Biocatalytic Oxidative [3 + 2] Cycloaddition Enables Divergent Synthesis of (-)-α-Cyclopiazonic Acid and Derived Alkaloids.

The asymmetric construction of highly congested polycyclic architectures remains a formidable challenge in chemical synthesis. Biocatalysis offers exquisite stereocontrol, yet the repertoire of enzyme-catalyzed cycloadditions remains notably limited. Here, we elucidate the intriguing oxidative [3 + 2] cycloaddition capability of a flavoenzyme CpaO and develop it as a robust biocatalyst for asymmetric construction of the pentacyclic scaffold of (-)-α-Cyclopiazonic acid ((-)-α-CPA), a nanomolar inhibitor of sarco/endoplasmic reticulum calcium(II)-dependent ATPase. This work presents not only the most concise, scalable, and fully asymmetric synthesis of (-)-α-CPA to date but also unlocks the collective access to its highly oxidized, structurally diverse family members, thereby enriching the scenarios of enzyme-catalyzed bonding strategies in natural product synthesis.