A new and facile preparation of tert-butyl (3R,5S)-6-hydroxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate

Article abstract of DOI:10.1016/j.tetasy.2007.09.026

A facile method for the preparation of tert-butyl (3R,5S)-6-hydroxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate is described by a chemoenzymatic approach. In this method, one hydroxyl stereocenter at C5 is obtained with a high ee value (up to 98.0%) via an enzymatic transesterification resolution of l-chloro-3-(4-methylbenzyloxy)-2-propanol. The other hydroxyl stereocenter at C3 was built with 98.0% de, by acid-hydrolysis of a 1,3-diol-acetonide syn/anti-10. It is noteworthy that the reduction of β-hydroxy ketone 8 with sodium borohydride can be carried out smoothly in aqueous isopropyl alcohol with a high diastereomeric ratio syn/anti (dr_s:a) of 4.0:1.

Full text of DOI:10.1016/j.tetasy.2007.09.026

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2454–2461
A new and facile preparation of tert-butyl
(3R,5S)-6-hydroxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate
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 20 August 2007; accepted 21 September 2007
Available online 23 October 2007
Abstract—A facile method for the preparation of tert-butyl (3R,5S)-6-hydroxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate is
described by a chemoenzymatic approach. In this method, one hydroxyl stereocenter at C5 is obtained with a high ee value (up to
98.0%) via an enzymatic transesterification resolution of l-chloro-3-(4-methylbenzyloxy)-2-propanol. The other hydroxyl stereocenter
at C3 was built with 98.0% de, by acid-hydrolysis of a 1,3-diol-acetonide syn/anti-10. It is noteworthy that the reduction of b-hydroxy
ketone 8 with sodium borohydride can be carried out smoothly in aqueous isopropyl alcohol with a high diastereomeric ratio syn/anti
(drs:a) of 4.0:1.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
convenient synthesis of enantiomerically and diastereomer-
ically pure b,d-dihydroxycarboxylate moiety is crucial for
the preparations of statins. Much research has been pub-
lished regarding this topic since 1980. In most research,
one chiral hydroxyl group is introduced by chiral raw
materials4 or asymmetric synthesis,5 and the other chiral
hydroxyl group can be obtained by sodium borohydride
HMG-CoA reductase inhibitors (statins), such as simvasta-
tin1 1 and atorvastatin2 2 (Fig. 1), have been widely used to
reduce low density lipoprotein (LDL) levels in blood with
less side effects. Statins have a common structure, b,d-
dihydroxycarboxylate 3 or its closed chain analogue 4.3 A
F
HO
O
OH OH
O
O
O
O-
Ca2+
2
N
O
CH3
HN
Ph
O
H3C
2
1
HO
O
OH OH
O
O
O
O
O
R1
HO
OR2
Ot-Bu
R3
5
3
4
Figure 1. Statins and key intermediates.
*
Corresponding author. Tel./fax: +86 571 87952363; e-mail: lryang@zju.edu.cn
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.09.026

F. Sun et al. / Tetrahedron: Asymmetry 18 (2007) 2454–2461
2455
reduction in the presence of triethylborane or diethyl(meth-
oxy)borane as complexing agents.6 Recently, Wolberg7
described the stereoselective synthesis of a chiral b,d-
dihydroxy ester, which comprised of a Baker’s yeast reduc-
tion and a syn-selective borohydride reduction. However,
all these methods were all involved rather low reaction tem-
peratures (below ꢀ60 ꢁC), and flammable and expensive
borane reagents. Reduction of the b,d-diketo ester by the
method of ruthenium catalysts8 or biocatalysts9 is a
straightforward and flexible approach. For example, Car-
pentier succeeded in providing syn-3,5-dihydroxyesters via
ruthenium-catalyzed transfer hydrogenation. The diaste-
reomeric excess achieved was, nevertheless, limited to
80% at best.8a Highly enantioselective reduction of ethyl
6-benzyloxy-3,5-dioxohexanoate by the microbe of Acine-
tobacter. sp. SCI 13874 was reported, although the diaste-
reoselectivity given was unsatisfactory (63% de).9b
Chloro-3-(4-methylbenzyloxy)-2-propanol 7f was formed
after the epoxide was treated with NH4Cl in DMSO.11
Compound (R)-7f was obtained by a lipase-catalyzed
asymmetric esterification in the mixed solvent (n-hexane/
acetonitrile, 3:1, v/v) with 98.0% ee (chiral HPLC analysis).
b-Hydroxy ketone 8 was formed in an overall yield of 58%
from (R)-7f by the addition with sodium cyanide, followed
by hydroxyl group protection12 and condensation with
tert-butyl 2-bromoacetate.13 Compound 8 was then re-
duced by sodium borohydride in aqueous isopropyl alco-
hol in 0 ꢁC, giving syn/anti-9 with drs:a 4.0:1. After the
acid-catalyzed protection of syn/anti-9 with 2,2-dimethoxy-
propane, syn/anti-10 was treated with aqueous acid to ful-
fill the selective preparation of syn-10.14 The resulting syn-
10 was easily separated from anti-9 by silica gel chromato-
graphy in 65% yield with drs:a 100:1 (GC analysis). Finally,
hydrogenolysis of the benzyl protecting group afforded 5
with 98.0% de.
