Review

. 2017 Apr 26;117(8):5226-5333.

doi: 10.1021/acs.chemrev.6b00478. Epub 2016 Dec 12.

Oxidative Cyclization in Natural Product Biosynthesis

Man-Cheng Tang¹, Yi Zou¹, Kenji Watanabe², Christopher T Walsh³, Yi Tang¹

Affiliations

¹ Department of Chemical and Biomolecular Engineering, and Department of Chemistry and Biochemistry, University of California, Los Angeles , 420 Westwood Plaza, Los Angeles, California 90095, United States.
² Department of Pharmaceutical Sciences, University of Shizuoka , Shizuoka 422-8526, Japan.
³ Stanford University Chemistry, Engineering, and Medicine for Human Health (ChEM-H), Stanford University , 443 Via Ortega, Stanford, California 94305, United States.

PMID: 27936626
PMCID: PMC5406274
DOI: 10.1021/acs.chemrev.6b00478

Review

Oxidative Cyclization in Natural Product Biosynthesis

Man-Cheng Tang et al. Chem Rev. 2017.

. 2017 Apr 26;117(8):5226-5333.

doi: 10.1021/acs.chemrev.6b00478. Epub 2016 Dec 12.

Authors

Man-Cheng Tang¹, Yi Zou¹, Kenji Watanabe², Christopher T Walsh³, Yi Tang¹

Affiliations

¹ Department of Chemical and Biomolecular Engineering, and Department of Chemistry and Biochemistry, University of California, Los Angeles , 420 Westwood Plaza, Los Angeles, California 90095, United States.
² Department of Pharmaceutical Sciences, University of Shizuoka , Shizuoka 422-8526, Japan.
³ Stanford University Chemistry, Engineering, and Medicine for Human Health (ChEM-H), Stanford University , 443 Via Ortega, Stanford, California 94305, United States.

PMID: 27936626
PMCID: PMC5406274
DOI: 10.1021/acs.chemrev.6b00478

Abstract

Oxidative cyclizations are important transformations that occur widely during natural product biosynthesis. The transformations from acyclic precursors to cyclized products can afford morphed scaffolds, structural rigidity, and biological activities. Some of the most dramatic structural alterations in natural product biosynthesis occur through oxidative cyclization. In this Review, we examine the different strategies used by nature to create new intra(inter)molecular bonds via redox chemistry. This Review will cover both oxidation- and reduction-enabled cyclization mechanisms, with an emphasis on the former. Radical cyclizations catalyzed by P450, nonheme iron, α-KG-dependent oxygenases, and radical SAM enzymes are discussed to illustrate the use of molecular oxygen and S-adenosylmethionine to forge new bonds at unactivated sites via one-electron manifolds. Nonradical cyclizations catalyzed by flavin-dependent monooxygenases and NAD(P)H-dependent reductases are covered to show the use of two-electron manifolds in initiating cyclization reactions. The oxidative installations of epoxides and halogens into acyclic scaffolds to drive subsequent cyclizations are separately discussed as examples of "disappearing" reactive handles. Last, oxidative rearrangement of rings systems, including contractions and expansions, will be covered.

