Pirkle-type chiral stationary phases

The Pirkle-type chiral stationary phases are quite stable and exhibit good chiral selectivities to a wide range of solute types. These CSPs are also popular for the separation of many drug enantiomers and for amino acid analysis. Primarily, direct chiral resolution of racemic compounds were achieved on these CSPs. However, in some cases, prederivatization of racemic compounds with achiral reagents is required. The applications of these phases are discussed considering re-acidic, re-basic, and re-acidic-basic types of CSP. These CSPs have also been found effective for the chiral resolution on a preparative scale. Generally, the normal phase mode was used for the chiral resolution on these phases. However, with the development of new and more stable phases, the reversed phase mode became popular. 

Finn JM, Rational design of Pirkle type chiral stationary phases, in Chromatographic Chiral Separations, Zief M, Crane LJ (Eds.), Chromatographic Science Series Vol. 40, Marcel Dekker, New York (1988). 

A. M. Dyas, M. L. Robinson, and A. F. Fell, Direct separation of nadolol enantiomers on a Pirkle-type chiral stationary phase, J. Chromatogr., 536 351 (1991). 

Figure 2.20 Proposed three-point interaction model between Pirkle-type chiral stationary phase and the best orientations of 3-aminobenzo[n]pyrene for maximum interaction. (Adapted from Ref. Ill with permission.)...

The determination of (R)- and (S)-glutethimide and the corresponding 4-hydroxyglutethimide metabolites in human serum and urine using a Pirkle-type chiral stationary phase" (35). In this study, a validated assay was developed using an (S)-N-(3,5-dintrobenzoyl)leudne CSP and gradient elution with hexane isopropanol acetonitrile mobile phases. 

Uray, G., Kosjek, B. Simultaneous enantioseparation of flobufen and its diastereomeric metabolites on ULMO, a pirkle type chiral stationary phase. Enantiomer, 2000, 5, 329-332. 

Blum AM, Lynam KG, Nicolas EC. Use of a new Pirkle-type chiral stationary phase in analytical and preparative subcritical fluid chromatography of pharmaceutical compounds. Chirality 1994 6 302-313. 

Mourier PA, Eliot E, Caude M, Rosset R. Anal Chem 1985 57 2819. Macaudiere P, Tambute A, Caude M, Rosset R, Alembik MA, Wainer IW. Resolution of enantiomeric amides on a Pirkle-type chiral stationary phase. J Chromatogr 1986 371 159. 

Suzuki, T, Timofei, S., luoras, B.E., Uray, G., Verdino, P. and Fabian, W.M.F. (2001a) Quantitative structure-enantioselective retention relationships for chromatographic separation of arylalkylcarbinols on Pirkle type chiral stationary phases./. Chromat., 922, 13-23. 

A. M. Blum and K. G. Lynam, Use of a New Pirkle-Type Chiral Stationary Phase in Analytical and Preparative Subcritical Fluid Chromatography of Pharmaceutical Compounds, Chirality, 6(1994)302. 

Figure 4.14 Schematic illustration of the principles underlying design of Pirkle-type chiral stationary phases (CSPs). (a) Illustration of the concept of reciprocity a single enantiomer of a racemate which separates well on the CSP shown on the left, when used to produce a second CSP shown at the right, will usually afford separation of the enantiomers of analytes that are structurally similar to the chiral selector of the first CSP. Reproduced from Pirkle et al, J. Org. Chem. 57 (1992), 3854, Copyright (1992), with permission of the American Chemical Society, (b) Two CSPs that exhibit reciprocal behavior, and (c) enantiomeric recognition model for the more stable diastereomeric complex between (S)-naproxen dimethylamide and the Whelk-0-1 (3R,4R) analog. Note that hydrogen atoms bonded to carbons are omitted for clarity. Reproduced from Wolf and Pirkle (2002), Tetrahedron 58, 3597, copyright (2002), with permission from Elsevier.

C. Fernandes, M. E. Tiritan and M. Pinto, Small Molecules as Chromatographic Tools for HPLC Enantiomeric Resolution Pirkle-Type Chiral Stationary Phases Evolution, Chromatographia, 2013, 76, 871. 

There is a wide variety of commercially available chiral stationary phases and mobile phase additives.32 34 Preparative scale separations have been performed on the gram scale.32 Many stationary phases are based on chiral polymers such as cellulose or methacrylate, proteins such as human serum albumin or acid glycoprotein, Pirkle-type phases (often based on amino acids), or cyclodextrins. A typical application of a Pirkle phase column was the use of a N-(3,5-dinitrobenzyl)-a-amino phosphonate to synthesize several functionalized chiral stationary phases to separate enantiomers of... 

