Efficient dynamic kinetic resolution of secondary alcohols with a novel tetrafluorosuccinato ruthenium complex

Article abstract of DOI:10.1016/j.tetasy.2006.08.003

Dynamic kinetic resolution (DKR) of a series of secondary alcohols has been conducted with a novel dinuclear ruthenium complex, bearing tetrafluorosuccinate and (rac)-BINAP ligands as the racemization catalyst. Novozym 435 has been used as the enzyme, and isopropyl butyrate as the acyl donor. Five substrates underwent DKR successfully: an aliphatic and an aromatic secondary alcohol, an aromatic alcohol with an electron-withdrawing substituent on the phenyl ring, an aromatic alcohol bearing an electron-donating substituent on the ring and a heteroaromatic secondary alcohol. The catalyst performed optimally at 70 °C. Typically the reaction reached complete conversion within 1 day with 0.1 mol % of racemization catalyst relative to the substrate. The addition of the ketone corresponding to the substrate stabilizes the active Ru complex and, therefore, increases the rate of the reaction.

Full text of DOI:10.1016/j.tetasy.2006.08.003

Tetrahedron: Asymmetry 17 (2006) 2299–2305
Efficient dynamic kinetic resolution of secondary alcohols
with a novel tetrafluorosuccinato ruthenium complex
Sjoerd F. G. M. van Nispen,a Jeroen van Buijtenen,a Jef A. J. M. Vekemans,a
Jan Meuldijkb and Lumbertus A. Hulshofa,*
aLaboratory of Macromolecular and Organic Chemistry, Eindhoven University of Technology, PO Box 513, 5600 MB Eindhoven,
The Netherlands
bProcess Development Group, Eindhoven University of Technology, PO Box 513, 5600 MB Eindhoven, The Netherlands
Received 26 July 2006; accepted 3 August 2006
Abstract—Dynamic kinetic resolution (DKR) of a series of secondary alcohols has been conducted with a novel dinuclear ruthenium
complex, bearing tetrafluorosuccinate and (rac)-BINAP ligands as the racemization catalyst. Novozym 435 has been used as the enzyme,
and isopropyl butyrate as the acyl donor. Five substrates underwent DKR successfully: an aliphatic and an aromatic secondary alcohol,
an aromatic alcohol with an electron-withdrawing substituent on the phenyl ring, an aromatic alcohol bearing an electron-donating sub-
stituent on the ring and a heteroaromatic secondary alcohol. The catalyst performed optimally at 70 °C. Typically the reaction reached
complete conversion within 1 day with 0.1 mol % of racemization catalyst relative to the substrate. The addition of the ketone corre-
sponding to the substrate stabilizes the active Ru complex and, therefore, increases the rate of the reaction.
Ó 2006 Published by Elsevier Ltd.
1. Introduction
complete conversion of the racemate into the desired enan-
tiomer (Scheme 1).4 In principle, 100% of the (R)-ester can
hence be obtained with 100% ee from a racemic alcohol.
Many substrates were converted into the enantiopure ester
with good yields, including a broad range of substituted
aromatic and aliphatic secondary alcohols and secondary
diols. The (S)-esters could be obtained when using subtili-
sin instead of a lipase and with the appropriate ruthenium
catalyst, even chiral primary amines were selectively
Over the past decade, there has been an ever increasing
demand for enantiopure compounds, mainly for pharma-
ceutical applications. Different enantiomers, in general,
exhibit different biological activities and easy access to
these compounds is, therefore, of paramount importance.
Optically active secondary alcohols are valuable building
blocks for such pharmaceuticals. These alcohols can be
produced by asymmetric synthesis from the corresponding
ketone, which is usually readily available using either
enzymatic or chemo catalysis.1,2 However, on an industrial
scale, enantiopure alcohols are often isolated by resolution
of the corresponding racemate.3 Many approaches are
based on the (R)-selective lipase catalyzed transesterifica-
tion of secondary alcohols, which normally proceed with
high enantioselectivity. An inherent drawback of this
strategy is that the maximum yield is limited to 50%.
