CN109734600A - 一种手性β羟基酸酯类化合物的合成方法 - Google Patents

一种手性β羟基酸酯类化合物的合成方法 Download PDF

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CN109734600A
CN109734600A CN201811536129.9A CN201811536129A CN109734600A CN 109734600 A CN109734600 A CN 109734600A CN 201811536129 A CN201811536129 A CN 201811536129A CN 109734600 A CN109734600 A CN 109734600A
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蒋俊
刘洪鑫
王娜
李娟�
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Wenzhou University
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Abstract

本发明公开了一种手性β羟基酸酯类化合物的合成方法，其特征在于，所述方法包含下列步骤：以醛类化合物与丙二酸单烷基酯为原料，在有机溶剂中，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羟基酸酯类化合物。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羟基酸酯骨架结构分子；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意义、工业生产价值和社会经济效益。

Description

一种手性β羟基酸酯类化合物的合成方法
技术领域
本发明涉及有机化学领域，特别是指一种手性β羟基酸酯类化合物及其通过脱羧aldol加成的合成方法。
背景技术
手性β羟基酸酯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。手性β羟基酸酯是合成手性β羟基酸、β-氨基酸、青霉素、生物信息素等的重要前体。手性β-羟基取代羧酸酯是众多天然产物(胡桃霉素A、芦荟酸等)的主体估价以及诸多药物分子尤其是抗抑郁和多动症的精神类药物(氟西汀、度洛西汀、阿托西汀)的重要合成中间体，并且可以直接快速高效的合成手性药物分子Phenylpropanoid，因此，开发绿色高效的合成手性β-取代羧酸酯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手性β-羟基取代的羧酸酯类化合物利用不对称Mukaiyama Aldol反应和β-酮羧酸酯通过不对称氢化还原来实现。但是，由于对该类反应认识的局限，存在底物需提前构建、产物结构官能团兼容性受限、反应条件不温和等缺陷。在此基础上，设计开发新的底物结构，实现一类结构新颖的手性β羟基酸酯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手性β羟基酸酯类化合物以及含多官能团的手性β羟基酸酯类化合物的报道极少。基于此，为了进一步了解脱羧加成反应的性质，拓展该反应类型和应用，为手性β羟基酸酯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
本发明实施例所要解决的技术问题在于，提供一种手性β羟基酸酯的合成方法。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、具有高立体选择性的手性β羟基酸酯类化合物合成方法。
为实现上述目的，本发明的技术方案是该方法包括：
以醛类化合物与丙二酸单烷基酯为原料，在有机溶剂中，以金属化合物、有机酸盐以及手性配体为催化剂，进行脱羧aldol加成反应，反应完毕后经过分离纯化得到的手性β羟基酸酯类化合物，该手性β羟基酸酯类化合物的结构式为：
所述醛类化合物的结构式为：
R1-CHO
所述丙二酸单烷基酯的结构式为
所述的R1选自下列之一：烷基、带氟、氯、溴、硝基、烷基、烷氧基等取代的苯基或其它类芳基；所述的R1优选为对硝基苯基；
所述的R2选自下列之一：甲基、乙基、丙基、丁基、异丙基、叔丁基；所述的R2优选为烷基；
所用的有机溶剂为不与反应物和产物发生反应的有机溶剂。
进一步设置是所述的有机溶剂选自下列一种或者任意几种的组合：二氯甲烷、乙酸乙酯、四氢呋喃、乙腈、甲苯、甲醇、氯仿。
进一步设置是所用有机溶剂的质量是原料的1-200倍，优选为20-50倍。
进一步设置是所述的醛类化合物与丙二酸单烷基酯的摩尔投料比为1:1-5，优选为1：2。
进一步设置是所述的催化剂中金属化合物选自下列一种或者任意几种的组合：三氟甲磺酸铜、硫酸铜、醋酸铜、醋酸钯、氟化亚铁、醋酸银、四水合醋酸镍、乙酰丙酮镍、氟化镍、六水合氯化镍、硫酸镍、高氯酸镍、双三苯基膦氯化镍。
