Removal of the acyl donor residue allows the use of simple alkyl esters as acyl donors for the dynamic kinetic resolution of secondary alcohols

Article abstract of DOI:10.1016/j.tetasy.2005.02.028

The dynamic kinetic resolution of secondary alcohols using a lipase and a ruthenium catalyst as developed by Baeckvall required some improvements to make it suitable for its use in an industrial process. The use of p-chlorophenyl acetate as acyl donor is not desirable in view of the toxicity of the side product. We herein report that simple alkyl esters can be used as acyl donors if the alcohol or ketone residue formed during the enzymatic acylation is continuously removed during the reaction. The addition of a ketone speeds up the racemisation process and allowed us to reduce the amounts of enzyme and ruthenium catalyst. The scope of this method was explored and a suitable range of acyl donors found. Various benzylic and aliphatic alcohols were reacted using isopropyl butyrate or methyl phenylacetate as acyl donor and in most cases the ester was isolated in >95% yield and 99% ee. Furthermore, it was demonstrated that the alcohol by-products of the enzymatic resolution could be used as the hydrogen source in the asymmetric reductive transesterification of ketones.

Full text of DOI:10.1016/j.tetasy.2005.02.028

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1603–1610
Removal of the acyl donor residue allows the use
of simple alkyl esters as acyl donors for the dynamic
kinetic resolution of secondary alcohols
Gerard K. M. Verzijl,* Johannes G. de Vries and Quirinus B. Broxterman
DSM Research, Life Sciences—Advanced Synthesis, Catalysis and Development, PO Box 18, 6160 MD Geleen, The Netherlands
Received 3 January 2005; accepted 24 February 2005
Abstract—The dynamic kinetic resolution of secondary alcohols using a lipase and a ruthenium catalyst as developed by Ba¨ckvall
required some improvements to make it suitable for its use in an industrial process. The use of p-chlorophenyl acetate as acyl donor
is not desirable in view of the toxicity of the side product. We herein report that simple alkyl esters can be used as acyl donors if the
alcohol or ketone residue formed during the enzymatic acylation is continuously removed during the reaction. The addition of a
ketone speeds up the racemisation process and allowed us to reduce the amounts of enzyme and ruthenium catalyst. The scope
of this method was explored and a suitable range of acyl donors found. Various benzylic and aliphatic alcohols were reacted using
isopropyl butyrate or methyl phenylacetate as acyl donor and in most cases the ester was isolated in >95% yield and 99% ee.
Furthermore, it was demonstrated that the alcohol by-products of the enzymatic resolution could be used as the hydrogen source
in the asymmetric reductive transesterification of ketones.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
an enzymatic resolution with a transition metal-medi-
ated redox racemisation is arguably one of the best
methods to produce optically active esters9 (Scheme 1).
Optically active secondary alcohols are important build-
ing blocks for pharmaceuticals, agrochemicals and
liquid crystals. Relevant methods for their preparation
from readily available ketones are asymmetric processes
such as catalytic hydrogenations,1a hydrosilylations,1b
transfer hydrogenations,1a,2 hydroborations3 and
bio-reductions.4 Alternatively, enantiomerically pure sec-
ondary alcohols can also be obtained by the kinetic res-
olution5 of racemic mixtures using either asymmetric
catalytic oxidation6 or chiral chromatography. High
enantioselectivity in kinetic resolutions can also be
achieved by enzymatic transesterification.7 However,
an important drawback of kinetic resolutions is the
intrinsically low maximum theoretical yield of 50%. In
some special circumstances, it is possible to obtain a the-
oretical yield of 100% by carrying out substrate racemi-
sation under the resolution conditions. Such processes
constitute a very special subclass of kinetic resolution
reactions known as dynamic kinetic resolution
(DKR).8 The DKR of secondary alcohols by combining
OH
R2
(S)-1
O
OH
R2
OAcyl
R2
M
MH2
M
Enzyme
R1
R1
R2
R1
(R)-1
R1
Acyl donor
MH2
2
3
Redox racemisation
Enzymatic resolution
Scheme 1. The dynamic kinetic resolution of secondary alcohols.
In this concept, the two enantiomers of the substrate are
equilibrated by a redox reaction with the continuous
removal of one of the enantiomers using stereoselective
enzymatic acylation. Hydrolysis of the optically active
ester produced will give the corresponding enantiopure
secondary alcohol.
