Transition-State Structure for the Quintessential SN2 Reaction of a Carbohydrate: Reaction of α-Glucopyranosyl Fluoride with Azide Ion in Water

Chan, Jefferson; Sannikova, Natalia; Tang, Ariel; Bennet, Andrew J.

doi:10.1021/ja506092h

Cited by 41 publications

(43 citation statements)

References 42 publications

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“…This observation is analogous to those recorded in the Ca 2+ /NMe 3 -promoted sucrose glycosylation using α-D-fluoroglycosides under aqueous conditions; 56 so too, this observation recalls that of Jencks in the study of displacement of α-D-fluoroglucose by azide ion, later studied computationally. 55,57,58,59 The observed increase in conversion as a function of increased salt concentration is also consistent with the ionic-strength dependence of a generic S N 2 reaction mechanism, also observed by Jencks. 55 The stereochemical purity of the product is independent of reaction duration; under 1.0 M reaction conditions, only the β-anomer product was observed after 10 min and after 24 h reaction times.…”

Section: Resultssupporting

confidence: 88%

Rapid phenolic O-glycosylation of small molecules and complex unprotected peptides in aqueous solvent

et al. 2018

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Glycosylated natural products and synthetic glycopeptides represent a significant and growing source of biochemical probes and therapeutic agents. However, methods that enable the aqueous glycosylation of endogenous amino acid functionality in peptides without the use of protecting groups are scarce. Here, we report a transformation that facilitates the efficient aqueous O-glycosylation of phenolic functionality in a wide range of small molecules, unprotected tyrosine, and tyrosine residues embedded within a range of complex, fully unprotected peptides. The transformation, which uses glycosyl fluoride donors and is promoted by Ca(OH), proceeds rapidly at room temperature in water, with good yields and selective formation of unique anomeric products depending on the stereochemistry of the glycosyl donor. High functional group tolerance is observed, and the phenol glycosylation occurs selectively in the presence of virtually all side chains of the proteinogenic amino acids with the singular exception of Cys. This method offers a highly selective, efficient, and operationally simple approach for the protecting-group-free synthesis of O-aryl glycosides and Tyr-O-glycosylated peptides in water.

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Section: Resultssupporting

confidence: 88%

Rapid phenolic O-glycosylation of small molecules and complex unprotected peptides in aqueous solvent

et al. 2018

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“…The full suite of experimental KIEs were used to inform a computed transition state for the displacement, which is best considered as an exploded associative transition one (Table 15). 328 Knowledge of this mechanism enabled Miller, Schepartz, and their coworkers to develop a method for the O -glycosylation of simple alcohols from unprotected glycosyl fluorides using calcium salts as promotors. 329…”

Section: Kinetic Isotope Effect Measurementsmentioning

confidence: 99%

The Experimental Evidence in Support of Glycosylation Mechanisms at the S_N1–S_N2 Interface

et al. 2018

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A critical review of the state-of-the-art evidence in support of the mechanisms of glycosylation reactions is provided. Factors affecting the stability of putative oxocarbenium ions as intermediates at the S1 end of the mechanistic continuum are first surveyed before the evidence, spectroscopic and indirect, for the existence of such species on the time scale of glycosylation reactions is presented. Current models for diastereoselectivity in nucleophilic attack on oxocarbenium ions are then described. Evidence in support of the intermediacy of activated covalent glycosyl donors is reviewed, before the influences of the structure of the nucleophile, of the solvent, of temperature, and of donor-acceptor hydrogen bonding on the mechanism of glycosylation reactions are surveyed. Studies on the kinetics of glycosylation reactions and the use of kinetic isotope effects for the determination of transition-state structure are presented, before computational models are finally surveyed. The review concludes with a critical appraisal of the state of the art.

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“…17,19 This includes substitution with retention of anomeric configuration when using methoxide, 20 and the rate retardation induced by blocking the C2 oxygen with a methyl group. 21,22 For the related reaction of 4-nitrophenyl -D-mannopyranoside (which shares a 1,2-trans relationship), 22 the carbon-13 kinetic isotope effect (KIE) for C1 is (1.026 ± 0.006), 23 which is in agreement with SN2 reactions on glycosides, 24 and the ratio of kL/kH >1 indicates a concerted rather than dissociative mechanism. The oxygen-18 KIE for the C2-oxygen is greater than unity (1.044 ± 0.0060), implicating its direct involvement in the reaction.…”

Section: Introductionmentioning

confidence: 61%

pH Dependent Mechanisms of Hydrolysis of 4-Nitrophenyl β-D-Glucoside

Alhifthi¹,

Williams

2021

Preprint

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1,2-trans-Glycosides hydrolyze through different mechanisms at different pH values, but systematic studies are lacking. Here we report the pH-rate constant profile for the hydrolysis of 4-nitrophenyl β-D-glucoside. An inverse kinetic isotope effect (k(H3O+)/k(D3O+) = 0.63) in the acidic region indicates that the mechanism requires the formation of the conjugate acid of the substrate for the reaction to proceed, with heterolytic cleavage of the glycosidic C-O bond. Reactions in the pH-independent region exhibit general catalysis with a single proton in flight, a normal solvent isotope effect of kH/kD = 1.5, and when extrapolated to zero buffer concentration show a small solvent isotope effect k(H2O)/k(D2O) = 1.1, consistent with water attack through a dissociative mechanism. In the basic region, solvolysis in 18O-labelled water and H2O/MeOH mixtures allowed detection of bimolecular hydrolysis and neighboring group participation, with a minor contribution of nucleophilic aromatic substitution. Under mildly basic conditions, a bimolecular concerted mechanism is implicated through an inverse solvent isotope effect of k(HO–)/k(DO–) = 0.5 and a strongly negative entropy of activation (DS‡ = –13.6 cal mol–1 K–1). Finally, at high pH, an inverse solvent isotope effect of k(HO–)/k(DO–) = 0.6 indicates that the formation of 1,2-anhydrosugar is the rate determining step.

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Transition-State Structure for the Quintessential S_N2 Reaction of a Carbohydrate: Reaction of α-Glucopyranosyl Fluoride with Azide Ion in Water

Cited by 41 publications

References 42 publications

Rapid phenolic O-glycosylation of small molecules and complex unprotected peptides in aqueous solvent

Rapid phenolic O-glycosylation of small molecules and complex unprotected peptides in aqueous solvent

The Experimental Evidence in Support of Glycosylation Mechanisms at the S_N1–S_N2 Interface

pH Dependent Mechanisms of Hydrolysis of 4-Nitrophenyl β-D-Glucoside

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Transition-State Structure for the Quintessential SN2 Reaction of a Carbohydrate: Reaction of α-Glucopyranosyl Fluoride with Azide Ion in Water

Cited by 41 publications

References 42 publications

Rapid phenolic O-glycosylation of small molecules and complex unprotected peptides in aqueous solvent

Rapid phenolic O-glycosylation of small molecules and complex unprotected peptides in aqueous solvent

The Experimental Evidence in Support of Glycosylation Mechanisms at the SN1–SN2 Interface

pH Dependent Mechanisms of Hydrolysis of 4-Nitrophenyl β-D-Glucoside

Contact Info

Product

Resources

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Transition-State Structure for the Quintessential S_N2 Reaction of a Carbohydrate: Reaction of α-Glucopyranosyl Fluoride with Azide Ion in Water

The Experimental Evidence in Support of Glycosylation Mechanisms at the S_N1–S_N2 Interface