Synthetic and stereochemical aspects of enantioselective copper catalysed C-H insertion reactions leading to cyclopentanones and sultones

Shiely, Amy E.

Synthetic and stereochemical aspects of enantioselective copper catalysed C-H insertion reactions leading to cyclopentanones and sultones

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Date

2018

Authors

Shiely, Amy E.

Publisher

University College Cork

Abstract

This thesis describes the synthesis of a series of α-diazocarbonyl compounds including α-diazoβ-keto sulfones, α-diazo-β-keto phosphine oxides, 2-diazo-1,3-diketones and αdiazosulfonates, and their reactivity in intramolecular copper–bis(oxazoline)–NaBARF catalysed C–H insertion reactions. Excellent enantioselectivities of up to 91% ee were achieved in the synthesis of cyclopentanones and up to 95% ee in the synthesis of sultones. Chapter One contains a comprehensive review providing an insight into the effect of substitution on the outcome of transition metal catalysed intramolecular C–H insertion reactions of α-diazocarbonyl compounds. This overview specifically focuses on the influence of the carbene substituent and the substituent adjacent to the C–H insertion site. Chapter Two focuses on the synthesis and subsequent C–H insertion reactions of a range of αdiazocarbonyl compounds leading to cyclopentanone formation, including the first examples of asymmetric C–H insertion of α-diazo-β-keto phosphine oxides and 2-diazo-1,3-diketones. Detailed investigation of the impact of the electron withdrawing group at the diazo carbon was undertaken. Within the sulfone series the compounds investigated were designed to enable exploration of both steric and electronic influences; steric effects were found to be much more significant than electronic effects in influencing the enantiocontrol. With phosphine oxides and ketones the ligand trends observed were similar to those obtained with the analogous α-diazoβ-keto sulfones, however, the level of enantiocontrol achieved was lower. In general it was found that increasing the electron withdrawing character of the group attached to the carbene carbon led to a decrease in reaction time and an increase in enantiocontrol. Chapter Three focuses on the synthesis and subsequent C–H insertion reactions of a range of α-diazosulfonates, including the first reports of the synthesis of α-diazosulfonates bearing ketone and methyl ester moieties on the carbene carbon. Notably asymmetric synthesis of sultones through C–H insertion has been achieved for the first time, with excellent levels of enantiocontrol of up to 95% ee achieved with CuCl2–bis(oxazoline)–NaBARF. The C–H insertion reactions of α-diazosulfonates produced both cis and trans -sultones, while ligand trends were similar to those seen with the C–H insertion reactions of α-diazo-β-oxo sulfones. Overall, the enantioselectivities obtained in the C–H insertion reactions of α-diazosulfonates mirrored those seen with the thiopyrans, albeit with lower levels of diastereocontrol. Because the reaction pathway accessible from the sultone is clearly distinct from those accessible from the sulfone insertion products this work substantially broadens the scope of our copper mediated asymmetric C–H insertion reactions. Chapter Four 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 analysis and assignment of absolute stereochemistry included in the Appendices.

Keywords

Enantioselective C-H insertion , Copper catalysed C-H insertion , Cyclopentanone formation , Sultone formation , α-Diazocarbonyl compounds , α-Diazo-β-keto sulfones , α-Diazosulfonates

Citation

Shiely, A. E. 2018. Synthetic and stereochemical aspects of enantioselective copper catalysed C-H insertion reactions leading to cyclopentanones and sultones. PhD Thesis, University College Cork.