r′-Hydroxy Enones as Achiral Templates for Lewis Acid-Catalyzed Enantioselective Diels-Alder Reactions Claudio Palomo, ², * Mikel Oiarbide, ² Jesu ´ s M. Garcı ´a, ‡ Alberto Gonza ´ lez, ‡ and Elena Arceo ‡ Departamento de Quı ´mica Orga ´ nica I, Facultad de Quı ´mica, UniVersidad del Paı ´s Vasco, Apdo. 1072, 20080 San Sebastia ´ n, Spain, and Departamento de Quı ´mica Aplicada, UniVersidad Pu ´ blica de NaVarra, Campus de Arrosadı ´a 31006 Pamplona, Spain Received June 20, 2003; E-mail: qoppanic@sc.edu.es The field of asymmetric catalysis has produced remarkable results in the area of the Diels-Alder reaction, 1 where a high degree of development has been achieved in both fundamentals 1,2 and synthetic applications. 3 While chiral amines have recently been applied as catalysts of Diels-Alder reactions involving enals 4 and enones 5 as dienophiles, enantioselectivity during Diels-Alder cycloadditions is most often effected by chiral ligand-bearing metal complexes. Catalysts for producing the cycloadducts in high ee’s include the Evans C 2 -symmetric bis(oxazoline)-metal complexes 6 which have proven to be very successful when N-enoylimides I are employed as dienophiles. It appears that these substrates have become the standard test for new catalyst development, while other achiral templates have been much less investigated. 7 In this context, application of the chiral relay concept 8 to improve asymmetric induction has been recently realized. 9 Despite these advances, unmet challenges remain with regard to reactivity and selectivity for challenging substrates. For example, dienes other than the highly reactive cyclopentadiene have been less documented and, with most of the enantioselective methods so far developed, inferior results are obtained. 10 R′-Hydroxy enones II constitute attractive chelating ketone dienophiles. 11 Chiral R′-hydroxy enones (ketols) in both Lewis acid catalyzed and uncatalyzed diastereoselective Diels- Alder reactions were introduced by Masamune, 12 who showed that the internal hydrogen bond activation operating in these ketols is sufficient for promoting their reaction with the highly reactive cyclopentadiene. Recently, within a broad project aimed at estab- lishing the potential of ketols as carboxylic acid surrogates in the context of diastereo- and enantioselective C-C bond forming transformations, 13 our group has documented the Brønsted acid- catalyzed Diels-Alder reaction of chiral R′-hydroxy enones. 14 The remarkable efficiency of these R′-hydroxy enones, even against less reactive dienes, was interpreted on the basis of an intermolecular hydrogen bond network activation. While the above observations reveal some interesting features inherent to R′-hydroxy enones, to the best of our knowledge, the use of achiral R′-hydroxy enones II as templates in enantioselective Diels-Alder reactions has not been reported yet. We envisaged that these templates may give rise to well ordered transition structures for high enantiocontrol provided that: (a) upon combination with chiral Lewis acids, tight templates as in III 15 are generated and (b) there is a substantial energy preference for the enone to adopt the s-cis arrangement over the s-trans. 16 To evaluate this hypothesis, enone 4 was prepared from 1-lithio- 1-methoxyallene and acetone, 17 and its reactivity against a variety of dienes in the presence of chiral Lewis acids was examined, Table 1. Concordant with our expectations, cycloadduct 5, from the reaction of 4 with cyclopentadiene carried out in the presence of catalyst 1a (10 mol %), was indeed formed with essentially perfect endo-selectivity and enantioselectivity at -78 °C. The less reactive cyclohexadiene did not react with 4 under the same conditions but at ambient temperature a clean reaction took place and, most notably, almost complete selectivity was achieved (endo:exo ratio >99:1, ee g 98%). Of major significance were the results with more problematic dienes. With isoprene and catalyst 1a, a 99:1 regioisomeric ratio and an 81% ee were obtained, a result that could be improved to >99:1 regioisomeric ratio and 88% ee by perform- ² Universidad del Paı ´s Vasco. ‡ Universidad Pu ´blica de Navarra. Figure 1. N-Enoylimides I typically used as achiral templates in enanti- oselective Diels-Alder reactions, and the alternative enones II, along with the Lewis acid catalysts considered in this work. Table 1. Reaction of R′-hydroxy Enone 4 with Representative Dienes Catalyzed by 1a and 1d a a Reactions conducted at 0.5 mmol scale in CH2Cl2. Molar ratio of enone: diene:catalyst 1:5:0.1. b Ratio of regio- or cis/trans isomers, as applicable, determined by 13 C NMR. c Determined by 13 C NMR. d Enantiomeric excess of the major regio- or diastereoisomer, as applicable, determined by HPLC. n.d.) not determined. e Using 2 mol % of catalyst. Published on Web 10/28/2003 13942 9 J. AM. CHEM. SOC. 2003, 125, 13942-13943 10.1021/ja0368002 CCC: $25.00 © 2003 American Chemical Society