En Route to the Transformation of Glycoscience: A Chemist’s Perspective on Internal and External Crossroads in Glycochemistry

Journal of the American Chemical Society, Journal Year: 2020, Volume and Issue: 143(1), P. 17 - 34

Published: Dec. 22, 2020

Carbohydrate chemistry is an essential component of the glycosciences and fundamental to their progress. This Perspective takes position that carbohydrate chemistry, or glycochemistry, has reached three crossroads on path transformation glycosciences, illustrates them with examples from author's other laboratories. The first these potential inflexion points concerns mechanism glycosylation reaction role protecting groups. It argued experimental evidence supports bimolecular SN2-like mechanisms for typical reactions over unimolecular ones involving stereoselective attack naked glycosyl oxocarbenium ions. Similarly, it does not support long-range stereodirecting participation remote esters through bridged bicyclic dioxacarbenium ions in organic solution presence counterions. Rational design improvement must take into account roles counterion concentration. A second between mainstream glycan synthesis. case made only real difference synthesis formation C–O rather than C–C bonds, diastereocontrol, strategy, tactics, elegance being critical importance both areas: chemists should feel comfortable taking this fork road, just as traveling opposite direction. third medicinal where there are equally many opportunities traffic either have advanced enormously past decade so, but creativity, input, ingenuity scientists all fields needed address sophisticated challenges remain, least which development a broader more general array stereospecific reactions.

Language: Английский

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Glycosyl Oxocarbenium Ions: Structure, Conformation, Reactivity, and Interactions

Accounts of Chemical Research, Journal Year: 2021, Volume and Issue: 54(11), P. 2552 - 2564

Published: April 30, 2021

ConspectusCarbohydrates (glycans, saccharides, and sugars) are essential molecules in all domains of life. Research on glycoscience spans from chemistry to biomedicine, including material science biotechnology. Access pure well-defined complex glycans using synthetic methods depends the success employed glycosylation reaction. In most cases, mechanism reaction is believed involve oxocarbenium ion. Understanding structure, conformation, reactivity, interactions this glycosyl cation predict outcome Account, building our contributions topic, we discuss theoretical experimental approaches that have been decipher key features cations, their structures reactivity.We also highlight that, a chemical perspective, can be described as continuum, unimolecular SN1 with naked cations intermediates bimolecular SN2-type mechanisms, which role counterions donors. All these factors should considered discussed herein. The importance dissociative mechanisms (involving contact ion pairs, solvent-separated solvent-equilibrated pairs) reactions highlighted.The calculations dynamics, reactivity discussed, highlighting advances field now allow access conformational preferences variety ions reactivities under SN1-like conditions.Specifically, ground-breaking use superacids generate emphasized, since it has permitted characterization structure conformation superacid solution by NMR spectroscopy.We pay special attention ions, conditions, counterions, possible intra- or intermolecular participation functional groups may stabilize nature acceptor, either weak strong nucleophile. We recent investigations different perspectives, identified involved ionic intermediates, estimating lifetimes studying other molecules. context, emphasize relationship between modulate sensitivity way modifying enzymes (glycosyl hydrolases transferases) build cleave glycosidic linkages nature. This comparison provides inspiration regulate stability cations.

Language: Английский

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Guidelines for O-Glycoside Formation from First Principles

ACS Central Science, Journal Year: 2021, Volume and Issue: 7(9), P. 1454 - 1462

Published: Aug. 13, 2021

With a view to reducing the notorious complexity and irreproducibility of glycosylation reactions, 12 guidelines for choice concentration, temperature, counterions are adumbrated.

Language: Английский

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Automated Quantification of Hydroxyl Reactivities: Prediction of Glycosylation Reactions

Angewandte Chemie International Edition, Journal Year: 2021, Volume and Issue: 60(22), P. 12413 - 12423

Published: Feb. 26, 2021

Abstract The stereoselectivity and yield in glycosylation reactions are paramount but unpredictable. We have developed a database of acceptor nucleophilic constants (Aka) to quantify the nucleophilicity hydroxyl groups influenced by steric, electronic structural effects, providing connection between experiments computer algorithms. subtle reactivity differences among on various carbohydrate molecules can be defined Aka, which is easily accessible simple convenient automation system assure high reproducibility accuracy. A diverse range donors acceptors with well‐defined promoters were organized processed designed software program “GlycoComputer” for prediction without involving sophisticated computational processing. importance Aka was further verified random forest algorithm, applicability tested synthesis Lewis skeleton show that accurately estimated.

