FULL PAPER DOI: 10.1002/ejoc.201402802 Controlled Acid-Mediated Regioselective O-Desilylations for Multifunctionalization of Cyclodextrins Jiamin Gu, [a][‡] Tong Chen, [a][‡] Ping Zhang, [a] and Chang-Chun Ling* [a] Keywords: Synthetic methods / O-Desilylation / Cyclodextrins / Silyl ethers / Regioselectivity A highly valuable tri-/tetra-functionalization method is re- ported 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 dif- ferentiate not only primary O-silyl groups from secondary groups, but also O-silyl groups of the same type with iden- tical chemical reactivity. This methodology differs from other Introduction The ability to obtain structurally well-defined multisub- stituted cyclodextrin (CD) hosts is essential for the design of sophisticated, yet functional systems for various applica- tions such as artificial enzymes, [1] gene delivery systems, [2] sensors, [3] tailored macrocyclic ligands, [4] and novel supra- molecular assemblies. [5] This requires access to well-devel- oped synthetic methodologies that permit the precise intro- duction of functionalities to a CD molecule at desired sites. Despite the development of a number of synthetic methods for CD modifications, [6] compared with other fields, pro- gress in CD derivatization has been relatively slow during the last decade. This is probably due to the particular nature of CD molecules because although only three types of hy- droxyl groups exist in a CD, each type consists of 6, 7, or 8 copies (respectively for α-, β- or γ-CD) with identical chemical reactivity. Thus, any attempt to regioselectively functionalize one type of hydroxyl group will have to over- come a significant challenge due to the formation of many regioisomers including positional isomers that are very challenging to separate, which usually results in low yields of the desired compounds. Typically, monosubstitution of CDs, such as mono-6-tosylation, give a yield of around 30%. Among the published methods, regioselective trityl- ations, [7,8] sulfonylations, [9] silylations, [10] halogenations, [11] [a] Alberta Glycomics Centre, Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary Alberta T2N 1N4, Canada E-mail: ccling@ucalgary.ca http://www.chem.ucalgary.ca/research/groups/ccling/ [‡] These two authors contributed equally to this work. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201402802. Eur. J. Org. Chem. 2014, 5793–5805 © 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5793 conventional monofunctionalization methods of natural CDs, which only allow for a direct twofold differentiation of hy- droxyl 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. and alkylations [12] have been most used. All these method- ologies permit direct modifications of natural CDs by tak- ing advantage of the steric bulk of the reagents. Another innovative strategy is based on the use of diisobutylalumi- num hydride (DIBAL-H) to reductively remove one or more benzyl or methyl groups from per-O-benzylated or per-O-methylated CD derivatives. [13] Recently, our group has extended this strategy to remove 1–2 silyl groups from per-6-O-silylated CD derivatives in a highly regio- and chemoselective manner, [14] and we found that the DIBAL- mediated O-desilylations required much less reagent com- pared with the related O-dealkylations. Here, we report that the acid concentrations in the reaction media could be ele- gantly exploited to carry out stepwise O-desilylations for CD chemistry. This methodology provides several opportu- nities to introduce different types of chemical functionali- ties to a CD during the course of chemical modifications to afford tri- or tetrafunctionalized CDs. Results and Discussion For O-desilylation requiring no regioselectivity, including the full removal of silyl groups from compounds such as 3,6-di-O-persilylated β-CD derivative 4a [15] to obtain 7 (Scheme 1), the use of tetra-n-butylammonium fluoride (TBAF) [15,16] is most common. However, despite its high efficiency, the TBAF method can be problematic, especially when the formed product is polyhydroxylated and thus has enhanced water-solubility; this makes product purification either by extraction or by chromatography difficult because the quaternary ammo- nium salts are partially soluble both in organic and aqueous media, and because the product could have similar reten-