CN114904577A - 手性多孔交联寡肽聚合物不对称催化剂及其制备方法 - Google Patents
手性多孔交联寡肽聚合物不对称催化剂及其制备方法 Download PDFInfo
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Abstract
本发明公开了手性多孔交联寡肽聚合物不对称催化剂及其制备方法,该催化剂的制备通过将具有催化功能的含有芳香氨基酸单元的寡肽进行化学交联制备出一种手性多孔交联寡肽聚合物不对称催化剂,或通过将含有芳香氨基酸单元的寡肽进行化学交联后,通过后修饰的方法引入催化位点,制备手性多孔交联寡肽聚合物不对称催化剂。本发明的手性多孔交联寡肽聚合物不对称催化剂能够催化多种不对称反应,具有比表面积大、催化效率高、对映选择性高和可循环利用等优点;相对于脯氨酸等小分子手性有机催化剂,极大缩短了反应时间,提高了转化率和对映选择性。该催化剂制备方法简单、成本低、效率高,有良好的市场前景。
Description
技术领域
本发明涉及多孔材料,催化剂和不对称催化领域,主要涉及手性多孔交联寡肽聚合物不对称催化剂及其制备方法,具体涉及手性多孔交联寡肽聚合物合成,催化活性基团负载及由此催化剂催化的不对称反应。
背景技术
近几十年来,随着手性药物的不断开发和使用,合成新型不对称催化剂成为研究热点之一。在过去几十年中,使用的手性催化剂多为酶和金属配合物。近年来随着绿色化学的提出非均相有机催化剂成为研究重点。非均相有机催化剂通常是由小分子物质聚合而成,具有无毒和廉价的特点。这使得非均相有机催化剂在药物的合成中非常适用。
带有手性结构的氨基酸广泛的存在与自然界中,是一种廉价,易得的手性化合物。随着研究不断深入发现由2-50个氨基酸所组成的多肽可以做为手性催化剂的良好载体使用。多肽具有模块化特性,可以通过替换单个的氨基酸残基来微调其反应活性和对应选择性,以及仿生属性。因此设计多肽催化剂的关键因素是将具有催化能力的官能团,纳入适当的手性环境的三维结构中。同时可以通过设计多肽的结构使其在常用的有机溶剂中难容,方便多次回收利用。然而由于多肽之间的结合多为分子间作用力,多次循环后特殊的手性环境被破坏导致催化活性下降。
多相催化剂易于回收和重复利用,但很难确定影响催化活性的活性位点。因此,可以通过设计具有活性催化结合位点的载体来弥补与均相催化剂之间的差距。多孔超交联聚合物(HCP)具有较大的比表面积,稳定的理化性质和大量的表面官能团。多孔超交联聚合物可以通过简单的反应获得。其多孔结构可以增加反应物与催化活性中心接触的机会。因此,由寡肽超交联合成的手性聚合物可以做为催化剂或载体。
发明内容
本发明的目的在于但不仅限于为不对称催化反应提供一种价廉、高效、可回收和高对映选择性的新型手性多孔交联寡肽聚合物不对称催化剂及其制备方法。
本发明的新型手性多孔交联寡肽聚合物不对称催化剂是可以通过替换不同氨基酸微调结构的超交联寡肽聚合物;催化剂活性位点均匀的分布在催化剂中显著提高催化剂的催化效率有效缩短催化反应时间。
本发明的目的可以通过以下方法实现:
手性多孔交联寡肽聚合物不对称催化剂合成方法,包括以下两种方式:
方式一:通过具有催化功能的含芳香氨基酸的寡肽与交联剂之间的亲电取代反应合成手性多孔交联寡肽聚合物不对称催化剂。
方式二:催化剂经以下步骤进行制备
步骤一:通过不具催化功能的含芳香氨基酸的寡肽与交联剂之间的亲电取代反应和成手性多孔交联寡肽聚合物前体。
