Total synthesis of the calphostins: Application of Fischer carbene complexes and thermodynamic control of atropisomers

The total syntheses of the potent protein kinase C inhibitors calphostins A , B, C, and D as well as a variety of structural analogues are reported. An aminobenzannulation reaction of an enantiopure chromium Fischer carbene co mplex is utilized to prepare a pentasubstituted naphthylamine. After optimi zation of side-chain substituents, conversion of the naphthylamine to an o- naphthoquinone was followed by biomimetic oxidative dimerization using trif luoroacetic acid and air yielding a 1:2 P/M mixture of atropisomeric peryle nequinones. Thermal equilibration to a 3:1 P:M atropisomeric ratio and sepa ration of the perylenequinones followed by side chain desymmetrization and functionalization led to the total synthesis of enantio- and diastereomeric ally pure calphostin C in only twelve steps from commercially available sta rting materials. In addition, calphostins A, B, D, and several structural a nalogues were prepared to evaluate biological activities.