Efficient lipase-catalyzed kinetic resolution of 4-arylmethoxy-3-hydroxybutanenitriles: application to an expedient synthesis of a statin intermediate

Article abstract of DOI:10.1016/j.tetasy.2006.10.037

The kinetic resolution of 4-arylmethoxy-3-hydroxybutanenitriles was investigated by lipase-catalyzed transesterification in organic solvents. A high enantioselectivity was obtained via reaction with vinyl acetate in a mixed solvent (n-heptane/acetonitrile 1:1), which was catalyzed by the lipase from Artgribacter sp. A better selectivity was demonstrated when the number of substituents on the aryl ring increased. (S)-4-Arylmethoxy-3-hydroxybutanenitriles can be obtained with enantiomeric excesses of up to 98.0% by this method. Furthermore we have developed a novel route to synthesize tert-butyl (S)-6-benzyloxy-5-hydroxy-3-oxohexanoate, a key intermediate for the preparation of HMG-CoA reductase inhibitors (statins).

Full text of DOI:10.1016/j.tetasy.2006.10.037

Tetrahedron: Asymmetry 17 (2006) 2907–2913
Efficient lipase-catalyzed kinetic resolution of
4-arylmethoxy-3-hydroxybutanenitriles: application to an
expedient synthesis of a statin intermediate
Fenglai Sun, Gang Xu, Jianping Wu and Lirong Yang*
Institute of Bioengineering College of Material Science and Chemical Engineering, Zhejiang University, Hangzhou 310027, China
Received 19 September 2006; revised 24 October 2006; accepted 26 October 2006
Abstract—The kinetic resolution of 4-arylmethoxy-3-hydroxybutanenitriles was investigated by lipase-catalyzed transesterification in
organic solvents. A high enantioselectivity was obtained via reaction with vinyl acetate in a mixed solvent (n-heptane/acetonitrile
1:1), which was catalyzed by the lipase from Artgribacter sp. A better selectivity was demonstrated when the number of substituents
on the aryl ring increased. (S)-4-Arylmethoxy-3-hydroxybutanenitriles can be obtained with enantiomeric excesses of up to 98.0% by
this method. Furthermore we have developed a novel route to synthesize tert-butyl (S)-6-benzyloxy-5-hydroxy-3-oxohexanoate, a key
intermediate for the preparation of HMG-CoA reductase inhibitors (statins).
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
ing trifluoroacetic acid (TFA)4 or FeCl3,5 which offers
potential routes to prepare chiral diols.
4-Arylmethoxy-3-hydroxybutanenitriles 1 (Scheme 1) have
been extensively investigated and employed in synthetic
chemistry.1,2 Chiral 4-arylmethoxy-3-hydroxybutanenitr-
iles are useful chiral building blocks in asymmetric synthe-
sis, as the cyano group is a precursor of many groups, such
as amino and carbonyl. Furthermore, substituted benzyl
groups can be easily cleaved by methods including hydro-
genolysis with catalytic Pd/C3 and acid hydrolysis in reflux-
The resolution of racemic alcohols, catalyzed by lipases in
organic solvents, is currently widely used today.6 However,
there are few reports on the preparation of chiral 4-aryl-
methoxy-3-hydroxybutanenitriles by the method of
lipase-catalyzed
transesterification.
Previously,
an
enzymatic kinetic resolution of the structurally similar 3-
hydroxy-4-phenoxybutanenitrile was reported by utilizing
lipase PS (Pseudomonas cepacia lipase).7 There are also
other enzymatic methods described for the preparation of
similar structures, but most of them are based on lipase cat-
alyzed hydrolysis reactions,8 such as Anthonsen’s re-
searches, which reports on the enzymatic resolution of a
similar substrate structure, 3-chloro-1-benzyloxy-2-propa-
nol.9 To obtain 4-arylmethoxy-3-hydroxybutanenitriles
with high ee values by lipase-catalyzed transesterification
still remains an attractive target.
OH
OH
O
O
O
CN
O
OtBu
R
(S)-1a-g
2
a R: H
b R; 4-Cl
c R: 2,4-Cl,
d R: 4-CH3
e
f
g
R: 4-CH3O,
R: 2,4,6-CH3
R: 4-F
Herein we report an enzymatic synthesis to prepare chiral
4-arylmethoxy-3-hydroxybutanenitriles, as well as develop
a novel route to synthesize tert-butyl (S)-6-benzyloxy-5-hy-
droxy-3-oxohexanoate 2 (Scheme 1), a key intermediate for
the preparation of HMG-CoA reductase inhibitors.10
There are already many reports on the synthesis of tert-
butyl (S)-6-benzyloxy-5-hydroxy-3-oxohexanoate, however,
Scheme 1.
*
Corresponding author. Tel./fax: +86 571 87952363; e-mail: lryang@
zju.edu.cn
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.10.037

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F. Sun et al. / Tetrahedron: Asymmetry 17 (2006) 2907–2913
most of them have drawbacks such as starting from chiral
raw materials,11,12 employing low temperatures,13–15 or
expensive catalysts.12,13,15
ribacter sp. and the lipase from Alcaligenes sp. showed
higher E-values (entries 10 and 11). However, the results
were far from expected.
2.2. Choice of solvents
2. Results and discussion
2.1. Screening of lipases
Organic solvents play very important roles in enzyme-cata-
lyzed reactions.16 Therefore, we turned our attention to test
different solvents and the results are listed in Table 2. It was
observed that two lipases in many solvents produced higher
E-values than those in vinyl acetate. In most cases, the
lipase from Artgribacter sp. showed a better selectivity than
the lipase from Alcaligenes sp.
