Obtention of enantiomerically pure 5,5,5-trifluoro-l-isoleucine and 5,5,5-trifluoro-l-alloisoleucine

• We have developed a simple alternative for the synthesis of racemic 5,5,5-trifluoroisoleucine.
• We report the first methodology for the resolution of the racemic mixture into enantiomerically pure 5,5,5-trifluoro-l-isoleucine and 5,5,5-trifluoro-l-alloisoleucine.
• Resolution was achieved based on enantiomeric preference exhibited by Aspergillus mellus acylase I towards N-acetyl-5,5,5-trifluoro-l-isoleucine as substrate.
• Subsequent treatment with porcine kidney acylase I allows access to enantiomerically pure 5,5,5-trifluoro-l-alloisoleucine.

The fluorinated amino acids 5,5,5-trifluoro-l-isoleucine and 5,5,5-trifluoro-l-alloisoleucine constitute a pair of diastereoisomers with attractive properties as synthons for the obtention of biologically active molecules. However, difficulties in their synthesis and chiral resolution have restricted their use to a few examples of in vivo and in vitro applications. Here we described an alternative synthetic pathway for these highly valuable fluorinated amino acids and further resolution into enantiomerically pure samples by aminoacylase-catalyzed hydrolysis of their N-acetyl derivates. Resolution is achieved by means of distinctive preference toward substrate stereochemistry exhibited by acylase I from Aspergillus melleus compared to the analogous enzyme derived from porcine kidney. Straightforward access to enantiomerically pure samples for these fluorinated amino acids will definitely expand their relevance as building blocks for the production of new drugs and innovative biomaterials.

Our graphical abstract shows a sequential enzymatic methodology for the resolution of a racemic mixture of four N-acetyl-2-amino-5,5,5-trifluoro-3-methylpentanoic acid isomers into enantiomerically pure 5,5,5-trifluoro-l-isoleucine and 5,5,5-trifluoro-l-alloisoleucine. Sustainability of this approach is shown through an arrow that represents recycling of the resulting d-isomers. The simplicity of the graphical abstract also reflects the simplicity of this methodology.Figure optionsDownload as PowerPoint slide