Chapter 31. Solid-Phase Synthesis: Applications to Combinatorial Libraries

Abstract

Publisher Summary This chapter discusses a comprehensive survey of templates and skeletons for which a solid-phase synthesis has been reported for library synthesis. The chapter also discusses a survey of the reactions that have been performed on solid support along with a discussion on some issues specific to solid-phase synthesis. Libraries of discrete compounds have been prepared by parallel synthesis in a spatially addressable fashion, where compound location indicates the compound structure. For peptides and oligonucleotides, rapid and sensitive sequencing strategies are available for determining the compound structure. The backbones or templates, for which solid-phase synthesis has been reported, are categorized as: nonpeptide oligomers, privileged structures, novel templates, designed templates targeted toward a particular receptor or enzyme class, and structures for lead optimization. Many reactions have been demonstrated on the solid-support. These reactions are categorized into carbon-heteroatom bond forming reactions, carbon-carbon bond forming reactions, cycloadditions, and multicomponent reactions. The linkage element for covalently attaching a compound to the solid support deserves special consideration. The linker should be stable to the reaction conditions employed in the synthesis sequence, but should be cleavable under conditions that do not degrade the product. Linkage to the solid support is generally accomplished, using a functional group that is a part of the targeted molecule or that is appended onto the structure. Many different analytical techniques are currently being used to evaluate the solid-phase reactions or compounds bound to the solid support. Functional group titration is often used to monitor the reactions. Many advances continue to be made in the synthesis of small-molecule libraries on solid supports, including the development of new support materials. Equally important efforts are being made in the computational methods for library design and database management, analytical evaluation, automation and instrumentation for synthesis and purification, and methods for high-throughput biological evaluation.