Friedel-Crafts Reactions for Biomolecular Chemistry

Chemical tools and principles have become central to biological and medical research/applications by leveraging a range of classical organic chemistry reactions. Friedel-Crafts alkylation and acylation are arguably one of the most well-known and used synthetic methods for preparation of small molecules but its use in biological and medical fields are relatively less frequent than the other reactions, possibly owing to the notion about its plausible incompatibility with biological systems. This Review demonstrates advances of Friedel-Crafts alkylation and acylation reactions in a variety of biomolecular chemistry fields. With the discoveries and applications of numerous biomolecule-catalyzed or –assisted processes, the reactions have garnered considerable interests in biochemistry, enzymology, and biocatalysis. Despite the challenges of reactivity and selectivity of biomolecular reactions, the alkylation and acylation reactions demonstrated its utility for construction and functionalization of all the four major biomolecules (i.e., nucleosides, carbohydrates/saccharides, lipids/fatty acids, and amino acids/peptides/proteins), and their diverse applications in biological, medical, and material fields are discussed. As the alkylation and acylation reactions are often fundamental educational components of organic chemistry courses, the Review is intended for both experts and nonexperts by discussing their basic reaction patterns (with the depiction of each reaction mechanism in the Electronic Supplementary Information) and relevant real-world impacts in order to enrich chemical research and education. The significant growth of biomolecular Friedel-Crafts reactions described here is a testament to its broad importance and utility, and the further development and investigation of the reactions will surely be the focus in the organic biomolecular chemistry fields.