Stereoselective Glycosylation Research Articles

Synthesis of C-glycosides by Ti-catalyzed stereoselective glycosyl radical functionalization

<h2>Summary</h2> <i>C</i>-Alkyl glycosides occur widely in nature and are indispensable in drug development programs, owing to their diverse range of medicinal properties. Previous synthetic efforts often utilize stoichiometric reagents, and catalytic methods that afford such glycosides exhibit limited scope. Here, we describe a stereoselective Ti-catalyzed regime that efficiently merges a vast array of readily available glycosyl chlorides with activated olefins, through stereocontrolled glycosyl radical addition to deliver an assortment of <i>C</i>-alkyl glycosides. By employing alkynes as radical acceptors, the present strategy is amenable to the synthesis of <i>C</i>-alkenyl glycosides bearing a <i>Z</i> olefin appendage. The unexpected greater reactivity of glycosyl chlorides (compared with simple tertiary chloroalkanes) in the presence of an organotitanium complex is elucidated through mechanistic and computational studies. Utility of the protocol is underscored by the concise preparation of therapeutically important carbohydrates and glycopeptide conjugates, which are difficult to access using alternative approaches.

Total Synthesis of the All-Rare Sugar-Containing Pentasaccharide Repeating Unit of the O-Polysaccharide of Plesiomonas shigelloides Strain 302-73 (Serotype O1).

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.

Synthesis of Rare 6-Deoxy-d-/l-Heptopyranosyl Fluorides: Assembly of a Hexasaccharide Corresponding to Campylobacter jejuni Strain CG8486 Capsular Polysaccharide.

Campylobacter jejuni is the leading cause of human diarrheal diseases and has been designated as one of highly resistant pathogens by the World Health Organization. The C. jejuni capsular polysaccharides feature broad existence of uncommon 6dHepp residues and have proven to be potential antigens to develop innovative antibacterial glycoconjugation vaccines. To address the lack of synthetic methods for rare 6dHepp architectures of importance, we herein describe a novel and efficient approach for the preparation of uncommon d-/l-6dHepp fluorides that have power as glycosylating agents. The synthesis is achieved by a C1-to-C5 switch strategy relying on radical decarboxylative fluorination of uronic acids arising from readily available allyl d-C-glycosides. To further showcase the application of this protocol, a structurally unique hexasaccharide composed of →3)-β-d-6didoHepp-(1→4)-β-d-GlcpNAc-(1→ units, corresponding to the capsular polysaccharide of C. jejuni strain CG8486 has been assembled for the first time. The assembly is characterized by highly efficient construction of the synthetically challenging β-(1,2-cis)-d-ido-heptopyranoside by inversion of the C2 configuration of β-(1,2-trans)-d-gulo-heptopyranoside, which is conveniently obtained by anchimerically assisted stereoselective glycosylation of the orthogonally protected 6dgulHepp fluoride. Ready accessibility of 6dHepp fluorides and the resulting glycans could serve as a rational starting point for the further development of synthetic vaccines fighting Campylobacter infection.

Synthesis of Pentasaccharide Repeating Unit Corresponding to the Cell Wall O-Polysaccharide of Salmonella enterica O55 Strain Containing a Rare Sugar 3-Acetamido-3-deoxy-d-fucose

AbstractA pentasaccharide repeating unit corresponding to the cell wall O-antigen of Salmonella enterica O55 containing a rare sugar, 3-acetamido-3-deoxy-d-fucose has been synthesized as its p-methoxyphenyl glycoside using a sequential stereoselective glycosylation strategy. A suitably functionalized 3-azido-3-deoxy-d-fucose thioglycoside derivative was prepared in very good yield and used in the stereoselective glycosylation reaction. Functionalized monosaccharide intermediates were prepared judiciously and stereoselectively assembled to get the desired pentasaccharide derivative in excellent yield.

Glycosyl Sulfonates Beyond Triflates.

While glycosyl triflates are frequently invoked as intermediates in many chemical glycosylation reactions, the chemistry of other glycosyl sulfonates remains comparatively underexplored. Given the reactivity of sulfonates can span several orders of magnitude, this represents an untapped resource for the development of stereoselective glycosylation reactions. This personal account describes our laboratories efforts to take advantage of this reactivity to develop β-specific glycosylation reactions. Initial investigations led to the development of 2-deoxy-sugar tosylates as highly selective donors for β-glycoside synthesis, an approach which has been used to great success by our group and others for the construction of deoxy-sugar oligosaccharides and natural products. Subsequent studies demonstrate that "matching" the reactivity of the sulfonate to that of the sugar donor leads to highly selective SN 2-glycosylations with a range of substrates.

