Asymmetric Synthesis of Tetracyclic Pyrroloindolines and Constrained Tryptamines by a Switchable Cascade Reaction

Corien de Graaff, Lisa Bensch, Sjoerd J Boersma, Răzvan C Cioc, Matthijs J van Lint, Elwin Janssen, Nicholas J Turner, Romano V A Orru, Eelco Ruijter

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)14133-14136
Number of pages4
JournalAngewandte Chemie - International Edition
Volume54
Issue number47
DOIs
Publication statusPublished - 16 Nov 2015

Keywords

  • Indoles/chemical synthesis
  • Molecular Structure
  • Pyrroles/chemical synthesis
  • Tryptamines/chemical synthesis

Cite this

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. / Asymmetric Synthesis of Tetracyclic Pyrroloindolines and Constrained Tryptamines by a Switchable Cascade Reaction. In: Angewandte Chemie - International Edition. 2015 ; Vol. 54, No. 47. pp. 14133-14136.
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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.",
keywords = "Indoles/chemical synthesis, Molecular Structure, Pyrroles/chemical synthesis, Tryptamines/chemical synthesis",
author = "{de Graaff}, Corien and Lisa Bensch and Boersma, {Sjoerd J} and Cioc, {Răzvan C} and {van Lint}, {Matthijs J} and Elwin Janssen and Turner, {Nicholas J} and Orru, {Romano V A} and Eelco Ruijter",
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Asymmetric Synthesis of Tetracyclic Pyrroloindolines and Constrained Tryptamines by a Switchable Cascade Reaction. / 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.

In: Angewandte Chemie - International Edition, Vol. 54, No. 47, 16.11.2015, p. 14133-14136.

Research output: Contribution to JournalArticleAcademicpeer-review

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T1 - Asymmetric Synthesis of Tetracyclic Pyrroloindolines and Constrained Tryptamines by a Switchable Cascade Reaction

AU - de Graaff, Corien

AU - Bensch, Lisa

AU - Boersma, Sjoerd J

AU - Cioc, Răzvan C

AU - van Lint, Matthijs J

AU - Janssen, Elwin

AU - Turner, Nicholas J

AU - Orru, Romano V A

AU - Ruijter, Eelco

N1 - © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PY - 2015/11/16

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N2 - 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.

AB - 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.

KW - Indoles/chemical synthesis

KW - Molecular Structure

KW - Pyrroles/chemical synthesis

KW - Tryptamines/chemical synthesis

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M3 - Article

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EP - 14136

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