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Installation of electron-donating protective groups, a strategy for glycosylating unreactive thioglycosyl acceptors using the preactivation-based glycosylation method.

ABSTRACT: Preactivation-based chemoselective glycosylation is a powerful strategy for oligosaccharide synthesis with its successful application in assemblies of many complex oligosaccharides. However, difficulties were encountered in reactions where glycosyl donors bearing multiple electron-withdrawing groups failed to glycosylate hindered unreactive acceptors. In order to overcome this problem, it was discovered that the introduction of electron-donating protective groups onto the glycosyl donors can considerably enhance their glycosylating power, leading to productive glycosylations even with unreactive acceptors. This observation is quite general and can be extended to a wide range of glycosylation reactions, including one-pot syntheses of chondroitin and heparin trisaccharides. The structures of the reactive intermediates formed upon preactivation were determined through low-temperature NMR studies. It was found that for a donor with multiple electron-withdrawing groups, the glycosyl triflate was formed following preactivation, while the dioxalenium ion was the major intermediate with a donor bearing electron-donating protective groups. As donors were all cleanly preactivated prior to the addition of the acceptors, the observed reactivity difference between these donors was not due to selective activation encountered in the traditional armed-disarmed strategy. Rather, it was rationalized by the inherent internal energy difference between the reactive intermediates and associated oxacarbenium ion like transition states during nucleophilic attack by the acceptor.

SUBMITTER: Zeng Y

PROVIDER: S-EPMC2661424 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Installation of electron-donating protective groups, a strategy for glycosylating unreactive thioglycosyl acceptors using the preactivation-based glycosylation method.

Zeng Youlin Y Wang Zhen Z Whitfield Dennis D Huang Xuefei X

The Journal of organic chemistry 20080923 20

Preactivation-based chemoselective glycosylation is a powerful strategy for oligosaccharide synthesis with its successful application in assemblies of many complex oligosaccharides. However, difficulties were encountered in reactions where glycosyl donors bearing multiple electron-withdrawing groups failed to glycosylate hindered unreactive acceptors. In order to overcome this problem, it was discovered that the introduction of electron-donating protective groups onto the glycosyl donors can con ...[more]

PMID: 18808187

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Project description:The central role of Coulombic interactions in enzyme catalysis has inspired multiple approaches to sculpting electrostatic potential fields (EPFs) for controlling chemical reactivity, including ion gradients in water microdroplets, the tips of STMs, and precisely engineered crystals. These are powerful tools because EPFs can affect all reactions, even those whose mechanisms do not involve formal charges. For some time now, supramolecular chemists have become increasingly proficient in using encapsulation to control stoichiometric and catalytic reactions. However, the field has not taken advantage of the broad range of nanocontainers available to systematically explore how EPFs can affect reactions within their inner-spaces. With that idea in mind, previously, we reported on how positively and negatively charged supramolecular capsules can modulate the acidity and reactivity of thiol guests bound within their inner, yoctoliter spaces (Cai, X.; Kataria, R.; Gibb, B. C. J. Am. Chem. Soc. 2020, 142, 8291-8298; Wang, K.; Cai, X.; Yao, W.; Tang, D.; Kataria, R.; Ashbaugh, H. S.; Byers, L. D.; Gibb, B. C. J. Am. Chem. Soc. 2019, 141, 6740-6747). Building on this, we report here on the cyclization of 14-bromotetradecan-1-amine inside these yoctoliter containers. We examine the rate and activation thermodynamics of cyclization (Eyring analysis), both in the absence and presence of exogenous salts whose complementary ion can bind to the outside of the capsule and hence attenuate its EPF. We find the cyclization rates and activation thermodynamics in the two capsules to be similar, but that for either capsule attenuation of the EPF slows the reaction down considerably. We conclude the capsules behave in a manner akin to covalently attached electron donating/withdrawing groups in a substrate, with each capsule enforcing their own deviations from the idealized SN2 mechanism by moving electron density and charge in the activated complex and TS, and that the idealized SN2 mechanism inside the theoretical neutral host is relatively difficult because of the lack of solvation of the TS.

Dataset Information

Installation of electron-donating protective groups, a strategy for glycosylating unreactive thioglycosyl acceptors using the preactivation-based glycosylation method.

Publications

Installation of electron-donating protective groups, a strategy for glycosylating unreactive thioglycosyl acceptors using the preactivation-based glycosylation method.

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