This concept was first proven by Williams and co-work-
ers.10 Ba¨ckvall et al. realised a significant breakthrough
by identifying a compatible catalyst combination of
immobilised lipase B from C. antarctica (commercially
traded as Novozymꢁ 435) for the resolution and a ruthe-
nium-based racemisation catalyst, originally developed
*
Corresponding author. Tel.: +31 (0)46 4767813; fax: +31 (0)46
4767103; e-mail: gerard.verzijl@dsm.com
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.02.028

1604
G. K. M. Verzijl et al. / Tetrahedron: Asymmetry 16 (2005) 1603–1610
Ph
Ph
O
O
Ph
Ph
Ru-catalyst 4 (2 mol %),
Ph
Ph
H
H
OH
R2
OAc
Novozym 435
Ru Ru
Ph
CO
R1
R1
R2
Ph
OC
Acyl donor (3 eq.)
toluene
CO OC
1
3
4
Scheme 2.
by Shvo 4, which turned out to be very effective for the
DKR of secondary alcohols (Scheme 2).11 However, the
use of vinyl acetate or isopropenyl acetate as the acyl
donor was identified as being disadvantageous due to
the formation of acetaldehyde or acetone, respectively,
which caused undesired side reactions. Employing
p-chlorophenyl acetate as the acyl donor solved the
problem, releasing p-chlorophenol as a non-interfering
residue.
was described starting from ketones in ethyl acetate.
Molecular hydrogen was employed in the hydrogenation
of the pro-chiral ketone to racemic alcohol in combin-
ation with a DKR in ethyl acetate (acyl donor for enzy-
matic transesterification) using the same ruthenium
racemisation catalyst.13 Over a period of 96 h, the reac-
tion mixture was concentrated to one-third in volume
every 24 h followed by volume replenishment with fresh
ethyl acetate. Slow transesterification was recognised as
a major drawback in the use of ethyl acetate. Recently,
Park et al. reported an efficient DKR using isopropenyl
acetate as acyl donor.14 For this purpose, a novel, more
active catalyst was developed. A low degree of alcohol
oxidation was achieved without the aid of a ketone as
co-catalyst. Unfortunately, high catalyst loadings (up
to 8 mol % Ru) are necessary to perform DKR at room
temperature with reasonable yields. Also Ba¨ckvall et al.
have recently reported that the use of(Ph5Cp)Ru-
(CO)2X] (X = Cl, Br) allows the use of isopropenyl ace-
tate, but 5 mol % of this ruthenium catalyst was needed
for a fast rate.11c Reasonable yields of acylated diols
could be obtained by the same group with a combina-
tion of isopropenyl acetate and 4 mol % of the Shvo cat-
A number of patents have since been published in this
field.12 For environmental and economic reasons,
p-chlorophenyl acetate has to be replaced by an alterna-
tive acyl donor. For industrial applications, only simple
acyl donors that are available in bulk are of interest.
However, depending on the acyl donor, kinetic resolu-
tion can lead to by-products, which in the presence of
a redox racemisation catalyst, are either non-oxidative
or oxidative, as illustrated in Scheme 3.
Kinetic resolution with isopropyl acetate generates iso-
propanol. Isopropanol acts as a hydrogen source, effec-
tively creating reductive conditions in the presence of a
redox racemisation catalyst (non-oxidative). Unfortu-
nately, problems arise due to the reversibility of the
transesterification with isopropanol in the enzymatic
resolution and therefore the reaction ends in equilib-
rium. The solution for this problem was the introduction
of enol-esters as acylating agents, which lead to irrevers-
ible transesterifications because of the formation of alde-
hydes or ketones. However, aldehydes and ketones are
hydrogen acceptors and act as oxidants in the presence
of a redox racemisation catalyst (oxidative). As demon-
strated with p-chlorophenyl acetate, enzymatic kinetic
resolution reactions can be shifted towards the product
by the use of irreversible acyl donors, which release
non-interfering by-products.11a,b,d Thus, chemically
speaking p-chlorophenyl acetate is an excellent acylating
agent since it circumvents the above problems. How-
ever, it generates the toxic side product p-chlorophenol,
thus making this compound less desirable from an envi-
ronmental perspective. To date, only a few examples of
simple esters have been reported. A practical method
alyst
4 using Lipase B from Candida antartica,
particularly in the presence of hydrogen to suppress ke-
tone formation.11d
We have found that selective distillation of the residue
of the acyl donor after enzymatic conversion in DKR
is a convenient method to overcome the described prob-
lems,12a,b giving the optically active esters in high
yields and eeÕs at low catalyst loadings. In the case of
an enzymatic resolution leading to a non-oxidative by-
product, selective removal of the released volatile alco-
hol shifts the equilibrium of the reaction towards the
desired product. Likewise, volatile oxidant by-products
can be removed when enol-esters are employed. Herein,
we report our results concerning the DKR of (RS)-1-
phenylethanol 1a using standard esters as acylating
agents. Furthermore, we also report the DKR of a num-
ber of aliphatic and benzylic secondary alcohols in a
standardised procedure with isopropyl butyrate or
methyl phenylacetate as acylating agent.