Herein, we report a facile route to the synthesis of tert-
butyl (3R,5S)-6-hydroxy-3,5-O-isopropylidene-3,5-dihydr-
oxyhexanoate 5 by a chemoenzymatic approach (Scheme
1). The advantage of this approach is that two hydroxyl
stereocenters (C3 and C5) could be obtained with high
enantiomeric and diastereomeric purity by an enzymatic
transesterification at 30 ꢁC and diastereomer-differentiating
hydrolysis at the room temperature, respectively.
2.2. Synthesis of hydroxyl stereocenters at C5
Considering our interest in building the chiral C5 of 5 by
an enzymatic method, we aimed to resolve 1-chloro-3-aryl-
methoxy-2-propanols 7a–f (Scheme 2) by lipase-catalyzed
esterification and to find a suitable substrate used in the
synthetic route. Although optically active 1-chloro-3-
benzyloxy-2-propanol could be prepared from chiral
epichlorohydrin, which could be obtained from racemic
epichlorohydrin by catalytic asymmetric synthesis,15 enzy-
matic methods afforded an alternative and effective way
for the synthesis of chiral 1-chloro-3-benzyloxy-2-propa-
nol. Many enzymatic methods have been reported, but
most of them were based on lipase-catalyzed hydrolysis
reactions.16 In our previous report,17 (S)-4-arylmethoxy-
3-hydroxybutanenitriles were prepared by the method of
lipase-catalyzed esterification, but only moderate enantio-
2. Results and discussion
2.1. Synthetic route
In the present synthetic strategy, commercially available
racemic epichlorohydrin 6 was used as the starting material
(Scheme 1). Treatment of 6 with p-methylbenzyl alcohol in
the presence of a base gave epoxide in high yields.10 l-
OH
OH
O
a
b
Cl
O
Cl
O
Cl
7f
6
(R)-7f
OH
OH
O
OH
O
O
O
O
O
c
d
f
O
O
O
Ot-Bu
Ot-Bu
Ot-Bu
syn/anti-9, drs:a=4.0:1
8
O
O
O
e
g
O
Ot-Bu
syn-10, drs:a=100:1
syn/anti-10, drs:a=4.0:1
O
O
O
HO
Ot-Bu
5
Scheme 1. Reagents and conditions: (a) (i) epichlorohydrin, 40% NaOH aq, n-Bu4NBr, 10 ꢁC, 24 h, 80%; (ii) DMSO, NH4Cl, 75–80 ꢁC, 8 h, 85%; (b) vinyl
acetate, the lipase from Alcaligenes sp. (PL), a mixed solvent (n-hexane/acetonitrile = 3:1, v/v), 30 ꢁC, 25 h, 48%; (c) (i) NaCN, DMSO, 70 ꢁC, 7 h, 80%;
t
(ii) TMSCl, Et3N, THF, 0 ꢁC, 12 h, 95%; (iii) BrCH2CO2 Bu, Zn, MeSO3H, THF, reflux 4 h, then, 3 M HCl; 0 ꢁC, 3 h, 76%; (d) NaBH4, i-PrOH/H2O,
0 ꢁC, 4 h, 85%; (e) Me2C(OMe)2, cat. camphor sulfonic acid, rt, 4 h, 95%; (f) 0.50 M p-TsOH, CH2Cl2, rt, 10 h, 65%; (g) 20 atm H2, cat. 10% Pd/C, EtOAc,
32 ꢁC, 16 h, 90%.

2456
F. Sun et al. / Tetrahedron: Asymmetry 18 (2007) 2454–2461
OH
OH
OAc
Lipase
O
Cl
O
Cl
O
Cl
R
R
R
AcO
7a-f
(S)-11a-f
(R)-7a-f
Scheme 2.
meric ratios (mostly from 24 to 75) were obtained. In order
to obtain better enantiomeric ratios, we continued our re-
search to resolve 7a–f (Scheme 2), since these compounds
can be easily converted to 4-arylmethoxy-3-hydroxy-
butanenitriles by treating with sodium cyanide.
strates plays a great role on enzymatic selectivity.19 For an-
other, the substituted benzyl groups can be easily cleaved
by the method of hydrogenolysis with catalytic Pd/C.20
Seven substrates 7a–f were studied and the results are given
in Table 3. When 7a–d were chosen as the substrates, the
selectivity was dropped. Better results with E-values higher
than 200 were obtained when substrates 7e and 7f were cat-
alyzed by the lipase from Alcaligenes sp. (PL). The lipase
was particularly selective toward the (R)-7f enantiomer.
