Chemoenzymatic dynamic kinetic resolution of β-halo alcohols. An efficient route to chiral epoxides

Article abstract of DOI:10.1021/jo026157m

Enzymatic resolution of β-chloro alcohols in combination with ruthenium-catalyzed alcohol isomerization led to a successful dynamic kinetic resolution (conversion up to 99% and ee up to 97%). The efficiency of the DKR is dramatically reduced when β-bromo alcohols are used. The presence of the bromo substituent causes decomposition of the ruthenium catalysts, which triggers the progressive deactivation of the enzyme. The synthetic utility of this procedure has been illustrated by the practical synthesis of different chiral epoxides.

Full text of DOI:10.1021/jo026157m

Ch em oen zym a tic Dyn a m ic Kin etic Resolu tion of â-Ha lo Alcoh ols.
An Efficien t Rou te to Ch ir a l Ep oxid es
Oscar Pa`mies* and J an-E. Ba¨ckvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
SE-10691 Stockholm, Sweden
jeb@organ.su.se; pamies@organ.su.se
Received J uly 9, 2002
Enzymatic resolution of â-chloro alcohols in combination with ruthenium-catalyzed alcohol
isomerization led to a successful dynamic kinetic resolution (conversion up to 99% and ee up to
97%). The efficiency of the DKR is dramatically reduced when â-bromo alcohols are used. The
presence of the bromo substituent causes decomposition of the ruthenium catalysts, which triggers
the progressive deactivation of the enzyme. The synthetic utility of this procedure has been
illustrated by the practical synthesis of different chiral epoxides.
SCHEME 1. Dyn a m ic Kin etic Resolu tion (DKR)
In tr od u ction
Dynamic kinetic resolution (DKR) has become an
active and important area of research in organic synthe-
sis.1 DKR is a powerful tool to prepare enantiomerically
enriched compounds in high yields that overcomes the
limitation of the maximum 50% yield in the traditional
kinetic resolution (Scheme 1).2 We have recently devel-
oped an easy approach to perform DKR on alcohols in
which the traditional enzymatic kinetic resolution is
combined with an in situ racemization of the substrate
using a ruthenium-hydrogen-transfer catalyst.3
SCHEME 2
In the past few years, we and others have applied this
DKR approach to the preparation of different function-
alized alcohols (i.e., hydroxy esters,4 hydroxy nitriles,5
azido alcohols,6 allylic alcohols7) that would lead to
interesting building blocks for the synthesis of high-value
compounds (e.g., pharmaceuticals, natural products, etc.).
includes among others the formation of chiral epoxides
and â- and γ-amino alcohols, widely used as adrenergic
receptor blockers and immune stimulants (Scheme 2).8
Previous attempts to use â-halo alcohols in DKR were
unsuccessful and gave only moderate ee’s and yields.3b,9
We now report our investigations toward the efficient
synthesis of enantiopure â-halo acetates from â-halo
alcohols 1 via DKR.
Chiral â-halo alcohols are important structural ele-
ments for asymmetric catalysis. Thus, a wide range of
different compounds are accessible due to the versatility
conferred by the presence of the halogen that can readily
act as a good leaving group. The possible transformations
Resu lts a n d Discu ssion
Kin etic Resolu tion . A primary requirement for a
successful DKR is that the KR conditions are compatible
with the racemization process. Therefore, we screened
different commercially available lipases in the kinetic
resolution of 2-chloro-1-phenylethanol 1a under different
reaction conditions. 4-Chlorophenyl acetate 3 was used
as acyl donor since it is known to be compatible with
ruthenium-catalyzed racemization of alcohols. The use
of vinyl acetate, commonly used as acyl donor, results in
(1) For recent reviews on DKR, see: (a) El Gihani, M. T.; Williams,
J . M. J . Curr. Opin. Chem. Biol. 1999, 3, 11. (b) Strauss, U. T.; Felfer,
U.; Faber, K. Tetrahedron: Asymmetry 1999, 10, 107. (c) Azerad, R.;
Buisson, D. Curr. Opin. Biotechnol. 2000, 11, 565. (d) Huerta, F. F.;
Minidis, A. B. E.; Ba¨ckvall, J .-E. Chem. Soc. Rev. 2001, 30, 321.
