Design,synthesis And Application Of Spiro Indane-based Phosphine-oxazoline Ligands

Chiral phosphine-oxazoline（PHOX）ligands have proven to be the privileged ligands in transition-metal catalyzed asymmetric reactions.Among them,spiro phosphine-oxazoline ligands exhibit impressive catalytic performance in asymmetric hydrogenation,construction of C-C bond and C-X（X=O,N）bond as well as other types of reactions because of their superior stability and rigidity.So far,there are three kindsofspirophosphine-oxazolineskeletonsreported:spirobiindane,spiro[4.4]nonadiene and hexamethyl-1,1′-spirobiindane.All the ligands possess C₂-symmetrical structure.Therefore,the development of a novel backbone of chiral spiro phosphine-oxazoline ligands,expanding its application in the asymmetric catalytic reaction of transition metals is a very important and challenging task.Based on the rigidity and stability of the spiro skeleton as well as different electronic effects and spatial effects of non C₂-symmetrical ligands which can provide more effective asymmetric control for some reactions,spiro indane-based phosphine-oxazoline ligands are designed.The oxazoline is connected to indane by spirocarbon stereogenic center.Oxazoline ring is part of the spiro skeleton.The ligand is more rigid because the rotation is hindered after the coordination of nitrogen with transition-metal.The transitional conformation in asymmetric reactions is reduced.7-bromo-1-indanone reacted with R-phenylglycinol by condensation,Streker reaction,hydrolysis and oxidation to get S-aminoamide followed by hydrolysis,reduction,cyclizationandsubstitutiontoobtainfivespiromono-indane-based phosphine-oxazoline（SMI-PHOX）ligands.The optical purity of the ligands analyzed by HPLC was close to 100%.The single crystal of phosphine oxide ligand was obtained and the absolute configuration was determined.Compared with the other three ligands,SMI-PHOX ligands possess potentially distinct features:（i）first spiro indane-based phosphine-oxazoline ligand with non-C₂-symmetric skeleton in asymmetric metal catalysis;（ii）better stability and higher rigidity;（iii）only one chiral center avoiding the complex stereochemistry;（iv）modularity by changing easily accessible carboxylic acid and ClPR₂².Application of SMI-PHOX ligands in reactions of 1,3-diphenylallyl acetates and symmetrical 1,3-dicarbonyl substrates.The optimal reaction conditions including solvent,temperature,Pd precursor,ligand type and molar ratio of substrates were established.Under the optimized conditions,the substrate scope of the reaction was examined.Ligands exhibited excellent catalytic performance for symmetric1,3-dicarbonyl compounds,especially forα-malonates with certain steric hindrance.For 1,3-diarylallyl acetate substrates bearing different substituents,high yields（up to97%）and enantioselectivities（up to 99.3%ee）were obtained.The ligand was applied to the asymmetric allylic alkylation of cinnamyl acetate withα-substituted malonic acids to construct chiral quaternary carbon with moderate enantioselectivity（71.2%ee）.Considering the important biological activities of enantiopure indole derivatives,SMI-PHOX ligands were applied in Pd-catalyzed allylic alkylation of indoles.The effects of solvent,temperature,Pd precursor,type and amount of ligand,and substrates on the reaction were investigated.Under optimized conditions,high yields（up to 98%）and enantioselectivities（up to 98%ee）were obtained with a broad scope of indole derivatives.Besides,for allyl acetates with either EDG or EWG on the aromatic ring,the enantiocontrol of ligands was excellent（91-97%ee）.The ligand was determined to be the most efficient P,N-ligand for this reaction.The SMI-PHOX ligand was applied in Pd-catalyzed asymmetric allylic etherification with hard aliphatic alcohols as nucleophiles to further expand the application of the ligand in asymmetric allylation.The optimal reaction conditions were determined by screening ligands,bases,solvents and temperature.The cooresponding 20 products were obtained with high yields（up to 99%）and high enantioselectivities（up to 99%ee）.For benzyl alcohols,heteroaryl benzyl alcohols,alkyl alcohols with different electronic effects and steric effects,the reactions afforded the products with high yields and enantioselectivities.The palladium trifluoroacetate/SMI-PHOX were examined for asymmetric addition of arylboronic acids to cyclic N-sulfonyl imines.Under the optimal conditions,the reactions of five-membered ring ketimines bearing alkyl,phenyl and ester which have lower activity could afford the products with theα-quaternary carbon center in high yields（94-99%）and enantioselectivities（96-99%ee）.Excellent yields（98-99%）and enantioselectivities（98-99%ee）were also obtained for six-membered ring aldimine andα-ester substituted ketimines.Six-membered ring ketimine bearingα-methyl gave the product with relatively low yield（81%）but high enantioselectivity（99%ee）.The absolute configuration of the product was determined by HPLC.The plausible mechanism was proposed.