Amino acids, preparation azlactonization

Azlactones have been of interest mainly as intermediates in the synthesis of other compounds. Saturated azlactones are obtained most often from the corresponding amino acids and are used in preparing derivatives of those amino acids. Unsaturated azlactones, on the other hand, usually are prepared by condensing an aldehyde with an acylglycine and are used in the synthesis of the corresponding amino and keto acids. Four methods by which azlactones can be prepared are discussed in the following paragraphs. 

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 preparation of the first unsaturated azlactone was reported in 1883 by Plochl/40 who condensed benzaldehyde with hippuric acid in presence of acetic anhydride. This approach was later used by Erlenmeyer/41 who extended the procedure to include other aldehydes and also established the usefulness of azlactones as intermediates in the synthesis of DHAs. The method involves the condensation of an A-acylglydne 4 with aldehydes and ketones in the presence of acetic anhydride and anhydrous sodium acetate (Scheme 2)J41 t5l Other catalysts such as copper(II) acetate/46 lead acetate/47,48 potassium carbonate/49 or potassium hydrogen carbonate 50 have also been used. The reaction proceeds via formation of an azlactone 5, which then condenses with the appropriate aldehyde or ketone to give unsaturated azlactone 6. Reaction of 6 with a nucleophile such as OH, OR, or NHR leads to the corresponding A-acyl-DHA derivatives 7. Reaction with the sodium salt of an amino acid gives a DHA containing dipeptide acid. 51 ... 

In this case, the amino acid is already oxidized at the (3-position and elimination of the hydroxy group, as the acetate, generates the double bond. Reaction of the unsaturated azlactone and the free base of an amino acid ester produces the dipeptides containing APhe. This approach has been extensively used in the preparation of a series of APhe containing peptides15 63 ... 

Protected amino acids with either a free amino or carboxyl function can usually be prepared by proven methods or are even commercially available. Therefore stages (i) - (iii) may be considered as simple routine nowadays, although great care must be taken that the protected starting materials are pure enantiomers. The reactions that cause most trouble are in stages (iv), (v) and (vii). In these stages an activated carboxyl group is involved and the chiral centre adjacent to it is at peril from racemization. A typical reaction which causes epimerization is azlactone formation. With acids or bases these cyclization products may reversibly enolize and racemize. Direct racemization of amino acids has also been observed. 

Whereas preparation of a-amino acid derivatives by asymmetric allylation of an acyclic iminoglycinate gave a modest enantioselectivity (62% ee) in an early investigation [189], the use of conformationally constrained nucleophiles in an analogous alkylation resulted in high selectivities (Scheme 8E.43) [190], With 2-cyclohexenyl acetate, the alkylation of azlactones occurred with good diastereomeric ratios as well as excellent enantioselectivities. This method provides very facile access to a variety of a-alkylamino acids, which are difficult to synthesize by other methods. When a series of azlactones were alkylated with a prochiral gem-diacetate, excellent enantioselectivities were uniformly obtained for both the major and minor diastereom-ers (Eq. 8E.20 and Table 8E.12). 

This method is mainly restricted to the synthesis of amino acids with aromatic side-chains since the required unsaturated azlactones [e.g. (30)] are most readily prepared using aromatic aldehydes. Typically, benzaldehyde condenses under the influence of base with the reactive methylene group in the azlactone (29) which is formed by the dehydration of benzoylglycine (28) when the latter is heated with acetic anhydride in the presence of sodium acetate (cf. Expt 8.21). The azlactone ring is readily cleaved hydrolytically and compounds of the type (30) yield substituted acylaminoacrylic acids [e.g. (31)] on boiling with water. Reduction and further hydrolysis yields the amino acid [e.g. phenylalanine,... 

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). 

One general synthetic difficulty in the preparation of acid chlorides of amino acids, particularly those in which the (X-NH2 is protected by acylation, is the formation of azlactones. Tosyl derivatives partially avoid this difficulty. 

Azlactone synthesis. Use of the reagent in the azlactone synthesis of amino acids is illustrated by a procedure for the preparation of DL-phenylalanine. - A mixture of 0.5 mole each of benzaldehyde, hippuric acid, and anhydrous sodium acetate is treated with 153 g. of acetic anhydride, and the mixture heated and stirred until the... 

Fig. 3 Overall sequence for azlactone synthesis, hydrogenation, and hydrolysis for the preparation of amino acids.

