Study On Catalytic Asymmetric Transfer Hydrogenation And Allylic Vinylogous Michael Addition Reactions

This dissertation includes four parts: the first part of the article is a review for asymmetric transfer hydrogenation of prochiral ketones catalyzed by chiral ligand-transition metal complexes. The second part reports the asymmetric transfer hydrogenation of prochiral ketones catalyzed by hydrophobic dendritic (R,R)-1,2-diaminocyclohexane-transition metal complexes in water. In the third part, the direct asymmetric vinylogous Michael addition ofα,α-dicyanoolefins to nitroolefins catalyzed by bifunctional tertiary amine-thiourea organocatalysts is described. The fourth part is related to an improved synthetic route of antiparkinsonian drug—Rasagiline.Optically active second alcohols are important building blocks in organic synthesis and pharmaceutical chemistry. Since asymmetric transfer hydrogenation combines the advantages of simple operation, mild reaction condition, using nonhazardous reagents and high enantioselectivity, it has attracted increasing attention as a powerful complement to enantioselective hydrogenation of corresponding ketones. In the first part of the dissertation, the asymmetric transfer hydrogenation of ketones catalyzed by transition metal complexes—focused on the mechanism, the types of chiral ligands and its recent advances, has been reviewed.In the second part, Frechet-developed polyether dendrimers with peripheral benzyl groups were used as the wedges of monosulfonylated (R,R)-DACH. The synthesized core-functionalized hydrophobic dendritic catalysts coule be finely dissolved in the liquid substrates, therefore, the asymmetric transfer hydrogenation in the aqueous mixture still processed in a homogeneous way. Using acetophenone as the model substrate, compared to DCM-HCOOH/NEt₃ system, the dendritic catalysts exhibited much better catalytic activity in the aqueous media employing HCOONa as the hydrogen source, and better results were obtained using [RhCp^*Cl₂]₂ rather than [RuCl₂(η⁶-p-cymene)]₂ as the metal precursor. Moreover, the catalytic loading could be further decreased to 0.01mol% in H₂O-HCOONa system, and the excellent enantioselectivity was maintained (95% e.e.). This protocol was also feasible for a range of aromatic, heteroaromatic and functionalised ketones, exhibiting speciality for the carbonyl group of ketone and furnishing moderate to excellent conversions (69-＞99% conv. or yield) and enantioselectivities (52-97% e.e.). The catalyst could be easily precipitated from the mixture by adding hexane and reused several times without affecting the high catalytic efficiency.The third part is the study on direct asymmetric vinylogous Michael addition ofα,α-dicyanoolefins to nitroolefins catalyzed by bifunctional tertiary amine-thiourea organocatalysts. Owing to the strong electron-withdrawing power of double cyano groups, theγ-allylic protons of a,a-dicyanoolefins behave strong acidity, thus could be activated as nucleophiles by chiral tertiary amine moiety; moreover, the N-H groups of thiourea moiety could activate electrophiles possessing nitro group by the formation of double hydrogen-bondings. This synergistic activation mechanism of tertiary amine-thiourea organocatalysts has been demonstrated in our asymmetric Michael addition of a,a-dicyanoolefins to nitroolefins. Different catalysts, solvents, temperature and substrates were scanned. All of the catalysts displayed excellent regio-and diastereocontrol (anti/syn＞99%,＞99% d.e.). Under the optimal reaction conditions, moderate to excellent enantioselectivities (57-95% e.e.) have been achieved with low to good isolated yields. Moreover, for someα,α-dicyanoolefinic substrates, the enantioselectivities were much better than that catalyzed by modified cinchona alkaloids. However, moderate enantioselectivities with low yields were obtained using aliphaticα,α-dicyanoolefins or alkyl-substituted nitroolefin as the substrates, and further studies are underway to improve these reactions. The fourth part is about an improved synthetic route of the antiparkinsonian drug—Rasagiline, which is a selective irreversible MAO-B inhibitor, and behaves potent therapeutic effect on Parkinson's disease. Rasagiline was prepared from racemic 1-aminoindan by four unit reactions: N-Nitrobenzenesulfonylation, N-propargylation, deprotecting of Nos group and resolution, giving the total yield about 30%. This new route is likely to provide a promising approach for industrialization.