Studies On Enantioselective Palladium- And Nickel-Catalyzed Anti-Functionalized Cyclization Of Alkynes

Tri-and tetra-substituted cyclic alkenes are important synthetic intermediates,which are core skeletons of natural products and pharmaceuticals.Transition-metal-catalyzed difunctionalization and hydrofunctionalization of alkynes enabling stereoselective introduction of functional groups across the triple bond represents one among the most straightforward and efficient approaches for the synthesis of poly-substituted alkenes.A key challenge existed in these methods is how to control the regio-and stereo-selectivities.In this thesis,we have developed new methods for the construction of poly-substituted cyclic alkenes containing anα-nitrile quaternary stereocenter or chiral tertiary alcohol through transition-metal-catalyzed anti-functionalization of alkynes.In the first part,we developed a palladium-catalyzed anti-oxo-palladation of alkyne/desymmetrization of malononitrile to assemble enaminones containing anα-nitrile quaternary stereocenter.With 3,5-dinitrobenzoic acid as the nucleophile,the products obtained from the reaction,features high ee if in the solution,while the racemic product is precipitated.This chiral amplification via phase separation provides a new tool to enrich the enantioselecticity.In the second part,we demonstrated a Ni-H-catalyzed asymmetric anti-hydrometalative cyclization of alkynones to endo-and hetero-cyclic allylic alcohols involving migratory insertion of alkyne into Ni-H and cis/trans isomerization of alkenylnickel species.The combination of Ni（OTs）₂·6H₂O and Phox ligand has significant influence in tuning the regio-and enantio-selectivity.This reaction features excellent functional group tolerance and broad substrate scope.Alkynones with（hetereo）aryl,alkenyl or alkyl substituents were successfully cyclized to various dihydropyrans in good yields（24–81%yield）and enantioselectivities（60–98%ee）.In addition,Steriod-derived alkynones,S-and N-containing alkynones were also well compatible with this reaction.This study offers conceptually distinct alternative to coupling alkynes and carbonyls,as well as a new mode for anti-selective and enantioselective hydrofunctionalization of alkynes.In the third part,we further expanded the reaction mode of Ni H-catalyzed anti-hydrometalative cyclization of alkynones.We achieved the synthesis of dihydropyrans and tetrahydropyridines containing two vicinal chiral centers in good yield（39–84%yield）,regioselectivities（2.5:1–>20:1）and diastereoselectivities（>20:1）with natural lactic acids and amino acids derived alkynones as substrates.This reaction not only further expanded the substrate scope of anti-hydrometalative cyclization of alkynones catalyzed by Ni H,but provided a new method to the enantioselective synthesis of dihydropyrans and tetrahydropyridines.