Lipase-promoted dynamic kinetic resolution of racemic β-hydroxyalkyl sulfones

Article abstract of DOI:10.1016/j.tetasy.2005.05.005

A series of racemic aryl β-hydroxyalkyl sulfones have been successfully transformed into the corresponding optically active O-acetyl derivatives in high yields (up to 80%) with enantiomeric excesses more than 99% using a dynamic kinetic resolution procedure, in which a lipase-promoted kinetic resolution is combined with a concomitant ruthenium-catalysed racemization of the substrates.

Full text of DOI:10.1016/j.tetasy.2005.05.005

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2157–2160
Lipase-promoted dynamic kinetic resolution of racemic
b-hydroxyalkyl sulfones
a,
a
a
b
Piotr Kiełbasinski, * Michał Rachwalski, Marian Mikołajczyk, Marcel A. H. Moelands,
Binne Zwanenburgb and Floris P. J. T. Rutjesb,*
´
aCentre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of Heteroorganic Chemistry,
´ ´
Sienkiewicza 112, 90-363 Łodz, Poland
bRadboud University Nijmegen, Institute for Molecules and Materials, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Received 19 April 2005; accepted 2 May 2005
Available online 26 May 2005
Abstract—A series of racemic aryl b-hydroxyalkyl sulfones have been successfully transformed into the corresponding optically
active O-acetyl derivatives in high yields (up to 80%) with enantiomeric excesses more than 99% using a dynamic kinetic resolution
procedure, in which a lipase-promoted kinetic resolution is combined with a concomitant ruthenium-catalysed racemization of the
substrates.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Over the course of our investigations on the enzyme-
promoted syntheses of chiral heteroorganic com-
pounds,8,9 we became interested in the preparation of
b-hydroxyalkyl sulfones of high enantiomeric purity.
Taking into account the well-known drawback of
kinetic resolutions, in which the yield of the desired prod-
uct is limited to 50%, we focussed our attention on one
of the deracemization techniques,10 namely the dynamic
kinetic resolution,11 which combines kinetic resolution
with an in situ racemization of the starting material.12
As the products of interest are secondary alcohols, we
decided to adopt the procedure, which utilizes enzyme-
catalysed acetylation combined with ruthenium-cataly-
sed racemization.13,14 This procedure has recently been
applied for the dynamic kinetic resolution of a-hydroxy
acid esters15 and a- and b-hydroxyalkanephospho-
nates,16 which in both cases gave the desired O-acyl
derivatives in high yields and excellent eeꢀs (over 99%).
In this contribution we report on the dynamic kinetic
resolution of a series of racemic b-hydroxyalkyl sulfones
1.
Sulfones are an interesting class of compounds, which
are widely used in organic synthesis due to the ability
of the sulfonyl group to stabilise an adjacent carban-
ionic centre,1 with sulfones with a stereogenic carbon
atom being of particular interest. Optically active b-
hydroxyalkyl sulfones, for example, have been used as
building blocks in the synthesis of a variety of enantio-
pure cyclic compound classes, such as lactones,2–4 tetra-
hydrofurans5 and furanones.2 So far, these optically
active b-hydroxyalkyl sulfones have been synthesized
both by chemical methods, for example, via oxidation
of chiral b-hydroxyalkyl sulfoxides,3 and by biocatalytic
approaches. The latter comprise of bakerꢀs yeast-medi-
ated reduction of b-oxo sulfones leading to the (S)-enan-
tiomers of the corresponding b-hydroxyalkyl sulfones,6
and a lipase-catalysed acylation of racemic b-hydroxy-
alkyl sulfones, performed under kinetic resolution con-
ditions.7 Although the kinetic resolution procedure
allowed both enantiomers of a-, b- and c-hydroxyalkyl
sulfones to be obtained, only one lipase (Porcine pan-
crease lipase) was found effective with the enantiomeric
excesses of the products low to moderate.7
2. Results and discussion
2.1. Kinetic resolution of b-hydroxyalkyl sulfones
*
Corresponding authors. Fax: +48 42 6847126 (P.K.); fax: +31 24
3653393 (F.P.J.T.R.); e-mail addresses: piokiel@bilbo.cbmm.lodz.pl;
f.rutjes@science.ru.nl
Since the previous publication7 concerning enzyme-
promoted kinetic resolutions of hydroxyalkyl sulfones
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.05.005

