Exploiting the Distal Reactivity of Indolyl Methylenemalononitriles: An Asymmetric Organocatalyzed [4+2] Cycloaddition with Enals Enables the Assembly of Elusive Dihydrocarbazoles

Polycyclic indole architectures, including carbazole and hydrocarbazole skeletons, represent privileged structural motifs found in a number of natural alkaloids, many of which displaying interesting activities against a diverse set of biological targets.[1] Accordingly, the search for efficient methods for the assembly of these structures has drawn a great deal of attention in the synthetic organic chemistry community.[2,3] An unprecedented technique for the in situ generation of indolyl ortho-quinodimethanes from 2-methylindole-based methylenemalononitriles 1 by amine-mediated remote C(sp3)-H deprotonation was developed. These intermediates were efficiently trapped by diverse enals to provide a rapid entry to 2,9-dihydro-1H-carbazole-3-carboxyaldehyde structures 3 through a formal asymmetric [4+2] eliminative cycloaddition governed by a ?,?-diphenylprolinol trimethylsilyl ether catalyst.[4] A stepwise reaction mechanism of the formal catalytic asymmetric [4+2] cycloaddition of methylenemalononitrile 1a with enal 2a catalyzed by (S)-C1 is proposed. Parole chiave: asymmetric synthesis, cycloaddition heterocycles, organocatalysis, vinylogy Riferimenti: 1) A. G?uszynska, Eur. J. Med. Chem. 2015, 94, 405. 2) N. H. Krishna, A. P. Saraswati, M. Sathish, N. Shankaraiah, A. Kamal, Chem. Commun. 2016, 52, 4581. 3) Y. Li, F. Tur, R. P. Nielsen, H. Jiang, F. Jensen, K. A. Jørgensen, Angew. Chem. Int. Ed. 2016, 55, 1020; Angew. Chem. 2016, 128, 1032. 4) G. Rassu, C. Curti, V. Zambrano, L. Pinna, N. Brindani, G. Pelosi, and F. Zanardi, Chem. Eur. J. 2016, 22, 12637 - 12640 Ringraziamenti: Financial support provided by the Università degli Studi di Parma.