CN114057673B - 一种γ-或δ-取代的烷基手性内酯的合成方法 - Google Patents

一种γ-或δ-取代的烷基手性内酯的合成方法 Download PDF

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CN114057673B
CN114057673B CN202111514896.1A CN202111514896A CN114057673B CN 114057673 B CN114057673 B CN 114057673B CN 202111514896 A CN202111514896 A CN 202111514896A CN 114057673 B CN114057673 B CN 114057673B
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邓晋
邓臣强
傅尧
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Abstract

本发明公开了一种γ‑或δ‑取代的烷基手性内酯的合成方法，是将镍盐、手性双齿有机磷配体、脂肪族γ‑或δ‑酮酸及溶剂混合，在还原剂的作用下进行不对称还原反应，得到γ‑或δ‑取代的烷基手性内酯。本发明通过廉价的、绿色的、高效的均相手性镍磷络合物催化体系实现脂肪族γ‑和δ‑酮酸的不对称氢化，以优异的收率和高的对映选择性获得γ‑或δ‑取代的烷基手性内酯。

Description

一种γ-或δ-取代的烷基手性内酯的合成方法
技术领域
本发明属于有机合成领域，具体涉及一种γ-或δ-取代的烷基手性内酯的合成方法。
背景技术
可再生资源催化转化为有价值的化学品引起了学术界和工业界的广泛兴趣。生物质作为一种可再生、可持续的有机碳资源，被认为是最有前途的石油衍生物替代品。乙酰丙酸是一种重要的生物质衍生平台分子，可以转化为其他高附加值的化学品，如二醇、羧酸和内酯。与非手性内酯相比，手性内酯是构建许多重要天然产物和生物活性分子的通用构件。此外，它在自然界中也很普遍，尤其是许多水果的信息素和芳香成分，可用于香料添加剂。前手性分子的不对称氢化是构建手性化合物的最有力和最有效的策略之一。近几十年来，酮的不对称催化加氢在以钌、铑、铱为活性中心的贵金属催化剂方面取得了巨大的成就，表现出优异的催化活性和对映选择性。然而，由于这些贵金属的储量减少、价格高、毒性大，非常有必要用地球上储量丰富、价格低廉、环境友好的金属替代它们。
发明内容
本发明针对上述现有技术所存在的问题，提供了一种γ-或δ-取代的烷基手性内酯的合成方法，通过廉价的、绿色的、高效的均相手性镍磷络合物催化体系实现脂肪族γ-和δ-酮酸的不对称氢化，以优异的收率和高的对映选择性获得γ-或δ-取代的烷基手性内酯。
本发明γ-或δ-取代的烷基手性内酯的合成方法，包括如下步骤：
将镍盐、手性双齿有机磷配体、脂肪族γ-或δ-酮酸及溶剂混合，在还原剂的作用下进行不对称还原反应，得到γ-或δ-取代的烷基手性内酯。
所述镍盐包括醋酸镍、四水醋酸镍、三氟甲磺酸镍、六水四氟硼酸镍、六水高氯酸镍、乙酰丙酮镍或氯化镍，优选三氟甲磺酸镍。
所述手性双齿有机磷配体选自如下结构中的一种，优选(S,S)-Ph-BPE配体。
Figure BDA0003406557810000021
所述溶剂包括水、甲醇、乙醇、异丙醇、叔丁醇、四氢呋喃、二氯甲烷、三氟乙醇、六氟异丙醇、甲苯、1,4-二氧六环、乙酸乙酯或乙酸；优选三氟乙醇。
所述脂肪族γ-或δ-酮酸为具有如下通式的化合物：
Figure BDA0003406557810000022
其中n＝1、2或3，并且R表示为烷基或其他有机官能团如羧基。所述烷基包括但不限于C1-7烷基，如甲基、乙基、丙基、戊基、异丙基、叔丁基、环戊基、环己基等。
所述还原剂是氢气。加氢反应过程中，氢气压力为1-100atm，优选1-50atm。
进一步地，脂肪族γ-或δ-酮酸和镍盐的摩尔比为100:1-100:5；脂肪族γ-或δ-酮酸和手性双齿有机磷配体的摩尔比为100:1-100:5。
反应过程中，反应温度控制在30-100℃，优选45-65℃。
本发明的有益效果体现在：
本发明使用廉价的金属催化剂、产物ee值高、产物收率高，底物范围广，操作简单，反应条件温和，环境友好，易于大规模生产，具有很强的工业应用前景。
附图说明
图1是实施例1中不同温度和不同底物浓度的反应效果。
图2是(S)-γ-戊内酯的1H NMR谱图。
图3是(S)-γ-戊内酯的13C NMR谱图。
具体实施方式
实施例1：
3.6mg三氟甲磺酸镍和5.0mg(S,S)-Ph-BPE加入10ml Schlenk反应管中，加入2ml三氟乙醇并在室温搅拌20分钟，然后加入106mg乙酰丙酸，在Schlenk反应管上方插上氢气球，在50℃下反应12小时；反应结束后，加入NMP作为内标，然后进行气相色谱分析，γ-戊内酯的收率为96％，ee值为95％。检测条件为：色谱柱：Supelcoβ-DEXTM 225柱(df＝0.25μm，0.25mm i.d.×30m)，气化室温度：230℃，检测器温度：250℃.升温程序如下:100℃(8min)-5℃/min-200℃(7min)，柱流量：1.0mL/min。
操作过程与实施例1相似，其中将(S,S)-Ph-BPE配体替换为不同手性双齿有机磷配体，反应效果如表1：
表1
Figure BDA0003406557810000031
从表1中数据可以看出，使用轴手性配体能提供良好的收率，但获得的对映选择性较低(14-37％)。使用富电子的(Sc,Rp)-DuanPhos配体可以获得92％的γ-戊内酯的收率和56％ee。(S,S)-DuPhos、(S,S)-iPr-BPE和(S,S)-ChiralPhos配体没有氢化反应活性。而使用膦手性中心的配体(S,S)-BenzP*和(S,S)-QuinoxP*分别以90％和95％的收率获得产物，ee值分别为66％和80％。这些结果表明(S,S)-Ph-BPE为最优的配体。
操作过程与实施例1相似，其中将Ni(OTf)2替换为不同镍盐，反应效果如表2：
表2
Figure BDA0003406557810000041
从表2中数据可以看出，镍盐的阴离子对反应的氢化活性有重要的影响。当使用弱配位的阴离子如三氟甲磺酸根和四氟硼酸根，产物以96％的收率和95％ee获得。而使用醋酸根的镍盐，催化活性略微的降低但对映选择性保持不变。使用强配位能力阴离子的镍盐如氯离子，反应几乎没有活性。在该反应中最优的镍盐是三氟甲磺酸镍和六水四氟硼酸镍。
操作过程与实施例1相似，其中将三氟乙醇替换为不同的溶剂，反应效果如表3：
表3
Figure BDA0003406557810000042
从表3中数据可以看出，反应溶剂对氢化活性和对映选择性有明显的影响。当使用水作为溶剂，反应不发生。分别使用甲醇、乙醇或异丙醇作为溶剂，产率由11％提高到38％，对映选择性由69％提高到89％。而使用其他的非质子溶剂，均给出了低反应活性，对映选择性适中。
操作过程与实施例1相似，展示不同温度和不同底物浓度的反应效果，见图1。从图1中可以看出，反应温度对产物收率有显著影响，但不影响反应的对映选择性。增加反应温度，产物的收率增加，在50℃下，获得最高的收率。反应浓度对产率和对映选择性均有影响。随着反应浓度的增大，产物的收率降低。对映选择性在一定范围内保持不变，但继续增加反应浓度，对映选择性显著下降。
实施例2：
1.8mg三氟甲磺酸镍和1.25mg(S,S)-Ph-BPE加入10ml Schlenk反应管或高压反应釜中，加入2ml三氟乙醇并在室温搅拌20分钟，然后加入0.25mmol不同的脂肪族γ-或δ-酮酸底物。在1-50atm氢气压力下，反应温度为65℃下反应24小时。反应结束后，然后产物使用气相色谱进行分析，结果如表4所示：
表4
Figure BDA0003406557810000051
a2mL DCM，50℃；b5mol％Ni(OAc)2·4H2O/(S,S)-Ph-BPE，50℃；c随后Yamaguchi环化。
通过以上实施例可以看出，本发明发现了一种γ-和δ-取代的烷基手性内酯的制备方法，本发明具有如下优点：使用廉价的金属催化剂、产物ee值高、产物收率高，底物范围广，操作简单，反应条件温和，环境友好，易于大规模生产，具有很强的工业应用前景。

