Synthesis of 2′,3′-dideoxynucleosides via C-S bond cleavage: N-glycosylation of 2,3-dideoxy-1-[(2-pyridylmethyl)thio]glycoside

N-Glycosylation of 2,3-dideoxy-1-[(2-pyridylmethyl)thio]glycosides (1a) using several activators is described. NBS-promoted glycosylation reaction utilizing either the α- or β-thiodideoxyglycoside proceeded smoothly at −78 °C to give the corresponding dideoxynucleoside in a β-selective manner, presumably through a common glycosyl donor.     

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.     

Synthesis of oligo(α-D-glycosyl phosphate) derivatives by a phosphoramidite method via boranophosphate intermediates

An efficient method for the synthesis of short oligo(α-D-glycosyl boranophosphate) derivatives by using an α-D-glycosyl phosphoramidite as a monomer unit was developed. The synthesis of oligomers was carried out by repeating a cycle consisting of the condensation of the monomer unit with a terminal hydroxy group of carbohydrates, boronation of the resultant phosphite intermediates, and terminal deprotection. The phosphoramidite monomer unit was synthesized from the corresponding glycosyl iodide and methyl N,N-diisopropylphosphonamidate in a highly α-selective manner. Di- and tri(α-D-glycosyl boranophosphate) derivatives obtained by the synthetic cycle were converted into the corresponding H-phosphonate diester derivatives, which were then used to synthesize di- and tri(α-D-glycosyl phosphate) derivatives including a fragment of Leishmania glycocalyx lipophosphoglycans.     

First General Route to α-Azido/cyano Functionalised Hydroximoyl Chlorides

A general, straightforward route to α-azido/cyano functionalised hydroximoyl chlorides from conjugated nitro olefins by reaction with TMSNu-TiCl₄ (Nu = N₃, CN) is reported.     

Zinc triflate-promoted glycosidation: synthesis of lipid A disaccharide intermediates.

Zinc triflate was found to be superior to the heavy metal salts as a promoter in the Koenigs-Knorr type glycosidation reaction in the synthesis of lipid A disaccharide intermediates. It readily promoted the reaction of a complex glycosyl bromide with a reducing sugar moiety and gave the disaccharide with beta-selectivity in good yield. This method would be suitable for the bulk preparation of lipid A disaccharide intermediates.     

Cyclopropenium cation promoted dehydrative glycosylations using 2-deoxy- and 2,6-dideoxy-sugar donors

Dehydrative glycosylation reactions using 2-deoxy- and 2,6-dideoxy-sugar donors promoted by a combination of 3,3-dichloro-1,2-diphenylcyclopropene and tetrabutylammonium iodide (TBAI) are described. The reactions are α-selective and proceed under mild conditions at room temperature without the need for special dehydrating agents. The reaction is shown to be effective with a number of glycosyl acceptors, including those possessing acid and base sensitive functionality.     

α-Selective glycosidation of d-tagatofuranose with a 3,4-O-isopropylidene protection

An α-selective glycosidation reaction of d-tagatofuranose was successfully achieved using 3,4-O-isopropylidene-protected d-tagatofuranose as a glycosyl donor. A variety of glycosyl acceptors, including primary, secondary, and β-amino alcohols, and carbohydrates, can be used for this d-tagatofuranosidation reaction with complete α-selectivities and good yields (57–83%). The stereochemistries at the anomeric positions were determined by nuclear Overhauser effect spectroscopic correlations, as well as comparison of the chemical shifts in the ¹³C NMR spectra.     

A Highly Efficient Glycosidation of Glycosyl Chlorides by Using Cooperative Silver(I) Oxide–Triflic Acid Catalysis

Following our discovery that silver(I) oxide-promoted glycosylation with glycosyl bromides can be greatly accelerated in the presence of catalytic TMSOTf or TfOH, we report herein a new discovery that glycosyl chlorides are even more effective glycosyl donors under these reaction conditions. The developed reaction conditions work well with a variety of glycosyl chlorides. Both benzoylated and benzylated chlorides have been successfully glycosidated, and these reaction conditions proved to be effective in coupling substrates containing nitrogen and sulfur atoms. Another convenient feature of this glycosylation is that the progress of the reaction can be monitored visually; its completion can be judged by the disappearance of the characteristic dark color of Ag₂O.     

