Neighbouring Group Participation During Glycosylation: Do 2‐Substituted Ethyl Ethers Participate?

Abstract

AbstractThe development of new protecting groups that undergo neighbouring group participation (NGP) via six‐membered ring intermediates to promote the formation of α‐1,2‐cis glycosidic linkages complements the established use of 5‐ring NGP in terms of stereochemical outcome. A selection of glycosyl donors was synthesised that possessed novel 2‐iodo‐ and 2‐(phenylseleno)ethyl ether protecting groups in an attempt to promote highly α‐selective glycosylation by 6‐ring NGP. Although the fully armed donors produced α‐glucosides as the predominant reaction products, low‐temperature NMR studies did not show NGP by the observation of cyclised reaction intermediates. The corresponding disarmed glycosyl donors were unexpectedly less stereoselective. NMR spectroscopy revealed that the 2‐iodoethyl ether did not participate in any of the glycosylation processes; however, the 2‐(phenylseleno)ethyl ether did participate, and β‐configured cyclic intermediates were observed. The fact that considerable amounts of β‐glycoside product were formed in these latter cases indicated that the predominant reaction pathway to product did not occur through the observed cyclic species. Clearly, a fine balance exists during glycosylation reactions, and the reaction pathway to product depends on a variety of factors. Notably, the formation of cyclised intermediates by 6‐ring NGP is not on its own sufficient to ensure high levels of α‐stereoselectivity.