Chemoenzymatic Synthesis of Unnatural Ergot Alkaloid, Demethyl Chanoclavine

Ergot alkaloids are a structurally complex family of bioactive natural products whose chemical diversification remains challenging. Here we report a concise three-step chemoenzymatic synthesis of the unnatural ergot alkaloid demethyl-chanoclavine, featuring a fused tricyclic indole skeleton with a free amine. The strategy integrates TrpB-catalyzed indole alkylation and a protecting-group-free Pd-catalyzed cross-coupling. Therefore, an efficient engineered EasC-catalyzed decarboxylative cyclization that forges the C5–C10 bond with high efficiency. Computer-aided stability engineering converted EasC into a suitable biocatalyst capable of accepting an unnatural substrate, increasing its catalytic activity by over 15-fold relative to the wild type. The optimized process proceeds under mild conditions. This work demonstrates the power of combining enzyme engineering with modern cross-coupling chemistry to enable efficient access to structurally complex unnatural ergot alkaloids.