Enantioselectivity, swelling and stability of 4-hydroxyprolinol containing acrylic polymer beads in the asymmetric reduction of ketones

Article abstract of DOI:10.1016/j.tetasy.2011.12.001

A new 4-hydroxy-α,α-diphenyl-l-prolinol containing polymethacrylate, prepared without chromatography by a large scale adaptable synthesis, has been evaluated as a catalyst in the asymmetric reduction of 1-arylethanones. Using 1-(4-bromophenyl)ethanone as the model substance, the reduction was tested with various borane sources and solvents. The best swellings of the polymer and reactivity were observed in THF using N,N-diethylaniline borane complex as the hydride source. The selectivity in the reduction of 1-(4-bromophenyl)ethanone was found to depend on the substrate concentration and catalyst loading. Using the best conditions identified, a series of 1-arylethanones was reduced to their corresponding enantioenriched secondary alcohols. High rates and ee-values were obtained in the reduction of acetophenones containing electron withdrawing groups in the aromatic ring, whereas a moderate selectivity was the result for products containing electron donating aromatic substituents. Upon recovery of the polymer beads, it was found that vacuum drying led to extensive rupturing, while the bead structure was intact if washed with methanol and air dried at atmospheric pressure. Repeated use of the polymer catalyst gave the product alcohol with a lower 90% ee. Elemental analysis showed this to be due to the loss of the chiral prolinol unit.

Full text of DOI:10.1016/j.tetasy.2011.12.001

Tetrahedron: Asymmetry 22 (2011) 2172–2178
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselectivity, swelling and stability of 4-hydroxyprolinol containing
acrylic polymer beads in the asymmetric reduction of ketones
Thor H. Krane Thvedt a,b, Tor Erik Kristensen c,d, Eirik Sundby b, Tore Hansen d, Bård Helge Hoff a,
⇑
a Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO7491 Trondheim, Norway
b Sør-Trøndelag University College, E.C. Dahls Gate 2, NO-7004 Trondheim, Norway
c Norwegian Defence Research Establishment (FFI), PO Box 25, NO-2027 Kjeller, Norway
d Department of Chemistry, University of Oslo, PO Box 1033, Blindern, NO-0315 Oslo, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
A new 4-hydroxy-
a
,
a
-diphenyl-
L
-prolinol containing polymethacrylate, prepared without chromatogra-
Received 23 November 2011
Accepted 6 December 2011
Available online 7 January 2012
phy by a large scale adaptable synthesis, has been evaluated as a catalyst in the asymmetric reduction of
1-arylethanones. Using 1-(4-bromophenyl)ethanone as the model substance, the reduction was tested
with various borane sources and solvents. The best swellings of the polymer and reactivity were observed
in THF using N,N-diethylaniline borane complex as the hydride source. The selectivity in the reduction of
1-(4-bromophenyl)ethanone was found to depend on the substrate concentration and catalyst loading.
Using the best conditions identified, a series of 1-arylethanones was reduced to their corresponding
enantioenriched secondary alcohols. High rates and ee-values were obtained in the reduction of acetoph-
enones containing electron withdrawing groups in the aromatic ring, whereas a moderate selectivity was
the result for products containing electron donating aromatic substituents. Upon recovery of the polymer
beads, it was found that vacuum drying led to extensive rupturing, while the bead structure was intact if
washed with methanol and air dried at atmospheric pressure. Repeated use of the polymer catalyst gave
the product alcohol with a lower 90% ee. Elemental analysis showed this to be due to the loss of the chiral
prolinol unit.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
catalysts, and the simplest way of introducing diversity is by vary-
ing the size and the electronic properties of the R-group in struc-
The
a
,a-diphenylprolinol skeleton has been used extensively in
ture
I
(Fig. 1).13–15 Also, some C2 and C3 symmetric
asymmetric catalysis,1–3 with one of the more important transfor-
mations being the asymmetric reduction of prochiral ketones to
their corresponding enantioenriched secondary alcohols.4 The
homogenous Corey–Bakshi–Shibata reagents derived from diphe-
nylprolinol (Ia–b and analogues, Fig. 1),5,6 have previously been
used for the reduction of a number of ketones, giving the corre-
sponding alcohols in high enantiomeric excess (ee).7–11 These
catalysts can be pre-made or formed in situ from the diphenylpro-
linol. The selectivity can be tuned by the choice of solvent, reaction
temperature,12,13 the borane source, catalyst loading and slow
addition protocols. The effect on ee of changing these parameters
might be related not only to a stabilising effect on the favoured
transition state, but also to a disfavouring of the non catalysed bor-
ane reduction of the ketone, leading to a racemic product. An alter-
native strategy to increase the selectivity is to synthesise new
diphenylprolinol based systems have been evaluated in asymmet-
ric borane reductions.16–21
O
O
O
O
N
R
O
B
O
O
Ph
Ph
N
H
II
Ia: R= H
Ib: R= Me
HO
Ph
Ph
⇑
Corresponding author. Tel.: +47 7359 0877; fax: +47 7355 4256.
