环境友好型烃基膦酸酯类除草剂= Environmentally friendly alkylphosphonate herbicides

　　1.原创性专著，我国新农药创制的阶段性成果。 

　　本专著系统总结了我国新农药创制性的成果——烷基膦酸酯类除草剂的研发总结。从化合物的合成、毒性研究、作用机制，从中试到生产整个程序，为今后我国农药新创制提供一条有效途径。
　　本书可供广大新农药研发、生产等人员阅读，也可供高等学校农药、植保等相关专业师生阅读。

　　贺红武，华中师范大学，教授、所长，毕业于华中师范大学化学专业。在日本九州大学获农学博士学位。1989～1990年日本九州大学农学部农药化学研究室访问研究员，1996年晋升教授，1998～1999年德国美因兹大学药物化学研究所访问教授，1999年获博士生导师资格，2001年赴日本九州大学农学研究院农药化学研究室和日本神户大学农学部生物功能研究室进行为期3个月的学术访问。2007，8月-11月：日本九州大学农学研究院农药化学研究室，访问教授。
　　兼任社会职务：第六届国务院学位委员会植物保护学科评议组成员，中国化工学会农药专业委员会委员 ; 中国植物保护学会农药学分会委员；湖北省化学化工学会理事；湖北省化学化工学会农药专业委员会主任委员《世界农药》、《农药》、《现代农药》、《农药学学报》、《化学与生物工程》、《农药研究与应用》杂志编委。
　　长期从事有机化学、农药化学、有机磷化学以及新农药创制研究工作。先后承担国家及省部级的科研项目40余项，连续承担国家七.五，八.五，九.五十.五、十一.五国家新农药创制科技攻关项目。先后承担了六个农药新品种及一个农药增效剂的应用基础研究与工业化开发，其技术和成果在农药工业中得到创新性的应用和发展。为具有我国发明专利权的新型除草剂氯酰草膦（己获农药三证。）的发明人。
　　在新农药品种的创制研究、技术开发、产业化等工作中获得11项授权中国发明专利, 获得湖北省自然科学奖一等奖, *科技进步一等奖，*科技进步二等奖；湖北省科技进步二等奖二项；八?五”国家技术创新优秀项目奖等9项省部级科技奖励。2001年评为湖北省科技精英和全国优秀科技工作者。2009获得建国60周年中国农药工业突出贡献奖。

1.Overview.
1.1.Introduction.
1.1.1.Mode.of.Action.of.Herbicide.
1.1.2.Herbicide.Resistance.
1.1.3.New.Opportunity.for.Novel.Herbicides.
1.1.4.Basic.Methodology.for.Discovery.of.Hit/LeadCompounds.
1.2.Pyruvate.Dehydrogenase.Complex.(PDHc).
1.2.1.Function.of.PDHc.
1.2.2.Distribution.of.PDHc
1.2.3.Plant.PDHc.E1.as.Site.of.Action.of.Herbicide.
1.3.Progress.in.the.Research.of.PDHc.Inhibitors.
1.3.1.OP.Compounds.as.Inhibitors.of.E.coli.PDHc.
1.3.2.OP.Compounds.as.Inhibitors.of.Plant.PDHc.
1.3.3.Enzyme-Selective.Inhibition.of.OP.Compounds.
1.4.Design.of.Novel.PDHc.E1.Inhibitors.as.Herbicides.
1.4.1.Selecting.Plant.PDHc.E1.as.Target.of.NewHerbicide.
1.4.2.PDHc.E1.Inhibitor.Acylphosphonate.as.HitCompound.
1.4.3.Finding.Lead.Structure.IA.
1.4.4.Optimization.Strategy
1.5.Book.Chapter.Organization.
References

2.Alkylphosphonates.
2.1.(Alkyl.or.Substituted.Phenyl)Methylphosphonates.IA-IF.
2.1.1.Introduction.
2.1.2.Synthesis.of.O,O-Dialkyl1-Hydroxyalkylphosphonates.M2.
2.1.3.Synthesis.of.Substituted.Phenoxyacetic.Acids.Mand.Substituted.Phenoxyacetyl.Chlorides.M5.
2.1.4.Synthesis.of.IA-IF.
2.1.5.Spectroscopic.Analysis.of.IA-IF.
2.1.6.Crystal.Structure.Analysis.of.IC-7.
2.1.7.Herbicidal.Activity.of.IA-IF.
2.1.8.Structure-Herbicidal.Activity.Relationships.
2.1.9.Herbicidal.Activity.of.IC-22.
2.1.10.Summary.
2.2.Heterocyclylmethylphosphonates.IG-IJ.
2.2.1.Introduction.
2.2.2.Synthesis.of.IG-IJ.
2.2.3.Spectroscopic.Analysis.of.IG-IJ.
2.2.4.Crystal.Structure.Analysis.of.IH-18.and.IG-21.
2.2.5.Herbicidal.Activity.of.IG-IJ.
2.2.6.Structure-Herbicidal.Activity.Relationships.
2.2.7.Herbicidal.Activity.of.IG-21.
2.2.8.Summary.
2.3.(1-Phenyl-1,2,4-Triazol-3-yloxyacetoxy)Alkylphosphonates.IK.
2.3.1.Introduction.
2.3.2.Synthesis.of.IK.
2.3.3.Spectroscopic.Analysis.of.IK.
2.3.4.Herbicidal.Activity.of.IK.
2.3.5.Summary.
References

