Stereoselective reduction of menthone by molecularly imprinted polymers

Article abstract of DOI:10.1016/j.tetasy.2004.06.002

Polymeric chiral reductants selective for the reduction of (-)-menthone 1 to the diastereomeric products (-)-menthol 2 and (+)-neomenthol 3 were prepared by a covalentmolecular imprinting using 2 as the template. The LiAlH₄ derivatized imprinted polymers altered the natural outcome of the reduction reaction (LiAlH₄) from 2:1 [(-)-menthol:(+)-neomenthol] to 1:1. The reaction mechanism is discussed in terms of reaction site structure. The molecularly imprinted polymers demonstrated enantioselective recognition for 2 (0.15μmol enantioselective sites/g polymer) in batch binding experiments.

Full text of DOI:10.1016/j.tetasy.2004.06.002

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2431–2436
Stereoselective reduction of menthone by molecularly
imprinted polymers
Jimmy Hedin-Dahlstr o€ m, Siamak Shoravi, Susanne Wikman and Ian A. Nicholls*
Department of Chemistry and Biomedical Sciences, University of Kalmar, SE-391 82 Kalmar, Sweden
Received 27May 2004; accepted 4 June 2004
Abstract—Polymeric chiral reductants selective for the reduction of ())-menthone 1 to the diastereomeric products ())-menthol 2
and (+)-neomenthol 3 were prepared by a covalent molecular imprinting using 2 as the template. The LiAlH
4
derivatized imprinted
polymers altered the natural outcome of the reduction reaction (LiAlH
mechanism is discussed in terms of reaction site structure. The molecularly imprinted polymers demonstrated enantioselective
4
) from 2:1 [())-menthol:(+)-neomenthol] to 1:1. The reaction
recognition for 2 (0.15 lmol enantioselective sites/g polymer) in batch binding experiments.
ꢀ
2004 Elsevier Ltd. All rights reserved.
1
. Introduction
of limited size and containing minimal functionality.
Menthol has previously been used as a template for
11;12
Achieving the stereochemical integrity demonstrated in
many biological reactions is a major goal for synthetic
organic chemistry. In order to achieve this aim, a vast
number of different strategies has been investigated, for
noncovalent molecular imprinted polymers
and silica
13
based gels. The single hydroxyl present in the template
suggested the use of a covalent imprinting strategy,
which should facilitate the positioning of reactive func-
tionality. The reaction system selected for investigation
was the reduction of the terpenoid ())-menthone 1 by
1
2
3
example, chiral Lewis acids, cavitands, catalytic anti-
4
5
bodies, cyclodextrins and, more recently, molecularly
6
imprinted polymers (MIPs).
4
LiAlH (Scheme 1). This reaction yields two diastereo-
meric products, ())-menthol 2 and (+)-neomenthol 3.
7
14
Molecular imprinting involves the formation of cavities
Reductions of 1 using ())-menthone reductase, cyclo-
15
16
in synthetic polymer matrices that are of complementary
functional and structural character to a predetermined
template. Appropriately functionalized monomers form
complexes, either covalent or noncovalent, with the
template, which are subsequently fixed into a rigid net-
work polymer by polymerization in the presence of an
excess of an inert crosslinking monomer. Removal of the
template reveals recognition sites that are selective for
the original template structure. MIPs have been utilized
in an ever increasing number of application areas, for
example, biosensor recognition elements, solid phase
extraction matrices, chromatographic stationary phases
dextrins, LiAlH
production of 2 over 3.
4
or sodium on alumina favour the
LiAlH /THF
4
+
O
OH
OH
Polymer
1
2
3
Scheme 1. Reduction of ())-menthone 1 by LiAlH
menthol 2 and (+)-neomenthol 3.
4
yielding ())-
8
and for the mediation of synthetic reactions, both as
10
catalysts and as moderators.