E-mail
addresses:
bhoff@chem.ntnu.no,
Bard.Helge.Hoff@chem.ntnu.no
Figure 1. Structure of prolinol based catalyst Ia–b, and the polymethacrylate
supported catalyst II.
(B.H. Hoff).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.12.001

T. H. Krane Thvedt et al. / Tetrahedron: Asymmetry 22 (2011) 2172–2178
2173
The challenges with low molecular weight catalysts include
separation from the product and reuse of the catalyst. These short-
comings have been addressed using fluorous tags,22–25 magneti-
cally recoverable26 or ionic liquid based catalysts.27 Alternatively,
the chiral unit can be covalently immobilised on an insoluble
carrier matrix.28 Diarylprolinol catalysts have been made by
anchoring to polystyrene via the R-group on the boron atom
(Fig. 1),29 the aryl part,30–32 via sulfonamides to the nitrogen,33,34
and to polyethylene.35 Challenges with such modified or immobi-
lised systems are usually related to the lower activity, and main-
taining a high selectivity upon repeated use.
Recently, a new method for preparing polymer linked 4-hydro-
xy-a,a-diphenyl-L
-prolinol catalysts was developed.36,37 Since this
protocol is based on a ‘bottom up’ approach without any chromato-
graphic purifications, the procedure is well suited for large scale
synthesis.28 In order to investigate the scope of the new and readily
obtainable polymethacrylate, II (Fig. 1), we herein report its use in
the asymmetric borane reduction of ketones.
Figure 2. Microscopy image of the methacrylate polymer II.
lyst in THF with borane dimethylsulfide complex as the hydride
source (Scheme 2).
In contrast to homogenous oxazaborolidine catalysts such as I,
polymer based catalysis is most conveniently performed using an
amino alcohol as the pre-catalyst. Polymer II was allowed to react
with the borane dimethylsulfide complex for 30 min to produce
the active catalyst, prior to the addition of substrate ketone. In
refluxing THF, this gave a variable 60–90% ee. Lowering the reac-
tion temperature and portion-wise additions of the ketone and
the reducing agent did not improve the situation. By allowing cat-
alyst II to stir with dimethylsulfide borane complex in THF over-
night, analysis of the reaction mixture by 1H NMR spectroscopy
indicated decomposition of the polymer as the reason for the var-
iable enantioselectivity. Stability testing of II as described above
revealed that the use of NaBH4 in combination with BF3ꢀdiethyleth-
erate also caused decomposition. While the polymer II appeared
stable to the NaBH4/trimethylsilyl chloride system, it failed to give
conversion of 1a to 5a in test reactions. On the other hand using
the N,N-diethylaniline borane complex, polymer decomposition
was not detected by 1H NMR, and the product 5a could be obtained
with reproducible ee-values. Further testing using 1a and the N,N-
diethylaniline borane complex, revealed that the reduction could
be performed at 30 °C and only required one hour for full
conversion.
2. Results and discussion
Polymethacrylate II was prepared by a suspension co-polymerisa-
tion of O-(2-methacryloyloxy-ethylsuccinoyl)-trans-4-hydroxy-
a,a-
diphenyl- -prolinol, methyl methacrylate and ethyleneglycol dimeth-
L
acrylate (Scheme 1). 2,20-Azobis(2-methylbutyronitrile) (AMBN) was
used as the initiator, polyvinyl alcohol as a suspension stabiliser, while
KI inhibits the polymerisation in the aqueous phase.36 The acrylic poly-
mer was isolated by filtration, and the appearance of the fresh catalyst
is shown in Figure 2.
By having a low degree of cross binder, as for II, a microporous
polymer bead is formed. These are rather compact in dry form with
pores of insufficient size to allow for efficient mass transfer. How-
ever, when suspended in a suitable solvent, the polymer can swell,
allowing for entry of the reagents. Good swelling of the methacry-
late polymer, II, was observed in THF (Fig. 3) and dichloromethane
(not shown). The swelling was complete within 1.5–2 h depending
on the bead size.
The use of other solvents, such as 2-methyltetrahydrofurane,
acetonitrile, toluene or diethyl ether gave a low degree of swelling
and was therefore not suited as the reaction medium. Poor swell-
ing was also seen in MeOH and water.
We then investigated how a change in the catalyst loading and
substrate concentration affected the selectivity (Table 1). The
experiments in entries 1–6 represent a two-level factorial design
with catalyst amount and substrate concentration as variables.
Since the selectivity in asymmetric reductions often depends on
the electronic properties of the substrate ketone,12,38,39 and the
catalyst loading, the initial investigations were performed with
1-(4-bromophenyl)ethanone 1a as substrate, using 30 mol % cata-
O
O
O
O
O
O
O
O
O
O
O
AMBN
O
Toluene/water
Polyvinyl alcohol
OMe
O
O
O
O
O
K2CO3/KI
HN
HN
Ph
HO Ph
II
Ph
HO
Ph
Scheme 1. Synthesis of the methacrylate polymer II.

