Identification of enantioselective extractants for chiral separation of amines and aminoalcohols

Abstract

The major obstacle for the introduction of fractional reactive extraction as a chiral separation method in the chemical and pharmaceutical industries is the lack of versatile enantioselective extractants. Therefore, a rational approach is developed to transfer the extensive knowledge of chiral selectors reported in the literature on chiral recognition and other chiral separation techniques to extraction. Based on a similarity in separation mechanisms, it was expected that chiral selectors originating from a technique in which chiral recognition takes place in the liquid phase are most likely to function as enantioselective extractant. Using this approach, a selection of promising extractants was made from the literature and experimentally evaluated for the enantioseparation of aminoalcohols and amines. As a result, four enantioselective extractant systems, namely, dibutyl-L-tartrate with boric acid, N-(2-hydroxydodecyl)-L-hydroxyproline Cu(II) complex, N-dodecyl-L-hydroxyproline Cu(II) complex, and azophenolic crown ether, have been identified. The azophenolic crown ether system performed the best and demonstrated an enantioselectivity between 1.3-5.0 for five out of six test compounds. Identification of the enantioselective extractant systems was highly facilitated by the developed rational transfer approach that, although partially qualitative, appeared capable of reducing more than 50 encountered candidates to only three promising systems for further experimental evaluation. Therefore, it is expected that this approach can be successfully applied to identify enantioselective extractants for other classes of enantiomers as well.

Principles, Concepts and Strategies of Stereoselective Synthesis

“…119 Two main mechanisms of enantiomeric extraction and enantiomeric recognition in a biphasic system have been recently discussed. 131 Enantiomeric liquid-liquid extraction has already found some applications for the separation of drug enantiomers. [132][133][134][135] Supercritical fluid extraction technology recently became a versatile tool in the purification, enantioseparation, and large-scale production of enantiomers of pharmaceuticals and is gaining popularity in the pharmaceutical industry.…”

The Use of N‐Type Ligands in the Enantioselective Liquid–Liquid Extraction of Underivatized Amino Acids

“…[18,19] A minimal selectivity of 1.5 is generally viewed being necessary to avoid the requirement for an excessive number of fractional extraction steps. [20] With a versatile host, the separation of racemates of an entire class of compounds is potentially achievable. Chiral hosts can also be applied catalytically in U-tubes or membranes.…”

Equilibrium Studies on Reactive Extraction of α‐Cyclohexyl‐mandelic Enantiomers Using Hydrophilic β‐Cyclodextrin Derivatives Extractants

“…As the operational selectivity is calculated from the ratio of the D values, a selectivity lower than about 1.1 can not be determined accurately by single extraction experiments. 21 The yield of an enantiomer is expressed as the fraction of the organic feed that ends up in the aqueous extract phase:…”