Firstly, the enantioselective resolution of racemic 4-benzyl-
oxy-3-hydroxy-butanenitrile 1a was carried out by employ-
ing different lipases in vinyl acetate. The results are listed in
Table 1. Of the 11 lipases employed, the lipase from Artg-
Table 1. Transesterification of 1a with vinyl acetate using various lipases
Entry
Source
Supplier
Alcohol
ee (%)
Acetate
ee (%)
C (%)
E
1
2
3
4
5
6
7
8
9
Novozym 435
Candida antarctia
Pseudomos cepacia
Rhizopus delemar
Pseudomonas stu.
Lipase QL
Novo Nordisk
Fluka
Fluka
11.3
4.5
2.9
10.4
4.9
8.1
73.3
1.1
63.6
73.7
42.8
31.4
16.2
16.1
30.2
6.1
28.1
24.9
12.8
22.8
32.2
57.8
26.5
21.7
15.2
25.5
44.8
22.3
74.1
8.0
2.1
1.4
1.4
2.1
1.2
1.9
3.2
1.3
2.8
3.9
5.6
Fluka
Meito Sangyo
Meito Sangyo
Novo Nordisk
Fluka
Fluka
Fluka
Lipoprime
Penicilium
Phizopus sp.
Alcaligenes sp.
Artgribacter sp.
73.6
69.6
42.6
10
11
IMCAC
a All reactions were carried out by stirring a mixture of 1a (50 mg), lipase (10 mg), and vinyl acetate (2 mL) at 30 ꢁC for 24 h.
b Lipase from Artgribacter sp. was a gift from Professor Xiufen Kou of Institute of Microbiology, Chinese Academy of China (IMCAC).
Table 2. Transesterification of 1a with vinyl acetate in various solvents
Entry
Solvent
Source
Time (h)
7.5
Alcohol
ee (%)
Acetate
ee (%)
C (%)
E
1
2
3
4
5
6
7
8
Toluene
Artgribacter sp.
Alcaligenes sp.
7.7
19.9
34.6
53.5
18.3
27.1
2.2
4.0
THF
Artgribacter sp.
Alcaligenes sp.
34
12.2
24.1
66.2
60.2
15.6
26.7
5.5
6.2
i-Pr2O
Artgribacter sp.
Alcaligenes sp.
7.5
11.2
88.7
58.6
21.3
16.0
80.6
4.2
3.8
1,4-Dioxane
Cyclohexane
n-Hexane
n-Heptane
Acetonitrile
Artgribacter sp.
Alcaligenes sp.
11.0
7.5
16.8
13.5
33.6
26.2
33.3
34.0
2.3
1.9
Artgribacter sp.
Alcaligenes sp.
7.5
25.7
96.2
63.4
24.4
28.8
79.8
5.7
5.2
Artgribacter sp.
Alcaligenes sp.
11.0
7.5
99.0
95.5
52.1
44.4
65.0
68.2
14.8
8.9
Artgribacter sp.
Alcaligenes sp.
11.0
7.5
99.0
95.2
61.2
42.4
61.8
69.1
20.3
8.3
Artgribacter sp.
11
20
40
11
19.8
28.4
33.7
29.6
93.0
92.7
92.5
87.2
17.4
25.4
26.7
25.4
39.4
36.1
35.6
19.6
Alcaligenes sp.
9
n-Heptane/acetonitrile (1:1)
Artgribacter sp.
Alcaligenes sp.
15.0
54.3
86.0
89.5
68.7
37.7
55.6
31.2
14.5
10
11
n-Heptane/acetonitrile (1:5)
n-Heptane/acetonitrile (9:1)
Artgribacter sp.
50.0
15.0
32.8
91.6
26.4
31.4
19.0
Artgribacter sp.
98.0
62.9
60.1
a All reactions were carried out by stirring a mixture of 1a (40 mg), lipase (10 mg), and vinyl acetate (0.1 mL) in 2 mL solvent at 30 ꢁC.

F. Sun et al. / Tetrahedron: Asymmetry 17 (2006) 2907–2913
2909
In acetonitrile (entry 8), the lipase from Artgribacter sp.
produced a high enantioselectivity, but too low a reaction
rate. In non-polar solvents such as n-hexane and n-heptane
(entries 6 and 7), lipase from Artgribacter sp. showed high
E-values and high rates. However, the solubility of the sub-
strate in these solvents was very low. To achieve high E-
values, adequate rates and good solubilities, we attempted
to use mixed solvents (entries 9–11). The mixed solvent (n-
heptane/acetonitrile = 1:1) was chosen as the reaction
solvent.
ingly, enzymatic selectivity could be improved upon by the
introduction of substituents on the aryl rings. With the
number of substituents increased, a greater selectivity was
seen. The enantioselectivity of the lipase from Artgribacter
sp. toward 1a–g can be interpreted using a simple rule pro-
posed.18 For secondary alcohols, the lipase preferentially
transforms one enantiomer, and its enantioselectivity is
high when the substituents at the stereocenter differ signif-
icantly in size. In our case, the size of the group on one side
of the stereogenic center increases as the number of substit-
uents on the aryl ring is increased. Therefore, the enantio-
selectivity of the lipase from Artgribacter sp. is improved
when the substituent changes from H to a trimethyl group
(Table 3).
2.3. Effect of substituents
After the solvents were screened, the E-value was greatly
increased. Here, we continued to study substituent changes
on the aryl rings (1a–g), as shown in Scheme 2. For one
reason, the structure of substrates has a great influence in
enzymatic selectivity;17 for another, all the arylmethoxy
groups can be removed to give the same product-diols.
Besides, the substituents on the aryl rings also make the
cleaved reaction more convenient.
