The Enantioselective Synthesis of Oxygen-Containing Heterocycles via Pd-catalysed Decarboxylative Asymmetric Transformations

Transition metal catalysed systems remain the common pool from which many asymmetric transformations are derived. Pd-mediated decarboxylative transformations present mild asymmetric techniques to synthesise quaternary and tertiary stereocentres in carbonyl-containing compounds that have a wide scope of utility. The decarboxylative asymmetric allylic alkylation (DAAA) builds on previous methodologies that exploit allyl-containing compounds, to generate quaternary stereocentres in high yields and enantioselectivities. Many publications have since expanded the functionality of substrates utilised. However, substituents at the α-position of the resulting products are typically sterically small groups, or functionality distant from the reaction centre. Our research group focuses on the installation of α-aryl containing groups at the α-position of β-keto allyl ester substrates that, when applied to the DAAA reaction, generate products with sterically hindered, quaternary stereocentres. The group has been successful with this, reporting on several non-heterocyclic/heterocyclic substrates which afforded the corresponding products in similarly high yields and enantioselectivities to their less sterically hindered counterparts (up to >99% ee). The decarboxylative asymmetric protonation is another reaction of interest to the group, utilising the same substrate type. This is a powerful technique which can be used to generate products with α-aryl-containing tertiary stereocentres. First reported by Muzart in 1992, utilising an achiral Pd-complex with a chiral proton source for asymmetric induction. Later expanded by Stoltz in 2006, instead an achiral proton source was used with a chiral Pd-complex to generate tertiary stereocentres in high enantioselectivites. Similarly, functionality at the resulting stereocentres remains mostly limited to less sterically hindered substituents. We applied the same substrate types in both methodologies to synthesise more sterically hindered tertiary stereocentres in similarly high enantioselectivities (up to 95% ee).

The aim of this project was to expand the scope of both reaction types along with our group’s aryllead triacetate methodology to synthesise sterically hindered chiral centres in other oxygen-containing hetereocycles, including benzofuranones, tetrahydropyranones and cyclic siloxyketones. In Chapter 2 the synthesis of 17 novel benzofuranone containing α-aryl-β-keto allyl ester substrates is described, exploring the substitution on the backbone of the ring and on the aryl group itself. These were applied to the DAAA reaction where the optimised conditions gave the sterically hindered products in high enantioselectivities of up to 96% ee. In Chapter 3, 12 novel α-aryl-β-keto allyl ester substrates containing the tetrahydropyranone motif were synthesised, varying in substitution around the aryl ring. The DAAA reaction was reoptimised and the resulting products were obtained in high yields and excellent enantioselectivities, up to >99% ee. In Chapter 4, 9 substrates were applied to the DAP reaction, using a chiral proton source ((-)-ephedrine) with an achiral palladium complex, affording the products of the reaction in up to 85% ee. In these cases, substrates with aryl groups bearing di-ortho substitution patterns or naphthyl groups gave the highest levels of enantioselectivity, these values decreased when moving to substrates with mono-ortho substituents or those with no ortho groups at all. In Chapter 5, we attempted to repeat work by Stoltz on the synthesis of cyclic siloxyketones hoping to apply our aryllead triacetate methodology to install bulky aryl groups at the α-position. In the DAAA reaction this would afford potential access to sterically hindered all-carbon quaternary stereocentres in an acyclic motif. However, difficulty with the preproduction of the literature conditions meant we were only able to repeat 7 of the 8 steps needed to synthesise the model substrate.