Asymmetric Organocatalysis: Cinchona Alkaloids Derivatives-catalyzed Asymmetric "Interrupted" Feist-Bénary Reaction

Asymmetric organocatalysis is asymmetric organic synthesis catalyzed by organic molecules. Compared to bioorganic catalysis and organometallic catalysis, their preparative advantages are notable: usually the reaction can be performed under an aerobic atmosphere with solvent, stable than enzymes or other bioorganic catalysts. Also, these small organic molecules can be anchored to a solid support and reused more conveniently than organomentallic/bioorganic analogs, and show promising adaptability to high-throughout screening and process chemistry.The Feist-Bénary reaction is a convenient method to synthesis multi- substituted furanderivatives. This reaction generally involved the base-promoted condensation ofα- dicarbonyl compounds withβ-haloketones to produce furans. The reaction can be stopped at the hydroxydihydrofuran stage as the"interrupted"Feist-Bénary (IFB) reaction. Hydroxydihydrofuran derivatives are important intermediate for their existing many biologically active natural products and chiral medicine. In 2005, Calter et al reported organocatalytically asymmetric IFB reaction by commercially available diphenylpyrimidinyl derivative and obtained multisubstitued chiral 2,3-dihydrofuran derivatives, and the enantioselectivity was 17-96%.Our group started the asymmetric IFB research in 2006 and adopted a serials of cinchona alkaloids derivatives to the reaction of ethyl bromopyruvate with 1,3-cyclohexadione. We found the subtle change of the catalyst structure can influence the enantioselectivity dramatically. Furthermore, the catalytic results were controlled by many factors. So we want to search for more potent organocatalyst by changing the electronic effect and stereo effect.In this thesis, we designed, synthesized and characterized 31 cinchona alkaloids derivatives, including 2,6-pyridinedicarboxylic esters, sulfonic esters, triazole ethers, anthraquinone ethers, amines and thioureas. we further applied them to the IFB reaction of 1,2-diones and ethyl bromopyruvate. Excellent chemical yield were obtained in almost all reactions.1. Ester derivatives of cinchona alkaloids(1) Six new compounds A1-A6 were prepared by the 2,6- dipyridicaboxylic acid as the starting materials with high yields, mild condition and less side-reaction;(2) The ester compounds A1-A8 were applied to IFB reaction of 1,3-cyclohexadione, 1,3-cyclopentanedione and acyclic dione, the ee value increased gradually. One hand, the highest enantioselectivity were obtained in the reaction ofβ-phenyl ethyl bromopyruvate by dihydrquinine derivative A3 and the ee value was 94%. On the other hand, when the substrate wasβ-propyl ethyl bromopyruvate, the highest diastereoselectivity were obtained (more than 95:5); (3) When the catalyst amounts were improved from 5%mol to 10%mol, the enantioselectivity were increased by 3-5%, and the change had no influence on the chemical yields and diastereoselectivities;(4) The asymmetric inductions of sulfonic esters A7-A8 were inferior to that of the pyridinedicarboxylic esters A1-A6.2. Ether derivatives of cinchona alkaloids(1) Ether derivatives of cinchona alkaloids B1-B8 were synthesized and purified;(2) The enantioselectivities of ethers B1-B8 were dissatisfying and there were no notably difference between triazole ethers B1-B6 anthraquinone ethers B7-B8. The ee values were about 60-70% of all the three substrate: no-substituted,β-phenyl andβ-propyl ethyl bromopyruvate;(3) The derivatives of QN, QD, DHQ and DHQD had better asymmetric induction than those of CN, CND, Which demonstrated that the–OCH3 substitution in the catalyst structure have spatial fixation effect and it is beneficial to stereoselectivity;(4) The eight organocatalyst had excellent diastereoselectivities to the substrate ofβ-propyl ethyl bromopyruvate. And moderate diastereoselectivities to theβ-phenyl substrate, which were similar to the previous ester catalysts.3. Amino derivatives of cinchona alkaloids(1) Ether derivatives of cinchona alkaloids C1-C9 were synthesized and purified;(2) The enantioselectivities of cinchona alkaloids amino derivatives C1-C9 were inferior to those of ethers and esters in the asymmetric IFB reaction. The ee values were mostly about 30%; (3) When the primary amines were converted to secondry amines, there were no improvement in stereoselectivities, which showed the substitute of–NH2 have little influence on the formation of intermediate and the attack of nucleophilic reagent;(4) The absolute configuration of 9-NH2 is (R) or (S) did not influent the diastereoselectivity and stereoselectivity and it was not the key factor of asymmetric induction.4. Thioureas derivatives of cinchona alkaloids(1) Thiourea derivatives of cinchona alkaloids D1-D6 were synthesized and purified;(2) The asymmetric results of thioureas D1-D6 in the IFB reactions were very disappointing. And the thiourea of 9-natural configuration had lower stereoeffect than that of 9-epi configuration;(3) Whether there are–OCH3 substitute on quinoline ring have no effect on the catalytic results, which was different from the ester derivatives;(4) Similar to the ester A1-A8 and the ether B1-B8, the thioureas D1-D6 have excellent diastereoselectivities towards the substrate ofβ-propyl ethyl bromopyruvate and no distinctly stereoselective difference between theβ-propyl andβ-pheyl substrate.Furthermore, we purposed the mechanism of asymmetric IFB reaction by the previous catalyst structure and catalytic results.