Catalytic Asymmetric Synthesis Of Axially Chiral Cyclohexadienylidene Compounds

Axially chiral compounds are a class of ubiquitous chiral compounds which could be generally classified into atropisomers,allenes,spiranes and spiroindanes based on the nature of chirality axis.Over the past decade,axially chiral scaffolds are increasingly encountered and utilized in asymmetric catalysis as ligands and catalysts,bioactive compounds as well as chiral materials.Much of the research activity has comprised the catalytic enantioselective construction and application of known axially chiral frameworks during recent years.By contrast,attention devoted to explore new chemical space of axial chirality is relatively limited.The development of new axially chiral frameworks has profound scientific significance as it does not only enrich the current collection of axially chiral compounds,but will also promote the development of pharmaceutical molecules and materials that containing axial chirality.The classification of axially chiral frameworks is based on the nature of stereogenic axis.Guided by the structural properties of atropisomers and allenes,we hypothesized that a replacement of a C=C double bond in allene with a planar cyclohexadiene ring would yield cyclohexadiene-type scaffolds that contain a stereogenic axis.In this underexplored design,due to the co-planarity of cyclohexadiene and the exocyclic double bond,axial chirality should arise when the E/Z geometry of this double bond is fixed.In this thesis,a new class of axially chiral cyclohexadiene compounds was developed through three strategies: asymmetric condensation,catalytic asymmetric dearomatization and desymmetrization.The detailed research contents are as follows:The asymmetric condensation reaction of spiro[4.5]trienones with hydroxylamines is explored to construct axially chiral cyclohexadienyl oximes under the catalysis of chiral phosphoric acid(CPA)which will control the E/Z geometry of the double bond to define the axial chirality.By modulating the 3,3’-aryl substituents on CPA backbones,three CPA catalysts were found to optimally process the asymmetric condensation to furnish37 cyclohexadienyl oximes with excellent yields and enantiomeric excess.With respect to O-aryl,O-benzyl or O-allylhydroxylamine as the nucleophilic partner,the electrophiles could encompass cyclohexadienones built from spirolactones or spirooxindoles(up to96%,96% ee).The reaction outcomes could be conserved on preparative scale synthesis.Besides,the synthetic importance of the method and the obtained enantioenriched products are further validated through a series of stereoretentive transformations.The axial stability of these new compounds has also been verified: the stereochemical purities are perfectly maintained in different solvents at 100 °C.Kinetic studies show a distinct linear relationship between the initial reaction rates and catalyst concentrations,hinting at the first-order dependence of rate on catalyst concentration.There is also a linear correlation between the enantiomeric purity of the catalyst and the ee of the product.These results indicating that only one CPA molecule participates in the rate-and enantiodetermining step.The second synthetic approach involves CPA-catalyzed dearomatization reaction of azobenzene compounds with indoles as nucleophiles to afford the axially chiral adducts with rotationally impeded C=N bond in generally high efficiency with remarkable chemo-,regio-,and enantiocontrol.This reaction which constructs axially chiral compounds via dearomatization of benzene ring represents a step forward in catalytic asymmetric dearomatization reactions as this chemistry has only been applied to derive central chirality.In the optimization process,the best-performing catalysts and nucleophiles were identified and these conditions successfully furnished 27 axially chiral cyclohexadienyl hydrazones with good yields(up to 97%)and excellent stereoselectivities(up to 99%).It is worth mentioning that the catalyst loading could be lowered to 0.5 mol%,which is a practical advantage compared to the usual requirement of high catalyst loading in smallmolecule catalysis.The high stability of the derived axially chiral structures is exemplified in the kinetic racemization experiment where the rotational barrier of model product was determined to be 135.0 k J/mol.Besides,it is found that the enantiomeric purity of the catalyst and the enantioselectivity of the product are linearly correlated and there is a first-order kinetic relationship between the reaction rate and the catalyst concentration,indicating that only one CPA molecule participates in the rate-and enantiodetermining step.Overall,the reaction features operational simplicity,high efficiency,excellent stereocontrol as well as scalability.The exocyclic carbon-nitrogen double bond of cyclohexadiene could be varied to carbon-carbon double bond,furnishing an alternative class of axially chiral cyclohexandienylidene compounds.Enantioselective condensation strategy was developed on achiral symmetric cyclohexadienylidenes that harbor benzaldehyde as identical terminal substituents on the double bond.In this reaction,the chiral phosphoric acid exhibits high chiral recognition ability in directing the condensation of the aldehyde functionality with hydrazine or hydroxylamine.With this protocol,16 axially chiral analogues were obtained in up to 82% yield and 90% ee.The enantioenriched products contain another free aldehyde group that allows synthetic transformation to further enrich the structural variety.