Diversity oriented synthesis: a challenge for synthetic chemists

This article covers the diversity-oriented synthesis (DOS) of small molecules in order to generate a collection of pure compounds that are attractive for lead generation in a phenotypic, high-throughput screening approach useful for chemical genetics and drug discovery programmes. Nature synthesizes a rich structural diversity of small molecules, however, unfortunately, there are some disadvantages with using natural product sources for diverse small-molecule discovery. Nevertheless we have a lot to learn from nature. The efficient chemical synthesis of structural diversity (and complexity) is the aim of DOS. Highlights of this article include a discussion of nature's and synthetic chemists' strategies to obtain structural diversity and an analysis of molecular descriptors used to classify compounds. The assessment of how successful one diversity-oriented synthesis is vs another is subjective; therefore we use freely available software (www.cheminformatics.org/diversity) to assess structural diversity in any combinatorial synthesis.