Diversity-Oriented Synthesis Of Natural Product Like Libraries Containing A 3-Methylbenzofuran Moiety For The Discovery Of New Chemical Elicitors

Natural products(NPs),which have been optimized over time in a long process of natural selection,and their structures are the result of the co-evolution of plants with their biotic environments.NPs have been and continue to be a major source of the biological molecules from which many drugs and pesticides as well as elicitors have been developed.Since many of NPs are defense molecules against other organisms,NPs are essential sources of new chemical elicitors.So the synthesis and screening of small-molecule libraries based on NPs or NP-like structures is a significant way new chemical elicitors are developed.The 3-methylfuran framework was found in a variety of NPs with diverse biological activities.Moreover,these compounds are plant secondary metabolites,conferring host resistance against plant invaders.We report the diversity-oriented synthesis of a NP-like library,in which the 3-methylfuran core is fused in angular attachment to nine common NP scaffolds,including coumarin,chalcone,flavone,flavonol,isoflavones,flavanone,isoquinolinone,carbonylhydrazone and pyrazoline.The dissertation mainly contains five fields as follows:1.Synthesis of angular furanocoumarins NP-like library.The compound 3 was prepared in 3 steps directly from commercially available cyclohexane-1,3-diketone and ethyl 2-chloroacetoacetate.This process involved the cycloaddition of cyclohexane-1,3-diketones with ethyl 2-chloroacetoacetate followed by the base-catalyzed dehydration to give the 3-methyltetrahydrobenzofuran 1.The ester 1 was hydrolyzed to afford 2 by treatment with KOH in aqueous ethanol.Treatment of 2 with Cu powder in diethylene glycol containing pyridine heated at 170-175? for 10 h to give the crude product 3.Substrate 3 was formylated using an excess of NaH in the presence of ethyl formate in toluene to give 4 followed by the dehydrogenation-aromatization reaction to 7.For the synthesis of 3-methylfuranocoumarins 10,we used piperidine as the promoter to test the reaction between aldehyde 7 and different active methylene compounds.2.Synthesis of angular furanoflavonoids NP-like library.We designed a divergent synthetic pathway to synthesize angular furanoflavonoids obtained from the versatile key substrate 3,including furanochalcone,furanoflavonol,furanoflavone,furanoisoflavones and furanoflavanone.3.Synthesis of furano nitrogen-containing NP-like library.We designed a divergent synthetic pathway to synthesize furano nitrogen-containing library obtained from the versatile key substrate 3,including furano isoquinolinones,furano carbonylhydrazone and furanopyrazoline.4.Computationally assess the structural diversity of furano libraries.To computationally assess the structural diversity,the structural features of our 3-methylfuran library were analyzed in terms of their chemical properties in the context of the chemical space using PCA(principal component analysis).Twenty physicochemical properties of these compounds were analyzed using a public,web-based tool.These physico-chemical properties represent each compound as a vector in 20-dimensional space.The 20-dimensional vector can be reduced to two-dimensional vectors by an orthogonal transformation and plotted as a scatter plot.5.Screening of candidate elicitors from synthesized chemicals and Effects of candidate elicitors on the survival rates of BPH.To discover new candidate elicitors,we used a high-throughput screening system that we had previously established to evaluate these synthesized chemicals for their potential to induce the ?-glucuronidase(GUS)activity.To explore whether the candidate elicitors can elicit plant defense and thus influence herbivore performance,we chose the most promising compounds to evaluate their effects on the survival rate of BPH nymphs.