Asymmetric Synthesis of (–)-9-epi-Metazocine

Abstract

(–)-9-epi-Metazocine was synthesized through an Evans syn aldol reaction, ring-closing metathesis reaction and intramolecular radical cyclization.

Key word

asymmetric - drug development - aldol - ring-closing ­metathesis - radical cyclization

• References

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• 12 Compound 5: To a solution of thiazolidinethione propionate 7 (4.27 g, 16.1 mmol) in CH₂Cl₂ (100 mL) at 0 °C, was added TiCl₄ (1.86 mL, 16.9 mmol); a characteristic orange slurry formed. After 10 min, (–)-sparteine (3.78 g, 16.1 mmol) was added, and the color changed to a deep red. After stirring for 30 min, the mixture was cooled to –78 °C, N-methylpyrrolidinone (NMP; 1.6 mL, 16.1 mmol) was added and the mixture was stirred for an additional 10 min. Aldehyde 6 (4.06 g, 17.7 mmol) in CH₂Cl₂ (20 mL) was added and the mixture was stirred at –78 °C for 1 h. After a further 2.5 hours stirring at 0 °C, the reaction was quenched with sat. NH₄Cl. After separation of layers, the aqueous layer was further extracted with CH₂Cl₂ (2 × 30 mL) and the combined organic extract was dried over anhydrous Na₂SO₄ and evaporated in vacuo. The residue was purified by chromatography (petroleum ether–EtOAc, 10:1) to afford 5 (6.0 g, 76%) as yellow liquid; [α] _d ¹⁸ –79.3 (c 2.0, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ = 7.37–7.33 (m, 2 H), 7.29–7.27 (m, 3 H), 7.19 (d, J = 8.4 Hz, 1 H), 7.11 (d, J = 2.8 Hz, 1 H), 6.82 (dd, J = 2.4, 8.4 Hz, 1 H), 5.37–5.31 (m, 1 H), 4.62–4.56 (m, 1 H), 4.24 (br s, 1 H), 3.77 (s, 3 H), 3.37 (dd, J = 6.8, 11.2 Hz, 1 H), 3.21 (dd, J = 3.6, 13.2 Hz, 1 H), 3.07–3.00 (m, 1 H), 2.90–2.86 (m, 3 H), 1.38 (d, J = 6.8 Hz, 3 H); ¹³C NMR (CDCl₃, 100 MHz): δ = 201.0, 177.6, 158.8, 136.3, 131.9, 129.3, 129.2, 128.8, 127.1, 124.9, 118.0, 113.5, 71.9, 68.6, 55.4, 42.7, 39.6, 36.7, 31.9, 10.8; HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₅BrNO₃S₂: 494.0454; found: 494.0463
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• 15 Compound 16: To a solution of alcohol 15 (0.68 g, 2.3 mmol) in THF (30 mL) was added Ph₃P (0.65 g, 2.5 mmol), DIAD (0.51 g, 2.5 mmol), and diphenylphosphoryl azide (0.96 g, 2.7 mmol) at 0 °C and stirring was continued for 12 h. The solvent was removed in vacuo and the residue was purified by chromatography (petroleum ether–EtOAc,100:1) to afford 16 (0.6 g, 80%) as a colorless liquid; [α] _d ¹⁸ +74.0 (c 1.0, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ = 7.21 (d, J = 8.4 Hz, 1 H), 7.12 (d, J = 2.8 Hz, 1 H), 6.84 (dd, J = 2.8, 8.4 Hz, 1 H), 4.91 (s, 1 H), 4.90 (s, 1 H), 3.80 (s, 3 H), 3.62–3.57 (m, 1 H), 3.12 (dd, J = 2.8, 14.0 Hz, 1 H), 2.58 (dd, J = 10.8, 14.4 Hz, 1 H), 2.52–2.45 (m, 1 H), 1.81 (s, 3 H), 1.22 (d, J = 6.8 Hz, 3 H); ¹³C NMR (CDCl₃, 100 MHz): δ = 159.0, 146.3, 132.3, 129.5, 124.5, 118.0, 113.6, 112.7, 65.5, 55.5, 45.7, 37.6, 20.0, 16.1; IR: 3366, 2961, 2925, 2853, 2102, 1604, 1492, 1243, 1034 cm^–1; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₉BrN₃O: 324.0706; found: 324.0718
