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Published December 9, 2022 | Accepted Version + Supplemental Material
Journal Article Open

Catalytic asymmetric C-H insertion reactions of vinyl carbocations


From the preparation of pharmaceuticals to enzymatic construction of natural products, carbocations are central to molecular synthesis. Although these reactive intermediates are engaged in stereoselective processes in nature, exerting enantiocontrol over carbocations with synthetic catalysts remains challenging. Many resonance-stabilized tricoordinated carbocations, such as iminium and oxocarbenium ions, have been applied in catalytic enantioselective reactions. However, their dicoordinated counterparts (aryl and vinyl carbocations) have not, despite their emerging utility in chemical synthesis. We report the discovery of a highly enantioselective vinyl carbocation carbon–hydrogen (C–H) insertion reaction enabled by imidodiphosphorimidate organocatalysts. Active site confinement featured in this catalyst class not only enables effective enantiocontrol but also expands the scope of vinyl cation C–H insertion chemistry, which broadens the utility of this transition metal–free C(sp³)–H functionalization platform.

Additional Information

© 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. We thank S. Virgil, B. Stoltz, and S. Reisman for instrumentation; M. Shahgholi for mass spectrometry support; D. Vander Velde for NMR expertise; and M. Takase and S. Khan for x-ray crystallography analysis. Work by the Houk group used computational and storage services associated with the Hoffman2 Shared Cluster provided by UCLA Institute for Digital Research and Education's Research Technology Group. The Sigman Group's computational work was supported by the Center for High Performance Computing at the University of Utah. Financial support for this work was provided by the National Institutes of Health National Institute of General Medical Sciences (R35 GM12893 to H.M.N. and R35 GM136271 to M.S.S.) and the National Science Foundation (CHE-1764328 to K.N.H.; DGE-1650604 to B.W. and S.P.). S.K.N. thanks the US Public Health Service (USPHS) National Research Service Award (T32GM008496). We thank the Beckman Institute (support of the Caltech Center for Catalysis and Chemical Synthesis and the x-ray crystallography facility), the Dow Next-Generation Educator Fund (grant to Caltech), and the UCLA Molecular Instrumentation Center for NMR instrumentation and x-ray crystallography. Author contributions: H.M.N., S.K.N., C.G.W., B.W., and S.P. designed and conducted experiments. Computational studies were conducted by J.J.W. and directed by K.N.H. Statistical modeling of data was performed by B.C.H. and J.W., and M.S.S. supervised. H.M.N., M.S.S., S.K.N., C.G.W., B.W., B.C.H., J.J.W., and J.W. prepared the manuscript. Data and materials availability: All crystallographic data are available free of charge from the Cambridge Crystallographic Data Centre under CCDC 2201595, CCDC 2201596, CCDC 2201597, CCDC 2201598, CCDC 2201599, and CCDC 2201600. All other data are provided in the supplementary materials. The authors declare that they have no competing interests.

Attached Files

Accepted Version - nihms-1877321.pdf

Supplemental Material - science.ade5320_data_s1.zip

Supplemental Material - science.ade5320_sm.pdf


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Additional details

August 22, 2023
October 25, 2023