OH
OAc
R2
OH
OAc
R2
O
lipase
lipase
+
+
R1
R1
R2
R1
3
OAc
1
OAc
3
oxidative
non-oxidative
by-product
by-product
Scheme 3. Enzymatic resolution leading to non-oxidative or oxidative by-products (the remaining (S)-alcohol has been omitted for clarity).

G. K. M. Verzijl et al. / Tetrahedron: Asymmetry 16 (2005) 1603–1610
1605
2. Results and discussion
2.1. DKR with simple esters
the distillation pressure, the DKR conditions found
for the reaction with isopropenyl acetate were also
shown to be suitable for the DKR with other acylating
agents. The chemical yields and enantioselectivities ob-
served using these acylating agents are summarised in
Table 2.
Esterification of 1a was carried out using lipase B from
C. antarctica (Novozymꢁ 435) as enantioselective acyl-
ating catalyst, ShvoÕs ruthenium catalyst 4 as redox
racemisation catalyst, isopropenyl acetate as acylating
agent and toluene as solvent. In order to avoid compet-
itive distillation of the acyl donor, distillation conditions
had to be optimised for each specific acyl donor sepa-
rately, as illustrated for isopropenyl acetate in Table 1.
Table 2. DKR with various simple esters as acylating agenta
4, Novozym 435,
OH
OAc
acetophenone 2a
Ph
Ph
acylating agent (2 eq.),
toluene, 70oC, p (mbar)
1a
3a
In order to determine optimal DKR conditions, 1-
phenylethanol 1a (8 mmol) was treated with isopropenyl
acetate (16 mmol) at 70 ꢂC under distillation conditions
at various pressures in the presence of acetophenone 2a
as ketone co-catalyst, Novozymꢁ 435 and racemisation
catalyst 4. As can be seen in Table 1, relatively low yields
were achieved at pressures below 210 mbar (entries 1–2)
due to the loss of isopropenyl acetate. A high yield and
ee was obtained by distillation at 210 mbar in the pres-
ence of 25 mol % 2a (entry 3). In this particular case, less
oxidation was observed in comparison with DKR under
more rigorous distillation conditions, indicating that an-
other oxidation mechanism is involved when carrying
out distillation at lower pressures. Presumably, a cata-
lytic dehydrogenation process becomes active when ace-
tone and the acyl donor have completely disappeared.
Oxidation was kept to a minimum at 210 mbar and only
a trace of 1a remained in the reaction mixture. The reac-
tion became rather slow upon further reduction of the
amount of catalysts (entries 4 and 5). Prolonging the
reaction from 15 to 24 h at atmospheric pressure gave
3a in 95% yield and 99% ee (entry 5). Reducing the
amount of co-catalyst 2a to 10 mol % (entry 6), detri-
mentally affected the reaction speed and as a conse-
quence we had to run the reaction for 22 h in order to
get a higher yield.
Entry Acylating agent
P
t
Ester
Ee
(%)
(mbar) (h) (%)
1
Isopropenyl acetate
Isopropyl acetate
Isopropyl acetate
Ethyl acetated
210
220
220
290
205
190
65
22
23
24
28
24
24
18
24
3a (97)
3a (99)
3a (63)
3a (83)
98
97
92
99
2b
3c
4
5
Methyl butyrate
Isopropyl butyrate
Isopropyl butyratee
5a (>99) >99
6
5a (>99)
5a (96)
6a (91)
99
99
7
8
Methyl phenylacetate 190
>99
a Reaction conditions: rac-1a (8 mmol), toluene (10 mL), acylating
agent (16 mmol), 2a (0.8 mmol), catalyst 4 (0.04 mmol) and Nov-
ozymꢁ 435 (60 mg), N2 atmosphere, T = 70 ꢂC, Dp (as indicated in
table).
b Over first 6 h 245 mbar, then slowly to 220 mbar.
c Without 2a.
d Acyl donor (3 equiv).
e o-Xylene as solvent.
