Enantioselective Total Synthesis of (−)-Hunterine A Enabled by a Desymmetrization/Rearrangement Strategy
Abstract
The first enantioselective total synthesis of (−)-hunterine A is disclosed. Our strategy employs a catalytic asymmetric desymmetrization of a symmetrical diketone and subsequent Beckmann rearrangement to construct a 5,6-α-aminoketone. A convergent 1,2-addition joins a vinyl dianion nucleophile and the enantioenriched ketone. The endgame of the synthesis features an aza-Cope/Mannich reaction and azide-olefin dipolar cycloaddition to complete the pentacyclic ring system. The synthesis is completed through a regioselective aziridine ring opening.
Copyright and License
© 2024 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY-NC-ND 4.0.
Acknowledgement
This manuscript is dedicated to Professor Larry E. Overman of the University of California, Irvine, on the occasion of his 80th birthday. The NIH-NIGMS (R35GM145239), Heritage Medical Research Investigators Program, and Caltech are thanked for the support of our research program. We thank Dr. David VanderVelde (Caltech) for NMR expertise; Dr. Mona Shagholi (Caltech) for mass spectrometry assistance; Dr. Michael Takase (Caltech) for assistance with X-ray crystallography; and Dr. Scott C. Virgil (Caltech) for instrumentation, HPLC, and SFC assistance. Additional thanks to Kevin Gonzalez, Ben Gross, Samir Rezgui, and Hao Yu for many helpful discussions. E.F.H. would like to thank the NSF GRFP for funding.
Additional Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c13590.
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Experimental procedures, spectroscopic data (1H NMR, 13C NMR, IR, and HRMS), and crystallographic data
CCDC 2308829–2308831 contain the supplementary crystallographic data for this paper.
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Additional details
- ISSN
- 1520-5126
- PMCID
- PMC10885145
- National Institutes of Health
- R35GM145239
- California Institute of Technology
- Heritage Medical Research Institute
- National Science Foundation
- NSF Graduate Research Fellowship
- Caltech groups
- Heritage Medical Research Institute