9
The objective of the present study was to examine the
possibility for MIP-directed synthesis using a template
2. Results and discussion
A series of polymers selective for the ())-enantiomer of
menthol were prepared using acrylate derivatized tem-
plate, ())-dimenthylfumarate 4 or ())-menthylacrylate
5, in copolymers of styrene 6 and divinylbenzene 7
*
Corresponding author. Tel.: +46-480-446258; fax: +46-480-446244;
e-mail: ian.nicholls@hik.se
0
957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.06.002

2432
J. Hedin-Dahlstr €o m et al. / Tetrahedron: Asymmetry 15 (2004) 2431–2436
(Scheme 2). A nonimprinted, reference polymer, REF,
was prepared using fumaric acid.
The reduction of ())-menthone 1 in THF solution with
LiAlH was quantitative (GC–MS) and furnished the
4
diastereomeric products 2 and 3 in a ratio of 2:1 (Fig. 2,
Table 1). The reference polymer, REF, afforded an
identical product distribution, once again in quantitative
yield. This indicates that the polymer matrix itself does
not influence the stereochemical outcome of the reaction.
In each case, thermally induced polymerization was
followed by reductive cleavage of the template by ex-
tended exposure to an excess of LiAlH to furnish the
corresponding primary alcohols (Scheme 3). FT-IR
analysis of the resultant polymers showed a decrease of
4
ꢀ
1
at least 75% of the carbonyl absorption at 1726 cm
However, the use of MIP1, based on ())-dimenthyl-
fumarate 4, induced a significant change in the outcome
of the reaction, whereby the product ratio was shifted
from approximately 2:1 to 1:1, in favour of the naturally
unfavoured product, (+)-neomenthol 3. In the case of
MIP2, which was synthesized using 2 equiv of ())-
menthylacrylate 5 instead of 4, a similar influence on
reaction outcome was observed, though the effect was
not as pronounced. MIP2 has the same composition as
MIP1 with respect to the number of ())-menthyl moie-
ties, though a slightly lower degree of cross-linking. In
the case of MIP3, the polymer was prepared using an
equimolar amount of 5 as compared to MIP1, that is
half the concentration of ())-menthyl moieties though
with the same degree of cross-linking. Reactions with
MIP3 produced the same product profile as seen with
the solution and REF reactions. Collectively, these re-
sults indicate that the number (stoichiometry) of tem-
plate structures, and their disposition in the resultant
ꢀ
1
and 1750 cm , respectively, (representative spectra are
shown in Fig. 1). Extended reaction times did not im-
prove the efficiency of the reduction reaction, thus it was
concluded that residual carbonyl absorption is due to
the presence of unreacted ester functionalities that were
inaccessible to the reagent. After work-up, the hydroxyl
moieties were reacted with LiAlH4 (treatment with
1 equiv, based upon theoretical number of sites) to yield
polymers with AlH -functionalities in the sites created
by removal of the template.
3
The reduction of ())-menthone was investigated using
three different reactions: (1) reduction with LiAlH ; (2)
4
reduction in the presence of the LiAlH
erence polymer and (3) reduction with each of the
LiAlH -activated imprinted polymers. After standard
4
-activated ref-
4
workup and extensive washing, the reaction products
were analyzed by GC–MS.
O
O
O
O
O
4
O
O
MeOH/CHCl , ABDV, 50 ˚C, 24 h
3
O
+
6
7
O
O
5
O
MeOH/CHCl , ABDV, 50 ˚C, 24 h
O
3
Scheme 2.
O
Li
i, ii
iii
R
AlH3
O
OH
O
4 4
Scheme 3. Reagents and conditions: (i) grinding, sieving/particle sizing; (ii) LiAlH (excess), THF, reflux 48 h; (iii) 1 equiv LiAlH , THF, reflux 24 h.

J. Hedin-Dahlstr €o m et al. / Tetrahedron: Asymmetry 15 (2004) 2431–2436
2433
sites, that is through having sites selective for ())-men-
thol in close proximity to one another.
The observed change in the stereochemical outcome of
the reaction in the presence of the imprinted polymer
MIP1 is concluded to arise from the presence of stereo-
selective reactive sites in the polymer. A proposed
pathway for the reduction of 1 is presented in Scheme 4.
