Total Synthesis of Diterpenoid Alkaloids

Diterpenoid alkaloids constitute a diverse family of polycyclic natural products characterised by compact, highly bridged frameworks and significant biological activities, including modulation of ion channels, analgesic and cardiotonic effects. The total synthesis of these compounds has long served as a proving ground for advancing synthetic methodology, owing to the challenge of assembling overlapping six‐ and five‐membered rings with multiple stereocentres and quaternary carbon centres. Over recent decades, chemists have developed strategies such as oxidative dearomatisation followed by intramolecular cycloaddition, radical cyclisations, metal‐mediated enyne cycloisomerisation and fragment coupling sequences to construct the core skeletons of C18, C19 and C20 diterpenoid alkaloids. Contemporary efforts emphasise concise, stereoselective routes that minimise protecting‐group manipulations and exploit cascade processes to streamline access to complex targets. Advances in retrosynthetic analysis, including bond‐network mapping, have further refined the planning of disconnections, enabling chemists to forecast optimal bond‐forming sequences. These synthetic achievements not only provide routes to scarce natural products but also afford analogues for pharmacological investigation, underlining the global importance of this research area for drug discovery and chemical biology.

Research from Nature Portfolio

Recent studies have achieved the first total synthesis of atropurpuran, an exemplar arcutane diterpenoid alkaloid distinguished by a congested tetracyclic core. A concise approach employs an oxidative dearomatisation to generate a cyclohexadienone intermediate, which undergoes an intramolecular Diels–Alder cycloaddition to forge two rings in one operation. Subsequent sequential aldol and ketyl–olefin cyclisations assemble the remaining bicyclic framework, and a chemoselective, stereoselective reduction installs the required allylic hydroxyl group. This milestone synthesis has demonstrated the power of tandem oxidative and pericyclic sequences to solve intricate ring architectures and has guided the design of related cascade strategies for other diterpenoid alkaloid targets.

Total Synthesis of Diterpenoid Alkaloids publication trend

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

Technical terms

Oxidative dearomatisation: conversion of an aromatic ring into a non-aromatic cyclohexadienone to enable subsequent cycloaddition.

Intramolecular Diels–Alder cycloaddition: a [4+2] cycloaddition occurring within a single molecule to construct bicyclic frameworks.

Semipinacol rearrangement: a 1,2-shift of an alkyl or aryl group adjacent to a cationic centre, often generating quaternary stereocentres.

Bond-network analysis: a retrosynthetic strategy that uses topological mapping of key bonds in a polycyclic framework to guide optimal bond disconnections.

References

1. Total synthesis of atropurpuran. Nature Communications (2016).
2. Total Syntheses of the C19 Diterpenoid Alkaloids (−)-Talatisamine, (−)-Liljestrandisine, and (−)-Liljestrandinine by a Fragment Coupling Approach. ACS Central Science (2021).
3. A Case for Bond‐Network Analysis in the Synthesis of Bridged Polycyclic Complex Molecules: Hetidine and Hetisine Diterpenoid Alkaloids. Angewandte Chemie International Edition (2020).
4. Recent Advances Towards Syntheses of Diterpenoid Alkaloids. Synthesis (2019).