Total Synthesis of Cyclic Peptides from Natural Sources

Abstract

Naturally occurring cyclic peptides are rich sources of bioactive compounds that can be developed as novel pharmaceuticals with high selectivity and potency. However, the scarcity of their existence in nature impedes their further applications, which make the chemical synthesis of these intriguing compounds an imperative task. In this thesis, the total syntheses of nine naturally occurring cyclic peptides, along with two of their analogues, are described and some of these compounds are also evaluated for potential biological activity. Dianthin I (Chapter 2), pseudostellarin A (Chapter 2), heterophyllin J (Chapter 2) are three cyclic pentapeptides consisting of all proteinogenic amino acids. Their total syntheses were achieved by preparing the protected linear peptide precursors via Fmoc-solid phase synthesis (Fmoc-SPPS) followed by a classic solution-phase peptide cyclization. The same strategy was also applied to the syntheses of onychocins and their analogues (Chapter 3), which are a series of cyclotetrapeptides featuring the alternative presence of NMe-Phe in the peptide sequence. The unusual cyclization reagent, 2-propanephosphonic acid anhydride, was employed in peptide cyclization, which not only furnished the desired cyclic tetrapetides in reasonable yields but also generated several unstable cyclic peptide conformers in addition to the stable trans,cis,trans,cis cyclopeptides. Talarolide A (Chapter 4) is a cyclic heptapeptide containing a hydroxamate moiety within the peptide backbone. The proposed structure of talarolide A was successfully prepared from three different cyclization sites using a similar synthetic strategy as mentioned above. Despite the mismatch of the NMR data between the synthetic talarolide A and the natural product, a detailed structural analysis using 2D NMR spectroscopy confirmed that the synthetic product has the reported structure of talarolide A. The structure of the original natural product is therefore questioned. In addition, the first synthesis of the anti-TB cyclic peptide callyaerin A (Chapter 5), containing a rare (Z)-2,3-diaminoacrylamide (DAA) bridging motif, was also accomplished. Fmoc-formylglycine-diethylacetal was used as a masked equivalent of formylglycine in the synthesis of the linear precursor. Subsequent intramolecular cyclization between the formylglycine residue and the N-terminal amine in the linear peptide precursor afforded the macrocyclic natural product in high yield. Synthetic callyaerin A possessed potent anti-TB activity (MIC100 = 32 μM) while its all-amide congener was inactive. A variable temperature NMR of callyearin A and its all-amide counterpart demonstrated the high conformational rigidity imposed by the DAA moiety on the peptide structure, thus indicating its potential as a novel conformational constraint for peptides.