Development of stereoselective synthesis of biologically active nitrogen-heterocyclic compounds: Applications for syntheses of natural product and organocatalyst

Iminosugars are biologically interesting compounds, since they can inhibit various glycosidases, and are considered as promising drug candidates, e.g, antidiabetes. We developed several methods for syntheses of various iminopyranose and iminofuranose derivatives. Our synthetic strategy was based on a combination of metathesis and asymmetric reaction. The first report regarding synthesis of (+)-isofagomine was based on ring-closing enyne metathesis and lipase-catalyzed kinetic resolution of allylic alcohols. The kinetic resolution was also applied to synthesis of various pipecolic acid derivatives, which were shown to act as effective organocatalysts for asymmetric Mannich reaction. As a second approach, iridium-catalyzed asymmetric allylic amination of allyl carbonate was used for the synthesis of 2-propylisofagomine. For the synthesis of polyhydrox-ylated pyrrolidines, we employed Pd-catalyzed allylic amination of butadiene monoxide developed by Trost and modified it. In the course of biological studies of synthetic compounds, we found that 1-C-butyl-L-arabino-iminofuranose (LAB) has potent inhibitory activities against α-glycosidases. Futhermore, we applied iridium-catalyzed allylic amination to the cyclization of allyl carbonate derivatives and found that the nosyl-protected amine could successfully cyclize to form a pyrrolidine ring in which the constructed sterogenic centers were controlled by the asymmetric catalyst. The method can be successfully applied to synthesis of (+)-bulgecinine and (+)-preussin.