IC/99/132

United Nations Educational Scientific and Cultural Organizationand

International Atomic Energy Agency

THE ABDUS SALAM INTERNATIONAL CENTRE FOR THEORETICAL PHYSICS

ENANTIOSELECTIVE TRANSPORT OF SOME AMINE COMPOUNDSTHROUGH LIQUID MEMBRANES

Lucia MutihacFaculty of Chemistry, University of Bucharest,

4-12, Blvd. Regina Elisabeta, Bucharest, 703401, Romania,

Radu Mutihac1

Faculty of Physics, University of Bucharest,P.O. Box MG-11, Bucharest-Magurele, Romania

andThe Abdus Salam International centre for Theoretical Physics, Trieste, Raly

and

Hans-Jiirgen BuschmannDeutsches Textilforschungszentrum Nord- West,

e.V., Frankenring 2, D-4W98, Germany.

Abstract

The possibility to use the macrocyclic receptors, such as chiral crown ethers, calixarenesand cyclodextrins, in enantiomeric recognition of some optically amine compounds like aminoacids or peptides by liquid membranes has been investigated. Hints on elucidation of chiralrecognition mechanism using chiraJ macrocyclic ligands as chiral selectors in enantioseparationby liquid membranes are presented. Also some factors influencing enantiomeric recognition ofsome amine compounds by chiral macrocyclic compounds have been figured out.

MIRAMARE - TRIESTE

September 1999

1 Regular Associate of the Abdus Salam ICTP.

I. Introduction

Enantiomeric separation of optically active compounds by liquid membranes is one of the

most important issues in biochemistry, chemistry and biomedicine. It is well known that during

the last decade the separation techniques such as gas-chromatography, supercritical fluid

chromatography, thin layer chromatography, high performance liquid chromatography, as well as

capillary electrophoresis have been extensively employed for the resolution of chiral compounds

on analytical and preparative scale. The capillary zone electrophoresis technique is extremely

useful for mechanistic studies because all measurements can be performed under defined

conditions and in pure aqueous solutions. Separation of optically active compounds through

liquid membranes using chiral macrocyclic receptors has also been investigated during the last

few years [1-4]. In supramolecular chemistry, liquid membranes are frequently used to evaluate

the complexation and transport properties of receptors.

In recent years numerous studies have been devoted to the synthesis of a variety of

macrocycles aiming to achieve enantiomeric resolution with chiral macrocycles [5,6]. The

enantioselective binding capability of chiral macrocyclic receptors such as crown ethers,

cryptands, cyclophanes and spherands, cyclodextrins and calixarenes (Figure 1) or their

derivatives as chiral selectors have been investigated for studying enantiomeric recognition of

some biologically active compounds [7,8].

The remarkable feature of chiral macrocyclic receptors to be employed in enantiomeric

recognition is given by the possibility of the macrorings to form stable complexes with certain

enantiomeric substrates. Several review articles have been published on the synthesis of chiral

macrocyclic compounds and their ability to recognize enantiomers. Zhang et al. [9] reported the

chiral macrocyclic, such as macrocyclic peptides, cyclophanamide-type macrocycles, Zn-

porphyrin-based macrocycles, and several other types of macrocycles involved in chiral

recognition of amine compounds. They also reported some factors which influence enantiomeric

recognition by macrocyclic compounds in homogeneous solution systems. The ability of chiral

macrocycles with carbohydrate attachments to realize chiral discrimination between enantiomers

of amine compounds has been reviewed by Stoddart [10,11].

The cyclodextrins (Figure 2) have been employed very extensively as chiral selector. The

cyclodextrins exhibit enantioselectivity in their reactions with chiral compounds [12] and they

have an important impact in separation processes.

In aqueous solution, cyclodextrins are able to include suitable guest molecules such as

aromatic compounds, carboxylic acids, azo dyes and other compounds forming inclusion

complexes (Figure 3).

These complexes serve as a model for the study of enzyme, and are also being proposed for

increased drug bioavailability and for the removal of harmful species from the human body. One

most interesting feature is their potential use in chiral discrimination of optically active

compounds by chiral macrocycles in liquid membranes.

