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Reported herein is the total synthesis of the trisaccharide repeating unit of Streptococcus pneumoniae zwitterionic polysaccharide Sp1 containing a rare sugar, 2-acetamido-4-amino-2,4,6-trideoxy-d-galactose (AAT), and three consecutive 1,2-cis-glycosidic linkages. The total synthesis was completed via highly stereoselective glycosylations and late-stage oxidation as key steps involving a longest linear sequence of 21 steps with 4.4% overall yield.

Herein, we report the total synthesis of the phosphorylated zwitterionic trisaccharide repeating unit of Photorhabdus temperata subsp. cinerea 3240. The efficient route involves regio- and stereoselective assembly of trisaccharide with rare deoxyamino sugar AAT at the nonreducing end, late stage oxidation, and installation of a phosphate linker on the trisaccharide. The total synthesis was completed via a longest linear sequence of 24 steps in 6.5% overall yield.

First total synthesis of the conjugation-ready pentasaccharide repeating unit of Plesiomonas shigelloides strain 302-73 (serotype O1) is reported. The complex target pentasaccharide is composed of all-rare amino sugars such as orthogonally functionalized d-bacillosamine, l-fucosamine, and l-pneumosamine linked through four consecutive α-linkages. The poor nucleophilicity of axial 4-OH of l-fucosamine and stereoselective glycosylations are the key challenges in the total synthesis, which was completed via a longest linear sequence of 27 steps in 3% overall yield.

Zwitterionic polysaccharides isolated from commensal bacteria are endowed with unique immunological properties and are emerging as immunotherapeutic agents as well as vaccine carriers. Reported herein is a total synthesis of the repeating unit of Bacteroides fragilis zwitterionic polysaccharide A1 (PS A1). The structurally complex tetrasaccharide unit contains a rare sugar 2-acetamido-4-amino-2,4,6-trideoxy-d-galactose (AAT) and two consecutive 1,2-cis glycosidic linkages. The repeating unit was efficiently assembled by rapid synthesis of d-galactosamine and AAT building blocks from cheap and abundant d-mannose via a one-pot SN2 displacement of 2,4-bistriflates and installation of all of the glycosidic bonds in a highly stereoselective manner. The total synthesis involves a longest linear sequence of 17 steps with 3.47% overall yield.

Herein we report an efficient total synthesis of lipid-anchor-appended core trisaccharides of lipoteichoic acids of Streptococcus pneumoniae and Streptococcus oralis Uo5. The key features include the expedient synthesis of the rare sugar 2,4,6-trideoxy-2-acetamido-4-amino-d-Galp building block via one-pot sequential SN2 reactions and the α-selective coupling of d-thioglucoside with the diacyl glycerol acceptor to construct a common disaccharide acceptor, which was utilized in the total synthesis of target molecules 1 and 2.

Herein, we report a strategy for the total synthesis of a structurally unique fungal glycolipid fusaroside. The first total synthesis of the proposed structure involved construction of the complex, branched lipid chain having a variety of alkenes with

Vibrio cholerae is a causative agent of the deadly pandemic - cholera. Among ~200 serogroups of V. cholerae, the O1 and O139 serogroups are mainly responsible for virulent cholera. Some other serogroups are also found to be associated with diarrhoea and minor outbreaks of cholera type diseases. The deadly pathogen is a threat for many developing countries, predominately in Asia and Africa, and still causes millions of deaths every year. A multicomponent glycoconjugate vaccine covering all the strains of V. cholerae is highly desired to prevent the spread of this disease. Here, we report the first total synthesis of a densely functionalized tetrasaccharide repeating unit of V. cholerae O43, which contains rare deoxy amino sugars D-quinosamine and D-viosamine attached with a rare amino acid N-acetyl-L-allothreonine. Synthesis of orthogonally protected rare sugars and unnatural amino acid building blocks, stereoselective construction of three consecutive 1,2-cis glycosidic linkages and the presence of five nitrogen atoms dispersed over four sugar units as well as carboxylic acid functionality makes the total synthesis a formidable task. The tetrasaccharide was assembled via a highly regio- and stereoselctive [3+1] glycosylation of fully functionalized, amino acid-bearing D-viosamine donor with the trisaccharide diol. The assembly of all-1,2-cis linked trisaccharide diol was expeditiously achieved in one-pot manner. Judicious selection of protecting groups and reaction conditions enabled access to the structurally complex, amino acid-attached tetrasaccharide repeating unit, which can be used for future biological studies directed towards development of vaccine. The synthetic strategy will be useful for accessing other structurally related complex bacterial glycans.

