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Usage

Uses

Used in Pharmaceutical Industry:
(S)-N-Fmoc-5,5,5,5,5,5-Hexafluoroleucine is used as a building block for the synthesis of enantiomerically pure (2S,3S)-5,5,5-trifluoroisoleucine and (2R,3S)-5,5,5-trifluoro-allo-isoleucine. These compounds are important in the development of pharmaceuticals, as they can exhibit unique biological activities and selectivity compared to their non-fluorinated counterparts. The incorporation of fluorine atoms can enhance the stability, lipophilicity, and metabolic properties of the resulting compounds, making them more effective and suitable for various therapeutic applications.

Upstream product

• 201930-84-9 (R)-5,5,5-Trifluoro-2-hydroxy-4-trifluoromethyl-pentanoic acid ethyl ester 
• 201930-82-7 5,5,5-trifluoro-2-oxo-4-trifluoromethyl-pent-3-enoic acid ethyl ester 
• 201930-83-8 5,5,5-trifluoro-2-oxo-4-trifluoromethyl-pentanoic acid ethyl ester 
• 82911-69-1 N-(9H-fluoren-2-ylmethoxycarbonyloxy)succinimide 
• 149560-64-5 (S)-5,5,5,5',5',5'-hexafluoroleucine 

Relevant academic research and scientific papers

Position-dependent impact of hexafluoroleucine and trifluoroisoleucine on protease digestion

Rapid digestion by proteases limits the application of peptides as therapeutics. One strategy to increase the proteolytic stability of peptides is the modification with fluorinated amino acids. This study presents a systematic investigation of the effects of fluorinated leucine and isoleucine derivatives on the proteolytic stability of a peptide that was designed to comprise substrate specificities of different proteases. Therefore, leucine, isoleucine, and their side-chain fluorinated variants were site-specifically incorporated at different positions of this peptide resulting in a library of 13 distinct peptides. The stability of these peptides towards proteolysis by α-chymotrypsin, pepsin, proteinase K, and elastase was studied, and this process was followed by an FL-RP-HPLC assay in combination with mass spectrometry. In a few cases, we observed an exceptional increase in proteolytic stability upon introduction of the fluorine substituents. The opposite phenomenon was observed in other cases, and this may be explained by specific interactions of fluorinated residues with the respective enzyme binding sites. Noteworthy is that 5, 5, 5-trifluoroisoleucine is able to significantly protect peptides from proteolysis by all enzymes included in this study when positioned N-terminal to the cleavage site. These results provide valuable information for the application of fluorinated amino acids in the design of proteolytically stable peptide-based pharmaceuticals.

Synthesis of enantiomerically pure (2S,3S)-5,5,5-trifluoroisoleucine and (2R,3S)-5,5,5-trifluoro-allo-isoleucine

A practical route for the stereoselective synthesis of (2S,3S)-5,5,5- trifluoroisoleucine (L-5-F3Ile) and (2R,3S)-5,5,5-trifluoro-alloisoleucine (D-5-F3-allo-Ile) was developed. The hydrophobicity of L-5-F3Ile was examined and it was incorporated into a m

Chemoenzymatic synthesis of (S)-hexafluoroleucine and (S)- tetrafluoroleucine

We have developed a short chemoenzymatic synthesis for both (S)-5,5,5,5′,5′,5′-hexafluoroleucine (Hfl) and (S)-5,5,5′,5′-tetrafluoroleucine (Qfl) on gram scale. Qfl was incorporated into a peptide using standard solid-phase peptide synthesis protocols to measure its helix propensity. The helix propensity for Qfl is 0.68 kcal·mol-1 more favorable compared to Hfl.

Helix propensity of highly fluorinated amino acids

Highly fluorinated amino acids have been used to stabilize helical proteins for potential application in various protein-based biotechnologies. To gain further insight into the effect of these highly fluorinated amino acids on helix formation exclusively, we measured the helix propensity of three highly fluorinated amino acids: (S)-5,5,5,5′,5′,5′-hexafluoroleucine (Hfl), (S)-2-amino-4,4,4-trifluorobutyric acid (Atb), and (S)-pentafluorophenylalanine (Pff). We have developed a short chemoenzymatic synthesis of Hfl with extremely high enantioselectivity (>99%). To measure the helix propensity (w) of the amino acids, alanine-based peptides were synthesized, purified, and investigated by circular dichroism spectroscopy (CD). On the basis of the CD data, the helix propensity of hydrocarbon amino acids can decrease up to 24-fold (1.72 kcal·mol-1·residue-1) upon fluorination. This difference in helix propensity has previously been overlooked in estimating the magnitude of the fluoro-stabilization effect (which has been estimated to be 0.32-0.83 kcal·mol-1·residue-1 for Hfl), resulting in a gross underestimation. Therefore, the full potential of the fluoro-stabilization effect should provide even more stable proteins than the fluoro-stabilized proteins to date. Copyright