N-Heterocycle synthesis via Pd(0)-catalysed C–H activation: kinetic resolution and Pd shift

Transition-metal-catalysed C–H bond functionalisation has exponentially developed as an efficient strategy for valuable molecules since the turn of the 21st century. Our group's research focuses on the activation and functionalisation of naturally abundant C–H bonds in organic molecules, which can develop new methodologies and applications, including asymmetric catalysis, mechanistic studies and total synthesis of natural products. However, it remains challenging and limited despite numerous C–H bond functionalisation methodologies developed until today when it comes to kinetic resolution via Pd(0)-catalysed C–H activation. This topic is underdeveloped despite great synthetic potential.
In this thesis, we aimed to develop a novel methodology on Pd(0)/Pd(II) catalysed C–H activation to achieve the total synthesis of a natural product and synthesis of the biologically valuable moiety.
This thesis is divided into kinetic resolution and remote construction of N-heterocycles.
In the first project, we identified that specific substrates showed the behaviour of parallel kinetic
resolution in excellent enantioselectivity by C(sp3)–H arylation. Then, that efficiency was envisioned to translate into the asymmetric framework construction of polycyclic natural alkaloid cryptowolinol.
In the second project, we developed remote construction of isoindolines. Interestingly, during the course
of investigations on kinetic resolution, an isoindoline product was serendipitously identified arising from
a novel 1,4-Pd shift and subsequent C(sp3)–C(sp2) bond formation. This new reactivity was exemplified in the synthesis of biologically exciting isoindolines. In addition, mechanistic studies were implemented to clarify the nature of this transformation. N-heterocyclic carbene ligands showed superior product selectivity compared to previously used phosphine-type ligands and proved to be critical to its success.
Keywords: C–C coupling, C–H activation, kinetic resolution, N-heterocycles, palladium, total synthesis,
cryptowolinol, 1,4-Pd shift, isoindoline