Total Synthesis of Natural Products through Photochemical Methods

Photochemical strategies have emerged as powerful tools for the total synthesis of structurally complex natural products, harnessing light energy to access reactive intermediates under mild conditions. These methods enable exceptional control over chemoselectivity, regioselectivity and stereoselectivity, often reducing the number of steps required to assemble intricate ring systems and quaternary stereocentres. Key transformations include photoenolization-mediated cycloadditions and light-induced hydrogen-atom transfers, which facilitate the construction of polycyclic frameworks and spiroacetal motifs that are ubiquitous in bioactive molecules. Advances in reactor technology, notably continuous-flow and microfluidic photoreactors, have further enhanced reaction efficiency and scalability, paving the way for sustainable, large-scale preparation of natural product targets and their analogues. By integrating photochemistry with modern catalytic and flow techniques, chemists are redefining step economy and enabling late-stage functionalisation of complex scaffolds, with significant implications for drug discovery and agrochemical development.

Research from Nature Portfolio

One foundational study introduced a Ti(Oi-Pr)4-promoted photoenolization/Diels–Alder reaction to forge highly substituted polycyclic rings bearing all-carbon quaternary stereocentres under mild photolytic conditions. This approach delivered a broad array of cycloadducts in high yields and stereoselectivities and was successfully employed in the total synthesis of oncocalyxone B. In addition, the same platform enabled late-stage modification of enone-bearing natural products, demonstrating the versatility of photoenol-mediated cycloadditions for both core construction and downstream diversification.

Total Synthesis of Natural Products through Photochemical Methods publication trend

The graph below shows the total number of articles in total synthesis of natural products through photochemical methods across all publications each year (not limited to Nature Index journals).

Technical terms

Total synthesis: The complete chemical assembly of a complex natural product from simple starting materials. Photochemical reaction: A transformation in which light initiates bond cleavage or formation via electronic excitation. Photoenolization: Generation of a reactive enol intermediate upon photoexcitation of an aromatic ketone or aldehyde. Diels–Alder reaction: A [4 + 2] cycloaddition between a conjugated diene and a dienophile to form six-membered rings. 1,6-Hydrogen atom transfer: Intramolecular transfer of a hydrogen radical over a six-atom distance upon photoexcitation, enabling C–H functionalisation. Spiroacetal: A bicyclic motif in which two rings share a single acetal carbon stereogenic centre. Microfluidic photoreactor: A flow-based reactor with microscale channels designed to optimise light penetration and heat transfer for photochemical processes.

References

1. Ti(Oi-Pr)4-promoted photoenolization Diels–Alder reaction to construct polycyclic rings and its synthetic applications. Nature Communications (2017).
2. Enantioselective Total Syntheses of Preussomerins: Control of Spiroacetal Stereogenicity by Photochemical Reaction of a Naphthoquinone through 1,6‐Hydrogen Atom Transfer. Angewandte Chemie (2022).
3. Microfluidic light-driven synthesis of tetracyclic molecular architectures. Beilstein Journal of Organic Chemistry (2018).