Chemical Clockwise Tridifferentiation of α‐ and β‐Cyclodextrins: Bascule‐Bridge or Deoxy‐Sugars Strategies

The selective and efficient functionalisation of large concave molecules is a chemical challenge opening the door to various applications, such as artificial enzymes. We propose here a method, based on deprotection of benzylated cyclodextrins, to selectively access a variety of complex structures with two or three new different functionalities on the primary platform. Our strategy is based on a mechanistic hypothesis involving the approach of an aluminium reagent between the primary oxygen atom and the endocyclic one of the same sugar unit. Due to its cyclic directionality, a change in steric hindrance on a given position of the cyclodextrin has a different effect on the clockwise or the counterclockwise directions. This concept is illustrated and exploited in two complementary ways: deoxygenation of the primary position of two diametrically opposed sugars induces a debenzylation reaction on the neighbouring clockwise sugars of α‐ and β‐cyclodextrins. Reversible capping, or bascule‐bridging, of the same pair of sugars has the same effect on the debenzylation of α‐cyclodextrin, but induces an important change of the geometry of β‐cyclodextrin, hence allowing the selective access to yet another functionalisation pattern. A combined use of deoxygenation and bascule‐bridging allows the access to an α‐cyclodextrin with its three pairs of primary functions differentiated and ready for further modifications. Bascule‐bridge or deoxy‐sugars are two complementary means to operate steric decompression and induce selective reactions to efficiently access a number of new patterns of functionalities on concave molecules.