A D ,L -prolinecatalyzeddiastereoselectivetrimolecular condensation:anapproachtotheone-potsynthesis ofperhydrofuro[3,2-b]pyran-5-ones I Gowravaram Sabitha, a, * M. Raj Kumar, a M. Shashi Kumar Reddy, a J. S. Yadav, a K. V. S. Rama Krishna b and A. C. Kunwar b a Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India b NMR Group, Indian Institute of Chemical Technology, Hyderabad 500 007, India Received 29 June 2004; revised 5 January 2005; accepted 14 January 2005 Available online 29 January 2005 Abstract—D,L-Proline was found to catalyze efficiently the one-pot trimolecular condensation of indoles, a sugar hydroxyaldehyde, and MeldrumÕs acid followed by intramolecular cyclization with evolution of carbon dioxide and elimination of acetone to afford 7- (1H-3-indolyl)-2,3-dimethoxyperhydrofuro[3,2-b]pyran-5-ones. The reaction proceeded cleanly at ambient temperature to afford the products in good yields with high diastereoselectivity. Ó 2005 Elsevier Ltd. All rights reserved. The preparation of substituted tryptophans 1 has been reported using the trimolecular condensation of indoles, with various aldehydes and MeldrumÕs acid catalyzed by proline under Yonemitsu conditions 2 to give the ad- ducts. Recently we demonstrated the utility of the sugar aldehyde derived from D-glucose for the synthesis of the furopyran core system. 3 To the best of our knowledge, the trimolecular condensation reaction using the chiral sugar aldehyde derived from D-glucose has not been ex- plored, which led us to investigate this reaction. We now report that the organocatalytic trimolecular condensa- tion reaction between indoles 1a–g, the sugar hydroxy- aldehyde 2, and MeldrumÕs acid (2,2-dimethyl-1,3- dioxane-4,6-dione, 3) furnishes the 7-(1H-3-indolyl)- 2,3-dimethoxyperhydrofuro[3,2-b]pyran-5-ones 4 4 as the exclusive products. The three-component reaction of indole 1b with sugar hydroxyaldehyde 2 (derived from D-glucose), and Mel- drumÕs acid 3 with a catalytic amount of D,L-proline in acetonitrile at ambient temperature afforded cis-fused furo[3,2-b]pyranone 4b as a single isomer in 76% yield (Scheme 1, Table 1, entry 2). We envisioned that proline would catalyze the domino Knoevenagel condensation of the sugar aldehyde 2 with MeldrumÕs acid 3 to pro- vide the alkylidene derivative of MeldrumÕs acid, then 0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2005.01.071 Keywords: D,L-Proline; Furo-pyranone; Indole; Trimolecular condensation. q IICT Communication No.: 040610. * Corresponding author. Tel./fax: +91 40 27160512; e-mail: sabitha@ins.iictnet.com N H O 2 N O O O O O O O O H OHC N H O O O O O O 2 N + + 1b 2 3 4b D,L-proline CH 3 CN, r.t. Scheme1. Tetrahedron Letters 46 (2005) 1659–1661 Tetrahedron Letters