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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.

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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.

References

  1. Choi, J. & Fu, G. C. Transition metal-catalyzed alkyl-alkyl bond formation: another dimension in cross-coupling chemistry. Science 356, eaaf7230 (2017).

    Article  Google Scholar 

  2. Everson, D. A. & Weix, D. J. Cross-electrophile coupling: principles of reactivity and selectivity. J. Org. Chem. 79, 4793–4798 (2014).

    Article  CAS  Google Scholar 

  3. Gu, J., Wang, X., Xue, W. & Gong, H. Nickel-catalyzed reductive coupling of alkyl halides with other electrophiles: concept and mechanistic considerations. Org. Chem. Front. 2, 1411–1421 (2015).

    Article  CAS  Google Scholar 

  4. Lucas, E. L. & Jarvo, E. R. Stereospecific and stereoconvergent cross-couplings between alkyl electrophiles. Nat. Rev. Chem. 1, 0065 (2017).

    Article  Google Scholar 

  5. Poremba, K. E., Dibrell, S. E. & Reisman, S. E. Nickel-catalyzed enantioselective reductive cross-coupling reactions. ACS Catal. 10, 8237–8246 (2020).

    Article  CAS  Google Scholar 

  6. Biffis, A., Centomo, P., Del Zotto, A. & Zecca, M. Pd metal catalysts for cross-couplings and related reactions in the 21st century: a critical review. Chem. Rev. 118, 2249–2295 (2018).

    Article  CAS  Google Scholar 

  7. Magano, J. & Dunetz, J. R. Large-scale applications of transition metal-catalyzed couplings for the synthesis of pharmaceuticals. Chem. Rev. 111, 2177–2250 (2011).

    Article  CAS  Google Scholar 

  8. Lovering, F., Bikker, J. & Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).

    Article  CAS  Google Scholar 

  9. Lovering, F. Escape from Flatland 2: complexity and promiscuity. MedChemComm 4, 515–519 (2013).

    Article  CAS  Google Scholar 

  10. Qian, X., Auffrant, A., Felouat, A. & Gosmini, C. Cobalt-catalyzed reductive allylation of alkyl halides with allylic acetates or carbonates. Angew. Chem. Int. Edn 50, 10402–10405 (2011).

    Article  CAS  Google Scholar 

  11. Liu, J. H. et al. Copper-catalyzed reductive cross-coupling of nonactivated alkyl tosylates and mesylates with alkyl and aryl bromides. Chem. Eur. J. 20, 15334–15338 (2014).

    Article  CAS  Google Scholar 

  12. Sanford, A. B. et al. Nickel-catalyzed alkyl–alkyl cross-electrophile coupling reaction of 1,3-dimesylates for the synthesis of alkylcyclopropanes. J. Am. Chem. Soc. 142, 5017–5023 (2020).

    Article  CAS  Google Scholar 

  13. Yu, X., Yang, T., Wang, S., Xu, H. & Gong, H. Nickel-catalyzed reductive cross-coupling of unactivated alkyl halides. Org. Lett. 13, 2138–2141 (2011).

    Article  CAS  Google Scholar 

  14. Xu, H., Zhao, C., Qian, Q., Deng, W. & Gong, H. Nickel-catalyzed cross-coupling of unactivated alkyl halides using bis(pinacolato)diboron as reductant. Chem. Sci. 4, 4022–4029 (2013).

    Article  CAS  Google Scholar 

  15. Erickson, L. W., Lucas, E. L., Tollefson, E. J. & Jarvo, E. R. Nickel-catalyzed cross-electrophile coupling of alkyl fluorides: stereospecific synthesis of vinylcyclopropanes. J. Am. Chem. Soc. 138, 14006–14011 (2016).

    Article  CAS  Google Scholar 

  16. Tollefson, E. J., Erickson, L. W. & Jarvo, E. R. Stereospecific intramolecular reductive cross-electrophile coupling reactions for cyclopropane synthesis. J. Am. Chem. Soc. 137, 9760–9763 (2015).

    Article  CAS  Google Scholar 

  17. Smith, R. T. et al. Metallaphotoredox-catalyzed cross-electrophile Csp3–Csp3 coupling of aliphatic bromides. J. Am. Chem. Soc. 140, 17433–17438 (2018).

    Article  CAS  Google Scholar 

  18. Zhang, W. et al. Electrochemically driven cross-electrophile coupling of alkyl halides. Nature 604, 292–297 (2022).

    Article  ADS  CAS  Google Scholar 

  19. Jana, S. K., Maiti, M., Dey, P. & Maji, B. Photoredox/nickel dual catalysis enables the synthesis of alkyl cyclopropanes via C(sp3)–C(sp3) cross electrophile coupling of unactivated alkyl electrophiles. Org. Lett. 24, 1298–1302 (2022).

    Article  CAS  Google Scholar 

  20. Bell, E. L. et al. Biocatalysis. Nat. Rev. Methods Primers 1, 46 (2021).

    Article  CAS  Google Scholar 

  21. Zhou, Q., Chin, M., Fu, Y., Liu, P. & Yang, Y. Stereodivergent atom-transfer radical cyclization by engineered cytochromes. Science 374, 1612–1616 (2021).

