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Palladium(II)-Catalysed sp 3 C–H Functionalisation of Hindered Amines and its Application in Synthesis of Astemizole Analogues 10.17863/CAM.13434 Ho, Danny Ka Hei Gaunt, Matthew J The development of a palladium-catalysed C–H carbonylation of hindered secondary amines is described. Central to this strategy is the temporary conversion of simple ketones into hindered secondary amines that facilitates a sterically promoted palladium-catalysed C–H activation. A range of functional groups are shown to be compatible with this catalytic process, and with exclusive regioselectivity for the terminal ethyl sp 3 C–H in most cases. This method allows an overall incorporation of a carboxyl group to the b-position of terminal ketones, generating 1,4- dicarbonyl moieties which are important synthetic building blocks. The sterically promoted C–H functionalisation strategy has been employed as the key step in the synthesis of a functionalised analogue of astemizole, a pharmaceutical agent which suffers from undesired hERG activity. The increased steric bulk around the tertiary amine, coupled with introduction of a polar hydroxyl group via the C–H acetoxylation reaction, is proposed to reduce binding to the hERG channel. The hERG profile of this analogue is not yet established. University of Cambridge 2016-09-01 Thesis Doctoral Doctor of Philosophy (PhD) en EPSRC https://www.repository.cam.ac.uk/handle/1810/267480 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/e68103a5-2867-47b8-9e34-10f18b690bbc/download 87eda9de84448d1f82354d60eee3eb5f https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/a232ad61-f1db-4e37-8188-b446df396ac6/download 1d1e86251d1dba211981201b06b2274d https://www.rioxx.net/licenses/all-rights-reserved/ CH activation Palladium functionalisation of ketones hindered secondary amines Catalysis