An insight into our research on vinyl sulfone-modified pyranosides and furanosides

This review describes the research by the authors on the synthesis of vinyl sulfone-modified carbohydrates and the application of this new class of Michael acceptors in the generation of a wide range of aminosugars, branched-chain sugars, cyclopropanted carbohydrates, densely functionalized cyclopropanes, isonucleosides and pyrroles.     

Diastereoselective michael initiated ring closure on vinyl sulfone-modified carbohydrates: a stereospecific and general route to alpha-substituted cyclopropanes

Suitably designed vinyl sulfone-modified furanosides act as substrates for Michael initiated ring closure reactions yielding cyclopropanated carbohydrates. The strategy is general in nature and gives access to cyclopropanes with predefined chiralities on three consecutive carbons with varying substitutions at the alpha-position.     

Diastereoselective C-C bond formation at C-5 of vinyl sulfone-modified hex-5-enofuranosyl carbohydrates: diversity-oriented synthesis of branched-chain sugars and beyond

This is the first report on the diastereoselective addition of carbon nucleophiles to vinyl sulfone-modified hex-5-enofuranosides. The stereoelectronic properties of the substituents at the C-3 position and their interactions with the incoming carbon nucleophiles control the diastereoselectivity of addition at the C-5 position, favoring the formation of l-ido derivatives as major products in most of the cases studied. This new concept of stereocontrolled carbon-carbon bond formation in vinyl sulfone-modified carbohydrates is general in nature. The novel chirons generated by this diversity-oriented synthetic method have been implemented in the preparation of a wide range of hexofuranosyl C-5 branched-chain sugars, bicyclic derivatives, chirally pure enals, and densely functionalized carbocycles.     

Diastereoselective addition of planar N-heterocycles to vinyl sulfone-modified carbohydrates: a new route to isonucleosides

Michael-type addition reactions of planar N-heterocycles at the C-2 positions of vinyl sulfone-modified carbohydrates provide an efficient and general route for the carbon-N-heterocycle bond formation. Therefore, the addition pattern of planar heterocycles, such as imidazole, triazole, thymine, and adenine to 3-C-phenylsulfonyl-hex-2-enopyranosides (1α/1β) and 3-C-p-toluenesulfonyl-pent-2-enofuranosides (2α/2β) was studied for developing a general methodology for the synthesis of new classes of isonucleosides possessing a carbon-N-heterocycle linkage at C-2 positions of furanosyl and pyranosyl sugars. To a great extent, the anomeric configurations of the starting vinyl sulfones play crucial roles in deciding the diastereoselectivity of addition of heterocycles. However, the trityl protected 3-C-p-toluenesulfonyl-hex-2-enopyranosides (33α/33β) were judged to be more practical starting materials for desulfonylation and deprotection for the synthesis of a new class of thymine and adenine deoxyisonucleosides.     

Synthesis of anomerically pure vinyl sulfone-modified pent-2-enofuranosides and hex-2-enopyranosides: a group of highly reactive Michael acceptors for accessing carbohydrate based synthons

Syntheses of the benzyl or the trityl protected α- and β-anomers of vinyl sulfone-modified pent-2-enofuranosides have been initiated by the ring opening of the suitably masked methyl α-lyxofuranosyl-epoxide or methyl β-ribofuranosyl-epoxide or by the nucleophilic displacement of the leaving groups in benzyl protected 3-O-tosyl xylofuranoside and 3-O-mesyl ribofuranoside by p-thiocresol. In case of the latter set of starting materials, α- and β-methyl glycosides formed in almost equal ratio only from the derivatives of d-xylose. For the synthesis of α- and β-anomers of vinyl sulfone-modified hex-2-enopyranosides, a d-glucose derivative was selected over a d-allose derivative as the starting material because the former almost exclusively produced the required methyl pyranosides whereas the latter produced a mixture. All sulfides were converted to vinyl sulfone-modified carbohydrates by the sequential application of oxidation, mesylation and base induced elimination reactions.     