´
P. Kiełbasinski et al. / Tetrahedron: Asymmetry 16 (2005) 2157–2160
2158
AcOR1
Lipase
reported only a single example of a b-hydroxyalkyl sul-
fone in combination with a single effective enzyme, we
decided to begin our studies by screening several lipases
for the enantioselective acetylation of selected b-hydr-
oxy sulfones rac-1. Thus, b-hydroxyalkyl sulfones rac-
1a and b were treated with an excess of vinyl acetate
in the presence of various lipases (Scheme 1). It should
be emphasized that the addition of catalytic amounts
of pyridine to the reaction medium proved crucial,17
since in the absence of pyridine, the reaction was very
slow or did not proceed at all. The resulting b-acet-
oxyalkyl sulfones 2a and 2b were separated from the
unreacted substrates using column chromatography
with the results summarized in Table 1. On inspection
of Table 1 it can be seen that the best results were ob-
tained when Candida antarctica lipase B (CAL-B) was
applied (E >100), although lipases AK and PS also
exhibited a reasonable stereoselectivity (E >50). In all
cases, the preferential formation of the esters derived
from the (R)-enantiomers of the substrates has been
observed, which is in agreement with the literature data.7
O
S
O
O
S
O
R
R
Ar
Ar
OH
OAc
Ru-catalyst
Pyridine-cat.
(R)-2
rac-1
a: Ar = Ph, R = Me
b: Ar = p-Tol, R = Me
c: Ar = p-Tol, R = Et
R1 = p-ClC6H4 4, CH=CH2
5
Scheme 2.
mentary to the bakerꢀs yeast-promoted reduction of the
corresponding b-oxo sulfones, which leads to (S)-2.6 A
general procedure, which is described in the Experimen-
tal, was applied to the substrates shown in Scheme 2
with the results shown in Table 2.
O
O
H
Ph
Ph
Ph Ph
Ru Ru
OC
CO
Ph
Ph
Ph
OC
CO
H
AcO
O
S
O
O
S
O
O
S
O
Lipase
3
R
R
R
Ar
Ar
Ar
Pyridine-cat.
OH
OH
OAc
The reactions were performed in toluene (or in some
cases in benzene with comparable results) at 30 °C in
the presence of a catalytic amount of pyridine. In the
first set of experiments, we used p-chlorophenyl acetate
4 as an acetylating agent, following the suggestion of
Pamies and Ba¨ckvall16 that this reagent, in contrast to the
commonly used vinyl acetate 5, is more compatible with
the ruthenium hydride catalyst 3 and gives better yields
of the acetylated products. However, we encountered
severe difficulties in separating the desired products from
the excess of 4 and the resulting p-chlorophenol via
chromatography. Therefore, in a later stage, we started
using vinyl acetate 5 as the acetylating agent and found
out that the product yields and enantioselectivities of
both reactions were comparable. The enantioselectivity
depended on the lipase used and generally ranged from
very good to excellent. As expected on the basis of ki-
netic resolution experiments, the best results were ob-
tained with the lipase from C. antarctica B (CAL-B).
rac-1
(S)-1
(R)-2
a: Ar = Ph, R = Me
b: Ar = p-Tol, R = Me
Scheme 1.
2.2. Dynamic kinetic resolution of b-hydroxyalkyl sulf-
ones 1
On the basis of the aforementioned results, we decided
to combine the enzyme-promoted kinetic resolution of
b-hydroxyalkyl sulfones 1 with a ruthenium-catalysed
racemization of the substrates using catalyst 3, origi-
nally prepared by Menasche and Shvo18 and later inves-
tigated and used by Pamies and Ba¨ckvall.16 Since the
dynamic kinetic resolution results in the formation of
only one product enantiomer, which on the basis of
our results (Scheme 1) is (R)-2, this approach is comple-
Table 1. Kinetic resolution of rac-1
Entry
Substrate
Lipase
cc (%)
(R)-2
Yieldb (%)
(S)-1
[a]D
Yieldb (%)
[a]D
ee (%)
Ed
58
a
a
1
2
3
4
1a
AK
CAL
LPL
PS
41
47
43
35
38
47
41
30
+0.5
+0.6
+0.45
+0.5
59
52
51
65
+8.5
+10.2
+9.0
65
85
65
51
127
26
+6.1
62
5
6
7
8
1b
AK
CAL
LPL
PS
39
46
43
35
36
46
43
35
+0.5
+0.6
+0.55
+0.4
58
38
49
53
+9.0
+10.0
+9.3
60
82
66
50
58
137
30
+7.2
45
a In chloroform.
b Isolated yield, relative to the racemic compound.
c Conversion (determined by 1H NMR).
d E = [ln(1 ꢀ c)(1 ꢀ ees)]/[ln(1 ꢀ c)(1 + ees)].

