Click chemistry has made a game-changing entry into the molecular sciences in the last two decades. The dream formulated by Sharpless et al. consisted of a series of reactions that are ‘modular, wide in scope, give very high yields, generate only inoffensive byproducts that can be removed by nonchromatographic methods, and are stereospecific’ (from: Sharpless and co-workers, Angew. Chem. Int. Ed. 2001, 2004). Although originally largely a goal on the horizon, most of these appealing properties have since been realized in a variety of reactions, resulting in the paradigm shift labeled ‘click chemistry’. However, one of these facets – intrinsic stereospecificity – has not been reached in the many types of click chemistry (CuAAC, SPAAC, thiol-ene, SPOCQ, IEDDA, ..) that have been developed in the last 20 years. Given the crucial role of chirality in Nature, my group therefore set out to develop intrinsically chiral click reactions. We published the first-ever example of such ‘chiral click’ in 2020 (Zuilhof and co-workers, Angew. Chem. Int. Ed. 2020, 7494), via a novel type of Sulfur-Fluorine Exchange (SuFEx) reaction indicated below:
This finding brings up two basic research questions:
– To which areas of chemistry can we adapt this entirely novel type of reaction to use its unique features? We are currently working on a range of topics in which this is the central element.
– Can we think of other, intrinsically chiral click reactions? Now it is clear that they do exist and can be made use of, the question is: can we find more?