Combinatorial chemistry solution-phase techniques

Two general methods are used to build a library of compounds by the general techniques of combinatorial chemistry solid-phase synthesis (SPS) and solution-phase synthesis. 

In the 1990s the technique of solid-phase organic synthesis (SPOS) became generally popular, but especially in the medicinal chemistry community, for lead detection and lead optimization via combinatorial techniques. The combination with microwave irradiation brought an elegant solution for the problem of the notoriously slower reactions compared to those in solution phase. 

Many of these new techniques are especially suited to the preparation of combinatorial libraries by solution phase parallel synthesis. This chapter provides a brief introduction to the concepts of strategy level purification, and then introduces fluorous chemistry with representative examples of reactions, reagents and techniques. 

An important tool for the fast characterization of intermediates and products in solution-phase synthesis are vibrational spectroscopic techniques such as Fourier transform infrared (FTIR) or Raman spectroscopy. These concepts have also been successfully applied to solid-phase organic chemistry. A single bead often suffices to acquire vibrational spectra that allow for qualitative and quantitative analysis of reaction products,3 reaction kinetics,4 or for decoding combinatorial libraries.5... 

Solid-phase methods are applicable to syntheses of sequence-specific oligomers and dendritic structures. The triazene chemistry developed for this specific purpose may also be useful in other types of syntheses. Further development of solid-phase syntheses of this type into combinatorial synthesis of oligomers is the next logical step. Solid-phase methods will never completely replace solution-phase approaches to oligomers, but either technique should be considered with respect to the special characteristics and requirements for the system under investigation. 

The advantages of heterogeneous solid phase in combinatorial chemistry, especially in terms of purification procedures, can be obtained also by solution-phase chemistry, using solid support assistance. The resin performs a specific function during the library synthesis and then is simply removed by filtration, leaving the pure library components in solution. A well-known adapted technique uses solid supported reagents or catalysts during a combinatorial synthesis, where the solid phase is filtered off and discarded after the reaction in which it was involved. A new application is represented by solid-phase purification, where one or more solid supports are added to trap the excess of... 

The use of supported reagents has always been recognized as a powerful tool in classical organic chemistry for a large number of applications, and excellent reviews covered this topic in the past [103-105]. Recently, this technique has been applied to solution-phase combinatorial chemistry, where it looks really promising in terms of simpler work-up procedures, elimination of excess reagents, and isolation of pure reaction products. 

Some particular features of the analysis of products obtained by combinatorial methods have impaired the use of NMR spectroscopy in the initial phase of the development of this technique. Combinatorial chemistry produces large number of compounds in a very short period of time, in small quantities and instead of using traditional glassware for synthesis employs 96-well microtiter plates to store, transport and sometimes even to synthesize the compounds of interest. Another issue is the need to characterize solution and solid samples, since solid phase synthesis is extensively used in combichem. In this context, the need of an efficient and universal sample analysis remains a challenge. Actually, most combichem programs obtain mass spectrometry and UV (photodiode-array detection) data on their samples but clearly the use of NMR spectroscopy provides a structural characterization unparalleled by the aforementioned techniques. In the last years an increasing number of new NMR methods opened the possibility for the utilization of this analytical technique for monitoring combinatorial chemistry reactions. The first part of this chapter will focus on the recent developments introduced in NMR spectroscopy to overcome these difficulties. 

Since the beginning, combinatorial chemistry has strongly depended on the techniques of solid-phase synthesis (SPS). For this reason a detailed presentation of solid-phase (SP) chemistry in which the differences compared to classical organic chemistry in solution are highlighted appears at the beginning of this book. 

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