Preparation method of natural product Tubulysin U
A technology of natural products and fragments, applied in the field of preparation of Tubulysin U, which can solve problems such as cumbersome purification steps and unfavorable industrial production
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Embodiment 1
[0013] Embodiment 1: the preparation of TubulysinU (1)
[0014] Synthesis of Compound 4
[0015] To a solution of compound 2 (0.57 g, 1.6 mmol) in methanol (10 mL) was added 3.5N hydrochloric acid solution (4.57 mL, 16 mmol), and the reaction was stirred at room temperature for 3 hours. After distilling off the solvent under reduced pressure, a pale yellow solid was obtained. The solid was dissolved in DMF (16 mL), and DIEA (1.39 mL, 8 mmol) and activated ester 3 (0.7 g, 2 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 40 hours. The solvent was distilled off under reduced pressure, and the crude product was separated and purified by silica gel chromatography (mobile phase: ethyl acetate:petroleum ether 1:1) to obtain compound 4 (white solid, 0.61 g, yield: 81%). M.p.: 169-170°C.[α] 25 D=+7.8(c=1.0inCH 2 Cl 2 ).IR3343, 3285, 1732, 1690, 1653, 1520, 1216, 1097cm -1 . 1 H NMR (CDCl 3 , 400MHz) δ0.89-0.96(m, 12H), 1.08-1.17(m, 1...
Embodiment 2
[0022] Embodiment 2: the preparation of Tuv fragment (2)
[0023] Synthesis of Compound 10
[0024] To a solution of compound 8 (2.58 g, 8.38 mmol) in tetrahydrofuran (80 mL) cooled to -78°C was added dropwise a solution of n-butyllithium tetrahydrofuran (2.5M, 0.37 mL, 9.3 mmol). After continuing to stir at this temperature for 1.5 hours, compound 9 (1.34 mL, 12.6 mmol) was added dropwise to the reaction mixture. After stirring at -78°C for 1 hour, the reaction was slowly warmed to 0°C over 2 hours. Add saturated sodium bicarbonate solution to terminate the reaction, then add diethyl ether to dilute, let stand, separate the organic phase, and then extract the aqueous phase with diethyl ether. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the solution was spin-dried, and the crude product was separated and purified by silica gel chromatography (mobile phase: ethyl acetate:petroleum ether 1:20) to obtain compound 10 (light yellow solid, ...
Embodiment 3
[0035] Embodiment 3: Preparation of Tup fragment (7)
[0036] Synthesis of compound 17
[0037] Ozone was bubbled into a solution of compound 16 (8.77g, 28.1mmol) in dichloromethane (300mL) at -78°C until the reaction solution turned blue, then argon was blown until the blue color disappeared, and triphenylphosphine (8.12g , 31mmol), slowly rose to room temperature, and stirred for 10 hours. The reaction solution was spin-dried, and the crude product was separated and purified by silica gel chromatography (mobile phase: ethyl acetate:petroleum ether 1:4) to obtain compound 17 (white solid, 7.36g, yield: 88%). M.p.: 122-124°C.[α] 25 D =-64.4 (c=1 in CHCl 3 ).IR2962, 2893, 1725, 1683, 1460, 1406, 1324, 1280, 1239, 1065cm -1 . 1 H NMR (CDCl 3 , 400MHz) δ0.98(s, 3H), 1.23(d, J=6.8Hz, 3H), 1.28(s, 3H), 1.32-1.44(m, 2H), 1.87-2.13(m, 5H), 2.62 (dd, J=18.1, 5.3, 1H), 2.98(dd, J=18.1, 8.5Hz, 1H), 3.43-3.55(m, 3H), 3.68-3.73(m, 1H), 3.89(dd, J= 7.5, 5.1Hz, 1H), 9.70(s, 1H). 1...
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