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. 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.

Organocatalytic click reactions to 1,4- and 1,5-disubstituted triazoles are rapidly emerging as most valuable alternatives to other triazole-forming protocols. Here the latest developments are discussed leading to intriguing synthetic possibilities.

Fungal unspecific peroxygenases (UPOs) represent an enzyme class catalysing versatile oxyfunctionalisation reactions on a broad substrate scope. They are occurring as secreted, glycosylated proteins bearing a haem-thiolate active site and rely on hydrogen peroxide as the oxygen source. However, their heterologous production in a fast-growing organism suitable for high throughput screening has only succeeded once—enabled by an intensive directed evolution campaign. We developed and applied a modular Golden Gate-based secretion system, allowing the first production of four active UPOs in yeast, their one-step purification and application in an enantioselective conversion on a preparative scale. The Golden Gate setup was designed to be universally applicable and consists of the three module types: i) signal peptides for secretion, ii) UPO genes, and iii) protein tags for purification and split-GFP detection. The modular episomal system is suitable for use in Saccharomyces cerevisiae and was transferred to episomal and chromosomally integrated expression cassettes in Pichia pastoris. Shake flask productions in Pichia pastoris yielded up to 24 mg/L secreted UPO enzyme, which was employed for the preparative scale conversion of a phenethylamine derivative reaching 98.6 % ee. Our results demonstrate a rapid, modular yeast secretion workflow of UPOs yielding preparative scale enantioselective biotransformations.