An asymmetric sp3–sp3 cross-electrophile coupling using ‘ene’-reductases

Haigen Fu, Jingzhe Cao, Tianzhang Qiao, Yuyin Qi, Simon J. Charnock, Samuel Garfinkle and Todd K. Hyster ()
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Haigen Fu: Cornell University
Jingzhe Cao: Cornell University
Tianzhang Qiao: Cornell University
Yuyin Qi: Prozomix
Simon J. Charnock: Prozomix
Samuel Garfinkle: Princeton University
Todd K. Hyster: Cornell University

Nature, 2022, vol. 610, issue 7931, 302-307

Abstract: 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 formation2–5. 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.

Date: 2022
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DOI: 10.1038/s41586-022-05167-1

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