Rapid assembly of molecular diversity via exploitation of isocyanide-based multi-component reactions

Molecular diversity is the variability of physical properties between molecules, viewed in terms of molecular shape, polarity/charge, lipophilicity, polarizability and flexibility. Due to their widespread medicinal properties, natural products were one of the original sources of molecular diversity; however, new developments in the search for novel pharmacological agents over the last decade have focused on the preparation of chemical libraries as the source of new leads for drug discovery. A plethora of personal synthesizers and new automation technologies have emerged to help fuel the lead discovery engines of drug discovery organizations. Multistep solid-phase syntheses of diverse libraries in excess of 10,000 products can now be prepared via split-and-mix techniques. Simultaneously, a multitude of more efficient, diversity- or target-oriented solution-phase chemical methodologies have appeared in the chemical literature, enabling the relatively facile construction of successful lead generation libraries with low full-time equivalent input and little capital expenditure. Isocyanide-related multi-component reactions hold a pre-eminent position in this regard, and are finding increasing applications in the discovery process of new drugs and agrochemicals. This review is the authors' personal assessment of advances in the field over the last two years (2002 to 2003), with little emphasis placed on highly mechanistic details.