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Recent Advances in Chiral Resolution through Membrane-Based Approaches.

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Separation Methods
Recent Advances in Chiral Resolution through
Membrane-Based Approaches
Carlos A. M. Afonso* and Jo¼o G. Crespo*
chiral resolution · chromatography · enzymes ·
need for chiral compounds in
enantiomerically pure form, mainly by
the pharmaceutical industry, creates a
considerable pressure for the development of new strategies for preparativescale resolution of racemic mixtures.[1]
Chromatographic methods, particularly
gas–liquid (GLC) and solid–liquid
(HPLC) chromatography, have been
for a long time the best approach for
analytical enantiomer separation.[2] Furthermore, chiral separation on a preparative scale by liquid chromatography
has proved to be a very efficient method
for a wide range of substrates. However,
apart from their advantageous high
efficiencies and broad applications,
chromatographic methods present the
disadvantage of being typically discontinuous. To circumvent this limitation,
the development of simulated moving
bed chromatography (SMB), which can
also be applied to supercritical-fluid
chromatography (SFC), allows a continuous process operation on a preparative
scale.[3] SMB chromatography is extremely useful for large-scale (and including chiral) separations; however, it
[*] Prof. C. A. M. Afonso
Departamento de Engenharia Qu"mica
Instituto Superior T&cnico
1049-001 Lisbon (Portugal)
Fax: (+ 351) 21-841-7122
Prof. J. G. Crespo
Departamento de Qu"mica
Faculdade de CiÞncias e Tecnologia
Universidade Nova de Lisboa
Campus da Caparica, 2829-516 Caparica
Fax: (+ 351) 21-294-8550
Angew. Chem. Int. Ed. 2004, 43, 5293 –5295
is necessary to perform a complex
experimental and theoretical optimization study for each substrate separation.
The high cost of stationary phases has
been a major limitation for the generalized use of this technique, and it is for
this reason that the SMB methodology is
mainly restricted to the final stages of
production of single enantiomers by
chiral separation, at which point simple
resolution by crystallization is not feasible.
More recently, capillary electrophoresis has emerged as a very powerful
analytical method for chiral separation,[4] and includes high-speed chiral
separation on a microchip electrophoresis device.[5] It is assumed that the
separation is possible owing to the
similar interactions between each enantiomer and the chiral selector as in the
case of chromatography. Consequently,
chiral selectors such as cyclodextrins
and amino acid derivatives are equally
effective in both separation techniques.
Moreover, because the chiral selectors
are actually dissolved in the solution in
which the differential migration for each
enantiomer occurs, other types of chiral
selectors (crown ethers, linear polysaccharides, macrocyclic antibiotics, transition-metal complexes, chiral surfactants,
and proteins) may also be employed.
Capillary electrophoresis will certainly
have a prosperous future for the resolution of ionic racemic substrates if
adequate engineering solutions are developed to extend its already remarkable chiral separation efficiency to a
preparative scale.
Optical resolution by enantioselective extraction is a very simple method
and was first demonstrated thirty years
ago by Cram and co-workers,[6] who
DOI: 10.1002/anie.200460037
used chiral crown ethers (in chloroform)
as efficient selectors for the enantioselective extraction of racemic ammonium salts from aqueous solution. Since
then, other efficient chiral selectors
emerged, such as organometallic complexes,[7] deoxyguanosine derivatives,[8]
borate complexes of 1,2-diols,[9] and
steroidal guanidinium and urea receptors.[10] In all of the reported examples,
which includes both the pioneering
catalytic resolving machine (W-tube device) described by Cram and co-workers[11] and the multiple dual-flow countercurrent batch extraction procedure,[12] the chiral selector is dissolved
in the organic phase, and the racemic
mixture is dissolved in the aqueous
phase. With this approach, in accord
with the “three-point rule”,[13] there is a
more effective preferential binding of
the chiral selector to one of the enantiomers in a solvent environment that is
less polar than the feeding aqueous
However, resolution based on dispersed-phase extraction presents significant limitations for preparative and
continuous operation, such as the lowcontact interfacial area and problems
inherent to phase dispersion and phase
coalescence. These limitations may be
minimized by using hollow-fiber membrane contactors.[14] A membrane contactor is a device that allows gas–liquid
or liquid–liquid mass transfer without
the dispersion of one phase within the
other, by passing the fluids on opposite
sides of a microporous membrane, typically with pore sizes between 0.2 and
0.05 mm. By selection of the membrane
material (both hydrophilic and hydrophobic membrane contactors are commercially available) and careful control
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
of the pressure difference between the
fluids, one of the fluids is immobilized
within the pores of the membrane so
that the fluid/fluid interface is located at
the mouth of each pore. This approach
offers a number of important advantages over conventional dispersed-phase
contactors, such as the absence of emulsions, no flooding at high flow rates, no
unloading at low flow rates, no need for
density difference between fluids or for
phase separation after contact, and
surprisingly high interfacial areas. Indeed, membrane contactors typically
offer 30 times more specific area than
in gas absorbers, and 500 times more
specific area than in liquid/liquid extraction columns.[14]
Different approaches have been reported for a large number of chiralresolution problems with liquid membrane systems.[10, 15] In one of the most
common approaches proposed, a solution of the chiral selector in a waterimmiscible solvent is pumped through
the interior of the fibers (lumen side),
while the aqueous-feed stream that
contains the racemic substrate circulates
in the shell side of the hollow-fiber
module. Owing to the high surface area,
efficient mass transfer can then take
place between the two phases. This
system can be duplicated through the
introduction of a second hollow-fiber
contactor in series, in which a stream
that contains the other enantiomer of
the chiral selector circulates in the lumen of the fibers. Other configurations
have been proposed, namely the use of a
hollow-fiber contactor with two independent sets of fibers in which the two
solvent phases containing the corresponding enantiomeric selectors circulate independently (Figure 1). After
extraction, each enantiomer may be
recovered from the corresponding
receiving phase by reextraction and/or
by solvent distillation, in such a way that
the enantiomeric selectors can also be
recovered and reused. Therefore, these
selectors are needed in only a catalytic
As each enantiomer is transported
from the source phase, the remaining
mixture would remain essentially racemic and a level of enantioselectivity for
each enantiomer would be maintained
as long as an adequate thermodynamic
driving force for transport is provided.
