Studies on the Selectivity Between Nickel-Catalyzed 1,2-cis-2-Amino Glycosylation of Hydroxyl Groups of Thioglycoside Acceptors with C(2)-Substituted Benzylidene N-Phenyl Trifluoroacetimidates and Intermolecular Aglycon Transfer of the Sulfide Group

The stereoselective synthesis of saccharide thioglycosides containing 1,2-cis-2-amino glycosidic linkages is challenging. In addition to the difficulties associated with achieving high α-selectivity in the formation of 1,2-cis-2-amino glycosidic bonds, the glycosylation reaction is hampered by undesired transfer of the anomeric sulfide group from the glycosyl acceptor to the glycosyl donor. Overcoming these obstacles will pave the way for the preparation of oligosaccharides and glycoconjugates bearing the 1,2-cis-2-amino glycosidic linkages because the saccharide thioglycosides obtained can serve as donors for another coupling iteration. This approach streamlines selective deprotection and anomeric derivatization steps prior to the subsequent coupling event. We have developed an efficient approach for the synthesis of highly yielding and α-selective saccharide thioglycosides containing 1,2-cis-2-amino glycosidic bonds, via cationic nickel-catalyzed glycosylation of thioglycoside acceptors bearing the 2-trifluoromethylphenyl aglycon with N-phenyl trifluoroacetimidate donors. The 2-trifluoromethylphenyl group effectively blocks transfer of the anomeric sulfide group from the glycosyl acceptor to the C(2)-benzylidene donor and can be easily installed and activated. The current method also highlights the efficacy of the nickel catalyst selectively activating the C(2)-benzylidene imidate group in the presence of the anomeric sulfide group on the glycosyl acceptors.     

Formation of beta-glucosamine and beta-mannose linkages using glycosyl phosphates

[reaction: see text] Glycosyl phosphates were examined for their utility in the synthesis of challenging glycosidic linkages. beta-Glucosamine glycosides were formed preferentially and in good yield. beta-Mannosides were constructed in high overall yield with modest anomeric selectivity. Interesting solvent and conformational influences on the stereochemical outcome of the coupling reactions were observed.     

“Armed-disarmed” glycosidation strategy based on glycosyl donors and acceptors carrying phosphoroamidate as a leaving group: A convergent synthesis of globotriaosylceramide

A stereocontrolled synthesis of globotriaosylceramide with three different glycosidic linkages has been accomplished by linear and convergent routes exploiting “armed-disarmed” glycosidation methodology based on glycosyl donors and acceptors carrying tetramethylphosphoroamidate as a leaving group. In particular, the convergent strategy featuring a coupling of a galactosyl-(1→4)-galactosyl donor with a glucosylceramide derivative has proven to be extremely efficient.     

Synthesis of Glycopeptides,Partial Structures of Biological Recognition Components [New Synthetic Methods (67)]

Glycopeptides are partial structures of the connecting regions of glycoproteins and, like these, always contain glycosidic bonds between the carbohydrate and peptide parts. Glycoproteins are not only widely distributed but are also decisive factors in post-translational biological selectivity, especially in biological recognition. Targeted syntheses of glycopeptides require stereoselective formation of the glycosidic bonds between the carbohydrate and the peptide parts and protective group methods that enable selective deblocking of only one functional group in these polyfunctional molecules. These heavy demands have been met by the well-established use of benzylic protective groups, which can be removed by hydrogenolysis, combined with the use of base-labile 2-phosphonioethoxycarbonyl (Peoc) or 9-fluorenylmethoxycarbonyl (Fmoc) protective groups or of bromoethyl esters, which can be removed under neutral conditions. The acidolysis of tert-butyloxycarbonyl (Boc) groups and of tert-butyl esters has also been successfully used, although, under acidic conditions, anomerization or rupture of the glycosidic bonds may occur, especially when nucleophiles are present. The stable, two-stage 2-(pyridyl)ethoxycarbonyl (Pyoc) protective groups allow a more reliable synthesis of complex glycopeptides since they can be removed, after modifications, under mild conditions. Particularly suitable for the synthesis of sensitive glycopeptides are the stable allyl protective groups. They can be removed from the complex glycopeptides in a highly selective and effective manner by means of noble-metal catalysts under practically neutral conditions. These methods have been employed to synthesize glycopeptides corresponding to partial structures of interesting glycoproteins. Deprotected glyopeptides representing tumor-associated antigen structures can be coupled to bovine serum albumin, which serves as a biological carrier molecule, without the necessity of using an artificial coupling component (spacer).     

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 Ph₃PAuOTf and Ph₃PAuNTf₂ (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 α‐selective glycosylation with a 2‐deoxy sugar donor and β‐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.     

