Highly fructose selective transport promoted by boronic acids based on a pentaerythritol core.

Article abstract of DOI:10.1021/ol015560x

We have designed and synthesized a highly lipophilic boronic acid (11) with a molecular shape that makes it much more effective at carrying sugars through organic membranes than a previously used steroidal boronic acid. The corresponding diboronic acid (1

Full text of DOI:10.1021/ol015560x

ORGANIC
LETTERS
2001
Vol. 3, No. 6
917-920
Highly Fructose Selective Transport
Promoted by Boronic Acids Based on a
Pentaerythritol Core
Scott P. Draffin, Peter J. Duggan,* and Sandhya A. M. Duggan
Centre for Green Chemistry, School of Chemistry, P.O. Box 23, Monash UniVersity,
Clayton, Melbourne, Victoria 3800, Australia
peter.duggan@sci.monash.edu.au
Received January 16, 2001
ABSTRACT
We have designed and synthesized a highly lipophilic boronic acid (11) with a molecular shape that makes it much more effective at carrying
sugars through organic membranes than a previously used steroidal boronic acid. The corresponding diboronic acid (12) was also found to
transport fructose ahead of glucose with a very high selectivity (7.6:1.0). Modeling suggests that 12 is able to carry two fructose molecules
at once in a complex stabilized through hydrogen bonding and ion pairing.
Boronic acids that are able to selectively transport carbohy-
drates across lipophilic membranes have potential applica-
tions in drug delivery1,2 and in environmentally benign
industrial sugar production.2,3 With the latter application in
mind, we have been investigating the inherent selectivity for
fructose transport exhibited by aryl boronic acids, with the
aim of developing a new method for the production of high
fructose syrup.
Figure 1 shows how the transport of a sugar out of an
alkaline aqueous departure phase, through a lipophilic
membrane, and into a slightly acidic aqueous receiving phase
can be promoted by a boronic acid. This transport process
is thought to be diffusion-controlled,2 with the formation of
the boronate esters at the interface being rapid and reversible.
Since, in this mechanism, every sugar molecule is co-
transported with a hydroxide ion, sugar transport can be
driven uphill via the application of a pH gradient across the
membrane.3
Membrane stability and ease of preparation of carriers are
of prime importance if this process is to become industrially
feasible. In our early experiments with bulk liquid mem-
branes (BLM’s),3 we tried to address these issues through
the use of a boronic acid derived from cholesterol, PBCC
(1, Figure 2).4 This highly lipophilic boronic acid, which is
expected to be resistant to leaching, unfortunately possesses
very poor transport properties in a BLM, with virtually no
sugar transport being observed under standard conditions.
(1) Riggs, J. A.; Hossler, K. A.; Smith, B. D.; Karpa, M. J.; Griffin, G.;
Duggan, P. J. Tetrahedron Lett. 1996, 37, 6303-6306.
(2) Smith, B. D.; Gardiner, S. J. AdV. Supramol. Chem. 1999, 5, 157-
202 and references sited therein.
(3) Karpa, M. J.; Duggan, P. J.; Griffin, G. J.; Freudigmann, S. J.
Tetrahedron 1997, 53, 3669-3678.
(4) James, T. D.; Harada, T.; Shinkai, S. J. Chem. Soc., Chem. Commun.
1993, 857-858.
10.1021/ol015560x CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/15/2001

Table 1. Sugar Fluxes through a Supported Liquid Membranea
flux (10-8 mol m-2 s-1
)
entry boronic acid/ester
fructose
glucose
ratio of fluxes
1
2
3
4
5
6
7
86
1
2
3
7.6
28.4
28.9
17.1
17.9
26.1
31.8
21
4.1
6.7
7.2
3.4
3.5
3.4
9.3
3.4
1.9
4.2
4.0
5.1
5.1
7.6
3.4
6.1
8
11
12
14
15
a Carrier dissolved in 2-nitrophenyl octyl ether (50 mM) with 1 equiv
of Aliquat 336 and supported on Accurel type 1E (12.6 cm2). Departure
phase (34 mL) contained 0.3 M fructose and glucose and was buffered at
pH 11.3 with 0.5 M Na2CO3. Receiving phase (34 mL) was buffered at pH
6.0 with 0.1 M Na2HCO3. Both phases were stirred with a magnetic stirring
bar at 250 rpm. Aliquots were removed at hourly intervals and analyzed in
triplicate for glucose with a coupled hexokinase-glucose-6-phosphate
dehydrogenase assay and fructose with the addition of phosphoglucose
isomerase, as previously described.5 Fluxes were determined from slopes
of plots of [total NADPH abs (340 nm)] vs time over periods of at least 5
h and the results averaged over two runs. T ) 298 K, flux uncertainty (
10%. b Data obtained in a previous study under slightly different conditions.5
Figure 1. Accepted mechanism for boronic acid mediated pH
driven sugar transport through an organic membrane (Q+
quaternary ammonium cation).3
)
We suggested that steroidal boronic acids of this type
probably self-assemble at the membrane interface, inhibiting
transport.3
More recently, we have been studying sugar transport
through supported liquid membranes (SLM’s) because these
membranes are more likely to be industrially useful than
BLM’s, and they require much lower quantities of carrier.5
We have now found that the poor transport properties of
PBCC, particularly for fructose, are not confined to the BLM
experiment (Table 1). The fructose flux promoted by PBCC
through an SLM does not compare well with that induced
by NPOEBA (2), the standard reference monoboronic acid
used in SLM transport experiments.5,6
of incorporating one, two, and three boronic acids into
carriers of similar shape and size. Scheme 1 shows the route
used to synthesize these boronic acids. The mono-, di-, and
tribromides (5-7) were readily prepared from pentaerythrityl
Scheme 1. Synthesis of Carriers with a Pentaerythritol Core
To circumvent the apparent interfacial problems presented
by PBCC, we have designed and synthesized a lipophilic
boronic acid (11) with an overall conical shape, through a
combination of a pentaerythritol core and the cheap, readily
available p-tert-octylphenol. The use of the pentaerythrityl
core also allowed us to prepare two closely related boronic
acids (12 and 13) with the purpose of comparing the effect
Figure 2.
918
Org. Lett., Vol. 3, No. 6, 2001

