Natural products. Antitubulin effect of congeners of <i>N</i>-acetylcolchinyl methyl ether: synthesis of optically active 5-acetamidodeaminocolchinyl methyl ether and of demethoxy analogues of deaminocolchinyl methyl ether

Abstract

Trimethoxy-substituted dihydrodibenzocycloheptenes 4–7, required for a structure–activity study measuring the inhibition of tubulin polymerization in vitro, were synthesized by four different routes: (1) Synthesis of 4 was achieved from 2,3-dimethoxybenzaldehyde via biphenyl aldehyde 17, chain lengthening to propionic acid 20, acid-catalyzed cyclization toward ketone 21, and removal of the carbonyl group. (2) Compound 5 was obtained by eliminating the sterically most hindered methoxy group in 25 or 26 by metal reduction in alcohol. (3) Compound 6 was prepared from biphenyl aldehyde 34 obtained by Grignard reaction on oxazoline 32. (4) Compound 7 was obtained by reductive deoxygenation of the tetrazolyl ether derivative of N-acetylcolchinol 41. The key role of the aromatic oxygen atoms in colchicine and allo congeners as points of interaction with the colchicine binding site on tubulin was demonstrated by the lack of inhibitory activity of compounds 4–7. Optically active 5-acetamide 8a,b isomers of N-acetylcolchinyl methyl ether 2 were obtained after chemical resolution of amine 47. The absolute configuration of the optical isomers 47a,b and 8a,b was determined by 1 H NMR and CD measurements. These compounds were found inactive as inhibitors of tubulin polymerization.