Mimicking oxidative radical cyclizations of lignan biosynthesis using redox-neutral photocatalysis

Noncanonical oxygenases are a family of Fe-containing enzymes that catalyze oxidative radical cyclizations. Despite creating key structural features that often define a natural product’s complexity, the mechanisms of these oxidations remain poorly understood and difficult to mimic. In this work, we show that noncanonical cyclizations from lignan biosynthesis can be recreated when presumed biosynthetic radicals are generated using photocatalysis. These conditions afford the ensuing electron rich radicals sufficient time to undergo challenging 5- or 11-membered ring formation that create the defining structural features of the highly oxidized lignans taiwankadsurins A, B and kadsuphilin N. By showing that these cyclizations can occur without enzymatic assistance, we provide a more general strategy for mimicking noncanonical transformations that should broaden their use in organic synthesis.

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Mimicking Noncanonical Oxidations with Redox-Neutral Photocatalysis

10.26434/chemrxiv.9745334 ◽

2019 ◽

Author(s):

Zheng Huang ◽

Jean-Philip Lumb

Keyword(s):

Organic Synthesis ◽

Structural Features ◽

Membered Ring ◽

Ring Formation ◽

Radical Cyclizations ◽

General Strategy ◽

Sufficient Time ◽

Lignan Biosynthesis

Noncanonical oxygenases are a family of Fe-containing enzymes that catalyze oxidative radical cyclizations. Despite creating key structural features that often define a natural product’s complexity, the mechanisms of these oxidations remain poorly understood and difficult to mimic. In this work, we show that noncanonical cyclizations from lignan biosynthesis can be recreated when presumed biosynthetic radicals are generated using photocatalysis. These conditions afford the ensuing electron rich radicals sufficient time to undergo challenging 5- or 11-membered ring formation that create the defining structural features of the highly oxidized lignans taiwankadsurins A, B and kadsuphilin N. By showing that these cyclizations can occur without enzymatic assistance, we provide a more general strategy for mimicking noncanonical transformations that should broaden their use in organic synthesis.

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Free radical cyclizations in alkaloid synthesis: (+)-heliotridine and (+)-hastanecine

Tetrahedron ◽

10.1016/s0040-4020(01)97176-5 ◽

1985 ◽

Vol 41 (19) ◽

pp. 3959-3971 ◽

Cited By ~ 72

Author(s):

Joong-Kwon Choi ◽

David J. Hart

Keyword(s):

Free Radical ◽

Radical Cyclizations ◽

Alkaloid Synthesis ◽

Free Radical Cyclizations

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Activation modes in biocatalytic radical cyclization reactions

Journal of Industrial Microbiology & Biotechnology ◽

10.1093/jimb/kuab021 ◽

2021 ◽

Author(s):

Yuxuan Ye ◽

Haigen Fu ◽

Todd K Hyster

Keyword(s):

Heme Iron ◽

Radical Cyclization ◽

Cytochrome P450 Monooxygenases ◽

Radical Cyclizations ◽

Cyclization Reactions ◽

Complex Molecules ◽

P450 Monooxygenases ◽

Non Heme Iron ◽

Essential Reactions ◽

Isopenicillin N

Abstract Radical cyclizations are essential reactions in the biosynthesis of secondary metabolites and the chemical synthesis of societally valuable molecules. In this review, we highlight the general mechanisms utilized in biocatalytic radical cyclizations. We specifically highlight cytochrome P450 monooxygenases (P450s) involved in the biosynthesis of mycocyclosin and vancomycin, non-heme iron- and α-ketoglutarate-dependent dioxygenases (Fe/αKGDs) used in the biosynthesis of kainic acid, scopolamine, and isopenicillin N, and radical S-adenosylmethionine (SAM) enzymes that facilitate the biosynthesis of oxetanocin A, menaquinone, and F420. Beyond natural mechanisms, we also examine repurposed flavin-dependent ‘ene’-reductases (ERED) for non-natural radical cyclization. Overall, these general mechanisms underscore the opportunity for enzymes to augment and enhance the synthesis of complex molecules using radical mechanisms.

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