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 β-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.