Trifluoroalanine

The antibacterial and antiviral properties of mono-, di-, and trifluoroalanines are connected to their capacity to inhibit, in an irreversible way, many enzymes (cf. Chapter 1) They have been the subject of numerous synthetic studies. We only report on the most recent and significant ones, without detailing the general methods of amino acid chemistry or the techniques of electrophilic fluorination, which have recently been reviewed. ... 

As early as the 1960s, some syntheses based on the addition of nucleophilic reagents (vinyl magnesium bromide, HCN, isonitrile) on A-acyl trifluoroacetaldi-mines (fluoral imine) have appeared. The acidic function is further introduced by an appropriate oxidation or hydrolysis. These approaches have allowed preparation of higher fluoroalkylated homologues of trifluoroalanine and of nonracemic trifluor-oalanines (vide infra). However, preparation of the acyl imine of fluoral is rather... 

Figure 5.3 Some examples of the synthesis of racemic trifluoroalanine. ...

Trifluoroalanine has also been prepared by reducing trifluoropyruvate imines (ethyl trifluoropyruvate is available commercially it is prepared either from per-fluoropropene oxide or by trifluoromethylation of ethyl or f-butyl oxalate). These imines are obtained by dehydration of the corresponding aminals or by Staudinger reaction. They can also be obtained by palladium-catalyzed carbonylation of trifluoroacetamidoyl iodide, an easily accessible compound (cf. Chapter 3) (Figure 5.4). Reduction of the imines affords protected trifluoroalanines. When the imine is derived from a-phenyl ethyl amine, an intramolecular hydride transfer affords the regioisomer imine, which can further be hydrolyzed into trifluoroalanine. ... 

While nonracemic trifluoroalanines can easily undergo racemization or dehydro-fluorination, many asymmetric syntheses oftrifluoroalanines have been proposed. These syntheses generally involve an asymmetric reduction step of an imine or an enamine. This step can be performed by utilizing either chiral catalysts or chiral auxiliaries. 

Asymmetric hydrogenation of imines derived from trifluoropyruvate, in the presence of a chiral complex of palladium (ligand = (R)-BINAP), affords ethyl (/f)-trifluoroalaninate with ca. 90% The ee values strongly depend on the solvent,... 

The asymmetric reduction of oximes of 2-trifluoroacetyl furan, by using diborane with a chiral amino alcohol, has also allowed synthesis of both enantiomers of trifluoroalanines in an elegant manner. The key step in this synthesis is the separation of the (Z) and ( ) isomers of the oximes (Figure 5.4). ... 

H N C00R= Alanine, leucine, serine, tyrosine, methionine, proline, etc. Figure 5.5 Synthesis of trifluoroalanine-containing dipeptides. 

Difluoroserine is unstable, but some O- and A -protected derivatives of ethyl difluoro-serinate have been prepared. As for trifluoroalanine, a good precursor is ethyl trifluoro-pyruvate. Synthesis is based on the addition of an alcohol on gem-difluoroenamine, resulting from the reductive cleavage of a C—F bond of an imine of ethyl trifluoro-pyruvate (cf. Chapter 2) (Figure 5.10). ... 

Fluoro amino acids have been incorporated into peptides, in order to ease the transport or reduce the systemic toxicity. Thus, trifluoroalanine, a powerful inhibitor of alanine racemase, is an essential enzyme for the biosynthesis of the cell wall of bacteria. It has a low antibiotic activity because of its very poor transport. In order to facilitate this transport, the amino acid has been incorporated into a peptide. This delivery allows a reduction of the doses, and thus the toxicity of the treatment is lowered.3-FIuorophenylaIanine (3-F-Phe) is a substrate of phenylalanine hydroxylase, which transforms it into 3-F-Tyr. 3-F-Tyr has a high toxicity for animals, due to its ultimate metabolization into fluorocitrate, a powerful inhibitor of the Krebs cycle (cf. Chapter 7). 3-F-Phe has a low toxicicity toward fungus cells, but when delivered as a tripeptide 3-F-Phe becomes an efficient inhibitor of the growth of Candida albicans. This tripeptide goes into the cell by means of the active transport system of peptides, where the peptidases set free the 3-F-Phe. ... 

Inhibition processes can highly depend on the number of fluorine atoms. Thus, while mono- and trifluoroalanine are good inhibitors of alanine racemase. 

Figure 8.6 Trifluoroalanine is transformed by a pyridoxal coenzyme into a covalently bound suicide substrate. ...

This is similar to the reactive intermediate of equation 9.13 here, though, the enzyme has evolved to deal with the intermediate and is not inactivated. However, a similar but far more reactive intermediate can be generated from the reaction of the enzyme with /3-trifluoroalanine (equation 9.15), which will alkylate the enzyme and inactivate it.20... 

The 1,3-proton shift reaction has also been applied to the synthesis of a-(perfluoroalkyl)-a-amino acids, specifically 3.3,3-trifluoroalanine.2 -26 Attempts to prepare the A-benzylimine of ethyl 3,3.3-trifluoro-2-oxopropanoate by direct condensation with benzylamine were very difficult due to the exceptionally high stability of the intermediate a-amino alcohol, which fails to dehydrate. By contrast, 1-phenylethanamine reacted with ethyl 3,3,3-trifluoro-2-oxo-propanoate to form ketimine 33 in 83 % yield.26 The 1,3-proton shift reaction of 33 is much faster than those of ketimines derived from perfluoroalkyl ketones or perfluoroaldehydes (see Table 5). Complete conversion in triethylamine required 6 hours at room temperature and afforded the isomeric Shiff base 34 in 92 % yield. Mild hydrolysis of Shifif base 34 gives a-amino ester 35, which in turn hydrolyzes to 3,3,3-trjfluoroalanine hydrochloride (36). 