2.4. Synthesis of tert-butyl (S)-6-benzyloxy-5-hydroxy-3-
oxohexanoate 2
After having obtained (S)-4-benzyloxy-3-hydroxybutane-
nitrile 1a by an enzymatic resolution, we developed a novel
route to synthesize tert-butyl (S)-6-benzyloxy-5-hydroxy-3-
oxohexanoate 2, which is a key intermediate for the prepa-
ration of HMG-CoA reductase inhibitors, as shown in
Scheme 3.
Seven substrates 1a–g with substituents on the aryl rings
were studied and the results are shown in Table 3. Interest-
OH
OH
OAc
Lipase
+
CN
O
CN
O
O
CN
AcO
R
R
R
(R)-8a-g
1a-g
(S)-1a-g
Scheme 2.
Table 3. Kinetic resolution of 4-arylmethoxy-3-hydroxybutanenitriles 1a–g
Substrate
R
Time (h)
Alcohol
ee (%)
Acetate
ee (%)
C (%)
E
a
b
c
d
e
f
H
4-Cl
45
60
70
52
68
98.0
96.2
96.1
97.0
96.3
92.7
99.0
70.0
85.0
90.1
81.3
82.3
99.0
85.0
58.3
53.1
51.6
54.4
53.9
48.3
53.8
24.8
48.5
75.6
40.0
40.6
2,4-Cl
4-CH3
4-CH3O
2,4,6-CH3
4-F
120
60
>200
63.9
g
a All reactions were carried out by stirring a mixture of 1a–g (5 mmol), lipase from Artgribacter sp. (250 mg) and vinyl acetate (25 mmol) in 50 mL solvent
(n-heptane/acetonitrile = 1:1) at 30 ꢁC.
b The reactions were allowed to exceed 50% conversion until the ees of the unreacted (S)-alcohols were satisfactory.
OH
O
a
O
b
Cl
c
BzlO
CN
O
BzlO
4
5
3
OH
O
OH
d
BzlO
BzlO
CN
OtBu
6
2
Scheme 3. Reagents and conditions: (a) 40% NaOH aq, n-Bu4NBr, 0 ꢁC, 24 h, 85%; (b) NaCN/H2O, MeOH, H2SO4, pH = 8–11, 40 ꢁC, 15 h, 80%; (c)
5 equiv vinyl acetate, lipase from Artgribacter sp., n-heptane/acetonitrile, 30 ꢁC, 40–60 h; (d) (i) 1.1 equiv TMSCl, 1.2 equiv Et3N, THF, 0 ꢁC, 12 h; (ii)
t
2.0 equiv BrCH2CO2 Bu, 3 equiv Zn, 0.01 equiv MeSO3H, THF, reflux 2 h, then, 3 N HCl, 0 ꢁC, 2 h overall 77%.

2910
F. Sun et al. / Tetrahedron: Asymmetry 17 (2006) 2907–2913
Firstly, 1-benzyloxy-2,3-epoxypropane 4 was prepared in
85% yield by the reaction of commercially available
racemic epichlorohydrin 3 with benzyl alcohol.19 We then
attempted to open the ring of epoxide 4 using NaCN in
aqueous–alcoholic conditions. When epoxide 4 was treated
with NaCN in aqueous condition under the usual condi-
tions, a complex mixture was obtained. The strong basicity
in the course of the reaction most likely prevents hydroxyl
group forming. Thus, we kept the pH strictly between 8.0
and 11.0 with H2SO4,20 which eventually allowed
b-hydroxynitrile 5 to be pure enough to be directly em-
ployed in the next step. The resulting racemic 4-benzyl-
oxy-3-hydroxybutanenitrile was resolved by a lipase-
catalyzed esterification using the lipase from Artgribacter
sp. It was shown by chiral HPLC (Chiralpak AD-H col-
umn) that the desired compound 6 could be achieved with
high enantiomeric excesses (P98% ee) in an isolated yield
of 40% from 5. In the last step, the hydroxyl group of b-
hydroxy nitrile 6 was protected by a trimethylsilyl group,21
determined by HPLC analyses (solvent: n-hexane/EtOH,
flow: 1.0 mL/min). The absolute configuration of (S)-4-
arylmethoxy-3-hydroxybutanenitriles 1a–g was assigned
by preparing the standards from (R)-epichlorohydrin
described in Scheme 3.
4.2. General procedure for the resolution of 4-arylmethoxy-
3-hydroxybutanenitriles 1
4-Arylmethoxy-3-hydroxybutanenitrile 1 (5 mmol) was dis-
solved in a mixed solvent (n-heptane/acetonitrile = 1:1,
50 mL), and to this solution lipase from Artgribacter sp.
(250 mg) and vinyl acetate (25 mmol) were added succes-
sively and shaken at 30 ꢁC in an orbital shaker. After about
50% completion of the reaction, as indicated by HPLC
analysis, the enzyme was filtered and washed with EtOAc.
The solvents were evaporated and purification was accom-
plished by column chromatography employing EtOAc–
hexane (1:4) as the eluent to afford the corresponding
(R)-acetates 8a–g, followed by the unreacted (S)-alcohol
1a–g.
t
then reacted with BrCH2CO2 Bu, according to the litera-
ture method,22 to form the target product 2, in an overall
yield of 77% from 6.
4.2.1. (S)-4-Benzyloxy-3-hydroxybutanenitrile 1a. Resolu-
tion of (S)-4-benzyloxy-3-hydroxybutanenitrile by employ-
ing the above general procedure for the resolution of
4-arylmethoxy-3-hydroxybutanenitriles 1 afforded (S)-1a
in 40% yield and ee 98.0% as a colorless oil; HPLC (Daicel
3. Conclusion
In conclusion, we have developed an efficient enzymatic
resolution of 4-arylmethoxy-3-hydroxybutanenitriles
1
Chiralpak AD-H), t(R)-1a = 11.5 min, t(S)-1a = 12.3 min,
20
using the lipase from Artgribacter sp. Enantioselective
(S)-4-arylmethoxy-3-hydroxybutanenitrile 1a was obtained
in the reaction with vinyl acetate in n-heptane/acetonitrile
solution. This method affords (S)-4-arylmethoxy-3-hydroxy-
butanenitriles with enantiomeric excesses of up to 98.0%.