(2) Faber, K. Biotransformations in Organic Media, 3rd ed.;
Springer: Graz, Austria, 1996.
(3) (a) Larsson, A. L. E.; Persson, B. A.; Ba¨ckvall, J .-E. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1211. (b) Persson, B. A.; Larsson, A.
L. E.; LeRay, M.; Ba¨ckvall, J .-E. J . Am. Chem. Soc. 1999, 121, 1645.
(4) (a) Huerta, F. F.; Laxmi, Y. R. S.; Ba¨ckvall, J .-E. Org. Lett. 2000,
2, 1037. (b) Huerta, F. F.; Ba¨ckvall, J .-E. Org. Lett. 2001, 3, 1209. (c)
Runmo, A.-B. L.; Pa`mies, O.; Fabert, K.; Ba¨ckvall, J .-E. Tetrahedron
Lett. 2002, 43, 2983. (d) Pa`mies, O.; Ba¨ckvall, J .-E. J . Org. Chem. 2002,
67, 1261.
(8) Powell, J . R.; Waimer, I. W.; Drayer, D. E. In Drug Stereochem-
istry Analytical Methods and Pharmacology; Marcel Dekker: New
York, 1998.
(9) Kinetic resolution of â-halo alcohols with Candida antarctica
lipase B (CALB) has been reported to proceed with low selectivity:
Rotticci, D.; Haefner, F.; Orrenius, C.; Norin, T.; Hult, K. J . Mol. Catal.
B: Enzym. 1998, 5, 267.
(5) (a) Pa`mies, O.; Ba¨ckvall, J .-E. Adv. Synth. Catal. 2001, 343, 726.
(b) Pa`mies, O.; Ba¨ckvall, J .-E. Adv. Synth. Catal. 2002, 344, 947.
(6) Pa`mies, O.; Ba¨ckvall, J .-E. J . Org. Chem. 2001, 66, 4022.
(7) Lee, D.; Huh, E. A.; Kim, M.-J .; J ung, H. M.; Koh, J . H.; Park,
J . Org. Lett. 2000, 2, 2377.
10.1021/jo026157m CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/20/2002
9006
J . Org. Chem. 2002, 67, 9006-9010

Efficient Route to Chiral Epoxides
TABLE 1. Kin etic Resolu tion of 1a a
SCHEME 3
entry enzyme
solvent
toluene
N-435 toluene
% 2b % ee of 2a c % ee of 1a c Ed
1
2
3
4
5
6
PS-C
42
11
23
98
99
98
92
92
95
71
16
18
82
91
93
210
230
115
60
TABLE 3. Dyn a m ic Kin etic Resolu tion of r a c-1a
AK
toluene
PS-C
PS-C
PS-C
cyclohexane 47
DIPEe
50
50
75
130
TBMEf
a
Reactions were carried out on a 0.2 mmol scale with 20 mg of
enzyme and 3 equiv of 3 in 2 mL of solvent at 60 °C for 5 h.
T
t
% yield
%
%
b
d
Determined by NMR. c % ee determined by GC. Enantiomeric
entry substrate
R
X
(°C) (h)
of 2b
eec 5b
ratio. e Diisopropyl ether. f tert-Butyl methyl ether.
