Sulfur-Directed Asymmetric 1,3-Dipolar Cycloadditions of Azomethine Ylides with Enantiopure Sulfinimines †,‡ Alma Viso,* ,§ Roberto Ferna ´ ndez de la Pradilla,* ,⊥ Carlos Guerrero-Strachan, ⊥ Marta Alonso, ⊥ Martı ´n Martı ´nez-Ripoll, | and Isabelle Andre ´ | Departamento de Quı ´mica Orga ´ nica I, Facultad de Quı ´mica, Universidad Complutense, E-28040 Madrid, Spain, and Instituto de Quı ´mica Orga ´ nica, CSIC, Juan de la Cierva, 3, E-28006 Madrid, Spain, and Departamento de Cristalografı ´a, Instituto de Quı ´mica-Fı ´sica Rocasolano, CSIC, Serrano 119, E-28006 Madrid, Spain Received February 21, 1997 1,3-Dipolar cycloadditions are fundamental processes in organic chemistry. 1 In particular, the reaction of azomethine ylides with alkenes is a powerful method for the synthesis of pyrrolidines since up to four stereo- centers are set in a single operation. 2 This has fueled intensive efforts toward the development of efficient chiral auxiliaries to render the process enantioselective. 3 In contrast, reports on cycloadditions between azo- methine ylides and imines are scarce, 4 despite the well- established synthetic potential of the resulting imidazo- lidines. 5 Furthermore, it should be noted that the asymmetric version of this process remains elusive. In this paper, we report the first examples of a highly diastereoselective 1,3-dipolar cycloaddition of azomethine ylides with chiral sulfinimines to produce enantiopure N-sulfinyl imidazolidines and the straightforward trans- formation of one of these cycloadducts into an example of a novel class of nonsymmetrical vicinal diamines. Enantiopure sulfinimines, readily available in both enantiomeric forms, 6 are versatile intermediates for enantioselective syntheses of a variety of targets. 7 These substrates display excellent facial selectivity upon reac- tion with a number of nucleophiles, and furthermore, removal or even recycling of the sulfinyl auxiliary is readily carried out under mild reaction conditions. 8 These desirable features, along with our interest in the development of sulfur-directed methodology, 9 attracted our attention to these intermediates as potential precur- sors to chiral imidazolidines by 1,3-dipolar cycloadditions with azomethine ylides. We selected sulfinimine 1 6a and N-benzylidene R-amino acid ester-derived ylide 3 10 for our initial studies. Stan- dard conditions (LiBr, Et 3 N, MeCN; AgOAc, DBU, Tol) failed to promote the desired cycloaddition. Dipole generation with LDA 10 was then examined, and to our delight, the reaction between sulfinimine 1 and phenyl- alanine-derived dipole 3 led to a fair yield of a 95:5 mixture of cycloadducts 6 and 7 11 (Scheme 1), along with 15-20% of unreacted starting material. From this mixture of 6 and 7, pure 6 (45-50%) was obtained by recrystallization (hexane:ether). The reaction between 1 and dipole 4 produced imidazolidines 8 and 9 in almost identical yield and selectivity to the case above. Simi- larly, the more reactive substrate 2 12 afforded excellent yields of adducts 10 and 12 as practically single isomers upon reaction with dipoles 3 and 5, respectively. The general structure of these adducts was readily derived from their spectral features, and the relative stereochemistry of the three ring chiral centers was deduced from differential NOE experiments. However, * To whom correspondence should be addressed. Phone: 34-(1)-562- 2900 ext 210. Fax: 34-(1)-564-4853. E-mail: RIF@CC.CSIC.ES. † Taken in part from the M.S. Theses of C.G.