NOVEL 3-METHYL POLYHYDROXYLATED INDOLIZIDINES: SYNTHETIC AND DFT STUDIES

Polyhydroxylated indolizidines constitute a prominent family of bicyclic iminosugars that has attracted considerable attention for their structural and biological relevance. In contrast, methyl substitution on the pyrrolidine ring in the position adjacent to the bridgehead nitrogen remains largely unexplored. Previous investigations from our group established an effective synthetic approach to these architectures based on a short sequence involving organometallic addition, Cope–House rearrangement, and cyclizative reductive amination. Herein, we describe the preparation of a novel library of 3-methylindolizidines from carbohydrate-derived nitrones via a one-pot method that integrates Grignard addition followed by O-acetylation. Formation of the methyl-substituted pyrrolidine intermediate is achieved through a stereoselective Cope–House rearrangement, whereas closure of the bicyclic scaffold is accomplished by reductive amination. Furthermore, Density Functional Theory (DFT) studies were carried out to investigate the mechanistic features of both the organometallic addition step and the Cope–House rearrangement, providing computational support for the observed reactivity and selectivity.