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

Angewandte Chemie
Andrew BallardAndrew G Leach

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.

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Citations

Nov 12, 2019·Chemistry : a European Journal·Andrew BallardAndrew G Leach
Mar 19, 2019·Expert Opinion on Drug Discovery·Andrew BallardNiklaas J Buurma
Aug 4, 2020·Chemistry : a European Journal·Holly E BonfieldMarc Reid
Nov 24, 2019·Bioorganic & Medicinal Chemistry Letters·Wayne ChildersMarlene A Jacobson

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Methods Mentioned

BETA
circular dichroism

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