Practical Synthesis of Chiral Sultam Auxiliaries: 3-Substituted- 1,2-benzisothiazoline 1,1-Dioxides Kyo Han Ahn,* Cheol Ham, Seung-Kee Kim, and Chang-Woo Cho Department of Chemistry and Center for Biofunctional Molecules, Pohang University of Science & Technology (POSTECH), San 31 Hyoja-dong, Pohang 790-784, Republic of Korea Received May 23, 1997 The sultam compounds 1 and 2 are an important class of chiral auxiliaries, developed by Oppolzer and co- workers. 1 They are structurally simpler than the well- known Oppolzer’s camphorsultam auxiliary 2 and have a benzene chromophore which makes their detection easier. Sultam 1 has been shown to be a highly selective chiral auxiliary in asymmetric alkylations, acylations, aldoliza- tions, and Diels-Alder reactions. 1b,c Both enantiomers of sultam 1 are synthesized from an inexpensive starting material, saccharin (4), in two steps: 1a (1) methyllithium addition to saccharin to give the corresponding N- sulfonylimine 5a; (2) asymmetric hydrogenation of the sulfonylimine with a Ru-BINAP catalyst. Sultam 2 is also an excellent chiral auxiliary, particularly for the 1,3- dipolar cycloaddition of nitrile oxides, for which moderate stereoselectivities were observed with sultam 1. 1d In spite of the excellent stereofacial discrimination of sultam auxiliary 2, its usefulness as a chiral auxiliary has not been explored fully, probably owing to its multistep preparation. Each enantiomer of sultam 2 was prepared by chemical resolution of the racemic mixture via N-(S)- camphorsulfonylated sultams. 1d Sultam 3 has been briefly tested as an auxiliary in a racemic form in the Diels-Alder reaction. 1b Because it has a phenyl group which could possibly participate in π-π interactions during the cycloaddition stage, it would be of interest to study it and its analogs as chiral auxiliaries further. As a continuing project toward the development and utiliza- tion of chiral auxiliaries in asymmetric reactions, 3 we have studied a more efficient synthesis of chiral 3-sub- stituted sultam compounds. Here we report a practical synthesis of the sultam auxiliaries 2 and 3 in high enantiomeric excess which is also applicable to the synthesis of other structural analogs. We studied the asymmetric reduction of N-sulfo- nylimine 5b using several ruthenium-BINAP catalysts such as (R)-RuCl 4 (BINAP) 2 Et 3 N, 1a (R)-Ru(OAc) 2 (BINAP), 4 and (R)-RuCl 2 (BINAP) 5 under ca. 5 atm of hydrogen pressure but failed to reduce the imine bond. However, we were pleased to find that the transfer hydrogenation with Noyori’s RuCl(TsDPEN)(benzene) catalyst 6 pro- duced desired sultams in high enantioselectivity. Thus, the transfer hydrogenation of 5b 1d in the presence of 0.5 mol % (S,S)-RuCl(TsDPEN)(benzene) afforded (S)-2 7 in 91% ee. The crude extracted product was crystallized, providing optically pure compound in 75% isolated yield. The enantiopurity was determined by 19 F NMR and GC analyses of the corresponding N-acylated derivative prepared using (R)-Mosher’s acid chloride. 8 For the practical synthesis of chiral sultam 3, it was necessary to improve the synthetic yield of N-sulfonylimine 5c from saccharin. Addition of benzylmagnesium chloride to saccharin in degassed THF at -78 to 25 °C gave 5c in low yields (20-30%), as precedented in the literature. 1b However, by changing the solvent from THF to Et 2 O, the yield could be increased to 67%. 9 Then, subsequent ruthenium-catalyzed transfer hydrogenation of 5c as above gave (S)-3 in 93% ee. Recrystallization of the extracted product gave essentially optically pure product. The absolute configuration of (S)-3 was unambiguously determined from the X-ray crystal structure of its N- acryloylsultam derivative 6. 10 Our results indicate that the transfer hydrogenation method, which has been demonstrated to be highly effective in the asymmetric reduction of imines, can be equally extended to N- sulfonylimines. 11 In summary, we have developed an efficient synthesis of chiral 3-substituted-1,2-benzisothiazoline 1,1-dioxides 2 and 3 which involves no chromatographic separation. Because these sultam derivatives are excellent chiral auxiliaries, their application in asymmetric syntheses now becomes more feasible. An extension of the transfer hydrogenation method to other N-sulfonylimine com- (1) (a) Oppolzer, W.; Wills, M.; Starkemann, C.; Bernardinelli, G. Tetrahedron Lett. 1990, 31, 4117. (b) Oppolzer, W.; Wills, M.; Kelly, M. J.; Signer, M.; Blagg, J. Tetrahedron Lett. 1990, 31, 5015. (c) Oppolzer, W.; Rodriguez, I.; Starkemann, C.; Walther, E. Tetrahedron Lett. 1990, 31, 5019. (d) Oppolzer, W.; Kingma, A. J.; Pillai, S. K. Tetrahedron Lett. 1991, 32, 4893. An attempted asymmetric hydro- genation of 5b under the same conditions that were used for the synthesis of 1 gave only traces of racemic sultam 2. (2) (a) Oppolzer, W. Tetrahedron 1987, 43, 1969. (b) Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241. (3) (a) Ahn, K. H.; Lee, S.; Lim, A. J. Org. Chem. 1992, 57, 5065. (b) Ahn, K. H.; Yoo, D. J.; Kim, J. S. Tetrahedron Lett. 1992, 33, 6661. (4) Kitamura, M.; Tokunaga, M.; Noyori, R. J. Org. Chem. 1992, 57, 4053. (5) Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Tetrahe- dron Lett. 1991, 32, 4163. (6) (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562. (b) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916. (7) R-Description for this (-)-2 in the literature should be corrected to S according to the sequence rule: Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; John Wiley & Sons, Inc.: New York, 1994; pp 101-112. (8) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (9) The solvent must be degassed by flushing with an inert gas; otherwise, the dimerization of benzyl Grignard reagent significantly reduces the addition yield. For the addition of Grignard reagents to saccharin, see: Abramovitch, R. A.; Smith, E. M.; Humber, M.; Purtschert, B.; Srinivasan, P. C.; Singer, G. M. J. Chem. Soc., Perkin Trans. I 1974, 2589. (10) The authors have deposited atomic coordinates for 6 with the Cambridge Crystallographic Data Centre. The coordinates can be obtained, on request, from the Director, Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K. (11) After completion of our work, asymmetric hydrogenation of N-tosylimines, with low to moderate enantioselectivities, by Ru II - BINAP complexes under high-H2 pressure has been reported; see: Charette, A. B.; Giroux, A. Tetrahedron Lett. 1996, 37, 6669. 7047 J. Org. Chem. 1997, 62, 7047-7048 S0022-3263(97)00917-1 CCC: $14.00 © 1997 American Chemical Society