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Photoenzymatic catalysts are attractive for stereoselective radical reactions because the transformation occurs within tunable enzyme active sites. When using flavoproteins for non-natural photoenzymatic reactions, reductive mechanisms are often used for radical initiation. Oxidative mechanisms for radical formation would enable abundant functional groups, such as amines and carboxylic acids, to serve as radical precursors. However, excited state flavin is short-lived in many proteins because of rapid quenching by the protein scaffold. Here we report that adding an exogenous Ru(bpy)3 2+ cofactor to flavin-dependent ‘ene’-reductases enables the redox-neutral decarboxylative coupling of amino acids with vinylpyridines with high yield and enantioselectivity. Additionally, stereo-complementary enzymes are found to provide access to both enantiomers of the product. Mechanistic studies indicate that Ru(bpy)3 2+ binds to the protein, helping to localize radical formation to the enzyme’s active site. This work expands the types of transformation that can be rendered asymmetric using photoenzymatic catalysis and provides an intriguing mechanism of radical initiation.
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Pyridylmethyl Radicals for Enantioselective Alkene Hydroalkylation Using “Ene”-Reductases
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.
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- Award ID(s):
- 2342328
- PAR ID:
- 10507426
- Publisher / Repository:
- American Chemical Society
- Date Published:
- Journal Name:
- ACS Catalysis
- Volume:
- 13
- Issue:
- 22
- ISSN:
- 2155-5435
- Page Range / eLocation ID:
- 14680 to 14684
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1021/acscatal.3c03771
