Asymmetric C-Alkylation of Nitroalkanes via Enzymatic Photoredox Catalysis

Abstract

Tertiary nitroalkanes and the corresponding α-tertiary amines represent important motifs in bioactive molecules and natural products. The C-alkylation of secondary nitroalkanes with electrophiles is a straightforward strategy for constructing tertiary nitroalkanes; however, controlling the stereoselectivity of this type of reaction remains challenging. Here, we report a highly chemo- and stereoselective C-alkylation of nitroalkanes with alkyl halides catalyzed by an engineered flavin-dependent “ene”-reductase (ERED). Directed evolution of the old yellow enzyme from Geobacillus kaustophilus provided a triple mutant, GkOYE-G7, capable of synthesizing tertiary nitroalkanes in high yield and enantioselectivity. Mechanistic studies indicate that the excitation of an enzyme-templated charge-transfer complex formed between the substrates and cofactor is responsible for radical initiation. Moreover, a single-enzyme two-mechanism cascade reaction was developed to prepare tertiary nitroalkanes from simple nitroalkenes, highlighting the potential to use one enzyme for two mechanistically distinct reactions.

Synthetic Approaches to the Challenging Direct C‐Alkylation and C‐Allylation of Unactivated Nitroalkanes

“…Later on, a modified version of the same process was proved effective in leading the nitroalkylated compounds 146 from α-chlorocarbonyls 145 (Scheme 43). [81] The engineered ERED enzyme GkOYE-G7 was successfully employed in this process under cyan LED irradiation especially using α-chloro-N,N-dimethylacetamides and 2-nitropropylaryl derivatives.…”

“…Later on, a modified version of the same process was proved effective in leading the nitroalkylated compounds 146 from α‐chlorocarbonyls 145 (Scheme 43). [81] …”

Photoredox-Nickel Dual-Catalyzed C-Alkylation of Secondary Nitroalkanes: Access to Sterically Hindered α-Tertiary Amines

“…We now report the development of a new catalyst system, employing both a nickel catalyst and an iridium co-catalyst under visible light conditions that allow alkylation of secondary nitroalkanes with unactivated alkyl iodides to produce tertiary nitroalkanes (Figure , bottom) . In addition, these conditions are general; they provide excellent reactivity for monoalkylation of all classes of nitroalkane substrates (nitromethane, primary, and secondary nitroalkanes).…”

Biocatalytic reduction of alkenes in micro-aqueous organic solvent catalysed by an immobilised ene reductase

“…The performance of these biocatalysts is promising because of their high regio-, stereo-, and chemoselectivity, an expanding enzyme portfolio, substrate scope and type of chemical reactions they can catalyse. [6][7][8] Currently, more than 60 OYEs are characterised from plantae, fungi, bacteria, algae and cyanobacteria, divided across different classes. 4,7 Class III represents thermophilic-like OYEs, among which the thermostable TsOYE (formerly CrS), isolated from Thermus scotoductus SA-01, 9 catalyses a wide range of activated alkene substrates and has potential for scale-up.…”