You Yang

Gold(I)-Catalyzed Glycosylation with Glycosyl ortho-Alkynylbenzoates as Donors: General Scope and Application in the Synthesis of a Cyclic Triterpene Saponin

Glycosyl ortho-alkynylbenzoates have emerged as a new generation of donors for glycosidation under the catalysis of gold(I) complexes such as Ph(3)PAuOTf and Ph(3)PAuNTf(2) (Tf = trifluoromethanesulfonate). A wide variety of these donors, including 2-deoxy sugar and sialyl donors, are easily prepared and shelf stable. The glycosidic coupling yields with alcohols are generally excellent; even direct coupling with the poorly nucleophilic amides gives satisfactory yields. Moreover, excellent alpha-selective glycosylation with a 2-deoxy sugar donor and beta-selective sialylation have been realized. Application of the present glycosylation protocol in the efficient synthesis of a cyclic triterpene tetrasaccharide have further demonstrated the versatility and efficacy of this new method, in that a novel chemoselective glycosylation of the carboxylic acid and a new one-pot sequential glycosylation sequence have been implemented.

Total Synthesis and Structural Revision of TMG-chitotriomycin, a Specific Inhibitor of Insect and Fungal β-N-Acetylglucosaminidases

TMG-chitotriomycin, a potent and selective inhibitor of the beta-N-acetylglucosaminidases that possesses an unique N,N,N-trimethyl-d-glucosamine (TMG) residue, is revised to be the TMG-beta-(1-->4)-chitotriose instead of the originally proposed alpha-anomer via its total synthesis, for which a highly convergent approach was developed in which the sterically demanding (1-->4)-glycosidic linkages are efficiently constructed by the Au(I)-catalyzed glycosylation protocol with glycosyl o-hexynylbenzoates as donors.

Shape-controlled synthesis and growth mechanism of one-dimensional nanostructures of trigonal tellurium

Single crystalline one-dimensional (1D) nanostructures of trigonal tellurium (t-Te) with well-controlled shapes and sizes were synthesized by the hydrothermal reduction of Na2TeO3 in a mixed solution of ethanol and water at 100 °C. The formation of various 1D nanostructures of t-Te was mainly determined by properly controlling the nucleation and growth rate of t-Te in different reaction media. In acidic solution (1 M of HCl), the reaction gave nanowires with diameters of ∼30–100 nm, while in alkaline solution (1 M of NaOH), it yielded tubular crystals with diameters of ∼1–2 μm. The diameters of tubular crystals could also be controlled by adjusting the NaOH concentration. When polymer surfactant poly(vinyl pyrrolidone) (PVP) was presented in the alkaline solution, the reaction would produce uniform nanowires with diameters of ∼25 nm. Based on the TEM and SEM studies, the formation mechanisms for these 1D nanostructures were rationally interpreted. The crystallinity of the nanowires and the tubular crystals were determined by HRTEM, ED, and XRD.

Total synthesis of the core tetrasaccharide of Neisseria meningitidis lipopolysaccharide, a potential vaccine candidate for meningococcal diseases

The first total synthesis of the core tetrasaccharide α-GlcNAc-(1 → 2)-α-Hep-(1 → 3)-α-Hep-(1 → 5)-α-Kdo of Neisseria meningitidis LPS is achieved in a convergent and stereocontrolled [2 + 2] approach, whereby heptose building blocks obtained by de novo synthesis were fine-tuned for the effective assembly of the 1 → 5 linked Hep-Kdo disaccharide. The synthetic strategy incorporates an α-linked spacer at the reducing end of the tetrasaccharide for use as a handle during subsequent conjugation to a carrier protein.

Diversity-oriented synthesis of inner core oligosaccharides of the lipopolysaccharide of pathogenic Gram-negative bacteria.

Lipopolysaccharide (LPS) is a potent virulence factor of pathogenic Gram-negative bacteria. To better understand the role of LPS in host-pathogen interactions and to elucidate the antigenic and immunogenic properties of LPS inner core region, a collection of well-defined L-glycero-D-manno-heptose (Hep) and 3-deoxy-α-D-manno-oct-2-ulosonic acid (Kdo)-containing inner core oligosaccharides is required. To address this need, we developed a diversity-oriented approach based on a common orthogonal protected disaccharide Hep-Kdo. Utilizing this new approach, we synthesized a range of LPS inner core oligosaccharides from a variety of pathogenic bacteria including Y. pestis, H. influenzae, and Proteus that cause plague, meningitis, and severe wound infections, respectively. Rapid access to these highly branched core oligosaccharides relied on elaboration of the disaccharide Hep-Kdo core as basis for the elongation with various flexible modules including unique Hep and 4-amino-4-deoxy-β-L-arabinose (Ara4N) monosaccharides and branched Hep-Hep disaccharides. A regio- and stereoselective glycosylation of Kdo 7,8-diol was key to selective installation of the Ara4N moiety at the 8-hydroxyl group of Kdo moiety of the Hep-Kdo disaccharide. The structure of the LPS inner core oligosaccharides was confirmed by comparison of (1)H NMR spectra of synthetic antigens and isolated fragments. These synthetic LPS core oligosaccharides can be covalently bound to carrier proteins via the reducing end pentyl amine linker, to explore their antigenic and immunogenic properties as well as potential applications such as diagnostic tools and vaccines.

Chemical synthesis of saponins.