At nearly 50% conversion, unreacted alcohol (R)-7f was
obtained in 98% ee and the corresponding acetate (S)-11f
in 96% ee. Therefore, 7f was chosen as the intermediate
in our synthetic route to build the hydroxyl stereocenter
at C5 of 5.
2.2.1. Lipase screening. Firstly, the resolution of racemic
1-chloro-3-benzyloxy-2-propanol 7a was performed by
employing different lipases in vinyl acetate and the results
are listed in Table 1. It was observed that the reactions cat-
alyzed by the lipase from Alcaligenes sp. (QL) (Table 1, en-
try 6) proceeded with good enantioselectivity, but with only
relatively low conversions after 20 h. The uses of some en-
zymes resulted in low-selective reactions (Table 1, entries
1–5). The lipase from Alcaligenes sp. (PL) showed higher
E-values and better reaction rates (Table 1, entry 7). There-
fore, the lipase from Alcaligenes sp. (PL) was chosen in the
following reactions.
2.3. Synthesis of hydroxyl stereocenter at C3
In general, syn-dihydroxy esters were synthesized according
to Prasad’s method.6 However, this method involved using
flammable triethylborane or diethyl(methoxy)borane, and
a very low temperature (<ꢀ60 ꢁC). We found a facile
way to prepare the protected syn-diol syn-10 by a three-step
method; first the asymmetric reduction of b-hydroxy
ketone 8; then the acetonide protection of syn/anti 9,
and lastly, the acid-catalyzed hydrolysis of syn/anti-10
(Scheme 1).
2.2.2. Effect of solvent. Solvent variation in a lipase-cata-
lyzed kinetic resolution is known to influence the enantiose-
lectivity as well as the reaction rate.18 In the present study,
eight solvents were examined by using Alcaligenes sp. (PL)
lipase (Table 2). It was observed that i-Pr2O and toluene
were not suitable for obtaining good enantioselectivities
(Table 2, entries 1 and 2). In n-hexane, the reaction pro-
ceeded very quickly, but the E-value was unsatisfactory
(Table 2, entry 3). Moreover, it took a long reaction time
to reach 50% conversion in pure acetonitrile (Table 2, en-
tries 4 and 5). To achieve high E value and an adequate
rate, we attempted to mixed solvents (Table 2, entries 6–
8). In these solvents, they both gave high enantioselectivi-
ties and good reaction rates. Therefore, the mixed solvent
(n-hexane/acetonitrile, 3:1, v/v) was selected as the suitable
reaction solvent.
Solvents may affect the stereochemistry of reduction with
sodium borohydride.21 Therefore, we first attempted to
reduce 8 with sodium borohydride in different solvents
(Table 4). It was found that in aqueous ethyl alcohol, the
diastereomeric ratio (drs:a) of syn/anti-9 was 2.0:1. When
aqueous isopropyl alcohol was chosen,a higher drs:a value
(4.0:1) was obtained. This exciting result encouraged us
to develop an effective acid-catalyzed hydrolysis method
for the synthesis of syn-10.14
2.2.3. Effect of the substituent. Here we continued to study
the effects of different substituents on the aryl rings on the
enzymatic resolution of the substrates, as shown in Scheme
2 and Table 3. For one reason, the structure of the sub-
After acetonide protection of syn/anti-9, syn/anti-10 was
treated with aqueous acid to fulfill the selective preparation
Table 1. Transesterification of 7a with vinyl acetate using various lipasesa
Entry
Lipase source
Time (h)
ee (%)
Conversion (%)
E
Alcohol
Acetate
1
2
3
4
5
6
7
Candida antarctica
Lipoprime.TM
15
7.5
15
15
7.5
20
33.5
66.3
14.3
33.7
51.3
13.3
66.2
33.8
57.3
65.2
42.9
71.2
81.5
78.4
49.8
53.6
18.0
44.0
41.8
14.0
47.1
2.7
7.1
5.5
3.4
9.8
Pseudomonas sp.
Rhizopus delemar
Artgribacter sp.
Alcaligenes sp.(QL)
Alcaligenes sp.(PL)
11.2
16.2
7.5
a All reactions were carried out by stirring a mixture of 7a (50 mg), lipase (5 mg), and vinyl acetate (2 mL) at 30 ꢁC.

