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

C. A. Merlic, C. C. Aldrich, J. Albaneze-Walker, A. Saghatelian, J. Mammen

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52 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1297-1309
Number of pages13
JournalJournal of Organic Chemistry
Volume66
Issue number4
DOIs
StatePublished - Feb 23 2001

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