Total Synthesis of (-)-Protulactone B and Assessment of Its Antibacterial and Antifungal Activity.

A total synthesis of the structurally unique fungal metabolite (-)-protulactone B is reported. The convergent strategy is based on methyl α-l-rhamnopyranoside as a chiral pool starting material. A novel method for the stereoselective inversion of the C3 configuration of the rhamnoside precursor was developed, proceeding through a cyclic carbonate intermediate. Furthermore, an unprecedented, one-pot transformation mediated by dibutyltin oxide was discovered, enabling chemoselective cleavage of a cyclic carbonate with concurrent formation of a six-membered δ-lactone. This efficient sequence (8 longest linear steps, 20.2% overall yield) provided ample material for biological evaluation. The synthetic (-)-protulactone B exhibited selective antimicrobial activity against specific Gram-negative pathogens, a profile distinct from its inactive congener protulactone A. This work provides a practical synthetic route and novel methodologies that will facilitate further study of this natural product family.