Asymmetric Total Synthesis of Nigerone and ent-Nigerone: Enantioselective Oxidative Biaryl Coupling of Highly Hindered Naphthols



An enantioselective synthesis of the chiral bisnaphthopyrone natural product nigerone and its enantiomer, ent-nigerone, has been realized. The use of constrained 2-naphthol substrates was critical to producing highly functionalized chiral 1,1′-binaphthols via asymmetric oxidative biaryl coupling with 1,5-diaza-cis-decalin copper complexes. The final natural product was formed via a key eight-step isomerization process of the coupling product, bisisonigerone, and proceeded with retention of the biaryl configuration. The axial configurations of bisisonigerone and nigerone were definitively established by a combination of circular dichroism (CD) measurements and quantum chemical CD calculations.