Isocyanide Chemistry: Driving Multicomponent API Synthesis

Abstract:

Isocyanides are among the most reactive and versatile functional groups, especially in modern organic synthesis. Their peculiar electronic structure, which includes a divalent carbon bearing both nucleophilic and electrophilic character, enables their participation in a wide range of reactions. Their involvement is evident in Multi-Component Reactions (MCRs) involving nucleophilic substitution of isocyanides, yielding highly functionalised scaffolds in a single synthetic operation. Moreover, synthetic applications of isocyanides are further expanded by their applications in coordination chemistry, where they act as ligands towards transition metals. Remarkably, many reactions based on isocyanides proceed under relatively mild conditions, which adds to the advantage of operational simplicity and high atom economy. These advantages aid in the synthesis of extensive molecular libraries, most of which serve as essential substrates for the synthesis of Active Pharmaceutical Ingredients (APIs). Moreover, appropriately adjusting reaction parameters, such as solvent and temperature, and using asymmetric catalysts, enhances the chemo- and stereo-selectivity of the reaction. This level of fine-tuning of reaction parameters significantly enhances the bioconjugation strategies for peptides and proteins, as well as the late-stage functionalization of drug molecules and natural products. This manuscript aims to comprehensively highlight the naturally and industrially relevant reactions involving the synthesis of isocyanides, their optimisation through strategic modifications to reaction conditions, and their wide applications in MCRs, bioconjugation chemistry, and the synthesis of API substrates and intermediates.