糖苷配合物与DNA作用机理的电化学研究进展

本文综述了糖苷配合物的合成、表征、生物功能及糖化学研究现状，并对糖苷功能配合物与DNA的作用机理及生物功能的电分析化学研究进行了探讨。着重讨论了应用电分析化学、谱学方法、单晶X-射线衍射分析来研究糖苷功能配合物。引用文献39篇。     

Total Synthesis of Belizentrin Methyl Ester: Report on a Likely Conquest

The assigned structure of the dinoflagellate‐derived toxin belizentrin was prepared by total synthesis in form of the corresponding methyl ester for stability reasons. The successful route features an unusual solution for the preparation of a recalcitrant ylide on a C‐glycosidic segment; moreover, it involves an asymmetric hetero‐Diels–Alder reaction en route to the tertiary hemiacetal substructure, a Negishi cross‐coupling of two elaborate building blocks, and a macrocyclization based on an intramolecular aminolysis of a spirolactone. A modified Kocienski olefination ultimately allowed the polyol side chain to be attached to the macrocycle although this transformation faced the exceptional base sensitivity of this polyunsaturated target compound.     

Differently Glycosidated 2‐Amino‐2‐deoxy‐d‐glucopyranosiduronic Acids as Building Blocks in Peptide Synthesis

Seven differently glycosidated sugar amino acids (SSAs) derived from glucosamine have been prepared. Following standard solution‐phase peptide‐coupling procedures, the glycosidated 2‐amino‐2‐deoxy‐D ‐glucopyranosiduronic acids were condensed with natural amino acids to furnish useful heterodi‐ and ‐trimeric building blocks to be used in peptide synthesis. Combinations of these building blocks yielded hetero‐oligomeric peptides with two sugar amino acid units in different distances to each other. These were prepared to evaluate the influence of glycosidic side chains on the peptide backbone. Conformations of selected examples were examined by means of ROESY spectroscopy in combination with molecular dynamics (MD) simulations and circular‐dichroism (CD) studies.     

Synthesis of the Salmonella type E(1) core trisaccharide as a probe for the generality of 1-(benzenesulfinyl)piperidine/triflic anhydride combination for glycosidic bond formation from thioglycosides

A synthesis of a chromogenic glycoside of the Salmonella anatum group E(1) core trisaccharide is presented in which all three glycosidic bonds, a 1,2-cis-equatorial, a 1,2-trans-axial, and a 1,2-trans-equatorial linkage representing three of the four main classes of glycosidic bond, are formed with thioglycoside donors activated under a single set of conditions by the combination of 1-(benzenesulfinyl)piperidine and trifluoromethanesulfonic anhydride. 2,3-O-Carbonyl- and 2,3-O-isopropylidene-alpha-L-rhamnopyranosyl thioglycosides are found to be highly alpha-selective rhamnosyl donors under these conditions.     

Phenanthroline‐Catalyzed Stereoretentive Glycosylations

Carbohydrates are essential moieties of many bioactive molecules in nature. However, efforts to elucidate their modes of action are often impeded by limitations in synthetic access to well‐defined oligosaccharides. Most of the current methods rely on the design of specialized coupling partners to control selectivity during the formation of glycosidic bonds. Reported herein is the use of a commercially available phenanthroline to catalyze stereoretentive glycosylation with glycosyl bromides. The method provides efficient access to α‐1,2‐cis glycosides. This protocol has been performed for the large‐scale synthesis of an octasaccharide adjuvant. Density‐functional theory calculations, together with kinetic studies, suggest that the reaction proceeds by a double S_N2 mechanism.     

糖缀合物的化学合成

本文介绍近年来各种糖缀合物化学合成的研究进展,包括各种糖苷键的化学合成方法以及各种特殊复杂糖缀合物,如糖肽、糖蛋白、糖脂的化学合成策略。     

Directed evolution of new glycosynthases from Agrobacterium beta-glucosidase: a general screen to detect enzymes for oligosaccharide synthesis

BACKGROUND: Oligosaccharide synthesis is becoming increasingly important to industry as diverse therapeutic roles for these molecules are discovered. The chemical synthesis of oligosaccharides on an industrial scale is often prohibitively complex and costly. An alternative, that of enzymatic synthesis, is limited by the difficulty of obtaining an appropriate enzyme. A general screen for enzymes that catalyze the synthesis of the glycosidic bond would enable the identification and engineering of new or improved enzymes. RESULTS: Glycosynthases are nucleophile mutants of retaining glycosidases that efficiently catalyze the synthesis of the glycosidic linkage by condensing an activated glycosyl fluoride donor with a suitable acceptor sugar. A novel agar plate-based coupled-enzyme screen was developed (using a two-plasmid system) and used to select an improved glycosynthase from a library of mutants. CONCLUSIONS: Plate-based coupled-enzyme screens of this type are extremely valuable for identification of functional synthetic enzymes and can be applied to the evolution of a range of glycosyl transferases.     

Synthesis of molluscicidal agent cyanolide a macrolactone from D-(-)-pantolactone

An efficient synthesis of potent molluscicidal agent cyanolide A, a glycosidic 16-membered macrolide, starting from D-(-)-pantolactone is reported. Highly stereoselective aldol, oxa-Michael addition, and Yamaguchi macrolactonization are the key steps in the present synthesis.     

