We describe here the diastereocontrolled formal racemic syntheses of tricyclic marine alkaloids, lepadiformines A, B, and C as well as their C2 epimers, featuring divergent and stereoselective syntheses of the N-acetyl-8a-cyanodecahydroquinoline frameworks and the base-mediated intramolecular cyclization to establish the spiral quaternary center of the tricyclic framework from sterically well-defined α-aminonitrile 2. The approach allows us to accomplish the tricyclic core structure efficiently from readily available starting materials through simple operations. An unexpected pair of consecutive epimerizations at two contiguous stereocenters is observed on the basis of single-crystal X-ray analyses of the intermediates and derivatives. The findings have been successfully applied to the total synthesis of 2-epi-lepadiformine C. The epimerization mechanism has been elucidated through a series of deuterium-labelling-controlled experiments.

The total synthesis of tricyclic marine alkaloid fasicularin (1b) has been accomplished from a novel sterically well-defined α-aminonitrile 7, featuring a novel double consecutive epimerization process and Ir-catalyzed reductive functionalization of a tertiary γ-lactam. The required configuration is obtained through the thermodynamically stereoselectively driven isomerization of a readily available 8a-cyanodecahydroquinoline framework. The strategy allows us to achieve the tricyclic core structures efficiently from affordable starting materials through simple operations.