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.
- Highly Diastereo- and Enantioselective Synthesis of Cyclohepta[b]indoles by Chiral-Phosphoric-Acid-Catalyzed (4+3) Cycloaddition,
Coralie Gelis, Guillaume Levitre, Jérémy Merad, Pascal Retailleau, Luc Neuville, Géraldine Masson,
Angew. Chem. Int. Ed. 2018.