tetrabromide by treatment with p-tert-octylphenol and potas-
sium carbonate in DMF. By variation in the ratio of bromide
to phenol, and the application of careful flash chromatog-
raphy, all three bromides could be produced in pure form.
NPOEBA and related carboxylate esters had previously been
synthesized through the direct alkylation of p-carboxyphenyl
boronic acid;5,6 however, the boronic acid products produced
in these reactions are usually difficult to isolate from the
often complex reaction mixtures. We have optimized the
preparation of such esters by first protecting the boronic acid
of p-carboxyphenyl boronic acid with the stable pinacol
protecting group, which appears to minimize side reactions
and make the products easier to isolate. Yields of the highly
hindered protected boronic acids (8-10) were also enhanced
by the use of CsCO3, an excess of KI, and the use of DMA
as the solvent. Deprotection to the boronic acids (11-13)
was achieved through a simple treatment with HCl in
aqueous acetone.
The fluxes of fructose and glucose through o-nitrophenyl-
octyl ether (NPOE) supported on porous polypropylene
Accurel,5 promoted by the pentaerythrityl boronic acids and
esters, are shown in Table 1. No leaching of carriers from
the membrane was observed during these transport experi-
ments. Interestingly, we have found that for monoboronic
acids such as NPOEBA and 11 it is not necessary to cleave
the pinacol boronate ester prior to incorporation in the
membrane. Deprotection apparently occurs very rapidly at
the start of the transport experiment, with the results obtained
with NPOEBA (2) and pinacol-protected NPOEBA (3)
(Table 1, entries 2 and 3) and 8 and 11 (Table 1, entries 4
and 5), each within experimental error. We saw this as a
potentially attractive solution to the solubility problems
encountered with triboronic acids such as 13, which are not
usually soluble in NPOE. Unfortunately, the apparent rapid
deprotection observed with the monoboronic acids did not
occur with the di- and triboronic acids (12 and 13). The
dipinacol ester (9) gave significantly reduced fluxes of
fructose and glucose when compared with 12, and the
tripinacol ester (10) did not appear to promote sugar transport
at all. The low solubility of the triboronic acid (13) in NPOE
has prevented us from performing transport experiments with
this compound.
Given the importance of fructose to the food and beverage
industry,6a another long-term aim of our research is to
develop sugar carriers that are highly selective for fructose.
As demonstrated by the NPOEBA transport results (Table
1, entry 1), monoboronic acids naturally show a strong
preference to transport fructose ahead of glucose, despite
extracting fructose with a much lower selectivity.3,5 We
originally rationalized this transport preference through a
realization that the most stable boronate esters of glucose
are formed with its furanose form.7 This form is not readily
available in aqueous solution, and under the kinetically
controlled transport experiment, we felt that this lack of
availability of the furanose form of glucose is enough to
retard glucose flux relative to fructose. This theory appears
to be supported by the transport results obtained with
Shinkai’s diboronic acid (14),8 shown in Table 1. This
diboronic acid is known to bind strongly to the furanose form
of glucose,7 and in fact, we have now found that in extraction
experiments performed at pH 11, a combination of 14 and
Aliquat 336 extracts glucose into 1,2-dichloroethane ahead
of fructose in a ratio of 1.8:1.0. This preference for glucose
extraction exhibited by 14 is the highest we have observed,
yet 14 still selects for fructose in the transport experiment
(Table 1, entry 7), despite promoting a relatively high glucose
flux.
We have previously tried to improve fructose selectivity
by making a series of diboronic acids with a variable linker,5
and observed an improvement in selectivity (6.1:1.0), with
the diboronic acid (15) that molecular modeling suggested
was most capable of bonding to the pyranose form of fructose
in two places (Figure 3).5 Similar modeling with 12 shows
Figure 3.
In terms of improving sugar flux by adjusting the molec-
ular shape of the carrier, it is gratifying to find that moving
from the steroidal structure of PBCC to the overall conical
shaped carrier based on a pentaerythritol core significantly
improves carrier performance. The monoboronic acid (11),
despite having a considerably higher molecular weight than
PBCC, promotes a fructose flux 2.2 times greater than that
produced by PBCC. We have therefore achieved the principal
aim of this investigation, which was to produce a highly
lipophilic boronic acid by a simple synthetic route with a
molecular shape that does not inhibit sugar transport.
that the bite angle and size for this compound is inappropriate
for it to readily bond to the pyranose form of fructose in
two places. We were therefore surprised to find that the
fructose selectivity exhibited by 12 (Table 1, entry 6) is
significantly better than that of 15 and is the highest eVer
recorded.
Fructose is also able to form very stable monoboronate
esters in its furanose form, an example of which is 16.9
Glucose is incapable of forming similarly stable monobor-
onate esters, so it is possible that much of the observed
(5) Gardiner, S. J.; Smith, B. D.; Duggan, P. J.; Karpa, M. J.; Griffin,
G. J. Tetrahedron 1999, 55, 2857-2864.
(6) (a) Paugam, M.-F.; Riggs, J. A.; Smith, B. D. J. Chem. Soc., Chem.
Commun. 1996, 2539-2540. (b) Paugam, M.-F.; Bien, J. T.; Smith, B. D.;
Chrisstoffels, L. A. J.; de Jong, F.; Reinhoudt, D. N. J. Am. Chem. Soc.
1996, 118, 9820-9825.
(7) Norrild, J. C.; Eggert, H. J. Am. Chem. Soc. 1995, 117, 1479-1484.
(8) Tsukagoshi, K.; Shinkai, S. J. Org. Chem. 1991, 56, 4089-4091.
(9) Norrild, J. C.; Eggert, H. J. Chem. Soc., Perkin Trans. 2 1996, 2583-
2588.
Org. Lett., Vol. 3, No. 6, 2001
919

