Harnessing an Unconventional Hydroamination Step to Access Novel Polyhydroxylated 3-Methylindolizidines

Polyhydroxylated indolizidines represent a well-known and extensively investigated class of bicyclic iminosugars. However, the introduction of a methyl substituent within the pyrrolidine ring adjacent to the bridgehead nitrogen atom constitutes an unexplored substitution pattern. Recent studies carried out in our group demonstrated that such frameworks can be efficiently assembled through a concise synthetic sequence involving an organometallic addition, a Cope–House rearrangement, and a final reductive amination strategy. In this work, we report the synthesis of a new series of 3-methylindolizidines starting from sugar-derived nitrones through an efficient one-pot protocol combining Grignard addition and subsequent O-acetylation. The key methyl-substituted pyrrolidine unit is generated via a Cope–House rearrangement, while a final cyclizative reductive amination furnishes the desired bicyclic structure. In addition, Density Functional Theory (DFT) calculations were employed for the first time to provide mechanistic insight into both the organometallic addition and the Cope–House rearrangement.