The synthesis, resolution, and applications of 3,3'-substituted BINAP ligands in asymmetric catalysis

Catalytic asymmetric synthesis is one of the most powerful methods for the construction of an array of enantiomerically enriched compounds. The design and synthesis of chiral bisphosphine ligands is an important area of research towards developing highly enantioselective transition metal-catalyzed asymmetric reactions. BINAP 8 represents one of the most heralded bisphosphine ligands for asymmetric catalysis. Substitution in the 3,3'-positions of the BINAP backbone provides the greatest opportunity for both steric and electronic perturbation of catalyst properties. This dissertation details the synthesis and applications of a series of novel 3,3'-substituted BINAP ligands 383-386.; Beginning from readily available 4-bromo-2-naphthol (367), ether and ester substituted ligands 383-386 are prepared in a seven step procedure. Optical resolution is achieved through a diastereoselective Ullmann coupling, followed by separation by column chromatography and trituration with tert-butyl methyl ether. Standard alkylation or acylation introduces the desired substituents, and following reduction of the phosphine oxides, 3,3'-substituted BINAP ligands are afforded in good yields. Structural characterization of ligand-PdCl2 adducts reveals that the chiral pocket found in BINAP is maintained upon incorporation of 3,3'-substitution, however structural variations in the ligand bite angle and torsion angle are present. Electronic modification at the phosphorus donor follows that expected.; The novel ligands are compared to BINAP in Pd- and Rh-catalyzed asymmetric transformations. The 3,3'-substituted BINAP ligands generally provid catalysts of increased selectivity over BINAP derived catalysts, often times with the opposite product configuration, despite the ligands being of the same axial configuration. The greatest disparity is observed in the hydrogenation of alpha-acetamidoacrylic acids 199, as products of near enantiopurity are obtained upon use of the 3,3'-substituted BINAP ligands compared to poor levels of enantioselectivity for Rh-BINAP systems.; Close structural study of metal-ligand adducts illustrates great differences in the ligand orientation about the metal center. While these differences may be active in the reversal of product stereochemistry for many reactions, solution state study of the systems contradicts this. Investigation of the asymmetric hydrogenation of methyl-2-acetamidocinnamate (174b) by spectroscopic and experimental methods confirms that the 3,3'-substituted BINAP ligands operate under a dissimilar mechanistic pathway. The 3,3'-substituted BINAP ligands alter the reactivity of diastereomeric olefin-metal adduct intermediates, resulting in the formation of the product of opposite absolute configuration.