Axially Chiral Biaryl Synthesis And Their Applications Involving Cyclic Diaryliodonium Salt Chemistry

Biaryl atropisomerism is a typical type of axial chirality arising from a large degree of steric hindrance to rotation about an aryl-aryl single bond,generally require three or more non-hydrogen groups in the ortho position of the chiral axis,which is ubiquitous in many valuable scaffolds.Diverse functions need to be supported by multiple structural types,which in turn need to be based on diversified synthetic methods.Therefore,the development of efficient synthetic methods for such compounds is a hot topic in the field of organic chemistry.In this dissertation,a systematic study on the catalytic asymmetric synthesis of axially chiral biaryls and their applications involving cyclic diaryliodonium salt chemistry has been conducted.This dissertation contains four chapters:The first chapter: The widespread applications of axially chiral biaryls,their classical synthetic strategies,and the application of diaryliodonium salts in asymmetric reactions are reviewed.Biaryl atropisomerism is ubiquitous in complex biologically active compounds,natural products,chiral ligands,chiral organocatalysts and functional materials.There are mainly four classical synthetic strategies for the construction of biaryl atropisomerism: enantioselective Ar-Ar couplings;atropisomerism via construction of one or two(hetero)aromatic rings;central-to-axial chirality exchange;resolution of racemic biaryls and desymmetrization of prochiral substrates.Because of its high reactivity,linear diaryliodonium salt has its unique advantages as arylation reagent in asymmetric synthesis.However,poor atomic economy directly limits its practicality.Cyclic diaryliodonium salt contains a biaryl skeleton in its own structure,after an asymmetric ring opening reaction,axially chiralbiaryls can be generated directly.The second chapter is about the enantioselective synthesis of axially chiral biaryls via copper-catalyzed acyloxylation of cyclic diaryliodonium salts.The axially chiral acyloxylated biaryls could be obtained efficiently by copper-bisoxazoline catalyzed ring opening of cyclic diaryliodonium salts with readily available commerical(hetero)aromatic and aliphatic carboxylic acids as the starting materials(up to 99% yield,99% ee).To reveal the origin of regio-/enantioselectivity and the possible reaction mechanism,the density functional theory calculations were conducted.The late-stage functionalization of these small-molecule drugs that contain carboxylic acid motifs worked smoothly with the optimized conditions and furnished the desired drug-like products.These axially chiral acyloxylated products could be converted into various valuable biaryls by diversity-oriented transformations with excellent enantioselectivities.The third chapter is about the enantioselective synthesis of axially chiral biaryls via Cu-catalyzed thiolation of cyclic diaryliodonium salts.The axially chiral biaryls bearing sulfur and iodine functional groups could be obtained by copper-bisoxazoline catalyzed ring opening of cyclic diaryliodonium salts with 2-mercaptobenzoxazole and 2-mercaptobenzothiazole derivatives as the starting materials(up to 99% yield,99% ee).The products could be converted into a wild range of aryl alkyl sulfides in good yields and excellent enantioselectivities under simple conditions.These axially chiral biaryls can be employed as chiral hypervalent iodine reagents and have potential applications in catalytic asymmetric reactions.Various control experiments and competition experiments were conducted,on the basis of the results with thiol-containing substrates under optimized conditions,we envisioned that the enantioselectivity was influenced by the coordinating effect of both sulfur and nitrogen through a Cu-mercaptobenzoxazole complex.The fourth chapter is about the synthesis of potential colorectal cancer stem cell inhibitors containing 4-hydroxycoumarins with cyclic diaryliodonium salts.As cancer stem cell play key roles in self-renewal and multipotent differentiation potential of cancer cells,novel types of compounds that can effectively target cancer stem cells are urgently needed.To our best of knowledge,there is no reports indicated that the derivatives of coumarin could target cancer stem cells.The coumarinyl biaryl compounds could be obtained efficiently by copper-catalyzed biarylation of commercially available 4-hydroxycoumarins with cyclic diaryliodonium salts.In addition,the functionalized biaryls followed by an intramolecular Heck-type crosscoupling reaction afforded various novel 7-membered poly(hetero)aryl coumarin derivatives.Among them,compound 4.5e displayed potent colorectal cancer stem cell inhibitory activity.