The objective of this research work was to carry out the first total synthesis of Cyclotheonamide C (CtC), a macrocyclic pentapeptide isolated from the sponge Theonella swinhoei, which is a powerful inhibitor of thrombin and other serine proteases. It has several unique structural features, including a vinylogous dehydrotyrosine (V-ΔTyr) and an α- ketohomoarginine (K-Arg), and represents a considrable synthetic challenge. We reasoned that the key feature of the total synthesis of CtC would involve the creation of the K-Arg moiety or an approriate surrogate, α-Hydroxyhomoarginine (H-Arg) in advanced peptide intermediates. Three different strategies for achieveing this are proposed: they are designated "Passerini - Acyl Migration" (PAM), "Masked Acyl Cyanide" (MAC) and "α-Keto-Acyl Cyanide" (KAC). The first chapter of the thesis is a short appraisal of all known previous syntheses of members of the Ct family (essentially concerning CtA, CtB, CtEB2B and CtEB3B). After the presentation of the three strategies for the construction of the H-Arg or K-Arg moieties, in chapter II, chapters III and IV are devoted respectively to the preparation of electrophilic peptides (aldehydes and α-ketocyanophosphoranes) and nucleophilic peptides (amines and isonitiles) which are necessary for the execution of the different strategies. We also describe the first construction of the V-ΔTyr moiety within a dipeptide, using several approaches (palladium cross-coupling and Wadsworth-Emmons reactions) and revealed the particular reactivity of this totally conjugated system. In chapter V, the three strategies PAM, MAC and KAC are developed to furnish several linear and hence macrocyclic pentapeptide advanced intermediates. Deprotection and oxidation steps formally complete the total synthesis of CtC. To our knowledge, this chemistry involved in the PAM and MAC strategies has never been applied to such elaborate structures. Procedures according to the KAC strategy are the most advanced, and have allowed characterization of the first synthetic sample of CtC by LC-MS.
