Studies toward the Total Synthesis of Nogalamycin: Construction of the Complete ABCDEF-Ring System via a Convergent Hauser Annulation

The convergent synthesis of the complete ABCDEF-ring system within nogalamycin, an anthracycline natural product, was studied. The pivotal Hauser annulation for the anthraquinone core construction was achieved by the fusion of two highly functionalized segments: a cyanophthalide (the AB-ring segment) and a tricyclic quinone monoketal (the DEF-ring segment). Key transformations toward the AB-ring segment include an enantioselective enolate α-hydroxylation, a diastereoselective hydroboration-oxidation, and a directed aromatic lithiation-formylation. To prepare the DEF-ring segment for annulation, a mild dearomatization of the F-ring phenol group by (diacetoxyiodo)­benzene (PIDA) was employed.