An Enyne Metathesis Approach to the Angucycline Natural Products
|dc.contributor.advisor||Larsen, David Samuel|
|dc.contributor.author||Moodie, Lindon William Kirk|
|dc.identifier.citation||Moodie, L. W. K. (2013). An Enyne Metathesis Approach to the Angucycline Natural Products (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/4063||en|
|dc.description.abstract||The 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.publisher||University of Otago|
|dc.rights||All 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.title||An Enyne Metathesis Approach to the Angucycline Natural Products|
|thesis.degree.name||Doctor of Philosophy|
|thesis.degree.grantor||University of Otago|
Files in this item
There are no files associated with this item.
This item is not available in full-text via OUR Archive.
If you are the author of this item, please contact us if you wish to discuss making the full text publicly available.