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Title: Palladium(II)-catalysed sp 3 C–H functionalisation of hindered amines and its application in synthesis of astemizole analogues
Author: Ho, Danny Ka Hei
ISNI:       0000 0004 6425 5272
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2016
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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.
Supervisor: Gaunt, Matthew J. Sponsor: EPSRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: CH activation ; Palladium ; functionalisation of ketones ; hindered secondary amines ; Catalysis