CN105481622A - 一种α-氧代-α,β-不饱和羧酸的不对称氢化方法 - Google Patents

一种α-氧代-α,β-不饱和羧酸的不对称氢化方法 Download PDF

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CN105481622A
CN105481622A CN201510926067.2A CN201510926067A CN105481622A CN 105481622 A CN105481622 A CN 105481622A CN 201510926067 A CN201510926067 A CN 201510926067A CN 105481622 A CN105481622 A CN 105481622A
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asymmetric hydrogenation
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张绪穆
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WUHAN KAITE LISI TECHNOLOGY Co Ltd
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Abstract

本发明涉及一种α-氧代-α,β-不饱和羧酸的不对称氢化方法，其中含有ChenPhos手性配体的金属配合物是一类高转化效率催化剂，特别是该催化剂可以通过不对称氢化合成脑啡肽酶抑制剂Sacubitril中核心骨架，这类抑制剂是美国食品药品管理局批准的药物LCZ696中成分之一。本发明方法是底物适用范围广、高效的α-氧代-α,β-不饱和羧酸的不对称氢化方法。

Description

一种α-氧代-α,β-不饱和羧酸的不对称氢化方法
技术领域
本发明涉及一种α-氧代-α,β-不饱和羧酸的不对称氢化方法，其中含有ChenPhos手性配体的金属配合物是一类高转化效率催化剂，特别是该催化剂可以通过不对称氢化合成脑啡肽酶抑制剂Sacubitril中核心骨架，这类抑制剂是美国食品药品管理局批准的药物LCZ696中成分之一。
背景技术
光学纯α-氧代羧酸类化合物是一类重要的有机合成中间体，并作为农作物保护剂在农业化学领域有着广泛的应用1。而且，它们显示出重要的药理学性质，可用于益智，降胆固醇和高脂血症2。许多α-芳氧基和α-烷氧基肉桂酸衍生物作为潜在的对过氧化物酶体增殖物激活受体(PPARs)激动剂在治疗Ⅱ型糖尿病方面备受关注3。下面展示了几种具有手性α-氧基羧酸骨架的的生物活性化合物。
通过过渡金属配合物催化α,β-不饱和羧酸的不对称氢化反应是合成手性羧酸类化合物简单直接的手段。在过去的数十年里，各式各样的手性金属配合物已被开发，并在催化α-芳基或α-烷基取代的α,β-不饱和羧酸类化合物的不对称氢化方面表现出极好的反应活性和对映选择性4。但是，用于α-芳氧基或α-烷氧基取代的α,β-不饱和羧酸化合物不对称氢化的高效催化剂报道较少。自从2004年，Maligres和Krska5首次报道利用钌-BINAP配合物催化α-芳氧基丁烯酸的不对称氢化反应以来，一系列用于α-氧代α,β-不饱和羧酸不对称氢化的其他催化体系被报道。例如：周其林6开发的用于α-芳氧基丁烯酸的不对称氢化的Ru/双齿膦配体体系[Ru(OAc)2/SFDP]，Puentener7发展的用于α-甲氧基肉桂酸的不对称氢化的Ru(OAc)2/(S)-TMBTP体系。诸如Houspis8设计的Rh-Walphos配合物，Whittall4p研究的Rh-Trifer等这类Ru/双齿膦配体催化剂在α-乙氧基肉桂酸的不对称氢化表现出好的催化效果。而此催化反应所能取得最好结果的催化体系是周其林9报道的具有手性螺环骨架的铱-膦-噁唑啉配合物催化剂，但是反应中需外加入碱促进反应。尽管已有大量的研究报道，但是大多数催化剂的底物适用范围较窄，且高催化效率和高对映选择性的实例报道较少。因此，有鉴于α-氧代羧酸类化合物的重要性，发展此类高效催化剂仍然是值得深入研究的。
发明内容
本发明所要解决的技术问题是提供一类底物适用范围广、高效的α-氧代-α,β-不饱和羧酸的不对称氢化方法。
我们一直致力于发展新型、高效的催化剂用于实现具有广泛应用价值的不对称氢化转化。我们先前报道的手性配体ChenPhos/Rh催化体系能够非常高效地催化α-烷基肉桂酸和2-取代-2-链状烯醇这两类化合物的不对称氢化[10]。在此工作的基础上，我们推测并验证了此催化体系应该同样适用于α-氧代-α,β-不饱和羧酸的不对称氢化。反应式及ChenPhos的一种结构式如下：
