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.

New principles for glycoside-bond formation.

Glycosylation is arguably the most important reaction in the field of glycochemistry, yet it involves one of the most empirically interpreted mechanisms in the science of organic chemistry. The β-mannopyranosides, long considered one of the more difficult classes of glycosidic bond to prepare, were no exception to this rule. A number of logical but circuitous routes for their preparation were described in the literature, but they were accompanied by an even greater number of mostly ineffective recipes with which to access them directly. This situation changed in 1996 with the discovery of the 4,6-O-benzylidene acetal as a control element permitting direct entry into the β-mannopyranosides, typically with high yield and selectivity. The unexpected nature of this phenomenon demanded study of the mechanism, leading first to the demonstration of the α-mannopyranosyl triflates as reaction intermediates and then to the development of α-deuterium kinetic isotope effect methods to probe their transformation into ...

Mechanism of a Chemical Glycosylation Reaction

A general, mild, and efficient 1,2-migration/cycloisomerization methodology toward multisubstituted 3-thio-, seleno-, halo-, aryl-, and alkyl-furans and pyrroles, as well as fused heterocycles, valuable building blocks for synthetic chemistry, has been developed. Moreover, regiodivergent conditions have been identified for C-4 bromo- and thio-substituted allenones and alkynones for the assembly of regioisomeric 2-hetero substituted furans selectively. It was demonstrated that, depending on reaction conditions, ambident substrates can be selectively transformed into furan products, as well as undergo selective 6-exo-dig or Nazarov cyclizations. Our mechanistic investigations have revealed that the transformation proceeds via allenylcarbonyl or allenylimine intermediates followed by 1,2-group migration to the allenyl sp carbon during cycloisomerization. It was found that 1,2-migration of chalcogens and halogens predominantly proceeds via formation of irenium intermediates. Analogous intermediate can also be...

/pdf/metal-catalyzed-1-2-shift-of-diverse-migrating-groups-in-2agkzx1hww.pdf

Metal-Catalyzed 1,2-Shift of Diverse Migrating Groups in Allenyl Systems as a New Paradigm toward Densely Functionalized Heterocycles

A set of cycloisomerization methodologies of alkynyl ketones and imines with concurrent acyloxy, phosphatyloxy, or sulfonyloxy group migration, which allow for the efficient synthesis of multisubstituted furans and N-fused heterocycles, has been developed. Investigation of the reaction course by way of employing 17O-labeled substrates allowed for elucidation of the mechanisms behind these diverse transformations. It was found that, while the phosphatyloxy migration in conjugated alkynyl imines in their cycloisomerization to N-fused pyrroles proceeded via a [3,3]-sigmatropic rearrangement, the analogous cycloisomerization of skipped alkynyl ketones proceeds through two consecutive 1,2-migrations, resulting in an apparent 1,3-shift, followed by a subsequent 1,2-migration through competitive oxirenium and dioxolenylium pathways. Investigations of the 1,2-acyloxy migration of conjugated alkynyl ketones en route to furans demonstrated the involvement of a dioxolenylium intermediate. The mechanism of cycloisomerization of skipped alkynyl ketones containing an acyloxy group was found to be catalyst dependent; Lewis and Bronsted acid catalysts caused an ionization/SN1' isomerization to the allene, followed by cycloisomerization to the furan, whereas transition metal catalysts evoked a Rautenstrauch-type mechanistic pathway. Furthermore, control experiments in the cycloisomerization of skipped alkynyl ketones under transition metal catalysis revealed that, indeed, these reactions were catalyzed by transition metal complexes as opposed to Bronsted acids resulting from hydrolysis of these catalysts with eventual water. Further synthetic utility of the obtained phosphatyloxy-substituted heterocycles was demonstrated through their efficient employment in the Kumada cross-coupling reaction with various Grignard reagents.

Mechanistically Diverse Copper-, Silver-, and Gold- Catalyzed Acyloxy and Phosphatyloxy Migrations: Efficient Synthesis of Heterocycles via Cascade Migration/Cycloisomerization Approach

The main focus of this perspective lies in the discussion of the recent mechanistic theories and supporting experimental evidences that have been put forth in an attempt to advance our understanding of the factors affecting chemical glycosylation.

Mechanism of chemical O-glycosylation: from early studies to recent discoveries.