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Cl 60 48
Cl 70 48
Cl 80 48
Cl 70 72
Cl 70 72
74
85
79
96
95
95
9
3
2
3
1
TABLE 2. Lip a se-Ca ta lyzed Kin etic Resolu tion of r a c-1a
93 (85)d 95
69 (58)d 96
p-OMeC6H4
p-FC6H4
Ph
p-OMeC6H4
benzyl
Cl 70 72 >99 (91)d 93 <1
Br 70 72
Br 70 72
Cl 70 72
Cl 70 72
63
97
95
9
5
2
0
0
39e
9f
10g
11g
82 (74)d 91
% yield % ee % ee
1g
1h
PhOCH2
87
98
85
87
entry substrate
R
X
of 2b of 2c of 1c Ed
1-naphthyl-OCH2 Cl 70 72
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
Cl
Cl
Cl
Br
Br
Cl
Cl
42
46
47
43
41
46
54
55
56
98
97
95
97
96
88
82
83
65
71 210
87 185
85 105
72 140
77 115
a
Conditions: 0.2 mmol of rac-1, 0.6 mmol of 3, 4 mol % of 4,
p-OMeC6H4
p-FC6H4
Ph
p-OMeC6H4
benzyl
b
20 mg of PS-C lipase, and 2 mL of toluene. Yield measured by
NMR. Isolated yields in parentheses. c Enantiomeric excess mea-
d
sured by GC or HPLC. Reaction performed at 0.6 mmol scale.
e 61% of unreacted starting material. f 5 mg of enzyme used. 2.5
g
74
97
99
86
35
40
55
1
mg of enzyme used.
PhOCH2
1-naphthyl-OCH2 Cl
(iPr)OCOCH2
Cl
different substituents in the para position of the aromatic
ring influence the enantiomeric ratio and therefore the
efficiency of the process (entries 1-3). The effect of the
halogen group at the â-position was investigated compar-
ing substrates 1a and 1b with 1d and 1e, containing
chloro and bromo substituents at the â-positions, respec-
tively. The results indicate that the enzyme is more
selective for the chloro substrates than for the bromo
substrates. For the benzyl (1f) and aryloxymethyl deriva-
tives (1g and 1h ), the kinetic resolution proceed with low
enantiomeric ratios (entries 6-8). The KR of the isopropyl
4-chloro-3-hydroxybutanoate 1i proceed with very low
enantioselectivity (entry 9), probably due the similar size
of both substituents.
Dyn a m ic Kin etic Resolu tion . On the basis of our
preliminary results on KR, we combined the KR of â-halo
alcohols 1 using PS-C and the acyl donor 3 with a
ruthenium-catalyzed racemization process via hydrogen
transfer with catalyst 4. A feature of this catalyst is that
no addition of external base is needed as a co-catalyst,
since one of the coordinating sites of the ligand acts as a
basic center (Scheme 3).13 This is an important advantage
to other potential ruthenium/base racemization catalytic
systems, since the presence of an external base could
induce cyclization of the substrates to epoxides. The
results are summarized in Table 3. In all cases, small
amounts of ketone 5, formed during the hydrogen-
transfer process, were observed.
a
Conditions: 0.2 mmol of rac-1, 0.6 mmol of 3, 20 mg of
b
Pseudomonas sp. lipase (PS-C) in 2 mL of toluene at 60 °C. Yield
determined by NMR after 5 h. c Optical purity measured by GC
d
or HPLC. Enantiomeric ratio.
the formation of acetaldehyde after the acyl transfer
process, which interferes with the ruthenium-hydrogen-
transfer catalysts usually employed in the DKR.10 The
results are summarized in Table 1.
Although the enzyme Candida antarctica lipase B (N-
435) showed the highest enantiomeric ratio (entry 2), the
best combination of activity and selectivity was obtained
using Pseudomonas sp. lipase (PS-C) (entry 1).11 The use
of Pseudomonas fluorescens lipase (AK) show low activity
and selectivity under our conditions (entry 3).12 Moreover,
the results showed that the selectivity is very dependent
on the solvent. Thus, the best selectivity was observed
in toluene (entry 1), while the transesterification in
ethers and cyclohexane proceeded with significantly
lower enantiomeric ratios (entries 4-6).
We then applied this procedure to a series of â-halo
alcohols. The results are given in Table 2. The kinetic
resolution of different para-substituted 2-chloro-1-phenyl
alcohol derivatives 1a -c indicated that the presence of
(10) Ba¨ckvall, J .-E.; Chowdhury, R. L.; Karlsson, U.; Wang, G. Z.