The conformational properties of glycosidic linkages

The developments in stereochemistry which have made possible our present appreciation of the preferred orientation of the aglycon for a glycopyranoside are briefly reviewed. Recent studies in this laboratory are presented wherein, for model compounds, measurements were made of the coupling constant between the ¹³C-aglyconic carbons and anomeric hydrogens as an estimate of the torsion angles, of ¹³C-chemical shifts as a measure of relative steric compressions at the anomeric centers, and of contributions to the molecular rotations by units of conformational asymmetry defined by atoms about the glycosidic bond. These measurements are compared to the results of hard-sphere calculations. It is concluded that the exo-anomeric effect offers an important resistance to rotation about the anomeric carbon to glycosidic bond (φ angles) and that the preferred conformation for a glycopyranoside arise mainly from rotation about the aglyconic carbon to glycosidic oxygen bond (ψ angles).     

N-trifluoroacetyl sialyl phosphite donors for the synthesis of alpha(2 --> 9) oligosialic acids

[reaction: see text] A new method for the synthesis of alpha(2 --> 9) oligosialic acids is developed using phosphite sialyl donors that are protected with a C-5 N-trifluoroacetyl (NHTFA) substituent. Compared with conventional donors, these donors gave a higher degree of alpha-anomeric selectivity during glycosidic bond formation and better yields during iterative sialylation in the synthesis of oligosialic acids.     

Synthesis of the glycopeptidolipid of Mycobacterium avium Serovar 4: first example of a fully synthetic C-mycoside GPL

The preparation of the glycopeptidolipid (GPL) present in the cell wall of Mycobacterium aviumSerovar 4, namely 3,4-di-O-Me-alpha-L-Rhap-(1-->1)[R-C(21)H(43)CH(OH)CH(2)CO-D-Phe-[4-O-Me-alpha-L-Rhap-(1-->4)-2-O-Me-alpha-L-Fucp-(1-->3)-alpha-L-Rhap-(1-->2)-6-deoxy-alpha-L-Talp-(1-->3)]-D-allo-Thr-D-Ala-L-Alaol] (1), is described. The synthesis was based on the disconnection of the final structure into four building blocks, an L-rhamnosyl pseudodipeptide, a 6-deoxy-L-talosyl dipeptide, a trisaccharide donor, and a 3-hydroxyalkanoic acid. The key steps are the creation of the glycosidic linkage between the trisaccharide donor, used as a pentenyl glycoside, and the 6-deoxy-L-talose unit of an appropriate D-Phe-O-(6-deoxy-L-talosyl)-D-allo-Thr derivative and the final coupling of the two glycodipeptide fragments. Pentenyl glycosides were shown to provide useful donors in several glycosylation steps. This work constitutes the first synthesis of the full structure of a so-called "polar mycoside C" GPL.     

An efficient glycosylation protocol with glycosyl ortho-alkynylbenzoates as donors under the catalysis of Ph3PAuOTf

A new and powerful glycosylation protocol with glycosyl ortho-alkynylbenzoates as donors and Ph₃PAuOTf as a promoter is disclosed. The donors are readily available and stable; the glycosidic coupling yields are generally excellent; the promotion system is catalytic, neutral, and orthogonal to the known glycosylation conditions.     

Chemoselective ligation applied to the synthesis of a biantennary N-linked glycoform of CD52

We report here a strategy for the synthesis of N-linked glycopeptide analogues that replace the glycosidic linkages extending from the core pentasaccharide with thioethers amenable to construction by chemoselective ligation. The key building block, a pentasaccharide-Asn analogue containing two thiol residues, was incorporated into CD52 by 9-fluorenylmethoxycarbonyl (Fmoc)-based solid-phase peptide synthesis. An undecasaccharide mimetic was then readily generated by alkylation of this glycopeptide with an N-bromoacetamido trisaccharide. The rapid assembly of a complex type N-linked glycopeptide mimetic was accomplished using this technique.     

Synthesis of branched Man5 oligosaccharides and an unusual stereochemical observation

Branched mannopentaoses were synthesized through two routes. While assembly from the nonreducing end to the reducing end was more convergent with fewer intermediate steps, two diastereomers were obtained. On the other hand, synthesis from the reducing end to the nonreducing end yielded the mannopentaose with the desired stereochemistry as a single isomer. Our results suggest that it is still challenging to reliably predict stereochemical outcome of a glycosylation reaction. It is necessary to thoroughly characterize anomeric configurations of newly formed glycosidic linkages in complex oligosaccharide synthesis.     

Synthesis of beta-C-galacto-pyranosides with fluorine on the pseudoanomeric substituent

[reaction: see text] beta-C-galacto-Pyranosides with CHF and CF2 substitutes for the glycosidic oxygen were prepared through a four-step sequence starting from a central 1-thio-1,2-O-isopropylidene acetal alcohol and different alpha-fluoro- and alpha,alpha-difluoro acids. The key step in the synthesis is the oxocarbenium cyclization of an intermediate enol ether-thioacetal to a C1-substituted glycal.