Reactive Intermediates in Peptide Synthesis: First Crystal Structures andab InitioCalculations of 2-Alkoxy-5(4H)-oxazolones from Urethane-Protected Amino Acids

Abstract

The structures of the 2-alkoxy-5(4H)-oxazolones derived from 2,2,6,6-tetramethyl-4-[(benzyloxycarbonyl)amino]-1-oxypiperidine-4-carboxylic acid and 2,2,6,6-tetramethyl-4-[(9‘-fluorenylmethoxycarbonyl)amino]-1-oxypiperidine-4-carboxylic acid have been solved by single-crystal X-ray diffraction. The overall geometry of their oxazolone ring compares well with that of 2-alkyl-5(4H)-oxazolones. However, the bond distance from C2 to the exocyclic O(2) atom is shorter than expected for a (sp2)C−O single bond, thus suggesting a significant involvement of a O(2) lone pair in the electron delocalization of the CN π-system. These two structures represent the first examples of 2-alkoxy-5(4H)-oxazolones in the crystal state. Ab initio molecular orbital calculations have been performed on (4S)-2-methoxy-4-methyl-5(4H)-oxazolone and (4S)-2,4-dimethyl-5(4H)-oxazolone [as simple models for 2-alkoxy- and 2-alkyl-5(4H)-oxazolones, respectively, derived from the chiral protein amino acid l-Ala] both in the neutral and deprotonated state. The calculated geometries of the 2-alkoxy- and 2-alkyl-5(4H)-oxazolone systems at the MP2/6-31+G(d,p) level agree well with those experimentally determined in the crystal state. The calculated energetics of deprotonation show only modest differences between the two systems. Conversely, a theoretical investigation of the reaction of model oxazolones with ammonia as a nucleophile indicates that for 2-alkoxy-5(4H)-oxazolones the activation energy of the rate-determining step is significantly lower and the overall stabilization energy is larger than for 2-alkyl-5(4H)-oxazolones. The implications of these results with respect to coupling and racemization of urethane-protected amino acids in peptide synthesis are outlined.