Intramolecular Nickel-Catalyzed Reductive Coupling: Enantioselective Synthesis of Tetrahydroisoquinolines and Related...

The P-chiral phosphine AntPhos was found to be the ligand of choice for nickel-catalyzed intramolecular reductive coupling reactions of 5-amino substituted 2,4-dienoates bearing a tethered aldehyde. This approach to heterocyclic compounds has little precedent in the literature; it provides, inter alia, ready access to hydroxylated tetrahydroisoquinoline derivatives comprising an anti-configured amino alcohol motif, which are difficult to make in optically active form otherwise. These compounds qualify for diverse downstream functionalization as exemplified by the swift elaboration of a representative member of the series into a fluorinated heterocyclic building block as well as into the core region of potently cytotoxic phenanthroquinolizidine alkaloids in two differently substituted formats. Detailed NMR studies in combination with crystallographic data allowed the reactive oxanickelacycle intermediates primarily formed to be characterized with regard to the bonding mode of the allylnickel subunit that they comprise. Moreover, insights into conformational aspects pertinent to the understanding of the stereochemical course of this metal-catalyzed C─C-bond formation were gained, which leads to the generation of two stereogenic centers at the vic-amino alcohol subunit.