The Synthesis Of Novel Cinchona Alkaloids-derived Phosphite Ligands And Their Application In Asymmetric Catalytic Reaction

In recent years, phosphites have emerged as suitable ligands for many metal -catalyzed asymmetric processes. Due to their easy preparation from readily available alcohols, phosphites ligands are extremely attractive for catalysis. Simultaneously, the availability of many alcohols makes simple ligand-tuning possible, which allows the synthesis of many series of chiral ligands screened for high activity and selectivity. In addition, phosphites are less sensitive to oxidation than phosphines, which also makes their application more convenient.The Cinchona alkaloids quinine, quindine, cinchonidine and cinchonine are extracted from the bark of the cinchona tree and can be produced on a commercial scale. Because of their special structure, they can be employed as"privileged"ligands backbone. The hydroxyl group at C9 in Cinchona alkaloid structure could be readily modified to give phosphites. So in our work, a novel family of phosphites was designed and synthesized from Cinchona alkaloids and enantiopure diol. The application of these new phosphites to palladium-catalyzed asymmetric allylic alkylation (AAA) of 1,3-diphenyl-2-propenyl acetate was also investigated. Furthermore, their organocatalytic ability in asymmetric desymme -trization of meso-hydrobenzoin was also examined.Catalytic asymmetric epoxidation (AE) holds a prominent place in asymmetric catalysis due to the fundamental importance of epoxides in organic chemistry. The AE reaction ofα,β-enones activated by chiral amine salts, a kind of organocatalyst, makes the preparation of chiral epoxides more simple and convenient. So some chiral diamine as organocatalyst in AE reaction ofα,β-enones were tested in our experiments.The work focuses on the reaction catalyzed by transitional-metal-ligands complexes and organocatalysts. It covers the following 5 aspects:1. Ten novel phosphites were synthesized from cinchonine, cinchonodine, quinine, quinidine, dihydroquinine and dihydroquindine with the yields ranged from 56% to 75%. Their structures were also confirmed by 1H NMR, 13C NMR, 31P NMR and MS.2. With the target ten ligands in hand, attention was turned to investigate their potential utilities in AAA reaction of 1,3-diphenyl-2-propenyl acetate with the dimethyl malonate as nucleophile. The results can be summarized as follows:(1) The best results were obtained by L1-CN with the chemical yields up to 100% and the enantioselectivities up to 94%ee.(2) Cinchonine and quindine-derived ligands L1-CN, L1-QND exhibited better catalytic activity and stereoselectivity than their pseudo-enantiomers L1-CND, L1-QN did. The configuration of C8, C9 have effect on the catalytic ability.(3) Not the structure backbone of cinchona alkaloid in ligands but that of enantiopure 1,2-diphenyl-1,2-ethanediol was responsible for the configurations of products. (4) The solvent was found to influence the reaction activity greatly when L1-CN was used in AAA reaction. No expected product was obtained in DMF with only lesser one in toluene, THF and CH3CN. CH2Cl2 was proved to be the proper solvent for AAA reaction.(5) In AAA reaction catalyzed by L1-CN-Pd complex, the base additives only influenced the asymmetric induction to some extent. The addition of KOAc could improve the enantioselectivity of AAA reaction.3. The effect of nucleophiles and temperature on AAA reaction was also probed.The conclusions were drawn as follows:(1) The reaction, with acetylacetone rather than dimethyl malonate as nucleophile gave the corresponding products with high yields. Similar improvement was also found in the same reaction when 3-methyl-2,4 -pentanedione was employed as nucleophile.(2) The dependence of temperature in the AAA reaction was also found. Like most of asymmetric catalysis reactions, the substrates conversion decreased and the enantioselectivity was improved when temperature was lowered. At -40℃, the best stereoselectivity was obtained.4. L1-CN ligand was also assessed in Rh and Ir-catalyzed asymmetric transfer hydrogenation and asymmetric hydrogenation. However, both failed.5. Phosphites L1-CN, L2, L3 and L4 were applied in organocatalytic aymmetric desymmerization of meso-hydrobenzoin. L4 gave the best result with 42% yield and 53%ee.6. Three kinds of cinchona alkaloids derivatives A6, A7, A8 were synthesized and applied in the amine-catalyzed AE reaction ofα,β-unsaturated enones. The catalytic activities and enantioselectivities of other amines A1~A5 in the reactions were also examined. The results were summarized as follows:(1) In the AE reactions of chalcone, A6 was found to give a better enantiomeric excess (74.8%ee) than other seven chiral amines.(2) The influence of oxidants on the reaction activity and enantioselectivity was observed. TBHP was proved to be the most suitable in amine-catalyzed AE reaction of chalcone. Simultaneously, reactions carried out in different solvents produced similar optical yields though only n-hexane can give the best chemical yield (75%).(3)β-CD-derived diamine A5 also showed a little asymmetric induction(33% yield, 24.8%ee). It's the first example thatβ-CD-derived diamine be employed as organocatalyst in AE reaction.(4) Several chalcone derivatives were converted to the corresponding optically active epoxides in the presence of A6. But the results showed that enones with para electron-donating substituents in theβ-phenyl group can produce better enantioselectivities.