The main goal of this review is to investigate some aspects of the possibility to use the chiral

macrocyclic receptors in enantiomeric recognition of optically amine compounds by liquid

membranes.

II. Some general principles of enantioseparation

In discriminanting enantiomers chromatographically or by other ways, the principle of

reciprocity is of fundamental value and importance [13]. Therefore, a chiral selector can become

a chiral selectand and further on, a chiral selectand can become a chiral selector. Generally, the

chiral molecular recognition models are based on isolated, single molecules. But this is not the

situation in real life and the understanding of chiral recognition at the macro molecular level is

limited. This aspect has generated much of the research in the field of molecular modeling.

In elucidating chiral recognition mechanism using cyclodextrins as chiral selectors in

enantioseparation by capillary electrophoresis the NMR plays an important role. NMR

spectroscopy provides useful information on complexation, the ^//-dependence of the selector-

solute interactions, and this technique also shows a clear differentation between inclusion and

other external interactions. The selector-solute interactions in capillary electrophoresis mimic the

receptor-ligand interaction in solution.

III. Chiral Macrocycles Receptors

III. 1. Chiral Crown Ethers

The possibility of optically active crown ethers to be used in separation of enantiomers in

liquid chromatography has been discovered by Cram and his co-workers [6,7,14,15], Their

studies have been focused on the chiral recognition of amino acids by binaphthyl-contaming

macrocycles. In high-performance liquid chromatography, the separation of various optically

active has been accomplished by utilizing chiral crown ether as stationary phases.

Kuhn et al. [16] have investigated the chiral recognition mechanism between 18-crown-6

tetracarboxylic acid (Figure 4) with several optically active amines by means of open-tube

capillary zone electrophoresis. Also, they have proposed two recognition mechanisms a) steric

barrier of the host carboxylic acid groups for naphthylethylamine, and b) coulombic interactions

in the case of Gly-Phe, which are confirmed by thermodynamic studies on the host-guest

complexes.

Armstrong et al. [17] have studied the influence of the distance between the amine function

and the chiral center of dipeptides in HPLC using a chiral crown ether with hydrophobic

substituents as stationary phase. They have observed good resolution when the amine group was

adjacent to the stereogenic center and the dipeptides of the glycyl amino acid displayed poor

resolution. In opposition, Kuhn et al. [16] have shown that g!ycyl-D,L-phenylalanine (Gly-Phe)

was resolved although the chiral center was in the 5-position to the primary amine. Studies based

on molecular models of the 18-crown-6 tetracarboxylic acid-Gly-Phe complex have demonstrated

that chiral recognition occurs predominantly due to the hydrogen bonds rather than because of the

steric barrier mechanisms. Recognition is performed on hydrogen bonds between the acidic

functional group of the dipeptide with the crown ether side chains. In the case of nonpolar

substituents like methyl, phenyl or naphthyl groups there is not the possibility to bind with the

polar crown ether substituents. So, recognition is based on mere steric barrier mechanisms and

depends on the size of the substituents. By varying the pH value of the carrier electrolyte the

mechanism could be influenced in the opposite way.

Somogyi et al. [18] have reported circular dichroism studies on the enantiomeric recognition

of some chiral aralkyl ammonium salts by some chiral pyridmo-18-crown-6 hosts (Figure 5).

Chiral pyridino-18-crown-6 macrocycles containing five oxygen donor atoms in the crown

ring show good recognition towards guest ammonium enantiomers. When one or more macroring

oxygen atoms are replaced by nitrogen atoms, the resulting macrocycle displays a much lower

degree of or not at all enantiomeric recognition [9], Their results have demonstrated that the main

factors which determine the formation and relative stability of the host-guest complexes of

pyridino-18-crown-6 ethers with aralkyl ammonium salts are the H-bondings and 7m interaction.

The attractive hydrogen bondings exist between the ammonium group of the guest and three

acceptor hetereoatoms of the host macrocycles and the attractive %n interaction acts between the

aromatic group of the cation and the pyridine ring of the host. There are also the repulsive

interactions between the alkyl group of the aralkyl ammonium salt guest and the substituents at

the chiral centers of the host macrocycle. These above-mentioned interactions were confirmed by

X-ray crystalographic [19], NMR [20], and MS [21] studies.

