Synthesis Of Disaccharides Research Articles

Nontraditional Synthesis of Disaccharides via Acyclic Vinylic Ether Intermediates: Catalytic C-O Cross-Coupling as the Enabling Link.

We describe complementary methods for synthesizing acyclic vinylic ethers from two carbohydrate-derived synthons. We compare a nonstereoselective olefination approach with a stereoselective catalytic C-O cross-coupling method, preparing 1,2-disubstituted vinylic ethers with complexity on both sides of the ether linkage. Upon epoxidation/in situ oxacyclization of acyclic vinylic ethers, we synthesized disaccharides with α-d-galacto-, α-d-talo-, β-d-allo-, and α-d-altropyranoside stereochemistry, from d-lyxose and d-ribose precursors. Stereoselective CuI/CyDMEDA-catalyzed C-O cross-couplings offer considerable potential for broadly implementing this nontraditional strategy for glycoside synthesis.

Strained Ion Pair Interactions-Driven Anion-Assisted Concerted Addition of Ketoximes/Aldoximes and Hydroxamic Acids to Glycals.

Oximes and hydroxylamides are notable for their role as coupling partners in organic synthesis. However, their direct application as acceptors in O-glycosylation with glycal donors remains largely unexplored. Herein, we introduce a novel 2-deoxy glycosylation method for synthesizing N-O linked glycosides facilitated by sterically strained 2,4,6-tri-tert-butylpyridinium salts. This approach offers a broad substrate range, high tolerance for functional groups, and easy scalability, resulting in glycosyl oximes and glycosyloxyamines with exclusive α-selectivity and excellent yields. The effectiveness of this method is showcased through functionalization of glycosylated products, late-stage modification of bioactive drug molecules, and disaccharide synthesis. This innovative strategy offers an alternative route and holds promise for wide-ranging applications in the construction of bioactive N-O-linked glycosides in the future. The unique catalytic mechanism by the sterically hindered pyridinium salt has been studied via 1H NMR, IR, UV-vis, and fluorescence studies.

Combining an Enhanced Polyphosphate Kinase-Driven UDP-Glucose Regeneration System with the Screening of Key Glycosyltransferases for Efficient In Vitro Synthesis of Nucleoside Disaccharides.

Nucleoside disaccharides are essential glycosides that naturally occur in specific living organisms. This study developed an enhanced UDP-glucose regeneration system to facilitate the in vitro multienzyme synthesis of nucleoside disaccharides by integrating it with nucleoside-specific glycosyltransferases. The system utilizes maltodextrin and polyphosphate as cost-effective substrates for UDP-glucose supply, catalyzed by α-glucan phosphorylase (αGP) and UDP-glucose pyrophosphorylase (UGP). To address the low activity of known polyphosphate kinases (PPKs) in the UDP phosphorylation reaction, a sequence-driven screening identified RhPPK with high activity against UDP (>1000 U/mg). Computational design further led to the creation of a double mutant with a 2566-fold increase in thermostability at 50 °C. The enhanced UDP-glucose regeneration system increased the production rate of nucleoside disaccharide synthesis by 25-fold. In addition, our UDP-glucose regeneration system is expected to be applied to other glycosyl transfer reactions.

Chemical Synthesis of a Disaccharide from Vibrio vulnificus Biotype 2 Serovar A O-Antigen Containing a Rare l-GalpNAmA

AbstractThe bacterium Vibrio vulnificus can cause severe infections internally and externally. The mortality rate of V. vulnificus-associated gangrene and septicemia has increased due to antibiotic resistance and the absence of human vaccine. Bacterial carbohydrates have been widely used in the development of bacterial vaccines. Here, a rare l-GalpNAmA-containing disaccharide that exists in V. vulnificus biotype 2 serovar A O-antigen was synthesized from d-glucose and l-galactose. An investigation on the influence of different linkers on the disaccharide synthetic efficiency indicated that the amine linker has more practicality. Two α-glycosidic linkages were constructed with good stereoselectivity by using nonparticipating C2 azido group and solvent effect. An orthogonal protection strategy allowed introductions of carboxyl and acetamidino (Am) groups at the disaccharide stage. The synthesis of the amine-linked disaccharide will provide a basis for the preparation of the trisaccharide repeating unit and longer fragments of V. vulnificus biotype 2 serovar A O-antigen, as well as other complex glycans.

Chemical Synthesis of a Densely Functionalized Aminodisaccharide from Fusobacterium nucleatum ATCC 23726 O-Antigen.