Lipopolysaccharides (LPSs) play key roles in humoral immunity. Recently, the LPS structure of the Psychrobacter cryohalolentis K5T strain was reported. Due to the presence of unnatural amino sugars and branched linkages, its structure is unique. Herein we report the total synthesis of an LPS analogue of P. cryohalolentis K5T. After overcoming the issues like ring conformation changes and elimination of triflate, we were able to develop a strategy for the synthesis of the newly reported 2,3,4-triacetamido-2,3,4-trideoxy-l-arabinose derivative. Coupling of different donors with suitable acceptors from the nonreducing end to the reducing end and further functional group modifications delivered the protected LPS hexasaccharide repeating unit. After functional group modifications, we were unable to oxidize the hindered primary hydroxyl group to synthesize the target molecule. Alternatively, removal of the permanent protecting groups afforded the LPS hexasaccharide repeating unit analogue of Psychrobacter cryoh...

The first total synthesis of the trisaccharide repeating unit of the O-specific polysaccharide of Pseudomonas fluorescens BIM B-582 is reported. This efficient synthesis involves consecutive 1,2- cis glycosylations including β-l-rhamnosylation and α selective coupling of rare 4-deoxy-d- xylo-hexose as the key steps. The synthetic trisaccharide is equipped with an aminopropyl linker at the reducing end to allow for conjugation to proteins and microarrays for further immunological studies.

The first total synthesis of the branched oligosaccharide OSE-1 of Mycobacterium gordonae (strain 990) is reported. An intramolecular aglycon delivery approach was used for constructing the desymmetrized 1,1'-α,α-linked trehalose moiety. A [3+2] glycosylation of the trisaccharide donor and trehalose acceptor furnished the right hand side pentasaccharide. Regioselective O3 glycosylation of L-rhamnosyl 2,3-diol allowed expedient synthesis of the left hand side tetrasaccharide. The nonasaccharide was assembled in a highly convergent fashion through a [4+5] glycosylation.

A beta-C-galactosyl ceramide was synthesized in a stereoselective manner, employing a Sharpless AD reaction and olefin cross metathesis as key steps.

The first total synthesis of the phosphorylated trisaccharide repeating unit of Providencia alcalifaciens O22 is reported. The trisaccharide contains rare deoxyamino sugar AAT at the reducing end and d-glyceramide 2-phosphate at the other end. The efficient synthesis involves one-pot assembly of trisaccharide and late-stage phosphorylation as key steps.

Efficient and rapid transformation of cheaply available l-rhamnose into all the isomeric 6-deoxy-l-hexoses via regio- and stereoselective nucleophilic displacements of triflates is reported. The synthesis entails regioselective protections, one-pot double displacements of triflates, and cascade inversions. The methodology allows facile access to all the rare 6-deoxy-l-hexoses as stable thioglycoside building blocks.

Bacterial glycoproteins and oligosaccharides contain several rare deoxy amino L-sugars which are virtually absent in the human cells. This structural difference between the bacterial and host cell surface glycans can be exploited for the development of carbohydrate based vaccines and target specific drugs. However, the unusual deoxy amino L-sugars present in the bacterial glycoconjugates are not available from natural sources. Thus, procurement of orthogonally protected rare L-sugar building blocks through efficient chemical synthesis is a crucial step toward the synthesis of structurally well-defined and homogeneous complex glycans. Herein, we report a general and expedient methodology to access a variety of unusual deoxy amino L-sugars starting from readily available L-rhamnose and L-fucose via highly regioselective, one-pot double serial and double parallel displacements of the corresponding 2,4-bistriflates using azide and nitrite anions as nucleophiles. Alternatively, regioselective monotriflation at O2, O3, and O4 of L-rhamnose/L-fucose allowed selective inversions at respective positions leading to diverse rare sugars. The orthogonally protected deoxy amino L-sugar building blocks could be stereoselectively assembled to obtain biologically relevant bacterial O-glycans, as exemplified by the first total synthesis of the amino linker-attached, conjugation-ready tetrasaccharide of O-PS of Yersinia enterocolitica O:50 strain 3229 and the trisaccharide of Pseudomonas chlororaphis subsp. aureofaciens strain M71.

Chemical synthesis of a bacterial glycolipid BbGL1 is reported in two steps starting from per-O-TMS D-galactose. The key features are glycosyl iodide mediated beta-stereoselective glycosylation in the absence of neighboring group participation and regioselective acylation.

The D-glucosamine derivative (III) is efficiently transformed into oxazolidinone of D-xylosamine (IV), D-allosamine and D-ribosamine.

A high-yielding coupling of a new and stable type of glycosyl donors, namely 2-allyloxyphenyl glycoside, with a variety of alcohols via NIS/TfOH reagent combination as effective activators at room temperature is described here.

