Oxidative Cyclization in Natural Product Biosynthesis

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. The 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 installation of epoxides and halogens into acyclic scaffolds to drive subsequent cyclizations are separately discussed as examples of “disappearing” reactive handles. Lastly, oxidative rearrangement of rings systems, including contractions and expansions will be covered.

Visualizing the Reaction Cycle in an Iron(II)- and 2-(Oxo)-glutarate-Dependent Hydroxylase

“…34–35 The vanadyl ion (V IV -oxo) has been shown to occupy divalent cation binding sites in proteins, and, in a recent study, to mimic the H•-abstracting ferryl intermediate (Fe IV =O) in Fe/2OG enzymes. 36 Vanadium(IV) is a d 1 ion with a ground-state total electron spin quantum number ( S ) of 1/2, and the VioC•vanadyl•succinate•L-Arg complex therefore exhibits an electron paramagnetic resonance (EPR) spectrum with octet splitting due to hyperfine coupling with the 51 V nucleus (100% natural abundance, I = 7/2; fig. S7).…”

Late-Stage Terpene Cyclization by an Integral Membrane Cyclase in the Biosynthesis of Isoprenoid Epoxycyclohexenone Natural Products

“…All subsequently characterized Pyr4 homologs from indole-diterpene and meroterpenoid pathways work in tandem with a flavin-dependent monooxygenase to cyclize the linear terpene unit in a two-step reaction, during which the “disappearing” epoxide serves as the site of proton-initiated cyclization steps. 12 In contrast, MacJ identified here represents the first example of a membrane-bound type II cyclase that can cyclize a terpene through direct protonation of the terminal olefinic bond without requiring the epoxidation step. Our phylogenetic analysis showed that many homologs of MacJ of unknown function are found in the same subclade as MacJ 19 , suggesting new cyclized meroterpenoid natural products may be mined from these pathways.…”

“…11 During cyclization of the terpene portion of most hybrid terpene natural products such as in indole diterpenes and meroterpenoids (polyketide-terpene), a family of TCs, known as membrane-bound meroterpenoid TCs, use the epoxide-opening mechanism as in OSC to initiate the reaction. 12 In these pathways, TC-catalyzed cyclization typically occurs early in the biosynthetic pathway as a scaffold building step, and is following by post-cyclization modifications to yield the final products. In contrast, we expect cyclization of macrophorin to occur as a late-stage biosynthetic transformation, with the linear yanuthone as a possible precursor.…”

A Cascade of Redox Reactions Generates Complexity in the Biosynthesis of the Protein Phosphatase‐2 Inhibitor Rubratoxin A

“…[1] Many of the redox transformations are unprecedented in primary metabolism and can lead to significant morphing of the polyketide product, as illustrated in the biosynthesis of aflatoxin. [1] Many of the redox transformations are unprecedented in primary metabolism and can lead to significant morphing of the polyketide product, as illustrated in the biosynthesis of aflatoxin.…”