[Total synthesis of somatostatin-28 (author's transl)]

Abstract

The total synthesis of the octacosapeptide corresponding to the proposed primary structure of porcine somatostatin-28 is described. The synthesis has been performed using a protection scheme of maximum selectivity (acid labile side chain protection based on tert-butyl alcohol and 1-adamantol derived protecting groups in combination with the S-tert-butylthio group for reversible and selective blocking of the cysteine thiol functions and the 2-nitrophenylthio group for the temporary protection of the alpha-amino functions of intermediate segments) and of carefully selected fragments. Upon assembly in sequence order of the four suitably protected fragments related to sequences 18-28, 15-17, 8-14 and 1-7, the asymmetric disulfides were reduced by exposure of the fully protected octacosapeptide to phosphines. Subsequently, the final deprotection was performed with trifluoroacetic acid and the resulting dihydrosomatostatin-28 was then converted by air oxidation into the "cyclic peptide". Gel filtration on Biogel P-6 and ion-exchange chromatography on Biogel CM-2 produced somatostatin-28 at a high degree of purity. Comparative analysis of the synthetic and natural product by means of chromatographic, immunological and biological assays confirmed the structure proposed for this putative precursor of somatostatin-14.