Synthetic Carbohydrate Chemistry Research Articles

Regiodivergent Functionalization of Protected and Unprotected Carbohydrates using Photoactive 4‐Tetrafluoropyridinylthio Fragment as an Adaptive Activating Group

AbstractThe selective functionalization of carbohydrates holds a central position in synthetic carbohydrate chemistry, driving the ongoing quest for ideal approaches to manipulate these compounds. In this study, we introduce a general strategy that enables the regiodivergent functionalization of saccharides. The use of electron‐deficient photoactive 4‐tetrafluoropyridinylthio (SPyf) fragment as an adaptable activating group, facilitated efficient functionalization across all saccharide sites. More importantly, this activating group can be directly installed at the C1, C5 and C6 positions of biomass‐derived carbohydrates in a single step and in a site‐selective manner, allowing for the efficient and precision‐oriented modification of unprotected saccharides and glycans.

Emerging Advances of the Radical Pathway Glycosylation Enabled by Bench‐Stable Glycosyl Donors: Glycosyl Sulfoxides, Glycosyl Sulfones, and Glycosyl Sulfinates

AbstractIn synthetic carbohydrate chemistry, the modification of glycosyl radicals pathway stands as a central area of focus. The radical‐based reactions often demonstrate remarkable compatibility with various functional groups owing to the mild initiation conditions. In particular, the identification of novel glycosyl radical precursors, combined with advanced reaction techniques, has substantially broadened the scope of glycosyl compound synthesis. Despite the presence of versatile donors, the synthesis of noble donors is still addressed as a synthetic need and challenges associated with sugar chemistry. Currently, a new class of glycosyl radical precursors has been developed which enables the production of C‐, S‐, O‐, and N‐glycosides efficiently. In this light, we highlight strategies towards bench‐stable glycosyl sulfoxides, sulphone, and sulfite donors that can enable the site‐, regio‐ and stereoselective transformation of protected or naked sugar synthons in synthetic carbohydrate chemistry. Here, this review article covers the recent developments in the selective glycosyl radical diversification such as glycosyl alkylation, arylation, alkenylation, sulfuration, C−H activation, and DNA conjugation via the bench‐stable donors along with mechanistic aspects, challenges, and future directions.

Regiodivergent Functionalization of Protected and Unprotected Carbohydrates using Photoactive 4-Tetrafluoropyridinylthio Fragment as an Adaptive Activating Group.

The selective functionalization of carbohydrates holds a central position in synthetic carbohydrate chemistry, driving the ongoing quest for ideal approaches to manipulate these compounds. In this study, we introduce a general strategy that enables the regiodivergent functionalization of saccharides. The use of electron-deficient photoactive 4-tetrafluoropyridinylthio (SPyf) fragment as an adaptable activating group, facilitated efficient functionalization across all saccharide sites. More importantly, this activating group can be directly installed at the C1, C5 and C6 positions of biomass-derived carbohydrates in a single step and in a site-selective manner, allowing for the efficient and precision-oriented modification of unprotected saccharides and glycans.

Transformations of carbohydrate derivatives enabled by photocatalysis and visible light photochemistry.

This review article highlights the diverse ways in which recent developments in the areas of photocatalysis and visible light photochemistry are impacting synthetic carbohydrate chemistry. The major topics covered are photocatalytic glycosylations, generation of radicals at the anomeric position, transformations involving radical formation at non-anomeric positions, additions to glycals, processes initiated by photocatalytic hydrogen atom transfer from sugars, and functional group interconversions at OH and SH groups. Factors influencing stereo- and site-selectivity in these processes, along with mechanistic aspects, are discussed.