Completely oxidation-free conditions will never be
achieved with isopropenyl acetate. Even at optimal con-
ditions at least a trace amount of ketone derived from
the substrate will be present in the reaction mixture.
Therefore, the exclusion of the ketone effect is impossi-
ble for isopropenyl acetate.
In a similar manner to that described for isopropenyl
acetate, a variety of potentially inexpensive, simple acyl-
ating agents was studied in the DKR. By varying only
We also wished to study the influence of the ketone
co-catalyst on the racemisation rate. DKR without a
ketone co-catalyst is preferred, since the isolation of
Table 1. DKR of 1a employing isopropenyl acetate as acylating agenta
4, Novozym 435,
acetophenone 2a
OH
OAc
Ph
Ph
isopropenyl acetate (2 eq.),
toluene, 70oC, p (mbar)
1a
3a
Entry
2a (mol %)
Novozym 435 (mg/mol)
4 (mol %)
Pressure (mbar)
Time (h)
3a (%)
Ee (%)
1
25
25
25
25
25
60
60
60
30
30
0.5
0.5
200
205
210
210
215
15
15
15
15
15
2
64
91
98
78
91
98
98
98
99
99
95
98
98
2
3
0.5
4
5b
0.25
0.25
4
99
6
10
60
0.5
210
15
22
94
97
a Reaction conditions: rac-1a (8 mmol), toluene (10 mL), isopropenyl acetate (16 mmol), 2a, catalyst 4 and Novozymꢁ 435 (see table for further
details), N2 atmosphere, T = 70 ꢂC, Dp.
b Distillation was terminated after 15 h.

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G. K. M. Verzijl et al. / Tetrahedron: Asymmetry 16 (2005) 1603–1610
the product is less complicated. Generating isopropanol
by enzymatic transesterification (non-oxidative by-prod-
uct), isopropyl acetate was investigated in the DKR
under permanent distillation conditions in the absence
of ketone as co-catalyst. Unfortunately, DKR of 1a
without the aid of 2a was accompanied by a dramatic
negative effect on the racemisation rate and as a conse-
quence a low yield and disappointing enantiomeric
excess was obtained (entry 3). In comparison with iso-
propyl acetate, the use of the more volatile ethyl acetate
furnished 3a in lower yields. Selective distillation of eth-
anol becomes rather difficult, since the boiling points of
ethyl acetate and ethanol are very close.
2.2. Other ketones as co-catalyst
In general, a DKR with catalyst 4 needs the aid of a
ketone as co-catalyst for effective racemisation. The
effectiveness of the co-catalyst strongly depends on the
equilibration conditions between the ketone (co-cata-
lyst) and the substrate alcohol, which in turn is affected
by the difference in oxidation potential of the co-catalyst
and the ketone derived from the substrate alcohol.15
More specifically, the best racemisation conditions are
obtained in the presence of the ketone derived from
the substrate alcohol. For practical reasons, we prefer
to have a general methodology for all types of sub-
strates. To fulfil this purpose, we investigated benzo-
phenone and 2,4-dimethyl-3-pentanone as possible
alternative co-catalysts in the DKR of 1a (Table 3). At
the beginning of the reaction, 1a partially oxidises to
acetophenone 2a and the co-catalyst reduces to the cor-
responding alcohol resulting in the temporary storage of
hydrogen in the co-catalyst. Steric bulk in co-catalyst
side chains avoids transformation of the produced co-
catalyst alcohol to ester by the enzyme. In the final stage
of the DKR process, the co-catalyst alcohol will deliver
back its hydrogen to the substrate ketone giving racemic
substrate alcohol and in combination with the enzymatic
acylation will approach the theoretical yield of 100%
without formation of interfering side products.16
Using methyl butyrate allowed us to lower the pressure
a bit further and this, in combination with the more vol-
atile methanol, resulted in a more effective DKR. Since
methanol and isopropanol have reductive properties, al-
most complete conversion of 1a took place with excel-
lent ee when the reaction was carried out with methyl
butyrate or isopropyl butyrate, respectively (entries 5
and 6).
Using high boiling esters as acylating agents allowed us
to further enhance the distillation conditions (entries 6–
8). It was also anticipated that the boiling point differ-
ence between the reaction medium and the volatile
by-products could be improved using a high boiling sol-
vent as well. In contrast, however, replacing toluene as
the solvent of choice by o-xylene did not bear out these
expectations significantly (entry 7). In a 24 h reaction
time, complete conversion was obtained in o-xylene as
well.
