基于纤维素的键合型手性高效液相色谱固定相的研发

Chiral high-performance liquid chromatography (HPLC) has attracted more and more attention in the past decades and was been recognized as the most popular and reliable tool for the analysis of the enantiomer purity of drugs and natural products and the separation of enantiomers in asymmetric synthesis. The key and core of chiral chromatography is the chiral stationary phase (CSP). Among many CSPs, cellulose-based CSPs are known to exhibit high chiral recognition abilities to a broad range of chiral compounds and have been recognized as the most powerful CSPs. The commercial CSPs are traditionally prepared by coating cellulose derivatives on microporous silica gel, which can only be used with a very limited range of solvents as the mobile phases. The strict limitation of compatible solvents has become the main drawback in the method development in practical applications. Therefore, chemical immobilization of cellulose derivatives on silica gel has been considered as a direct approach to conferring the universal solvent compatibility upon such CSPs. However, lack of control in currently reported strategies for cellulose functionalization under heterogeneous reaction conditions and the complexity of the preparation process may limit the application of covalently bonded cellulose-based CSPs. In this project, we will explore a unique homogeneous functionalization reaction to modify cellulose carbamate derivatives with uniformly distributed reactive functionalities. The functional cellulose derivatives will be coated and covalently bonded onto silica gel. The chiral recognition properties of the covalently bonded CSPs will be evaluated after being packed in the HPLC column. Unlike the heterogeneously functionalized cellulose, homogeneously functionalized cellulose prepared by our synthetic strategy will maintain its three-dimensional helical structure, which is conducive to improve the chiral recognition abilities of CSPs.

近年来，手性色谱分离在药物、天然产物和不对称合成等领域越来越受到重视。手性色谱的关键和核心是手性固定相（CSP）材料。其中，基于纤维素的CSP因其品种繁多、通用性强、负载量大等优点被广泛使用。目前大部分商品化纤维素色谱柱是物理涂覆型的，耐溶剂性能较差。键合型纤维素CSP将克服涂覆型CSP耐溶剂性差的缺点，但是受纤维素官能化过程可控性、制备工艺和技术的限制，使其或者分离效率低，或者可重复性差，未能实现使用寿命和分离性能的同时提高。本项目将着手解决这一难题，发展新的化学键合技术，制备具有优异性能的化学键合型纤维素CSP，并进行产业化探索。采用我们独特的均相反应技术对纤维素氨基甲酸酯衍生物进行官能化，再与修饰的硅胶载体进行化学键合，从而制备新型键合型CSPs。与非均匀修饰的键合型纤维素CSPs不同，均匀修饰的纤维素衍生物，能够更大程度地保持纤维素固有的三维螺旋结构，从而保证其高效的手性分离能力。

高效液相色谱技术（HPLC）是一种分离光学异构体获得光学纯品的有效手段，因其高效、方便、快速等优点，越来越受关注。手性固定相（CSP）是手性色谱发展的关键和核心，在众多CSPs材料中，纤维素基CSPs因其品种繁多、通用性强、负载量大等优点被广泛使用。传统的纤维素基CSPs大多是物理涂覆型的，耐溶剂性差，限制了流动相的选择。然而向流动相中添加一定量的极性溶剂甚至是纤维素衍生物的良溶剂往往能有效地提高手性分离能力，为了有效地改善CSPs的耐溶剂性，人们将纤维素衍生物化学键合到硅胶基质上制备键合型CSPs。目前，键合型CSPs的制备方式主要有两种：1）通过纤维素衍生物上修饰的活性官能团与硅胶上修饰的活性官能团发生化学反应，在硅胶表面键合上一层纤维素衍生物的“分子刷”；2）纤维素衍生物通过修饰的活性官能团相互交联，在硅胶表面形成一层纤维素衍生物的交联层。两种途径都需要对纤维素衍生物进行有效的官能化，但是如果引入的活性官能团过多或者官能团分布不均都将对CSPs的手性分离能力造成影响。所以，发展一种可控均匀地官能化方法极为重要。于是，我们发展了一种独特地均相修饰纤维素衍生物的技术，获得了较小官能度且官能团分布均匀的纤维素衍生物，将其与修饰的硅胶载体进行化学键合，制备了新型的键合型CSPs。与涂覆型CSPs对比，键合型CSPs在保证手性分离能力的同时耐溶剂性显著增强，尤其是在使用含有THF和氯仿等良溶剂后，手性分离能力依然保持。通过本项目的研究，为制备键合型纤维素基CSPs提供了一种有效的新方法，为纤维素基CSPs的应用提供了一个崭新的平台。