Efficient and versatile formation of glycosidic bonds via catalytic strain-release glycosylation with glycosyl ortho−2,2-dimethoxycarbonylcyclopropylbenzoate donors

Catalytic glycosylation is a vital transformation in synthetic carbohydrate chemistry due to its ability to expediate the large-scale oligosaccharide synthesis for glycobiology studies with the consumption of minimal amounts of promoters. Herein we introduce a facile and efficient catalytic glycosylation employing glycosyl ortho−2,2-dimethoxycarbonylcyclopropylbenzoates (CCBz) promoted by a readily accessible and non-toxic Sc(III) catalyst system. The glycosylation reaction involves a novel activation mode of glycosyl esters driven by the ring-strain release of an intramolecularly incorporated donor-acceptor cyclopropane (DAC). The versatile glycosyl CCBz donor enables highly efficient construction of O-, S-, and N-glycosidic bonds under mild conditions, as exemplified by the convenient preparation of the synthetically challenging chitooligosaccharide derivatives. Of note, a gram-scale synthesis of tetrasaccharide corresponding to Lipid IV with modifiable handles is achieved using the catalytic strain-release glycosylation. These attractive features promise this donor to be the prototype for developing next generation of catalytic glycosylation.

Diversification of Glycosyl Compounds via Glycosyl Radicals.

Glycosyl radical functionalization is one of the central topics in synthetic carbohydrate chemistry. Recent advances in metal-catalyzed cross-coupling chemistry and metallaphotoredox catalysis provided powerful platforms for glycosyl radical diversification. In particular, the discovery of new glycosyl radical precursors in conjunction with these advanced reaction technologies have significantly expanded the space for glycosyl compound synthesis. In this Minireview, we highlight the most recent progress in this area starting from 2021, and the reports included will be categorized based on different reaction types for better clarity.

Diversification of Glycosyl Compounds via Glycosyl Radicals

AbstractGlycosyl radical functionalization is one of the central topics in synthetic carbohydrate chemistry. Recent advances in metal‐catalyzed cross‐coupling chemistry and metallaphotoredox catalysis provided powerful platforms for glycosyl radical diversification. In particular, the discovery of new glycosyl radical precursors in conjunction with these advanced reaction technologies have significantly expanded the space for glycosyl compound synthesis. In this Review, we highlight the most recent progress in this area starting from 2021, and the reports included will be categorized based on different reaction types for better clarity.

Sweet Synthesis

Sweet Synthesis

Recent advances in stereoselective 1,2-cis-O-glycosylations.

For the stereoselective assembly of bioactive glycans with various functions, 1,2-cis-O-glycosylation is one of the most essential issues in synthetic carbohydrate chemistry. The cis-configured O-glycosidic linkages to the substituents at two positions of the non-reducing side residue of the glycosides such as α-glucopyranoside, α-galactopyranoside, β-mannopyranoside, β-arabinofuranoside, and other rather rare glycosides are found in natural glycans, including glycoconjugate (glycoproteins, glycolipids, proteoglycans, and microbial polysaccharides) and glycoside natural products. The way to 1,2-trans isomers is well sophisticated by using the effect of neighboring group participation from the most effective and kinetically favored C-2 substituent such as an acyl group, although high stereoselective synthesis of 1,2-cis glycosides without formation of 1,2-trans isomers is far less straightforward. Although the key factors that control the stereoselectivity of glycosylation are largely understood since chemical glycosylation was considered to be one of the useful methods to obtain glycosidic linkages as the alternative way of isolation from natural sources, strictly controlled formation of these 1,2-cis glycosides is generally difficult. This minireview introduces some of the recent advances in the development of 1,2-cis selective glycosylations, including the quite recent developments in glycosyl donor modification, reaction conditions, and methods for activation of intermolecular glycosylation, including the bimodal glycosylation strategy for 1,2-cis and 1,2-trans glycosides, as well as intramolecular glycosylations, including recent applications of NAP-ether-mediated intramolecular aglycon delivery.

Synthesis and Glycosidation of Anomeric Halides: Evolution from Early Studies to Modern Methods of the 21st Century.

Advances in synthetic carbohydrate chemistry have dramatically improved access to common glycans. However, many novel methods still fail to adequately address challenges associated with chemical glycosylation and glycan synthesis. Since a challenge of glycosylation has remained, scientists have been frequently returning to the traditional glycosyl donors. This review is dedicated to glycosyl halides that have played crucial roles in shaping the field of glycosciences and continue to pave the way toward our understanding of chemical glycosylation.

