Evaluation of higher-order multicomponent reactions and biological applications of their products

Multicomponent reactions (MCRs) are by far the most successful class of reactions leading to high structural diversity and molecular complexity through a single transformation. As part of the ongoing search for pharmacologically active lead structures, the obtained structural diversity allows for the fast exploration of a large chemical space. Not surprisingly, the development of MCRs, leading to new structural frameworks or serving as key transformations in the total synthesis of natural products, has expanded rapidly over the last few decades. To date a multitude of new three- and four-component reactions have already been described; however, examples of ‘‘higher-order’’ MCRs where five or even more components are combined in a single reaction vessel are remarkably scarce. With the growing interest for biologically active small molecules at the end of the 20th century, the application of MCRs to create libraries of such small, drug-like molecules was investigated with a steadily increasing intensity by industry and academia as a result of its superiority over other approaches (i.e. the use of readily available starting materials, inexpensive and easy to carry out chemistry, broad product spectra, high diversity in few steps, ease of automation, etc). This tutorial review aims to critically describe the developments achieved in recent years, charting the ideas, challenges, and milestone reactions that were essential for the progress of this field.