Photoinduced Radical Alkylation And Application In Peptide Synthesis

It is well known that a series of drug molecules contain chemical bonds of sp~3-hybridized carbon to other hybrid carbon atoms,such as bendamustine,indoleamine 2,3-dioxygenase inhibitor(IDO),and tirofiban.Therefore,the construction of C-C bonds based on sp~3-hybridized carbon,especially the construction of C(sp~2)-C(sp~3)bonds and C(sp~3)-C(sp~3)bonds,have became the core mission in drug synthesis.In the past several decades,transition metal catalyzed cross-coupling reactions were extremely important strategies for the building of C-C bonds in modern organic synthesis.Chemists have developed a lot of strategies for achieving the coupling reactions of unsaturated carbons.However,these ionic coupling reactions are not suitable for the electrophilic alkylation reagents C(sp~3)-X.It is mainly attributed to the difficulty of oxidative addition between alkyl electrophiles and low-valent transition metals,aliphatic carbon chain can not stabilize transition metal via?-electron result in the weak bonding energy of metal-carbon bonds,followed by the?-H elimination of alkyl electrophiles.In recent years,with the continuous development and application of photosensitizers such as ruthenium,iridium,copper,palladium,gold,iron and organic dyes,photoredox-mediated reaction systems have been developed rapidly.Photochemical reactions can achieve many chemical transformations under mild conditions that were not easily realized in the past and receive extensive attentions from chemists.Photoinduced single electron transfer between alkyl electrophile or alkyl nucleophile and photoredox catalyst can promote the generation of alkyl radical.The oxidative addition of alkyl radicals to metal species or direct coupling with other radicals provides a new direction for the construction of C(sp~3)-C bonds.This dissertation comprises four chapters.The first part introduced the radical alkylation reactions of various alkyl radical precursors in recent years,including some radical alkylation strategies of aromatic compounds,olefins and sp~3-hybridized carbon.The alkyl radical precursors involved mainly include alkyl halides,aliphatic carboxylic acids and their redox-active esters(NHPI ester and TCNHPI ester),alkyl boronic acid,potassium alkyltrifluoroborate,alkyl 1,4-dihydropyridines,ammonium alkylbis(catecholato)silicates,zinc sulphinate salts,and other simple alkane compounds.The second part described the synthesis of alkyl-substituted alkenes.The first copper(II)-promoted decarboxylative coupling reaction of?,?-unsaturated acids with alkyl iodides under ultraviolet light irradiation was achieved,and target products were obtained in excellent regio-and stereoselectivity.Mild reaction conditions and excellent functional group compatibility allow this strategy to be applied to the alkylated modification of complex molecules.The third part involved the synthesis of unnatural?-amino acids.Using aliphatic carboxylic acids redox-active esters as alkylation reagents,we enabled the first visible-light-induced and copper-catalyzed radical alkylation of glycine derivatives?-C(sp~3)-H bond.In view of amino acids possesses the basic skeleton of peptides,this strategy can also be applied to the modification of peptides and achieve the alkylated modification of glycine segment.Furthermore,the removal of N-protecting group enabled the conversion of amino acid derivatives to unnatural?-amino acids.The fourth part explored the activation and alkylation strategy of C(sp~3)-H bond under transition metal free condition.we described the first example of ultraviolet light-induced,iodide-catalyzed C(sp~3)-H alkylation with unactivated alkyl chlorides without the assistance of transition metal catalysts and realized the synthesis of a series of?-amino acids derivatives.Compared to alkyl bromides and alkyl iodides,alkyl chlorides have a high abundance but are difficult to activate.Therefore,this might open a door for the application of alkyl chlorides for other types of cross coupling reaction under transition-metal-free conditions.