Organocatalytic Asymmetric
1,3-Dipolar Cycloaddition of Nitrones to Nitroolefins

Wei Du; Yan-Kai Liu; Lei Yue; Ying-Chun Chen

doi:10.1055/s-0028-1087300

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Synlett 2008(19): 2997-3000
DOI: 10.1055/s-0028-1087300

LETTER

Organocatalytic Asymmetric 1,3-Dipolar Cycloaddition of Nitrones to Nitroolefins

Wei Du, Yan-Kai Liu, Lei Yue, Ying-Chun Chen*
Key Laboratory of Drug-Targeting and Drug Deliver System of Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. of China
Fax: +86(28)85502609; e-Mail: ycchenhuaxi@yahoo.com.cn; e-Mail: ycchen@scu.edu.cn;

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Publication History

Received 1 August 2008
Publication Date:
23 October 2008 (online)

Abstract
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Abstract

The asymmetric 1,3-dipolar cycloaddition of nitrones to nitroolefins was investigated by employing novel thiourea-containing organocatalysts. This transformation exhibited excellent diastereoselectivities (generally >99:1 dr) and moderate to high enantioselectivities (up to 88% ee). A 2,3-diaminopropanol derivative with three contiguous chiral centers was efficiently prepared from one cycloaddition adduct.

Key words

dipolar cycloaddition - nitrones - nitroolefins - thiourea - orgaoncatalysis

Supporting Information

References and Notes

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14

β-Nitrostyrene exhibited very sluggish reactivity in the catalytic 1,3-dipolar cycloaddition even at much higher temperature (>50 ˚C).

16

Thiourea-pyrrole catalysts 1f-k were prepared in a similar procedure as 1e, see ref. 14.

17

General Procedure for the Asymmetric 1,3-Dipolar Cycloaddition Reaction
Catalyst 1j (6.6 mg, 0.01 mmol, 10 mol%), nitrone 2a (20.0 mg, 0.1 mmol) and 4 Å MS (50 mg) were stirred in redistilled MTBE (0.4 mL) at 0 ˚C. Then nitroolefin 3a (14.0 mg, 0.12 mmol) in MTBE (0.1 mL) was added. After 6 d, product 4a was isolated by FC on SiO₂ eluted with EtOAc-PE as an oil; 24.5 mg, 79% yield; R _f = 0.5 (PE-EtOAc, 15:1); [α]_D ^²0 -101.3 (c 1.00 in CH₂Cl₂); 82% ee, determined by HPLC analysis [Daicel chiralcel OD, n-hexane-i-PrOH (95:5), 1.0 mL/min, λ = 254 nm, t _R(major) = 7.70 min, t _R(minor) = 11.16 min]. ^¹H NMR (400 MHz, CDCl₃): δ = 7.44-7.41 (m, 2 H), 7.35-7.33 (m, 3 H), 7.21-7.17 (m,
2 H), 7.04-6.98 (m, 3 H), 5.29 (dd, J = 9.2, 7.2 Hz, 1 H), 4.80 (t, J = 7.2 Hz, 1 H), 4.74 (d, J = 9.2 Hz, 1 H), 2.08-2.03 (m, 1 H), 1.14 (d, J = 6.8 Hz, 3 H), 1.02 (d, J = 6.8 Hz, 3 H) ppm. ^¹³C NMR (50 MHz, CDCl₃): δ = 148.1, 133.3, 129.2, 128.8, 128.7, 128.2, 124.1, 116.4, 94.5, 84.7, 73.0, 30.7, 19.0, 17.9 ppm. ESI-HRMS: m/z calcd for C₁₈H₂₀N₂O₃ + Na: 335.1372; found: 335.1320.

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General Procedure for the Synthesis of 2,3-Diamino-propanol 5 Compound 4a (31 mg, 0.1 mmol, 99% ee) and NiCl₂˙6H₂O (100 mg, 0.4 mmol) were stirred in MeOH (1 mL) and THF (0.5 mL) at r.t. for 10 min. Then NaBH₄ (33 mg, 0.9 mmol) was added in portions at 0 ˚C. After stirring for 5 min, EtOAc (5 mL) and H₂O (5 mL) were added. After filtration, the filtrate was extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over Na₂SO₄ and concentrated. The residue and (Boc)₂O (26 mg, 0.12 mmol) were dissolved in CH₂Cl₂ and stirred for 2 h. The solvent was then removed in vacuo, and the residue was purified by flash chromatography on SiO₂ (EtOAc-PE) to give N-Boc-diaminopropanol 5 as an oil; 35 mg, 91% yield for two steps; R _f = 0.4 (PE-EtOAc, 5:1); [α]_D ^²0 +18.6 (c 0.70 in CH₂Cl₂); 99% ee, determined by HPLC analysis [Daicel chiralcel AD, n-hexane-i-PrOH (90:10), 1.0 mL/min, λ = 254 nm, t _R(minor) = 5.48 min, t _R(major) = 9.32 min]. ^¹H NMR (400 MHz, CDCl₃): δ = 7.33-7.28 (m, 4 H), 7.23-7.21 (m, 1 H), 7.11-7.07 (m, 2 H), 6.70-6.67 (m, 1 H), 6.59-6.57 (m, 2 H), 5.46 (s, 1 H), 5.12 (d, J = 8.4 Hz, 1 H), 4.84-4.77 (m, 1 H), 4.03 (s, 1 H), 3.54 (s, 1 H), 1.86-1.84 (m, 1 H), 1.30 (s, 9 H), 1.06 (d, J = 6.8 Hz, 3 H), 1.02 (d, J = 6.4 Hz, 3 H) ppm. ^¹³C NMR (50 MHz, CDCl₃): δ = 155.4, 147.0, 140.6, 129.1, 128.5, 127.1, 126.9, 118.3, 114.8, 79.6, 78.8, 58.6, 56.1, 29.9, 28.2, 19.4, 18.2 ppm. ESI-HRMS: m/z calcd for C₂₃H₃₂N₂O₃ + H: 385.2491; found: 385.2453.

19

CCDC-700901 (6) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Supplementary Material

Supporting Information