Concise Synthesis of (−)-Cycloclavine and (−)-5-epi-Cycloclavine via Asymmetric C–C Activation

To illustrate the synthetic significance of C–C activation methods, here we describe an efficient strategy for the enantioselective total syntheses of (−)-cycloclavine and (−)-5-epi-cycloclavine, which is enabled by an asymmetric Rh-catalyzed “cut-and-sew” transformation between benzocyclo­butenones and olefins. Despite the compact structure of cycloclavine with five-fused rings, the total synthesis was accomplished in 10 steps with a 30% overall yield. Key features of the synthesis include (1) a Pd-catalyzed tandem C–N bond coupling/allylic alkylation sequence to construct the nitrogen-tethered benzocyclobutenone, (2) a highly enantioselective Rh-catalyzed carboacylation of alkenes to forge the indoline-fused tricyclic structure, and (3) a diastereoselective cyclopropanation for preparing the tetrasubstituted cyclopropane ring. Notably, an improved catalytic condition has been developed for the nitrogen-tethered cut-and-sew transformation, which uses a low catalyst loading and allows for a broad substrate scope with high enantioselectivity (94–99% e.e.). The C–C activation-based strategy employed here is anticipated to have further implications for syntheses of other natural products that contain complex fused or bridged rings.