Synthesis and physical chemical properties of 2-amino-4-(trifluoromethoxy)butanoic acid – a CF₃O-containing analogue of natural lipophilic amino acids

Abstract

2-Amino-2-(trifluoromethoxy)butanoic acid (O-trifluoromethyl homoserine) was synthesized as a racemate and in both enantiomeric forms. The measured pK and log D values establish the compound as a promising analogue of natural aliphatic amino acids.

Hydrolysis, polarity, and conformational impact of C-terminal partially fluorinated ethyl esters in peptide models

“…3 ). In contrast, among the partially fluorinated methyl ethers OCF n H 3− n , the lipophilicity of the methoxy group is the lowest, while the fluoromethoxy group is the most lipophilic (log P : CF 3 > CHF 2 > CH 2 F ≈ CH 3 ) [ 44 , 64 ]. These differences were explained by the mutual intramolecular compensation of the C–O dipole and the dipole from the partial fluorination [ 65 ].…”

Synthesis of complex unnatural fluorine-containing amino acids

“…Acyclic non-aromatic motifs are the most prevalent in naturally occurring amino acids. Therefore, the ability to access either fluorinated analogues or completely novel acyclic motifs is of utmost importance for applications such as biological probes and peptide therapeutics [ [133] , [134] , [135] , [136] , [137] , [138] , [139] ]. There have been many reports of the synthesis of singly fluorinated analogues of naturally occurring acyclic amino acids [ 12 ].…”

Preparative Method for Asymmetric Synthesis of (S)-2-Amino-4,4,4-trifluorobutanoic Acid

“…As presented in Figure 1, the differences projected by several biphenyl rotational values are relatively modest, suggesting steric mimicry between these two groups, though the effective functional mimicry is very much dependent upon the actual biochemical settings [67]. In this context, the bioisosteric relationships between CF3 and i-Pr can be used for 2-amino-4,4,4-trifluorobutanoic acid 1 [68][69][70][71][72][73][74][75][76] substitution for leucine 2 in the de novo design of biologically active peptides and peptidomimetics [77][78][79][80][81][82][83]. As part of our ongoing research program focused on the application of fluorinated tailor-made AAs in pharmaceutical discovery, we needed a convenient access to large quantities of Fmoc-2amino-4,4,4-trifluorobutanoic acid 1 in both enantiomeric forms.…”