CN108191664B - 一种β羟基酸类化合物及其合成方法 - Google Patents
一种β羟基酸类化合物及其合成方法 Download PDFInfo
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 239000003446 ligand Substances 0.000 claims abstract description 29
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/56—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/734—Ethers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
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Abstract
本发明公开了一种β羟基酸类化合物及其合成方法，所述方法包含下列步骤：以的α，β不饱和酮酸酯类化合物与丙二酸为原料，在有机溶剂A中，金属与手性配体为催化剂的条件下直接充分反应，反应结束后反应液经分离纯化得到所述的高立体选择性的β羟基酸类化合物。本发明是首次利用过渡金属醋酸镍与手性配体(4)为催化剂，促进不饱和酮酸酯与丙二酸类化合物脱羧加成得到高收率、高立体选择性的β羟基酸类化合物。其有益效果主要体现在：1，操作简单；2，能快速构建高立体选择性的β羟基酸骨架结构分子；3，反应收率高，立体选择性好。故本发明具有较高的基础研究价值和社会经济效益。
Description
技术领域
本发明涉及有机化学领域，特别是指一种β羟基酸类化合物及其通过脱羧aldol加成的合成方法。
背景技术
β-取代羧酸及其衍生物广泛存在于众多天然产物和药物分子中，是有机合成中以及药物开发工程中的重要中间体。β-羟基羧酸是合成β-氨基酸、青霉素、生物信息素等的重要前体。手性β-羟基取代羧酸是众多天然产物(两性霉素B、泰乐菌素、蔷薇霉素)的组成核心单元，并且对于发展新的血小板集落刺激因子有重要的作用，因此，开发绿色高效的合成β-取代羧酸及其衍生物的合成策略具有重要意义。
从现有的报道来看，构建重要的有机合成中间体与众多药物活性分子的核心骨架的β-羟基取代的羰基类化合物利用脱羧-Aldol反应来实现。但是，由于对该类反应认识的局限，存在底物结构受限、产物收率很低、对映选择性差等缺陷。在此基础上，设计开发新的底物结构，实现一类结构新颖的β羟基酸类化合物的合成具有重要的的理论研究意义和实际应用价值。此外，现有的报道具有诸多局限，构建高立体选择性的β羟基酸类化合物以及含多官能团的β羟基酸类化合物的报道极少。基于此，进一步了解脱羧加成反应的性质，拓展该反应类型和应用，为β羟基酸骨架结构分子开发设计新的合成途径，对于药物分子的开发设计以及基础方法学研究都具有重要的推动作用。
发明内容
本发明现有技术存在的缺点与不足，提供一种β羟基酸类化合物。
本发明的第二个目的是，提供一种β羟基酸类化合物的合成方法，该方法操作简单、工艺合理、低毒性、反应条件温和、反应收率高、产品质量好、具有高立体选择性。
为实现第一个目的，本发明的技术方案为一种β羟基酸类化合物，其结构式为：
式中，R1代表氢、氟、氯、溴、硝基、烷基、烷氧基或芳基中的一种；R2代表甲基、乙基、异丙基或叔丁基中的一种。
为实现本发明的第二个发明目的，其技术方案包括以下步骤：
以α，β不饱和酮酸酯类化合物与丙二酸为原料，在有机溶剂A中，加入金属与手性配体以摩尔比1：1-1.5混合反应10-120分钟得到催化剂，在0-60℃温度的条件下直接充分反应3-120小时，反应完毕后经过分离纯化得到所述脱羧aldol加成的β羟基酸类化合物；
进一步设置为所述α，β不饱和酮酸酯类化合物与丙二酸的结构式为
式中，R1代表氢、氟、氯、溴、硝基、烷基、烷氧基或芳基；所述的R1优选为氢；R2代表甲基、乙基、异丙基或叔丁基。所述的R2优选为烷基；
进一步设置为所述的有机溶剂A为不与反应物和产物发生反应的有机溶剂，是二氯甲烷、乙酸乙酯、四氢呋喃、乙腈、甲苯、甲醇、氯仿中的一种或者任意几种的组合，优选为下列之一：四氢呋喃、乙腈。
进一步设置为所述有机溶剂A的质量是原料的1-50倍，优选为20-30倍。
进一步设置为所述的α，β不饱和酮酸酯与丙二酸的摩尔投料比为1:1-5，优选为1：3。
