Diverse Synthesis of C-Glycosides by Stereoselective Ni-Catalyzed Carboboration of Glycals.

C-Glycosides are important structures that are common to natural products and pharmaceutical agents. Established methods for their synthesis involve the reaction of an activated anomeric carbon. In this study, we report a conceptually new approach that involves the stereoselective Ni-catalyzed carboboration of glycals. In these reactions, not only is a C-C bond formed at the anomeric carbon, but a synthetically useful C-B bond is also installed. Upon C-B oxidation, differentially protected C-glycosides to be formed. In addition, stereospecific manipulation of the C-B bond leads to diverse C-glycosides. Finally, we report the application of this method in the synthesis of established C-glycosides, such as C-glycosyl amino acids, as well as a strategy to make all possible diastereomers at C1 and C2.

Catalytic glycosylation for minimally protected donors and acceptors.

Oligosaccharides have myriad functions throughout biological processes1,2. Chemical synthesis of these structurally complex molecules facilitates investigation of their functions. With a dense concentration of stereocentres and hydroxyl groups, oligosaccharide assembly through O-glycosylation requires simultaneous control of site, stereo- and chemoselectivities3,4. Chemists have traditionally relied on protecting group manipulations for this purpose5-8, adding considerable synthetic work. Here we report a glycosylation platform that enables selective coupling between unprotected or minimally protected donor and acceptor sugars, producing 1,2-cis-O-glycosides in a catalyst-controlled, site-selective manner. Radical-based activation9 of allyl glycosyl sulfones forms glycosyl bromides. A designed aminoboronic acid catalyst brings this reactive intermediate close to an acceptor through a network of non-covalent hydrogen bonding and reversible covalent B-O bonding interactions, allowing precise glycosyl transfer. The site of glycosylation can be switched with different aminoboronic acid catalysts by affecting their interaction modes with substrates. The method accommodates a wide range of sugar types, amenable to the preparation of naturally occurring sugar chains and pentasaccharides containing 11 free hydroxyls. Experimental and computational studies provide insights into the origin of selectivity outcomes.

sp2-Iminosugar azobenzene O-glycosides: Light-sensitive glycosidase inhibitors with unprecedented tunability and switching factors.

The conventional approach to developing light-sensitive glycosidase activity regulators, involving the combination of a glycomimetic moiety and a photoactive azobenzene module, results in conjugates with differences in glycosidase inhibitory activity between the interchangeable E and Z-isomers at the azo group that are generally below one-order of magnitude. In this study, we have exploited the chemical mimic character of sp2-iminosugars to access photoswitchable p- and o-azobenzene α-O-glycosides based on the gluco-configured representative ONJ. Notably, we achieved remarkably high switching factors for glycosidase inhibition, favoring either the E- or Z-isomer depending on the aglycone structure. Our data also indicate a correlation between the isomeric state of the azobenzene module and the selectivity towards α- and ß-glucosidase isoenzymes. The most effective derivative reached over a 103-fold higher inhibitory potency towards human ß-glucocerebrosidase in the Z as compared with the E isomeric form. This sharp contrast is compatible with ex-vivo activation and programmed self-deactivation at physiological temperatures, positioning it as a prime candidate for pharmacological chaperone therapy in Gaucher disease. Additionally, our results illustrate that chemical tailoring enables the engineering of photocommutators with the ability to toggle inhibition between α- and ß-glucosidase enzymes in a reversible manner, thus expanding the versatility and potential therapeutic applications of this approach.

Stereoselective Synthesis of ß-S-Glycosides via Palladium Catalysis.