III. 2. Cyclodextrins

The properties (i.e., solubility in aqueous media, hydrophobicity of the cavity, and the very

important chirality) are of major importance in applications of cyclodextrins. The diversity of

applications involving cyclodextrins have a strong impact in separation processes (i.e.,

enantiomeric separations, HPLC bonded phases, stationary phases in gas chromatography),

spectroscopy, and electrochemical analysis [22-29], Cyclodextrins have the ability of forming

diastereomeric supramolecules assemblies allowing the resolution of enantiomers in thin layer

chromatography, supercritical fluid phase chromatography, and in zone cappilary electrophoresis.

This property confers to the cyclodextrins the possibility to be used in analytical science for

enantioseparations. The stereoselectivity of cyclodextrins by complexation was discovered by

Cramer (1952) [30]. Particularly p-cyclodextrin [HPLC] [31] and GC [32], but also systems

containing cyclodextrins as mobile phase additives, including electromigration techniques (i.e.,

capillary electrophoresis) have proven the usefulness in good enantiodifferentiation. Also

cyclodextrin derivatives (i.e. ethers, esters, carbamates, etc) have been used as chiral stationary

phases in liquid chromatography and gas chromatography; some relevant examples have been

published [33,34]. The shape and size of the chiral cavities are well defined and even

computerized molecular modeling has been used to characterize the inclusion complexes and to

explain the enantioseparation process.

Armstrong et at. [35] reported the resolution of a variety of racemic compounds by reversed-

phase TLC with mobile phases containing a highly concentrated solution of p-cyclodextrin. They

showed that the R enantiomer is longer retained on the column with a separability factor

a =1.20. The separated chiral compounds include the drug labetatol and mephytoin,

methallocenes, crown ethers, methyl p-toluenesulfinate, nornicotine derivatives, and several

dansyl- and p-naphthylamide-substituted amino acids. The potential of cyclodextrins as chiral

selectors in free solution has been demonstrated for the first time by Fanali [36], Terabe [37]

indicated the first application of charged cyclodextrins as a potential chiral selector in capillary

electrokinetic chromatography. Chiral separations by capillary electrophoresis have been

accomplished by utilizing solubilization with optically active micelles, ligand-exchange

complexation or host-guest complexation with cyclodextrins [38], p-cyclodextrin with both

positive and negative charges on the C-6 carbons of two adjacent glucose rings have shown

enantioselective recognition of L- and D-tryptophan based on a three-point interaction [39].

By using carboxymethyl-p-cyclodextrin as chiral selector in capillary electrophoresis, Schmitt

et at. [40] studied the enantioseparation of a mixture of basic drugs containing doxylamine,

ephedrine, dimethindine and propanolol. The responsible of resolution for enantiomers by the

cbiral selector above-mentioned was considered the hydrogen bonding ability of the polar

carboxymethyl function.

In analytical science, the cyclodextrins are used for enantioseparations in gas chromatography,

high-performance liquid chromatography, supercritical fluid chromatography, and capillary

electrophoresis. The cyclodextrins-containing mobile phases are used for the enantiomeric

separations of various chiral compounds like mephenytoin, barbiturates [41], phenylalanine[42],

a-pinene [43], and pseudoephedrine [44]. A number of interesting applications of chiral

recognition by cationic and anionic derivatives of cyclodextrins have been published.

Specifically, the cationic cyclodextrin derivatives containing amino and alkylamino groups were

employed as chiral selectors in capillary electrophoresis [44-47]. A more detailed study of

charged cyclodextrin derivatives as chiral selectors for the enantioseparation in capillary

electrophoresis has been reported by Chankvetadze et al. [47]. They established that ionic

cyclodextrin derivatives, especially cyclodextrin alkyl sulfates, exhibit a chiral recognition ability

for a basic racemates (the most important factor in this process is the high counter-current

mobility of the chiral selector) and neutral racemic compounds. For enantioseparation of the

thalidomide molecule and its neutral metabolites has been used a carboxymethylated-p-

cyclodextrin as chiral selector.

