Chiral Amplification through the Interplay of Racemizing Conditions and Asymmetric Crystal Growth
J. Am. Chem. Soc. , Volume 145 - Issue 1 p. 436- 442
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.
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|The Netherlands Organisation for Scientific Research (NWO)|
|J. Am. Chem. Soc.|
van Dongen, S.W, Ahlal, I, Leeman, M, Kaptein, B, Kellogg, R.M, Baglai, I, & Noorduin, W.L. (2023). Chiral Amplification through the Interplay of Racemizing Conditions and Asymmetric Crystal Growth. J. Am. Chem. Soc., 145(1), 436–442. doi:10.1021/jacs.2c10584