Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines

The development of a general method utilizing a hydroxymethyl directing group for asymmetric hydrogenation of 1,3-disubstituted isoquinolines to provide chiral 1,2,3,4-tetrahydroisoquinolines is reported. The reaction, which utilizes [Ir(cod)Cl](2) and a commercially available chiral xyliphos ligand, proceeds in good yield with high levels of enantioselectivity and diastereoselectivity (up to 95% ee and >20:1 dr) on a range of differentially substituted isoquinolines. Directing-group studies demonstrate that the hydroxymethyl functional group at the C1 position is more efficient at enabling hydrogenation in comparison to other substituents, although high levels of enantioselectivity were conserved across a variety of polar and nonpolar functional groups. By utilization of the generated chiral beta-amino alcohol as a functional handle, the synthetic utility is further highlighted via the synthesis of 1,2-fused oxazolidine, oxazolidinone, and morpholinone tetrahydroisoquinolines in one step. Additionally, a non-natural analogue of the tetrahydroprotoberberine alkaloids was successfully synthesized.