Synthetic Strategies for Indole Alkaloids

Indole alkaloids encompass a vast class of natural products distinguished by the fusion of an indole nucleus with diverse structural motifs. Their complex architectures and potent biological activities have inspired an array of synthetic strategies. Traditional approaches rely on retrosynthetic analysis to identify key bond disconnections, enabling convergent or linear assembly of the indole core. Biomimetic and enantioselective routes emulate biosynthetic pathways and control stereochemistry, respectively. Transition-metal methods, notably palladium- and copper-catalysed cross-couplings, facilitate direct C–H functionalisation and ring-construction. Cascade or tandem reactions consolidate multiple bond-forming steps into single operations, accelerating access to polycyclic scaffolds. Modular and divergent tactics permit late-stage diversification, while macrocyclisations and C–H activation techniques address medium- and large-ring targets. Together, these developments underpin scalable and sustainable syntheses and broaden the utility of indole alkaloids in drug discovery and agrochemical applications.

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Synthetic Strategies for Indole Alkaloids publication trend

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

Technical terms

Retrosynthetic analysis: A planning strategy that dissects a target molecule into simpler, readily available precursors by reversing envisaged synthetic steps.

Biomimetic synthesis: An approach that imitates natural biosynthetic pathways to assemble complex structures.

Cascade reaction: A sequence of two or more consecutive bond-forming transformations carried out in a single reaction vessel without isolation of intermediates.

Palladium-catalysed domino reaction: A process in which palladium mediates successive bond-forming steps to construct complex molecules in one operation.

Friedel–Crafts alkylation: A Lewis-acid-promoted electrophilic aromatic substitution that introduces alkyl groups onto aromatic rings.

Enantioselective synthesis: A method that preferentially produces one enantiomer of a chiral molecule over its mirror image.

References

1. Recent Advances in the Synthesis of 3,n-Fused Tricyclic Indole Skeletons via Palladium-Catalyzed Domino Reactions. Molecules (2023).
2. Methods of Lysergic Acid Synthesis—The Key Ergot Alkaloid. Molecules (2022).
3. One-Pot Synthesis of Polynuclear Indole Derivatives by Friedel–Crafts Alkylation of γ-Hydroxybutyrolactams. Molecules (2023).