Unsaturated 5 -oxazolones amino acids

Several approaches to the 1,2,3-triazole core have been published in 2000. Iodobenzene diacetate-mediated oxidation of hydrazones 152 led to fused 1,2,3-triazoloheterocycles 153 <00SC417>. Treatment of oxazolone 154 with iso-pentyl nitrite in the presence of acetic acid gave 1,2,3-triazole 155, a precursor to 3-(W-l,2,3-triazolyl)-substituted a,P-unsaturated a amino acid derivatives <00SC2863>. Aroyl-substituted ketene aminals 156 reacted with aryl azides to provide polysubstituted 1,23-triazoles 157 <00HC387>. 2-Aryl-2T/,4/f-imidazo[43-d][l,2,3]triazoles 159 were prepared from the reaction of triethyl AM-ethyl-2-methyl-4-nitro-l//-imidazol-5-yl phosphoramidate (158) with aryl isocyanates <00TL9889>. 

The azlactones of a-benzoylaminocinnamic acids have traditionally been prepared by the action of hippuric acid (1, Ri = Ph) and acetic anhydride upon aromatic aldehydes, usually in the presence of sodium acetate. The formation of the oxazolone (2) in Erlenmeyer-Plochl synthesis is supported by good evidence. The method is a way to important intermediate products used in the synthesis of a-amino acids, peptides and related compounds. The aldol condensation reaction of azlactones (2) with carbonyl compounds is often followed by hydrolysis to provide unsaturated a-acylamino acid (4). Reduction yields the corresponding amino acid (6), while drastic hydrolysis gives the a-0X0 acid (5). ... 

The first syntheses of a-allenic a-amino acids [131,133] took advantage of Steg-lich s [134] protocol for the oxazole-Claisen rearrangement of unsaturated N-ben-zoylamino acid esters (Scheme 18.46). Thus, treatment of the propargylic ester 143 with triphenylphosphine and tetrachlormethane furnished the allenic oxazolone 144, which was converted into the amino acid derivative 145 by methanolysis. Stepwise deprotection finally led to the allenic DOPA analog 146, which shows a much higher decarboxylase-inhibiting activity than a-vinyl- and a-ethynyl-DOPA [133],... 

When p-arylserines rather than glycine are used as the starting amino acid, cyclization occurs concomitant with dehydration to afford the corresponding unsaturated 5(4//)-oxazolone." ... 

One of the fundamental cleavage reactions of the heterocyclic ring in unsaturated oxazolones is the conversion to acids or esters. This process leads to dehydroamino acid derivatives from which a wide variety of amino acids are prepared by hydrogenation. The side chain of the final amino acid is determined by the aldehyde used to prepare the unsaturated oxazolone. For example, benzalde-hyde and an A -acylglycine afford 2-acylaminocinnamic acids 434 after hydrolysis of the oxazolone 433. In turn, 434 are excellent precursors to phenylalanine. 

Other alcohols ring-open unsaturated oxazolones including glycerol that was used to prepare monoglycerides of acylamino acids.In addition, alcoholysis with 3,4,4-trifluorobut-3-enol leads to amino acid fluorobutenyl esters that are used as pesticides.Finally, (dimethylamino)ethanol and other amino alcohols have also been used to obtain the corresponding aminoalkyl esters. 

Amino acids " " and aminobenzoic acids " " react as nitrogen nucleophiles to effect ring opening of unsaturated 5(4//)-oxazolones. Cyclization of the intermediate acylamino amide has opened the way for the synthesis of new series of imidazolones that now incorporate a carboxylic acid moiety into the N-1 substituent. These compounds are readily further elaborated into derivatives with diverse biological activity. 

Therefore, suitable unsaturated oxazolones can be used as intermediates to prepare dehydropeptides wherein the synthetic strategy used will depend on the position of the double bond in the final compound. If the double bond is located in the N-terminal amino acid, ring opening of the oxazolone 516 with the appropriate amino acid or peptide generates the desired dehydropeptide 517 directly. 

It is well known that hydrogenation of dehydroamino acid derivatives derived from ring opening of unsaturated 5(4H)-oxazolones affords new racemic amino acids and, in some cases, enantiomerically pure compounds. On the other hand, a number of attempts have been made to hydrogenate the double bond of the unsaturated oxazolone itself. For example, 4-benzyl-2-methyl-5(4//)-oxazolone was prepared from 4-benzylidene-2-methyl-5(4H)-oxazolone using Raney Ni as a catalyst. This process is reported to be a general procedure to prepare saturated oxazolones directly (Scheme 7.194). 