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Figures

**Scheme 1**
Catalytic Cycle of Cytochrome P450

**Scheme 2**
Catalytic Cycle of Nonheme Iron α-KG-Dependent Oxygenase

**Scheme 3**
Catalytic Cycle of Radical SAM Enzyme

**Scheme 4**
Catalytic Cycle of Copper-Dependent Tyrosinase

**Scheme 5**
Catalytic Cycle of Flavin-Dependent Monooxygenase

**Scheme 6**
NAD(P)H-Dependent Reductases and Dehydrogenases

**Scheme 7**
Models of Radical Cyclization in Natural Product Biosynthesis

**Scheme 8**
P450-Catalyzed Phenol Coupling Reactions in Glycopeptide Biosynthesis

**Scheme 9**
Mechanistic Proposal of C-C and C-O Phenol Coupling Catalyzed by P450

**Scheme 10**
Oxidative Coupling in Indolocarbazole Biosynthesis

**Scheme 11**
Mechanistic Proposal for Chromopyrrolic Acid Formation

**Scheme 12**
Proposed Catalytic Mechanism of Indole Coupling in Indolocarbazole Biosynthesis

**Scheme 13**
Alternative Proposal for the Mechanism of StaP

**Scheme 14**
Proposed Catalytic Mechanism for the Last C-N Coupling Step in Staurosporine Biosynthesis

**Scheme 15**
Formation of the Communesin Core by the P450 CnsC

**Scheme 16**
Biomimetic Synthesis of Communesin K by Movassaghi

**Scheme 17**
Possible Mechanisms of CYP121 catalyzed C-C coupling in Mycocyclosin Pathway

**Scheme 18**
Possible Mechanisms of P450-catalyzed C-C Coupling in Herquline Pathway

**Scheme 19**
Proposed Pathway for C-C Coupling in Usnic Acid

**Scheme 20**
Computationally Predicted Oxidative Cyclization Mechanism of VrtK

**Scheme 21**
Proposed Radical Mediated Cyclization in Brefeldin A Biosynthesis

**Scheme 22**
P450 Catalyzed C-C Coupling in Salutaridine and Magnoflorine Biosynthesis

**Scheme 23**
P450 Catalyzed Phenol Coupling in Amaryllidaceae Alkaloid Biosynthesis

**Scheme 24**
Diradical Combination in (+)-Pinoresinol Biosynthesis

**Scheme 25**
Possible Mechanisms of GsfF catalyzed C-O Coupling in Griseofulvin Biosynthesis

**Scheme 26**
Multi-copper Protein Catalyzed C-O Coupling to from Grisan-Containing Compounds

**Scheme 27**
Heterodimeric Radical Coupling in Tubocurarine Biosynthesis

**Scheme 28**
Proposed Mechanisms of P450-catalyzed Formation of Tetrahydrofuran in Aureothin

**Scheme 29**
Proposed mechanisms of P450 Catalyzed Oxidative Cyclization in Penitrem D Pathway

**Scheme 30**
Proposed Oxidative Cyclization Mechanisms in Pyrrocidine Biosynthesis

**Scheme 31**
Proposed Mechanism of P450 Catalyzed Phenoxy Radical Addition in Salinamide Pathway

**Scheme 32**
Mechanism of Reactions Catalyzed by Allene Oxide Synthase (CYP74A)

**Scheme 33**
P450 Catalyzed Formation of Methylenedioxy Bridge in Natural Products

**Scheme 34**
Possible Mechanisms of P450 Catalyzed C-N Coupling in Fumitremorgin C Pathway

**Scheme 35**
Possible Mechanisms of P450-Catalyzed C-N Coupling in Indolactam Pathway

**Scheme 36**
Possible Mechanisms of P450 Catalyzed C-S Coupling in Griseoviridin Pathway

**Scheme 37**
Possible Mechansims of the EasH Catalyzed Cyclopropane Formation in Cycloclavine

**Scheme 38**
Mechanism of SnoK Catalyzed C-C Coupling in Nogalamycin Biosynthesis

**Scheme 39**
Biosynthetic Pathway of (−)-4-Desmethylepipodophyllotoxin in Mayapple

**Scheme 40**
cpEasH Catalyzed C-O coupling in Dihydroergotamine Biosynthesis

**Scheme 41**
Oxidative Cyclization in Orthosomycin Biosynthesis

**Scheme 42**
Mechanism of Oxidative Cyclization During Clavaminic Acid Formation

**Scheme 43**
Proposed Mechanism of Epoxide Formation in Scopolamine by Hyoscyamine 6β-Hydroxylase

**Scheme 44**
Proposed Mechanism of FtmOx1 Catalyzed Endoperoxide Formation

**Scheme 45**
Mechanism of C-N Coupling in Capreomycidine Formation

**Scheme 46**
Mechanisms of Methylproline Formation in NRP Natural Products

**Scheme 47**
Biosynthesis of Fosfomycin and Proposed Mechanism of HppE

**Scheme 48**
Mechanism of Isopenicillin N Synthase

**Scheme 49**
Proposed Catalytic Cycle of Rieske Oxygenases in Prodiginine Biosynthesis

