Negishi Cross-Coupling Reaction as a Route to Isocombretastatins

Abstract

A series of isocombretastatins A has been synthesized by a new method based on the Negishi cross-coupling reaction in 19–84% yields. Five of the synthesized compounds exhibit high cytotoxic activity in nanomolar concentrations (IC₅₀ = 1–100 nМ) towards Jurkat, K562, Colo357, and A549 cell lines.

Key words

isocombretastatins - antitubulin agents - turbo Grignard reagent - Negishi cross-coupling - cytotoxicity

• References and Notes

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• 20 Synthesis of 1-Iodo-1-(3′,4′,5′-trimethoxyphenyl)-ethylene (3) Ph₃P (7.86 g, 30 mmol) was added to a solution of CBr₄ (4.98 g, 15 mmol) in CH₂Cl₂ (60 mL) at 0 °C under argon atmosphere. The resulting solution was stirred at 0 °C for 25 min. 3,4,5-Trimethoxybenzaldehyde (1.96 g, 10 mmol) in CH₂Cl₂ (20 mL) was added dropwise. The solution was stirred at 0 °C for 1.5 h. The solvent was removed under reduced pressure, and the resulting oil was purified by column chromatography on silica gel (PE–EtOAc, 4:1) to give 1,1-dibromo-2-(3′,4′,5′-trimethoxyphenyl)ethylene (3.27 g, 9.3 mmol, 93%) as pale yellow crystals. 1,1-Dibromo-2-(3′,4′,5′-trimethoxyphenyl)ethylene (3 g, 8.52 mmol) was dissolved in THF (30 mL) and cooled to –78 °C. n-BuLi (12.9 mL, 32.38 mmol, 2.5 M in hexane) was added dropwise for 30 min. The solution was stirred at –78 °C for 2 h. Then sat. NH₄Cl (20 mL) was added, and the solution was warmed to r.t. The solution was extracted with EtOAc, the combined organic layers were washed with brine, dried over Na₂SO₄, then concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (PE–EtOAc, 3:1) to give 2 (1.63 g, 8.43 mmol, 99%) as a white solid. Ni(dppe)Cl₂ (24 mg, 0.046 mmol) was placed in a dry argon-flushed Schlenk flask equipped with a stir bar and sealed with a septum. THF (5 mL) was added through a syringe, followed by dropwise addition of DIBAL-H (4.18 mL, 1 M solution in toluene, 4.18 mmol) at r.t. (gas evolution occurs as DIBAL-H is added). The resulting solution was cooled to 0 °C and 3,4,5-trimethoxyphenyl-acetylene (445 mg, 2.32 mmol) in THF (4 mL) was added slowly. The resulting black solution was allowed to warm to r.t. and stirred for 2 h. A solution of I₂ in THF (5 mL, 1.768 g, 6.96 mmol) was added into the hydroalumination reaction mixture at –78 °C. The resulting dark brown solution was stirred for 1.5 h. Then a sat. solution of sodium potassium tartrate (10 mL) was added to the reaction mixture, followed by stirring for 10 min at r.t. The organic layer was separated, and the aqueous layer was extracted with MeOt-Bu, the combined organic layers were washed with brine, dried over Na₂SO₄, then concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (PE–EtOAc, 8:1) to give 3 (602 mg, 1.88 mmol, 81%) as light yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 6.72 (s, 2 H), 6.39 (d, J = 1.7 Hz, 1 H), 6.02 (d, J = 1.7 Hz, 1 H), 3.87 (s, 6 H), 3.84 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 152.56, 138.66, 137.49, 126.95, 107.24, 105.63, 60.96, 56.25.
• 21 Preparation of 5a-OMOM (Typical Procedure) A dry argon-flushed Schlenk flask, equipped with a magnetic stirrer and a septum, was charged with a solution of 1-iodo-1-(3′,4′,5′-trimethoxyphenyl)ethylene (3, 48 mg, 0.15 mmol) in dry THF (1.5 mL). The solution of i-PrMgCl·LiCl (0.17 mL of 0.97 M solution in THF, 0.165 mmol) was added slowly at –20 °C, and the reaction mixture was stirred at this temperature for 20 min to complete the I–Mg exchange. A 1 M solution of ZnCl₂ (0.15 mL of 1 M solution in THF, 0.15 mmol) was added dropwise for 1 min at –20 °C, and the reaction mixture was warmed to r.t. 3-(Methoxymethoxy)-4-methoxyphenyl iodide (44 mg, 0.15 mmol) was placed in a round-bottom flask under argon. Solution of Pd(OAc)₂ (1.35 mg, 0.006 mmol) and SPhos (3.7 mg, 0.009 mmol) in THF (1 mL) was added, followed by dropwise addition of prepared solution of organozinc reagent (0.15 mmol) over a period of 1 min at r.t. The reaction mixture was stirred at r.t. for 5 h, poured into sat. aq NH₄Cl solution and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (PE–EtOAc, 5:1) to give 5a-OMOM (44 mg, 0.122 mmol, 81%) as brown oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.18 (d, J = 2.0 Hz, 1 H), 6.98 (dd, J = 8.4, 2.0 Hz, 1 H), 6.86 (d, J = 8.4 Hz, 1 H), 6.56 (s, 2 H), 5.38 (s, 1 H), 5.34 (s, 1 H), 5.21 (s, 2 H), 3.90 (s, 3 H), 3.87 (s, 3 H), 3.81 (s, 6 H), 3.50 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 153.00, 152.92, 149.88, 149.45, 145.97, 137.30, 134.12, 122.85, 116.87, 112.96, 111.34, 105.74, 95.68, 61.02, 56.36, 56.22, 56.02.