Recovery Strategy Of Cinchona Alkaloid-derived Primary Amine Chiral Organocatalysts In Asymmetric Catalytic Reactions

In recent years, chiral organocatalysts widely used as novel catalysts in various asymmetric catalysis grew rapidly. Based on the idea of green chemistry, we exploit the recycled technology and reuse of expensive organocatalysts to improve the catalytic efficiency of organocatalysts in this thesis.According to the structural characteristics of natural cinchona alkaloid, four exotic chiral organocatalysts,9-amino-(9-deoxy) cinchona alkaloids le/lf (8S,9R) and lg/lh (8R,9S) were conveniently synthesized for the first time through two con-versions of the configurations at 8 and 9-positions using cinchonidine/quinine (8S,9R), cinchonine/quinidine (8R,9S) as raw materials. This synthetic route possessed high yields and enriched the configurations of cinchona alkaloid-derived primary amine organocatalysts. Based on this, three strategies including the immobilization of organo-catalyst, water-soluble organocatalyst and homogeneous catalysis/two-phase separation were developed to achieve the recovery of cinchona alkaloid-derived primary amine organocatalysts.Using cinchonidine/cinchonine as raw materials, a series of cinchonidine/cincho-nine-attached phosphonic acids (2a-2f) with the different arm lengths were successful-ly synthesized through Mistunobu reaction, free radical addition reaction and hydro-lysis reaction. These organocatalyst-attached phosphonic acids could be successfully immobilized into the backbone of Fe3O4 magnetic nanoparticles to afford novel magn-etic (MNPs)-supported organocatalysts 4b1-4b3/4e1-4e3 by facile one-pot co-precipita-tion method using-PO3H2 as anchor point. Meanwhile, MNPs-supported organocata-lysts 3a-3f, prepared by the surface-modification method, were investigated in detail as comparative samples. The porous structure, composition, loaded organocatalyst and morphology of MNPs-supported organocatalysts 3b and 4bi-4b3 had been characteriz-ed by IR, TG, XRD, N2 adsorption and desorption isotherms,31P NMR, VSM and TEM. MNPs-supported organocatalysts 4b1-4b3 possessed the high and tunable loading capacities of organocatalyst (0.18-0.52 mmol/g),2-25 nm regular mesopores and 10.6-44.06 emu/g saturated magnetization. In the asymmetric direct aldol reaction of cyclohexanone with p-nitrobenzaldehyde, the optimal experimental conditions were screened out:20 ℃, cat:4b3(5.0 mol%),1.5 mL H2O, p-nitrobenzaldehyde (56.0 mg, 0.37 mmol), cyclohexanone (0.7 g,7.1 mmol), TfOH (9.0 mg,0.06 mmol). Furthermore, various o, m and p-substituted benzaldehydes with electron-withdrawing substituents including -NO2,-X and -CN afforded corresponding aldol adducts in good yields (86-100%) and excellent stereoselectivities(anti/syn= 82:18-98:2 and 93-98% ee ant’i). Moderate to good yields (36-97%) and stereoselectivities(anti/syn= 82:18-96:4 and 75-97% ee ant’i) for the aromatic benzaldehydes with strong electron-donating substituents (-CH3 and -OCH3)were also satisfactorily achieved. Moreover, these MNPs-supported organocatalysts could be quantitatively recovered from the reaction mixture using an external magnet, and reused six times with excellent catalytic performance (93% yield, anti/syn= 89/11 and 96% ee anti), which provides a feasible method for large-scale manufacture.A series of cinchonidine-derived phosphonic acids 2a-2f with good solubilities in water were prepared. At pH= 2, the distribution coefficient of catalyst 2b (D= 4.56) in water/cyclohexanone biphase was measured by fluorescence spectra, which implied that 99% of water-soluble organocatalyst 2b can be recycled by extraction three times. In the asymmetric direct aldol reaction of cyclohexanone with p-nitrobenzaldehyde, the optimal experimental conditions were obtained:20 ℃,2b (7.5 mol%),1.0 mL H2O, HClO4 (15.0 mol%),p-nitrobenzaldehyde (56.0 mg,0.37 mmol), cyclohexanone (0.7 g,7.1 mmol). Under the optimal conditions, an excellent catalytic performance had been achieved for the aromatic aldehydes including both electron-withdrawing and electron-donating substituents. The separation of these water-soluble organocayalyst could be easily realized by using a separatory funnel to perform a liquid-liquid extraction. The excellent catalytic performance without significant loss (98% yield, anti/syn= 82/18 and 95% ee anti) was retained after water-soluble organocatalyst 2b was reused five times.Based on the concept of one-phase catalysis and two-phase separation, a practical recyclable strategy for homogeneous cinchona alkaloid-derived primary amine organo-catalysts was provided by regulating the solubility in water/organic biphase by means of protonation and deprotonation of primary and tertiary amine groups. By means of mold enantioselective aldol, vinylogous Michael and double-Michael organocascade reactions, the third reusability of the organocatalysts (li, lk and lm) were investigated in detail, and it was found that all the organocatalysts were effective as the original catalytic performances including the yields and stereoselectivities. Furthermore, the recovered organocatalysts retained the similar excellent stereoselectivities as the fresh organocatalysts in the tenth reused times. However, the slightly decreased yields were resulted from the formation of inactive intermediates derived from organocatalysts. In addition, the catalyst li can be efficiently used in large-scale reaction and achieved the excellent catalytic performance (90% yield,97% ee anti, anti/syn= 94:6) after three cycles.In this thesis, using cinchona alkaloid-derived primary amine organocatalysts as examples, MNPs-supported organocatalyst, water-soluble organocatalyst and acid/base-regulated homogeneous organocatalyst were planned to provide recovery strategy for expensive organocatalysts. It is believed that the use of organocatalyst will be more reasonable with further intensive study in the near future, and the application of org-anocatalysts will not be limited in research but also in industry.