2174
T. H. Krane Thvedt et al. / Tetrahedron: Asymmetry 22 (2011) 2172–2178
Figure 3. Microscopy image of the methacrylate polymer II swelled in THF for 30 min (A) and 60 min (B) at room temperature.
A contour plot on how the ee varied with substrate concentration
and catalyst loading is shown in Figure 4.
OH
O
Catalyst II
Free borane and diborane are present in equilibrium concentra-
tions depending on both temperature and initial borane amount.7
A plausible explanation for the effect of substrate concentration
on the ee is that at higher solvent volumes more free borane will
be available, thus resulting in a higher rate for the non catalysed
pathway.
Reducing agent
THF
Br
Br
5a
1a
Scheme 2. Asymmetric borane reduction of 1a using catalyst II.
To investigate the substrate scope of the reaction, various ke-
tones were reduced on a 0.25 mmol scale using 6 mol % of catalyst
II (Scheme 3). The addition of the substrate was carried out in one
portion. The reactions were performed in triplicates to reveal the
reproducibility and possibly detect shortcomings in the procedure.
The mean ee-value and standard deviation are shown in Table 2.
For all substrates, except for 1l (Table 2, entry 12), full conver-
sion was obtained within 1 h reaction time at 30 °C, indicating a
very active catalyst. The highest selectivity was obtained in the
reduction of ketones being moderately activated by electron with-
drawing groups, thus (R)-5a and (R)-5g–i were obtained with ee-
values in the range 95–99%. On the other hand, acetophenones
containing more electron donating substituents gave mediocre
ee-values (77.7–90.7%). In retrospect, this might be due to the low-
er intrinsic reactivity of these ketones in relation to the stability of
the catalyst.
Table 1
Effect of solvent amount and polymer catalyst II loading on selectivity in the
reduction of 1a
Entry Substrate concn (mM) Cat. loadinga (mol %) Conv.b (%) eeb (%)
1
2
3
4
5
6
7
8
9
50
125
50
31
125
31
125
62.5
31
16
18
6
18
6
30
30
6
6
6
6
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
95.0
96.0
95.0
90.0
97.0
96.0
97.0
95.0
93.0
90.0
10
a
Based on mole of nitrogen/weight unit determined by elemental analysis.
Measured by GC.
b
For the ketones containing a-fluorine atoms, the ee-values de-
pended on the number of fluorine atoms. 2-Fluor-1-phenyletha-
none 2c (entry 13) was reduced in 94% ee. For the sake of
comparison, the use of Me-CBS Ib at ꢁ20 °C, gave 6c in 96.5%
ee.9 Reduction of the 2,2,2-trifluoroacetophenones 4a and 4c under
identical conditions gave the racemic products 8a and 8c (entries
15 and 16). Recently, Me-CBS Ib has been used in the reduction
of 4c to give 8c in 1.7% ee.15 The lack of selectivity in the reduction
of 4c was explained by the low coordinating ability of the carbonyl
oxygen to the Lewis acid centre, and the high reactivity for the
non-catalysed reduction by borane.15
Scale-up of the reductions of 1a and 1g–i (2.5 mmol scale) using
6 mol % of catalyst, led to the product alcohols being formed in 92–
99% ee. While the ee-values of products 5a and 5i were main-
tained, a slight drop in selectivity was observed for the products
5g–h. A challenge with reactions using polymer supported cata-
lysts could be that the product of the reaction is trapped within
the matrix. In the isolation of 5a, four washes were required to re-
cover the product from the polymer matrix.
30
ee
<
90.0
91.5
93.0
94.5
96.0
96.0
90.0
91.5
93.0
94.5
–
–
–
–
>
25
20
15
10
20
40
60
80
100
120
Substrate conc. (mM)
Figure 4. Enantiomeric excess (ee, %) as a function of substrate concentration and
mol % of catalyst.
When the reuse of the methacrylate polymer II was tested with
1a as a substrate, this gave 5a in 90% ee. Microscopy analysis of the
recovered II revealed an extensive rupturing of the beads (Fig. 5).
No clear indication for loss of the carbonyl function was seen using
IR-spectroscopy.
The ee-values increased at higher catalyst loading, but also
when applying less solvent (Table 1, entry 2). The effect of sub-
strate concentration was then investigated further (entries 7–10),
confirming that less solvent was beneficial in terms of selectivity.
Our investigation revealed that the rupturing of the polymer
bead was caused by vacuum drying prior to reuse. This could be

T. H. Krane Thvedt et al. / Tetrahedron: Asymmetry 22 (2011) 2172–2178
2175
R1:
O
OH
II (6 mol %)
OH
O
p-CF3 g
p-CN h
p-NO2 i
o-Me j
p-Br a
p-MeO b
H c
R
R
N,N-diethylaniline-BH3
THF, 30 °C, 1 h.
CH3
CH3
p-F d
p-Me e
p-t-Bu f
R1
R1
m-Me k
1-4
5-8
5l
1l
R= CH3 1, 5, CH2F 2, 6, CHF2 3, 7, CF3 4, 8.