Fusobacterium nucleatum, a colorectal-cancer-associated oncomicrobe, can trigger or accelerate numerous pathologies. We report the first synthesis of a conjugation-ready disaccharide containing six amino groups from F. nucleatum ATCC 23726 O-antigen. Rare 2,3-diamido-d-glucuronic acid amide and 2-acetamido-4-amino-d-fucose were synthesized from d-glucosamine through configuration inversion, nucleophilic substitution, C6 oxidation, and C6 deoxygenation. A judicious choice of protecting groups and reaction conditions enabled the selective installation of N-acetyl, N-propanoyl, N-formyl, and carboxamido groups.

Four novel Cit7GlcTs functional in flavonoid 7-O-glucoside biosynthesis are vital to flavonoid biosynthesis shunting in citrus.

Citrus fruits have abundant flavonoid glycosides (FGs), an important class of natural functional and flavor components. However, there have been few reports about the modification of UDP-glycosyltransferases (UGTs) on flavonoids in citrus. Notably, in flavonoid biosynthesis, 7-O-glucosylation is the initial and essential step of glycosylation prior to the synthesis of flavanone disaccharides, the most abundant and iconic FGs in citrus fruits. Here, based on the accumulation of FGs observed at the very early fruit development stage of two pummelo varieties, we screened six novel flavonoid 7-O-glucosyltransferase genes (7GlcTs) via transcriptomic analysis and then characterized them in vitro. The results revealed that four Cg7GlcTs possess wide catalytic activities towards various flavonoid substrates, with CgUGT89AK1 exhibiting the highest catalytic efficiency. Transient overexpression of CgUGT90A31 and CgUGT89AK1 led to increases in FG synthesis in pummelo leaves. Interestingly, these two genes had conserved sequences and consistent functions across different germplasms. Moreover, CitUGT89AK1 was found to play a role in the response of citrus to Huanglongbing infection by promoting FG production. The findings improve our understanding of flavonoid 7-O-glucosylation by identifying the key genes, and may help improve the benefits of flavonoid biosynthesis for plants and humans in the future.

Synthesis of Sucrose-Mimicking Disaccharide by Intramolecular Aglycone Delivery.

Rare sugars are known for their ability to suppress postprandial blood glucose levels. Therefore, oligosaccharides and disaccharides derived from rare sugars could potentially serve as functional sweeteners. A disaccharide [α-d-allopyranosyl-(1→2)-β-d-psicofuranoside] mimicking sucrose was synthesized from rare monosaccharides D-allose and D-psicose. Glycosylation using the intermolecular aglycon delivery (IAD) method was employed to selectively form 1,2-cis α-glycosidic linkages of the allopyranose residues. Moreover, β-selective psicofuranosylation was performed using a psicofuranosyl acceptor with 1,3,4,6-tetra-O-benzoyl groups. This is the first report on the synthesis of non-reducing disaccharides comprising only rare d-sugars by IAD using protected ketose as a unique acceptor; additionally, this approach is expected to be applicable to the synthesis of functional sweeteners.

Activation of glycosyl methylpropiolates by TfOH

Activation of glycosyl methylpropiolates by TfOH was investigated. Armed and superarmed glycosyl donors can be activated by use of 0.2 equivalent TfOH whereas 1.0 equivalent of TfOH was required for the activation of the disarmed glycosyl donors. All the glycosidations gave very good yields. The method is suitable for synthesis of glycosides and disaccharides and it may result in the hydrolysis of the interglycosidic bond if the sugar at the non-reducing end is armed or superarmed. These problems are not seen when gold-catalyzed activation procedures are invoked for the activation of glycosyl alkynoates.

Synthesis of a spacer-armed disaccharide structurally related to the M antigenic fragment of Brucella O-polysaccharides

Synthesis of a spacer-armed disaccharide structurally related to the M antigenic fragment of Brucella O-polysaccharides

Synthesis of disaccharides for the study of human blood antibodies capable of recognizing the inner Glcβ1-3GalNAc disaccharide fragment of bacterial polysaccharides

Disaccharides with the terminal Glcβ1-3 motif were synthesized as probes for studying human blood antibodies. An antibody isolated using Glcβ1-3GalNAcα–Sepharose was found to bind the inner part of the polysaccharide [–4GlcA6LThr3Acβ1-6Galβ1-6Glcβ1-3GalNAc6Acβ1–]n as evidenced by the use of a printed glycan array and inhibition assays.

