A New Organocatalytic Desymmetrization Reaction Enables the Enantioselective Total Synthesis of Madangamine E
Shinya Shiomi, Benjamin D. A. Shennan, Ken Yamazaki, Ángel L. Fuentes de Arriba, Dhananjayan Vasu, Trevor A. Hamlin, Darren J. Dixon
Abstract
High Resolution Image Download MS PowerPoint Slide The enantioselective total synthesis of madangamine E has been completed in 30 steps, enabled by a new catalytic and highly enantioselective desymmetrizing intramolecular Michael addition reaction of a prochiral ketone to a tethered β,β′ -disubstituted nitroolefin. This key carbon–carbon bond forming reaction efficiently constructed a chiral bicyclic core in near-perfect enantio- and diastereo-selectivity, concurrently established three stereogenic centers, including a quaternary carbon, and proved highly scalable. Furthermore, the pathway and origins of enantioselectivity in this catalytic cyclization were probed using density functional theory (DFT) calculations, which revealed the crucial substrate/catalyst interactions in the enantio-determining step. Following construction of the bicyclic core, the total synthesis of madangamine E could be completed, with key steps including a mild one-pot oxidative lactamization of an amino alcohol, a two-step Z -selective olefination of a sterically hindered ketone, and ring-closing metatheses to install the two macrocyclic rings.