New routes to acyltetramic acids and analogues
thesisposted on 20.11.2014 by James P. Bullous
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3-acyltetramic acids, such as reutericyclin, belong to a group of natural products which contain a 5-membered pyrrolidine-2,4-dione heterocycle with an acyl group at the 3-position. Molecules containing this motif have been shown to contain a wealth of desirable bio-activity such as antibiotic, antitumor, antiviral, antiulcerative, fungicidal and cytotoxic properties. The motivation for synthetic efforts towards reutericyclin and analogues is that it has been shown to have potential as an antibiotic treatment against superbug C. difficile. Our synthetic approach used a pyrroloisoxazole bicyclic system as a masked form of the acyltetramic acid core structure, which enables us to make selective modifications towards these bio-active products and produce more analogues suitable for biological testing. We report the synthesis of several novel compounds closely related to a masked reutericyclin as well as elaborations at the C-3 methyl group through aldol chemistry. The route began with a naturally occurring amino acid that underwent N-protection, carboxyl reduction and conversion to an oxime. This oxime is precursor to a nitrile oxide used in a 1,3-dipolar cycloaddition to achieve a substituted isoxazole that was deprotected and, through an intramolecular peptide coupling reaction, provided the pyrroloisoxazole core as the masked acyltetramic acid. Acylation reactions were completed upon this pyrroloisoxazole using butyllithium as a base and a range of acyl chlorides. Other developments made in this synthesis were the isolation of the chlorinated oxime and its use in a solvent study and significant improvements in the peptide coupling reaction. Also, synthetic efforts were made to produce an analogue of the natural product laccarin A using this methodology.