Ni-Catalyzed Enantioselective Desymmetrization: Development of Divergent Acyl and Decarbonylative Cross-Coupling Reactions
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1.
California Institute of Technology
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2.
Princeton University
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3.
University of Utah
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4.
Technical University of Berlin
- 5. Amgen, Inc
Abstract
Ni-catalyzed asymmetric reductive cross-coupling reactions provide rapid and modular access to enantioenriched building blocks from simple electrophile precursors. Reductive coupling reactions that can diverge through a common organometallic intermediate to two distinct families of enantioenriched products are particularly versatile but underdeveloped. Here, we describe the development of a bis(oxazoline) ligand that enables the desymmetrization of meso-anhydrides. When secondary benzylic electrophiles are employed, doubly stereoselective acyl cross-coupling proceeds to give ketone products with catalyst control over three newly formed stereogenic centers. Alternatively, use of primary alkyl halides in the presence of an additional halogen atom transfer catalyst results in decarbonylative alkylation to give enantioenriched beta-alkyl acids. Analysis of reaction rates for a range of both catalysts and substrates supports the notion that tuning the different electrophile activation steps with the two catalysts is required for enhanced reaction performance. These studies illustrate how reaction design can diverge a common Ni-acyl intermediate to either acyl or decarbonylative coupling products and highlight how dual ligand systems can be used to engage unactivated alkyl halides in Ni-catalyzed asymmetric reductive coupling.
Copyright and License
The content is available under CC BY NC ND 4.0
Acknowledgement
We gratefully acknowledge Dr. Scott Virgil and the Caltech Center for Catalysis and Chemical Synthesis for access to analytical equipment. We thank the Dow Next Generation Educator Funds and Instrumentation Grants for their support of the Beckman Institute X-ray Crystallography Facility at Caltech, as well as the Caltech CCE NMR facility and Multiuser Mass Spectrometry Laboratory. We thank Dr. Michael K. Takase and Preston J. Mott for assistance with X-ray crystallography.
Supplemental Material
Funding
NSF Center for Synthetic Organic Electrochemistry, CHE-2002158 (M.S.S., S. E. R.) National Institutes of Health GM-R35GM118191 (S. E. R.) Amgen, Inc. Chem-Bio-Engineering Awards at Caltech (S. E. R.) National Science Foundation grant DGE-2139433 (A. D. H. M.) DFG Postdoctoral Research Fellowship (S. R.)
Contributions
A.D.H.M., A.M.S., N.F.L., and S.E.R. conceived of the study; A.D.H.M. and A.M.S. performed reaction discovery and scope development experiments, S.R. helped evaluate substrate scope, J.T. performed catalyst synthesis and mechanism studies; A.H. conducted the electroanalytical studies; N.F.L., K.Q., A.T.P., M.S.S., and S.E.R oversaw the research; A.D.H.M., A.H., M.S.S. and S.E.R. wrote the manuscript, A.M.S. helped edit the manuscript.
Conflict of Interest
N.F.L., K.Q., A.T.P. are employed by Amgen, Inc.
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Additional details
- National Institutes of Health
- GM-R35GM118191
- NSF Center for Synthetic Organic Electrochemistry, University of Utah
- CHE-2002158
- National Science Foundation
- DGE-2139433
- Deutsche Forschungsgemeinschaft
- Amgen (United States)
- Publication Status
- Submitted