进一步设置是所述的催化剂体系中手性配体选自下列一种或者任意几种的组合
优选为为手性配体L5。
进一步设置是所述的催化剂体系中盐选自下列一种或者任意几种的组合；
所述的催化剂体系中金属与盐的摩尔比为1：1-3。
进一步设置是所述的催化剂与醛类化合物比例为1wt％-20wt％，优选为10wt％，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。
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。
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羟基酸酯类化合物。进一步，淋洗液为石油醚与乙酸乙酯混合物，石油醚与乙酸乙酯比例为20：1-2：1，优选为10：1-5：1。
优选实施例中，本发明是首次利用六水合氯化镍、邻硝基苯甲酸钾和噁唑啉骨架的手性配体L5催化普通醛与丙二酸单烷基酯发生脱羧aldol加成反应，合成手性β羟基酸酯类化合物。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。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动性的前提下，根据这些附图获得其他的附图仍属于本发明的范畴。
图1本发明实施例中反应产物结构式图。
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，下面将结合附图对本发明作进一步地详细描述。
优选实施例
本发明具体推荐所述的手性β羟基酸酯类化合物的化学合成方法按照如下步骤进行：室温条件下，将金属催化剂与有机酸盐加入反应釜中，用溶剂A充分溶解后，充分搅拌30-60分钟，再向反应釜中加入手性配体充分搅拌30-60分钟，然后加入普通醛与丙二酸单烷基酯，在20-30℃的条件下，搅拌使其反应40-72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手性β羟基酸酯类目标化合物。
实施例1
R1为对硝基苯基的醛，R2为甲基的丙二酸单甲酯与催化剂的物质的量比为1.0：2.0：0.1投料，即底物对硝基苯甲醛302mg(2mmol)、丙二酸单甲酯472mg(4mmol)、四水合醋酸镍49.6mg(0.2mmol)、手性配体L1 72.6mg(0.22mmol)；有机溶剂为四氢呋喃6.0g，其总用量为底物对硝基苯甲醛的20倍。
室温条件下，将金属催化剂与手性配体L1加入反应釜中，用四氢呋喃充分溶解后，充分搅拌30-60分钟，再向反应釜中加入对硝基苯甲醛与丙二酸单甲酯，在30℃的条件下，搅拌使其反应72小时后结束。
反应完毕后分离纯化，干燥后得到白色固体，即为所述的手性β羟基酸酯类目标化合物1a 101.3mg，收率45％，对映选择性过量为2％ee，纯度为99.0％具体结构为：
数据表征：
Daicel Chiralpak AS,hexane/iso-propanol＝90/10,flow rate 1.0mL/min,25℃:tR(major)＝17.1min,tR(minor)＝21.3min.1H NMR(500MHz,CDCl3)δ8.20(d,J＝8.7Hz,2H),7.57(d,J＝8.6Hz,2H),5.29-5.20(m,1H),3.76(d,J＝5Hz,2H),3.74(s,3H),2.83-2.69(m,2H).13C NMR(126MHz,CDCl3)δ172.27,149.77,147.29,126.52,123.76,69.36,52.10,42.82.
实施例2
底物对硝基苯甲醛302mg(2mmol)、丙二酸单甲酯472mg(4mmol)、四水合醋酸镍49.6mg(0.2mmol)、手性配体L3 73.5mg(0.22mmol)；有机溶剂为四氢呋喃6.0g，其总用量为底物对硝基苯甲醛的20倍。
室温条件下，将金属催化剂与手性配体L3加入反应釜中，用四氢呋喃充分溶解后，充分搅拌30-60分钟，再向反应釜中加入对硝基苯甲醛与丙二酸单甲酯，在30℃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 60.1mg，收率27％，对映选择性过量为9％ee，纯度为98.8％。
实施例3
底物对硝基苯甲醛302mg(2mmol)、丙二酸单甲酯472mg(4mmol)、四水合醋酸镍49.6mg(0.2mmol)、手性配体L5即(4)86.5mg(0.22mmol)；有机溶剂为四氢呋喃6.0g，其总用量为底物对硝基苯甲醛的20倍。
室温条件下，将金属催化剂与手性配体L5加入反应釜中，用四氢呋喃充分溶解后，充分搅拌30-60分钟，再向反应釜中加入对硝基苯甲醛与丙二酸单甲酯，在30℃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 128.3mg，收率57％，对映选择性过量为60％ee，纯度为99.8％。
实施例4