´
P. Kiełbasinski et al. / Tetrahedron: Asymmetry 16 (2005) 2157–2160
2159
Table 2. Dynamic kinetic resolution of rac-1
[a]D of 1c
ee (%)b of 1c
a
a
Entry
Substrate
Enzyme
Yield (%) of 2
[a]D of 2
1
2
3
4
1a
AK
CAL
LPL
PS
66
70
68
64
ꢀ0.8
ꢀ1.0
ꢀ0.8
ꢀ1.1
ꢀ9.6
ꢀ12.0
ꢀ9.5
90
>99
90
ꢀ11.8
>99
5
6
7
8
1b
1c
AK
CAL
LPL
PS
75
79
70
75
ꢀ1.0
ꢀ1.1
ꢀ0.6
ꢀ0.9
ꢀ3.6
ꢀ4.4
ꢀ4.0
ꢀ4.4
ꢀ10.2
ꢀ11.6
ꢀ6.5
90
>99
50
ꢀ10.3
90
9
AK
CAL
LPL
PS
30
ꢀ5.7
ꢀ9.2
ꢀ8.8
ꢀ9.2
85
>99
90
10
11
12
42d
30
34
>99
a In chloroform.
b Determined by 1H NMR.
c Obtained via reduction of 2 with BH3ÆMe2S in THF.
d Vinyl acetate was used as the acetyl donor.
Surprisingly, much lower yields and enantioselectivities
were observed in the acetylation of 1c, although it differs
from 1b only by one methylene group in the alkyl chain.
Nevertheless, it must be stressed that under these cir-
cumstances, we were never able to obtain the b-acet-
oxyalkyl sulfones 2 in quantitative yields. In all cases,
unusual by-products were isolated in low yields, which
are probably complexes of 1 with the ruthenium catalyst
3. These products were yellow and upon treatment with
acids gave unreacted 1 and decomposition products of
the catalyst 3. It is noteworthy that similar findings were
reported by Pamies and Ba¨ckvall.16
3. Conclusions
An efficient dynamic kinetic resolution of racemic b-
hydroxyalkyl sulfones has been achieved using lipase
mediated acetylation with p-chlorophenyl acetate or
vinyl acetate as the acyl donors and a ruthenium catalyst
for the in situ racemization of the substrate.
4. Experimental
4.1. General
Finally, the ee values of the b-hydroxyalkyl sulfones 1
The enzymes were purchased from AMANO or FLU-
KA. NMR spectra were recorded on Bruker instruments
at 200 MHz with CDCl3 or C6D6 as solvents. Optical
rotations were measured on a Perkin–Elmer 241 MC
polarimeter. Column chromatography was carried out
using Merck 60 silica gel. TLC was performed on Merck
60 F254 silica gel plates. The enantiomeric excess (ee) val-
1
were determined by H NMR using (R)-1,10-bi-2-naph-
thol as a chiral solvating agent. However, this method
could not be directly applied to the b-acetoxyalkyl sulf-
ones 2, since no separation of the NMR peaks was ob-
served. Therefore, they had to be transformed into the
corresponding hydroxy derivatives. Attempts aimed at
a straightforward hydrolysis or methanolysis failed,
despite the fact that Chinchilla et al.7 reported successful
examples of this particular transformation, albeit with
a certain degree of racemization. To accomplish this
transformation in a satisfactory manner, we applied a
borane/dimethyl sulfide complex, which proved to be
very efficient in removing the acetyl group under mild
conditions leading to the desired b-hydroxyalkyl sulf-
ones 1 in quantitative yields without any racemization
(Scheme 3).
1
ues were determined by H NMR, using (R)-1,10-bi-2-
naphthol as a chiral solvating agent. 4-Chlorophenyl
acetate was prepared according to the procedure de-
scribed by Persson et al.13
4.2. Synthesis of racemic 1—general procedure
A solution of a corresponding aryl methyl sulfone in
THF was cooled to ꢀ78 °C. At this temperature, under
argon, equimolar amounts of 2.5 M n-BuLi and, after
20 min of stirring, the corresponding aldehyde was
added. The mixture was stirred and monitored by
TLC. After 3 h, 5% aqueous NH4Cl was added, the
solution extracted with chloroform and dried over
MgSO4. The solvent was evaporated to yield pure b-
hydroxyalkyl sulfone 1. Other methods of preparation
of 1 and their spectral data were described by Crumbie
et al.6
O
S
O
O
S
O
.
BH3 SMe2
R
R
Ar
Ar
THF
OAc
OH
(R)-2
(R)-1
a: Ar = Ph, R = Me
b: Ar = p-Tol, R = Me
c: Ar = p-Tol, R = Et
4.3. Kinetic resolution of 1—general procedure
A mixture of racemic 1 (1 mmol), enzyme (20 mg), vinyl
acetate (2 mL) and pyridine (five drops) was stirred in
Scheme 3.

