N-heterocyclic Carbene-nickel Catalyzed Diastereodivergent Heteroenyne Cyclizations

Transition metal catalyzed enyne cyclizations are one of the most efficient tools to construct cyclic compounds,for which metallacycles are widely used as the key intermediates.Although many types of enyne cyclizations with different partners have been developed,highly effective diastereodivergent ones have not been achieved.In particular,multi-substituted 6-membered heterocyclic scaffolds exist in many bioactive natural or artificial molecules,making it is of great importance to realize diastereodivergent synthesis of such scaffolds.This thesis aims at development of switchable diastereoselective formation of nickelacyclopentene intermediate under NHC-Ni catalysis,so as to realize varieties of diastereodivergent enyne cyclizations involving the similar intermediates.First,the hydroacylative cyclization of 1,n-heteroenynes（n=7,8）with aldehydes under IPr-Ni（0）catalysis was investigated,and a diastereodivergent synthesis of the corresponding heterocycles bearingγ-enone was achieved.By optimization of substrate addition manner,a high hydroacylative cyclization over enyne homo dimerization ratio was obtained.Then,highly diastereoselective and also highly diastereodivergent hydroacylative cyclization were observed by manipulating hetero-substituents on enynes.Propargyl enynes bearing O or NH tether afforded 1,3-syn products,while those bearing NMs tether afforded 1,3-anti products.The strategy was found also applicable to allyl enynes,in which O or NH enynes favored 1,4-anti selectivity,while NMs enynes favored1,4-syn selectivity.Ligand effect study indicated the reaction was not a sole substrate-controlled process,and ligand also played a key role for the observed switchable diastereoselectivity,especially for those enynes with NMs.The diastereodivergent cyclization has a wide substrate scope.C1-subsituted and C1,C2-disubstituted 1,7-heteroenynes,as well as 1,8-heteroenynes are all good substrates,and either aromatic or aliphatic aldehydes are good cyclization partners.Preliminary DFT calculation suggested that the diastereodivergent synthesis is closely related the relative stability of the nickelacyclopentene intermediates.Second,a diastereodivergent heteroenyne reductive cyclization was achieved,afforded the corresponding alkyl substituted heterocycles.By using 2-phenyl ethanol as reductant,a greener enyne reductive cyclization was realized under IPr-Ni（0）catalysis.The above diastereodivergent strategy was found also applicable to the reductive cyclization,with similar diastereoselective preference and comparable efficiency.Ligand effect study showed once again that the diastereodivergent synthesis is a cooperation of enyne hetero-substituent and NHC ligand.The reductive cyclization has a wider range of substrate scope.In addition to C1-substituted and C1,C2-disubstituted 1,7-heteroenynes,internal 1,7-enynes and 1,8-heteroenynes are also good substrates.Notably,by using enyne with a gem-disubstituted alkene tether,a quaternary carbon stereocenter on heterocycles could be constructed diastereodivergently.D-labelling experiment supported the mechanism based on nickelacyclopentene formation rather than Ni-H insertion.The cyclization product could be converted to a linear chain enol with retained stereocenters.Third,the newly developed diastereodivergent strategy above was also examined in hydrosilylative cyclization of 1,7-azaenynes under IPr-Ni（0）catalysis in the presence of Et₃Si H.It afforded the corresponding silyl substituted heterocycles effectively.Besides,synthetic applications of the recently developed（NHC）Ni catalyzed[3+2]hydroalkenylation-rearrangement cascade（HARC）by the group were investigated.The cyclization products were examined as key starting materials for a range of olefin functionalization methodology,including Diels-Alder reaction,epoxidation,ozonolysis,halogenation-rearrangement and fluorohydroxylation.Several very interesting carbon skeletons could be obtained easily with high diastereoselectivity in one step or in cascade.