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

Abstract

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 stereocenter, and proved highly scalable. Furthermore, the pathway and origins of enantioselectivity in this catalytic cyclisation 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 oxidation-lactamisation, a two-step Z-selective olefination of a sterically hindered ketone, and ring-closing metatheses to install the two macrocyclic rings.

Madangamine alkaloids: Madness and tranquility

“…[10] A recent approach contributed by the Douglas group featured Pd-catalysed C-C bond activation and cyanoamidation cascades. [15] Nevertheless, only three groups completed the total syntheses of selected madangamine alkaloids, including the Bosch and Amat, [16][17][18] Sato and Chida [8,19] and Dixon [20] groups.…”

“…In 2022, the Dixon group reported the total synthesis of madangamine E, featuring an organocatalyst-enabled enantioselective desymmetrization to access the bridged A-C ring (Scheme 1c). [20] At the outset, a 9-step sequence from acetal 15 was applied to prepare nitroolefin 16. Asymmetric Michael addition with a thiourea catalyst was developed to form bicyclic intermediate 17 in 95% yield with 99% ee.…”