1、Study On The Design,Synthesis And Biological Activities Of Novel Sodium-glucose Co-transporter 2(SGLT2)Inhibitors 2、Study Of Cascade Reaction Catalyzed By Coinage Metal

This dissertation includes two parts:1) Study on the design, synthesis and biological activities of novel Sodium-glucose Co-transporter 2(SGLT2) Inhibitors.2) Study of cascade reaction catalyzed by coinage metal.1) Study on the Design, Synthesis and Biological Activities of Novel Sodium-glucose Co-transporter 2(SGLT2) Inhibitors Diabetes is a progressive metabolic disease characterized by hyperglycemia. It also brings many complications. Now diabetes has become a very serious problem about health, economy and society all over the world. Although there are many kinds of anti-diabetic drugs, they bring lots of side-effects. The blood glucose leves many patients are not controlled effectively. Therefore, we should develop a new drug to solve the problem. With the deeper understanding of diabetes, a new mechanism to restrict the blood pressure is brought up. SGLT2 can reabsorb more than 90% glucose in kidney. By using SGLT2 inhibitors, glucose will be secreted so that it lowers the level of blood sugar, which is a new target for synthesis of drugs. And thus SGLT2 inhibitors are becoming more and more attractive for chemists and pharmacologists. Therefore, we make the deeply study of Design, Synthesis and Biological Activities of novel Sodium-glucose Co-transporter 2(SGLT2) inhibitors.During the development of C-glycosides as our own SGLT2 inhibitors, a promising class of trans-cyclohexane-bearing C-glucosides were discovered, among which 1-deoxy-1-{4-methoxy-3-[(trans-4-n-propylcyclohexyl)methyl]phenyl}-β-D-glucose was found to be the most promising one that is even more potent than dapagliflozin in an in vivo assay. Further evaluation on this potent SGLT2 inhibitor needs a large quantity of sample, but the original synthetic route is not very reproducible and thus not very practical, which requires us to optimize the original synthetic route.After considerable effort, we herein would like to report an optimized synthetic route to 1-deoxy-1-{4-methoxy-3-[(trans-4-n-propylcyclohexyl)methyl]phenyl}-β-D-glucose, which has been proved to be notably practical and reproducible: In continuation of the earlier work, the 3-OH in glucose moiety of dapagliflozin was modified, and the compounds thus obtained were evaluated in in vitro assays, leading to the discovery of a highly potent SGLT2 inhibitor 3-oxodapagliflozin with much higher SGLT2/SGLT1 selectivity. Further evaluations in two in vivo animal models (?) in this study was also discussed in details: We make the modifications at the 6-OH position in the sugar ring of (1S)-1-deoxy-1-[4-methoxy-3-(trans-n-propyl-cyclohexyl)methylphenyl]-D-glucose, which is a potent SGLT2 inhibitor discovered earlier in our laboratories, resulted in the discovery of a much more potent SGLT2 inhibitor which was the 6-deoxy derivative of (1S)-1-deoxy-1-[4-methoxy-3-(trans-n-propyl-cyclohexyl)methylphenyl]-D-glucose1.4 We accomplished the resolution of 2-(5-bromo-2-chlorophenyl)-2-(4-ethoxyphenyl)acetic acid by crystallizations of its L- and D-menthyl esters from petroleum ether to afford the optically pure esters.The advantages of this method are, i) the starting materials and reagents are inexpensive, ii) the resolution step is scalable since crystallization was involved, and iii) this method is able to produce individual enantiomers with any purities needed by repeated crystallizations when necessary. The relevant absolute conFigureurations were determined unambiguously by single-crystal X-ray diffractions. This method might well be extended to the synthesis of other enantiomerically pure diarylethanes:2) Study of Cascade Reaction Catalyzed by Coinage MetalMulti-substituted heterocyclics are very important structural fragment of natural products and non-natural products with biological activity, and the synthetic route to the heterocyclic molecules attacts extensive attention. The effective economical and atomic method to develop the synthesis of heterocyclic molecules is a very interesting area. Among the most of synthetic strategy, the transition metals with π acid (Au, Ag, Cu) catalytic reaction is one of the most attcting organic synthesis methodology. This strategy can be used from the easily available starting materials and can be conducted under mild conditions to build complex molecules. So we make further study of Cascade reaction catalyzed by coinage metal to develop new synthetic methods and make deeply understanding of the reaction mechanism.We developed a highly efficient selective synthesis of spiro aminals by introducing a small TMS group. More important, the directing group disappeared in situ without further deprotection step. A very interesting kinetic-thermodynamic balance was observed in this reaction and a binuclear gold catalysis was proposed to explain the reaction mechanism. A detailed study of the mechanism such as isolation of gold intermediates is underway in our laboratory:We developed a new approach for the synthesis of gem-diiodoalkenes. Stereoselective synthesis of (E) or (Z)-iodoalkenes were also achieved with copper catalysis or gold catalysis. A possible Cu(Ⅰ)/Cu(Ⅲ) catalytic cycle was proposed. The obtained iodoalkenes were successfully used in the further palladium-catalyzed Suzuki, Heck, and Sonogoshira coupling reactions, allowing access to a wide variety of multi-subsituted alkenes, dienes, trienes and enynes:...