School of Chemistry - Theses

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Author: Shabanibalajadeh, Sadegh × Start date: 2000 × Subject: natural product ×

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    Total synthesis of complex biologically active cyclic peptides
    Shabanibalajadeh, Sadegh ( 2020)
    Cyclic peptide natural products have played an essential role in drug development and biomedical research, with drugs such as vancomycin, penicillin, and cyclosporine revolutionising modern medicine. Modification of cyclic peptides improves a number of their pharmacological properties such as target selectivity, binding affinity and specificity, proteolytic stability, oral bioavailability, and reduced toxicity. In addition to improvement of the pharmacological properties, current advances in peptide synthesis, rational drug design, and structure determination have assisted the development of novel macrocyclic peptides. The growing interest in peptide-based drugs in organic synthesis and medicinal research, along with the promising efficacy of cyclic peptides, offers many opportunities for the development of cyclic peptides towards the treatment of several diseases. This research project focused on the total synthesis of complex biologically active cyclic peptides. Specifically, three projects where undertaken: -Total synthesis of asperipin-2a -A new method for the macrolactonisation of peptides through a thioamide strategy: total synthesis of seongsanamide E and Kahalalide B. -Total synthesis of seongsanamide B Asperipin-2a is a modified bicyclic hexapeptide which possesses two aryl-alkyl ether bridges. The unusual structure of asperipin-2a, together with its unknown configuration and potent biological activity, prompted us to investigate a route toward its total synthesis. The ether bridges were successfully synthesised through an aziridine ring opening reaction and a Mitsunobu reaction. The diastereomers were separated and 2D-NMR spectroscopy together with X-ray crystallography were employed to identify the absolute configuration of stereogenic centres. The synthetic route was continued and the total synthesis of asperipin-2a was performed. In the second project, a new macrolactonisation strategy was investigated employing a Ag(I)-promoted transformation of peptide thioamides. Linear peptide thioamides were synthesised using general SPPS protocols incorporating amino thioacyl benzotriazolidines as thioacylating agents and the macrolactonisation in the presence of silver carbonate was investigated. The project highlighted a new method for the macrolactonisation of peptides through silver-assisted thioamide cyclisation. Moreover, this new method enabled the preparation of a range of depsipeptide ring sizes and could overcome the common drawbacks of standard macrolactonisation methods including cyclisation yields and limited reactivity of the Thr/Ser hydroxyl group. The final chapter entails the total synthesis of the seongsanamide B. The main challenge in the synthesis of seongsanamide B was the formation of the biaryl ether linkage in the highly functionalised bicyclic macrolactone. Initial efforts towards the synthesis of seongsanamide B focused on the synthesis of the biaryl ether linkage. The dopa and phenylalanine-boronic acid starting materials were synthesised. An early stage esterification and a late stage construction of the biaryl ether was elected. On resin esterification of dopa, solution-phase macrolatonisation, and a late stage intramolecular Evans-Chan-Lam coupling reaction furnished seongsanamide B.