底物对硝基苯甲醛302mg(2mmol)、丙二酸单甲酯472mg(4mmol)、四水合醋酸镍49.6mg(0.2mmol)、手性配体L5即(4)86.5mg(0.22mmol)；有机溶剂为四氢呋喃6.0g，其总用量为底物对硝基苯甲醛的20倍。
室温条件下，将金属催化剂与手性配体L5加入反应釜中，用四氢呋喃充分溶解后，充分搅拌30-60分钟，再向反应釜中加入对硝基苯甲醛与丙二酸单甲酯，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 83.3mg，收率37％，对映选择性过量为77％ee，纯度为99.6％。
实施例5
底物对硝基苯甲醛302mg(2mmol)、丙二酸单甲酯472mg(4mmol)、醋酸镍35.2mg(0.2mmol)、手性配体L5即(4)86.5mg(0.22mmol)；有机溶剂为四氢呋喃6.0g，其总用量为底物对硝基苯甲醛的20倍。
室温条件下，将金属催化剂与手性配体L5加入反应釜中，用四氢呋喃充分溶解后，充分搅拌30-60分钟，再向反应釜中加入对硝基苯甲醛与丙二酸单甲酯，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 105.8mg，收率47％，对映选择性过量为77％ee，纯度为99.5％。
实施例6
底物对硝基苯甲醛302mg(2mmol)、丙二酸单甲酯472mg(4mmol)、醋酸镍35.2mg(0.2mmol)、邻硝基苯甲酸钠盐75.6mg(0.4mmol)、手性配体L5即(4)86.5mg(0.22mmol)；有机溶剂为四氢呋喃6.0g，其总用量为底物对硝基苯甲醛的20倍。
室温条件下，将金属催化剂与邻硝基苯甲酸钠盐加入反应釜中，用四氢呋喃充分溶解后，充分搅拌30-60分钟，再向反应釜中手性配体L5即(4)继续搅拌30-60分钟，然后加入普通醛与丙二酸单烷基酯，在20℃的条件下，搅拌使其反应24小时后结束。
其余同实施例1，得目标产物1a 119.3mg，收率53％，对映选择性过量为80％ee，纯度为99.2％。
实施例7
底物对硝基苯甲醛302mg(2mmol)、丙二酸单甲酯472mg(4mmol)、六水合氯化镍47.2mg(0.2mmol)、邻硝基苯甲酸钠盐75.6mg(0.4mmol)、手性配体L5即(4)86.5mg(0.22mmol)；有机溶剂为四氢呋喃6.0g，其总用量为底物对硝基苯甲醛的20倍。
其余同实施例6，得目标产物1a 121.5mg，收率54％，对映选择性过量为88％ee，纯度为99.7％。
实施例8
底物对硝基苯甲醛302mg(2mmol)、丙二酸单甲酯472mg(4mmol)、六水合氯化镍47.2mg(0.2mmol)、邻硝基苯甲酸钾盐82mg(0.4mmol)、手性配体L5即(4)86.5mg(0.22mmol)；有机溶剂为四氢呋喃6.0g，其总用量为底物对硝基苯甲醛的20倍。
其余同实施例6，得目标产物1a 126mg，收率56％，对映选择性过量为90％ee，纯度为99.3％。
实施例9
底物对硝基苯甲醛302mg(2mmol)、丙二酸单甲酯472mg(4mmol)、六水合氯化镍47.2mg(0.2mmol)、邻硝基苯甲酸钾盐82mg(0.4mmol)、手性配体L5即(4)86.5mg(0.22mmol)；有机溶剂为四氢呋喃6.0g，其总用量为底物对硝基苯甲醛的20倍。
室温条件下，将金属催化剂与邻硝基苯甲酸钠盐加入反应釜中，用四氢呋喃充分溶解后，充分搅拌30-60分钟，再向反应釜中手性配体L5即(4)继续搅拌30-60分钟，然后加入普通醛与丙二酸单烷基酯，在15℃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 200.3mg，收率89％，对映选择性过量为92％ee，纯度为99.6％。
实施例10-41，对应产物1b-1ag。
底物为不同取代基的醛(2mmol)、丙二酸单烷基酯(4mmol)、六水合氯化镍47.2mg(0.2mmol)、邻硝基苯甲酸钾盐82mg(0.4mmol)、手性配体L5即(4)86.5mg(0.22mmol)；有机溶剂为四氢呋喃，其总用量为底物对硝基苯甲醛的20倍。
室温条件下，将金属催化剂与邻硝基苯甲酸钠盐加入反应釜中，用四氢呋喃充分溶解后，充分搅拌30-60分钟，再向反应釜中手性配体L5即(4)继续搅拌30-60分钟，然后加入普通醛与丙二酸单烷基酯，在15℃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，结果如图1所示：
实施例9-41(1a-1ag)的具体表征数据:
实施例9
Methyl 3-hydroxy-3-(4-nitrophenyl)propanoate(1a):89％yield,[α]D 25＝+18.97(c＝0.26in CHCl3),5.29-5.20(m,1H),3.76(d,J＝5Hz,2H),3.74(s,3H),2.83-2.69(m,2H).13C NMR(126MHz,CDCl3)δ172.27,149.77,147.29,126.52,123.76,69.36,52.10,42.82.
