Solid-phase synthesis of substituted 3-amino-3′-carboxy-tetrahydrocarbazoles

Abstract

Two related solid-phase synthesis routes have been developed allowing the synthesis of 3-amino-3′-carboxy substituted tetrahydrocarbazole derivatives. Diversity can be introduced at the amino and carboxy functionalities and at the nitrogen and the aromatic ring of the tetrahydrocarbazole moiety. Both routes rely on Fmoc-protected 1-amino-4-oxocyclohexanone carboxylic acid as central core element. Derivatization of the carboxy function is achieved with amines, derivatization of the amino functionality is possible by reaction with alkyl halides, isocyanates, activated alcohols, sulfonic acid chlorides or carboxylic acids. The tetrahydrocarbazole scaffold is generated by Fischer indole cyclization with phenyl hydrazine derivatives, thereby introducing diversity in the aromatic moiety. N-Alkylation at the indole nitrogen with alkyl halides delivers N-substituted derivatives.