S-Glycosides are more resistant to enzymatic and chemical hydrolysis and exhibit higher metabolic stability than common O-glycosides, demonstrating their widespread application in biological research and drug development. In particular, ß-S-glycosides are used as antirheumatic, anticancer, and antidiabetic drugs in clinical practice. However, the stereoselective synthesis of ß-S-glycosides is still highly challenging. Herein, we report an effective ß-S-glycosylation using 3-O-trichloroacetimidoyl glycal and thiols under mild conditions. The C3-imidate is designed to guide Pd to form a complex with glucal from the upper face, followed by Pd-S (thiols) coordination to realize ß-stereoselectivity. This method demonstrates excellent compatibility with a broad scope of various thiol acceptors and glycal donors with yields up to 87% and a ß/α ratio of up to 20:1. The present ß-S-glycosylation strategy is used for late-stage functionalization of drugs/natural products such as estrone, zingerone, and thymol. Overall, this novel and simple operation approach provides a general and practical strategy for the construction of ß-thioglycosides, which holds high potential in drug discovery and development.

A mild deprotection of isopropylidene ketals from 2-deoxyglycosides using AcOH/H2O/DME: An efficient regioselective deprotection of terminal isopropylidene ketals.

This paper describes a mild and efficient catalytic deprotection method for isopropylidene ketals and benzylidene acetals using AcOH/H2O/DME(1,2-Dimethoxyethane). The method effectively removes ketal and acetal protecting groups from 2-deoxyglycosides which are prone to hydrolysis under acidic conditions. Moreover, it enables the selective removal of the terminal ketal over an internal one.

Efficient synthesis of indole-chalcones based glycohybrids and their anticancer activity.

Indole based glycosides belong to the class of pharmacologically active molecules and found in diverse natural compounds. Herein, we report the synthesis of 1,2,3-triazole bridged chirally enriched diverse indole-chalcones based glycohybrids. Three series of glycohybrids were designed and efficiently synthesized using d-glucose, d-galactose and d-mannose derived 1-azido glycosides. The reactions sequence involved were, the synthesis of indole derived chalcones which were formed via Claisen-Schmidt condensation reaction and subsequently N-propargylation which leads to the production of N-propargylated indole-chalcones. The N-propargylated indole-chalcones get transformed into 1,2,3-triazole bridged indole-chalcone based glycohybrids by reacting with 1-azido sugar glycosides under click-chemistry reaction conditions. Further, the biological activity of synthesized glycohybrids (n = 27) was assessed in-vitro against MDA-MB231, MCF-7, MDA-MB453 cancer, and MCF-10A normal cell lines. The selected compounds showed potent anti-oncogenic properties against MCF-7 and MDA-MB231 breast cancer cell line with IC50 values of 1.05 µM and 11.40 µM respectively, with very good selectivity index (SI > 161). The active compounds show better binding affinity as compared to co-crystallized inhibitor 1-(tert-butyl)-3-(p-tolyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (PP1) with HCK (PTKs) proteins in molecular docking studies.

Synthesis and Biological Activities of Scleropentaside D.

We report the first total synthesis of scleropentaside D, a unique C-glycosidic ellagitannin, from the ketal derivative of scleropentaside A employing site-selective O4-protection of C-acyl glycoside and copper-catalyzed oxidative coupling reaction of galloyl groups as the key steps. Our study confirms the proposed structure of this natural product, scleropentaside D, and demonstrates its effectiveness as an inhibitor of α-glycosidase.

Palladium-catalyzed Suzuki-Miyaura cross-couplings of stable glycal boronates for robust synthesis of C-1 glycals.

C-1 Glycals serve as pivotal intermediates in synthesizing diverse C-glycosyl compounds and natural products, necessitating the development of concise, efficient and user-friendly methods to obtain C-1 glycosides is essential. The Suzuki-Miyaura cross-coupling of glycal boronates is notable for its reliability and non-toxic nature, but glycal donor stability remains a challenge. Herein, we achieve a significant breakthrough by developing stable glycal boronates, effectively overcoming the stability issue in glycal-based Suzuki-Miyaura coupling. Leveraging the balanced reactivity and stability of our glycal boronates, we establish a robust palladium-catalyzed glycal-based Suzuki-Miyaura reaction, facilitating the formation of various C(sp2)-C(sp), C(sp2)-C(sp2), and C(sp2)-C(sp3) bonds under mild conditions. Notably, we expand upon this achievement by developing the DNA-compatible glycal-based cross-coupling reaction to synthesize various glycal-DNA conjugates. With its excellent reaction reactivity, stability, generality, and ease of handling, the method holds promise for widespread appication in the preparation of C-glycosyl compounds and natural products.