Scheme 3. Substrates investigated in reduction using II as catalyst.
Table 2
the chiral prolinol unit. The stability problem excludes the reuse
of this methacrylate polymer in borane reductions, and will direct
work towards a further generation of such catalysts. Also, the pos-
sible use of II as a ligand in the metal catalysed asymmetric trans-
fer hydrogenation with 2-propanol as hydrogen donor will be the
subject of continued work.
Asymmetric reduction of 1a–l and 2c, 3c, 4a, and 4c in 0.25 mmol scale using catalyst
II (6 mol %) in THF with N,N-diethylaniline borane complex (1 mol equiv)
Entry Compd R
R1
Conv. %
(1 h)
ee
(%)
SDa Configuration
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
2c
3c
4a
4c
CH3 p-Br
CH3 p-OMe
CH3 H
CH3 p-F
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
ꢂ50
>99
>99
>99
>99
97.0 0.0 (R)
77.7 1.2 (R)
87.3 1.2 (R)
89.3 0.6 (R)
81.0 0.0 (R)
89.0 1.0 (R)
95.3 0.6 (R)
98.3 1.2 (R)
99.0 0.0 (R)
86.7 0.6 (R)
90.7 0.6 (R)
78.7 1.5 (R)
94.3 1.2 (S)
74.0 0.0 (S)
0.0 0.0 rac
0.0 0.0 rac
2.1. Comparison of catalyst II with other prolinol systems
CH3 p-Me
CH3 p-t-Bu
CH3 p-CF3
CH3 p-CN
CH3 p-NO2
CH3 o-Me
CH3 m-Me
To evaluate the usefulness of 4-hydroxy-a,a-diphenyl-L-prolin-
ol as a structural element in catalysts for borane reduction, a liter-
ature review was undertaken. The structures of the most
interesting catalysts identified are shown in Figure 6 and the selec-
tivities obtained are compiled in Table 3. In a few cases (1f, 1k and
4a) diphenylprolinol catalysed borane reductions have previously
not been performed.
b
CH3
CH2F H
CHF2
CF3 p-Br
CF3
H
Catalyst Ia has been used with success, but since it is air and
moisture sensitive, other derivatives are more attractive.5 Me-
CBS Ib reduces acetophenones in high ee.7,44 However, when using
alternative hydride sources, low catalyst loading or ambient tem-
perature the selectivity is not always excellent.40,42 The use of
the phenyl analogue Ic seems to have advantages in the reduction
of 1-(4-nitrophenyl)ethanone 1i,12 while the derivatives Id–e are
good catalysts for the preparation of the trifluoroalcohol 8c. Of
all the bi- and tridentate catalysts prepared and tested,16–21 cata-
lyst IV appears to be the most efficient. Catalyst IV16 performs
especially well in the reduction of 2,2,2-trifluoro-1-phenyletha-
none 4c and 1-(3,5-dinitrophenyl)ethanone (95% ee, data not
shown). The isolation and reuse of IV were carried out by crystal-
lisation with a 70% recovery. The bidentate catalyst III used in
10 mol % loading gave a high 97% ee for the reduction of 1-(4-
bromophenyl)ethanone 1a and 1-(4-fluorophenyl)ethanone 1d.
By anchoring the prolinol unit via a sulfonamide linker to poly-
styrene, a recyclable catalyst, Va, was developed. Using a catalyst
loading of 25 mol %, 84–96% ee was obtained under reflux condi-
tions.33,34 For the sake of comparison, two other sulfonamides,
Vb–c are included.27,33 Immobilisation of the chiral prolinol by
attachment via the aryl part also seems to be a viable strategy. Cat-
alyst VI,35 containing a polyethylene backbone was tested at 45 °C
H
The reactions were performed at 30 °C for 1 h.
a
Standard deviation for three parallel runs.
1-(Naphthalen-1-yl)ethanone see Scheme 3.
b
avoided if the polymer was dried at atmospheric pressure and
especially if it was de-swelled with methanol prior to drying.
A stability test of polymer II was performed with N,N-diethylan-
iline borane complex in THF for 24 h. When the recovered beads
were dried under atmospheric pressure, they appeared intact as
judged from IR and microscopy. We were also unable to detect
diphenylprolinol fragments by 1H NMR in the concentrated reac-
tion mixture or in the washes. Additional reuse experiments of cat-
alyst II with 1a as the substrate (1 h reaction) did not give the same
high selectivity as in the initial run. Also, applying different wash-
ing protocols including repeated THF and methanol washes had no
apparent effect on the selectivity.
Finally, elemental analysis of the recovered beads revealed a
44% loss of nitrogen content after 24 h. Therefore, it can be con-
cluded that polymer II is reductively cleaved by borane liberating
Figure 5. (A) Ruptured recovered polymer after vacuum drying, (B) Ruptured recovered polymer compared with fresh catalyst.

