An Asymmetric sp3–sp3 Cross-Electrophile Coupling Using Biocatalysis

05 May 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


The catalytic asymmetric construction of Csp3–Csp3 bonds remains one of the foremost challenges in organic synthesis. Metal-catalyzed cross-electrophile couplings have emerged as a powerful tool for C–C bond formation. However, these catalysts struggle to differentiate Csp3-electrophiles leading to dimerization of the starting material, and there are no general catalysts for asymmetric couplings. Here, we report a highly chemo- and enantioselective Csp3–Csp3 cross-electrophile couplings 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.


cross-electrophile coupling

Supplementary materials

Supplemental Information
General Procedures, Crystallography Data, NMR spectra and HPLC traces


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.