title: Mechanism of Glycosylation of Anomeric Sulfonium Ions.
abstract: Anomeric sulfonium ions are attractive glycosyl donors for the stereoselective installation of 1,2-cis glycosides. Although these donors are receiving increasing attention, their mechanism of glycosylation remains controversial. We have investigated the reaction mechanism of glycosylation of a donor modified at C-2 with a (1S)-phenyl-2-(phenylsulfanyl)ethyl chiral auxiliary. Preactivation of this donor results in the formation of a bicyclic β-sulfonium ion that after addition of an alcohol undergoes 1,2-cis-glycosylation. To probe the importance of the thiophenyl moiety, analogs were prepared in which this moiety was replaced by an anisoyl or benzyl moiety. Furthermore, the auxiliaries were installed as S- and R-stereoisomers. It was found that the nature of the heteroatom and chirality of the auxiliary greatly influenced the anomeric outcome and only the one containing a thiophenyl moiety and having S-configuration gave consistently α-anomeric products. The sulfonium ions are sufficiently stable at a temperature at which glycosylations proceed indicating that they are viable glycosylation agents. Time-course NMR experiments with the latter donor showed that the initial rates of glycosylations increase with increases in acceptor concentration and the rate curves could be fitted to a second order rate equation. Collectively, these observations support a mechanism by which a sulfonium ion intermediate is formed as a trans-decalin ring system that can undergo glycosylation through a bimolecular mechanism. DFT calculations have provided further insight into the reaction path of glycosylation and indicate that initially a hydrogen-bonded complex is formed between sulfonium ion and acceptor that undergoes SN2-like glycosylation to give an α-anomeric product.
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia , 315 Riverbend Road, Athens, Georgia 30602, United States.|Department of Chemistry, University of Georgia , Athens, Georgia 30602, United States.
authors.forename: Tao
authors.initials: T
authors.lastname: Fang
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia , 315 Riverbend Road, Athens, Georgia 30602, United States.|Department of Chemistry, University of Georgia , Athens, Georgia 30602, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia , 315 Riverbend Road, Athens, Georgia 30602, United States.|Department of Chemistry, University of Georgia , Athens, Georgia 30602, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia , 315 Riverbend Road, Athens, Georgia 30602, United States.|Department of Chemistry, University of Georgia , Athens, Georgia 30602, United States.|Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, and Bijvoet Center for Biomolecular Research, University of Utrecht , Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: Geert-Jan
authors.initials: GJ
authors.lastname: Boons
mesh_terms: D005960:Glucosides / Q000138:chemical synthesis; D006031:Glycosylation; D008956:Models, Chemical; D013237:Stereoisomerism; D013452:Sulfonium Compounds / Q000737:chemistry*
chemical_list: D005960:Glucosides; D013452:Sulfonium Compounds