实施例10
Ethyl 3-hydroxy-3-(4-nitrophenyl)propanoate(1b):81％yield,[α]D 25＝+21.92(c＝0.26in CHCl3),enantiomeric excess:86％,DaicelChiralpak AS,hexane/iso-propanol＝90/10,flow rate 1.0 mL/min,25℃:tR(minor)＝13.4min,tR(major)＝17.8min.1H NMR(500MHz,CDCl3)δ8.17(d,J＝8.7Hz,2H),7.54(d,J＝8.6Hz,2H),5.21(dt,J＝7.9,3.8Hz,1H),4.16(q,J＝7.1Hz,2H),3.78(d,J＝3.6Hz,1H),2.83-2.58(m,2H),1.24(t,J＝7.1Hz,3H).13C NMR(126MHz,CDCl3)δ171.90,149.82,147.43,126.52,123.73,69.38,61.20,42.98,14.09.
实施例11
Propyl 3-hydroxy-3-(4-nitrophenyl)propanoate(3c):90％yield；[α]D 25＝
(minor)＝10.4min,tR(major)＝14.3min.1H NMR(500MHz,CDCl3)δ8.17(d,J＝8.7Hz,2H),7.54(d,J＝8.7Hz,2H),5.21(s,1H),4.06(t,J＝6.7Hz,2H),3.79(s,1H),2.83-2.57(m,2H),1.67-1.47(m,2H),0.90(t,J＝7.4Hz,3H).13C NMR(126MHz,CDCl3)δ172.00,149.84,147.41,126.53,123.72,69.38,66.78,42.94,21.84,10.26.
实施例12
Butyl 3-hydroxy-3-(4-nitrophenyl)propanoate(1d):89％yield,[α]D 25＝(minor)＝8.8min,tR(major)＝10.6min.1H NMR(500MHz,CDCl3)δ8.18(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),5.21(dd,J＝7.9,3.8Hz,1H),4.11(t,J＝6.7Hz,2H),3.77(d,J＝3.6Hz,1H),2.78-2.65(m,2H),1.62-1.52(m,2H),1.38-1.28(m,2H),0.90(t,J＝7.4Hz,3H).13C NMR(126MHz,CDCl3)δ171.98,149.81,147.43,126.52,123.72,69.39,65.08,42.95,30.50,19.03,13.59.
实施例13
Isopropyl 3-hydroxy-3-(4-nitrophenyl)propanoate(1e):87％yield,δ8.19(d,J＝8.7Hz,2H),7.55(d,J＝8.5Hz,2H),5.24-5.17(m,1H),5.05(dt,J＝12.5,6.3Hz,1H),3.78(d,J＝3.1Hz,1H),2.78-2.60(m,2H),1.23(dd,J＝7.7,6.6Hz,6H).13C NMR(126MHz,CDCl3)δ171.50,149.80,147.15,126.52,123.73,69.41,68.95,43.17,21.74,21.72.
实施例14
Tert-butyl 3-hydroxy-3-(4-nitrophenyl)propanoate(1f):75％yield,[α]D 25＝-49.62(c＝0.13in CHCl3),(d,J＝8.7Hz,2H),5.17(d,J＝7.8Hz,1H),3.85(s,1H),2.65(qd,J＝16.6,6.3Hz,2H),1.45(s,9H).13C NMR(126MHz,CDCl3)δ171.41,149.89,147.40,126.52,123.69,82.20,69.49,43.81,28.05.
实施例15
Methyl 3-(4-fluorophenyl)-3-hydroxypropanoate(1g):71％yield,[α]D 25＝-20.41(c＝0.29in CHCl3),2H),5.10(t,1H),3.70(s,3H),3.39(d,J＝2.6Hz,1H),2.70(qd,J＝16.3,6.4Hz,2H).13CNMR(126MHz,CDCl3)δ172.58,163.30,161.34,138.33,127.39,127.33,115.45,115.28,69.68,51.85,43.19.
实施例16
Methyl 3-(3-fluorophenyl)-3-hydroxypropanoate(1h):74％yield,[α]D 25＝-41.61(c＝0.26in CHCl3),Hz,2H),6.86(td,J＝8.5,2.3Hz,1H),5.06-4.94(m,1H),3.70(d,J＝3.7Hz,1H),3.59(s,3H),2.65-2.54(m,2H).13C NMR(126MHz,CDCl3)δ172.46,163.91,161.96,145.45,145.40,130.07,130.00,121.23,121.20,114.61,114.45,112.76,112.59,69.64,69.62,51.87,43.15.
