Somatostatin conformationally restricted

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. 

The peptides (17)-(22) were prepared by the usual solid-phase method of peptide synthesis utilizing different resins. The structures of D-Phe (22a) and its conformationally restricted phenylalanine analogue D-Tic (tetrahy-droisoquinoline-3-carboxyIic acid, 22b) positioned at the A-terminal position of the somatostatin analogues are shown. 

The first successful application of conformational restriction to peptide chemistry was carried out by Veber et al. at Merck, (36), who were trying to simplify the structure of somatostatin (8) (Fig. 15.5) to produce an orally active derivative. Their approach was to introduce conformational restraints into the mac-... 

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