Azlactone, formation from

Azlactone Formation from P-Hydroxy-a-amino Acids... 

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. 

Azlactones. Formation of these products from A7-acylglycine and aldehydes in acetic anhydride in the presence of KF-AI2O3 appctfently requires a lower temperature. 

Peters applied the cooperative activation by a soft bimetallic catalyst 220, a hard Br0nsted acid, and a hard Bronsted base to the formation of highly enantio-enriched, diastereomerically pure masked a-amino acids 225 bearing adjacent tetrasubstituted and tertiary carbon stereocenters on the basis of a domino azlactone formation/Michael addition reaction starting from N-benzoylated amino acids 221 and a,P-unsaturated ketones 180 (Scheme 11.47). Since the activated catalyst was stable toward acetic anhydride, the in situ formation of azlactones 223 could be achieved through O-acylation with acetic anhydride of N-benzoylated amino acids... 

Scheme 4 Formation of Azlactones from p-Hydroxy-a-amino Acids1 1...

In another type of reaction, CH-acidic compounds in the presence of a strong base react with aldonitrones by C—C bond formation to form a hydroxylamine. Formed from the reaction of (78) and dimethyl malonate, the adduct (81) undergoes cyclization to an azlactone <71LA(748)143>. 

The azlactone can be recrystallized from alcohol, carbon tetrachloride, or from ethyl acetate with addition of petroleum ether. Aqueous solvents should be avoided, since the azlactone ring is easily opened by water. When alcohol is used for recrystallization, there is some danger of opening the azlactone ring with the formation of an ester, particularly on prolonged heating of the solution. 

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). 

But the formation of azlactones as intermediates cannot explain all the observations made in this field. Thus it has been mentioned already that ketene racemizes AT-methyltryptophan. Carter and Stevens (1940) state that certain acyl derivatives of ir-proline and W-methyl-n-phenyl-alanine are rapidly racemized by the action of acetic anhydride in glacial acetic acid. In the same paper it is also reported that the addition of various azlactones to a solution of benzoyl-p-methoxyphenylalanine in acetic acid produces fairly rapid racemization of the acyl derivative. An azlactone can obviously not be formed from a compound such as proline, and there is no evidence that structures such as XLIII exist and even if they exist, there is no apparent reason why they should be so easily racemized. There is a possibility of the transient formation of a dipolar structure such as XLV, which is analogous to the formula proposed for sydnones (Baker and Ollis, 1946). But a more likely explanation is that both ketene and acetic anhydride can form mixed anhydrides with acylamino acids, which can then rearrange to form azlactones and acetic acid. Reference has already been made to the action of ketene on carboxylic acids to produce mixed anhydrides and similar reactions have been observed with acetic anhydride. The marked racemization of such structures is partly explained by the strongly electronegative character of the anhydride group. Such an explanation is supported by the findings... 

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