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Merging organocatalysis and gold catalysis: enantioselective synthesis of tetracyclic indole derivatives through a sequential double Friedel-Crafts type reaction.

Annulated indoles, fused at the C2and C3-position, are chemically and biologically interesting as key structural motifs in many natural products and as pharmaceutically active substances. Furthermore, annulated, tetracyclic indoles containing a seven-membered ring, such as in 1 (Scheme 1), have shown anticancer activities on leukemia and colon cell lines, as well as antiproliferative activities through DNA intercalation. However, accessing such seven-membered-ring-containing polycycles is synthetically challenging owing to the preferential six-membered-ring formation in the cyclisation step. The reactivities of the indole C3and C2-position, as well as the indole nitrogen, provide many opportunities to access enantiopure, annulated indole derivatives. This can be achieved, for example, with an intramolecular Friedel–Crafts type reaction or an aza-Michael addition of the indolic nitrogen on a suitable acceptor. While reports on the enantioselective synthesis of polycyclic indoles using various catalytic activation modes, especially in the fields of organocatalysis and gold catalysis, are numerous, most of such synthetic strategies required substrates containing a prefunctionalised indole, either on the C3or the C2-position (Scheme 1). In view of limited precedence for the synthesis of annulated indoles from C3,C2-unsubstituted indoles 2, we hypothesised that chiral, polycyclic indoles could be accessed enantioselectively through a single-pot tandem operation. To the best of our knowledge, an enantioselective variant of such a transformation is not yet known. Moreover, we envisioned that the recent surge in utilising one-pot, multicatalytic, tandem reactions combining distinct organocatalytic and transition-metal cycles could be used as a viable strategy to obtain enantiopure, annulated indoles. This emerging area has also spurred some efforts in utilising indole as a key substrate in enantioselective, sequential reactions. In our synthetic planning, we were interested in combining both organocatalysis and gold catalysis, especially the latter to access nonconventional molecular frameworks through domino and rearrangement reactions. It is worth noting that the pioneering studies on gold catalysis by Echavarren et al. and Zhang et al., as well as very recent reports, allowed complex functionalisations of indole substrates containing an intramolecular tethered alkyne. We now wish to report an efficient and highly enantioselective one-pot, multicatalytic, C2/C3-annulation of indoles, giving rise to tetracyclic, seven-membered-ring-containing derivatives 1. The new protocol utilises the bifunctional ortho-alkyne-substituted nitrostyrenes 3 as substrates, allowing two sequential Friedel–Crafts type reactions. The nitroalkene moiety is activated through hydrogen-bonding organocatalysis, to incorporate the stereochemical information in the first Friedel–Crafts reaction,and the alkyne functionality provides access to gold catalysis and its alkynophilicity, to effect the second Friedel–Crafts/ring expansion cascade. [a] C. C. J. Loh, J. Badorrek, Prof. Dr. G. Raabe, Prof. Dr. D. Enders Institute of Organic Chemistry RWTH Aachen University Landoltweg 1, 52074 Aachen (Germany) Fax: (+49) 241-809-2127 E-mail : enders@rwth-aachen.de Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201102793. Scheme 1. Strategy comparison between current work and known methods.