We have also developed a valuable method to synthesize
hexane/EtOH 92:8, flow: 1.0 mL/min; ½aꢀD ¼ ꢁ3:3
(c 3.3, CHCl3); IR (film): 3432, 3063, 2926, 2253, 1458,
1
1235 cmꢁ1; H NMR (400 MHz, CDCl3): d 7.30–7.39 (m,
5H), 4.57 (d, J = 10.4 Hz, 2H), 4.06–4.12 (m, 1H), 3.50–
3.59 (m, 2H), 2.74 (d, J = 5.6 Hz, 1H), 2.60 (m, 2H); 13C
NMR (400 MHz, CDCl3): d 137.19, 128.45, 127.95,
127.75, 117.25, 73.493, 72.02, 66.34, 22.38; MS (70 eV,
EI) m/z (%): 191 (M+, 7), 161 (4), 107 (8), 91 (100), 65 (11).
tert-butyl
(S)-6-benzyloxy-5-hydroxy-3-oxohexanoate.
Studies on a number of extensions to this work are cur-
rently underway.
4.2.2. (S)-4-(4-Chlorobenzyloxy)-3-hydroxybutanenitrile 1b.
Resolution of 4-(4-chlorobenzyloxy)-3-hydroxybutanenit-
rile by employing the above general procedure for the res-
olution of 4-arylmethoxy-3-hydroxybutanenitriles 1 affor-
ded (S)-1b in 49% yield and ee 96.2% as a colorless oil;
4. Experimental
4.1. General
HPLC (Daicel Chiralpak AD-H), t(R)-1b = 26.6 min, t(S)-1b
=
All reagents were of commercial grade with purity >98%
and used as provided without further purification. Artgri-
bacter sp. lipase was a gift from Professor Xiufen Kou of
Institute of Microbiology, Chinese Academy of China.
28.7 min, hexane/EtOH 92:8, flow: 1.0 mL/min;
20
½aꢀD ¼ ꢁ2:6 (c 3.2, CHCl3); IR (film): 3447, 2925, 2253,
1598, 1492, 1090 cmꢁ1 1H NMR (400 MHz, CDCl3): d
;
7.34 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 4.53 (s,
2H), 4.08–4.12 (m, 1H), 3.50–3.58 (m, 2H), 2.79 (d,
J = 5.2 Hz, 1H), 2.61 (m, 2H); 13C NMR (400 MHz,
CDCl3): d 135.72, 133.65, 129.02, 128.28, 117.27, 72.64,
72.14, 66.27, 22.43; MS (70 eV, EI) m/z (%): 225 (M+, 9),
190 (11), 141 (19), 125/127 (100/33), 89 (29), 42 (6).
1
Other lipases are commercial enzymes. H and 13C NMR
spectra were measured in CDCl3 and recorded on a Bruc-
ker Avance-400 (400 MHz) spectrometer with TMS as
the internal standard. GC–MS spectra were recorded on
a HP-6890/MS-5973 spectrometer. Mass spectra were re-
corded on an Esquire-LC spectrometer. Melting points
were taken on electrothermal melting point apparatus
and are uncorrected. Infrared (IR) spectra were recorded
on a Nicolet 560 spectrometer. Optical rotations were mea-
sured on an AUTOPOL IV digital polarimeter. HPLC was
performed on a Chiralpak AD-H column (Daicel) and
monitored by UV (224 nm). Column chromatography
was performed on a Merck silica gel 60 (230–400 mesh).
TLC analyses were performed on Merck 60 PF 254 silica
gel plates. Conversion and enantiomeric purities were
4.2.3. (S)-4-(2,4-Dichlorobenzyloxy)-3-hydroxybutanenitrile
1c. Resolution of 4-(2,4-dichlorobenzyloxy)-3-hydroxy-
butanenitrile by employing the above general procedure
for the resolution of 4-arylmethoxy-3-hydroxybutanenitriles
1 afforded (S)-1c in 45% yield and ee 96.1% as a white solid;
HPLC (Daicel Chiralpak AD-H), t(R)-1c = 11.2 min, t(S)-1c
=
14.4 min, hexane/EtOH 85:15, flow: 1.0 mL/min; mp
20
54–57 ꢁC; ½aꢀD ¼ ꢁ0:6 (c 3.7, CHCl3); IR (KBr): 3448,
3079, 2927, 2250 cmꢁ1 1H NMR (400 MHz, CDCl3): d
;

F. Sun et al. / Tetrahedron: Asymmetry 17 (2006) 2907–2913
2911
20
7.40 (d, J = 1.6 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.25–7.28
(m, 1 Hz), 4.63 (s, 2H), 4.13–4.17 (m, 1H), 3.59–3.68 (m, 2H),
2.62–2.65 (m, 2H); 13C NMR (400 MHz, CDCl3): d 134.25,
117.79, 133.54, 130.13, 129.24, 127.14, 117.21, 72.56, 70.05,
66.33, 22.46; MS (70 eV, EI) m/z (%): 233 (M+, 8), 218 (7),
203 (1), 147 (2), 133 (100), 117 (18), 91 (12), 77 (5).
