Enantiopurity by directed evolution of crystal stabilities and nonequilibrium crystallization

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Pinetre, Clément and van Dongen, Sjoerd W. and Brandel, Clément and Léonard, Anne-Sophie and Charpentier, Maxime D. and Dupray, Valérie and Oosterling, Kasper and Kaptein, Bernard and Leeman, Michel and Kellogg, Richard M. and ter Horst, Joop H. and Noorduin, Willem L. (2025) Enantiopurity by directed evolution of crystal stabilities and nonequilibrium crystallization. Journal of the American Chemical Society, 147 (10). pp. 8864-8870. ISSN 1520-5126 (https://doi.org/10.1021/jacs.5c00569)

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Abstract

Crystallization is a powerful method to isolate enantiopure molecules from racemates if enantiomers self-sort into separate enantiopure crystals. Unfortunately, this behavior is unpredictable and rare (5–10%), as both enantiomers predominantly crystallize together to form racemic crystals, hindering any such chiral sorting. These unfavorable statistics might be overcome using nonequilibrium conditions. Therefore, we systematically characterize energy differences (ΔGΦ) between racemic and enantiopure crystal phases for libraries of target molecules (phenylglycine, praziquantel) with different chemical modifications. Surprisingly, these libraries reveal wide but similar continuous distributions of ΔGΦ, wherein similar chemical modifications group together. This grouping allows a directed evolution strategy to discover racemic crystals with low ΔGΦ for isolating desired enantiomers by crystallization under nonequilibrium conditions. Comparison with over a hundred previously reported compounds suggests that as many as half of all chiral molecules may kinetically form enantiopure crystals (∼50%). These insights open new previously unconsidered possibilities for isolating

ORCID iDs

Pinetre, Clément, van Dongen, Sjoerd W., Brandel, Clément, Léonard, Anne-Sophie, Charpentier, Maxime D., Dupray, Valérie, Oosterling, Kasper, Kaptein, Bernard, Leeman, Michel, Kellogg, Richard M., ter Horst, Joop H. ORCID logoORCID: https://orcid.org/0000-0003-0118-2160 and Noorduin, Willem L.;
CORE (COnnecting REpositories)