Highly Stereoselective [3+2] Cycloadditions of Nitrile Oxides to Methyl 4-O-Acryloyl-6-deoxy-2,3-O-(t-butyldimethylsilyl)-α-d-glucopyranoside

Abstract

The [3+2] cycloadditions of benzonitrile oxide or pivalo­nitrile oxide to methyl 4-O-acryloyl-6-deoxy-2,3-di-O-(t-butyl­dimethylsilyl)-α-d-glucopyranoside provided the respective adducts, each as virtually a single diastereomer. By reductive remova­l of the carbohydrate template from each adduct, the respectiv­e (R)-enriched Δ²-isoxazoline derivative was obtained.

asymmetric synthesis - [3+2] cycloadditions - nitrile oxide­s - d-glucose - chiral auxiliary

References and Notes

1a Cintas P. Tetrahedron  1991,  47:  6079 

1b Seyden-Penne J. Chiral Auxiliaries and Ligands in Asymmetric Synthesis   Wiley; New York: 1995. 

1c Kunz H. Angew. Chem., Int. Ed. Engl.  1993,  32:  336 

1d Rück K. Kunz H. Chiral Auxiliaries in Cycloadditions   Wiley; New York: 1995. 

1e Hultin PG. Earle MA. Sudharshan M. Tetrahedron  1997,  53:  14823 

2a Totani K. Nagatsuka T. Takao K. Ohba S. Tadano K. Org. Lett.  1999,  1:  1447 

2b Munakata R. Totani K. Takao K. Tadano K. Synlett  2000,  979 

2c Nagatuska T. Yamaguchi S. Totani K. Takao K. Tadano K. Synlett  2001,  481 

2d Totani K. Nagatsuka T. Yamaguchi S. Takao K. Ohba S. Tadano K. J. Org. Chem.  2001,  66:  5965 

2e Nagatsuka T. Yamaguchi S. Totani K. Takao K. Tadano K. J. Carbohydr. Chem.  2001,  20:  519 

2f Totani K. Asano S. Takao K. Tadano K. Synlett  2001,  1772 

3a For a recent review on [3+2] cycloadditions, see: Gothelf KV. Jorgensen KA. Chem. Rev.  1998,  98:  863 

3b For a recent paper on the sugar-based stereoselective [3+2] cycloadditions of nitrile oxide, see: Desroses M. Chéry F. Tatibouët A. De Lucchi O. Rollin P. Tetrahedron: Asymmetry  2002,  13:  2535 

4a Hassner A. Rai KML. Synthesis  1989,  57 

4b Rai KML. Hassner A. Indian J. Chem., Sect. B  1997,  36:  242 

5

All new compounds gave spectroscopic data (¹H, ¹³C NMR, IR, and HRMS) in agreement with the structures depicted. Yields refer to purified sample by chromatography on silica gel.

