Stereochemical variations on the colchicine motif. Part 4. A remote metalation approach toward a colchicine analog with a five-membered B-ring.
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.
Berg
U
U
Department of Chemistry, Lund University, Sweden.
Bladh
H
H
D003078:Colchicine / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013237:Stereoisomerism; D013816:Thermodynamics; D014404:Tubulin / Q000378:metabolism
D014404:Tubulin; D003078:Colchicine