实施例17
Methyl 3-(2-fluorophenyl)-3-hydroxypropanoate(1i):72％yield,[α]D 25＝-62.79(c＝0.26in CHCl3),flow rate 1.0mL/min,25℃:tR(major)＝8.5min,tR(minor)＝24.3min.1H NMR(500MHz,CDCl3)δ7.42(dd,J＝10.8,4.2Hz,1H),7.15(dt,J＝13.4,7.2Hz,1H),7.04(t,J＝7.5Hz,1H),6.94-6.85(m,1H),5.35-5.24(m,1H),3.72-3.63(m,1H),3.59(s,3H),2.64(qd,J＝16.3,6.3Hz,2H).13C NMR(126MHz,CDCl3)δ172.58,160.41,158.46,129.72,129.62,129.14,129.08,127.25,127.22,124.35,124.32,115.28,115.11,64.52,64.50,51.83,41.89.
实施例18
Methyl 3-(4-chlorophenyl)-3-hydroxypropanoate(1j):76％yield,[α]D 25＝4H),5.24-4.93(m,1H),3.71(s,3H),3.52-3.46(m,1H),2.79-2.61(m,2H).13C NMR(126MHz,CDCl3)δ172.54,141.07,133.50,128.69,127.07,69.62,51.94,43.08.
实施例19
Methyl 3-(3-bromophenyl)-3-hydroxypropanoate(1k):72％yield,[α]D 25＝min,tR(minor)＝41.2min.1H NMR(500MHz,CDCl3)δ7.53(s,1H),7.40(d,J＝7.8Hz,1H),7.27(d,J＝7.6Hz,1H),7.21(t,J＝7.8Hz,1H),5.13-5.05(m,1H),3.71(s,3H),3.58(s,1H),2.75-2.64(m,2H).13C NMR(126MHz,CDCl3)δ172.47,144.92,130.85,130.12,128.86,124.28,122.67,69.59,51.95,43.08.
实施例20
Methyl 3-(2-bromophenyl)-3-hydroxypropanoate(1l):71％yield,[α]D 25＝-41.67(c＝0.25in CHCl3),7.33(t,J＝7.4Hz,1H),7.12(td,J＝7.8,1.5Hz,1H),5.43(dd,J＝9.8,2.2Hz,1H),3.72(s,3H),3.68(s,1H),2.85(dd,J＝16.5,2.6Hz,1H),2.55(dd,J＝16.5,9.8Hz,1H).13C NMR(126MHz,CDCl3)δ172.71,141.53,132.65,129.10,127.84,127.33,121.40,69.25,51.95,41.47.
实施例21
Methyl 3-(4-cyanophenyl)-3-hydroxypropanoate(1m):72％yield,[α]D 25＝
min,tR(minor)＝16.0min.1H NMR(500MHz,CDCl3)δ7.64(d,J＝8.1Hz,2H),7.50(d,J＝8.1Hz,2H),5.19(t,J＝6.4Hz,1H),3.72(s,3H),2.72(d,J＝6.4Hz,2H).13C NMR(126MHz,CDCl3)δ172.24,147.94,132.36,126.42,118.65,111.47,69.51,52.05,42.89.
实施例22
Methyl 3-(3-cyanophenyl)-3-hydroxypropanoate(1n):72％yield,[α]D 25＝-45.97(c＝0.34in CHCl3),min.1H NMR(500MHz,CDCl3)δ7.69(s,1H),7.60(d,J＝7.8Hz,1H),7.57(d,J＝7.7Hz,1H),7.46(t,J＝7.7Hz,1H),5.15(d,J＝1.6Hz,1H),3.72(s,3H),3.63(d,J＝2.7Hz,1H),2.71(d,J＝6.4Hz,2H).13C NMR(126MHz,CDCl3)δ172.34,144.07,131.40,130.14,129.41,129.35,118.64,112.67,69.24,52.07,42.87.
实施例23
Methyl 3-(2-cyanophenyl)-3-hydroxypropanoate(1o):70％yield,[α]D 25＝-50.67(c＝0.13in CHCl3),7.50(t,J＝7.4Hz,1H),7.42(d,J＝7.6Hz,1H),6.91(s,1H),4.93(dd,J＝10.5,3.0Hz,1H),3.78(s,3H),3.03(dd,J＝17.1,3.4Hz,1H),2.47(dd,J＝17.0,10.6Hz,1H).13C NMR(126MHz,CDCl3)δ171.48,170.47,146.01,132.00,131.91,128.58,123.96,122.38,52.99,52.15,39.34.
