Synthesis of the chiral selector heptakis(6‐O‐methyl)‐β‐cyclodextrin by phase‐transfer catalysis and hydrazine‐mediated transfer‐hydrogenation

Abstract

The exhaustive primary‐side alkylation of cyclodextrins has never been achieved directly. The undesired and simultaneous derivatization of the secondary hydroxyl moieties generates intricate isomeric mixtures that are challenging to purify, analyse and characterize. The aim of this study was to develop a chromatography‐free and up‐scalable strategy towards the preparation of per‐6‐O‐methylated cyclodextrin and to test the compound as potential chiral selector. The target molecule was prepared according to a five‐step synthesis by using methyltriphenylphosphonium bromide as catalyst under heterogeneous conditions. The removal of benzyl moieties, used as temporary secondary‐side protecting groups, was attained by applying hydrazine‐carbonate in the presence of Pd/C. All the intermediates were obtained in high yields, thoroughly characterized and their purity was assessed by ad‐hoc developed HPLC methods. The per‐6‐O‐methylated β‐cyclodextrin showed promising chiral recognition ability as background electrolyte additive in cyclodextrin‐modified capillary electrophoresis using the recreational drug methylene‐dioxypyrovalerone as model compound. Additionally, a model for the inclusion geometry between the single isomer host and the selected drug was developed based on the extensive 2D NMR analysis. The versatility of the proposed synthetic strategy opens the way to the industrial production of homogeneously primary‐alkylated cyclodextrins and to their wide application in chiral separation of various drugs.

Challenging Bioanalyses with Capillary Electrophoresis

“…Cyclodextrins modified with different functional groups were used to resolve different drug enantiomers including methylated β-cyclodextrin for psychoactive drugs in under 4 minutes. 81 Another report synthesized 10 different methylated β-cyclodextrins to determine an optimized modification for chiral selection, which was found to be the heptakis (2,6-di-O-methyl)-β-cyclodextrin. 84 Sulfated β-cyclodextrins were used to determine enantiomeric impurities in the sedative dexmedetomidine.…”

“…Cyclodextrins are cyclic sugar molecules with a cavity that enables enantioselective separations of chiral drugs. β-Cyclodextrin − and β-cyclodextrin derivatives ,,− are the most common additives used for chiral separations, although α-cyclodextrins and γ-cyclodextrin derivatives , have also been reported. Cyclodextrins modified with different functional groups were used to resolve different drug enantiomers including methylated β-cyclodextrin for psychoactive drugs in under 4 min .…”

Polysaccharide- and β-Cyclodextrin-Based Chiral Selectors for Enantiomer Resolution: Recent Developments and Applications

“…A chiral selector, based on heptakis(6- O -methyl)-β-cyclodextrin, was synthesized in five steps, under heterogeneous, chromatography-free, and up-scalable conditions, by Balint et al [ 74 ]. The compound showed promising properties towards the separation of the drug methylenedioxypyrovalerone, as a model analyte in capillary electrophoresis.…”

A Simple Synthesis Route for Selectively Methylated β-Cyclodextrin Using a Copper Complex Sandwich Protecting Strategy

“…These protocols employ the use of tert -butyldimethylsilyl chloride for primary side protection followed by a wide variety of secondary side protection (methylation, acetylation, benzylation, etc.) [ 8 ] with subsequently improved variants [ 9 ] and a relatively recent work by the cyclodextrin specialized laboratory CycloLab [ 10 ]. Moreover, even though highly efficient steps are now available, the multiple-step reactions needed to achieve the result bring down the total yield of the reaction to a reported value ranging between 40% and 70% [ 9 , 10 ].…”

“…[ 8 ] with subsequently improved variants [ 9 ] and a relatively recent work by the cyclodextrin specialized laboratory CycloLab [ 10 ]. Moreover, even though highly efficient steps are now available, the multiple-step reactions needed to achieve the result bring down the total yield of the reaction to a reported value ranging between 40% and 70% [ 9 , 10 ]. All the above-mentioned syntheses, summarized in Figure 1 offer good but expensive commercial products.…”