进一步设置为所述的催化剂体系中金属为三氟甲磺酸铜、硫酸铜、醋酸铜、醋酸钯、氟化亚铁、醋酸银、醋酸镍、乙酰丙酮镍、氟化镍、氯化镍、硫酸镍、高氯酸镍、双三苯基膦氯化镍中的一种或者任意几种的组合；优选为下列之一：醋酸镍、乙酰丙酮镍、氟化镍、氯化镍。
进一步设置为所述的催化剂体系中手性配体为下列一种或者任意几种的组合：
优选为下列之一：手性配体(4)
进一步设置为所述的催化剂与原料α，β不饱和酮酸酯类化合物比例为1％-20％，优选为10％。
进一步设置为本发明所述的催化剂体系中金属与手性配体的摩尔比为1：1-1.5，优选为1：1.1。
进一步设置为本发明所述的催化剂体系中金属与手性配体的反应时间为10-120分钟，优选为30-60分钟。
进一步设置为本发明中，反应温度为0-60℃，优选为20-30℃，反应时间一般在3-72小时，优选为40-60小时。
进一步设置为本发明所述的分离纯化采用的是柱层析分离纯化法。反应结束后所得反应液蒸出溶剂，经湿法上样进行柱层析分离纯化干燥即得目标产物β羟基酸类化合物。进一步设置为，淋洗液为二氯甲烷与甲醇混合物，二氯甲烷与甲醇比例为60：1-10：1，优选为40：1-20：1。
本发明是首次利用乙酰丙酮镍和噁唑啉骨架的手性配体(4)催化α，β不饱和酮酸酯与丙二酸发生脱羧aldol加成反应，合成结构新颖的不饱和β羟基酸类化合物。其有益效果主要体现在：1，操作简单；2，成本低廉；3，反应收率高；4，具有高立体选择性。故本发明具有较高的基础研究价值和社会经济效益。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚，下面结合具体的实施案例对本发明进一步说明。应该理解为，本发明实施案例的制备方法仅用于说明本发明，而不是对本发明的限制，本发明的保护范围并不仅限于此，在本发明的构思前提下，对本发明制备方法的简单改进都属于本发明要求保护的范围。
优选实施例
本发明具体推荐所述的不饱和β羟基酸类化合物的化学合成方法按照如下步骤进行：室温条件下，将金属催化剂与手性配体加入反应釜中，用溶剂A充分溶解后，充分搅拌30-60分钟，再向反应釜中加入α，β不饱和酮酸酯与丙二酸，在20-30℃的条件下，搅拌使其反应40-60小时，实时监测反应进程，反应完毕后分离纯化，干燥后即得到所述的不饱和β羟基酸类目标化合物。
实施例1
R1为氢，R2为异丙基的α，β不饱和酮酸酯、丙二酸与催化剂的物质的量比为1.0：3.0：0.1投料，底物苯基α，β不饱和酮酸异丙酯436mg(2mmol)、丙二酸624mg(6mmol)、醋酸钯45mg(0.2mmol)、手性配体(4)129mg(0.22mmol)；有机溶剂为四氢呋喃8.9g，其总用量为底物α，β不饱和酮酸酯的20倍。
室温条件下，将金属催化剂与手性配体(4)加入反应釜中，用四氢呋喃充分溶解后，充分搅拌30-60分钟，再向反应釜中加入苯基α，β不饱和酮酸异丙酯与丙二酸，在20℃的条件下，搅拌使其反应118小时后结束。
反应完毕后分离纯化，干燥后得到白色固体，即为所述的不饱和β羟基酸类目标化合物1a 189mg，收率34％，对映选择性过量为10％ee，纯度为99.0％具体结构为：
数据表征：
(E)-3-hydroxy-3-(isopropoxycarbonyl)-5-phenylpent-4-enoic acid(1a):[α]D 20＝+3.8(c＝0.551in EA)；enantiomeric excess:10％,Daicel Chiralpak IA,hexane/iso-propanol＝90/10,flow rate 1.0mL/min,25oC:tR(minor)＝9.75min,tR(major)＝15.63min；1H NMR 1H NMR(500MHz,Acetone-d6)δ7.38(m,2H),7.32(m,2H),7.26(m,1H),6.89(d,J＝15.8Hz,1H),6.21(d,J＝15.8Hz,1H),5.13(m,1H),3.14(d,J＝16.3Hz,1H),2.77(d,J＝16.3Hz,1H),1.30(d,J＝0.9Hz,3H),1.29(d,J＝0.9Hz,3H)；HRMS(BRUKERmicrOTOF-QII)exact mass calcd for(C16H20O5Na)+requires m/z 301.1052,found m/z301.1055.