In the case, when acetophenone 2a was used as racemi-
sation co-catalyst, it was partially reduced by transfer
hydrogenation with isopropanol stemming from the
enzymatic reaction resulting in a slightly higher yield
than the theoretical one (entry 1). Surprisingly, a high
yield and enantiomeric excess were achieved with methyl
butyrate in the presence of 2,4-dimethyl-3-pentanone
(entry 2). Optically active butyrate ester 3a was obtained
in 97% yield and 99% ee in 40 h. Since the performance
of both, 2,4-dimethyl-3-pentanone and benzophenone,
as co-catalyst in DKR is nearly the same (entries 3
and 4), we decided to employ 2,4-dimethyl-3-pentanone
as the co-catalyst of choice. In contrast to benzophen-
The utilisation of acylating agents with different acyl
chain bulkiness is also crucial for enhancing the enantio-
selectivity. A suitable acyl donor for many enzymatic
transformations is methyl phenylacetate and this reagent
is of particular interest when enantioselectivities in
enzymatic transesterifications need to be improved
(entry 8).
Table 3. Different ketones as co-catalyst in the DKR of 1aa
O
4, Novozym 435,
O
OH
O
C3H7
ketone (10 mol%)
toluene, 70oC, 190 mbar
O
C3H7
+
(2 eq.)
1a
5a
Entry
Co-catalyst
t (h)
3a (%)
Ee (%)
1b
2c
Acetophenone 2a
2,4-Dimethyl 3-pentanone
24
24
40
40
40
102
90
99
99
99
99
99
97
95
3
4
2,4-Dimethyl 3-pentanone
Benzophenone
95
a Reaction conditions: rac-1a (8 mmol), toluene (10 mL), iso-propyl butyrate (16 mmol), co-catalyst (0.8 mmol), catalyst 4 (0.04 mmol) and
Novozymꢁ 435 (60 mg), N2 atmosphere, T = 70 ꢂC, p ! 190 mbar.
b Complete conversion of 1a in conjunction with partial transfer hydrogenation of 2a.
c Methyl butyrate used as acyl donor at 205 mbar.

G. K. M. Verzijl et al. / Tetrahedron: Asymmetry 16 (2005) 1603–1610
1607
Table 4. DKR of benzylic and aliphatic secondary alcohols 1a–mc
one, 2,4-dimethyl-3-pentanone can be easily removed by
distillation at the end of the reaction.
O
4, Novozym 435,
2,4-dimethyl-3-pentanone (10 mol %)
OH
R2
O
C3H7
2.3. Combined transfer hydrogenation and DKR
R1
R1
R2
isopropyl butyrate (2 eq.),
toluene, 70oC, 190 mbar
Since most racemic alcohols are prepared from the cor-
responding ketones we were interested to test the possi-
bility of combining a transfer hydrogenation and a
DKR in a domino reaction. This is indeed possible
according to the process shown in Scheme 4.
1 a-m
(R)-5 a-m
1
2
1a R1=Ph; R2=Me
1g R = -FC6H4; R =Me
1h R1=PhOCH2; R2=Me
1i R1=2-furyl; R2=Me
p
OH
1b R1=Ph; R2=Et
1c R1=p-ClC6H4; R2=Me
1d R1=p-OMeC6H4; R2=Me 1k R1=n-C6H13; R2=Me
1e R1=m-CF3C6H4; R2=Me 1l R1=t-Bu; R2=Me
1m R1=c-C6H11; R2=Me
n
The reaction was initiated by the addition of a substoi-
chiometric amount (15 mol %) of iso-propanol gener-
ating 1a by catalytic transfer hydrogenation at
atmospheric pressure catalysed by 4. In the presence of
lipase, enantioselective acylation of 1a with isopropyl
butyrate afforded the corresponding butyrate ester 5a
with generation of isopropanol as by-product. At the
same time, the produced iso-propanol was used as
hydrogen source for further reduction of ketone. At
atmospheric pressure however, ketone 2a was converted
to optically active ester 5a in only 10% yield in 4 h, indi-
cating that the system equilibrates with acetone and
isopropanol. Continuing the reaction by selective
distillation of acetone at 300 mbar shifts the equilibrium
furnishing 5a in 50% yield and >99% ee after 68 h. In
this experiment it has been shown for the first time that
starting with only a substoichiometric amount of iso-
propanol, a reasonable yield can be obtained for the
conversion of a ketone to an optically active ester by
combining a catalytic transfer hydrogenation/racemis-
ation and an enzymatic resolution that produces a hydro-
gen source as by-product. Unfortunately, distillation of
acetone is accompanied by removal of isopropanol to a
certain extent, leading to incomplete conversion.