OH
OCOR´´
enzyme, acylating agent
fast
R
R´
R
R´
desired
enantiomer
ruthenium
catalyzed
racemization
OH
OCOR´´
A solution for this problem is presented by chemoenzy-
matic dynamic kinetic resolution (DKR). In this applica-
tion of tandem catalysis, in situ racemization enables the
enzyme, acylating agent
slow
R
R´
R
R´
undesired
undesired
enantiomer
enantiomer
*
Corresponding author. Tel.: +31 40 2473134; fax: +31 40 2451036;
e-mail: l.a.hulshof@tue.nl
Scheme 1. Dynamic kinetic resolution of secondary alcohols.
0957-4166/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2006.08.003

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S. F. G. M. van Nispen et al. / Tetrahedron: Asymmetry 17 (2006) 2299–2305
transformed into the corresponding (R)-amide via DKR.5
In a similar approach, we and others have recently reported
on the conversion of a racemic monomer into the enantio-
pure polymer.6 (R)-Polyesters were obtained in good yield
and selectivity from x-substituted e-caprolactones.
OH
OH
1 (0.025 mol%)
Ph
(S)-2a
Scheme 2. Racemization of (S)-1-phenylethanol.
Ph
rac-2a
K2CO3, toluene
In the literature, the performance of various Ru-based
racemization catalysts has been reported. The performance
of these Ru catalysts varied considerably. Ba¨ckvall et al.
recently reported that the racemization catalyst [(Ph5Cp)-
Ru(CO)2X] (X = Cl, Br) enables DKR at ambient temper-
ature with reaction times ranging from 3–24 h for most
substrates, although it required 5 mol % of Ru catalyst.4e,f
with and without the presence of acetophenone 3a. Pre-
sumably, the active catalyst deactivates in the absence of
acetophenone (Table 1, entries 1 and 2); the best result
was obtained at 70 °C. When the conversion is defined
according to Eq. 1, it can be derived that the racemization
obeys first-order kinetics9
Early investigations used p-chlorophenyl acetate as the acyl
donor, since p-chlorophenol does not interfere with the
racemization reaction.4b However, due to environmental
and economic considerations, this acyl donor is highly
undesirable. Verzijl et al. developed a process to perform
the DKR using simple esters, such as isopropyl buty-
rate.4g,7 The isopropanol formed by the transesterification
is continuously removed at reduced pressure. This ap-
proach enables a large scale application of DKR.
eeðtÞ
XðtÞ ¼ 1 ꢀ
ð1Þ
eeð0Þ
Table 1. Racemization of 2a using 1 as a racemization catalysta
Entry
T (°C)
Ketone (mmol)
Time (min)
eeb (%)
1
2
70
100
No ketone
No ketone
180
180
6.5
27.1
Recently, we introduced a novel dinuclear ruthenium com-
plex bearing tetrafluorosuccinate and phosphine ligands
(Fig. 1).8 Promising results were obtained in the acceptor-
less dehydrogenation of 1-phenylethanol. We then became
interested in its application as a racemization catalyst in
DKR. Herein, we report on the DKR of various secondary
alcohols using complex 1 as the racemization catalyst giv-
ing high yields and high ee.
O
3
4
5
6
7
8
70
100
100
100
100
100
180
0.5
0.1
0.4
1.0
0.2
3.3
3a (0.7 mmol)
O
40
F
F
F
3a (0.7 mmol)
P
O
O
O
P
F
Ru
O
H
H
O
O
O
H
CO
80
= rac-BINAP
P
OC
P
P
O
H
Ru
O
F
3a (1.0 mmol)
O
O
F
O
P
F
F
80
1
4a (1.1 mmol)
Figure 1. Dinuclear ruthenium complex bearing tetrafluorosuccinate and
phosphine ligands (complex 1).
