Novel synthetic methodology employing organosulfur chemistry in the synthesis of chalcone derivatives

Murphy, Chloe C.

Restriction lift date: 2030-06-10

Novel synthetic methodology employing organosulfur chemistry in the synthesis of chalcone derivatives

dc.availability.bitstream	embargoed
dc.check.chapterOfThesis	Section 2.6 to be redacted permanently. 10 year embargo on entire thesis.	en
dc.check.date	2030-06-10
dc.contributor.advisor	Maguire, Anita R.	en
dc.contributor.advisor	Collins, Stuart	en
dc.contributor.author	Murphy, Chloe C.
dc.contributor.funder	Irish Research Council	en
dc.date.accessioned	2020-09-01T12:39:54Z
dc.date.available	2020-09-01T12:39:54Z
dc.date.issued	2020-05
dc.date.submitted	2020-05
dc.description.abstract	Highly functionalised a-thio-b-chloroenones are extremely useful synthetic intermediates. Their formation through a N-chlorosuccinimide (NCS) mediated chlorination cascade is a powerful synthetic methodology which transforms an unreactive sp3 b-carbon into a highly reactive sp2 b-carbon.a-Thio-b-chloroenones have the potential to act as Michael acceptors, dienophiles, and dipolarophiles, and can undergo Stille coupling making them highly versatile synthetic intermediates. They can also undergo sulfur oxidation enabling further functionalisation. The first chapter is a literature review of Stille coupling involving b-haloenone systems, including where this is embedded as a substructure, e.g. in aromatic systems, from 1996 onwards. The diversity of examples of the use of this transformation in the construction of complex natural products and other materials, including polymers, highlights the synthetic utility of this C–C bond forming reaction, and its robustness across a wide range of substrates. The results of the work carried out in this project are discussed in detail in chapter two. This includes the synthesis of novel a-thio-b-chloropropenones which, for the first time, incorporate substitution on the thiobenzyl ring. The b-chloropropenones form as a mixture of E and Z isomers, with the Z isomer predominating. This work was the first time that the E and Z isomers were separated and individually characterised. The scope of the chlorination cascade was also expanded to include a longer alkyl chain, thereby forming a library of novel a-thio-b-chlorobutenones and pentenones which contain a methyl or ethyl group in the b-position rather than hydrogen. While the b-chlorobutenones and pentenones also form as a mixture of E and Z isomers, a decrease in stereoselectivity is observed with the extended chain length, and the E isomer predominates. Chemoselective oxidation of the a-thio-b-chloropropenones, butenones and pentenones to the sulfoxide level was achieved using Oxone®. While all of the b-chloroenones formed both E and Z sulfoxide isomers, equilibration to the thermodynamically favoured E sulfoxide was observed for the chloropropenones. The reactivity of the b-chloroenones in nucleophilic addition/elimination reactions with nitrogen, oxygen, and sulfur nucleophiles, at both the sulfide and sulfoxide level, is described. Overall, reaction at the sulfoxide level was seen to be more efficient; furthermore the efficiency of nucleophilic addition decreased as the length of the alkyl chain increased. At the sulfide level of oxidation, it was noted that the Z isomer reacted faster than the E isomer. Of particular significance in this work is the synthesis of a series of novel chalcone derivatives which were prepared using Stille coupling. Six a-thiochalcones and five a-sulfinylchalcones synthesised in this work were accepted by the National Cancer Institute (NCI) for testing and were found to be extremely potent growth inhibitors. The third chapter details the experimental procedures used in this work and describes the spectroscopic details of all of the compounds synthesised in this body of work including full characterisation of all novel compounds.	en
dc.description.status	Not peer reviewed	en
dc.description.version	Accepted Version	en
dc.format.mimetype	application/pdf	en
dc.identifier.citation	Murphy, C. C. 2020. Novel synthetic methodology employing organosulfur chemistry in the synthesis of chalcone derivatives. PhD Thesis, University College Cork.	en
dc.identifier.endpage	288	en
dc.identifier.uri	https://hdl.handle.net/10468/10438
dc.language.iso	en	en
dc.publisher	University College Cork	en
dc.rights	© 2020, Chloe C. Murphy.	en
dc.rights.uri	https://creativecommons.org/licenses/by-nc-nd/4.0/	en
dc.subject	a-thio-b-chloroenones	en
dc.subject	Stille coupling	en
dc.subject	Chalcones	en
dc.subject	Nucleophilic addition	en
dc.subject	Sulfur oxidation	en
dc.subject	Organosulfur chemistry	en
dc.title	Novel synthetic methodology employing organosulfur chemistry in the synthesis of chalcone derivatives	en
dc.type	Doctoral thesis	en
dc.type.qualificationlevel	Doctoral	en
dc.type.qualificationname	PhD - Doctor of Philosophy	en