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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.

l-Rhamnose forms the key components of important antigenic oligo- and polysaccharides of a variety of pathogens. Obtaining 1,2-cis stereoselectivity in the glycosylation of l-rhamnoside is quite challenging due to the unavailability of neighboring group participation and disfavoring of the anomeric effect and stereoelectronic effect of the substituents on the C-2 axial position. Nevertheless, various methodologies have been developed exploiting diverse pathways for obtaining β-stereoselectivity in the glycosylation of l-rhamnose. This review describes the recent advances in β-l-rhamnosylation and its applications in the total synthesis of β-l-rhamnose-containing biologically important oligosaccharides.

Trehalose containing glycolipids have been isolated from various species of mycobacteria, fungi and worms. Owing to their versatile biological roles, and heterogenicity of the natural isolates, there is great interest in the synthesis of trehalose glycolipids. In this review we discuss recent developments in the total synthesis of biologically important and structurally complex trehalose glycoconjugates and oligosaccharides.

The bacterial cell wall is a quintessential drug target due to its critical role in colonization of the host, pathogen survival, and immune evasion. The dense cell wall glycocalyx contains distinctive monosaccharides that are absent from human cells, and proper assembly of monosaccharides into higher-order glycans is critical for bacterial fitness and pathogenesis. However, the systematic study and inhibition of bacterial glycosylation enzymes remains challenging. Bacteria produce glycans containing rare deoxy amino sugars refractory to traditional glycan analysis, complicating the study of bacterial glycans and the creation of glycosylation inhibitors. To ease the study of bacterial glycan function in the absence of detailed structural or enzyme information, we crafted metabolic inhibitors based on rare bacterial monosaccharide scaffolds. Metabolic inhibitors were assessed for their ability to interfere with glycan biosynthesis and fitness in pathogenic and symbiotic bacterial species. Three metabolic inhibitors led to dramatic structural and functional defects in Helicobacter pylori. Strikingly, these inhibitors acted in a bacteria-selective manner. These metabolic inhibitors will provide a platform for systematic study of bacterial glycosylation enzymes not currently possible with existing tools. Moreover, their selectivity will provide a pathway for the development of novel, narrow-spectrum antibiotics to treat infectious disease. Our inhibition approach is general and will expedite the identification of bacterial glycan biosynthesis inhibitors in a range of systems, expanding the glycochemistry toolkit., Metabolic inhibitors based on rare bacterial monosaccharide scaffolds interfere with bacterial glycan biosynthesis in a bacteria-selective manner.

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.

Pseudomonas aeruginosa belongs to the group of three "critical priority" multi-drug-resistant pathogens listed by WHO and is responsible for severe and often deadly infections such as bloodstream infections and pneumonia. Staphylococcus aureus is also a "high priority" pathogen which is a major cause of serious nosocomial infections such as bacteremia, sepsis, and endocarditis. Owing to their ability to adapt resistance to almost any antibiotics, vaccines against these pathogens are urgently required. These pathogens express structurally unique and densely functionalized glycans on their surfaces which are absent on the host cells. Such carbohydrate antigens are valuable targets for the development of glycoconjugate vaccines and diagnostics. Here, we report the first total synthesis of the conjugation-ready trisaccharide repeating unit of Pseudomonas aeruginosa O11 via a highly stereoselective and efficient assembly of a rare l-fucosamine- and d-fucosamine-containing 1,2-cis-linked disaccharide motif and its regioselective glycosylation at O3. A systematic study was conducted for the notoriously difficult glycosylation with the most unreactive axial 4-OH of the rare disaccharide, and the successful outcome was utilized to accomplish the total synthesis of an aminopropyl linker-attached trisaccharide repeating unit of Staphylococcus aureus capsular polysaccharide type 5, which is also a potential antigen for immunotherapy and vaccine development. The judicious selection of protecting groups and reaction conditions allowed the stereoselective assembly and selective functional group interconversions to access the structurally complex linker-attached trisaccharide repeating units, which are valuable tools for immunological evaluation and vaccine development. The strategy is useful for the synthesis of other structurally related complex glycans.

