Biomolecular templates define the outcomes of enzymatic reactions in some of the most fundamental of biological processes, such as DNA replication, transcription and translation. In synthetic chemistry, molecular templates have enabled the synthesis of highly complex molecular architectures and interlocked structures. With Enzyme-Mediated Dynamic Combinatorial Chemistry, we explore the possibility of using synthetic templates to direct enzymatic reactions and obtain alternative products to those generated in Nature. 

α-, β- and γ-cyclodextrin (CD) are industrially important macrocyclic hosts formed from 6, 7, and 8 α-1,4-linked glucopyranose units. While cyclodextrins are usually considered as stable, static molecules, we generate dynamic mixtures of interconverting cyclodextrins by the action of cyclodextrin glucanotransferase (CGTase). As the system is dynamic, the product distribution can be manipulated via supramolecular interactions with template molecules.¹ We use templates to direct the selective synthesis of ‘natural’ cyclodextrins as well as modified cyclodextrins, and employ stimuli-responsive templates to control the system using light and redox chemistry.

Large-ring cyclodextrins, formed from more than 8 glucose units have received very little attention due to synthetic inaccessibility. Using the approach of template-directed enzymatic synthesis, we can now obtain δ-CD (formed from 9 glucose units) in unprecedented yields² and on a multi-gram scale.³ Investigations are ongoing to explore the molecular recognition capabilities of this newly accessible macrocyclic host.

[1]  1. D. Larsen, S. R. Beeren, Chem. Sci., 2019, 10, 9981–9987.
[2]  A. Erichsen, G. H. J. Peters, S. R. Beeren, J. Am. Chem. Soc., 2023, 145, 4882–4891.
[3]  K. Hansen, A. Erichsen, D. Larsen, S. R. Beeren, J. Am. Chem. Soc., 2025, 147, 13851–13858.