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The asymmetric synthesis of isochromans related to the aphid pigments

Joll, Cynthia Ann (1995) The asymmetric synthesis of isochromans related to the aphid pigments. PhD thesis, Murdoch University.

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Many of the naturally occurring benzoisochromanquinones exhibit notable biological activity, being potential antibiotics or antineoplastic agents. The synthetic work described in this thesis is directed towards the asymmetric synthesis of Quinone A 2, Quinone A 3 and Deoxyquinone A 4, three derivatives of the naturally occurring benzoisochromanquinone aphid pigments, protoaphin-fb, protoaphin-sl and deoxyprotoaphin, respectively.

In the first chapter, a comprehensive review of a category of benzoisochromanquinone natural products related to the aphid pigment derivatives is presented, highlighting their structures, occurrence and biological activities. This is followed by a discussion of the isolation and structural elucidation of the aphid pigments themselves. The racemic synthesis of the aphid pigment derivatives 2, 3 and 4, and the asymmetric syntheses of several related naturally occurring benzoisochromanquinones are reviewed in the latter part of the chapter.

An approach to the first chiral synthesis of Quinone A 2, Quinone A' 3 and Deoxyquinone A 4, through a key intermolecular reaction between a metal phenolate and a chiral aldehyde, is detailed in Chapter Two.

It was first necessary to prepare an aromatic compound which is a suitable precursor to the benzyne 189. The assembly of two different precursors is described, and the yields of their respective conversions to the intermediate benzyne 189 and in situ cycloaddition reaction with 2-methoxyfuran compared.

Model studies of the key intermolecular reaction, using 4,5,7-trimethoxynaphthalene-1-ol and the 1-ethoxyethyl ether of (2S)-2-hydroxypropanal, are then presented. This reaction was highly diastereoselective and this was controlled by the choice of the metal. Thus, the product of addition of the titanium phenolate differed from that of the magnesium phenolate only at the newly created chiral centre.

Chapter Three deals with the application of the reaction between metal phenolates and chiral aldehydes to intramolecular processes. Firstly, commercially available 2,5-dihydroxyacetophenone was transformed into the differentially protected 5-benzyloxy-2-methoxyacetophenone. This was followed by extension of the side chain by formation of an ether with (S)-ethyl lactate. Ultimately, two diastereomeric optically-pure phenols, each bearing an aldehydic side chain derived from (S)-ethyl lactate, were prepared.

These were each treated separately with both titanium tetraisopropoxide and ethyl magnesium bromide and the products of the four reactions examined in detail. In the case of the bromomagnesium phenolates, the yields of cyclized products were poor, and for one of these diastereomeric phenolates the stereoselectivity of cyclization was only average. For the titanium phenolates, high yields of products of intramolecular cyclization were obtained. The diastereoselectivity of the cyclization reaction was only 3:1 in one case, but in the other, which produced the required benzopyran analogous to Quinone A, the cyclization was completely diastereoselective. Thus, the first chiral synthesis of a benzopyranquinone having the same absolute stereochemistry as the enantiomer of Quinone A, i.e., quinone 234, is presented.

Item Type: Thesis (PhD)
Murdoch Affiliation(s): School of Physical Sciences, Engineering and Technology
Notes: Note to the author: If you would like to make your thesis openly available on Murdoch University Library's Research Repository, please contact: Thank you.
Supervisor(s): Giles, Robin and Tilbrook, Matthew
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