实施例2
底物苯基α，β不饱和酮酸异丙酯436mg(2mmol)、丙二酸624mg(6mmol)、醋酸铜40mg(0.2mmol)、手性配体(4)129mg(0.22mmol)；有机溶剂为四氢呋喃8.9g，其总用量为底物α，β不饱和酮酸酯的20倍。
室温条件下，将金属催化剂与手性配体(4)加入反应釜中，用四氢呋喃充分溶解后，充分搅拌30-60分钟，再向反应釜中加入苯基α，β不饱和酮酸异丙酯与丙二酸，在20℃的条件下，搅拌使其反应108小时后结束。
其余同实施例1，得目标产物1a 317mg，收率57％，对映选择性过量为35％ee，纯度为98.8％。
实施例3
底物苯基α，β不饱和酮酸异丙酯436mg(2mmol)、丙二酸624mg(6mmol)、醋酸银33mg(0.2mmol)、手性配体(4)129mg(0.22mmol)；有机溶剂为四氢呋喃8.9g，其总用量为底物α，β不饱和酮酸酯的20倍。
室温条件下，将金属催化剂与手性配体(4)加入反应釜中，用四氢呋喃充分溶解后，充分搅拌30-60分钟，再向反应釜中加入苯基α，β不饱和酮酸异丙酯与丙二酸，在20℃的条件下，搅拌使其反应108小时后结束。
其余同实施例1，得目标产物1a 167mg，收率30％，对映选择性过量为9％ee，纯度为99.2％。
实施例4
底物苯基α，β不饱和酮酸异丙酯436mg(2mmol)、丙二酸624mg(6mmol)、四水合醋酸镍50mg(0.2mmol)、手性配体(4)129mg(0.22mmol)；有机溶剂为四氢呋喃8.9g，其总用量为底物α，β不饱和酮酸酯的20倍。
室温条件下，将金属催化剂与手性配体(4)加入反应釜中，用四氢呋喃充分溶解后，充分搅拌30-60分钟，再向反应釜中加入苯基α，β不饱和酮酸异丙酯与丙二酸，在20℃的条件下，搅拌使其反应72小时后结束。
其余同实施例1，得目标产物1a 49.5g，收率89％，对映选择性过量为89％ee，纯度为99.0％，。
实施例5
底物苯基α，β不饱和酮酸异丙酯4.6mg(2mmol)、丙二酸624mg(6mmol)、乙酰丙酮镍50mg(0.2mmol)、手性配体(4)129mg(0.22mmol)；有机溶剂为四氢呋喃8.9g，其总用量为底物α，β不饱和酮酸酯的20倍。
室温条件下，将金属催化剂与手性配体(4)加入反应釜中，用四氢呋喃充分溶解后，充分搅拌30-60分钟，再向反应釜中加入苯基α，β不饱和酮酸异丙酯与丙二酸，在20℃的条件下，搅拌使其反应60小时后结束。
其余同实施例1，得目标产物1a 517mg，收率93％，对映选择性过量为90％ee，纯度为99.3％。
实施例6
底物苯基α，β不饱和酮酸异丙酯436mg(2mmol)、丙二酸624mg(6mmol)、乙酰丙酮镍50mg(0.2mmol)、手性配体(4)129mg(0.22mmol)；有机溶剂为乙酸乙酯8.9g，其总用量为底物α，β不饱和酮酸酯的20倍。
室温条件下，将金属催化剂与手性配体(4)加入反应釜中，用四氢呋喃充分溶解后，充分搅拌30-60分钟，再向反应釜中加入苯基α，β不饱和酮酸异丙酯与丙二酸，在20℃的条件下，搅拌使其反应72小时后结束。
其余同实施例1，得目标产物1a 234mg，收率42％，对映选择性过量为80％ee，纯度为99.0％。
实施例7
底物苯基α，β不饱和酮酸异丙酯436mg(2mmol)、丙二酸624mg(6mmol)、乙酰丙酮镍50mg(0.2mmol)、手性配体(4)129mg(0.22mmol)；有机溶剂为乙腈8.9g，其总用量为底物α，β不饱和酮酸酯的20倍。
室温条件下，将金属催化剂与手性配体(4)加入反应釜中，用四氢呋喃充分溶解后，充分搅拌30-60分钟，再向反应釜中加入苯基α，β不饱和酮酸异丙酯与丙二酸，在20℃的条件下，搅拌使其反应62小时后结束。
其余同实施例1，得目标产物1a 490mg，收率88％，对映选择性过量为48％ee，纯度为98.8％。
实施例8
底物苯基α，β不饱和酮酸异丙酯436mg(2mmol)、丙二酸624mg(6mmol)、乙酰丙酮镍50mg(0.2mmol)、手性配体(4)129mg(0.22mmol)；有机溶剂为甲苯8.9g，其总用量为底物α，β不饱和酮酸酯的20倍。
室温条件下，将金属催化剂与手性配体(4)加入反应釜中，用四氢呋喃充分溶解后，充分搅拌30-60分钟，再向反应釜中加入苯基α，β不饱和酮酸异丙酯与丙二酸，在20℃的条件下，搅拌使其反应108小时后结束。
其余同实施例1，得目标产物1a 55mg，收率10％，对映选择性过量为21％ee，纯度为98.6％。
实施例9-26
含不同取代基的α，β不饱和酮酸酯(2mmol)、丙二酸624mg(6mmol)、乙酰丙酮镍51mg(0.2mmol)、手性配体(4)129mg(0.22mmol)；有机溶剂为四氢呋喃8.9g(1mL)，其总用量为底物α，β不饱和酮酸酯的20倍。
室温条件下，将金属催化剂与手性配体(4)加入反应釜中，用四氢呋喃充分溶解后，充分搅拌30-60分钟，再向反应釜中加入苯基α，β不饱和酮酸异丙酯与丙二酸，在20℃的条件下，搅拌使其反应60小时后结束。
其余同实施例1，得目标产物1，结果如下所示：
实施例9-26的核磁共振表征数据:
实施例9:
(E)-5-(3,4-dichlorophenyl)-3-hydroxy-3-(isopropoxycarbonyl)pent-4-enoic acid(1b):[α]D 20＝+2.8(c＝0.449in EA)；enantiomeric excess:90％,DaicelChiralpak IA,hexane/iso-propanol＝90/10,flow rate 1.0mL/min,25℃:tR(minor)＝9.75min,t R(major)＝15.63min；1H NMR(500MHz,Acetone-d6)δ7.44(d,J＝1.9Hz,1H),7.37(d,J＝8.3Hz,1H),7.18(dd,J＝8.3,1.9Hz,1H),6.80(d,J＝15.7Hz,1H),6.20(d,J＝15.7Hz,1H),5.12(m,1H),3.11(d,J＝16.2Hz,1H),2.73(d,J＝16.2Hz,1H),1.30(d,J＝0.9Hz,3H),1.29(d,J＝0.9Hz,3H)；13C NMR(126MHz,CDCl3)δ172.65,172.65,170.46,136.18,132.76,131.77,130.46,128.75,128.38,126.09,75.07,70.78,51.91,43.41,21.71,21.53；HRMS(BRUKER micrOTOF-QII)exact mass calcd for(C16H18Cl2O5Na)+requires m/z 369.0272,found m/z369.0270。
实施例10:
(E)-3-hydroxy-3-(isopropoxycarbonyl)-5-(4-nitrophenyl)pent-4-enoicacid(1c):[α]D 20＝+3.3(c＝0.413in EA)；enantiomeric excess:90％,Daicel ChiralpakIA,hexane/iso-propanol＝90/10,flow rate 1.0mL/min,25℃:tR(minor)＝20.87min,t R(major)＝29.80min；1H NMR(500MHz,Acetone-d6)δ8.17(d,J＝8.7Hz,2H),7.50(d,J＝8.8Hz,2H),6.97(d,J＝15.8Hz,1H),6.39(d,J＝15.8Hz,1H),5.13(m,1H),3.14(d,J＝16.2Hz,1H),2.75(d,J＝16.2Hz,1H),1.31(s,3H),1.29(s,3H)；13C NMR(126MHz,CDCl3)δ172.41,170.35,147.27,142.47,133.09,129.04,127.40,124.01,75.20,70.95,51.97,43.35,21.70,21.52；HRMS(BRUKER micrOTOF-QII)exact mass calcd for(C16H19NO7Na)+requires m/z 346.0903,found m/z 346.0908。
实施例11:
(E)-5-(4-fluorophenyl)-3-hydroxy-3-(isopropoxycarbonyl)pent-4-enoicacid(1d):[α]D 20＝+3.2(c＝0.243in EA)；enantiomeric excess:90％,Daicel ChiralpakIA,hexane/iso-propanol＝90/10,flow rate 1.0mL/min,25℃:tR(minor)＝9.41min,t R(major)＝16.72min；1H NMR(500MHz,Acetone-d6)δ7.39–7.28(m,2H),7.00(t,J＝8.6Hz,2H),6.84(d,J＝15.8Hz,1H),6.12(d,J＝15.8Hz,1H),5.20–5.07(m,1H),3.12(d,J＝16.3Hz,1H),2.75(d,J＝16.3Hz,1H),1.30(s,3H),1.29(s,3H)；13C NMR(126MHz,Acetone-d6)δ172.95,170.63,163.57,161.60,132.25,129.74,128.39,128.32,128.17,115.63,115.46,75.07,70.54,51.85,43.50,21.70,21.53；HRMS(BRUKER micrOTOF-QII)exactmass calcd for(C16H19FO5Na)+requires m/z 319.0958,found m/z 319.0961。
实施例12:
(E)-5-(4-chlorophenyl)-3-hydroxy-3-(isopropoxycarbonyl)pent-4-enoicacid(5e):[α]D 20＝+3.1(c＝0.379in EA)；enantiomeric excess:88％,Daicel ChiralpakIA,hexane/iso-propanol＝90/10,flow rate 1.0mL/min,25℃:tR(minor)＝10.01min,t R(major)＝16.79min；1H NMR(500MHz,Acetone-d6)δ7.33–7.26(m,4H),6.85(d,J＝15.8Hz,1H),6.19(d,J＝15.8Hz,1H),5.18–5.09(m,1H),3.13(d,J＝16.3Hz,1H),2.75(d,J＝16.3Hz,1H),1.31(s,3H),1.30(s,3H)；13C NMR(126MHz,Acetone-d6)δ172.85,170.58,134.57,133.74,129.72,129.07,128.79,128.00,75.10,70.61,51.87,43.46,21.70,21.53；HRMS(BRUKER micrOTOF-QII)exact mass calcd for(C16H19ClO5Na)+requires m/z335.0662,found m/z 335.0669。
实施例13:
(E)-5-(4-bromophenyl)-3-hydroxy-3-(isopropoxycarbonyl)pent-4-enoicacid(1f):[α]D 20＝+3.0(c＝0.338in EA)；enantiomeric excess:86％,Daicel ChiralpakIA,hexane/iso-propanol＝90/10,flow rate 1.0mL/min,25℃:tR(minor)＝10.50min,t R(major)＝17.37min；1H NMR(500MHz,Acetone-d6)δ7.43(d,J＝8.4Hz,2H),7.23(d,J＝8.4Hz,2H),6.82(d,J＝15.8Hz,1H),6.20(d,J＝15.8Hz,1H),5.17–5.08(m,1H),3.12(d,J＝16.3Hz,1H),2.74(d,J＝16.3Hz,1H),1.30(s,3H),1.29(s,3H)；13C NMR(126MHz,Acetone-d6)δ172.80,170.57,135.01,131.74,129.80,129.19,128.31,121.91,75.11,70.63,51.88,43.43,21.71,21.54；HRMS(BRUKER micrOTOF-QII)exact mass calcd for(C16H19BrO5Na)+requires m/z 379.0157,found m/z 379.0157。
实施例14:
(E)-3-hydroxy-3-(isopropoxycarbonyl)-5-(4-methoxyphenyl)pent-4-enoicacid(1g):[α]D 30＝+2.9(c＝0.126in EA)；enantiomeric excess:86％,Daicel ChiralpakIA,hexane/iso-propanol＝90/10,flow rate 1.0mL/min,25℃:tR(minor)＝12.65min,t R(major)＝24.16min；1H NMR(500MHz,Acetone-d6)δ7.31(d,J＝8.7Hz,2H),6.85(d,J＝8.6Hz,2H),6.83–6.79(m,1H),6.06(d,J＝15.8Hz,1H),3.69(s,3H),3.13(d,J＝16.3Hz,1H),2.75(d,J＝16.3Hz,1H),1.30(s,3H),1.29(s,3H)；13C NMR(126MHz,Acetone-d6)δ173.16,170.76,159.60,131.75,130.27,128.83,128.31,128.01,126.22,114.04,75.12,70.39,55.31,51.81,43.56,21.71,21.51；HRMS(BRUKER micrOTOF-QII)exact mass calcdfor(C17H22O6Na)+requires m/z 331.1158,found m/z 331.1157。
实施例15:
(E)-3-hydroxy-3-(isopropoxycarbonyl)-5-(p-tolyl)pent-4-enoic acid(1h):[α]D 20＝+3.3(c＝0.352in EA)；enantiomeric excess:86％,Daicel Chiralpak IA,hexane/iso-propanol＝90/10,flow rate 1.0mL/min,25℃:tR(minor)＝9.48min,t R(major)＝16.5min；1H NMR(500MHz,Acetone-d6)δ7.16(s,1H),7.10(dd,J＝20.3,7.8Hz,2H),6.82(d,J＝15.8Hz,1H),6.14(d,J＝15.8Hz,1H),5.13(dd,J＝12.5,6.2Hz,1H),3.14(d,J＝16.3Hz,1H),2.76(d,J＝16.2Hz,1H),2.25(s,3H),1.30(s,3H),1.29(s,3H)；13C NMR(126MHz,Acetone-d6)δ173.13,170.76,136.73,133.71,130.81,129.88,129.71,128.00,127.28,125.67,124.28,75.15,70.40,51.82,43.51,29.08,21.55,19.53；HRMS(BRUKERmicrOTOF-QII)exact mass calcd for(C18H24O5Na)+requires m/z 315.1208,found m/z315.1209。
实施例16:
(E)-5-(3,4-dimethylphenyl)-3-hydroxy-3-(isopropoxycarbonyl)pent-4-enoic acid(1i):[α]D 20＝+3.3(c＝0.352in EA)；enantiomeric excess:86％,DaicelChiralpak IA,hexane/iso-propanol＝90/10,flow rate 1.0mL/min,25℃:tR(minor)＝9.48min,t R(major)＝16.5min；1H NMR(500MHz,Acetone-d6)δ7.16(s,1H),7.10(dd,J＝20.3,7.8Hz,2H),6.82(d,J＝15.8Hz,1H),6.14(d,J＝15.8Hz,1H),5.13(dd,J＝12.5,6.2Hz,1H),3.14(d,J＝16.3Hz,1H),2.76(d,J＝16.2Hz,1H),2.25(s,3H),2.25(s,3H),1.30(s,3H),1.29(s,3H)；13C NMR(126MHz,Acetone-d6)δ173.13,170.76,136.73,133.71,130.81,129.88,129.71,128.00,127.28,125.67,124.28,75.15,70.40,51.82,43.51,29.08,21.55,19.53；HRMS(BRUKER micrOTOF-QII)exact mass calcd for(C18H24O5Na)+requires m/z 329.1365,found m/z 329.1368。
