Cyclohepta[b]indoles : A Privileged Structure Motif in Natural Products and Drug Design

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Accounts of Chemical Research. 2016, 49(11), pp. 2390-2402. ISSN 0001-4842. eISSN 1520-4898. Available under: doi: 10.1021/acs.accounts.6b00265
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Seven-membered rings fused with an indole are termed cyclohepta[b]indoles. Compounds exhibiting this structure motif display a broad spectrum of biological activities, ranging from inhibition of adipocyte fatty-acid-binding protein (A-FABP), deacetylation of histones, inhibition of leukotriene production p53, antituberculosis activities, and anti-HIV activities. These biological profiles are found in natural products containing the cyclohepta[b]indole motif, as well as in pharmaceuticals that contain this structure motif. Therefore, the biology of molecules derived from the skeleton of cyclohepta[b]indoles, as well as cyclopenta- and cyclohexa[b]indoles, has attracted considerable interest from the pharmaceutical industry as potential therapeutics in recent years. This is reflected by more than two dozen patents that have been issued in the past decade, solely based on the cyclohepta[b]indole structure motif. The efficient preparation of highly functionalized and unsymmetrically substituted cyclohepta[b]indoles has therefore become of central interest for synthetic organic chemists. Historically, this structure motif most often has been prepared by means of a Fischer indole synthesis. Although very robust and useful, this reaction poses certain limitations. Especially unsymmetrically functionalized cyclohepta[b]indoles are not suitable for a Fischer indole type synthesis, since product mixtures are inevitable. Therefore, novel methodologies to overcome these synthetic obstacles have been developed in recent years. This Account introduces all natural products and pharmaceutical compounds exhibiting the cyclohepta[b]indole motif. The structural variability within cyclohepta[b]indole alkaloids in combination with the broad range of organisms where these alkaloids have been isolated from, strongly suggests that the cyclohepta[b]indole is somehow a "privileged" structure motif. The organisms producing these compounds range from evergreen trees (actinophyllic acid) to cyanobacteria (ambiguinines). The synthetic methodologies to construct these molecular scaffolds (natural and unnatural in origin) are in turn highlighted and discussed with regard to their potential to access highly functionalized and unsymmetrical cyclohepta[b]indoles, for which they specifically have been designed. The methods are classified with respect to reaction type and whether or not they are enantioselective. Finally, the syntheses of cyclohepta[b]indole natural products are presented, thereby in each case, focusing on the construction of this structure motif in the course of the respective total synthesis. As a conclusion, we end by contrasting the methodological progress in the field with the actual successful application of the newly developed methods to the synthesis of complex structures to pinpoint the urgent requirement for further synthetic development for efficient synthetic design of this "privileged" structure motif.

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ISO 690STEMPEL, Erik, Tanja GAICH, 2016. Cyclohepta[b]indoles : A Privileged Structure Motif in Natural Products and Drug Design. In: Accounts of Chemical Research. 2016, 49(11), pp. 2390-2402. ISSN 0001-4842. eISSN 1520-4898. Available under: doi: 10.1021/acs.accounts.6b00265
BibTex
@article{Stempel2016-10-06Cyclo-37459,
  year={2016},
  doi={10.1021/acs.accounts.6b00265},
  title={Cyclohepta[b]indoles : A Privileged Structure Motif in Natural Products and Drug Design},
  number={11},
  volume={49},
  issn={0001-4842},
  journal={Accounts of Chemical Research},
  pages={2390--2402},
  author={Stempel, Erik and Gaich, Tanja}
}
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