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 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.
Merlic
C A
CA
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, USA. merlic@chem.ucla.edu
Aldrich
C C
CC
Albaneze-Walker
J
J
Saghatelian
A
A
Mammen
J
J
D006838:Hydrocarbons; D007536:Isomerism; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry*; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis*; D013057:Spectrum Analysis; D013816:Thermodynamics
D006838:Hydrocarbons; D009281:Naphthalenes; C061465:calphostin complex; C030011:carbene; D008697:Methane