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α-取代烯基膦酸酯的合成及应用研究
Synthesis and Application of the α-Substituted Alkenylphosphonates
【作者】 张莉;
【作者基本信息】 太原理工大学 , 化学工程与技术, 2018, 博士
【摘要】 许多药物分子含有α-取代烯基膦酸酯结构。研究表明,将药物分子中的羧酸基团替换成膦酸或者膦酸酯,是提高或改变分子生物活性的一种有效策略,在药物的开发和筛选中应用广泛。在有机合成方面,通过α-取代烯基膦酸酯可以合成多种有机磷化合物,包括抗疟疾药物膦胺霉素衍生物。合成α-取代烯基膦酸酯的方法主要有:加成/消除串联反应、脱羧亚甲基化反应、过渡金属催化的偶联反应、炔烃的磷氢化加成反应,以及自由基反应。然而,普适高效的合成方法目前还没有文献报道。因此,设计并合成新型的亲电偶联体,通过成熟的碳碳偶联策略较系统地合成α-取代烯基膦酸酯仍具有极大的研究价值。并且,随着合成方法的发展,开发α-取代乙烯膦酸酯的应用价值将会得到更多关注。本论文的研究工作包括三方面:开发新型亲电偶联体α-(类)卤代烯基膦酸酯,通过碳碳偶联反应系统地合成α-取代烯基膦酸酯,以及通过α-取代乙烯膦酸酯合成α-取代烷基膦酸酯和1-取代环丙烷膦酸酯。其主要研究内容和实验结果如下:(1)发展普适高效的方法合成α-取代乙烯膦酸酯。以α-氯或溴代乙烯膦酸酯为亲电偶联体,Pd(OAc)2/tBu3PH.BF4和Pd2(dba)3/SPhos催化条件下甲苯溶液中的Suzuki反应实现了乙烯膦酸酯α-碳的烷基化、芳基化、炔基化反应,收率为42%-99%。该方法具有较好的官能团兼容性和底物普适性。此外,该反应适合克级产物的合成,模型反应放大至50 mmol反应效率没有明显下降,得到α-苯基乙烯膦酸二乙酯的收率为96%。(2)开发了新型亲电偶联体α-膦酸酯乙烯芳基磺酸酯。在7 mol%Pd(OAc)2/15 mol%SPhos催化条件下甲苯溶液中,α-膦酸酯乙烯芳基磺酸酯与芳基硼酸进行Suzuki反应,合成α-芳基乙烯膦酸酯的收率在60%-99%之间。以烷基或杂环芳基三氟硼酸钾为亲核偶联体时,同样的催化条件下甲苯/水溶液中,α-膦酸酯乙烯芳基磺酸酯的Suzuki反应可得到目标偶联产物收率为35%-99%。(3)发展一种高效通用的方法合成α-烷基烯基膦酸酯。在DMA溶液中5 mol%Pd(OAc)2/10 mol%SPhos催化条件下,α-(类)卤代烯基膦酸酯的Negishi反应合成了α-烷基烯基膦酸酯,收率在56%-98%之间。该方法适合一级烷基锌试剂、苄基锌试剂和二甲基锌,而且具有良好的官能团兼容性,能够容忍CN、Cl、CO2Et等官能团。此外,该方法具有一定的实用性,适合克级产物的合成。(4)发展CuH催化还原α-取代乙烯膦酸酯合成α-取代乙基膦酸酯的方法。以10 mol%Cu(OAc)2.H2O为铜源,10 mol%PPh3或3-8 mol%BDP为配体,3当量的聚甲基氢硅氧烷为氢源,在甲苯溶液中40 oC反应条件下现时产生CuH试剂还原α-取代乙烯膦酸酯,得到α-取代乙基膦酸酯产率为80%-99%。该方法具有高度的选择性,仅还原与膦酸酯直接相连的C=C双键而保留其它位置的C=C、NO2、CN、COMe等官能团。此外,该方法能够较好地兼容卤代芳基,也适合产物的克级合成。与2-苯丙烯酸酯的竞争反应结果表明,α-苯乙烯膦酸酯的还原更难进行,但可重复性更好。(5)探索光催化α-芳基乙烯膦酸酯与烷基自由基的反应。以烷基羧酸或烷基三氟硼酸钾为烷基自由基前体,在DMSO溶液中9 W LED灯带照射2mol%Ir[dF(CF3)ppy]2(dtbbpy)PF6催化条件下,α-芳基乙烯膦酸酯可进行类Giese反应,以80%-95%的产率合成α-芳基烷基膦酸酯。该反应可作为汇聚式合成膦胺霉素衍生物的关键步,用于膦胺霉素衍生物前体的合成。进一步的研究结果表明,以双(邻苯二酚)-氯甲基硅化18-冠醚-6合钾为氯甲基自由基前体,同样的反应条件下α-芳基乙烯膦酸酯能够进行环丙烷化反应,得到α-芳基环丙烷膦酸酯。该方法对其它Michael受体和1,1-二芳基乙烯也普适,环丙烷化合物产率在34%-98%之间。
【Abstract】 The structure ofα-substituted alkylphosphonates is present in many drug molecules.Study shows that substitution of a carboxylic acid unit by a phosphonic acid or phosphonate moiety in biologically active organic compounds is a promising strategy for increasing the potency and/or selectivity of the original activity,which is widely applied to the drug’s development and optimization.Moreover,many organophosphorus compounds can be synthesized via theα-substituted alkylphosphonates,including fosmidomycin derivatives.The major methods to synthesize theα-substituted alkylphosphonates include addition/elimination tandem reaction,decarboxylative condensation,transition-metal catalyzed cross-coupling reactions,hydrophosphinylation of the alkynes,and the radical reactions.However,there is no general and efficient protocol to incorporate alkyl,(hetero)aryl,alkenyl,and alkynyl substituents at theα-carbon of the ethenylphosphonates.Therefore,there is still much valuable work left in designing and synthesizing the electrophilic coupling partners,and it is also interesting to apply these electrophilic coupling partners to synthesize theα-substituted alkylphosphonates via the strategy of C-C coupling.Additionally,more concern will be devoted to a synthetic application of theα-substituted vinylphosphonates with the development of synthetic methods.This thesis consists of three parts,including the development of new class of electrophilic coupling partners,the synthesis of a wide range of theα-substituted alkenylphosphonates,and the synthesis of theα-substituted alkylphosphonatesand1-substitutedcyclopropylphosphonatesviatheα-substituted vinylphosphonates.The major research contents and