o‑(p‑Methoxyphenylethynyl)phenyl Glycosides: Versatile New Glycosylation Donors for the Highly Efficient Construction of Glycosidic Linkages

• Published in: Journal of the American Chemical Society Vol. 139; no. 36; pp. 12736 - 12744
• Main Authors: Hu, Yang, Yu, Ke, Shi, Li-Li, Liu, Lei, Sui, Jing-Jing, Liu, De-Yong, Xiong, Bin, Sun, Jian-Song
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.09.2017; Amer Chemical Soc
• Subjects: Carbohydrate Conformation; Chemistry; Chemistry, Multidisciplinary; glycosides; Glycosides - chemistry; glycosidic linkages; Glycosylation; Lewis bases; odors; Physical Sciences; protocols; Science & Technology; Streptococcus pneumoniae; trisaccharides; BETA-MANNOPYRANOSIDES; LATENT-ACTIVE GLYCOSYLATION; BUILDING-BLOCKS; 2-ALLYLPHENYL GLYCOSIDES; NATURAL-PRODUCTS; OLIGOSACCHARIDE SYNTHESIS; ORTHO-ALKYNYLBENZOATES; INTERRUPTED PUMMERER REACTION; LEAVING GROUP; TRIFLUOROMETHANESULFONIC ANHYDRIDE
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.7b07020

A novel alkyne-activation-based glycosylation protocol using o-(p-methoxy­phenyl­ethynyl)­phenyl (MPEP) glycoside was established. The glycosyl MPEP donors were shelf-stable and could be prepared efficiently via Sonogashira reaction from the corresponding o-iodo­phenyl (IP) glycosides. The outstanding stability of IP glycosides as well as their efficient transformations to MPEP glycosides dramatically facilitates the syntheses of MPEP glycosyl donors and IP glycosyl acceptors. Furthermore, they make the MPEP glycosylation protocol applicable to the latent-active oligo­saccharide and glyco­conjugate synthetic strategy, with IP glycosides as the latent form and MPEP glycosides as the active form, as illustrated by the highly efficient fabrication of Streptococcus pneumoniae type 3 trisaccharide. The phenolic glycoside nature of MPEP glycosides bestows on the new glycosyl donors enhanced stability compared to their thio­glycoside counterparts toward activation conditions applied for glycosyl trichloro­acetimidate (TCAI) and o-alkynyl­benzoate (ABz) donor. Thus, MPEPs can also be utilized in the selective one-pot glycosyl­ation strategy, as exemplified by the syntheses of oligo­saccharides via successive glycosyl­ations with glycosyl TCAI, ABz, and EPMP as donors. Despite sharing identical promotion conditions with thio­glycoside donors, the odor-free starting material (IP), the stable departure structure of the leaving group (3-iodo­benzo­furan), and the decreased nucleo­philicity of the o-MPEP glycoside help to eliminate the three major short­comings of the thioglycoside donors (unpleasant odor of starting material, detrimental interference of the cleaved leaving group, and aglycon intra- or intermolecular migration) while maintaining the prominent features of the thio­glycoside methodology, including the broad substrate scopes, the mild promotion conditions, the stability of glycosyl donors, and the versatile applications in existing glycoside synthesis strategies. Based on the experimental results, a mechanism for MPEP activation was proposed, which was supported by systematic mechanistic investigations, including trapping of active intermediates, design of a vital disarmed rhamnosyl donor, and isolation and characterization of the departure species of the leaving group.