In Perspectives in Coordination Chemistry; Williams, A. F., Floriani,
C., Merbach, A. E., Eds.; Helvetica Chimica Acta: Basel, 1992; p 463.
(11) PS-C lipase has been already successfully used in the KR of
â-halo alcohols; see: Bevinakatti, H. S.; Banerji, A. A. J . Org. Chem.
1991, 56, 5372.
(12) As an example of AK lipase transesterification of â-halo
alcohols, see: Hiratake, J .; Inagaki, M.; Nishioka, T.; Oda, J . J . Org.
Chem. 1988, 53, 6130.
Under “standard” conditions (i.e., 60 °C and 4 mol %
of 4), good enantioselectivity (96% ee) was achieved for
substrate 1a. However, the racemization proceeded slowly,
(13) Pa`mies, O.; Ba¨ckvall, J .-E. Chem. Eur. J . 2001, 7, 5052.
J . Org. Chem, Vol. 67, No. 25, 2002 9007

Pa`mies and Ba¨ckvall
F IGURE 1. Racemization of (S)-1a and (S)-1d vs time.
F IGURE 2. Formation of acetate 2d under DKR conditions:
(a) acyl donor 3 immediately added; (b) acyl donor 3 added
after 24 h.
resulting in a moderate yields of 2a after 48 h (entry 1).
In previous studies, we have shown that increasing the
temperature led to a significantly higher racemization
rate.6 Therefore, we performed the DKR at higher tem-
peratures (entries 2 and 3). At 70 °C, the activity was
better; however, at 80 °C, the activity was similar to that
at 60 °C. This can be explained by the partial deactivation
of the enzyme at this temperature.14 Interestingly, smaller
amounts of ketone 5a were formed at 70 and 80 °C than
at 60 °C.
The introduction of a methoxy substituent in the para
position of the phenyl moiety has a negative effect on the
efficiency of the process (entry 5). However, the presence
of a fluoro substituent in the para position has a slightly
positive effect on the outcome of the reaction (entry 6).
This is most likely due to the faster racemization of the
latter substrate.
TABLE 4. Ep oxid e F or m a tion
entry
substrate
R
% eeb
1
2
3
4
5
6
2a
2b
2c
2f
2g
2h
Ph
95
94c
92
90
83
86
p-OMeC6H4
p-FC6H4
benzyl
PhOCH2
1-naphthyl-OCH2
a
Conditions: 0.5 mmol of (S)-2, 3 equiv of LiOH, and 5 mL of
b
ethanol (95%) at room temperature. Enantiomeric excess mea-
sured by chiral GC or HPLC. c % ee measured on the correspond-
ing 1-(4-methoxyphenyl)ethanol obtained by reaction of 6c with
LiAlH4.15
The efficiency of the DKR is severely reduced when the
chloro substituent is replaced by a bromo substituent
(entries 4 and 5 vs 7 and 8). A possible explanation can
be found in the lower racemization rates of â-bromo
alcohols compared to â-chloro alcohols. Figure 1 suggests
that the presence of a bromo substituent at the â-carbon
results in decomposition of the racemization catalyst 4.
However, this cannot explain why acetate 2d is obtained
in a better ee than 2a , since the enzymatic KR proceeds
with better enantiopreference for 1a than 1d . Also, it is
difficult to rationalize why the KR limit of 50% is not
reached for substrate 1e. A likely explanation of these
results is that the enzyme undergoes deactivation. To
learn more about the causes of the deactivation, we first
investigated if the substrate poisons the enzyme. For this
purpose, we premixed the substrate with the enzyme in
toluene at 70 °C during 24 h and studied the kinetic
resolution of substrate 1d after addition of the acyl donor
3. Comparison of this with the normal kinetic racemiza-
tion indicates that the enzyme is not poisoned by the
substrate. We then studied if the decomposition of the
ruthenium catalyst 4 can affect the enzyme. For this
purpose, we premixed the substrate 1d with the enzyme
and the ruthenium catalyst 4 in toluene at 70 °C during
24 h and studied the formation of acetate 2d after
addition of the acyl donor 3. Comparison of this with the
formation of acetate 2d under normal DKR conditions
clearly indicates that the decomposition of the ruthenium
catalyst is responsible for the progressive deactivation
of the enzyme (Figure 2).
