Synthesis of triazolyl-linked polysialic acids

A new approach for the synthesis of triazolyl-linked α-(2-9) oligosialic acids by iterative copper(I)-catalyzed alkyne–azide cycloaddition (CuAAC) and desilylation has been developed. By using propargyl α-sialoside 5 and trimethylsilylated-propargyl 9-azido-α-sialoside 3 as building blocks, triazolyl-linked α-(2-9) di- to octa-sialic acids were constructed in good to moderate yields. Finally, the pseudo-α-(2-9)-oligosialic acids were obtained very smoothly via O-deprotection. The oligosialic acids with a triazolyl-linkage represent a new type of pseudooligosialic acids. This protocol may find applications in the preparation of oligosialic acid analogues with biological importance.     

Synthesis of nor-C-linked neuraminic acid disaccharide: a versatile precursor of C-analogs of oligosialic acids and gangliosides

The Neu5Acalpha(2,8)Neu5Ac disaccharide is an important constituent of tumor related antigen, however, the O-linkage is catabolically unstable. Vaccination with a catabolically stable sialic acid C-glycoside analog might enhance immunogenicity. The synthesis of Neu5Ac nor-C-disaccharide 20R/S, corresponding to versatile precursors of C-analogs of oligosialic acid and gangliosides, is reported. The synthesis of the protected acceptor was not straightforward, as ester, silyl ether, and isopropylidene protection failed to afford desired C-linked disaccharide. Allyl ether protection of hydroxyl groups and acetyl protection of the acetamido facilitated the successful synthesis of the 8-aldehyde neuraminyl acceptor. Samarium mediated C-glycosylation afforded the desired nor-C-disaccharide as a mixture of two separable diastereomers.     

High-performance CE: an effective method to study lactonization of alpha2,8-linked oligosialic acid

A sensitive and efficient method using high-performance CE (HPCE) and neuraminidase hydrolysis was developed to study the lactonization and hydrolysis of alpha2,8-pentasialic acid. Eleven lactone species of pentasialic acid formed in glacial acetic acid were detected and classified into three groups based on the number of carboxylic acids: monolactones with four carboxylic acids, dilactones with three carboxylic acids, and trilactones with two carboxylic acids. These lactones eluted between the original pentamer (with five carboxylic acids) and the fully lactonized species (with one carboxylic acid) in HPCE. Eight of the isomers were identified by hydrolysis with neuraminodase. Results obtained from previous reports and from this study together reveal a general rule for predicting the subtle difference in the acidity of each carboxylic acid in oligosialic acids: the closer the carboxylic acid is to the nonreducing end, the more acidic it is. Therefore, the elution order of lactone isomers having the same number of carboxylic groups can be predicted from the position of the free carboxylic groups in pentasialic acid. We used this principle and the results of hydrolysis with neuraminidase to identify hexamer lactone isomers separated by HPCE.     

Synthetic study on α(2→8)-linked oligosialic acid employing 1,5-lactamization as a key step

An attempt to synthesize α(2→8)-linked oligosialic acid utilizing a 1,5-lactamized sialyl acceptor is described. 1,5-Lactamization was experimentally proven to proceed only for α-sialoside, which was integrated into the synthetic cycle of oligosialic acid as a chemical sorting step to collect the desired α-sialoside and as a transformation step to produce a reactive sialyl acceptor for the next sialylation. Lactamized oligosialyl acceptors served as favorable coupling partners for sialylation, providing high stereoselectivities and high yields.     

Anomeric reactivity-based one-pot synthesis of heparin-like oligosaccharides

A highly efficient one-pot methodology is described for the synthesis of heparin and heparan sulfate oligosaccharides utilizing thioglycosides with well-defined reactivity as building blocks. L-Idopyranosyl and D-glucopyranosyl thioglycosides 5 and 10 were used as donors due to low reactivity of uronic acids as the glycosyl donors in the one-pot synthesis. The formation of uronic acids by a selective oxidation at C-6 was performed after assembly of the oligosaccharides. The efficiency of this programmable strategy with the flexibility for sulfate incorporation was demonstrated in the representative synthesis of disaccharides 17, 18, tetrasaccharide 23, and pentasaccharide 26.     

A stereoselective approach for the synthesis of alpha-sialosides

A highly efficient synthesis of the human melanoma associated antigen GD(3) derivative has been described. A key feature of the synthetic approach was the use of sialyl donors that were protected with a C-5 trifluoroacetamide moiety. These sialyl donors gave high yields and excellent alpha-anomeric selectivities in direct glycosylations with a wide variety of glycosyl acceptors ranging from C-8 hydroxyls of sialic acids and C-3 hydroxyls of galactosides to reactive primary alcohols.     