Developments in the stereoselective synthesis of benzopyran, benzopyrone and flavonoid based natural product analogues using C-glycosides as an intrinsic chiral synthon.

Stereoselective synthesis is essential for propelling mainstream academia toward a relentless pursuit of novel and cutting-edge strategies for constructing molecules with unparalleled precision. Naturally derived benzopyrans, benzopyrones, and flavonoids are an essentially prominent group of oxa-heterocycles, highly significant targets in medicinal chemistry owing to their extensive abundance in biologically active natural products and pharmaceuticals. The molecular complexity and stereoselectivity induced by heterocycles embedded with C-glycosides have attracted considerable interest and emerged as a fascinating area of research for synthetic organic chemists. This present article emphasizes the existing growths in the strategies involving the diastereoselective synthesis of C-glycosylated benzopyrans, benzopyrones, and flavonoids using naturally acquired glycones as chiral synthons.

HPLC-Based Automated Synthesis and Purification of Carbohydrates.

Reported herein is a new HPLC-based automated synthesizer (HPLC-A) capable of a temperature-controlled synthesis and purification of carbohydrates. The developed platform allows to perform various protecting group manipulations as well as the synthesis of O- and N-glycosides. A fully automated synthesis and purification was showcased in application to different carbohydrate derivatives including glycosides, oligosaccharides, glycopeptides, glycolipids, and nucleosides.

Biosynthesis and Anticancer Activity of Genistein Glycoside Derivatives.

As a beneficial natural flavonoid, genistein has demonstrated a wide range of biological functions via regulating a number of targets and signaling pathways, such as anti-cancer, antioxidant, antibacterial, antiinflammatory, antifungal, antiviral, iron chelation, anti-obesity, anti-diabetes, and anti-hypertension. Pub- Med/Medline and Web of Science were searched using appropriate keywords until the end of December 2023. Despite its many potential benefits, genistein's clinical application is limited by low hydrophilicity, poor solubility, and suboptimal bioavailability due to its structure. These challenges can be addressed through the conversion of genistein into glycosides. Glycosylation of active small molecules may enhance their solubility, stability, and biological activity. In recent years, extensive research has been conducted on the synthesis, properties, and anticancer activity of glycoconjugates. Previous reviews were devoted to discussing the biological activities of genistin, with a little summary of the biosynthesis and the structure-activity relationship for their anticancer activity of genistein glycoside derivatives. Therefore, we summarized recent advances in the biosynthesis of genistein glycosylation and discussed the antitumor activities of genistein glycoside derivatives in a structure-activity relationship, which may provide important information for further development of genistein derivatives.

Pd-catalyzed stereoselective synthesis of chromone C-glycosides.

Herein, we present an efficient Pd-catalysed method for stereoselective synthesis of chromone C-glycosides from various glycals. We successfully applied this method to various glycals with different protecting groups, yielding the corresponding glycosides in 41-78% yields. Additionally, we investigated the potential of this approach for the late-stage modification of natural products and pharmaceutical compounds linked to glycals, leading to the synthesis of their respective glycosides. Furthermore, we extended our research to gram-scale synthesis and demonstrated its applicability in producing various valuable products, including 2-deoxy-chromone C-glycosides. In summary, our work introduces a novel library of chromone glycosides, which holds promise for advancing drug discovery efforts.

A Strain-Promoted Divergent Chemical Steroidation Unveils Potent Anti-Inflammatory Pseudo-Steroidal Glycosides.