本发明的α-氧代-α,β-不饱和羧酸的不对称氢化方法，以Rh的前体与ChenPhos络合物作为手性催化剂，以极性质子溶剂为反应溶剂。所述ChenPhos结构式为：
Rh的前体包括[Rh(COD)2]BF4，[Rh(NBD)2]BF4，[Rh(NBD)2]SbF6，[Rh(COD)Cl]2，[Rh(NBD)Cl]2，[Rh(NBD)Cl]2等。
所述极性质子溶剂包括甲醇、乙醇、2,2,2-三氟乙醇、异丙醇和叔丁醇。
较优的反应条件为，使用20个大气压的氢气，使用0.1mol％ChenPhos-铑络合物，室温反应20小时。
本发明阐述了以Rh-ChenPhos络合物作为手性催化剂催化α位芳氧基和烷氧基取代的α,β-不饱和羧酸高效不对称氢化，制备高光学纯的手性α位氧代羧酸衍生物。Rh-ChenPhos催化体系的优点：1)与周其林院士的铱催化体系相比，此催化体系无需通过外加碱来实现高的催化活性和对映选择性；2)反应具有非常高的立体控制(对映选择性高达99％)和TONs(单位活性中心上转化了的反应物的分子数，高达5000)；3)溶剂效应对反应对映选择性控制有较大影响，在适当的溶剂中，如CF3CH2OH，溶剂与催化剂以及底物之间的较强的离子相互作用对反应的立体选择性有导向作用。
具体实施方式
下面实验操作中，对空气或水分敏感的化合物参与的所有的反应都是在氮气氛围下在干燥的反应釜或手套箱中进行的。除非另有说明，所有的试剂和溶剂均从商业供应商处购买而无需进一步纯化。无水溶剂从Sigma-Aldrich处购买，并通过注射器转移。柱色谱纯化产品使用的硅胶(0.06-0.20毫米)和薄层色谱(TLC)使用得硅胶板(GF254)购自Merk公司。[Rh(COD)Cl]2，[Rh(COD)2]BF4和[Rh(COD)2]SbF6从贺利氏公司购买。高效液相色谱溶剂(正己烷)购买来自阿尔法公司，异丙醇购自Sigma-Aldrich公司。
1H-NMR，13C-NMR和31P-NMR光谱记录在布鲁克皇冠(400MHz)光谱仪中，氘代氯仿为溶剂、四甲基硅烷(TMS)作为内标。化学位移单位是百万分之一(PPM)，在1HNMR中以TMS的化学位移是0ppm和氘代氯仿的化学位移是7.26ppm和在13CNMR中氘代氯仿的化学位移是77ppm为参照的。数据表示成：多样性(S＝单峰，D＝二重峰，T＝三重峰，Q＝四重峰，M＝多重峰)，赫兹(Hz)的耦合常数和自然数信号区域一体化。13CNMR和31PNMR数据去耦化处理。对映体过量值是通过在Agilent1200系列高效液相色谱法同时测定仪器的手性柱上测定的。新化合物通过高分辨质谱(HRMS)进一步表征。
实施例1，金属前体的影响
最初选定(Z)-2-甲氧基-3-苯基丙烯酸(1a)作为模板底物对反应进行考察，令我们高兴的是：以甲醇做溶剂，20atm氢气压力下，[Rh(COD)2]BF4(1.0mol％；NBD＝2,5-norbornadiene)和ChenPhos(1.1equivalentwithrespecttoRh)原位生成的ChenPhos-Rh络合物能够顺利催化底物1a全部进行氢化转化，并得到87％的ee值(表1，entry1)。受这个结果的鼓舞，我们接下来对金属前体进行考察，发现不同类型的铑源给出了相似的结果，其中[Rh(NBD)Cl]2给出了最好的结果，ee值也仅提高了2％；铱源方面，[Ir(COD)Cl]2给出了与铑相似的ee值，但是催化活性明显较低。
[a]反应条件:0.2mmol,底物浓度0.1mol/L,溶剂2mL,催化剂1.0mol％.[b]1HNMR分析的结果.[c]手性HPLC分析的结果.[d]S/C＝1000.[e]S/C＝5000.实施例2溶剂的影响
溶剂效应在不对称催化中发挥着非常重要的作用，特别是对于铑催化的不对称氢化；因此，针对这个反应，我们首先筛选了甲醇、乙醇、2,2,2-三氟乙醇、异丙醇和叔丁醇这几个常见的极性质子溶剂。
使用乙醇时，ee值可以达到95％；有趣的是，当醇的位阻和PKa增大时，产物的ee值急剧下降。因此推测醇类溶剂参与离子相互作用，如果醇具有合适的位阻、电子效应和和PKa，溶剂参与的二级相互作用会有利于提高催化剂的催化效率，反之对反应不利。当反应使用非极性和极性非质子等其他类型的溶剂时，催化剂的效率和立体控制都不理想。以2,2,2-三氟乙醇作为溶剂，使用0.1mol％当量的[Rh(Chenphos)Cl]2，反应可以完全转化，并得到高达95％的ee值。在进一步的考察中发现，在对映选择性保持同时TONs可达到5000。
实施例3底物的适用性
确定以CF3CH2OH作溶剂，20个大气压的氢气，使用0.1mol％ChenPhos-铑络合物，室温反应20小时为最优氢化条件后，接着对反应的底物适用性进行考察。
[a-b]反应条件:0.2mmol,底物浓度0.1mol/L,溶剂2mL,催化剂0.1mol％.所有的例子底物完全反应.[b]手性HPLC确定，构型通过文献对比确定.
