Enantioselective Construction Of α-quaternary Amino Acid Via Copper Catalysis

Amino acids are the most important structural units of living organisms,exhibiting various physicochemical and biological properties,and serving as the basic building blocks of peptides and proteins to construct complex biological systems.Stereoselective rigid α-quaternary amino acids with tetrasubstituted stereocenters display racemization stability and are widely used in the construction of peptides and proteins with enhanced biological properties.Furthermore,α,α-disubstituted α-amino acids are the key components of some bioactive molecules.The enantioselective construction of α-quaternary amino acids has been developed by asymmetric synthesis strategies such as metal-catalysis,organo-catalysis and cooperative catalysis.These methods provide a solid foundation for drug discovery,natural product synthesis and advanced functional material development.As a result,achieving an effective and precise stereoselective synthesis of α-quaternary amino acids is a kind of hot scientific issue.This thesis mainly focused on the enantioselective synthesis of the α-quaternary amino acid via copper catalysis.The difluoromethyl moiety which is widely used in the field of agrochemical and pharmaceutical science has unique biological activities.The stereochemical control of direct difluoromethyl transformation via the difluorocarbene species,on the other hand,has not been developed.We presented a copper-catalyzed enantioselective difluoromethylation reaction via difluorocarbene species.This reaction employed difluoromonochloromethane(Freon-22),an abundant raw material,as the direct precursor of difluorocarbene species,systematically delivering efficient stereoselective synthesis of corresponding α-quaternary difluoromethyl amino acid derivatives.Furthermore,using this de novo asymmetric difluoromethylation strategy,we were able to achieve the stereoselective synthesis of the drug molecule DFMO,which will aid efforts in both drug discovery and development.Alkynyl moiety is a type of unsaturated group with the synthetic potential of the carbon-carbon triple bond.However,the internal alkyne functional group has received far less attention to provide a series of unprecedented asymmetric transformations through the propargylation process.We described a novel Ni/Cu bimetallic catalysis for the regio-and enantioselective propargylation of amino acid-derived Schiff bases,affording α-quaternary propargyl amino acid derivatives in high yield with excellent enantioselectivity.This reaction provided not only a reliable method for the stereoselective synthesis of propargyl compounds,but also a versatile approach for the development of a wide range of useful stereocontrolled reactions.Based on the Ni/Cu synergistic catalysis,we demonstrated a unified stereodivergent propargylation reaction of amino acid-derived Schiff bases.The collaboration of two chiral metal catalysts allowed for the efficient enantioselective synthesis of all enantiomers of α-quaternary propargyl amino acid compounds containing adjacent stereocenters.Furthermore,we were able to create four stereoisomers of the bioactive molecule Amathaspiramide D and its analogs.This dual catalysis system not only opens up a new platform for the precise construction of complex natural products and drug molecules containing multiple chiral moieties,but also broadens the scope of cooperative catalysis.