First Stereocontrolled Reduction of Isoxazoline by Hydrogenolysis: A New Route to Iminosugars via Cyclic Sulfates

Abstract

The synthesis of four new trihydroxylated piperidines, considered as analogues of 1-deoxynojirimycin (DNJ) and 1-deoxy-mannojirimycin (DMJ), was achieved using cyclic sulfate substituted isoxazoline derivatives. The key step is the one-pot reduction of an isoxazoline to an amine which undergoes intramolecular attack on the sulfate ester with high stereoselectivity and regioselectivity. The isoxazoline precursors were obtained by the 1,3-dipolar cycloaddition reaction between 2,2-dimethyl-4-vinyl-1,3-dioxolane and 1-benzyloxy-2-nitroethane.

cyclic sulfates - iminosugars - piperidines - cycloadditions - glycosidase inhibitors

References

1 Watson AA. Fleet GWJ. Asano N. Molyneux RJ. Nash RJ. Phytochemistry  2001,  56:  265 

2 Asano N. Nash RJ. Molyneux RJ. Fleet GWJ. Tetrahedron: Asymmetry  2000,  11:  1645 

3 Stütz AE. Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond   Wiley-VCH; Weinheim: 1999. 

4 Chapleur Y. Carbohydrate Mimics - Concepts and Methods   Wiley-VCH; Weinheim: 1998. 

5 Kajimoto T. Liu KKC. Pederson RL. Zhong Z. Ichikawa Y. Porco JAJ. Wong C.-H. J. Am. Chem. Soc.  1991,  113:  6187 

6 Takayama S. Martin R. Wu R. Laslo K. Siuzdak G. Wong C.-H. J. Am. Chem. Soc.  1997,  119:  8146 

7 Hecquet L. Lemaire M. Bolte J. Demuynck C. Tetrahedron Lett.  1994,  35:  8791 

8 Lemaire M. Valentin ML. Hecquet L. Demuynck C. Bolte J. Tetrahedron: Asymmetry  1995,  6:  67 

9 Jang KC. Jeong IY. Yang MS. Choi SU. Park KH. Heterocycles  2000,  53:  887 

10 Ichikawa Y. Igarashi Y. Ichikawa M. Suhara Y. J. Am. Chem. Soc.  1998,  120:  3007 

11 Andersen SM. Ekhart C. Lundt I. Stütz AE. Carbohydr. Res.  2000,  326:  22 

12 Jaeger V. Schwab W. Buss V. Angew. Chem., Int. Ed. Engl.  1981,  20:  601 

13 Mueller I. Jaeger V. Tetrahedron Lett.  1982,  23:  4777 

14 Jaeger V. Schohe R. Tetrahedron  1984,  40:  2199 

15 Jaeger V. Mueller I. Tetrahedron  1985,  41:  3519 

16 Jaeger V. Mueller I. Paulus EF. Tetrahedron Lett.  1985,  26:  2997 

17 Jaeger V. Schroeter D. Synthesis  1990,  556 

18 Wade PA. D’Ambrosio SG. Price DT. J. Org. Chem.  1995,  60:  6302 

19 de Blas J. Carretero JC. Dominguez E. Tetrahedron: Asymmetry  1995,  6:  1035 

20 Schaller C. Vogel P. Jaeger V. Carbohydr. Res.  1998,  314:  25 

21 Mueller R. Leibold T. Paetzel M. Jaeger V. Angew. Chem., Int. Ed. Engl.  1994,  33:  1295 

22 Gefflaut T. Martin C. Delor S. Besse P. Veschambre H. Bolte J. J. Org. Chem.  2001,  66:  2296 

23 Mukaiyama T. Hoshino T. J. Am. Chem. Soc.  1960,  82:  5339 

24 Kantorowski EJ. Brown SP. Kurth MJ. J. Org. Chem.  1998,  63:  5272 

25 Byun HS. He LL. Bittman R. Tetrahedron  2000,  56:  7051 

26 Gao Y. Sharpless KB. J. Am. Chem. Soc.  1988,  110:  7538 

27

Typical Procedure for Preparation of 15. A solution of 13 (1.08 g, 3.45 mmol) in anhyd MeOH (50 mL) was stirred under H₂ in the presence of 10% Pd/C (500 mg) and anhyd Na₂CO₃ (183 mg, 1.73 mmol) for 6 h. The solids were removed by filtration through a membrane filter (0.2 µm) and the filtrate concentrated under vacuum. The residue was neutralized with HCl 1N, then purified over an acidic resin (Dowex 50WX8, 200-400 mesh) using water as eluent. Compound 15 was isolated as a white solid in 82% yield (892 mg).