charge-neutral package. Modeling of similar esters formed
with 14 and 15 shows that these diboronic esters cannot place
the fructose fragments in suitable positions to take advantage
of such stabilizing effects. The diester of 14 is unlikely to
form for steric reasons, and the diester formed with 15 cannot
bring the fructose fragments close enough together, with
modeling predicting the formation of a single, 1.91 Å
hydrogen bond.
In summary, we have designed and synthesized two new
lipophilic boronic acids (11 and 12) that have an overall
conical shape, which promote facile and highly selective
transport of fructose through an SLM. The high selectivity
for fructose shown by the diboronic acid 12 may indicate
that it is able to transport two molecules of fructose at the
same time as a part of a complex stabilized by hydrogen
bonds and ion pairing. This prediction is difficult to confirm
experimentally, but we have initiated a careful investigation
of the structures of the boronate esters involved in transport,
the results of which will be reported in due course.
Interestingly, Shinkai’s diboronic acid (14) also selectively
transports fructose over glucose, despite being able to form
very stable esters with glucose and being able to extract
glucose into organic solvents more readily than it can
fructose.
Figure 4. Molecular mechanics10 structure of diboronate ester
formed between 12 and two molecules of fructose in the furanose
form.
boronic acid promoted fructose flux results from transport
of monoboronate esters of its furanose form. Given that these
esters have a lower molecular weight than the diboronates
formed with glucose, and that the effect of size on diffusion
rates will be magnified when the large ammonium counter-
ions are taken into account, the ability to bind fructose as a
monoboronate ester may be an important contributing factor
in the demonstrated preference for boronic acids to selec-
tively transport fructose. These considerations have led us
to model the diboronate ester formed between one molecule
of 12 and two fructose molecules in the furanose form
(Figure 4).10 These calculations have shown that two stabiliz-
ing hydrogen bonds (1.17 and 1.07 Å) can be formed
between the two fructose fragments in this diester11 and that
this structure nicely accommodates the quaternary am-
monium counterions (omitted for clarity) into an overall
Acknowledgment. We thank Dr. Jens Norrild, University
of Copenhagen, for the generous gift of 14, Tim Altamore
for preparing 3, and Dr. Peter Nichols for assistance with
molecular modeling. We gratefully acknowledge financial
support from the Australian Research Council and Monash
University.
Supporting Information Available: Synthetic details and
characterization data for compounds 3 and 5-12 along with
the experimental procedure used for transport experiments
and associated absorbance vs time plots. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) Insight II, Discover Minimisation Module, MSI, San Diego, CA.
(11) Shinkai and co-workers have recently suggested that a similar type
of H-bonding might occur in difructose boronate diesters appended to poly-
(L-lysine); Kobayashi, H.; Nakashima, K.; Ohshima, E.; Hisaeda, Y.;
Hamachi, I.; Shinkai, S. J. Chem. Soc., Perkin Trans. 2 2000, 997-1002.
OL015560X
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Org. Lett., Vol. 3, No. 6, 2001