3.Salts.of.Alkylphosphonates.
3.1.Alkali.Metal.Salts.of.O-Alkyl.Alkylphosphonic
Acids.IIA-IIE.
3.1.1.Introduction.
3.1.2.Synthesis.of.IIA-IIE.
3.1.3.Spectroscopic.Analysis.of.IIA-IIE.
3.1.4.Crystal.Structure.Analysis.of.IIB-20.
3.1.5.Herbicidal.Activity.of.IIA-IIE.
3.1.6.Summary.
3.2.Alkali.Metal.Salts.of.Alkylphosphonic.Acids.IIF,IIGandIIH.
3.2.1.Introduction.
3.2.2.Synthesis.of.IIF,.IIG.and.IIH.
3.2.3.Spectroscopic.Analysis.of.IIF,.IIG.and.IIH.
3.2.4.Herbicidal.Activity.of.IIF,.IIG.and.IIH.
3.2.5.Summary.
3.3.t-Butylaminium.Salts.of.Alkylphosphonates.IIJ.
3.3.1.Introduction.
3.3.2.Synthesis.of.IIJ
3.3.3.Spectroscopic.Analysis.of.IIJ.
3.3.4.Crystal.Structure.Analysis.of.IIJ-
3.3.5.Herbicidal.Activity.of.IIJ.
3.3.6.Summary.
References

4.Alkylphosphinates.
4.1.Alkylphosphinates.IIIA-IIIG.
4.1.1.Introduction.
4.1.2.Synthesis.of.Dichloro(Methyl)Phosphine.M10.
4.1.3.Synthesis.of.O-Methyl.(1-Hydroxyalkyl)-Methylphosphinates.M12.
4.1.4.Synthesis.of.IIIA-IIIG.
4.1.5.Spectroscopic.Analysis.of.IIIA-IIIG.
4.1.6.Crystal.Structure.Analysis.of.IIIE-
4.1.7.Herbicidal.Activity.of.IIIA-IIIG.
4.1.8.Summary.
4.2.Sodium.Salts.of.Alkylphosphinic.Acids.IIIH.
4.2.1.Introduction.
4.2.2.Synthesis.of.IIIH
4.2.3.Spectroscopic.Analysis.of.IIIH.
4.2.4.Herbicidal.Activity.of.IIIH.
4.2.5.Summary.
4.3.[(5-Methylisoxazol-3-yloxyacetoxy)Alkyl]-Methylphosphinates.IIIJ.
4.3.1.Introduction.
4.3.2.Synthesis.of.IIIJ.
4.3.3.Spectroscopic.Analysis.of.IIIJ.
4.3.4.Herbicidal.Activity.of.IIIJ.
4.3.5.Summary.
References

5.Cyclic.Phosphonates.and.Caged.Bicyclic.Phosphates.
5.1.Cyclic.1-Hydroxyalkylphosphonates.IVA.and.IVB
5.1.1.Introduction.
5.1.2.Synthesis.of.IVA.and.IVB.
5.1.3.Spectroscopic.Analysis.of.IVA.and.IVB.
5.1.4.Crystal.Structure.Analysis.of.IVA-3.
5.1.5.Herbicidal.Activity.of.IVA.and.IVB.
5.1.6.Summary.
5.2.Cyclic.Alkylphosphonates.IVC-IVF.
5.2.1.Introduction.
5.2.2.Synthesis.of.IVC-IVF.
5.2.3.Spectroscopic.Analysis.of.IVC-IVF.
5.2.4.Crystal.Structure.Analysis.of.IVC-
5.2.5.Herbicidal.Activity.of.IVC-IVF.
5.2.6.Summary.
5.3.Caged.Bicyclic.Phosphates.IVG.and.IVH.
5.3.1.Introduction.
5.3.2.Synthesis.of.IVG.and.IVH.
5.3.3.Spectroscopic.Analysis.of.IVG.and.IVH.
5.3.4.Crystal.Structure.Analysis.of.IVG-
5.3.5.Herbicidal.Activity.of.IVG.and.IVH.
5.3.6.Summary.
References

