The Synthesis of Dehydrodopamine Containing Natural Products

Abstract

The dehydrodopamine structural motif is found widely throughout the world of natural products, being particularly prevalent in products isolated from marine species. This unique structure arises from post-translational modification of a C-terminus tyrosine residue, and gives rise to interesting biochemical functions in the molecules in which it resides. This thesis focuses on the development of methods into the synthesis of enamide derivatives of dehydrodopamine, with the ultimate application of these methods being in the synthesis of natural products. Model studies proved Buchwald-type copper catalysed cross-coupling reactions to be widely applicable in the synthesis of dehydrodopamines. The methods developed in these model reactions displaying a wide tolerance for a variety of substrates, while also conserving the stereochemical properties of the employed starting materials. Following these findings, the developed synthetic procedures were used in combination with solid phase peptide synthesis techniques in attempts to access a range of short dehydrodopamine containing peptides. The synthesis of the natural pentapeptide tunichrome Sp-1 22 was achieved, along with a series of differentially protected analogues (Fmoc/TBS-106, Fmoc-109, Fmoc/O-methyl-111, and O-methyl-110), as well as the unnatural [D-Pro]4-diastereomer 107 – with these compounds proving to have potent anti-oxidative activity in vitro. NMR characterisation studies of tunichrome Sp-1 revealed the existence of an additional cis-prolyl isomer of the compound that was present in the original isolation publication but was not characterised at the time. Significant progress was also made into the synthesis of the potent antimicrobial octapeptide plicatamide 23, with the synthesis of the Fmoc/Trt/TBS-protected structure (117) achieved. Deprotection of this compound however proved problematic, with plicatamide proving unstable under the attempted purification procedures. The synthesised library of tunichrome Sp-1 analogues was subjected to testing in oxidative conditions, revealing a widespread ability for these compounds to undergo polymerisation. These compounds demonstrated a wide array of addition reactions upon the present dehydrodopyl and DOPA residues. The extent to which polymerisation occurred appears to reinforce the predicted activity of tunichrome class of compounds as cross-linking agents within tunicate species.