Controlled Acid‐Mediated Regioselective O‐Desilylations for Multifunctionalization of Cyclodextrins

A highly valuable tri-/tetra-functionalization method is reported for cyclodextrin (CD) chemistry by taking advantage of the acid-sensitivity of the O-silyl ether group and also the geometry of CD macrocycles. The controlled acid-mediated O-desilylations from the easily accessible per-3,6-O-silylated CD derivatives provide unprecedented regioselectivity to differentiate not only primary O-silyl groups from secondary groups, but also O-silyl groups of the same type with identical chemical reactivity. This methodology differs from other conventional monofunctionalization methods of natural CDs, which only allow for a direct twofold differentiation of hydroxyl groups in a CD, because the current method permits the synthesis of tri- and tetra-functionalized CDs in a short reaction sequence. Most importantly, the developed method has been found to be applicable to all α-, β-, and γ-CDs and the obtained CD intermediates are versatile. Furthermore, we demonstrate that these processes are practical and can be carried out on multigram scales.