Molecular Diversity By Design

摘要

Many organic syntheses are target-oriented - each multi-step route is designed to make just one compound. But now a diversity-oriented synthesis can make 80 different molecular skeletons in just a few steps. Genome biology is shining a bright light on the origins of human disease. Unfortunately, the biological targets emerging as ideal points for therapeutic intervention are often viewed as being extremely difficult, if not impossible, to modulate with small molecules - which is a problem, because most drugs are small molecules. But is this view justified? Drug hunters search for candidates for drug-discovery programmes by screening large numbers of compounds in biological assays. Perhaps these collections simply lack compounds from structural classes that would modulate the targets identified by genomics studies. Reporting in Angewandte Chemie, Morton et al. describe an ingenious synthetic pathway that will help to populate screening collections with structurally diverse compounds. For many decades, organic chemists have searched for ways of making naturally occurring small molecules (known in the field as natural products). These objects of affection pose strategic challenges: can sequences of reactions be devised that turn simple, readily available compounds into more complex target compounds? In the more-notable successes, the resulting syntheses have provided insights into such fundamental areas as conformational analysis (the study of the dynamic shapes of molecules), general principles of reactivity, and biosynthesis and life's prebiotic origins. Natural-product syntheses have on several occasions served as starting points for drug development, and they have revealed gaps in the methods of organic synthesis, providing motivation to fill them.