Stereochemical features of enantioselective copper- and rhodium-mediated transformations of alpha-diazocarbonyl compounds

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dc.contributor.advisor Maguire, Anita en Brouder, Thomas A. 2021-05-25T10:47:12Z 2021-05-25T10:47:12Z 2020-08-13 2020-08-13
dc.identifier.citation Brouder, T. A. 2020. Stereochemical features of enantioselective copper- and rhodium-mediated transformations of alpha-diazocarbonyl compounds. PhD Thesis, University College Cork. en
dc.identifier.endpage 578 en
dc.description.abstract This thesis describes the synthesis of a series of α-diazocarbonyl compounds including α diazo β oxosulfones, α diazo β ketosulfones and an α-diazoketone, and their reactivity in intramolecular copper–bis(oxazoline)–NaBARF-catalysed C–H insertion reactions, intramolecular rhodium(II)-catalysed C–H insertion reactions, and copper and rhodium(II)-catalysed oxonium ylide formation and subsequent rearrangement. Excellent levels of diastereo- and enantioselectivity of up to 98:2 d.r. and up to 98% ee were achieved in the synthesis of fused thiopyran dioxides using our copper catalyst system, and up to 92% ee in the synthesis of thiopyran dioxides using our novel rhodium(II) mandelate-based catalysts. The most substantive advance in this research was the demonstration of highly enantioselective desymmetrisation in C–H insertion through use of either copper or rhodium catalysts with α diazo β oxosulfones. Chapter One focuses on progress over the past three decades in transition-metal-catalysed intermolecular C–H insertion reactions of α-diazocarbonyl compounds. This overview aims to provide an insight into factors influencing chemo-, regio-, diastereo- and enantioselectivity of intermolecular C–H insertion reactions, and how this intermolecular reaction, once believed to be of limited synthetic use, has now become a very powerful method in late stage compound modification. Catalyst design and understanding, coupled with successive alterations to rhodium(II) carboxylate catalysts, have provided great insight into achieving high levels of selectivity during intermolecular C–H insertion reactions of α-diazocarbonyl compounds. Chapter Two focuses on the synthesis and subsequent copper-catalysed intramolecular C–H insertion reactions of a range of α diazocarbonyl compounds leading to fused thiopyran dioxide and cyclopentanone formation, including the first example of desymmetrisation in the formation of a six-membered heterocycle by C–H insertion of an α diazocarbonyl compound. Within the sulfone series, the compounds investigated were designed to enable exploration of both the conformational properties at the site of C–H insertion and electronic properties at the carbene carbon. Diastereoselectivity was highly dependent on the conformational flexibility at the site of C–H insertion, while enantioselectivity was relatively unaffected and consistently high. The ligand trends observed in the formation of the fused thiopyran dioxide series via desymmetrisation, as well as, the sense and extent of the enantioselection, were entirely consistent with those obtained in earlier work from our team focused on enantioselective C–H insertion into freely rotating alkyl chains. In terms of the electronic effect, only modest variation was observed in the outcome of desymmetrisation when the substituent on the carbene was altered from an ester to a ketone moiety. Desymmetrisation in the formation of a fused cyclopentanone resulted in lower levels of enantioselectivity in comparison to the fused thiopyran dioxides. Chapter Three focuses on the synthesis and subsequent rhodium(II)-catalysed intramolecular C–H insertion reactions of α-diazo-β-oxosulfones, including the first reports of use of novel rhodium(II) mandelate-based catalysts in the synthesis of thiopyran dioxides. Notably, excellent levels of enantiocontrol of up to 92% ee were achieved in the synthesis of thiopyran dioxides using these novel rhodium(II) catalysts. The cis-thiopyran dioxide diastereoisomer was selectively synthesised using the chiral copper catalyst system, while the trans-thiopyran dioxide was preferentially formed using the chiral rhodium(II) mandelate-based catalysts. For the first time, the trans-thiopyran dioxides were formed with high levels of enantiocontrol, thereby enabling selective access to either the cis- or trans-thiopyran dioxides with excellent enantiopurity, albeit with lower levels of regioselectivity in comparison to the copper-catalysed reactions. Efficient desymmetrisation was achieved using the rhodium(II) mandelate-based catalysts, expanding the scope and utility of these novel catalysts. Chapter Four focuses on the synthesis of two α-diazocarbonyl compounds and their subsequent use in asymmetric transition-metal-catalysed oxonium ylide formation and rearrangement. The α-diazocarbonyl compounds were selected to enable comparison to the reactivity of a previously investigated α-diazoester to establish the impact of replacement of the ester moiety by either a phenyl sulfone or phenyl ketone moiety. Use of the copper–bis(oxazoline)–NaBARF catalyst system led successfully to the [2,3] sigmatropic rearrangement product in good to high yields, however, no asymmetric induction was achieved during product formation. Interestingly, for the phenyl ketone derivative the chemoselectivity of the reaction with the rhodium(II) catalysts was quite different, with the C–H insertion pathway favoured over oxonium ylide formation in certain instances; enantioselectivities of up to 74% ee were recorded for the C–H insertion product, but importantly, the oxonium ylide product also demonstrated enantioenrichment through use of the rhodium(II) catalysts unlike the copper catalysts. Clearly, substituent effects in this series play a more important role in the reaction outcome. Chapter Five contains the full experimental details for the synthesis and spectroscopic and analytical characterisation of all compounds synthesised in this project, with details of chiral stationary phase HPLC and crystallographic studies which enabled assignment of absolute stereochemistry included in the Appendices. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2020, Thomas A, Brouder. en
dc.rights.uri en
dc.subject Transition-metal-catalysed en
dc.subject Copper catalysis en
dc.subject Rhodium catalysis en
dc.subject Desymmetrisation en
dc.subject Oxonium ylide en
dc.subject C-H Insertion en
dc.subject Enantioselective copper- and rhodium-mediated transformations en
dc.subject Alpha-diazocarbonyl compounds en
dc.title Stereochemical features of enantioselective copper- and rhodium-mediated transformations of alpha-diazocarbonyl compounds en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD - Doctor of Philosophy en
dc.internal.availability Full text not available en
dc.description.version Accepted Version en
dc.contributor.funder Irish Research Council for Science, Engineering and Technology en
dc.description.status Not peer reviewed en Chemistry en
dc.check.chapterOfThesis Chapter 1, Chapter 2, Chapter 3, Chapter 4, Chapter 5, Appendices en
dc.internal.conferring Summer 2021 en
dc.internal.ricu Analytical and Biological Chemistry Research Facility en
dc.availability.bitstream embargoed 2031-05-30

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© 2020, Thomas A, Brouder. Except where otherwise noted, this item's license is described as © 2020, Thomas A, Brouder.
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