Synthesis Of Isodityrosine Moiety Of Natural Cyclopeptides Seongsanamides A-D And Its Derivatives

Recently,the introduction of natural privileged structures,such asα-keto amide and gem-dimethyl moieties,into the structure of drugs approved for the market and lead compounds has emerged as an efficient way in drug design.Isodityrosine is a tyrosine dimer containing oxidatively coupled aromatic nuclei,and the tyrosine units are linked through a biaryl ether moiety.A large class of biologically cyclopeptides containing this structural unit exist in nature,which have a wide range of pharmaceutical activities,such as Seongsanamides A-D、K-13、Bouvardin and RAs.Meanwhile,diaryl ether（DE）is a functional scaffold existing widely both in natural products and new drugs approved into the market.The synthesis of isodityrosine usually starts from available natural amino acid,which limits the diversity of synthesis of its derivatives.In recent years,transition-metal-catalyzed C–H functionalization has attracted much attention,has recently emerged as an efficient and direct tool in introduction of functional groups and construction of molecular skeletons,extension of carbon-chains.Palladium-catalyzed C（sp³）-H arylation using amides as derecting groups can provide a general and practical access to various natural and unnatural aromatic amino acids.Based on diversity-oriented synthetic strategy,this dissertation is mainly focused on Ullmann-type coupling reaction of tyrosine and DOPA derivatives with aryl iodides to provide the isodityrosine and its derivatives bearing a diaryl ether.Moreover,tyrosine and DOPA derivatives were provided by palladium-catalyzed C（sp³）-H arylation of an alanine derivative based on directing strategies.Including the follow three parts:1.Arylation ofβ-C（sp³）–H bonds of alanine derivatives using amides as directing groupsA palladium-catalyzed monoarylation ofβ-methyl C（sp³）–H of an alanine derivative with aryl iodides using a 2-methylthioanline amide auxiliary is described,providing a practical method for synthesis variousβ-aryl amino acids.This reaction condition is mild and was found to be compatible with a broad range of functional groups with important applications such as formyl,acetyl,cyano,nitro,iodine,tert-butyloxycarbonyl protecting group and esters groups.Then we provide a synthetic route for DOPA derivatives by removing the directing group followed by the Dakin oxidation of the corresponding aldehyde intermediate.This protocol provides a general and practical synthetic access to a variety of DOPA derivatives and tyrosine derivatives2.Synthesis of isodityrosine and its derivativesA Ullmann coupling reaction of 4-O-methyl-DOPA derivatives and4-iodine-phenylalanine derivatives under mild conditions（Cu I/Cs₂CO₃/N,N-dimethylglycine）is described,providing a practical route for synthesis isodityrosine and its derivatives.The structure of isodityrosine derivatives is characterized by linkage of two amino acid chains on the diaryl ether skeleton.Then we extended 4-iodine-phenylalanine derivatives to aryl iodide and synthesized a series of 4-methoxy-3-aryloxyphenylalanine derivatives,which structure is characterized by linkage of one amino acid chains on the diaryl ether scaffold.In combination with various aromatic amino acids derived from palladium-catalyzed C（sp³）-H functionalization,this protocol can provide more choices and inspiration for the diversity-oriented synthesis isodityrosine and phenylalanine derivatives bearing a diaryl ether moiety.3.Synthesis of 4,4’-oxy-bis-phenylalanine and its derivativesA Ullmann coupling reaction of tyrosine derivatives and 4-iodine-phenylalanine derivatives under mild conditions（Cu I/Cs₂CO₃/N,N-dimethylglycine）is described,providing a practical method for synthesis 4,4’-oxy-bis-phenylalanine and its derivatives.Then we extended 4-iodine-phenylalanine derivatives to aryl iodide and synthesized a series of 4-aryloxyphenylalanine derivatives bearing a diaryl ether moiety.Meanwhile,we proceeded to investigate the effect of protecting groups at the N-terminal and C-terminal of coupling substrates on the reaction yield.A broad range of useful functional groups were tolerated,such as formyl,acetyl,cyano,halogen,alkoxy,nitro,tert-butyloxycarbonyl protecting group and esters groups.Given the significant value of diaryl ether,this method may have good application prospect in the discovery and development of new drug and pesticide.