6

The [3+2] Cycloaddition of 2 using Benzonitrile Oxide in CH₂Cl₂; Preparation of Methyl 6-deoxy-4-O-[(5R)-3-phenyl-Δ²-isoxazoline-5-carbonyl]-2,3-di-O-t-butyldimethylsilyl-α-d-glucopyranoside (3 R). To a cooled (0 °C) stirred solution of 2 (211 mg, 0.459 mmol) in CH₂Cl₂ (4 mL) was added benzonitrile oxide (274 mg, 2.28 mmol). The mixture was stirred at r.t. for 4 h, then diluted with EtOAc (20 mL), and washed with sat. aq NH₄Cl (10 mL
× 3). The organic layer was dried over anhyd Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc-hexane = 1:40) to give 262 mg (96%) of 3 R as colorless oil. Compound 3 R: TLC, R_f 0.47 (EtOAc-hexane = 1:6); IR(neat): 3100-2800, 1750, 1600 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ: 0.10, 0.11, 0.12 (total 12 H, 3s), 0.85, 0.93 (each 9 H, each s), 1.10 (3 H, d, J = 6.6 Hz), 3.37 (3 H, s), 3.52 (1 H, dd, J = 11.2, 16.8 Hz), 3.67 (1 H, dd, J = 3.7, 9.2 Hz), 3.80 (1 H, dd, J = 6.3, 16.8 Hz), 3.83 (1 H, m), 4.01 (1 H, t, J = 9.2 Hz), 4.62 (1 H, d, J = 3.7 Hz), 4.74 (1 H, dd, J = 9.2, 9.9 Hz), 5.14 (1 H, dd, J = 6.3, 11.2 Hz), 7.40-7.70 (5 H, m); ¹³C NMR (75 MHz, CDCl₃) δ: -4.49, -4.39, -3.39, -3.06, 17.32, 17.88, 18.41, 25.87 × 3, 26.12 × 3, 38.00, 54.92, 65.16, 71.62, 74.45, 78.12, 78.58, 100.06, 126.94 × 2, 128.77 × 2, 130.53 × 2, 156.37, 169.40; HRMS: m/z calcd for C₂₈H₄₆NO₆Si₂ (M⁺ - OCH₃): 548.2864, found 548.2872.

7

The [3+2] cycloaddition was best achieved in CH₂Cl₂ (96%). In benzene, the cycloaddition provided 3 R in 92% yield, and the dr of the adducts was 99:1.

8

We also conducted the Lewis acid (2 equiv)-mediated cycloaddition of 2 with benzonitrile oxide. The results are as follows: 1) BF₃·OEt₂/CH₂Cl₂/-78 °C/6 h (97% recovery of 2), 2) ZnI₂/CH₂Cl₂/-78 °C/6 h (90% recovery of 2), 3) Yb(OTf)₃/CH₂Cl₂/-78 °C/6 h (27% of the adduct, dr = ca 6:1, 47% recovery of 2), 4) MgBr₂/CH₂Cl₂/-78 °C to r.t./6 h (49% of the adduct, dr = ca 7:1, 47% recovery of 2).

9

Compound 4 R: TLC, R_f 0.54 (EtOAc-hexane = 1:6); IR(neat): 3100-2800, 1750, 1600 cm^-1: ¹H NMR (300 MHz, CDCl₃) δ: 0.07, 0.09, 0.10 (total 12 H, 3s), 0.83, 0.92 (each 9 H, each s), 1.10 (3 H, d, J = 6.2 Hz), 1.22 (9 H, s), 3.14 (1 H, dd, J = 11.0, 16.9 Hz), 3.36 (3 H, s), 3.38 (1 H, dd, J = 5.9, 16.9 Hz), 3.65 (1 H, dd, J = 3.3, 9.2 Hz), 3.82 (1 H, dq, J = 6.2, 9.2 Hz), 3.98 (1 H, t, J = 9.2 Hz), 4.62 (1 H, d, J = 3.3 Hz), 4.70 (1 H, t, J = 9.2 Hz), 4.94 (1 H, dd, J = 5.9, 11.0 Hz); ¹³C NMR (75 MHz, CDCl₃) δ: -4.49, -4.43, -3.39, -3.06, 17.30, 17.86, 18.42, 25.86 × 3, 26.14 × 3, 28.05 × 3, 32.80, 37.54, 54.92, 65.19, 71.60, 74.45, 77.81, 77.89, 100.06, 165.83, 169.88; HRMS m/z calcd for C₂₆H₅₀NO₆Si₂ (M⁺ - OCH₃): 528.3177, found 528.3147.

