New oxazoline-based ligands for application in asymmetric synthesis

Abstract

Asymmetric catalysis is a powerful tool in the synthesis of optically pure compounds by providing excellent possibilities to introduce enantioselectivity using small amounts of an enantiomerically pure catalyst. Among the large variety of asymmetric ligands that have emerged since the start of aymmetric catalysis, enantiopure C2-symmetric bisoxazoline ligands have been identified as a 'privileged' class of ligands with applications in numerous enantioselective metal-catalysed transformations, e.g. Mukaiyama aldol and Michael reactions, hetero-Diels-Alder reactions and allylic alkylations. More recently, non-C2-symmetric oxazoline-based P,N-ligands have been developed for use in additional types of asymmetric transformations. This thesis describes the synthesis of several novel extended aryl-substituted bisoxazoline ligands. Phenylbisoxazoline, (1-naphthyl)- and (2-naphthyl)bisoxazoline were obtained from the corresponding enantiopure amino acids, obtained through an enzymatic resolution process. Alternatively, (9-anthryl)bisoxazoline was prepared using preparative chiral HPLC. The absolute stereochemistry of the intermediate amino alcohols was elucidated using CD. The scope and limitations of the new bisoxazoline ligands in known reactions, and more specifically the steric influence of the aryl substituent were investigated. Besides the ligands were tested in several new reactions, e.g. the Mukaiyama aldol reaction to an intermediate in the synthesis towards natural product (+)-tanikolide. Several techniques, i.e. X-ray crystallography, modelling studies and EPR measurements, were applied to characterise the catalyst complexes and to predict the outcome of reactions. Furthermore, these ligands were applied in an enantio- and diastereoselective tandem reaction to chromanes, involving oxa-Michael addition and subsequent intramolecular Friedel-Crafts type alkylation. VCD was applied to assign the absolute stereochemistry of the product. Finally, the synthesis of PhOH-ox, involving an enzymatic resolution, was described. This so-called N,O-ligand belongs to a new class of oxazoline-based bidentate ligands where the chiral centre is located in the backbone and was used in the enantioselective addition of diethylzinc to benzaldehyde.