Potassium tert-butoxide mediated stereoselective/direct Mannich reaction of α-substituted-γ-lactams with in situ generated aryl N-silyl imines
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1.
California Institute of Technology
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2.
University of Pittsburgh
Abstract
A potassium tert-butoxide (KOt-Bu)-mediated Mannich reaction between α-substituted-γ-lactams and N-silyl imines is reported. N-silyl imines are generated in situ from readily available aryl nitriles and directly combined with the lactams, without preformation of the lactam enolate, to afford the α-quaternary center-bearing Mannich bases in high yield and with high diastereoselectivity (24 examples). This reaction is shown to be catalytic with respect to KOt-Bu and the catalytic mechanism has been investigated using density functional theory calculations. The computational investigations suggest that the diastereoselectivity is controlled by explicit interactions between a binuclear potassium complex and both the imine nitrogen and the enolate oxygen atoms in the selectivity-determining transition states. The Mannich products are shown to be useful in accessing novel spirocyclic pyrrolidines.
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Supplemental Material
Acknowledgement
The authors thank Dr Scott Virgil and Alex Cusumano for helpful discussions, David VanderVelde for NMR assistance, Dr Michael Takase for XRD assistance, and Dr Mona Shahgholi for mass spectrometry assistance. The authors thank the Beckman Institute for their support of the Caltech XRD facility, as well as the Dow Next Generation Instrument Grant. The authors (BMS and TDC) thank NIH (R35GM145239) and the Heritage Medical Research Institute Investigator Program. Further financial support for this work was provided by NSF (CHE-2247505 to P. L.). Computational studies were performed at the Center for Research Computing at the University of Pittsburgh and the Advanced Cyberinfrastructure Coordination Ecosystem: Services & Support (ACCESS) program supported by NSF. Constructive discussions within the Catalysis Innovation Consortium facilitated this collaborative study.
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Additional details
- National Institutes of Health
- R35GM145239
- National Science Foundation
- CHE-2247505
- Available
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2025-04-14Published online
- Caltech groups
- Division of Chemistry and Chemical Engineering (CCE)
- Publication Status
- Published