Using cyclodextrins as chiral selector in capillary zone electrophoresis made possible to

enantiomeric separation of a large variety of chiral compounds such as DL-tryptofan and

(±)-epinephrine [47] and epkedrine, norephedrine, norepinphrine, isoproterenol [48], terbutaline,

and propranolol [40].

III. 3. Calixarenes

The calixarenes (Figure 1), that is the receptors prepared from phenols and aldehydes by an

acid-catalyzed condensation [49], exhibit the enantiomeric recognition ability towards optically

active molecules. These compounds are the third major class of supramolecular host systems

along with the crown ethers and the cyclodextrins. Ptetraskiewicz et al. [50] have studied the

chiral recognition of some amino acid (alanine, valine, leucine and tryptophan) by chiral

calix[4]resorcinarenes of Mannich-base type, containing (S)(-)-phenylethylamine, and

(lR,2S)(-)norephedrine in Langmuir films. The chirat discrimination of amino acids above-

mentioned was observed through the changes in the surface area, which was different for D- and

L- forms. It is known that calix[4]resorcinarene has four important conformers: cone, flattened

partial cone, 1,3-alternate and flattened cone [51]. The mod of complexation of calixarenes

strongly depends on the nature of the guest species and the concentrations of the guest and host

molecules.

Of particular relevance are the studies performed in water since most of the biological

processes take place in such media. Following this approach, it was found that the

tetrasulphonatocalix[4]arenes [52] are able to form inclusion complexes with several charged and

uncharged guest species in water. The complexation of the a-amino acids with these compounds

has been achieved by inserting the aromatic or aliphatic apolar group into the calixarene cavity.

Chiral recognition properties of homooxacalix[3]arene towards picrate salts of alanine ethyl

ester and phenylalanine ethyl ester have recently studied by Shinkai et al. [53], ]H NMR spectral

studies suggested that homooxacalix[3]arene bound ammonium cations through hydrogen-

bonding interactions with three oxygen atoms.

IV. Liquid Membranes in Enantioseparation

The potential applications of membrane processes in separation and purification of biological

compounds have been investigated during the last few years [54-57]. Research in this field has

been focused on biomimetic aspects of the systems. The technique of separation through liquid

membranes combines the selectivity of extraction with active transport of compounds.

Separation of optically active compounds by liquid membranes has been of current interest [1-

3]. It is known that in biological systems the interaction receptor-ligand operates in solution.

Thus, there are important advantages of the techniques that operate in free solution rather than

other techniques which use immobilized selectors because in this latter case the chiral recognition

might be diminished. Following this reason, the computational chemistry has been applied in this

field of life science and moreover, analytical chemistry involving chirality phenomena has come

up with many chiral molecular recognition models.

Lipophilic membrane proteins may be considered of interest, in the case when they are used as

enantioselective membranes by separating optical isomers in a continuous flow system. Along

this line, Pirkle et al. developed systems involving an enantioselective transport through a silicon

supported liquid membrane [58].

IV. 1. Crown Ether-Mediated Enantioselective Transport of Amino aAcids

Kozbial et al. [59] studied the enantioseparation of some amino acids (phenylglycine,

phenylalanine and tryptophan) by a chiral crown ether incorporating a methyl a-D-

mannopyranoside in a ternary system of a limited mutual miscibility: water - ethanol - 2,2,4 -

trimethylpentane.

These investigations of enantiomeric discrimination of amino acids above-mentioned have

been performed by transport experiments across a liquid membrane, liquid-liquid extraction and

partitioning liquid chromatography. The highest enantioseparation has been observed in

extraction experiments with the following order of enantioselection: PhAla > Trp > PhGly. The

enantioselective transport of DL- phenylalanine through a polymeric membrane plasticized with

o - nitrophenyl octyl ether and using a chiral crown ether as carrier was investigated by Shinbo et

al [60]. The experimental results obtained showed that the transport behaviour was dependent on

the polymer type, membrane thickness, and the nature of amino acids. The fluxes increased with

the increase in lipophilicity of the amino acids. The amino acids bearing bulky side groups gave

high optical resolution ratios. Also Shinbo et al. [4] have studied the enantioselective transport of

a varitey of amino acids and amines through a supported liquid membrane containing chiral

crown ether, 2, 3:4, 5-bis [ l,2-(3-phenylnaphtho)]- 1,6,9, 12, 15, 18 - hexaoxacycloeicosa-2, 4-

diene (Figure 6).

