Copper

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Carbon–oxygen bonds are commonplace in organic molecules, including chiral bioactive compounds; therefore, the development of methods for their construction with simultaneous control of stereoselectivity is an important objective in synthesis. The Williamson ether synthesis, first reported in 18501, is the most widely used approach to the alkylation of an oxygen nucleophile, but it has significant limitations (scope and stereochemistry) owing to its reaction mechanism (SN2 pathway). Transition-metal catalysis of the coupling of an oxygen nucleophile with an alkyl electrophile has the potential to address these limitations, but progress so far has been limited2,3,4,5,6,7, especially with regard to controlling enantioselectivity. Here we establish that a readily available copper catalyst can achieve an array of enantioconvergent substitution reactions of α-haloamides, a useful family of electrophiles, by oxygen nucleophiles; the reaction proceeds under mild conditions in the presence of a wide variety of functional groups. The catalyst is uniquely effective in being able to achieve enantioconvergent alkylations of not only oxygen nucleophiles but also nitrogen nucleophiles, giving support for the potential of transition-metal catalysts to provide a solution to the pivotal challenge of achieving enantioselective alkylations of heteroatom nucleophiles.

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Support has been provided by the National Institutes of Health (National Institute of General Medical Sciences, R01–GM109194 and R35–GM145315), the Beckman Institute (support for the Caltech Center for Catalysis and Chemical Synthesis, EPR Facility and X-ray Crystallography Facility), the Dow Next-Generation Educator Fund (grant to Caltech) and Boehringer–Ingelheim Pharmaceuticals. We thank R. Anderson, H. Cho, S. Munoz, P. H. Oyala, F. Schneck, M. K. Takase and X. Tong for assistance and discussions.

Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA

Caiyou Chen & Gregory C. Fu

College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, People's Republic of China

Caiyou Chen

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C.C. performed all experiments. C.C. and G.C.F. wrote the paper. Both authors contributed to the analysis and the interpretation of the results.

Correspondence to Gregory C. Fu.

The authors declare no competing interests.

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

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a. Functional-group compatibility. b. Other families of electrophiles.

a. Exploration of a radical intermediate. b. Synthesis and catalytic activity of Cu(LX*)(MeCN). c. DFT studies of the spin density of Cu(LX*)(OPh): BP86-d3(BJ)/def2-TZVP/SMD(THF); contour values of 0.048 and 0.020 for N and K, respectively.

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Chen, C., Fu, G.C. Copper-catalysed enantioconvergent alkylation of oxygen nucleophiles. Nature (2023). https://doi.org/10.1038/s41586-023-06001-y

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Received: 05 September 2022

Accepted: 22 March 2023

Published: 30 March 2023

DOI: https://doi.org/10.1038/s41586-023-06001-y

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