摘要
α-氨基亚膦酸是天然氨基酸的重要含磷结构类似物，是继氨基羧酸、氨基磺酸后在生物体内发现的第三类氨基酸。α-氨基亚膦酸作为天然氨基酸的含磷类似物具有许多重要的生理作用，特别是其中的磷原子具有四面体结构，与羧酸衍生物水解的中间体十分相似，具有抗肿瘤活性、植物生长调节剂、除草、杀菌和抑制酶活性如对高血压蛋白还原酶，HIV蛋白酶的抑制活性。α-羟基亚膦酸酯也是一类重要的有机反应中间体，不仅本身具有一定的生物活性，而且还是合成各种亚膦酸酯衍生物的重要中间体，许多由α-羟基亚膦酸酯合成的亚膦酸酯衍生物也显示了令人注目的农药活性及药物活性。
Pudovik反应即亚磷酯与醛的加成反应，是合成α-羟基亚膦酸酯方便而有效的方法，本论文初次选择氨水作为Pudovik反应的碱催化剂，尝试在水溶液中进行Pudovik反应。在水相中进行反应操作简单易行，对环境比较友好，经硅胶柱层析纯化得到产物，其产率为62-96％。
本论文系统地合成了α-氨基亚膦酸酯(A)，α-羟基亚膦酸酯(B)，α-氨基亚膦酸酯衍生物(C)和α-羟基亚膦酸酯衍生物(D)等61个含磷系列化合物，其中新化合物31个，文献未报道的晶体结构30个。对它们的~1HNMR、~(13)C NMR、~(31)PNMR、质谱、红外、元素分析等化学谱图作详细表征。由于亚膦酸酯含有P-C键，论文采用从头算法计算出α-羟基(氨基)亚膦酸酯的~1J_(CP)自旋偶合常数，计算值~1J_(cal)和实验值~1J_(exp)基本一致，磷碳之间的一键偶合裂分常数~1J_(P-C)在154-168 Hz之间。并用X-ray单晶衍射对所合成30个化合物的晶体结构进行详细解释，分别得到它们的晶系、空间群、单胞参数(a，b，c，α，β，γ)、单胞体积、化合物密度和衍射指标等晶体参数以及原子坐标、热参数、键长、键角、二面角、分子间氢键、化合物三维结构图和晶体堆积图等相关结构信息。
晶体中以氢键堆积方式主要有两种。一种是α-氨基亚膦酸酯分子Ⅰ酰胺上的氨基作为氢键给体与分子Ⅱ磷上的氧形成一对氢键，而分子Ⅱ酰胺上的氨基作为氢键给体与分子Ⅰ磷上的氧形成另外一对氢键，这样两个分子由两个氢键结合在一起形成一个“面对面”的单元在晶体的生长方向形成晶体网络。另一种是α-羟基亚膦酸酯分子Ⅰ的羟基作为氢键给体与分子Ⅱ磷上的氧形成一对氢键，而分子Ⅱ的羟基作为氢键给体与分子Ⅲ磷上的氧形成另外一对氢键，这样分子间由氢键连在一起形成一串“手拉手”的单元在晶体的生长方向形成晶体网络。而对于其他不含磷杂原子的分子一般以π-π堆积成晶体。
对合成的α-羟基(氨基)亚膦酸酯及其衍生物进行电喷雾质谱裂解规律的研究：在电喷雾质谱加钠正离子模式下，化合物在失去一个丙烯分子或两个丙烯分子后，会继续失去一个水分子。在ESI-MS/MS~3的质谱中出现了丰富的碎片峰，其中有失去一个二异丙基亚磷酸酯的碎片离子和两个重排离子峰。重排离子是在钠离子的作用下，螯合了磷原子上的氧原子和羰基氧原子形成七员环中间体，使磷原子上的一个氧原子迁移到羰基碳上而生成的取代苯甲酸加钠离子。化合物中烷氧基，磷酰基及α-位氢的存在对重排起重要作用，论文中又用高分辨质谱和同位素离子峰来证明这些新颖的重排离子峰。
ESI-MS质谱研究发现了合成的α-氨基亚膦酸酯衍生物可以与ATP分子发生弱相互作用，并形成1：1的非共价复合物。荧光光谱研究表明α-氨基亚膦酸酯衍生物猝灭了ATP的荧光，猝灭过程是由于形成了非共价复合物而引起的静态猝灭。并且通过分子动力学模拟方法——构象分析与分子对接，观察到化合物C7与ATP形成两对氢键，一对是化合物的氨基作为氢键给体与ATPγ位磷上的氧形成氢键，另一对是腺苷上的氨基作为氢键给体与化合物磷上的氧原子形成氢键。
本论文初步研究了L-脯氨酸及其衍生物对Pudovik反应手性碳碳原子的不对称选择性影响。考察溶剂体系、碱、反应温度和反应物摩尔比对α-羟基亚膦酸酯α位手性碳碳原子的不对称选择性影响。
论文中还初步考察了部分α-氨基(羟基)亚膦酸酯化合物的抗菌和抗Raji人淋巴癌细胞的生物活性，发现它们具有一定的生物活性。
α-Aminophosphonates,as phosphorus analogs of amino acids,and their derivativeshad attracted much attention for their broad biological activities,such as herbicide,antibacterial,enzymatic inhibitor,antiviral and antitumor activitives.
Pudovik reaction is a well known reaction for the synthesis of phosphorus estercontaining a P-C bond by the addition of aldehyde to phosphonate.In this dissertation,agreen chemistry method was tried by using 25 % aqueous ammonia as the base catalystfor the Pudovik reaction.The products were purified by silica gel columnchromatography with the yields of 62-96 %.The merits of the reaction are the shortpath of synthesis,aqueous media substituted for the organic phase and easily purificationprocedure.