Regio and Stereoselective One-Pot Synthesis of 2-Deoxy-3-thio Pyranoses and Their O-Glycosides from Glycals.

A reaction of glycals with two different types of nucleophiles in the presence of SnCl4 enabled one-pot rapid access to 2-deoxy-3-thio pyranoses and their O-glycosides. The process involves thioaryl substitution at C-3 with stereoretention and α-selective O-glycosylation at C-1 from d-glycals, thus combining two reactions with three interventions. The present methodology features an attractive three-component coupling (1:1.2:1.5 ratio) with operational simplicity at 0 °C in 10-20 min. This stereoselective one-pot 1,3-difunctionalization approach of glycals is compatible with wide range of primary and secondary alcohols affording products in good to excellent yields. This methodology was successfully extended toward disaccharide synthesis. Several control experiments suggested a plausible reaction mechanism and rationale behind regio and stereoselectivity. The reaction strategy possesses an intrinsic ability for the synthesis of various natural products and drug molecules.

Synthesis of Sug1-4GalNAcα disaccharides and their interaction with human blood antibodies

Disaccharides Sug1-4GalNAcα-Osp (Sug = Gal, Glc, GalNAc, GlcNAc in α- or β-configuration) were synthesized as spacer (sp) glycosides. Their strong interaction with serum antibodies of healthy donors was demonstrated using a printed glycan array (PGA).

Pd-catalyzed synthesis of hetero 1,2-interlinked C-disaccharides by coupling of iodo glycals with glycals.

A facile synthesis of C1-C2 interlinked disaccharides is achieved from readily available iodo-glycals and unsubstituted glycals. Ester-protected donors reacted with ether-protected acceptors under Pd-Ag catalysis to access C-disaccharides bearing C-3 vinyl ether, which upon ring opening by Lewis acid furnished pi-extended conjugated orthogonally protected chiral ketones. Benzyl deprotection and reduction of the double bonds resulted in a fully saturated disaccharide stable toward acid hydrolysis.

Stereoselective Synthesis of 2-Deoxythiosugars from Glycals.

2-deoxythiosugars are more stable than 2-deoxysugars occurring broadly in bioactive natural products and pharmaceutical agents. An effective and direct methodology to stereoselectively synthesize α-2-deoxythioglycosides catalyzed by AgOTf has been developed. Various alkyl thiols and thiophenols were explored and the desired products were formed in good yields with excellent α-selectivity. This method was further applied to the syntheses of S-linked disaccharides and late-stage 2-deoxyglycosylation of estrogen, L-menthol, and zingerone thiols successfully.

New methods for the synthesis of 2-(2,2,2-trichloroethoxy)-(3,4,6-tri-O-acetyl-1,2-dideoxy-α-D-glucopyrano)-[2,1-d]-2-oxazoline and its use for stereo-, chemo- and regioselective glycosylation

New methods for the synthesis of the title oxazoline 2 from the corresponding 2-deoxy-2-(2,2,2- trichloroethoxycarbonylamino)glucosyl bromide were developed. The target 2-(2,2,2-trichloroethoxy) gluco-[2,1-d]-2-oxazoline 2 can be synthesized under conditions of halide ion catalysis, using triethylamine as a base. The synthesized 2-(2,2,2-trichloroethoxy)-2-oxazoline glycosyl donor was used for stereo-, regio-, and chemoselective glycosylation reactions under extremely mild conditions. The undesirable side reaction of intermolecular aglycone transfer between an ethyl thioglycoside glycosyl acceptor and the 2-(2,2,2-trichloroethoxy)-2-oxazoline glycosyl donor occurred to a relatively small extent. Regio-, and chemoselectivity of the disaccharide synthesis with the oxazoline glycosyl donor depended on the reaction conditions.

Synthesis of Hexenuloses and a Library of Disaccharides Possessing 3-oxo-glycal Unit.

An expeditious method for the synthesis of monosaccharides and disaccharides possessing 3-oxo-glycal units is revealed. Several monosaccharides and disaccharide-derived glycals are converted to the corresponding hexenuloses in three steps involving halo-alkoxylation, dehydrohalogenation, and ketalyzation reactions. A number of 3-oxo-glycals are synthesized to show the methodology's importance and generality. Further, the protocol is successfully applied to synthesize a rare-sugar disaccharide donor unit present as part of the trisaccharide moiety in the reported natural product, versipelostatin.

