Synthesis and Application of Novel Peptidic and Oxazoline Based Ligands for Asymmetric Catalysis

Geoghegan, Paul
This thesis describes the synthesis and application of four novel chiral ligand classes. These were all hydroxyamide or oxazoline ligands with an L-pyroglutamic acid derived terminus. These ligands were applied as part of catalytic systems to the catalysis of three main asymmetric transformations, an alkylation reaction, an alkynylation reaction and transfer hydrogenation reaction. Chapter one introduces the current state of the art with respect to chiral hydroxyamide ligands and oxazoline ligands. The comprehensive section on chiral hydroxyamide ligands has recently been published as a review paper in ACS Catalysis. Chapter two outlines the synthesis of the four novel classes of ligand: - hydroxyamide ligands based on a dipeptide framework, capped by a pyroglutamate at one terminus - hydroxyamides based on a tripeptide framework , capped by a pyroglutamate at one terminus - two different types of oxazoline ligands which had the pyroglutamate at one end of the carbon chain and the oxazoline at the other, which differed in the location of functionality on the carbon backbone. A modular approach was used to synthesize chiral ligands, with the chirality originating from the chiral pool. The various synthetic methods employed are discussed, and where ligands were made by several methods, they are compared. The characterisation of all the ligands is discussed in detail. Electronic and steric properties of the ligand compounds were varied, and the electronic properties of the ligands were found to have a minor influence on the levels of enantioselectivity induced by the ligands. The influence of the steric properties was more important, especially where the ligands contained phenyl groups. The application of the ligands to the three main reactions and several other minor reactions are discussed in detail. The dipeptide based ligands were used in a ruthenium-catalysed transfer hydrogenation reaction where one ligand gave the product in 72% ee though the conversion was poor. The ligands were also used in two titanium-catalysed reactions, an alkylation where ees of up to 74% were achieved and a phenyl acetylene addition where more modest selectivities were observed. The tripeptide based ligands were used in a ruthenium-catalysed transfer hydrogenation reaction where they were far less selective than the dipeptides achieving ees of only 20%. The ligands were also used in the alkylation where ees of 21% were achieved and a phenyl acetylene addition where again modest selectivities were observed. The oxazoline ligands were applied to the alkylations, where they gave very modest selectivities of ~20% ee, to the transfer hydrogenation where they gave selectivity of up to 27% ee and the alkynylation where again they gave modest selectivity. This chapter also discusses the potential reasons for selectivity where it is observed. The sense of chiral induction looks to be determined by the absolute configuration of the pyroglutamate module of the ligands as the (R)-enantiomer of the chiral products was in excess in all cases, and the (S)-pyroglutamate was common to all the ligands. Chapter 3 gives full experimental details for all of the reactions described in the thesis.
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Attribution-NonCommercial-NoDerivs 3.0 Ireland