    Article  ADS  CAS  Google Scholar 

  22. Chatterjee, A. et al. An enantioselective artificial Suzukiase based on the biotin–streptavidin technology. Chem. Sci. 7, 673–677 (2015).

    Article  Google Scholar 

  23. Pierron, J. et al. Artificial metalloenzymes for asymmetric allylic alkylation on the basis of the biotin–avidin technology. Angew. Chem. Int. Edn 47, 701–705 (2008).

    Article  CAS  Google Scholar 

  24. Ballini, R., Bosica, G., Fiorini, D., Palmieri, A. & Petrini, M. Conjugate additions of nitroalkanes to electron-poor alkenes: recent results. Chem. Rev. 105, 933–972 (2005).

    Article  CAS  Google Scholar 

  25. Gildner, P. G., Gietter, A. A. S., Cui, D. & Watson, D. A. Benzylation of nitroalkanes using copper-catalyzed thermal redox catalysis: toward the facile C-alkylation of nitroalkanes. J. Am. Chem. Soc. 134, 9942–9945 (2012).

    Article  CAS  Google Scholar 

  26. Gietter, A. A. S., Gildner, P. G., Cinderella, A. P. & Watson, D. A. General route for preparing β-nitrocarbonyl compounds using copper thermal redox catalysis. Org. Lett. 16, 3166–3169 (2014).

    Article  CAS  Google Scholar 

  27. Rezazadeh, S., Devannah, V. & Watson, D. A. Nickel-catalyzed C-alkylation of nitroalkanes with unactivated alkyl iodides. J. Am. Chem. Soc. 139, 8110–8113 (2017).

    Article  CAS  Google Scholar 

  28. Devannah, V., Sharma, R. & Watson, D. A. Nickel-catalyzed asymmetric C-alkylation of nitroalkanes: synthesis of enantioenriched β-nitroamides. J. Am. Chem. Soc. 141, 8436–8440 (2019).

    Article  CAS  Google Scholar 

  29. Kornblum, N., Carlson, S. C. & Smith, R. G. Replacement of the nitro group by hydrogen. J. Am. Chem. Soc. 100, 289–290 (1978).

    Article  CAS  Google Scholar 

  30. Tanner, D. D. et al. The mechanism of the radical chain transformation of nitroalkanes to alkanes using triaryl- or trialkyltin hydrides. J. Org. Chem. 55, 3321–3325 (1990).

    Article  CAS  Google Scholar 

  31. Roth, H. G., Roth, H. G., Romero, N. A. & Nicewicz, D. A. Experimental and calculated electrochemical potentials of common organic molecules for applications to single-electron redox chemistry. Synlett 27, 714–723 (2016).

    CAS  Google Scholar 

  32. Durchschein, K. et al. Reductive biotransformation of nitroalkenes via nitroso-intermediates to oxazetes catalyzed by xenobiotic reductase A (XenA). Org. Biomol. Chem. 9, 3364–3369 (2011).

    Article  CAS  Google Scholar 

  33. Biegasiewicz, K. F. et al. Photoexcitation of flavoenzymes enables a stereoselective radical cyclization. Science 364, 1166–1169 (2019).

    Article  ADS  CAS  Google Scholar 

  34. Page, C. G. et al. Quaternary charge-transfer complex enables photoenzymatic intermolecular hydroalkylation of olefins. J. Am. Chem. Soc. 143, 97–102 (2020).

    Article  Google Scholar 

  35. Huang, X. et al. Photoenzymatic enantioselective intermolecular radical hydroalkylation. Nature 584, 69–74 (2020).

    Article  ADS  CAS  Google Scholar 

  36. Fu, H. et al. Ground-state electron transfer as an initiation mechanism for biocatalytic C–C bond forming reactions. J. Am. Chem. Soc. 143, 9622–9629 (2021).

    Article  CAS  Google Scholar 

  37. Sandoval, B. A., Meichan, A. J. & Hyster, T. K. Enantioselective hydrogen atom transfer: discovery of catalytic promiscuity in flavin-dependent ‘ene’-reductases. J. Am. Chem. Soc. 139, 11313–11316 (2017).

    Article  CAS  Google Scholar 

  38. Fukuyama, M. et al. Thermodynamic and kinetic acidity properties of nitroalkanes. Correlation of the effects of structure on the ionization constants and the rate constants of neutralization of substituted 1-phenyl-1-nitroethanes. J. Am. Chem. Soc. 92, 4689–4699 (1970).

    Article  CAS  Google Scholar 

  39. Cai, S., Zhang, S., Zhao, Y. & Wang, D. Z. New approach to oximes through reduction of nitro compounds enabled by visible light photoredox catalysis. Org. Lett. 15, 2660–2663 (2013).

    Article  CAS  Google Scholar 

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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 610, 302–307 (2022). https://doi.org/10.1038/s41586-022-05167-1

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