Synthesis of heterocyclic natural products and analogues

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Thesis type
(Thesis) Ph.D.
Date created
Organic compounds that contain rings composed of carbon and other atoms such as nitrogen, oxygen, sulfur or phosphorus are referred to as heterocyclic compounds. Compounds of this type are frequently encountered in natural products and a majority of all biologically-active molecules are heterocycles. This thesis concerns the synthesis of three distinct classes of heterocyclic natural products and analogues. Likonide B and smenochromene C are two structurally-related oxygen-containing heterocyclic marine natural products that feature a unique ansa-bridged farnesyl quinol moiety which is considered to be an interesting structural motif for synthetic studies. The total syntheses of these two natural products were completed in an efficient manner from commercially-available starting materials. The employment of a phenylboronic acid-mediated condensation reaction of phenols and a,b-unsaturated aldehydes, and a palladium-catalyzed O-allylation reaction constituted a potentially biomimetic total synthesis of these two natural products. Platensimycin, an oxygen-containing heterocyclic compound, is a new class of antibiotic. Its complex tetracyclic ketolide structure motif represents a considerable synthetic challenge. By manipulating the oxygenation pattern of this tetracyclic core, it was proposed that an asymmetric domino double Stetter reaction of an achiral molecule could be used to prepare the tricyclic skeleton of this compound with all the stereogenic centres correctly installed in a single synthetic transformation. After considerable experimentation, the key achiral compound was prepared in five steps from commercially-available starting materials. Preliminary studies were then undertaken to effect this key transformation. The synthesis and applications of 2,3-disubstituted pyrroles, a class of nitrogen-containing heterocycle, were also investigated. The ultimate-goal of this project was to develop an efficient synthesis of 7-phosphatryptophan, a synthetic analogue of the natural a-amino acid tryptophan that could exhibit different fluorescent properties to that of the natural substrate for biophysical studies. En route to the synthesis of 7-phosphatryptophan, a novel method to construct 2-chloro-3-carboxylate pyrrole was developed and optimized. It was also envisioned that this compound could serve as a central building block for the preparation of a series of potentially biologically-active heterocycles. In this regard, a series of pyrrole derivatives were synthesized via various palladium-catalyzed cross-coupling reactions for future biological activity studies.
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Thesis advisor: Wilson, Peter D.
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