Tandem Dearomatization/Enantioselective Allylic Alkylation of Pyridines

Creators: Greßies, Steffen; Süße, Lars; Casselman, Tyler; Stoltz, Brian M.

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Abstract

Herein, we report a multistep one-pot reaction of substituted pyridines leading to N-protected tetrahydropyridines with outstanding enantioselectivity (up to 97% ee). An iridium(I)-catalyzed dearomative 1,2-hydrosilylation of pyridines enables the use of N-silyl enamines as a new type of nucleophile in a subsequent palladium-catalyzed asymmetric allylic alkylation. This telescoped process overcomes the intrinsic nucleophilic selectivity of pyridines to synthesize enantioenriched, C-3-substituted tetrahydropyridine products that have been otherwise challenging to access.

Additional Information

© 2023 The Authors. Published by American Chemical Society. Attribution 4.0 International (CC BY 4.0) 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. S.G. and L.S. gratefully acknowledge the Alexander von Humboldt Foundation for a Feodor Lynen fellowship (2019–2020). The authors acknowledge the NIH-NIGMS (R35GM145239 and R01GM080269), as well as the Heritage Medical Research Investigator Program, for funding this research. CCDC 2234165 contains the supplementary crystallographic data for this paper.

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