Trifluoroacetylation amino acids

Scheme 25 Sammakia s chiral alcohol catalyzed KR of a-acetoxy- and a-(At-trifluoroacetyl) amino acid-At-acyloxazolidinethiones [231, 232]...

N-trifluoroacetyl amino acids have been reported as stable at -10°C over a 2-week period (53) and the TFA n-butyl esters are stable for about 72 hr when stored at 0 C in a nitrogen atmosphere (32). Reasonable stability of derivatives is necessary for repetitive analyses when many samples are prepared and stored prior to chromatography. Instability of silyl derivatives to hydrolysis has been a major problem which has led to decreased activity in research on these materials. The efficient treatment of amino acids with N,0-bis(trimethylsilyl)acetamide (51) and subsequent GLC of the derivatives is now used only occasionally as a result of instability of the derivatives. 

D4. Darbre, A., and Blau, K., Trifluoroacetylated amino acid esters The stability of the derivatives of cysteine, hydrox3 roline, serine, threonine and t rrosine. Biochim. Biophys. Acta 100, 298-300 (1965). 

Trifluoroacetyl amino acids. Amino acids and peptides can be N-trifluoro-acetylated with this reagent in DMSO.1... 

Most of the reported applications of this technique involve the direct resolution of derivatised enantiomers on chiral stationary phases. The earliest successful resolution of yV-trifluoroacetyl amino acid esters on glass capillary columns coated with N-trifluoroacetyl-5-isoleucine lauryl ester (2) was effected in 1966. Superior stationary phases developed quickly, such as (3), in which the additional amide bond may interact via hydrogen bonding. These chiral supports work well for the separation of A -perfluoracylated derivatives of a given amino acid. However, their low thermal stability (190 C maximum) and appreciable volatility have inhibited their use for the simultaneous... 

The disadvantage is that trifluoroacetyl amino acids readily racemize. The group may be removed by sodium hydroxide at room temperature conditions that do not affect most other protecting groups. 

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]. 

Nonvolatile analytes must be chemically converted to a volatile derivative before analysis. For example, amino acids are not sufficiently volatile to analyze directly by gas chromatography. Reacting an amino acid with 1-butanol and acetyl chloride produces an esterfied amino acid. Subsequent treatment with trifluoroacetic acid gives the amino acid s volatile N-trifluoroacetyl- -butyl ester derivative. 

Diamide Chiral Separations. The first chiral stationary phase for gas chromatography was reported by GH-Av and co-workers in 1966 (113) and was based on A/-trifluoroacetyl (A/-TFA) L-isoleucine lauryl ester coated on an inert packing material. It was used to resolve the tritiuoroacetylated derivatives of amino acids. Related chiral selectors used by other workers included -dodecanoyl-L-valine-/-butylamide and... 

The synthesis and the quantitative gas chromatographic analysis of stable, yet volatile, A/-trifluoroacetyl- -butyl esters of amino acids has been estabhshed (124). An extensive review of subsequent advances ia gas chromatographic iastmmentation has been provided (125). 

AcOH, HBr, 10°, 10 min, 70% yield. Phthaloyl or trifluoroacetyl groups on amino acids are stable to these conditions benzyloxycarbonyl (Cbz) or /-butoxycarbonyl (BOC) groups are cleaved. 

TRIFLUOROACETYLATION OF AMINES AND AMINO ACIDS UNDER NEUTRAL, MILD CONDITIONS N-TRIFLUOROACET ANILIDE AND N-TRIFLUOROACETYL-l-TYROSINE... 

The original procedure for the trifluoroacetylation of amino acids used trifluoroacetic anhydride [Acetic acid, trifluoro-, anhydride].4 This reagent, although inexpensive and readily available, has certain disadvantages it is a highly reactive compound and thus has caused undesired reactions such as the cleavage of amide or peptide bonds,5 unsymmetrical anhydrides are formed between the newly formed A-trifluoroacetylamino acids and the by-product trifluoroacetic acid, and excess trifluoroacetic anhydride has caused racemization of asymmetric centers. 

N-Trifluoroacetylations of amino acid esters by a pyrazolide are described in reference [121]. 

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>. 

A study was made of the effects of derivatization on the 13C analysis of amino acid enantiomers. Conventional isotope ratio MS and GC-isotope ratio MS were used. The latter method requires volatilization of the analytes, which was accomplished by introducing O-isopropyl and A-trifluoroacetyl groups, causing a change in the 13C analysis of the original analytes. It was proposed to use a set of known standards for such analyses, which are applied in geological studies68. 

The resolution of a-methylvaline had not been reported at the time this work was done. Subsequently, Turk, et al. published the resolution of trifluoroacetyl-a-methylvaline by carboxy-peptidase A (O. Some comments on the absolute configuration of the amino acids will be made later. 

In each case the starting amino acid was 99.8% optically pure, as shown by gas chromatography of the trifluoroacetyl methyl esters on Chirasil-Val Note 2). ... 

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

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... 

Saturated 5(4//)-oxazolones are easily obtained from //-acylamino acids in the presence of a cyclization agent and have been used extensively in coupling reactions as synthetic equivalents of a-amino acids in the synthesis of peptides. In this context, tautomeric equilibrium can be a significant problem due to the racemization associated with the isomerization. For example, trifluoroacetylation of tryptophan in ether affords the 5(4//)-oxazolone 5 without racemization. However, upon dissolution in acetonitrile, 5 completely racemizes. Further, upon heating, an aqueous dioxane solution of 5 cleanly isomerizes to the isomeric 5(2//)-oxazolone 6 (Scheme 7.2). 

Racemization is not encountered when 4-unsubstituted-5(477)-oxazolones or 4,4-disubstituted-5(477)-oxazolones are used as reagents. Indeed, 4-unsubstituted-5(47/)-oxazolones function as glycine synthons in the synthesis of A-acylglycyl-a-amino acids. For example, aminolysis of 2-(trifluoromethyl)-5(47/)-oxazolone with a-methylphenylalanine affords A-(trifluoroacetyl)glycyl-a-methylphenylalanine. 4,4-Disubstituted-5(4//)-oxazolones, readily available by alkylation of the monosubstituted derivatives, are very useful intermediates in the synthesis of peptides that incorporate ot,ot-disubstituted amino acids. As an example, 4-(aryl-methyl)-2-phenyl-4-(trifluoromethyl)-5(4//)-oxazolones 260 are key intermediates... 

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