Language: Английский

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Ab Initio Molecular Dynamics Simulations of the S_N1/S_N2 Mechanistic Continuum in Glycosylation Reactions

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(3), P. 1577 - 1589

Published: Jan. 13, 2021

We report a computational approach to evaluate the reaction mechanisms of glycosylation using

Language: Английский

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Anomeric Triflates versus Dioxanium Ions: Different Product-Forming Intermediates from 3-Acyl Benzylidene Mannosyl and Glucosyl Donors

The Journal of Organic Chemistry, Journal Year: 2024, Volume and Issue: 89(3), P. 1618 - 1625

Published: Jan. 18, 2024

Minimal structural differences in the structure of glycosyl donors can have a tremendous impact on their reactivity and stereochemical outcome glycosylation reactions. Here, we used combination systematic reactions, characterization potential reactive intermediates, in-depth computational studies to study disparate behavior systems involving benzylidene glucosyl mannosyl donors. While these been studied extensively, no satisfactory explanations are available for observed between 3-

Language: Английский

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The Stereoselectivity of Neighboring Group-Directed Glycosylation Is Concentration-Dependent

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 5, 2025

The formation of 1,2-trans-glycosides taking advantage neighboring group participation by stereodirecting esters at the 2-position glycosyl donors is widely held to be a robust and reliable protocol. Examples abound, however, cases in which less-than-perfect selectivity obtained, causing practitioners survey different or resort alternative strategies quest for optimal selectivities yields. Consideration mechanism particular competing process SN2-like glycosylation with activated covalent leads hypothesis that imperfect selectivity, more careful attention reaction concentration stoichiometry may beneficial. Three case studies are presented demonstrate dependence group-directed reactions targeting both 1,2-trans-equatorial 1,2-trans-axial glycosides. Higher concentrations, whether achieved through increased acceptor:donor fixed stoichiometry, mostly lead erosion 1,2-trans-selectivity as becomes increasingly important. These observations underline importance rational, mechanism-based approach general importantly suggest simple enhancing displaying 1,2-trans-selectivity, namely, moving regime.

Language: Английский

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Recent Advances in Stereoselective Chemical O-Glycosylation Reactions

Frontiers in Molecular Biosciences, Journal Year: 2022, Volume and Issue: 9

Published: June 14, 2022

Carbohydrates involving glycoconjugates play a pivotal role in many life processes. Better understanding toward glycobiological events including the structure–function relationship of these biomolecules and for diagnostic therapeutic purposes tailor-made vaccine development synthesis structurally well-defined oligosaccharides (OS) become important. Efficient chemical glycosylation high yield stereoselectivity is however challenging depends on fine tuning protection profile to get matching glycosyl donor–acceptor reactivity along with proper use other important external factors like catalyst, solvent, temperature, activator, additive. So far, methods have been reported several reviews also. In present review, we will concentrate our discussion recent trend α- β-selective reactions during past decade.

Language: Английский

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Stereoselective Synthesis of 2-Deoxy Glycosides via Iron Catalysis

Organic Letters, Journal Year: 2023, Volume and Issue: 25(5), P. 832 - 837

Published: Jan. 26, 2023

An Fe-catalyzed 2-deoxy glycosylation method was developed from 3,4-O-carbonate glycals directly at room temperature. This novel approach enabled facile access to alkyl and aryl glycosides in high yields with exclusive α-stereoselectivity, tolerating various alcohols, phenols, glycals. The synthetic utility advantage of this strategy have been demonstrated by the modification six natural products construction a tetrasaccharide.

Language: Английский

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Detection and Characterization of Rapidly Equilibrating Glycosylation Reaction Intermediates Using Exchange NMR

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(48), P. 26190 - 26201

Published: Nov. 27, 2023

The stereoselective introduction of glycosidic bonds (glycosylation) is one the main challenges in chemical synthesis carbohydrates. Glycosylation reaction mechanisms are difficult to control because, many cases, exact reactive species driving product formation cannot be detected and outcome explained by primary intermediate observed. In these reactions expected take place via other low-abundance intermediates that rapid equilibrium with a Curtin-Hammett scenario. Despite this principle being well-known organic synthesis, mechanistic studies investigating model glycosylation complicated challenge detecting extremely short-lived responsible for formation. Herein, we report utilization between stable, readily observed α-glycosyl triflate order infer structure former employing exchange NMR. Using technique, enabled detection such as β-glycosyl triflates glycosyl dioxanium ions. This demonstrates power NMR unravel aim build catalog kinetic parameters, allowing understanding eventual prediction reactions.

Language: Английский

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