Parallel kinetic resolutions of monosubstituted succinic anhydrides catalyzed by a modified cinchona alkaloid.

Efficient kinetic resolution processes continue to play a critical role in asymmetric synthesis.1 Using two chiral reagents to effect two parallel running enantioselective resolution reactions, Vedejs and co-workers demonstrated that, through minimizing a buildup of the less reactive enantiomer by simultaneously consuming both enantiomers of the racemic starting material, the two resolution reactions work synergistically to render the efficiency of the parallel kinetic resolution dramatically higher than that of each of the individual enantioselective resolution reactions.2 Parallel kinetic resolution thus represents an especially attractive strategy to maximize the enantiomeric excess attainable for a product generated via kinetic resolution reactions. However, the development of catalytic parallel kinetic resolutions that affords synthetically useful efficiency with an extensive range of substrates remains highly challenging.3-6 We report here a broadly effective parallel kinetic resolution mediated by a single organic catalyst that transforms readily accessible racemic monosubstituted succinic anhydrides into synthetically valuable chiral succinate mono esters in high enantiomeric excesses. We recently discovered that modified cinchona alkaloids are highly effective chiral Lewis base catalysts for desymmetrization of cyclic anhydrides.7,8 In view of the synthetic utility of optically active monosubstituted succinate mono esters (2, 3),9,10 we began to explore their asymmetric synthesis via a modified cinchona alkaloid-catalyzed kinetic resolution of racemic monosubstituted succinic anhydrides (eq 1). Reaction of racemic 2-methylsuccinic anhydride (1a, R ) Me) with methanol (10 equiv) in ether at room temperature in the presence of (DHQD)2AQN (10 mol %) was completed in 4 h to afford mono esters 4 and 5 in a ratio of 39:61 (entry 1, Table 1). Furthermore, 4 and 5 were shown by GC analyses to be formed at similar rates throughout the course of the reaction. Surprisingly, we found that 4 and 5 were produced in 74 and 67% ee, respectively. This data indicated that the two enantiomers of anhydride 1a were converted to optically active hemiesters 4 and 5, respectively, at similar rates via two parallel enantioselective methanolyses of divergent regioselectivities catalyzed by a common catalyst, (DHQD)2AQN. Further evaluations of a variety of reaction parameters revealed that the enantioselectivity of the parallel kinetic resolution is influenced considerably by the structure of the alcohol (Table 1). Increasing the size of the alcohol from methanol to n-propanol significantly enhances the enantioselectivity of the reaction (entries 1-3, Table 1). On the other hand, the use of 2-propanol almost completely halted the reaction. Importantly, the (DHQD)2AQNcatalyzed parallel kinetic resolution of 1a with triflouroethanol at -24 °C afforded succinates 4 and 5 in synthetically useful enantiomeric excesses (entry 6, Table 1). The divergent regioselectivity of the (DHQD)2AQN-catalyzed alcoholysis for (R)and (S)-2-methyl succinic anhydrides (Rand S-1a), respectively, is demonstrated experimentally (Scheme 1). Commercially available optically pure Rand S-2-methyl succinic acids were converted respectively to the corresponding optically pure 2-methyl succinic anhydrides (Rand S-1a), which were next individually subjected to (DHQD)2AQN-catalyzed trifluoroethanolysis. While R-1a was converted to succinates R-7a and -6a in a ratio of 97:3, the alcoholysis of S-1a under the identical condition affords S-6a and -7a in a ratio of 92:8. We also demonstrated that, with a given enantiomer of 1a (Ror S-1a), the regioselectivity of ring-opening alcoholysis can be controlled by choosing either (DHQD)2AQN or (DHQ)2AQN as the catalyst * To whom correspondence should be addressed. (1) For reviews see: (a) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. AdV. Synth. Catal. 2001, 343, 5. (b) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249. (2) (a) Vedejs, E.; Rozners, E. J. Am. Chem. Soc. 2001, 123, 2428. (b) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1997, 119, 2584. (3) For a review, see: Eames, J. Angew. Chem., Int. Ed. 2000, 39, 885. (4) For examples using chiral metal complexes, see: (a) Bertozzi, F.; Crotti, P.; Macchia, F.; Pineschi, M.; Feringa, B. L. Angew. Chem., Int. Ed. 2001, 40, 930. (b) Doyle, M. P.; Dyatkin, A. B.; Kalinin, A. V.; Ruppar, D. A.; Martin, S. F.; Spaller, M. R.; Liras, S. J. Am. Chem. Soc. 1995, 117, 11021. (c) Visser, M. S.; Hoveyda, A. H. Tetrahedron 1995, 51, 4383. (d) Bolm, C.; Schlingloff, G. J. Chem. Soc., Chem. Commun. 1995, 1247. (e) Martin, S. F.; Spaller, M. R.; Liras, S.; Hartmann, B. J. Am. Chem. Soc. 1994, 116, 4493. (5) For examples using enzymes, see: (a) Ozegowski, R.; Kunath, A.; Sehick, H. Liebigs Ann. 1995, 1699. (b) Mischitz, M.; Faber, K. Tetrahedron Lett. 1994, 35, 81. (c) Petit, F.; Furstoss, R. Tetrahedron: Asymmetry 1993, 4, 1341. (d) Alphand, V.; Furstoss, R. J. Org. Chem. 1992, 57, 1306. (6) For a kinetic resolution involving two different reactions for a complete conversion of starting material to a single optically active product, see: Feng, X.; Shu, L.; Shi, Y. J. Am. Chem. Soc. 1999, 121, 11002. (7) Chen, Y.; Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2000, 122, 9542. (8) For catalytic desymmetrizations of cyclic anhydrides with natural cinchona alkaloids, see: (a) Hiratake, J.; Yamamoto, Y.; Oda, J. J. Chem. Soc., Chem. Commun. 1985, 1717. (b) Bolm, C.; Schiffers, I.; Dinter, C. L.; Gerlach, A. J. Org. Chem. 2000, 65, 6984. (9) For select applications of monosubstituted chiral succinates, see: (a) Sibi, M.; Deshpande, P. K. J. Chem. Soc., Perkin Trans. 1 2000, 1461. (b) Evans, D. A.; Wu, L. D.; Wiener, J. J. M.; Johnson, J. S.; Ripin, D. H. B.; Tedrow, J. S. J. Org. Chem. 1999, 64, 6411. (10) For preparations of chiral succinates via catalytic asymmetric hydrogenations, see: Burk, M. J.; Bienewald, F.; Harris, M.; Zanotti-Gerosa, A. Angew. Chem., Int. Ed. 1998, 37, 1931. Table 1. (DHQD)2AQN-Catalyzed Parallel Kinetic Resolution of Methylsuccinic Anhydride