Studies On Aryl Migration Strategy-based Cross-electrophile Coupling For The Synthesis Of Amino Acids

Amino acids and their derivatives are a class of important compounds with special physical and chemical properties and pharmacological activities,and they have a wide variety of applications in chemicals,medicine,and food.Among amino acid drugs,the peptide drugs have the advantages of high efficiency and small side-effects,but they also have the shortcomings of being easily degraded by proteases in the body,not easily passing through the blood-brain barrier and short half-life.Medicine researchers often introduce suitable peptide moiety into an active peptide chain.The un-natural amino acid fragments can enhance its anti-degradation performance and improve the affinity with the receptor.Therefore,the development of the synthetic methods for unnatural amino acid molecular or modification is still of great significance.Based on the above background,this thesis mainly employs the Smiles rearrangement strategy toward some unnatural amino acid derivatives through remote reduction cross-coupling.The main research contents are as follows:The first part,reviews the research progress of reductive cross-coupling and Smiles rearrangement in the field of organic synthetic chemistry in the past few years.In the second part,with dibenzylamine as the starting materials,we developed a method to prepareβ-bromo amino acid esters effectively through reductive condensation,LDA-mediated C-H lithiation,nucleophilic addition,and hydroxyl Appel bromination.We successfully synthesized 23 kinds ofβ-bromo amino acid esters through the synthetic route.The preparation route for the cross-coupling partner features easily available raw materials,the use of classic synthesis steps,simple operation,and high yield.The third part,we developed a new type of reduce cross-coupling reaction based on the Smiles rearrangement strategy,and effectively synthesized more than 50 kinds ofβ-arylated amino acid derivatives.In the reaction process,first,zinc powder is used to reduce Ni(II)on-site to obtain Ni(I)active species,and then it was oxidized and inserted the carbon-bromine bond to generate alkyl radicals,which switched on the radical rearrangement relay reaction.Then,this reaction underwent intramolecular free radicals attacking the remote aromatic ring to undergo dearomatization,carbon-carbon bond cleavage/aryl group migration,and finally a relatively stableα-aminoalkyl radical is formed,which will interact with Ar Ni(II)Br sequentially.Next,transmetalation occurs to enable the construction of the C(sp~3)-C(sp~2)bond.This novel method has good stereoselectivity,and a wide scope of substrates,which can simultaneously introduce different aromatic rings on amino acidβ-position and N-alkyl group,thereby providing an efficient new method for the synthesis of phenylalanine compounds.In the fourth part,several control experiments were carried out and in-depth analysis was carried out,the possible reaction mechanism process was proposed,and density functional calculation(DFT)was used to verify the rationality of the proposed mechanism process.