14] Combinatorial chemistry: A liquid-phase approach

Abstract

The development of bioavailable organic compounds in a combinatorial format is obligatory for the advancement of combinatorial chemistry from a pharmaceutical standpoint. Ingrained early on in this quest for reaction methodologies, leading to “small molecule” libraries, was the need for simple product isolation, facile manipulation of the “portioning-mixing” technique, and the ability to drive a reaction to completion. Polymer-supported synthesis has emerged as one of the most important tools in research efforts focused on the construction of nonoligopeptide/nucleotide libraries. As promising as the “solid-phase” method in a combinatorial format seems, it has certain drawbacks. The most notable of these is the heterogeneous reaction conditions that can lead to some of the following potential problems: (1) nonlinear kinetic behavior, (2) unequal distribution and/or access to the chemical reaction, (3) solvation problems, and (4) pure synthetic problems, associated with solid-phase synthesis. Because of these potential limitations that solid-phase synthesis presents, alternative methodologies have been sought out from a combinatorial point of view. This chapter describes a liquid-phase methodology and shows its utility in the synthesis of a peptide and sulfonamide library. This chapter has shown how a technology termed “liquid-phase combinatorial synthesis” can simplify and further accelerate the combinatorial chemical process. This methodology combines the advantages that classic organic synthesis offers, in solution with those that solid-phase synthesis can provide. The findings here indicate that the reaction scope of liquid-phase combinatorial synthesis (LPCS) should be general. Its value to high-throughput screening assays could be of particular merit, since multimilligram quantities of each library member can be obtained.