Synthesis of the Aeromonas veronii strain Bs8 disaccharide repeating unit

Presented herein is the synthesis of the Aeromonas veronii disaccharide repeating unit which has been achieved in 11 steps starting from d-fucose and d-galactosamine.

Rubus idaeus L. fruit nutrients are affected by different growing technologies

The biochemical compounds of red raspberry (Rubus idaeus L.) fruits cultivated with conventional growing technology and on a nutrient substrate were studied during 2019–2020 at the Federal Horticultural Research Center for Breeding, Agrotechnology and Nursery, Moscow, Russia. The antioxidant activity, phenolic compounds, and ash constituents of the fruits and the metabolites of the alcoholic extract of the raspberries were determined. The effect of growing technologies, i.e., conventional vs. nutrient substrate, on the accumulation of macro- and microelements in raspberry fruits was established. In red raspberries grown on nutrient substrate, the antioxidant activity decreased by 25 times (aqueous extract) and 1.5 times (alcoholic extract). The K and Na contents and Se contents of red raspberries grown on nutrient substrate were 1.5 and 3 times higher than those of raspberries of grown with conventional technology. Raspberries grown with conventional technology contained 2 times more Ca, Ni, and Mn and 7.4 times more Fe than raspberries grown on nutrient substrate. The total amount of elements in raspberries grown through soilless cultivation was 5.5% higher than that in berries grown conventionally. A total of 48 compounds were identified in the alcoholic extracts, and only 29 substances were found in berries grown on a nutrient substrate. Sugar and citric acid constituted the largest share of red raspberry components. Fructose and turanose disaccharide synthesis in raspberries grown on nutrient substrate was 20% higher than that in conventionally grown raspberries. A total of 48 organic compounds with different biological activities were identified. They included five substances with antimicrobial activity, three phenolic substances, eight organic acids, four sugar acids, nine amino acids, and 19 sugars and their derivatives. At the same time, 42 compounds were found in raspberries grown with traditional technology, and 21 compounds were identified in raspberry fruits grown on nutrient substrate. Three fatty acids, namely, ɑ-linoleic acid (polyunsaturated omega-6 fatty acid), palmitic acid, and stearic acid (saturated fatty acid), along with cinnamic acid, shikimic acid, and chrysin were found in berries grown conventionally.

Solvent‐Free Glycosylation from per‐O‐Acylated Donors Catalyzed by Methanesulfonic Acid

AbstractThe huge importance of carbohydrates and their derivatives in biomedical and industrial applications call for the development of streamlined and sustainable procedures for their synthetic elaboration. Here reported a novel glycosylation method based on direct activation of readily available per‐O‐acylated (acetylated or benzoylated) donors, promoted under air by methanesulfonic acid as a cheap and green catalyst in the absence of any solvent. Besides the beneficial avoidance of toxic and polluting organic solvents, these conditions were found critical for activating such poorly reactive donors with a very small catalyst loading (only 5 mol %), instead of stoichiometric Lewis acid promoters typically employed. Desired glycosides were quickly obtained, in most cases with high 1,2‐transstereoselectivity. Other main advantages over reported glycosylations with similar donors are the limited stoichiometric excess of the acceptor (or the donor), the easy applicability and low cost of the procedure and the wide target scope, also covering the synthesis of disaccharides and other non‐trivial glycosides with applicable potential.

Exploration of GH94 Sequence Space for Enzyme Discovery Reveals a Novel Glucosylgalactose Phosphorylase Specificity

The substantial increase in DNA sequencing efforts has led to a rapid expansion of available sequences in glycoside hydrolase families. The ever-increasing sequence space presents considerable opportunities for the search for enzymes with novel functionalities. In this work, the sequence-function space of glycoside hydrolase family 94 (GH94) was explored in detail, using a combined approach of phylogenetic analysis and sequence similarity networks. The identification and experimental screening of unknown clusters led to the discovery of an enzyme from the soil bacterium Paenibacillus polymyxa that acts as a 4-O-β-d-glucosyl-d-galactose phosphorylase (GGalP), a specificity that has not been reported to date. Detailed characterization of GGalP revealed that its kinetic parameters were consistent with those of other known phosphorylases. Furthermore, the enzyme could be used for production of the rare disaccharides 4-O-β-d-glucosyl-d-galactose and 4-O-β-d-glucosyl-l-arabinose. Our current work highlights the power of rational sequence space exploration in the search for novel enzyme specificities, as well as the potential of phosphorylases for rare disaccharide synthesis.