title: Asymmetric Synthesis of Tetracyclic Pyrroloindolines and Constrained Tryptamines by a Switchable Cascade Reaction.
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.
authors.affiliation: Department of Chemistry and Pharmaceutical Sciences and Amsterdam Institute of Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands).
authors.forename: Corien
authors.initials: C
authors.lastname: de Graaff
authors.affiliation: Department of Chemistry and Pharmaceutical Sciences and Amsterdam Institute of Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands).
authors.forename: Lisa
authors.initials: L
authors.lastname: Bensch
authors.affiliation: Department of Chemistry and Pharmaceutical Sciences and Amsterdam Institute of Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands).
authors.forename: Sjoerd J
authors.initials: SJ
authors.lastname: Boersma
authors.affiliation: Department of Chemistry and Pharmaceutical Sciences and Amsterdam Institute of Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands).
authors.forename: Răzvan C
authors.initials: RC
authors.lastname: Cioc
authors.affiliation: Department of Chemistry and Pharmaceutical Sciences and Amsterdam Institute of Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands).
authors.forename: Matthijs J
authors.initials: MJ
authors.lastname: van Lint
authors.affiliation: Department of Chemistry and Pharmaceutical Sciences and Amsterdam Institute of Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands).
authors.forename: Elwin
authors.initials: E
authors.lastname: Janssen
authors.affiliation: School of Chemistry, University of Manchester and Manchester Institute of Biotechnology, 131 Princess Street, Manchester, M1 7DN (UK).
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Turner
authors.affiliation: Department of Chemistry and Pharmaceutical Sciences and Amsterdam Institute of Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands).
authors.forename: Romano V A
authors.initials: RV
authors.lastname: Orru
authors.affiliation: Department of Chemistry and Pharmaceutical Sciences and Amsterdam Institute of Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands). e.ruijter@vu.nl.
authors.forename: Eelco
authors.initials: E
authors.lastname: Ruijter
mesh_terms: D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry; D014363:Tryptamines / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D007211:Indoles; D011758:Pyrroles; D014363:Tryptamines
keywords: asymmetric synthesis; bioactive compounds; cascade reactions; synthetic methods; tryptamines