Figure 1. System for the resolution of aqueous
racemic mixtures by simultaneous membrane
extraction using two organic phases (ORG),
each containing an adequate chiral selector (R
and S forms, respectively).
In the event that a given selector–
substrate combination afforded an undesirably low level of enantioselectivity,
further membrane units could be added
(staging). Cussler and co-workers have
used a hydroxyproline-derived chiral
selector (typically employed in chiral
ligand-exchange chromatography) in a
hollow-fiber device.[16] Owing to selectivities of less than 2.5, these researchers
used countercurrent flow of the two
phases to cause each fiber to function as
a low-efficiency “chromatography” column. This procedure enhances the extent of separation and allows a complete
separation of the enantiomers.
Although transport through the liquid-membrane phase takes place by
diffusion, the extremely high specific
surface of the hollow fibres compensates
for this effect and allows sufficiently
high mass-transfer rates. The recent
development of new solvents (such as
ionic liquids) and the design of solvent
phases has led to liquid contactors with
increased stability and long-term performance. This hollow-fiber-membrane
resolution system is certainly appropriate for scale-up resolutions under continuous operation. However, there is
still the problem associated with obtainment of a high level of optical purity,
owing to the need for a high number of
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
sequential stages of phase equilibrium
as occurs in chromatography. To address
this issue, other processes based on the
combination of countercurrent fractionation and liquid-membrane technology
have been described.[17]
In the past, it has been demonstrated
that enantiospecific chiral selectors are
extremely difficult to obtain and, as
expected, they are very specific. To
circumvent this limitation, a very interesting approach was recently proposed
which combines a fluorous-organic extraction and an enzyme-mediated enantiospecific esterification reaction with a
highly fluorinated group to allow one
enantiomer to be partitioned into the
fluorous phase as a fluorinated ester.[18]
More recently, Goto and co-workers[19]
employed a similar approach: Ibuprofen
was resolved by the selective conversion
of (S)-ibuprofen to (S)-ibuprofen methyl ester with an enantioselective lipase
from Candida Rugosa (CRL) at the feed
interface of a supported liquid membrane (SLM) that contains an ionic
liquid.[20] The ionic-liquid phase allows
the selective transport of the morehydrophobic ibuprofen methyl ester
from the aqueous-feed phase to the
receiving phase. At the interface of the
receiving phase, the (S)-ibuprofen methyl ester is hydrolyzed to (S)-ibuprofen
by another lipase from porcine pancreas
(PPL). As (S)-ibuprofen is more hydrophilic it is not transported back through
the supported ionic-liquid phase (Figure 2). This system has great appeal for
continuous operation. Goto and coworkers presented batch studies for
operation during 2.5 days which demonstrated that the employed SLM is stable
under the conditions selected.
More recently Rmaile and Schlenoff[21] demonstrated that optically active
polyelectrolyte multilayers (PEMUs)
made from polypeptides can be used as
membranes for analytical chiral separation in capillary electrophoresis, with
racemic ascorbic acid and DOPA (3,4dihydroxyphenylalanine) as substrate
models. Very interesting conclusions
could be drawn from this study: First,
it was observed that optically active
multilayers produce chiral separations.
Second, a multilayer made from two
optically active polyelectrolytes was
more selective for one of the enantiomers (d-ascorbic acid in their study) than a
Angew. Chem. Int. Ed. 2004, 43, 5293 –5295
Figure 2. System for the resolution of ibuprofen described by
Goto and co-workers,[19] based on the combination of sequential
enantioselective enzymatic esterification (enzyme CRL), selective
transport through a supported liquid membrane, which contains
an ionic liquid, and enzymatic hydrolysis (enzyme PPL).
multilayer that comprised only one
active polyelectrolyte. It was also observed that the reversal of the chirality
of polyelectrolytes within the multilayer
led to inversion of the selectivity for l
over d isomers. Finally, PEMU membranes presented higher fluxes than
other reported chiral membranes, which
appears extremely promising in the
future for applications in preparative
chiral separations.
In conclusion, the processes based
on membrane technology will most
certainly become very important for
continuous operation, but at the moment still suffer from being generally
less enantioselective. A solution to the
problem requires the development of
efficient engineering solutions that can
provide a high number of equilibrium
stages in compact equipment. We expect
that other efficient solutions will emerge
based on the current remarkable developments reported for analytical applications. The key points for continuous
enantiomer separation are, in first place,
the nature of the chiral selector, which
should exhibit a high level of differentiation of interaction with each enantiomer, and second, the use of this
property through extension of the effect
Angew. Chem. Int. Ed. 2004, 43, 5293 –5295
and continuous operation. Both aspects are
still open for new solutions to be developed,
but the discovery of
apoenzymes,[22] with a
broad range of applications as well as moreimmediate procedures
to achieve them, will
certainly have a high
impact on the development of this field.
Published Online:
tember 21, 2004
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