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 language | English |
|---|---|
| Pages (from-to) | 14133-14136 |
| Number of pages | 4 |
| Journal | Angewandte Chemie - International Edition |
| Volume | 54 |
| Issue number | 47 |
| DOIs | |
| Publication status | Published - 16 Nov 2015 |
Keywords
- Indoles/chemical synthesis
- Molecular Structure
- Pyrroles/chemical synthesis
- Tryptamines/chemical synthesis
Cite this
}
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 Journal › Article › Academic › peer-review
TY - JOUR
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
Y1 - 2015/11/16
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
U2 - 10.1002/anie.201507041
DO - 10.1002/anie.201507041
M3 - Article
VL - 54
SP - 14133
EP - 14136
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
SN - 1521-3773
IS - 47
ER -