Biomimetic Total Synthesis of Natural Products

Biomimetic total synthesis harnesses insights from nature’s own pathways to construct structurally intricate natural products in the laboratory. By emulating enzymatic cascade reactions, researchers achieve rapid assembly of multiple rings, stereocentres and functional groups from relatively simple precursors. This approach often employs designed catalysts or reagents that recreate key biosynthetic microenvironments, enabling high selectivity and efficiency. Advances in catalyst design, supramolecular organisation and light‐driven activation have expanded the repertoire of accessible scaffolds, from terpenoids and alkaloids to aromatic polyketides. Such strategies not only elucidate biosynthetic mechanisms but also facilitate sustainable routes to valuable molecules used in medicine, agriculture and perfumery. Ongoing efforts focus on merging computational prediction with innovative reaction engineering to streamline synthesis, reduce step counts and enhance overall yield. The biomimetic paradigm continues to transform complex molecule production, offering scalable routes to scarce natural derivatives and new analogues with potential biological activity.

Research from Nature Portfolio

Recent work describes a catalytic asymmetric polyene cyclization that converts homofarnesol into the valuable fragrance (−)-ambrox and the sesquiterpene lactone (+)-sclareolide in a single step. Using a highly Brønsted‐acidic imidodiphosphorimidate catalyst in fluorinated alcohols, the reaction proceeds via a concerted mechanism akin to enzyme catalysis, achieving exceptional diastereo- and enantioselectivity. Another study employs in situ-formed fluorinated‐alcohol–amine supramolecular clusters as artificial cyclases, triggering enzyme-like polyene cyclisations across a broad terpene scope. By controlling substrate conformation within dynamic assemblies, these clusters mirror natural terpene cyclases in efficiency and stereocontrol. A complementary advance introduces a convergent reverse two-phase strategy, in which radical redox cyclisation under iridium photoredox catalysis forges aromatic abietane and podocarpane frameworks in only eight steps, showcasing a biomimetic reversal of cyclisation and oxidation phases to expedite synthesis.

Biomimetic Total Synthesis of Natural Products publication trend

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

Technical terms

Biomimetic total synthesis: Imitation of natural biosynthetic pathways to assemble complex molecules.

Polyene cyclization: A cascade reaction that forms multiple carbon–carbon bonds and ring systems from linear polyenes.

Enantioselective catalysis: Catalytic processes that preferentially generate one mirror-image isomer.

Supramolecular assembly: Organisation of molecules via non-covalent interactions to create an enzyme-like microenvironment.

Radical cyclization: Ring formation through free-radical intermediates.

Photoredox catalysis: Light-driven single-electron transfer processes enabling novel reaction pathways.

References

1. The catalytic asymmetric polyene cyclization of homofarnesol to ambrox. Nature (2024).
2. Enzyme-like polyene cyclizations catalyzed by dynamic, self-assembled, supramolecular fluoro alcohol-amine clusters. Nature Communications (2023).
3. Unified short syntheses of oxygenated tricyclic aromatic diterpenes by radical cyclization with a photoredox catalyst. Communications Chemistry (2023).
4. Biomimetic total synthesis of the reported structure of (+)-selaginedorffone B. Chemical Science (2024).
5. Short, Divergent, and Enantioselective Total Synthesis of Bioactive ent-Pimaranes. Organic Letters (2022).