½aꢀD ¼ ꢁ1:4 (c 3.0, CHCl3); IR (film): 3449, 3072, 2924,
2254, 1604, 1224 cmꢁ1 1H NMR (400 MHz, CDCl3): d
;
7.27–7.31 (m, 2H), 7.03–7.07 (m, 2H), 4.53 (s, 2H), 4.09–
4.13 (m, 1H), 3.50–3.59 (m, 2H), 2.59–2.62 (m, 2H); 13C
NMR (400 MHz, CDCl3): d 163.60, 161.15, 133.02,
132.98, 129.57, 129.50, 117.27, 115.42, 115.21, 72.74,
72.01, 66.30, 22.40; MS (70 eV, EI) m/z (%): 209 (M+, 4),
179 (3), 164 (2), 125 (8), 109 (100), 83 (9).
4.2.4. (S)-4-(4-Methylbenzyloxy)-3-hydroxybutanenitrile 1d.
Resolution of 4-(4-methylbenzyloxy)-3-hydroxybutane-
nitrile by employing the above general procedure for the
4.2.8. (R)-3-Acetyloxy-4-benzyloxy-3-hydroxybutanenitrile
8a. Resolution of 4-benzyloxy-3-hydroxybutanenitrile 1a
by employing the above general procedure for the resolu-
tion of 4-arylmethoxy-3-hydroxybutanenitrile 1 afforded
(R)-8a in 53% yield and an ee 70.0% as a colorless oil;
resolution of 4-arylmethoxy-3-hydroxybutanenitriles
1
afforded (S)-1d in 41% yield and ee 97.0% as a colorless
oil; HPLC (Daicel Chiralpak AD-H), t(R)-1d = 32.2 min;
t(S)-1d = 35.2 min; hexane/EtOH 95:5, flow: 1.0 mL/
20
min; ½aꢀD ¼ ꢁ2:6 (c 3.0, CHCl3); IR (film): 3445, 2920,
HPLC (Daicel Chiralpak AD-H), t(R)-8a = 6.2 min, t(S)-8a
6.6 min, hexane/EtOH 92:8, flow: 1.0 mL/min;
½aꢀD ¼ þ3:4 (c 3.0, CHCl3); IR (film): 3064, 2959, 2252,
1744, 1232 cmꢁ1 1H NMR (400 MHz, CDCl3): d 7.31–
=
1
2253, 1745 cmꢁ1; H NMR (400 MHz, CDCl3): d 7.22 (d,
20
J = 8.4 Hz, 2H), 7.18 (d, J = 8.0 Hz), 4.52 (s, 2H), 4.07
(m, 1H), 3.48–3.57 (m, 2H), 2.52–2.63 (m, 2H), 2.35 (s,
3H); 13C NMR (400 MHz, CDCl3): d 137.78, 134.20,
129.17, 127.96, 117.43, 73.40, 71.94, 66.35, 22.41, 21.09;
MS (70 eV, EI) m/z (%): 205 (M+, 11), 190 (7), 175 (2),
121 (6), 105 (100), 77 (10).
;
7.36 (m, 5H), 5.11–5.16 (m, 1H), 4.57 (d, J = 4.4 Hz,
2H), 3.58–3.69 (m, 2H), 2.79 (dd, J = 5.6 Hz, J = 1.6 Hz,
2H), 2.10 (s, 3H); 13C NMR (400 MHz, CDCl3): d
169.82, 137.16, 128.45, 127.95, 127.68, 116.18, 73.51,
68.79, 67.43, 20.74, 19.91; MS (70 eV, EI) m/z (%): 233
(M+, 1), 190 (3), 173 (3), 143 (3), 126 (36), 91 (100), 43 (26).
4.2.5. (S)-4-(4-Methoxybenzyloxy)-3-hydroxybutanenitrile
1e. Resolution of 4-(4-methoxybenzyloxy)-3-hydroxy-
butanenitrile by employing the above general procedure
for the resolution of 4-arylmethoxy-3-hydroxybutanenitriles
1 afforded (S)-1e in 45% yield and ee 96.3% as a colorless
oil; HPLC (Daicel Chiralpak AD-H), t(R)-1e = 29.0 min,
4.2.9.
(R)-3-Acetyloxy-4-(4-chlorobenzyloxy)-3-hydroxy-
butanenitrile 8b. Resolution of 4-(4-chlorobenzyloxy)-3-
hydroxybutanenitrile by employing the above general pro-
cedure for the resolution of 4-arylmethoxy-3-hydroxy-
butanenitriles 1 afforded (R)-8b in 48% yield and ee
85.0% as a colorless oil; HPLC (Daicel Chiralpak AD-H),
t(S)-1e = 33.5 min, hexane/EtOH 90:10, flow: 1.0 mL/
20
min; ½aꢀD ¼ ꢁ1:8 (c 3.0, CHCl3); IR (film): 3447, 2958,
2935, 2252, 1611, 1244 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 7.25 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.49 (s,
2H), 4.06–4.08 (m, 1H), 3.81 (s, 3H), 3.47–3.57 (m, 2H),
2.56–2.59 (m, 2H); 13C NMR (400 MHz, CDCl3): d
159.34, 129.39, 129.19, 117.19, 113.80, 73.11, 71.67, 66.32,
55.13, 22.32; MS (70 eV, EI) m/z (%): 221 (M+, 8), 203
(3), 137 (29), 121 (100), 43 (15).
t(R)-8b = 14.5 min, t(S)-8b = 16.3 min, hexane/EtOH 92:8,
20
flow: 1.0 mL/min; ½aꢀD ¼ þ4:0 (c 5.0, CHCl3); IR (film):
3053, 2961, 2252, 1744, 1463, 1231 cmꢁ1
;
1H NMR
(400 MHz, CDCl3): d 7.34 (d, J = 8.4 Hz, 2H), 7.26 (d,
J = 8.0 Hz, 2H), 5.12–5.14 (m, 1H), 4.53 (d, J = 4 Hz, 2H),
3.58–3.69 (m, 2H), 2.79 (dd, J = 5.2 Hz, J = 2.4 Hz, 2H),
2.10 (s, 3H); 13C NMR (400 MHz, CDCl3): d 169.69,
135.66, 133.56, 120.07, 120.50, 116.05, 72.58, 68.90,
67.24, 20.64, 19.82; MS (70 eV, EI) m/z (%): 267 (M+, 1),
224 (3), 207 (6), 141 (33), 125 (100), 89 (16), 43 (39).