F. Sun et al. / Tetrahedron: Asymmetry 18 (2007) 2454–2461
Table 2. Transesterification of 7a with vinyl acetate in various solventsa
2457
Entry
Solvent
Time (h)
ee (%)
Conversion (%)
E
Alcohol
Acetate
1
2
3
4
5
6
7
8
Toluene
i-Pr2O
n-Hexane
Acetonitrile
15.0
9.5
6.5
31.0
60.0
50.0
35.0
25.0
52.3
74.8
95.0
44.1
70.5
97.1
96.3
97.5
68.5
74.2
70.7
98.0
96.6
90.3
89.8
88.2
56.8
50.2
57.3
33.1
41.9
51.8
51.7
52.5
9.0
15.0
20.9
153
123
82.8
74.2
69.3
Acetonitrile
n-Hexane/acetonitrile (1:3)
n-Hexane/acetonitrile (1:1)
n-Hexane/acetonitrile (3:1)
a All reactions were carried out by stirring a mixture of 7a (40 mg), the lipase from Alcaligenes sp. (PL) (5 mg) and vinyl acetate (0.1 mL) in 2 mL solvent at
30 ꢁC.
Table 3. Kinetic resolution of 1-chloro-3-arylmethoxy-2-propanols 7a–fa
Entry
Substrate
R
Time (h)
ee (%)
Conversion (%)
E
Alcohol
Acetate
1
2
3
4
5
6
7a
7b
7c
7d
7e
7f
H
25
35
20
30
30
30
97.3
96.8
98.2
98.1
96.7
98.0
88.5
84.5
90.1
91.5
96.0
96.0
52.3
53.4
52.1
51.7
50.1
50.5
70
49
90
103
200
226
2,4-Cl
4-CH3O
4-F
4-Cl
4-CH3
a All reactions were carried out by stirring a mixture of 7a–f (5 mmol), the lipase from Alcaligenes sp. (PL) (125 mg) and vinyl acetate (15 mmol) in the
50 mL mixed solvent (n-hexane/acetonitrile, 3:1,v/v) at 30 ꢁC.
Table 4. Reduction of 8 in different solventsa
Entry
Solvent
syn/anti-9 (drs:a
)
Yield (%)
1
2
3
Ethyl alcohol/H2O (4:1,v/v)
Methyl alcohol/H2O (4:1,v/v)
Isopropyl alcohol/H2O (4:1,v/v)
2.0:1
3.2:1
4.0:1
86
87
85
a 4.0 g (12.4 mmol) 8, 0.54 g (14.6 mmol) NaBH4, 0 ꢁC, 4 h.
the hydroxyl stereocenter at C5, l-chloro-3-(4-methyl-
benzyloxy)-2-propanol 7f was enantioselectively resolved
by lipase from Alcaligenes sp. (PL) in the mixed solvent
(n-hexane/acetonitrile, 3:1) with a high ee value (up to
98.0%). Another hydroxyl stereocenter at C3 was built by
a three-step method; first the sodium borohydride reduc-
tion of b-hydroxy ketone 8 in aqueous isopropyl alcohol
with a high diastereomeric ratio (drs:a = 4.0:1), then aceto-
nide protection, followed by hydrolysis of syn/anti-10 with
p-TsOH solution (0.50 M). Compound syn-10 was ob-
tained in 65% yield and 98.0% de. By hydrogenolysis of
the benzyl protecting group, compound 5 was obtained
with high enantiomeric and diastereomeric purity (98.0%
ee, 98.0% de).
O
O
O
O
Ot-Bu
Ot-Bu
syn/anti-10 Table 5
(drs:a=4.0:1)
syn-10, drs:a=100:1
OH
OH
O
O
anti-9, drs:a=1:2.5
Scheme 3. Diastereomer-differentiating hydrolysis of syn/anti-10.
of syn-10 (Scheme 3). In order to optimize the reaction con-
ditions, the effects of acid species and reaction time on the
reaction were examined (Table 5). It was found that the
aqueous solution of p-TsOH (0.50 M) was most effective
in this reaction.
4. Experimental
4.1. General
All reagents were of commercial grade with purity >98%
and used as provided without further purification. Candida
antarctica (Novozym 435) and Lipoprime.TM were pur-
chased from Novo Nordisk; Alcaligenes sp. (PL), Alcalige-
nes sp. (QL) from Meito Sangyo; Pseudomonas sp.,
3. Conclusion
In conclusion, an efficient asymmetric synthesis of 5 has
been described by a chemoenzymatic approach. To obtain

2458
F. Sun et al. / Tetrahedron: Asymmetry 18 (2007) 2454–2461
Table 5. Resolution of syn/anti-10 in different conditions
Entry
Conditions
syn-10 (drs:a
)
Yield of syn-10 (%)
anti-9 (drs:a
)
Yield of anti-9 (%)
1
2
3
4
5
1 M HCl (8 mL),a 30 h
4.0:1
8.0:1
70.0:1
9.0:1
/
/
/
2 M HCl (3 mL),a 20 h
80
60
80
65
1:5.0
1:1.5
1:6.0
1:2.5
10
21
11
25
3 M HCl (3 mL),a 15 h
0.35 M p-TsOH (4 mL),a 20 h
0.50 M p-TsOH (4 mL),a 10 h
100:1
a Aqueous solution, CH2Cl2 (5 mL), (2 g, 7.6 mmol) syn/anti-10 (drs:a = 4.0:1), 18 ꢁC.