Over the years, carbohydrates have increasingly become an important class of compounds contributing significantly to the target specific drug discovery and vaccine development. Several oligosaccharides contain L-hexoses that are biologically relevant as therapeutic and diagnostic tools. Since, L-hexoses and deoxy L-hexoses are not readily available in large amount and pure form, attention is drawn towards development of cost effective and high yielding synthetic routes for their procurement. In this review we give an update on the recent developments in strategies for synthesis of L-hexoses and deoxy L-hexoses.

Attempted nucleophilic displacements of l-rhamnosyl 2,4-bistriflates led to serendipitous formation of a chiral diene via competing cascade eliminations. The reaction also followed the same pathway with d-rhamnosyl and d-mannosyl 2,4-bistriflates substrates providing access to dienes with opposite stereochemistry. The reaction presumably proceeds through E2 elimination of C2 triflate followed by allylic rearrangement. The easily accessible chiral dienes would be useful in the synthesis of natural products.

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

Mycobacterium tuberculosis (Mtb) serves as the epitome of how lipids-next to proteins-are utilized as central effectors in pathogenesis. It synthesizes an arsenal of structurally atypical lipids (C60-C90) to impact various membrane-dependent steps involved in host interactions. There is a growing precedent to support insertion of these exposed lipids into the host membrane as part of their mode of action. However, the vital role of specific virulence-associated lipids in modulating cellular functions by altering the host membrane organization and associated signaling pathways remain unanswered questions. Here, we combined chemical synthesis, biophysics, cell biology, and molecular dynamics simulations to elucidate host membrane structure modifications and modulation of membrane-associated signaling using synthetic Mycobacterium tuberculosis sulfoglycolipids (Mtb SL). We reveal that Mtb SL reorganizes the host cell plasma membrane domains while showing higher preference for fluid membrane regions. This rearrangement is governed by the distinct conformational states sampled by SL acyl chains. Physicochemical assays with SL analogues reveal insights into their structure-function relationships, highlighting specific roles of lipid acyl chains and headgroup, along with effects on autophagy and cytokine profiles. Our findings uncover a mechanism whereby Mtb uses specific chemical moieties on its lipids to fine-tune host lipid interactions and confer control of the downstream functions by modifying the cell membrane structure and function. These findings will inspire development of chemotherapeutics against Mtb by counteracting their effects on the host-cell membrane.

Carbohydrates contain numerous hydroxyl groups and sometimes amine functionalities which lead to a variety of complex structures. In order to discriminate each hydroxyl group for the synthesis of complex oligosaccharides, protecting group manipulations are essential. Although the primary role of a protecting group is to temporarily mask a particular hydroxyl/amino group, it plays a greater role in tuning the reactivity of coupling partners as well as regioselectivity and stereoselectivity of glycosylations. Several protecting groups offer anchimeric assistance in glycosylation. They also alter the solubility of substrates and thereby influence the reaction outcome. Since oligosaccharides comprise branched structures, the glycosyl donors and acceptors need to be protected with orthogonal protected groups that can be selectively removed one at a time without affecting other groups. This minireview is therefore intended to provide a discussion on new protecting groups for amino and hydroxyl groups, which have been introduced over last ten years in the field of carbohydrate synthesis. These protecting groups are also useful for synthesizing non-carbohydrate target molecules as well.

Fungal glycolipids emmyguyacins A and B inhibit the pH-dependent conformational change of hemaglutinin A during replication of the Influenza virus. Herein, we report the first total synthesis and structure confirmation of emmyguyacins A and B. Our efficient route, which involves regioselective functionalization of trehalose, allows rapid access to adequate amounts of chemically pure emmyguyacin analogues including the desoxylate derivatives for SAR studies.

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.

Carbohydrates, which are ubiquitously distributed throughout the three domains of life, play significant roles in a variety of vital biological processes. Access to unique and homogeneous carbohydrate materials is important to understand their physical properties, biological functions, and disease-related features. It is difficult to isolate carbohydrates in acceptable purity and amounts from natural sources. Therefore, complex saccharides with well-defined structures are often most conviently accessed through chemical syntheses. Two major hurdles, regioselective protection and stereoselective glycosylation, are faced by carbohydrate chemists in synthesizing these highly complicated molecules. Over the past few years, there has been a radical change in tackling these problems and speeding up the synthesis of oligosaccharides. This is largely due to the development of one-pot protection, one-pot glycosylation, and one-pot protection-glycosylation protocols and streamlined approaches to orthogonally protected building blocks, including those from rare sugars, that can be used in glycan coupling. In addition, new automated strategies for oligosaccharide syntheses have been reported not only for program-controlled assembly on solid support but also by the stepwise glycosylation in solution phase. As a result, various sugar molecules with highly complex, large structures could be successfully synthesized. To summarize these recent advances, this review describes the methodologies for one-pot protection and their one-pot glycosylation into the complex glycans and the chronological developments associated with automated syntheses of oligosaccharides.

