Anomeric Selectivity Research Articles

Efficient convergent synthesis of 1,3-diazepinone nucleosides by ring-closing metathesis and direct glycosylation.

A new and highly efficient ring-closing metathesis-based strategy was developed for the synthesis of the cyclic urea 1,3-diazepinone, presenting significant improvement upon previous methods. Using a direct glycosylation approach, analogues of the potent cytidine deaminase (CDA) inhibitor diazepinone riboside were then synthesized including 2'-deoxyribo-, 2'-deoxy-2'-fluoroarabino-, and 2'-deoxy-2',2'-difluoro-diazepinone nucleosides, all with moderate to good yield and excellent anomeric selectivity. Crucially, in contrast to the previous multistep linear synthesis of 2'-deoxyribo- and 2'-deoxy-2'-fluoroarabino-diazepinone nucleosides, this is the first report of direct glycosylation to access these nucleosides. Overall, we report efficient convergent routes to multiple 2'-modified-diazepinone nucleosides for further evaluation as CDA and potential APOBEC3 inhibitors.

Origins of Temperature-Dependent Anomeric Selectivity in Glycosylations with an L-Idose Thioglycoside.

L-Idose thioglycosides are useful glycosyl donors for the construction of glycosaminoglycan oligosaccharides. When activated with NIS and catalytic TMSOTf in the presence of methanol, the stereoselectivity of O-glycosylation displays an intriguing dependence on the reaction temperature, with an increased preference for formation of the α-glycoside at higher temperatures. Using a combination of vt-NMR spectroscopy and DFT calculations, we show how a simple mechanistic model, based on competing reactions of the iodinated thioglycoside, can explain the main features of the temperature dependence. In this model, the increased selectivity at high temperature is attributed to differences among the entropy and energy terms of the competing reaction pathways. Neighbouring-group participation (giving an intermediate acyloxonium ion) plays an increasingly dominant role as temperature is raised. The general features of this kinetic regime may also apply more broadly to other glycosylations that likewise favour α-glycoside formation at high temperature.

Reaction Rate and Stereoselectivity Enhancement in Glycosidations with O-Glycosyl Trihaloacetimidate Donors due to Catalysis by a Lewis Acid-Nitrile Cooperative Effect.

Activation of O-glycosyl trihaloacetimidate glycosyl donors with AuCl3 as a catalyst and pivalonitrile (tBuCN) as a ligand led to excellent glycosidation results in terms of yield and anomeric selectivity. In this way, various β-d-gluco- and β-d-galactopyranosides were obtained conveniently and efficiently. Experimental studies and density functional theory (DFT) calculations, in order to elucidate the reaction course, support formation of the tBuCN-AuCl2-OR(H)+ AuCl4- complex as a decisive intermediate in the glycosidation event. Proton transfer from this acceptor complex to the imidate nitrogen leads to donor activation. In this way, guided by the C-2 configuration of the glycosyl donor, the alignment of the acceptor complex enforces the stereoselective β-glycoside formation in an intramolecular fashion, thus promoting also a fast reaction course. The high stereocontrol of this novel 'Lewis acid-nitrile cooperative effect' is independent of the glycosyl donor anomeric configuration and without the support of neighboring group or remote group participation. The power of the methodology is shown by a successful glycoalkaloid solamargine synthesis.

On the influence of solvent on the stereoselectivity of glycosylation reactions

Methodology development in carbohydrate chemistry entails the stereoselective formation of C–O bonds as a key step in the synthesis of oligo- and polysaccharides. The anomeric selectivity of a glycosylation reaction is affected by a multitude of parameters, such as the nature of the donor and acceptor, activator/promotor system, temperature and solvent. The influence of different solvents on the stereoselective outcome of glycosylation reactions employing thioglucopyranosides as glycosyl donors with a non-participating protecting group at position 2 has been studied. A large change in selectivity as a function of solvent was observed and a correlation between selectivity and the Kamlet-Taft solvent parameter π* was found. Furthermore, molecular modeling using density functional theory methodology was conducted to decipher the role of the solvent and possible reaction pathways were investigated.