Rhizopus delemar from Fluka and Artgribacter sp. was a
gift from Professor Xiufen Kou of the Institute of Micro-
biology, Chinese Academy of China (IMCAC). 1H and
13C NMR spectra were measured in CDCl3 and recorded
on a Brucker Avance-400 (400 MHz) spectrometer with
TMS as the internal standard. GC–MS spectra were re-
corded on a HP-6890/MS-5973 spectrometer. Mass spectra
were recorded on an Esquire-LC spectrometer. Infrared
(IR) spectra were recorded on a Nicolet 560 spectrometer.
Optical rotations were measured on an AUTOPOL IV dig-
ital polarimeter. HPLC was performed on a Chiralpak
AD-H column (Daicel) and monitored by UV (224 nm).
Conversion and enantiomeric purities of 1-chloro-3-aryl-
methoxy-2-propanols were determined by HPLC analyses
(solvent: n-hexane/EtOH); the ees of the corresponding
acetates were calculated by using standard curves. Diaste-
reomeric purities were determined by GC analyses on
AT.SE-30 column (30 m · 0.20 mm · 0.33 lm). The abso-
lute configurations of 1-chloro-3-arylmethoxy-2-propanols
7a–f were assigned by preparing standards from (R)-
epichlorohydrin.
t(R-7b) = 10.1 min, hexane/EtOH 90:10, flow: 1.0 mL/min;
1H NMR (400 Hz, CDCl3): d 7.27–7.36 (m, 3H), 4.61 (s,
2H), 4.01–4.05 (m, 1H), 3.60–3.70 (m, 4H), 2.51 (d,
J = 5.6 Hz, 1H); 13C NMR (100 Hz, CDCl3): 134.1,
133.9, 133.7, 129.9, 129.2, 127.1, 71.3, 70.2, 70.0, 46.0;
MS (70 eV, EI) m/z (%): 268/270 (M+, 5/5), 194/196 (4/
4), 159/161 (100/66), 123 (12), 89 (13).
4.2.3.
(R)-1-Chloro-3-(4-methyoxybenzyloxy)-2-propanol
(R)-7c. This compound was obtained as a yellow oil in
20
45% yield and 98.2% ee; ½aꢁD ¼ þ1:9 (c 3.9, CHCl3); HPLC
(Daicel Chiralpak AD-H), t(S-7c) = 82.6 min, t(R-7c)
=
1
87.9 min, hexane/EtOH 99:1, flow: 1.0 mL/min; H NMR
(400 Hz, CDCl3): d 7.25 (d, J = 7.2 Hz, 2H), 6.89 (d,
J = 8.4 Hz, 2H), 4.49 (s, 2H), 3.96–3.99 (m, 1H), 3.57–
3.65 (m, 2H), 3.55 (d, J = 5.2 Hz, 2H), 3.00 (s, 3H), 2.56
(br s, 1H); 13C NMR (100 Hz, CDCl3): 159.2, 129.6,
129.3, 113.7, 73.07, 70.4, 70.17, 55.1, 45.9; MS (70 eV,
EI) m/z (%): 230/232 (M+, 15/5), 137 (10), 121 (100), 91
(5), 78 (10).
4.2.4. (R)-1-Chloro-3-(4-fluorobenzyloxy)-2-propanol (R)-
7f. This compound was obtained as a yellow oil in 45%
4.2. General procedure for the resolution of 1-chloro-3-
arylmethoxy-2-propanols 7a–f
20
yield and 98.1% ee; ½aꢁD ¼ þ2:4 (c 1.8, CHCl3); HPLC
(Daicel Chiralpak AD-H), t(S-7d) = 17.1 min, t(R-7d)
=
1
Racemic 7a–f (5 mmol) was dissolved in a mixed solvent
(n-hexane/acetonitrile = 3:1, 50 mL). To this solution, the
lipase from Alcaligenes sp. (PL) (125 mg) and vinyl acetate
(15 mmol) were added successively and shaken at 30 ꢁC for
20–30 h. After about 50% conversion was reached (moni-
tored by HPLC), the enzyme was filtered and washed with
ethyl acetate (30 mL). The solvent was evaporated and
purification was accomplished by chromatography on silica
gel, employing EtOAc/hexane (1:4) as the eluent to afford
the corresponding acetate (S)-11a–f, followed by the unre-
acted alcohol (R)-7a–f.
