Formation and Reactions of 2-Substituted 4,4-Dimethyl-5(4H)-oxazolones. The 5(4H)-Oxazolone as a Stable Intermediate in Peptide Bond Formation

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Abstract
The reaction of Boc–Leu3–Aib–OH with H–Leu3–OBzl using DCC as a coupling reagent proceeded via the exclusive 2-substituted 4,4-dimethyl-5(4H)-oxazolone formation followed by a slow aminolysis. Similar treatment of Boc–Leu3–Aib–OH with DCC in the presence of p-nitrophenol did not produce a p-nitrophenyl ester, but produced the 2-substituted 4,4-dimethyl-5(4H)-oxazolone (1) in a high yield within 20 min. The high potential for the oxazolone formation of Boc–Leun–Aib–OH (n=3 and 4) is apparently attributed to the conformational effect of C-terminal Aib residues, namely, the restriction of the backbone dihedral angles φ and ψ of Aib residues. Ring-opening reactions of oxazolones with hydroxy compounds were easily monitored by following the disappearance of the intense oxazolone peak at 1820 cm−1. The oxazolone (1) reacted faster with HOSu than H–Leu3–OBzl, followed by the slow aminolysis of the succinimide ester produced. In contrast, HOBt did not react with the oxazolones derived from Boc–Leu3–Aib–OH (n=3 and 4), but strongly catalyzed the aminolysis of the oxazolones in dichloromethane to form peptide bonds in nearly quantitative yields. A little catalytic effect of acetic acid on the oxazolone aminolysis indicated that the oxazolone aminolysis in the presence of HOBt did not proceed through a simple acid catalytic pathway, but proceeded through a biphilic (electrophilic–nucleophilic) pathway.

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