Pyridylmethyl Radicals for Enantioselective Alkene Hydroalkylation Using “Ene”-Reductases

Abstract

Aromatic electron-deficient heterocycles, such as pyridines, are found in many biologically relevant structures, including those with medicinal applications. Methods for their substitution can streamline the synthesis of valuable molecules and allow access to unexplored chemical space. However, enantioselective methods for these derivatizations remain lacking, especially at remote stereocenters. Here, we present a photoenzymatic reaction for the reductive coupling of electron-deficient heterocycles with alkenes using flavin-dependent "ene"-reductases. This transformation results in the generation of a γ-stereocenter with high enantioselectivity. We propose that this light-driven transformation proceeds via excitation of a transient enzyme−substrate complex, enabling the enzyme to access the reductive potential needed for radical initiation when the substrates are bound in the active site. This work represents a stereoselective method for synthesizing derivatives of pyridine and similar heterocycles and an expansion of the substrate capabilities of "ene"-reductases in chemical synthesis.

Single-Electron Oxidation-Initiated Enantioselective Hydrosulfonylation of Olefins Enabled by Photoenzymatic Catalysis

“…Thus, GluER-W100F-W342F was identified as the optimal mutant for the scope studies. To the best of our knowledge, the W100F and W342F mutations have yet to be reported in prior photoenzymatic systems. − To demonstrate the synthetic utility of the method, the model reaction was scaled up to 1 mmol, and 3a was obtained in 66% yield with 96:4 er (Figure a). Control experiments using DMSO or CH 3 CN instead of THF as the cosolvent resulted in diminished yield and enantiopurity of 3 (Figure c).…”

“…By fine-tuning substituents of the peptide thiol catalysts, Knowles, Miller, and Houk recently reported an elegant asymmetric hydroamination reaction that accommodates acyclic olefins, although a sterically hindered substituent such as tert -butyl is generally required for the enol ester substrates to achieve a high enantioselectivity. Having realized the challenges associated with acyclic olefins using small-molecule catalysts and inspired by previous work on photoenzymatic catalysis, − we questioned whether we could develop complementary oxidation-initiated photoenzymatic hydrofunctionalization reactions that are compatible with acyclic olefins and allow the use of easily oxidized radical precursors as the substrate. Herein, we report the realization of such a goal by developing an oxidative photoenzymatic enantioselective hydrosulfonylation of olefins using an engineered gluconobacter ene-reductase (GluER) (Scheme c).…”

“…In this context, the Hyster group made a pioneering contribution in 2016 by merging visible light with non-natural photoenzymes to tackle this challenge. , Through photoexcitation of nicotinamide-dependent ketoreductases, highly enantioselective HAT was achieved via radical hydrodehalogenation of lactones . Following this breakthrough, the groups of Hyster, Zhao, Xu and Wu, and others have extensively investigated photoexcitation of flavin-dependent “ene”-reductases (ERs) for enantioselective HAT in the context of hydrodehalogenation and hydrofunctionalization of olefins. It should be noted that all of these reactions are initiated by single-electron reduction of the substrate via the formation of an electron donor–acceptor (EDA) complex (Scheme b).…”

From Ground-State to Excited-State Activation Modes: Flavin-Dependent “Ene”-Reductases Catalyzed Non-natural Radical Reactions

“…We tested a series of GluER homologues and discovered that the ERED from G. morbifer (MonstER) could couple 4-(chloromethyl)­pyridine 43 with α-methylstyrene in 71% yield with 94:6 er using violet light (Figure ). In these reactions, the remaining mass balance is the hydrodehalogenated starting material. Presumably, the π-system of chloromethylpyridine enables CT-complex formation without the alkene.…”

Asymmetric Synthesis of α-Chloroamides via Photoenzymatic Hydroalkylation of Olefins

“…Our group and others previously demonstrated that flavin-dependent “ene”-reductases (EREDs) could catalyze the intermolecular hydroalkylations of olefins using α-halocarbonyl compounds as radical precursors. − Building upon these foundational methods has enabled a variety of stereoselective reactions involving the formation of C–C, − C–N, , C–O, and C–S bonds . These reactions proceed via the single electron reduction of the alkyl halide by flavin hydroquinone (FMN hq ) to afford a radical intermediate that reacts with the alkene to afford an alkyl radical.…”