Cyclodextrins are cyclic oligomers of glucose. Their central cavities can hold small molecules, making them attractive for sensor and drug delivery applications. The most common cyclodextrins, CD6, CD7, and CD8, are made commercially via enzymatic processes. The smallest one previously chemically synthesized is CD5. Now Hidetoshi Yamada and coworkers at Kwansei Gakuin University report that they have chemically synthesized the smallest possible cyclodextrins, CD3 and CD4 (Science 2019, DOI: 10.1126/science.aaw3053). To achieve the synthesis, the researchers added a bridge between the O-3 and O-6 oxygen atoms of each glucose ring, which created a bicyclic structure. The bridge adjusts the conformation of the scaffold, shifting the glucose ring to a conformation that favors the α-1,4-glycosidic bond formation needed to make the desired strained cyclodextrins. Although the researchers were able to obtain CD3 and CD4, the synthesis worked better for the trimer than for the tetramer. However, they could make only limited amounts of either oligomer. Yamada and coworkers are working on scaling up the reaction to gram quantities.