O
40
2. Results and discussion
4b (0.9 mmol)
2.1. Racemization of (S)-1-phenylethanol
O
First the racemization of (S)-1-phenylethanol (S)-2a was
investigated. The reaction was carried out with complex 1
as the racemization catalyst and with toluene as the sol-
vent. K2CO3 was used to activate the catalyst (Scheme 2).
180
4c (1.0 mmol)
a Reaction conditions: (S)-2a (4.5 mmol), toluene (4.5 mL), ketone 3a or
4a–c, catalyst 1 (0.0011 mmol) and K2CO3 (1.5 mmol), Ar atmosphere.
b Determined by chiral GC; calculated values.
In order to determine the optimal reaction conditions, the
racemization of (S)-2a was performed at 70 °C and 100 °C

S. F. G. M. van Nispen et al. / Tetrahedron: Asymmetry 17 (2006) 2299–2305
2301
A linear relationship between ꢀln(1 ꢀ X) and time (t) can
then be obtained. Figure 2 shows a short induction period
during the first minutes of the reaction, which is attributed
to activation of the catalyst by K2CO3. In the absence of
3a, first-order kinetics is not obeyed (Fig. 2, entries A
and B) and a dramatic reduction of the rate of racemiza-
tion is observed. Moreover, catalyst deactivation is faster
at 100 °C.
was converted to acetophenone. The equilibrium, as given
in Scheme 3, was reached before racemization was com-
plete, indicating that the racemization occurs via transfer
hydrogenation. This contrasts with the racemization mech-
anism, which was reported for [(Ph5Cp)Ru(CO)2Cl].4f For
[(Ph5Cp)Ru(CO)2Cl], it was determined that the ketone ob-
tained from the alcohol remains in the coordination sphere
of the Ru atom during racemization and does not exchange
with the free ketone. With aliphatic diisopropyl ketone 4c,
transfer hydrogenation was considerably slower, resulting
in a concomitantly lower rate of reaction (Table 1, entry 8).
D
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
2.2. DKR of secondary alcohols
C
DKR of 2a was carried out with immobilized Candida ant-
arctica Lipase B (Novozym 435) as the enantioselective
acylating catalyst and ruthenium catalyst 1 as the racemiza-
tion catalyst. Isopropyl butyrate was used as the acylating
agent and isopropanol was removed at a reduced pressure.7
DKR of 2a was performed with and without the presence
of 3a, using only 0.1 mol % of complex 1 with respect to
the substrate. DKR without a ketone is preferred, since
the isolation of the product is less complicated.
)
ln(1-X
A
B
0
50
100
Time [min]
150
200
High yields and excellent ee values were obtained for each
entry (Table 2). Figure 3a shows the conversion based on
enantiomeric balance (eb) versus time. The eb is a measure
of the conversion of the (S)- into the (R)-enantiomer (see
Eq. 2)7
Figure 2. ꢀln(1 ꢀ X) as a function of time for the racemization of (S)-2a
catalyzed by complex 1 (0.025 mol %) without acetophenone at 70 °C (A;
Table 1, entry 1) and at 100 °C (B; Table 1, entry 2) and in the presence of
acetophenone at 70 °C (C; Table 1, entry 3) and at 100 °C (D; Table 1,
entry 4).
NR-alcoholðtÞ þ NR-esterðtÞ ꢀ NS-alcoholðtÞ ꢀ NS-esterðtÞ
XebðtÞ ¼
NR-alcoholðtÞ þ NR-esterðtÞ þ NS-productðtÞ þ NS-esterðtÞ
The addition of 3a to the reaction mixture resulted in first-
order behavior at 70 °C as well as at 100 °C. It should be
noted that at 100 °C, the presence of acetophenone resulted
in a dramatic increase in the rate of racemization (Table 1,
entries 4 and 5; Fig. 2, entry D). Apparently, the presence
of 3a keeps the catalyst active. An optimal rate of reaction
was obtained when 0.7 mmol of 3a was added (16 mol % in
relation to the substrate) (Table 1, entry 4); larger amounts
reduced the rate of racemization, probably because of
occupation of the active site of the catalyst by 3a.
