Synthetic approach to the antimalarial bipyrdyl enediyne

Shimmon, Ronald

Synthetic approach to the antimalarial bipyrdyl enediyne

Shimmon, Ronald

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Publication Type:: Thesis
Issue Date:: 2005

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Field	Value	Language
dc.contributor.author	Shimmon, Ronald
dc.date.accessioned	2017-01-23T02:10:06Z
dc.date.available	2017-01-23T02:10:06Z
dc.date.issued	2005
dc.identifier.uri	http://hdl.handle.net/10453/75637
dc.description	University of Technology, Sydney. Dept. of Chemistry, Material and Forensic Science.	en_AU
dc.description	NO FULL TEXT AVAILABLE. Access is restricted indefinitely. The hardcopy may be available for consultation at the UTS Library.
dc.description.abstract	NO FULL TEXT AVAILABLE. Access is restricted indefinitely. ----- The primary objective of this project was the design and synthesis of a particular bipyridyl enediyne. This novel compound has potential as an antitumor and antimalarial agent. Further objectives of this project were to screen this bipyridyl enediyne for antimalarial or antitumor activity and to determine its mode of action. Structural features were included in the design of this particular bipyridine enediyne to make it a promising antimalarial agent. The starting material for the synthesis of the target bipyridyl enediyne is expensive so a model test synthesis of l,8-dipyridin-3-yl-oct-4-ene-2,6-diyne was designed to optimise the preparation to form the bipyridyl enediyne using 3-pyridyl carbinol as a precursor (see Chapter 2). Although the synthesis of 3-[-1-(t-butyldimethyl-silanyloxy)-4-chloro-but-2- ynyl] pyridine was achieved, it was in a moderate yield. This compound was a key intermediate for the cyclisation of the bipyridyl enediyne but attempts to synthesise the desired enediyne failed. This route was therefore abandoned in favour of other strategies. The pathways described in Chapter 3 relied on 3,3'-disubstituted-2,2'-bipyridines. In order to obtain the key intermediate for the synthesis of the target compound, it was planned to introduce a propargyl protected alcohol using an organometallic reagent in the 3,3'- positions of bipyridine. Although several novel 3,3'-disubstituted-2,2'-bipyridine derivatives were synthesised, the attempts to introduce the propargyl protected alcohol at the 3-position either failed or produced undesired products. Section 4.1 approaches the target molecule using 1,10-phenanthroline-5,6-dione as a starting point. The addition of Grignard reagents derived from tetrahydropyranyl protected propargyl alcohol proceeded smoothly to afford the expected bis-adduct of phenanthroline-5,6-diol (41). Treatment of compound (41) with lead tetraacetate afforded the unstable diketone (42), which, followed by Luche reduction, affording bis diols (47). Silylation of the diol mixture with t-butyldimethylchlorosilane afforded the bis-silyl ethers (48). Selective removal of the tetrahydropyranyl group in the presence of t- butyldimethyl-silyl ethers provide (50), which in tum was transformed into an unstable dichloride (51 ). Unfortunately, attempts to convert (51) to the bipyridyl enediyne by two different methods reported by Nicolaou and by Jones both failed. Section 4.3 describes an approach to the bipyridyl enediyne via McMurry coupling using a dimethyl acetal as precursor. Addition of 3,3-dimethoxy-1-propyne to 1,10- phenanthroline-5,6-dione using a Grignard reagent afforded compound (54). Oxidation of compound (54) gave compound (55) and reduction of compound (55) afforded compound (56). Protection of compound (56) gave compound (57). This route was impeded, as the hydrolysis of the acetal group could not be accomplished even with protocols reported in the literature. This unusual result toward hydrolysis of the acetal group did not allow the synthesis of the target compound using the method described in Chapter 4. Time was a critical factor that prohibited the synthesis of the target compound. Chapter 5 provides methods for the synthesis of 3,3'-disubstituted-2,2'-bipyridine which were published in Chemistry Letters in volume 33, issue 1, page 78, 2004 [1].	en_AU
dc.format	Thesis (PhD)
dc.language.iso	en_AU	en_AU
dc.rights	The author owns the copyright in this thesis including all reproduction and reuse rights for the work. The work may not be altered without the permission of the copyright owner. Attribution is essential when quoting or paraphrasing from this thesis.
dc.rights	info:eu-repo/semantics/closedAccess
dc.title	Synthetic approach to the antimalarial bipyrdyl enediyne	en_AU
dc.type	Thesis	en_AU
utslib.copyright.status	closed_access

Abstract:

NO FULL TEXT AVAILABLE. Access is restricted indefinitely. ----- The primary objective of this project was the design and synthesis of a particular bipyridyl enediyne. This novel compound has potential as an antitumor and antimalarial agent. Further objectives of this project were to screen this bipyridyl enediyne for antimalarial or antitumor activity and to determine its mode of action. Structural features were included in the design of this particular bipyridine enediyne to make it a promising antimalarial agent. The starting material for the synthesis of the target bipyridyl enediyne is expensive so a model test synthesis of l,8-dipyridin-3-yl-oct-4-ene-2,6-diyne was designed to optimise the preparation to form the bipyridyl enediyne using 3-pyridyl carbinol as a precursor (see Chapter 2). Although the synthesis of 3-[-1-(t-butyldimethyl-silanyloxy)-4-chloro-but-2- ynyl] pyridine was achieved, it was in a moderate yield. This compound was a key intermediate for the cyclisation of the bipyridyl enediyne but attempts to synthesise the desired enediyne failed. This route was therefore abandoned in favour of other strategies. The pathways described in Chapter 3 relied on 3,3'-disubstituted-2,2'-bipyridines. In order to obtain the key intermediate for the synthesis of the target compound, it was planned to introduce a propargyl protected alcohol using an organometallic reagent in the 3,3'- positions of bipyridine. Although several novel 3,3'-disubstituted-2,2'-bipyridine derivatives were synthesised, the attempts to introduce the propargyl protected alcohol at the 3-position either failed or produced undesired products. Section 4.1 approaches the target molecule using 1,10-phenanthroline-5,6-dione as a starting point. The addition of Grignard reagents derived from tetrahydropyranyl protected propargyl alcohol proceeded smoothly to afford the expected bis-adduct of phenanthroline-5,6-diol (41). Treatment of compound (41) with lead tetraacetate afforded the unstable diketone (42), which, followed by Luche reduction, affording bis diols (47). Silylation of the diol mixture with t-butyldimethylchlorosilane afforded the bis-silyl ethers (48). Selective removal of the tetrahydropyranyl group in the presence of t- butyldimethyl-silyl ethers provide (50), which in tum was transformed into an unstable dichloride (51 ). Unfortunately, attempts to convert (51) to the bipyridyl enediyne by two different methods reported by Nicolaou and by Jones both failed. Section 4.3 describes an approach to the bipyridyl enediyne via McMurry coupling using a dimethyl acetal as precursor. Addition of 3,3-dimethoxy-1-propyne to 1,10- phenanthroline-5,6-dione using a Grignard reagent afforded compound (54). Oxidation of compound (54) gave compound (55) and reduction of compound (55) afforded compound (56). Protection of compound (56) gave compound (57). This route was impeded, as the hydrolysis of the acetal group could not be accomplished even with protocols reported in the literature. This unusual result toward hydrolysis of the acetal group did not allow the synthesis of the target compound using the method described in Chapter 4. Time was a critical factor that prohibited the synthesis of the target compound. Chapter 5 provides methods for the synthesis of 3,3'-disubstituted-2,2'-bipyridine which were published in Chemistry Letters in volume 33, issue 1, page 78, 2004 [1].

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