Biogenetic Chiral Deep Eutectic Solvents that Produce Self-Assembled Chiroptical Materials

Deep eutectic solvents (DESs) show particular properties compared to ionic liquids and other traditional organic solvents. Controlled synthesis of chiral materials in DESs is unprecedented due to the complex interplays between DESs and solutes. In this work, all bio-derived chiral DESs were prepared using choline chloride or cyclodextrin as hydrogen bonding acceptors and natural chiral acids as donors, which performed as chiral matrices for the rational synthesis of chiroptical materials by taking advantage of the efficient chirality transfer between the DESs and solutes. In a very selective manner, building units with molecular pockets could facilitate strong binding affinity towards chiral acid components of DESs disregarding the presence of competitive hydrogen bonding acceptors. Chirality transfer from DESs to nanoassemblies leads to chirality amplification in the presence of minimal amounts of entrapped chiral acids, thanks to the spontaneous symmetry breaking of solutes during aggregation. This work utilizes chiral DESs to control supramolecular chirality, and illustrates the structural basis for the fabrication of DES-based chiral materials.     

Efficient stereoselective synthesis of gamma-N-glycosyl asparagines by N-glycosylation of primary amide groups

The efficient and elegant synthesis of N-glycosides by N-glycosylation of asparagine-containing peptides is described. Glycosylation of primary amides with glycosyl N-phenyltrifluoroimidates in the presence of a catalytic amount of TMSOTf in nitromethane smoothly proceeded to provide the corresponding N-glycosyl amino acids in excellent yields. This coupling method was adaptable to the coupling of various glycosyl donors with amino acids and peptides.     

Preparation of 4-pentenoic acid ester of Neu5Ac and 4-pentenyl glycoside of Neu5Ac and their application to glycosylation

Novel sialosyl donors, 4-pentenoic acid ester of N-acetylneuraminic acids (Neu5Ac) and 4-pentenyl glycoside of Neu5Ac were successfully prepared from the corresponding per-O-acetylated 2-hydroxy and 2-chloro derivatives of Neu5Ac, respectively and applied to the synthesis of O-sialosides.     

Solid-phase synthesis of peptide and glycopeptide thioesters through side-chain-anchoring strategies

An efficient new strategy for the synthesis of peptide and glycopeptide thioesters is described. The method relies on the side-chain immobilization of a variety of Fmoc-amino acids, protected at their C-termini, on solid supports. Once anchored, peptides were constructed using solid-phase peptide synthesis according to the Fmoc protocol. After unmasking the C-terminal carboxylate, either thiols or amino acid thioesters were coupled to afford, after cleavage, peptide and glycopeptide thioesters in high yields. Using this method a significant proportion of the proteinogenic amino acids could be incorporated as C-terminal amino acid residues, therefore providing access to a large number of potential targets that can serve as acyl donors in subsequent ligation reactions. The utility of this methodology was exemplified in the synthesis of a 28 amino acid glycopeptide thioester, which was further elaborated to an N-terminal fragment of the glycoprotein erythropoietin (EPO) by native chemical ligation.     

New copper-mediated O-arylations of phenols with arylstannanes

A novel method for the synthesis of diaryl ethers with phenols and arylstannanes under mild conditions is described. This copper-mediated O-arylation is feasible using DMAP in acetonitrile and is complementary to the use of boronic acids as aryl donors. The reaction is tolerant of a wide range of substituents and sterically hindered coupling partners.     

First O-glycosylation of hydroxamic acids

The first O-glycosylation of hydroxamic acids is reported. This process involves the use of glycosyl N-phenyl trifluoroacetimidates as glycosyl donors in the presence TMSOTf and 4 A molecular sieves in dichloromethane. Under such conditions, a wide range of new glycosyl donors including glucosyl, galactosyl, mannosyl, glucuronyl, and ribosyl hydroxamates were prepared in good to high yields. This procedure appears to be an advantageous alternative for the synthesis of glycosyl hydroxamates of biological interest.     

Determination of amino acids in human blood serum by reversed-phase high-performance liquid chromatography in the isocratic elution mode

A procedure is developed for the determination of 15 amino acids in human blood serum usingortho-phthalic aldehyde in combination with 2-mercaptoethanol or sodium sulfite as the reagent for the precolumn synthesis of derivatives with their subsequent separation by reversed-phase high-performance liquid chromatography in the isocratic elution mode using electrochemical detection. Conditions of the quantitative conversion of amino acids to corresponding derivatives were determined;ortho-phthalic—mercaptoethanol andortho-phthalic/sulfite derivatives of amino acids are stable during the whole cycle of analysis. The total time of separation is 80 min. The detection limits are 0.5-5 pmol (at the signal-to-noise ratio equal to 2). The procedure is used for the determination of glutamic acid, asparagine, serine, glutamine, histidine, taurine, alanine, arginine, methionine, isoleucine, ornithine, leucine, phenylalanine, lysine, and tryptophane in blood serum of healthy donors and of sick with alcoholism before and after treatment     