Reinvestigation of SnCl4 catalyzed efficient synthesis of 2,3-unsaturated glycopyranosides

The Ferrier rearrangement is a powerful tool to prepare 2,3-unsaturated glycopyranosides. We have reinvestigated SnCl4 catalyzed Ferrier rearrangements through direct allylic substitution of the hydroxyl group at the C-3 position of glycals, resulting in the formation of stereoselective 2,3-unsaturated glycosides at 0 °C. The catalytic amount of SnCl4 (0.1 equiv.) was successfully used to promote this transformation on 3,4,6-tri-O-acetyl-D-glucal, 3,4,6-tri-O-acetyl-D-galactal and 3,4-di-O-acetyl-D-arabinal using various nucleophiles viz alcohols, azide and thiols to form a variety of 2,3-unsaturated glycopyranosides (pseudoglycals). This straightforward process is notable for its strong anomeric selectivity, excellent yields and shorter reaction time.

Activation of Stable and Recyclable Phenylpropiolate Glycoside (PPG) Donors by Iron Catalysis

AbstractThe glycosylation reaction is one of the important aspects of carbohydrate chemistry, where two different units are frequently linked through C–O bonds. In the pursuit of advancing this field, the design and development of sustainable catalytic methods for O-glycosylation, which can provide an alternate and effective tool to traditional protocols involving stoichiometric promoters and classical donors, are considered as highly challenging, yet important facets of glycochemistry. Herein, we report a simple and efficient Fe(III)-catalyzed method for O-glycosylation through the activation of bifunctional phenylpropiolate glycoside (PPG) donors. This mild and effective method involves the use of the inexpensive and less toxic FeCl3 as catalyst and easily synthesizable, benchtop-stable glycosyl ester-based PPG donors, which react with various sugar as well as non-sugar-based acceptors to deliver the corresponding O-glycosides in good yields with moderate anomeric selectivity, along with regeneration of easily separable phenylpropiolic acid. Importantly, d-mannose and l-rhamnose-based PPG donors afforded the corresponding O-glycosides in high α-anomeric selectivity. The reaction conditions were further explored for the synthesis of trisaccharides.

Dynamic Kinetic Stereoselective Glycosylation via RhII and Chiral Phosphoric Acid‐Cocatalyzed Carbenoid Insertion to the Anomeric OH Bond for the Synthesis of Glycoconjugates

AbstractChemical synthesis of glycoconjugates is essential for studying the biological functions of carbohydrates. We herein report an efficient approach for the stereoselective synthesis of challenging α‐linked glycoconjugates via a RhII/chiral phosphoric acid (CPA)‐cocatalyzed dynamic kinetic anomeric O‐alkylation of sugar‐derived lactols via carbenoid insertion to the anomeric OH bond. Notably, we observed excellent anomeric selectivity, excellent diastereoselectivity, broad substrate scope, and high efficiency for this glycosylation reaction by exploring various parameters of the cocatalytic system. DFT calculations suggested that the anomeric selectivity was mainly determined by steric interactions between the C2‐carbon of the carbohydrate and the phenyl group of the metal carbenoid, while π/π interactions with the C2−OBn substituent on the carbohydrate substrate play a significant role for diastereoselectivity at the newly generated stereogenic center.

Dynamic Kinetic Stereoselective Glycosylation via RhII and Chiral Phosphoric Acid-Cocatalyzed Carbenoid Insertion to the Anomeric OH Bond for the Synthesis of Glycoconjugates.

