A complete series of 6-deoxy-monosubstituted tetraalkylammonium derivatives of α-, β-, and γ-cyclodextrin with 1, 2, and 3 permanent positive charges

Abstract

SummaryAn efficient synthetic route toward the preparation of a complete series of monosubstituted tetraalkylammonium cyclodextrin (CD) derivatives is presented. Monotosylation of native CDs (α-, β-, γ-) at position 6 gave the starting material. Reaction of monotosylate (mono-Ts-CD) with 45% aqueous trimethylamine gave CDs substituted with one cationic functional group in a single step. Derivatives equipped with a substituent containing two cationic sites separated by an ethylene or a propylene linker were prepared by reacting mono-Ts-CD with neat N,N,N’-trimethylethane-1,2-diamine or N,N,N’-trimethylpropane-1,3-diamine and subsequent methylation by CH3I in good yields. Finally, analogues bearing a moiety with three tetraalkylammonium sites were synthesized by reacting mono-Ts-CD with bis(3-aminopropyl)amine and subsequent methylation. The majority of the presented reactions are very straightforward with a simple work-up, which avoids the need of chromatographic separation. Thus, these reactions are suitable for the multigram-scale production of monosubstituted cationic CDs.

Optimized methods for preparation of 6I-(ω-sulfanyl-alkylene-sulfanyl)-β-cyclodextrin derivatives

“…For the preparation of the starting compound for all syntheses – Ts-β-CD ( 1 ) – we recently described [ 17 ] a modification of one of the commonly used method [ 18 ]. The modification consisted in the repeated recrystallization from 50% water–methanol which yielded a very pure product with no interfering impurities (di- or tri-Ts-β-CD) or unreacted β-CD.…”

Monosubstituted Cyclodextrins as Precursors for Further Use

“…Although some authors do not purify the product, it is recommended the crude product be treated by chromatography [148,151,159] or recrystallised from water [149,152,153,157] or 50 % MeOH in H 2 O. [160,161] Subsequent substitution of the tosyl CD derivative with sodium azide is carried out in water [148][149][150]159] or DMF. [147,152,157] The final step, when the amine is formed, involves reduction with triphenylphosphine in the presence of aqueous ammonia [148,152,159] or water.…”

Mono-6-Substituted Cyclodextrins—Synthesis and Applications

“…On the other hand, if a proper purification method is used, yields are usually in the range of 20-35% [ 46 , 47 ]. In our experience, the most practical purification method of Ts-β-CD consists of the three times repeated crystallization of the crude product from 50% MeOH/water solution giving an overall yield of around 25% and removing reliably unreacted β-CD and over-tosylated by-products [ 56 ].…”