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, 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.

Advances in Catalytic Asymmetric Construction of Quaternary Stereogenic Centers by Conjugate Addition to β,β‐Disubstituted Nitroalkenes

“…Intramolecular Michael Addition of a Prochiral Ketone to a Tethered β,β‐Disubstituted Nitroalkene : Dixon and coworkers reported a novel organocatalytic desymmetrizing intramolecular Michael addition as a key step for the enantioselective total synthesis of Madangamine E [66] (Scheme 15). [22] A bifunctional thiourea organocatalyst ( Cat‐5 ) and benzoic acid (BzOH) were used to facilitate the intramolecular Michael addition of a prochiral ketone to a tethered β,β‐disubstituted nitroalkene. This strategy enabled the construction of the bicyclic madangamine core ( 62 ) featuring an all‐carbon quaternary stereocenter as a single diastereomer in outstanding yield and enantioselectivity (95% yield and>99% ee ).…”

“…[5] The β‐nitro compounds with quaternary stereocenters formed via conjugate addition to β,β‐disubstituted nitroalkenes can be easily transformed into several important species such as β 2,2 ‐amino acids and γ‐aminobutyric acids (GABAs) [6,7,8] . Therefore, the past few decades have witnessed the extensive development of catalytic asymmetric conjugate additions to β,β‐disubstituted nitroalkenes and the emergence of the corresponding elegant strategies [9–60] …”

Visible-light-driven PCy3-promoted deselenization of 1,2-diselenides

“…[21][22][23][24][25] The oxidant-induced selenoxide elimination as a key step has found wide applications in the total synthesis of drugs and natural products. [26][27][28][29] The subsequent development of reductive systems such as Ph 3 SnH, 30 LiBHEt 3 , 31 Fig. 1 Selected important organoselenium compounds.…”

Amino Acid-Derived Ionic Chiral Catalysts Enable Desymmetrizing Cross-Coupling to Remote Acyclic Quaternary Stereocenters

“…These elegant studies require judicious choices of benzylic substituents (e.g., tert -Bu group and protected amino groups) at trisubstituted carbons, which are pivotal to the long-range enantioinduction . Recently, catalytic desymmetrization of 1,3-dicarbonyl and malononitrile derivatives to access quaternary stereocenters has gained increasing traction. , By contrast, it has remained a formidable challenge to establish stereogenic quaternary carbons through desymmetrization of remote reaction sites because their spatial distancing necessitates long-range stereocontrol, which is exacerbated by the requirement to discern nonhydrogen groups attached to the sterically congested prochirality center. − To date, catalytic desymmetrization has been achieved only at the ortho positions of the geminal arenes in the context of diaryl quaternary carbon stereocenters …”