Oxidative Chemistry in Natural Product Synthesis

Oxidative chemistry occupies a central role in the construction of complex natural products, enabling the installation of key functional groups, formation of carbon–carbon and carbon–heteroatom bonds, and modulation of molecular architecture in a single operation. Traditional oxidative methods, often reliant on stoichiometric metal oxidants or harsh reagents, have in recent years given way to more selective, catalytic, and environmentally benign approaches. Enzymatic oxidations, photoredox catalysis and electrochemical methods now allow precise control over reactivity and selectivity, even in densely functionalised settings. These advances facilitate late‐stage diversification and streamline synthetic sequences, reducing the number of steps and waste generated. Global significance arises from applications in drug discovery, agrochemical development and the synthesis of molecular probes, where oxidative transformations provide direct access to pharmacophores such as epoxides, hydroxylated frameworks, quinones and cross‐linked biaryl motifs. Increasing attention to sustainability has also driven the adoption of catalytic aerobic oxidations and renewable catalysts, underscoring the practical utility of oxidative methods in contemporary natural product synthesis.

Research from Nature Portfolio

Recent studies have demonstrated the power of biocatalytic oxidation to achieve site‐selective C–H functionalisation in complex alkaloid frameworks. Enzyme engineering of cytochrome P450 variants now permits hydroxylation at previously inaccessible positions, enabling concise access to hydroxylated terpenoid and indole‐derived scaffolds. In a complementary advance, photoredox‐mediated oxidation coupled with organocatalysis has been used to effect radical cascades, forging multiple rings in a single photo‐induced step and delivering intricate polycyclic structures under mild conditions. Electrochemical oxidation methods have also emerged as a versatile platform for C–C bond formation: anodic oxidation of electron‐rich substrates triggers radical‐polar crossover sequences that install cross‐coupled biaryl linkages in one pot, obviating the need for pre‐functionalised coupling partners and minimising reagent waste.

Oxidative Chemistry in Natural Product Synthesis publication trend

The graph below shows the total number of articles in oxidative chemistry in natural product synthesis across all publications each year (not limited to Nature Index journals).

Technical terms

Photoredox catalysis: Use of visible‐light‐activated catalysts to generate radical species for selective bond‐forming reactions under mild conditions.

Cytochrome P450: A family of heme‐containing enzymes capable of regio‐ and stereoselective oxidation of unactivated C–H bonds.

Radical‐polar crossover: A mechanistic sequence in which a radical intermediate undergoes further oxidation or reduction to form a cationic or anionic species that participates in subsequent bond formation.

Aerobic oxidation: Oxidative processes that employ molecular oxygen as the terminal oxidant, offering a green alternative to stoichiometric oxidants.

Dearomatisation: Conversion of an aromatic ring into a non‐aromatic or partially saturated structure, enabling installation of three‐dimensional complexity.

References

1. Intermolecular dearomative C2-arylation of N -Ac indoles activated by FeCl 3. Chemical Communications (2016).
2. Versatile Biaryls and Fused Aromatics through Oxidative Coupling of Hydroquinones with (Hetero)Arenes. ChemistrySelect (2024).