Chemical synthesis of the rare D-Fuc3NAc containing tetrasaccharide repeating unit of the O-antigenic polysaccharide from E. coli O74

Chemical synthesis of the tetrasaccharide repeating unit of the O-antigen from E. coli O74 is accomplished by a convergent [2 + 2] block synthesis strategy. The challenging rare D-Fuc3NAc has been prepared using DTBP and TIPST mediated deoxygenation reaction. Other monosaccharide synthons are prepared through rational protecting group manipulations and the stereoselective glycosylations are achieved either by the activation of thioglycoside or glycosyl trichloroacetimidate. The target tetrasaccharide is made in the form of its 2-aminoethyl glycoside to facilitate further glycoconjugate formation without affecting the anomeric stereochemistry.

Highly Stereoselective Glycosylation Reactions of Furanoside Derivatives via Rhenium (V) Catalysis.

A novel approach for the formation of anomeric carbon-functionalized furanoside systems was accomplished through the employment of an oxo-rhenium catalyst. The transformation boasts a broad range of nucleophiles including allylsilanes, enol ethers, and aromatics in addition to sulfur, nitrogen, and hydride donors, able to react with an oxocarbenium ion intermediate derived from furanosidic structures. The excellent stereoselectivities observed followed the Woerpel model, ultimately providing 1,3-cis-1,4-trans systems. In the case of electron-rich aromatic nucleophiles, an equilibration occurs at the anomeric center with the selective formation of 1,3-trans-1,4-cis systems. This anomalous result was rationalized through density functional theory calculations. Different oxocarbenium ions such as those derived from dihydroisobenzofuran, pyrrolidine, and oxazolidine heterocycles can also be used as a substrate for the oxo-Re-mediated allylation reaction.

Self-Promoted Stereoselective Glycosylations - Past, Present, Future.

Self-promoted glycosylations have generally not received much attention, despite having the advantages of being easy to perform and often highly stereoselective. This account covers the work done in this field and the mechanistic aspects of self-promoted glycosylations are discussed, with a main focus on the stereoselectivity of the reactions. Most self-promoted glycosylations utilize trichloroacetimidate donors, but examples of self-promoted reactions with other donors have been described and will be discussed. Self-promoted glycosylation strategies can provide a basis for new stereoselective glycosylation methodologies.

Rhamnogalacturonan II: Chemical Synthesis of a Substructure Including α-2,3-Linked Kdo*.

The synthesis of a fully deprotected Kdo-containing rhamnogalacturonan II pentasaccharide is described. The strategy relies on the preparation of a suitably protected homogalacturonan tetrasaccharide backbone, through a post-glycosylation oxidation approach, and its stereoselective glycosylation with a Kdo fluoride donor.

Synthesis of Mannosidase-Stable Man3 and Man4 Glycans Containing S-linked Manα1→2Man Termini.

Oligomannose glycans are of interest as HIV vaccine components, but they are subject to mannosidase degradation in vivo. Herein, we report the synthesis of oligosaccharides containing a thio linkage at the nonreducing end. A thio-linked dimannose donor participates in highly stereoselective glycosylations to afford trimannose and tetramannose fragments. Saturation transfer difference nuclear magnetic resonance (STD NMR) studies show that these glycans are recognized by HIV antibody 2G12, and we confirm that the reducing terminal S-linkage confers complete stability against x. manihotis mannosidase.

One-pot iterative glycosylations toward a tetrasaccharide related to the O-specific polysaccharide from Escherichia coli O132

An efficient synthetic strategy has been developed for the synthesis of a tetrasaccharide related to the O-specific polysaccharide from Escherichia coli O132 as their 2-aminoethyl glycosides in a very good yield by adopting sequential glycosylation followed by in-situ removal of the p-methoxybenzyl (PMB) group in the same reaction pot. Furthermore, the synthetic route was adapted by carrying out three stereoselective iterative glycosylations followed by in situ removal of the PMB group in one pot. The stereochemical outcomes of all the glycosylation steps were excellent with satisfactory yields.