The initial orientation of the ester in the binding cavity
determines the position of the resultant hydroxyl in the
template-selective cavity. Subsequent derivatization with
LiAlH , places the reactive functionality so that hydride
4
delivery to the Si-face of the ketone 1 is favoured, which
leads to the production of 3.
i
iii
Li
+
AlH3
O
HO
HO
O
ii
Figure 1. Infrared spectra of MIP1 (left) and REF (right), before
template removal (dotted line) and after (black line).
1
2
3
Scheme 4. Reagents and conditions: (i) Re-facial hydride delivery; (ii)
Si-facial hydride delivery; (iii) 1 equiv of 1, THF, reflux 24 h.
To provide additional insight into the selectivity of the
reactive site, comparable reaction studies were per-
formed using (+)-menthone 8, to yield (+)-menthol 9
and ())-neomenthol 10 (Scheme 5). In this case, MIP1
induced a similar product distribution to that obtained
in the solution reaction, 32% 9 and 68% 10 This obser-
vation highlights the stereochemical integrity of the
reactive sites, that is the stereoselectivity of the polymer
induced reactivity.
In order to gauge the inherent stereoselectivities of the
resultant polymers, a series of batch binding studies was
performed using the nonactivated forms of MIP1 and
REF, that is with residual primary hydroxyl function-
alities. Studies over the range 0.5 lg/mL–5 mg/mL of the
menthol isomers (heptane, 298 K), showed that optimal
enantioselectivity was observable at 5 lg/mL. At this
concentration a clear distinction between the binding of
the ())- and (+)-enantiomers of menthol was evident
Figure 2. GC–MS traces from the reduction of ())-menthone 1 to yield
(
4
))-menthol 2 and (+)-neomenthol 3 using LiAlH , REF and MIP1.
(
Fig. 3, Table 2). The nonspecific binding to the polymer
Table 1. ())-Menthone reduction ratios
matrix is reflected in the binding to REF. The recogni-
tion of 2 by MIP1 is superior to that of its enantiomer
and its diastereoisomers.
a
Reductant
(+)-Neomenthol (%)
())-Menthol (%)
LiAlH
REF
4
32 ± 1
34 ± 3
45 ± 3
39 ± 3
321 ± 3
68 ± 1
66 ± 3
55 ± 3
61 ± 3
69 ± 3
b
MIP1
MIP2
MIP3
The enantioselective binding is concluded to arise from
the presence of template selective sites. The theoretical
c
a
b
c
Minimum of three experiments with triplicate GC–MS analysis of
each.
MIP1: 3 mmol ())-dimenthylfumarate; MIP2: 6 mmol ())-menthyl-
acrylate and MIP3: 3 mmol ())-menthyl acrylate.
LiAlH /THF
4
+
O
OH
OH
Polymer
76% reduction of ())-menthone.
8
9
10
polymer, both influence the stereochemical outcome of
the reaction. Moreover, the results imply that some gain
is achieved by coordinating the localization of template
Scheme 5. Reduction of (+)-menthone 8 by LiAlH4 yielding (+)-
menthol 9 and ())-neomenthol 10.

2434
J. Hedin-Dahlstr €o m et al. / Tetrahedron: Asymmetry 15 (2004) 2431–2436
0
0
0
0
0
0
0
0
0
0
0
.500
number of sites selective for 2 in MIP1 is 158 lmol/g
17
polymer (dry weight). The enantioselectivity demon-
strated in the batch binding experiments using MIP1
translates to 0.15 lmol/g polymer of sites with selectivity
exclusively for 2. This data provides additional evidence
in support of the presence of sites selective for the
template.
.450
.400
.350
.300
.250
.200
.150
.100
.050
.000
SEM analysis of MIP1 and REF showed that they have
similar morphologies prior to template cleavage (Fig. 4)
though, in the case of MIP1, template cleavage results in
a somewhat rougher structure. BET-surface analysis
(Table 3) indicates a relatively larger gas accessible sur-
face area in the case of the MIP1 after template cleavage,
though relatively little change to REF. This may, to some
extent, reflect an increase in surface area arising from the
presence of polymer cavities/sites left by the template.
