High-throughput combinatorial synthesis of discrete compounds in multimilligram quantities: non-chemical encoding and directed sorting

Abstract

Abstract Over the past few years the pharmaceutical community’s need to generate and screen chemical libraries with large diversity has fuelled the rapid development of combinatorial chemistry (1, 2). Research areas such as high-throughput solution (3, 4) and solid phase (5-7) synthesis, the development of novel solid supports and linkers (Chapters 6 and 7) (8, 9), as well as new powerful encoding strategies (10-14) (Chapter 1) have received exceptional attention due to their central role in the development of this field. The chemical encoding strategies (15, 16), coupled with the split and pool technique (17) (Chapters 1-3) greatly increase the efficiency of combinatorial synthesis and screening. However, these strategies produce each member of the library in very small amounts (nanograms to micrograms), making subsequent multiple screenings and characterization procedures quite difficult. Although traditional parallel synthesis (18, 19) in combination with the remarkable recent progress in laboratory automation (19) produces larger quantities of material, it still lacks the efficiency of the split and pool technique particularly for the preparation of very large libraries. We have recently developed two new combinatorial synthesis strategies employing non-chemical encoding and directed sorting in a batch synthesis fashion (10, 11) that combine both the advantages of split and pool and parallel synthesis. These strategies are capable of producing large combinatorial libraries and delivering milligram quantities of each library member. This chapter discusses the development of these two non-chemical encoding techniques: radiofrequency (Rf) tagging (10) and bar coding (11) in combination with a directed sorting strategy, and their application to the synthesis of combinatorial libraries of a variety of chemical structures.