En route to a carbohydrate-based vaccine against Burkholderia cepacia

We report a very high yielding first total synthesis of trisaccharide 5, alpha-D-Rhap-(1 --> 3)-alpha-D-Rhap-(1 --> 4)-alpha-D-Galp, corresponding to the repeating unit 1 of an O-polysaccharide present in the lipopolysaccharide of clinical isolate of Burkholderia cepacia. The approach included two successive glycosylations, based on D-rhamnosyl trichloroacetimidate donors 12 and 14. The oligosaccharide 5 has been further functionalized by photochemical coupling or cross-metathesis with non-natural amino acid derivatives. Trisaccharidylamino acids 16 and 17 are now available, with the aim of preparing a novel synthetic carbohydrate-based vaccine.     

Ynamide‐Mediated Thiopeptide Synthesis

Exploration of the full potential of thioamide substitution as a tool in the chemical biology of peptides and proteins has been hampered by insufficient synthetic strategies for the site‐specific introduction of a thioamide bond into a peptide backbone. A novel ynamide‐mediated two‐step strategy for thiopeptide bond formation with readily available monothiocarboxylic acids as thioacyl donors is described. The α‐thioacyloxyenamide intermediates formed from the ynamides and monothiocarboxylic acids can be purified, characterized, and stored. The balance between their activity and stability enables them to act as effective thioacylating reagents to afford thiopeptide bonds under mild reaction conditions. Amino acid functional groups such as OH, CONH₂, and indole NH groups need not be protected during thiopeptide synthesis. The modular nature of this strategy enables the site‐specific incorporation of a thioamide bond into peptide backbones in both solution and the solid phase.     

Mechanistic information from pressure acceleration of hydride formation via proton binding to a cobalt(I) macrocycle

The effect of pressure on proton binding to the racemic isomer of the cobalt(I) macrocycle, CoL(+) (L = 5,7,7,12,14,14-hexamethyl-1,4,8,11-tetraazacyclotetradeca-4,11-diene), has been studied for a series of proton donors using pulse radiolysis techniques. The second-order rate constants for the reaction of CoL(+) with proton donors decrease with increasing pK(a) of the donor acid, consistent with a reaction occurring via proton transfer. Whereas the corresponding volumes of activation (DeltaV) are rather small and negative for all acids (proton donors) with pK(a) values below 8.5, significantly larger negative activation volumes are found for weaker acids (pK(a) > 9.5) containing OH groups as proton donors. In the latter case, the observed DeltaV for these protonation reactions show a correlation with the reaction volumes (DeltaV degrees (ion)) for the ionization of the weak acids with a slope of 0.44, indicating that bond dissociation of the weak acid molecule bound to the metal center proceeds approximately halfway at the transition state along the reaction coordinate in terms of volume changes.     

“Anti‐Electrostatic” Halogen Bonding

Halogen bonding is often described as being driven predominantly by electrostatics, and thus adducts between anionic halogen bond (XB) donors (halogen‐based Lewis acids) and anions seem counterintuitive. Such “anti‐electrostatic” XBs have been predicted theoretically but for organic XB donors, there are currently no experimental examples except for a few cases of self‐association. Reported herein is the synthesis of two negatively charged organoiodine derivatives that form anti‐electrostatic XBs with anions. Even though the electrostatic potential is universally negative across the surface of both compounds, DFT calculations indicate kinetic stabilization of their halide complexes in the gas phase and particularly in solution. Experimentally, self‐association of the anionic XB donors was observed in solid‐state structures, resulting in dimers, trimers, and infinite chains. In addition, co‐crystals with halides were obtained, representing the first cases of halogen bonding between an organic anionic XB donor and a different anion. The bond lengths of all observed interactions are 14–21 % shorter than the sum of the van der Waals radii.     

Solid-phase synthesis of O-glycosylated Nalpha-Fmoc amino acids and analysis by high-resolution magic angle spinning NMR

Direct O-glycosylation of amino acids bound to TentaGel resin with a number of glycosyl trichloroacetimidate donors results in high yields. The glycosylation reaction can be easily monitored by analyzing the bead-bound amino acids with high-resolution magic angle spinning (HR-MAS) NMR. These studies pave a new way for the construction of "one-bead one-compound" O-glycopeptide libraries with standard amino acid building blocks and appropriate glycosyl trichloroacetimidate donors.     

Effect of phthalic and salicylic acids on the synthesis and properties of polyaniline films

Effects of phthalic and salicylic acids on the kinetics of the synthesis of polyaniline (PAN) at platinum and on the PAN doping and degradation are studied, along with the adsorption behavior of these acids during the synthesis and degradation of PAN. Effect of additives on the PAN properties is determined by the interaction between additives and PAN. The acids make no impact on the PAN synthesis kinetics and affect only the PAN doping and degradation.