4.2.6. (S)-4-(2,4,6-Trimethylbenzyloxy)-3-hydroxybutane-
nitrile 1f. Resolution of 4-(2,4,6-trimethylbenzyloxy)-3-
hydroxybutanenitrile by employing the above general pro-
cedure for the resolution of 4-arylmethoxy-3-hydroxy-
butanenitriles 1 afforded (S)-1f in 45% yield and ee 92.7% as
4.2.10. (R)-3-Acetyloxy-4-(2,4-dichlorobenzyloxy)-3-hydroxy-
butanenitrile 8c. Resolution of 4-(2,4-dichlorobenzyl-
oxy)-3-hydroxybutanenitrile by employing the above
general procedure for the resolution of 4-arylmethoxy-3-
hydroxybutanenitriles 1 afforded (R)-8c in 47% yield and
ee 90.1% as a colorless oil; HPLC (Daicel Chiralpak AD-H),
a colorless oil; HPLC (Daicel Chiralpak AD-H), t(R)-1f
=
13.3 min, t(S)-1f = 16.5 min, hexane/EtOH 95:5, flow:
20
1.0 mL/min; ½aꢀD ¼ þ3:0 (c 3.0, CHCl3); IR (film):
3445, 2920, 2253, 1745 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 6.87 (s, 2H), 4.58 (s, 2H), 4.05–4.07 (m, 1H), 3.53–3.62 (m,
2H), 2.58 (dd, J = 6.4 Hz, J = 3.6 Hz, 2H), 2.35 (s, 6H), 2.27
(s, 3H); 13C NMR (400 MHz, CDCl3): d 138.07, 137.71,
130.33, 129.00, 117.17, 72.00, 67.45, 66.44, 22.27, 20.88,
19.44; MS (70 eV, EI) m/z (%): 233 (M+, 8), 218 (7), 203
(1), 147 (2), 133 (100), 117 (18), 91 (12), 77 (5).
t(R)-8c = 9.6 min, t(S)-8c = 13.1 min, hexane/EtOH 98:2,
20
flow: 1.0 mL/min; ½aꢀD ¼ þ4:6 (c 4.5, CHCl3); IR
(film): 3094, 2958, 1740, 1465 cmꢁ1; H NMR (400 MHz,
1
CDCl3): d 7.39 (d, J = 2.0 Hz, 1H), 7.37 (d, J = 8.4 Hz,
1H), 5.14–5.19 (m, 1H), 4.62 (d, J = 3.6 Hz, 2H), 3.66–
3.77 (m, 2H), 2.82 (dd, J = 5.6 Hz, J = 3.6 Hz, 2H), 2.12
(s, 3H); 13C NMR (400 MHz, CDCl3): d 169.74, 134.08,
133.55, 129.87, 129.09, 127.07, 116.01, 69.96, 69.44,
67.25, 20.67, 19.87; MS (70 eV, EI) m/z (%): 275 (M+, 1),
216 (1), 147 (5), 132 (100), 117 (15), 91 (9), 43 (12).
4.2.7.
(S)-4-(4-Fluorobenzyloxy)-3-hydroxybutanenitrile
1g. Resolution of (S)-4-(4-fluorobenzyloxy)-3-hydroxy-
butanenitrile by employing the above general procedure
for the resolution of 4-arylmethoxy-3-hydroxybutanenitr-
iles 1 afforded (S)-1g in 50% yield and ee 99.0% as a color-
less oil; HPLC (Daicel Chiralpak AD), t(R)-1g = 34.2 min,
t(S)-1g = 37.3 min, hexane/EtOH 95:5, flow: 1.0 mL/min;
4.2.11. (R)-3-Acetyloxy-4-(4-methylbenzyloxy)-3-hydroxy-
butanenitrile 8d. Resolution of 4-(4-methylbenzyloxy)-
3-hydroxybutanenitrile by employing the above general

2912
F. Sun et al. / Tetrahedron: Asymmetry 17 (2006) 2907–2913
procedure for the resolution of 4-arylmethoxy-3-hydroxy-
butanenitriles 1 afforded (R)-8d in 50% yield and ee
81.3% as a colorless oil; HPLC (Daicel Chiralpak AD-H),
2.10 (s, 3H); 13C NMR (400 MHz, CDCl3): d 169.78,
163.57, 161.12, 132.96, 132.93, 129.46, 129.37, 116.10,
115.37, 115.14, 72.71, 68.78, 67.30, 20.65, 19.85; MS
(70 eV, EI) m/z (%): 251 (M+, 0.5), 208 (3), 191 (5), 161
(3), 125 (25), 109 (100), 43 (25).
t(R)-8d = 13.0 min,
95:5, flow: 1.0 mL/min; ½aꢀD ¼ þ4:0 (c 3.0, CHCl3); IR
t(S)-8d = 13.4 min,
hexane/EtOH
20
1
(film): 3003, 2977, 2930, 1712 cmꢁ1; H NMR (400 MHz,
CDCl3): d 7.22 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.4 Hz,
2H), 5.11–5.13 (m, 1H), 4.52 (d, J = 5.2 Hz, 2H), 3.55–
3.66 (m, 2H), 2.78 (dd, J = 5.6 Hz, J = 1.2 Hz, 2H), 2.35
(s, 3H), 2.1 (s, 3H); 13C NMR (400 MHz, CDCl3): d
170.06, 137.85, 134.22, 129.22, 128.00, 117.40, 73.46,
71.97, 66.45, 22.47, 21.14, 19.97; MS (70 eV, EI) m/z (%):
247 (M+,3), 204 (3), 187 (5), 121 (35), 105 (100), 77 (101),
43 (17).
