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dc.contributor.advisorLarsen, David Samuel
dc.contributor.authorMoodie, Lindon William Kirk
dc.identifier.citationMoodie, L. W. K. (2013). An Enyne Metathesis Approach to the Angucycline Natural Products (Thesis, Doctor of Philosophy). University of Otago. Retrieved from
dc.description.abstractThe research in this thesis aimed to identify a common intermediate that would allow the collective synthesis of structurally diverse members of the angucycline antibiotics and their analogues. The Diels-Alder reaction is a key synthetic transformation towards these goals, but requires suitably functionalised, enantioenriched semicyclic dienes. Ring-closing enyne metathesis (RCEM) was recognised as an efficient method for diene construction. Enyne, (±)-2.130, was synthesised from alcohol 2.120 in an overall yield of 66% over 8 steps. RCEM of (±)-2.130, catalysed by Grubbs’ 1st generation catalyst, provided the separable dienes (±)-2.157 and (±)-2.158. The Sharpless asymmetric dihydroxylation (SAD) was integrated into this synthetic route, which enabled the synthesis of optically active dienes (+)-2.157 and (+)-2.158 (overall combined yield 63% from 2.120, 95.1% per step). Mosher’s ester analysis suggested that the SAD reaction in the latter route induced high levels of enantioselectivity (er > 95:5). The Diels-Alder chemistry of dienes (+)-2.157 and (+)-2.158 was investigated using N-phenylmaleimide (3.3). (+)-2.157 and 3.3 produced two endo cycloadducts, in a ratio of 39:61, resulting from the dienophile reacting with the diastereotopic faces of the diene syn and anti to the allylic hydroxyl group, respectively. The reaction of (+)-2.158 and 3.3 formed only the endo-syn cycloadduct, which underwent spontaneous lactonisation to afford lactone (-)-3.6, as confirmed by X-ray crystallography. These studies confirmed the relative 1,3-configurations of both dienes. (-)-Tetrangomycin (4.1) was synthesised to demonstrate the applicability of RCEM toward angucycline synthesis. The Diels-Alder reaction of semicyclic diene (+)-4.191 and bromojuglone 1.63 yielded cycloadduct (+)-4.190, as the sole diastereomer, in 87% yield. The reaction was facially specific, with the dienophile approaching the diene from the face anti to the allylic C-1 hydroxyl group. Treatment of this adduct with PDC initiated a cascade reaction, oxidising the C-1 hydroxyl group and aromatising the B-ring in a single reaction step. Subsequent acetate deprotection completed the total synthesis of (-)-tetrangomycin (4.1) (26% yield from (+)-2.157). Synthetic studies towards analogues of the biologically active angucycline landomycinone were conducted. The Lewis acid catalysed Diels-Alder reaction of (±)-2.157 and juglone (1.55) afforded cycloadduct (±)-5.7. A facially selective epoxidation and two subsequent oxidations yielded (±)-5.113 in 86% yield from (±)-5.7. Treatment of (±)-5.113 with silica gel induced an isomerisation to install an allylic hydroxyl group at the C-5 position. Methodology was also developed that transformed the C-5 hydroxyl group of the angucycline skeleton into the corresponding phenolic functionality. During the course of this work an interesting ring fragmentation process was discovered. Angucyclines containing the trans-5,6-diol motif were also targeted. This required dienes that were oxygenated at the 1,3- and 8- positions. Unprecedented methodology was developed where a tandem intermolecular alkyne/enol ester and ring-closing metathesis process produced complex semicyclic dienes as inseparable mixtures of isomers. In response to this problem, the metathesis of enynone (±)-5.200 and vinyl acetate was conducted, forming (±)-5.199 as a 1.0:1.3 mixture of the E and Z isomers. Acid catalysed isomerisation resulted in the isolation of diene (±)-5.199 in 77% yield as predominantly the desired E isomer (94:6).
dc.publisherUniversity of Otago
dc.rightsAll items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectOrganic Chemistry
dc.subjectNatural Products
dc.subjectTotal Synthesis
dc.subjectEnyne Metathesis
dc.subjectTandem Reactions
dc.subjectDiels Alder
dc.titleAn Enyne Metathesis Approach to the Angucycline Natural Products
dc.language.rfc3066en of Philosophy of Otago
otago.openaccessAbstract Only
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