Articles and Theses – 2023

Sjoerd W. van Dongen, Imane Ahlal, Michel Leeman, Bernard Kaptein, Richard M. Kellogg, Iaroslav Baglai, and Willem L. Noorduin, Chiral Amplification through the Interplay of Racemizing Conditions and Asymmetric Crystal Growth, J. Am. Chem. Soc. 145 (2023), 1, 436–442.

Affiliations

• AMOLF, Science Park 104, 1098 XG, Amsterdam, The Netherlands.
• Symeres, Kadijk 3, 9747 AT, Groningen, The Netherlands.
• InnoSyn BV, Urmonderbaan 22, 6167 RD, Geleen, The Netherlands.
• Van ‘t Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands

Amplification of enantiomeric excesses (ee) is routinely observed during chiral crystallization of conglomerate crystals for which the enantiomers undergo racemization in solution. Although routes comprising a combination of crystal growth and dissolution are frequently used to obtain enantiopure molecules, crystal growth by itself has rather been considered as a source of enantiomeric erosion and discounted as a potential source of enantiomeric amplification. Counterintuitively, we here
demonstrate striking enantiomeric amplification during crystal growth for clopidogrel and tert-leucine precursors. Based on a mechanistic framework, we identify that the interplay between racemization and crystal growth rates elicits this surprising effect. The asymmetric amplification of the solid phase ee can be enhanced by increasing the mass of grown material relative to the product, such that small amounts of seeds of only 60% ee already result in virtually exclusive growth of the majority
phase. These results impact our understanding of asymmetric amplification mechanisms during crystallization and offer a tangible basis for practical production of enantiopure molecules.