实施例17:
(E)-5-(3-fluorophenyl)-3-hydroxy-3-(isopropoxycarbonyl)pent-4-enoicacid(1j):[α]D 20＝+2.9(c＝0.343in EA)；enantiomeric excess:86％,Daicel ChiralpakIA,hexane/iso-propanol＝90/10,flow rate 1.0mL/min,25℃:tR(minor)＝8.42min,t R(major)＝16.15min；1H NMR(500MHz,Acetone-d6)δ7.28(dd,J＝10.9,4.8Hz,1H),7.14(d,J＝7.7Hz,1H),7.08(d,J＝10.0Hz,1H),6.95(td,J＝8.4,2.3Hz,1H),6.87(d,J＝15.8Hz,1H),6.22(d,J＝15.8Hz,1H),5.18–5.10(m,1H),3.14(d,J＝16.2Hz,1H),2.76(d,J＝16.2Hz,1H),1.32(s,3H),1.30(s,3H)；13C NMR(126MHz,Acetone-d6)δ172.80,170.54,164.03,162.08,138.43,130.11,129.83,122.79,114.95,113.06,75.08,70.65,51.87,43.44,21.69,21.52；HRMS(BRUKER micrOTOF-QII)exact mass calcd for((C16H19FO5Na)+requires m/z 319.0958,found m/z 319.0964。
实施例18:
(E)-5-(3-bromophenyl)-3-hydroxy-3-(isopropoxycarbonyl)pent-4-enoicacid(1k):[α]D 20＝+3.4(c＝0.452in EA)；enantiomeric excess:86％,Daicel ChiralpakIA,hexane/iso-propanol＝90/10,flow rate 1.0mL/min,25℃:tR(minor)＝9.13min,t R(major)＝16.36min；1H NMR(500MHz,Acetone-d6)δ7.52(s,1H),7.40–7.33(m,1H),7.30–7.26(m,1H),7.18(t,J＝7.8Hz,1H),6.82(d,J＝15.8Hz,1H),6.21(d,J＝15.8Hz,1H),5.12(hept,J＝6.2Hz,1H),3.12(d,J＝16.2Hz,1H),2.74(d,J＝16.2Hz,1H),1.30(d,J＝1.8Hz,3H),1.29(d,J＝1.7Hz,3H)；13C NMR(126MHz,Acetone-d6)δ172.77,170.53,138.23,130.91,130.06,129.53,125.63,122.79,75.08,70.70,51.89,43.44,21.72,21.54；HRMS(BRUKER micrOTOF-QII)exact mass calcd for(C16H19FO5Na)+requires m/z 379.0157,found m/z 379.0157。
实施例19:
(E)-3-hydroxy-3-(isopropoxycarbonyl)-5-(3-methoxyphenyl)pent-4-enoicacid(1l):[α]D 20＝+2.4(c＝0.234in EA)；enantiomeric excess:82％,Daicel ChiralpakIA,hexane/iso-propanol＝90/10,flow rate 1.0mL/min,25℃:tR(minor)＝11.25min,t R(major)＝20.90min；1H NMR(500MHz,Acetone-d6)δ7.27–7.23(m,1H),6.98(d,J＝7.6Hz,1H),6.91(s,1H),6.85(d,J＝15.8Hz,1H),6.82(dd,J＝8.2,2.0Hz,1H),6.20(d,J＝15.8Hz,1H),5.12(dd,J＝12.5,6.3Hz,1H),3.70(s,3H),3.14(d,J＝16.3Hz,1H),2.76(d,J＝16.2Hz,1H),1.31(s,3H),1.29(s,3H)；13C NMR(126MHz,Acetone-d6)δ172.97,170.68,159.83,137.51,130.80,129.60,128.80,119.41,113.64,112.23,75.13,70.53,55.25,51.85,43.47,21.70,21.54；HRMS(BRUKER micrOTOF-QII)exact mass calcd for(C17H22O6Na)+requires m/z 331.1158,found m/z 331.1159。
实施例20:
(E)-3-hydroxy-3-(isopropoxycarbonyl)-5-(m-tolyl)pent-4-enoic acid(1m):[α]D20＝+3.3(c＝0.287in EA)；enantiomeric excess:84％,Daicel Chiralpak IA,hexane/iso-propanol＝90/10,flow rate 1.0mL/min,25℃:tR(minor)＝8.42min,t R(major)＝15.88min；1H NMR(500MHz,Acetone-d6)δ7.20(p,J＝7.6Hz,3H),7.08(d,J＝7.1Hz,1H),6.85(d,J＝15.8Hz,1H),6.19(d,J＝15.8Hz,1H),5.13(dt,J＝12.5,6.3Hz,1H),3.14(d,J＝16.3Hz,1H),2.76(d,J＝16.3Hz,1H),2.34(s,3H),1.31(s,3H),1.30(s,3H)；13C NMR(126MHz,Acetone-d6)δ173.04,170.71,138.20,136.01,130.96,128.86,128.52,128.26,127.47,123.96,75.16,70.47,51.84,43.50,21.71,21.55,21.36；HRMS(BRUKER micrOTOF-QII)exact mass calcd for(C17H22O5Na)+requires m/z 315.1208,found m/z 315.1211。
实施例21:
(E)-5-(2-fluorophenyl)-3-hydroxy-3-(isopropoxycarbonyl)pent-4-enoicacid(1n):[α]D 20-＝+2.9(c＝0.212in EA)；enantiomeric excess:84％,DaicelChiralpak IA,hexane/iso-propanol＝90/10,flow rate 1.0mL/min,25℃:tR(minor)＝8.06min,t R(major)＝15.49min；1H NMR(500MHz,Acetone-d6)δ7.41(td,J＝7.7,1.4Hz,1H),7.23(ddd,J＝15.0,5.3,1.6Hz,1H),7.09(t,J＝7.3Hz,1H),7.02(dd,J＝17.6,11.4Hz,2H),6.34(d,J＝16.0Hz,1H),5.19–5.10(m,1H),3.15(d,J＝16.2Hz,1H),2.78(d,J＝16.2Hz,1H),1.31(s,3H),1.30(s,3H)；13C NMR(126MHz,Acetone-d6)δ172.87,170.59,161.50,159.51,131.33,129.37,128.14,124.13,123.79,115.93,115.75,75.25,70.56,51.84,43.41,21.64,21.52；HRMS(BRUKER micrOTOF-QII)exact mass calcd for(C16H19FO5Na)+requires m/z 319.0958,found m/z 319.0954。
实施例22:
(E)-3-hydroxy-3-(isopropoxycarbonyl)-5-(o-tolyl)pent-4-enoic acid(1o):[α]D 20＝+2.8(c＝0.327in EA)；enantiomeric excess:81％,Daicel Chiralpak IA,hexane/iso-propanol＝90/10,flow rate 1.0mL/min,25℃:tR(minor)＝10.51min,t R(major)＝20.90min；1H NMR(500MHz,Acetone-d6)δ7.39(d,J＝7.6Hz,1H),7.26–7.21(m,1H),7.17(d,J＝16.0Hz,1H),6.91(t,J＝7.5Hz,1H),6.86(d,J＝8.2Hz,1H),6.25(d,J＝16.0Hz,1H),5.15–5.12(m,1H),3.70(s,3H),3.15(d,J＝16.3Hz,1H),2.78(d,J＝16.2Hz,1H),2.25(s,3H),1.31(s,3H),1.30(s,3H)；13C NMR(126MHz,Acetone-d6)δ173.18,170.79,157.06,129.88,129.14,127.26,125.91,125.07,120.56,110.96,75.39,70.30,55.40,51.79,43.52,21.62；HRMS(BRUKER micrOTOF-QII)exact mass calcd for(C17H22O6Na)+requires m/z315.1208,found m/z 315.1217。
实施例23:
(E)-3-hydroxy-3-(isopropoxycarbonyl)-5-(naphthalen-2-yl)pent-4-enoicacid(1p):[α]D 20＝+3.4(c＝0.256in EA)；enantiomeric excess:80％,Daicel ChiralpakIA,hexane/iso-propanol＝90/10,flow rate 1.0mL/min,25℃:tR(minor)＝11.87min,t R(major)＝21.01min；1H NMR(500MHz,Acetone-d6)δ7.84–7.76(m,4H),7.57(dd,J＝8.5,1.2Hz,1H),7.51–7.42(m,2H),7.06(d,J＝15.8Hz,1H),6.34(d,J＝15.8Hz,1H),5.22–5.11(m,1H),3.19(d,J＝16.3Hz,1H),2.82(d,J＝16.3Hz,1H),1.33(s,3H),1.32(s,3H)；13C NMR(126MHz,Acetone-d6)δ173.04,170.71,133.54,133..50,133.20,131.01,128.79,128.28,128.09,127.67,127.09,126.37,126.14,123.64,75.27,70.56,51.87,43.56,21.74,21.57；HRMS(BRUKER micrOTOF-QII)exact mass calcd for(C20H22O5Na)+requires m/z351.1208,found m/z 351.1208。
