Selective Synthesis of Cyclohepta[b]indoles

  • Author: Angewandte Chemie International Edition
  • Published Date: 03 September 2018
  • Source / Publisher: Angewandte Chemie International Edition/Wiley-VCH
  • Copyright: Wiley-VCH Verlag GmbH & Co. KGaA
thumbnail image: Selective Synthesis of Cyclohepta[<i>b</i>]indoles

Cyclohepta[b]indole units make up the structural core of many bioactive molecules and natural products. However, the synthesis of the characteristic seven-membered ring in a simple and enantioselective manner is challenging.

Géraldine Masson and colleagues, Université Paris-Sud, Gif-Sur-Yvette, France, have developed a Brønsted-acid-catalyzed (4+3) cycloaddition reaction that allows the preparation of diversely substituted cyclohepta[b]indoles. The strategy involves a reaction between an indolyl iminium and a dienecarbamate species (transition state pictured, Cbz = carboxybenzyl).

The chiral phosphoric acid catalyst (R)‐3,3'‐bis(2,4,6‐triisopropylphenyl)‐1,1'‐binaphthyl‐2,2'‐diyl hydrogenphosphate was used to generate the reactive cation from 3-indolylmethanol derivatives and to control the stereoselectivity of the cycloaddition. The reaction was performed in toluene at 0 °C to room temperature in the presence of molecular sieves as a desiccant. Cyclohepta[b]indoles containing three stereogenic centers were obtained in good yields and with high levels of diastereo- and enantioselectivity.

This work is the first example of an enantioselective phosphoric acid-catalyzed (4+3) cycloaddition and provides a straightforward route to optically active cyclo-hepta[b]indoles. The whole process occurs with water as the sole waste product. The researchers also demonstrated that simple post-transformations offer an access to a wide range of cyclohepta[b]indole moieties.


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