Хіральне розділення похідних β-СF3-α-проліну

• Date: 2025
• Author Affiliations: Mykhailo O. Redka — V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine; Enamine Ltd., Kyiv, Ukraine; Oleksandr S. Liashuk — Taras Shevchenko National University of Kyiv, Kyiv, Ukraine; Enamine Scientific Research Institute (SRI), Kyiv, Ukraine; Ivan S. Kondratov — V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine; Enamine Germany GmbH, Frankfurt am Main, Germany; Oleksandr O. Grygorenko — Taras Shevchenko National University of Kyiv, Kyiv, Ukraine; Enamine Ltd., Kyiv, Ukraine; Enamine Scientific Research Institute (SRI), Kyiv, Ukraine
• Keywords: keywords
• Main Authors: Redka, Mykhailo O., Liashuk, Oleksandr S., Kondratov, Ivan S., Grygorenko, Oleksandr O.
• Format: Article
• Language: English
• Published: V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2025
• Subjects: флуор; пролін; енантіомерне розділення; флуоровані будівельні блоки
• Online Access: https://bioorganica.com.ua/index.php/journal/article/view/118
• Journal Title: Ukrainica Bioorganica Acta

An operationally simple and scalable preparation of all four stereoisomers of N-Boc β-CF₃-α-proline in high enantiomeric purity is described. Acylation of racemic cis-β-CF₃-α-proline with (S)-2-phenylpropanoic acid under standard amide coupling conditions affords a pair of diastereomeric amides that can be resolved by normal-phase column chromatography on multi-gram scale (up to 37 g per isomer). Subsequent acidic cleavage of the N,C-protection groups induce complete epimerization at the amino acid center; N-Boc protection of the resulting mixture followed by chromatographic separation provides individual N-Boc β-CF₃-α-proline stereoisomers with ee > 95%. The same sequence applied to both diastereomeric intermediate N-acyl derivatives furnishes the full set of four N-Boc β-CF₃-α-prolines in only three synthetic steps, without the need for chiral chromatography. This robust resolution protocol transforms β-CF₃-α-proline ester into a easily accessible chiral building block for peptide synthesis, conformational studies and medicinal chemistry applications.