1f n=2
1j n=1
Entry
Substrate
4
(mol %)
Enzyme
(mg)
t
5a–ma
(%)
Ee
(%)
(h)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
0.5
0.5
0.5
0.5
1
60
60
60
60
60
60
40
40
40
40
40
40
68
40
68
40
40
40
40
40
40
96
94
99
>99
99
96
93
>99
>99
>99
91
90
0.5
92>99
91
98
7
1g
0.5
60
99
99
8
1h
1i
1
10
20
75
87
84
95
9
0.5
0.5
0.5
0.5
0.5
10
11
12
13
1j
30
20
87
99
95
1k
1l
90
120
60
75b
97
97
>99
1m
a GC assay yield.
b Reaction was carried out at 210 mbar (p ! 210 mbar in order to
suppress distillation of 1l).
c Reaction conditions: rac-alcohol (8 mmol), toluene (10 mL), iso-
propyl butyrate (16 mmol), 2,4-dimethyl-3-pentanone (0.8 mmol),
catalyst 4 and Novozymꢁ 435 (see table for further details), N2
atmosphere, T = 70 ꢂC, p ! 190 mbar.
2.4. DKR of secondary alcohols with isopropyl butyrate
The scope of our system is illustrated by the transform-
ation of a wide range of different secondary alcohols.
Using the conditions established in the above studies,
both benzylic and aliphatic secondary alcohols 1a–m
were converted to the corresponding optically active
butyrate esters 5a–m (Table 4). All of the reactions
shown were performed with reagent grade, unpurified
materials.
methyl to ethyl 1b (entries 1–2). To our surprise, we
found that the ratio between the rates of the catalytic re-
dox racemisation and the enzymatic acylation were very
similar for all benzylic substrates. Prolonging of the
reaction time from 40 to 68 h did not result in a signifi-
cant higher yield of 5f (entry 6). In contrast, 1g was
almost completely converted to the product by
continuation of the DKR for a longer period (entry 7).
For the other substrates, optimisation of the catalyst
amounts for each substrate was essential for a high level
of enantioselectivity (entries 8–12). In sharp contrast to
previous reports,11a Novozymꢁ 435 appeared to have a
Substituents on the aromatic ring did not affect the
results significantly (entries 1–7), nor did the prolongation
of the alkyl chain adjacent to the carbinol group from
O
O
O
O
C3H7
+
4, Novozym 435,
O
O
C3H7
+
toluene, i-PrOH (cat.),
70oC, P --> 300 mbar, 68 h
(2 eq.)
2a
5a
Cy: 50 %
e.e.: > 99 %
Scheme 4.

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G. K. M. Verzijl et al. / Tetrahedron: Asymmetry 16 (2005) 1603–1610
lower stereoselectivity for 1h. Unfortunately, attempts
to improve the selectivity by examining the balance be-
tween the enzyme and racemisation catalyst did not lead
to enhancement of the enantioselectivity (entry 8).
For substrate 1a, the DKR was also demonstrated with
methyl phenylacetate under the standard conditions
developed for isopropyl butyrate (entry 1). Surprisingly,
the simple replacement of isopropyl butyrate as the acyl
donor resulted in a tremendous improvement in the
enantioselectivity of 1h. As recently pointed out in the
literature, the enantioselectivity of 1-(2-furyl) ethanol
1i, an interesting chiral building block, could also be im-
proved by the application of other lipases using iso-
propenyl acetate as an acylating agent.17 However, with
Novozymꢁ 435 acting as lipase, it gave a good perfor-
mance in the DKRÕs with methyl phenylacetate as acyl-
ating agent affording the product ester in high yield and
enantiomeric excess. The enantioselectivity of the reso-
lution of 2-octanol 1k using methyl phenylacetate as
acylating agent could also be improved.
Heteroaromatic substrate alcohol 1i bearing an oxygen
atom on the aromatic ring, is an excellent substrate for
the enzymatic reaction. Diminishing the enzyme amount
was necessary to preserve the enantioselectivity of the
reaction (entry 9). For the same reason, the enzyme
reaction was retarded by lowering the enzyme quantity
for the cyclic aromatic substrate 1j and 2-octanol 1k.
