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

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.

Racemisation in Chemistry and Biology

“…CD has been successfully applied to measure the racemisation of severals ystems. [85][86][87] Analogous to CD spectroscopy,t he process of racemization can also be monitored by using the rotationo fp lane-polarized light by using polarimeters and measuring, for example, the optical rotatory power [a] D . [57,71] Chiral chromatographic methodsh avep rovedo fs ignificant utility fors tudying racemization.…”

“…[22,55] Aq uantitative approach to rates of general-base-catalysed racemisation across compound classes was recently described in which two computational and two practical methods complemento ne another to provide differing levels of speed and throughput and different levels of accuracy. [85] Measurements of the rate of racemisation exploited NMR spectroscopy to follow deuterium incorporation or circulard ichroism to follow racemisationd irectly.T hese techniques were used to expand the availables et of racemisation rate constants. One computational approachc onsiders the contributiono fg roups adjacent to ac arbanion to its stability, this technique can be rapidlya pplied to sets of many compounds.…”

“…Alternatively, the ability to use both non‐deuterated and fully deuterated buffers provides convenient direct access to the solvent kinetic isotope effects. CD has been successfully applied to measure the racemisation of several systems . Analogous to CD spectroscopy, the process of racemization can also be monitored by using the rotation of plane‐polarized light by using polarimeters and measuring, for example, the optical rotatory power [ α ] D …”

“…This mechanism also suggests that the formation of d ‐Asp could be from l ‐Asn, rather than l ‐Asp. Recent results have suggested that anionic intermediates that have the possibility of aromatic character can enhance racemisation liability and it is noteworthy that the keto–enol tautomer of 55 would fall into this category . Other studies have cast doubt on the relevance of cyclic species favouring a homolysis via a radical …”

Computational study of optical properties, and enantioselective synthesis of di-substituted esters of hydantoic and thiohydantoic acids

“…If a large excess of base is used, racemization and/or formation of hydantoin or thiohydantoin (Ballard et al, 2018) take place without formation of optically active hydantoic and thiohydantoic acid. Previously reported that ester of isocyanate reacts with an amine to produce ester of hydantoic acid.…”