Pyrrolo[2,1-b]thiazole Derivatives by Asymmetric 1,3-Dipolar Reactions of Thiazolium Azomethine Ylides to Activated Vinyl Sulfoxides Jose ´ Luis Garcı ´a Ruano,* Alberto Fraile, M. Rosario Martı ´n,* Gema Gonza ´lez, and Cristina Fajardo Departamento de Quı ´mica Orga ´nica, UniVersidad Auto ´noma de Madrid, Cantoblanco, 28049 Madrid, Spain joseluis.garcia.ruano@uam.es ReceiVed July 31, 2008 1,3-Dipolar reactions of thiazolium azomethine ylides to enantiopure cyclic and acyclic vinyl sulfoxides provide an efficient access to polyfunctionalized pyrrolo[2,1-b][1,3]thiazoles in a highly regio- and stereoselective manner. Regioselectivity can be inverted by modifying the position of the sulfinyl group at the double bond of the sulfinylfuranones. The sulfoxide is the main controller of the endo selectivity of these processes as well as of the π-facial selectivity in reactions of (Z)-3-p-tolylsulfinylacrylonitriles. In contrast, the π-facial selectivity in reactions of 5-alkoxy-3-p-tolylsulfinyl furan-2(5H)-ones is mainly controlled by the configuration at C-5, affording the anti adducts with respect to the alkoxy group as the major or exclusive adducts. Introduction The interest in polyhydroderivatives of pyrrolo[2,1-b]thia- zoles is related to the wide scope of their biological activities, allowing their use as hepatoprotective, hypoglycemic (an- tidiabetic), antibiotic, anticonvulsant, antiinflammatory, or antileukemic agents, bactericides, or as dopaminergic neu- rotransmissors in CNS in vivo and dipeptidyl peptidase IV (DPP-IV) inhibitors. 1 There is a rich history regarding the preparation and im- portance of tetrahydropyrrolo[2,1-b]thiazol-5(6H)-one scaffolds. There are reports of solution- 2 and solid-phase 3 syntheses of derivatives of this bicyclic scaffold. The majority rely on the formation of thiazolidine intermediate through the reaction of -amino thiols (generally L-cysteine) with γ-formyl acid deriva- tives or their corresponding acetals 3d in the presence of stannous chloride. Additionally, polyhydropyrrolo[2,1-b]thiazoles, with no lac- tam moiety in their skeleton, have interesting pharmacological properties and have been successfully used as intermediates in the synthesis of pyrrolidines, such as racemic R-allokainic 4a and kainic acids 4b or 2S,4R-4-methylpyrrolidine-2,4-dicarboxylate. 5 However, the antecedents of the asymmetric synthesis of polyhydropyrrolo[2,1-b]thiazoles are scarce. Katritzky 6 and Beaupere 7 obtained this system via a condensation reaction with L-cysteine ester and D-monosaccharides as chiral reagents, (1) (a) Campbell, D. A.; Betancort, J. M.; Winn, D. T. US Patent US 2006009518, 2006. (b) Wagner, H.; Schoenafinger, K.; Jaehne, G.; Gaul, H.; Buning, C.; Tschank, G.; Werner, U. PCT Int. WO 2005012312, 2005; Chem. Abstr. 2005, 142, 219272. (c) Abe, T.; Matsunaga, H.; Mihira, A.; Sato, C.; Ushirogochi, H.; Sato, K.; Takasaki, T.; Venkatesan, A. M.; Mansour, T. S. US Pat. US 2004132708, 2004; Chem. Abstr. 2004, 141, 550737. (d) Aicher, T. D.; Cheon, S. H.; Nadelson, J.; Simpson, W. R. J.; Houlihan, W. J. Eur. Pat. EP 702015, 1996; Chem. Abstr. 1996, 124, 343285. (e) Suzuki, N.; Nakayama, A.; Saijo, T.; Hasegawa, M.; Yokohama, S. Japanese Patent 04145086, 1992; Chem. Abstr. 1992, 117, 212487. (f) Tverdokhlebov, A. V. Heterocycles 2007, 71, 761– 798, and references cited therein. (2) Qiu, W.; Gu, X.; Soloshonok, V. A.; Carducci, M. D.; Hruby, V. J. Tetrahedron Lett. 2001, 42, 145–148. (3) (a) Scott, W. L.; Martynnow, J. G.; Huffman, J. C.; O’Donnell, M. J. J. Am. Chem. Soc. 2007, 129, 7077–7088, and references cited therein. (b) Nielsen, T. E.; Le Quement, S.; Meldal, M. Gu, X.; Ying, J.; Agnes, R. S.; Navratilova, E.; Davis, P.; Stahl, G.; Porreca, F.; Yamamura, H. I. Org. Lett. 2005, 7, 3601–3604. (c) Hruby, V. J. Org. Lett. 2004, 6, 3285–3288. (d) Cayley, A. N.; Cox, R. J.; Me ´nard-Moyon, C.; Schmidt, J. P.; Taylor, R. J. K. Tetrahedron Lett. 2007, 48, 6556–6560. (4) (a) Kraus, G. A.; Nagy, J. O. Tetrahedron 1985, 41, 3537–3545. (b) Monn, J. A.; Valli, M. J. J. Org. Chem. 1994, 59, 2773–2778. (5) Esslinger, C. S.; Titus, J.; Koch, H. P.; Bridges, R. J.; Chamberlin, A. R. Bioorg. Med. Chem. 2002, 10, 3509–3515. (6) Katritzky, A. R.; Zhang, Y.; He, H.-Y. ArkiVoc 2002, 161, 170. 10.1021/jo801705d CCC: $40.75  2008 American Chemical Society 8484 J. Org. Chem. 2008, 73, 8484–8490 Published on Web 10/08/2008