**Scheme 50**
Proposed Mechanism of C-C coupling in Streptide Biosynthesis

**Scheme 51**
Proposed mechanism of C-C Coupling in Menaquinone Biosynthesis

**Scheme 52**
Proposed Mechanism of Radical-SAM Enzyme Catalyzed Cyclopropanation in Jawsamycin

**Scheme 53**
Mechanism of C-S Coupling Steps in Biotin Biosynthesis

**Scheme 54**
Proposed Mechanisms of C-S Coupling Steps in Subtilosin Biosynthesis

**Scheme 55**
Models of Nonradical Cyclization in Natural Product Biosynthesis

**Scheme 56**
Reduction-Enabled Cyclization in Nostocyclopeptide A2 Biosynthesis

**Scheme 57**
Pictet-Spengler Reactions in Saframycin A Biosynthesis

**Scheme 58**
Reduction-Enabled Hetero Diel-Alder Cyclization in Leporin Biosynthesis

**Scheme 59**
Hydride-Mediated Cyclization in Ikarugamycin Biosynthesis

**Scheme 60**
Reductive Cyclization of Iridoid by Iridoid Synthase in Plants

**Scheme 61**
The Reaction Catalyzed by Berberine Bridge Enzyme in S-Scoulerine Biosynthesis

**Scheme 62**
Proposed Role of BBE in Fumoisoquins Biosynthesis

**Scheme 63**
Proposed Mechanism of Tetrahydrocannabinol Biosynthesis

**Scheme 64**
Desaturative Macrocyclization in Lankacidin Biosynthesis

**Scheme 65**
Desaturative Cyclization in Cyclopiazonic acid Biosynthesis

**Scheme 66**
Mechanism of Chlorizidine A Cyclization

**Scheme 67**
Selected Natural Products that Contain Oxazole and Thiazole Rings

**Scheme 68**
Mechanisms of Oxazole and Thiozole Formation

**Scheme 69**
Disulfide Bond Formation from Dithiols in Natural Products Biosynthesis

**Scheme 70**
Examples of Disulfide Variants in Leinamycin and Echinomycin

**Scheme 71**
Formation of L-Pipecolic Acid in Natural Products

**Scheme 72**
Cyclization of Chanoclavine-I to D-Lysergic Acid

**Scheme 73**
Oxidative Formation of 6,6-Spiroacetal as Shown in Reveromycin

**Scheme 74**
Oxidative Scaffold Maturation in Fungal Indole Alkaloid Biosynthesis

**Scheme 75**
Transient Oxidation of Catechols to Set up Cyclization

**Scheme 76**
Oxidative Formation of Phenalenone

**Scheme 77**
Flavoenzyme Catalyzed Favorskii Rearrangement in Enterocin Biosynthesis

**Scheme 78**
Cyclization of L-Ornithine to Piperazic Acid in NRP Natural Products

**Scheme 79**
Proposed Formation of Furanone Scaffold in Aurafuron A Biosynthesis

**Scheme 80**
Proposed Diels-Alder Reaction in Sordarin Biosynthesis

**Scheme 81**
Oxidation Mediated [4+2] Cyclizations in Solanapyrone Biosynthesis

**Scheme 82**
On-Assembly Line Diels-Alder Reaction During Lovastatin Biosynthesis

**Scheme 83**
Cyclization Steps in Spinosyn A Biosynthesis

**Scheme 84**
[4+2] Cyclization in Formation of 5,6-Spirocycle in Abyssomicin C

**Scheme 85**
[4+2] Cyclizations in Formation of *cis*-Decalin and 5,6-Spirocycle in Pyrroindomycin B

**Scheme 86**
Models of Cyclization via Epoxidation in Natural Product Biosynthesis

**Scheme 87**
P450 and Flavoenzyme Catalyzed Formation of Epoxides

**Scheme 88**
Cyclic Polyethers formation via Epoxide Intermediates

**Scheme 89**
Mechanism of Polyether Formation in Monensin Biosynthesis

**Scheme 90**
Mechanism of Polyether Formation in Nanchangmycin Biosynthesis

**Scheme 91**
Proposed mechanism of Polyether Formation in Heronapyrrole Biosynthesis

**Scheme 92**
Cyclic Ethers formation via Epoxide Intermediates in Solamin and Aurovertin

**Scheme 93**
Triterpene Cyclization via Epoxide and Cation Intermediates

**Scheme 94**
Engineering of Squalene-Hopene Cyclase as a Protonase

**Scheme 95**
Alternative Triterpene Cyclization in Yardenone and Abudinol Biosynthesis

**Scheme 96**
Epoxide Mediated Cyclization in Xiamycin Biosynthesis

**Scheme 97**
Epoxide Mediated Cyclization in Paxilline and Emindoles Biosynthesis

**Scheme 98**
Epoxide Mediated Cyclization in Anominine, Aflavinine and Tubingensin Biosynthesis

**Scheme 99**
Epoxide Mediated Cyclization in Pyripyopene Biosynthesis

**Scheme 100**
Biosynthetic Pathway of Fungal Meroterpenoids