The development of novel agents with immunoregulatory effects is a keen way to combat the growing threat of inflammatory storms to global health. To synthesize pseudo-steroidal glycosides tethered by ether bonds with promising immunomodulatory potential, we develop herein a highly effective deoxygenative functionalization of a novel steroidal donor (steroidation) facilitated by strain-release, leveraging cost-effective and readily available Sc(OTf)3 catalysis. This transformation produces a transient steroid-3-yl carbocation which readily reacts with O-, C-, N-, S-, and P-nucleophiles to generate structurally diverse steroid derivatives. DFT calculations were performed to shed light on the mechanistic details of the regioselectivity, underlying an acceptor-dependent steroidation mode. This approach can be readily extended to the etherification of sugar alcohols to enable the achievement of a diversity-oriented, pipeline-like synthesis of pseudo-steroidal glycosides in good to excellent yields with complete stereo- and regiospecific control for anti-inflammatory agent discovery. Immunological studies have demonstrated that a meticulously designed cholesteryl disaccharide can significantly suppress interleukin-6 secretion in macrophages, exhibiting up to 99% inhibition rates compared to the negative control. These findings affirm the potential of pseudo-steroidal glycosides as a prospective category of lead agents for the development of novel anti-inflammatory drugs.

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.

Direct Synthesis of Glycosyl Chlorides from Thioglycosides.

Reported herein is a new method for the direct synthesis of glycosyl chlorides from thioglycosides using sulfuryl chloride at rt. A variety of thioglycosides and thioimidates could be used as substrates. Both acid- and base-sensitive protecting groups were found compatible with these reaction conditions. Preliminary investigation of the reaction mechanism indicates chlorination of the leaving group at the anomeric sulfur as the key step of the reaction.

Syntheses of α(2,8) Sialosides Containing NeuAc and NeuGc by Using Double Carbonyl-Protected N-Acyl Sialyl Donors.

We report on the syntheses of NeuAc and NeuGc-containing glycosides via the use of double carbonyl-protected N-acetyl sialyl donors. The 7-O,9-O-carbonyl protection of an N-acyl-5-N,4-O-carbonyl-protected sialyl donor markedly increased the α-selectivity during glycosylation, particularly when glycosylating the C-8 hydroxyl group of sialic acids. The N-acyl carbamates were selectively opened with ethanethiol under basic conditions to provide N-acyl amines. It is noteworthy that N-glycolyl carbamate was more reactive to nucleophiles by comparison with the N-acetyl carbamate due to the electron-withdrawing oxygen in the N-acyl group and however, allowed selective opening of the carbamates without the loss of N-glycolyl groups. To demonstrate the utility of the approach, we began by synthesizing α(2,3) and α(2,6) sialyl galactosides. Glycosylation of the hydroxy groups of galactosides at the C-6 position with the NeuAc and NeuGc donors provided the corresponding sialyl galactoses in good yields with excellent α-selectivity. However, glycosylation of the 2,3-diol galactosyl acceptor selectively provided Siaα(2,2)Gal. Next, we prepared a series of α(2,8) disialosides composed of NeuAc and NeuGc. Glycosylation of NeuGc and NeuAc acceptors at the C-8 hydroxyl group with NeuGc and NeuAc sialyl donors provided the corresponding α(2,8) disialosides, and no significant differences were detected in the reactivities of these acceptors.

A "biphasic glycosyltransferase high-throughput screen" identifies novel anthraquinone glycosides in the diversification of phenolic natural products.

The sugar moieties of many glycosylated small molecule natural products are essential for their biological activity. Glycosyltransferases (GTs) are enzymes responsible for installing these sugar moieties on a variety of biomolecules. Many GTs active on natural products are inherently substrate promiscuous and thus serve as useful tools in manipulating natural product glycosylation to generate new combinations of sugar units (glycones) and scaffold molecules (aglycones) in a process called glycodiversification. It is important to have an effective screening tool to detect the activity of promiscuous enzymes and their resulting glycoside products. Toward this aim, we developed a strategy for screening natural product GTs in a high-throughput fashion enabled by rapid isolation and detection of chromophoric or fluorescent glycosylated natural products. This involves a solvent extraction step to isolate the resulting polar glycoside product from the unreacted aglycone acceptor substrate and the detection of the formed glycoside by the innate absorbance or fluorescence of the aglycone moiety. Using our approach, we screened a collection of natural product GTs against a panel of precursors to therapeutically important molecules. Three GTs showed previously unreported promiscuity toward anthraquinones resulting in novel ε-rhodomycinone glycosides. Considering the pharmaceutical value of clinically used anthraquinone glycosides that are biosynthesized from an ε-rhodomycinone precursor, and the significance that the sugar moiety has on the biological activity of these drugs, our results are of particular importance toward the glycodiversification of therapeutics in this class. The GTs identified and the novel compounds they produce show promise toward new biocatalytic tools and therapeutics.

