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With the picolinyl (Pic) group as a C-1 located directing group and N 3 as versatile precursor for C5-NH 2 , a novel 1-Pic-5-N 3 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., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Thiourea mediates cooperative glycosidation through hydrogen bonding. N,N'-Diarylthiourea as cocatalyst enforces an SN2-type acid-catalyzed glycosidation even at room temperature (see scheme; Bn=benzyl). From O-(α-glycosyl) trichloroacetimidates as glycosyl donors and various acceptors, β-glycosides are preferentially or exclusively obtained., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Streptococcus pneumoniae LTA is a highly complex glycophospholipid that consists of nine carbohydrate residues: three glucose, two galactosamine and two 2-acetamino-4-amino-2,4,6-trideoxygalactose (AATDgal) residues that are each differently linked, one ribitol and one diacylated glycerol (DAG) residue. Suitable building blocks for the glucose and the AATDgal residues were designed and their synthesis is described in this paper. These building blocks permitted the successful synthesis of the core structure Glcβ(1-3)AATDgalβ(1-3)Glcα(1-O)DAG in a suitably protected form for further chain extension (1 b, 1 c) and as unprotected glycolipid (1 a) that was employed in biological studies. These studies revealed that 1 a as well as 1 lead to interleukin-8 release, however not via TLR2 or TLR4 as receptor.

Based on the crystal structures of human alpha-GalCer-CD1d and iNKT-alpha-GalCer-CD1d complexes, nonglycosidic analogues of alpha-GalCer were synthesized. They activate iNKT cells resulting in dendritic cell maturation and the priming of antigen-specific T and B cells. Therefore, they are attractive adjuvants in vaccination strategies for cancer and infectious diseases.

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.

Solid-phase oligosaccharide synthesis is based on a hydroxymethylbenzyl benzoate spacer linker which is connected to the Merrifield resin (1 P). Glycosylation was performed with O-glycosyl trichloroacetimidates of glucosamine, mannose, and galactose permitting chain extension (2e, 5e), branching (4b, 7b, 8b), and chain termination (3t, 6t, 9t) with the use of O-benzyl, O-benzoyl, and N-dimethylmaleoyl as permanent and O-fluorenylmethoxycarbonyl (Fmoc) and O-phenoxyacetyl (PA) as temporary protecting groups. The steps required on solid phase are i) glycosylation under TMSOTf catalysis, ii) selective cleavage of the temporary protecting groups, Fmoc with NEt3 and PA with 0.5 equivalents of NaOMe in CH2Cl2/MeOH, and iii) product cleavage from the resin with 4.0 equivalents of NaOMe in CH2Cl2/MeOH and following O-acetylation for convenient product isolation. Thus a highly successful synthesis of a small library of seventeen N-glycan structures was made possible comprising the N-glycan pentasaccharide core structure 53 and two further chain extended hexa- and heptasaccharide N-glycans with a glucosamine or a lactosamine residue, respectively, which is attached to one of the mannose residues of the core structure (56 and 59).

In naturally occurring glycopeptides and glycoproteins the glycan residues generally possess N- and O-linkages to the peptide backbone. Here we report the synthesis of the corresponding S-linked glycopeptides by a convergent strategy to provide compounds which should be quite stable to glycosidases. To this end, peptides that contain beta-bromoalanine and gamma-bromohomoalanine were generated either directly by bromination of serine and homoserine residues, respectively, or by standard ligation of the corresponding amino acids. 1-Thiosugars of O-acetyl protected GalNAc, GlcNAc, and lactose were prepared by known procedures. Reaction of the thiosugars with these peptides in an ethyl acetate/water two-phase system, which contained TBAHS and NaHCO(3), or in a one-phase system that consists of DMF/water and which contains NaHCO(3), led to the desired S-linked glycopeptides cleanly and in almost quantitative yield. This reaction also worked well for O-unprotected 1-thiosugars.

The sialyl Lewis X (sLeX) epitope has become a prominent target for biological studies because of its role in inflammation through binding to selectins. This epitope is located at the terminal end in glycosphingolipids and a lactose unit serves as spacer to the ceramide moiety. This paper focuses on the influence of the spacer structure and spacer length in regard to the mobility of the sLeX epitope. To this end sLex neoglycolipids 1a-c, with one, two, or three lactose units as spacer between the sLeX tetrasaccharide epitope and the membrane anchor, were synthesized. The synthetic strategy was also applied to the synthesis of the corresponding Lewis X (LeX) derivatives. The glycolipids were inserted in model membranes, and the tumbling frequencies of the sLex tetrasaccharide epitopes were then analysed by NMR spectroscopy. A nonaethylene glycol spacer decouples the carbohydrate moiety from the membrane mobility while (oligo-)lactoses act as more rigid distance keepers between the Lewis epitope and the surface of the membrane. Quantification of the different degrees of decoupling was possible by analysis of rotational correlation times.

How do retaining glycosyltransferases function? To answer this question, UDP-Gal and galactose were covalently linked to form disubstrate analogues 1, of which surprisingly 1β and not 1α inhibited α(1-3)-galactosyltransferases very well. An understanding of this inhibition is a key to the pharmacological prevention of hyperacute rejection in pig to primate xenotransplantation., (© 2001 WILEY-VCH Verlag GmbH, Weinheim, Fed. Rep. of Germany.)

