1,3-Azaprotio Cyclotransfer Reaction for the Synthesis of New 3-Methylindolizidines

Polyhydroxylated indolizidines, such as Castanospermine 1 (Figure 1a), represent a deeply investigated class of iminosugars known for their biological activity (i.e. anticancer, antimetastatic, and antiviral ones).1 In addition, naturally occurring polyhydroxylated pyrrolizidines with a methyl substituent adjacent to the bridge-head nitrogen atom, such as hyacinthacines A3 2 and B3 3, can inhibit intestinal lactase displaying antidiabetic activity.1,2 However, the only example of 5-methylindolizidine found in nature, namely Steviamine 4, did not show interesting inhibitory activity.3 Nonetheless, the synthesis and the biological activity of polyhydroxylated indolizidines bearing a methyl substituent adjacent to nitrogen in the pyrrolidine moiety have never been reported. Herein we report the first synthesis of polyhydroxylated 3-methylindolizidines III exploiting enantiomerically pure nitrones I derived from low-cost sugars (Figure 1b); the key methyl pyrrolidine moiety has been assembled with a stereoselective, timesaving, and 100% atom economical method using a 1,3-azaprotio cyclotransfer reaction4 (Cope-House reaction,5 Figure 1c) on the intermediate alkenyl-hydroxylamines.