Asymmetric Michael Addition of Malonates to Enones Catalyzed by an α-d-Glucopyranoside-Based Crown Ether

Abstract

The chiral monoaza-15-crown-5 lariat ether annelated to methyl-4,6-O-benzylidene-α-d-glucopyranoside has been applied as a phase-transfer catalyst in several Michael addition reactions under mild conditions affording the adducts with good to excellent enantioselectivities. In the addition of α-substituted diethyl malonates to trans-chalcones, the substituents of the reactants had a significant impact on the yield and enantioselectivity. Among the reactions of substituted diethyl malonates, that of diethyl-2-acetoxymalonate gave the best results (up to 97% ee). New phase-transfer-catalyzed cyclopropanation reactions (MIRC reactions) of a few enones were also developed using diethyl 2-bromomalonate as the nucleophile. The corresponding chiral cyclopropane derivatives were formed with enantioselectivities up to 92% from 2-benzylidenemalononitrile starting materials, in up to 60% enantiomeric excess using 2-benzylidene-1,3-diphenyl-1,3-propanediones, and in up to 88% optical purity applying trans-chalcones as the starting materials.

Key words

phase-transfer catalysis - sugar-based crown ethers - asymmetric Michael reactions - asymmetric cyclopropanations - enantioselectivity

• References and Notes

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• 11a General Procedure for the Michael Additions Unsaturated compound (1 mmol), substituted malonate (1.5 mmol), and the crown ether (0.15 mmol) were dissolved in a mixture of anhydrous THF (0.6 mL) and Et₂O (2.4 mL) and dry Na₂CO₃ (2 mmol) was added. The reaction mixture was stirred at r.t. After completion of the reaction, the organic phase was concentrated in vacuo, and the residue was taken up in CH₂Cl₂ (10 mL), washed with cold 10% HCl (3 × 10 mL), then with H₂O (10 mL), dried (Na₂CO₃ and Na₂SO₄), and concentrated. The crude product was purified by preparative TLC using silica gel and hexane–EtOAc (5:1) as the eluent. The enantioselectivities were determined by chiral HPLC analysis using a Chiralpack AD-H column, (20 °C, 256 nm, hexane–i-PrOH = 90:10, 0.8 mL/min) in comparison with authentic racemic materials.
• 11b Compound 5a: yield 72%; [α]_D ²² + 9.4 (c 1, CHCl₃); ee 96%; t _r (major enantiomer) = 9.9 min, t _r (minor enantiomer) = 13.2 min. ¹H NMR (500 MHz, CDCl₃): δ = 7.90 (d, J = 7.5 Hz, 2 H, ArH), 7.53 (t, J = 7.5 Hz, 1 H, ArH), 7.43 (t, J = 7.5 Hz, 2 H, ArH), 7.35 (d, J = 7.5 Hz, 2 H, ArH), 7.26–7.20 (m, 3 H, ArH), 4.37 (dd, J = 8.5, 4.0 Hz, 1 H, PhH), 4.24–4.16 (m, 2 H, OCH₂), 4.02–3.89 (m, 2 H, OCH₂), 3.67 (dd, J = 16.0, 4.0 Hz, 1 H, COCH₂), 3.59 (dd, J = 17.5, 8.5 Hz, 1 H, COCH₂), 2.23 (s, 3 H, COCH₃), 1.23 (t, J = 7.0 Hz, 3 H, CH₂CH ₃), 1.06 (t, J = 7.0 Hz, 3 H, CH₂CH ₃) ppm. HRMS: m/z calcd for C₂₄H₂₆O₇: 426.1679; found: 426.1680.
