472 J. Org. Chem. 2010, 75, 472–475 Published on Web 12/16/2009 DOI: 10.1021/jo9021327 r 2009 American Chemical Society pubs.acs.org/joc L-Proline-Catalyzed Three-Component Domino [3þ2þ1] Annulation for the Regio- and Diastereoselective Synthesis of Highly Substituted Thienothiopyrans Containing Three or Four Stereocenters Sethuraman Indumathi, † Subbu Perumal,* ,† and J. Carlos Men endez* ,‡ † Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, India and ‡ Departamento de Quı´mica Org  anica y Farmac eutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain subbu.perum@gmail.com, josecm@farm.ucm.es Received October 4, 2009 L-Proline-catalyzed three-component reactions of ethyl 2- [(2-oxo-2-arylethyl)sulfonyl]acetate or ethyl 2-[(2-ethoxy- 2-oxoethyl)sulfonyl]acetate, aromatic aldehydes, and 5- aryltetrahydro-3-thiophenone furnished a variety of highly substituted thieno[3,2-c]thiopyran derivatives. This facile transformation presumably occurs via a one-pot domino sequence of enamine formation/aldol condensation/Mi- chael addition/6-exo-trig cyclization/elimination and in- volves the creation in a single operation of three C-C bonds and the generation of three new stereocenters with complete diastereoselectivity in all cases and a fourth one in ca. 7:3 diastereomeric ratio when starting from a 5-sub- stituted tetrahydro-3-thiophenone derivative. Cyclic sulfides are useful templates to facilitate and con- trol various chemical transformations. 1 In particular, thio- pyran derived scaffolds have been used to construct a variety of synthetic targets. 2 Members of the thienothiopyran class have attracted much interest since they were reported to possess antiglaucoma activity. 3 In fact, Trusopt (dorzol- amide hydrochloride) is one of the most popular topically active carbonic anhydrase inhibitors (CAI), which causes a decrease in the aqueous humor secretion and therefore reduction of the intraocular pressure. 4 Furthermore, com- pounds with thiophene substructures have found remarkable applications as electroactive and light-emitting materials in a variety of opto-electronic devices and optical transducers in biosensors as well as fluorescent markers for biopolymers. 5 The biological importance of thienothiopyrans, in con- junction with our interest in novel domino processes in organic synthesis, 6 led us to study the synthesis of thienothio- pyrans 4-17 employing L-proline as a catalyst. This choice was prompted by the fact that L-proline is an abundant and inexpensive amino acid capable of catalyzing diverse organic transformations, in both enantio- and nonenantioselective fashions, including aldol, 7 Mannich, 8 Michael, 9 and unsym- metric Biginelli 10 reactions as well as Diels-Alder/Knoeve- nagel 11 and other domino processes. 12 The efficacy of L-proline in diverse organic transformations is ascribable to multiple catalytic roles it can play, such as an acid or a base or both simultaneously, as a nucleophile and its ability to form enamine/iminium intermediates upon reaction with carbonyl/R,β-unsaturated carbonyl compounds. Stirring at room temperature for 24 h a solution of ethyl 2-[(2-oxo-2-arylethyl)sulfonyl]acetate or ethyl 2-[(2-ethoxy- 2-oxoethyl)sulfonyl]acetate 1, a 5-aryltetrahydro-3-thiophe- none derivative 2 (R 2 = Ar), 13 and an aromatic aldehyde 3 in an equimolar ratio in the presence of L-proline (50 mol %) in methanol furnished the thieno[3,2-c]thiopyran derivatives (1) (a) Vedejs, E.; Krafft, G. A. Tetrahedron 1982, 38, 2857. (b) Ingall, A. H. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, UK, 1984; Vol. 3, p 885. (2) (a) Hachem, A.; Toupet, L.; Gree, R. Tetrahedron Lett. 1995, 36, 1849. (b) Ward, D. E.; Gai, Y. Synlett 1995, 261. (c) Ward, D. E.; Man, C. C.; Guo, C. Tetrahedron Lett. 1997, 38, 2201. (3) Baldwin, J. J.; Ponticello, G. S.; Anderson, P. S.; Christy, M. E.; Murcko, M. A.; Randall, W. C.; Schwam, H.; Sugrue, M. F.; Springer, J. P.; Gautheron, P.; Grove, J.; Mallorga, P.; Viader, M. P.; McKeever, B. M.; Navia, M. A. J. Med. 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