Palladium-Catalysed Decarboxylative Asymmetric Allylic Alkylation of Thietane-1,1-Dioxides for the Synthesis of Enantioenriched Spirocycles

Laidlaw, Gillian (2022) Palladium-Catalysed Decarboxylative Asymmetric Allylic Alkylation of Thietane-1,1-Dioxides for the Synthesis of Enantioenriched Spirocycles. PhD thesis, UNSPECIFIED.

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Abstract

Structurally novel stereofunctionalised heterocyclic building blocks are becoming increasingly important in the field of medicinal chemistry as a means of facilitating drug discovery through improved physicochemical properties. As such, asymmetric synthetic methods to access previously unexplored enantiopure heterocycles are highly sought after. The work disclosed in this thesis involves the development of a palladium-catalysed decarboxylative asymmetric allylic alkylation (Pd-DAAA) of thietane-1,1-dioxides bearing a carbonyl side-chain to afford novel enantioenriched building blocks. Unlike the stereoselective allylic alkylation of cyclic enolates with a fixed alkene geometry, this approach necessitated the alkylation of linear enolate intermediates, which is substantially more difficult to achieve enantioselectively due to the implication of E/Z enolate isomers. The reaction process was successfully optimised to install an -sulfonyl tetrasubstituted centre with high levels of enantioselectivity from racemic starting materials. In addition, an extensive substrate scope investigation of ketone and ester enolates bearing aromatic, heteroaromatic and alkyl groups illustrated broad utility of this method, enabling access to a range of products with up to 96% ee. This investigation revealed that esters were slightly more successful substrates than ketones in terms of enantioselectivity, and that substitution of the allylic ester was not well tolerated. The geometry of the acyclic enolate intermediate was probed to determine its impact on the sense and magnitude of the enantioselectivity in the Pd-DAAA reaction. It was found that a palladium-mediated interconversion of enolate intermediates takes place, furnishing products with high ee from racemic -ketoester starting materials without the need for pre-formed geometrically pure enolate precursors. Several studies were performed to gain more insight into the mechanism of the reaction. An enolate crossover experiment showed significant enolate exchange, tentatively suggesting that an outer-sphere alkylation mechanism is in operation. Finally, the utility of this Pd-DAAA methodology was demonstrated in the transformation of one of the enantioenriched thietane-1,1-dioxide building blocks into a novel spirocycle. This spirocycle was proven amenable to various transformations, further demonstrating its potential in medicinal chemistry applications.

Item Type:
Thesis (PhD)
ID Code:
171358
Deposited By:
Deposited On:
07 Jun 2022 11:30
Refereed?:
No
Published?:
Published
Last Modified:
25 Jan 2023 01:19