Investigation On Cinchona Alkaloids And Derivatives-catalyzed Asymmetric "Interrupted" Feist-Bénary Reaction

The furans are an important class of heterocyclic compounds. Their characteristic structure results in the important applications in pharmaceuticals, pesticides, herbicides, chemical intermediates etc. The Feist-Bénary reaction provides a convenient access to highly substituted furans. The reaction process involves the base-promoted condensation ofβ-dicarbonyl compounds withα-haloketones to produce hydroxydihydrofurans, followed by elimination to form furans. This reaction can stop at hydroxydihydrofuran stage as"Interrupted"Feist-Bénary (IFB) reaction by controlling the experimental conditions and give the chiral hydroxydihydrofuran by using chiral base as catalyst. However, few reports on the synthesis of the chiral dihydrofurans have appeared. Calter and co-workers first reported the application of pyrimidinyl- cinchona alkaloid catalysts in IFB reactions to achieve chiral hydroxydihydrofuran. They coupled different substituted pyrimidinyls with cinchona alkaloids to afford a series of catalysts and found that diphenylpyrimidinyl derivatives gave optimal asymmetric induction. Interestingly, slight changes of the catalysts significantly affected the enantiomeric purity of products (14-98%ee). Here we applied many types of cinchona alkaloid derivatives and otherβ-aminoalchohol compounds in IFB reactions and investigated the effects of solvent, temperature and catalyst amount on the enantioselectivities in order to find the proper catalyst and optimize reaction condition.This thesis aims at the investigation of IFB reaction regulation and the development of economical, simple and highly effective organic catalysts. It mainly focuses on the following aspects:1. Seven 1,4-dichlorophthalazine-derivatized cinchona alkaloid catalysts were synthesized and applied in asymmetric IFB reaction. The conclusions were summarized as follows:(1) In the asymmetric IFB reaction of ethyl bromopyruvate with 1,3-cyclohexadione, All the catalysts caused the reaction to proceed in high yields within 10 min. (DHQD)2PHAL (1d) gave the highest enantioselectivity while free cinchona alkaloids gave low enantioselectivities. Compared with the corresponding double substituted catalyst 1a, the single quinine substituted catalyst 1g gave lower enantioselectivity.(2) The solvent was found to have an important effect on the enantioselectivity of the reaction. No expected product was obtained in CH3OH with 1a and 1b as catalyst. CH2Cl2 was a proper solvent for most of free cinchona alkaloids to achieve higher enantioselectivities, while THF was a better solvent for all the 1,4-dichlorophthalazine derivatives.(3) Temperature influenced the asymmetric induction to some extent. When the temperature was lowered from -78℃to -100℃, enantioselectivities could be improved approximately 4-7%.(4) The amount of catalyst was changed to investigate its influence on the yields and enantioselectivities. The results indicated that 5 mol% of catalyst was the optimal amount and 3 mol% amount caused a slight decrease in asymmetric induction. Furthermore, increasing the amount of catalyst to 10 mol% even 20 mol% was not effective in improving the enantioseletivities of the reaction while decreasing the catalyst amount to 1 mol% led to approximately a 15% decrease in enantioselectivities. The reported catalyst amount was 10mol%, however, we found that 5mol% catalyst was enough to achieve the optimal enantioseletivities.(5) Catalysts 1a-d were applied in the reactions of racemic, secondary -bromoketones and 1,3-cyclohexadione. The results indicated that differently substituted bromoketoesters obviously affected the enantioselectivities of products. Good enantioselectivites were achieved in the reaction of phenyl substituted bromoketoester (58-90%ee), while modest and low enantioselectivites were obtained with the methyl substituted derivative (33-55%ee) and the propyl substituted derivative (10-33%ee) respectively.