Enantiopurity by directed evolution of crystal stabilities and nonequilibrium crystallization

Clément Pinetre; Sjoerd W. van Dongen; Clément Brandel; Anne-Sophie Léonard; Maxime D. Charpentier; Valérie Dupray; Kasper Oosterling; Bernard Kaptein; Michel Leeman; Richard M. Kellogg; Joop H. ter Horst; Willem L. Noorduin

doi:10.1021/jacs.5c00569

Enantiopurity by directed evolution of crystal stabilities and nonequilibrium crystallization

Clément Pinetre, Sjoerd W. van Dongen, Clément Brandel, Anne-Sophie Léonard, Maxime D. Charpentier, Valérie Dupray, Kasper Oosterling, Bernard Kaptein, Michel Leeman, Richard M. Kellogg, Joop H. ter Horst, Willem L. Noorduin

Strathclyde Institute Of Pharmacy And Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

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

Original language	English
Pages (from-to)	8864-8870
Number of pages	7
Journal	Journal of the American Chemical Society
Volume	147
Issue number	10
Early online date	24 Feb 2025
DOIs	https://doi.org/10.1021/jacs.5c00569
Publication status	Published - 12 Mar 2025

Funding

C.P., C.B., and V.D. acknowledge Région Normandie for its financial support as part of the RIN Recherche 2020 “Chair of Excellence Industrial Crystallization Fundamentals”, grant agreement no.20E04717. S.W.v.D. acknowledges funding from OCENW.KLEIN.155, which is financed by the Dutch Research Council (NWO). S.W.v.D. and W.L.N. acknowledge funding from the National Growth Fund project “Big Chemistry” (1420578), funded by the Ministry of Education, Culture and Science. A.S.L. and W.L.N. acknowledge funding from the European Research Council (consolidator grant no. 101044764-CHIRAL). This research received funding for M.C. and J.H.t.H. as part of the CORE ITN Project by the European Union’s Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie grant agreement no. 722456 CORE ITN. M.C. and J.H.t.H. thank the EPSRC Future Continuous Manufacturing and Advanced Crystallization Research Hub (Grant ref.:EP/ P006965/1) for funding this work.

Keywords

Crystallization
crystals
molecular structure
molecules
reaction products

Access to Document

10.1021/jacs.5c00569Licence: CC BY 4.0

Pinetre-etal-JACS-2025-Enantiopurity-by-directed-evolution-of-crystal-stabilities-andFinal published version, 2.06 MBLicence: CC BY 4.0

Future Continuous Manufacturing and Advanced Crystallisation Research Hub (CMAC Hub)
Florence, A. (Principal Investigator), Brown, C. (Co-investigator), Halbert, G. (Co-investigator), Johnston, B. (Co-investigator), Markl, D. (Co-investigator), Nordon, A. (Co-investigator), Price, C. J. (Co-investigator), Sefcik, J. (Co-investigator) & Ter Horst, J. (Co-investigator)
EPSRC (Engineering and Physical Sciences Research Council)
1/01/17 → 30/09/24
Project: Research

Cite this

Pinetre, C., van Dongen, S. W., Brandel, C., Léonard, A.-S., Charpentier, M. D., Dupray, V., Oosterling, K., Kaptein, B., Leeman, M., Kellogg, R. M., ter Horst, J. H., & Noorduin, W. L. (2025). Enantiopurity by directed evolution of crystal stabilities and nonequilibrium crystallization. Journal of the American Chemical Society , 147(10), 8864-8870. https://doi.org/10.1021/jacs.5c00569

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title = "Enantiopurity by directed evolution of crystal stabilities and nonequilibrium crystallization",

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",

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Pinetre, C, van Dongen, SW, Brandel, C, Léonard, A-S, Charpentier, MD, Dupray, V, Oosterling, K, Kaptein, B, Leeman, M, Kellogg, RM, ter Horst, JH & Noorduin, WL 2025, 'Enantiopurity by directed evolution of crystal stabilities and nonequilibrium crystallization', Journal of the American Chemical Society , vol. 147, no. 10, pp. 8864-8870. https://doi.org/10.1021/jacs.5c00569

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AU - Pinetre, Clément

AU - van Dongen, Sjoerd W.

AU - Brandel, Clément

AU - Léonard, Anne-Sophie

AU - Charpentier, Maxime D.

AU - Dupray, Valérie

AU - Oosterling, Kasper

AU - Kaptein, Bernard

AU - Leeman, Michel

AU - Kellogg, Richard M.

AU - ter Horst, Joop H.

AU - Noorduin, Willem L.

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N2 - 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

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Enantiopurity by directed evolution of crystal stabilities and nonequilibrium crystallization

Abstract

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Keywords

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Future Continuous Manufacturing and Advanced Crystallisation Research Hub (CMAC Hub)

Cite this