| Cyano groups are a particularly important kind of pharmacophore.The cyano–containing quaternary carbon chiral centers are found to be widely present in natural products and pharmaceutical active molecules showing significant medicinal value.The quick and efficient construction of cyano–containing quaternary carbon centers via the development and improvement of asymmetric catalysis has been one of the current focuses and hotspots in the field of chemical synthesis.The desymmetrical strategy is one of the most straightforward tools to construct quaternary carbon chiral centers.However,due to the special properties of cyano groups,the research on constructing nitrile–containing all–carbon quaternary stereocenters through the desymmetrical reactions of easily available disubstituted malononitriles was still under–developed and rarely reported.In this thesis,we have developed two new high–efficient and highly stereoselective routes to build cyano–containing quaternary carbon chiral centers based on the chiral nickel–catalyzed alkynyl addition and intramolecular cyclization cascade reaction strategy to meet the challenges and to solve the limitations of the existing technologies.In the first part of our work,we employed chiral nickel catalysis to go through the isomerization of alkynyl nickel Z / E from alkynyl substituted malonitrile and aryl boric acid.According to Ni–C insertion/cyclization and desymmetricalization,a five to seven membered chiral quaternary carbonitrile cycloalkenone was successfully synthesized with high stereoselectivity.This reaction has good yield and enantioselectivity,as well as broad–spectrum substrate adaptability and good functional group compatibility.It provides a newly well–designed strategy for the highly stereoselective construction of cyano–substituted quaternary carbon chiral centers.Through a series of mechanism experiments,we speculated the possible mechanism of the transformation,in which the selective addition of cyano groups may be the rate–deciding step and enantioselectivity determining step.In the second part of the work,by utilizing nickel and silane reagents to form the nickel–hydrogen active species,the Ni–H insertion/cyclization desymmetric strategy was developed to synthesize cyclic ketene compounds with cyano–chiral quaternary carbon centers.The reaction exhibited good activities and excellent chiral–controlling abilities,and it also possesses good substrate suitability and functional group tolerance.This reaction not only achieved highly enantioselective desymmetrical construction of cyano–containing quaternary carbon chiral centers successfully,but also performed great significant contribution for Ni–H catalyzed asymmetric cyclization of alkyne functional groups. |
