Total Synthesis of Natural Product Sesquiterpenes

Natural product sesquiterpenes, defined by their fifteen-carbon skeletons, exhibit a rich structural diversity and a broad spectrum of biological activities. The quest to achieve their enantioselective total synthesis has driven advances in reaction design, stereocontrol and cascade strategies. Core challenges include the construction of densely functionalised polycyclic frameworks, the installation of contiguous quaternary stereocentres and the precise oxidation patterns that underpin bioactivity. Modern approaches leverage biocatalytic mimicry, radical-based cyclisations and orchestrated rearrangements to streamline synthetic sequences and enhance scalability. Achieving efficient total syntheses not only provides access to scarce natural targets but also permits systematic modification through structure–activity relationship studies, facilitating the development of novel analogues with improved stability, selectivity and therapeutic potential. Collectively, these endeavours underscore the global significance of sesquiterpene synthesis in drug discovery and chemical biology.

Research from Nature Portfolio

A recent study has demonstrated how minimal structural variations in picrotoxinin analogues can dramatically improve pharmacological selectivity and synthetic efficiency. By incorporating a methyl group at the C5 position, researchers designed simplified analogues that exhibit enhanced metabolic stability and altered ion-channel antagonism profiles. This advance was made possible through an optimized synthetic route that reduces step count and affords material in sufficient quantity for comprehensive structure–activity relationship evaluations. The work exemplifies how targeted modifications informed by total synthesis can yield analogues with refined biological properties, opening new avenues for insecticide design and neuroscience tools.

Total Synthesis of Natural Product Sesquiterpenes publication trend

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

Technical terms

Sesquiterpene: A terpenoid natural product built from three isoprene units (C15).

Total synthesis: The complete chemical assembly of a target molecule from simple starting materials.

Quaternary carbon: A carbon atom bonded to four other carbon atoms, often challenging to construct.

Structure–activity relationship (SAR): Systematic study of how molecular modifications affect biological activity.

Semipinacol rearrangement: A rearrangement involving migration of a carbon substituent adjacent to an alcohol under acidic or Lewis acidic conditions to form a new carbon framework.

References

1. C5 methylation confers accessibility, stability and selectivity to picrotoxinin. Nature Communications (2023).
2. Asymmetric Total Synthesis of Illisimonin A. Journal of the American Chemical Society (2023).
3. Total Synthesis of the Humulene‐Derived Sesquiterpenoid (‐)‐Integrifolian‐1,5‐dione. ChemistryEurope (2024).