Xiangming Zhu

New Principles for Glycoside‐Bond Formation

Increased understanding of the important roles that oligosaccharides and glycoconjugates play in biological processes has led to a demand for significant amounts of these materials for biological, medicinal, and pharmacological studies. Therefore, tremendous effort has been made to develop new procedures for the synthesis of glycosides, whereby the main focus is often the formation of the glycosidic bonds. Accordingly, quite a few review articles have been published over the past few years on glycoside synthesis; however, most are confined to either a specific type of glycoside or a specific strategy for glycoside synthesis. In this Review, new principles for the formation of glycoside bonds are discussed. Developments, mainly in the last ten years, that have led to significant advances in oligosaccharide and glycoconjugate synthesis have been compiled and are evaluated.

The First Synthesis of a Thioglycoside Analogue of the Immunostimulant KRN7000

The first total synthesis of a thioglycoside analogue of KRN7000, a potential immunostimulant, is described. Two key intermediates are alpha-galactosyl thiol 4 and phytosphingosine derivative 5, which were both prepared from D-galactose.

Activation of human invariant natural killer T cells with a thioglycoside analogue of α-galactosylceramide.

Activation of CD1d-restricted invariant NKT (iNKT) cells with the glycolipid α-galactosylceramide (α-GalCer) confers protection against disease in murine models, however, clinical trials in humans have had limited impact. We synthesized a novel thioglycoside analogue of α-GalCer, denoted α-S-GalCer, and tested its efficacy for stimulating human iNKT cells in vitro. α-S-GalCer stimulated cytokine release by iNKT cells in a CD1d-dependent manner and primed CD1d(+) target cells for lysis. α-S-GalCer-stimulated iNKT cells induced maturation of monocyte-derived dendritic cells into antigen-presenting cells that released IL-12 and small amounts of IL-10. The nature and potency of α-S-GalCer and α-GalCer in human iNKT cell activation were similar. However, in contrast to α-GalCer, α-S-GalCer did not activate murine iNKT cells in vivo. Because of its enhanced stability in biological systems, α-S-GalCer may be superior to α-GalCer as a parent compound for developing adjuvant therapies for humans.

Synthesis of α-Glycosyl Thiols by Stereospecific Ring-Opening of 1,6-Anhydrosugars

Treatment of 1,6-anhydrosugars with commercially available bis(trimethylsilyl) sulfide in the presence of trimethylsilyl triflate led to the formation of α-glycosyl thiols. All the reactions were highly stereoselective and afforded the α-glycosyl thiols in good to excellent yields. By this procedure, a variety of 1,6-anhydrosugars, differing in their sugar units, glycosidic linkages, and protecting group pattern, were converted smoothly into the corresponding α-glycosyl thiols, which could be of great utility in thioglycoside chemistry. It is noteworthy that 1,6-anhydrosugars carrying the 2-O-acyl group and 1,6-anhydrosugar-containing oligosaccharides could also be ring-opened stereospecifically under the same conditions to give rise to the corresponding 1-thiosugars in high yields. Thus, a very concise and efficient access to α-glycosyl thiols of great value was established.

Synthesis of glycosylthiols and reactivity studies.

The acid-catalyzed reaction of 1,2-anhydro-3,4,6-tri-O-benzyl-α-d-glucopyranose (7) as glycosyl donor with bis-trimethylsilyl sulfide as acceptor affords the α-thiol. Hence, this sterically hindered S-nucleophile as acceptor should provide with O-glycosyl trichloroacetimidates as glycosyl donors that have nonparticipating groups at C-2, glycosylthiols with the thiol group in axial position. This was confirmed for various donors (4, 16-19) with the exception of the corresponding mannosyl donor (20). However, powerful participating groups at C-2 of the donor (23-28) governed the anomeric selectivity.

Synthesis of β-d-arabinofuranosides: stereochemical differentiation between d- and l-enantiomers

The glycosylation of 3,5-O-di-tert-butylsilylene-protected d-thioarabinofuranosides with a range of glycosyl acceptors using NIS/AgOTf as promoters proceeded in a stereoselective manner to give the corresponding beta-D-arabinofuranosides in high yields.

Synthesis of an S-linked glycopeptide analog derived from human Tamm-Horsfall glycoprotein.

Direct base catalyzed S-glycosylation of a cysteine and a homocysteine containing peptide with O-acetyl protected bromides in DMF-water solution furnished two glycopeptide fragments. The two glycopeptide fragments were linked to the target glycopeptide with two S-glycosyl residues mimicking a part of Tamm-Horsfall glycoprotein.

α-Galactosylceramides and analogues – important immunomodulators for use as vaccine adjuvants

A vaccine adjuvant is a substance that is added to improve the effectiveness of a vaccine. Adjuvants are immune potentiators that can elicit an early innate immune response to help in the generation of strong and long-term protection against infection. The adjuvant can enhance the immune system so t...

Thioperoxide-Mediated Activation of Thioglycoside Donors

Thioperoxide (1) in combination with trimethylsilyl trifluoromethanesulfonate (TMSOTf) provides a powerful thiophilic promoter system, capable of activating different thioglycosides. Both armed and disarmed thioglycosides were activated effectively in the presence of different glycosyl acceptors, giving glycosidation products in high to excellent yields. A plausible activation pathway was also proposed and supported by isolating side-products trifluoromethylphenyl disulfide (CF3SSPh) and alkene (42).

Synthesis of α-S-linked glycopeptides in water containing solution

α-Thiols of N-acetylglucosamine and of N-acetylgalactosamine react with β-bromoalanine containing peptides at pH 8.5 under phase transfer conditions or, alternatively, in aqueous DMF, cleanly to α-S-linked glycopeptides. Thus, mimetics of important O-glycopeptides can be readily prepared.