ABSTRACT
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 diastereo-selectivity (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 than other substituents, although high levels of enantioselectivity were conserved across a variety of polar and non-polar functional groups. By utilizing the generated chiral ß-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 analog of the tetrahydroprotoberberine alkaloids was successfully synthesized.
ABSTRACT
The bis-tetrahydroisoquinoline (bis-THIQ) natural products have been studied intensively over the past four decades for their exceptionally potent anticancer activity, in addition to strong Gram-positive and Gram-negative antibiotic character. Synthetic strategies toward these complex polycyclic compounds have relied heavily on electrophilic aromatic chemistry, such as the Pictet-Spengler reaction, that mimics their biosynthetic pathways. Herein, we report an approach to two bis-THIQ natural products, jorunnamycin A and jorumycin, that instead harnesses the power of modern transition-metal catalysis for the three major bond-forming events and proceeds with high efficiency (15 and 16 steps, respectively). By breaking from biomimicry, this strategy allows for the preparation of a more diverse set of nonnatural analogs.