A novel methodology for the regioselective O6 acylation of the 2,3-diaryl trehaloses to access Mycobacterium tuberculosis sulfolipid SL-3 and related 2,3,6-triester glycolipid analogues is reported for the first time. The methodology was successfully extended to achieve the first total synthesis of the tetraacylated trehalose glycolipid from Mycobacterium paraffinicum. The corresponding 2,3,6'-triesters trehalose glycolipids were also synthesized starting from the common 2,3-diacyl trehalose. These synthetic glycolipids are potential candidates for serodiagnosis and vaccine development for tuberculosis.

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.

Herein, we report, for the first time, a strategy to differentiate O4/O4′ positions of 1,1′-α,α-trehalose via regioselective protection or site-selective functionalization and its application in the first chemical synthesis of succinoyl trehalose lipids. The biosurfactant glycolipids were obtained in 11–12 steps starting from trehalose in time span of 8–10 days and 11–12% overall yields.

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.

N-glycosylation, the covalent attachment of glycans to select protein target Asn residues, is a post-translational modification performed by all three domains of life. In the halophilic archaea Haloferax volcanii, in which understanding of this universal protein-processing event is relatively well-advanced, genes encoding the components of the archaeal glycosylation (Agl) pathway responsible for the assembly and attachment of an N-linked pentasaccharide have been identified. As elsewhere, the N-linked glycan is assembled on phosphodolichol carriers before transfer to target Asn residues. However, as little is presently known of the Hfx. volcanii Agl pathway at the protein level, the seemingly unique ability of Archaea to use dolichol phosphate (DolP) as the glycan lipid carrier, rather than dolichol pyrophosphate used by eukaryotes, remains poorly understood. With this in mind, a chemoenzymatic approach was taken to biochemically study AglG, one of the five glycosyltransferases of the pathway. Accordingly, a novel regio- and stereoselective reduction of naturally isolated polyprenol gave facile access to S-dolichol via asymmetric transfer hydrogenation under very mild conditions. This compound was used to generate glucose-charged DolP, a precursor of the N-linked pentasaccharide, as well as DolP-glucose-glucuronic acid and DolP-glucuronic acid. AglG, purified from Hfx. volcanii membranes in hypersaline conditions, like those encountered in situ, was subsequently combined with uridine diphosphate (UDP)-glucuronic acid and DolP-glucose to yield DolP-glucose-glucuronic acid. The in vitro system for the study of AglG activity developed here represents the first such tool for studying halophilic glycosyltransferases and will allow for a detailed understanding of archaeal N-glycosylation.

Bacterial glycans contain rare, exclusively bacterial monosaccharides that are frequently linked to pathogenesis and essentially absent from human cells. Therefore, bacterial glycans are intriguing molecular targets. However, systematic discovery of bacterial glycoproteins is hampered by the presence of rare deoxy amino sugars, which are refractory to traditional glycan-binding reagents. Thus, the development of chemical tools that label bacterial glycans is a crucial step toward discovering and targeting these biomolecules. Here, we explore the extent to which metabolic glycan labeling facilitates the studying and targeting of glycoproteins in a range of pathogenic and symbiotic bacterial strains. We began with an azide-containing analog of the naturally abundant monosaccharide N-acetylglucosamine and discovered that it is not broadly incorporated into bacterial glycans, thus revealing a need for additional azidosugar substrates to broaden the utility of metabolic glycan labeling in bacteria. Therefore, we designed and synthesized analogs of the rare deoxy amino 7-sugars N-acetylfucosamine, bacillosamine, and 2,4-diacetamido-2,4,6-trideoxygalactose and established that these analogs are differentially incorporated into glycan-containing structures in a range of pathogenic and symbiotic bacterial species. Further application of these analogs will refine our knowledge of the glycan repertoire in diverse bacteria and may find utility in treating a variety of infectious diseases with selectivity.

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.

