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Angew Chem Int Ed Engl. 2018 Jan 22;57(4):982-985. doi: 10.1002/anie.201709163. Epub 2017 Nov 15.

Quantitative Prediction of Rate Constants for Aqueous Racemization To Avoid Pointless Stereoselective Syntheses.

Author information

1
Physical Organic Chemistry Centre, School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, UK.
2
Pharmaceutical Chemistry Department, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region, Iraq.
3
AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, SK10 4TG, UK.
4
AstraZeneca R+D, Pepparedsleden 1, 43183, Mölndal, Sweden.
5
AstraZeneca, Charter Way, Silk Road Business Park, Macclesfield, SK10 2NA, UK.
6
School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, L3 3AF, UK.

Abstract

Racemization has a large impact upon the biological properties of molecules but the chemical scope of compounds with known rate constants for racemization in aqueous conditions was hitherto limited. To address this remarkable blind spot, we have measured the kinetics for racemization of 28 compounds using circular dichroism and 1 H NMR spectroscopy. We show that rate constants for racemization (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 racemization that are usefully accurate. When applied to recent publications describing the stereoselective synthesis of compounds of purported biological value, the calculations reveal that racemization would be sufficiently fast to render these expensive syntheses pointless.

KEYWORDS:

computational chemistry; drug design; kinetics; racemization; stereoselective synthesis

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