A
B
C
D
E
Figure 3. Binding of menthol stereoisomers (5 lg/mL) to MIP1. A: ())-
menthol 2; B: (+)-menthol 9; C: (+)-neomenthol 3; D: ())-neomenthol
a
Table 3. BET surface area analyses prior and after template removal
Prior
After
10; E: average of isomer binding to REF. B=T is the ratio of bound
2
2
over total added analyte. The results are based on quadruplicate
experiments with triplicate analyses of each. Error bars represent RSD
for the calculated binding.
Polymers
BET (m /g)
Polymers
BET (m /g)
REF
MIP1
145.4
127.3
REF
MIP1
140.2
158.7
a
Performed on a Micrometrics ASAP 2400, samples were degassed at
00 ꢁC for 24 h before analysis.
1
Table 2. Menthol isomer binding in heptane
a
b
c
MIP1
B=T
RSD
3
. Conclusions
(
(
(
(
))-Menthol
+)-Menthol
0.4170.015
0.338
0.321
0.014
0.011
0.004
0.014
+)-Neomenthol
))-Neomenthol
In summary, polymers selective for ())-menthol have
been synthesized and, after derivatization with LiAlH ,
0.294
0.245
4
d
REF
used to alter the stereochemical outcome of the reduction
of menthone 1 to ())-menthol 2 and (+)-neomenthol 3 in
favour of the naturally unfavoured product. Moreover,
this study demonstrates that this covalent molecular
imprinting strategy is amenable to relatively small,
poorly functionalized organic structures, and that chiral
a
Minimum of four experiments with triplicate GC–MS analysis of
each.
b
c
B=T is the ratio of bound over total added analyte.
RSD is the relative standard deviation.
Average binding of the menthol isomers.
d
Figure 4. SEM pictures of REF (top), and MIP1 (bottom) before template removal (A and C) and after (B and D) at 7200· magnification.

J. Hedin-Dahlstr €o m et al. / Tetrahedron: Asymmetry 15 (2004) 2431–2436
2435
reductants based on such small organic compounds can
be prepared. This underscores the potential for using
the molecularly imprinted technique to produce tailor-
made reagents for stereoselective organic synthesis.
filtrated and reduced in vacuo (rotary evaporator) to
furnish a yellow oil (3.51 g). Flash column chromatog-
raphy (silica gel, heptane/ethyl acetate; 9:1) afforded a
20
colourless oil (2.90 g, 69%). ½aŠ ¼ )83.6 (c 0.97,
D
2
5
19
ꢀ1
CH
2
Cl
2
), lit. ½aŠ ¼ )85.4. IR(neat) 1721, 1195 cm ;
D
1
H NMR: d 0.75 (d, 3H), 0.9 (dd, 6H), 1.0 (m, 2H), 1.4
m, 2H), 1.65 (m, 3H), 1.85 (m, 1H), 2.0 (m, 1H), 4.75 (m,
(
1
H), 5.8 (d, J ¼ 10 Hz, 1H), 6.0 (dd, J ¼ 17, 10 Hz, 1H),
13
4
. Experimental section
6.4 (d, J ¼ 17Hz, 1H); C NMR: d 16.4, 20.7, 22.0, 23.5,
6.3, 31.4, 34.2, 40.9, 47.1, 74.3, 129.0, 130.1, 165.8. MS
(EI, 70 eV) m=z 210 (M+). Spectral properties were in
2
4
.1. General methods
19
agreement with those previously reported.
IR spectra were recorded on an Avatar 320 FT-IR
spectrometer. Solid samples were analyzed using the
diffuse reflectance mode employing KBr as dispersant.
4.3. MIP1 (nonreduced form)
1
13
H and C NMR spectra were acquired at 250 and
2.5 MHz, respectively, on a Bruker AC-250 MHz
6
A solution of styrene (120 mmol), divinylbenzene
(120 mmol) and ())-dimenthylfumarate (3 mmol) in
anhydrous methanol (7.5 mL) and chloroform (20.1 mL)
was stirred at rt. ABDV (azobis-[2,4-dimethylvaleronit-
rile]) (300 mg) was added and the mixture was sonicated
under vacuum. The resultant solution was purged with
instrument. Elemental analyses were performed by Mi-
krokemi AB (Uppsala, Sweden). Optical rotation was
measured on a Perkin–Elmer 141 polarimeter.
