Synthesis and characterization of randomly 2,3-O-sulfoalkylated beta-cyclodextrins for use in chiral capillary electrophoresis

Abstract

Chiral separation of enantiomers is of vast significance in synthetic chemistry. Determining the enantiomeric purity of a product is necessary in the pharmaceutical industry. Recent studies in capillary electrokinetic chromatography (cEKC) have suggested that anionic cyclodextrins (CDs) are powerful chiral resolving agents. The purpose of this research was to synthesize a series of highly charged heptakis(randomly-2,3-O-sulfoalkyl)- ß- CDs, characterize the CDs, and apply the CDs to chiral separations of aryl alcohols. The synthesis focused on the sulfobutylation of heptakis(6-O-methyl)- ß- CD and heptakis(6-O-tert-butyldimethylsilyl)- ß-CD as well as the sulfopropylation of heptakis(6-O-tert-butyldimethylsilyl)- ß-CD. The degree of sulfoalkylation of the final products was determined by hydrophilic interaction chromatography (HILIC) with a low temperature evaporative light scattering detector (LT-ELSD). The synthesis of heptakis(6-O-methyl)- ß- CD was obtained by a lengthy protection/deprotection reaction scheme utilizing the acetylation of the secondary hydroxyl groups, with an overall yield of 43% in 5 steps. The sulfobutylation of heptakis(6-O-methyl)- ß-CD and heptakis(6-O- tert-butyldimethylsilyl)- ß-CD produced low degrees of substitution (DS <1.0). The sulfopropylation of heptakis(6-O-tert-butyldimethylsilyl)- ß-CD in tetrahydrofuran (THF) resulted in much higher degree of substitution, with DS of 3.3, 4.6, and 6.1, which increased with amount of added 18-crown-6 ether. Also, an increase in the DS (6.1 and 8.4) was observed when changing the solvent from THF to N, N-dimethylformamide. Chiral resolution studies of relevant aryl alcohols using potassium heptakis(randomly 2,3-O-sulfopropyl)- ß-CD (DS 8.4), potassium heptakis(2,3-di-O-methyl-6-O- sulfopropyl)- ß-CD (DS 4.5) and the single isomer potassium heptakis(2,3-di-O-methyl-6-O-sulfobutyl)- ß-CD were performed. Resolution of the enantiomers of the aryl alcohols is dependent on the distance of the chiral center from the aromatic ring and the substituent on the secondary rim of the cyclodextrin.