Deoxy sugars. General methods for carbohydrate deoxygenation and glycosidation.

Deoxy sugars represent an important class of carbohydrates, present in a large number of biomolecules involved in multiple biological processes. In various antibiotics, antimicrobials, and therapeutic agents the presence of deoxygenated units has been recognized as responsible for biological roles, such as adhesion or great affinity to receptors, or improved efficacy. The characterization of glycosidases and glycosyltranferases requires substrates, inhibitors and analogous compounds. Deoxygenated sugars are useful for carrying out specific studies for these enzymes. Deoxy sugars, analogs of natural substrates, may behave as substrates or inhibitors, or may not interact with the enzyme. They are also important for glycodiversification studies of bioactive natural products and glycobiological processes, which could contribute to discovering new therapeutic agents with greater efficacy by modification or replacement of sugar units. Deoxygenation of carbohydrates is, thus, of great interest and numerous efforts have been dedicated to the development of methods for the reduction of sugar hydroxyl groups. Given that carbohydrates are the most important renewable chemicals and are more oxidized than fossil raw materials, it is also important to have methods to selectively remove oxygen from certain atoms of these renewable raw materials. The different methods for removal of OH groups of carbohydrates and representative or recent applications of them are presented in this chapter. Glycosidic bonds in general, and 2-deoxy glycosidic linkages, are included. It is not the scope of this survey to cover all reports for each specific technique.

Synthesis and Preliminary Anticancer Activity Assessment of N-Glycosides of 2-Amino-1,3,4-thiadiazoles.

The addition of 2-amino-1,3,4-thiadiazole derivatives with parallel iodination of differently protected glycals has been achieved using a double molar excess of molecular iodine under mild conditions. The corresponding thiadiazole derivatives of N-glycosides were obtained in good yields and anomeric selectivity. The usage of iodine as a catalyst makes this method easy, inexpensive, and successfully useable in reactions with sugars. Thiadiazole derivatives were tested in a panel of three tumor cell lines, MCF-7, HCT116, and HeLa. These compounds initiated biological response in investigated tumor models in a different rate. The MCF-7 is resistant to the tested compounds, and the cytometry assay indicated low increase in cell numbers in the sub- G1 phase. The most sensitive are HCT-116 and HeLa cells. The thiadiazole derivatives have a pro-apoptotic effect on HCT-116 cells. In the case of the HeLa cells, an increase in the number of cells in the sub-G1- phase and the induction of apoptosis was observed.

Synthesis, biological evaluation, and molecular docking studies of deoxygenated C-glycosides as LpxC inhibitors.

The bacterial deacetylase LpxC is a promising target for the development of novel antibiotics being selectively active against Gram-negative bacteria. In chiral pool syntheses starting from d- and l-ribose, a series regio- and stereoisomeric monohydroxytetrahydrofuran derivatives was synthesized and tested for LpxC inhibitory and antibacterial activities. Molecular docking studies were performed to rationalize the obtained structure-activity relationships. The (2S,3R,5R)-configured 3-hydroxytetrahydrofuran derivative ent-8 ((2S,3R,5R)-N,3-Dihydroxy-5-(4-{[4-(morpholinomethyl)phenyl]ethynyl}phenyl)tetrahydrofuran-2-carboxamide) was found to be the most potent LpxC inhibitor (Ki = 3.5 µM) of the synthesized series of monohydroxytetrahydrofuran derivatives and to exhibit the highest antibacterial activity against E. coli BL21(DE3) and the D22 strain.