Synthesis, application, and mechanistic studies of the asymmetric addition of organozinc reagents to 3,4-dihydroisoquinoline N-oxide

Tetrahydroisoquinolines (THIQ) are an important structural motif in many alkaloids, and they display significant biological and pharmacological properties. A majority of these compounds possess a chiral center at the C-1 position, while stereoisomers at this position exhibit very different activities. Thus, the enantioselective synthesis of 1-substituted-THIQs is of great interest to both organic and medicinal chemists.;In this thesis, we first report the enantioselective addition of vinylzinc reagents to 3,4-dihydroisoquinoline N-oxide. With an N-acylethylenediamine ligand as the catalyst, we obtained a group of chiral N-hydroxyl-1-vinyl-THIQs in 62-85% yield and 90-95% ee. A variety of aliphatic, cyclic and aromatic vinylzinc reagents were employed in the reaction. This method was used to synthesize a single enantiomer of the unnatural amino acid N-Cbz-D-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid.;Next, we describe a novel, expedient synthesis of chiral 1-aryl-THIQs, in which the key step is the asymmetric addition of arylzinc reagents to 3,4-dihydroisoquinoline N-oxide catalyzed by the diamine ligand. With aryl pinacolyl boronic esters as arylzinc precursors, we achieved good yields (35-99%) and excellent enantioselectivities (97-99% ee) in the reaction. This methodology was demonstrated through the enantioselective synthesis of the GlaxoSmithKline drug -- Solifenacin.;Finally, we investigated the mechanism of the enantioselective addition of arylzinc reagents to 3,4-dihydroisoquinoline N-oxide. We adopted a systematic strategy to study this complex system by using a wide range of NMR techniques. This includes, 1D and 2D NMR, Diffusion-Order NMR spectroscopy, Job plot, NMR titration, and in-situ NMR kinetic measurement. Through these studies, we obtained information about bonding, structure and molecular interactions of reactive intermediates along the reaction pathway. We also found that the reaction occurs via a binuclear-zinc intermediate, in which one zinc atom serves as a Lewis acid while the other zinc atom carries the aryl nucleophile. Comparison of reaction rates showed that the catalyzed arylation reaction proceeds faster than the non-catalyzed process. Altogether, we propose a catalytic cycle for the asymmetric arylation reaction. The preference for formation of the (S)-product was rationalized by examining the conformations of different transition states.