Design,Synthesis Of Chiral Oxazoline-containing Ligands And Their Applications In Asymmetric Reactions

Chiral small molecules can exert powerful effects on the functions of macromolecules that comprise living systems.This remarkable ability makes them useful,both as research tools for understanding life processes and as pharmacologic agents for promoting and restoring health.Therefore,the high efficiency and specificity of the synthesis of chiral compounds has become the focus of research in recent years.From the perspective of organic synthesis,new catalytic reactions and the design of new catalysts are always the core of organic synthesis.On the one hand,chemists aim to find the efficient catalyst,particularly the low-cost,environmentally friendly chiral catalyst in the asymmetric catalytic reaction in recent years.On the other hand,although various catalytic system currently composed of broad chiral ligands and additives for the synthesis of the chiral tertiary carbon center have been explored,the construction of chiral quaternary stereocentres remains a significant challenge.In this thesis,two series ion-tagged chiral oxazoline ligands were designed and synthesized.We aim to obtain high catalytic activity and high enantioselectivity,and good recovery and recycle of the catalyst in asymmetric reactions,to enrich diversity of chiral ligands at the same time.On the other hand,in organic chemistry,chiral drugs containing trifluoromethyl group have excellent properties,and the quaternary carbon center widely exists in many natural products and pharmaceutical molecules,so approaches to construction of quaternary carbon center and compounds with chiral trifluoromethyl group have become one of the most interesting and challenging topics for synthetic chemists,which has important significance for the synthesis of a variety of complex molecular structure.In view of this,we have successfully established catalytic systems using chiral ligands,to synthesize a series of chiral quaternary carbon center bearing trifluoromethyl group and another series of spiro pyrrolidine compounds,which provide more potentially active small molecules for drug development.?1?Synthesis of ion-tagged chiral oxazoline ligandsNovel ion-tagged bisoxazoline ligands,with an ion tagged onto the 4,4'-position of the box,have been designed and prepared through seven or eight step reactions for the first time.Compared to the previous studies,the imidazolium group here,in addition to facilitating catalyst recovery and reuse,is mainly involved in the catalytic process,directly affecting the enantioselectivity of asymmetric catalysis.In addition,through anion exchange method,we got chiral bisoxazoline ligands containing different anions.All the intermediates and the final ligands were confirmed by NMR and high resolution mass spectra.?2?Application of ion-tagged chiral oxazoline ligands in asymmetric Henry reactionThe new chiral ionic salt modified bisoxazoline ligands and metal complexes as catalysts showed excellent enantioselectivity in asymmetric Henry reaction.Through the screening of various reaction conditions,the optimal one was obtained:L2-Cu?OAc?₂complexes as catalyst?10mol%?,methanol as solvent,24h at 0^oC.The asymmetric Henry reaction was performed with different aromatic aldehydes with electron-withdrawing and electron-donating substituents under the optimized conditions.Among them,the substrate3,4-dimethoxybenzaldehyde can get the highest ee value of 94%.Moreover,the catalyst was successfully recycled six times,without an obvious loss in activity or enantioselectivity.The catalytic activity and enantioselectivity could maintained more than 90%,even after the sixth cycles.Calculations of the geometry of the complex Cu?OAc?₂-L1 and Cu?OAc?₂-L2 with the deprotonated nitromethane were performed with the B3LYP/6-31G?d?level of theory using the Gaussian03 software package.A theoretical mechanistic study was conducted to explain the origin of the enantioselectivity and how the size of anions affects the reaction.?3?Asymmetric construction of pyrrolidines bearing a trifluoromethylated quaternary stereogenic center for the first timeWe have developed the first catalytic asymmetric synthesis of pyrrolidines bearing a unique trifluoromethylated quaternary stereogenic center via the 1,3-dipolar cycloaddition of?-trifluoromethyl-?,?-disubstituted nitroalkenes as the dipolarophiles.This method provides a reliable strategy for construction of polysubstituted pyrrolidines with a trifluoromethylated quaternary stereocenter at the C-3 position.The easy availability of the substrates and the potential bioactivity of the enantioenriched trifluoromethylated pyrrolidine derivatives make this methodology particularly interesting in medicinal chemistry and organofluorine chemistry.Based on the results,the optimal reaction conditions for the asymmetric 1,3-dipolar cycloaddition were as follows:10 mol%Cu?CH₃CN?₄ClO₄/L1 as the catalyst,CH₂Cl₂ as the solvent,and 10 mol%DIPEA as the base at 0^oC.The reaction provides pyrrolidines with high diastereoselectivities?up to>98:2 d.r.?and excellent enantioselectivities?up to>99.9 ee?.Based on the configuration of the product,the enantioselectivity could be rationalized by using a proposed transition state.It can be illustrated that the positon of the substituents on the aromatic ring of azomethine ylides affect the result through the steric impact.This can reasonably explain that ortho-substituted azomethine ylides leads to higher enantioselectivities than para-and meta-ones.To further confirm the regiochemical control of this cycloaddition and determine the absolute configuration of the adduct,single-crystal X-ray diffraction study was performed,and its absolute configuration was determined to be exo-?2R,3R,4S,5R?and the results were consistent with the proposed one.?4?Catalytic synthesis of spiro pyrrolidines bearing one unique spiro quaternary centerWe successfully present the first catalytic synthesis of spiro pyrrolidines bearing one quaternary center and one unique spiro quaternary center by employing homoserine lactone derived cyclic imino esters as the dipoles and?,?,?-trisubstituted olefins as the dipolarophlies.The optimal reaction conditions for the 1,3-dipolar cycloaddition were as follows:10 mol%Cu?ClO₄?₂/L5 as the catalyst,anhydrous tetrahydrofuran as the solvent,and 10 mol%DIPEA as the base at room temperature for 12h.The reaction provides pyrrolidines with good yield and high diastereoselectivities?up to>98:2 d.r.?.To determine the relative configuration of the adduct,single-crystal X-ray diffraction study was performed.