步骤二:将带有催化位点的化合物通过化学反应对步骤一中所得手性多孔交联寡肽聚合物前体进行修饰,引入有机催化位点,制得手性多孔交联寡肽聚合物不对称催化剂。
所述方式一具体为:氮气气氛下,将具有催化功能的含芳香氨基酸的寡肽、交联剂、交联催化剂以一定质量比加入反应瓶中,之后加入适量的反应溶剂。氮气保护下在一定温度进行反应生成固形物,经过滤洗涤直接制得手性多孔交联寡肽聚合物催化剂。
所述方式二中步骤一具体为:将不具催化功能的含芳香氨基酸的寡肽、交联剂、交联催化剂以一定质量比加入反应瓶中,之后加入适量的反应溶剂。氮气保护下在一定温度下进行反应生成固形物,经过滤洗涤制得手性多孔交联寡肽聚合物前体。
所述方式二中步骤二具体为:手性多孔交联寡肽聚合物前体的修饰可通过亲核取代反应、偶联反应等将带有催化位点的基团引入交联寡肽前体,获得手性多孔交联寡肽聚合物不对称催化剂。
所述芳香氨基酸包括但不限于苯丙氨酸、苯甘氨酸、酪氨酸、色氨酸、组氨酸、氨基苯甲酸、氨基苯磺酸等含芳环的氨基酸中的一种或多种;含芳香氨基酸的寡肽为:寡肽结构中含有一个或多个芳香氨基酸单元的具有光学活性的寡肽或上述寡肽的混合物;交联剂包括但不限于1,4-对二氯苄、联苯二氯苄、二甲氧基甲烷中的一种或混合物。
交联催化剂包括但不限于三氯化铁、三氯化铝、浓硫酸、浓磷酸中的一种或混合物;反应溶剂包括但不限于1,2-二氯乙烷、二甲基亚砜、硝基甲烷中的一种或混合物。
所述带有催化位点的化合物包括但不限于金鸡纳碱、脯氨酸、羟脯氨酸、胺、胍等含氮类有机碱及其衍生物,磷酸、磺酸等布朗斯特酸衍生物中的一种或和混合物。
所述含芳香氨基酸的寡肽/交联剂/交联催化剂质量比为1/1~1.5/2~3;反应溶剂用量与反应物比例为5~50mL/g;反应温度为室温~100摄氏度;反应时间为2-48小时。
一种手性多孔交联寡肽聚合物不对称催化剂,由以上任意一种方法制备而成。
与现有技术相比,本发明的有益效果是:
本发明首先通过寡肽与交联剂之间的亲电取代反应合成了手性多孔交联寡肽聚合物不对称催化剂或载体。将催化活性基团接入聚合物载体中制备出手性催化剂。本发明的新型不对称催化剂能够催化多种不对称反应,具有比表面积大、催化效率高、对映选择性高和可循环利用等优点;相对于脯氨酸等小分子手性有机催化剂,极大缩短了反应时间,提高了转化率和对映选择性,该催化剂制备方法简单、成本低、效率高,有良好的市场前景。
附图说明
图1为本发明实例1所获得的手性多孔交联寡肽聚合物不对称催化剂的扫描电子显微镜图;
图2为本发明实例1所获得的手性多孔交联寡肽聚合物不对称催化剂的红外光谱;
图3为本发明实例1所获得的手性多孔交联寡肽聚合物不对称催化剂的核磁谱图;
图4为本发明实例1所获得的手性多孔交联寡肽聚合物不对称催化剂的氮气吸附等温线;
图5为本发明实例1中由手性多孔交联寡肽聚合物不对称催化剂催化曼尼希反应产物的色谱图。
具体实施方式
下面结合具体实施例对本发明作更详细的描述:
实施例1:
1.合成手性多孔交联寡肽聚合物前体:氮气气氛下,将Boc-L-苯丙氨酸-苯丙氨酸(1.0毫摩尔),联苯二氯苄(1.0毫摩尔),三氯化铁(3.0毫摩尔)加入反应瓶中,之后加入40毫升1,2-二氯乙烷和10毫升二甲氧基甲烷。将盛有反应物的反应瓶置于油浴锅中,在80摄氏度下反应48小时。反应结束后将反应所得固形物滤出,并放入索氏提取器中用甲醇提取24-96小时。提取结束后将固形物放入乙酸乙酯中,加入适量的浓盐酸常温反应24h,脱除保护基。反经过滤洗涤制得手性多孔交联寡肽聚合物前体。
