Natural Product Chemistry of Sesquiterpenoids

Sesquiterpenoids are a diverse class of natural products constructed from three isoprene units, giving rise to a remarkable array of carbon frameworks including monocyclic, bicyclic and polycyclic scaffolds. Common structural types include germacrane, eudesmane, aromadendrane and the distinctive lindenane skeleton found predominantly in the Chloranthaceae family. Biosynthesis proceeds via the mevalonate or methylerythritol phosphate pathways in plants, fungi and marine organisms, with terpene synthases and downstream tailoring enzymes generating structural complexity through cyclisation, oxidation and rearrangement. The inherent lipophilicity and stereochemical richness of sesquiterpenoids underpin a broad spectrum of biological activities such as anti-inflammatory, anti-microbial, anti-cancer and insecticidal effects. Advances in spectroscopic methods have accelerated the discovery and structural elucidation of new sesquiterpenoids, while synthetic and biomimetic routes now enable access to scarce or unstable congeners. Research in this field integrates phytochemical exploration, metabolic engineering and total synthesis to unlock the therapeutic potential of sesquiterpenoid natural products and to inspire novel scaffolds for drug development.

Research from Nature Portfolio

Recent studies have focused on the total synthesis of complex lindenane-type sesquiterpenoid dimers, addressing challenges of stereochemical density and ring complexity. One approach employs a modified biomimetic Diels–Alder cycloaddition to construct the heptacyclic core of shizukaols, achieving control over ten contiguous stereocentres and providing scalable access to these bioactive dimers. A complementary strategy uses a base-mediated thermal [4+2] cycloaddition of an in situ generated furyl diene with various dienophiles, enabling divergent syntheses of multiple lindenane dimeric frameworks. These methodologies not only furnish synthetic standards for biological evaluation but also illuminate plausible biosynthetic pathways operative in nature.

Natural Product Chemistry of Sesquiterpenoids publication trend

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

Technical terms

Sesquiterpenoid: A terpene class composed of three isoprene units, exhibiting diverse cyclic and acyclic carbon frameworks.

Lindenane-type sesquiterpenoid: A polycyclic subclass characterised by a unique bicyclo[5.3.0]decane core, common in Chloranthaceae plants.

Diels–Alder cycloaddition: A pericyclic [4+2] reaction between a diene and a dienophile used to form six-membered rings.

Biomimetic synthesis: A strategy that replicates natural biosynthetic steps to assemble complex molecular architectures.

Mevalonate pathway: A metabolic route in eukaryotes producing isoprenoid precursors for terpene biosynthesis.

References

1. A review on the chemical constituents and pharmacological efficacies of Lindera aggregata (Sims) Kosterm. Frontiers in Nutrition (2023).
2. A comprehensive review on the chemical constituents, sesquiterpenoid biosynthesis and biological activities of Sarcandra glabra. Natural Products and Bioprospecting (2023).
3. Total syntheses of shizukaols A and E. Nature Communications (2018).
4. A unified strategy toward total syntheses of lindenane sesquiterpenoid [4 + 2] dimers. Nature Communications (2019).
5. Genus Chloranthus: A comprehensive review of its phytochemistry, pharmacology, and uses. Arabian Journal of Chemistry (2022).