(6) To explore the scope of the substrates, 1a-d were applied in the reactions of ethyl bromopyruvate with 1,3-Cyclopentanedione. The corresponding products were obtained in good yield (73-78%). The enantiomeric purity of products were higher than the values of 1,3-Cyclopentanedione products.(7) Catalysts 1a-d were applied in the reactions with alicyclicβ–dicarbonyl compounds as the substrates, excellent catalytic activity but little asymmetric induction was observed. 2. Six 3,6-dichloropyridazine-derivatized cinchona alkaloid catalysts were synthesized and applied in IFB reaction. The conclusions were summarized as follows:(1) In the asymmetric IFB reaction of ethyl bromopyruvate with 1,3-cyclohexadione, (DHQD)2PYDZ 2d gave the highest enantioselectivity (89%ee) while (DHQ)2PYDZ 2c gave the lowest enantioselectivity(53%ee). Compared with corresponding double substituted catalyst 2a and 2b, the single substituted catalyst 2e and 2f gave lower enantioselectivities.(2) Instead of 1,3-cyclohexadione, When1,3-Cyclopentanedione was used as substrate, the reaction proceeded in good yields within 10 min and (DHQD)2PYDZ 2d gave the highest enantioselectivity (80%ee). The ee values of products were a little lower than the values of 1,3- cyclohexadione products.(3) In the presence of catalyst 2d, the asymmetric IFB reactions of ethyl bromopyruvate with 1,3-cyclohexadione were performed in seven different solvent. The results showed that solvent has important effect on yield and enantioselectivity. Acetone was found to be the better solvent to give 81% ee while THF be the best solvent for stereoselectivity (89%ee). Catalyst showed moderate asymmetric induction in acetoacetate or acetonitrile (61%ee and 51%ee, respectively) and poor asymmetric induction in chloroform or dioxane (33%ee and 21%ee, respectively). When choosing DMF as solvent, no expected product was obtained.(4) In the asymmetric IFB reaction ofβ-phenyl substituted bromoketones with 1,3-cyclohexadione, (DHQ)2PYDZ 2c gave the highest enantioselectivity (93%ee) while (QD)2PYDZ 2b gave the lowest enantioselectivity(70%ee). Howerer, (DHQD)2PYDZ 2d showed the best asymmetric induction in the reaction of methyl or propyl substituted bromoketones.3. C9-OH of cinchona alkaloid was substituted with trimethylsilyl chloride to synthesize four cinchona alkaloid-9O-TMS derivatives 3a-d. Compared with free cinchona alkaloids, the catalysts 3a-d showed the better asymmetric induction.4. Benzoyl chloride, phthaloyl dichloride, isophthaloyl dichloride and terephthaloyl dichloride were reacted with cinchona alkaloids to form 16 esters type catalysts 4a-d, 5a-d, 6a-d and 7a-d. Their catalytic activities and enantioselectivities in asymmetric IFB reactions were summarized as follows:(1) The esters type catalysts were used in the reaction of ethyl bromopyruvate with 1,3-cyclohexadione, low to moderate enantioselectivities (22-75%ee) were observed.(2) In the asymmetric IFB reaction ofβ-phenyl substituted bromoketones, both single and double substituted esters catalysts showed good asymmetric induction (80-92%ee) and no obvious difference. Among these catalysts, terephthalate- cinchona alkaloid derivatives 7a-d gave the highest enantioselectivities (90-91%ee). So the ester type cinchona alkaloid derivatives should be the preferable catalysts for the IFB reaction withβ-phenyl substituted bromoketones as substrate.(3) In the reaction ofβ-methyl or propyl substituted bromoketones with 1,3-cyclohexadione, phthalate-cinchona alkaloid derivatives 5a-d gave the highest enantioselectivities (55-75%ee).5. Application of otherβ-animoachohol compounds 19-31 in asymmetric IFB reaction. Only two compounds showed a little asymmetric induction ( 14-19%ee) . 6. We designed and synthesized a new type of chiral phosphine ligand 32 with rigidity skeleton. Its Rh complexation was applied to asymmetric hydrogenation reaction of N-acetamidocinnamic acid. But low enantioselectivity (15%ee) was observed.