Vinyl sulfone- and vinyl sulfoxide-modified tetrahydrofurans: a preliminary account of the enantiomeric synthesis of and diastereoselectivity of addition to new classes of Michael acceptors

Enantiomerically pure 2-hydroxymethylene substituted-2,5-dihydro-3-(arylsulfonyl)- and 2-hydroxymethylene substituted-2,5-dihydro-3-(arylsulfinyl)-furans have been prepared from easily accessible carbohydrate derivatives for the first time. The strategy for accessing both these sulfones and sulfoxides is more efficient than the methods reported so far for the synthesis of this type of compounds. Hydroxymethylene group is sufficient to impose diastereoselectivity on the addition of a wide range of nucleophiles to vinyl sulfone-modified tetrahydrofurans. The benzyl protected hydroxymethylene group also suppresses the influence of chirally pure sulfoxides as two diastereomeric vinyl sulfoxide-modified tetrahydrofurans afforded the Michael adducts with same configurations at C-3 and C-4; this has been established by oxidizing the adducts, which were found to be identical to the products obtained by adding the same nucleophiles to the corresponding vinyl sulfones. These highly reactive Michael acceptors may be considered as a new addition to the arsenals of synthetic chemists interested in the functionalization of tetrahydrofurans.     

One‐Pot Synthesis of Unprotected Anomeric Glycosyl Thiols in Water for Glycan Ligation Reactions with Highly Functionalized Sugars

Chemical synthesis of oligosaccharide conjugates is essential for studying the functional relevance of carbohydrates, and this task would be facilitated considerably if reliable methods for the anomeric ligation of unprotected sugars in water were available. Here, a method for the preparation of anomeric glycosyl thiols from complex unprotected mono‐, di‐, and oligosaccharides is presented. By exploiting the neighboring‐group effect of the 2‐acetamido‐group, 1,2‐oxazolines are generated and converted into 1‐glycosyl thioesters through treatment with 1‐thioacids. The unprotected anomeric glycosyl thiolates released in situ were conjugated to Michael acceptors, aliphatic halogenides, and aziridines to furnish versatile glycoconjugates. Conjugation of amino acids and proteins was accomplished using the thiol–ene reaction with terminal olefins. This method gives efficient access to anomeric glycosyl thiols and thiolates, which enables anomeric ligations of complex unprotected glycans in water.     

A diastereoselective and general route to 5-amino-5-deoxysugars: influence of C-3 substitution on the addition of amines to C-5 of vinyl sulfone-modified hex-5-enofuranosyl carbohydrates

In the synthesis of vinyl sulfone-modified hex-5-enofuranosides, the E/Z ratios of the products are influenced by the stereoelectronic property of a group present at the C-3 position. This observation has been utilized to influence the diastereoselectivity of addition of amines to C-5 of vinyl sulfone- modified hex-5-enofuranosides, which are efficient Michael acceptors. The stereoelectronic effect of OMe attached to the beta-face of C-3 (gluco derivative) is sufficient to impose diastereoselectivity overwhelmingly in favor of l-ido-aminosugars when the Michael acceptor is reacted with both primary and secondary amines. 3-O-Benzylated gluco derivative is also effective in producing l-ido-aminosugars but only in reactions with primary amines. The selectivity is lost when an allo derivative with OBn at the alpha-face of C-3 is used. Selected products were desulfonated to establish this new approach as a general and versatile strategy for accessing 5-amino-5-deoxysugars.     

Synthesis of Carbohydrates with an Anomeric Thiol Moiety for Elaboration into Metabolically Stable Thioglycosides

ABSTRACT

The synthesis of thioglycosides for use as metabolically stable biological probes is an area of continued interest. This paper describes the synthesis of functionalised carbohydrates which contain an anomeric thio group. During the course of this work we have examined the most viable route into compounds such as the specifically functionalised carbohydrates 36 and 37, and have also investigated the usefulness of disulfides as protecting groups for anomeric thiols.     