Saponins are a large family of amphiphilic glycosides of steroids and triterpenes found in plants and some marine organisms. By expressing a large diversity of structures on both sugar chains and aglycones, saponins exhibit a wide range of biological and pharmacological properties and serve as major active principles in folk medicines, especially in traditional Chinese medicines. Isolation of saponins from natural sources is usually a formidable task due to the microheterogeneity of saponins in Nature. Chemical synthesis can provide access to large amounts of natural saponins as well as congeners for understanding their structure-activity relationships and mechanisms of action. This article presents a comprehensive account on chemical synthesis of saponins. First highlighted are general considerations on saponin synthesis, including preparation of aglycones and carbohydrate building blocks, assembly strategies, and protecting-group strategies. Next described is the state of the art in the synthesis of each type of saponins, with an emphasis on those representative saponins having sophisticated structures and potent biological activities.

Recent Advances in the Chemical Synthesis of C-Glycosides

Advances in the chemical synthesis of C-pyranosides/furanosides are summarized, covering the literature from 2000 to 2016. The majority of the methods take advantage of the construction of the glycosidic C-C bond. These C-glycosylation methods are categorized herein in terms of the glycosyl donor precursors, which are commonly used in O-glycoside synthesis and are easily accessible to nonspecialists. They include glycosyl halides, glycals, sugar acetates, sugar lactols, sugar lactones, 1,2-anhydro sugars, thioglycosides/sulfoxides/sulfones, selenoglycosides/telluroglycosides, methyl glycosides, and glycosyl imidates/phosphates. Mechanistically, C-glycosylation reactions can involve glycosyl electrophilic/cationic species, anionic species, radical species, or transition-metal complexes, which are discussed as subcategories under each type of sugar precursor. Moreover, intramolecular rearrangements, such as the Claisen rearrangement, Ramberg-Bäcklund rearrangement, and 1,2-Wittig rearrangement, which usually involve concerted pathways, constitute another category of C-glycosylations. An alternative to the C-glycosylations is the formation of pyranoside/furanoside rings after construction of the predetermined glycosidic C-C bonds, which might involve cyclization of acyclic precursors or D-A cycloadditions. Throughout, the stereoselectivity in the formation of the resultant C-glycosidic linkages is highlighted.

Antigenic Potential of a Highly Conserved Neisseria meningitidis Lipopolysaccharide Inner Core Structure Defined by Chemical Synthesis

Neisseria meningitidis is a leading cause of bacterial meningitis worldwide. We studied the potential of synthetic lipopolysaccharide (LPS) inner core structures as broadly protective antigens against N. meningitidis. Based on the specific reactivity of human serum antibodies to synthetic LPS cores, we selected a highly conserved LPS core tetrasaccharide as a promising antigen. This LPS inner core tetrasaccharide induced a robust IgG response in mice when formulated as an immunogenic glycoconjugate. Binding of raised mouse serum to a broad collection of N. meningitidis strains demonstrated the accessibility of the LPS core on viable bacteria. The distal trisaccharide was identified as the crucial epitope, whereas the proximal Kdo moiety was immunodominant and induced mainly nonprotective antibodies that are responsible for lack of functional protection in polyclonal serum. Our results identified key antigenic determinants of LPS core glycan and, hence, may aid the design of a broadly protective immunization against N. meningitidis.

Epitope Recognition of Antibodies against a Yersinia pestis Lipopolysaccharide Trisaccharide Component

Today, the process of selecting carbohydrate antigens as a basis for active vaccination and the generation of antibodies for therapeutic and diagnostic purposes is based on intuition combined with trial and error experiments. In efforts to establish a rational process for glycan epitope selection, we employed glycan array screening, surface plasmon resonance, and saturation transfer difference (STD)-NMR to elucidate the interactions between antibodies and glycans representing the Yersinia pestis lipopolysaccharide (LPS). A trisaccharide epitope of the LPS inner core glycan and different LPS-derived oligosaccharides from various Gram-negative bacteria were analyzed using this combination of techniques. The antibody-glycan interaction with a heptose substructure was determined at atomic-level detail. Antibodies specifically recognize the Y. pestis trisaccharide and some substructures with high affinity and specificity. No significant binding to LPS glycans from other bacteria was observed, which suggests that the epitopes for just one particular bacterial species can be identified. On the basis of these results we are beginning to understand the rules for structure-based design and selection of carbohydrate antigens.

Efficient synthesis of a library of heparin tri- and tetrasaccharides relevant to the substrate of heparanase

The glycosylation reaction for construction of the challenging α-GlcN–(1→4)-GlcA/IdoA linkages has been investigated carefully. A standard protocol was thus fixed that employed 2-azido-glucopyranosyl N-phenyl trifluoroacetimidates as donors, TMSOTf as a catalyst, toluene as a solvent, and −30 °C as the working temperature. With this protocol, a variety of mono- and disaccharide donors and acceptors were condensed reliably to provide the corresponding coupled tri- and tetrasaccharides in satisfactory yields and α-selectivity, whereas a remote protecting group or a sugar unit in either the donor or the acceptor did affect considerably the outcome. The resulting tri- and tetrasaccharides bearing orthogonal protecting groups were then converted efficiently into the corresponding heparin tri- and tetrasaccharides via a robust approach involving saponification, O-sulfation, azide reduction, N-sulfation/N-acetylation, and global debenzylation. These heparin tri- and tetrasaccharides are structurally relevant to ΔHexA(2S)–GlcN(NS,6S)–GlcA–GlcN(NS,6S), a reported substrate of heparanase, and therefore could be exploited to examine the substrate specificity of this important enzyme.