P‐Chiral (Biaryl phosphine)gold(I) Complexes in Asymmetric Cyclizations of Diverse 1‐Aryl‐1,6‐enynes

Despite significant advances in the development of C‐centered, axial, or planar chiral phosphine ligands in asymmetric catalysis, P‐chiral monodentate phosphine ligands remain underexplored. Especially in gold catalysis, monodentate P‐chiral phosphine ligands have not been employed because of the inherent geometrical challenges. In this article, the synthesis of new monodentate P‐chiral phosphine ligands is presented, which bear substituted biaryl units. The approach is based on desymmetrization of alkyl(diphenyl)phosphine oxides by directed ortho ‐metalation and iodination. The enantioenrichment was achieved by crystallization. The biaryl unit was formed by a Suzuki–Miyaura coupling. Stereoretentive reduction by Ti(O i Pr) 4 /hydrosilane gave the phosphines, which were transformed in situ to stable chiral gold(I) complexes, which were characterized by X‐ray crystallography and spectroscopic methods. The complexes were applied in asymmetric cycloisomerization reactions of diverse 1,6‐enynes providing tricyclic 5/6/6 compounds in good to excellent yields, good regioselectivity, and mostly high enantioselectivity. Hexafluoroisopropanol (HFIP) proved to be optimal as the solvent and activator since it enabled direct application of the gold chloride complexes and proved beneficial to achieve high reactivity and asymmetric induction. The method was applied to the synthesis of a podophyllotoxin analog, which proved to be moderately active against selected cancer cell lines but not against normal human cells.