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*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

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
Early online date17 Jan 2022
DOIs
Publication statusPublished - 26 Jan 2022

Bibliographical note

Funding Information:
S.S. acknowledges funding from the European Union’s Horizon 2020 research and innovation framework programme under the Marie Skłodowska-Curie Grant Agreement No. 797329 and thanks the Uehara memorial Foundation for a postdoctoral fellowship. B.D.A.S. is grateful to the Centre for Doctoral Training in Synthesis for Biology and Medicine for a studentship, generously supported by GlaxoSmithKline, MSD, Syngenta, and Vertex and thanks the Oxford-Leon E & Iris L Beghian Scholarship for funding. K.Y. thanks the Honjo International Scholarship Foundation for a postgraduate scholarship. T.A.H. thanks The Netherlands Organization for Scientific Research (NWO) for financial support. This work was carried out on the Dutch national e-infrastructure with the support of SURF Cooperative. D.V. and A.L.F.A. acknowledge funding from the European Union’s Horizon 2020 research and innovation framework programme under the Marie Skłodowska-Curie Grant Agreement Nos. 703789 and 660125. Kristina Aertker is thanked for early work on starting material preparation. Xiaoyu Xu is thanked for preliminary work. The authors thank Dr. Heyao Shi (University of Oxford) for X-ray data collection and Dr. Amber L. Thompson (Oxford Chemical Crystallography Service) for X-ray mentoring and structure determination.

Publisher Copyright:
© 2022 The Authors. Published by American Chemical Society.

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