Design, Synthesis And Bioactivity Studies Of Chiral Phosphonates And Chalcone Derivatives Based On Natural Products

It has been attention that chiral pesticides possess high efficacy,small dosage,less "three wastes",the environmental advantages of ecological security,and so on.Chiral pestcides is one of important research direction of the green pesticide.But there are two major factors in restricting the development of chiral pesticides:（1）The method about preparing chiral pesticides is not mature enough and there are someshortcomings such as expensive and unstable catalyst,low catalytic activity,narrow substrate and harsh reaction conditions,unknown chiral catalytic mechanism,and so on.（2）The mechanism of the bioselectivity of the enantiomers of chiral pesticidee is still unclear.Therefore,be faced to these challenges,we will synthesize chiral monomer with high bioactivity based on racemate pestcides and highly active natural products and investigate its catalytic mechanism and bioselective mechanism of chiral pesticides via effective methods.Firstly,based on the motif of the racemic “dufulin”,high optical activity “dufulin” derivatives were designed and synthesized via chiral thiourea catalysts.Then the agricultural biological and bioselective activity of the title chiral compounds were investigated.And the origins of bioselective activities were further investigated.The conclusions are shown as follows:（1）Based on the motif of the racemic “dufulin”,18 imines with 4-methyl-2-yl-benzothiazole（A1^A18）were designed and synthesized.Through reaction condition optimization for enantioselective hydrophosphonylation,18 pairs chiral “dufulin” derivatives（Ia^Ir）were synthesized with highly yields and ee via thiourea-quinine or thiourea-quinindium catalysts.（2）The structures of compounds（Ia^Ir）were characterized by ¹H NMR,¹³C NMR,HMRS.The absolute configuration of compound If obtained by Q1 catalyst was determined to be R by X-ray crystallography.The absolute configuration of all other products（I）was assigned by analogy.Optical activity of chiral compounds（Ia^Ir）were tested using polarimeter and HPLC with chiral IA colum.（3）The reaction mechanism was proposed that the diphenyl phosphite attacked the complex of catalyst Q1 and imine A in five-member ring via experiments and DFT.（4）The antiviral activities of chiral “dufulin” derivatives（Ia^Ir）against cucumber mosaic virus（CMV）were tested by means of half leaf.The results showed that（R）-compounds generally exhibited higher antiviral activity than the corresponding（S）-enantiomer.Among them,compounds（R）-Ⅰb,Ⅰe,Ⅰf and Ⅰj displayed the inhibitory effect of curative activity with values of 72.3,70.2,71.4 and 64.2%,respectively,which is significantly higher than that of Ningnanmycin（45.3%）and Dufulin（50.4%）at 500μg/m L.Accordingly,compounds（S）-Ⅰb,Ⅰe,Ⅰf and Ⅰj displayed the curative activity with values of 25.1,42.1,54.5 and 47.3%,respectively,which is obviously lower than that of（R）-compounds.And compound Ib exhibited the evident bioselective activities.Compound（R）-Ⅰf possess the protective activity of 67.4%,which is obviously higher than that of Ningnanmycin（47.9%）and Dufulin（54.1%） at 500μg/m L.Compounds（R）-Ⅰb,Ⅰe,Ⅰf and Ⅰj displayed the inhibitory effect of inactive activity with values of 96.3,93.4,94.1 and 90.7%,respectively,which is significantly higher than that of Ningnanmycin（71.3%）and Dufulin（78.2%）.In view of the curative,protective,inactive activity of the chiral compounds（Ia^Ir）,compound（R）-If could have great potential for further development as chiral antivirus agents.（5）The interaction between chiral compound Ib and potential target protein（CMV-CP）was investigated via fluorescence titration.The results showed that the binding constant（K_a）of（R）-Ib,（S）-Ib,Ningnanmycin and Dufulin with CMV-CP is 2.19 × 10⁵,1.17 × 10⁴,5.25 × 10⁴,2.40 × 10⁴ L/mo L,respectively.Results of the binding studies are consistent with our experimental observations that compounds exhibited the antivirus activity.Molecular docking between chiral Ib and CMV-CP was performed.The interactions between both enantiomers of 3b and CMV-CP can likely occur in the binding pocket defined by five residues（Phe58,Thr57,Val218,His55 and Ala147）.The binding energy of（R）-Ib with CMV-CP（-8.74 Kcal/mol）is lower than that of（S）-Ib（-6.57 Kcal/mol）.The difference in the selective bioactivity could be affected by the combination mode of the three-dimensional space.Secondly,based on the motif of the diverse activities chalcones,high optical activity chalcones derivatives were designed and synthesized via chiral thiourea catalysts.Then the agricultural biological and bioselective activity of the title chiral compounds were investigated.The conclusions are shown as follows:（1）Based on the motif of the diverse chalcones,a series of chiral thioureas（Q1^Q6）derived from quinine have been tested as catalysts in the enantioselective Michael additions of nitromethane to chalcones containing pyridine（AA1^AA13）.The best results are obtained with the bifunctional catalyst prepared from 3,5-di（trifluoromethyl）-aniline under solvent-free conditions.13 pairs chiral γ-nitroketones（IIa^IIm）were synthesized with highly yields and ee via thiourea-quinine or thiourea-quinindium.（2）The structures of compounds（IIa^IIm）were characterized by ¹H NMR,¹³C NMR,HMRS.The absolute configuration of compound IIa obtained by Q1 catalyst was determined to be S by X-ray crystallography.The absolute configuration of all other products（II）was assigned by analogy.Optical activity of chiral compounds（IIa^IIm）were tested using polarimeter and HPLC with chiral IA colum.（3）The reaction mechanism was proposed that nitromethane attacked the complex of catalyst Q1 and chalcone AA1 in more hydrogen bonding interaction via experiments and DFT.（4）The antibacterial activities of chiral γ-nitroketones derivatives（IIa^IIm）against rice bacterial leaf blight were tested by turbidity method.The result showed that（S）-compounds generally exhibited higher antibacterial activity than the corresponding（R）-enantiomer.Among them,compounds（S）-Ⅱb,Ⅱh and Ⅱm displayed showed good antibacterial activity（inhibition,100,100 and 57% respectively）,which is significantly higher than that of Bismerthiazol（inhibition,55%）.at 100 μg/m L.Accordingly,compounds（R）-Ⅱb,Ⅱh and Ⅱm displayed the activity with values of 65.0,57.0 and 35.0%,respectively,which is obviously lower than that of（S）-compounds.Therefore,chiral γ-nitroketones derivatives（IIa^IIm）also exhibited the evident bioselective activities.