Strategies Development For Multiple Functionalizations Of Azaarenes And Their Applications In Synthesis Of Alkaloids

This dissertation contains three parts.The first part is about a Bronsted acid and chiral amine co-catalyzed chemo-and enantioselective ?-alkylation/cyclization cascade reaction of quinolinylmethanols with enals.Cinchona alkaloids such as quinine and quinidine occupy a unique position in medicinal chemistry and asymmetric catalysis.Chiral quinolinylmethanolic scaffold is a core structure in cinchona alkaloids.In the current synthesis methods,intruduction of chiral quinolinylmethanolic structure needs to undergo Suzuki or Aldol reaction,asymmetric oxidation successively,resulting in low reaction efficiency.In order to introduce chiral quinolinylmethanolic structures to target molecules all at once,we employs readily accessible quinolinylmethanols as one of the reacting substances directly.A new reactivity,harnessed by TfOH-promoted chemoselective activation of the ?-C-H over the O-H bond in the alcohols as a nucleophile,is achieved for the first time.The new reactivity is successfully engineered with an iminium catalysis in a synergistic manner to create a powerful conjugate addition-cyclization cascade process for synthesis of chiral quinoline derived y-butyrolactones in good yields and with good to excellent enantioselectivities.The method enables the first total synthesis of natural product broussonetine in three steps.The second part is about highly regio-,diastereoselective 1,3-dipolar cycloaddition of nitrones to vinylquinolines.Isoxazolidines are privileged scaffolds frequently found in a large number of natural products and biologically active molecules.More importantly,these compounds also serve as important building blocks that are readily converted into y-amino alcohols.The 1,3-dipolar cycloaddition(1,3-DC)of nitrones and alkenes is the most straightforward method to prepare isoxazolidine compounds.Despite numerous alkenes have been developed as dipolarphiles in recent years,regio-and stereoselectivity of this reaction still represent a challenge for chemists.Herein we chose vinylquinolines as novel dipolarophile partners for the first time and controlled reaction's regioselectivity via changing reaction conditions,achieving different products with the same substrates.Under microwave(MW)irradiation with water as solvent in a sealed system,5-substituted isoxazolidines were produced.The reaction is fast and highly efficient.4-substituted isoxazolidines were obtained as major products with high regio-,diastereoselective when a lewis acid TMSOTf was used as catalyst.The mild conditions,good substrate tolerance and atom economy of this method will facilitate many potential applications.The third part is about metal-free oxidative cross-dehydrogenative coupling of azaarenes with aldehydes.Benzyl tetrahydroisoquinoline alkaloids represent one kind of the most important natural products and exhibit extensive structural diversity and wide biological activity,possessing broad prospect of developing new drugs.1-benzyl tetrahydroisoquinoline is the core structure in benzyl tetrahydroisoquinoline alkaloids.The efficient construction of 1-benzyl tetrahydroisoquinoline is the key to synthesize benzyl tetrahydroisoquinoline alkaloids.In the current synthesis methods,the most used are Bischler-Napieralski cyclization and Pictet-Spengler cyclization.Those reactions possess several disadvantages such as rigorous reaction condition,low reaction efficiency and complicated substrates synthesis process.In recent years,modular synthesis based on molecular buliding blocks became powerful tools for rapid synthesis of small molecules.Guiding by this strategy,we developed a mild and efficient metal-free oxidative cross-dehydrogenative coupling of azaarenes with aldehydes.Subsequently a new synthetic route of 1-benzyl tetrahydroisoquinoline was exploited,which laid the foundation of synthesizing different kinds of benzyl tetrahydroisoquinoline alkaloids.