[reaction: see text] A coupling of 2-O-arylmethylated D-glucose-derived thioglycosides with various alcohols in the presence of DMTST as an activator is described. The requisite glycosyl donors are efficiently prepared by one-pot procedures. When the aryl groups are phenyl, p-methoxyphenyl, 1-naphthyl, and 2-naphthyl groups, a mixture of alpha- and beta-anomeric O-glycosides is obtained under the conditions, whereas when the aryl group is the 9-anthracenyl group, a highly stereoselective formation of the unusual C-glycosides in good yields via neighboring group participation of the 9-anthracenylmethyl group followed by coupling with a variety of alcohols is observed. Three new chiral centers including a quaternary carbon are created in one single step.

A novel and convenient route for the synthesis of biologically potent and rare L-hexose derivatives from D-glucose is described. Conversion of diacetone-alpha-D-glucose (14) into 1,2:3,5-di-O-isopropylidene-beta-L-idofuranose (19) was efficiently carried out in two steps. Orthogonal isopropylidene rearrangement of compound 19 led to 1,2:5,6-di-O-isopropylidene-beta-L-idofuranose (27), which underwent regioselective epimerization at the C3 position to give the L-talo- and 3-functionalized L-idofuranosyl derivatives. Hydrolysis of compound 19 under acidic conditions furnished 1,6-anhydro-beta-L-idopyranose (35) in excellent yield, which was successfully transformed into the corresponding L-allo, L-altro, L-gulo, and L-ido derivatives via regioselective benzylation, benzoylation, triflation and nucleophilic substitution as the key steps. Applications of these 1,6-anhydro-beta-L-hexopyranoses as valuable building blocks to the syntheses of 4-methylcoumarin-7-yl-alpha-L-iduronic acid and the disaccharide moieties of bleomycin A(2) as well as heparan sulfate are highlighted.

The total synthesis of the title trisaccharide involves the transformation of D-mannose into an orthogonally protected acetamido-amino sugar building block, two stereoselective glycosylations, selective attachment of a glutaric acid linker, and an amide bond formation.

Herein we report a one-pot and efficient method for the synthesis of a 1,2-cis fused furanoside bicyclic oxazolidinone derivative of D-glucosamine via pyranose to furanose conversion and concomitant cyclization involving the N-Troc group. The D-glucosamine oxazolidinone derivative was efficiently transformed into oxazolidinones of D-xylosamine, D-allosamine and D-ribosamine.

M. tuberculosis sulfoglycolipids SL-1 and Ac(2)SGL are highly immunogenic and potential vaccine candidates. A short and efficient methodology is reported for the synthesis of SL-1 and Ac(2)SGL analogues via regioselective functionalization of alpha,alpha-D-trehalose employing a highly regioselective late stage sulfation, as a key step. The SL-1 analogues 3a and 4 were obtained in 10 and 9 steps in 13.4% and 23.9% overall yields, respectively. The Ac(2)SGL analogue 5 was synthesized in 5 steps in 18.4% yield.

The MECA-79 antigen is a sulfated mucin type core-1 extended O-glycan which is a potential anti-inflammatory agent. Herein we report a total synthesis of MECA-79 via a convergent [2 + 2] glycosylation route. The synthesis relies on efficient transformation of D-glucosamine into the orthogonally protected Tn antigen derivative and its elaboration into the TF antigen en route to MECA-79.

The first total synthesis of Ch HF-PS, a cell wall trisaccharide repeating unit of B. cereus, is reported. The synthetic trisaccharide is appended with an aminopropyl linker at the reducing end to allow for conjugation to proteins and microarrays. The convergent synthesis involves transformation of D-mannose into an orthogonally protected rare AAT sugar building block, two consecutive alpha-stereoselective glycosylations, beta-selective attachment of the linker by solvent participation, and amide bond formation, as key steps.

Total synthesis of the bacillosamine containing L-serine linked O-trisaccharide of Neisseria meningitidis is described. The synthesis entails installation of two consecutive alpha-linkages including the coupling of bacillosamine with L-serine derivative. (C) 2014 Elsevier Ltd. All rights reserved.