4.3. General procedure for the preparation of 2
4.3.1. 1-Benzyloxy-2,3-epoxypropane 4. A mixture of 40%
w/w aqueous sodium hydroxide (120 mL), benzyl alcohol
(10.37 g, 96.0 mmol), tetrabutylammonium bromide
(TBAB) (1.5 g, 4.7 mmol) was vigorously stirred at room
temperature and placed in an ice bath. Epichlorohydrin
(35.33 g, 384 mmol) was gradually added over 20 min.
The progress of the reaction was monitored by TLC. After
24 h, the reaction was complete and the reaction mixture
poured on ice/water (60 mL). The aqueous phase was ex-
tracted with diethyl ether (2 · 50 mL). The organic phase
was washed with brine to neutrality, dried with magnesium
sulfate, filtered, evaporated to dryness, and distilled to
yield 1-benzyloxy-2,3-epoxypropane 4 (13.38 g, 85%) as a
colorless oil with purity > 98% by GC. IR (film): 2958,
4.2.12. (R)-3-Acetyloxy-4-(4-methoxybenzyloxy)-3-hydroxy-
butanenitrile 8e. Resolution of 4-(4-methoxybenzyloxy)-
3-hydroxybutanenitrile by employing the above general
procedure for the resolution of 4-arylmethoxy-3-hydroxy-
butanenitriles 1 afforded (R)-8e in 50% yield and ee
82.3% as a white solid; mp 46–49 ꢁC; HPLC (Daicel
Chiralpak AD-H), t(R)-8e = 16.5 min, t(S)-8e = 19.6 min,
20
1
hexane/EtOH 90:10, flow: 1.0 mL/min; ½aꢀD ¼ þ4:2
2874, 1598, 1234, 1095; H NMR (400 MHz, CDCl3): d
(c 5.0, CHCl3); IR (KBr): 2959, 2252, 1744, 1612, 1513,
7.26–7.35 (m, 5H), 4.62 (dd, J = 23.2 Hz, J = 12.0 Hz,
2H), 3.78 (dd, J = 11.6 Hz, J = 3.2 Hz, 1H), 3.46 (dd,
J = 11.6 Hz, J = 6.0 Hz, 1H), 3.16–3.20 (m, 1H), 2.78–
2.80 (m, 1H); 2.62 (dd, J = 4.8 Hz, J = 2.4 Hz, 1H). 13C
NMR (400 MHz, CDCl3): d 137.91, 128.43, 127.75,
73.30, 70.81, 50.87, 44.26; MS (70 eV, EI) m/z (%): 164
(M+, 9), 107 (72), 91 (100), 79 (29).
1232 cmꢁ1 1H NMR (400 MHz, CDCl3): d 7.26 (d,
;
J = 8.4 Hz, 2H), 6.89 (d, J = 8.0 Hz, 2H), 5.10–5.12 (m,
1H), 4.50 (d, J = 6 Hz, 2H), 3.80 (s, 3H), 3.54–3.65 (m,
2H), 2.77 (dd, J = 5.2 Hz, J = 1.6 Hz, 2H), 2.10 (s, 3H);
13C NMR (400 MHz, CDCl3): d 169.86, 159.44, 129.41,
129.31, 116.31, 113.88, 73.194, 68.56, 67.51, 55.22, 20.77,
19.94; MS (70 eV, EI) m/z (%): 363 (M+, 8), 220 (1), 203
(2), 137 (29), 121 (100), 78 (8), 43 (15).
4.3.2. (S)-4-(Benzyloxy)-3-hydroxybutanenitrile 6. To a
solution of 4 (3.94 g, 24 mmol) in MeOH (30 mL) were
simultaneously added 30% aqueous solution of NaCN
(1.76 g, 36 mmol) and 98% H2SO4 (1.65 g, 16.5 mmol) over
1 h at room temperature, keeping its pH strictly between 8
and 11. Then the reaction mixture was stirred at 40 ꢁC for
15 h. The completion of the reaction was confirmed by
TLC. After the reaction was completed, methanol was
evaporated under reduced pressure. Water (10 mL) was
added and extracted with diethylether (40 mL). The organ-
ic phase was washed with brine to neutrality, dried with
magnesium sulfate, filtered, evaporated to dryness, and dis-
4.2.13.
(R)-3-Acetyloxy-4-(2,4,6-trimethylbenzyloxy)-3-
hydroxybutanenitrile 8f. Resolution of 4-(2,4,6-trimeth-
ylbenzyloxy)-3-hydroxybutanenitrile by employing the
above general procedure for the resolution of 4-arylmeth-
oxy-3-hydroxybutanenitriles 1 afforded (R)-8f in 47% yield
and ee 99.0% as a white solid; mp 80–83 ꢁC; HPLC (Daicel
Chiralpak AD-H), t(R)-8f = 7.1 min, t(S)-8f = 7.4 min,
20
hexane/EtOH 95:5, flow: 1.0 mL/min; ½aꢀD ¼ þ8:0 (c 3.0,
CHCl3); IR (KBr): 3003, 2965, 2250, 1732, 1242 cmꢁ1
;
1H NMR (400 MHz, CDCl3): d 6.86 (s, 2H), 5.08–5.11
(m, 1H), 4.57 (s, 2H), 3.59–3.70 (m, 2H), 2.75 (d,
J = 5.6 Hz, 2H), 2.34 (s, 6H), 2.26 (s, 3H), 2.09 (s, 3H);
13C NMR (400 MHz, CDCl3): d 169.84, 137.97, 137.74,
130.29, 120.90, 116.18, 68.63, 67.53, 20.89, 20.73, 19.88,
19.43; MS (70 eV, EI) m/z (%): 275 (M+, 1), 216 (1), 147
(5), 132 (100), 117 (15), 91 (9), 43 (12).
tilled to yield 4-(benzyloxy)-3-hydroxybutanenitrile
6
(3.67 g, 80%). Resolution of 4-benzyloxy-3-hydroxybutane-
nitrile by employing the above general procedure afforded
(S)-4-benzyloxy-3-hydroxybutanenitrile 6, ee 98.0%.
