Pirkle-concept CSPs

Most Pirkle-concept CSPs had either a K-accepior or a K-donor moiety. However, the commercialized Whelk-O 1 CSP is a hybrid of rr-acceptor and rr-donor CSPs tsee Fig. 9.25). It has been designed to have a cleft-like binding site formed by orthogonally arranged 3,5-dinitrobenzoyl and tetrahydrophenanthrene moieties aromatic groups are... 

A CSP based on the analogues 3,5-dinitrobenzoylated 1,2-diphenylethane-1,2-diamine (DNB-DPEDA) (see Fig. 9.26a) [349-353] has been commercialized by Regis under the tradename Ulmo. This CSP has proven to be excellent for the direct separation of aryl alcohol enantiomers without derivatization (see Fig. 9.26b) [349,351]. This improved Pirkle-concept CSP, that contains also ir-acidic as well as moderate n-basic aromatic binding sites, nicely resolved a wide variety of chiral drugs [350] and compounds of pharmaceutical interest [352]. 

ENANTIOSEPARATION OF PHARMACEUTICALLY RELEVANT CHIRAL COMPOUNDS USING PIRKLE-CONCEPT CSPs... 

An interesting feature of the terguride-based CSP is its self-recognition ability, i.e. the terguride-based CSP can be used to separate the enantiomers of terguride [392]. This self-recognition phenomenon is often observed also for Pirkle-concept CSPs. 

Enantioseparations in SEC have been reported for several CSPs. including native and derivatized cyclodextrin-based CSPs [427-432. Pirkle-concept CSPs [77,336-338,347,348,363,365,433,434], polysaccharide type CSPs [137.435-438], macrocyclic antibiotic type CSPs [436], and others. 

The brush-type (Pirkle-type) CSPs have been used predominantly under normal phase conditions in LC. The chiral selector typically incorporates tt-acidic and/or n-basic functionality, and the chiral interactions between the analyte and the CSP include dipole-dipole interactions, n-n interactions, hydrogen bonding, and steric hindrance. The concept of reciprocity has been used to facilitate the rational design of chiral selectors having the desired selectivity [45]. 

CSPs based on chiral selectors related to the Pirkle concept... 

All the CSPs related to the Pirkle concept have the following features in common. 

For example, polymer-supported CSPs with Pirkle-concept SOs (e.g. (S)-valine-3,5-dimethylaniIide) attached to monodisperse macroporous polymethaciylate beads gave reasonable enantioselectivity and efficiency for 3,5-dinitrobenzamido derivatives of a-amino acids under normal-phase conditions [368.370], It could be demonstrated that such a CSP based on polymeric particles provided enhanced enantioselectivities... 

Recent strategies in CSP development and optimization related to the Pirkle concept and to low molecular weight synthetic chiral selectors. In the attempt to proceed more effectively with the development of new tailor-made CSPs, solid-phase syntheses and combinatorial chemistry approaches involving SO and/or CSP libraries have been tested. 

The application of the reciprocality concept has led to the design of various phases of the Ji-donor/acceptor type [61, 62]. One successful phase is the Whelk-O 1 CSP developed by Pirkle and Welch [63-65]. 

On a more rational basis (concept of reciprocity), Pirkle and Welch also developed a particular CSP for the separation of the enantiomers of the analgesic agent naproxen and other nonsteroidal anti-inflammatory drugs (NSAID) [88]. It appeared later that this CSP had a relatively broad application range [89]. 

General discussions of enantioselective recognition are given in a number of reviews.A prevalent concept is the "three-point rule. formulated by Pirkle. as Chiral recognition requires a minimum of three simultaneous interactions between the CSP(/receptor) and at least one of the enantiomers, with one of these interactions being stereochemically dependent. Schematically ... 

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.

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