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 <i>Pestalotiopsis adusta</i>, 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.