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Quantitative prediction of rate constants for aqueous racemization to avoid pointless stereoselective syntheses

Ballard, Andrew, Ahmad, Hiwa O., Narduolo, Stefania, Rosa, Lucy, Chand, Nikki, Cosgrove, David A., Varkonyi, Peter, Asaad, Nabil, Tomasi, Simone, Buurma, Niklaas J. and Leach, Andrew G. 2018. Quantitative prediction of rate constants for aqueous racemization to avoid pointless stereoselective syntheses. Angewandte Chemie International Edition 57 (4) , pp. 982-985. 10.1002/anie.201709163

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Abstract

Racemisation has a large impact upon the biological properties of molecules but the chemical scope of compounds with known rate constants for racemisation in aqueous conditions was hitherto limited. To address this remarkable blind spot, we have measured the kinetics for racemisation of 28 compounds using circular dichroism and 1H NMR spectroscopy. We show that rate constants for racemisation (measured by ourselves and others) correlate well with deprotonation energies from quantum mechanical (QM) and group contribution calculations. Such calculations thus provide predictions of the second-order rate constants for general-base-catalyzed racemisation that are usefully accurate. When applied to recent publications describing the stereoselective synthesis of compounds of purported biological value, the calculations reveal that racemisation would be sufficiently fast to render these expensive syntheses pointless

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Publisher: Wiley
ISSN: 1433-7851
Funders: Engineering and Physical Sciences Research Council
Date of First Compliant Deposit: 7 November 2017
Date of Acceptance: 25 October 2017
Last Modified: 09 Sep 2020 10:00
URI: http://orca.cf.ac.uk/id/eprint/106303

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