Study On The Synthesis Methodology And Bioactivity Of Nitrogen-Containing Heterocycles And β-Keto Sulfones

Heteroatomic compounds,a class of important organic compounds,widely exist in biomacromolecules and natural products.Furthermore,heteroatomic compounds is one of the important parts of the material basis of traditional Chinese medicines and important source for drug development.For example,numerous important bioactive molecules(nucleic acids,proteins,vitamins,hormones),blockbuster drugs such as the artemisinin(anti-malarial drug),paclitaxel(anti-cancer drug)and ginkgolid(cardiovascular drug)contain one or more heteroatoms(N,O or S).In particular,nitrogen heterocyclic compounds and sulfur-containing compounds are commonly used in medicine,pesticides,fine chemicals,materials and other fields due to their broad range of biological activities and versatile chemical properties.The development of simple,efficient,economical and practical synthetic methods to construct these heteroatomic compounds could provide abundant candidates for bio-evaluation and drug discovery.The dissertation consists of four parts as follows:1 Literature reviewIn the introduction part,a general review on the synthesis and biological studies of nitrogen-containing heterocyclic compounds and sulfur-containing compounds,such as fused quinazolinones,polysubstituted indoles and β-ketosulfones.2 Synthesis and anti-malarial activity study of fused quinazolinone compoundsIn the second chapter,we have developed two efficient synthetic strategies including oxidative cyclization and electrochemical cyclization between readily available isatin/isatoic anhydride and cyclic amine,offering polycyclic fused quinazolinones.The reaction performed smoothly without additional transition-metal catalysts,acids and bases.This method also provides direct and efficient synthetic approaches to Rutaecarpine alkaloids of Euodiae Fructus in good yield.Additionally,the newly synthesized products were evaluated to exhibit moderate to good antimalarial activity against chloroquine drug-sensitive Plasmodium falciparum 3D7 strain.3 Catalyst-regulated the site-selectivity of QIKs for the construction of polysubstituted indoles and benzofuransQuinone imine ketals(QIKs)are flexible feedstocks with multiple reactive sites including carbon-carbon double bonds(C=C),carbon-nitrogen double bonds(C=N)and ketal structures,which are commonly used as electrophilic aryl source in organic synthesis.Due to the competition between these electrophilic reactive sites,the regioand chemoselective transformation of QIKs is still a challenging task.In the third chapter,a catalyst-regulated divergent reaction between QIKs and 1,3-dicarbonyl compounds has been established,providing tuneable approaches to five types of versatile skeletons for the first time including a series of highly functionalized indoles,benzofurans and 2-aryl-1,3-dicarbonyl derivatives.These new strategies here will broaden avenues for the utilization of quinone imine ketals and provide straight-forward access to polysubstituted indole and benzofuran derivatives.Bioevaluation indicated that the synthesized benzofuran derivatives display moderate to good anti-tumor activities.4 Air-triggered decarboxylative oxysulfonylation for the synthesis of βketosulfonesIn the fourth chapter,we established an efficient decarboxylative oxysulfonylation between arylpropiolic acids and sodium sulfinates for the construction of βketosulfones.This is the first study on the construction C-S bond via air-triggered decarboxylative-coupling transformations without any transition metals and additives.Mechanistic studies have also been conducted to reveal that the reaction proceeds via a radical mechanism.Molecular dioxygen as both green oxidant and oxygen source.Additionally,the reaction showed good functional group compatibility.A series of reported biologically active molecules,including potential anti-analgesics,11β-HSD inhibitors and CES inhibitors,can be prepared in gram scale through this method after simple recrystallization.Moreover,the obtained β-ketosulfone products can be further transformed into structurally diverse complex molecules.In summary,we have developed a series of efficient,green and sustainable methods for the rapid synthesis of various heteroatomic compounds,including polycyclic fused quinazolinones,β-ketosulfones,polysubstituted indole and benzofuran derivatives,which provides a basis for further biological screening and modification.