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

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 varie...

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Bibliographic Details
Published in:Angewandte Chemie Vol. 127; no. 47; pp. 14339 - 14342
Main 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
Format: Journal Article
Language:English
German
Published: Weinheim WILEY‐VCH Verlag 16.11.2015
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Subjects:
Asymmetric synthesis
Asymmetrische Synthesen
Asymmetry
Biologisch aktive Verbindungen
Capsaicin receptors
Cascade chemical reactions
Chemistry
Cholinesterase
Cholinesterase inhibitors
Constraints
Derivatives
Functional groups
Imines
Indoles
Inhibitors
Ion channels
Reaction mechanisms
Reaktionskaskaden
Serotonin
Stoichiometry
Synthesemethoden
Synthesis (chemistry)
Tryptamine
Tryptamines
ISSN:0044-8249, 1521-3757
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Summary: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. Am Scheideweg: Unterbrochene Fischer‐Indolsynthesen mit Arylhydrazinen und chiralen bicyclischen Iminen ergeben abhängig von den Reaktionsbedingungen selektiv entweder tetracyclische Pyrroloindoline oder tricyclische Tryptamin‐Analoga. Die optisch hoch reinen Produkte lassen sich leicht in medizinisch bedeutende Verbindungen umsetzen.
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ISSN:0044-8249
1521-3757
DOI:10.1002/ange.201507041