18.2 min, hexane/EtOH 93:7, flow: 1.0 mL/min; H NMR
(400 Hz, CDCl3): d 7.27–7.31 (m, 2H), 7.02–7.06 (m, 2H),
4.52 (s, 2H), 3.99–4.01 (m, 1H), 3.58–3.67 (m, 2H), 3.59
(d, J = 5.2 Hz, 2H), 2.51 (br s, 1H); 13C NMR (100 Hz,
CDCl3): 163.6, 161.2, 133.4, 133.3, 129.6, 129.5, 115.5,
115.2, 72.8, 70.8, 70.2, 45.9; MS (70 eV, EI) m/z (%): 218
(M+, 7), 165 (1), 144/146 (4/1.3), 125 (10), 109 (100), 83
(10).
4.2.5. (R)-1-Chloro-3-(4-chlorobenzyloxy)-2-propanol (R)-
7e. This compound was obtained as a colorless oil in
20
47% yield and 96.7% ee; ½aꢁD ¼ þ2:2 (c 3.2, CHCl3); HPLC
4.2.1. (R)-1-Chloro-3-benzyloxy-2-propanol (R)-7a. This
(Daicel Chiralpak AD-H), t(S-7e) = 18.8 min, t(R-7e)
=
1
compound was obtained as a colorless oil in 43% yield
19.6 min, hexane/EtOH 95:5, flow: 1.0 mL/min; H NMR
(400 Hz, CDCl3): d 7.33 (d, J = 8.8 Hz, 2H), 7.26 (d,
J = 8.4 Hz, 2H), 4.52 (s, 2H), 3.98–4.01 (m, 1H), 3.59–
3.67 (m, 2H), 3.58 (d, J = 4.8 Hz, 2H), 2.57 (br s, 1H);
13C NMR (100 Hz, CDCl3): 136.0, 133.5, 128.9, 128.5,
72.6, 70.8, 70.1, 45.9; MS (70 eV, EI) m/z (%): 234/236
(M+, 10/6), 160 (7/4), 141 (14), 125/127 (100/34), 89 (15).
20
and 97.3% ee; ½aꢁD ¼ þ1:5 (c 3.3, CHCl3); HPLC (Daicel
Chiralpak AD-H), t(S-7a) = 12.0 min, t(R-7a) = 12.8 min,
1
hexane/EtOH 92:8, flow: 0.9 mL/min; H NMR (400 Hz,
CDCl3): d 7.30–7.38 (m, 5H), 4.56 (s, 2H), 3.97–4.02 (m,
1H), 3.58–3.67 (m, 2H), 3.59 (d, J = 4.0 Hz, 2H), 2.59 (br
s, 1H); 13C NMR (100 Hz, CDCl3): 137.5, 128.4, 127.8,
127.7, 73.43, 70.8, 70.2, 45.9; MS (70 eV, EI) m/z (%): 200/
202 (M+, 15/5), 126/128 (6/2), 107 (10), 91 (100), 65 (12).
4.2.6. (R)-l-Chloro-3-(4-methylbenzyloxy)-2-propanol (R)-
7f. This compound was obtained as a colorless oil in
20
4.2.2.
(R)-1-Chloro-3-(2,4-dichlorobenzyloxy)-2-propanol
47% yield and 98.0% ee; ½aꢁD ¼ þ2:0 (c 3.5, CHCl3); HPLC
(R)-7b. This compound was obtained as a colorless oil
(Daicel Chiralpak AD-H), t(S-7f) = 21.9 min, t(R-7f) =
20
1
in 44% yield and 96.8% ee; ½aꢁD ¼ þ2:2 (c 3.4, CHCl3);
23.4 min, hexane/EtOH 92:8, flow: 0.9 mL/min; H NMR
HPLC (Daicel Chiralpak AD-H), t(S-7b) = 9.2 min,
(400 Hz, CDCl3): d 7.23 (d, J = 8.0 Hz, 2H), 7.17 (d,

F. Sun et al. / Tetrahedron: Asymmetry 18 (2007) 2454–2461
2459
J = 7.6 Hz, 2H), 4.52 (s, 2H), 3.96–4.01 (m, 1H), 3.58–3.67
(m, 2H), 3.58 (d, J = 4.4 Hz, 2H), 2.35 (s, 3H); 13C NMR
(100 Hz, CDCl3): 137.6, 134.4, 129.1, 127.8, 73.3, 70.6,
70.2, 45.9, 21.1; MS (70 eV, EI) m/z (%): 214 (M+, 11),
199 (2), 140/142 (5/1.7), 121 (9), 105 (100), 77 (10).
