基于双向协同识别作用的双水相手性萃取拆分研究

As a green separation and purification technology, aqueous two-phase extraction possesses such advantages as high biocompatibility, fast mass-transfer, improved enrichment efficiency, and continuous operation possibility etc. In this proposal, for the first time, a novel enantioselective extraction system of bidirectional synergetic recognition-based aqueous two-phase system (BDSR-ATPS) will be developed. For a given β-cyclodextrin (β-CD) derivative (or polysaccharide derivative, PSD), the tailor-made chiral ionic liquid with oppositely preferential recognition capability will be synthesized. Then the combination of chiral ionic liquid and β-CD derivative (or PSD) will be employed as constituent and chiral selector simultaneously to form BDSR-ATPS. Given the fact that these two types of constituents would be preferentially enriched in top and bottom phases respectively, high enantioseparation efficiency can be achieved owing to the bidirectional synergetic effects. As a consequence, their phase-forming characteristics would be qualitatively and quantitatively analyzed, and a general continuous phase forming rate model and enantioselective partition theory would be established. Moreover, liquid chromatography is expected to be used for screening appropriate pairs of phase-forming agents, and a chemometric approach of response surface methodology is employed in securing key process parameters and rapidly optimizing their values. The potential of BDSR-ATPS coupled with multi-stage extraction plants for preparing enantiopure compounds will be investigated and the corresponding mathematical model of mass-transfer will also be established. The whole research work will be guided by separation science of chemical engineering and mathematical statistics, which would significantly enrich the enantioseparation theory, and facilitate the exploration and development of new enantioseparation technologies with high practicability.

双水相萃取是一种新型的绿色分离纯化技术，具有生物兼容性好、传质速率快、富集效率高及适合连续操作等优点,本项目将其应用于手性拆分领域，构建一种手性双向协同识别双水相萃取体系。定向合成与β-环糊精衍生物(或多糖类衍生物)手性识别倾向相反的手性离子液体，将其与β-环糊精衍生物(或多糖类衍生物)组合作为构建双水相体系的两种成相组分，这两类手性拆分物质分别富集于上下两相，通过双向协同识别作用实现手性对映异构体的高效拆分。系统地定性定量分析该类体系的成相特点，构建具有普适性的连续相成相速率理论模型及手性选择性分配理论；借助液相色谱筛选合适的成相组分对；利用响应表面法提取关键过程参数并对参数值进行快速优化；尝试将手性双向协同识别双水相体系与多级萃取设备联用，建立相应的传质数学模型。本研究将化工分离科学与数理统计学有机结合，丰富了手性分离理论与实践，有助于应用性较强的手性拆分技术的探索与发展。

研究表明手性药物对映体对人体的作用及用途存在着明显的差异甚至完全相反，因此如何获取单一构型手性对映体的研究受到越来越多的关注。外消旋体拆分是在手性助剂的作用下将两个对映异构体分开，以获取高光学纯度的对映单体，该方法理论成熟、易于操作、实用性强，是目前大规模获取光学纯手性物质较为常用的方法。而双水相萃取作为一种新型的绿色分离纯化技术，具有生物兼容性好、传质速率快、富集效率高及适合连续操作等优点，适用于开发手性药物拆分方法。.因此，本项目提出了基于双相协同识别双水相萃取技术的药物对映体拆分策略，在两相中定向添加手性识别倾向相反的手性拆分剂，通过双向协同识别作用实现手性对映异构体的高效拆分；基于此，项目首先基于金鸡碱、硫脲衍生物及焦谷氨酸模块的立体选择性构建了一系列不对称催化体系，并以此为基础构建具有高效手性识别性能的手性识别模块；将手性识别模块功能化至水滑石、量子点及碳纳米材料上制备了具有手性选择性分离和识别性能的新型复合材料；并以相关手性识别复合材料为基础，实现了多种手性化合物的对映选择性吸附分离及荧光响应；同时基于可见光氧化还原催化反应特性，探讨了光催化-有机催化协同催化体系的催化性能，为新型手性拆分剂的高效合成提供了新途径。上述研究结果为手性拆分剂、手性识别模块的设计合成及其应用于手性药物分离分析提供了有益的参考，促进了化工分离新技术及手性识别新方法的探索与发展。依托于项目主体研究内容，项目还开展了杂环骨架多元化合成、天然产物中异构体的分离纯化及复杂生物体系中生物小分子的电化学、表面拉曼增强(SERS)及荧光量子点(QDs)检测等方面的研究工作，促进了有机合成、分析化学、药物化学等相关学科的发展。项目实施期间总计在Angew. Chem. Int. Edit., Anal. Chem., Org. Lett., Chem. Commun.等期刊上发表SCI论文36篇(均已标注资助)，培养博士生6名、硕士生12名。