Catalysis

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

Authors

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.

Content

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Supplementary material

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Electronic Supporting Information
Electronic Supporting Information for "A New Organocatalytic Desymmetrization Reaction Enables the Enantioselective Total Synthesis of Madangamine E", including synthetic procedures, computational methods and analysis, and synthetic, crystallographic and computational data.
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Checkcif report
Checkcif report for single crystal X-ray structures.
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Crystallographic Data
Crystallographic data for single crystal X-ray structures (CIF format)