For the benzyl (1f) and aryloxymethyl (1g and 1h )
derivatives, the DKR under the conditions used for 1a
(i.e., 100 mg PS-C/mmol product, 70 °C, 4 mol % 4) gave
the acetates in moderate enantioselectivity (around 70%
ee for 1f and 1g and around 60% ee for 1h ). This is due
to the lower enantiopreference of the enzyme for these
substrates (vide infra). To obtain better enantioselectiv-
ity, we took full advantage of the DKR. Thus, by reducing
the enzyme/ruthenium catalyst ratio, the enzymatic
acylation became the rate-determining step and the
enantioselectivity was therefore substantially improved
(entries 9-11).
Syn th etic Ap p lica tion s. A wide range of synthetic
applications of this dynamic kinetic resolution procedure
can be envisaged. For instance, the hydrolysis of acetates
2 with LiOH in ethanol gave the corresponding epoxides
6 almost quantitatively (yields > 95%) in good enantio-
meric excess. The results are summarized in Table 4. The
absolute stereochemistry of (S)-6a was established by
comparison with a commercially available sample of (S)-
phenylethylene oxide. Independently, the absolute ster-
eochemistry of 6b was established by derivatization to
the corresponding (R)-1-(4-methoxyphenyl)ethanol.15
The synthetic utility of chiral epoxides is well-known.
Thus, for instance, they can be stereoselectively opened
by azides,16 cyanide derivatives,17 and amines,18 giving
easy access to aziridines and â-and γ-amino alcohols.
(14) The optimum performance of the PS-C is set to 50-60 °C. PS-C
product sheet from Amano Pharmaceutical Co., Ltd.
(15) Nieduzak, T. R.; Margolin, A. L. Tetrahedron: Asymmetry 1991,
2, 113.
9008 J . Org. Chem., Vol. 67, No. 25, 2002

Efficient Route to Chiral Epoxides
TABLE 5. Meth od s Used to Assa y En a n tiom er ic Excess.
Chiral aziridines are important intermediates in organic
synthesis19 and are present in several in bioactive
molecules (e.g., radiation sensitizers and enzyme inhibi-
tors).20 Chiral â- and γ-amino alcohols are important
structural elements in chiral ligands for asymmetric
catalysis21 as well as in biologically active compounds
(e.g., â-adrenergic receptor blockers and immune stimu-
lants).22
substrate
ee assay
conditionsa
tR (R)
tR (S)
1a
2a
1b
2b
1c
2c
1d
2d
1e
2e
1f
GC
GC
GC
GC
GC
GC
GC
GC
GC
GC
GC
GC
HPLC
HPLC
HPLC
HPLC
GC
A
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
C
C
23.5
21.9
25.1
24.8
23.7
22.2
24.2
23.1
25.8
25.4
23.6
23.1
31.1
12.3
32.2
18.7
26.5
26.9
23.3
22.4
25.3
25.0
23.5
22.6
24.0
23.4
25.7
25.5
23.7
23.3
18.5
13.4
34.1
16.9
26.6
27.0
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. All reactions were
carried out under dry argon atmosphere using standard
Schlenck techniques. Solvents were purified by standard
procedures. Solvents for HPLC use were spectrometric grade.
All other reagents are commercially available and were used
without further purification. Racemic â-halo alcohols 1b-e,i
were obtained from the corresponding commercially available
halo ketones 5 by reduction with sodium borohydride under
standard conditions. â-Halo alcohols 1f-h were prepared by
ring opening of the corresponding epoxide by LiCl and CuCl2
in THF.23 Racemic â-halo acetates 2 were obtained from the
corresponding alcohols by reaction with acetic anhydride under
standard conditions. Acyl donor 3 was prepared according to
a literature procedure.3b Ruthenium catalyst 4 was synthesized
according to a literature procedure4a and recrystallized from
CH2Cl2/pentane prior to use. Lipases PS-C type II and AK were
a generous gift from Amano Pharmaceutical Co. Ltd.