Introducing 77Se NMR Spectroscopy to Analyzing Galectin -Ligand Interaction.

Their emerging nature as multifunctional effectors explains the large interest to monitor glycan binding to galectins and to define bound-state conformer(s) of their ligands in solution. Basically, NMR spectroscopy facilitates respective experiments. Towards developing new and even better approaches for these purposes, extending the range of exploitable isotopes beyond 1H, 13C, and 15N offers promising perspectives. Having therefore prepared selenodigalactoside and revealed its bioactivity as galectin ligand, monitoring of its binding by 77Se NMR spectroscopy at a practical level becomes possible by setting up a 2D 1H, 77Se CPMG-HSQBMC experiment including CPMG-INEPT long-range transfer. This first step into applying 77Se as sensor for galectin binding substantiates its potential for screening relative to inhibitory potencies in compound mixtures and for achieving sophisticated epitope mapping. The documented strategic combination of synthetic carbohydrate chemistry and NMR spectroscopy prompts to envision to work with isotopically pure 77Se-containing β-galactosides and to build on the gained experience with 77Se by adding 19F as second sensor in doubly labeled glycosides.

DFT Based Comparative Studies of Some Glucofuranose and Glucopyranoside Esters and Ethers

Carbohydrate-based molecular scaffolding received significant interest due to its impact on the drug discovery and development in synthetic carbohydrate chemistry during the last couple of decades. In this respect, four glucose compounds in the furanose and pyranose forms with ester and ether functionality were selected for their structural, thermodynamic and chemical reactivity studies. PASS predication indicated that the glucose in the six-membered pyranose form was more prone to biological properties compared to their five-membered furanose form. Also, in the pyranose form acetate ester (3) had more potentiality than the ethyl ether (4). The HOMO-LUMO energy gaps were almost similar for both monosubstituted furanose and pyranose glucose indicating their almost similar reactivities. It was also inferred that these 6-O-substituted compounds followed Lipinski’s rule with the acceptable range of ADMET levels, and hence, safe from lethal proarrhythmic risks. Hopefully, these results can be used in the near future for their probable pharmaceutical use without any remarkable toxicity.

Exploiting non-covalent interactions in selective carbohydrate synthesis.

Non-covalent interactions (NCIs) are a vital component of biological bond-forming events, and have found important applications in multiple branches of chemistry. In recent years, the biomimetic exploitation of NCIs in challenging glycosidic bond formation and glycofunctionalizations has attracted significant interest across diverse communities of organic and carbohydrate chemists. This emerging theme is a major new direction in contemporary carbohydrate chemistry, and is rapidly gaining traction as a robust strategy to tackle long-standing issues such as anomeric and site selectivity. This Review thus seeks to provide a bird's-eye view of wide-ranging advances in harnessing NCIs within the broad field of synthetic carbohydrate chemistry. These include the exploitation of NCIs in non-covalent catalysed glycosylations, in non-covalent catalysed glycofunctionalizations, in aglycone delivery, in stabilization of intermediates and transition states, in the existence of intramolecular hydrogen bonding networks and in aggregation by hydrogen bonds. In addition, recent emerging opportunities in exploiting halogen bonding and other unconventional NCIs, such as CH-π, cation-π and cation-n interactions, in various aspects of carbohydrate chemistry are also examined.

GH47 and Other Glycoside Hydrolases Catalyze Glycosidic Bond Cleavage with the Assistance of Substrate Super-arming at the Transition State.

Super-armed glycosyl donors, whose substituents are predominantly held in pseudoaxial positions, exhibit strongly increased reactivity in glycosylation through significant stabilization of oxocarbenium-like transition states. Examination of X-ray crystal structures reveals that the GH47 family of glycoside hydrolases have evolved so as to distort their substrates away from the ground state conformation in such a manner as to present multiple C-O bonds in pseudoaxial positions and so benefit from conformational super-arming of their substrates, thereby enhancing catalysis. Through analysis of literature mutagenic studies, we show that a suitably placed aromatic residue in GHs 6 and 47 sterically enforces super-armed conformations on their substrates. GH families 45, 81, and 134 on the other hand impose conformational super-arming on their substrates, by maintaining the more active ring conformation through hydrogen bonding rather than steric interactions. The recognition of substrate super-arming by select GH families provides a further parallel with synthetic carbohydrate chemistry and nature and opens further avenues for the design of improved glycosidase inhibitors.

