Total Synthesis of Cyclotheonamides, Potent Inhibitors of Thrombin

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Cyclotheonamides(A and B), potent andselective inhibitor of the serine protease thrombine, were isolated fron a marine sponge of the genus Theonalla. They are cyclic pentapeptides containing two, so far umknown, amino acid components, a vinylogous tyrosine and alpha-keto arginine. We have undertaken total synthesis of the interesting cyclic peptides for evaluation of their biological activities.The preparation of the protected E-vinylogous tyrosine ester was carried out by a new one-pot reaction in high selectivity from the protected amino alclhol derived from D-tyrosine. The synthesis of the alpha-keto arginine was accomplished as alpha-hydroxy acid after homologation of L-arginine. The protected 2,3-diaminopropionic acid was synthesixed fron Z-L-asparagine according the lzumiya method.With the three unusual amino acids in hand, toral synthesis of cyclothenamide B was set out. The dipeptide, H-Dpr-Pro-OR, and tripeptide, Boc-alpha-hydroxyArg-the-vinylTyr-OH, were coupled with our method. Thus obtained pentapeptide after deprotection was cyclized with pentafluorophenyl diphenylphosphinate to give the cyclic precursor in high yield. Oxidation of the alpha-hydroxy acid moiety to alpha-keto acid one with Dess-Martin reagent furmished the cyclotheonamide B.