α-Selective Organocatalytic Synthesis of 2-Deoxygalactosides

Alpha rules: A thiourea acts as an efficient organocatalyst for the glycosylation of protected galactals to form oligosaccharides containing a 2-deoxymonosaccharide moiety. The reaction is highly stereoselective for α-linkages and proceeds by way of a syn-addition mechanism.     

Synthesis of glycosaminoglycan oligosaccharides. Part 4: Synthesis of aza-l-iduronic acid-containing analogs of heparan sulfate oligosaccharides as heparanase inhibitors

The synthesis of three azasugar-containing analogs of the disaccharide units of heparan sulfate, which are potential inhibitors of the enzyme heparanase, is reported. Synthetic routes were developed for the preparation of l-ido-nojirimycin type glycosyl acceptors with O-4 free. Glycosylation of these acceptors with an O-6 functionalized 2-azido-2-deoxy-d-glucose thioglycoside donor afforded the α-linked disaccharides in good yields. The advantages of using the 4-nitrobenzenesulfonyl group for the protection of the ring nitrogen of azasugars were demonstrated.     

Synthesis of N-Glycosides by Silver-Assisted Gold Catalysis

The synthesis of N-glycosides from stable glycosyl donors in a catalytic fashion is still challenging, though they exist ubiquitously in DNA, RNA, glycoproteins, and other biological molecules. Herein, silver-assisted gold-catalyzed activation of alkynyl glycosyl carbonate donors is shown to be a versatile approach for the synthesis of purine and pyrimidine nucleosides, asparagine glycosides and quinolin-2-one N-glycosides. Thus synthesized nucleosides were subjected to the oxidation–reduction sequence for the conversion of Ribf- into Araf- nucleosides, giving access to nucleosides that are otherwise difficult to synthesize. Furthermore, the protocol is demonstrated to be suitable for the synthesis of 2’-modified nucleosides in a facile manner. Direct attachment of an asparagine-containing dipeptide to the glucopyranose and subsequent extrapolation to afford the dipeptide disaccharide unit of chloroviruses is yet another facet of this endeavor.     

DISAL glycosyl donors for the synthesis of a linear hexasaccharide under mild conditions

[reaction: see text] The new class of glycosyl donors with a methyl 3,5-dinitrosalicylate (DISAL) anomeric leaving group has proved efficient for glycosylation under strictly neutral, mildly basic, or mildly acidic conditions. Here, we report the synthesis of novel DISAL disaccharide glycosyl donors prepared by easy nucleophilic aromatic substitution. These DISAL donors proved efficient in the synthesis of a starch-related hexasaccharide under very mild conditions. Glycosylations proceeded with alpha-selectivity and were compatible with Trt protecting groups.     

Synthesis of glycosaminoglycan oligosaccharides. Part 5: Synthesis of a putative heparan sulfate tetrasaccharide antigen involved in prion diseases

The synthesis of the putative prion-associated heparan sulfate tetrasaccharide containing two d-glucuronic acid units is reported. Key to the synthesis were the differentiation of the N-acetylated and N-unsubstituted glucosamine units, the high-yielding glucosylation at O-4 of an N-acetyl-d-glucosamine derivative and the α-selective glycosylation of the 4′-OH group of a β-d-GlcpA-(1→4)-d-GlcpNAc disaccharide building block with a disaccharide thioglycoside donor.     

Michael addition of α-azido ketones on iminocoumarin derivatives: an efficient access to new functionalized azido chromenes

A facile one-pot synthesis of functionalized azido chromenes was achieved by Michael addition of α-azido ketones on iminocoumarin derivatives obtained from salicylaldehydes and malononitrile. Synthesized azido chromenes were successfully transformed into triazolyl chromenes by the [3+2] cycloaddition reaction.     

An approach for disaccharide chiron synthesis using a Ferrier-type rearrangement

We report a new approach for the synthesis of new chiral synthons in which two unsaturated sugars are linked via a glycosidic bond. The di-unsaturated disaccharide can be further functionalized using effective, highly selective methods and used in convergent syntheses of relatively complex glycoconjugates. Our approach utilizes in situ generation of active glycosyl donors via Ferrier-type rearrangement under phase-transfer conditions and subsequent reaction with a nucleophile.     

