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An asymmetric sp3sp3 cross-electrophile coupling using ‘ene’-reductases

Abstract

The catalytic asymmetric construction of Csp3–Csp3 bonds remains one of the foremost challenges in organic synthesis1. Metal-catalysed cross-electrophile couplings (XECs) have emerged as a powerful tool for C–C bond formation2,3,4,5. However, coupling two distinct Csp3 electrophiles with high cross-selectivity and stereoselectivity continues as an unmet challenge. Here we report a highly chemoselective and enantioselective Csp3–Csp3 XEC between alkyl halides and nitroalkanes catalysed by flavin-dependent ‘ene’-reductases (EREDs). Photoexcitation of the enzyme-templated charge-transfer complex between an alkyl halide and a flavin cofactor enables the chemoselective reduction of alkyl halide over the thermodynamically favoured nitroalkane partner. The key C–C bond-forming step occurs by means of the reaction of an alkyl radical with an in situ-generated nitronate to form a nitro radical anion that collapses to form nitrite and an alkyl radical. An enzyme-controlled hydrogen atom transfer (HAT) affords high levels of enantioselectivity. This reactivity is unknown in small-molecule catalysis and highlights the potential for enzymes to use new mechanisms to address long-standing synthetic challenges.

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Fig. 1: Photoenzymatic asymmetric XEC reactions.
Fig. 2: Scope of the photoenzymatic XECs.
Fig. 3: Derivatization of the enzymatic products.
Fig. 4: Mechanistic experiments.

Data availability

The data supporting the findings in this study are available within the paper and its Supplementary Information. Crystallographic models and structure factors have been deposited in the Protein Data Bank with accession number 7TNB for CsER.

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Acknowledgements

We thank P. Jeffrey for assistance with X-ray structure determination and the staff of NSLS-II beamline AMX (17-ID-1) for help with data collection. We thank the Stache group and the Musser group for use of their equipment and the Collum group for use of their computational resources. We thank Y. Zheng for assistance with docking and S. Sun and J. Turek-Herman for discussion. The research reported here was supported by the NIH National Institute of General Medical Sciences (R01GM127703). This work made use of the Cornell University NMR Facility, which is supported, in part, by the NSF through MRI award CHE-1531632.

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Authors

Contributions

H.F. and J.C. performed and analysed the experiments. T.Q. performed the DFT calculations. Y.Q. and S.J.C. performed metagenomic mining and prepared the CsER enzyme. S.G. collected the crystallographic data of CsER. H.F. and T.K.H. designed the experiments. T.K.H. directed the project. The manuscript was prepared with feedback from all the authors.

Corresponding author

Correspondence to Todd K. Hyster.

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Competing interests

S.J.C. and Y.Q. are employed by Prozomix, the company that provided the sequence for CsER. The other authors declare no competing interests.

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Fu, H., Cao, J., Qiao, T. et al. An asymmetric sp3sp3 cross-electrophile coupling using ‘ene’-reductases. Nature (2022). https://doi.org/10.1038/s41586-022-05167-1

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