Reactive intermediates in peptide synthesis: First crystal structures and ab initio calculations of 2-alkoxy-5(4H)-oxazolones from urethane-protected amino acids

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'-fluorenylmethycarbonyl)amino]-1-oxycarbonylpiperidine-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 C-2 to the exocyclic O(2) atom is shorter than expected for a (sp(2))C-O single bond, thus Suggesting a significant involvement of a O(2) lone pair in the electron delocalization of the C=N pi-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 front 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.