A new synthetic approach to biaryls of the rhazinilam type. Application to synthesis of three novel phenylpyridine-carbamate analogues

Abstract

The synthesis of three novel racemic phenylpyridine-carbamate analogues of rhazinilam and their biological evaluation as inhibitors of microtubule assembly and disassembly by interaction with tubulin are described. The sterically hindered ortho-disubstituted biaryl unit as the challenging key structural element is first obtained by a sequential regiocontrolled nucleophilic addition of a lithium ortho-lithiohomobenzylic alkoxide species to 3-bromo-5-oxazolyl pyridine as the electrophile and a subsequent oxidation step. The incorporation of the amino group by replacement of the bromide has been achieved using a Buchwald–Hartwig amination coupling. Ultimate deprotection steps furnished free-amino and free-hydroxyl appendages which were connected by phosgenation to furnish the nine-membered median carbamate ring.