Organic & Biomolecular Chemistry Cite this: Org. Biomol. Chem., 2011, 9, 3386 www.rsc.org/obc PAPER Novel pyrrolidine-thiohydantoins/thioxotetrahydropyrimidinones as highly effective catalysts for the asymmetric Michael addition† Christoforos G. Kokotos, Dimitris Limnios, Despoina Triggidou, Maria Trifonidou and George Kokotos* Received 25th November 2010, Accepted 11th February 2011 DOI: 10.1039/c0ob01083a The synthesis of novel organocatalysts consisting of a pyrrolidine moiety and a thiohydantoin or a thioxotetrahydropyrimidinone ring is described. The compound combining the pyrrolidine with the thioxotetrahydropyrimidinone was found to be a highly effective catalyst for the Michael reaction. Low catalyst loadings (1–2.5%) can be employed leading to quantitative yields and excellent stereoselectivities in the reaction between cyclic ketones and nitroolefins. Introduction At the end of the first decade of the 21st century, organocatalysis now constitutes a well recognized methodology complementing transition metal complex-mediated catalysis and biocatalysis in the armoury of asymmetric synthesis. 1 Over the last decade, a wide variety of organocatalysts have been developed presenting distinct mechanisms of action. 2 Among the existing organocat- alysts, proline 3 and related aminocatalysts, chiral thioureas ini- tially proposed by Jacobsen 4 and imidazolidinones developed by MacMillan 5 represent the major organocatalyst categories. 6 The five-membered secondary amine structure of pyrrolidine is considered to be a “privileged” structure able to activate carbonyl compounds through the formation of enamine intermediates. In combination with other functional groups, it provides bifunctional molecules such as chiral diamines 1 and 2, 7 sulfonamide 3, 8 diaryl- prolinols 4 and the corresponding TMS ethers, 9 amides like 5, 10 (Fig. 1) able to catalyze a variety of asymmetric transformations. In addition, it has been demonstrated that compounds containing Fig. 1 Some pyrrolidine-based organocatalysts. Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, 15771, Athens, Greece. E-mail: gkokotos@ chem.uoa.gr; Fax: (+ 30) 210 7274761; Tel: (+ 30) 210 7274462 † Electronic supplementary information (ESI) available. See DOI: 10.1039/c0ob01083a a primary amino group, 11 like the alanine derivative 6 (Fig. 1), 12 may also catalyse asymmetric reactions, including the Michael reaction. In the last few years, our group proposed 4-substituted prolines 13a,b and proline sulfonamides, 13c homoproline and dipep- tide sulfonamides, 13d heterocyclic analogues of homoproline 13e as well as chiral primary amine-thioureas 13f as improved catalysts for the aldol and Michael reactions. In an effort to search for new and improved catalytic motives, we focused on developing new bifunctional catalysts combining the secondary amine of the pyrrolidine ring with a new chiral template. To this end, we thought of the thiohydantoin ring or the corresponding six-membered ring as the appropriate scaffold. In the present work, we present the synthesis of novel pyrrolidine-based bifunctional molecules incorporating a thiohydantoin or a 2-thioxotetrahydropyrimidin- 4-one ring and the evaluation of these catalysts in the Michael reaction. Results and discussion The rationale for the design of the new catalysts is illustrated in Fig. 2. For the construction of the catalyst, apart from the pyrrolidine ring, a chiral template capable of creating either hydrogen bonds or a bulky environment is required. Bearing in mind the amino acid chemistry and the ease of thioureas Fig. 2 Design of the new catalysts. 3386 | Org. Biomol. Chem., 2011, 9, 3386–3395 This journal is © The Royal Society of Chemistry 2011