Palladium-catalyzed asymmetric benzylation of prochiral nucleophiles [electronic resource]

This dissertation details research in the development of palladium-catalyzed asymmetric benzylation. This methodology expands the scope of palladium-catalyzed substitution chemistry and represents a novel means for synthesizing chiral molecules via addition of a benzyl group. Prochiral nucleophiles, wherein enantiodiscrimination occurs during nucleophilic attack on a cationic pi-benzyl-palladium intermediate, are utilized in the reaction with achiral electrophiles. Initial investigations into use of 1,3-dicarbonyls as nucleophiles revealed that high reactivity could be achieved with methyl carbonate electrophiles under palladium catalysis at high reaction temperature. Asymmetric induction was achieved using a chiral Trost-style bisphosphine ligand, which proved to be superior to other chiral phosphine ligands. Optimization with respect to various reaction parameters was performed, and moderate enantioselectivity with a number of 1,3-diketone nucleophiles was realized. We next describe the use of oxindoles, privileged scaffolds in medicinal chemistry, as nucleophiles for asymmetric benzylation methodology. Initial screening revealed the importance of the substituent on the nitrogen atom, with a free N-H yielding the highest enantioselectivity. Investigation of ligand, solvent, temperature, and additive effects identified a set of conditions to provide high yield and enantioselectivity for the reaction between 3-aryl oxindoles and benzylic methyl carbonate electrophiles. A number of substitution patterns were well-tolerated on the oxindole moiety. The electrophile scope included naphthalene-, indole-, benzofuran-, and furan-substituted electrophiles. This research is the first reported palladium-catalyzed asymmetric benzylation of a prochiral nucleophile. The reaction proceeds under mild conditions and generates a quaternary stereocenter. Benzylic methyl carbonate electrophiles were found to be unreactive. Modest conversion of benzylic phosphates was observed, although with moderate enantioselectivity. Azlactones represent a masked amino acid, and were studied as nucleophiles in asymmetric benzylation to provide precursors to chiral quaternary amino acids. Conditions for highly asymmetric benzylation of azlactone nucleophiles with naphthyl and heterocyclic methyl carbonate electrophiles were developed using a Trost-style ligand for asymmetric induction. Investigation into expansion of scope to include monocyclic benzylic electrophiles was also conducted on these highly reactive nucleophiles. Modest reactivity was observed with carbonate electrophiles; phosphate electrophiles, which contain a more labile leaving group, found greater success in the transformation. A diethyl phosphate leaving group was employed for electron-rich aryl rings, while a diphenyl phosphate was required for high reactivity of electron-neutral substrates. The utility of the methodology was demonstrated in a synthesis of alpha-methyl-D-dopa via a one-step azlactone hydrolysis.

Keywords: Chemistry
Advisor: Trost Barry M. primary advisor. Thesis advisor
Burns Noah advisor. Thesis advisor
Huestis Wray advisor. Thesis advisor