Quantitative Prediction of Rate Constants for Aqueous Racemization To Avoid Pointless Stereoselective Syntheses. Issue 4 (15th November 2017)

• Record Type: Journal Article
• Authors: Ballard, Andrew; Ahmad, Hiwa O.; Narduolo, Stefania; Rosa, Lucy; Chand, Nikki; Cosgrove, David A.; Varkonyi, Peter; Asaad, Nabil; Tomasi, Simone; Buurma, Niklaas J.; Leach, Andrew G.
• Is Part Of: Angewandte Chemie international edition. Volume 57:Issue 4(2018)
• Page Start: 982
• Page End: 985
• Publication Date: 2017-11-15
• Subjects: computational chemistry -- drug design -- kinetics -- racemization -- stereoselective synthesis; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201709163
• Languages: English
• ISSNs: 1433-7851

Abstract

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. Abstract : The racemization potential of complex organic molecules has been predicted using simple quantum mechanical calculations and a group additivity scheme. Organic chemists can first check whether a given synthetic target will be configurationally stable before embarking on a potentially lengthy and expensive chiral synthesis.