Stereoselective Syntheses of Certain Natural Products and their Analogues from Chiral-pool and Enzymatically-derived Building Blocks
Creators: name: Buckler, Joshua Neil Victor Timshell
Publisher: name: The Australian National University
Year: 2017
Subjects: Total Synthesis
Galanthamine
cis-1,2-dihydrocatechol
natural products
tartaric acid
aspergillusol B
neolignan
GGCE

description: This thesis is comprised of six scientific articles and is preceded by an overview that contextualises all of this published/submitted work. The first section of this thesis is comprised of Publications 1-3 and is concerned with the synthesis of novel, oxygenated analogues of the natural and non-natural enantiomeric forms of the Amaryllidaceae alkaloid galanthamine, a reversible and selective acetylcholine esterase (AChE) inhibitor that is used clinically in the treatment of Alzheimer’s disease. Specifically, Publication 1 is an invited book chapter that details synthetic approaches to galanthamine and certain analogues pursued by the Banwell Group. It contextualises the strategy employed in preparing oxygenated analogues of galanthamine by the author in latter part of the first section of this thesis. Publication 2 is an invited review article that showcases the methodologies that have been developed within the Banwell Group for manipulating enzymatically-derived and homochiral cis-1,2-dihydrocatechols so as to generate a significant range of biologically active natural products. Publication 3 describes the synthesis of certain oxygenated derivatives of both (+)- and (–)-galanthamine and the evaluation of these as AChE inhibitors. The second section of this thesis is comprised of Publications 4 and 5. These detail the synthesis of certain polyfunctionalized, cyclohexene-based chirons from L-(+)- and D-(–)-tartaric acid, respectively, and their elaboration into various natural product scaffolds. Specifically, Publication 4 describes the preparation of the aforementioned chirons from L-(+)-tartaric acid and its elaboration to the enantiomer of a key intermediate described in Publication 3 that is used to produce oxygenated analogues of (–)-galanthamine. Publication 5 further demonstrates the utility of these new chirons in total synthesis by employing the enantiomer of this chiron (prepared from D-(+)-tartaric acid) as a key intermediate in the first total synthesis of the structurally unusual natural product aspergillusol B. The final section of this thesis is comprised of Publication 6. This details work on the total synthesis of the four diastereomeric forms of the pro-angiogenic guaiacylglycerol 8-O-4ʹ-coniferyl ethers (GGCE) in an effort to establish the role stereochemistry plays on their capacities to act as pro-angiogenic agents. The syntheses feature an Evans/Seebach syn-aldol reaction utilising auxiliaries derived from either L-(+)- or D-(–)-valine. In the case of syntheses of the anti-compounds this was followed by a Mitsunobu inversion of the benzylic alcohol. The four diastereomers were assessed for their pro-angiogenic properties in a human microvascular endothelial cell tubule assay. Whilst they were all active, the compounds containing the 8S-ether linkage were the most potent.