The synthesis of structurally diverse and structurally complex collections of small molecules remains a major challenge to synthetic chemists. We illustrate the diversity-oriented synthesis (DOS) of small molecule collections to directly address this need, directed towards the search for new antibacterials with novel modes of action.[1,2]
Drug discovery programs use large collections of small molecules to look for lead structures from biological assays. The success of this approach depends upon the collection of compounds (and luck). Chemists are demanding the rapid preparation of collections of highly pure small molecules that are structurally diverse. Combinatorial chemistry has answered this need to an extent; however, most combinatorial libraries produce compounds of very limited structural diversity. Since only building block diversity has been employed the resulting compounds have the same stereochemistry, functional groups and scaffold. This is not desired if you want a diverse library, such as when you are looking for a phenotype in a biological screen, especially where there is no known small molecule hit.
Figure 1. Comparison of Target-Oriented Synthesis versus Diversity-Oriented Synthesis.
In contrast to target-oriented synthesis (TOS), DOS is not aimed at one particular target, and retrosynthetic analysis is therefore not applicable directly (Figure 1). Instead we need to identify complexity-generating reactions and pathways that give structural diversity. In order to design a synthetic pathway leading to a collection of compounds with different scaffolds requires the use of branch points, where a common substrate is used in different reactions that give different skeletons.