**Scheme 101**
Enzyme-Catalyzed Cationic Epoxide Rearrangements in Quinolone Alkaloid Biosynthesis

**Scheme 102**
Proposed Cyclization Mechanism during Aurachin A Biosynthesis

**Scheme 103**
Oxetane Formation via an Epoxide Intermediate During Paclitaxel Maturation

**Scheme 104**
Proposed Epoxide Intermediates in Acetylaranotin and Gliotoxin Biosynthesis

**Scheme 105**
Indole Epoxidation as a Key Step in Fungal Indole Alkaloid Biosynthesis

**Scheme 106**
Indole Epoxidation in Notoamide Biosynthesis

**Scheme 107**
Indole Epoxidation Sets Up Spirocycle Formation in Spirotryprostatin

**Scheme 108**
Indole Epoxidation Mediated Carbazole Formation in Xiamycin Biosynthesis

**Scheme 109**
Indole Epoxidation Mediated Cyclization in Plant Metabolite Biosynthesis

**Scheme 110**
Epoxidation Mediated Cyclization in Heronamides Biosynthesis

**Scheme 111**
Epoxidation Mediated Oxo-Spiro Ring Formation in Pseurotin A Biosynthesis

**Scheme 112**
Cyclopentenone Formation in Jasmonic acid and Clavulone I Biosynthesis

**Scheme 113**
Models of Cyclization via Halogenation in Natural Product Biosynthesis

**Scheme 114**
Catalytic Cycles of Vanadium Haloperoxidases and α-KG Dependent Halogenase

**Scheme 115**
VHPO Catalyzed Formation of Merochlorins

**Scheme 116**
Halogenation as a Key Step in SF2415B3 Biosynthesis

**Scheme 117**
Bromination Triggered Cyclization in Laurencin, Laureatin and Snyderol Biosynthesis

**Scheme 118**
Chlorination Mediated Cyclopropane Formation During Curacin A Biosynthesis

**Scheme 119**
Chlorination Mediated Cyclopropane Formation During Coronatine Biosynthesis

**Scheme 120**
Chlorination Mediated Cyclopropane Formation During Kutzneride Biosynthesis

**Scheme 121**
Oxidative Ring Contraction to Form Viridicatin

**Scheme 122**
P450 Catalyzed Ring Contraction in Gibberellic Acid 12 Biosynthesis

**Scheme 123**
Dioxabicyclo[3.2.1]octane Formation in Saliniketals Biosynthesis

**Scheme 124**
Oxidative Ring Contraction in Griseorhodin A Biosynthesis

**Scheme 125**
Oxidative Ring Contraction in Spirotryprostatin G Biosynthesis

**Scheme 126**
Cyclopentenone Ring Formation in Xenovulene A Biosynthesis

**Scheme 127**
Baeyer-Villiger Oxidation in Pentalenolactone Biosynthesis

**Scheme 128**
Baeyer-Villiger Oxidation in Preaustinoid A1 Biosynthesis

**Scheme 129**
Baeyer-Villiger Oxidation in Cytochalasin Biosynthesis

**Scheme 130**
P450 Catalyzed Baeyer-Villiger Ring Expansion in Brassinosteroid Biosynthesis

**Scheme 131**
Oxidative Ring Expansion in Desacetoxycephalosporin C Biosynthesis

**Scheme 132**
Tropolone Ring Formation in Stipitatic Acid Biosynthesis

**Scheme 133**
Oxidative Ring Expansion in Acetylaranotin Biosynthesis

**Scheme 134**
P450 Catalyzed Tetramic Acid to Pyridone in Aspyridone Biosynthesis

**Scheme 135**
P450 Catalyzed Ring Expansion in Penitrem A Biosynthesis

**Scheme 136**
Ring Modifications in Anditomin Biosynthesis

**Scheme 137**
Proposed Mechanisms of Carbon Scaffold Rearrangement during Fumagillin Biosynthesis

**Scheme 138**
Tri-aminal Formation during Meleagrin Biosynthesis

**Scheme 139**
Xanthone Formation via a Cryptic Demethoxylation in Xantholipin Biosynthesis

**Scheme 140**
Angular Polyaromatic Framework Formation in Chartreusin Biosynthesis

**Scheme 141**
Proposed pathways of Oxazolidinone Formation in Jadomycin Biosynthesis

**Scheme 142**
Anthracycline to Angucycline Rearrangement in PD116198 Biosynthesis

**Scheme 143**
Oxidative Ring Arrangements During Aflatoxin Maturation

**Scheme 144**
Oxidative Rearrangements in Betalamic Acid Biosynthesis

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References

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Oxidative Cyclization in Natural Product Biosynthesis

Affiliations

Oxidative Cyclization in Natural Product Biosynthesis

Authors

Affiliations

Abstract

Figures

References

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