Studies On Selective Reduction Of Nitrogen-containing Heterocyclic And Conjugated Enynes By Metal Nanoclusters And Their Products Antifungal Activity

Natural products have long been an important source of inspiration for drug discovery.To date,numerous drugs or the discovery of their matrix originated from natural products.Although witnessed of large quantity,diverse skeletons and various species,the active components in natural products are generally of low content,which is far from meeting human demands.Therefore,it is of great significance to use synthetic methods for stereo-controllable construction of various derivatives similar to the core skeleton of natural products and improve their biological activity.Chiral 1,2,3,4-tetrahydroquinoline and 2,3-dihydroindole derivatives as common structural units in many bioactive natural products and pharmaceutical molecules as well as a class of nitrogen hetero alkaloids,have always been the focus of chemists.So far,a variety of asymmetric synthetic methods have been successfully developed for these two types of compounds to achieve the total synthesis of many chiral natural drugs,such as torcetrapib,oxamniquine,vinblastine,strychnine,vinblastine,and some other commercially available drugs.Among the numerous asymmetric synthetic methods,direct asymmetric catalytic hydrogenation of quinoline and indole derivatives is one of the most green and economic technique for the synthesis of chiral 1,2,3,4-tetrahydroquinoline and 2,3-dihydroindole.In recent years,hydrogenation system involving chiral metal nanoclusters has become the frontier and hot spot in the field of metal nanocatalysis.The system integrates the advantages of traditional homogeneous and heterogeneous catalysis and avoids the substrate limitation of traditional metal complexes.Unsaturated hydrocarbons have been the research focus of organic chemists for hundreds of years.Dendralenes,one of the important types of acyclic cross-conjugated olefins,were assumed to be unstable for since their discovery,which restricted their further development.In the past two decades,more and more researchers have paid attention to these "forgotten" compounds because of their unique structure and application value.Various unsubstituted and polysubstituted[n]-Dendralenes(n=3,4,5...)and their natural structures have been reported successively,and their applications have been extended to polymer chemistry,theoretical chemistry,material chemistry,electrochemistry and the rapid synthesis of natural products.However,the stereoselective synthesis of Dendralenes still remains the most challenging field,especially the synthesis of(Z)and(Z,Z)-[3]-Dendralenes.Therefore,considering the ultra-high catalytic activity and excellent selectivity of metal nanoclusters,it is necessary to develop a series of new nanocatalysts to achieve the eco-friendly synthesis of(Z)and(Z,Z)-[3]-Dendralenes with high efficiency and chemical selectivity.In recent years,more and more chemists and pharmacists have been devoted to the research on natural products and their derivatives,with various natural products and their synthetic methods reported.Among which,the derivatives of natural products such as tetrahydroquinoline,dihydroindole and dendrarenes have attracted great attention because of their unique physical,chemical and biological properties.Furthermore,the derivatives have been widely used in pesticides,medicine,materials,chemical industry and other fields.So far,a variety of methods have been reported for the construction of these three types of structural units,but challenges still remain in stereo control of the skeleton configuration.Therefore,it is of vital significance to explore new methods for the stereoselective synthesis of compounds with biologically active skeleton and specific spatial configuration.The antibacterial activity of these compounds is worth studying.Based on the metal covalent(carbon-palladium)bond stabilized palladium nanoclusters and secondary phosphine-oxygen stabilized palladium-gold nano-alloys developed by our group,a series of chiral 1,2,3,4-tetrahydroquinoline,chiral 2,3-dihydroindole,and(Z)or(Z,Z)-[3]-Dendralenes with stereo configuration were synthesized and the antifungal activity was screened.Compared with traditional metal complex,the advantage of utilizing nanoclusters is highlighted with high catalytic activity and selectivity.The details are summarized as follows:(?)1?Asymmetric hydrogenation of quinolines and indoles with binaphthyl nano-palladium catalyst(BIN-PdNPs)Nitrogen-containing heterocyclic derivatives such as 1,2,3,4-tetrahydroquinoline and 2,3-dihydroindole are important natural products,which are widely used in pesticides(fungicides,herbicides,insecticides etc.)and medicine(anti-inflammatory,anti-cancer,anti-tumor,anti-virus etc.)fields.In this work,asymmetric catalytic hydrogenation of quinoline and indole derivatives were achieved for the first time with palladium nanoparticles stabilized by metal covalent bonds.This strategy overcomes the difficulty that traditional chiral metal complexes cannot achieve chiral induction for some substrates.Optimal reaction conditions were obtained through screening of chiral ligands,solvents,additives and other conditions.It was found that this method has extensive functional group tolerance and substrate applicability.When the substrate is quinoline,the target product can be obtained with high yield and moderate to good enantioselectivity for both alkyl and aryl substitution of R2;Moreover,when the substrate is indole,the asymmetric hydrogenation can also be realized with excellent yield.Under the optimal conditions,25 optically active 1,2,3,4-tetrahydroquinoline and 2,3-dihydroindole derivatives were synthesized.Meanwhile,a possible reaction mechanism is proposed based on the nature of nanocatalysis and experimental phenomena.In addition,the synthesis of the racemic 1,2,3,4-tetrahydroquinoline is achieved in a green and highly efficient manner using H2O as a hydrogen