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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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This content will become publicly available on March 18, 2027
Photodriven Sm-Catalyzed Asymmetric Ketyl-Olefin Coupling
SmI2 is a privileged, single-electron reductant employed in the synthesis of diverse products. Though traditionally used in (super)stoichiometric amounts, SmI2 has recently been employed catalytically with viable turnover strategies. Enantioselective reductive cross-coupling reactions mediated by SmI2 are scarce and asymmetric methods that use catalytic quantities of SmI2 are unknown. Herein, we report an enantioselective ketyl-olefin coupling, employing a SmI2-derived catalyst with a widely available chiral pyridine-bis(oxazoline) (PyBOX) ligand and a commercially available Ir photocatalyst. A combination of optical, electrochemical, and computational data reveals that a Sm-stabilized PyBOX radical is the reactive species responsible for initiating the reductive coupling step.
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- Award ID(s):
- 2002158
- PAR ID:
- 10682046
- Publisher / Repository:
- American Chemical Society
- Date Published:
- Journal Name:
- Journal of the American Chemical Society
- Volume:
- 148
- Issue:
- 10
- ISSN:
- 0002-7863
- Page Range / eLocation ID:
- 10828 to 10834
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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