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

Abstract

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.

O-Glycosylation Enabled by N-(Glycosyloxy)acetamides

“…The reaction of donor 20 (19.2 mg, 0.036 mmol) and acceptor 8 (12.1 mg, 0.026 mmol) was performed as described in the general procedure C, affording 46 (22.3 mg, 93% yield). The 1 H NMR data for 46 are in accordance with those reported previously …”

Recent advances in reagent-controlled stereoselective/stereospecific glycosylation

“…Through an indirect manner, for examples, hydrogen bonding, steric blocking, ring locking and conformational restrictions, stereocontrol could be realized [12]. On the other hand, direct approaches, which include anomeric effect, tuning of anomeric leaving group, neighboring group participation and intramolecular aglycon delivery, were also reported to be successful in targeting stereoselectivity [13][14][15]. While donor-controlled stereoselectivity has been efficient, tedious multi-step syntheses of glycosyl donors are often unavoidable.…”

DBN‐Catalyzed Regioselective Acylation of Carbohydrates and Diols in Ethyl Acetate

“…The preparation of high value‐added carbohydrates and building blocks for oligosaccharide synthesis still remains the most important scientific problem in carbohydrate chemistry . Regioselective acylation is of great importance in the synthesis of valuable oligosaccharide structural units because it facilitates the protection and deprotection of hydroxyl groups and the synthesis of target building blocks .…”