ð2Þ
In Figure 3b, the ee of 2a during the reaction is depicted.
Enzymatic transesterification results in a rapid increase of
the ee of 2a during the first hours of the reaction [conver-
sion of (R)-2a into (R)-5a]. At higher conversions, the
amount of racemization catalyst 1 in the reaction mixture
in relation to the substrate increases, leading to a decrease
Table 2. DKR of 2, using 1 as a racemization catalyst and Novozym 435
as an acylating catalyst under various conditionsa
To gain more insight into the reaction mechanism, the
influence of other ketones on the racemization of (S)-2a
was also investigated (Table 1, entries 6–8).10 Apparently,
all ketones stabilized the active catalyst, as first-order
kinetics was obeyed in all cases.
O
Novozym 435,
OH
OH
1 (0.1 mol%)
O
C3H7
+
isopropyl butyrate (2 eq.),
K2CO3, toluene, 70 °C
Ph
Ph
2a
5a
The results of the racemization reactions in the presence of
ketones, benzophenone 4a or 4-methyl-acetophenone 4b,
demonstrated that the catalyst activity was similar to that
with acetophenone 3a (Table 1, entries 6 and 7). Transfer
hydrogenation was observed, resulting in the rapid forma-
tion of the corresponding alcohol as well as acetophenone
(Scheme 3). At equilibrium, 80–100% of the original ketone
Entry 3a (mmol) Novozym 435 Time (h) 5a (%) eeb (%)
(mg/mol)
1
2
3
0.07c
1.8
11
11
23
23
23
10
99
>99
98
>99
>99
>99
1.8
a Reaction conditions: rac-2a (9 mmol), toluene (9 mL), isopropyl butyrate
(18 mmol), catalyst 1 (0.009 mmol) and K2CO3 (3.8 mmol), Ar atmo-
sphere, T = 70 °C, reduced pressure to ensure gentle reflux (approxi-
mately 200 mbar).
b Determined by chiral GC; calculated values.
c Reaction performed without addition of extra acetophenone; 0.07 mmol
was present as an impurity in the starting alcohol, however.
[Ru]
O
OH
OH
R'
Scheme 3. Transfer hydrogenation of ketones and 1-phenylethanol.
O
+
+
R
R'
Ph
R
Ph

2302
S. F. G. M. van Nispen et al. / Tetrahedron: Asymmetry 17 (2006) 2299–2305
For this reason, the ketone corresponding to the substrate
was used for each DKR.
6
5
4
3
2
1
0
B
DKR of 2-octanol 2b gave a high yield and high ee within
10 h when 2-octanone 3b was added. However, the amount
of complex 1 was increased by a factor 4 and the amount of
Novozym 435 was decreased by a factor 4, when compared
to the DKR of 2a in the presence of ketone. In the absence
of 3b, a considerably lower rate of reaction was obtained
(Table 3, entry 4).
A
)
C
eb
ln(1-X
a-Methyl-4-(trifluoromethyl)benzyl alcohol 2c (Table 3,
entry 5), a substrate bearing an electron-withdrawing sub-
stituent on the phenyl ring, gave a high yield with excellent
ee. For this DKR, a slightly longer reaction time of 30 h
and double the amount of enzyme were required, when
compared to the DKR of 2a in the presence of ketone.
0
5
10
15
20
25
Time [h]
100
80
60
40
20
0
An aromatic alcohol bearing an electron-releasing substitu-
ent on the ring, a-methyl-4-methoxybenzyl alcohol 2d, was
also successfully converted into the enantiomerically pure
butyrate ester. A slightly longer reaction time was required
(Table 3, entry 6).
