A Key Cope-House Reaction Accomplishes the First Stereoselective Synthesis of Polyhydroxylated 3-Methylindolizidines

Polyhydroxylated indolizidines, such as Castanospermine 1, with various substitution patterns, represent a deeply investigated class of iminosugars known for their biological activity (i.e. glycosidases inhibition, anticancer, antimetastatic, and antiviral activities). However, related 5-methyl substituted indolizidines, such as Steviamine 2, did not show interesting inhibitory activity. On the other hand, naturally occurring polyhydroxylated pyrrolizidines – which can be considered as ring-contracted versions of indolizidines – with a methyl substituent adjacent to the bridge-head nitrogen atom, such as hyacinthacines A3 and B3, inhibit intestinal lactase displaying antidiabetic activity. This suggests a possible biological activity for indolizidines bearing a methyl substituent adjacent to nitrogen in the pyrrolidine moiety, which, however, have not been synthesized so far. This work aims to present the first synthetic route to polyhydroxylated 3-methylindolizidines III, starting with enantiomerically pure nitrones I derived from low-cost sugars, and using the Cope-House reaction as the key step for the construction of the key methyl pyrrolidine moiety II. The biological activity of the final products is under evaluation