Rethinking Carbohydrate Synthesis: Stereoretentive Reactions of Anomeric Stannanes

In this Concept article, recent advances are highlighted in the synthesis and applications of anomeric nucleophiles, a class of carbohydrates in which the C1 carbon bears a carbon–metal bond. First, the advantages of exploiting the carboanionic reactivity of carbohydrates and the methods for the synthesis of mono- and oligosaccharide stannanes are discussed. Second, recent developments in the glycosyl cross-coupling method resulting in the transfer of anomeric configuration from C1 stannanes to C-aryl glycosides are reviewed. These highly stereoretentive processes are ideally suited for the preparation of carbohydrate-based therapeutics and were demonstrated in the synthesis of antidiabetic drugs. Next, the application of the glycosyl cross-coupling method to the preparation of Se-glycosides and to glycodiversification of small molecules and peptides are highlighted. These reactions proceed with exclusive anomeric control for a broad range of substrates and tolerate carbohydrates with free hydroxyl groups. Taken together, anomeric nucleophiles have emerged as powerful tools for the synthesis of oligosaccharides and glycoconjugates and their future applications will open new possibilities to incorporate saccharides into small molecules and biologics.     

Dynamic Kinetic Stereoselective Glycosylation via RhII and Chiral Phosphoric Acid-Cocatalyzed Carbenoid Insertion to the Anomeric OH Bond for the Synthesis of Glycoconjugates

Chemical synthesis of glycoconjugates is essential for studying the biological functions of carbohydrates. We herein report an efficient approach for the stereoselective synthesis of challenging α-linked glycoconjugates via a Rh^II/chiral phosphoric acid (CPA)-cocatalyzed dynamic kinetic anomeric O-alkylation of sugar-derived lactols via carbenoid insertion to the anomeric OH bond. Notably, we observed excellent anomeric selectivity, excellent diastereoselectivity, broad substrate scope, and high efficiency for this glycosylation reaction by exploring various parameters of the cocatalytic system. DFT calculations suggested that the anomeric selectivity was mainly determined by steric interactions between the C2-carbon of the carbohydrate and the phenyl group of the metal carbenoid, while π/π interactions with the C2−OBn substituent on the carbohydrate substrate play a significant role for diastereoselectivity at the newly generated stereogenic center.     

Lewis acid-catalyzed stereoselective lactonization and subsequent glycosidation of 2-C-malonyl carbohydrates

Gold(III) bromide is a suitable catalyst for the stereoselective cyclization of 2-C-malonyl carbohydrates to the anomeric center under retention of one ester group. Reopening of the lactones with alcohols in the presence of TMSOTf affords allyl, propargyl and benzyl glycosides with high α-selectivity.     

Reductive fragmentation of carbohydrate anomeric alkoxy radicals. Synthesis of alditols with potential utility as chiral synthons

A series of anomeric nitrate esters and N-phthalimido glycosides of carbohydrates in furanose and pyranose forms have been synthesized in order to generate the corresponding alkoxy radicals and study the C1-C2 fragmentation reaction under reductive conditions. This reaction constitutes a two-step method for the transformation of carbohydrates into the corresponding alditols with one less carbon. Using this methodology, interesting four- and five-carbon building blocks for natural products synthesis possessing D-erythritol, D-threitol, D-xylitol, and D-arabinitol stereochemistry have been prepared. The synthesis of 1,2-O-isopropylidene-beta-L-threose (40) and 1-acetamido-2,4,5-tri-O-acetyl-D-arabinitol (50) have also been achieved from 1,2:5,6-di-O-isopropylidene-beta-D-glucofuranose and 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-D-glucopyranose, respectively.     