在最优氢化条件下，不同类型的α-芳氧基和α-烷基α,β-不饱和酸底物都可以完全转化并给出非常理想的对映选择性。底物芳环上取代基的位置和位阻效应对此氢化策略几乎没有影响，带有取代基的α-芳氧基和α-烷基α,β-不饱和羧酸底物都可以顺利转化，其中萘基底物的氢化产物ee值高达99％(2m)；值得注意的是，含有芳杂环的底物同样适用于此反应并给出了非常优秀的对映选择性；更重要的是手性产物2d和2r分别是制备Ertiprotafib[12]和Ragaglitazar[13]的关键中间体，这两个化合物是新型PPARA&PPARC激动剂，用于治疗Ⅱ型糖尿病。
实施例4控制实验
为了更深入的了解α-氧基官能化的α,β不饱和羧酸类底物的不对称氢化转化过程，我们进行了两组对照实验，用于验证配体的二甲基氨基和羧酸单元之间的离子相互作用是否对反应的高对映选择性起作用。一方面，在最优氢化条件下以相应的不饱和酯为底物，反应没有发生，全部回收原料(公式1)；另一方面，当反应加入50mol％当量的三乙胺时，尽管底物完全转化，对映选择性急剧下降到46％(公式2)，这可能是由于外加碱与配体以及底物发生相互作用从而干扰对反应的立体控制。这些结果验证了了我们最初设想，即此催化体系中的离子相互作用对反应取得较高对映选择性发挥着至关重要的作用。
实施例5Chenphos/铑配合物体系在脑啡肽酶抑制剂sacubitril核心结构的制备中的应用
本发明这种高对映选择性的氢化反应可以应用到对脑啡肽酶抑制剂sacubitril(AHU377)核心结构的合成，这是一个新的FDA批准的药物LCZ696的成分之一(方案5)。在我们的模型研究中，我们以市售易得的(R)-苯丙氨酸为起始原料，经过氨基的保护和羧基的还原得到氨基醇5，接着Swern氧化后生成相应的醛6。然后，通过Horner-Wadsworth-Emmons反应成功制得α-取代的不饱和酯7，水解后得到相应的不饱和酸8。以该α-取代的不饱和酸为底物，应用手性chenphos/铑催化剂体系，可高立体选择性得到目标产物。此外，该手性产物9是化合物tubulysins的一个关键合成碎片，tubulysins是一系列线性四肽，它们在干扰微管结构和抑制微管蛋白聚合方面展现非凡的抗有丝分裂活性14。上述这些结果展现了chenphos/铑催化体系在有机合成中的的潜在应用价值。
化合物5在干燥的四氢呋喃中加入氢化钠，0℃条件下加入triethyl2-phosphonopropionate，冷却至-78℃条件下滴加化合物4。室温反应3小时后使用饱和氯化铵溶液淬灭。用乙醚萃取有机相，干燥、浓缩、柱层析(石油醚/乙酸乙酯体系)得到为无色油状化合物5。
化合物6在5的乙醇溶液中加入氢氧化钠的乙醇溶液(3M)，回流两个小时。冷却、浓缩后在0℃条件下加入盐酸(3M)，冷却至-78℃条件下滴加化合物4。室温反应3小时后使用饱和氯化铵溶液淬灭。用乙酸乙酯萃取有机相，干燥、浓缩、重结晶(正己烷/乙酸乙酯体系)得到为白色固体化合物6。其表证数据：1HNMR(400MHz,CDCl3)δ7.31-7.16(m,5H),6.62(d,J＝12Hz,1H),4.62(brs,2H),2.93-2.76(m,2H),1.71(s,3H),1.41(s,9H).其非对映异构体6‘数据：1HNMR(400MHz,CDCl3)δ7.26-7.17(m,5H),6.63(s,1H),4.65(brs,2H),2.93-2.79(m,2H),1.69(s,3H),1.41(s,9H).