Chiral stationary phases for the separation of enantiomers (optically active isomers) are becoming increasingly important. Among the first types to be synthesized were chiral amino acids ionically or covalently bound to amino-propyl silica and named Pirkle phases after their originator. The ionic form is susceptable to hydrolysis and can be used only in normal phase HPLC whereas the more stable covalent type can be used in reverse phase separations but is less stereoselective. Polymeric phases based on chiral peptides such as bovine serum albumin or a -acid glycoproteins bonded to... 

Chiral separations result from the formation of transient diastereomeric complexes between stationary phases, analytes, and mobile phases. Therefore, a column is the heart of chiral chromatography as in other forms of chromatography. Most chiral stationary phases designed for normal phase HPLC are also suitable for packed column SFC with the exception of protein-based chiral stationary phases. It was estimated that over 200 chiral stationary phases are commercially available [72]. Typical chiral stationary phases used in SFC include Pirkle-type, polysaccharide-based, inclusion-type, and cross-linked polymer-based phases. 

There are numerous chiral stationary phases available commercially, which is a reflection of how difficult chiral separations can be and there is no universal phase which will separate all types of enantiomeric pair. Perhaps the most versatile phases are the Pirkle phases, which are based on an amino acid linked to aminopropyl silica gel via its carboxyl group and via its amino group to (a-naphthyl)ethylamine in the process of the condensation a substituted urea is generated. There is a range of these type of phases. As can be seen in Figure 12.23, the interactions with phase are complex but are essentially related to the three points of contact model. Figure 12.24 shows the separation of the two pairs of enantiomers (RR, SS, and RS, S,R) present in labetalol (see Ch. 2 p. 36) on Chirex 3020. 

Many types of chiral stationary phase are available. Pirkle columns contain a silica support with bonded aminopropyl groups used to bind a derivative of D-phenyl-glycine. These phases are relatively unstable and the selectivity coefficient is close to one. More recently, chiral separations have been performed on optically active resins or cyclodextrins (oligosaccharides) bonded to silica gel through a small hydrocarbon chain linker (Fig. 3.11). These cyclodextrins possess an internal cavity that is hydro-phobic while the external part is hydrophilic. These molecules allow the selective inclusion of a great variety of compounds that can form diastereoisomers at the surface of the chiral phase leading to reversible complexes. 

Pirkle-Type and Related Chiral Stationary Phases... 

In view of the importance of chiral resolution and the efficiency of liquid chromatographic methods, attempts are made to explain the art of chiral resolution by means of liquid chromatography. This book consists of an introduction followed by Chapters 2 to 8, which discuss resolution chiral stationary phases based on polysaccharides, cyclodextrins, macrocyclic glyco-peptide antibiotics, Pirkle types, proteins, ligand exchangers, and crown ethers. The applications of other miscellaneous types of CSP are covered in Chapter 9. However, the use of chiral mobile phase additives in the separation of enantiomers is discussed in Chapter 10. 

Macaudiere P, Lienne M, Tambute A, Caude M, Pirkle type and related chiral stationary phases for enantiomeric resolution, in Chiral Separations by HPLC, Krstulovic AM (Ed.), Ellis Horwood, New Y>rk (1989). 

The most popular and commonly used chiral stationary phases (CSPs) are polysaccharides, cyclodextrins, macrocyclic glycopeptide antibiotics, Pirkle types, proteins, ligand exchangers, and crown ether based. The art of the chiral resolution on these CSPs has been discussed in detail in Chapters 2-8, respectively. Apart from these CSPs, the chiral resolutions of some racemic compounds have also been reported on other CSPs containing different chiral molecules and polymers. These other types of CSP are based on the use of chiral molecules such as alkaloids, amides, amines, acids, and synthetic polymers. These CSPs have proved to be very useful for the chiral resolutions due to some specific requirements. Moreover, the chiral resolution can be predicted on the CSPs obtained by the molecular imprinted techniques. The chiral resolution on these miscellaneous CSPs using liquid chromatography is discussed in this chapter. 

The chiral recognition mechanisms in NLC and NCE devices are similar to conventional liquid chromatography and capillary electrophoresis with chiral mobile phase additives. It is important to note here that, to date, no chiral stationary phase has been developed in microfluidic devices. As discussed above polysaccharides, cyclodextrins, macrocyclic glycopeptide antibiotics, proteins, crown ethers, ligand exchangers, and Pirkle s type molecules are the most commonly used chiral selectors. These compounds... 

---