A
C
e(2a)
Finally, the DKR of the heteroaromatic 1-(2-furyl)ethanol
2e was investigated (Table 3, entry 7). DKR of this sub-
strate was complete after 23 h, resulting in a poor ee of
79%, however. Experiments with increased loading of race-
mization catalyst 1 did not lead to higher ee values. Verzijl
et al. described that DKR of this substrate in combination
with isopropyl butyrate as the acylating agent resulted in
limited enantioselectivity. Improved results were reported
employing methyl phenylacetate as the acyl donor.4g
B
0
5
10
15
20
25
Time [h]
Figure 3. DKR of 2a at 70 °C, with 0.1 mol % 1 as a racemization catalyst
in the absence of acetophenone (A; Table 2, entry 1), in the presence of
1.8 mmol of 3a (B; Table 2, entry 2) and in the presence of 1.8 mmol of 3a
with double the amount of enzyme (C; Table 2, entry 3). Toluene is used as
the solvent. (a) Conversion based on enantiomeric balance (Xeb) versus
reaction time. As first-order kinetics are obeyed, ꢀln(1 ꢀ Xeb) is plotted,
(b) ee of 2a versus reaction time.
3. Conclusions
Dinuclear ruthenium complex 1, bearing tetrafluorosucci-
nate and (rac)-BINAP ligands, was successfully applied in
the DKR of various secondary alcohols.
of the ee. Reaction in the presence of 1.8 mmol of 3a shows
a considerably lower ee implying faster racemization
(Fig. 3b, entry B) and a rate-limiting enzymatic reaction.
Therefore, the reaction was performed with double the
amount of enzyme, resulting in faster transesterification
and therefore a higher ee of 2a during the reaction
(Fig. 3b, entry C). Complete conversion with high ee of
the product was achieved within 10 h (Table 2, entry 3;
Fig. 3a, entry C).
The DKR of (rac)-2a with isopropyl butyrate as the acyl
donor and Novozym 435 as the enzyme was performed
effectively at 70 °C when 0.10 mol % of complex 1 was used
as the racemization catalyst. Activation of the Ru catalyst
with K2CO3 was necessary. Reaction in the presence of
ketone was complete within 10 h with an excellent ee of
the product (>99%). Without ketone, complete reaction
was achieved in 23 h, giving an ee >99% as well.
In order to investigate the scope of the catalyst, an ali-
phatic secondary alcohol as well as aromatic alcohols bear-
ing either an electron-releasing or an electron-withdrawing
substituent on the phenyl ring were subjected to DKR.
Furthermore, a heteroaromatic alcohol, 2-furyl ethanol,
was tested in DKR with catalyst 1 (Table 3). From a com-
mercial point of view, it is more attractive to use one
ketone for all substrates. DKR reactions with ketones,
other than the corresponding one, showed disappointing
results, however. In addition, there are no advantages
with respect to the isolation of the product as a result of
transfer-hydrogenation between ketone and substrate.
Besides the aromatic alcohol 2a, four other substrates were
shown to undergo the DKR successfully, using complex 1
as the racemization catalyst. Those substrates represent
an aliphatic secondary alcohol (2-octanol), an aromatic
alcohol bearing an electron-withdrawing substituent on
the phenyl ring (a-methyl-4-(trifluoromethyl)benzyl alco-
hol), an aromatic alcohol bearing an electron-donating
substituent on the ring (a-methyl-4-methoxybenzyl alco-
hol) and a heteroaromatic secondary alcohol (1-(2-
furyl)ethanol). Addition of the ketone corresponding to
the alcohol is beneficial for the stability of the active
Ru-complex and hence for the reaction rate and yield.

