ABSTRACT
The explosively growing field of combinatorial chemistry clearly has its roots in Merrifield's solid-phase synthetic approaches [1]. All aspects of this approach for the assembly of peptides were extensively developed in the 20 years following Merrifield's initial publication [2-5]. The concept of rapidly constructing large numbers of compounds in parallel was first presented by Geysen et al. (pins) [6] and Houghten (free resin in mesh packets-"teabags") [7] in 1984 and 1985, respectively. As is true for all combinatorial strategies, these two seminal parallel synthesis methods were first applied to the synthesis of peptides. They are now the most widely used means of preparing combinatorial libraries of all types, including peptidomimetics [810], oligonucleotides [11,12], and oligosaccharides [13 -15]. The success of all solid-phase synthetic approaches is indicated by the capability to drive reactions on polymer supports to completion (often >99.8%), the ability to remove readily excess reagents and starting materials, and ease of automation. The design and development of strategies for the synthesis of individual and combinatorial libraries of heterocyclic compounds have been areas of intense research over the past 5 years. It is of note that Leznoff [16,17] and Crowley and Rapoport [18] carried out the solid-phase synthesis of heterocycles from 1972 to 1977, but this powerful approach remained virtually untapped for 15 years until the solid-phase synthesis of libraries of diazepines was reported by Bunin and Ellman in 1992 [19].