Bacterial glycoconjugates comprise atypical deoxy amino sugars that are not present on the human cell surface, making them good targets for drug discovery and carbohydrate-based vaccine development. Unfortunately, they cannot be isolated with sufficient purity in acceptable amounts, and therefore chemical synthesis is a crucial step toward the development of these products. Here we describe a detailed protocol for the synthesis of orthogonally protected bacterial deoxy amino hexopyranoside (2,4-diacetamido-2,4,6-trideoxyhexose (DATATDH), d-bacillosamine, d-fucosamine, and 2-acetamido-4-amino-2,4,6-trideoxy-dgalactose (AATAATAAT)), d-glucosamine and d-galactosamine building blocks starting from beta-d-thiophenylmannoside. Readily available beta-d-thiophenylmannoside was first converted into the corresponding 2,4-diols via deoxygenation or silylation at C6, followed by O3 acylation. The 2,4-diols were converted into 2,4-bis-trifluoromethanesulfonates, which underwent highly regioselective, one-pot, double-serial and double-parallel displacements by azide, phthalimide, acetate and nitrite ions as nucleophiles. Thus, d-rhamnosyl-and d-mannosyl 2,4-diols can be efficiently transformed into various rare sugars and d-galactosamine, respectively, as orthogonally protected thioglycoside building blocks on a gram scale in 1-2 d, in 54-85% overall yields, after a single chromatographic purification. This would otherwise take 1-2 weeks. d-Glucosamine building blocks can be prepared from beta-d-thiophenylmannoside in four steps via C2 displacement of triflates by azide in 2 d and in 66-70% overall yields. These procedures have been applied to the synthesis of l-serine-linked trisaccharide of Neisseria meningitidis and a rare disaccharide fragment of the zwitterionic polysaccharide (ZPSPS) A1 (ZPSPS A1) of Bacteroides fragilis.

Synthesis of beta-C-D-galactosyl D- and L-alanines is carried out via a highly stereoselective Grignard reaction of glycosyl iodides, Sharpless dihydroxylation and S(N)2 displacement of the corresponding mesylate or tosylate. Alternatively, attempted triflation of the intermediate alcohols triggers a stereoselective debenzylative cyclization leading to interesting bicyclic trans-fused compounds.

The first synthesis of maradolipid, a unique dissymmetrically 6,6'-di-O-acylated trehalose glycolipid isolated from C. elegans, is accomplished in five steps starting from trehalose in 45% overall yield. The short synthesis relies on dissymmetrization of trehalose core via regioselective acylation of a 2,3,4,2',3',4'-hexa-O-TMS trehalose 6,6'-diol derivative as a key step.

Carbohydrates and glycoconjugates play important roles in complex life processes. Development of carbohydrate-based therapeutics is a major focus of our laboratory requiring the synthesis of glycolipid antigens for biological evaluation. Stereoselective formation of O- and C-glycosides is one of the central challenges in carbohydrate synthesis. In this pursuit, we employ glycosyl iodides as unique glycosyl donors to construct functionally enriched appendages on the anomeric center of the sugar moiety in a highly efficient and stereoselective manner. These constructs can be used to rapidly synthesize a panoply of glycoside analogs for biological studies. In this minireview, glycosyl iodide mediated syntheses of α-linked O-glycolipids such as KRN 7000 and BbGL2 as well C-glycolipid analogs are described.

Synthesis of a C-analogue of bacterial glycolipid BbGL2 is reported using Grignard reaction of in situ generated beta-galactosyl iodide and subsequent olefin cross metathesis reaction of C-vinyl galactoside as key steps. [reaction: see text]

The total syntheses of tetrahydroxy-LCB 1, alpha-galactosyl ceramide 2, and 1,4-dideoxy-1,4-imino-L-ribitol 3 via D-allosamine derivatives as common synthons are described here.

[reaction: see text] Introduction of a sugar unit at either the O5 or O6 position of various neamine derivatives in excellent selectivity and yields is described here. Application to the synthesis of kanamycin analogues is also highlighted.

A first synthesis of the trisaccharide moiety of the phyteumosides and its cholesteryl analog is described using easily accessible and regioselectively protected D-glucose, L-rhamnose and D-galactose building blocks via a linear glycosylation approach. The two glycosyl donors were prepared as thiophenyl (SPh) glycosides. Trichloroacetimidate (TCAl) coupling was employed for the first glycosylation step while thioglycoside activation was used for the second glycosylation to assemble the O-allyl trisaccharide. After removal of the anomeric allyl group, the trisaccharide was converted into a TCAl donor. Using cholesterol as an acceptor in combination with acetonitrile as a participating solvent to achieve beta-selectivity in glycosylation, a phyteumoside analog was obtained.

An efficient route for the synthesis of orthogonally protected D-galactosamine thioglycosides via one-pot double serial and double parallel displacements of the D-mannosyl-2,4-bis-trifluoromethanesulfonates by azide and nitrite ions is described. These building blocks were utilized to synthesize the rare disaccharide moiety of the zwitterionic polysaccharide of Bacteroides fragilis and the selectively protected Tn antigen