Asymmetric rhodium-catalysed conjugate arylation is an important carbon–carbon bond forming reaction of increasing industrial relevance. The control of enantioselectivity has been explored extensively in the published literature, however the competing deboronation reaction has received little attention. This uncontrolled side-reaction often necessitates the use of up to 10 equivalents of the arylboron reagent, rendering the methodology unattractive for large scale industrial purposes.
In this thesis, a pharmaceutically-relevant rhodium-catalysed conjugate addition of an arylboronic acid pinacol ester to an unsaturated ester with heteroaryl functionality has been investigated, with significant improvements to the enantioselectivity, chemoselectivity and green metrics made compared with a previous process used on kilogram scale. The original process delivered poor enantioselectivity, required uneconomical rhodium loadings and a large excess of the arylboron reagent.
A cheaper and highly selective catalyst system was identified following extensive and informed investigations into the behaviour of different ligand and rhodium salt combinations. The optimised process utilises an inexpensive chiral ligand from a ligand class previously overlooked by industry. The new system delivers up to 97% ee with virtually complete selectivity for the desired conjugate arylation reaction over the competing protodeboronation reaction. Furthermore, factors that are important for the success and selectivity of the desired reaction have been efficiently identified using a statistical Design of Experiment approach. This has enabled the loading of the precious metal catalyst to be lowered by > 85% whilst maintaining 97% selectivity for the 1,4-addition reaction over protodeboronation.
An empirical investigation of the structural motifs of the substrates and the ligand that were important in enabling a high selectivity for conjugate arylation over protodeboronation to be achieved is also presented. The heteroaryl functionality of the enoate was found to contribute to the selectivity, but could prevent consumption of the arylboron reagent altogether if a suitable sterically-shielding group was not present. The structural motifs of the ligand had a significant impact on the chemoselectivity of the reaction, with electronic factors, steric factors and functionality affecting the relative amounts of conjugate arylation product and protodeboronation product.
Computational chemistry and an analysis of published crystallographic data enabled the high selectivity for conjugate arylation over protodeboronation that the optimised reaction process affords to be rationalised. Ligands expected to facilitate the exchange of a solvent molecule bound to the metal centre for the enoate electrophile delivered the highest selectivities for conjugate arylation. Conversely, ligands and arylboron reagents expected to impede the exchange of a bound solvent molecule for the enoate electrophile gave elevated levels of the protodeboronation product.
| Date of Award | 4 Jun 2019 |
|---|
| Original language | English |
|---|
| Awarding Institution | - University Of Strathclyde
|
|---|
| Sponsors | University of Strathclyde |
|---|
| Supervisor | Glenn Burley (Supervisor) & Marc Reid (Supervisor) |
|---|