Synthesis of the sialylated pentasaccharide repeating unit of the capsular polysaccharide of Streptococcus group B type VI

An efficient synthetic strategy has been developed for the synthesis of the sialic acid containing pentasaccharide repeating unit of the cell wall O-antigen of Streptococcus group B type VI strain involving stereoselective α-glycosylation of sialic acid thioglycoside derivative. Stereoselective glycosylation of glycosyl trichloroacetimidate derivatives and thioglycosides were carried out using perchloric acid supported over silica (HClO4–SiO2) as a solid acid catalyst. A panel of sialic acid donors has been screened for achieving satisfactory yield and stereochemical outcome of the glycosylation reaction.

Donor Preactivation‐Based Glycosylation: An Efficient Strategy for Glycan Synthesis

AbstractCarbohydrates have gained a lot of appreciation in the past few decades due to their important roles in numerous biological events. Acquiring a structurally well‐defined carbohydrate compound is essential for the understanding of its functions. Although some innovative methods have been developed for the synthesis of complex oligosaccharides, glycan synthesis is in general still a time‐consuming and difficult work. Herein, we will introduce the preactivation‐based glycosylation strategy, which is an efficient protocol independent of the reactivity of glycosyl donor. This review will focus on summarizing the versatile applications of preactivation strategy in stereoselective glycosylation and one‐pot assembly of biologically important oligosaccharides and even polysaccharides. What is the most favorite and original chemistry developed in your research group?Preactivation‐based one‐pot glycosylation strategy and applications.How do you get into this specific field? Could you please share some experiences with our readers?I got into this field when I was a research associate in 1996. My supervisor, Prof. Chi‐Huey Wong, gave me a research topic for synthesis of oligosaccharide libraries. At that moment, as a beginner, I did not know too much carbohydrate chemistry, just to learn and to do it. The importance and challenge of carbohydrates attracted me.What is the most important personality for scientific research?Curiosity, passion, and creative thinking.How do you supervise your students?In my opinion, before the graduate students start a specific project, their experimental skills need to be well trained. During the period of graduate studies, the enhancement of abilities to analyze problems and to solve problems is very important. The graduate students should always keep an eye on the unusual experimental phenomena.What's your hobbies?Reading history books.What is your favorite journals?The journals publishing the latest research works in chemistry and medical science.

Calixanthomycin A: Asymmetric Total Synthesis and Structural Determination.

We report the first asymmetric total synthesis and structural determination of calixanthomycin A. Taking advantage of a modular strategy, a concise approach was developed to assemble the hexacyclic skeleton with both enantiomers of the lactone A ring. Stereoselective glycosylation coupled the angular hexacyclic framework with a monosaccharide fragment to produce calixanthomycin A and its stereoisomers. This enable us to determine and assign the absolute configuration of C-25 (25S) and monosaccharide (derivative of l-glucose).

β-Selective Glycosylation Using Axial-Rich and 2-O-Rhamnosylated Glucosyl Donors Controlled by the Protecting Pattern of the Second Sugar.

Herein, we describe two counterexamples of the previously reported β/α-selectivity of 96/4 for glycosylation using ethyl 2-O-[2,3,4-tris-O-tert-butyldimethylsilyl (TBS)-α-L-rhamnopyranosyl]-3,4,6-tris-O-TBS-thio-β-D-glucopyranoside as the glycosyl donor. Furthermore, we investigated the effects of protecting group on the rhamnose moieties in the glycosylation with cholestanol and revealed that β-selectivity originated from the two TBS groups at the 3-O and 4-O positions of rhamnose. In contrast, the TBS group at the 2-O position of rhamnose hampered the β-selectivity. Finally, the β/α-selectivity during the glycosylation was enhanced to ≥99/1. The results obtained herein suggest that the protecting groups on the sugar connected to the 2-O of a glycosyl donor with axial-rich conformation can control the stereoselectivity of glycosylation.

Conversion of N-acyl amidines to amidoximes: a convenient synthetic approach to molnupiravir (EIDD-2801) from ribose.

