Transition Metal-Catalyzed C–C Bond Formation With Radical Intermediates And Its Applications In The Synthesis Of Unnatural Amino Acids

Due to the growing demand for unnatural amino acids in proteomics and peptide drug discovery,the existing natural amino acids are far from enough to satisfy the growing demand for scientific research,as well as manufacturing.Therefore,the structurally diverse synthesis of biologically active unnatural amino acids has become an important research topic.Glycine,as the basicα-amino acid skeleton,can be used to synthesize structurally diverse unnatural amino acids through the radical alkylation on itsα-site,and the key of this transformation relies on the selective formation of C_（sp³）–C_（sp³）bonds.The construction of C_（sp³）–C_（sp³）bond via classical polar reaction method is highly sensitive to steric hindrance,and the structure of substrates has significant limitations.Given the unique properties of free radicals,it has attracted much attention to capture alkyl radicals via electrophilic acceptors for the construction of C_（sp³）–C_（sp³）bonds in recent years.According to the type of electrophilic acceptors,the specific process can be categorized into radical-radical coupling,radical addition to unsaturated system and transition-metal catalyzed cross coupling.The method of constructing C_（sp³）–C_（sp³）bonds through radical-radical coupling has been applied to theα-alkylation of glycine derivatives,but this kind of reaction generally requires the existence of long-lived alkyl radical and cannot avoid side reactions such as homocoupling in principle.This dissertation aims to develop a new catalytic reaction system which can achieve its own redox neutruality,and realize the C_（sp³）–C_（sp³）bond formation with the participation of electrophilic acceptors.Since the imine generated in situ can capture alkyl radicals efficiently to form C_（sp³）–C_（sp³）bonds,the reaction is not only applicable to a wide range of alkyl substrates,but also avoids side reactions such as homocoupling to a certain extent.The specific research content is as follows:1)Theα-alkylation of glycine derivatives withγ,δ-unsaturated oxime esters catalyzed by a complex of iron（Ⅱ）and phenanthroline-based ligand was investigated.24 unnatural amino acid derivatives containing pyrroline groups were obtained in 39～89%yields.The main competing pathway is iminoacyloxylation caused by the oxidation of alkyl radical to carbocation,while the addition of 3,4,7,8-tetramethyl-1,10-phenanthroline could effectively inhibit this process.In addition,the mechanism of the reaction was studied and a possible radical-polar reaction mechanism was proposed.2)The reaction of glycine derivatives and N-fluorosulfonamides catalyzed by a copper（Ⅱ）/bidentate phosphine complex was investigated.The oxidative coupling between a saturated C_（sp³）–H bond and anα-C_（sp³）–H bond of N-aryl glycine derivatives was realized based on the intramolecular 1,5-HAT process.In addition,27 unnatural amino acid derivatives containing a sulfonamide group were obtained in 40～83%yields.Besides the oxidation of alkyl radical intermediates to carbocations,there were also selectivity issues of intramolecular HAT and intermolecular HAT in this reaction.The addition of bidentate phosphine ligands could promote the conversion of nitrogen-centered radicals to alkyl radicals,and the alkylation yield of most N-aryl glycine derivatives was significantly improved.In addition,for more electron-rich N-（4-methoxyphenyl）glycine derivatives,reducing the concentration could inhibit intermolecular HAT to a certain extent without affecting the intramolecular hydrogen migration process,resulting in an increase in alkylation yield from 17%to 42%.3)The visible-light induced reaction of glycine derivatives and phosphonium salt[Ph₃P⁺CF₂H]Br^-in the presence of a catalytic copper（I）complex was investigated.11 difluoroalanine derivatives were obtained in 41～89%yields through theα-difluoromethylation of N-aryl glycine derivatives.With the addition of excessive amounts of alkenes,a three-component radical cascade reaction of phosphonium salt,olefins and glycine derivatives was achieved.28 unnatural amino acid derivatives containing difluoroalkyl group were obtained in 45～78%yields.Non-conjugated monosubstituted,disubstituted,and cyclic alkenes,and conjugated ones such as vinyl acetate and styrenes were compatible in the above three component reactions.Based on the control experiments,two possible mechanistic pathways of the reaction were proposed.