Total Synthesis of Amaryllidaceae Alkaloids

The total synthesis of Amaryllidaceae alkaloids has undergone significant evolution over the past decade. These structurally complex natural products, characterised by polycyclic frameworks and multiple stereocentres, have inspired diverse strategic approaches. Early endeavours focused on step-by-step ring construction and stereochemical control through classical protecting-group manipulations and stoichiometric chiral auxiliaries. More recent pathways exploit cascade reactions, catalytic asymmetric methodologies, and chemoenzymatic transformations to streamline access and improve enantioselectivity. Advances in transition-metal catalysis, such as palladium-mediated cyclisations, and the integration of biocatalytic steps have reduced step count and enhanced scalability. These innovations have not only deepened understanding of reaction mechanisms and stereochemical relay but also opened routes to gram-scale preparations and analogue diversification for biological evaluation. The intersection of modern catalysis and biosynthetic logic is now driving the field towards more sustainable, efficient routes to key representatives such as lycorine, narciclasine and zephyranthine.

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Total Synthesis of Amaryllidaceae Alkaloids publication trend

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

Technical terms

Enantioselective synthesis: A method that preferentially produces one mirror-image form of a chiral molecule.

Michael/Michael cascade: A sequential pair of conjugate addition reactions that form multiple bonds and stereocentres in one operation.

Hydrogen borrowing alkylation: A catalytic process in which a substrate temporarily donates hydrogen to a catalyst and then recovers it to form a new C–C bond.

Chemoenzymatic synthesis: A strategy combining enzymatic steps with conventional chemical reactions to build complex molecules.

Intramolecular Heck cyclization: A palladium-catalysed reaction that forms carbon–carbon bonds within a molecule, constructing ring systems.

Asymmetric dihydroxylation: A catalytic process that adds two hydroxyl groups across an alkene in a stereochemically controlled manner.

References

1. Short, enantioselective, gram-scale synthesis of (−)-zephyranthine. Chemical Science (2021).
2. Extension of hydrogen borrowing alkylation reactions for the total synthesis of (−)-γ-lycorane. Chemical Communications (2022).
3. Design and Synthesis of C-1 Methoxycarbonyl Derivative of Narciclasine and Its Biological Activity. Molecules (2022).