Palladium(II)-Catalysed sp 3 C–H Functionalisation of Hindered Amines and its Application in Synthesis of Astemizole Analogues

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.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2016

Author dc:creator

• Ho, Danny Ka Hei

Advisor dc:contributor.advisor

• Gaunt, Matthew J

• CH activation
• Palladium
• functionalisation of ketones
• hindered secondary amines
• Catalysis

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/e68103a5-2867-47b8-9e34-10f18b690bbc/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

en

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.13434

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/267480