【作者】 程司堃；

【导师】 张生勇；

【作者基本信息】 第四军医大学 ， 药理学， 2004， 博士

【摘要】 手性β-氨基醇和手性邻二醇在有机合成中具有重要的用途。它们是理想的手性合成砌块，可用于合成紫杉醇、美托洛尔、普萘洛尔、沙丁胺醇和氨基酸等多种手性药物。一般制备手性β-氨基醇和手性邻二醇需经多步反应，而Sharpless报道的催化不对称二羟化（AD）反应和不对称氨羟化（AA）反应，在手性锇催化剂的存在下，通过一步反应就可将潜手性烯烃直接转变成手性邻二醇或手性β-氨基醇类化合物。Sharpless因此分享了2001年诺贝尔化学奖。 目前AD和AA反应虽然可以通过一步反应得到手性化合物，但很少用于手性β-氨基醇和手性邻二醇的大规模制备。其主要原因是一方面AA反应复杂，所适用的烯烃底物有限，而且常常伴随有副产物生成，使得目标产物的分离和纯化相对困难；另一方面AD和AA反应使用的催化剂由手性配体和OsO₄配位形成，而手性配体和OsO₄价格昂贵，且OsO₄毒性大，大规模生产受到限制。 因此，为满足生命科学和制药领域对大量手性化合物的需求，近年来不对称催化反应研究工作者致力于优化反应条件；研究新型高效且价格低廉的手性配体及其催化剂体系；有效回收和重复使用过渡金属配合物手性催化剂，努力实现不对称催化合成工业化。第四军医大学博士学位论文本课题主要从以下四方面开展了研究工作:一、首次合成了“二聚体”金鸡纳生物碱衍生物配体（QN）ZAQN 并用改进的方法合成了手性配体（DHQD）ZPYDz，在选择的 氧化一供氮试剂存在下，率先将三个配体（QN）ZPHAL、 （QN）ZAQN和（DHQD）ZpYDZ应用于一系列潜手性烯烃的 AA反应，研究了配体对烯烃AA反应化学、区域和立体选 择性的影响;扩展了（QN）ZPHAL在AA反应的底物范围，首 次应用于四种肉桂酸甲醋的反应，立体选择性为92一99%ee。二、研究了在手性配体（QN）ZPHAL存在下改变反应介质对苯乙 烯AA反应化学产率和立体选择性的影响。三、设计并率先合成了可溶性高聚物负载手性配体 QN一AQN一OPEG一OMe，并用于一系列烯烃的AD反应，研究 了反应活性以及配体的可回收和重复使用情况。四、将可回收和重复使用的高聚物负载手性配体 QN一AQN一OPEG一OMe应用到临床常用药美托洛尔（商品名: 倍他乐克）手性中间体的首次不对称合成，取得了令人满意 的结果。本论文包括六部分: 第一部分:（QN）ZPHAL一050;催化芳香链端烯烃和 反式肉桂酸酷的AA反应1、手性配体（QN）ZPHAL的合成 以奎宁和l，4一二氯一2，3一二氮杂蔡为原料经亲核取代反应生成（QN）ZPHAL，化学产率为72%。2、（QN）ZpHAL一050;催化烯烃AA反应研究 在正丙醇:水（l:l）的介质中，当底物/配体/KZOsOZ（OH）4/N-氯代氨基甲酸节酷物质的量之比为1:0.05:0.04:3 .1时，反应体系不仅具有单一的化学选择性，而且区域选择性也很高，主产物均第四军医大学博士学位论文为节胺。反应产率为48一76%。所得AA产物中，最低的光学纯度为85%ee，最高的可达99%ee以上。 将正丙醇和水的比例增加到1.7:1，苯乙烯的AA反应产率从48%提高到57%，而且产物的光学纯度由85%增至93%ee。第二部分:（QN）ZPHAL一050;催化反式肉桂酸甲酷的AA反应 研究了反式肉桂酸甲酷在（QN）ZPHAL一050;催化剂催化下AA反应的化学、区域和立体选择性。在相似的实验条件下，对五种肉桂酸甲醋类底物的立体选择性优秀（92一99%ee），化学产率为52一70%。对氯肉桂酸甲醋AA产物的ee值大于99%，化学产率为70%。反应的主产物均为节胺，这是由于肉桂酸甲酷中的苯环与配体一050;配合物中配体的甲氧基哇琳结合腔之间存在偶极一偶极相互作用，有利于氮原子加成到节基碳上。第三部分:（QN）ZAQN一050;催化反式肉桂酸甲酷的AA反应1、手性配体（QN）ZAQN的合成 以奎宁和1，4一二氟葱醒为原料，经过亲核取代反应生成（QN）ZAQN，化学产率为85%。2、（QN）ZAQN一0504催化烯烃AA反应研究 在正丙醇/水（1:1）的溶剂体系中，当底物/配体服20502（OH）4/N-氯代氨基甲酸节酷的物质的量之比为1:0.05:0.04:3.1时，手性配体对五种底物的立体选择性优秀，ee值均大于90%，化学产率为50一70%。配体在对甲基肉桂酸甲醋的AA中立体选择性最高，产物的光学纯度为96%ee。与配体（QN）ZpHAL相比，（QN）ZAQN一050;催化剂在肉桂酸酷类底物的AA反应中，区域选择性相反，产生的主产物为节醇。对甲基肉桂酸甲酷的AA反应区域选择性最好（节醇:节胺二98:2），这可能第四军医大学博士学位论文是由于底物烯烃在与饿一配体配合物亲电加成的方式与（QN）ZPHAL相反，但具体的作用方式还有待进一步研究。第四部分:（DHQD）ZpYDZ一050;催化芳香链端烯烃和反式肉桂酸酷的AA反应l、手性配体（DHQD）ZpYDZ的合成 用NaH作为碱，以二氢奎尼定和3，6一二氯哒嗦为原料，经过亲核取代反应生成（DHQD）ZPYDZ，化学产率为78%。与文献方法相比，反应条件温和，产率高。2、（DHQD）ZpYDZ一050;催化烯烃AA反应研究 在正丙醇/水（1:1）的溶剂体系中，当底物/配体/K20soZ（oH）4/N-氯代氨基甲酸节醋的物质的量之比为1:0.08:0 .06:3.1时更多还原