28 Barco A. Benetti S. De Risi C. Marchetti P. Pollini GP. Zanirato V. Tetrahedron  1999,  55:  5923 

29 Ghavami A. Johnston BD. Pinto BM. J. Org. Chem.  2001,  66:  2312 

30

All new compounds reported here were racemic and gave satisfactory spectral data (¹H and ¹³C NMR, IR, mass). Selected spectral data (¹H and ¹³C), 15: ¹H NMR (300 MHz, D₂O): δ = 1.78 (ddd, 1 H, J = 13 Hz), 1.96 (ddd, 1 H, J = 13, 3.5, 3.5 Hz), 3.24 (dd, 1 H, J = 14, 1 Hz), 3.52 (m, 1 H), 3.63 (dd, 1 H, J = 11, 8 Hz), 3.71 (dd, 1 H, J = 11, 8 Hz), 3.81 (dd, 1 H, J = 14, 3 Hz), 4.03 (ddd, 1 H, J = 13, 3.5, 3.5 Hz), 4.61 (s, 2 H), 4.75 (m, 1 H), 7.43 (m, 5 H). ¹³C NMR (100 MHz, D₂O): δ = 30.3 (C₄), 48.6 (C₁), 57.8 (C₅), 66.9 (C₃), 71.8 (C₆ or C₇), 75.7 (C₂), 75.9 (C₇ or C₆), 131.3-131.6
(C_9-10-11), 139.8 (C₈). 17: ¹H NMR (300 MHz, D₂O): δ = 1.86 (AB, 1 H, J = 13 Hz), 1.91 (AB, 1 H), 3.21 (dd, 1 H, J = 14, 1 Hz), 3.46 (dd, 1 H, J = 14, 3 Hz), 3.53 (m, 1 H), 3.66 (dd, 1 H, J = 11, 8 Hz), 3.75 (dd, 1 H, J = 11, 4 Hz), 3.99 (m, 1 H), 4.17 (m, 1 H), 4.65 (s, 2 H), 7.46 (m, 5 H). ¹³C NMR (75 MHz, D₂O): δ = 29.8 (C₄), 50.9 (C₁), 57.9 (C₅), 67.6 (C₃), 69.6 (C₂), 72.0 (C₆ or C₇), 76.0 (C₆ or C₇), 131.4-131.7
(C_9-10-11), 140.0 (C₈). 18: ¹H NMR (300 MHz, D₂O): δ = 1.80 (ddd, 1 H, J = 13 Hz), 2.00 (ddd, 1 H, J = 13, 3.5, 3.5 Hz), 3.28 (dd, 1 H, J = 14, 1 Hz), 3.42 (dddd, 1 H, J = 13, 8, 4, 3.5 Hz), 3.68 (dd, 1 H, J = 12.5, 8 Hz), 3.81 (dd, 1 H, J = 12.5, 4 Hz), 3.86 (dd, 1 H, J = 14, 3 Hz), 4.08 (ddd, 1 H, J = 13, 4.5, 3.5 Hz), 4.79 (m, 1 H). ¹³C NMR (75 MHz, D₂O): δ = 30.1 (C₄), 48.5 (C₁), 59.7 (C₅), 64.0 (C₆), 68.5 (C₃), 75.6 (C₂). 16: ¹H NMR (400 MHz, (CD₃)₂SO): δ = 1.42 (ddd, 1 H, J = 13, 13, 13 Hz), 2.00 (ddd, 1 H, J = 13, 4.5, 4.5 Hz), 2.81 (dd, 1 H, J = 13, 11 Hz), 3.40 (m, 1 H), 3.50 (m, 1 H), 3.56-3.80 (m, 3 H), 4.12 (m, 1 H), 4.55 (AB, 2 H, J = 12 Hz), 7.36 (m, 5 H). ¹³C NMR (100 MHz, D₂O): δ = 32.2 (C₄), 44.7 (C₁), 53.7 (C₅), 68.1 (C₃), 69.6 (C₆), 72.6 (C₇), 74.4 (C₂), 127.9-128.6 (C_9-10-11), 137.9 (C₈).