Catalytic hydrogenolysis in liquid ammonia. Cleavage of Nalpha-benzyloxycarbonyl groups from cysteine-containing peptides with tert-butyl side chain protection. Application to a stepwise synthesis of somatostatin.
To exemplify the extension to synthesis of sulfur-containing peptides of the Nalpha-benzyloxycarbonyl and side chain tert-butyl protective group combination, somatostatin has been synthesized via incremental chain elongation starting from the COOH-terminal cysteine. Cleavage of the Nalpha-benzyloxycarbonyl groups was achieved in high yield, at each stage, by palladium-catalyzed hydrogenation in liquid ammonia. All side chain functionalities including the cysteine thiol groups were blocked by tert-butyl-derived groups. Each gave rise to individual n.m.r. signals which permitted sensitive characterization of all intermediate protected peptides. Mild conditions were used for the removal of all protecting groups from the completed somatostatin tetradecapeptide. The tert-butyl thiol protective groups were readily and completely cleaved by mercuric acetate at pH 4. Oxidation of dihydrosomatostatin with potassium ferricyanide provided somatostatin in good yield. The results indicate that the absolute selectivity between alpha-amine and side chain protective group cleavage afforded by Nalpha-benzyloxycarbonyl hydrogenolysis in the presence of omega-tert-butyl groups may now be extended to synthesis of cysteine- and methionine-containing peptides.
D000595:Amino Acid Sequence; D000641:Ammonia; D000818:Animals; D001593:Benzyl Compounds / Q000138:chemical synthesis; D002384:Catalysis; D055598:Chemical Phenomena; D002621:Chemistry; D003545:Cysteine / Q000031:analogs & derivatives*; D010446:Peptide Fragments; D051381:Rats; D013004:Somatostatin / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
D001593:Benzyl Compounds; D010446:Peptide Fragments; D013004:Somatostatin; D000641:Ammonia; D003545:Cysteine