Stereochemical variations on the colchicine motif. Part 4. A remote metalation approach toward a colchicine analog with a five-membered B-ring.

Abstract

Attempts to prepare a colchicine analog with a 5-membered B-ring by remote metalation of N,N-diethyl-3,4,5-trimethoxy-2-(5'-methoxy-4'-oxo-2', 5',7'-cycloheptatrienyl)-benzamide (2) led to ring contraction of the methoxytropone ring to the p-methoxycarbonylphenyl derivative (3). Dynamic 1H NMR investigations showed that the biaryl amide 2 exists as a mixture of diastereomers due to hindered rotation around both aryl-aryl and aryl-amide bonds, with rotational barriers of ca. 63 kJ mol-1. The colchicine and allocolchicine analogs 2 and 3 do not notably affect tubulin polymerization, despite the structural similarities with active analogs. The reduced tubulin binding activity of 2 and 3 may be a result of increasing steric bulk.