Development of Diverse Range of Biologically Relevant Carbohydrate-Containing Molecules: Twenty Years of Our Journey*.

There is an increasing demand for significant amount of carbohydrate-containing molecules owing to their complete chemical, biological, and pharmacological investigations to better understand their role in many important biological events. Clinical studies of a wide range of simple carbohydrates or their derivatives, glycohybrids, glycoconjugates, and neoglycoconjugates have been conducted worldwide for the successful treatment of various frontline diseases. Herein, a brief perspective of carbohydrate-based molecular scaffolding and my experience during the last 20 years in the area of synthetic carbohydrate chemistry, mainly for their impact in drug discovery & development, is presented.

Selective Acetylation of the Primary Hydroxyl Group in Methyl D-Hexopyranosides with a Mixture of Acetic Anhydride and Acetic Acid

6-O-Acetylated derivatives of D-hexopyranosides are valuable intermediates in synthetic carbohydrate chemistry. We have developed a new simple procedure for selective acetylation of the primary hydroxyl group in methyl D-hexopyranosides consisting in treatment with a mixture of acetic anhydride and acetic acid at 50°C. As a result, corresponding 6-acetates were formed in 40–50% yield.

Palladium-Catalyzed O - and N -Glycosylation with Glycosyl Chlorides

Despite the significant progress in carbohydrate chemistry, there remains a pressing need for efficient and practical glycosylation methods using simple glycosyl donors and with high atom economy. ...

Progress toward the Development of Glycan-Based Vaccines against Campylobacteriosis.

As one of the main causes of bacterial diarrhea and a major risk factor for triggering Guillain-Barré autoimmune syndrome, campylobacteriosis, that is, Campylobacter spp. infections, represents a major health issue worldwide. There is thus a pressing need for developing an effective and broad-coverage campylobacteriosis vaccine. Campylobacter jejuni, an encapsulated, multidrug resistant Gram-negative bacterium, expresses virulence-associated capsular polysaccharides (CPSs), which constitute exquisite targets for the design of glycoconjugate vaccines. In that context, synthetic carbohydrate chemistry acts as a crucial enabling technology for the preparation of homogeneous constructs while allowing antigenic epitopes to be deciphered and probed at the molecular level. This review aims at covering recent developments in CPS-based campylobacteriosis vaccines as well as in the total syntheses of C. jejuni-related mono- and oligosaccharide mimics.

The 2,2-Dimethyl-2-(ortho-nitrophenyl)acetyl (DMNPA) Group: A Novel Protecting Group in Carbohydrate Chemistry

The 2,2-dimethyl-2-(ortho-nitrophenyl)acetyl (DMNPA) group was introduced to synthetic carbohydrate chemistry as a protecting group (PG) for the first time. Benefiting from a unique chemical structure and novel deprotection conditions, the DMNPA group can be cleaved rapidly and mutually orthogonal to other PGs. Orchestrated application of the DMNPA group with other PGs led to the highly efficient synthesis of the glycan of thornasterside A.

Simple and Efficient Preparation of O- and S-GlcNAcylated Amino Acids through InBr3-Catalyzed Synthesis of β- N-Acetylglycosides from Commercially Available Reagents.

The facile synthesis of serine, threonine, and cysteine β-glycosides using commercially available peracetylated β- N-acetylglucosamine (β-Ac4GlcNAc) and catalytic amounts of indium bromide (InBr3) is described. This method involves only inexpensive reagents that require no further modification or special handling. The reagents are simply mixed, dissolved, and refluxed to afford the GlcNAcylated amino acids in great yields (70-80%). This operationally simple procedure should facilitate the study of O-GlcNAcylation without necessitating expertise in synthetic carbohydrate chemistry.