New Methods for the Synthesis of Biologically Active Natural Products

Abstract

This thesis consists of seven scientific articles and is preceded by an overview that contextualises all of this submitted/published work.

Publication 1 is a literature review on the chemistry of the palladium-catalysed intramolecular Alder-ene (IMAE) reaction, a powerful method for the construction of carbon-carbon bonds. It focusses only on the cyclisation reactions of hetero-atom linked 1,6-enynes to form cis-fused hexahydro-indoles and -benzofurans. It serves to contextualise some of the author's other published research in the area.

Publication 2 consists of an invited book chapter that reviews the Banwell Group's efforts to synthesis the Amaryllidaceae alkaloid galanthamine, as well as analogues thereof, in order to further investigate the biological properties of such compounds.

Similarly, Publication 3 reports a seventeen-step reaction sequence that was used to synthesise rac-galanthamine. This route featured an intramolecular Alder-ene cyclisation and a Diels-Alder/aromatisation reaction sequence to install the tricyclic framework of the natural product.

Publication 4 describes the first total synthesis of the Illicium-derived sesquineolignan simonsol C, a natural product that is structurally similar to galanthamine. This twelve-step synthesis of simonsol C featured a Mitsunobu reaction and an intramolecular Heck reaction to establish the tetracyclic framework of simonsol C.

A second-generation synthesis of rac-galanthamine is reported in Publication 5. This investigation, which used methodology developed in the aforementioned synthesis of simonsol C, involved, as a key step, an intramolecular Heck reaction to install the tricyclic framework of rac-galanthamine.

Publication 6 describes investigations concerned with establishing the reactivity profile of N-methoxy-N-methylcyanoformamide and its capacity to introduce the Weinreb amide functionality into organic frameworks. Specifically, it describes the reaction of this cyanoformamide with various enolates and organometallic species. Publication 7 details the synthesis of N-methoxy-N-methylcyanoformamide (a previously unreported compound) via a two-step procedure.

The Appendix to the thesis is comprised of a report arising from single-crystal X-ray analysis of a key compound synthesized by the author. This analysis and the derived reports are the result of studies carried out by Dr Brett Schwartz. Show more