A New Organocatalytic Desymmetrization Reaction Enables the Enantioselective Total Synthesis of Madangamine E

• Published in: Journal of the American Chemical Society Vol. 144; no. 3; pp. 1407 - 1415
• Main Authors: Shiomi, Shinya, Shennan, Benjamin D. A, Yamazaki, Ken, Fuentes de Arriba, Ángel L, Vasu, Dhananjayan, Hamlin, Trevor A, Dixon, Darren J
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 26.01.2022
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.1c12040

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.