Total synthesis of three important trehalose containing tetra-saccharides isolated from Mycobacterium smegmatis is reported for the first time, using regioselective opening of benzylidene acetals and stereoselective glycosylations as key steps. The 1,2-cis stereoselectivity in the glycosylation reactions was achieved using anchimeric assistance from a remote participating group, steric effects and solvent participation. The synthetic strategy can also be utilized for the assembly of structurally related oligosaccharides from M. tuberculosis.

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.

Bacteria often contain rare deoxy amino sugars which are absent in the host cells. This structural difference can be harnessed for the development of vaccines. Over the last fifteen years, remarkable progress has been made toward the development of novel and efficient protocols for obtaining the rare sugar building blocks and their stereoselective assembly to construct conjugation ready bacterial glycans. In this review, we discuss the total synthesis of a variety of rare sugar containing bacterial glycoconjugates which are potential vaccine candidates.

Making ends meet: The L-gulopyranosyl trichloroacetimidate and 1,6-anhydro-2,3-di-O-benzyl-beta-L-gulopyranose, efficiently derived from L-ascorbic acid, were individually used as a starting unit and an elongation unit to prepare L-guluronic acid linked alginate oligosaccharides in excellent alpha selectivity and in good yields.

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.

Detailed protocols for the regioselective protection of individual hydroxyls in monosaccharide units are described here. This expedient methodology incorporates up to seven reaction sequences, obviating the necessity to carry out intermittent tedious work-ups and time-consuming purifications. Using this TMSOTf-catalyzed one-pot protocol, the 2,3,4,6-tetra-O-trimethylsilylated hexopyranosides bearing an anomeric group could be transformed into a whole set of differentially protected 2-alcohols, 3-alcohols, 4-alcohols, 6-alcohols and fully protected monosaccharides in high yields. These tailor-made glycosyl donors and acceptors can then be used for stereoselective one-pot glycosylation for oligosaccharide synthesis. The total time for the preparation of a purified protected sugar unit ranges between 1 and 2 d. This process would otherwise take 1-2 weeks.

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.

Covering: 1964 to 2013 Bacteria have unusual glycans on their surfaces which distinguish them from the host cells. These unique structures offer avenues for targeting bacteria with specific therapeutics and vaccine. However, these rare sugars are not accessible in acceptable purity and amounts by isolation from natural sources. Thus, procurement of orthogonally protected rare sugar building blocks through efficient chemical synthesis is regarded as a crucial step towards the development of glycoconjugate vaccines. This Highlight focuses on recent advances in the synthesis of the bacterial deoxy amino hexopyranoside building blocks and their application in constructing various biologically important bacterial O-glycans.

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.

Several N-linked glycoproteins have been identified in archaea and there is growing evidence that the N-glycan is involved in survival and functioning of archaea in extreme conditions. Chemical synthesis of the archaeal N-glycans represents a crucial step towards understanding the putative function of protein glycosylation in archaea. Herein the first total synthesis of the archaeal L-asparagine linked hexasaccharide from Methanothermus fervidus is reported using a highly convergent [3+3] glycosylation approach in high overall yields. The synthesis relies on efficient preparation of regioselectively protected thioglycoside building blocks for orthogonal glycosylations and late stage N-aspartylation.

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.

Trehalose dibenzylidene and substituted dibenzylidene acetals were reductively opened either at O6 or O4 in a regioselective manner by using a DIBAL stock solution prepared in toluene or dichloromethane, respectively, to achieve desymmetrization of the trehalose core. The method was applied to synthesize various biologically important unsymmetrically substituted trehalose glycoconjugates, including a mycobacterial trisaccharide, a 4-epi-trehalosamine analog and a maradolipid.

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.

[Structure: see text] An efficient synthesis of the entire set of suitably protected 48 disaccharide building blocks for the assembly of a heparin and heparan sulfate oligosaccharide library is described here.

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]

[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 triethylsilane-reductive etherification of the trimethylsilyl ethers with a variety of carbonyl compounds in good yields at room temperature employing 0.5 mol% Cu(OTf) 2 as an extremely efficient catalyst is described here.

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

Bacteria have unusual glycans which are not accessible by isolation. Herein, we describe a general and divergent strategy for the synthesis of the rare, bacterial deoxy amino hexopyranoside building blocks from d-mannose. The methodology is applied to the first total synthesis of the l-serine linked trisaccharide of Neisseria meningitidis.