Base-catalyzed glycosylations provide the basis for a new and general entry to the synthesis of mucin-type O-glycans. The desired α-linked 2-acetamidoglycosyl amino acids B are accessible selectively starting from glycals of type A. Fmoc=9-fluorenylmethoxycarbonyl., (© 2001 WILEY-VCH Verlag GmbH, Weinheim, Fed. Rep. of Germany.)

2,3-Dehydroneuraminic acid derivative 5 was transformed in five efficient steps into sialyl donor 2, which has a phenylthio group on the beta-side of the 3-position for anchimeric assistance and a diethyl phosphite residue as leaving group at the anomeric carbon. The known GM3 intermediate 10 was transformed into the 4b,4c,8c-O-unprotected acceptor 3, which was then allowed to react with 2 by using TMSOTf as catalyst and acetonitrile as solvent to afford the desired tetrasaccharide 12, which has an alpha(2-8)-linkage between two neuraminic acid residues. Removal of the phenylthio group gave intermediate 13, which was transformed into O-tetraosyl trichloroacetimidate 16 as glycosyl donor. Application of the azidosphingosine glycosylation procedure furnished GD3 (1) in high overall yield. Comparison of synthetic GD3 with bovine-brain-derived GD3 showed that there were similar effects in GD3-triggered uncoupling of mitochondrial respiration and in induction of apoptosis in oligodendrocytes.

Sialyl Lewis X (sLeX)/selectin-mediated leukocyte rolling along endothelial cells has recently gained wide interest. In this paper the influence of the spacer length of laterally clustered neoglycolipids 1a-d on cell rolling in a dynamic test system is investigated. The required di-O-hexadecyl glycerols with none, and with three, six, or nine ethylene glycol units as spacer groups (compounds 4a-d) could be readily obtained. The synthesis of 1-O-thexyldimethylsilyl-protected sLeX 24 was based on sialylation of 2,3,4-O-unprotected galactose derivative 11 with sialyl phosphite 8 as donor; this afforded the desired disaccharide 12, which was transformed into trichloroacetimidate 14 as disaccharide donor. Reaction of 3-O-unprotected glucosamine derivative 18 with fucosyl donor 20 afforded disaccharide 21, which was transformed into the 4-O-unprotected derivative 23. Reaction of 14 with 23 furnished the desired tetrasaccharide 24 in good yield. Transformation of 24 into the trichloroacetimidate 26 as donor, followed by the reaction with 4a-d as acceptor gave, after deprotection, the target molecules 1a-d. For comparison, 4d was also connected with a sialyl residue (-->31) and with an N-acetylglucosamine residue (-->34). Compounds 1c and 1d with a hexaethylene glycol and a nonaethylene glycol spacer, respectively, were much more efficient in mediating selectin-dependent cell rolling in the dynamic test system than compounds 1a and 1b, which had no spacer (1a), or only a triethylene glycol spacer (1b).

The strong dependence of the NOE on the molecular mobility rendered the weak bond of a homotypical carbohydrate-carbohydrate recognition detectable in a simplified model system. The membrane-bound Le X trisaccharide 1, which functions as a receptor, transiently binds the dissolved Le X trisaccharide 2, thus slowing down its rotational diffusion. This kind of molecular recognition plays an important part in cell adhesion., (© 1999 WILEY-VCH Verlag GmbH, Weinheim, Fed. Rep. of Germany.)

A 200- to 1000-fold higher affinity for sialyltransferase is shown by compounds 1 and 2 relative to the natural substrate. These inhibitors, which are derived from the transition state of S N 1-type sialyltransfer, contain a flat ring that is attached through a carbon atom with a phosphonate and a cytidine monophosphate group., (© 1998 WILEY-VCH Verlag GmbH, Weinheim, Fed. Rep. of Germany.)

Repetitive glycosylation on a sulfanylalkyl-functionalized Merrifield resin leads to the branched, complex pentasaccharide 1 in 20% overall yield in ten steps when appropriately protected O-glycosyl trichloroacetimidates are used as glycosyl donors. A decisive factor here was the tuning of the reaction conditions for the solid-phase glycosylation and the conditions for selective removal of the protecting groups and for cleavage of the samples from the resin for characterization. The subsequent cleavage of the product was achieved with a thiophilic reagent that does not attack the O-glycosidic linkages., (© 1998 WILEY-VCH Verlag GmbH, Weinheim, Fed. Rep. of Germany.)

Reaction of gluconolactone 2 with allylmagnesium bromide at low temperatures afforded ketopyranose 3, which could easily be converted into open-chain ketoses (R)-6 and (S)-6. Their reaction with lithioacetylide 9 afforded propargylic alcohol derivatives (R)-10 and (S)-10, which could not be cyclized directly to the desired C-ketosides. They were converted by standard procedures into (R)-14 and (S)-14 and then into dicobalthexacarbonyl complexes (R)-16 and (S)-16. A facile acid-catalyzed ring closure gave the desired C-ketosides (R)-18 α/β and (S)-18α/β, respectively, in different ratios. In order to demonstrate that removal of the protective groups and hydrogenation of the CC triple bond proceed smoothly, (R)-18 α was transformed into the deprotected target molecule (R)-1 α. For the assignment of the new chiral centers at C-2/2' and at C-8, (S)-18α was transformed into azido derivative (S)-22α, which underwent intramolecular cycloaddition to afford the spiro derivative (S)-25α. Because of the conformational constraints in this molecule, unequivocal configurational assignment was possible with the help of NMR data., (Copyright © 1996 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)