Enzymatic and chiral HPLC resolution of α-azido acids and amides

For the first time, enzymatic resolution of α-azido acid amides has been successfully demonstrated with high yields and enantiomeric excess. In one case dynamic kinetic resolution was achieved leading to more than 50% yield of the enantiomerically pure azido acid. Chiral HPLC was also used to separate racemic α-azido acids and the separation process was automated. Two routes to enantiopure α-azido acid building blocks for solid-phase peptide synthesis have, therefore, been established.     

Direct and stereoselective synthesis of 1,3-cis-3- arylsulphonaminodeoxydisaccharides and oligosaccharides

The 3-aminoglycosides are ubiquitous in biologically important classes of glycoconjugates and naturally occurring oligosaccharides. Despite the rapid growth in the development of synthetic method of 3-amino glycosides, the current state-of-the art suffers from limited substrate scope, low yields, long reaction times, and anomeric mixtures. This work presents a novel direct method for the synthesis of 1,3-cis-3-arylsulphonaminodeoxydisaccharides and oligosaccharides via α-selective glycosylation and hydroamination of glycal in a one-pot manner. This efficient multicomponent reaction methodology provides ready access to 1,3-cis-3-arylsulphonaminodeoxydisaccharides and oligosaccharides and allows derivatization by variation of each component.     

Stereoselective synthesis of 3-azido-2,3-dideoxy-D-ribose derivatives and its utilization for the synthesis of anti-HIV nucleosides

Detail account of the synthesis of 3′-azido nucleosides utilizing 3-azido-2,3-dideoxy-D-ribose derivative 7 as the key intermediate was described. The key intermediate 7 was synthesized from D-mannitol in 8 steps in a preparative scale. The Michael reaction of the azide group with α,β-unsaturated-γ-butyrolactone 4 was affected by the steric bulkiness of the substituent at the 5-O position. A bulky t-butyldiphenylsilyl substitution at 5-O gave almost exclusively the α-azido adduct 5b , while unsubstitution at 5-O produced 1:1 mixture of α-and β-adducts. The ratio of α to β anomers in the condensation between azido acetate 7a and pyrimidine bases for the preparation of AZT and AZDU was greatly influenced by the solvent and the Lewis acid catalyst used. In the synthesis of 12 (AZDU, CS-87), the combination of dichloroethane and trimethylsilyl triflate gave an optimal result, while in the case of 14 (AZT), various conditions gave similar ratio of α,β anomers. The azido intermediate 7b was also utilized for the synthesis of several 3′-azido purine-like nucleosides 16–27 . The glycosylation was also affected by the Lewis acid catalyst. Boron trifluoride etherate gave the desired N₁-glycosylated compounds in which the α-anomer was major, but other catalysts such as trimethylsilyl triflate or stannic chloride produced N₂-glycosylated compounds as the major products. The newly synthesized purine-like compounds have been tested against HIV, however, none of them showed any significant activity.     

A novel synthesis, including asymmetric synthesis, of α-quaternary α-amino acid methyl esters from ketones via sulfinyloxiranes

Sulfinyloxiranes were synthesized from ketones and chloromethyl p-tolyl sulfoxide in two steps in almost quantitative yields. The sulfinyloxiranes were treated with NaN₃ in the presence of NH₄Cl to afford α-azido aldehydes, which were oxidized with iodine in the presence of KOH in methanol to give α-azido methyl esters in good overall yields. Catalytic hydrogenation of the α-azido esters afforded α-quaternary α-amino acid methyl esters in quantitative yields. Starting from β-tetralone and optically pure (R)-chloromethyl p-tolyl sulfoxide, an asymmetric synthesis of optically pure (R)-(+)-methyl 2-aminotetraline-2-carboxylate was realized in good overall yields.     

A dimethoxytriazine type glycosyl donor enables a facile chemo-enzymatic route toward α-linked N-acetylglucosaminyl-galactose disaccharide unit from gastric mucin

An efficient chemo-enzymatic process for construction of the α-linked disaccharide unit (GlcNAcα1-4Gal) found in gastric mucin has been developed. The process consists of a one-step preparation of a novel triazine type glycosyl donor in water and the subsequent transglycosylation to a galactose derivative catalysed by α-N-acetylglucosaminidase.