2176
T. H. Krane Thvedt et al. / Tetrahedron: Asymmetry 22 (2011) 2172–2178
O
Ph
Ph
O
O
O
OH
N
O
P
O
S
O
S
O
O
OH
Ph
Ph
N
H
-
N
N
BF4
N
N
N
N
R
O
O
N
O
O
N
B
+
HO
HO
O
N
H
HO
N
Ph
Ph
Ph
Ph
Ph
Ph
Ph
OH
HO
Ph
Ph
Ph
Ph
Ph
HO
Ph
Ia: R= H
II
III
IV
Va
Vb
Ib: R= Me
Ic: R= Ph
Ph
Id: R= 2, 4, 6-F3-C6H2
Ie: R= bicyclononane
H
N
H
N
H
N
H
N
O
S
HO
HO
HO
HO
C6F3
N
O
O
C8F17
H3C
C6F13
IX
HO
Ph
Ph
3
C8F17
VI
VII
VIII
Vc
Figure 6. Different prolinol based catalysts.
Table 3
Comparison of selectivities for the use of CBS catalysts I–IX
Compd
R
R1
Selectivity in borane reduction (ee, %)
Ib (100 mol %)
Ib–e
II (6 mol %)
III–IV
Va–c
VI–VII
VIII–IX
1a
1b
1c
1d
CH3
CH3
CH3
CH3
p-Br
p-OMe
H
99.0a
97.0 bc
98.0 cd
95.0 bc
98.0 cd
95.0 bc
98.0 be
96.0 cd
97.0
97.0 IIIk
95.0 IVl
93.0 IIIk
93.0 IVl
96.0 IIIk
95.0 IVl
97.0 IIIk
95.0 IVl
90.0 IIIk
—
96.0 am
92.0 cn
84.0 am
82.0 cn
95.5 am
88.0 cn
75.0 bo
91.0 cn
—
—
—
99.5a
99.0a
78.0
87.5
89.5
—
91.0 VIIIr
89.0 IXs
95.0 VIIIt
93.0 IXs
95.0 VIp
97.0 VIIq
p-F
>99.5a
1e
1g
1h
1i
CH3
CH3
CH3
CH3
p-Me
p-CF3
p-CN
p-NO2
>99.5a
98.5a
98.0a
98.5a
94.0 be
—
81.0
95.5
98.5
99.0
96.0 VIp
—
—
—
92.0 IXs
86.0 IXs
—
—
—
94.0 bf
85.0 bg
99.0 cd
—
—
91.0 IIIk
95.0 IVl
—
96.5 am
90.0 cn
91.0 bo
—
—
1j
1l
CH3
CH3
o-Me
Naphthyl
—
—
86.5
78.5
—
—
—
96.0 bh
99.0 ei
—
94.0 IIIk
61.0 VIIq
2c
3c
4c
CH2F
CHF2
CF3
H
H
H
96.5b
—
—
94.5
74.0
—
—
—
—
—
—
—
—
76.5 IXs
90.0 dj
93.0 ei
0.0
95.0 IVl
—
—
<1 IXs
The ee-values have been rounded to the nearest 0.5-value.
k
Catalyst. III (10 mol %), hexane, BH3–THF, 50 °C.17
Catalyst IV (5 mol %), THF, BH3–SMe2, room temperature.16
Catalyst Va (25 mol %), THF, NaBH4/Me3SiCl, reflux.33,34
Catalyst Vc (5 mol %), THF, BH3–SMe2, reflux.21
Catalyst Vb (15 mol %), toluene, BH3–SMe2, reflux.27
Catalyst VI (10 mol %), THF, BH3–SMe2, 45 °C.35
Catalyst VII (30 mol %), THF, BH3–SMe2, 22 °C.32
Catalyst VIII (10 mol %), THF, BH3–THF, rt.23
a
Catalyst Ib (100 mol %), CH2Cl2, ꢁ20 °C.7
l
m
n
o
p
q
r
Catalyst Ib (100 mol %), dimethoxyethane, ꢁ20 °C.9
b
c
Catalyst Ib (5 mol %), BF3–OEt2/LiH.40
Catalyst Ic (10 mol %), toluene, BH3–SMe2, 25 °C.12
d
Catalyst Ib (10 mol %), THF, BH3–SMe2, 45 °C.35
e
f
Catalyst Ib (5 mol %), THF, BH3–SMe2, 25 °C.41
Catalyst Ib (2 mol %), THF, BH3–THF, room temp.42
g
Catalyst Ib (10 mol %), toluene, N,N-diethylaniline–BH3, 23 °C.43
h
s
Catalyst IX (10 mol %), toluene, B(OMe)3, BH3–THF, rt.22
Catalyst VIII (10 mol %), THF, B(OMe)3, BH3–SMe2, rt.24
i
Catalyst Ie (10 mol %), THF, BH3–THF, 0 °C.14
t
Catalyst Id (10 mol %), THF, BH3–SMe2, 40 °C.15
j
using 10 mol % of catalyst. It was possible to reuse VI, but the selec-
tivity in the second cycle of reduction dropped to 78% ee. Other
examples include catalyst VII,32 with a polystyrene backbone. The
reductions were performed at room temperature for 18 h using
30 mol % catalyst. The selectivity was maintained over eight cycles
with a 3% loss of catalyst per run. Other structurally related polymer
catalysts have failed to give enantioselective processes.31,45
method is that the exotic HFE-7500 solvent has to be used. Cat-
alyst IX,22 with a straight chain fluorous tag, was tested in
refluxing toluene (10 mol %). The selectivites were slightly lower
than in the case of VIII. Catalyst IX was recovered in 32–84%
yield. In the reduction of 1c the ee-value went from 93% to
37% in the second cycle of use, although the structure and the
enantiomeric purity of IX were maintained.