The remaining alcohol with a low enantiomeric excess
and the corresponding ketone are present in the final
reaction mixture in different ratios for all substrates
tested. The ratio of alcohol and ketone depended on
the equilibration conditions, which in turn depended
on the oxidation potential of both the substrate ketone
and 2,4-dimethyl-3-pentanone co-catalyst.
3. Conclusion
The low cost and lack of appreciable toxicity of com-
mon alkyl esters makes their use as acyl donors both
economically and environmentally attractive.18 For the
first time we have demonstrated a very efficient DKR
of secondary alcohols using non-excessive amounts
(2equiv) of simple esters as acylating agents together
with selective distillation of the acyl donor residue.
The DKR is very effective with respect to catalyst load-
ing and requires only small quantities of Ru-catalyst 4
(up to 0.25 mol %) and Novozymꢁ 435. Furthermore,
we have reported the potential use of the liberated alco-
hol residue as a mild hydrogen source in the reduction of
ketones followed by stereoselective transesterification
for the synthesis of optically active esters.
Following the standard procedure for 1l, the enzyme
reaction became slow due to the extra steric bulk on
the substrate. An acceptable reaction speed was
achieved by doubling the amount of lipase. Unfortu-
nately, standard distillation conditions gave less than
the expected yield due to substrate distillation. Repeat-
ing the reaction at a higher distillation pressure afforded
5l in only 75% yield.
Substrate alcohol 1m approximately resembles the steric
bulk of 1a inducing a high enantioselectivity of the en-
zyme with a similar catalyst ratio. 1-Cyclohexylalcohol
1m represents a successful example of the DKR of sec-
ondary aliphatic alcohols. Alcohol 1m was resolved in
remarkably good yield and excellent enantiomeric excess
(entry 13).
An important drawback of catalyst 4 in the DKR is the
use of ketone as co-catalyst, which complicates the iso-
lation of the product. Furthermore, Ru3CO12 the raw
material for the preparation of the racemisation catalyst
is not readily available in large quantities at acceptable
costs. In due course, we will report the solutions we have
found for these remaining problems, including a simple
isolation of the product, alternative catalysts and cata-
lyst recovery.12a
As outlined before, improving the enantioselectivity can
be accomplished by selection of the proper acylating
agent. In the next set of experiments, it is demonstrated
that for 1h, 1i and 1k, the insufficient enantioselectivities
obtained with isopropyl butyrate could be enhanced
through the use of methyl phenylacetate (Table 5).
Table 5. DKR using methyl phenylacetate as acyl donora
4. Experimental
4.1. General
O
4, Novozym 435,
2,4-dimethyl-3-pentanone (10 mol %)
Ph
OH
R2
1a, h, i, k
O
R1
R1
R2
methyl phenylacetate (2 eq.),
toluene, 70oC,190 mbar
Solvents, substrates 1a–m, acylating agents (simple es-
ters), ketones, Ru3CO12 and tetraphenylcyclopentadi-
enone were obtained commercially and used without
further purification. Novozymꢁ 435 is commercially
available immobilised Candida Antartica Lipase B.
6a, h, i, k
Entry Substrate 4 (mol %) Enzyme (mg) Yield (%) Ee (%)
1
2
3
4
1a
1h
1i
0.5
1
60
20
30
20
93
88
94
84
>99
>99
99
4.2. [(C4Ph4COHOCC4Ph4)(l-H)][(CO)4Ru2]419
0.5
0.5
1k
>99
Catalyst 4 was prepared from Ru3CO12 and tetrapheny-
lcyclopentadienone according to the literature.19 1H
NMR (300 MHz, CDCl3) d (ppm) À18.3 (s, Ru-H),
7.1 (m, phenyls), 13C NMR (75 MHz, CDCl3) d (ppm)
88.1 (s), 103.9 (s), 127.2 (d), 127.9 (d), 128.1 (d), 128.2
a Reaction conditions: rac-alcohol (8 mmol), toluene (10 mL), methyl
phenylacetate (16 mmol), 2,4-dimethyl-3-pentanone (0.8 mmol), cat-
alyst 4 and Novozymꢁ 435 (see table for further details), N2 atmo-
sphere, T = 70 ꢂC, p ! 190 mbar, 40 h.

G. K. M. Verzijl et al. / Tetrahedron: Asymmetry 16 (2005) 1603–1610
1609
(d), 130.6 (s), 131.0 (s), 131.4 (d), 132.4 (d), 154.6 (s),
201.2 (s).
