Pd-Catalysed Decarboxylative Asymmetric Transformations of Heterocycles

Pd-catalysed decarboxylative transformations provide mild yet effective routes for the asymmetric syntheses of tertiary and quaternary a-stereocentres in carbonyl-containing compounds. The decarboxylative asymmetric allylic alkylation (DAAA) reaction was first reported in 2004. Since then, significant efforts have been made to continue expanding the scope of the reaction, with initial work focused on substrates with relatively sterically small groups in the a-position, such as methyl, ethyl, benzyl, etc. Our group’s research in the area is centred on installing aryl groups to the a-position to enable the generation of sterically hindered stereocentres in high enantioselectivities. This approach has been successfully applied in the synthesis of a range of carbocyclic and heterocyclic products in enantioselectivities of up to >99% ee. The decarboxylative asymmetric protonation (DAP) reaction is another transformation that is of interest to our group, producing a-tertiary stereocentres with high levels of asymmetric induction, from the same substrates that are employed in the DAAA. As with our DAAA, our group has successfully extended the scope of the DAP methodology to include bulky a-aryl-containing substrates. The chiral P,N ligand system and the chiral amino alcohol protocol have been applied in the synthesis of α-aryl tertiary stereocentres from a range substrates, obtaining high yields and enantioselectivities of up to 95% ee. The aim of this PhD was to further expand the scope of both the DAAA and DAP reactions to include three additional heterocycles: 3,4-dihydroquinolinones, 2,3-dihydroquinolinones and tetrahydrothiopyranones. This commenced with the expansion of our group’s a-arylation methodology to prepare the substrates for catalysis, which bear the a-aryl moiety that is central to our contribution to the area. The synthesis of the N-heterocyclic substrates, the 3,4-dihydroquinolinones and 2,3-dihydroquinolinones, is detailed in Chapter 2. 18 novel a-aryl 3,4-dihydroquinolinone substrates were successfully synthesised, which includes 15 a-aryl variations and 3 N-protecting group variations. 13 novel a-aryl 2,3-dihydroquinolinone substrates were also successfully synthesised, all of which involved steric and electronic variations to the a-aryl moiety. Chapter 3 details the application of the 3,4-dihydroquinolinone substrates to the DAAA reaction. A substrate scope of 11 examples generated products in up to 68% ee. Chapter 4 describes the synthesis of sterically hindered a-aryl tertiary stereocentres from 3,4-dihydroquinolinones and 2,3-dihydroquinolinone substrates via DAP. It was found that (1R,2S)-(–)-ephedrine as the chiral proton source afforded high yields & enantioselectivities, of up to 90% ee. A substrate scope of 29 examples demonstrated that the highest levels of enantioselectivity are linked to the presence of ortho-substitution on the a-aryl group. Finally, Chapter 5 explores the synthesis of the thiopyranone substrates and their application to the DAAA catalysis. Efforts were applied in the optimisation of the in situ arylation protocol to access the desired substrates for catalysis, however the reactivity issue is not possible to overcome. Work was also carried out on the optimisation of the racemic reaction of the model substrate. The substrate scope revealed a clear reactivity trend based on the electronic nature of the substrates. 5 a-allyl-a-aryl thiopyranones were synthesised in good yields & in up to 99% ee.