results of every subject are as follows:(1)An efficient and versatile protocol to synthesize variousα-substituted vinylphosphonateswasdevelopedviapalladiumcatalyzedSuzuki cross-coupling reaction.Using theα-halo vinylphosphonates as the electrophilic coupling partners,Pd(OAc)2/tBu3PH.BF4 or Pd2(dba)3/SPhos as the catalyst,a wide range ofα-alkyl,aryl,heteroaryl,alkynyl substituted vinylphosphonates could be nicely accessed in 42%-99%yields under the mild conditions.A good functional group tolerance and a broad substrate scope were also demonstrated.The mode reaction could be scaled up to 50 mmol without decline in efficiency,and get accessed to diethylα-phenyl vinylphosphonate in 96%yield.(2)A new class of electrophilic coupling partners was developed.With theα-phosphonovinyl arylsulfonates as the electrophilic coupling partners,α-aryl vinylphosphonates could be smoothly accessed in 60%-99%yields via 7 mol%Pd(OAc)2/15 mol%SPhos catalyzed Suzuki reaction of organoboronic acid in toluene.Under the same reaction conditions,α-(hetero)aryl and alkyl vinylphosphonates could be produced in 35%-99%yields with potassium trifluoroborates as the nuclephilic coupling partners in toluene/H2O.(3)A general and efficient method to synthesize a wide range ofα-alkyl alkenylphosphonates was developed.Withα-(pseudo)halo alkenylphosphonates as the electrophilic coupling partners,variousα-alkyl alkenylphosphonates could be accessed in 56%-98%yields via 5 mol%Pd(OAc)2/10 mol%SPhos catalyzed Negishi reaction in DMA.This reaction was suitable for primary alkyl organozinc reagents,a broad of benzylzinc reagents,and dimethylzinc,and could be compatible with many functional groups such as CN,Cl,CO2Et.Additionally,this methodology was suitable to the gram-synthesis of the cross-coupling products.(4)A gentle and economical method to synthesize theα-substituted ethylphosphonates was developed via the CuH catalyzed reduction of theα-substituted vinylphosphonates.The CuH catalyst was generated in situ from the mixture of 10 mol%Cu(OAc)2,10 mol%PPh3 or 3-8 mol%BDP,and 3equivalent PMHS at 40 oC.This protocol features high selectivity because the hydrogenation only take place in the phosphono substituted C=C bond keeping untouched other functional groups such as C=C,NO2,CN,COMe,and produced theα-alkyl or(hetero)aryl ethylphosphonates in 80%-99%yields.Moreover,this method could be well compatible with halogenated aryl.Compared with the acrylate,the hydrogenation of a vinylphosphonate is more difficult and reproducible.(5)As a good radical acceptor,photo-catalyzed reactions of theα-aryl vinylphosphonates were explored.With alkyl trifluoroborate or carboxylic acid as the alkyl radical precursors,Giese-type reaction of theα-aryl vinylphosphonates undergo smoothly under the standard conditions of 2 mol%Ir[dF(CF3)ppy]2(dtbbpy)PF6 in DMSO 9 W blue LED stirring for 12 h,and get accessed to theα-aryl alkylphosphonates in 80%-95%yields.As a critical step,this protocol was successfully applied to the synthesis of the fosmidomycin derivative.A further study showed that cyclopropylphosphonates compounds couldbeaccessedwith2equivalentpotassium[18-Crown-6]bis(catecholato)-chloromethylsilicate as the chloromethyl radical precursor under the same standard conditions.Interestingly,this method was suitable for other Michael radical acceptors and 1-substitutent-1-aryl olefins,and get the1,1-disubstituted cyclopropanes in 34%-98%yields.
【Key words】 α-substituted; alkenylphosphonates; cross-coupling reaction; reduction; cyclopropanation;