functionality

Abstract

A second ‘cholaphane’ framework is manifested in the title compound 8, which has been prepared from methyl 3α,7α, 12α-triacetoxycholanoate 9 in 23% overall yield. The synthesis involves the Knoevenagel condensation of ketone 11 with malononitrile to give dicyanomethylene derivative 12, equatorialselective addition to the latter of an organocuprate derived from aryl bromide 15, conversion of the resulting adduct into amino acid 22, and cyclodimerisation. The framework of 8 has less conformational freedom and a better-defined cavity than the ‘first-generation’ cholaphanes 2, and also bears externallydirected functionality.