Oxidative Cyclization in Natural Product Biosynthesis

Area of Science:

• Biochemistry
• Organic Chemistry
• Natural Product Biosynthesis

Background:

• Oxidative cyclizations are crucial in natural product biosynthesis, enabling the formation of complex molecular scaffolds.
• These transformations from acyclic precursors to cyclic products yield structural rigidity and biological activity.
• Dramatic structural alterations in natural products often arise from oxidative cyclization events.

Purpose of the Study:

• To review the diverse strategies utilized by nature for creating new intra(inter)molecular bonds through redox chemistry.
• To provide a comprehensive overview of both oxidation- and reduction-enabled cyclization mechanisms, with a focus on oxidative pathways.
• To highlight the role of specific enzymes and cofactors in driving these complex transformations.

Main Methods:

• Discussion of radical cyclizations catalyzed by P450, nonheme iron, alpha-ketoglutarate (α-KG)-dependent oxygenases, and radical S-adenosylmethionine (SAM) enzymes.
• Examination of nonradical cyclizations facilitated by flavin-dependent monooxygenases and NAD(P)H-dependent reductases.
• Analysis of oxidative installations of epoxides and halogens as 'disappearing' reactive handles and oxidative rearrangements of ring systems.

Main Results:

• Illustrates the use of molecular oxygen and S-adenosylmethionine in one-electron manifolds for forging bonds at unactivated sites.
• Demonstrates the application of two-electron manifolds in initiating cyclization reactions via flavin and NAD(P)H-dependent enzymes.
• Covers oxidative ring contractions and expansions as significant biosynthetic rearrangements.

Conclusions:

• Nature utilizes a sophisticated array of redox strategies for oxidative cyclization in natural product biosynthesis.
• Enzymatic catalysis, involving both radical and nonradical pathways, is key to forming complex molecular architectures.
• Understanding these mechanisms provides insights into biosynthetic pathways and potential synthetic applications.