Catalytic hydrogenation of the exocychc double bond of several oxazolones 611, in the presence of acetic acid, gives a-acylamino alcohols 613 via the saturated derivatives 612 (Scheme 7.196). Selected examples of amino acid derivatives and amino alcohols available from reduction of unsaturated oxazolones are shown in Table 7.45 (Fig. 7.56). 

TABLE 7.45. AMINO ACID, AMINO ESTER AND AMINO ALCOHOL DERIVATIVES FROM HYDROGENATION OF UNSATURATED 5(4//)-OXAZOLONES... 

Since (Z)- and ( )-stereoisomers of unsaturated oxazolones can be obtained using appropriate isomerization procedures, cis and trans isomers of cyclopropane derivatives can be obtained in a stereoselective manner, although special care must be taken with experimental conditions to obtain the best stereoselectivity. Both racemic cis- and fraui-l-amino-2-phenylcyclopropanecarboxylic acid 641 and 644 have been obtained from the corresponding (Z)- or ( )-4-benzylidene-2-phenyl-5(4//)-oxazolone 621 and 642 using diazomethane. Care was taken to affect the... 

Fluorination of unsaturated 5(47/)-oxazolones 758 affords the expected difluori-nated derivatives 759. Basic hydrolysis of 759 yields a p-fluoro-a-keto acid 760 that is reductively aminated to give an e t/jw-p-fluoro-a-amino acid 761... 

On the other hand, as synthetic equivalents of amino acids, unsaturated oxazolones are and will continue to be very important intermediates for the synthesis of new non-proteinogenic a-amino acids, particularly for the asymmetric synthesis of these compounds using diastereo- or enantioselective methodologies. In addition, the exocyclic double bond will continue as an important focus to build new constrained amino acids for the design of peptides with improved properties. 

H)-Oxazolones react readily with nucleophiles, C(5) and C(2) be ing possible sites for attack, and, in the case of unsaturated azlactones, C(a) as well (see 199-201). It has been proved by using water labelled with lsO that the acid-catalyzed hydrolysis of unsaturated azlactones proceeds by alkyl-oxygen fission (equation 42). The formation, hydrolysis and reduction of 4-methylene-5(4H)-oxazolones is a well-established method for the synthesis of a-amino acids, e.g. phenylalanine (equation 43). The addition of hydrazoic acid to 5(4H)-oxazolones without methylene groups at C(4) likewise occurs exclusively at C(2) to yield tetrazoles by ring-opening and recyclization (equation 44). 

However, most nucleophiles attack 5-oxazolones at the carbonyl group and the products are derivatives of a-amino acids formed by acyl-oxygen fission. Thus the action of alcohols, thiols, ammonia and amines leads, respectively, to esters, thioesters and amides orthophosphate anion gives acyl phosphates (Scheme 18). The use of a-amino acids in this reaction results in the establishment of a peptide link. Cysteine is acylated at the nitrogen atom in preference to the sulfur atom. Enzymes, e.g. a-chymotrypsin and papain, also readily combine with both saturated and unsaturated azlactones. A useful reagent for the introduction of an a-methylalanine residue is compound (202). Both the trifluoroacetamido and ester groups in the product are hydrolyzed by alkali to give a dipeptide. The alkaline hydrolyzate may be converted into the benzyloxycarbonyl derivative, which forms a new oxazolone on dehydration. Reaction with an ester of an amino acid then yields a protected tripeptide (equation 45). 

Bergmann s synthesis (1926) is still used to prepare unsaturated azlactones containing only alkyl substituents. It consists of the treatment of a-alkyl a- (a-halogenoacyl)amino acids with acetic anhydride and it involves the isomerization of an intermediate 2-methylene-5(2H)-oxazolone. An example is given in equation (153). 

Arylmethylene-5(2i/)-oxazolones, unsaturated pseudooxazolones , are prepared by the combined action of acetic anhydride and pyridine on a-(/3-chloroarylacetyl) amino acids (equation 159) or on a-acryloylamino acids (equation 160). 

The conversion of an ce-(a -haloacyl)-amino acid into an unsaturated azlactone has not been studied extensively. A proposed mechanism is shown in the above equations. On treatment with acetic anhydride and pyridine at room temperature, N-chloroacetyl-dl-/3-phenylalanine is converted into a-acetaminocinnamic azlactone (yield, 80%) and N-chloroacetyl-l-tyrosine into 2-methyl-4r-p-acetoxybenzal-5-oxazolone. This reaction has been applied in the sjmthesis of an a-keto acid from the corresponding ce-amino acid. a-Bromopropionyl-dl-methionine was converted into the unsaturated azlactone by the action of acetic anhydride and sodium acetate. Dilute hydrochloric acid was added, and the reaction mixture was heated in a water bath for five minutes, yieldii a-keto-7-methiolbutyric acid, which was isolated as the phenylhydra-zone. ... 

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