Synthetic Strategies in Natural Product Synthesis

Natural products continue to serve as inspiring targets for synthetic chemists, owing to their structural complexity and profound impact on medicine, agriculture and materials science. Modern synthetic strategies span classical retrosynthetic analysis, protecting‐group choreography and asymmetric catalysis, alongside emerging paradigms such as biocatalysis and C–H functionalisation. Cascade and biomimetic approaches emulate nature’s own pathways, enabling concise assembly of polycyclic frameworks with multiple stereocentres. Site‐selective C–H bond activation methods reduce reliance on stepwise functional group interconversions, while transient directing groups and engineered enzymes afford precise regio‐ and stereocontrol. Semisynthetic routes leverage abundant natural scaffolds to access highly oxidised derivatives with minimal de novo steps. Together, these tools have transformed the synthesis of terpenoids, alkaloids, steroids and polyketides, delivering new avenues for analogue generation, mechanistic study and scalable production of complex targets.

Research from Nature Portfolio

A unified biocatalytic platform has been developed to install a C19‐hydroxyl moiety onto steroidal precursors with high efficiency and enantioselectivity. This strategy enables multi‐gram‐scale access to 19‐hydroxylated pregnanes and related 19‐nor steroids in four to nine steps, streamlining preparation of key pharmaceutical intermediates and revising previously assigned structures. In parallel, a transient chiral pyridine‐imino directing group was shown to guide site‐selective C–H hydroxylation of pentacyclic triterpenoids at the D/E rings. Application of a Cu‐mediated aerobic oxidation on the abundant oleanane framework delivered several saponins and highly oxidised congeners via sequential, regioselective oxidations. A concise asymmetric route to C19/C20 tetracyclic terpenoid skeletons has likewise been established, furnishing both natural and enantiomeric analogues that display potent and selective agonism of ERβ and cytotoxicity in glioblastoma models.

Synthetic Strategies in Natural Product Synthesis publication trend

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

Technical terms

Biocatalysis: Use of enzymes or whole cells to perform chemical reactions under mild, aqueous conditions with high chemo- and stereoselectivity.

Site-selective C–H activation: Targeted functionalisation of specific carbon–hydrogen bonds within a molecule to install new functional groups without prior derivatisation.

Transient directing group: A reversible covalent appendage that guides reactivity to a desired site and is removed in situ after bond formation.

Biogenetic space-guided synthesis: Strategy that harnesses hypothetical or known biosynthetic pathways to inform disconnections and streamline synthetic routes.

Anionic annulation: Cyclisation process in which an anionic intermediate undergoes ring closure, forming new ring systems in a single operation.

References

1. A biocatalytic hydroxylation-enabled unified approach to C19-hydroxylated steroids. Nature Communications (2019).
2. Site-selective C-H hydroxylation of pentacyclic triterpenoids directed by transient chiral pyridine-imino groups. Nature Communications (2020).
3. A synthesis strategy for tetracyclic terpenoids leads to agonists of ERβ. Nature Communications (2019).
4. Biogenetic space-guided synthesis of rearranged terpenoids. Chemical Communications (2023).
5. Development of a Cross‐Conjugated Vinylogous [4+2] Anionic Annulation and Application to the Total Synthesis of Natural Antibiotic (±)‐ABX. Angewandte Chemie International Edition (2020).