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The Pursuit of Chiral Anion Exchange-Type Selectors: From Concept to Application


by NorbertMMaier, Chiral Technologies, Inc., 800 N Five Points Road,West Chester, PA 19380 USA. Email: nmaier@chiraltech.com


The major progress achieved in liquid phase enantiomer separation technology and its crucial contributions to modern drug development efforts is well documented [1]


.With drug discovery trends increasingly focusing on more polar “bio-like” target


compounds, unmet needs concerning the resolution of polar ionizable and/or permanently charged chiral compounds are becoming apparent.Most of the established chiral stationary phases show poor chiral recognition performance for charged compounds, a situation that is often exacerbated by solubility issues, mobile phase incompatibilities and general lack of retention. In most cases, basic or acidic additives have to be used to suppress the ionic character of charged compounds to achieve efficient enantiomer separation, adding considerable levels of complexity and compromise to analytical and preparative method development.


Ion exchange-type chiral selectors capable of exploiting instead of suppressing the ionic nature of these compoundsmay provide an appealing solution to the problem. They can be expected to provide a number of striking benefits, such as simplifiedmethod development taking advantage of well understood retentionmechanisms, and the compatibility with aqueousmedia, a feature that certainly facilitates the bioanalytical monitoring of charged compounds in biological fluids and the use ofmass sensitive detectionmodes. In terms of preparative applications, ion exchange-type selectors are appealing because of their inherently strong intermolecular interactions, ensuring high loading capacities and broadmobile phase compatibility, factors that allow for flexibility in the development of highly productive separation processes with improved ecological performance characteristics.


Over the last two decades, major advances in this field of the development of broadly applicable ion exchange-type chiral selectors have been achieved by the group of ProfessorWolfgang Lindner at the University of Vienna [2]


. Lindner’s research efforts in this


area have not only contributed to a deepened understanding of molecular mechanisms governing enantioselective recognition of charged chiral molecules, but also established compelling evidence for the practical utility of chiral ion exchange-type selectors in addressing challenging real- world applications. The output of these efforts has provided scientists in pharmaceutical and industrial research


settings with new chromatographic tools to tackle the challenges associated with analytical and preparative resolution of ionic chiral compounds.


The following review is an attempt to provide a brief overview of these accomplishments. Because of the limited format available for these discussions the treatment addresses onlymajormilestones within the rich body of studies. Emphasis will be paced on demonstrating achievements by application- relevant examples rather than enumerating academic exercises. Readers interested in a more detailed coverage are referred to comprehensive reviews [2-4]


.


2. Cinchona Alkaloid Carbamate Anion-Type Selectors


A crucial aspect in the development of anion exchange-type selectors for chiral acids was the choice of appropriatemolecular templates providing a high level of preformed chiral recognition complementarity for the target analytes. After evaluation of numerous synthetic scaffolds, Cinchona alkaloids, specifically quinine and quinidine, were selected as promising core structures. This choice wasmotivated by a number of considerations. Cinchona alkaloids offer basic quinuclidine functionality embedded in a stereochemically well-defined environment in close proximity to functional groups with rather diversemolecular interaction potential. In addition, Cinchona alkaloids are readily available at scale at reasonable cost. Cinchona alkaloids incorporate several functional groups readily accessible to chemicalmodification


(C9-hydroxy and the C11 vinyl group), a feature that was considered essential for dedicated structure-based optimization of the chiral recognition potential and elaboration of suitable immobilization chemistries. And finally, quinine and quinidine provide well- documented pseudoenantiomeric behavior in many chiral recognition applications [5, 6]


allows controlling the preferences of Cinchona-mediated chiral recognition events by switching between the individual alkaloids.


Exploratory studies using chiral stationary phases incorporating native Cinchona alkaloids produced rather disappointing results. For example, when a CSP comprising native quinine attached via its C11 vinyl group tomercaptopropyl-modified silica gel was evaluated in buffered hydro-organicmobile


phases very low levels of enantioselectvity (α < 1.2) forN-3,5-dinitrobenzoyl amino acids [7]


.


These observations were consistent with the results reported by others employing CSPs incorporating native cinchona alkaloids for normal phase applications [8]


, which


. It was concluded


that the functional group repertoire integrated in native Cinchona alkaloids is insufficient to support effective enantioselective binding of acidic analytes. It was reasoned that the rather modest chiral recognition capabilitiesmight be enhanced by providing supportive molecular interactionmotifs by introduction of additional functional groups at the central C9- position. To test this hypothesis, a considerable number of focused libraries of Cinchona-based selectors were synthesized and evaluated in terms of their chiral separation performance under ion exchange


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