ABSTRACT
Following the introduction of chloromethylpolystyrene resin by Merrifield in 1963 (1), solid-phase synthesis was rapidly adopted as the method of choice for the synthesis of peptides and oligonucleotides (2-5). Surprisingly, solid-phase synthesis did not receive much attention from the wider synthetic community, and thus the ensuing 25 years of solid-phase research focused largely on the development of “ biopolymer-friendly” solid supports (2-7), improved pro tecting group strategies (8,9), and new synthetic methods for the construction of amide and phosphate bonds (2-5,10,11). Consequently, the solid-phase synthesis of complex peptides and oligonucleotides has become routine and, in many cases, automated. Over the last 10 years the power of solid-phase synthesis has been recognized by medicinal chemists (12-17). The attention of this new audience has shifted the focus of solid-phase research away from the synthesis of large biopolymers, which uses a small set of established chemistries and building blocks. Instead, solid-phase research has broadened to the application of a wide range of chemistries for the synthesis of small molecules that bear little resem blance to peptides or oligonucleotides. These sea changes have been accompanied
by a number of new challenges, two of which are particularly relevant to this chapter.
