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

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)1407-1415
Number of pages9
JournalJournal of the American Chemical Society
Volume144
Issue number3
DOIs
Publication statusPublished - Jan 26 2022
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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