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Quaternary stereocentres via catalytic enantioconvergent nucleophilic substitution reactions of tertiary alkyl halides

Abstract

The development of efficient methods, particularly catalytic and enantioselective processes, for the construction of all-carbon quaternary stereocentres is an important (and difficult) challenge in organic synthesis due to the occurrence of this motif in a range of bioactive molecules. One conceptually straightforward and potentially versatile approach is the catalytic enantioconvergent substitution reaction of a readily available racemic tertiary alkyl electrophile by an organometallic nucleophile; however, examples of such processes are rare. Here we demonstrate that a nickel-based chiral catalyst achieves enantioconvergent couplings of a variety of tertiary electrophiles (cyclic and acyclic α-halocarbonyl compounds) with alkenylmetal nucleophiles to form quaternary stereocentres with good yield and enantioselectivity under mild conditions in the presence of a range of functional groups. These couplings, which probably proceed via a radical pathway, provide access to an array of useful families of organic compounds, including intermediates in the total synthesis of two natural products, (–)-eburnamonine and madindoline A.

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Fig. 1: Catalytic asymmetric synthesis of quaternary stereocentres via stereoconvergent nucleophilic substitution reactions of racemic tertiary alkyl electrophiles.
Fig. 2: Mechanistic studies.
Fig. 3: Applications of the coupling products.

Data availability

The data that support the findings of this study are available in the Supplementary Information (experimental procedures and characterization data). Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 1958912 (13), 1958913 (81), and 1965146 (80). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

This paper is dedicated to the memory of Professor Jonathan Williams (University of Bath). Support has been provided by the NIGMS (R37-GM62871) and the Dow Next Generation Educator Fund (grant to Caltech). We thank S.M. Batiste, L.M. Henling, H. Huo, F. Schneck, M.K. Takase, S.C. Virgil and W. Zhang for assistance and helpful discussions.

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Z.W. and Z.-P.Y. performed all experiments. Z.W. and G.C.F. wrote the manuscript. All authors contributed to the analysis and the interpretation of the results.

Corresponding author

Correspondence to Gregory C. Fu.

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The authors declare no competing interests.

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Peer review information Nature Chemistry thanks the anonymous reviewers for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

General information, preparation of ligands and electrophiles, catalytic enantioconvergent alkenylations, effect of reaction parameters, studies of functional group compatibility, derivatization of the coupling products, applications to the formal total synthesis of natural products, mechanistic studies, assignments of absolute configuration, references, NMR spectra and determination of stereoselectivity, Tables 1–5 and Figs. 1–3.

Supplementary Data 1

Crystallographic data for compound 13. CCDC reference 1958912.

Supplementary Data 2

Crystallographic data for compound 80. CCDC reference 1965146.

Supplementary Data 3

Crystallographic data for compound 81. CCDC reference 1958913.

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Wang, Z., Yang, ZP. & Fu, G.C. Quaternary stereocentres via catalytic enantioconvergent nucleophilic substitution reactions of tertiary alkyl halides. Nat. Chem. 13, 236–242 (2021). https://doi.org/10.1038/s41557-020-00609-7

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