Photoexcitation of flavoenzymes enables a stereoselective radical cyclization

Abstract

Photoexcitation is a common strategy for initiating radical reactions in chemical synthesis. We found that photoexcitation of flavin-dependent “ene”-reductases changes their catalytic function, enabling these enzymes to promote an asymmetric radical cyclization. This reactivity enables the construction of five-, six-, seven-, and eight-membered lactams with stereochemical preference conferred by the enzyme active site. After formation of a prochiral radical, the enzyme guides the delivery of a hydrogen atom from flavin—a challenging feat for small-molecule chemical reagents. The initial electron transfer occurs through direct excitation of an electron donor-acceptor complex that forms between the substrate and the reduced flavin cofactor within the enzyme active site. Photoexcitation of promiscuous flavoenzymes has thus furnished a previously unknown biocatalytic reaction.

Mechanistic basis for tuning iridium hydride photochemistry from H2 evolution to hydride transfer hydrodechlorination

“…The highly efficient reduction is noteworthy because alkyl chlorides are traditionally challenging substrates in photoredox catalysis reactions that rely on SET pathways. 7,8,[64][65][66] The unusual reactivity with unactivated alkyl chlorides is attributed to the incorporation of a reactive metal-hydride bond in the photocatalyst, which engenders a long-lived charge-transfer excited state and enables a self-quenching pathway that effectively couples light absorption and bond-forming PCET steps. 36,45 Although the net reaction is a hydride transfer from iridium to CH 2 Cl 2 , two different C-H bond-forming pathways are involved in the transformation.…”

Enabling protein-hosted organocatalytic transformations

“…Additionally, repurposing avin-dependent enzymes for novel photo-redox reactions represent a valuable avenue for articial enzyme design. [156][157][158] In summary, this review illustrated that the design of articial organocatalytic enzymes has become an exciting area of research and it will play critical roles in both chemical and synthetic biology research in future.…”

Extending the Library of Light‐Dependent Protochlorophyllide Oxidoreductases and their Solvent Tolerance, Stability in Light and Cofactor Flexibility

“…Interestingly, these positions are not the amino acids responsible for direct NADPH binding as deduced from the recently published crystal structure from Synechocystis. [27] As selected enzymes, which are in nature not light-dependent, have been shown to possess promiscuous activity under the influence of light, [28][29] LPORs as NADPH-dependent natural photoenzymes may be targets for further studies of light dependent reactions.…”