Total Synthesis of the Cephalotaxus Alkaloids. A Problem in Nucleophilic Aromatic Substitution

The synthesis of cephalotaxine and cephalotaxinone has been achieved in 12-16% overall yield from pyrrolidone and 3,4-methylenedioxyphenylacetic acid. The strategy includes a key step which requires overall intramolecular nucleophilic aromatic substitution of an enolate anion onto an unactivated aromatic ring. Several methods give successful ring closure including addition to a transient aryne (15% yield), coupling via a σ-arylnickel complex (30%), and addition to a transient aryl radical generated from alkali metal reduction (45%) or from irradiation (94%).