Catalytic Asymmetric Construction Of ?-Ethynyl-containing Heteroatom-substituted Tetrasubstituted Stereocenters

This thesis aims to develop catalytic enantioselective methods to construct?-ethynyl-containing heteroatom-substituted tetrasubstituted stereocenters.It includes two parts of research work,the kinetic resolution of?-ethynyl substituted tertiary alcohols via copper-catalyzed azide-alkyne cycloaddition,and the electrophilic alkynylation of monofluorinated enol silyl ethers.The detailed results are listed below:In the first part,a type of novel chiral Pybox ligands bearing a bulky phosphite group at the C4 position of pyridine moiety is developed,and successfully applied to the kinetic resolution of racemic acetal-substituted terminal tertiary propargyl alcohols via CuAAC reaction.This methodology allowed the isolation of various chiral?-1,2,3-triazole substituted tertiary alcohols in 73->99%yield with 82-92%ee.Meanwhile,the unreacted?-ethynyl substituted tertiary alcohols could be recovered in 39-50%yields with enantioselectivities up to 99%ee.The recovered?-ethynyl substituted tertiary alcohols featuring an alkynyl group and a masked aldehyde group,could undergo a variety of diversifying reactions to afford structurally diverse valued-added tertiary alcohols.This catalyst system is also successfully extended to kinetic resolution of?-fluoroalkyl substituted ethynyl tertiary alcohols via CuAAC reaction,providing a facile access to 3,4-dihydronaphthalen-1?2H?-one-based chiral tertiary alcohols bearing?-monofluoro-and difluoroalkyl groups,with s factor up to211.The kinetic resolution of?-ethynyl substituted?-tetrasubstituted amino acid derivatives via CuAAC reaction is also tried,with up to 61%ee and 48%ee being obtained for the recovered substrate and?-1,2,3-triazole product,respectively.In the second part,the asymmetric electrophilic alkynylation of monofluorinated enol silyl ethers and cyclic alkynyl hypervalent iodine reagents is attempted.AuCl₃ or DABCO is identified as efficient catalysts to mediate this reaction well to afford the desired?-fluorinated alkynyl ketone,but the corresponding catalytic asymmetric version remains for further study,as only up to 6%ee value is observed after screening different chiral Au?III?complexes and bifunctional tertiary amine-hydrogen bond donor catalysts.During this study,a highly enantioselective protonation reaction of monofluorinated enol silyl ethers is developed through analyzing the side product.Accordingly,by using 10 mol%cinchonidine-derived bifunctional squaramide as the catalyst and 1.0 equiv of H₂O as proton source,together with 2,2,2-trifluoroethanol as the solvent,a variety of highly value-added enantioenriched?-fluoroketones that are difficult to access by other methods can be readily obtained in good to excellent yields and ee values.In addition,this method also could be extended to the synthesis of chiral?-deuterated?-fluoroketones in the presence of D₂O or MeOD.