An efficient method is described for the preparation of molnupiravir (EIDD-2801) an antiviral agent via regioselective conversion of an N-acyl-nucleoside intermediate, generated through stereo and regioselective glycosylation of protected ribose and N4-acetyl cytosine, to an amidoxime. This method avoids use of expensive starting materials, enzymes, complex reagents, and cumbersome purification procedures.

Recent Development of Stereoselective Glycosylation Reactions

Recent Development of Stereoselective Glycosylation Reactions

Synthetic trisaccharides reveal discrimination of endo-glycosidic linkages by exo-acting α-1,2-mannosidases in the endoplasmic reticulum.

A tri-antennary Man9GlcNAc2 glycan on the surface of endoplasmic reticulum (ER) glycoproteins functions as a glycoprotein secretion or degradation signal after regioselective cleavage of the terminal α-1,2-mannose residue of each branch. Four α-1,2-mannosidases-ER mannosidase I, ER degradation-enhancing α-mannosidase-like protein 1 (EDEM1), EDEM2, and EDEM3-are involved in the production of these signal glycans. Although selective production of signal glycans is important in determining the fate of glycoproteins, the branch-discrimination abilities of the α-1,2-mannosidases are not well understood. A structural feature of the Man9GlcNAc2 glycan is that all terminal glycosidic linkages of the three branches are of the α-1,2 type, while the adjacent inner glycosidic linkages are different. In this study, we examined whether the α-1,2-mannosidases showed branch specificity by discriminating between different inner glycosides. Four trisaccharides with different glycosidic linkages [Manα1-2Manα1-2Man (natural A-branch), Manα1-2Manα1-3Man (natural B-branch), Manα1-2Manα1-6Man (natural C-branch), and Manα1-2Manα1-4Man (unnatural D-branch)] were synthesized and used to evaluate the hypothesis. When synthesizing these oligosaccharides, highly stereoselective glycosylation was achieved with a high yield in each case by adding a weak base or tuning the polarity of the mixed solvent. Enzymatic hydrolysis of the synthetic trisaccharides by a mouse liver ER fraction containing the target enzymes showed that the ER α-1,2-mannosidases had clear specificity for the trisaccharides in the order of A-branch > B-branch > C-branch ≈ D-branch. Various competitive experiments have revealed for the first time that α-1,2-mannosidase with inner glycoside specificity is present in the ER. Our findings suggest that exo-acting ER α-1,2-mannosidases can discriminate between endo-glycosidic linkages.

Predicting glycosylation stereoselectivity using machine learning.

Predicting the stereochemical outcome of chemical reactions is challenging in mechanistically ambiguous transformations. The stereoselectivity of glycosylation reactions is influenced by at least eleven factors across four chemical participants and temperature. A random forest algorithm was trained using a highly reproducible, concise dataset to accurately predict the stereoselective outcome of glycosylations. The steric and electronic contributions of all chemical reagents and solvents were quantified by quantum mechanical calculations. The trained model accurately predicts stereoselectivities for unseen nucleophiles, electrophiles, acid catalyst, and solvents across a wide temperature range (overall root mean square error 6.8%). All predictions were validated experimentally on a standardized microreactor platform. The model helped to identify novel ways to control glycosylation stereoselectivity and accurately predicts previously unknown means of stereocontrol. By quantifying the degree of influence of each variable, we begin to gain a better general understanding of the transformation, for example that environmental factors influence the stereoselectivity of glycosylations more than the coupling partners in this area of chemical space.

Influence of Remote Picolinyl and Picoloyl Stereodirecting Groups for the Stereoselective Glycosylation

AbstractSugar compounds generally consist of several hydroxyl groups, responsible for the generation of complex oligosaccharides and are discriminated against or manipulated by using protecting groups. The protecting groups in carbohydrate chemistry adopt a central position in controlling stereoselectivity of glycosylation reaction. In all, picoloyl (Pico) and picolinyl (Pic) group are scrutinize as admirable protecting groups for the evaluation of efficient and convenient glycosyl donors which in turn, synthesize both 1,2‐cis‐ and 1,2‐trans‐linked complex and challenging oligosaccharides stereoselectively either through hydrogen bond mediated aglycone delivery (HAD) or by neighbouring group participation. This review explores the recent advances in the use of picoloyl (Pico) and picolinyl (Pic) as stereo‐directing groups for high facial α‐ or β‐stereoselectivity and its applications in the synthesis of biologically important oligosaccharides.