2.手性多孔交联寡肽聚合物前体的修饰:将Fmoc-L-脯氨酸2.0克,N,N'-二环己基碳二亚胺6.0克,超交联苯丙氨酸二肽1.0克,及反应溶剂二氯甲烷20毫升加入反应瓶中在氮气氛围中反应7d。反应结束后常压抽滤,提纯产物,收集固形物。然后将其加入乙酸乙酯中,放入适量的浓盐酸常温反应24小时。脱除保护基。反应完成后常压过滤提纯产物,制得手性多孔交联寡肽聚合物催化剂。
3.使用上述合成的催化剂催化对甲氧基苯胺,对硝基苯甲醛和丙酮的不对称曼尼希反应。氮气气氛下,在反应器中依次加入8.0毫克手性介孔寡肽聚合物催化剂,2.0毫升三氯甲烷,1.0毫摩尔丙酮,0.5毫摩尔对硝基苯甲醛,0.6毫摩尔对甲氧基苯胺摇匀。反应50秒后使用过滤针头过滤回收催化剂。使用柱层析法分离纯化产物,使用的流动相为正己烷/异丙醇=9/1体积比,使用旋转蒸发仪将溶剂旋干,最后将剩余的产物放入30摄氏度的真空干燥箱中真空干燥至恒重,收率95%。
4.测试催化产物的对映体过剩率。在常温常压下称取2.0毫克产品溶解到混合溶剂中(正己烷/丙醇=9/1,体积比)。然后将产物溶液注入高效液相色谱中进行测试,使用AD-H手性柱,流动相为正己烷/异丙醇=9/1体积比,流速为1.0毫升/分钟。产物对映体过剩率为95%。
实施例2:
1.使用上述合成的催化剂催化对甲氧基苯胺,对硝基苯甲醛和苯乙酮的不对称曼尼希反应。氮气气氛下,在反应器中依次加入8.0毫克手性介孔寡肽聚合物催化剂,2.0毫升三氯甲烷,1.0毫摩尔苯乙酮,0.5毫摩尔对硝基苯甲醛,0.6毫摩尔对甲氧基苯胺摇匀。反应50秒后使用过滤针头过滤回收催化剂。使用柱层析法分离纯化产物,使用的流动相为正己烷/异丙醇=9/1体积比,使用旋转蒸发仪将溶剂旋干,最后将剩余的产物放入30摄氏度的真空干燥箱中真空干燥至恒重,收率92%。
2.测试催化产物的对映体过剩率。在常温常压下称取2.0毫克产品溶解到混合溶剂中(正己烷/丙醇=9/1,体积比)。然后将产物溶液注入高效液相色谱中进行测试,使用AD-H手性柱,流动相为正己烷/异丙醇=90/10体积比,流速为1.0毫升/分钟。产物对映体过剩率为99%。
实施例3:
1.使用上述合成的催化剂催化环己酮和反式-β-硝基苯乙烯的不对称迈克尔加成反应。氮气气氛下,在反应器中依次加入8.0毫克手性介孔寡肽聚合物催化剂,4.0毫升甲醇,0.5毫摩尔反式-β-硝基苯乙烯,0.6毫摩尔环己酮摇匀。将密封后的反应器放入25摄氏度的磁力搅拌器中反应4天,反应完成后使用过滤针头过滤回收催化剂。使用柱层析法分离纯化产物,使用的流动相为正己烷/异丙醇=9/1体积比,使用旋转蒸发仪将溶剂旋干,最后将剩余的产物放入30摄氏度的真空干燥箱中真空干燥至恒重,收率94%。
2.测试催化产物的对映体过剩率。在常温常压下称取2毫克产品溶解到混合溶剂中(正己烷/丙醇=9/1,体积比)。然后将产物溶液注入高效液相色谱中进行测试,使用AD-H手性柱,流动相为正己烷/异丙醇=90/10体积比,流速为1.0毫升/分钟。产物对映体过剩率为97%。
综上,本发明公开了一种手性多孔交联寡肽聚合物不对称催化剂及其制备方法,该催化剂的制备通过将具有催化功能的含有芳香氨基酸单元的寡肽进行化学交联制备出一种手性多孔交联寡肽聚合物不对称催化剂,或通过将含有芳香氨基酸单元的寡肽进行化学交联后,通过后修饰的方法引入催化位点,制备手性多孔交联寡肽聚合物不对称催化剂。本发明的手性多孔交联寡肽聚合物不对称催化剂能够催化多种不对称反应,具有比表面积大、催化效率高、对映选择性高和可循环利用等优点;相对于脯氨酸等小分子手性有机催化剂,极大缩短了反应时间,提高了转化率和对映选择性。该催化剂制备方法简单、成本低、效率高,有良好的市场前景。
