Versatile Glycosyl Sulfonates in β‐Selective C‐Glycosylation

C‐Glycosides are both a common motif in many bioactive natural products and important glycoside mimetics. We demonstrate that activating a hemiacetal with a sulfonyl chloride, followed by treating the resultant glycosyl sulfonate with an enolate results in the stereospecific construction of β‐linked C‐glycosides. This reaction tolerates a range of acceptors and donors, including disaccharides. The resulting products can be readily derivatized into C‐glycoside analogues of β‐glycoconjugates, including C‐disaccharide mimetics.     

Generation of Glycosyl Radicals from Glycosyl Sulfoxides and Its Use in the Synthesis of C‐linked Glycoconjugates

We here report glycosyl sulfoxides appended with an aryl iodide moiety as readily available, air and moisture stable precursors to glycosyl radicals. These glycosyl sulfoxides could be converted to glycosyl radicals by way of a rapid and efficient intramolecular radical substitution event. The use of this type of precursors enabled the synthesis of various complex C‐linked glycoconjugates under mild conditions. This reaction could be performed in aqueous media and is amenable to the synthesis of glycopeptidomimetics and carbohydrate‐DNA conjugates.     

Investigations of Scope and Mechanism of Nickel‐Catalyzed Transformations of Glycosyl Trichloroacetimidates to Glycosyl Trichloroacetamides and Subsequent,Atom‐Economical,One‐Step Conversion to α‐Urea‐Glycosides

The development and mechanistic investigation of a highly stereoselective methodology for preparing α‐linked‐urea neo‐glycoconjugates and pseudo‐oligosaccharides is described. This two‐step procedure begins with the selective nickel‐catalyzed conversion of glycosyl trichloroacetimidates to the corresponding α‐trichloroacetamides. The α‐selective nature of the conversion is controlled with a cationic nickel(II) catalyst, [Ni(dppe)(OTf)₂] (dppe=1,2‐bis(diphenylphosphino)ethane, OTf=triflate). Mechanistic studies have identified the coordination of the nickel catalyst with the equatorial C₂‐ether functionality of the α‐glycosyl trichloroacetimidate to be paramount for achieving an α‐stereoselective transformation. A cross‐over experiment has indicated that the reaction does not proceed in an exclusively intramolecular fashion. The second step in this sequence is the direct conversion of α‐glycosyl trichloroacetamide products into the corresponding α‐urea glycosides by reacting them with a wide variety of amine nucleophiles in presence of cesium carbonate. Only α‐urea‐product formation is observed, as the reaction proceeds with complete retention of stereochemical integrity at the anomeric C?N bond.     

The Implications of (2S,4S)‐Hydroxyproline 4‐O‐Glycosylation for Prolyl Amide Isomerization

The conformations of peptides and proteins are often influenced by glycans O‐linked to serine (Ser) or threonine (Thr). (2S,4R)‐4‐Hydroxyproline (Hyp), together with L ‐proline (Pro), are interesting targets for O‐glycosylation because they have a unique influence on peptide and protein conformation. In previous work we found that glycosylation of Hyp does not affect the N‐terminal amide trans/cis ratios (K_trans/cis) or the rates of amide isomerization in model amides. The stereoisomer of Hyp—(2S,4S)‐4‐hydroxyproline (hyp)—is rarely found in nature, and has a different influence both on the conformation of the pyrrolidine ring and on K_trans/cis. Glycans attached to hyp would be expected to be projected from the opposite face of the prolyl side chain relative to Hyp; the impact this would have on K_trans/cis was unknown. Measurements of ³J coupling constants indicate that the glycan has little impact on the C^γ‐endo conformation produced by hyp. As a result, it was found that the D ‐galactose residue extending from a C^γ‐endo pucker affects both K_trans/cis and the rate of isomerization, which is not found to occur when it is projected from a C^γ‐exo pucker; this reflects the different environments delineated by the proline side chain. The enthalpic contributions to the stabilization of the trans amide isomer may be due to disruption of intramolecular interactions present in hyp; the change in enthalpy is balanced by a decrease in entropy incurred upon glycosylation. Because the different stereoisomers—Hyp and hyp—project the O‐linked carbohydrates in opposite spatial orientations, these glycosylated amino acids may be useful for understanding of how the projection of a glycan from the peptide or protein backbone exerts its influence.     

