Racemization oxazolinones

Compounds of types (286) and (287) are in tautomeric equilibria with 4- or 5-hydroxyazoles. However, the non-aromatic form is sometimes by far the most stable. Thus oxazolinone derivatives of type (287) have been obtained as optically active forms they undergo racemization at measurable rates with nucleophiles (77AHC(21)175). Reactions of these derivatives are considered under the aromatic tautomer. 

Racemic 6-benzoyloxycyclocitral (246) has been converted to (S)-6-hydroxycyclo-citral (248) via the oxazolinone (247). (248) was obtained in 63% enantiomeric excess247). 

Treatment of an a-amino acid with an anhydride in the presence of pyridine, known as the Dakin-West reaction,[1431 gives access to a racemic a-amido ketone.1 44 1451 The mechanism involves formation of an oxazolinone (98)J146 In the modified Dakin-West reaction, the oxazolinone is reacted with an acid chloride (Scheme 33)J136 139] Due to the rapid epimer-ization of the oxazolinones, a diastereomeric mixture of product 99 is obtained. No detailed protocol has been published so far for the modified Dakin-West synthesis applied to (oxomethyleneamino) peptides, but the procedure is adapted from that already reported for (oxomethylene) peptides containing the tp[CO-CH2] link.1147 ... 

In the most commonly detected pathway of racemization azlactones (5(4if)-oxazolones, 5-oxazolinones) are implicated. Proton abstraction from these cyclic intermediates results in a resonance stabilized carbanion... 

Merrifield s original idea was based on the general scheme of stepwise condensation of N-protected amino acids to the first one, which is linked with its carboxyl function by an ester bond to the insoluble polymer support. This way of solid phase peptide synthesis resulted from the well-known risk of racemization during activation of peptidic carboxyl components, which is minimized in activated amino acid derivatives, N-acylated by urethane-type protecting groups [40] (Fig. 7). Depending on the chosen method, the C-terminal activation of N-protected peptides tends to racemize a certain amount of the material because of the possible formation of an oxazolinone intermediate [41] (Fig. 8). 

Most of the activation methods known from conventional peptide synthesis in solution were explored on polymer concerning their desired reactivity in relation to side reactions, which are particularly unfavorable if the by-products are also bound to the support. Though urethane-masked amino acids generally are shielded from racemization under controlled conditions, this problem limits the use of peptidic building blocks C-terminally activated, since they tend to form the redoubtable oxazolinone intermediate from which the abstraction of a -proton is facilitated (Fig. 40). Recent results indicated a chance to overcome this problem and will be mentioned in the proper section of this chapter. 

A general synthesis of tryptophan involves condensation of 3-formyl-indole with oxazolinones derived from N-acyl-glycine. Recently, Kirby and Varley 225) have used this method to synthesize tryptophan stereoselectively labelled with tritium and deuterium in the p-methylene group. The synthesis employed is depicted in the following scheme (21) to (24) and (25). The hydrogenation step leading to the racemate... 

Another approach for the coupled racemization step has been used for compounds having an acidic hydrogen on the stereocenter. Examples of such compounds are chiral acyl donors such as a-substituted esters which are prone to base-catalyzed racemization via an enolate intermediate. This approach has been frequently used and a few examples will be given here to illustrate the utility (Scheme 11). The first examples involve oxa-zolinones where it was found that porcine pancreatic lipase and lipase from Aspergillus sp. exhibited opposite enantiopreferences [106,107]. The remaining oxazolinone was spontaneously racemized via the enolate intermediate and both (l)- and (D)-iV-benzoyl amino acids could be produced this way in high chemical and optical yields. The p Ka values of thio esters are lower than those of oxo esters [108]. This has been used in the lipase-... 

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