Total synthesis of the calphostins: application of fischer carbene complexes and thermodynamic control of atropisomers

J Org Chem. 2001 Feb 23;66(4):1297-309. doi: 10.1021/jo0014663.


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 complex is utilized to prepare a pentasubstituted naphthylamine. After optimization of side-chain substituents, conversion of the naphthylamine to an o-naphthoquinone was followed by biomimetic oxidative dimerization using trifluoroacetic acid and air yielding a 1:2 P/M mixture of atropisomeric perylenequinones. Thermal equilibration to a 3:1 P:M atropisomeric ratio and separation of the perylenequinones followed by side chain desymmetrization and functionalization led to the total synthesis of enantio- and diastereomerically pure calphostin C in only twelve steps from commercially available starting materials. In addition, calphostins A, B, D, and several structural analogues were prepared to evaluate biological activities.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Hydrocarbons
  • Isomerism
  • Methane / analogs & derivatives*
  • Methane / chemistry*
  • Molecular Structure
  • Naphthalenes / chemical synthesis*
  • Spectrum Analysis
  • Thermodynamics


  • Hydrocarbons
  • Naphthalenes
  • calphostin complex
  • carbene
  • Methane