【Abstract】 The chiral β -amino alcohol and vicinal diol moieties appear in numerous chiral drugs, such as Taxol, Propranolol, Metoprolol, Salbutamol and Amino acids etc.. The asymmetric aminohydroxy-lation (AA) and dihydroxylation (AD) discovered by Sharpless and his coworkers have rapidly become invaluable synthetic tools in organic chemistry. The great value is given in the possibility of introducing a chiral vicinal diol and β -amino alcohol moieties from readily available prochiral olefms in a single step. Expectively, Sharpless shared the Nobel Chemistry Prize in 2001.Although the reactions have had widespread applications in organic synthesis, there have been few large-scale industrial productions of chiral β -amino alcohol and vicinal diol. In many cases, problems arise that appear to be related to some combination of the following issues: 1) A A reaction still lacks the extensive substrate scope. 2) Chemo-, regio- and enantioselectivities in AA reaction cause by-products, which make the separation of the "target" molecule troublesome. 3) The chiral catalyst complex in AD and AA reactions are formed in situ by chiral ligand and osmium tetraoxide. Not only are chiral ligands and osmium tetraoxide quite expensive, but Osmium tetraoxide is also highly toxic.Recently, scientists devoted themselves to optimizing reaction condition, developing novel highly effective and cheap chiral ligand and catalysis system, recovering and reusing chiral catalysts (transition metal complex) to promote the large-scale preparation of chiral compounds.In this project, researches were carried out as follows:Firstly, a dimeric cinchona alkaloid derivative ligand, (QN)2AQN, was synthesized for the first time. And the other ligand (DHQD)2PYDZ was synthesized in a modified method. Then, three chiral ligands (QN)2PHAL, (QN)2AQN and (DHQD)2PYDZ were applied to the AA reactions of a series of prochiral olefins to study the effect of the ligands on the chemo-, regie- and enantioselectivities in A A reaction. The substrate scope was expanded in the A A reaction of five methyl cinnamates with excellent enantioselectivities by using (QN)2PHAL as chiral ligand.Secondly, the effect of solvent system on chemical yield and enantio- selectivities in AA reaction of styrene was investigated.Thirdly, design and synthesis of a soluble polymer-bound ligand: QN-AQN-OPEG-OMe for the asymmetric dihydroxylation of a series of olefins. Furthermore, the reaction activities and the recovery of chiral ligand were studied.Fourthly, the soluble polymer-bound ligandQN-AQN-OPEG-OMe was applied to the asymmetric synthsis of chiral intermadiate of the widely prescribed drug metoprolol (Betaloc) with satisfactory results for the first time.This dissertation consists of six parts:Part I : Asymmetric aminohydroxylation of terminal aromaticolefins and f-cinnamic ester catalyzed by(QN)2PHAL-OsO4 complexa. Synthesis of (QN)2PHALA mixture of quinine, 1,4-dichlorophthalazine, KOH and K2CO3 in dry toluene were refluxed, with azeotropic removal of water for 14h, to afford (QN)2PHAL in 72% yield by chromatography (eluent, Me2CO: EtOAc:Et3N = 450:50:30) .b. A A reactionEffective experimental conditions for 1 mmol olefins in the AA reactions employed 3.1 equiv. benzyl jV-chlorocarbamate (the oxidant and nitrogen source), 4mol% K2OsO2(OH)4 and 5mol% (QN)2PHAL and nPrOH/H2O(1:1), excellent enantioselectivity as well as specific regio and chemoselectivity were observed. 85-99%ee and 48-76% isolated chemical yields of the products were achieved.The AA raction of styrene in the solvent system (nPrOH/H2O 1.7:1) could increase the chemical yield from 48% to 57% and the optical purity of the products from 85% to 93%ee.Part II: Asymmetric aminohydroxylation of E-methyl cinnamates catalyzed by (QN)2PHAL-OsO4 complexChemo-, regio- and enantioselectivities of five methyl cinnamates in AA reactions were studied. In the similar experimental condition, five methyl cinnamates reacted smoothly to give the B -amino alcohol i更多还原