实施例24
Methyl 4-(1-hydroxy-3-methoxy-3-oxopropyl)benzoate(1p):74％yield,[α]D 25＝-32.39(c＝0.21inhexane/iso-propanol＝95/5,flow rate 1.0mL/min,25℃:tR(minor)＝20.3min,tR(major)＝23.4min.1H NMR(500MHz,CDCl3)δ7.99(d,J＝8.1Hz,2H),7.43(d,J＝8.4Hz,2H),5.17(s,1H),3.89(s,3H),3.70(s,3H),3.53(s,1H),2.77-2.68(m,2H).13C NMR(126MHz,CDCl3)δ172.02,166.83,147.60,129.86,129.60,125.59,69.87,52.07,51.93,42.99.
实施例25
Methyl 3-(1-hydroxy-3-methoxy-3-oxopropyl)benzoate(1q):76％yield,[α]D 25＝-55.47(c＝0.14in1H),7.97-7.88(m,1H),7.58(d,J＝7.5Hz,1H),7.41(t,J＝7.7Hz,1H),5.17(dd,J＝8.4,4.3Hz,1H),3.89(d,J＝0.7Hz,3H),3.70(s,3H),2.79-2.68(m,2H).13C NMR(126MHz,CDCl3)δ172.55,166.90,143.00,130.44,130.23,128.99,128.67,126.85,69.85,52.13,51.93,43.07.
实施例26
Methyl 3-(4-formylphenyl)-3-hydroxypropanoate(1r):79％yield,[α]D 25＝1H),7.81(d,J＝8.2Hz,2H),7.51(d,J＝8.1Hz,2H),5.17(s,1H),3.78-3.73(m,1H),3.67(s,3H),2.73-2.67(m,2H).13C NMR(126MHz,CDCl3)δ191.91,172.30,149.46,135.87,129.99,126.26,69.81,51.96,43.00.
实施例27
Methyl 3-(3-formylphenyl)-3-hydroxypropanoate(1s):85％yield,[α]D 25＝＝15.1min,tR(major)＝16.7min.1H NMR(500MHz,CDCl3)δ10.00(s,1H),7.89(s,1H),7.79(d,J＝7.6Hz,1H),7.65(d,J＝7.7Hz,1H),7.52(t,J＝7.6Hz,1H),5.21(t,J＝7.8Hz,1H),3.72(s,3H),3.58(d,J＝3.5Hz,1H),2.80-2.71(m,2H).13C NMR(126MHz,CDCl3)δ192.10,172.50,143.74,136.43,131.74,129.28,129.14,126.84,69.64,51.98,42.97.
实施例28
Methyl 3-hydroxy-3-(2-methoxyphenyl)propanoate(1t):70％yield,[α]D 25＝-43.00(c＝0.13in CHCl3),J＝7.4Hz,1H),6.86(d,J＝8.2Hz,1H),5.39-5.31(m,1H),3.84(s,3H),3.71(s,3H),3.48(d,J＝4.2Hz,1H),2.82(dd,J＝16.1,3.4Hz,1H),2.71(dd,J＝16.1,9.3Hz,1H).13C NMR(126MHz,CDCl3)δ172.96,156.04,130.58,128.60,126.54,120.82,110.36,66.55,55.25,51.71,41.61.
实施例29
Methyl 3-hydroxy-3-(3-methoxyphenyl)propanoate(1u):71％yield,[α]D 25＝-16.46(c＝0.24in CHCl3),6.93(d,J＝8.5Hz,2H),6.82(dd,J＝8.1,1.8Hz,1H),5.10(dd,J＝9.0,3.7Hz,1H),3.80(s,3H),3.71(s,3H),3.36(br,1H),2.72(qd,J＝16.3,6.4Hz,2H).13C NMR(126MHz,CDCl3)δ172.70,159.84,144.29,129.59,117.90,113.39,111.17,70.25,55.22,51.86,43.22.
实施例30
Methyl 3-([1,1'-biphenyl]-4-yl)-3-hydroxypropanoate(1v):72％yield,[α]D 25＝9.35(c＝0.36in CHCl3),4H),7.35(t,J＝7.3Hz,1H),5.24-5.17(m,1H),3.75(s,3H),3.26(d,J＝3.4Hz,1H),2.80(qd,J＝16.4,6.4Hz,2H).13C NMR(126MHz,CDCl3)δ172.75,141.51,140.84,140.75,128.78,127.35,127.33,127.09,126.12,51.90,43.10.
实施例31
Methyl 3-(2-ethynylphenyl)-3-hydroxypropanoate(1w):75％yield,[α]D 25＝-45.20(c＝0.24in CHCl3),＝7.6Hz,1H),7.25(t,1H),5.57(d,J＝9.7Hz,1H),3.74(s,3H),3.48(d,J＝3.1Hz,1H),3.36(s,1H),2.90(dd,J＝16.5,2.7Hz,1H),2.66(dd,J＝16.5,9.8Hz,1H).13C NMR(126MHz,CDCl3)δ172.91,144.85,132.89,129.38,127.25,125.29,119.19,82.79,81.00,68.26,51.88,41.95.
