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Mutasynthesis approaches to the preparation of streptorubin B analogues

By Stuart W. Haynes


Prodiginines are a large family of red-pigmented tripyrrole-based antibiotics.\ud Their biosynthesis in Streptomyces coelicolor A3(2), by enzymes encoded in the\ud red gene cluster, involves the condensation of 4-methoxy-2,2′-bipyrrole-5-\ud carboxaldehyde (MBC) and 2-undecylpyrrole, catalysed by the RedH enzyme to\ud give undecylprodiginine. This is followed by the mechanistically interesting\ud oxidative carbocyclisation, catalysed by RedG to give streptorubin B.\ud In this thesis prodiginine analogues have been generated by a mutasynthetic\ud approach, in which chemically synthesised analogues of intermediates MBC and\ud 2-undecylpyrrole were fed to mutant strains of S. coelicolor in which one of the\ud genes required to biosynthesise MBC or 2-undecylpyrrole (redM or redL\ud respectively) have been deleted. RedH and RedG have been shown to display\ud relatively broad substrate tolerances and several analogues of both\ud undecylprodiginine and streptorubin B have been generated by this approach. A\ud variety of factors which are potentially limiting to substrate tolerances have been\ud probed, including the steric size, alkyl chain hydrophobicity and introduction of\ud π-electrons.\ud The absolute stereochemistry of streptorubin B has been investigated by a\ud mutasynthetic approach in which 2-undecylpyrrole, stereospecifically labelled\ud with deuterium, is fed to a mutant strain of S. coelicolor unable to biosynthesise\ud 2-undecylpyrrole. During the course of the investigation streptorubin B was\ud analysed on a homochiral stationary phase HPLC and evidence of both ent- and\ud dia-streptorubin B was discovered in the natural product isolated from S.\ud coelicolor. When the position of the deuterium label from the mutasynthesis\ud experiment was investigated by 1H-NMR and 2H-NMR the partial epimerization\ud of the synthetic material became apparent. This made the definitive\ud determination of the absolute stereochemistry of streptorubin B impossible.\ud However, a tentative assignment of the absolute stereochemistry was possible.\ud This was supported by comparison with the related natural products\ud metacycloprodigiosin, the stereochemistry of which was established here by CD\ud spectroscopy and chiral HPLC analyses, and roseophilin

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