ortho-Methoxycarbonylethynylphenyl Thioglycosides (MCEPTs): Versatile Glycosyl Donors Enabled by Electron-Withdrawing Substituents and Catalyzed by Gold(I) or Cu(II) Complexes.

With easily accessible and operator-friendly reagents, shelf-stable ortho-methoxycarbonylethynylphenyl thioglycosides were efficiently prepared. Based on these MCEPT glycoside donors, a novel glycosylation protocol featuring mild and catalytic promotion conditions with Au(I) or Cu(II) complexes, expanded substrate scope encompassing challenging donors and acceptors and clinically used pharmaceuticals, and versatility in various strategies for highly efficient synthesis of glycosides has been established. The practicality of the MCEPT glycosylation protocol was fully exhibited by highly efficient and scalable synthesis of surface polysaccharide subunits of Acinetobacter baumannii via latent-active, reagent-controlled divergent orthogonal one-pot and orthogonal one-pot strategies. The underlying reaction mechanism was investigated systematically through control reactions, leading to the isolation and characterization of the vital catalyst species in MCEPT glycosylation, the benzothiophen-3-yl-gold(I) complex. Based on the results obtained both from control reactions and from studies leading to the glycosylation protocol establishment, an operative mechanism was proposed and the effect of the vital catalyst species reactivity on the results of metal-catalyzed alkyne-containing donor-involved glycosylation was disclosed. Moreover, the mechanism for C-glycosylation side product formation from ortho-(substituted)ethynylphenyl thioglycoside donors with electron-donating substituents was also illuminated.

8-(Methyltosylaminoethynyl)-1-naphthyl (MTAEN) Glycosides: Potent Donors in Glycosides Synthesis.

With 8-(methyltosylaminoethynyl)-1-naphthyl (MTAEN) glycoside as donors, a novel and efficient glycosylation protocol has been established. The MTAEN glycosylation protocol exhibits the merits of shelf-stable donors, mild catalytic promotion conditions, considerably extended substrate scope encompassing both free alcohols, silylated alcohols, nucleobases, primary amides, and C-type nucleophile acceptors, and applicability to various one-pot strategies for highly efficient synthesis of oligosaccharides, such as orthogonal one-pot, single-catalyst one-pot, and acceptor reactivity-controlled one-pot strategies.

Synthetic Investigation toward QS-21 Analogues.

With glycosyl o-alkynylbenzotes as donors, a highly efficient protocol to construct the challenging glycosidic linkages at C3-OH of C23-oxo oleanane triterpenoids is disclosed, on the basis of which different strategies for the highly efficient synthesis of QS-21 analogues with the west-wing trisaccharide of QS-21 have been established.

Total Synthesis and Structural Revision of Rebaudioside S, a Steviol Glycoside.

The total synthesis of rebaudioside S, a minor steviol glycoside from the leaves of Stevia rebaudiana, was investigated via a modular strategy, culminating not only in the first and highly efficient synthesis of Reb-S and analogues thereof but also in the revision of the originally proposed structure. The modular strategy dictated the application of C2-branched disaccharide Yu donors to forge C-13 steviol glycosidic linkages, posing considerable challenges in stereoselectivity control. Through systematic investigations, the effect of the internal glycosidic linkage configuration on the glycosylation stereoselectivity of 1,2-linked disaccharide donors was disclosed, and the intensified solvent effect by the 4,6-O-benzylidene protecting group was also observed with glucosyl donors. Through the orchestrated application of these favorable effects, the stereoselectivity problems were exquisitely tackled.

The first total synthesis of rebaudioside R.

With easily available monosaccharides and steviol as starting materials, the first total synthesis of rebaudioside R with a xylosyl core in the C13-OH linked sugar chain was accomplished via two distinct approaches. The first approach features the stepwise installation of branch-sugar residues via an order of C2-OH first and then C3-OH of the xylosyl core, laying a firm foundation for the synthesis of analogues with different branch sugars, while the second route features the introduction of the C13 trisaccharide sugar chain via a convergent strategy, securing the overall synthetic efficiency. Through the synthetic study, the effect of protecting groups (PGs) at the vicinal hydroxy group on the reactivity of OH acceptors was illustrated.

Dual-Participation Protecting Group Solves the Anomeric Stereocontrol Problems in Glycosylation Reactions.

The 2,2-dimethyl-2-(ortho-nitrophenyl)acetyl (DMNPA) group permits, via robust neighboring group participation (NGP) or long distance participation (LDP) effects, the stereocontrolled 1,2-trans, 1,2-cis, as well as ß-2,6-dideoxy glycosidic bond generation, while suppressing the undesired orthoester byproduct formation. The robust stereocontrol capability of the DMNPA is due to the dual-participation effect from both the ester functionality and the nitro group, verified by control reactions and DFT calculations and further corroborated by X-ray spectroscopy.

The 2,2-Dimethyl-2-(ortho-nitrophenyl)acetyl (DMNPA) Group: A Novel Protecting Group in Carbohydrate Chemistry.

The 2,2-dimethyl-2-(ortho-nitrophenyl)acetyl (DMNPA) group was introduced to synthetic carbohydrate chemistry as a protecting group (PG) for the first time. Benefiting from a unique chemical structure and novel deprotection conditions, the DMNPA group can be cleaved rapidly and mutually orthogonal to other PGs. Orchestrated application of the DMNPA group with other PGs led to the highly efficient synthesis of the glycan of thornasterside A.

1-Picolinyl-5-azido Thiosialosides: Versatile Donors for the Stereoselective Construction of Sialyl Linkages.

With the picolinyl (Pic) group as a C-1 located directing group and N3 as versatile precursor for C5-NH2 , a novel 1-Pic-5-N3 thiosialyl donor was designed and synthesized, based on which a new sialylation protocol was established. In comparison to conventional sialylation methods, the new protocol exhibited obvious advantages, including excellent α-stereoselectivity in the absence of a solvent effect, broad substrate scope encompassing the challenging sialyl 8- and 9-hydroxy groups of sialic acid acceptors, flexibility in sialoside derivative synthesis, high temperature tolerance and easy scalability. In particular, the applicability to the synthesis of complex and bioactive N-glycan antennae when combined with the MPEP glycosylation protocol via the "latent-active" strategy has been shown. Mechanistically, the excellent α-stereoselectivity of the novel sialylation protocol could be attributed to the dramatic electron-withdrawing effect of the protonated Pic groups, which was supported by control reactions and DFT calculations.