Synthetic Study on Acremoxanthone A: Construction of Bicyclo [3.2.2]nonane CD Skeleton and Fusion of AB Rings

Abstract

Toward the total synthesis of acremoxanthone A, a model study has revealed a convergent approach to construct the ABCDE ring system. The key steps include: (1) an effective construction of the bicyclo[3.2.2]nonane skeleton, (2) protocol for generating the bridgehead anion and trapping, and (3) 1,3-dipolar cycloaddition of a nitrile oxide to the internal alkene.

Key words

natural products - anthraquinone - xanthone - bridgehead - bicyclic compounds - halogen–lithium exchange - cycloaddition

• References and Notes

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• 15 Experimental Procedure for the Palladium-Catalyzed Conjugate Addition A mixture of enone 8 (4.82 g, 14.3 mmol), Pd(OAc)₂ (641 mg, 2.86 mmol), Ph₃P (3.00 g, 11.4 mmol), and i-Pr₂NEt (29.9 mL, 171 mmol) in DMA (240 mL) was degassed by sonication under reduced pressure. After stirring for 3 h at 110 °C, the reaction was stopped by adding sat. aq NH₄Cl, and the mixture was extracted with Et₂O (4×). The combined organic extracts were washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, hexane–EtOAc = 9:1 to 8:1) to afford ketone 9 (2.51 g, 68%) and ketone 10 (608 mg, 17%) both as white solids. R_f = 0.43 (hexane–acetone = 4:1). mp 98–99 °C (Et₂O–hexane, colorless plate). ¹H NMR (600 MHz, CDCl₃): δ = 1.42 (s, 3 H), 1.52 (s, 3 H), 1.92–2.01 (m, 1 H), 2.66–2.73 (m, 1 H), 2.67 (br d, J = 19.2 Hz), 2.76 (dd, 1 H, J = 19.2, 6.0 Hz), 3.19 (d, 1 H, J = 17.4 Hz), 3.23–3.32 (m, 1 H), 3.51 (d, 1 H, J = 17.4 Hz), 4.38 (dd, 1 H, J = 8.7, 6.9 Hz), 7.10–7.19 (m, 3 H), 7.19–7.25 (m, 1 H). ¹³C NMR (150 Hz, CDCl₃): δ = 26.5, 27.5, 34.7, 38.3, 41.0, 44.3, 77.9, 84.5, 110.9, 126.8, 127.4, 129.6, 130.6, 132.4, 141.2, 210.0. IR (ATR): 2991, 2937, 1727, 1385, 1253, 1220, 1081, 987, 884, 756, 715 cm^–1. HRMS (APCI): m/z calcd for C₁₆H₁₈NaO₃ [M + Na]⁺: 281.1154; found: 281.1148.
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• 27 Experimental Procedure for the Nucleophilic Addition of Bridgehead Anion A flask was charged with t-BuLi (1.69 M in n-pentane, 479 μL, 810 μmol), to which a solution of iodide 2 (79.4 mg, 270 μmol, azeotropically dried with toluene) in THF (3.0 mL) was added at –78 °C. After stirring for 10 min at this temperature, a solution of aldehyde 23 (347 mg, 891 μmol, azeotropically dried with toluene) in THF (6.0 mL) was added. The reaction was allowed to warm gradually to 0 °C over 1.5 h. After stirring for 30 min at this temperature, the reaction was stopped by adding sat. aq NH₄Cl, and the mixture was extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried ­(Na₂SO₄), and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, hexane–toluene–acetone = 7:1:1) to afford alcohol 28 (121 mg, 80%) as colorless oil. R_f = 0.29 (hexane–EtOAc = 2:1). ¹H NMR (600 MHz, CDCl₃): δ = 2.33 (s, 3 H), 2.34 (br s, 1 H), 2.47 (s, 3 H), 2.55 (br d, 1 H, J = 17.1 Hz), 3.08 (br d, 1 H, J = 17.1 Hz), 3.75 (dd, 1 H, J = 6.6, 6.3 Hz), 3.78 (s, 3 H), 3.93 (br, 1 H), 4.13 (br, 1 H), 4.20 (br, 1 H), 4.62 (br, 1 H), 4.91–5.16 (m, 3 H), 5.40–5.53 (m, 1 H), 5.73 (d, 1 H, J = 8.0 Hz), 6.38 (dd, 1 H, J = 8.0, 6.3 Hz), 6.42 (d, 1 H, J = 8.1 Hz), 6.54 (dd, 1 H, J = 8.1, 6.6 Hz), 6.65 (s, 1 H), 6.90 (d, 1 H, J = 7.2 Hz), 6.93–7.04 (m, 2 H), 7.04–7.14 (m, 2 H), 7.40 (d, 2 H, J = 8.1 Hz), 7.87 (d, 2 H, J = 8.1 Hz). ¹³C NMR (150 MHz, CDCl₃): δ = 21.7, 22.0, 34.6, 43.7, 46.2, 46.9, 55.9, 73.3, 78.5, 111.3, 117.9, 119.6, 120.7, 125.2, 126.2, 127.1, 129.6, 129.7, 130.1, 130.6 (2 C), 132.4, 132.5, 133.70, 133.72, 136.7, 139.0, 139.5, 142.9, 144.9, 158.5. IR (neat): 3542, 2937, 1355, 1303, 1167, 913, 730, 539, 505 cm^–1. ESI-HRMS: m/z calcd for C₃₃H₃₆NO₅S [M + H]⁺: 558.2309; found: 558.2302.
• 28 Das B, Holla H, Mahender G, Banerjee J, Reddy MR. Tetrahedron Lett. 2004; 45: 7347
• 29 Experimental Procedure for 1,3-Dipolar Cycloaddition To a solution of hemiacetal (Z)-30′ (8.2 mg, 23 μmol) in MeCN (0.5 mL) were added NaHCO₃ (2.5 mg, 30 μmol) and PhI(OAc)₂ (9.6 mg, 30 μmol) at 0 °C. After stirring for 16 h at room temperature, the reaction was stopped by adding sat. aq NH₄Cl, and the mixture was extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by PTLC (hexane–EtOAc = 1:1) to afford isoxazoline 31 (6.6 mg, 80%) as a white solid. R_f = 0.43 (hexane–EtOAc = 1:1). ¹H NMR (600 MHz, CDCl₃): δ = 2.46 (s, 3 H), 3.06 (d, 1 H, J = 18.0 Hz), 3.74 (dd, 1 H, J = 6.6, 1.2 Hz), 3.78 (d, 1 H, J = 18.0 Hz), 3.98 (s, 3 H), 4.21 (d, 1 H, J = 10.5 Hz), 5.20 (dd, 1 H, J = 10.5, 1.2 Hz), 5.63 (d, 1 H, J = 9.0 Hz), 6.58 (dd, 1 H, J = 9.0, 6.6 Hz), 7.04 (s, 1 H), 7.10–7.15 (m, 2 H), 7.17 (d, 1 H, J = 7.6 Hz), 7.18–7.23 (m, 1 H), 7.61 (s, 1 H). ¹³C NMR (150 MHz, CDCl₃): δ = 22.0, 35.7, 45.6, 50.1, 56.3, 56.8, 82.0, 116.5, 117.4, 121.1, 126.4, 126.5, 127.5, 128.9, 131.98, 132.00, 135.3, 135.7, 136.5, 142.0, 150.2, 156.9, 197.4. IR (neat): 2924, 2852, 1687, 1602, 1311, 1066, 900, 753, 733 cm^–1. ESI-HRMS: m/z calcd for C₂₃H₂₀NO₃ [M + H]⁺: 358.1443; found: 358.1442.