Easy Access to Modified Cyclodextrins via an Intramolecular Radical Approach

A simple methodology to modify the primary face of cyclodextrins (CDs) is described. The 6-O-yl radical of α-, β-, and γCD abstracts regioselectively the H5, located in the adjacent Dglucose unit, by an intramolecular 1,8-hydrogen atom transfer reaction through a geometrically restricted nine-membered transition state to give a stable 1,3,5-trioxocane ring. The reaction has been extended to 1,4-diols of αand β-CD to give the corresponding bistrioxocanes. The C2-symmetric bis-trioxocane corresponding to αCD is a stable crystalline solid whose structure was confirmed by Xray diffraction analysis. The calculated geometric parameters confirm that the primary face is severely distorted toward a narrower elliptical shape for this rim. The design of nanosystems as novel drug carrier systems that allow controlled release is currently a topic of great relevance in medical research to treat a wide variety of diseases, including cancer therapy. In this regard, cyclodextrins (CDs) are of interest as nanocarriers because of their ability to encapsulate biomolecules. These naturallyoccurring macrocyclic oligosaccharides composed of 1,4-α-linked glucose units are conical in shape and have an internal cavity creating a hydrophobic microenvironment, while the outside is hydrophilic due to the presence of the hydroxyl groups. These properties are responsible for their aqueous solubility and ability to form host-guest or inclusion complexes with a wide range of molecules, making them one of the most important supramolecular host families. These features illustrate the potential utility of CDs as drugand gene-delivery vehicles, enzyme mimics, or catalysis, among others. Native CDs are rarely well-suited to pharmaceutical applications, so their modification is necessary to tune their chemo-physical properties such as to enhance their solubility, change the size cavity or improve their complexing ability. Taking advantage of the different accessibility and reactivity of the hydroxyl groups, efficient and selective chemical modifications have been carried out by allowing for instance grafting substituents to different positions to access amphiphilic CD, and hence to fascinating molecular architectures. It is also worthwhile to mention the synthetic reports that generate significant changes in the cavity shape by altering the conformation of glucose residues. Despite the great deal of methodologies employed, radical processes are practically unknown in these macromolecules because in simple carbohydrates they mostly involve the anomeric position, which is committed in the cyclic CD structure. In fact, we have found a single example in the literature concerning intermolecular radical attack on CDs and it is based in EPR experiments with reactive oxygen-centered free radicals generated in aqueous solutions. Scheme 1. HAT reactions in Hexp-(1s4)-Hexp systems. As part of our ongoing research program on radical chemistry in carbohydrates, we have recently described a novel 1,8-hydrogen atom transfer reaction (1,8-HAT) between the two pyranose units in Hexp-(1s4)-Hexp disaccharide systems through a nine-membered transition state (TS). The process is initiated by a primary 6-O-yl radical (I) generated under oxidative conditions, which abstracts regioselectively the hydrogen at C5 to give a C5-radical (II) which, after oneelectron oxidation, collapses into the 1,3,5-trioxocane (IV) via an oxacarbenium ion intermediate (III) (Scheme 1). Alternatively, the 6-O-yl radical (I) may abstract the H1 through a sevenmembered TS to generate a C1-radical (V) which finally stabilizes via the oxacarbenium (VI) to give the spiro ortho ester (VII). We have demonstrated that this regioselectivity is not only [a] Dr. D. Alvarez-Dorta, Dr. E. I. León, Dr. A. Martín, Dr. I. PérezMartín, Prof. Dr. E. Suárez Síntesis de Productos Naturales Instituto de Productos Naturales y Agrobiología del CSIC Carretera de la Esperanza 3, 38203, La Laguna, Tenerife (Spain) E-mail: [email protected] [email protected] [b] Dr. A. R. Kennedy WestCHEM Department of Pure and Applied Chemistry University of Strathclyde 295 Cathedral Street, Glasgow G1 1XL, Scotland (UK) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201412300. H +