The Synthetic Methods Of Several Fluorinated Bioactive Compounds

Fluorinated compounds are of great importance in the realm of agricultural, pharmaceutical and material industry. During the past few years, the development of fluorinated compounds has drawn science researchers’ extensive attention, because the introduction of fluorine could significantly change the properties of the molecules. Although speedy development of the research on fluorinated compounds has been achieved in the last decade, there are still some challenging works need to be accomplished.Despite the attentions that have been focus on fluorinated drug, only dozens of compounds found in nature containing fluorine. Chemical synthesis is the main approach to fluorinated compounds since there are limited strategies to obtain these molecules by other kinds of methods, such as biosynthesis. Nowadays, methods for the introduction of single fluorine atom have achieved considerable progress, accompanied by a slightly less developed strategies for the incorporation of trifluoromethyl, nevertheless, studies on the preparation of difluoromethylated or monofluoromethylated compounds are quite insufficient. Compared with the synthesis of racemic analogues, enantioselective synthesis of fluorinated compounds will be more difficult.This dissertation comprises six chapters.In the first part, we highlighted the importance of fluorine in the area of medical chemistry. We use specific examples to illustrate the influence of fluorine on the activity, stability and other properties of drugs. We also summarized the strategies to introduce fluorinated groups into small molecules. The direct introduction of fluorinated groups by fluorinating agents and the employment of fluorinated substrates.The second part involved a highly enantioselective vinylogous Michael-type reaction of β,β-disubstituted nitroalkenes. A series of biologically important chiral oxindoles, featuring a trifluoromethylated all-carbon quaternary chiral center, were obtained in good yields with excellent enantioselectivities(up to >99% ee). The reaction which was preceded under mild conditions, catalyzed by quinine-derived bifunctional catalyst, was demonstrated to have a high level of site-selectivity. The anti-cancer activities of the products were also studied.The third part disclosed a dehydrosilylative difluoroamidation of α-Csp3–H of tetrahydroisoquinolines with α,α-difluoro-α-TMS-acetamides. The process, which occurs at ambient temperature in the absence of any transition metals, provides direct access to a broad range of α,α-difluoroacetamide-substituted tertiary amine derivatives in high yields. Moreover, the method was successfully applied in the Csp3–H-directed difluorophosphorylation and difluorocarboxylation under the same conditions.The fourth part reported the first example of decarboxylative difluoroacetamidation of α,β-unsaturated carboxylic acids by using difluoromethyl-substituted carbonyl compounds was disclosed. The procedure which mediated by low-cost and benign CuSO4, furnished a broad range of difluorinated alkenes in remarkable yields with only E configuration in most of the cases. Moreover, the product could be smoothly transformed to the corresponding difluorofunctionalized ester and alcohol in high yields.A class of o-(trimethylsilyl)aryl fluorosulfates was synthesized by a concise method and successfully used as aryne precursors in the fifth part. Different trapping agents such as azides, furans, and acyl acetoacetates could successfully react with the aryne precursors under mild conditions with good to excellent yields.At last, we make a summary of the thesis and put forward the general directions of the future.On the basis of the literature reports and our experimental results, we disclosed several methods for the synthesis of fluorinated compounds. Preparation methods for the compounds with trifluoromethylated all-carbon quaternary chiral center, dehydrosilylative difluoroamidation of α-Csp3–H of tetrahydroisoquinolines, as well as decarboxylative difluoroacetamidation of α,β-unsaturated carboxylic acids have been achieved here. We also developed a new type of aryne precursors, which with low fluorine containing, independence of external fluorine sources, and cheap starting materials, will pave the way to the industrial application of arynes.