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

The catalytic asymmetric construction of C sp 3 –C sp 3 bonds remains one of the foremost challenges in organic synthesis 1 . Metal-catalysed cross-electrophile couplings (XECs) have emerged as a powerful tool for C–C bond formation 2 – 5 . However, coupling two distinct C sp 3 electrophiles with high cross-selectivity and stereoselectivity continues as an unmet challenge. Here we report a highly chemoselective and enantioselective C sp 3 –C sp 3 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.