The fluorous-tag type proline catalyst VIII was used at room
temperature (10 mol % catalyst) in both THF23 and hydrofluoroe-
ther HFE-7500.24 In the latter solvent, VIII could be recovered
by extraction (94% recovery/cycle). A drop in ee from 94% to
88% was observed over eight cycles.24 The drawback of the
The methacrylate based catalyst II presented herein, has the
benefit of short reaction time compared to the other polymer
bonded catalysts. This suggests that the introduction of a linker
at the 4-position of the prolinol is a viable strategy. The highest
utility of II is in the reduction of acetophenones having electron

T. H. Krane Thvedt et al. / Tetrahedron: Asymmetry 22 (2011) 2172–2178
2177
withdrawing substituents on the aromatic ring, where II compares
favourably with all other catalysts. In its present form, the use of
catalyst II in comparison with the low molecular weight catalysts
has the benefit of easier product separation.
ethanol 7c and 1-(4-bromophenyl)-2,2,2-trifluoroethanol 8a were
analysed using HPLC and a Chiracel OD column (0.46 cm ꢃ 25 cm),
mobile phase: hexane/2-propanol (95:5), flow rate 1.0 mL/min,
(S)-7c: 11.7 min, (R)-7c: 14.0 min, (R)-8a: 8.3 min, (S)-8a: 10.6 min.
The absolute configurations were determined as follows: (S)-1-
aryl-2-ethanols 5a–d and 5g–i were prepared by enzyme catalysed
resolution using lipase B from Candida antarctica and vinyl acetate
as the acyl donor. 1H NMR and the specific rotation corresponded
with those reported previously. The absolute configuration of
5e–f and 5j–k were based on the known eluting order of the
compounds in the given column.48,49 The stereochemistry of
(R)-1-(naphthalen-1-yl)ethanol 5l was determined using a refer-
ence standard from Aldrich, the stereochemistries of 6c, 7c and
8c were determined using reference material from asymmetric
transfer hydrogenation, while the stereochemistry of 8a was deter-
mined by the reduction of 4a using Geotrichum candidum acetone
powder as described by Nakamura et al.50
3. Conclusion
A new polymer supported 4-hydroxy-a,a-diphenyl-L-prolinol
catalyst has been prepared by a large scale adaptable suspension
co-polymerisation. The microporous polymer beads were investi-
gated in the asymmetric reduction of 1-arylethanones. The catalyst
showed good swelling behaviour and high activity in THF at room
temperature. Moderate to excellent selectivities were obtained in
the reduction of a series of 1-arylethanones using N,N-diethylani-
line borane complex as the reducing agent. The highest ee-values
were obtained with ketones having electron withdrawing substit-
uents on the aromatic ring, giving the corresponding secondary
alcohols in a 95–99% ee. These selectivities compare favourably
with other diphenylprolinol type catalysts. The highly activated
trifluoromethyl ketones gave racemic products. Reuse experiments
identified a loss in selectivity, due to reductive cleavage liberating
the prolinol unit.
4.3. Methacrylate polymer II
O-(2-Methacryloyloxyethylsuccinoyl)-trans-4-hydroxy-
a,a-di-
phenyl-
L
-prolinol hydrochloride36 (5.89 g, 11.4 mmol) was sus-
pended in CH2Cl2 (40 mL) and aqueous K2CO3 (10%, 40 mL) was
added. The mixture was stirred vigorously for 5 min and separated.
The aqueous phase was extracted with CH2Cl2 (40 mL) and the
combined organic phases were dried over anhydrous MgSO4, fil-
tered and evaporated in vacuo to give a nearly colourless oil of
4. Experimental
4.1. Chemicals
O-(2-methacryloyloxyethylsuccinoyl)-trans-4-hydroxy-
a,a-diphe-
O-(2-Methacryloyloxyethylsuccinoyl)-trans-4-hydroxy-
a,a-di-
nyl- -prolinol in quantitative yield.
