Now, Todd K. Hyster and co-workers present a photobiocatalytic strategy to perform Csp3–Csp3 cross-electrophile couplings between alkyl halides (1) and nitroalkanes (2) with high chemo- and enantioselectivities. Crucial for this success was the design of a reaction mechanism (pictured) involving nitronates (5) as suitable coupling reagents, which are formed in situ from 2 under basic conditions. Notably, nitronates are usually not used as electrophiles in cross-coupling reactions. The key to achieving the cross-selectivity was the employment of flavin-dependent ‘ene’-reductases (EREDs) to control the electron-transfer events. Although the reduction of 2 is thermodynamically favoured, the enzyme overrides this preference by forming charge-transfer complexes with 1 exclusively, allowing them to be selectively reduced instead. The resulting primary alkyl radical (4) then couples with 5 to form a nitro radical anion (6) that further develops into a tertiary alkyl radical (7) on releasing nitrite. Such mesolytic cleavage of 6 is unusual for non-enzymatic radical reactions, indicating that this process is mediated by the protein. Moreover, the enzyme also controls the radical terminating hydrogen atom transfer step facilitating high levels of enantioselectivity of the final product. The researchers were able to selectively access both enantiomers of the coupling product by using EREDs from different organisms under cyan light irradiation. Furthermore, the reaction can be run on a preparative scale, and shows a good substrate scope. Notably, molecular photoredox catalysts reduced the nitroalkane to the oxime, thus failing the targeted coupling reaction. This work testifies to the unique selectivity and reactivity that can be achieved with enzymes.
Original reference: Nature https://doi.org/10.1038/s41586-022-05167-1 (2022)
This is a preview of subscription content, access via your institution