The purified products includeα-aminophosphonates(A),α-hydroxyphosphonates(B),the derivatives ofα-amino phosphonates(C)and the derivatives ofα-hydroxyphosphonates(D).Their structures were confirmed by elemental analysis,~1H NMR,~(13)CNMR,~(31)p NMR,MS and IR.The compounds contained P-C bonding with the couplingconstant ~1J_(P-C)154-168 Hz,which is consistent with the calculated value.Theirantibacterial and antitumor activities were tested in the experiments.
The structures of thirty compounds were determined by X-ray diffractometer.Theircrystal parameters such as the crystal system,space group,unit cell dimension(a,b,c,α,β,γ),cell volume and limiting indices were obtained.And the structure information suchas atomic coordinates,equivalent isotropic displacement parameters,bond lengths,bondangles,torsion angles,hydrogen bond and packing figures were collected.
These synthesized phosphonate esters were investigated by positive ionelectrospray ionization mass spectrometry(ESI-MS)in conjunction with tandem massspectrometry(MS/MS).It was found that for the sodium adduct there were two novel rearrangement reactions,in which phosphoryl oxygen atom migrated to the carbonylcarbon and a cleavage occurred at the amide bond,or a benzyl amine fragment was lostand the phosphorus compound was reduced.However,when the methyl groupsubstituted for the isopropyl group,these migrations were inhibited.A possiblemechanism was proposed.And the high-resolution mass spectrum was also applied toidentify the formula of these novel rearrange fragment ions.These results showed thatESI-MS is an useful tool for structural determination ofphosphonate ester.
The ESI-MS technique was also applied to study on the weak non-covalentinteraction between ATP andα-aminophosphonates.In fluorescence experiment,thefluorescence intensity of ATP was quenched with the increasing concentration ofα-aminophosphonates.Molecular modeling also provided the possible interactionmodel,namely,there are two pairs of hydrogen bond between them.
Furthermore,optical active L-Proline was used as catalysis in Pudovik reaction.Thereaction conditions were optimized in different solvent systems,bases,reactedtemperature and reactant molar ratio.The enantioselectivity through the derivatives ofL-Proline(G)is moderate.
引文
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