All examined amino acids were separated into their enantiomers, and the highest separation

was observed for phenylglycine. Amino acids having bulky side groups gave large optical

resolution ratios, and lipophilic amino acids gave high fluxes. Optically active amines displayed

resolution ratios remarkably small compared with those of amino acids.

Bryjak et al. [61] evaluated the transport enantioselectivity of underivatized amino acid

hydrochlorides (Ala, Leu, Phe, Met, Ser, Thr, GIu) through liquid chiral alcohols (nopol and

(2S)- (-)-methyl-l-butanol) immobilized in the pores of a polyethylene film. The degree of

stereoselectivity of the permeation process varied from 0.39 to 1.52. This process was influenced

by the type of the chiral receptor and the properties of the amino acid. Chiral alcohols used as

membrane phase offer enantiomer separation comparable to the chromatographic methods.

Naemura et al. [62 ] studied the differential transport of racemic ammonium salts through bulk

H2O/CHCI3 liquid membranes containing chiral macrcycles with various cyclic units

incorporated into macrocycles. Using two lariat ethers bearing N-pivot dipeptide arms, Gokel et

al. [63,64], described the enantioselective transport of Z- amino acids (Z = benzyloxy-carbonyl)

and dipeptide K+ carboxylates through a bulky chloroform membrane. The study indicated that

the macrocycles used in experiments exhibited efficient chiral recognition properties.

V. Conclusions

The present review covers some aspects of possibilities to use the chiral macrocycles receptors

in enantiomeric recognition of amine compounds. Separation of optically active compounds

through liquid membranes using chiral macrocyclic receptors has been achieved. Some aspects

concerning the mechanisms of enantiomeric recognition of amine compounds using chiral

macrocyclic receptors have been briefly presented.

Acknowledgments

The present work has been supported by the NATO Life Science and Technology

Collaborative Linkage Grant 974819 and has been done within the framework of the

Associateship Scheme of the Abdus Salam International Centre for Theoretical Physics (ICTP),

Trieste, Italy.

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12

FIGURE CAPTIONS

Figure 1. The chemical structures of some macrocyclic ligands and calixarenes.

Figure 2. The structure of a-, p-, and y- cyclodextrin

Figure 3. Some inclusion complexes of cyclodextrins.

Figure 4. Chemical structure of 18-crown-6-tetracarboxylic acid [16].

Figure 5. Chiral pyridino-18-crown-6 macrocycles [18].

Figure 6. Chiral crown ether [4],

13

Cn-O: 16-Crown-S (16CS)B - 1 : 1l-Crown-€ (1«C£)n«2i «1-Cr«wn-7 (21C7)

o

o o

Benio-1 8-Crotm n-6(B1BC6)

Dlb*nio-18-Crown-6(DB18C6)

M02

Ct 0 o1 I

CI.D.HC6

CIDrcycloheiano-1 B-Crown-G

AO H O,

B-H: 1, 10.Diai»-1 «-Cr»wn-6(t.t)

Dideoyl-1, 10-Oiata-1 «-Crown-6(002.21

1, IO'Dithia-IS-Crown-6(OT1SC6)

Dike(o-4-Ooto<ypyri»J<na-11CrownS(DKOotoiy P1SC6)

, Cfl

p-tert-bulylcaliK[4Jarene p-tort-but»lc«lln[6]arene(cf8]«)

Macrocycles

Fig.l

CCL

15

16

"O*

6 ^COOH

" COOH

0

Fig.

JS.S>-1: X= Hi. R=CH,(S.5)-2:X=S,~R=CH3

(S.5)-3. X=0. R=CH3

.=H,, R=Ph8:X=O R=H,

j - ^ ^ - ^ J ^ ^ "

(J.51-6: X=O, R,=Ph. R2=CH3

{S.S)-7: X=S, R,=CH,-Ph, R:=H

Fig.5

Fig.6

17