实施例32
methyl-3-hydroxy-3-(7-methoxybenzo[d][1,3]dioxol-5-yl)propanoate(1x):71％yield,[α]D 25＝-38.30Hz,2H),5.96(s,2H),5.04(d,J＝6.3Hz,1H),3.90(s,3H),3.73(s,3H),3.20(s,1H),2.70(qd,J＝16.3,6.4Hz,2H).13C NMR(126MHz,CDCl3)δ172.66,149.00,143.67,137.32,134.75,105.30,101.49,99.93,70.32,56.63,51.89,43.31.
实施例33
Methyl 3-hydroxy-3-(naphthalen-2-yl)propanoate(1y):81％yield,[α]D 25＝-13.56(c＝0.23in CHCl3),5.35-5.24(m,1H),3.72(d,J＝7.5Hz,3H),3.45(d,J＝2.9Hz,1H),2.83(qd,J＝16.4,6.4Hz,2H).13C NMR(126MHz,CDCl3)δ172.77,139.88,133.31,133.06,128.43,128.03,127.69,126.25,126.02,124.47,123.69,70.46(s),51.92,43.14.
实施例34
Methyl 3-hydroxy-3-(naphthalen-1-yl)propanoate(1z):82％yield,[α]D 25＝-53.54(minor)＝40.2min.1H NMR(500MHz,CDCl3)δ8.06(d,J＝8.3Hz,1H),7.89(d,J＝7.9Hz,1H),7.80(d,J＝8.2Hz,1H),7.71(d,J＝7.1Hz,1H),7.58-7.41(m,3H),5.94(d,J＝9.6Hz,1H),3.78(s,3H),3.34(d,J＝3.1Hz,1H),2.94(dd,J＝16.6,2.9Hz,1H),2.86(dd,J＝16.6,9.7Hz,1H).13C NMR(126MHz,CDCl3)δ173.06,137.97,133.80,129.97,129.04,128.35,126.32,125.64,125.52,122.95,122.75,67.37,51.99,42.56.
实施例35
Methyl 3-(anthracen-9-yl)-3-hydroxypropanoate(1aa):78％yield,[α]D 25＝-21.63(c＝0.26in CHCl3),10.7Hz,1H),3.32(d,J＝2.8Hz,1H),2.85(dd,J＝16.8,3.1Hz,1H).13C NMR(126MHz,CDCl3)δ172.97,132.28,131.68,129.38,129.19,128.57,125.94,124.85,124.60,77.29,77.04,76.78,67.32,52.00,41.59.
实施例36
Methyl(E)-3-hydroxy-5-(4-nitrophenyl)pent-4-enoate(1ab):79％yield,CDCl3)δ8.18(d,J＝8.6Hz,2H),7.51(d,J＝8.6Hz,2H),6.77(d,J＝15.9Hz,1H),6.41(dd,J＝15.9,5.4Hz,1H),4.78(s,1H),3.75(s,3H),3.23(s,1H),2.72(dd,J＝16.5,3.8Hz,1H),2.64(dd,J＝16.5,8.5Hz,1H).13C NMR(126MHz,CDCl3)δ172.42,147.15,142.96,134.70,128.55,127.08,124.00,77.25,77.00,76.75,68.26,51.98,40.94.
实施例37
Methyl 3-hydroxy-4-oxo-4-phenylbutanoate(1ac):71％yield,[α]D 25＝+15.01(c＝0.12in MeOH),NMR(500MHz,CDCl3)δ7.92(d,J＝7.5Hz,2H),7.59(t,J＝7.4Hz,1H),7.48(t,J＝7.7Hz,2H),5.41(d,J＝5.0Hz,1H),4.04(s,1H),3.67(s,3H),2.86(dd,J＝15.9,3.4Hz,1H),2.60(dd,J＝15.9,8.0Hz,1H).13C NMR(126MHz,CDCl3)δ199.85,170.90,134.05,133.42,128.95,128.64,70.22,52.06,40.17.
实施例38
(1ad):76％yield,[α]D 25＝-13.32(c＝0.51in CHCl3),enantiomeric excess:84％,Daicel Chiralpak AS,(126MHz,CDCl3)δ172.39,91.60,68.56,68.17,68.11,66.56,66.47,66.04,51.81,42.65,29.71.