Chemical synthesis of glycoconjugates is essential for studying the biological functions of carbohydrates. We herein report an efficient approach for the stereoselective synthesis of challenging α-linked glycoconjugates via a RhII /chiral phosphoric acid (CPA)-cocatalyzed dynamic kinetic anomeric O-alkylation of sugar-derived lactols via carbenoid insertion to the anomeric OH bond. Notably, we observed excellent anomeric selectivity, excellent diastereoselectivity, broad substrate scope, and high efficiency for this glycosylation reaction by exploring various parameters of the cocatalytic system. DFT calculations suggested that the anomeric selectivity was mainly determined by steric interactions between the C2-carbon of the carbohydrate and the phenyl group of the metal carbenoid, while π/π interactions with the C2-OBn substituent on the carbohydrate substrate play a significant role for diastereoselectivity at the newly generated stereogenic center.

Potassium carbonate-mediated β-selective anomeric O-alkylation with primary electrophiles: Application to the synthesis of glycosphingolipids

Stereoselective construction of a variety of β-glycosides can be achieved using abundant and inexpensive K2CO3-mediated stereoselective anomeric O-alkylation of sugar lactols with primary electrophiles. In addition, application of this methodology to the synthesis of various azido-modified glycosphingolipids has been accomplished in good yields and excellent anomeric selectivity using sphingosine-derived primary triflate.

Domino meta-C-H Ethyl Glycosylation by Ruthenium(II/III) Catalysis: Modular Assembly of meta-C-Alkyl Glycosides.

Glycosyl anomeric radical addition reactions have been well-explored and proved efficient for the C-alkyl glycosides synthesis, but multicomponent Domino transformations for the rapid and controllable construction of structurally diversified C-alkyl glycosides in a single step are still rare. In contrast, we, herein, report a ruthenium(II)-catalyzed Domino meta-C-H ethyl glycosylation, enabling the construction of challenging meta-C-alkyl glycosides. Our ruthenium(II) catalysis was reflected by the mild reaction condition, exclusive meta-site selectivity and high levels of anomeric selectivity. In addition, the ruthenium(II)-catalyzed Domino meta-C-H glycosylation allowed for the synthesis of versatile 1,2-trans-C-alkyl glycosides with commercially available vinyl arenes, acrylates and easily accessible glycosyl bromides.

Glycosylation of vicinal di- and trifluorinated glucose and galactose donors.

The acid-catalysed formation of glycosidic bonds is more difficult when glycosyl donors are fluorinated, especially at the 2-position. Here we report high-yielding glycosidation and glycosylation reactions of 2,3-difluorinated- and 2,3,4-trifluorinated gluco- and galactopyranoside donors with a variety of acceptors under conventional trichloroacetimidate/TMSOTf activation in moderate to high anomeric selectivities. This methodology allows access to highly fluorinated glycans, illustrated with the synthesis of a pentafluorinated disaccharide.

Metal-Free Synthesis of Acyl Glycosides and Application to Oligosaccharide Synthesis.

Oligosaccharides are involved in numerous biological processes. Achieving optimal anomeric selectivity and regioselectivity remains challenging. Herein, we present a method for the oxidative glycosylation of thioglycosides with hypervalent iodine reagents derived from carboxylic acid to form C-O bonds. The reaction of thioglycosides with various hypervalent iodine carboxylates afforded acyl O-glycosyl compounds. These acyl O-glycosyl compounds could react with thioglycoside acceptors to produce disaccharides; trisaccharides and tetrasaccharides could be synthesized by repeating this method.

α-Selective Glucosylation Can Be Achieved with 6-O-para-Nitrobenzoyl Protection.

A systematic study of the effect of various 6-O-acyl groups on anomeric selectivity in glucosylations with thioglycoside donors was conducted. All eight different esters were found to induce moderate-to-high α-selectivity in glucosylation with l-menthol with the best being 6-O-p-nitrobenzoyl. The effect appears to be general across various glucosyl acceptors, glucosyl donor types, and modes of activation. No evidence was found in favor of distal participation.

Remote C-H Glycosylation by Ruthenium(II) Catalysis: Modular Assembly of meta-C-Aryl Glycosides.

