Asymmetric Synthesis of Tetracyclic Pyrroloindolines and Constrained Tryptamines by a Switchable Cascade Reaction. Issue 47 (25th September 2015)

• Record Type: Journal Article
• Authors: de Graaff, Corien; Bensch, Lisa; Boersma, Sjoerd J.; Cioc, Răzvan C.; van Lint, Matthijs J.; Janssen, Elwin; Turner, Nicholas J.; Orru, Romano V. A.; Ruijter, Eelco
• Is Part Of: Angewandte Chemie international edition. Volume 54:Issue 47(2015)
• Page Start: 14133
• Page End: 14136
• Publication Date: 2015-09-25
• Subjects: asymmetric synthesis -- bioactive compounds -- cascade reactions -- synthetic methods -- tryptamines; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201507041
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: The interrupted Fischer indole synthesis of arylhydrazines and biocatalytically generated chiral bicyclic imines selectively affords either tetracyclic pyrroloindolines or tricyclic tryptamine analogues depending on the reaction conditions. We demonstrate that the reaction is compatible with a variety of functional groups. The products are obtained in high optical purity and in reasonable to good yield. We present a plausible reaction mechanism to explain the observed reaction outcome depending on the stoichiometry of the acid mediator. To demonstrate the synthetic utility of our method, pharmaceutically relevant examples of both product classes were synthesized in highly efficient reaction sequences, including a phenserine analogue as a potential cholinesterase inhibitor and constrained tryptamine derivatives as selective inhibitors of the 5‐HT6 serotonin receptor and the TRPV1 ion channel. Abstract : One way or the other : The interrupted Fischer indole synthesis of arylhydrazines and chiral bicyclic imines selectively affords either tetracyclic pyrroloindolines or tricyclic tryptamine analogues depending on the reaction conditions. The products were obtained in high optical purity and readily elaborated to medicinally important compounds.