The Paternò-Büchi Reaction Diversifies Rifamycin Scaffolds and Enhances Antibacterial Activity.

Abstract

Rifamycins display structural diversity and broad bioactivities, with the intrinsic reactivity of their polyketide chain and quinone ring providing a foundation for photochemical reactions. Herein, we constructed the mutant strain Δrif-orf3_16::rifR+rif-orf19 by deleting post-PKS modification genes of rifamycin, yielding 34a-deoxyrifamycin W (1a) and its derivatives (2a-4a). Subsequent sunlight irradiation of these compounds triggered an intramolecular Paternò-Büchi reaction coupled with Michael addition, producing oxetane-rifamycins A-D (1b-4b). They feature a unique 4/6/6/6/6/17 hexacyclic scaffold and exhibit potent anti-MRSA activity. Density functional theory (DFT) calculations elucidated the formation mechanism of the oxetane-rifamycin scaffold.