N-acyldehydrodipeptides were readily prepared either by the condensation of N -acyldehydro-a-amino acids with a-amino acid esters or by the reaction of the azlactones of dehydro-a-amino acid with a-amino acid esters (eq. 1). Asymmetric hydrogenation of the N-acyldehydrodipeptides thus obtained (eq. 2) was carried out by using rhodium complexes with a variety of chiral diphosphines such as -Br-Phenyl-CAPP (3), Ph-CAPP (3), (-)BPPM (4), (+)BPPM (4), (-)DIOP ( ), (+)DIOP ( ), diPAMP (6), Chiraphos (7), Prophos (S), BPPFA (9) and CBZ-Phe-PPM (Fig. 1)(10). The chiral catalysts were prepared in situ from chiral diphosphine ligand with [Rh(NBD)2l -CIO4 (NBD = norbomadiene). Typical results are summarized in Tables I-V. 

Azlactones. Bi(OAc)3 is a useful catalyst for the preparation from a-amino acids. 

This reaction has been modified to heat amino acid with trifiuoroacetic anhydride to form 4-substituted-2-(trifluoromethyl)-6-oxazolone, which can react with the succeeding amino acid to form peptide. The azlactone with a saturated side chain can be prepared from Qf-keto acid and subjected to the peptide synthesis. 

This reaction has general application in the preparation of peptide. The azlactone itself can be converted into of-keto acid or of-amino acid. ... 

Processes for the Rh-duphos-catalyzed hydrogenation of several a-amino acid derivatives with a variety of structural elements were developed and carried out on a scale of up to multihundred kilograms by Dow/Chirotech [23] which also assisted in developing a process for a bis-amino acid intermediate for Nycomed [24], Similartechnology was used by Chirotech for Dr. Reddy s to make a substituted D-phenylalanine, an intermediate for a new therapeutic agent [25]. In this case, the enamide ester was prepared in situ by methanolysis of the corresponding azlactone (Fig. 4). 

The molybdenum and tungsten complexes catalyze reactions of soft nucleophiles, such as malonates, related 1,3-dicarbonyl compoimds, and nitroalkanes. Azlactones are also soft carbanions, and Trost has shown that complexes formed from molybdenum and the bis(pyridine) ligands catalyze enantioselective and diastereoselective allylation of azlactones with allylic phosphates to form quaternary amino acids (Equation 20.40). In these reactions, the nucleophile adds to the more substituted position of the allylic electrophile, and a stereocenter is formed at both the allyl carbon and the azlactone carbon. One route to the protease inhibitor tipranavir by the molybdenum-catalyzed allylation with 1,3-dicarbonyl compounds was demonstrated by Trost (Equation 20.41), and the Merck process group used related allylation chemistry with Trost s bis(pyridine) ligand to prepare the cyclopentanone precursor to various analogs of tipranavir (Equation 20.42). 

Amino acids react with potassium thiocyanate to form a thia-zolone derivative (a thiohydantoin). The azlactone of glycine can be used as a synthetic intermediate for the preparation of substituted amino acids. 

Use the azlactone of glycine to prepare the allyl, benzyl, and 4,4-diphenylbu-tyl derivatives. Convert each to the appropriate amino acid. 

The dipeptide azlactone (208) has been converted to the protected unsaturated dipeptide (209) by oxidation with DDQ followed by methanolysis. Two reports have appeared on the conversion of a-keto-acids and esters into a,j3-unsaturated amino-acid derivatives. In the first the anhydride (210) is prepared from an a-keto-acid, then converted into (211) with ethanol. The second example... 

Kobayashi et al. also applied the catalyst to asymmetric 1,4-addition reactions of azlactones with acrylates [66]. The active a-proton of the azlactone (5(4H)-oxazolone) skeleton showed a low pKa value compared to that of the alanine Schiff bases, because the anion formed is stabilized via enol formation and aromatization. After 1,4-addition reactions with acrylates, the 2-substituted glutamic acid derivatives formed could be obtained via hydrolysis using a weak acid. It was found that Pybox 3 prepared from alaninol derivatives was effective for this reaction. The desired products were obtained in good yields with good enantios-electivities. Several amino acid derivatives containing aUcyl chains in the a-position were screened, and the leucine derivative (R = Bu) showed the best enantio-selectivity in this reaction (Table 16, entry 8). 

Saturated a-acylamino acids are prepared by acylation of o-amino acids or, less frequently, by reduction of the corresponding unsaturated compounds. It sometimes is possible to effect both the preparation of the o cylamino acid and the formation of the azlactone by heating the amino add with a large excess of acetic anhydride. Leucine and phenylalanine give excellent yields of azlactones under these conditions. However, this method is not satisfactory with alanine, diiodotyrosine, isovaline," or a-amiiioisobutyric acid," which yield products of high molecular weight. 

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