A-Trifluoromethyl amino acid

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

Another powerful approach to prepare a-amino acids bearing an aromatic or unsaturated side chain in /I (but also many other compounds) is based on the reactivity of 5-fluoro-4-trifluoromethyloxazole, a starting material easily accessible from hexafluoroacetone. The fluorine atom in the 5 position is easily displaced by an allylic or benzylic alcohol. Then, the obtained ethers spontaneously undergo a Claisen rearrangement to afford, after acidic hydrolysis, an a-trifluoromethyl amino acid... 

Figure 5.31). Functional modification of the double bond leads to numerous analogues of proteogenic or nonproteogenic a-trifluoromethyl amino acids. 

Numerous peptides have been prepared starting from trifluoromethylalanine. 31, 120 Cyclopeptides containing a-trifluoromethyl amino acids have also be prepared. Some peptidic coupling performed with other a-trifluoromethyl amino acids involve protease catalysis (subtilisin, a-chymotrypsin, carboxypeptidase Y, trypsin, etc.). ... 

Replacement of some amino acids in a peptide by an a-trifluoromethyl amino acid influences the stability of the peptide toward different proteases (e.g., a-chymotrip-sins). Thus, for steric reasons, introducing a trifluoromethyl group in the P] position... 

Figure5.31 Synthesis of a-trifluoromethyl amino acids starting from trifluoromethyl fluorooxazole by Claisen rearrangement. ...

A special one-pot deprotection-transacylation method involves coupling of activated Fmoc amino acids with Aloc-protected amino acid esters.The Aloc-deprotection proceeds with palladium/phenylsilane in the presence of the acylating species. Using Fmoc-Phe-F the synthesis of the sterically demanding dipeptide Fmoc-Phe-(Me)Aib-OMe was accomplished in a yield of 65% A similar one-pot approach to the acylation of the even more difficult hindered and weakly nucleophilic a-trifluoromethyl amino acid esters involves the intermediate A-Teoc protection. Thus treatment of ( )-Teoc-a-(a-CF3)Leu-OMe with Fmoc-Gly-F and a catalytic amount of tetraethylammonium fluoride in acetonitrile at 50 °C for 1-2 weeks gave ( )-Fmoc-Gly-(a-CF3)Leu-OMe (77%... 

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)... 

The possibility of studying the structure and dynamic properties of proteins by F NMR requires the use of labeled proteins with fluorine. Various approaches can be envisioned trifluoroacetylation or derivatization of side chains by direct fluorination or trifluoromethylation or with small fluorinated molecules. It is also possible to incorporate a fluorinated amino acid into a protein, by using either a classical chemical synthesis or a biosynthetic approach. It is obvious that the chemical synthetic... 

The unpurified a-amino esters obtained after the two first steps were acylated with (+)-MTPA chloride (MTPA = a-methoxy-a-(trifluoromethyl)phenylacetic acid) to afford the (+)-MTPA amides 41. In the case of R = CH2Ph, the final compound 41 was found to be identical to the (+)-MTPA amide derived from L-phenylalanine. The (2S) configuration was correlated for 41 and capillary GC analysis proved that the diastereomeric ratio (2S) (2R) was > 200 1. 

Asymmetric dihydroxylation of trifluoromethylalkenes is also useful for construction of enantio-enriched trifluoromethylated diols usable for trifluoromethylated amino acids with chiral hydroxyl group. Thus, Sharpless AD reaction of 16 provides diol 17 with excellent enantioselectivity. Regioselective and stereospecific replacement of the sulfonate moiety in 18 with azide ion enables the introduction of nitrogen functionality. A series of well-known chemical transformation of 19 leads to 4,4,4-trifluorothreonine 20 (see Scheme 9.6) [16]. Dehydroxylative-hydrogenation of 21 by radical reaction via thiocarbonate and subsequent chemical transformation synthesize enantio-enriched (S)-2-amino-4,4,4-trifluoro-butanoic acid 22 [16]. Both enantiomers of 20 and 22 were prepared in a similar manner from (2R,3S)-diol of 17. 

Homg, J. C. and Raleigh, D. P. (2003) < >-Values beyond the ribosomally encoded amino acids kinetic and thermodynamic consequences of incorporating trifluoromethyl amino acids in a globular protein. Journal of the American Chemical Society, 125(31), 9286-9287. 

The Tcrom ester is prepared from the cesium salt of an A/-protected amino acid by reaction with 2-(trifluoromethyl)-6-chromylmethyl bromide (DMF, 25°C, 4h,... 

Kawase described a direct and general synthesis of 2,4-disubstituted 5-(trifluoromethyl)oxazoles 500 from reaction of an A -acyl-A-benzyl amino acid 499 with trifluoroacetic anhydride in pyridine (Scheme 1.136). In general, the best... 

TABLE 1.34. 2,4-DISUBSTITUTED-5-(TRIFLUOROMETHYL)OXAZOLES EROM A-ACYEATED AMINO ACIDS AND TEAA... 

MAD MOM MorLys (S)-MTPA Methylaluminumbis[2,6-di(fcrr-butyl)-4-methylphenoxide] Methoxymethyl (2S)-2-Amino-6-(4-morpholinyl)hexanoic acid (S)-a-Methoxy-a-(trifluoromethyl)benzeneacetic acid... 

Racemic compounds separated using alkylated CF6 as the selector in GC includes P-lactams, trifluoroacetyl derivatized amino acids, and tartaric acid esters [47]. Hydrogen bonding is of critical importance for enantiomeric separations in GC. On permethylated CF6, a-(trifluoromethyl)benzyl alcohol was baseline separated, whereas esters of this alcohol were less retained and no separation was observed (Table 3). Furthermore, no separation was observed for native a-methylbenzyl alcohol, which is a weaker hydrogen bond donor than a-(trifluoromethyl)benzyl alcohol. Likewise, enantiomers of A-acetylated amino acids were poorly separated or not separated, whereas A-trifluoroacetylated amino acids are very well separated [47]. 

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. ... 

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)... 

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