Annulations of 5-Phenylthiobutenolides and First Synthesis of (±)-Indanostatin

Abstract

The first synthesis of indanostatin was achieved in 6 steps. Key steps included a butenolide annulation, oxidation to an indanetrione, and reaction with acetone.

Key words

5-phenylthiobutenolides - indanostatin - Hauser–Kraus ­annulation - hydroquinones - indanedione

• References and Notes

• 1 Chen M, Shao C, Wang K, Xu Y, She Z, Wang C. Tetrahedron 2014; 70: 9132
• 2 Miyake Y, Ito C, Tokuda H, Osawa T, Itoigawa M. Biosci., Biotechnol., Biochem. 2010; 74: 1120
• 3 Kim K, Cui X, Lee D, Ko W, Sohn JH, Yim JH, An R, Kim Y, Oh H. Int. J. Mol. Sci. 2014; 15: 23749
• 4 Hayakawa Y, Kobayashi T, Izawa M. J. Antibiot. 2013; 66: 731
• 5 Hassan NP. S, Naysmith BJ, Sperry J, Brimble MA. Tetrahedron 2015; 71: 7137
• 6 Salles AG, Zarra S, Turner RM, Nitschke JR. J. Am. Chem. Soc. 2013; 135: 19143
• 7 Saito I, Kuo YH, Matsuura T. Tetrahedron Lett. 1986; 27: 2757
• 8 Fariña F, Parellada MD. J. Org. Chem. 1988; 53: 3330
• 9 Morris JC, McErlean CS. P. Org. Biomol. Chem. 2016; 14: 1236
• 10 Buckle DR, Morgan NJ, Ross JW, Smith H, Spicer BA. J. Med. Chem. 1973; 16: 1334
• 11 Campagna F, Carotti A, Casini G, Macripò M. Heterocycles 1990; 31: 97
• 12 3-Methyl-5-(phenylthio)furan-2(5H)-one (5)To a stirred solution of 5-hydroxy-3-methylfuran-2(5H)-one (1.14 g, 10 mmol) in toluene (100 mL) was added p-toluene­sulfonic acid (PTSA, 50 mg) followed by thiophenol (1.10 g, 10 mmol), and the mixture was heated at 80 °C for 15 h. Toluene was removed under reduced pressure. The crude residue was then diluted with EtOAc (50 mL) and washed by water and brine, dried over Na₂SO₄, and concentrated. Purification by column chromatography gives the product as solid 5 (1.80 g, 87%). ¹H NMR (400 MHz, CDCl₃): δ = 7.64–7.46 (m, 2 H), 7.40–7.28 (m, 3 H), 6.96 (p, J = 1.6, 1 H), 6.11 (p, J = 1.9, 1 H), 1.83 (t, J = 1.8, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.84, 144.96, 134.12, 132.15, 130.20, 129.27, 129.15, 85.86, 10.59. HRMS (ESI-QTOF): m/z calcd for [M + H]⁺: 207.0474; found: 207.0470.General Procedure for Hauser–Kraus Annulation of 5To a stirred solution of 5 (206 mg, 1.0 mmol, 1.0 equiv) in THF (3.0 mL) was added LiO^tBu (1.0 M in THF, 3.0 mL, 3.0 equiv) at –78 °C. And the mixture was stirred for 30 min at the same temperature. Then the unsaturated ester (1.5 equiv, 1.5 mmol) in THF (1.0 mL) was added dropwise to the mixture, and the mixture was stirred at –78 °C for 30 min. Then the mixture was warmed to room temperature and stirred overnight. HCl (aq, 2 N, 10 mL) was added to quench the reaction, and the aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over Na₂SO₄ and concentrated. Purification by column chromatography gives the product.Methyl 2,5-Dihydroxy-3-methylbenzoate (6a)White solid, 150 mg, yield 82%. ¹H NMR (400 MHz, CDCl₃): δ = 10.61 (s, 1 H), 7.10 (d, J = 3.2, 1 H), 6.89 (d, J = 3.2, 1 H), 5.54 (br, 1 H), 3.89 (s, 3 H), 2.21 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.80, 154.32, 147.08, 128.15, 125.17, 112.10, 111.42, 52.48, 15.91. HRMS (ESI-QTOF): m/z calcd for [M – H]^–: 181.0506; found: 181.0502.Methyl 2,5-Dihydroxy-3,6-dimethylbenzoate (6b)White solid, 151 mg, yield 77%. ¹H NMR (400 MHz, CDCl₃): δ = 10.78 (s, 1 H), 6.83 (s, 1 H), 3.96 (s, 1 H), 2.39 (s, 3 H), 2.19 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.41, 154.90, 145.75, 124.76, 123.91, 122.33, 112.68, 52.31, 15.98, 14.38. HRMS (ESI-QTOF): m/z calcd for [M – H]^–: 195.0663; found: 195.0662.Methyl 2,5-Dihydroxy-6-(methoxymethyl)-3-methylbenzoate (6c)White solid, 133 mg, yield 59%. ¹H NMR (400 MHz, CDCl₃): δ = 10.40 (s, 1 H), 8.10 (br, 1 H), 6.90 (s, 1 H), 4.98 (s, 2 H), 3.95 (s, 3 H), 3.44 (s, 3 H), 2.21 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.21, 153.90, 