L
phenyl- -prolinol hydrochloride was prepared as described previ-
L
A three-necked 250 mL round bottomed flask was charged with
ously.36 The acetophenones 1a–k, 1-acetonaphthone 1l, 2,2,2-trifl-
uoro-1-phenylethanone 4c, borane diethylaniline complex, borane
dimethylsulfide complex, (R)-1-(naphthalen-1-yl)ethanol 5l, methyl
methacrylate, ethyleneglycol dimethacrylate, 2,20-azobis(2-meth-
ylbutyronitrile), polyvinyl alcohol and potassium iodide were pur-
chased from Aldrich. 1-(4-Bromophenyl)-2,2,2-trifluoroethanone
4a was from Apollo, 2,2-difluoro-1-phenylethanone 3c from Alfa
Aesar, whereas 2-fluoro-1-phenylethanone 2c was synthesised
as described previously.46,47
5
an egg-shaped magnetic stirring bar (1½ ꢃ /8 in), potassium io-
dide (57 mg, 0.34 mmol), K2CO3 (193 mg, 1.40 mmol) and
0.5 wt % aqueous polyvinyl alcohol (Mw ꢂ205,000 and 88% hydro-
lysis, 150 mL). A mixture of all the O-(2-methacryloyloxy-ethyl-
succinoyl)-trans-4-hydroxy-a,a-diphenyl-L-prolinol together with
methyl methacrylate (16.05 g, 160 mmol), ethyleneglycol dimeth-
acrylate (0.69 g, 3.50 mmol), toluene (20 mL) and 2,20-azobis(2-
methylbutyronitrile) (218 mg, 1.13 mmol) was prepared and
added carefully to the aqueous solution under stirring, and the sys-
tem was flushed with N2 for 5 min. The suspension was polymer-
ized under N2 in a heating mantle at 80 °C for 19 h at a constant
stirring rate of 700 rpm. The suspension was allowed to cool and
then poured into a beaker containing MeOH (300 mL). The beads
were allowed to settle by gravity, and the supernatant was dec-
anted off. The process was repeated once more after the addition
of MeOH (300 mL). The beads were then vacuum-filtered and
washed with water (2000 mL), MeOH (100 mL), THF (300 mL)
and finally MeOH (300 mL). Drying at room temperature for 23 h
gave colourless polymer beads (20.21 g). CHN-Analysis: N, 0.88;
C, 60.53; H, 7.66. (prolinol loading: 0.62 mmol/g of N). IR (neat,
cmꢁ1): 3801, 3734, 3648, 2952, 1718, 1240, 1143.
4.2. Analyses
NMR spectra were recorded with Bruker Avance DPX
400 MHz. 1H chemical shifts are in ppm rel. to TMS. Coupling
constants are in Hertz. HPLC was performed using an Agilent
1100 series system with a DAD detector. GC was performed
using a Varian 3380. IR was performed with Thermo Nicolet
Nexus FT-IR spectrophotometer. Microscopy was performed with
a Carl Zeiss Axio Imager.A1 with an AxioCam MRc5 camera. To-
tal carbon, hydrogen and nitrogen were determined by a Carlo
Erba EA1110 elemental analyser.
The enantiomeric excess of 5a–l, 6c and 8c were determined
using GC and a CP-Chirasil-Dex CB column, column pressure:
10 psi, split flow: 30 mL/min, isothermal programs, 5a (145 °C):
(R)-5a: 10.7 min, (S)-5a: 12.0 min, 5b (90 °C): (R)-5b: 22.8 min,
(S)-5b: 25.2.0 min, 5c (100 °C): (R)-5c: 18.3 min, (S)-5c: 21.2 min,
5d (125 °C): (R)-5d: 6.3 min, (S)-5d: 7.1 min, 5e (120 °C): (R)-5e:
9.3 min, (S)-5e: 10.7 min, 5f (135 °C): (R)-5f: 14.8 min, (S)-5f:
15.5 min, 5g (115 °C): (R)-5g: 13.1 min, (S)-5g: 16.5 min, 5h
(160 °C): (R)-5h: 10.7 min, (S)-5h: 12.3 min, 5i (160 °C): (R)-5i:
18.7 min, (S)-5i: 21.4 min, 5j (140 °C): (R)-5j: 5.3 min, (S)-5j:
6.1 min, 5k (130 °C): (R)-5k: 6.6 min, (S)-5k: 7.1 min, 5l (160 °C):
(R)-5l: 12.1 min, (S)-5l: 13.0 min, 5l (160 °C): (R)-5l: 12.1 min, (S)-
5l: 13.0 min, 6c (115 °C): (S)-6c: 14.5 min, (R)-6c: 16.4 min, 8c
(115 °C): (S)-8c: 17.0 min, (R)-8c: 18.3 min. 2,2-Difluoro-1-phenyl-
4.4. Asymmetric reduction
4.4.1. Small scale reactions
Catalyst II (25 mg, 0.0155 mmol of N) was weighed out in a 4 mL
tube with a screw cap and septum, and the atmosphere was ex-
changed with argon. Dry THF (1 mL) and the reduction agent
(0.25 mmol) were added using a syringe, and the mixture was sha-
ken at 30 °C for 30 min. Then, the ketone (0.25 mmol) dissolved in
dry THF (1 mL) was added to the reaction flask using a syringe and
the mixture was shaken for another 60 min at 30 °C. For analysis, a
sample (0.5 mL) was withdrawn, diluted with CH2Cl2, washed with
aqueous H2SO4 (0.5 M, 3 ꢃ 0.5 mL) and water (0.5 mL) and dried.
