The Cope-House reaction in domino processes: synthesis of 3-methylindolizidines related to Castanospermine

Iminosugars are carbohydrate analogues in which the endocyclic oxygen atom is replaced by nitrogen. They are one of the most prominent classes of glycomimetics, exerting their biological activity as antibiotic, antiviral, antitumoral, and therapeutic agents1. The biological activity of polyhydroxylated indolizidines has already been reported, as well as of polyhydroxylated pyrrolizidines bearing a methyl substituent adjacent to the bridge-head nitrogen atom. Nevertheless, the synthesis of polyhydroxylated 3-methylindolizidines has not been accomplished yet, and their bioactivity is unknown. Herein, we report the synthesis of 3-methylindolizidines analogous to Castanospermine 1, starting from inexpensive sugar-based nitrones 2 and using the Cope-House reaction as a key step within domino processes. Biological assays on final indolizidines are ongoing. Furthermore, we are currently investigating new synthetic strategies based on pinacol type cross-coupling reactions, either assisted by SmI2 or by Ru-photocatalysis, to insert a hydroxyl substituent at C1 and access indolizidines more structurally related to the naturally occurring compound 1.