6.Optically.Active.Alkylphosphonates.
6.1.Optically.Active.1-Hydroxyalkylphosphonates.IVB.and.M2.
6.1.1.Introduction.
6.1.2.Asymmetric.Synthesis.of.1-Hydroxyalkylphosphonates
IVB.and.M2.via.Hydrophosphonylation.
6.1.3.Asymmetric.Synthesis.of.1-HydroxyalkylphosphonatesM2.via.Hydroxylation
6.1.4.Summary.
6.2.Optically.Active.(Substituted.Phenyl)methylphosphonates.IA,IEandIF.
6.2.1.Introduction.
6.2.2.Synthesis.of.Optically.Active.IA,.IE.and.IF.
6.2.3.Herbicidal.Activity.of.Optically.Active.IA,IEandIF.
6.2.4.Summary.
6.3.Optically.Active.Substituted.Ethylphosphonates.IA.and.IC.
6.3.1.Introduction.
6.3.2.Synthesis.of.Optically.Active.IA.and.IC.
6.3.3.Herbicidal.Activity.of.Optically.Active.IA.and.IC.
6.3.4.Aquatic.Toxicity.of.Optically.Active.IA.and.IC.
6.3.5.Summary.
References

7.Biochemical.Mechanism.of.Alkylphosphonates.
7.1.Molecular.Docking.and.3D-QSAR.Studies.
7.1.1.Introduction.
7.1.2.Binding.Conformational.Analysis.
7.1.3.CoMFA.and.CoMSIA.Analysis.
7.1.4.Validation.of.the.3D-QSAR.Models.
7.1.5.Molecular.Docking.
7.1.6.Molecular.Alignment.and.3D-QSAR.Modeling.
7.1.7.CoMFA.Analysis.and.CoMSIA.Analysis.Modeling.
7.1.8.PLS.Calculations.and.Validations.
7.1.9.Summary.
7.2.Enzyme.Inhibition.
7.2.1.Introduction.
7.2.2.Inhibitory.Potency.Against.Plant.PDHc.
7.2.3.Kinetic.Experiment.of.PDHc.
7.2.4.Selective.Enzyme.Inhibition.
7.2.5.Structure-Activity.Relationships.
7.2.6.Assay.of.PDHc.from.Plant.
7.2.7.Assay.of.PDHc.from.E.coli.and.Pig.Heart.
7.2.8.Assay.of.Other.Enzymes.
7.2.9.Summary.
References.

8.Evaluation.and.Application.of.Clacyfos.and.HWS.
8.1.Evaluation.of.Clacyfos.
8.1.1.Introduction.
8.1.2.Physiochemical.Properties.
8.1.3.Stability.of.Clacyfos.
8.1.4.Herbicidal.Activity.in.Greenhouse.
8.1.5.Systemic.Property.of.Clacyfos.
8.1.6.Rainfast.Characteristics.of.Clacyfos.
8.1.7.Field.Trials.of.Clacyfos.
8.1.8.Toxicity.Evaluation.
8.1.9.Environmental.Fate.
8.1.10.Residues.
8.1.11.Adsorption.of.Clacyfos.on.Soils.
8.1.12.Ecological.Effects.
8.1.13.Summary.
8.2.Evaluation.of.HWS.
8.2.1.Introduction.
8.2.2.Physiochemical.Properties.
8.2.3.Herbicidal.Activity.in.Greenhouse.
8.2.4.Systemic.Property.of.HWS.
8.2.5.Rainfast.Characteristics.of.HWS.
8.2.6.Field.Trials.of.HWS.
8.2.7.Toxicity.Evaluation.
8.2.8.Ecological.Effects.
8.2.9.Summary.

