Saturated N-heterocycles are prevalent motifs in bioactive compounds and represent important structures for pharmaceutical screening. As such, synthetic methods that can readily access these derivatives with high regio- and stereocontrol would be of significant value for the discovery of new therapeutics.
Catalytic C–H functionalisation offers high potential for the iterative and divergent synthesis of substituted N-heterocycles from simple cyclic precursors. The research in this thesis describes the selective synthesis of cis-3,4-disubstituted pyrrolidines and piperidines by Pd-catalysed C(sp3)–H functionalisation with aryl iodides.
As described in chapter 3, high regio- and stereoselectivity is achieved using an aminoquinoline amide directing group at C(3), with C(4)-functionalisation always preferred over competing C(2). Divergent directing group removal delivers various biologically relevant building blocks, containing amide, carboxylic acid and alcohol functionalities.
The synthetic utility of this protocol for drug discovery applications is described in chapter 4. C(4)–H arylation followed by directing group removal enables the stereocontrolled formal synthesis of antidepressant (–)-paroxetine and the total synthesis of enantiopure Br- and I-paroxetine analogues. Furthermore, the synthesis of a library of arylated pyrrolidine and piperidine fragments for pharmaceutical screening is demonstrated.
Mechanistic investigations into the observed regio- and stereoselectivity are discussed in chapter 5. Deuteration studies, kinetic analysis and DFT calculations suggest reversible C–H activation to occur at different positions on the ring. Subsequent stereodetermining oxidative addition of PdII to PdIV and turnover-limiting reductive elimination deliver the C(4)-arylated products as cis-diastereomers. During this study, evidence for a fast catalyst deactivation process is observed.
Attempts to overcome this limitation are finally discussed in chapter 6. This ultimately results in the development of an improved 4-dimethylamino-8-quinolinyl amide directing group. This novel removable auxiliary provides a faster reaction rate, higher yields and a broader substrate scope, and enables the late-stage functionalisation of complex biorelevant compounds.