Enantioselective Total Synthesis of Natural Products

Enantioselective total synthesis refers to the construction of complex natural molecules in a manner that delivers a single desired mirror‐image form. The approach combines stepwise bond‐forming reactions with precise control of stereochemistry, often at multiple contiguous centres, to replicate or improve upon nature’s architects. Such endeavours underpin the discovery and development of pharmaceuticals, agrochemicals and materials by supplying pure enantiomers that exhibit improved efficacy, reduced side effects and predictable biological interactions. Key challenges include the installation of quaternary stereocentres, the orchestration of cascade reactions and the diversification of densely functionalised scaffolds. Modern solutions draw upon transition‐metal catalysis, organocatalysis, photoredox processes and biocatalysis to achieve high levels of enantiocontrol under mild conditions. The global significance of these methods is reflected in their contributions to sustainable supply chains, the elaboration of natural‐product analogues and the advancement of mechanistic understanding in stereoselective catalysis.

Research from Nature Portfolio

Recent studies have harnessed visible‐light photoredox catalysis to effect diastereoselective dearomative prenylation and reverse‐prenylation of electron‐deficient indoles. A tandem radical addition/Ireland–Claisen rearrangement sequence under mild conditions enables the rapid assembly of 2,3‐disubstituted indolines with excellent diastereoselectivity (>20:1). The methodology accommodates both tertiary and secondary α‐silylamines, delivering lactam‐fused indolines in one‐pot syntheses. Proposed mechanistic experiments elucidate a photoredox‐driven radical pathway. Preliminary biological assays reveal that the resulting scaffolds exhibit promising anticancer activity, demonstrating the utility of this approach for accessing chiral alkaloid frameworks.

Enantioselective Total Synthesis of Natural Products publication trend

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

Technical terms

Enantioselectivity: The preferential formation of one enantiomer over its mirror image in a chemical reaction.

Total synthesis: The complete chemical assembly of a complex natural molecule from simple building blocks.

Quaternary stereocentre: A carbon atom bonded to four distinct substituents, presenting a significant stereochemical challenge.

Photoredox catalysis: A method that uses light to trigger single‐electron transfer events, enabling radical reactions under mild conditions.

Decarboxylation: A process in which a carboxyl group is removed from a molecule, often generating reactive intermediates for further bond formation.

References

1. Photoredox-catalyzed diastereoselective dearomative prenylation and reverse-prenylation of electron-deficient indole derivatives. Nature Communications (2023).
2. Ni-catalyzed asymmetric decarboxylation for the construction of carbocycles with contiguous quaternary carbon stereocenters. Chemical Science (2025).
3. Synthesis and Structure–Activity Analysis of Novel Potential Antifungal Cyclotryptamine Alkaloid Derivatives. Molecules (2023).
4. Total Synthesis of (−)-Glionitrin A and B Enabled by an Asymmetric Oxidative Sulfenylation of Triketopiperazines. Journal of the American Chemical Society (2021).