title: Copper(II)-complex directed regioselective mono-p-toluenesulfonylation of cyclomaltoheptaose at a primary hydroxyl group position: an NMR and molecular dynamics-aided design.
abstract: Interactions between cyclomaltoheptaose (β-cyclodextrin, βCD) and p-toluenesulfonyl chloride (TsCl) were investigated using MD simulations, both in vacuum, approximating the hydrophobic environment of the CD cavity, and with water as a solvent. In both cases, the minimum energy adiabatic paths, and the mean force potentials (MFP) for the insertion of TsCl along a reaction coordinate perpendicular to the CD plane, were calculated for the two possible orientations of TsCl. The results show a preferred entry of TsCl in the CD cavity with the sulfonyl chloride group pointing to the primary hydroxyls rim. In each orientation, two energy minima for the complex are detected in vacuum that reflect the H-H contacts between host and guest observed by NMR spectroscopy (ROESY, NOESY). These separate minima collapsed into a single broader minimum, when the solvent was introduced in the simulations. The resulting association constant between TsCl and βCD (K(a) ≈ 100 M(-1)) is in good agreement with the NMR results (K(a) = 102 ± 12 M(-1)) in deuterated water solution at 298 K. Advantage has been taken of the dynamics of the reagent inclusion to set up a one step process involving a transient Cu(2+) chelate at the secondary hydroxyls rim position for the electrophilic monoactivation of βCD at the primary hydroxyls rim using water as solvent.
authors: Département de Pharmacochimie Moléculaire, Institut de Chimie Moléculaire, CNRS et Université de Grenoble (UMR 5063-FR 2607), BP 53, F-38041 Grenoble, France.
authors: Ho
authors: H
authors: Law
authors: Juan M
authors: JM
authors: Benito
authors: José M García
authors: JM
authors: Fernández
authors: Laszlo
authors: L
authors: Jicsinszky
authors: Serge
authors: S
authors: Crouzy
authors: Jacques
authors: J
authors: Defaye