Multicomponent Reactions Applied to Total Synthesis of Biologically Active Molecules: A Short Review

Multicomponent reactions (MCRs) are processes in which three or more starting materials are combined in the same reaction vessel, forming an adduct that contains all or most of the atoms of the starting materials. MCRs are one-pot processes that provide attractive advantages for the total synthesis of target molecules. These reactions allow rapid access to structurally complex adducts from particularly simple starting materials. Moreover, MCRs are generally intrinsically associated with principles of green syntheses, such as atom economy, minimization of isolation, and purification of synthetic intermediates, leading to large solvent economies and avoiding the production of large amounts of reaction waste. Thus, synthetic routes employing multicomponent reactions are generally more convergent, economical and often allow higher overall yields. In total synthesis, the use of MCRs has been mainly applied in the preparation of key advanced intermediates. Progress in the use of MCRs in total synthesis has been described over the last decades, including not only classical MCRs reactions (e.g. isocyanide-based transformations), but also non-traditional multicomponent reactions. Furthermore, reports concerning stereoselective multicomponent transformations are still scarce and present further development opportunities. This review aims to provide a general overview of the application of MCRs as key steps in the rapid preparation of structurally complex derivatives and fine chemicals. In special, some selected examples have been successfully applied for medicinal purposes. Finally, in some representative cases, either key intermediates formed during the reaction vessel or corresponding transition states have been disclosed in order to provide insights into the reaction mechanisms.