Application Of Radical Migration Tandem Reaction And C-O Cross Coupling In Serine Arylation Modification

Amino acid is a functional molecule with important physiological activities and is the basic structural unit of many drug molecules,such as clinical antiarrhythmic drug tokanide and histone deacetylase（HDACs）inhibitors.In addition,they are also important intermediates in organic synthesis and can be used in the synthesis of peptides and pseudo peptides.The synthesis and modification of functional amino acids has always been a hot spot in the field of organic synthesis.Focusing on the development of new methods for the synthesis and modification ofβ/γ-C/O-arylated silk/threonine ester,this paper developed new synthetic methods such as nickel catalyzed aryl radical migration series reduction cross coupling and photo/nickel synergistic catalyzed C-O cross coupling reaction,and synthesized a series of potentially bioactive phenylalanine derivatives.The main contents of this paper are as follows:In the first part,various types of radical rearrangement reactions in recent years are reviewed,including radical carbon→carbon migration,radical carbon→heteroatom,and radical heteroatom→carbon atom.At the same time,the research status ofβ/γ-arylation of amino acids was also reviewed.In the second part,N-benzyl-β-bromoamino acid ester,a precursor of free radical rearrangement,was efficiently synthesized from natural amino acids through three simple reaction steps.Using these amino acid esters as precursors,in the presence of Ni Br₂（dme）/4,4-dimethoxybipyridine/Zn catalytic system,the cross coupling reaction of free radical remote migration series reduction with aryl bromide was successfully carried out.The construction of double carbon carbon bond was completed in one step,andβ-aryl substituted serine esters were successfully synthesized.From the perspective of mechanism,the reaction is a target series reaction formed by C（sp³）as the central"link"combined with aryl radical rearrangement and cross coupling.In conclusion,this reaction has the advantages of high diastereoselectivity,mild reaction conditions（room temperature）,"one-step"reaction and so on.It provides a convenient way for the synthesis of functionalized phenylalanine which is difficult to be synthesized by conventional methods.In the third part of the work,a series ofβ-aryl silk/threonine sulfonates were synthesized by using cheap and stable silk/threonine sulfonates as rearrangement precursors and Li Br as halogen exchanger under the catalysis of nickel.It is worth mentioning that the o-sulfonate of serine is used to replace theβ-bromoamino acid ester as the rearrangement precursor in this reaction,which has the characteristics of easy availability of raw materials and simple operation,and provides another simple and alternative route for the synthesis of phenylalanine and its derivatives.In the fourth part,a visible light/nickel synergistic catalytic system was developed to successfully realize the C-O cross coupling reaction betweenβ-hydroxyl amino acid esters and aryl bromide.In the presence of Ni Br₂（dme）/Ir[FCF₃（CF₃）ppy]₂（dtbbpy）PF₆catalytic system,a series of amino acid aryl ethers with novel structure were synthesized by C-O cross coupling reaction of two simple and easy coupling precursors under the irradiation of 5 w Blue LED lamp.This synthetic method provides an important reference for the C-O cross coupling of aliphatic alcohols and aryl halides,and provides a simple way for the later modification of serine.