Trifluoromethyl Amino Acids

Oxazol-5(2H)-one, 2-benzylidene-4-methyl-tautomerism, 6, 186 Oxazol-5(2ff)-one, 2-methylene-isomerization, 6, 226 Oxazol-5(2H)-one, 2-trifluoromethyl-acylation, 6, 201 Oxazol-5(4ff)-one, 4-allyl-thermal rearrangements, 6, 199 Oxazol-5(4H)-one, 4(arylmethylene)-Friedel-Crafts reactions, 6, 205 geometrical isomerism, 6, 185 Oxazol-5(4ff)-one, 4-benzylidene-2-phenyl-configuration, 6, 185 photorearrangement, 6, 201 Oxazol-5(4ff)-one, 4-benzyl-2-methyl-Friedel-Crafts reactions, 6, 205 Oxazol-5(4ff)-one, 4-methylene-in amino acid synthesis, 6, 203 Oxazol-5(4ff) -one. 2-trifluoromethyl-hydrolysis, 6, 206 Oxazolones... 

The Tcrom ester is prepared from the cesium salt of an N-protected amino acid by reaction with 2-(trifluoromethyl)-6-chromylmethyl bromide (DMF, 25°, 4 h, 53-89% yield). Cleavage of the Tcrom group is effected by brief treatment with n-propylamine (2 min, 25°, 96% yield). It is stable to HCl/dioxane, used to cleave a BOC group. ... 

W-(Methoxycarbonyl)triphenylphosphine imide reacts with methyl trifluoro-pyruvate to form methyl A -methoxycarbonyl 2 immo-3,3,3 trifluoropropionate m 95% yield This convenient building block easily adds nucleophiles such as Gngnard reagents without competing side reactions at the ester group to form trifluoromethylated amino acids [J.S] (equation 31)... 

Similarly, 1-alkylpyrroles, indoles, furans, thiophenes [60], a-picoline [61], enols, malonates [76], and organometallic compounds [56, 62] react with acyl imines of trifluoropyruvates to give derivatives of a-trifluoromethyl a-amino acids... 

Lipase-catalyzed methanolysis of racemic N-benzyloxycarbonyl (Cbz) amino acid trifluoroethyl esters carrying aliphatic side chains afforded the L-methyl esters and the D-trifluoromethyl esters (Figure 6.16). The released alcohol (CF3CH2OH) is a weak nucleophile that cannot attack the ester product. The nucleophilidty of the leaving group is depleted by the presence of an electron-withdrawing group [63]. 

This approach has been mainly applied to peptide-based inhibitors of proteases, where the inhibitory molecule is a peptide with a transition state isostere appended to it, and the cognate substrate is simply a peptide of the same amino acid sequence, but lacking the isostere functionality. Examples where good correlations between the free energy of inhibitor binding and the free energy of kcJKM have been found, include peptide-trifluoromethyl ketone inhibitors of human leukocyte elastase (Stein et al., 1987) and peptide-phosphonamidate inhibitors of the metalloprotease ther-molysin (Bartlett and Marlowe, 1983). 

Kubyshkin VS, Komarov IV, Afonin S, Mykhailiuk PK, Grage SL, Ulrich AS (2011) Trifluoromethyl-substituted a-amino acids as solid state 19F-NMR labels for structural studies of membrane-bound peptides. In Gouvemeur V, Miiller K (eds) Fluorine in pharmaceutical and medicinal chemistry from biophysical aspects to clinical applications. Imperial College Press (in press)... 

Mikhailiuk PK, Afonin S, Chemega AN, Rusanov EB, Platonov MO, Dubinina GG, Ber-ditsch M, Ulrich AS, Komarov IV (2006) Conformationally rigid trifluoromethyl-substituted alpha-amino acid designed for peptide structure analysis by solid-state F-19 NMR spectroscopy. Angew Chem Int Edit 45 5659-5661... 

The a-methoxylated products are highly useful building blocks for the construction of a carbon-carbon bond a to the trifluoromethyl and diflu-oromethyl groups, which is difficult to obtain by other methods, as shown in Scheme 6.15. Thus, a-tri and a-difluoromethylated a-aminonitriles, which are precursors to the corresponding fluorinated a-amino acids, have been prepared in good yields, and flourinated homoallyanilines have been also successfully prepared [44]. in addition, tri- and difluoromethylated tetra- and dihydroquinoline derivatives can be prepared by cationic polar cycloaddition in high yields [45]. 

