Merging Chemo- and Biocatalysis to Facilitate the Syntheses of Complex Natural Products: Enantioselective Construction of an N‑Bridged [3.3.1] Ring System in Indole Terpenoids

Although the molecular structural motif of indole-fused azabicyclo[3.3.1]­nonane is common in biologically significant natural products, its catalytic asymmetric synthesis remains underexplored. Herein, we report a catalytic approach for the formal synthesis of more than 20 types of sarpagine/macroline alkaloids. Two key steps are the amide insertion reaction using a metal-carbene species based on cheap copper and biocatalytic asymmetric desymmetrization, producing the desired chiral N-bridged [3.3.1] scaffold. The enzymatic step proceeds highly enantioselectively when using lipase from Candida rugosa, which turned out to be the best for breaking the symmetry. Late-stage introduction of an indole unit with functionalities then established a diversity-oriented synthetic pathway toward indole terpenoid variants.