The Highly Enantioselective Cross-aldol Reaction Between Ketones And Trifluoromethyl Ketones Catalyzed By Chiral Thiourea And ?-Turn Tetrapeptides

Due to special properties of fluorine atom,fluorine-containing organic compounds play an increasingly important role in medicine,agricultural chemistry and materials science,in which trifluoromethyl-containing compounds are greatly interesting and paramount.Since trifluoromethyl group has special properties such as strong electron-withdrawing capability,large steric hindrance,high lipophilicity and so on,the introduction of trifluoromethyl group into new drugs and agrochemical products is attracting more and more attentions.In this paper,trifluoromethyl ketones were used as the source of trifluoromethyl group to enantioselectively produce enantipure trifluoromethyl tertiary alcohols via cross-aldol reactions,and the asymmetric aldol reaction of aromatic ketones and aliphatic ketones as aldol donors to trifluoromethyl ketones as aldol acceptors were catalyzed by chiral tertiary amine-based thioureas and tetrapeptides,respectively.There are three chapters in this dissertation.In chapter one,the special properties of fluorine-containing organic compounds are introduced in detail,including mimic,block,steric and inductive effects.The application of fluorine-containing compounds in medicine is illustrated as well.Then,the research progress and status of various organic asymmetric catalytic reactions involving trifluoromethyl ketones are reviewed.In chapter two,the direct asymmetric Aldol reaction of o-hydroxyacetophenones to trifluoromethyl ketones catalyzed by a number of chiral tertiary-amine-based thioureas as organocatalysts is described for the first time.A series of trifluoromethyl tertiary alcohol compounds were afforded with high yield and enantioselectivity.The gram-scale reaction was successfully carried out,which donated potential practicality to this protocol.Finally,the products were similarly used to readily prepare two different compounds having pharmacological activity and synthetic utility in chiral drug synthesis,respectively.In addition,we determined the absolute configuration of the product by X-ray single crystal diffraction,and discussed the mechanism of the reaction.In chapter three,the asymmetric Aldol reaction of acetone to trifluoromethyl ketones was catalyzed by tetrapeptides with ?-turn structure,and moderate-to-good enantioselectivity were obtained.Compared to the catalytic results of natural papain,tetrapeptides synthesized by us obtained higher enantioselectivity of the reaction.In summary,two kinds of catalytic enantioselective aldol reactions of trifluoromethyl ketones for enantiopure trifluoromethyl tertiary alcohols are reported in ths dissertation.The first work demonstrated that N,N-diethyl-tertiary-amine-based thiourea was the optimal organocatalyst,highly catalyzing cross-aldol reaction of o-hydroxyacetophenones as aldol donors with trifluoromethylketones as aldol acceptors for the first time to our best knowledge.Gram-scale reaction was possible with no decrease in yield and enantioselectivity.Two medicinally interesting compounds were readily prepared from the aldol prodcuts in high yield and enantioselectivity,showing high potential in utility of this work.The second work reports in this dissertation that a number of synthetic tetrapeptides were able to catalyze enantioselective cross-aldol reaction of acetone and trifluoromethyl ketones for the first time.Compared to the results catalyzed by papain,the tetrapeptides used in this work obtained higher enantioselectivity,showing promising future of artificial enzymes in this transformation.