4.3.3. tert-Butyl (S)-6-(benzyloxy)-5-hydroxy-3-oxohexano-
ate 2. To a stirred solution of 6 (0.95 g, 5 mmol) in THF
(30 mL) was added triethylamine (0.61 g, 6 mmol) at 0 ꢁC.
To the mixture was added Me3SiCl (0.59 g, 5.5 mmol) and
the mixture warmed to room temperature. After 12 h, aq
10% NH4Cl solution was added and the organic layer sep-
arated. The concentration of the separated organic layer
provided (1-(benzyloxy)-3-chloropropan-2-yloxy)trimeth-
ylsilane (1.25 g, 95%) as a colorless oil.
4.2.14.
(R)-4-Acetyloxy-(4-fluorobenzyloxy)-3-hydroxy-
butanenitrile 8g. Resolution of 4-(4-fluorobenzyloxy)-3-
hydroxybutanenitrile by employing the above general pro-
cedure for the resolution of 4-arylmethoxy-3-hydroxy-
butanenitriles 1 afforded (R)-8g in 45% yield and ee
85.0% as a colorless oil; HPLC (Daicel Chiralpak AD-H),
t(R)-8g = 14.4 min, t(S)-8g = 15.5 min, hexane/EtOH 95:5,
20
flow: 1.0 mL/min; ½aꢀD ¼ þ3:0 (c 3.0, CHCl3);
IR (film): 3072, 2938, 2873, 2253, 1744, 1231 cmꢁ1
;
1H
To a stirred suspension of commercial zinc powder (0.78 g,
12 mmol) in THF (30 mL) was added MeSO3H (0.4 mg,
0.04 mmol) at room temperature. The mixture was refluxed
for 15 min and (1-(benzyloxy)-3-chloropropan-2-yloxy)tri-
NMR (400 MHz, CDCl3): d 7.27–7.31 (m, 2H), 7.02–7.06
(m, 2H), 5.10–5.16 (m, 1H), 4.53 (d, J = 4.4 Hz, 2H),
3.57–3.68 (m, 2H), 2.79 (dd, J = 5.2 Hz, J = 2.4 Hz, 2H),

F. Sun et al. / Tetrahedron: Asymmetry 17 (2006) 2907–2913
2913
J. P.; Yang, L. R. J. Mol. Catal. B: Enzym. 2004, 31, 67–
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7. Kamal, A.; Khanna, G. B. R. Tetrahedron: Asymmetry 2001,
12, 405–410.
methylsilane (1.05 g, 4.0 mmol) was added. Then to the
mixture BrCH2CO2 Bu (1.44 g, 8 mmol) was added over
t
1 h. After 2 h, the mixture was cooled to 0–5 ꢁC and aq
3 M HCl (10 mL) was added dropwise. After 2 h, all the
organic volatiles were removed in vacuo and the remaining
mixture was extracted with EtOAc (2 · 30 mL) . The sepa-
rated organic layer was washed with H2O, dried with
MgSO4, and concentrated. Column chromatography
8. (a) Itoh, T.; Takagi, Y.; Nishiyama, S. J. Org. Chem. 1991,
56, 1521–1524; (b) Itoh, T.; Tagaki, Y.; Murakami, T.;
Hiyama, Y.; Tsukube, H. J. Org. Chem. 1996, 61, 2158–2163.
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10. (a) Thottathil, J. K.; Pendri, Y.; Li, W. S.; Kronenthal, D. R.
US5,278,313, 1994; (b) Kizaki, N.; Yamada, Y.; Yasohara,
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(EtOAc/hexane, 1:4) of the residue afforded 2 (1.0 g,
20
81%) as a colorless oil. ½aꢀD ¼ ꢁ13:6 (c 2.0, CHCl3); IR
(film): 3063, 2977, 2930, 1712; 1H NMR (400 MHz,
CDCl3): d 7.27–7.36 (m, 5H), 4.54 (s, 2H), 4.27–4.29 (m,
1H), 3.43–3.51 (m, 2H), 3.38 (s, 2H), 2.90 (br s, 1H), 2.75
(d, J = 5.6 Hz, 2H), 1.46 (s, 9H); 13C NMR (400 MHz,
CDCl3): d 202.96, 166.14, 137.80, 128.40, 127.73, 127.70,
82.14, 73.36, 73.10, 66.67, 51.16, 46.14, 27.91. MS (ESI):
m/z = 639.0 (2M+Na)+, 331.2 (M+Na)+.
Acknowledgments
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hedron 1993, 49, 1997–2010.
15. Beck, G.; Jendralla, H.; Kesseler, K. Synthesis 1995, 1014–
1018.
We thank the Chinese National Natural Science Founda-
tion (No. 20336010), Key Project of Chinese National Pro-
grams for Fundamental Research and Development (No.
2003CB716008) and The 10th Five Years Key Programs
for Science and Technology Development of China for
their financial support.
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