An Asymmetric sp3–sp3 Cross-Electrophile Coupling Using ‘Ene’-Reductases – Nature

The catalytic asymmetric construction of Csp³–Csp³ bonds remains one of the foremost challenges in organic synthesis.¹ Metal-catalyzed cross-electrophile couplings (XEC) have emerged as a powerful tool for C–C bond formation.^2-5 However, coupling two distinct Csp³-electrophiles with high cross- and stereoselectivity continues as an unmet challenge. Here, we report a highly chemo- and enantioselective Csp³–Csp³ XEC between alkyl halides and nitroalkanes catalyzed by flavin-dependent ‘ene’-reductases. Photoexcitation of the enzyme-templated charge-transfer complex between an alkyl halide and flavin cofactor enables the chemoselective reduction of alkyl halide over the thermodynamically favored nitroalkane partner. The key C–C bond-forming step occurs via 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 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.