Organocatalytic Asymmetric Synthesis of Natural Products

The asymmetric synthesis of natural products using small organic molecules as catalysts has emerged as a powerful tool to construct complex, chiral architectures under mild conditions. By harnessing the inherent chirality of organocatalysts, chemists have achieved highly selective transformations that rival traditional metal-based methods in both efficiency and environmental profile. This approach encompasses diverse reaction manifolds including Michael additions, cycloadditions and cyclisations to forge carbon–carbon and carbon–heteroatom bonds with precise stereochemical control. Recent advances have focused on modular catalyst design, enabling fine-tuning of activity and selectivity for a wide array of natural product frameworks such as tetrahydropyrans, spirocycles and polycyclic ethers. These methods not only streamline the synthesis of biologically active compounds but also facilitate rapid access to novel analogues by exploiting cascade and dynamic kinetic resolution strategies. The resulting protocols often operate at ambient temperature, obviate the need for metal reagents and tolerate sensitive functional groups, thus aligning with the principles of green chemistry and broadening the scope of target molecules accessible through asymmetric catalysis.

Research from Nature Portfolio

Seminal work has introduced a dynamic kinetic resolution approach to access highly enantioenriched six-membered oxacycles featuring multiple stereocentres in a single operation. A chiral bifunctional organocatalyst selectively binds a reversibly formed intermediate, exploiting both hydrogen bonding and anomeric effects to achieve outstanding enantio- and diastereocontrol. The methodology delivers tetrahydropyran frameworks bearing fully substituted chiral centres, which can be elaborated into diverse motifs found in natural products and therapeutic leads. This platform has inspired further exploration of catalyst–substrate recognition patterns and the extension of dynamic resolution strategies to other heterocyclic scaffolds.

Organocatalytic Asymmetric Synthesis of Natural Products publication trend

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

Technical terms

Organocatalyst: A small organic molecule that accelerates chemical reactions by providing a chiral environment, without the use of metals.

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

Diastereoselectivity: The selective formation of one diastereomer over others when multiple stereocentres are created in a reaction.

Dynamic kinetic resolution: A process in which racemisation of an intermediate is coupled with a selective transformation, allowing complete conversion to a single enantiomer.

Oxa-Michael reaction: A conjugate addition in which an oxygen nucleophile adds to an α,β-unsaturated carbonyl compound, forming a C–O bond.

References

1. Organocatalytic enantio- and diastereoselective cycloetherification via dynamic kinetic resolution of chiral cyanohydrins. Nature Communications (2017).
2. Enantioselective “clip-cycle” synthesis of di-, tri- and spiro-substituted tetrahydropyrans. Organic & Biomolecular Chemistry (2022).