The conversion and ee were analysed by GC or HPLC.

2178
T. H. Krane Thvedt et al. / Tetrahedron: Asymmetry 22 (2011) 2172–2178
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Catalyst II (245 mg, 0.0155 mmol of N) was weighed out in a 30 mL
tube with a screw cap and septum, and the atmosphere was exchanged
with argon. Dry THF (10 mL) and N,N-diethylaniline–BH3 complex
(2.5 mmol, 450 lL) were added using a syringe, and the mixture was
shaken at 30 °C for 30 min. 1-(4-Bromophenyl)ethanone 1a (2.5 mmol,
498 mg) dissolved in dry THF (10 mL) was added to the reaction flask in
one portion. The reaction was agitated for another 60 min at 30 °C. The
solution was filtered, and the filter residue containing the catalyst was
washed with THF (5 ꢃ 3 mL). The filtrate was concentrated, diluted
with CH2Cl2 (30 mL), washed with aqueous H2SO4 (0.5 M, 3 ꢃ 20 mL)
and then water (20 mL). After drying over Na2SO4, filtration and sol-
vent evaporation at reduced pressure, the crude product was purified
by silica-gel column chromatography (pentane/EtOAc, 7:3), yielding
a clear oil (442 mg, 2.12 mmol, 88%), ee: 97%, ½a D22
¼ þ34:8 (c 1.03,
ꢄ
CHCl3). lit.51 98% ee,
½
a 2D2
ꢄ
¼ þ39:8 (c 0.375, CHCl3). 1H NMR
(400 MHz, CDCl3) d: 1.48 (d, J = 6.4, 3H), 1.76 (br s, OH), 4.87 (q,
J = 6.4, 1H), 7.25 (m, 2H), 7.47 (m, 2H).
4.5.2. (R)-1-(4-(Trifluoromethyl)phenyl)ethanol (R)-5g52
The reaction was performed as described in Section 4.5.1 start-
ing with 1g. This gave 396 mg (2.08 mmol, 83%) of a clear oil, ee:
92% ½a 2D0
ꢄ
¼ þ31:6 (c 1.04, CHCl3). lit.52 ee: 94% ½a D20
¼ þ34:9 (c
ꢄ
1.0, CHCl3). 1H NMR (400 MHz, CDCl3) d: 1.51 (d, J = 6.5, 3H), 1.85
(br s, OH), 4.98 (q, J = 6.5, 1H), 7.49 (m, 2H), 7.61 (m, 2H).
4.5.3. (R)-4-(1-Hydroxyethyl)benzonitrile (R)-5h53,54
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Chem. 2010, 75, 1620–1629.
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The reaction was performed as described in Section 4.5.1 starting
with 1h. This gave 349 mg (2.35 mmol, 95%) of a clear oil, ee: 96.0
½
a 2D5
ꢄ
¼ þ43:1 (c 1.02, CHCl3), lit.55 (S)-5h ee: 72%, ½a 2D5
¼ ꢁ63:6 (c
ꢄ
2.41, CHCl3). 1H NMR (400 MHz, CDCl3) d: 1.50 (d, J = 6.4, 3H), 1.88
(br s, OH), 4.97 (q, J = 6.4, 1H), 7.49 (m, 2H), 7.65 (m, 2H).
4.5.4. (R)-1-(4-Nitrophenyl)ethanol (R)-5i56,57
The reaction was performed as described in Section 4.5.1 start-
ing with 1i. This gave 390 mg (2.33 mmol, 93%) of a clear oil, ee: 99,
½
a 2D3
ꢄ
¼ þ32:3 (c 1.03, CHCl3), lit.56 ee: 88.4, ½a D23
¼ þ35:1 (c 1.46,
ꢄ
CHCl3). 1H NMR (400 MHz, CDCl3) d: 1.53 (d, J = 6.6, 3H), 1.91 (br
s, OH), 5.03 (q, J = 6.6, 1H), 7.55 (m, 2H), 8.21 (m, 2H).
43. Bichlmaier, I.; Siiskonen, A.; Finel, M.; Yli-Kauhaluoma, J. J. Med. Chem. 2006,
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Acknowledgements
46. Fuglseth, E.; Krane Thvedt, T. H.; Førde Møll, M.; Hoff, B. H. Tetrahedron 2008,
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Anders Jahres Foundation and INNER ERA NET are acknowledged
for financial support. Roger Aarvik is thanked for technical assis-
tance and Dr. David Barriet for helpful discussions. Sør-Trøndelag
University College is acknowledged for financing a PhD scholarship.
47. Thvedt, T. H. K.; Fuglseth, E.; Sundby, E.; Hoff, B. H. Tetrahedron 2009, 65, 9550–
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