BET-surface analyses were performed on a Micromeritics
ASAP 2400 instrument. Samples were degassed at 100 ꢁC
for 24 h before analysis. SEM studies were carried out
using a JEOL JSM-35C Scanning electron microscope. A
Polaron Equipment Ltd. SEM Coating unit (E5100 Ser-
ies II, Cool sputter coater) was used for sample coating.
dry N at 0 ꢁC for 5 min. Polymerization was performed
2
at 50 ꢁC for 24 h. The solvents were removed and the
polymer was ground and sieved to yield particles in
the size range 50–60 lm. The polymer particles were
filtered under vacuum and dried before being stored
in a desiccator under vacuum until use. IR(KBr)
ꢀ
1
GC–MS analyses were performed using a CP-Chirasil-
Dex CB 25 m capillary column on a Shimadzu GC-17A
instrument equipped with Shimadzu QP-5000 MS
detector. GC-parameters: injection volume, 1 lL; carrier
gas, He; injector temperature, 250 ꢁC; interface temper-
ature, 200 ꢁC; column pressure, 50 psi; carrier gas flow,
1726 cm .
4.4. REF (nonreduced form)
A reference polymer was prepared using the procedure
described for MIP1, with the substitution of fumaric
acid (3 mmol) for ())-dimenthylfumarate. IR(KBr)
1
.0 mL/min; split ratio, 72; column oven temperature
program, 90 ꢁC (2 min) to 180 ꢁC, at 10 ꢁC/min.
ꢀ
1
1
750 cm .
Materials: all chemicals and reagents were purchased
from either Aldrich (Germany) or Fluka (Germany) and
were used as received unless otherwise stated. Solvents
used were purchased from Aldrich and were of HPLC
grade. Monomers containing inhibitors were distilled
under vacuum prior to use. Anhydrous THF was pre-
4.5. MIP2 and MIP3 (nonreduced forms)
The synthesis of MIP2 and MIP3 was performed as
described above for MIP1, though with the substitution
of ())-dimenthylfumarate 2 (3 mmol) with ())-menthyl
acrylate 5 (MIP2, 6.0 mmol; MIP3, 3.0 mmol).
pared by distillation from LiAlH under an inert
4
18
atmosphere (N
by distillation from Mg and I
2
). Anhydrous methanol was prepared
18
2
2
under N .
4.6. Polymer reductions
4
.2. ())-Menthyl acrylate 5
In a typical polymer reduction, LiAlH
522 mg) was carefully added to a slurry of the polymer
(MIP1, 4.50 g) in dry THF (70 mL) under N . The
2
4
(15 equiv,
Compound 5 was prepared by a modification of the
original procedure described by Lee–Ruff et al. To a
19
stirred cooled solution (0 ꢁC, ice) containing ())-menthol
solution was heated at reflux for 48 h. The reaction
mixture was carefully poured into water (800 mol) and
the polymer filtered off and washed successively with
HCl (1 M, 100 mL), water (100 mL), ethanol (95%,
100 mL) and diethyl ether (100 mL). The polymer was
then dried under vacuum overnight. FT-IR analyses
were used to determine the extent of ester reduction
(
(
3.12 g, 20 mmol) and pyridine (1.9 mL) in heptane
2
20 mL) under an atmosphere of under N was added
acryloyl chloride (2.18 g, 24 mmol) over a period of
0 min. Stirring was continued for 30 min., whereupon
3
the solution was allowed to warm to rt and stirring
continued overnight. The reaction mixture was washed
with saturated NaHCO3 (aq) (6 · 10 mL), water
ꢀ
1
(carbonyl absorption bands 1726 cm ) and acid
ꢀ
1
(
6 · 10 mL) and brine (6 · 10 mL). The combined aqueous
reduction (carbonyl absorption bands 1750 cm ).