References.
9.General.Methodology.
9.1.General.Synthetic.Procedure.
9.1.1.Chemicals,.Reagents,.and.Solvents.
9.1.2.O,O-Dialkyl.Phosphonates.M1.
9.1.3.O,O-Dialkyl.1-Hydroxyalkylphosphonates.M2.
9.1.4.O,O-Dialkyl.1-(Chloroacetoxy)-Alkylphosphonates.M3.
9.1.5.Substituted.Phenoxyacetic.Acids.M4.
9.1.6.Substituted.Phenoxyacetyl.Chlorides.M5.
9.1.7.O,O-Dialkyl.1-(Substituted.Phenoxyacetoxy)-Alkylphosphonates.IA-IJ.
9.1.8.Phenylhydrazinecarboxamide.M6.and.SodiumTriazol-3-olate.M7.
9.1.9.(1-Phenyl-1,2,4-Triazol-3-yloxyacetoxy)-Alkylphosphonates.IK.
9.1.10.Alkali.Metal.Salts.of.O-Alkyl.AlkylphosphonicAcids.IIA-IIE.
9.1.11.O,O-Bis(Trimethylsilyl).AlkylphosphonatesM8.and.Alkylphosphonic.Acids.M9.
9.1.12.Alkali.Metal.Salts.of.AlkylphosphonicAcids.IIF-IIH.
9.1.13.t-Butylaminium.Salts.of.Alkylphosphonates.IIJ.
9.1.14.Dichloro(Methyl)Phosphine.M10.
9.1.15.O-Methyl.Methylphosphinate.M11.
9.1.16.O-Methyl.(1-Hydroxyalkyl)MethylphosphinatesM12.
9.1.17.Alkylphosphinates.IIIA-IIIG.
9.1.18.Sodium.Salts.of.Alkylphosphinic.Acids.IIIH.
9.1.19.3-Hydroxy-5-Methylisoxazole.DerivativesM13-M16.
9.1.20.O-Methyl.[1-(5-Methylisoxazol-3-yloxyacetoxy)-Alkyl]Methylphosphinates.IIIJ.
9.1.21.1-Phenyl-2,2-Dimethyl-1,3-Propanediol.M17.
9.1.22.Cyclic.Phosphonates.M18.
9.1.23.Cyclic.1-Hydroxyalkylphosphonates.IVA.and.IVB.
9.1.24.Substituted.Phenoxypropionic.Acids.M19.
9.1.25.Substituted.Phenoxypropionyl.Chlorides.M20.
9.1.26.Cyclic.Alkylphosphonates.IVC-IVF.
9.1.27.4-(Hydroxymethyl)-2,6,7-Trioxa-1-Phosphabicyclo-[2.2.2]Octane-1-One/Thione.M21/M22.
9.1.28.Caged.Bicyclic.Phosphates.IVG.and.IVH.
9.1.29.Optically.Active.Cyclic.1-HydroxyalkylphosphonatesIVB.
9.1.30.O,O-Diethyl.(Substituted.Benzyl)PhosphonatesM23.
9.1.31.Optically.Active.1-Hydroxyalkylphosphonates.M2.
9.1.32.Optically.Active.(Substituted.Phenyl)-Methylphosphonates.IA,.IE,.and.IF.
9.1.33.1-Keto.Phosphonates.M24.and.VinylphosphonatesM25.
9.1.34.Optically.Active.1-Substituted.EthylphosphonatesIAandIC.
9.2.General.Information.of.Structural.Characterization.
9.3.Herbicidal.Activity.Assay.
9.3.1.Test.in.Petri.Dishes.
9.3.2.Test.in.Greenhouse.
References.
Index.

 

　　Agrochemicals are used to safeguard our agricultural products from damagescaused by weeds, diseases, or insects. The use of herbicides enables us to optimizethe labor utilization and to ensure both high yields and good quality of crops. Afterrepetitive application of herbicides over many years, the appearance of herbicide-resistant weeds has become a dif?cult problem confronting us. Currently, hundredsof herbicides have been available on the market, but their modes of action towardtarget weed species are rather limited. This situation calls for further research todiscover highly active, environmentally friendly herbicides with novel modes ofaction.
　　Pyruvate dehydrogenase complex (PDHc) is one of the most important oxido-reductases in living organisms. It catalyzes the oxidative decarboxylation ofpyruvate to form acetyl CoA, which is a pivotal process in cellular metabolism.PDHc has been reported as a potential target enzyme affected by some herbicidallyactive compounds. Regrettably, the PDHc inhibitors reported so far were not asactive as other commercial herbicides. Therefore PDHc as a potential herbicidaltarget needs further investigation.
　　Professor Hong-Wu He is a renowned scientist in the ?eld of pesticide science inChina. She is an expert in phosphorus chemistry and pesticide innovation, forwhich she has received many national honors. She is the ?rst one in China toinitiate research projects in the ?eld of novel PDHc inhibitors as potential herbi-cides. Through the systematic studies on molecular design, synthetic methodology,structural optimization, bioscreening, modeling etc., Professor He’s group discov-ered a new environmentally friendly herbicide, namely clacyfos (HW02), which hasthe characteristics of low toxicity, low residue, and is highly safe to bees, birds,?shes, and silkworm etc. As a new PDHc inhibitor, clacyfos exhibits a differentmode of action and shows no cross-resistance toward other conventional herbicides.Clacyfos has been approved in 2007 as a new post-emergence herbicide by theMinistry of Agriculture of China. It is expected that clacyfos will play a signi?cantrole in weed control.In this book, Prof. Hong-Wu He and co-authors systematically introduce theirwork on the PDHc inhibitor clacyfos, from its discovery, development to com-mercialization. This monograph is hereby highly recommended to our colleaguesand graduate students in the ?elds of pharmaceutical and pesticide research,phosphorus chemistry, chemical biology, life sciences, and etc. It will bring newinsights into the discovery of a novel herbicide, and the complex interdisciplinarywork involved. I thank the authors for sharing their expertize and experience withus, which will surely be valuable for our future research.April 2013 Zheng-Ming Li
　　Nankai University