The synthesis of 4,6-O-benzylidene-protected 2-deoxyarabino-, 3-deoxyarabino-, and 3-deoxyribothioglycosides is described and their glycosylation reactions, with activation by either 1-benzenesulfinyl piperidine/trifluoromethansulfonic anhydride or diphenyl sulfoxide/trifluoromethanesulfonic anhydride, studied. In contrast to the corresponding 4,6-O-benzylidene-protected glucosyl and mannosyl donors, which are alpha- and beta-selective, respectively, poor diastereoselectivity is observed in all cases. The reasons for this poor selectivity are discussed in terms of the interaction between the C2-O2 and C3-O3 bonds in the glucosyl and mannosyl donors and of the influence of this interaction on the ease of formation of the intermediate glycosyl oxacarbenium ions.

/pdf/on-the-influence-of-the-c2-o2-and-c3-o3-bonds-in-4-6-o-54ctd96c86.pdf

On the influence of the C2-O2 and C3-O3 bonds in 4,6-O-benzylidene-directed beta-mannopyranosylation and alpha-glucopyranosylation.

A series of 6-mono-, di-, and trifluoro analogs of S-phenyl 2,3,4-tri-O-benzyl-D- or L-thiorhamnopyranoside has been synthesized and used as donors in glycosylation reactions, with activation by the 1-benzenesulfinyl piperidine/triflic anhydride system. The stereochemical outcome of the glycosylation reactions was found to depend on the electron-withdrawing capability of the disarming substituent at the 6-position, i.e., on the number of fluorine atoms present. The results are explained with regard to the increased stability of the glycosyl triflates, shown to be intermediates in the reaction by low-temperature 1H NMR experiments, with increased fluorine content.

Synthesis and glycosylation of a series of 6-mono-, di-, and trifluoro S-phenyl 2,3,4-tri-O-benzyl-thiorhamnopyranosides. Effect of the fluorine substituents on glycosylation stereoselectivity.

A synthesis of the pentenyl glycoside of the tetrasaccharide side chain from the major glycoprotein of Bacillus anthracis by a [3 + 1] approach is described. The construction of the 1,2-trans-glycosidic linkage in the terminal anthrose moiety was achieved through the application of known α-nitrilium ion-mediated β-selective glycosylation methodology. An iterative glycosylation strategy was used for the assembly of the trirhamnan building block. A new route to the anthrose saccharide was developed from d-galactose.

/pdf/synthesis-of-the-antigenic-tetrasaccharide-side-chain-from-nr6h74tnmt.pdf

Synthesis of the antigenic tetrasaccharide side chain from the major glycoprotein of Bacillus anthracis exosporium.

On exposure to dichlorodicyanoquinone in wet dichloromethane at room temperature, equatorial 4-O-benzyl ethers are removed with moderate selectivity in the presence of other benzyl ethers in glycopyranosides and glycothiopyranosides.

/pdf/facile-oxidative-cleavage-of-4-o-benzyl-ethers-with-4j7x2lbq2x.pdf

Facile Oxidative Cleavage of 4-O-Benzyl Ethers with Dichlorodicyanoquinone in Rhamno- and Mannopyranosides

Synthesis and Glycosylation of a Series of 6-Mono-, Di-, and Trifluoro S-Phenyl 2,3,4-Tri-O-benzyl-thiorhamnopyranosides. Effect of the Fluorine Substituents on Glycosylation Stereoselectivity.

Olga Vinogradova

Papers

On the influence of the C2-O2 and C3-O3 bonds in 4,6-O-benzylidene-directed beta-mannopyranosylation and alpha-glucopyranosylation.

Synthesis and glycosylation of a series of 6-mono-, di-, and trifluoro S-phenyl 2,3,4-tri-O-benzyl-thiorhamnopyranosides. Effect of the fluorine substituents on glycosylation stereoselectivity.

Synthesis of the antigenic tetrasaccharide side chain from the major glycoprotein of Bacillus anthracis exosporium.

Facile Oxidative Cleavage of 4-O-Benzyl Ethers with Dichlorodicyanoquinone in Rhamno- and Mannopyranosides

Synthesis and Glycosylation of a Series of 6-Mono-, Di-, and Trifluoro S-Phenyl 2,3,4-Tri-O-benzyl-thiorhamnopyranosides. Effect of the Fluorine Substituents on Glycosylation Stereoselectivity.