Studies On Enantioselective ?-functionalization Of ?-carbonyl Compounds

Asymmetric reaction catalyzed by transition metal and chiral ligand complexes is one of the most important strategies for the asymmetric synthesis due to their high efficiency and excellent enantioselectivity.On the other hand,the ?-ketoester scaffolds have proven to be versatile synthetic substrates in the construction of new products which can be rapidly converted into a variety of natural products and bioactive compounds.Various functionalizations of this type scaffold have been finely developed,however,the reports on the ?-ketoesters which bearing less steric hindrance are relatively scarce due to the difficulty of stereo-control.Based on the literature survey,we synthesized a series of chiral bis(oxazoline)ligands and applied them in asymmetric ?-functionalizations of ?-carbonyl compounds.This dissertation includes seven chapters as follows:In chapter 1,the features of the ?-ketoesters and their application in drug synthesis were briefly summarized.In this context,the recent development of enantioselective ?-functionalization of ?-ketoesters to establish various bonds including carbon-carbon,carbon-nitrogen,carbon-oxygen,carbon-halogen and carbon-sulfur bond linkages was extensively reviewed,which is very relevant to my Ph.D.study.In chapter 2,advantages and advances in the synthesis of bis(oxazoline)ligands were briefly summarized and a series of chiral bis(oxazoline)ligands with diphenylamine scafford were synthesized.In chapter 3,a highly enantioselective conjugate addition of 2-substituted benzofuran-3(2H)-ones with ?,?-unsaturated ketones promoted by diphenylaminelinked bis(azoline)-Cu(OTf)2 has been developed,affording the Michael addition products with quaternary stereocenters in good to high yields(up to 95% yield)with excellent enantioselectivties(up to 99% ee),which features in:(1)excellent enantioselectivty;(2)broad substrate scope,especially for the substrates with less steric hindrance.The chiral Michael adducts could be readily converted to the polycyclic benzofuran-type framework via Robinson annulation.In chapter 4,a fast and highly enantioselective fluorination of ?-keto esters catalyzed by diphenylaminelinked bis(azoline)-Cu(OTf)2 complexes under solvent-free conditions has been developed using a planetary ball mill.High yields(up to 99% yield),high enantioselectivities(up to 99% ee)and shorter reaction times(4 min)were achieved with low catalyst loading.Compared with the tranditional strategies,the developed catalysis system has its advantages:(1)environmental benign,avoiding using toxic solvent;(2)broad substrate scope,the indanone carboxylate,benzofuran-3(2H)-ones and benzothiophen-3(2H)-ones,aliphatic cyclic and acyclic ?-ketoester derivativies were all well tolerated.In chapter 5,a highly enantioselective chlorinative dearomatization of ?-keto esters catalyzed by diphenylamine-linked bis(azoline)-Cu(OTf)2 complexes was developed.By using DCDMH as the chlorinating agents,the corresponding products were obtained in high yields(up to 99% yield)and high enantioselectivities(up to 90% ee)with low catalyst loading.Compared with the traditional strategies,the developed catalystic system has its advantages:(1)high catalystic efficiency;(2)simple operation.In chapter 6,a catalytic asymmetric amination with a bis(azoline)-Cu(OTf)2 complexes is described.A catalyst comprising Cu(OTf)2 and(S)-Ph-BOX was identified to promote the catalytic asymmetric amination of the nonprotected succinimide derivative with 10 mol% catalyst loading,providing a new synthetical strategy for the new aldose reductase inhibitor,AS-3201.In chapter 7,all the experiments sections as well as the characterization of the products were displayed.