Control of selectivity in palladium-catalysed cross-coupling reactions using a sulfonated phosphine ligand

Abstract

Non-covalent interactions are routinely used by enzymes to control selectivity of chemical reactions during biosynthesis. This prevalence in nature has inspired chemists to adapt these interactions to control selectivity in small molecule catalysis. This thesis describes efforts towards utilising non-covalent interactions to influence site-selectivity and enantioselectivity during palladium-catalysed cross-coupling reactions – a category of transformations used widely by synthetic chemists for many purposes.

This thesis focuses on members of the privileged dialkylbiarylphosphine ligand class, specifically sSPhos, which is the commercially available sulfonated variant of SPhos. The first part investigates the use of this ligand to impart site-selectivity in the cross-coupling of 3,4-dichloroarenes containing an acidic directing group. Selectivity was proposed to arise from an electrostatic interaction between the deprotonated substrate, the cation of the base and the anionic ligand.

An intriguing characteristic of sSPhos is that it is a chiral molecule due to its desymmetrisation upon sulfonation. Resolution of the two enantiomers was achieved initially by preparative supercritical fluid chromatography in collaboration with AstraZeneca, and later by chemical resolution using a chiral auxiliary, work described in this thesis. The second half of this thesis evaluates the efficacy of this new chiral ligand in two classes of asymmetric Suzuki-Miyaura coupling: desymmetrisation, and formation of atropisomers. Desymmetrisation was investigated on protected benzyhydrylamines resulting in good to excellent enantioselectivities being observed. The formation of atropisomeric biaryls was investigated with a wide range of coupling partners, with moderate to good enantioselectivity observed for coupling partners containing polar functionality. Excellent enantioselectivity was observed for the synthesis of 2,2’-biphenols: a scaffold prevalent in natural products as well as in numerous privileged catalysts.

Overall, this work demonstrates the utility of the privileged ligand sSPhos on controlling site- and enantio- selectivity in palladium-catalysed cross-coupling reactions using non-covalent interactions.