7.23 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 5.15–
5.58 (m, 1H), 4.52 (d, J = 5.2 Hz, 2H), 3.66–3.77 (m,
2H), 3.62–3.65 (m, 2H), 2.35 (s, 3H), 2.10 (s, 3H); 13C
NMR (100 Hz, CDCl3): 170.1, 137.5, 134.5, 129.0, 127.7,
73.2, 71.6, 67.9, 42.7, 21.1, 20.8; MS (70 eV, EI) m/z (%):
256 (M+, 4), 221 (3), 161 (6), 135/137 (18/6), 121 (37),
105 (100), 77 (9).
4.2.7. (S)-2-Acetoxy-1-chloro-3-benzyloxy-2-propanol (S)-
11a. This compound was obtained as a colorless oil in
20
1
42% yield and 88.5% ee; ½aꢁD ¼ þ7:3 (c 3.3, CHCl3); H
NMR (400 Hz, CDCl3): d 7.29–7.37 (m, 5H), 5.15–5.17
(m, 1H), 4.56 (d, J = 4.8 Hz, 2H), 3.67–3.78 (m, 2H),
3.64–3.66 (m, 2H), 2.10 (s, 3H); 13C NMR (100 Hz,
CDCl3): 170.0, 137.5, 128.3, 127.7, 127.6, 73.3, 71.58,
68.1, 42.7; MS (70 eV, EI) m/z (%): 242 (M+, 1), 207 (5),
147 (10), 135/137 (18/6), 107 (19), 91 (100), 77 (4).
4.3. Experimental procedure for the synthesis of 5
4.3.1. (R)-1-(4-methylbenzyloxy)-3-chloro-2-propanol (R)-
7f. A mixture of DMSO (100 mL), NH4Cl (42.8 g,
800.0 mmol), 1-(4-methybenzyloxy)-2,3-epoxypropane (71.2 g,
400.0 mmol) prepared according to the literature method10
was vigorously stirred at room temperature and then
heated at 75–80 ꢁC for 8 h. After the reaction was com-
plete, water (60 mL) was added and the mixture was
extracted with ethyl acetate (2 · 100 mL). The organic
phase was separated, dried with magnesium sulfate and dis-
tilled to yield 7f as a colorless oil (72.8 g, 85%). Resolution
of 7f (40.0 g, 18.7 mmol) by employing the above general
procedure 4.2 afforded (R)-7f (18.8 g, 47% yield, 98.0% ee).
4.2.8. (S)-2-Acetoxy-1-chloro-3-(2,4-dichlorobenzyloxy)-2-
propanol (S)-11b. This compound was obtained as a col-
20
orless oil in 43% yield and 84.5% ee; ½aꢁD ¼ þ6:8 (c 3.4,
1
CHCl3); H NMR (400 Hz, CDCl3): d 7.26–7.38 (m, 3H),
5.16–5.21 (m, 1H), 4.60 (d, J = 4.0 Hz, 2H), 3.67–3.8 (m,
4H), 2.11 (s, 3H); 13C NMR (100 Hz, CDCl3): 170.0,
133.9, 133.9, 133.4, 129.7, 129.0, 127.0, 71.4, 69.8, 68.7,
42.5, 42.2, 20.8; MS (70 eV, EI) m/z (%): 311 (M+, 1),
275/277 (7/5), 267/269 (5/5), 174 (31), 159 (100), 123 (13).
4.3.2. tert-Butyl (S)-6-(4-methybenzyloxy)-5-hydroxy-3-
oxohexanoate 8. DMSO (60 mL), (R)-7f (18.0 g,
87.8 mmol) and sodium cyanide (5.2 g, 106.1 mmol) were
added to a 250 mL flask and heated at 70 ꢁC for 7 h. After
the reaction was complete, water (60 mL) and ethyl acetate
(2 · 100 mL) were added. The organic phase was sepa-
rated, dried, and distilled. The residue was purified by
chromatography on silica gel to afford (S)-4-(4-methy-
benzyloxy)-3-hydroxybutanenitrile as a colorless oil (14.4 g,
80%).
4.2.9. (S)-2-Acetoxy-1-chloro-3-(4-methyoxybenzyloxy)-2-
propanol (S)-11c. This compound was obtained as a col-
20
orless oil in 45% yield and 90.1% ee; ½aꢁD ¼ þ8:8 (c 3.5,
CHCl3); 1H NMR (400 Hz, CDCl3):
d
7.25 (d,
J = 8.0 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.13–5.15 (m,
1H), 4.48 (d, J = 6.4 Hz, 2H), 3.80 (s, 3H), 3.64–3.76 (m,
2H), 3.60–3.62 (m, 2H), 2.09 (s, 3H); 13C NMR (100 Hz,
CDCl3): 170.1, 159.3, 129.6, 129.2, 113.7, 73.0, 71.6, 67.7,
55.1, 42.7, 20.8; MS (70 eV, EI) m/z (%): 272/274 (M+, 7/
2.5), 229 (2), 177 (4), 137 (50), 121 (100), 78 (11).
