Mechanistic studies of enantioselective alkene bromolactonisation reactions

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Title: Mechanistic studies of enantioselective alkene bromolactonisation reactions
Author(s): Jones, Alexander
Item Type: Thesis or dissertation
Abstract: Asymmetric alkene halofunctionalisation is a vibrant and rapidly expanding field. Several promising organocatalysts have emerged based on privileged binaphthyl phosphoric acid and cinchona alkaloid scaffolds. However, there is still significant potential for improvement. Many catalyst systems are limited in substrate scope and mechanistic understanding. In this thesis we describe the development of asymmetric bromolactonisation reactions catalysed by bis-cinchona alkaloid, (DHQD)2PHAL, as modified by added carboxylic acids. This combination delivers bromolactones with enantioselectivity at a comparable level to bespoke organocatalysts previously optimised for particular substrate classes. The utility of our system is based on the commercial availability of all reagents and the ability to tune the performance of (DHQD)2PHAL with reaction additives. The mode of substrate activation and the role of the carboxylic acid additive are investigated. Asymmetric induction is strongly influenced by the concentration and the stereoelectronic properties of the additive, and enantioselectivity deteriorates with reaction conversion in its absence. Interactions between carboxylic acids and (DHQD)2PHAL are characterised by crystallographic and equilibrium 1H NMR analysis. 2D-NOESY experiments indicate that acids significantly restrict the rotational flexibility of (DHQD)2PHAL in solution. We propose that catalyst rigidity is essential for maximisation of enantioselectivity. This hypothesis leads to the development of conformationally constrained catalyst derivatives which catalyse bromolactonisation with greater enantioselectivity than (DHQD)2PHAL. The relative stereoselectivities of successive alkene bromination and cyclisation steps, and the configurational stability of intermediate bromonium ions are elucidated. An unusual scenario is encountered whereby product e.r. is also determined by the regioselectivity of lactonisation. Finally, a unifying model for asymmetric induction is proposed which accounts for the absolute product configurations observed.
Content Version: Open Access
Publication Date: Mar-2014
Date Awarded: Jul-2014
URI: http://hdl.handle.net/10044/1/24940
Advisor: Braddock, Christopher
Armstrong, Alan
Sponsor/Funder: Engineering and Physical Sciences Research Council
GlaxoSmithKline
Department: Chemistry
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Chemistry PhD theses



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