Azlactones nucleophilic attack

One of the oldest methods for the preparation of DHAs is the ring opening of unsaturated azlactones by attack of a nucleophile on the carbonyl group. Several methods for the synthesis of unsaturated azlactones (Azl) have been developed over the years and the chemistry of these important intermediates has been reviewed/1,2 Following are the methods of their synthesis that have remained in use during the last few decades. 

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). 

The iV-tosyl imine 55, which reacts with azlactone 52 as an electrophile (presented earlier), also reacts with 52 in a 1,3-dipolar cycloaddition reaction to give pyrroles 228 and 229 (Fig. 4.81). The pyridine 230 and pyridone 231 apparently arise by addition of the azlactone to the imine and subsequent cycUza-tion. The product distribution depends highly on experimental conditions, and a,p-unsaturated A -alkyl- and A -arylimines undergo nucleophilic attack only by the azlactone to give pyridines. Erba and co-workersobserved a novel formation of... 

P,P-Disubstituted alkylidene derivatives of oxindole, azlactone, and y-butyrolactone are used as precursors of vinylogous enolates, which are highly stabilized owing to the heteroaromatic nature of the enolate components. Although these a,p-unsaturated carbonyl systems can act as electrophilic Michael acceptors, the presence of two p-substituents seems to suppress nucleophilic attack on the P-carbon. 

The carboxylate function will readily add to the cation, after which mixed anhydride formation will occur. This will in turn react with the amino function of a second amino acid to give peptide bond formation. Further, the mixed anhydride so formed does not accumulate in solution (its formation is rate limiting) but instead suffers immediate nucleophilic attack by the amine. Azlactone formation does not have a chance to occur, and so no significant racemization is observed during polypeptide synthesis. The mixed anhydride formed will be attacked by the second amino acid only at one of the two carbonyl functions, giving carbon dioxide and ethanol by-products. The reason for this has been discussed earlier (see peptide bond formation via acid anhydrides). 

Figure 3.9 An azlactone reacts with amine groups through a ring-opening process, creating amide bond linkages with the attacking nucleophile.

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). 

Azlactone is commonly utilized as a precursor of a-quatemary a-amino acids and various heterocyclic compounds [28-30]. Because the enol form of azlactone has aromatic character, facile deprotonation from the C4-position affords the corresponding enolate under the influence of various bases. Interestingly, the enolate ion shows ambident reactivity and attacks the electrophile at either the C4-position (a-addition) or the C2-position (y-addition), thus acting as an a-amino enolate or an acyl anion equivalent, respectively (Fig. 1). The site-selectivity associated with this enolate seems to be heavily dependent on its stereoelectronic characteristics, and introduction of a bulky substituent into the Cl- or C4-position suppresses the nucleophilicity at the particular position. 

The commonly accepted mechanism for the Steglich rearrangement, depicted in Scheme 40.2, involves a fast and reversible attack of the nucleophilic catalyst to the acyl of alkoxycarbonyl group, leading to an ion pair that in a slow irreversible step leads to the formation of the C4- or C2-substituted azlactone. If the nucleophile is chiral, the acyl cation can discriminate between the two enantiotopic faces of the azlactone enolate, affording enantiomerically enriched products. 

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