10

(a) Compound 5 R: TLC, R_f 0.19 (EtOAc-hexane = 1:1); IR(neat): 3500(br), 3100-2800 cm^-1; [a]_D ²² -170 (c 1.01, CHCl₃); ¹H NMR (300 MHz, CDCl₃) d 3.28 (1 H, dd, J = 7.9, 16.5 Hz), 3.39 (1 H, dd, J = 10.4, 16.5 Hz), 3.68 (1 H, dd, J = 4.3, 12.2 Hz), 3.87 (1 H, dd, J = 3.1, 12.2 Hz), 4.87 (1 H, dddd, J = 3.1, 4.3, 7.9, 10.4 Hz), 7.37-7.68 (5 H, m); ¹³C NMR (75 MHz, CDCl₃) d: 36.29, 63.63, 81.21, 126.68 × 2, 128.69 × 2, 130.17 × 2, 157.08; HRMS m/z calcd for C₁₀H₁₁NO₂ (M⁺): 177.0790, found 177.0790. (b) Curran and co-workers reported the preparation of 5 R from a 95:5 mixture of the [3+2] cycloaddition of the acryloyl amide of Oppolzer’s chiral sultam with benzonitrile oxide. They obtained the cycloadduct in a dr of 95:5, from which 5 R possessing [a]_D ²⁵ -161 (c 1.0, CHCl₃) was prepared: Curran, D. P.; Kim, B. H.; Daugherty, J.; Heffner, T. A. Tetrahedron Lett. 1988, 29, 3555. (c) On the other hand, Akiyama and Ozaki reported the preparation of 5 S, which relied on the [3+2] cycloaddition of the acryloyl ester of optically active cyclitol (l-chiro-inositol) with benzonitrile oxide. By this chiral auxiliary-based methodology, they obtained a 95:5 mixture of the cycloadduct. From the major cycloadduct, 5S possessing [a]_D ²⁵ +172 (c 1.0, CHCl₃) was prepared: Akiyama, T.; Okada, K.; Ozaki, S. Tetrahedron Lett. 1992, 33, 5766.

11

Compound 6 R: TLC, R_f 0.45 (EtOAc); IR(neat): 3480 (br), 3100-2800 cm^-1: [α]_D ²² -120 (c 0.88, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 1.21 (9 H, s), 2.88 (1 H, dd, J = 7.4, 16.7 Hz), 3.02 (1 H, dd, J = 10.4, 16.7 Hz), 3.55 (1 H, dd, J = 4.8, 12.0 Hz), 3.76 (1 H, m), 4.67 (1 H, dddd, J = 3.3, 4.8, 7.4, 10.4 Hz); ¹³C NMR (75 MHz, CDCl₃) δ: 3 × 28.03, 33.03, 35.69, 63.76, 80.09, 166.59; HRMS m/z calcd for C₈H₁₅NO₂ (M⁺): 157.1103, found 157.1105. Curran and co-workers reported the preparation of both 6 R and 6 S (each er = 95:5; [α]_D ²⁵
-127 (c 1.0, CHCl₃) for 6 R and [α]_D ²⁵ +124 (c 1.0, CHCl₃) for 6 S by the chiral auxiliary methodology. Using the same methodology, Akiyama and Ozaki obtained enantioenriched 6 S (dr of the cycloadduct = 91:9) possessing [α]_D ²⁰ +121 (c 1.68, CHCl₃). See ref. [10]

12

Retention times of racemic 7: t _R(S) = 17.1 min and t _R (R) = 19.7 min (DAICEL Chiralcel OD-H, 2-propanol-hexane = 1:8).

13

Retention times of racemic 8: t _R (S) = 22.0 min and t _R (R) = 25.2 min (DAICEL Chiralcel OJ-H, 2-propanol-hexane = 1:15).

14 Curran DP. Kim BH. Piyasena HP. Loncharich RJ. Houk KN. J. Org. Chem.  1987,  52:  2137 

15 The new template 9 was prepared from known compound 11 as shown below (Scheme 4). Compound 11 was prepared from tri-O-acetyl-d-glucal according to the reported procedure: Giuliano RM. Jordan AD. Gauthier AD. Hoogsteen K. J. Org. Chem.  1993,  58:  4979 

16

The dr of the cycloadduct 10 was precisely determined by the chiral HPLC analysis after converting the adduct into the isoxazoline derivative 7.