One‐Step Double Covalent Functionalization of Reduced Graphene Oxide with Xanthates and Peroxides

Radical functionalization of reduced graphene oxide has been achieved by reaction with a xanthate in the presence of peroxide as a radical initiator. X‐ray photoelectron spectroscopy, bulk elemental analyses, and thermogravimetric analyses showed that the xanthate grafting is covalent and efficient. The synthesis and use of seven xanthates and three peroxides showed that the highest grafting yield is obtained when xanthate and peroxide are introduced in stoichiometric amounts. It also revealed that the peroxide used as radical initiator is grafted at the graphenic surface during the functionalization. The method presented in this contribution therefore allows bifunctionalized reduced graphene oxide samples to be easily obtained in one single step. This method leads to undamaged graphene sheets with higher dispersibility than the pristine sample.     

From Polymer to Size‐Defined Oligomers: A Step Economy Process for the Efficient and Stereocontrolled Construction of Chondroitin Oligosaccharides and Biotinylated Conjugates Thereof: Part 1

Controlled acid hydrolysis of polymeric chondroitin sulfate of bovine origin afforded in good yield a basic disaccharide fragment that was used for the first time as a starting material for the expeditious preparation of a set of building blocks that in turn act as versatile synthons for the efficient and stereocontrolled construction of a collection of size‐defined chondroitin oligomers (from di‐ to octasaccharides). This step economy process allows their preparation as reducing species, fitted with a fluorophore, or as biotinylated conjugates; all useful tools for the preparation of microarrays, or as probes for the study of the biosynthesis of chondroitin sulfate.     

Masked Thiol Sugars: Chemical Behavior and Synthetic Applications of S‐Glycopyranosyl‐N‐monoalkyl Dithiocarbamates

The chemical behavior of S‐glycopyranosyl‐N‐monoalkyl dithiocarbamates (DTCs) as masked 1‐glycosyl thiols, easily prepared by the nucleophilic displacement of 1‐halo sugars with dithiocarbamate salts of primary amines, has been studied and synthetically exploited. This behavior relies on the abstraction of the proton of the carbamate functionality that allows controlled access to thiolate sugar intermediates. The basic character of the DTC salts used as reagents leads to thiolates that evolve in situ to symmetrical diglycosyldisulfides (DGDSs) when long reaction times are allowed. Alternatively, controlled unmasking of the thiolate function can be efficiently attained by treatment with an external base of isolated anomeric glycosyl DTCs, the formation of which is prevalent when using short reaction times. In this manner, a second methodology for the preparation of symmetrical DGDSs and a chemical protocol for the S‐glycosylation of any electrophilic substrate are established. The applications of this last strategy for the preparation of thioglycosyl vinyl sulfones, thiodisaccharides, and S‐linked homo‐ and heterodivalent neoglycoconjugates are described as a proof‐of‐concept of the great potential of the sugar DTCs in any chemical scenario in which the covalent attachment of a thiol sugar is required. The evaluation of the biological functionality of some divalent sulfurated sugar systems is also described.     

Spectrum–Structure Relationship in Carbohydrate Vibrational Circular Dichroism and Its Application to Glycoconjugates

Preliminary reports of the nature of the vibrational circular dichroism (VCD) peak at around 1145 cm^?1, which is characteristic of axial glycosidic sugars and is called the glycoside band (J. Am. Chem. Soc. 2004 , 126, 9496), have been throughly examined. Through systematic carbohydrate measurements, it was found that the sign of the glycoside band reflects not only the anomeric configuration but also the pyranose conformation. Isotope and theoretical studies characterized its vibrational mode as C1–H1 deformation coupled with C1–O1 stretching, which indicates its applicability to more‐complicated glycoconjugates. In this study, for the first time, carbohydrate VCD spectra were reliably predicted by means of density functional theory (DFT) calculations. The VCD technique was applied to glycopeptides, and simultaneous analysis of both the carbohydrate and aglycan parts was carried out.     

Efficient Iterative Synthesis of O‐Acetylated Tri‐ to Pentadecasaccharides Related to the Lipopolysaccharide of Shigella flexneri Type 3 a through Di‐ and Trisaccharide Glycosyl Donors

Protection against bacterial infections, including shigellosis, can be achieved by antibodies against the bacterial surface polysaccharide. In line with our efforts to develop vaccine candidates for shigellosis, we report herein the synthesis of penta‐, deca‐, and pentadecasaccharides as well as tri‐, octa‐, and tridecasaccharides as the endchain and intrachain fragments, respectively, of the surface polysaccharide of Shigella flexneri 3 a, a prevalent serotype. The syntheses relied on the efficiency of the trichloroacetimidate glycosylation chemistry, whereby iteration with di‐ and trisaccharide building blocks provided fragments made of up to three mono‐O‐acetylated polysaccharide repeating units. Pd(OH)₂‐mediated hydrogenation/hydrogenolysis enabled the concomitant removal or conversion of up to 31 protecting groups of 4 different origins to provide the targets as propyl glycosides. Oligosaccharides comprising the octasaccharide segment were shown to display high conformational similarities in solution.     