S. F. G. M. van Nispen et al. / Tetrahedron: Asymmetry 17 (2006) 2299–2305
Table 3. Dynamic kinetic resolution of various racemic alcoholsa
2303
Entry
Alcohol
Ketone (mmol)
Time (h)
Product
Yieldb,c (%)
eeb (%)
O
O
OH
O
C3H7
10
23
98
>99
>99
>99
1
2a
3a (1.8 mmol)
5a
O
O
C3H7
2
No ketoned
10
24
95
>99 (87)
>99
>99
5a
O
O
OH
O
O
C3H7
3e
10
23
99
>99
98
98
3b (1.6 mmol)
2b
5b
C3H7
O
O
4e
No ketone
23
86
87
5b
OH
O
O
C3H7
5f
30
96 (79)g
>99
F3C
F3C
F3C
2c
3c (1.6 mmol)
5c
O
O
OH
O
C3H7
6
31
98 (63)g
98
O
O
O
O
2d
3d (1.5 mmol)
5d
O
O
OH
O
O
O
7
23
98
79
C3H7
3e (1.4 mmol)h
2e
5e
a Reaction conditions: complex 1 (0.1 mol %), Novozym 435 (0.2 g), K2CO3 (0.5 g), alcohol (9 mmol), isopropyl butyrate (18 mmol) and corresponding
ketone were stirred in toluene (9 mL) under an argon atmosphere at 70 °C at reduced pressure (200 mbar).
b Determined by chiral GC; calculated values.
c In parenthesis: isolated yield.
d Reaction performed without addition of extra ketone, 0.07 mmol of ketone is present as an impurity in the starting alcohol, however.
e Novozym 435: 0.05 g; Ru-catalyst: 0.4 mol %.
f Novozym 435: 0.4 g.
g Product not separated from ketone; calculated yield.
h Ketone (1.4 mmol) was added in advance. Immediately at the start of the reaction this amount reduced to 0.4 mmol, however. Most likely, this can be
attributed to transfer hydrogenation between 2-furyl ketone and isopropanol, which is simultaneously distilled from the reaction mixture.

2304
S. F. G. M. van Nispen et al. / Tetrahedron: Asymmetry 17 (2006) 2299–2305
4. Experimental
4.6. (R)-a-Methyl-4-(trifluoromethyl)benzyl butyrate 5c
4.1. General
Purification by Kugelrohr distillation provided (R)-1-a-
methyl-4-(trifluoromethyl)benzyl butyrate 5c as a colour-
less liquid. H NMR (300 MHz, CDCl3) d (ppm) 0.95 (t,
1
All reactants were obtained from Aldrich, except for Nov-
ozym 435, which is obtained from Novozymes. Complex 1
was synthesized according to the literature.8 Substrates
were distilled before use. K2CO3 (ꢀ325 MESH, Aldrich,
347825) was used to activate complex 1.
3H, CH3), 1.55 (d, 3H, CH3), 1.69 (sextet, 2H, CH2),
2.35 (t, 2H, CH2), 5.94 (q, 1H, CH), 7.48 (d, 2H, Ar–
H2,6), 7.61 (d, 2H, Ar–H3,5). GC program: 35 min at
110 °C, 90 °C/min, 2 min at 200 °C. Retention times: tri-
fluoromethyl acetophenone: 6.3 min, (R)-a-methyl-4-(tri-
fluoromethyl)benzyl alcohol: 23.0 min, (R)-a-methyl-4-
(trifluoromethyl)benzyl butyrate: 26.7 min, (S)-a-methyl-
4-(trifluoromethyl)benzyl alcohol: 28.6 min.
1H NMR spectra were recorded on a Varian Mercury
Vx 300 spectrometer (300 MHz) using CDCl3 as solvent.
Chiral gas chromatography (GC) was performed on a
Shimadzu 6C-17A GC equipped with a Chrompack
Chirasil-DEX CB (DF = 0.25) column and an FID.
4.7. (R)-a-Methyl-4-methoxybenzyl butyrate 5d
Samples were injected using
autosampler.
a Shimadzu AOC-20i
Purification by Kugelrohr distillation provided (R)-a-
methyl-4-methoxybenzyl butyrate 5d as a colourless liquid.
1H NMR (300 MHz, CDCl3) d (ppm) 0.95 (t, 3H, CH3),
1.52 (d, 3H, CH3), 1.69 (sextet, 2H, CH2), 2.31 (t, 2H,
CH2), 3.80 (s, 3H, CH3), 5.88 (q, 1H, CH), 6.89 (d, 2H,
Ar–H3,5), 7.32 (d, 2H, Ar–H2,6). GC program: 20 min at
140 °C, 60 °C/min, 2 min at 200 °C. Retention times: 4-
methoxy acetophenone: 8.2 min, (R)-a-methyl-4-meth-
oxybenzyl alcohol: 10.8 min, (S)-a-methyl-4-methoxy-
benzyl alcohol: 11.5 min, (S)-a-methyl-4-methoxybenzyl
butyrate: 20.0 min, (R)-a-methyl-4-methoxybenzyl buty-
rate: 20.7 min.
