Oxazolone formation

AMIDE-BOND FORMATION AND THE SIDE REACTION OF OXAZOLONE FORMATION... 

FIGURE 1.7 Amide-bond formation and the side reaction of oxazolone formation. 

COUPLING, 2-ALKYL-5(4H)-OXAZOLONE FORMATION AND GENERATION OF DIASTEREOISOMERS FROM ACTIVATED PEPTIDES... 

FIGURE 1.9 Coupling, 2-alkyl-5(4//)-oxazolone formation and generation of diastereoiso-mers from activated peptides. 

Peptide-bond formation between an A -alkoxycarbonylamino acid and an amino-containing component usually proceeds in the same way as described for coupling an Y-acylamino acid or peptide (see Section 1.9), except for the side reaction (Figure 1.7, path B) of oxazolone formation. Aminolysis of the activated component (Figure 1.10, path A) gives the desired peptide. There are three aspects of the side reaction... 

The existence of a protonated oxazolone has been demonstrated indirectly by a simple experiment. When p-nitrophenol was added to an excess of 2-alkoxy-5(4//)-oxazolone in dichloromethane, a yellow color appeared. The color persisted until all the p-nitrophenol had been consumed by the oxazolone. The anion of p-nitro-phenol is yellow. The explanation for the color of the mixture is the presence of the p-nitrophenoxide anion that was generated by abstraction of the proton by the oxazolone. In summary, protonation of the O-acylisourea suppresses the side reaction of oxazolone formation as well as the side reaction of A-acylurea formation and accelerates its consumption by enhancing its reactivity and generating an additional good nucleophile that consumes it. Protonation of the oxazolone suppresses epimerization by preventing its enolization and also increases the rate at which it is consumed.4 68 78 79... 

IMPLICATIONS OF OXAZOLONE FORMATION IN THE COUPLINGS OF N-ALKOXYCARBONLYAMINO ACIDS IN THE PRESENCE OF TERTIARY AMINE... 

Figure 16.2. Racemization of activated iV-acyl amino acids as a result of oxazolone formation. X leaving group.

Since the discovery by Carpino et al.f l that A -Pbf-protected amino acids can be activated even as acid chlorides, such derivatives have been found to be well suited for the acylation of sterically demanding amino components (for details and experimental procedures, see Section 3.3.1). Oxazolone formation is prevented by this type of N -protection, racemization is not observed during activation and coupling.In line with these findings, further sulfonamide derivatives have been proposed such as l,3-benzothiazol-2-ylsulfonyl (Bts, 1Q4),[659,660] 5-methyl-l,3,4-thiadiazol-2-ylsulfonyl (105),f l 2-nitrophenylsulfonyl (oNbs, 4-nitrophenylsulfonyl (107),t l and 2,4-dinitrophenylsulfonyl group (108) (Scheme 49).f l... 

To prevent racemization, which was one of the limitations of the method (in some cases levels around 20% were reached), pre-formed isodipeptide units, such as Boc-Thr(Fmoc-Val)-OH, were introduced [75], On the basis of these previous results, a completely convergent approach to suppress racemization was also developed [76]. Thus, for a given peptide, an N-terminal fragment, bearing a C-terminal O-acyl isopeptide, was coupled to a C-terminal fragment. Owing to the presence of the urethane-protected Ser/Thr residue, oxazolone formation, and therefore racemization, is avoided. 

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