4.7. (R)-1-Indanyl butyrate 5j
Purification by flash chromatography (hexane/EtOAc)
afforded (R)-1-indanyl butyrate 5j (1.21 g, 74%) as a col-
4.3. General procedure for the dynamic kinetic resolution
of secondary alcohols 1a–m
20
D
1
ourless liquid. ½aŠ ¼ þ76:5 (c 1.00, CHCl3); H NMR
(300 MHz, CDCl3) d (ppm) 0.96 (t, 3H, CH3), 1.67 (sex-
tet, 2H, CH2), 2.12 (m, 1H, CH2), 2.31 (t, 2H, CH2),
2.53 (m, 1H, CH2), 2.92 (m, 1H, CH2), 3.10 (m, 1H,
CH2), 6.24 (dd, 1H, CH), 7.26 (m, 3H, Ar), 7.42 (d,
1H, Ar); 13C NMR (75 MHz, CDCl3) d (ppm) 14.0
(CH3), 18.9 (CH2), 30.6 (CH2), 32.7 (CH2), 36.8
(CH2), 78.4 (CH), 125.2 (CH), 125.9 (CH), 127.1
(CH), 129.2 (CH), 141.6 (C), 144.7 (C), 174.1 (C).
A mixture of rac-alcohol 1 (8 mmol), acyl donor
(16 mmol), 2,4-dimethyl-3-pentanone (91.4 mg, 0.8
mmol), Novozymꢁ 435 and 4 in toluene (10 mL) was
degassed with dry nitrogen at room temperature. The
DKR was carried out under stirring at 70 ꢂC and distil-
lation of the acyl donor residue conducted by a slow de-
crease of the pressure to 195 mbar over a period of 1 h.
The ees of the alcohol and ester, as well as the conver-
sion of the racemic alcohol, were monitored by chiral
4.8. (R)-2-Octyl phenylacetate 6k
GC analysis using
a
CP-Chirasil-DEX CB
Purification by flash chromatography (hexane/EtOAc)
afforded (R)-2-octyl phenylacetate 6k (1.25 g, 63%) as
(25 m · 0.25 mm) column with the exception of ester
6i. The ee of 6i was determined by hydrolysis of the ester
and ee determination of the corresponding alcohol. For
the ee determination of 1k and 1m, the alcohol was con-
verted to the acetate ester by derivatisation with acetic
anhydride in the presence of DMAP as acylation
catalyst.
20
D
1
a colourless liquid. ½aŠ ¼ À12:5 (c 1.04, CHCl3); H
NMR (300 MHz, CDCl3) d (ppm) 0.88 (t, 3H, CH3),
1.22 (m, 11H, b-CH3 + 4 · CH2), 1.59 (2 · m, 2H, dia-
stereotopic, b-CH2), 3.60 (s, 2H, CH2), 4.92(sextet,
1H, a-H), 7.30 (m, 5 H, Ph); 13C NMR (75 MHz,
CDCl3) d (ppm) 14.4 (CH3), 20.3 (CH3), 22.9 (CH2),
25.6 (CH2), 29.4 (CH2), 32.1 (CH2), 36.3 (CH2), 42.2
(CH2), 71.9 (CH), 127.3 (CH), 128.9 (CH), 129.6
(CH), 134.8 (C), 171.6 (C).
4.4. (R)-1-Phenylethyl butyrate 5a
Purification by flash chromatography (hexane/EtOAc)
afforded (R)-1-phenylethyl butyrate 5a (1.28 g, 83%) as
20
D
1
a colourless liquid. ½aŠ ¼ þ92:6 (c 0.99, CHCl3); H
Acknowledgements
NMR (300 MHz, CDCl3) d (ppm) 0.95 (t, 3H, CH3),
1.55 (d, 3H, CH3), 1.64 (sextet, 2H, CH2), 2.32 (t, 2H,
CH2), 5.91 (q, 1H, CH), 7.32(m, 5H, Ph); 13C NMR
(75 MHz, CDCl3) d (ppm) 14.0 (CH3), 18.9 (CH2),
22.6 (CH3), 36.9 (CH2), 72.4 (CH), 126.4 (CH), 128.1
(CH), 128.8 (CH), 142.3 (C), 173.3 (C).
We thank Hans Kierkels for his helpful discussions and
valuable advice with respect to the biocatalyst issue in
the project. We thank the Ministry of Economic affairs
for a subsidy under the EET scheme (EETK97107 and
EETK99104).
4.5. (R)-1-Phenylpropyl butyrate 5b
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