Vinylogous Mannich reaction in total synthesis of alkaloids.

Covering: up to July 2026The vinylogous Mannich reaction (VMR) enables γ-selective carbon-carbon bond formation between vinylogous nucleophiles and imines or iminium ions, yielding δ-aminocarbonyl frameworks. Compared with the classical Mannich reaction, VMR shows distinct advantages in remote functionalization and convergent bond formation, facilitating the rapid assembly of nitrogen-containing heterocycles, multiple stereogenic centers, and densely functionalized intermediates. As a result, this reaction has become an increasingly valuable strategy for generating complexity in the total synthesis of alkaloids and has been successfully applied to a wide range of alkaloid families, including piperidine, pyrrolidine, indole, Securinega, Stemona, phthalideisoquinoline, steroidal, and Daphniphyllum. This review presents a structured and concept-oriented overview of VMR-based alkaloid synthesis. Representative applications are organized according to the nature of the vinylogous nucleophiles, including both acyclic and cyclic dienol equivalents. Particular emphasis is placed on reaction design, stereochemical control, complexity generation, and the integration of VMR into asymmetric, collective, and biomimetic synthetic strategies. Overall, this review highlights the evolution of VMR from a methodological variant of the classical Mannich reaction into a broadly applicable approach for the efficient synthesis of structurally diverse alkaloids. It also provides perspectives on its future development in alkaloid synthesis.