Claims (5)

1.一种γ-或δ-取代的烷基手性内酯的合成方法，其特征在于包括如下步骤：
将镍盐、手性双齿有机磷配体、脂肪族γ-或δ-酮酸及溶剂混合，在还原剂氢气的作用下进行不对称还原反应，得到γ-或δ-取代的烷基手性内酯；
所述镍盐为三氟甲磺酸镍或六水四氟硼酸镍；
所述手性双齿有机磷配体选自如下结构中的一种：
Figure FDA0004220855160000011
所述溶剂为三氟乙醇；
反应过程中，反应温度控制在45-65℃；
所述脂肪族γ-或δ-酮酸为具有如下通式的化合物：
Figure FDA0004220855160000012
其中n＝1或2，R选自C1-7烷基、环戊基或环己基；
2.根据权利要求1所述的合成方法，其特征在于：
所述镍盐为三氟甲磺酸镍。
3.根据权利要求1所述的合成方法，其特征在于：
所述手性双齿有机磷配体为(S,S)-Ph-BPE配体。
4.根据权利要求1所述的合成方法，其特征在于：
加氢反应过程中，氢气压力为1-100atm。
5.根据权利要求1所述的合成方法，其特征在于：
脂肪族γ-或δ-酮酸和镍盐的摩尔比为100:1-100:5；脂肪族γ-或δ-酮酸和手性双齿有机磷配体的摩尔比为100:1-100:5。
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