1H and 13C NMR spectra were recorded in CDCl3 at 400 and
100 MHz, respectively. Solvents for extraction and chroma-
tography were technical grade and distilled before chroma-
tography was performed with Merck 60 silica gel. The enan-
tiomeric excess of compounds 1a -f,i and 2a -f was determined
by analytical GC employing a CP-Chirasil-Dex CB column
using racemic compounds as references. The enantiomeric
excess of all the other compounds was determined by GC
analysis on a Daicel, Chiracel OD-H column using racemic
compounds as references (Table 5).
2f
1g
2g
1h
2h
1i
2i
GC
a
Conditions A: 110 °C, 20 min; 20 °C/min to 200 °C. Conditions
B: hexane/2-propanol ) 9:1, 0.5 mL/min. Conditions C: 80 °C, 20
min; 10 °C/min to 200 °C.
evaporated, and the residue was analyzed. The product (S)-
2a was obtained in 45% conversion and in 98% ee. The 1H
NMR data are in agreement with those previously reported.12
13C NMR δ 21.2, 46.7, 75.3, 126.8, 128.9, 129.3, 137.4, 170.1.
(S)-1-Ch lor o-2-acetoxy-2-(p-m eth oxyph en yl)eth an e ((S)-
2
2b).24 1H NMR δ: 2.11 (s, 3H), 3.67 (dd, 1H, J H-H ) 11.6 Hz,
2
3
3J H-H ) 4.8 Hz), 3.77 (dd, 1H, J H-H ) 11.6 Hz, J H-H) 8.0
3
3
Hz), 3.80 (s, 3H), 5.89 (dd, 1H, J H-H ) 8.0 Hz, J H-H ) 4.6
Hz), 6.90 (m, 2H), 7.25 (m, 2H). 13C NMR, δ: 21.2, 46.6, 55.5,
75.0, 114.3, 128.3, 129.5, 160.1, 170.2.
(S)-1-Ch lor o-2-a cetoxy-2-(p-flu or op h en yl)eth a n e ((S)-
2c). The 1H NMR data are in agreement with those previously
reported.15 13C NMR, δ: 21.1, 46.5, 74.5, 115.8 (d, J C-F ) 28
Hz), 128.8 (d, J C-F ) 11.2 Hz), 133.2, 162.5 (d, J C-F ) 286.2
Hz), 170.0.
Gen er a l P r oced u r e for th e KR of Ha lo Alcoh ols. (S)-
1-Ch lor o-2-a cetoxy-2-p h en yleth a n e ((S)-2a ). In a typical
experiment, PS-C lipase (20 mg) was added to a solution of
1a (31.2 mg, 0.2 mmol) and 3 (102 mg, 0.6 mmol) in dry toluene
(2 mL) under argon. The resulting reaction mixture was stirred
at 60 °C for 5 h. The enzyme was then filtered off and washed
with toluene (3 × 5 mL). The combined toluene phases were
(S)-1-Br om o-2-a cetoxy-2-p h en yleth a n e ((S)-2d ).24 1H
2
3
NMR, δ: 2.08 (s, 3H), 3.59 (dd, 1H J H-H ) 10.8 Hz, J H-H
)
2
3
4.8 Hz), 3.65 (dd, 1H, J H-H ) 10.8 Hz, J H-H) 8.0 Hz), 5.97
(dd, 1H, J H-H ) 8.0 Hz, J H-H ) 4.8 Hz), 7.46 (m, 5H). 13C
NMR, δ: 21.2, 34.5, 75.1, 126.8, 128.9, 129.0, 137.9, 170.1.
(S)-1-Br om o-2-acetoxy-2-(p-m eth oxyph en yl)eth an e ((S)-
2e). The 1H NMR data are in agreement with those previously
reported.12 13C NMR, δ: 22.2, 45.2, 55.5, 74.8, 114.3, 128.2,
129.9, 160.2, 170.1.
