Organocatalyzed Asymmetric Michael Addition & Aldol Reactions And Synthesis Of PDK-1 Inhibitors

The whole thesis consists of two parts.1):design, synthesis and applications of novel organocatalysts in asymmetric Michael addition reactions and Aldol reactions. And 2):design, synthesis of the PDK-1 inhibitors.Catalyst is always the focus of organic synthesis, especially, when List found that L-proline could catalyze the Aldol condensation reaction, much attention has been paid to small organic molecule catalyst. At present, studies and applications of chiral cyclohexane diamines as small molecule have been regarded as one of the hottest fields in catalytic asymmetric reactions. Initial of this paper we first reported a new chiral primary amine catalyst that the parent nucleus is the cyclohexane diamine, and successfully used in the Michael addition of ketones to nitroolefins, first reported the asymmetric addition reaction product of 1-indanone to nitrostyrene (dr=3:1,87% ee). The reaction substrates possessed catholicity, and we obtained sixteen 4-aryl-5-nitro-2-ones derivatives with 33-94% yield and 57-96% ee. Secondly, we successfully found the asymmetric Michael reaction of maleimide with a-substituted aldehyde that catalyzed by primary amine-thiourea bifunctional catalyst on account of chiral cyclohexane diamine after screening of catalysts, solvents and other reaction conditions. Priorly, Cordova and coworkers had reported this reaction, but the result of the a-substituted aldehyde was very bad, we overcame the problem smoothly, and the reaction possessed the features:low catalyst loading, mild conditions, high yields and enantioselectivities. Not only the reaction substrates possessed catholicity, but also we got a batch of new structure chiral compounds. In the model reaction with the presence of 0.5 mol% catalyst, we got the desired product with 87% yield and 97% ee after 70 h. The configuration of the product was confirmed with X-ray diffraction by a single crystal. Thirdly was the Aldol reaction of isatins with aldehydes catalyzed by (S)-pyrrolidine tetrazole, prepared the chiral two contiguous quaternary centered 3-substituted-2-hydroxyindol-2-ones indole alkaloids after screening the reaction conditions. This structure constituted a core unit of a number of natural products and pharmaceuticals. In the experiment, we found that the enantioselectivity of the product can be increased to more than 97% ee after one recrystallisation with the solvent of acetic ether and petroleum.3-Phosphoinositide-dependent protein kinase-1 (PDK-1) is the upstream kinase of protein kinase B, which interacts with PtdIns (3,4,5) P3 and activates neighboring PKB. PDK-1 is also termed the master of AGC kinase. It activates many members of AGC kinase subfamily in addition to PKB. PDK-1 phosphorylates the conservative T-loop region of all these AGC members to gain their full activation, which subsequently adjust cellular metabolism, growth, proliferation, survival, anti-apoptosis and so on. But excessed activation can be lead to some diseases, so essential PDK-1 inhibitors become especially important. The thesis incorporated with computer-aided design, we designed seven PDK-1 inhibitors' synthetic routes and finally successfully synthetized the target compounds through Suzuki-coupling reaction and other reactions to build its aryl-aryl conjugation structures. With biological activity testing, we expect to obain high selectivity and high biological activity of PDK-1 inhibitors, in order to achieve the purpose of treatment of tumors.