Solution Phase Synthesis
Despite the focus on the use of solid-phase techniques for the synthesis of combinatorial libraries, there have been a few examples where libraries have successfully been made and screened in solution. Indeed some groups have expressed a preference for solution libraries because there is no prior requirement to develop workable solid-phase coupling and linking techniques. Panlabs have recently disclosed an interest in making large numbers of compounds as individual components using parallel, reliable solution chemistry.
The idea behind the method of generating libraries of small organic molecules is to combine a rigid core molecule supporting multiple reactive sites with a mixture of building blocks to produce a random mixture of polyfunctionalized structures, e.g. a molecule such as cubane tetra acid chloride could be combined with four molar equivalents of amines to produce tetra-substituted cubane compounds. This method of library generation has several advantages. First it is a powerful method of generating molecular diversity; in a single combinatorial step, the cubane core and 26 amines would produce theoretically 38 701 different tetra amides. Reactions are pushed to completion by the use of excess quantities of the reactive reagent, and are isolated by the solvent-solvent extraction. There is no further purification, and thus they prefer to describe these samples as "reaction products".
The groups from Glaxo and Pirrung have synthesized dimeric compounds using amide, ester or carbamate bond-forming reactions. Every library compound was prepared twice in mixtures of differing composition. Testing all of these mixtures allows identification of likely active compounds without the need to resynthesise every compound in an active mixture. The drawback for solution phase chemistry is the time-consuming purification of intermediates that is often required in between synthetic steps.