Halogenated cyclopropanes and enyzmatically-derived cis-1, 2-dihydrocatechols as versatile starting materials for natural product synthesis
Creators: name: Lan, Ping
Publisher: name: The Australian National University
Year: 2015

description: This thesis is comprised of five scientific articles and is preceded by an overview that contextualises all of this submitted/published work. Publication 1: Chemoenzymatic total synthesis and reassignment of the absolute configuration of ribisin C The ribisin family is comprised of four members, A-D, they were isolated from methanol extracts of the fruiting bodies of Phellinus ribis. Publication 1 describes the synthesis of the structure assigned to ribisin C. This synthetic work clearly established that the absolute configuration of ribisin C, the most bioactive member of the ribisin family, had been mis-assigned. Since there was a need to conduct systemic biological evaluations of the ribisin family, it was necessary to obtain samples of the true structure, the enantioisomer of the original structure. This was also achieved within 14 steps. Publication 2: Chemoenzymatic total syntheses of ribisins A, B and D, polyoxygenated benzofuran derivatives displaying NGF-potentiating properties This paper details the chemoenzymatic total syntheses of the ribisins A, B and D using a strategy similar to that presented in publication 1. As a result of this study, the originally assigned structures of ribisins A and D were confirmed while that of congener B was incorrect. The methodologies described in publications 1 and 2 have proven powerful and should allow for the development of a comprehensive SAR profile for the class. Publication 3: Devising new syntheses of the alkaloid galanthamine, a potent and clinically-deployed inhibitor of acetylcholine esterase (-)-Galanthamine is a key member of the Amaryllidaceae family alkaloids. It has been shown to be a potent, competitive and reversible inhibitor of acetylcholine esterase (AChE) as well as an allosterically potentiating ligand of the neuronal nicotinic receptor for acetylcholine. As testimony to its importance, (-)-galanthamine has been approved as a medicine for the treatment of mild to moderate forms of Alzheimer's disease and is currently used clinically in Europe, the United States and Japan. Owing to the high cost of its extraction and purification from plant sources, as well as the threats to the habitat of some of these, there is an ever increasing need for the development of practical total syntheses of (-)-galanthamine. This book chapter (publication 3) describes the range of studies reported in the literature on the synthesis of galanthamine. Publication 4: Synthesis of a D-ring isomer of galanthamine via a radical-based Smiles rearrangement reaction This publication describing work carried out by the author details a free-radical approach to a non-natural isomer of galanthamine. Publication 5: Chemoenzymatic synthesis of the enantiomer of 4,12-dihydroxysterpurene, the structure assigned to a metabolite isolated from the culture broth of Stereum purpureum A compound named 4,12-dihydroxysterpurene was first isolated from a culture broth of Stereum purpureum. The total synthesis of the enantiomer, of 4,12-dihydroxysterpurene is detailed in the author's final publication (publication 5) and this established that the structure assigned to the originally isolated natural product is incorrect.