MIP1: Anal. found: C, 90.3; H, 8.1. REF: Anal. found:
C, 88.7; H, 8.0.
phase was extracted with heptane (3 · 20 mL) and com-
4
bined with the initial organic phase, dried over Na SO ,
2

2436
J. Hedin-Dahlstr €o m et al. / Tetrahedron: Asymmetry 15 (2004) 2431–2436
4
.7. Polymer activation
References and notes
LiAlH (1 equiv per theoretical hydroxyl, 40 mg) was
4
1. Kolodiazhnyi, O. I. Tetrahedron 2003, 59, 5953–6018.
2
. (a) Che, C.-M.; Huang, J.-S. Coord. Chem. Rev. 2003, 242,
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added to a slurry of polymer (0.500 g) in dry THF
(30 mL) and the mixture was heated at reflux under N
for 24 h prior to use in subsequent reaction studies.
9
2
3
. (a) Pinalli, R.; Suman, M.; Dalcanale, E. Eur. J. Org.
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4.8. Reaction assays––representative example of ())-
menthone reduction using polymers
4
. (a) Wentworth, P.; Janda, K. D. Cell Biochem. Biophys.
2
001, 35, 63–87; (b) Hasserodt, J. Synlett. 1999, 12, 2007–
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617.
(
))-Menthone 2 (1 equiv per theoretical hydroxyl,
7.6 lL) was added to the activated polymer slurry
0.500 g/30 mL) and the mixture was heated at reflux for
4 h. The reaction mixture was poured into water
50 mL) and HCl(aq) (1 M, 5 mL) was added. The
reaction mixture was extracted with CH Cl
(3 · 20 mL),
the combined organic phases were washed with water
30 mL) and brine (30 mL). The polymer was collected
by vacuum filtration and washed extensively with
CH Cl . The combined organic phases were dried over
1
(
2
(
5
6
. Breslow, R.; Dong, S. D. Chem. Rev. 1998, 98, 1997–2011.
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9, 2025–2057.
7
. Molecularly Imprinted Polymers: Man Made Mimics of
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2
2
(
8
. Molecularly Imprinted Materials––Sensors and Other
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2
2
ꢀ
MgSO , filtered and concentrated to yield a mixture of
4
9. (a) Bystr o€ m, S. E.; B o€ rje, A.; Akermark, B. J. Am. Chem.
Soc. 1993, 115, 2081–2083; (b) Alexander, C.; Smith, C.
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the diastereomeric products (yield 85%). GC–MS anal-
ysis revealed >99% consumption of starting material in
all cases. Assays were performed in triplicate on each of
at least four separate batches of polymer. Solutions of
commercial ())-menthone, (+)-neomenthol, ())-neo-
menthol, (+)-menthol and ())-menthol (1 mg/mL) were
used as standards.
1
999, 121, 6640–6651.
1
0. (a) Mosbach, K.; Yu, Y.; Andersch, J.; Ye, L. J. Am.
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1
1. Milojkovic, S. S.; Kostoski, D.; Comor, J. J.; Nedeljkovic,
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4
.9. Representative binding experiments
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7
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The menthol isomer (0.5 mL, 10 lg/mL) was added to
.5 mL of polymer slurry (33.3 mg/mL, 2.2 mL) and
incubated at rt in glass vials for 19 h. Centrifugation at
0,000 rcf for 6 min was followed by removal of 700 lL
of the supernatant for GC–MS analysis. All experiments
were performed in quadruplicate.
1
1
1
0
5
4. McConkey, M. E.; Gershenzon, J.; Croteau, R. B. Plant
Physiol. 2000, 122, 215–223.
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1
1
987, 5, 439–442; (b) Divakar, S.; Narayan, M. S.; Shaw,
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Acknowledgements
1
1
6. Singh, S.; Dev, S. Tetrahedron 1993, 49, 10959–10964.
7. Based on 75% ± 5% template removal according to FT-IR
analysis.
We thank the Swedish Research Council (V.R.), the
Swedish Knowledge Foundation (K.K.S.), Sparbanken
Kronan Foundation, Graninge Foundation and the
University of Kalmar for financial support, and
Dr. Jesper G. Karlsson and Dr. Johan Svenson (both
Kalmar) for assistance with the SEM studies.
1
8. Perrin, D. D.; Armaregeo, W. L. F. Purification of
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