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Diels-Alder reactions of anthrone to synthesise asymmetric pyrrolidinones

Spencer-Briggs, Jenna (2019) Diels-Alder reactions of anthrone to synthesise asymmetric pyrrolidinones. PhD thesis, University of Sheffield.

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Abstract

Pyrrolidinone moieties with a tertiary stereogenic centre at the C-5 position are prevalent in a number of natural products and pharmaceuticals. A method to access these compounds in good enantioselectivity from N-benzyl maleimide has been established. By adapting literature methodology, the Diels-Alder reaction between N-benzyl maleimide and anthrone could be catalysed by quinidine, giving the desired cycloadduct in good yield and selectivity (85% and 85% ee, respectively). Base stability tests proved the cycloadduct to be stable under mildly basic conditions, allowing synthesis to progress without the need to protect the bridgehead hydroxyl group. Grignard addition to the cycloadduct furnished four hydroxy lactam derivatives in moderate yields (24-35%) with complete regioselectivity, confirmed by nOe studies. The Grignard reagent added selectively to the carbonyl distal to the bridgehead hydroxyl group. This is thought to be preferred due to hydrogen bonding between the proximal carbonyl oxygen and the proton on the bridgehead hydroxyl group. Surprisingly, all four derivatives were synthesised as a mixture of diastereoisomers, determined by 1H NMR spectroscopic analysis of the crude products. The hydroxy lactam derivatives were then reduced to the corresponding lactams using BF3.OEt2 and Et3SiH, in varying yields (29-91%). All four lactam derivatives were furnished as a single diastereoisomer, the identity of which was confirmed by analysis of the relevant coupling constants. The benefit of using anthrone was its potential to promote a room temperature oxide-anion accelerated retro-Diels-Alder. Using potassium hydride to catalyse the cycloreversion did not furnish the desired product and attempts to optimise the base catalysed reaction failed. Equally a thermal retro-Diels-Alder reaction of the functionalised cycloadduct was unsuccessful.

Item Type: Thesis (PhD)
Academic Units: The University of Sheffield > Faculty of Science (Sheffield) > Chemistry (Sheffield)
The University of Sheffield > Faculty of Science (Sheffield)
Depositing User: Dr Jenna Spencer-Briggs
Date Deposited: 11 Feb 2020 10:43
Last Modified: 11 Feb 2020 10:43
URI: http://etheses.whiterose.ac.uk/id/eprint/25909

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