Large-Scale Asymmetric Synthesis of Fmoc-(S)-2-Amino-6,6,6-Trifluorohexanoic Acid

Zizhen Yin; Hiroki Moriwaki; Hidenori Abe; Toshio Miwa; Jianlin Han; Vadim A Soloshonok

doi:10.1002/open.201900131

Large-Scale Asymmetric Synthesis of Fmoc-(S)-2-Amino-6,6,6-Trifluorohexanoic Acid

ChemistryOpen. 2019 Jun 7;8(6):701-704. doi: 10.1002/open.201900131. eCollection 2019 Jun.

Authors

Zizhen Yin¹, Hiroki Moriwaki², Hidenori Abe², Toshio Miwa², Jianlin Han¹, Vadim A Soloshonok^{3

4}

Affiliations

¹ College of Chemical Engineering Nanjing Forestry University Nanjing 210037 China.
² Hamari Chemicals Ltd. 1-4-29 Kunijima, Higashi-Yodogawa-ku Osaka 533-0024 Japan.
³ Department of Organic Chemistry I, Faculty of Chemistry University of the Basque Country UPV/EHU Paseo Manuel Lardizábal 3 20018 San Sebastián Spain.
⁴ IKERBASQUE Basque Foundation for Science María Díaz de Haro 3, Plaza Bizkaia 48013 Bilbao Spain.

Abstract

Here we report the first large-scale synthesis of Fmoc-(S)-2-amino-6,6,6-trifluorohexanoic acid via asymmetric alkylation of chiral Ni(II)-complex of glycine Schiff base with CF₃(CH₂)₃I. The synthesis was performed on over 100 g scale and can be recommended as the most advanced procedure for reliable preparation of large amounts of enantiomerically pure Fmoc-(S)-2-amino-6,6,6-trifluorohexanoic acid for protein engineering and drug design. Chiral auxiliary used in this protocol can be >90 % recovered and reused.

Keywords: amino acids; asymmetric synthesis; fluorine; large-scale synthesis; stereochemical outcome.