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Quantitative Prediction of Rate Constants for Aqueous Racemization To Avoid Pointless Stereoselective Syntheses |
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| Authors: | Dr Andrew Ballard Dr Hiwa O Ahmad Dr Stefania Narduolo Lucy Rosa Nikki Chand Dr David A Cosgrove Dr Peter Varkonyi Dr Nabil Asaad Dr Simone Tomasi Dr Niklaas J Buurma Dr Andrew G Leach |
| Affiliation: | 1. Physical Organic Chemistry Centre, School of Chemistry, Cardiff University, UK;2. Pharmaceutical Chemistry Department, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region, Iraq;3. AstraZeneca Pharmaceuticals, Mereside, Macclesfield, UK;4. AstraZeneca R+D, M?lndal, Sweden;5. AstraZeneca, Macclesfield, UK;6. School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, 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 1H 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 |
