Catalytic enantioselective reductive alkynylation of amides enables one-pot syntheses of pyrrolidine, piperidine and indolizidine alkaloids

• Published in: Nature communications Vol. 14; no. 1; pp. 6251 - 12
• Main Authors: Xu, Fang-Fang, Chen, Jin-Quan, Shao, Dong-Yang, Huang, Pei-Qiang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.10.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 140/131; 140/58; 639/638/309/2144; 639/638/403/977; 639/638/77/889; Agrochemicals; Alkaloids; Alkynes; Amides; Cancer; Cascade chemical reactions; Chemical reactions; Chemical synthesis; Drug development; Enantiomers; Humanities and Social Sciences; Ligands; multidisciplinary; Natural products; Organic chemistry; Piperidine; Pyrrolidine; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-41846-x

The primary objective in synthetic organic chemistry is to develop highly efficient, selective, and versatile synthetic methodologies, which are essential for discovering new drug candidates and agrochemicals. In this study, we present a unified strategy for a one-pot, catalytic enantioselective synthesis of α-alkyl and α,α′-dialkyl pyrrolidine, piperidine, and indolizidine alkaloids using readily available amides and alkynes. This synthesis is enabled by the identification and development of an Ir/Cu/ N -PINAP catalyzed highly enantioselective and chemoselective reductive alkynylation of α-unbranched aliphatic amides, which serves as the key reaction. This reaction is combined with Pd-catalyzed tandem reactions in a one-pot approach, enabling the collective, catalytic enantioselective total syntheses of eight alkaloids and an anticancer antipode with 90–98% ee . The methodology’s enantio-divergence is exemplified by the one-step access to either enantiomer of alkaloid bgugaine. Saturated α-alkyl aza-heterocycles are found in a wide array of bioactive molecules. Here, the authors disclosed a one-pot, catalytic enantioselective synthesis of pyrrolidine, piperidine and indolizidine alkaloids from amides and alkynes.