A New Process for the Total Synthesis of Sparstolonin B

Abstract

A novel and simple route was developed that gives sparstolonin B in high yields from affordable commercial compounds. A Diels–Alder strategy was used for the facile construction of the multisubstituted diphenyl ether. The xanthenone segment was obtained by cyclization in an intramolecular Friedel–Crafts reaction, followed by selective reduction of a ketone group and a transformation from a hydroxy group into a cyano group. The final part of the lactone was directly derived by the reduction of the cyano group with Raney nickel.

Key words

sparstolonin B - xanthenone - lactone - total synthesis - medicinal chemistry

• References and Notes

• 1 New address: L. Tong, School of Pharmaceutical Science, Peking University, 38 Xue Yuan Rd., Haidian Dist. Beijing, 100191, P. R. of China.
• 2 New address: M.-Y. Yao, School of Life Sciences, Fudan University, 2005 Songhu Rd, Yangpu District, Shanghai, 200438, P. R. of China.
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• 16 4,10-Dimethoxy-3H-pyrano[3,4,5-kl]xanthen-3-one (10) A mixture of nitrile 2 (8.8 g, 0.027 mol), pyridine (3.2 g, 0.04 mol), NaH₂PO₂ (4.75 g, 0.054 mol), AcOH (66 mL), H₂O (54 mL), and Raney nickel catalyst (1 g) was stirred for 5 h at 0 °C under argon. The mixture was then diluted with EtOAc (100 mL) and H₂O (100 mL), then filtered. The filtrate was extracted with EtOAc (2 × 100 mL), and the organic phase was washed with H₂O (80 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The crude residue was purified by flash chromatography [silica gel, PE–EtOAc (5:1)] to give a pale-yellow solid; yield: 6.4 g (80 %); mp 201–203 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.49 (s, 1 H), 7.33 (d, J = 9.0 Hz, 1 H), 7.02 (dd, J = 9.0, 2.8 Hz, 2 H), 6.88 (d, J = 10.3 Hz, 2 H), 4.01 (s, 3 H), 3.85 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 157.80, 156.26, 155.75, 144.02, 142.10, 134.57, 122.84, 121.64, 118.24, 116.51, 114.98, 112.33, 108.63, 108.42, 104.97, 56.61, 55.75. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₁₂NaO₅: 319.0582; found: 319.0571. Sparstolonin B (SsnB) A 1.0 M soln of BBr₃ in CH₂Cl₂ (85 mL, 0.085 mol) was added dropwise to a solution of xanthenone 10 (5.2 g, 0.017mol) in CH₂Cl₂ (180 mL) at –5 to 0 °C under argon, and the mixture was stirred for 1 h at r.t. The reaction was then quenched with ice–water (150 mL) and the mixture was extracted with CH₂Cl₂ (2 × 150 mL). The organic phase was washed with H₂O (80 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The crude residue was purified by flash chromatography [silica gel, PE–EtOAc (5:1)] to give a yellow solid; yield: 4.2 g (92%). ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.37 (s, 1 H), 9.54 (s, 1 H), 7.99 (s, 1 H), 7.49 (d, J = 9.0 Hz, 1 H), 7.11 (d, J = 2.8 Hz, 1 H), 7.08 (d, J = 9.0 Hz, 1 H), 7.03 (d, J = 8.9 Hz, 1 H), 6.83 (dd, J = 8.9, 2.8 Hz, 1 H). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 164.30, 155.35, 154.14, 143.13, 140.89, 135.27, 123.86, 120.14, 118.55, 118.49, 117.53, 114.94, 109.86, 108.00, 105.02. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₈NaO₅: 291.0269; found: 291.0261.