Unified Chemical Synthesis of Corynanthe-Sarpagine-Ajmaline Type Monoterpene Indole Alkaloids: A Biomimetic Approach

The biosynthesis and chemical synthesis of corynanthe-sarpagine-ajmaline type monoterpene indole alkaloids, which share a close structural relationship, have presented key challenges in this field for decades. Herein, we present a biomimetic synthesis strategy inspired by biosynthetic hypotheses, successfully achieving a unified chemical synthesis of various corynanthe-sarpagine-ajmaline type polycyclic alkaloids. The success of this approach is attributed to (1) the rapid construction of chemically synthesized intermediates that closely resemble universally accepted biosynthetic intermediates via a sequence of formal Michael addition and <i>retro</i>-Michael addition reactions; (2) the efficient synthesis of the key indole-fused <i>aza</i>-bicyclic [3.3.1]-nonane framework in the target molecules through regioselective oxidative dehydrogenation and intramolecular biomimetic Mannich cyclization for the first time; (3) leveraging TMSI-mediated intramolecular lactone cleavage/intramolecular N-alkylation cascade reaction to create the rigid 1-<i>aza</i> bicyclic [2.2.2]-octane system in the target molecules, with selectivity controlled by the reaction solvent.