Synthesis of somatostatin and [D-Trp8]-somatostatin

Experimental details for practical syntheses of somatostatin and D-Trp8-somatostatin are described. The peptides were assembled from three fragments which permit further syntheses of analogs with modifications at positions 1, 2 or 8. N alpha-Bpoc protecting groups were used for the two major fragments and these were selectively removed in the presence of the tert.-butyl derived amino acid side chain functionalities. The two cysteine residues were protected by acetamidomethyl groups. All the peptide intermediates were fully characterized and a 10-g synthesis of the protected tetradecapeptide is reported. Major fragments were coupled by the azide method in good yield. Dihydrosomatostatin and D-Trp8-dihydrosomatostatin were isolated, purified, characterized and cyclized. Polymeric side-product was successfully recycled (by reduction with dithiothreitol and reoxidation) to give an overall yield for the oxidation of 52%. Somatostatin and D-Trp8-somatostatin were purified by gel filtration or countercurrent distribution and the final products were fully characterized and determined to be > 97% pure by reversed phase high performance liquid chromatography.