title: In a glycosylation reaction how does a hydroxylic nucleophile find the activated anomeric carbon?
abstract: The mechanism by which nucleophilic hydroxyls are attracted to activated glycopyranosyl donors is not known. Besides the intrinsic attraction of oxygen centred negative dipoles towards the developing electron deficiency at the anomeric carbon only a few suggestions have been given in the literature. By studying the effect on Density Functional Theory (DFT) modelled glycosylation reactions on the presence of polar additives as tested with acetonitrile two possible effects have been identified. One was noted in a previous publication (Carbohydr. Res.2012, 356, 180-190) and two further examples discovered here that suggest that a lone pair of a nucleophile approaching a donor with a β-leaving group from the α-face can act as the antiperiplanar lone pair that assists leaving group departure. This interaction starts at just under a nucleophile C-1 separation of 3Å and has an incipient bond angle of O-5-C-1-Nuc(O or N) of very close to 90° which can be at C-1 with the p-type orbital at C-1-O-5 of the incipient oxacarbenium ion, that is, the LUMO of the activated donor. The 2nd interaction is less well studied and is suggested to be a similar bonding interaction which moves β-face nucleophiles to O-Nuc-C-1-leaving groups angles close to 180°.
authors: National Research Council, Human Health Therapeutics, 100 Sussex Drive, Ottawa, ON K1A 0R6, Canada. Electronic address: dennis.whitfield@nrc-cnrc.gc.ca.
authors: Dennis M
authors: DM
authors: Whitfield
mesh_terms: D000097:Acetonitriles / Q000737:chemistry; D002236:Carbohydrate Conformation; D002244:Carbon / Q000737:chemistry*; D006027:Glycosides / Q000737:chemistry; D006031:Glycosylation; D006860:Hydrogen Bonding; D006878:Hydroxides / Q000737:chemistry*; D000432:Methanol / Q000737:chemistry; D008958:Models, Molecular; D011789:Quantum Theory; D013237:Stereoisomerism
chemical_list: D000097:Acetonitriles; D006027:Glycosides; D006878:Hydroxides; D002244:Carbon; C031356:hydroxide ion; D000432:Methanol; C032159:acetonitrile
keywords: Antiperiplanar lone pair hypotheses; Glycosylation; Nucleophile; Oxacarbenium ion; Solvation