As shown in Scheme 2, a 3,3,3-trifluoroalanine derivative was obtained in 91% ee by asymmetric hydrogenation of the corresponding imino ester with a... 

Fig. 8.10 Postulated mechanism of inactivation of alanine racemase by j8,/3,/3-trifluoroalanine. (Reproduced with permissions from Faraci and Walsh, Biochemistry, 28, 434 (1989)).

Reminiscent of the irreversible inhibition of GABA-T by ethanolamine-O-sulfate (10). which involves enzyme-induced P elimination of sulfate to generate an electrophilic Michael acceptor, P-haloamino acids have been found to lead to irreversible inhibition via 8-elimination mechanisms. Thus bacterial alanine racemase is irreversibly inhibited by P-chloro-D-alanine (24), P-fluoroalanine (25) and by P,P,P-trifluoroalanine (26). P,P,P-Trifluoroalanine has also been found to be an irreversible inactivator of y-cystathionase (26, 27). the enzyme previously shown to be inactivated by propargylglycine (7). 

A spiro adduct is the result of the reaction of diazofluorene and perflu-oro-2-butyne (72AG(E)224, 72TL3479 74CB2027). With diazomethane and ethyl diazoacetate the above-mentioned trifluoromethyl-substituted alkynylamino and alkynyl hydroxy acid esters give a single [3 -t- 2] cycloadduct, namely the 2-(3-pyrazolyl)-3,3,3-trifluoroalanine and the 2-(3-pyrazolyl)-3,3,3-trifluorolactic acid derivatives, respectively (92LA947) (Scheme 71). 

Interestingly, the stereochemistry of the hydroxyl group on the imino nitrogen in oxime 10 affects the stereochemistry of hydroxylamine 11 (see Scheme 9.4). Thus, hydride reduction of either (Z)- or (E)-oximes 10 with hydroborane in the presence of chiral amino alcohols produces (S)- and (R)-A-benzyl oximes 11, respectively, as shown in the table in Scheme 9.4, which were subsequently transformed to (R)-and (S)-trifluoroalanine 12 [14]. 

Base-catalyzed deprotonation-alkylation of trifluoroalanine is not easy because a-trifluoromethylated carbanions readily undergo defluorination in general [90]. Therefore, a-alkylated trifluoroalanines have been prepared either by alkylation of imines obtained from trifluoropyruvates [54, 57]or by Strecker cyanation [56] to trifluoroketimines fol-... 

Demir, A. S., Sesenoglu, O. and Gercek-Arkin, Z. (2001) An asymmetric synthesis of both enantiomers of 2,2,2-trifluoro-l-furan-2-yl-ethylamine and 3,3,3-trifluoroalanine from 2,2,2-trifluoro-l-furan-2-yl-ethanone. Tetrahedron Asymmetry, 12, 2309-2313. 

Soloshonok, V. A. and Kuklar, V. P. (1997) Biomimetic transamination of a-keto perfluoro-carboxylic esters. An efficient preparative synthesis of P,p,P-trifluoroalanine. Tetrahedron, 53, 8307-8314. 

Guo, Y., Fujiwara, K. and Uneyama, K. (2006) A novel route to dipeptides via noncondensation of amino acids 2-Aminoperfluoropropene as a synthon for trifluoroalanine dipeptides. Org. Lett., 8, 827-829. 

In the above example, the enzyme accepted the drug as a bona fide visitor, only to find that it gained an awkward squatter impossible to move. Other apparently harmless visitors can turn into lethal assassins which actively attack the enzyme. Once again, it is the enzyme mechanism itself which causes the transformation. One example of this is provided by the irreversible inhibition of the enzyme alanine transaminase by trifluoroalanine (Fig. 4.23). 

Trifluoroalanine contains three fluorine atoms which are very similar in size to the hydrogen atoms in alanine. The molecule is therefore able to fit into the active site of the enzyme and take alanine s place. The reaction mechanism proceeds as before to give the dihydropyridine intermediate. However, at this stage, an alternative mechan-... 

Alexeev, D., Baxter, RL., Campopiano, D.J., et al. (2006) Suicide inhibition of alpha-oxamine synthases Structures of the covalent adducts of 8-amino-7-oxonona-noate synthase with trifluoroalanine. Orff. Biomol. Chem. 4, 1209-1212. 

The third reaction pattern in nucleophilic reaction to difluoroalkenes is addition. Protic nucleophiles such as amines and alcohols add sometimes to the difluoroalkenes in a manner of 1,2-addition to the double bond where both nucleophilic moiety and proton are incorporated into the double bond (Scheme 2.27). A difluoromethylene moiety is potentially a carbonyl synthon and a difluoroalkylidene moiety is a synthon of an amide [17] and an ester (53) [18]. l,l-Difluoro-2-aminoalkenes (52) (R1 = amino moiety) would be transformed to dipeptides (53) (RX = amino ester, R1 = amino moiety) on reacting with amino esters. This idea was realized by the reaction of 60 with a variety of amino esters, leading to a practical synthesis of trifluoroalanine dipeptides (62) as shown in Scheme 2.27 [ 19]. 

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