Trifluoromethylated amino acids, synthesis

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... 

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

Katagiri, T. Uneyama, K. Stereospecific substitution at a-carbon to trifluoromethyl group application to optically active fluorinated amino acid synthesis. Chirality 2003, 35, 4-9. 

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%... 

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... 

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... 

The second most prevalent method for synthesizing a,a-difluoroalkyl ketones is a modification of the Dakin-West acylation reaction. This method utilizes difluoroacetic anhydride to form an anhydride with the chosen amino acid, which rapidly cyclizes and activates the a-carbon, where acylation then occurs. Although this method has been used to synthesize many a,a-difluoroalkyl ketones (Table 5)J7A25 261 the modified Dakin-West reaction has primarily been used in the synthesis of trifluoromethyl ketones. Since the syntheses of a,a-difluoroalkyl and trifluoromethyl ketones are identical, the details of this method will be discussed in Section 15.1.4.3.1. 

Scheme 8 Synthesis of Trifluoromethyl Ketones by Reaction of (Trifluoromethyl)trimethylsilane with Amino Acid Oxazolidin-5-ones[301...

The synthesis (Scheme 9) begins with the appropriate 1-trifluoromethyl-substituted enol ether 43, where R1 is an amino acid side chain or another appropriate carbon chain. The enol ether undergoes reaction with MCPBA in CH2C12 to give the corresponding epoxy ether 44. The epoxy ether is cleaved by reaction of a wide variety of secondary amines to give the a-amino trifluoromethylated ketone 45. Only a few compounds have been synthesized by this method. 35,36 ... 

The first simple 5(2/f)-oxazolones were the trifluoromethyl derivatives obtained by treating a-amino acids with trifluoroacetic anhydride (equation 156). A general synthesis of 2,2-disubstituted 5(2/f)-oxazolones is the condensation of a- (hydroxylamino) acids with ketones (equation 157) (80S55). The dehydrogenation of 2,2-bis(trifluoromethyl)-5-oxazolidinones affords bis(trifluoromethyl) derivatives (equation 158) (79LA1547). 

In all cases it was reported that the trifluoromethyl group enhances the interaction in the prochiral ion pair, resulting in higher ee. The exception appears to be the asymmetric synthesis of a-amino acids via alkylation of the benzophenone Schiff base of glycine alkyl esters with allyl bromide, which produced a 56% ee with the trifluoromethyl-substituted catalyst compared to 66% with the unsubstituted catalysts TY-benzylcinchoninium chloride (3) or TY-benzylcinchonidinium chloride (4) (eq 5). ... 

Kuznetsova, L., Ungureanu, I. M., Pepe, A., et al. (2004) Trifluoromethyl- and difluoromethyl-P-lactams as useful building blocks for the synthesis of fluorinated amino acids, dipeptides, and fluoro-taxoids. Journal of Fluorine Chemistry 125, 487-500. 

Asensio, A., Bravo, P., Crucianelli, M., et al. (2001) Synthesis of nonracemic a-trifluoromethyl a-amino acids from sulfinimines of trifluoropyruvate. Eur. J. Org. Chem., 1449-1458. 

Wang, H., Zhao, X., Li, Y. and Lu, L. (2006) Solvent-controlled asymmetric Strecker reaction stereoselective synthesis of a-trifluoromethylated a-amino acids. Org. Lett., 8, 1379-1381. 

Soloshonok, V. A., Kukhar, V., Pustovit, Y. and Nazaretian, V. (1992) A new and convenient synthesis of S-trifluoromethyl-containing amino acids. SynLett., 657-658. 

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