Preparation method of optically pure 2,2-disubstituted-1,3-cyclopentanediol
A cyclopentanediol, double-substituted technology, applied in the field of synthesis of optically pure polychiral center compounds
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Embodiment 1
[0012] Example 1: Synthesis of 2,2-disubstituted-1,3-cyclopentanedione
[0013] 20mM 2-methyl-1,3-cyclopentanedione (or 2-ethyl-1,3-cyclopentanedione) was dissolved in 20mL NaOH solution (1M), stirred at room temperature for 30min until dissolved, then added 50mM bromine Benzyl (benzyl bromide benzene ring substituted derivatives, allyl bromide or propyne bromide), after continuous stirring at room temperature for 48h, post-treatment. Add 50 mL of dichloromethane for continuous extraction three times, the organic phase was washed twice with 30 mL HCl (1M), once with 30 mL saturated NaCl solution, and then the organic phase was washed with anhydrous NaSO 4 Dry for at least 3 hours or overnight, and rotary evaporate to obtain the crude product. The crude product was dissolved in a small amount of dichloromethane, and the diketone product was separated and purified by column chromatography.
Embodiment 2
[0014] Example 2: Synthesis of 2,2-disubstituted-1,3-cyclopentanediol
[0015] 100mL reaction, the substrate 2-methyl-2-benzyl-1,3-cyclopentanedione (25mM), glucose (75mM), NADP + (0.5g / L) was dissolved in a buffer solution with pH 7.0, and carbonyl reductase RasADH F12 (SEQ ID No.1) and glucose dehydrogenase were added to react at room temperature. After the conversion of the substrate was complete, the protein was removed after heating Finally, add carbonyl reductase Chkred12 (SEQ ID No.2) and glucose dehydrogenase, and continue the reaction at room temperature until the monocarbonyl reduction product is completely reduced to 2-methyl-2-benzyl-1,3-cyclo Pentylene glycol, extracted with ethyl acetate, dried over anhydrous sodium sulfate, separated and purified to obtain the product (1S,2r,3S)-2-methyl-2-benzyl-1,3-cyclopentanediol, optical purity 95%.
[0016] 1 H NMR (400MHz, CDCl 3 )7.21-7.39(m, 5H), 4.31(t, J=7.4Hz, 1H), 3.93(dd, J=5.8, 2.4Hz, 1H), 2.97(d, J=13.2Hz, ...
Embodiment 3
[0017] Example 3: Synthesis of 2,2-disubstituted-1,3-cyclopentanediol
[0018] 100mL reaction, the substrate 2-methyl-2-benzyl-1,3-cyclopentanedione (25mM), glucose (75mM), NADP + (0.5g / L) was dissolved in a buffer solution with pH 7.0, added carbonyl reductase RasADH F12 (SEQ ID No.1) and glucose dehydrogenase, reacted at room temperature, after the conversion of the substrate was complete, extracted with ethyl acetate Finally, after drying with anhydrous sodium sulfate, the hydroxyl group was protected by acetyl group after separation.
[0019] Add 25 mM of the acetylated protected substrate into 25 mL of methanol, and add 2.0 equivalents of sodium borohydride in batches. After the substrate is completely reacted, remove the solvent under reduced pressure, add saturated ammonium chloride solution, and extract with an equal volume of ethyl acetate. Dry over anhydrous sodium sulfate to obtain the product with an optical purity of 98%.
[0020] 1 H NMR (400MHz, CDCl 3 )7....
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