实施例24:
(E)-3-hydroxy-3-(methoxycarbonyl)-5-phenylpent-4-enoic acid(1q):[α]D 20＝+2.9(c＝0.333in EA)；enantiomeric excess:76％,Daicel Chiralpak AD-H,hexane/iso-propanol＝90/10,flow rate 1.0mL/min,25℃:tR(minor)＝13.75min,tR(major)＝19.65min；1H NMR(300MHz,Acetone-d6)δ7.42(d,J＝7.1Hz,2H),7.37–7.22(m,3H),6.83(d,J＝16.0Hz,1H),6.37(d,J＝15.9Hz,1H),3.33(s,3H),3.18(d,J＝16.2Hz,1H),2.70(d,J＝16.2Hz,1H)；HRMS(BRUKER micrOTOF-QII)exact mass calcd for(C14H16O5Na)+requires m/z 273.0739,found m/z 273.0742。
实施例25:
(E)-3-(ethoxycarbonyl)-3-hydroxy-5-phenylpent-4-enoic acid(1r):[α]D 20＝+4.0(c＝0.535in EA)；enantiomeric excess:85％,Daicel Chiralpak IA,hexane/iso-propanol＝90/10,flow rate 1.0mL/min,25℃:tR(minor)＝9.86min,tR(major)＝16.39min；1H NMR(500MHz,Acetone-d6)δ7.38(d,J＝7.2Hz,2H),7.31(t,J＝7.5Hz,2H),7.25–7.22(m,1H),6.88(d,J＝15.8Hz,1H),6.21(d,J＝15.8Hz,1H),4.36–4.21(m,2H),3.15(d,J＝16.3Hz,1H),2.77(d,J＝16.3Hz,1H),1.31(t,J＝7.1Hz,3H)；13C NMR(126MHz,Acetone-d6)δ173.52,170.83,135.98,130.96,128.67,128.20,127.30,126.81,75.23,62.58,51.92,43.49,14.10；HRMS(BRUKER micrOTOF-QII)exact mass calcd for(C15H18O5Na)+requires m/z 287.0895,found m/z 287.0890。
实施例26:
(E)-3-(tert-butoxycarbonyl)-3-hydroxy-5-phenylpent-4-enoic acid(1s):[α]D 20＝+3.3(c＝0.375in EA)；enantiomeric excess:72％,Daicel Chiralpak IA,hexane/iso-propanol＝90/10,flow rate 1.0mL/min,25℃:tR(minor)＝5.51min,tR(major)＝7.52min；1H NMR(300MHz,Acetone-d6)δ7.42(d,J＝7.1Hz,2H),7.37–7.22(m,3H),6.83(d,J＝16.0Hz,1H),6.37(d,J＝15.9Hz,1H),3.18(d,J＝16.2Hz,1H),2.70(d,J＝16.2Hz,1H),2.05(s,9H),；HRMS(BRUKER micrOTOF-QII)exact mass calcd for(C17H22O5Na)+requires m/z 315.1208,found m/z 315.1205。
以上所揭露的仅为本发明较佳实施例而已，当然不能以此来限定本发明之权利范围，因此依本发明权利要求所作的等同变化，仍属本发明所涵盖的范围。
Claims (4)
1.一种β羟基酸类化合物的合成方法，其特征在于，包括以下步骤：
以α，β不饱和酮酸酯类化合物与丙二酸为原料，在有机溶剂A中，加入金属催化剂与手性配体以摩尔比1：1-1.5混合反应10-120分钟得到催化剂，在20℃温度的条件下直接充分反应3-120小时，反应完毕后经过分离纯化得到所述脱羧aldol加成的β羟基酸类化合物；
所述的手性配体为：
所述α，β不饱和酮酸酯类化合物与丙二酸的结构式为：
式中，R1代表氢、氟、氯、溴、硝基、烷基、烷氧基或芳基；R2代表甲基、乙基、异丙基或叔丁基；
当有机溶剂A为四氢呋喃，则所述的金属催化剂为醋酸钯、醋酸铜、醋酸银、四水合醋酸镍或乙酰丙酮镍；
当有机溶剂A为乙酸乙酯、乙腈或甲苯，则所述的金属催化剂为乙酰丙酮镍。
2.根据权利要求1所述的一种β羟基酸类化合物的合成方法，其特征在于：所述有机溶剂A的质量是原料的1-50倍。
3.根据权利要求1所述的一种β羟基酸类化合物的合成方法，其特征在于：所述的α，β不饱和酮酸酯与丙二酸的摩尔投料比为1:1-5。
4.根据权利要求1所述的一种β羟基酸类化合物的合成方法，其特征在于：所述的催化剂与原料α，β不饱和酮酸酯类化合物的物质的量比例为1％-20％。
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