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Applications of the Bohlmann-Rahtz reaction in the synthesis of thiopeptide antibiotics

Merritt, Eleanor Anne 2008. Applications of the Bohlmann-Rahtz reaction in the synthesis of thiopeptide antibiotics. PhD Thesis, Cardiff University.

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Chemical degradation studies on micrococcin P1 have established that the stereochemistry of the valine residue in the natural product is S and not R as previously assigned in the literature. This confirms Ciufolini's hypothesis that the Bycroft-Gowland structure of MP1 differs from the natural product on stereochemical grounds. A range of conditions for the synthesis of amino acid-derived thiazoles have been investigated and previously reported conditions found to be unreliable. Evidence has been provided to suggest that racemisation in the Hantzsch thiazole synthesis occurs in the elimination step of the reaction. The peptide backbone of micrococcin P1 has been prepared in 10 steps and 44% overall yield, incorporating S-valine based on the results of our degradation studies. A microwave-assisted method for the conversion of sterically hindered (3-ketoesters to enamines has been devised, which is suitable for single- and multimode instruments, and for scale-up to produce multigram quantities of material. The central heterocyclic domain of the micrococcin thiopeptides has been prepared in 15 steps and 9% overall yield via a highly convergent strategy incorporating the Bohlmann-Rahtz pyridine synthesis and featuring an efficient two-directional thiazole elaboration. The micrococcin thiopeptide macrocycle has been synthesised in 20 steps and 4% overall yield. Three micrococcin P1 side chain dipeptides have been prepared, each incorporating different protecting groups, enabling a range of different approaches to the natural product to be investigated. HPLC analysis of degradation products from newly isolated cyclothiazomycin thiopeptides and comparison with synthetic material has provided evidence that the alanine-derived residue in the cyclothiazomycin core domain is of S stereochemistry, and not R as previously assigned in the literature.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Chemistry
Subjects: Q Science > QD Chemistry
ISBN: 9781303183249
Date of First Compliant Deposit: 30 March 2016
Last Modified: 12 Feb 2016 23:14

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