Stereochemical variations on the colchicine motif. Peracid oxidation of thiocolchicone. Synthesis, conformation and inhibition of microtubule assembly

Abstract

When 7-oxodesacetamidothiocolchicine (1) was treated with various peroxides in order to afford a Baeyer–Villiger rearrangement, a complex mixture of products was formed, which included the sulfoxide, (2) and sulfone, (3). When peracetic acid was used two additional products were formed; a C-ring lactone (4) and a ring-contracted allocolchicine derivative (5). The sulfoxide (2) was semi-preparatively resolved into enantiomers by chromatography on microcrystalline triacetylcellulose. Rotational barriers around the A–C pivot bond of 2, 4 and 5 were determined by dynamic ¹H NMR analysis. The compounds 2, 3, 4 and 7a exhibit moderate inhibition of tubulin polymerization, according to in vitro turbidity studies, whereas 5 was inactive.