source within 10 min(the fastest synthesis method as far as we know).The structure of the products was characterized by nuclear magnetic resonance spectroscopy(1H-NMR,1C-NMR),and the enantioselectivity of the target compounds was determined by high-performance liquid chromatography(HPLC).2?Regioselective catalytic hydrogenation of conjugated alkynes by secondary phosphine-stabilized palladium-gold nanoalloys(Au/PdNAs)Due to the alloy effect and effective inter-cluster electron transport effect,nano-alloys often exhibit better catalytic activity,stability and selectivity compared with those of single metal nano-clusters,which has become one of the hot topics in the field of nano-catalysis.Among which,palladium-gold nano-alloys as a type of "star" catalyst have attracted much attention.Secondary Phosphine Oxides(SPOs),a special class of pentavalent phosphine ligands,are more stable to water and air than traditional trivalent phosphine ligands,making them ideal stabilizers for nanoalloy.In this work,a series of new palladium-gold nano-alloys(Au/PdNAs)were prepared for the first time using secondary phosphorus oxides SPOs as stabilizers.The catalysts were fully characterized by a wide variety of techniques,such as transmission electron microscopy(TEM),x-ray photoelectron spectroscopy(XPS),x-ray powder diffraction(XRD),energy-dispersive x-ray spectroscopy spectrometry(EDX-Mapping),attenuated total reflectance-fourier transform infrared spectroscopy(ATR FT-IR),inductively coupled plasma-Mass spectrometry(ICP-MS),UV-vis and so on.Furthermore,these catalysts could be successfully applied to the selective hydrogenation of conjugated alkynes.It was also found that changes in palladium and gold content can precisely regulate the type and regioselectivity of catalytic reactions.The substrate adaptability was further investigated and selective catalytic hydrogenation of 21 conjugated alkynes was achieved with high yields and chemical selectivity.The compounds were characterized by nuclear magnetic resonance spectroscopy(1H-NMR,1C-NMR,31P-NMR),mass spectrometry(HRMS),infrared spectroscopy,melting point,and single crystal diffraction.3?Tandem reaction of alkynylation and selective hydrogenation to(Z)and(Z,Z)-[3]-Dendralenes by binaphthyl nano-palladium catalystIn recent years,an important class of acyclic cross-conjugated olefins such as dendralenes have attracted more and more researchers' attention due to its unique structure and application value.Although(Z)-[3]-Dendralenes are widely present in natural products such as plant essential oils and bilirubin.their stereoselective synthesis still remains as a challenging field,especially for(Z.Z)-[3]-Dendralenes.Only two cases have been reported up to now,but with either poor stereoselectivity or low yield.Based on the research of binaphthyl palladium nanoclusters and phosphine[3]-Dendralenes,a novel and highly efficient methodology for accessing(Z)and(Z,Z)-[3]-Dendralenes was developed in this work with metal covalent stabilized bond palladium nanoclusters as catalysts,aryl ether-substituted phosphine allenes and alkynes as starting substrates.The cascade alkynylation and selective hydrogenation was performed smoothly,affording phosphinyl(Z)-[3]-Dendralenes in high yield and stereoselectivity.It was found that the metal loading can significantly modulate the efficiency and selectivity of the nanocatalyst.Optimal reaction conditions were obtained by screening catalysts,solvents,additives and other conditions.Moreover,a possible pathway was proposed according to the control experiments.This strategy features broad functional group tolerance,good regioselectivity and stereoselectivity.A total of 38(Z)and(Z,Z)-[3]-Dendralenes derivatives were successfully synthesized,all of which were new and unreported compounds.In addition,derivatization investigation of a variety of(Z)-[3]-Dendralenes were also carried out.The compounds were characterized by nuclear magnetic resonance spectroscopy(1H-NMR,1C-NMR 31P-NMR),mass spectrometry(HRMS),infrared spectroscopy,melting point,and single crystal diffraction.4?Determination of antifungal activityThe fungicidal activities of all the target compounds against to Rhizoctonia solani,Botrytis cinerea,Alternaria solani,Alternaria mali,Colletrichum orbiculare,Fusarium graminearum,were tested by growth rate method.Based on the determination results,the structure-activity relationship was analyzed.The EC50 test of compounds with high activity(?>70%)were determined.The EC50 of compound A7 against Alternaria solani and compound A19 against Botrytis cinerea was 10.96 ?g/mL and 70.58 ?g/mL respectively;the EC50 of compound B14,B15 against Rhizoctonia solani was 14.94 ?g/mL,37.84 ?g/mL respectively;the EC50 of compound C4,C5,C6 against Rhizoctonia solani were 22.26 ?g/mL,26.22 ?g/mL,19.20?g/mL respectively.Through the activity study,it was found that the antifungal bioactivity of 1,2,3,4-tetrahydroquinoline and 2,3-dihydroindole compounds against Rhizoctonia solani,lternaria mali,Colletrichum orbiculare,Fusarium graminearum seems unsatisfactory,but they demonstrate certain antibacterial activity against cinereal and Alternaria solani;inhibitory activity of(Z)-[3]-Dendralenes products terminated with dimethyl and phenyl are generally unsatisfactory against Botrytis cinereal,Alternaria solani,Fusarium graminearum,Alternaria mali and Colletrichum orbiculare,but show certain antibacterial activity against Rhizoctonia solani.In summary,taking advantage of the higher catalytic activity and selectivity of metal nanoclusters,totally 88 derivatives of optically active 1,2,3,4-tetrahydroquinoline,optically active 1,2-dihydroindole,(Z)and(Z,Z)-[3]-Dendralenes were synthesized,including 25 chiral compounds,42 unreported new compounds.Studies on the antifungal activity of the synthesized compounds and key by-products showed that some compounds exhibit good inhibitory activity against the tested bacteria,providing a certain reference for the creation of new fungicides.