´
P. Kiełbasinski et al. / Tetrahedron: Asymmetry 16 (2005) 2157–2160
2160
isopropyl ether (5 mL) and chloroform (1 mL) at 30 °C.
The reaction was monitored by TLC and stopped at ca.
50% conversion (after 48 h). The reaction mixture was
filtered through a DowexÒ 50 W, the solvent then evap-
orated and the crude mixture separated by column chro-
matography (ethyl acetate/petroleum ether in gradient
from 1:100 to 1:1) to yield b-acetoxy-2 and unreacted
b-hydroxyalkyl sulfone 1.
(AB, 2H), 5.12–5.29 (m, 1H), 7.36 (d, J = 8.5, 2H),
7.77 (d, J = 8.5, 2H); 13C NMR (CDCl3): d = 10.9,
21.6, 23.1, 27.3, 59.9, 70.0, 129.1, 130.8, 137.4, 145.8,
170.8; MS (CI): m/z 271 (M+H); Anal. Calcd for
C13H18O4S: C, 57.76; H, 6.71; S, 11.86. Found: C,
57.96; H, 6.96; S, 11.73.
Acknowledgements
4.4. General procedure for the ruthenium and enzyme-
coupled dynamic kinetic resolution of 1
The work was carried out under a Polish–Dutch Joint
Research Project: ꢁDynamic kinetic resolution and
desymmetrization of sulfur and phosphorus compounds
using enzymesꢀ. Financial support from the Ministry of
Science and Information Society Technologies (Poland),
Grant No. 3 T09A 166 27 for P.K., is gratefully
acknowledged.
Catalyst [Ru(CO)4(l-H)(C4Ph4–COHOCC4Ph4)]
3
(20 mg, 0.02 mmol) and enzyme (40 mg) were added to
the mixture of racemic 1 (100 mg, 0.5 mmol), 4-chloro-
phenyl acetate 4 (250 mg, 1.5 mmol) or vinyl acetate
5 (1 mL) and pyridine (five drops) in toluene (prefera-
bly) or benzene (7–10 mL). The reaction was stirred at
30 °C and monitored by TLC. After 72 h, the reaction
mixture was filtered through a DowexÒ 50 W, the sol-
vent then evaporated and the crude mixture separated
by column chromatography (ethyl acetate/petroleum
ether 1:1 in gradient from 1:100 to 1:1) or by TLC (ethyl
acetate/petroleum ether 1:1) to yield the corresponding
b-acetoxyalkyl sulfone 2.
References
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alkyl derivative 1 by reduction with an equimolar
amount of BH3ÆMe2S in THF (2.0 M), for 1 h at
65 °C. THF was then evaporated, 5% aqueous KHCO3
added and the aqueous layer extracted with CH2Cl2 and
dried over MgSO4. After evaporation of the solvent,
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´
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´
Mikołajczyk, M., Kiełbasinski, P., Eds.; Kluwer Aca-
demic: Dordrecht, 2000, pp 161–191.
White solid, mp = 87–88 °C; 1H NMR (CDCl3):
d = 1.32 (d, J = 6.4, 3H), 1.74 (s, 3H), 3.17–3.55 (AB,
2H), 5.21–5.30 (m, 1H), 7.51–7.69 (m, 3H), 7.89 (d,
J = 8.4, 2H); 13C NMR (CDCl3): d = 20.29, 20.7, 60.6,
65.1, 128.1, 129.2, 133.8, 139.5, 169.6; MS (CI): m/z
243 (M+H); Anal. Calcd for C11H14O4S: C, 54.53; H,
5.82; S, 13.23. Found: C, 54.74; H, 5.81; S, 13.47.
_
´
´
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White solid, mp = 45–47 °C; 1H NMR (CDCl3):
d = 1.32 (d, J = 6.4, 3H), 1.80 (s, 3H), 2.44 (s, 3H),
3.15–3.53 (AB, 2H), 5.20–5.30 (m, 1H), 7.36 (d,
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d = 21.2, 21.7, 22.56, 61.7, 66.1, 129.1, 130.8, 137.4,
145.8, 170.6; MS (CI): m/z 257 (M+H); Anal. Calcd
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56.23; H, 6.22; S, 12.25.
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1
Yellow oil; H NMR (CDCl3): d = 0.82–0.89 (t, 3H),
1.62–1.69 (m, 2H), 1.80 (s, 3H), 2.44 (s, 3H), 3.18–3.48