• 11c Compound 5j: yield 73%; [α]_D ²² + 13.8 (c 1, CHCl₃); ee 97%; t _r (major enantiomer) = 24.9 min, t _r (minor enantiomer) = 22.8 min. ¹H NMR (500 MHz, CDCl₃): δ = 7.89 (dd, J = 7.5, 1.0 Hz, 2 H, ArH), 7.53 (t, J = 7.5 Hz, 1 H, ArH), 7.43 (t, J = 7.5 Hz, 2 H, ArH), 7.26 (d, J = 8.5 Hz, 2 H, ArH), 6.77 (d, J = 8.5 Hz, 2 H, ArH), 4.31 (dd, J = 8.5, 4.0 Hz, 1 H, ArCH), 4.24–4.15 (m, 2 H, OCH₂), 4.06–3.92 (m, 2 H, OCH₂), 3.75 (s, 3 H, ArOCH₃), 3.71 (dd, J = 18.0, 4.0 Hz, 1 H, COCH₂), 3.56 (dd, J = 18.0, 9.0 Hz, 1 H, COCH₂), 2.23 (s, 3 H, COCH₃), 1.23 (t, J = 7.0 Hz, 3 H, CH₂CH ₃), 1.10 (t, J = 7.0 Hz, 3 H, CH₂CH ₃) ppm. HRMS: m/z calcd for C₂₅H₂₈O₈: 456.1784; found: 456.1785.
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The corresponding coupling constants of 7.5 Hz (δ = 4.12 ppm, J = 7.5 Hz and δ = 3.89 ppm, J = 7.5 Hz) observed for the trans isomer are in agreement with the literature data. The corresponding constants would be J = 9.9 Hz in both cases for the cis compound. See:
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• 17a Compound 7a: yield 28%; [α]_D ²² +17.5 (c 1, CHCl₃); ee 88%; t _r (major enantiomer) = 5.0 min, t _r (minor enantiomer) = 9.3 min. ¹H NMR (500 MHz, CDCl₃): δ = 8.11 (d, J = 7.5 Hz, 2 H, ArH), 7.62 (t, J = 7.5 Hz, 1 H, ArH), 7.51 (t, J = 7.5 Hz, 2 H, ArH), 7.33–7.26 (m, 5 H, ArH), 4.14 (q, J = 7.0 Hz, 2 H, OCH₂), 4.12 (d, J = 7.5 Hz, 1 H, COCH), 4.00 (q, J = 7.0 Hz, 2 H, OCH₂), 3.89 (d, J = 7.5 Hz, 1 H, PhCH), 1.11 (t, J = 7.0 Hz, 3 H, CH₃), 0.99 (t, J = 7.0 Hz, 3 H, CH₃) ppm. HRMS: m/z calcd for C₂₂H₂₂O₅: 366.1467; found: 366.1470.
• 17b Compound 9d: yield 74%; [α]_D ²² –17.3 (c 1, CHCl₃); ee 92%; t _r (major enantiomer) = 4.3 min, t _r (minor enantiomer) = 5.0 min. ¹H NMR (500 MHz, CDCl₃): δ = 7.25 (d, J = 8.0 Hz, 2 H, ArH), 7.20 (d, J = 8.0 Hz, 2 H, ArH), 4.42 (q, J = 7.0 Hz, 2 H, OCH₂), 4.30–4.20 (m, 2 H, OCH₂), 3.92 (s, 1 H, ArCH), 2.35 (s, 3 H, ArCH₃), 1.38 (t, J = 7.0 Hz, 3 H), 1.21 (t, J = 7.0 Hz, 3 H) ppm. HRMS: m/z calcd for C₁₈H₁₈N₂O₄: 326.1267; found: 326.1270.
• 17c Compound 11a: yield 52%; [α]_D ²² +68.9 (c 1, CHCl₃); ee 60%; t _r (major enantiomer) = 11.9 min, t _r (minor enantiomer) = 41.1 min. ¹H NMR (500 MHz, CDCl₃): δ = 7.53 (d, J = 7.5 Hz, 2 H, ArH), 7.44 (d, J = 7.5 Hz, 2 H, ArH), 7.33 (d, J = 7.0 Hz, 2 H, ArH), 7.26–7.19 (m, 5 H, ArH), 7.14 (t, J = 7.5 Hz, 2 H, ArH), 7.10 (t, J = 7.5 Hz, 2 H, ArH), 5.64 (s, 1 H, PhCH), 4.47–4.40 (m, 1 H, OCH₂), 4.38–4.29 (m, 1 H, OCH₂), 3.87–3.80 (m, 1 H, OCH₂), 3.64–3.57 (m, 1 H, OCH₂), 1.35 (t, J = 7.0 Hz, 3 H, CH₃), 0.84 (t, J = 7.0 Hz, 3 H, CH₃). HRMS: m/z calcd for C₂₉H₂₆O₆: 470.1729; found: 470.1733.