Conformational restriction case studies

Alternatively, if the dehydroamino acid is C-terminal or is central in the peptide chain, then the oxazolone precursor to the dehydropeptide must be in position two in order to apply this methodology (Scheme 7.165). The requisite unsaturated 5(4//)-oxazolone intermediate 518 is obtained from the appropriate precursors following standard cyclization procedures and avoiding experimental conditions that would epimerize the chiral center. This methodology has been applied to access analogues of important peptides including dehydroaspartame, somatostatin, and dermorphin. In these cases, a dehydroamino acid was incorporated into the peptide backbone to study the relationship between conformational restriction and biological properties of the modified peptide. 

Caswell and Schmir (1979) that PLNM/ALPH effects will be observed only in conformationally restricted systems. These authors studied products of hydrolysis of -imidate [92] and an equimolar mixture of this and the Z-imidate [93] as a function of pH. The percentage of ester in both cases was quantitatively described by the same titration curve, the yield of 101% ester at low pH falling to 65% at high pH, with the change governed by an apparent p/fa-value of 10.2. Rotation about the C—O or C—N bonds of the tetrahedral intermediate [94] is thus fast compared with its decomposition across the whole pH range. 

Nevertheless, when this article is continued after two decades, it should not remain restricted to stereochemical problems. During that time, other very powerful methods will have been developed which are mostly easier and often also more reliable. Particularly, the recent development in X-ray analysis gives a completely reliable proof of configuration valid even for the isolated molecule in the case of conformation it may appear necessary to prove that it is unchanged in solution (see for instance Reference 3). While X-ray is the most reliable method, NMR spectroscopy is the fastest. It still uses some empirical rules and comparison with model compounds, but in a modem version (2-D NMR, NOE) it is also completely trustworthy. Therefore, many recent dipole-moment studies investigated compounds whose steric arrangement was already known, and attention was focused on the electron distribution on the individual bonds, or in conjugated systems. The difference in the point of view may be explained as follows. 

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