实施例39
Methyl 3-hydroxy-3-(thiophen-2-yl)propanoate(1ae):76％yield,[α]D 25＝-13.56(c＝0.15in CHCl3),MHz,MeOD)δ7.30(d,J＝4.5Hz,1H),6.99(d,J＝3.2Hz,1H),6.94(dd,J＝4.8,3.7Hz,1H),5.33(dd,J＝7.6,6.1Hz,1H),3.67(s,3H),2.83-2.78(m,2H).13C NMR(126MHz,MeOD)δ172.89,149.00,127.61,125.56,124.68,67.55,52.22,45.23.
实施例40
Methyl 3-hydroxy-4-oxopentanoate(1af):70％yield[α]D 25＝-11.01(c＝0.10in MeOH),3H),2.88(dd,J＝16.4,4.2Hz,1H),2.75(dd,J＝16.4,6.3Hz,1H),2.28(s,3H).13C NMR(126MHz,CDCl3)δ208.11,171.23,73.75,52.10,37.92,25.26.
实施例41
Methyl 3-hydroxy-5-phenylpentanoate(1ag):72％yield,[α]D 25＝hexane/iso-propanol＝95/5,flow rate 1.0mL/min,25℃:tR(minor)＝15.5min,tR(major)＝16.9min.1H NMR(500MHz,CDCl3)δ7.26-7.03(m,5H),4.08–3.84(m,1H),3.63(s,3H),2.79–2.70(m,1H),2.66–2.59(m,1H),2.41(qd,J＝16.5,6.0Hz,2H),1.82–1.71(m,1H),1.71–1.63(m,1H).13C NMR(126MHz,CDCl3)δ173.33,141.70,128.45,128.43,125.91,67.25,51.73,41.16,38.12,31.76.
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 (10)

1.一种手性β羟基酸酯类化合物的合成方法，其特征在于该方法包括：
以醛类化合物与丙二酸单烷基酯为原料，在有机溶剂中，以金属化合物、有机酸盐以及手性配体为催化剂，进行脱羧aldol加成反应，反应完毕后经过分离纯化得到的手性β羟基酸酯类化合物，该手性β羟基酸酯类化合物的结构式为：
所述醛类化合物的结构式为：
R1-CHO
所述丙二酸单烷基酯的结构式为
所述的R1选自下列之一：烷基、带氟、氯、溴、硝基、烷基、烷氧基等取代的苯基或其它类芳基；
所述的R2选自下列之一：甲基、乙基、丙基、丁基、异丙基、叔丁基；
所用的有机溶剂为不与反应物和产物发生反应的有机溶剂。
2.根据权利要求1所述的手性β羟基酸酯类化合物的合成方法，其特征在于：所述的有机溶剂选自下列一种或者任意几种的组合：二氯甲烷、乙酸乙酯、四氢呋喃、乙腈、甲苯、甲醇、氯仿。
3.根据权利要求1所述的手性β羟基酸酯类化合物的合成方法，其特征在于：所用有机溶剂的质量是原料的1-200倍。
4.根据权利要求1所述的手性β羟基酸酯类化合物的合成方法，其特征在于：所述的醛类化合物与丙二酸单烷基酯的摩尔投料比为1:1-5。
5.根据权利要求1所述的手性β羟基酸酯类化合物的合成方法，其特征在于：所述的催化剂中金属化合物选自下列一种或者任意几种的组合：三氟甲磺酸铜、硫酸铜、醋酸铜、醋酸钯、氟化亚铁、醋酸银、四水合醋酸镍、乙酰丙酮镍、氟化镍、六水合氯化镍、硫酸镍、高氯酸镍、双三苯基膦氯化镍。
6.根据权利要求1所述的手性β羟基酸酯类化合物的合成方法，其特征在于：所述的催化剂体系中手性配体选自下列一种或者任意几种的组合
7.根据权利要求1所述的手性β羟基酸酯类化合物的合成方法，其特征在于：所述的催化剂体系中有机酸盐选自下列一种或者任意几种的组合；
所述的催化剂体系中金属与盐的摩尔比为1：1-3。
8.根据权利要求1所述的手性β羟基酸酯类化合物的合成方法，其特征在于：所述的催化剂与醛类化合物比例为1wt％-20wt％，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。
9.根据权利要求1所述的手性β羟基酸酯类化合物的合成方法，其特征在于：所述的脱羧aldol加成反应的温度为0-60℃。
10.根据权利要求2所述的一种手性β羟基酸酯类化合物的合成方法，其特征在于：所述的脱羧aldol加成反应的反应时间为3-120小时。
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CN112851513A (zh) * 2021-01-23 2021-05-28 温州大学新材料与产业技术研究院 一种3-羰基5-羟基酯类化合物的合成方法
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