Highly alpha- and beta-selective radical C-glycosylation reactions using acontrolling anomeric effect based on the conformational restriction strategy. A study on the conformation-anomeric effect-stereoselectivity relationship in anomeric radical reactions

We hypothesized that, because the stereoselectivity of anomeric radical rea ctions was significantly influenced by the anomeric effect, which can be co ntrolled by restricting the conformation of the radical intermediate, the p roper conformational restriction of the pyranose ring of the substrates wou ld therefore make highly alpha- and beta -stereoselective anomeric radical reactions possible. Thus, the conformationally restricted 1-phenylseleno-D- xylose derivatives 9 and 10, restricted in a C-4(1)-conformation, and 11 an d 12, restricted in a C-1(4)-conformation, were designed and synthesized by introducing the proper protecting groups on the hydroxyl groups on the pyr anose ring as model substrates for the anomeric radical reactions. The radi cal deuterations with Bu3SnD and the C-glycosylation with Bu3SnCH2CH=CH2 or CH2 CHCN, using the C-4(1)-restricted substrates 9 and 10, afforded the co rresponding alpha -products (alpha/beta = 97:3-85:15) highly stereoselectiv ely, whereas the C-1(4)-restricted substrates 11 and 12 selectively gave th e fl-products (alpha/beta = 1:99-0:100). Thus, stereoselectivity was signif icantly increased by conformational restriction and was completely inverted by changing the substrate conformation from the C-4(1)-form into the C-1(4 )-form. Ab initio, calculations suggested that the radical intermediates pr oduced from these substrates possessed the typical C-4(1)- or C-1(4)-Confor mation, which was similar to that of the substrates, and that the anomeric effect in these conformations would be the factor controlling the transitio n state of the reaction. Therefore, the highly alpha- and beta -selective r eactions would occur because of the anomeric effect, which could be manipul ated by conformational restriction of the substrates, as expected. This wou ld be the first radical C-glycosylation reaction to provide both alpha- and beta -C-glycosides highly stereoselectively.