以氢键作用增强毛细管电泳手性拆分的正电型环糊精研究

Targeting at the challenge of 6-persubstituted and monosubstituted cationic cyclodextrins (CDs) as vesatile chiral selectors in capillary electrophoresis for the enantioseparation of amino acids as well as acidic and neutral racemates,two series of selectively di-substituted cationic β-CDs are proposed on the basis of our recent success in the development of methoxypropylammonium β-CD featuring hydrogen-bonding enhanced enantioseparation and selective disubstituted cationic CDs with different substituents. The two series of selectively modified β-cyclodextrins include 3-methoxypropyl-1-amonium disubstituted AB, AC and AD regioisomer β-CDs, as well as AC regioisomer β-CDs disubstituted with 3-methoxypropyl-1-amonium and triazole-based moieties. By preparation of the designed CD chiral selectors,the controllable synthetic approaches for selectively disubstituted cationic CDs will be explored and optimized. And the versatile enantioseparation ability of the as-prepared CDs towards amino acids as well as acidic and basic racemates will be validated. The effect of disubstitution pattern, substituent structure and number of charged sustituents on the enantioselectivities of CDs will be studied. And the mechanism with hydrogen-bonding enhanced enantioselectivities towards amino acids and hydroxy acids will be revealed. By optimizing the analytical parameters for the chiral separation, the optimal conditions for the enantioseparation of certain type of racemates will be secured. By strengthening the understanding of improvement of CDs' enantioselectivities by structure design, new research direction for achieving versatile high-performance chiral selectors may be opened.

针对全取代和单取代修饰正电型环糊精手性拆分剂对氨基酸类、酸性和中性消旋体手性拆分时缺乏广谱拆分能力的难题，以课题组深入研究的氢键增强手性拆分的甲氧基丙铵基环糊精和选择性双取代环糊精合成方法为基础，进一步巧妙设计了甲氧基丙铵基选择性6位AB、AC和AD双取代的双正电型环糊精，以及甲氧基丙铵基和三唑基取代基团6位AC双取代的单正电型环糊精；通过合成设计结构的手性拆分剂，探索可控、选择性双取代正电型环糊精的合成技术，验证其对氨基酸类、酸性和中性手性药物的广谱拆分能力；研究双取代位置、取代基结构和带电基团数目对环糊精手性拆分的影响，揭示双取代正电型环糊精对氨基酸和羟基酸消旋体的氢键增强手性拆分机理；考察分离条件对环糊精手性拆分能力的影响，获取特定类型消旋体的最佳拆分条件；深化通过环糊精结构设计提高其手性拆分能力的认识，为获得高效率广谱性环糊精手性拆分剂提供新的研究方向

针对全或单取代正电型环糊精的广谱拆分难题，课题组开展了深入系统研究，通过可控化学构建了系列多重作用增强的环糊精手性分离材料。通过引入含氧端基的正电基团，在环糊精与消旋体分子间构建氢键和静电作用，获得了对包括酸性、氨基酸甚至中性消旋体的广谱手性拆分，对酸性和氨基酸的手性分离度甚至超过10。① 利用Staudinger和Gabriel等反应，成功开发了烷氧/醇铵基、铵基烷基咪唑和咪唑鎓基烷铵基等6-位单取代正电型环糊精，在低环糊精浓度(~1 mM)下获得对酸性、氨基酸等大于10的手性分离度; ② 利用2,4,6-三甲基-苯磺酰氯为磺酰化试剂，通过非对称亲核取代，成功开发了较文献报道更为简捷可控的AC双取代环糊精合成方法。在更低浓度(~0.5 mM)下实现对酸性药物消旋体的基线分离。基于可控合成、构建多重作用增强手性分离环糊精材料的持续研究和深入，系统开展了环糊精结构与其手性分离能力的关联研究；建立了新型环糊精的手性识别模型、揭示手性拆分机理，为环糊精可控合成与手性分离研究提供了科学依据和可靠方法。