Organic chemistry

Enzyme

Combinatorial chemistry

Nitronate

Electrophile

Stereochemistry

Enantioselective synthesis

Catalysis

Medicinal chemistry

Nitroso

Chemistry

Nitro

Alkyl

Flavin group

Photochemistry

Nature

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. A highly chemoselective and enantioselective cross-electrophile coupling using ‘ene’-reductases is reported, and photoexcited enzymes demonstrate the ability to carry out reactions between electrophiles that are not known for small-molecule catalysis.

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