The Synthesis of Chiral P,N Ligands and Their Applications in Asymmetric Catalysis

The synthesis of enantiopure compounds is an area of exceptional interest for the pharmaceutical industry. The complex 3-dimensional nature of biological targets has led to the requirement for the synthesis of small drug molecules that can bind to these targets. A range of methodologies to synthesise and/or separate single enantiomers is described, giving examples, benefits, drawbacks and a general overview of the area. Work to date to produce axially chiral P,N ligands with a large barrier to rotation is described. Axially chiral phosphino-imidazoline ligands have shown exceptional activity in asymmetric transition metal-catalysis, however they are prone to epimerisation at elevated temperatures. Two approaches were taken to mitigate this: an increase in steric bulk around the axis and the tethering of the top ring to the bottom. This has led to the synthesis of two novel ligands, CR-1 and Ts-UCD-Phim, which were synthesised in an overall 9% (over 5 steps) and 10% yield (over 5 steps), respectively. Also described are various other routes to similar ligands yet to be completed. (S,S,Ra)-UCD-Phim is a known ligand from our own research group. Two routes common within our group for synthesising this ligand are described and their benefits and drawbacks have been compared. Another known type of ligand from our research group is a set of BoPhoz-type ligands and the synthesis of one example to date (two steps remaining) is presented as well as its potential applications discussed. An integral part of these axially chiral P,N ligands is their barrier to rotation and therefore the methods to calculate it play an important role in the ligands’ evaluation. To save time a method of calculating this barrier to rotation a priori would allow some element of evaluation of a ligand prior to synthesis. One such method is described therein using DFT and with results benchmarked against an experimental value for (S,S,Ra)-UCD-Phim. This method was subsequently applied to both CR-1 and Ts-UCD-Phim to determine their barriers to rotation. The library of ligands produced was then applied in three asymmetric reactions: a copper-catalysed borylation of styryl benzoxazoles (up to 91% yield and 64% ee), a copper-catalysed A3 coupling (up to 82% yield and 20% ee) and a palladium-catalysed allylic alkylation (60% yield and 89% ee). Finally, (S,S,Ra)-UCD-Phim was applied in a new copper-catalysed alkynylation of quinolones. Quinolones and their respective dihydroquinolone counterparts are prevalent throughout medicinal chemistry and as such, represent attractive targets for asymmetric synthesis. This project resulted in the synthesis of 22 dihydroquinolone products in yields of up to 92% and ees up to 97%. One of the dihydroquinolones was further functionalised to produce the natural product (-)-cuspareine in a 90% ee and a 10% yield over three steps. In summary, various known and novel chiral P,N ligands have been synthesised. This library has then been applied in a variety of asymmetric transition metal-catalysed reactions, both in established reactions that are benchmarks of this class of ligand as well as in a novel methodology.