Asymmetric redox-neutral radical cyclization catalysed by flavin-dependent ‘ene’-reductases

Abstract

Flavin-dependent 'ene'-reductases (EREDs) are exquisite catalysts for effecting stereoselective reductions. While these reactions typically proceed through a hydride transfer mechanism, we recently found that EREDs can also catalyze reductive dehalogenations and cyclizations via single electron transfer mechanisms. Here we demonstrate that these enzymes can catalyze redox-neutral radical cyclizations to produce enantioenriched oxindoles from α-haloamides. This transformation is a CC bond forming reaction currently unknown in nature and one for which there are no catalytic asymmetric examples. Mechanistic studies indicate the reaction proceeds via the flavin semiquinone/quinone redox couple, where ground state flavin semiquinone provides the electron for substrate reduction and flavin quinone oxidizes the vinylogous α-amido radical formed after cyclization. This mechanistic manifold was previously unknown for this enzyme family, highlighting the versatility of EREDs in asymmetric synthesis.

Photochemical Mechanism of Light-Driven Fatty Acid Photodecarboxylase

“… 7 Moreover, a mechanistic understanding of FAP photochemistry could be informative on the repurposing of thermally activated flavoenzymes as new photobiocatalysts. 9 − 11 In recent years, photoexcitation of flavin-dependent “ene” reductases has opened up new reaction channels, allowing these enzymes to catalyze ketone reduction 9 and asymmetric radical cyclization reactions. 10 , 11 These are exciting applications of flavoenzymes in photobiocatalysis.…”

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.…”

Intramolecular Dehydrogenative Coupling Approach to 2‐Oxindoles Using Fe(OAc)2/NaI/Na2S2O8

“…1b – 1u were all synthesized according to the method of 1a . [ 18 ] 1b , [ 26 ] 1e , [ 33 ] 1h , [ 24 ] 1l , [ 24 ] 1m , [ 22 ] 1n , [ 24 ] 1o , [ 24 ] 1r , [ 34 ] 1s [ 22 ] and 1t [ 36 ] had been reported. 1c , 1d , 1f , 1g , 1i , 1j , 1k , 1p , 1q and 1u were new.…”