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• 19 Compound 17: To a stirred solution of 4 (200 mg, 0.57 mmol) in CH₂Cl₂ (60 mL) Hoveyda–Grubbs II (28 mg, 0.045 mmol, 8 mol%) was added under an argon atmosphere. The mixture was heated at reflux for 24 h, then the solvent was removed in vacuum and the residue was purified by chromatography (EtOAc) to afford 17 (46 mg, 25%) as a colorless solid; [α] _d ¹⁶ +172 (c 1.0, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ = 7.11 (d, J = 2.4 Hz, 1 H), 7.03 (d, J = 8.8 Hz, 1 H), 6.81 (dd, J = 2.4, 8.8 Hz, 1 H), 5.71 (s, 1 H), 5.49 (s, 1 H), 3.78 (s, 3 H), 3.50–3.45 (m, 1 H), 2.96–2.84 (m, 2 H), 2.18 (q, J = 6.8 Hz, 1 H), 1.96 (s, 3 H), 1.19 (d, J = 6.8 Hz, 3 H); ¹³C NMR (CDCl₃, 100 MHz): δ = 165.2, 159.0, 156.0, 132.0, 128.8, 124.8, 118.8, 118.4, 113.7, 55.6, 55.5, 40.6, 37.6, 22.0, 17.7; IR: 3242, 2965, 2929, 2866, 1675, 1606, 1492, 1241, 1031 cm^–1; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₉BrNO₂: 324.0594; found: 324.0596
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• 21 Preparation of compound 18 (Scheme 4): To a solution of 3 (43 mg, 0.12 mmol) in benzene (10 mL) at reflux, was added dropwise a solution of Bu₃SnH (51 mg, 0.18 mmol) and AIBN (30 mg, 0.18 mmol) in benzene (10 mL) over 1 h by using a syringe. The mixture was then heated at reflux for 3 h. After evaporation of the solvent, the residue was purified by chromatography on silica gel (hexane–EtOAc, 2:1) to give 18 (27 mg, 87%); [α] _d ²² –77 (c 1.0, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ = 6.96 (d, J = 8.0 Hz, 1 H), 6.90 (d, J = 2.4 Hz, 1 H), 6.72 (dd, J = 2.4, 8.0 Hz, 1 H), 3.78 (s, 3 H), 3.53 (s, 1 H), 2.96 (s, 2 H), 2.93 (s, 3 H), 2.48 (d, J = 17.6 Hz, 1 H), 2.30 (d, J = 19.2 Hz, 1 H), 2.04 (q, J = 6.8 Hz, 1 H), 1.38 (s, 3 H), 1.19 (d, J = 7.2 Hz, 3 H); ¹³C NMR (CDCl₃, 100 MHz): δ = 169.0, 158.6, 145.3, 130.6, 123.7, 112.4, 111.5, 61.0, 55.3, 43.4, 36.9, 36.9, 34.2, 33.8, 24.1, 14.4; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₂₂NO₂: 260.1645; found: 260.1657
• 22 (–)-9-epi-metazocine (2b): [α] _d ¹⁷ +22.0 (c 0.5, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ = 6.95 (d, J = 8.0 Hz, 1 H), 6.80 (d, J = 2.4 Hz, 1 H), 6.61 (dd, J = 2.4, 8.0 Hz, 1 H), 3.13 (d, J = 17.6 Hz, 1 H), 2.92 (d, J = 5.6 Hz, 1 H), 2.67 (dd, J = 5.6, 17.6 Hz, 1 H), 2.44 (d, J = 6.8 Hz, 1 H), 2.36 (s, 3 H), 2.03 (d, J = 8.4 Hz, 2 H), 1.88 (q, J = 6.8 Hz, 1 H), 1.29 (s, 3 H), 1.26 (d, J = 7.2 Hz, 3 H), 1.10 (d, J = 9.6 Hz, 1 H); ¹³C NMR (CDCl₃, 100 MHz): δ = 154.1, 146.4, 129.1, 128.6, 113.0, 111.5, 60.1, 47.6, 43.0, 38.2, 34.9, 34.8, 27.3, 24.0, 15.0; IR: 3254, 2932, 2865, 1610, 1496, 1485, 1360, 769 cm^–1; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₂₂NO: 232.1696; found: 232.1692