Ab initio and density functional theory study of structures and energies for dimethoxymethane as a model for the anomeric effect

Ab initio molecular orbital theory and density functional theory calculations have been carried out on dimethoxymethane as a model for the anomeric effect. We optimized various conformations of dimethoxymethane using Gaussian 92 at the MP2/6-311 + + G**, MP2/DZP + Diffuse, MP2/6-31G**, and Becke3LYP/6-31G** levels of theory. These methods were evaluated based on their performance in reproducing structures and energies of dimethoxymethane when compared to experiment. This study also examined the structure and energy of dimethoxymethane as a function of dihedral angles for examining the anomeric effect at the MP2/6-31G** and Becke3LYP/6-31G** levels of theory. These calculations are qualitatively consistent with the anomeric effect observations in carbohydrates and with earlier calculations. Quantitative comparisons with earlier results reveal that dimethoxymethane has lower total energies, smaller rotational barriers, and shorter bond lengths than was previously determined. The Becke3LYP calculations were also compared to the MP2 results. The density functional theory findings show that the minimum energy structures correspond well with experimental and MP2 data. The total and relative energies from molecular orbital theory and density functional theory vary to some extent. Contour plots of the relative energies of dimethoxymethane were evaluated and compared to a relative energy contour plot determined by MM3. The contour plots were similar, showing slightly larger changes in energies for the MP2 results than for the Becke3LYP results, which in turn were slightly larger than the MM3 results. Density functional theory calculations are an excellent alternative method of calculation due to increased speed and reliable accuracy of the density functional calculations. These results will serve as a benchmark for modelling the anomeric effect in carbohydrates. © 1996 John Wiley & Sons, Inc.     

An Alternative Method for Anomeric Deacetylation of Per-acetylated Carbohydrates

An alternative method for anomeric deacetylation of fully acetylated carbohydrates has been developed using imidazole in methanol.     

Carbene‐Mediated Functionalization of the Anomeric C?H Bond of Carbohydrates: Scope and Limitations

Herein we investigate the scope and limitations of a new synthetic approach towards α‐ and β‐ketopyranosides relying on the functionalization of the anomeric C? H bond of carbohydrates by insertion of a metal carbene. A key bromoacetate grafted at the 2‐position is the cornerstone of a stereoselective glycosylation/diazotransfer/quaternarization sequence that makes possible the construction of a quaternary center with complete control of the stereochemistry. This sequence shows a good tolerance toward protecting groups commonly used in carbohydrate chemistry and gives rise to quaternary disaccharides with good efficiency. In the case of a disaccharide with a more restricted conformation, this functionalization process can be hampered by the steric demand next to the targeted anomeric position. In addition, the formation of transient orthoesters during the glycosylation step may also reduce the overall efficiency of the synthetic sequence.     

Glycosyl transfer to nitrogen via cycloaddition

[formula: see text] This letter describes the reduction to practice of a novel concept for functionalization of the anomeric carbon of carbohydrates with a nitrogen substituent. Thus, bisheterodienes with a thiono sulfur terminus and a sulfonylimine terminus are shown to undergo cycloaddition smoothly and stereoselectively to three different glycals.     

Specific band observed in VCD predicts the anomeric configuration of carbohydrates

The vibrational circular dichroism (VCD) technique was applied to carbohydrates and produced a glycoside characteristic VCD band, which was named the "glycoside band." It confirmed that this vibration was related to anomeric configurations of carbohydrates in the case of the d-series by means of isotope substitution. This band is defined as a negative, sharp, and intense VCD band at around 1145 cm-1, exhibited by d-sugars with an axial alpha-glycosidic linkage in the 4C1 conformation. As applications of this band, the VCD studies of the maltose-cellobiose mixture and the monitoring of the amyloglucosidase reaction were examined.     

Chemistry of β-trimethylsilylethanol. II. A new method for protection of an anomeric center in pyranosides

Protection of the anomeric center in various carbohydrates as a β-trimethylsilylethyl glycoside is reported. The free sugar can be regenerated using LiBF₄ in acetonitrile.     

Acid catalyzed rearrangement of vinyl and ketene acetals

Substituted vinyl and ketene acetals undergo smooth oxygen-to-carbon rearrangement with a catalytic amount of TMSOTf to afford chain-extended ketones or esters, respectively. The developed procedure has been applied to the stereoselective synthesis of C-glycosides from the corresponding anomeric vinyl ethers.