Biocatalytic Strategies towards [4+2] Cycloadditions

Long sought after [4+2] cyclases have sprouted up in numerous biosynthetic pathways in recent years, raising hopes for biocatalytic solutions to cycloaddition catalysis, an important problem in chemical synthesis. In a few cases, detailed pictures of the inner workings of these catalysts have emerged, but intense efforts to gain deeper understanding are underway by means of crystallography and computational modelling. This Minireview aims to shed light on the catalytic strategies that this highly diverse family of enzymes employs to accelerate and direct the course of [4+2] cycloadditions with reference to small‐molecule catalysts and designer enzymes. These catalytic strategies include oxidative or reductive triggers and lid‐like movements of enzyme domains. A precise understanding of natural cycloaddition catalysts will be instrumental for customizing them for various synthetic applications. Numerous examples of enzymes catalyzing [4+2] cycloadditions, an important reaction in synthetic organic chemistry, have been discovered in recent years. This Minireview discusses the biocatalytic strategies employed by natural [4+2] cyclases and designer enzymes created in the lab. These enzymes can potentially be developed into biocatalytic tools for organic synthesis in the future (see graphic).