-S. and M.A. ‡ Dedicated to the late Dr. Marı ´a Victoria Martı ´n (I. Q. O., CSIC). § Universidad Complutense. ⊥ Instituto de Quı ´mica Orga ´ nica. | Instituto de Quı ´mica-Fı ´sica Rocasolano. (1) 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984. (2) For a review, see: Tsuge, O.; Kanemasa, S. Adv. Heterocycl. Chem. 1989, 45, 231-349. (3) For leading references, see: (a) Galley, G.; Liebscher, J.; Pa ¨ tzel, M. J. Org. Chem. 1995, 60, 5005-5010. (b) Waldmann, H.; Bla ¨ ser, E.; Jansen, M.; Letschert, H.-P. Chem. Eur. J. 1995, 1, 150-154. (c) Grigg, R. Tetrahedron: Asymmetry 1995, 6, 2475-2486. (4) (a) Lown, J. W. In ref 1, Vol. 1, pp 653-732. (b) Bende, Z.; Bitter, I.; Toke, L.; Weber, L.;. Toth, G.; Janke, F. Liebigs. Ann. Chem. 1982, 2146-2152. (c) Grigg, R.; Donegan, G.; Gunaratne, H. Q. N.; Kennedy, D. A.; Malone, J. F.; Sridharan, V.; Thianpatanagul, S. Tetrahedron 1989, 45, 1723-1746. (d) Amornraksa, K.; Barr, D.; Donegan, G.; Grigg, R.; Ratananukul, P.; Sridharan, V. Ibid. 1989, 45, 4649-4668. (e) Lerestif, J. M.; Bazureau, J. P.; Hamelin, J. Tetrahedron Lett. 1993, 29, 4639-4642. (f) Padwa, A.; Dean, D. C.; Osterhout, H.; Precedo, L.; Semones, M. A. J. Org. Chem. 1994, 59, 5347-5357. (g) Nagao, Y.; Kim, K.; Komaki, Y.; Sano, S.; Kihara, M.; Shiro, M. Heterocycles 1994, 38, 587-593. (5) For leading references, see: (a) Alexakis, A.; Lensen, N.; Tran- chier, J.-P.; Mangeney, P.; Feneu-Dupont, J.; Declercq, J.-P. Synthesis 1995, 1038-1050. (b) Alexakis, A.; Tranchier, J.-P.; Lensen, N.; Mangeney, P. J. Am. Chem. Soc. 1995, 117, 10767-10768. (6) For leading references, see: (a) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Portonovo, P. S. Tetrahedron Lett. 1993, 34, 6229- 6232. (b) Yang, T.-K.; Chen, R.-Y.; Lee, D.-S.; Peng, W.-S.; Jiang, Y.- Z.; Mi, A.-Q.; Jong, T.-T. J. Org. Chem. 1994, 59, 914-921 and references cited therein. (7) For leading references, see: (a) Davis, F. A.; Szewczyk, J. M.; Reddy, R. E. J. Org. Chem. 1996, 61, 2222-2225. (b) Davis, F. A.; Portonovo, P. S.; Reddy, R. E.; Chiu, Y. Ibid. 1996, 61, 440-441. (c) Hose, D. R. J.; Mahon, M. F.; Molloy, K. C.; Raynham, T.; Wills, M. J. Chem. Soc., Perkin Trans. 1 1996, 691-703. (d) Garcı ´a Ruano, J. L.; Ferna ´ ndez, I.; del Prado Catalina, M.; Alcudia Cruz, A. Tetrahedron: Asymmetry 1996, 7, 3407-3414. (e) Fujisawa, T.; Kooriyama, Y.; Shimizu, M. Tetrahedron Lett. 1996, 37, 3881-3884. (f) Balasubra- manian, T.; Hassner, A. Ibid. 1996, 37, 5755-5758. (8) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M. J. Org. Chem. 1995, 60, 7037-7039. (9) (a) Marino, J. P.; Viso, A.; Ferna ´ ndez de la Pradilla, R.; Ferna ´ ndez, P. J. Org. Chem. 1991, 56, 1349-1351. (b) Arjona, O.; Ferna ´ ndez de la Pradilla, R.; Mallo, A.; Plumet, J.; Viso, A. Tetrahedron Lett. 1990, 31, 1475-1478. (c) Ferna ´ ndez de la Pradilla, R.; Castro, S.; Manzano, P.; Priego, J.; Viso, A. J. Org. Chem. 1996, 61, 3586- 3587. (10) Kanemasa, S.; Hayashi, T.; Tanaka, J.; Yamamoto, H.; Sakurai, T. J. Org. Chem. 1991, 56, 4473-4481 and previous papers from this group. (11) All new products were fully characterized by standard tech- niques. (12) Sulfinimine 2 was prepared in one step from p-nitrobenzalde- hyde by the procedure of Davis (ref 6a). Scheme 1 2316 J. Org. Chem. 1997, 62, 2316-2317 S0022-3263(97)00005-4 CCC: $14.00 © 1997 American Chemical Society