Tzschucke Carl Christoph, Markert Christian, Bannwarth Willi, Roller Sebastian, Hebel André, Haag Rainer
Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstrasse 21, 79104, Freiburg, Germany.
Angew Chem Int Ed Engl. 2002 Nov 4;41(21):3964-4000. doi: 10.1002/1521-3773(20021104)41:21<3964::AID-ANIE3964>3.0.CO;2-3.
The shift of paradigm in combinatorial chemistry, from large compound libraries (of mixtures) on a small scale towards defined compound libraries where each compound is prepared in an individual well, has stimulated the search for alternative separation approaches. The key to a rapid and efficient synthesis is not only the parallel arrangement of reactions, but simple work-up procedures so as to circumvent time-consuming and laborious purification steps. During the initial development stages of combinatorial synthesis it was believed that rational synthesis of individual compounds could only be achieved by solid-phase strategies. However, there are a number of problems in solid-phase chemistry: most notably there is the need for a suitable linker unit, the limitation of the reaction conditions to certain solvents and reagents, and the heterogeneous reaction conditions. Further disadvantages are: the moderate loading capacities of the polymeric support and the limited stability of the solid support. In the last few years several new separation techniques have been developed. Depending on the chemical problem or the class of compounds to be prepared, one can choose from a whole array of different approaches. Most of these modern separation approaches rely on solution-phase chemistry, even though some of them use solid-phase resins as tools (for example, as scavengers). Several of these separation techniques are based on liquid-liquid phase separation, including ionic liquids, fluorous phases, and supercritical solvents. Besides being benign with respect to their environmental aspects, they also show a number of advantages with respect to the work-up procedures of organic reactions as well as simplicity in the isolation of products. Another set of separation strategies involves polymeric supports (for example, as scavengers or for cyclative cleavage), either as solid phases or as soluble polymeric supports. In contrast to solid-phase resins, soluble polymeric supports allow reactions to be performed under homogeneous conditions, which can be an important factor in catalysis. At the same time, a whole set of techniques has been developed for the separation of these soluble polymeric supports from small target molecules. Finally, miscellaneous separation techniques, such as phase-switchable tags for precipitation by chemical modification or magnetic beads, can accelerate the separation of compounds in a parallel format.
组合化学的范式转变，从小规模的大型化合物库（混合物）转向在单个孔中制备每种化合物的特定化合物库，这激发了人们对替代分离方法的探索。快速高效合成的关键不仅在于反应的平行排列，还在于简单的后处理程序，以避免耗时费力的纯化步骤。在组合合成的初始开发阶段，人们认为只有通过固相策略才能实现单个化合物的合理合成。然而，固相化学存在一些问题：最明显的是需要合适的连接单元，反应条件受限于某些溶剂和试剂，以及非均相反应条件。进一步的缺点包括：聚合物载体的负载能力适中以及固体载体的稳定性有限。在过去几年中，已经开发了几种新的分离技术。根据化学问题或要制备的化合物类别，可以从一系列不同的方法中进行选择。这些现代分离方法大多依赖于溶液相化学，尽管其中一些使用固相树脂作为工具（例如作为清除剂）。其中一些分离技术基于液 - 液相分离，包括离子液体、氟相和超临界溶剂。除了在环境方面具有良性外，它们在有机反应的后处理程序以及产物分离的简便性方面也显示出许多优点。另一组分离策略涉及聚合物载体（例如作为清除剂或用于环化裂解），既可以作为固相，也可以作为可溶性聚合物载体。与固相树脂相比，可溶性聚合物载体允许在均相条件下进行反应，这在催化中可能是一个重要因素。同时，已经开发了一整套用于从小目标分子中分离这些可溶性聚合物载体的技术。最后，各种分离技术，如通过化学修饰进行沉淀的相切换标签或磁珠，可以加速化合物的平行分离。
