A Pull-Apart Strategy for Synthetic Rifamycins

Abstract

A practical synthetic strategy for the preparation of rifamycin analogues has been developed, enabling access to the first compound modified at the critical enol ether–ketal linkage with demonstrated antimicrobial activity. Leveraging a deconstruction strategy, the rifamycin ansa chain can be isolated and selectively modified to reveal a hydroxyl group at O6, providing a handle for structural diversification. In parallel, a synthesis of the naphthoquinone core, highlighted by a biomimetic oxidative cyclization of a polypropionate precursor, furnished the complete C1–C13 fragment. Reunion of these fragments provided a new rifamycin analog, denoted rifalene M, in which the synthetically challenging enol ether motif is replaced with a simple allylic linkage and retains antimicrobial activity.