The prevalence of C-aryl glycosides in biologically active natural products and approved drugs has long motivated the development of efficient strategies for their selective synthesis. Cross-couplings have been frequently used, but largely relied on palladium catalyst with prefunctionalized substrates, while ruthenium-catalyzed C-aryl glycoside preparation has thus far proven elusive. Herein, we disclose a versatile ruthenium(II)-catalyzed meta-C-H glycosylation to access meta-C-aryl glycosides from readily available glycosyl halide donors. The robustness of the ruthenium catalysis was reflected by mild reaction conditions, outstanding levels of anomeric selectivity and exclusive meta-site-selectivity.

Stereoselective 1,2-cis Furanosylations Catalyzed by Phenanthroline.

Stereoselective formation of the 1,2-cis furanosidic linkage, a motif of many biologically relevant oligosaccharides and polysaccharides, remains an important synthetic challenge. We herein report a new stereoselective 1,2-cis furanosylation method promoted by phenanthroline catalysts under mild and operationally simple conditions. NMR experiments and density functional theory calculations support an associative mechanism in which the rate-determining step occurs from an inverted displacement of the faster-reacting phenanthrolinium ion intermediate with an alcohol nucleophile. The phenanthroline catalysis system is applicable to a number of furanosyl bromide donors to provide the challenging 1,2-cis substitution products in good yield with high anomeric selectivities. While arabinofuranosyl bromide provides β-1,2-cis products, xylo- and ribofuranosyl bromides favor α-1,2-cis products.

Anomeric Thioglycosides Give Different Anomeric Product Distributions under NIS/TfOH Activation.

The reaction of a series of anomeric thioglycosides with various glycosyl acceptors and N-iodosuccinimide/catalytic triflic acid was investigated with respect to reactivity and anomeric selectivity. In general, β-configured donors were found to give a more β-selective reaction outcome compared to their α-configured counterparts. The relative reactivity of various thioglycosides was measured through competition experiments, and the following order was established: phenyl, tolyl, methyl, ethyl, isopropyl, and 1-adamantyl.

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.

New insights into the reactivity of 2-halo-glycals: Synthesis of novel iodinated O- and S-glycosides

We present the selective synthesis of new 2-iodo-2,3-unsaturated O- and S-glycosides. This is the first report on the Ferrier rearrangement of 2-halo-glycals with S-nucleophiles. We obtained α-glycosides in good yields and with high anomeric selectivity. We also describe the particular behavior of heteroaromatic thio sugar derivatives, where the C3 addition was performed in an alternative mechanism. We present a complete structure and conformation analysis by NMR.

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.

Influence of Configuration at the 4- and 6-Positions on the Conformation and Anomeric Reactivity and Selectivity of 7-Deoxyheptopyranosyl Donors: Discovery of a Highly Equatorially Selective l-glycero-d-gluco-Heptopyranosyl Donor.

The preparation of four per-O-benzyl-d- or l-glycero-d-galacto and d- or l-glycero-d-gluco heptopyranosyl sulfoxides and the influence of their side-chain conformations on reactivity and stereoselectivity in glycosylation reactions are described. The side-chain conformation in these donors is determined by the relative configuration of its point of attachment to the pyranoside ring and the two flanking centers in agreement with a recent model. In the d- and l-glycero-d-galacto glycosyl donors, the d-glycero-d-galacto isomer with the more electron-withdrawing trans,gauche conformation of its side chain was the more equatorially selective isomer. In the d- and l-glycero-d-gluco glycosyl donors, the l-glycero-d-gluco isomer with the least disarming gauche,gauche side-chain conformation was the most equatorially selective donor. Variable temperature NMR studies, while supporting the formation of intermediate glycosyl triflates at -80 °C in all cases, were inconclusive owing to a change in the decomposition mechanism with the change in configuration. It is suggested that the equatorial selectivity of the l-glycero-d-gluco isomer arises from H-bonding between the glycosyl acceptor and O6 of the donor, which is poised to deliver the acceptor antiperiplanar to the glycosyl triflate, resulting in a high degree of SN2 character in the displacement reaction.