3
3
(16) See, for instance: (a) Hamamoto, H.; Mamedov, V. A.; Kitamoto,
M.; Hayashi, N.; Tsuboi, S. Tetrahedron: Asymmetry 2000, 11, 4485.
(b) He, L.; Byun, H.-S.; Bittman, R. J . Org. Chem. 1998, 63, 5696. (c)
Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. J . Org. Chem. 1999,
64, 6094.
(17) See, for example: (a) Wade, P. A.; Bereznak, J . F.; Palfey, B.
A.; Carroll, P. J .; Dailey, W. P.; Sivasubramanian, S. J . Org. Chem.
1990, 55, 3045. (b) Mitchell, D.; Koenig, T. M. Synth. Commun. 1995,
25, 1231.
(18) See, for instance: (a) Chini, M.; Crotti, P.; Macchia, F. J . Org.
Chem. 1991, 56, 5939. (b) Prabhakaran, E. N.; Rajesh, V.; Dubey, S.;
Iqbal, J . Tetrahedron Lett. 2001, 42, 339. (c) Chuang, T.-H.; Sharpless,
K. B. Org. Lett. 2000, 2, 3555. (d) Tremblay, M. R.; Wentworth, P.;
Lee, G. E.; J anda, K. D. J . Comb. Chem. 2000, 2, 698.
(19) Deyrup, J . A. In The Chemistry of Heterocyclic Compounds;
Hassner, A., Ed.; J ohn Wiley & Sons: New York, 1993.
(20) (a) Tomasz, M.; J ung, M.; Verdine, G.; Nakanishi, K. J . Am.
Chem. Soc. 1984, 106, 7367. (b) Danishefsky, S.; Ciufolini, M. J . Am.
Chem. Soc. 1984, 106, 6424.
(21) (a) Blasser, H.-U. Chem. Rev. 1992, 92, 935. (b) Kolb, H. C.;
Van Nieeuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
(c) Pfaltz, A. In Advances in Catalytic Processes; Doyle, M. P., Ed.; J AI
Press: Greenwich, CT, 1995.
(S)-1-Ch lor o-2-a cetoxy-3-p h en ylp r op a n e ((S)-2f).25 1H
3
NMR, δ: 2.06 (s, 3H), 2.98 (d, 2H, J H-H ) 6.8 Hz), 3.50 (dd,
2
3
2
1H, J H-H ) 11.6 Hz, J H-H ) 5.0 Hz), 3.62 (dd, 1H, J H-H
)
11.6 Hz, 3J H-H ) 4.2 Hz), 5.21 (m, 1H), 7.28 (m, 5H). 13C NMR,
δ: 21.2, 37.7, 44.9, 73.6, 127.1, 128.8, 129.6, 136.3, 170.5.
(S)-1-Ch lor o-2-a cetoxy-3-p h en oxyp r op a n e ((S)-2g).26 1
H
)
2
3
NMR, δ: 2.11 (s, 3H), 3.77 (dd, 1H, J H-H ) 11.6 Hz, J H-H
2
3
5.2 Hz), 3.85 (dd, 1H, J H-H ) 11.6 Hz, J H-H) 4.8 Hz), 4.16
(m, 2H), 5.32 (m, 1H), 6.92 (m, 2H), 6.99 (m, 1H), 7.28 (m,
2H). 13C NMR, δ: 21.1, 42.7, 66.1, 71.3, 114.8, 121.7, 129.8,
158.4, 170.4.
(S)-1-Ch lor o-2-a cetoxy-3-(1-n a p h th oxy)p r op a n e ((S)-
2h ).11 1H NMR, δ: 2.14 (s, 3H), 3.83 (dd, 1H, 2J H-H ) 11.6 Hz,
2
3
3J H-H ) 5.2 Hz), 3.90 (dd, 1H, J H-H ) 11.6 Hz, J H-H ) 4.8
Hz), 4.30 (m, 2H), 5.41 (m, 1H), 7.17 (m, 2H), 7.36 (m, 1H),
7.46 M, 1H), 7.76 (m, 4H). 13C NMR, δ: 21.2, 42.8, 66.3, 71.3,
107.3, 118.8, 124.2, 126.8, 127.0, 127.9, 129.5, 129.8, 134.6,
156.4, 170.4.
