Azlactone activation

Aldehydes and ketones react with azolinones. The reaction between aldehydes and 2-phenyl-5-oxazolinone (131 Y = H), formed in situ from PhC0NHCH2C02H and AC2O, gives azlactones (131 Y = RCH). Similar reactions are given by 4-thiazolidinones, e.g. (132) gives (133) (79AHC(25)83), and 4-imidazolinones. In pyrazolin-5-ones the 4-position is sufficiently activated for condensation to occur with ketones in acidic media (Scheme 8) (66AH06)347). 

A recent report describes the conversion of A-formyl- and N-acetyl-L-leucine into optically active azlactones with dicyclohexyl-carbodiimide (DCC) [Eq. (29)]. Other cyclization reagents, e.g. acetic anhydride, POCI3, SOCI2, and polyphosphoric acid, cause racemiza-tion. These azlactones react with optically active amino acid esters to give esters of dipeptides with retention of activity. 

Oxazolones (azlactones) are a form of activated lactones, so they are included in this section. CAL-B is an effective catalyst for the DKR of various racemic four-substituted-5 (4H)-oxazolones, in the presence of an alcohol, yielding optically active N-benzoyl amino acid esters as illustrated in Figure 6.24 [40]. Enantioselective biotransformations of lactides [72,73] and thiolactones ]74] have also been reported. 

Table 1. Porous properties and enzymatic activities of monolithic poly(2-vinyl-4,4-dimethyl-azlactone-co-acrylamide-co-ethylene dimethacrylate) reactors3... 

Berkessel and co-workers have demonstrated the utility of the bifunctional cyclohexane-diamine catalysts in the dynamic kinetic resolution of azalactones (Schemes 60 and 61) [111, 112]. The authors proposed that the urea/thiourea moiety of the catalyst coordinates and activates the electrophilic azlactone. The allyl alcohol nucleophilicity is increased due to the Brpnsted base interaction with the tertiary amine of the catalyst. 

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. 

The best preventive measure against racemization in critical synthetic steps (e.g. fragment condensation, see p. 239) is to use glycine (which is achiral) or proline (no azlactone) as the activated carboxylic acid component. The next best choice is an aliphatic monoamino monocarboxylic acid, especially with large alkyl substituents (valine, leucine). Aromatic amino acids (phenylalanine, tyrosine, tryptophan) and those having electronegative substituents in the /7-position (serine, threonine, cysteine) are, on the other hand, most prone to racemization. Reaction conditions that inhibit azlactone formation and racemization are non-polar solvents, a minimum amount of base, and low temperature. If all precautions are taken, one still has to reckon with an average inversion of 1 % per condensation reaction. This means, for example, that a synthetic hectapeptide contains only 0.99100 x 100% = 37% of the fully correct diastereomer (see p. 233 f.). 

The synthetic steps are thus the conversion of IV-acetylglycine with acetic anhydride into 2-methyloxazol-5-one (62), followed by reaction of the active methylene group with benzaldehyde to afford the corresponding benzylidene derivative (61) (Expt 8.24 see also Section 5.14.3, p. 736). In a similar manner N-benzoylglycine gives 4-benzylidene-2-phenyloxazol-5-one. These azlactones have been used as starting materials for the preparation of phenylpyruvic acid and phenylalanine (Expts 5.175 and 5.182 respectively). 

Oxazolones (73), the saturated azlactones, have been studied intensively (B-57MI41801, B-57MI41802, 65AHC(4)75,69MI41800,77AHC(21)175). They show carbonyl and C=N absorptions in the 1820 and 1660 cm-1 regions, respectively. Azlactones derived from chiral a-amino acids, e.g. compound (74), can be obtained in optically active forms which racemize easily. The derived salts (75 R2 = H, Me or Ph) likewise exhibit optical activity they show intense carbonyl bands at 1890-1880 and C=N+ absorptions at ca. 1650 cm-. ... 

---