FULL PAPER DOI: 10.1002/ejoc.200701172 Synthesis of Novel Indole-Based Ring Systems by Acid-Catalysed Condensation from α-Amino Aldehydes and L-Trp-OMe Isabel M. Gomez-Monterrey, [a] Pietro Campiglia, [b] Alessia Bertamino, [a] Claudio Aquino, [a] Orazio Mazzoni, [a] Maria V. Diurno, [a] Rosa Iacovino, [c] Michele Saviano, [d] Marina Sala, [a] Ettore Novellino, [a] and Paolo Grieco* [a] Keywords: Indoles / Amino aldehydes / Catalysis / Condensation reactions / Heterocycles Acid-catalysed condensation of tryptophan with different α- amino aldehyde derivatives has been explored as a useful route to the synthesis of novel amino acid derived heterocy- cles and peptidomimetic scaffolds. By this approach, com- pounds containing a tetrahydro-β-carboline and a novel oc- tahydropyrrolo[3',2':3,4]pyrrolo[2,3-b]indole system have Introduction Amino acids and their derivatives are well known as ver- satile building blocks for pharmaceutical applications as well as essential starting points for the generation of molec- ular diversity. [1–3] In this context, and as part of a wide pro- gram to develop methodologies for generating peptidomi- metics, we have focused our attention on the potential of α- amino aldehydes as a source of diverse biologically useful core compounds. In this context we have recently reported an efficient con- densation of α-amino aldehydes with cysteine or penicill- amine to generate thiazolidine derivatives. [4] These struc- tures offer considerable promise as combinatorial motifs and as β-turn mimetics. Also, we have reported that the condensation between an α-amino aldehyde and -DOPA- OMe under acidic conditions furnishes the corresponding tetrahydroisoquinoline derivative which can subsequently be used as an intermediate template to form diazatricyclic lactam derivatives. [5] Herein we present the adaptation of this route, starting from α-amino aldehydes and -Trp- OMe, to the synthesis of compounds containing the well- [a] Department of Pharmaceutical and Toxicological Chemistry, University of Naples “Federico II”, 80131 Naples, Italy Fax: +39-081-678630 E-mail: pagrieco@unina.it [b] Department of Pharmaceutical Science, University of Salerno, 84084 Fisciano, Italy [c] Department of Environmental Sciences, Second University of Naples, 81100 Caserta, Italy [d] Institute of Biostructures and Bioimaging, CNR, 80134 Naples, Italy Supporting information for this article is available on the WWW under http://www.eurjoc.org or from the author. Eur. J. Org. Chem. 2008, 1983–1992 © 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1983 been efficiently synthesized. Here we report the characteri- zation of these new compounds and preliminary studies of the reactivity of the tetrahydro-β-carboline system. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008) known tetrahydro-β-carboline system [6] and a novel indole- based tetracyclic ring system, that is, the octahydropyr- rolo[3',2':3,4]pyrrolo[2,3-b]indole (Scheme 1). Scheme 1. Condensation of -Trp-OMe (1) with α-amino aldehydes 2–7. Fmoc-Gyl-H (2) and enantiopure protected α-amino al- dehydes Fmoc--Ala-H (3), Fmoc--Phe-H (4), Boc--Phe- H(5), Fmoc--Asp(tBu)-H (6) and Fmoc--Lys(Boc)-H (7) were prepared from the corresponding Fmoc--amino acids according to literature methods. [4a,7]