Studies toward Pestalachloride B: Synthesis of the 6/7/6 Tricyclic Scaffold

Antibiotic therapy is a critical part of modern healthcare, and the discovery of antibiotics with novel mechanisms of action is needed to combat the rise of antimicrobial resistance. Pestalachloride B, isolated from Pestalotiopsis adusta, is a compound belonging to the pestalone family of natural products which demonstrates potent and selective antimicrobial activity against clinically relevant, antimicrobial-resistant Gram-positive bacteria. Here, we report the first synthetic studies focused specifically on pestalachloride B. Two key disconnections were evaluated for the construction of the rare 6/7/6 tricyclic scaffold, and a key intramolecular Parham-type cyclization was found to afford the desired scaffold in 74% yield, enabling us to obtain a late-stage intermediate bearing the complete pestalachloride B framework in 8% overall yield over 11 steps.