Radical-Mediated C–H Functionalization: A Strategy for Access to Modified Cyclodextrins

A simple and efficient radical CH functionalization to access modified cyclodextrins (CDs) has been developed. The well-defined conformation of glycosidic and aglyconic bonds in alpha-, beta-, and gamma-CDs favors the intramolecular 1,8-hydrogen atom transfer (HAT) promoted by the 6(I)-O-yl radical, which abstracts regioselectively the hydrogen at C5(II) of the contiguous pyranose. The C5(II)-radical evolves by a polar crossover mechanism to a stable 1,3,5-trioxocane ring between two adjacent glucoses or alternatively triggers the inversion of one alpha-D-glucose into a 5-C-acetoxy-beta-L-idose unit possessing a C-1(4) conformation. The 6(I,IV)- and 6(I,III)-diols of alpha- and beta-CDs behave similarly to the monoalcohols, forming mostly compounds originating from two 1,8-HAT consecutive processes. In the case of 6(I,II)-diols the proximity of the two 6-O-yl radicals in adjacent sugar units allows the formation of unique lactone rings within the CD framework via a 1,8-HAT-beta-scission tandem mechanism. X-ray diffraction carried out on the crystalline 1,4- bis(trioxocane)-alpha-CD derivative shows a severe distortion toward a narrower elliptical shape for the primary face.