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Dynamic kinetic resolution of phosphines with chiral supporting electrolytes

Nature volume 643, pages 1288–1296 (2025)Cite this article

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Abstract

The synthesis of enantiopure compounds is a central focus in organic chemistry owing to the prevalence of chiral centres in biological systems and the impact of homochirality on molecular properties. With growing recognition of electrochemistry as a powerful tool to improve the scope and sustainability of organic synthesis1, increasing efforts have been directed towards developing asymmetric electrocatalytic reactions to access challenging chiral molecules2,3,4. However, many useful electrochemical reactions rely on direct electrolysis without a catalyst, making them inherently difficult to render enantioselective. Supporting electrolytes are integral to electrochemical systems and, in addition to ensuring sufficient solution conductivity, they can influence the rate and selectivity of electrochemical transformations5. Chiral supporting electrolytes can mediate asymmetric reactions via direct electrolysis, but their use in organic electrosynthesis remains largely unexplored6,7. Here we describe the use of substoichiometric chiral phosphate salts as supporting electrolytes to facilitate the oxidation of racemic trivalent phosphines to afford enantioenriched phosphine oxides. Our approach relies on a dynamic-kinetic-resolution strategy that exploits the rapid pyramidal inversion of an anodically generated phosphoniumyl radical cation8, while a high concentration of chiral phosphate at the electrode–electrolyte interface9,10 enhances enantioselective control during rate-limiting nucleophilic addition. Our results highlight the promise of chiral supporting electrolytes for promoting radical-ion-mediated asymmetric transformations.

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Fig. 1: Asymmetric direct electrolysis enabled by a chiral supporting electrolyte and DKR of trivalent phosphines via pyramidal inversion of a phosphoniumyl radical cation.
Fig. 2: Optimization and scope for substrates with a directing group.
Fig. 3: Optimization and scope for substrates without a directing group.
Fig. 4: Proposed mechanism and computational energy diagram.
Fig. 5: Mechanistic investigation of electrochemical phosphine oxidation mediated by a chiral supporting electrolyte.

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Data availability

All data supporting the findings of this work are available in the paper and its Supplementary Information. Full X-ray structural data are available free of charge from the Cambridge Crystallographic Data Centre (CCDC) under deposition numbers 2385247 and 2385248.

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Acknowledgements

This work was supported by NSF Center for Synthetic Organic Electrochemistry (CHE-2002158) and Bristol Myers Squibb Graduate Fellowship (K.M.). S.L. is grateful for a Camille Dreyfus Teacher-Scholar Award. We thank L. Novaes for initial contribution to the development of the thioether oxidation; I. Crooker for assistance in preparing supporting electrolytes and substrates; S. MacMillan for collecting and elucidating X-ray crystallography data; I. Keresztes for discussion on NMR structural analysis; A. L. Lai (funded by NIH R24GM146107 and R35GM148272) for help with electron paramagnetic resonance experiments; B. Gorski for reproducing the reaction; D. Toste for discussions on chiral phosphoric acid synthesis and catalysis; G. Laudadio for discussions on flow electrochemistry; Y. Yang for discussions on the electrode–electrolyte interface and electrical double layer; D. B. Collum for providing access to his computational resources; K. R. Meihaus for manuscript editing; and W.-C. C. Lee for figure editing.

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Author notes

  1. These authors contributed equally: Kaining Mao, Chenfei Liu

Authors and Affiliations

  1. Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA

    Kaining Mao, Chenfei Liu, Yi Wang, John M. Putziger, Nicholas I. Cemalovic, Cameron Muniz & Song Lin

  2. School of Engineering, Brown University, Providence, RI, USA

    Chaoxuan Gu & Yue Qi

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Contributions

S.L. and Y.Q. supervised the project. S.L., C.L. and K.M. conceived of the project. C.L., K.M. and C.M. performed synthetic experiments. K.M. and C.L. performed experimental mechanistic studies. Y.W. performed DFT calculations. C.G. performed molecular dynamics simulations. J.M.P. performed flow cell experiments. N.I.C. performed chemical space analysis. The paper was written by K.M., C.L., Y.W. and S.L., edited by C.G. and Y.Q., and approved by all authors.

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Correspondence to Song Lin.

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Mao, K., Liu, C., Wang, Y. et al. Dynamic kinetic resolution of phosphines with chiral supporting electrolytes. Nature 643, 1288–1296 (2025). https://doi.org/10.1038/s41586-025-09238-x

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