Unprecedented direct asymmetric total syntheses of 5,8'-naphthylisoquinoline alkaloids from their fully substituted precursors employing a novel Nickel/N,N-ligand-catalyzed atroposelective cross-coupling.

Abstract

A general and concise synthetic pathway for the preparation of four different 5,8'-coupled naphthylisoquinoline alkaloids, employing a specially developed nickel/N,N-ligand-catalyzed atroposelective Negishi coupling is reported. In the first reported direct atroposelective coupling of the fully substituted precursors, the naturally occurring cross-coupled products were generally obtained directly in reasonable yields and high optical purities. For the synthesis of the cross-coupling precursors, we employed a modification of Bringmann's known approach to the dihydroisoquinoline compounds and a newly developed route for the naphthalene building blocks. For the latter 1,8-dioxynaphthalene precursors, our strategy utilized Hartwig's borylation/methylation approach and included the efficient installation of orthogonal protecting groups.