4.2. General procedure for the racemization of (S)-1-
phenylethanol
A Schlenk tube was charged with (S)-1-phenylethanol
(0.55 g, 4.5 mmol), complex 1 (2.15 mg, 0.0011 mmol)
and toluene (4.5 mL) and then K2CO3 (0.2 g, 1.5 mmol)
was added. At time t = 0, the Schlenk tube was inserted
in an oil bath of the desired temperature. Small aliquots
of reaction mixture were taken for GC analysis.
4.3. Racemization in the presence of ketone
Acknowledgements
The procedure was similar to that of the general racemiza-
tion procedure, but with initial addition of the ketone.
Financial support from DSM Pharma Chemicals is grate-
fully acknowledged. We thank Gerard Verzijl and Rinus
Broxterman for helpful discussions.
4.4. General DKR procedure
Novozym 435 (0.10 g, 0,00034 mmol), complex 1 (0.018 g,
0.0093 mmol) and K2CO3 (0.5 g, 3.8 mmol) were dried in
a Schlenk tube under vacuum overnight at 50 °C in the
presence of P2O5. Under an Ar-atmosphere, the Schlenk
tube was charged with toluene (9 mL), substrate (9 mmol)
and isopropyl butyrate (18 mmol). The Schlenk tube was
inserted in an oil bath at 73 °C at time t = 0. The reaction
mixture was stirred at 70 °C for 23 h at a pressure of
200 mbar. Small aliquots of reaction mixture were taken
for GC analysis. For preparative purposes, the reaction
mixture was concentrated, filtered, washed with toluene
and concentrated in vacuum to yield the crude product.
References
1. (a) Biotransformations in Organic Chemistry, 5th ed.; Faber,
K., Ed.; 2004; (b) Garcia-Urdiales, E.; Alfonso, I.; Gotor, V.
Chem. Rev. 2005, 105, 313.
2. (a) Comprehensive Asymmetric Catalysis I–III, Jacobsen, E.
N.; Pfaltz, A.; Yamamoto, H., Eds.; 1999; Vol. 1; (b)
Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.;
2000; (c) Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler, F.;
Steiner, H.; Studer, M. Adv. Synth. Catal. 2003, 345, 103; (d)
Blaser, H.-U. Chem. Commun. 2003, 293.
3. Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Kesseler,
M.; Sturmer, R.; Zelinski, T. Angew. Chem. Int. Ed. 2004, 43,
788.
4.5. (R)-1-Phenylethyl butyrate 5a
4. (a) Dinh, P. M.; Howarth, J. A.; Hudnott, A. R.; Williams, J.
M. J.; Harris, W. Tetrahedron Lett. 1996, 37, 7623; (b)
Larsson, A. L. E.; Persson, B. A.; Ba¨ckvall, J.-E. Angew.
Chem. Int. Ed. 1997, 36, 1211; (c) Pamies, O.; Ba¨ckvall, J.-E.
Chem. Rev. 2003, 103, 3247; (d) Choi, J. H.; Choi, Y. K.;
Kim, Y. H.; Park, E. S.; Kim, E. J.; Kim, M.-J.; Park, J. J.
Org. Chem. 2004, 69, 1972; (e) Martin-Matute, B.; Edin, M.;
Bogar, K.; Ba¨ckvall, J. E. Angew. Chem. Int. Ed. 2004, 43,
6535; (f) Martin-Matute, B.; Edin, M.; Bogar, K.; Kaynak, F.
B.; Ba¨ckvall, J. E. J. Am. Chem. Soc. 2005, 127, 8817; (g)
Verzijl, G. K. M.; de Vries, J. G.; Broxterman, Q. B.