化合物7使用标准条件(氢气压力20atm，催化剂Rh-ChenPhos用量0.1mol％，三氟乙醇作溶剂，室温反应20小时)氢化还原6，分离得到白色固体化合物7。其表证数据：1HNMR(400MHz,CDCl3)δ7.30-7.16(m,5H),6.39(dd,J＝8,68Hz,0.48H),4.49(d,J＝8Hz,0.35H),3.95-3.78(m,1H),2.80-2.41(m,3H),1.95-1.89(m,1H),1.39and1.30(s,9H),1.16(d,J＝8Hz,3H)；13CNMR(100MHz,CDCl3)δ180.84,157.36,156.11,138.68,137.58,129.42,128.34,126.45,80.29,79.78,53.60,50.94,49.80,49.69,41.49,39.15,38.13,36.92,28.35,28.11,17.82,16.31.其非对映异构体7‘数据：1HNMR(400MHz,CDCl3)δ7.28-7.16(m,5H),6.41(dd,J＝8,68Hz,0.46H),4.52(d,J＝8Hz,0.41H),3.96-3.78(m,1H),2.80-2.41(m,3H),1.91-1.77(m,1H),1.40and1.30(s,9H),1.18(d,J＝8Hz,3H)；13CNMR(100MHz,CDCl3)δ184.30,180.90,177.74,157.29,157.11,156.03,138.54,137.67,133.25,129.43,128.35,126.44,126.36,126.28,100.00,49.79,41.48,38.96,36.89,36.35,29.70,28.35,28.11,17.79.
在本发明中，我们报道了chenphos/铑配合物可以作为一种高效的催化α-氧官能团化的α，β-不饱和酸不对称加氢反应的催化剂体系。控制实验表明，配体和底物之间的离子作用在适当的溶剂中实现高对映选择性起着至关重要的作用。Chenphos-铑配合物催化剂体系是对催化α-氧官能团化的α，β-不饱和酸有广泛的底物适用范围的不对称催化剂体系之一。
该催化剂体系成功的应用在新的药物LCZ696核心机构的构建。反应式如下：
通过对Boc保护的α，β-不饱和酸底物的高对映选择性氢化反应来合成脑啡肽酶抑制剂sacubitril核心结构:
高对映选择性氢化合成脑啡肽酶抑制剂sacubitril核心结构过程中，其中乙酰保护α，β-不饱和酸类底物是一类新型的中间体，包含中间体x和相应的乙酰基保护的手性中间体Y。中间体Y可以转换为Boc保护手性中间体Z。
本发明描述了一种特别提到优选实施例的方法。应该理解的是，上述的描述和例子只说明了这项发明。针对本发明的精髓和范畴，可以设计出各种可供选择的底物和修饰后的底物。
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Claims (8)

1.一种α-氧代-α,β-不饱和羧酸的不对称氢化方法，其特征在于，以Rh的前体与ChenPhos络合物作为手性催化剂，以极性质子溶剂为反应溶剂，所述ChenPhos结构为：
2.根据权利要求1所述的不对称氢化方法，其特征在于，Rh的前体包括[Rh(COD)2]BF4，[Rh(NBD)2]BF4，[Rh(NBD)2]SbF6，[Rh(COD)Cl]2，[Rh(NBD)Cl]2，或[Rh(NBD)Cl]2。
3.根据权利要求1所述的不对称氢化方法，其特征在于，所述极性质子溶剂包括甲醇、乙醇、2,2,2-三氟乙醇、异丙醇和叔丁醇。
4.根据权利要求1所述的不对称氢化方法，其特征在于，反应条件为，使用20个大气压的氢气，使用0.1mol％ChenPhos-铑络合物，室温反应20小时。
5.根据权利要求1所述的不对称氢化方法，其特征在于，该方法用于以下药物中间体和相关化合物的合成：
6.根据权利要求1所述的不对称氢化方法，其特征在于，该方法用于对FDA批准的药物LCZ696--脑啡肽酶抑制剂sacubitril的核心结构的合成。
7.根据权利要求1所述的不对称氢化方法，其特征在于，通过对Boc保护的α，β-不饱和酸底物的高对映选择性氢化反应来合成脑啡肽酶抑制剂sacubitril核心结构。
8.权利要求7所述不对称氢化方法过程中产生的中间体，包括中间体X、中间体Y和中间体Z：
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