Reaction of the thia-amino acid 392 with trifluoroacetic anhydride gave the 2,2,2-trifluoro-l-[7-(trifluoromethyl)-l//-pyrrolo[l,2-c]-[l,3]thiazol-6-yl] ethanone pyrrole 395. The formation of the pyrrole can be rationalized by a sequence involving trifluoroacetylation of the enamine 392 affording dione 393 followed by loss of water and carbon dioxide to give the aromatic product 395. These decarboxylations afford fluorinated derivatives of heterocyclic skeletons known to exhibit interesting biological activity (Scheme 58) <2000T7267>. 

Amino acids may be determined by measuring the amines obtained after the action of a carboxylase with a specific electrode for amines, which is based on a poly(vinyl chloride) membrane containing sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (166) as ion exchanger and tricresyl phosphate as solvent mediator. LOD was 20 and 50 i-M for tyroxine and phenylalanine, determined as tyramine (5) and phenethylamine (33), respectively364. 

CASRN 15457-05-3 molecular formula C13H7F3N2O5 FW 328.20 Chemical/Physical. When fluorodifen as an aqueous suspension was irradiated using UV light (A, = 300 nm), 4-nitrophenol and 4-(trifluoromethyl)-2-aminophenol formed as the major products (>90% of total product formation). In addition, 4-(trifluoromethyl)-2-nitrophenol formed as a minor product (<1%) as well as 4-hydroxy-3-nitrobenzoic acid. In methanol, photolysis of fluorodifen yielded 4-nitrophenol and 2-amino-4-(trifluoromethyl)anisole. In cyclohexanone, 4-nitrophenol and 3-(trifluoromethyl)nitrobenzene were formed (Ruzo et al., 1980). 

Various diastereomeric di-, tri-, and tetrapeptides that carry the sterically demanding trifluoromethyl group instead of the natural a-proton at different positions within these short peptide sequences have been designed, and their stability towards enzymatic hydrolysis has been investigated. The structures of the a-trifluoromethyl (aTfm)-substituted amino acids are shown in Scheme 1. From these studies we gained valuable information on how a-trifluoromethyl-substi-tuted peptides may interact with proteins. The aTfm amino acids used in this study combine the conformational restrictions [49-52] of C -dialkylation with the unique stereoelectronic properties of the fluorine atom and have shown interesting effects on peptide-enzyme interactions [53,54]. 

Based on the known substrate specificity of a-chymotrypsin, phenylalanine has been chosen as the amino acid at the Pi position (P-nomenclature according to Schechter and Berger) [55]. The a-proton at Pi has been substituted either by methyl or trifluoromethyl. Substitutions beyond Pi contain trifluoromethyl alanine or aminoisobutyric acid. Therefore, each fluorosubstitution can be compared to its natural as well as fluorine-free a-substituted analog, thereby enabling differentiation of the steric and electronic effects. Scheme 2 summarizes the amino acids that have been used in this study. 

Scheme 1. Structures of the native amino acids and their nonnatural a-substituted analogs. a-Trifluoromethyl phenylalanine as well as a-trifluoromethyl alanine have been used as racemic mixtures.

The trifluoroacetylation of amino acids yields a-amido trifluoromethyl... 

Imines and (Af,(9)-acetals from fluoral are useful precursors of trifluoromethyl nitrogen-containing molecules amines, amino alcohols, amino acids, peptidomimetic units, heterocycles, and so on (Figure 2.50). These simple Af-derivatives of fluoral are easily prepared from the hydrate or the hemiacetal. Imines of fluoral react in [2 + 1 ]... 

The numerous preparations of mono-, di-, tri-, and hexafluoro derivatives of valine, norvaline, leucine, norleucine, and isoleucine, using classical methods of amino acid chemistry (e.g., amination of an a-bromoacid, " azalactone, Strecker reaction, amidocarbonylation of a trifluoromethyl aldehyde, alkylation of a glycinate anion are not considered here. Pure enantiomers are generally obtained by enzymatic resolution of the racemate, chemical resolution, or asymmetric Strecker reaction. ... 

Preparation of a-Trifluoromethyl Amino Acids Since trifluoro-... 

Some functional modifications allow access to numerous analogues of amino acids, natural or not, starting from synthons prepared by the previous methods. This is illustrated by the preparation of a-trifluoromethyl arginine (Figure 5.30). ... 

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