Ring expansion approach for the synthesis of the (3S,4S)-hexahydroazepine core of balanol and ophiocordin

Abstract

A new and efficient formal total synthesis of (3S,4S)-balanol, a potent protein kinase C inhibitor, was accomplished from tri-O-acetyl-D-glucal. Balanol and ophiocordin consists of a chiral hexahydro azepine-containing fragment and a benzophenone fragment. The azepine core was prepared in chiral form through intramolecular aza Wittig reaction. A triphenylphosphine mediated ring expansion process was employed to form the seven-membered nitrogen heterocycle. The aldehyde equivalent key intermediate was treated with triphenylphosphine to give the azepine core. To demonstrate the applicability of the new route, a synthesis of the balanol is described.