New Method of Synthesis and Biological Evaluation of Some Combretastatin A-4 Analogues

Yulia B. Malysheva; Sebastien Combes; Alexey Yu. Fedorov; Paul Knochel; Andrei E. Gavryushin

doi:10.1055/s-0031-1290899

Synlett, Inhaltsverzeichnis

Synlett 2012; 23(8): 1205-1208
DOI: 10.1055/s-0031-1290899

letter

New Method of Synthesis and Biological Evaluation of Some Combretastatin A-4 Analogues

Yulia B. Malysheva

^aDepartment of Organic Chemistry, Lobachevsky State University of Nizhni Novgorod, 23 Gagarin avenue, 603950 Nizhni Novgorod, Russian Federation, Fax: +7(831)4658592 eMail: afnn@rambler.ru

,

Sebastien Combes

^bUMR-CNRS 6264, Université d’Aix-Marseille, Faculté des Sciences Saint-Jérôme, Case 521, 13397 Marseille Cedex 20, France, Fax: +33(4)9128829 eMail: sebastien.combes@univ-provence.fr

,

Alexey Yu. Fedorov

^aDepartment of Organic Chemistry, Lobachevsky State University of Nizhni Novgorod, 23 Gagarin avenue, 603950 Nizhni Novgorod, Russian Federation, Fax: +7(831)4658592 eMail: afnn@rambler.ru

,

Paul Knochel

^cDepartment Chemie, Ludwig Maximilians Universität München, Butenandtstr. 5-13, Haus F, 81377 München, Germany, Fax: +49(89)218077680 eMail: knoch@cup.uni-muenchen.de eMail: gavryushin@nanoscape.de

,

Andrei E. Gavryushin*

^cDepartment Chemie, Ludwig Maximilians Universität München, Butenandtstr. 5-13, Haus F, 81377 München, Germany, Fax: +49(89)218077680 eMail: knoch@cup.uni-muenchen.de eMail: gavryushin@nanoscape.de

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Abstract

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Abstract

A series of novel combretastatin A-4 analogues was synthesized in 36–64% yields by Negishi cross-coupling reaction under mild conditions. The prepared compounds exhibit good cytotoxicity against HBL100 epithelial cell lines (IC₅₀ = 0.022–10.31 µМ).

Key words

antitumor agents - cross-coupling - organometallic reagents - magnesium–zinc exchange - cytotoxicity

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Referenzen

References and Notes

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22 Preparation of (Z)-3,4,5-Trimethoxy-β-Iodostyrene (2)Into a flame-dried 2 L round-bottom flask equipped with a magnetic stirrer and a septum was placed iodomethylene-triphenylphosphonium iodide (62 g, 117 mmol).^19,23 The flask was then put under vacuum for 5 min and purged with nitrogen. Dry THF (350 mL) was added, and the yellow suspension was cooled to –20 °C. Then, NaHMDS in THF (62 mL of 1.9 M solution, 117 mmol) was added dropwise along the flask wall within 30 min. The mixture was stirred at –20 °C for 15 min, then cooled to –78 °C, and 3,4,5-trimethoxybenzaldehyde (17.6 g, 90 mmol) in THF (200 mL) was added at this temperature within 1 h with good stirring. The reaction was stirred in the cooling bath for 2 h more, and quenched while still cold with sat. aq NH₄Cl. Then Et₂O was added to the mixture, the layers were separated, and the aqueous layer was extracted with Et₂O. The combined organic layers were filtered to remove Ph₃PO, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (pentane–EtOAc, 4:1) to give 2 (20.5 g, 64 mmol, 71%, Z/E = 15:1) as a yellow oil. ¹H NMR (300 MHz, CDCl₃): δ = 7.20 (d, J = 8.6 Hz, 1 H), 6.91 (s, 2 H), 6.48 (d, J = 8.6 Hz, 1 H), 3.86 (s, 6 H), 3.85 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 152.8, 138.2, 138.1, 131.8, 105.8, 78.0, 60.8, 56.2. MS (EI): m/z (%) = 320 (100) [M]⁺, 306 (5), 303 (45), 276 (5), 150 (5). HRMS (EI): m/z calcd for C₁₁H₁₃IO₃: 319.9909; found: 319.9910 [M]⁺
23 Conway JC, Quayle P, Regan AC, Urch CJ. Tetrahedron 2005; 61: 11910
24 Typical Procedure for the Preparation of 4a-OTBSA dry nitrogen-flushed Schlenk flask, equipped with a magnetic stirrer and a septum, was charged with a solution of alkenyl iodide (320 mg, 1 mmol) in dry THF (3 mL). The solution of i-PrMgCl·LiCl (0.92 mL of 1.19 M in THF, 1.1 mmol) was added slowly at –40 °C, and the reaction mixture was stirred at this temperature for 15 min to complete the I–Mg exchange. A solution of ZnCl₂ (0.5 mL of 1 M in THF, 0.5 mmol) and NMP (0.1 mL) was added dropwise within 1 min, and the reaction was warmed to r.t. 4-Methoxy-3-(tert-butyldimethylsilyloxy)iodobenzene (400 mg, 1.1 mmol) and (A-^taPhos)₂PdCl₂ (14 mg, 0.02 mmol) were added. The reaction mixture was stirred at r.t. for 30 min, poured into sat. aq NH₄Cl solution, and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated to get brown oil. It was purified by flash chromatography on silica gel (pentane–EtOAc, 5:1) to give 4a-OTBS (267 mg, 0.62 mmol, 62%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃): δ = 6.85 (dd, J = 8.3, 2.1 Hz, 1 H), 6.79 (d, J = 2.1 Hz, 1 H), 6.73 (d, J = 8.3 Hz, 1 H), 6.50 (s, 2 H), 6.47 (d, J = 12.1 Hz, 1 H), 6.41 (d, J = 12.1 Hz, 1 H), 3.83 (s, 3 H), 3.77 (s, 3 H), 3.70 (s, 6 H), 0.93 (s, 9 H), 0.06 (s, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 153.1, 150.4, 144.7, 137.2, 133.2, 130.2, 129.8, 128.9, 123.0, 121.4, 111.8, 106.0, 61., 56.0, 55.6, 25.8, 18.5, –4.7. MS (EI): m/z (%) = 430 (40) [M]⁺, 373 (22), 359 (23), 358 (100), 343 (25). HRMS (EI): m/z calcd for C₂₄H₃₄O₅Si: 430.2176; found: 430.2180 [M]⁺

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