Tetrahedron: Asymmetry 2005, 16, 1603; (h) Kim, N.; Ko, S.
Purification by Kugelrohr distillation provided (R)-1-phen-
ylethyl butyrate 5a as a colourless liquid with a yield of
87%. H NMR (300 MHz, CDCl3) d (ppm) 0.95 (t, 3H,
CH3), 1.55 (d, 3H, CH3), 1.63 (sextet, 2H, CH2), 2.32 (t,
2H, CH2), 5.92 (q, 1H, CH), 7.32 (5H, Ar–H). GC pro-
gram: 10 min at 130 °C, 70 °C/min, 2 min at 200 °C. Reten-
tion times: (R)-1-phenylethanol: 5.9 min, (S)-1-phenyl-
1
ethanol: 6.2 min, tri-tert-butyl benzene: 9.7 min, (R)-1-
25
phenylethyl butyrate: 8.9 min. ½aꢁD = +91.3 (c 0.98,
CHCl3).

S. F. G. M. van Nispen et al. / Tetrahedron: Asymmetry 17 (2006) 2299–2305
2305
B.; Kwon, M. S.; Kim, M. J.; Park, J. Org. Lett. 2005, 7,
4523.
8. van Buijtenen, J.; Meuldijk, J.; Vekemans, J.; Hulshof, L. A.;
Kooijman, H.; Spek, A. L. Organometallics 2006, 25, 873.
9. For the reaction (S)-2 M (R)-2, with rate constants for the
forward and reverse reaction, k1 and kꢀ1, respectively, the
mass balance for the (S)-enantiomer can be derived: d[(S)-2]/
dt = ꢀk1 Æ[(S)-2] + kꢀ1 Æ[(R)-2]. In case of racemization by
an achiral catalyst k1 = k by definition, which results in:
d[(S)-2]/dt = k1Æ{[(R)-2] ꢀ ꢀ[(1S)-2]}. Introducing ee = {[(S)-2] ꢀ
[(R)-2]}/{[(S)-2] + [(R)-2]} gives d(ee)/dt = ꢀ2Æk1 Æee. The
conversion is defined as: X = 1 ꢀ (ee/ee0), which can be
rewritten as ee = {(1 ꢀ X)/ee0}. Now it can be derived that
dX/dt = 2Æk1 Æ(1 ꢀ X) or dX/(1 ꢀ X) = 2Æk1 Ædt, which is
consistent with overall first-order kinetics.
5. (a) Kim, M.-J.; Chung, Y. I.; Choi, Y. K.; Lee, H. K.; Kim,
D.; Park, J. J. Am. Chem. Soc. 2003, 125, 11494; (b) Boren,
L.; Martin-Matute, B.; Xu, Y. M.; Cordova, A.; Ba¨ckvall, J.
E. Chem. Eur. J. 2005, 12, 225; (c) Paetzold, J.; Ba¨ckvall, J. E.
J. Am. Chem. Soc. 2005, 127, 17620.
6. (a) van As, B. A. C.; van Buijtenen, J.; Heise, A.; Broxterman,
Q. B.; Verzijl, G. K. M.; Palmans, A. R. A.; Meijer, E. W. J.
Am. Chem. Soc. 2005, 127, 9964; (b) Hilker, I.; Rabani, G.;
Verzijl, G. K. M.; Palmans, A. R. A.; Heise, A. Angew. Chem.
Int. Ed. 2006, 45, 2130; (c) van Buijtenen, J.; van As, B. A. C.;
Meuldijk, J.; Palmans, A. R. A.; Vekemans, J. A. J. M.;
Hulshof, L. A.; Meijer, E. W. Chem. Commun. 2006, 3169.
7. Verzijl, G. K. M.; de Vries, J. G.; Broxterman, Q. B. WO
Patent 01/90396, 2001.
10. Reactions were performed at 100 °C as the strongest effect
of addition of acetophenone was obtained at this
temperature.