Palladium-Catalysed Carbonylation of Aliphatic Amines and its Application in the Total Synthesis of Cylindricine C

Change log
Hogg, Kirsten Fiona 

This thesis comprises three projects on the theme of catalytic C(sp3)–H carbonylation of secondary aliphatic amines.

Chapter 2 describes the development of a general methyl C–H carbonylation of secondary aliphatic amines to form synthetically useful β-lactam building blocks. Amines exhibiting a range of substitution patterns around the nitrogen functionality, and bearing a wide variety of functional groups, could be tolerated in the reaction. The desired β-lactam products were delivered in high yields, with excellent selectivity observed for the β-C–H position. Computational studies suggested that the reaction proceeds through a novel carbamoyl cyclopalladation pathway, which is distinct from classical cyclopalladation.

The subsequent discovery of a selective methylene C–H carbonylation of α-tertiary amines (ATAs) is discussed in chapter 3. By employing the ATA motif, remarkable levels of selectivity for β-methlyene C–H bonds were achieved, even in the presence of traditionally more reactive methyl C–H and C(sp2)–H bonds. Once more, the reaction was found to exhibit excellent functional group tolerance, delivering highly functionalised β-lactam building blocks in high yields and selectivity.

Chapter 4 presents work towards the total synthesis of the marine natural product (±)cylindricine C. The key step of this synthesis was demonstrated to proceed in good yield and excellent selectivity.

Gaunt, Matthew James
C-H activation, carbonylation, palladium catalysis, Aliphatic amines
Doctor of Philosophy (PhD)
Awarding Institution
University of Cambridge