α‐ and β‐Glycosyl Sulfonium Ions: Generation and Reactivity

Low‐temperature electrochemical oxidation of thioglycosides gave glycosyl triflates from which glycosyl sulfonium ions were produced (see scheme). The latter were characterized by NMR spectroscopy and cold‐spray mass spectrometry as a mixture of α‐ and β‐isomers (45:55). The α‐glycosyl sulfonium ion exhibited higher reactivity than the β‐glycosyl sulfonium ion in the reaction with methanol, which gave a mixture of α‐ and β‐methyl glycosides (41:59).

     

Chemical Synthesis of Burkholderia Lipid A Modified with Glycosyl Phosphodiester‐Linked 4‐Amino‐4‐deoxy‐β‐L‐arabinose and Its Immunomodulatory Potential

Modification of the Lipid A phosphates by positively charged appendages is a part of the survival strategy of numerous opportunistic Gram‐negative bacteria. The phosphate groups of the cystic fibrosis adapted Burkholderia Lipid A are abundantly esterified by 4‐amino‐4‐deoxy‐β‐L ‐arabinose (β‐L ‐Ara4N), which imposes resistance to antibiotic treatment and contributes to bacterial virulence. To establish structural features accounting for the unique pro‐inflammatory activity of Burkholderia LPS we have synthesised Lipid A substituted by β‐L ‐Ara4N at the anomeric phosphate and its Ara4N‐free counterpart. The double glycosyl phosphodiester was assembled by triazolyl‐tris‐(pyrrolidinyl)phosphonium‐assisted coupling of the β‐L ‐Ara4N H‐phosphonate to α‐lactol of β(1→6) diglucosamine, pentaacylated with (R)‐(3)‐acyloxyacyl‐ and Alloc‐protected (R)‐(3)‐hydroxyacyl residues. The intermediate 1,1′‐glycosyl‐H‐phosphonate diester was oxidised in anhydrous conditions to provide, after total deprotection, β‐L ‐Ara4N‐substituted Burkholderia Lipid A. The β‐L ‐Ara4N modification significantly enhanced the pro‐inflammatory innate immune signaling of otherwise non‐endotoxic Burkholderia Lipid A.     

Synthesis of Chlamydia Lipopolysaccharide Haptens through the use of α‐Specific 3‐Iodo‐Kdo Fluoride Glycosyl Donors

A scalable approach towards high‐yielding and (stereo)selective glycosyl donors of the 2‐ulosonic acid Kdo (3‐deoxy‐D ‐manno‐oct‐2‐ulosonic acid) is a fundamental requirement for the development of vaccines against Gram‐negative bacteria. Herein, we disclose a short synthetic route to 3‐iodo Kdo fluoride donors from Kdo glycal esters that enable efficient α‐specific glycosylations and significantly suppress the elimination side reaction. The potency of these donors is demonstrated in a straightforward, six‐step synthesis of a branched Chlamydia‐related Kdo‐trisaccharide ligand without the need for protecting groups at the Kdo glycosyl acceptor. The approach was further extended to include sequential iteration of the basic concept to produce the linear Chlamydia‐specific α‐Kdo‐(2→8)‐α‐Kdo‐(2→4)‐α‐Kdo trisaccharide in a good overall yield.     

自然氧化偶联及其在碳氢功能化反应中的应用

氧化偶联作为一种经济、高效的化学键构建模式,在有机合成化学中得到了广泛的应用.近年来, Klussmann、焦宁和霍聪德等课题组通过发展简单、直接的自然氧化偶联反应,成功实现了一些Csp³-H和Csp²-H功能化反应,在该领域中取得了重要进展.我们就他们近年来在该领域的研究进展作一亮点评述.     

Localized Template‐Driven Functionalization of Nanoparticles by Dynamic Combinatorial Chemistry

We have developed a method for the localized functionalization of gold nanoparticles using imine‐based dynamic combinatorial chemistry. By using DNA templates, amines were grafted on the aldehyde‐functionalized nanoparticles only if and where the nanoparticles interacted with the template molecules. Functionalization of the nanoparticles was controlled solely by the DNA template; only amines capable of interacting with DNA were bound to the surface. Interestingly, even though our libraries contained only a handful of simple amines, the DNA sequence influenced their attachment to the surface. Our method opens up new opportunities for the synthesis of multivalent, nanoparticle‐based receptors for biomacromolecules.