CYCLIDES · Synthesis of Cyclic Peptides using Efficient Carbon-Carbon Bond-Forming Reactions

Final Activity Report Summary - CYCLIDES (Synthesis of cyclic peptides using efficient carbon-carbon bond-forming reactions)

There are many examples of biologically actives peptides, including examples of acyclic and cyclic structures. Unlike their acyclic congeners, cyclic peptides exhibits substantial resistance to proteoloytic enzymes, and can exhibit both irreversible and reversible inhibition of such enzymes, and for this reason they are potential drugs. Some examples of natural products falling into this class include the angiotensin converting enzyme inhibitor K-13 and the aminopeptidase inhibitor OF4949-III. There is therefore substantial interest in the preparation of analogues of these compounds as potential therapeutic agents. Our own research group has prepared recently the shortest synthesis of K-13. Its synthesis involves the intramolecular coupling of organozinc reagent, with aryl iodides catalysed by palladium species. With this precedent, the objective of this project is to develop a synthetic route to the naturally occurring Biphenomycin B. Biphenomycin B is a cyclic tripeptide, exhibiting high antibiotic activities against Gram-positive, beta-lactam-resistant bacteria. The strategy that we planned to use involves an intramolecular double coupling of a highly functionalised tripeptide organozinc reagent, which can be prepared efficiently from simple starting material, with aryl diiodides catalysed by palladium (0). The benefit of this route is that the use of protection and deprotection steps is minimised, ensuring in this way an efficient synthesis. In order to assess this double coupling reaction, it was decided to prepare a simpler compound before facing the total synthesis of the Biphenomycin B. The compound chosen to synthesise was the also natural product dityrosine. Dityrosine has been found as a constituent of proteins, in fungi, insects and in several vertebrates, where it seems to be partially responsible for the elastic and insoluble qualities of the proteins containing it. In vivo generation of dityrosine appears also to be important to defend the organism from hostile environments. Therefore, its synthesis implies a similar strategy to the former case, a double-coupling reaction between an organozinc derivate of the natural and commercially aviable L-serine and an aryl diiodide derivative. Although the preparation of the organozinc L-serine derivative is previously reported in the literature, the access to the aryl diodide derivatives was not so obvious. After several attempts, the synthesis of these compounds was achieved in good yield. The double coupling reaction had been the main object of our study. Finally we have found suitable reactions conditions for the achievement of this reaction. The synthesis and isolation of dityrosine was performed in a 65% yield. This result implies a new, short and effective synthesis of this important natural product. The completion of this synthetic process has given us a good and deep understanding of the double-coupling reaction, since an assessment of this reaction in several reactions condition has been carried out. After gaining a good understanding of this reaction, we were ready to face the synthesis of the more structurally complicated Biphenomycin B. The synthesis of the aryl diiodide derivate has been achieved in good yield using a procedure described in the literature. Preparation of the tripeptide needed for the synthesis of the antibiotic, has been also been successful, although an improvement in some synthetic step is necessary before going ahead with the synthetic route. The early termination of the Fellowship, due to the Fellow obtaining permanent employment in the pharmaceutical industry, meant that this work has not yet been tackled.

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