Magnesium-Coordinated Chelation Control in 1,3-Dipolar Cycloaddition of Chiral α-Alkoxymethyl Ether Nitrile Oxide: Application to the Synthesis of (–)/(–)-cis-Clausenamide

Abstract

A facile regio- and diastereoselective nitrile oxide cycloaddition method using magnesium-coordinated chelation control of chiral α-alkoxymethyl ether nitrile oxide is reported. This reaction could be successfully applied as a key step in both the formal total synthesis of (–)-clausenamide and the total synthesis of (–)-cis-clausenamide.

Key words

cycloaddition - magnesium - nitrile oxide - diastereo­selectivity - natural products

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• 10 1,3-Dipolar Cycloaddition of Cinnamyl Alcohol (3) with α-Hydroxy-Protected Nitrile Oxides; Typical Procedure for 4c: To a solution of the (E)-cinnamyl alcohol (3) (796 mg, 5.94 mmol) and i-PrOH (1.50 mL, 17.8 mmol) in CH₂Cl₂ (187 mL) was added EtMgBr (1.0 mol/L in THF, 17.8 mL, 17.8 mmol) at 0 °C. The resulting mixture was stirred for 30 min at 0 °C. At this time, hydroximoyl chloride 4c (1.50 g, 6.53 mmol) in CH₂Cl₂ (100 mL) was added to the reaction dropwise by using a dropping funnel over 20 min, followed by two rinses with CH₂Cl₂ (5 mL each). The reaction mixture was stirred for 12 h and gently warmed to r.t., then the reaction was quenched with sat. aq NH₄Cl solution. The organic layer was separated and the aqueous layer was extracted with CH₂Cl₂ (3 × 40 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica gel column flash chromatography (hexane–EtOAc, 1:1) to give cycloadducts 5c/5c' (1.81 g, 85%) as a yellow oil. d.r. = 75:25 [integration of signals at δ = 5.40 (major) and 5.28 (minor) ppm in the ¹H NMR spectrum]. Major Cycloadduct 5c: [α]_D ²⁷ –160.7 (c 1.00, CHCl₃). IR (film): 3428, 3060, 3028, 2945, 2889, 2825, 1604, 1494, 1455, 1151, 1094, 1035, 902, 753 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.36–7.27 (m, 8 H), 7.17 (d, J = 6.8 Hz, 2 H), 5.40 (s, 1 H), 4.58 (dd, J = 5.6, 3.6 Hz, 1 H), 4.32 (dd, J = 60.4, 6.8 Hz, 2 H), 4.19 (d, J = 6.0 Hz, 1 H), 3.73–3.68 (m, 1 H), 3.59–3.53 (m, 1 H), 3.11 (s, 3 H), 1.94 (t, J = 6.4 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 161.5, 138.4, 137.3, 129.0, 128.5, 128.3, 127.9, 127.8, 127.1, 93.8, 89.9, 72.2, 63.1, 55.7, 55.4, 53.4. HRMS (FAB): m/z [M + H]⁺ calcd for C₁₉H₂₂NO₄: 328.1549; found: 328.1533.
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• 15 Spectroscopic Data for 13: [α]_D ²⁷ –184.1 (c 0.50, CHCl₃); mp 122–124 °C. IR (film) 3362, 3088, 3056, 3030, 2923, 2243, 1670, 1492, 1454, 1401, 1259, 1042, 911, 760 cm^–1. ¹H NMR (400 MHz, DMSO-d₆): δ = 7.28–7.06 (m, 8 H), 6.71–6.69 (m, 2 H), 5.34 (d, J = 3.6 Hz, 1 H), 4.64 (dd, J = 2.8, 3.2 Hz, 1 H), 4.28 (dd, J = 3.2, 5.2 Hz, 1 H), 3.82 (dt, J = 8.4, 12.4 Hz, 1 H), 2.91 (s, 3 H), 2.08–1.96 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.4, 141.2, 137.7, 128.4, 127.7, 127.3, 127.0, 126.8, 126.3, 72.1, 67.8, 40.7, 33.1, 30.1. HRMS (FAB): m/z [M + H]⁺ calcd for C₁₈H₂₀NO₂: 282.1494; found: 282.1522.
• 16 Synthesis of (–)-cis-Clausenamide (2): A mixture of 9 (350 mg, 1.07 mmol) and zinc dust (1.05 g, 16.0 mmol) was heated at 90 °C in AcOH–H₂O (10:1, 18 mL) for 3 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc, neutralized with sat. aq NaHCO₃ solution and washed with brine. The organic layer was dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by silica gel column flash chromatography (CHCl₃–MeOH, 15:1) to give (–)-cis-clausenamide (2) (272 mg, 86%). [α]_D ²⁶ –6.78 (c 1.00, CHCl₃); mp 194–196 °C. IR (film): 3299, 3209, 3181, 2919, 2852, 1684, 1661, 1454, 1404, 1239, 1214, 1103, 1023, 953, 910 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.29–7.19 (m, 10 H), 4.81 (d, J = 4.8 Hz, 1 H), 4.53 (d, J = 6.8 Hz, 1 H), 4.17 (dd, J = 6.0, 0.8 Hz, 1 H), 3.84 (dd, J = 6.0 Hz, 0.8 Hz, 1 H), 3.30 (br. s, 1 H), 2.61 (s, 3 H), 2.23 (br. s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 175.8, 140.6, 134.2, 130.0, 128.6, 128.2, 127.8, 126.7, 71.9, 71.8, 65.8, 47.5, 29.6. HRMS (FAB): m/z [M + H]⁺ calcd for C₁₈H₂₀NO₃: 298.1443; found: 298.1473.