Abstract:
This thesis describes the synthesis of the cyclodepsipeptide xenematide and the peptaibol culicinin D. Xenematide is shown to exhibit potent antibacterial activity against E. amylovora which is the pathogen that causes death of apple and pear trees. Two diastereomers of xenematide, namely (D-Trp-L-Trp)-xenematide and (D-Trp-L-Trp)-xenematide, were reported at the time of isolation. Synthesis of the two diastereomers of xenematide thus enables determination of the absolute stereochemistry of the natural product. The synthesis of xenematide was achieved by Fmoc-based solid phase peptide synthesis (SPPS) wherein key esterification between the secondary alcohol of the phenylacetyl-L-threonine residue and the carboxylic acid of β-alanine was accomplished using modified Yamaguchi esterification conditions. Comparison of the optical rotation and NMR data for the two synthetic peptides to that of the natural product established that the natural product contains the peptide sequence of phenylacetyl-L-Thr-L-Trp-D-Trp-β-Ala. Culicinin D is a linear peptaibol shown to exhibit inhibitory activity against phosphatase and tensin homolog (PTEN)-negative breast tumour cells. The synthesis of the peptaibol framework of culicinin D was achieved by Fmoc-based solid phase coupling of the appropriate building blocks including the unnaturally occurring AHMOD, AMD, and APAE residues. The synthesis of the AHMOD and AMD residues of culicinin D was accomplished in solution in 14 and 15 steps, respectively, while the synthesis of the APAE residue was achieved in 8 steps. Two Fmoc-protected AHMOD residues that are diastereomeric at the C-6 position were synthesized using the proposed strategy thus enabling incorporation into the peptaibol framework of culicinin D for absolute configuration of C-6 in the AHMOD residue. Comparison of the ¹H NMR data for the two synthetic peptides to the ¹H NMR data reported in the literature established that the chiral secondary alcohol at C-6 in the AHMOD residue to exhibit the (R) configuration.