149.28, 127.88, 125.66, 118.16, 110.60, 72.36, 58.51, 52.51, 16.16. HRMS (ESI-QTOF): m/z calcd for [M – H]^–: 225.0768; found: 225.0771.Dimethyl 3,6-Dihydroxy-4-methylphthalate (6d)White solid, 136 mg, yield 57%. ¹H NMR (400 MHz, CDCl₃): δ = 8.95 (s, 1 H), 8.89 (s, 1 H), 6.89 (s, 1 H), 3.85 (s, 3 H), 3.84 (s, 3 H), 2.21 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 169.87, 169.45, 152.14, 150.87, 134.80, 124.02, 111.80, 109.74, 52.62, 52.53, 16.44. HRMS (ESI-QTOF): m/z calcd for [M – H]^–: 239.0561; found: 239.0559.4,7-Dihydroxy-5-methyl-1H-indene-1,3(2H)-dione (9)To a solution of 6d (240 mg, 1.0 mmol, 1.0 equiv) in methanol (5.0 mL) and water (5.0 mL) was added NaOH (400 mg, 10.0 equiv) in an ice bath. The mixture was stirred at room temperature for 1 h. After the completion of the reaction, methanol was removed in vacuo, and the residue was acidified by concd HCl in an ice bath. The mixture was extracted with EtOAc (2 × 10 mL), and the combined organic layers were dried over Na₂SO₄ and concentrated. The residue was dissolved in acetic anhydride (10 mL), the mixture was heated overnight at reflux, and then was cooled down. Acetic anhydride was removed by distillation under reduced pressure. The residue was dissolved in acetic anhydride (2.0 mL) containing Et₃N (1.0 mL), and the solution was treated with ethyl acetoacetate (156 mg, 1.2 mmol). After stirring overnight, HCl (aq, 6 N, 10 mL) was added to the dark solution at room temperature. The solution was heated to 75 °C for 1.0 h. Aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over Na₂SO₄and concentrated. Hexane was added to the residue and solid was precipitated out. Product was collected by filtration. Brown solid, 92 mg, yield 48%. ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.03 (s, 1 H), 9.17 (s, 1 H), 7.05 (s, 1 H), 3.23 (s, 2 H), 2.19 (s, 3 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 200.43, 195.76, 148.25, 146.48, 136.80, 127.19, 126.39, 124.63, 46.41, 16.15. HRMS (ESI-QTOF): m/z calcd for [M – H]^–: 191.0350; found: 191.0353.2,4,7-Trihydroxy-5-methyl-2-(2-oxopropyl)-1H-indene-1,3(2H)-dione (or Indanostatin)To a solution of 9 (92 mg, 0.48 mmol, 1.0 equiv) and ammonium acetate (3.7 mg, 0.048 mmol, 0.1 equiv) in diethyl ether (5.0 mL) was added N-bromosuccinimide (NBS, 170 mg, 0.96 mmol, 2.0 equiv). The mixture was stirred at room temperature for overnight. After the completion of the reaction, the solution was diluted with diethyl ether (10 mL) and was washed with HCl (1 N, 5 mL) followed by brine. The organic layer was dried over Na₂SO₄ and concentrated. The residue was dissolved in DMSO (1.0 mL) and heated at 80 °C for 2.0 h. After cooling down, 1.0 mL water was added to the solution, and the mixture was stirred at room temperature for 1.0 h. Water and DMSO were removed by distillation under reduced pressure. And the residue was diluted with EtOAc (20 mL) and washed with HCl (1 N, 10 mL) followed by brine. The organic layer was dried over Na₂SO₄ and concentrated. The residue was dissolved in acetic acid (1.0 mL), and a few drops of acetone were added to the mixture. The reaction was heated at 55 °C for 6 h. After cooling down, acetic acid was evaporated in vacuo, the residue was diluted with EtOAc (10 mL) and was washed with HCl (1 N, 5 mL) followed by brine. The organic layer was dried over Na₂SO₄ and concentrated. Purification by column chromatography gives the product. Yellow solid, 69.1 mg, yield 55% ¹H NMR (400 MHz, acetone-d ₆): δ = 8.64 (s, 2 H), 7.19 (d, J = 0.9, 1 H), 3.39 (d, J = 1.4, 2 H), 2.32 (d, J = 0.8, 3 H), 2.11 (s, 3 H). ¹³C NMR (100 MHz, acetone-d ₆): δ = 205.63, 201.18, 198.51, 149.11, 148.07, 137.65, 127.10, 122.73, 121.50, 73.62, 47.61, 28.49, 14.92. HRMS (ESI-QTOF): m/z calcd for [M – H]^–: 263.0561; found: 263.0561.