Total Synthesis of Proposed Active Constituents in Echinacea. sp. and Chamaelirium luteum.

Matovic, Nicholas John (2007). Total Synthesis of Proposed Active Constituents in Echinacea. sp. and Chamaelirium luteum. PhD Thesis, School of Molecular and Microbial Sciences , University of Queensland.

       
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Author Matovic, Nicholas John
Thesis Title Total Synthesis of Proposed Active Constituents in Echinacea. sp. and Chamaelirium luteum.
School, Centre or Institute School of Molecular and Microbial Sciences
Institution University of Queensland
Publication date 2007
Thesis type PhD Thesis
Supervisor Dr James de Voss
Abstract/Summary Chapter one of this thesis contains a critical review of herbal medicine focusing on traditional medicine, active constituents, safety, quality assurance, efficacy and regulation of medicinal plant products, and the herbal medicine industry. A more detailed overview of Echinacea and False Unicorn products then follows, covering botanical descriptions, traditional and modern use, possible active constituents and documented biological activity. Chapter two describes the chemical synthesis of nine alkyl amides which occur naturally in Echinacea, which were required for use as authentic synthetic standards for quality control of Echinacea products. Their preparation was achieved by direct and flexible routes, with the aim of providing methodology for the convenient and cost effective preparation of these and analogous alkyl amides in research laboratories. These efficient syntheses relied upon robust methods for construction of subtly different unsaturated chemical moieties. Of particular utility was the development of an unprecedented methodology for preparation of methyl diynes, involving potassium tert-butoxide catalysed isomerisation of readily accessible terminal skipped diynes. The reagent Rieke zinc played a key role in the highly stereoselective cis-reduction of conjugated alkynes and was central to a practical synthesis of the two major alkyl amide components from Echinacea ((2E,4E,8Z,10Z)-N-isobutyldodeca-2,4,8,10-tetraenamide and (2E,4E,8Z,10E)-N-isobutyldodeca-2,4,8,10-tetraenamide). A short review of general methods for the cis-reduction of alkynes is also included in this chapter, and will be of use to synthetic organic chemists. Chapter three analyses the relative proportions of the two major alkyl amides in various E. purpurea and E. angustifolia extracts. This was achieved by concomitant use of GC/MS and synthetic alkyl amide standards. It was found that levels of the two major Echinacea. sp. alkyl amides fluctuate considerably within commercial preparations containing the species E. purpurea and E. angustifolia, which may help explain the differences in activity seen amongst Echinacea preparations. The identification of another alkyl amide 2E,4E,8E,10Z)-N-isobutyldodeca-2,4,8,10-tetraenamide), previously unreported to occur in Echinacea was also described. Chapter four describes the stereoselective synthesis of a steroidal aglycone which was crucial for determining the absolute C-23, C-24 stereochemistry contained within the major steroidal saponin previously isolated from False Unicorn (Chamaelirium luteum). The synthesis was accomplished in 16 steps from commercially available pregnenolone, after which it was shown that the synthetic 23R, 24S compound was spectroscopically identical to the natural material. Stereochemical assignments for the synthetic aglycone were then proven by X-ray crystallography. The key step in the synthesis involved the stereoselective introduction of the side chain at C-17 and C-20 utilising Anionic Oxy-Cope methodology.

 
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