Visible-Light-Induced（Asymmetric） C_sp3-H Functionalization Of Glycine Derivatives

The oxidative cross-dehydrogenative coupling(CDC)reaction has emerged rapidly as one of the most straightforward and atom-economical strategies for forming C-C bonds through the direct coupling of two C(sp3)-H bonds,as it does not require additional prefunctionalization of substrates,and thus largely reduces the number of reaction steps.Recently the direct α-C(sp3)-H functionalization of readily available glycine derivatives has proved to be a powerful tool for the rapid synthesis of unnatural α-substitued α-amino acids and heterocyclic compounds.Traditionally,reactions of this type often involve the use of stoichiometric amounts of oxidants and transition-metal catalysts,and some of them were performed under high reaction temperatures;moreover,the stereocontrol of such transformations is still highly challenging.In recent years,owing to its environmentally benign and mild reaction conditions,photoredox catalysis has become a powerful tool in organic synthesis.However,the examples on photoredox catalytic α-C(sp3)-H functionalization of glycine derivatives are still limited.The main research target of this thesis is focused on the visible light-induced direct oxidative(asymmetric)C(sp3)-H functionalization of glycine derivatives,accordingly,the contents of this thesis could be divided into the following five parts:First,a visible-light induced photocatalytic aerobic oxidative dehydrogenative coupling/aromatization tandem reaction of glycine derivatives with unactivated alkenes has been accomplished(Scheme 1).This visible light-driven protocol has been successfully applied to a broad scope of glycine esters and simple alkenes,giving rise to diverse substituted quinoline derivatives in 18-84% yield under mild(at room temperature under air atmosphere)and operationally simple reaction conditions.Second,a visible-light induced aerobic oxidative cross-coupling reaction between glycine derivatives and indoles has been developed for the efficient synthesis of 3,3’-bisindolylmethanes(BIMs)(Scheme 2).This method could achieve the concise synthesis of a series of 3,3’-bisindolylmethanes in moderate to good yields(39-96%)under mild conditions.The applicability of this method was highlighted in expedient total syntheses of the alkaloid natural products streptindole and arsindoline B in two steps,respectively.Moreover,this metal-free visible-light-induced protocol should have great potential in practical applications.Third,the combination of visible light-induced photoredox catalysis and chiral enamine catalysis has enabled the development of an enantioselective aerobic oxidative cross-dehydrogenative coupling between glycine derivatives and simple ketones or aldehydes(Scheme 3),which provides an efficient method for the rapid synthesis of enantiopure unnatural α-alkyl α-amino acid derivatives in good yield with excellent diastereo-(up to >99:1)and enantioselectivities(up to 97% ee).This process includes the direct photoinduced oxidation of glycine derivatives to an imine intermediate,followed by the asymmetric Mannich-type reaction with an enamine intermediate generated in situ from a ketone or aldehyde and a chiral secondary amine organocatalyst.Fourth,the combination of visible light-induced photoredox catalysis and chiral copper(Ⅱ)complex catalysis has enabled the development of an enantioselective aerobic oxidative cross-dehydrogenative coupling between glycine derivatives and nitroalkanes(Scheme 4).The method provides a mild and efficient method for the rapid synthesis of enantiopure β-nitro-α-amino acid derivatives in good yield(up to 85%)with excellent diastereo-(up to 97:3 dr)and enantioselectivities(up to 98% ee)under air atmosphere and room temperature.Further mechanism and application studies are still in progress.Fifth,a photoredox catalyst free,visible light-induced aerobic oxidative dehydrogenation [2 + 3] cyclization of glycine derivatives with styrene oxides have been achieved,which is enabled by the formation of an electron-donor-acceptor(EDA)complex(Scheme 5).This method provides a new and practical method for the rapid synthesis of substituted 1,3 oxazolidines under green and mild reaction conditions and simple operations,starting from simple and readily available starting materials.By this new method,40 substituted 1,3-oxazolidine compounds have been synthesized in moderate to good yields(32-77%).Moreover,the gram-scale preparation of the reaction makes this protocol very appealing for further application studies.