Claims (10)
1.手性多孔交联寡肽聚合物不对称催化剂的制备方法,其特征在于,包括以下两种方式:
方式一:通过具有催化功能的含芳香氨基酸的寡肽与交联剂之间的亲电取代反应合成手性多孔交联寡肽聚合物不对称催化剂;
方式二:催化剂经以下步骤进行制备:
步骤一:通过不具催化功能的含芳香氨基酸的寡肽与交联剂之间的亲电取代反应和成手性多孔交联寡肽聚合物前体;
步骤二:将带有催化位点的化合物通过化学反应对步骤一中所得手性多孔交联寡肽聚合物前体进行修饰,引入有机催化位点,制得手性多孔交联寡肽聚合物不对称催化剂。
2.根据权利要求1所述的手性多孔交联寡肽聚合物不对称催化剂的制备方法,其特征在于,所述方式一具体为:氮气气氛下,将具有催化功能的含芳香氨基酸的寡肽、交联剂、交联催化剂加入反应瓶中,之后加入反应溶剂,氮气保护下进行反应生成固形物,经过滤洗涤直接制得手性多孔交联寡肽聚合物催化剂。
3.根据权利要求1所述的手性多孔交联寡肽聚合物不对称催化剂的制备方法,其特征在于,所述方式二中步骤一具体为:将不具催化功能的含芳香氨基酸的寡肽、交联剂、交联催化剂加入反应瓶中,之后加入反应溶剂,氮气保护下进行反应生成固形物,经过滤洗涤制得手性多孔交联寡肽聚合物前体。
4.根据权利要求1所述的手性多孔交联寡肽聚合物不对称催化剂的制备方法,其特征在于,所述方式二中步骤二具体为:手性多孔交联寡肽聚合物前体的修饰可通过亲核取代反应或偶联反应将带有催化位点的基团引入交联寡肽前体,获得手性多孔交联寡肽聚合物不对称催化剂。
5.根据权利要求1所述的手性多孔交联寡肽聚合物不对称催化剂的制备方法,其特征在于,所述芳香氨基酸包括苯丙氨酸、苯甘氨酸、酪氨酸、色氨酸、组氨酸、氨基苯甲酸、氨基苯磺酸等含芳环的氨基酸中的一种或多种;含芳香氨基酸的寡肽为:寡肽结构中含有一个或多个芳香氨基酸单元的具有光学活性的寡肽或上述寡肽的混合物;交联剂包括但不限于1,4-对二氯苄、联苯二氯苄、二甲氧基甲烷中的一种或混合物。
6.根据权利要求2所述的手性多孔交联寡肽聚合物不对称催化剂的制备方法,其特征在于,交联催化剂包括但不限于三氯化铁、三氯化铝、浓硫酸、浓磷酸中的一种或混合物;反应溶剂包括但不限于1,2-二氯乙烷、二甲基亚砜、硝基甲烷中的一种或混合物。
7.根据权利要求3所述的手性多孔交联寡肽聚合物不对称催化剂的制备方法,其特征在于,交联催化剂包括但不限于三氯化铁、三氯化铝、浓硫酸、浓磷酸中的一种或混合物;反应溶剂包括但不限于1,2-二氯乙烷、二甲基亚砜、硝基甲烷中的一种或混合物。
8.根据权利要求1所述的手性多孔交联寡肽聚合物不对称催化剂的制备方法,其特征在于,带有催化位点的化合物包括但不限于金鸡纳碱、脯氨酸、羟脯氨酸、胺、胍等含氮类有机碱及其衍生物,磷酸、磺酸等布朗斯特酸衍生物中的一种或和混合物。
9.根据权利要求1所述的手性多孔交联寡肽聚合物不对称催化剂的制备方法,其特征在于,含芳香氨基酸的寡肽/交联剂/交联催化剂质量比为1/1~1.5/2~3;反应溶剂用量与反应物比例为5~50mL/g;反应温度为室温~100摄氏度;反应时间为2-48小时。
10.一种手性多孔交联寡肽聚合物不对称催化剂,其特征在于,由权利要求1-9任意一种方法制备而成。
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