(22) (a) Powell, J . R.; Waimer, I. W.; Drayer, D. E. In Drug
Stereochemistry Analytical Methods and Pharmacology; Marcel Dek-
ker: New york, 1998. (b) C. P. Kordik, A. B. Reitz, J . Med. Chem. 1999,
42, 181.
(24) Cozens, L.; O′Neill, M.; Bogdanova, R.; Schepp, N. J . Am. Chem.
Soc. 1997, 119, 10652
(23) Hoff, B. H.; Anthosen, T. Tetrahedron: Asymmetry 1999, 10,
1401.
(25) Kim, M. J .; Cho, H. J . Chem. Soc., Chem. Commun. 1992, 1411.
(26) Hoff, B. H.; Anthosen, T. Chirality 1999, 11, 760.
J . Org. Chem, Vol. 67, No. 25, 2002 9009

Pa`mies and Ba¨ckvall
(S)-Isop r op yl 4-Ch lor o-3-h yd r oxybu ta n oa te ((S)-2i).26
Gen er a l P r oced u r e for th e Ep oxid e F or m a tion . (S)-
P h en yleth ylen e Oxid e ((S)-6a ). To a solution of (S)-2a (89
mg, 0.5 mmol) in ethanol 95% (5 mL) was added LiOH (36
mg, 1.5 mmol). The resulting reaction mixture was stirred at
room temperature for 1 h. The mixture was diluted with H2O
(25 mL), the ethanol was evaporated, and the product was
extracted with ether (5 × 20 mL). The organic layer was dried
over Na2SO4 and concentrated to yield 59 mg (98%) of (S)-6a
in 95% ee. The absolute stereochemistry of (S)-6a was estab-
lished by comparison with a commercially available sample
of (S)-phenylethylene oxide.
3
1H NMR, δ: 1.22 (d, 6H, J H-H) 6.4 Hz), 2.06 (s, 3H), 2.68
(dd, 1H, 2J H-H ) 16.0 Hz, 3J H-H ) 6.8 Hz), 2.73 (dd, 1H, 2J H-H
3
2
) 16.0 Hz, J H-H ) 6.0 Hz), 3.68 (dd, 1H, J H-H ) 11.6 Hz,
3J H-H ) 4.8 Hz), 3.74 (dd, 1H, J H-H ) 11.6 Hz, J H-H ) 4.8
2
3
Hz), 5.02 (sp, 1H, J H-H ) 6.4 Hz), 5.38 (m, 1H). 13C NMR, δ:
3
21.0, 21.9, 36.9, 45.2, 68.6, 69.5, 169.3, 170.1.
Gen er a l P r oced u r e for th e DKR of Ha lo Alcoh ols. (S)-
1-Ch lor o-2-a cetoxy-2-p h en yleth a n e ((S)-2a ). Ruthenium
catalyst 4 (32.5 mg, 4 mol %) and PS-C lipase (60 mg) were
placed in a Schlenk flask under argon. A solution of 1a (93.9
mg, 0.6 mmol) and 3 (306 mg, 1.8 mmol) in dry toluene (6 mL)
under argon (2 min of argon bubbling) was transferred to the
ruthenium catalyst and the enzyme. The resulting reaction
mixture was stirred at 70 °C for 72 h. The enzyme was then
filtered off and washed with toluene (3 × 5 mL), the solvent
was evaporated, and the product was purified by flash chro-
matography (pentane/ethyl acetate 15/1) to yield 101 mg (85%)
of (S)-2a in 95% ee.
Ackn owledgm en t. Financial support from the Swed-
ish Foundation for Strategic Research is gratefully
acknowledged.
J O026157M
9010 J . Org. Chem., Vol. 67, No. 25, 2002