To a stirred solution of (S)-4-(4-methybenzyloxy)-3-
hydroxybutanenitrile (12.4 g, 60.5 mmol) in THF
(100 mL) was added triethylamine (6.8 g, 67.3 mmol) at
0 ꢁC. To the mixture was added Me3SiCl (6.8 g, 63.0
mmol). The reaction mixture was stirred at rt for 12 h, then
filtered, and evaporated to give (S)-4-(4-methybenzyloxy)-
3-(trimethylsilylhydroxy)butanenitrile (15.8 g, 95%) as a
colorless oil.
4.2.10. (S)-2-Acetoxy-1-chloro-3-(4-fluorobenzyloxy)-2-pro-
panol (S)-11d. This compound was obtained as a colorless
20
oil in 45% yield and 91.5% ee; ½aꢁD ¼ þ8:4 (c 3.7, CHCl3);
1H NMR (400 Hz, CDCl3): d 7.27–7.30 (m, 2H), 7.01–7.05
(m, 2H), 5.14–5.17 (m, 1H), 4.52 (d, J = 5.6 Hz, 2H), 3.66–
3.76 (m, 2H), 3.63–3.65 (m, 2H), 2.10 (s, 3H); 13C NMR
(100 Hz, CDCl3): 170.1, 163.5, 161.1, 133.3, 133.29,
129.4, 129.3, 115.3, 115.1, 72.6, 71.5, 68.0, 42.5, 20.8; MS
(70 eV, EI) m/z (%): 260 (M+, 0.5), 225 (4), 207 (6), 167
(7), 147 (11), 135 (24), 109 (55), 91 (100).
To a stirred suspension of commercial zinc powder (7.8 g,
120.0 mmol) in THF (60 mL) was added MeSO3H (4 mg,
0.4 mmol) and refluxed for 15 min. To the mixture (S)-4-
(4-methybenzyloxy)-3-(trimethylsilylhydroxy)butanenitrile
t
(15.8 g, 57.0 mmol) and BrCH2CO2 Bu (20.6 g, 114.4
4.2.11. (S)-2-Acetoxy-1-chloro-3-(4-chlorobenzyloxy)-2-pro-
panol (S)-11e. This compound was obtained as a colorless
mmol) were added. The reaction mixture was refluxed for
4 h, then cooled to 0–5 ꢁC after which 3 M HCl (200 mL)
was added dropwise. After 3 h, ethyl acetate (120 mL)
was added and the organic layer washed with saturated
NaHCO3 (50 mL). The separated organic layer was dried
and concentrated. Column chromatography on silica gel
20
oil in 47% yield and 96.0% ee; ½aꢁD ¼ þ8:9 (c 3.1, CHCl3);
1H NMR (400 Hz, CDCl3): d 7.33 (d, J = 8.8 Hz, 2H), 7.26
(d, J = 8.4 Hz, 2H), 5.14–5.17 (m, 1H), 4.52 (d, J = 5.2 Hz,
2H), 3.67–3.77 (m, 2H), 3.63–3.66 (m, 2H), 2.10 (s, 3H);
13C NMR (100 Hz, CDCl3): 170.1, 136.1, 133.5, 128.9,
128.5, 72.5, 71.5, 68.2, 42.6, 20.8; MS (70 eV, EI) m/z
(%): 276 (M+, 1), 241 (10), 181 (13), 140 (39), 125/127
(100/34), 89 (16).
(EtOAc/hexane, 1:4) of the residue afforded 8 (13.4 g,
20
76%) as a colorless oil. ½aꢁD ¼ ꢀ13:0 (c 2.5, CHCl3); IR
(film): 3442, 3063, 2978, 2926, 1733 cmꢀ1 1H NMR
;
(400 MHz, CDCl3): d 7.23 (d, J = 8.0 Hz, 2H), 7.17 (d,
J = 7.6 Hz, 2H), 4.51 (s, 2H), 4.28 (m, 1H), 3.41–3.50 (m,
2H), 3.39 (s, 2H), 2.97 (br s, 1H), 2.75 (d, J = 6.4 Hz,
2H), 2.35 (s, 3 H), 1.47 (s, 9H); 13C NMR (100 MHz,
CDCl3): d 203.0, 166.2, 137.5, 134.7, 129.1, 127.8, 82.1,
4.2.12. (S)-2-Acetoxy-l-chloro-3-(4-methylbenzyloxy)-2-pro-
panol (S)-11f. This compound was obtained as a colorless
20
oil in 48% yield and 96.0% ee; ½aꢁD ¼ þ8:7 (c 2.2, CHCl3); d

2460
F. Sun et al. / Tetrahedron: Asymmetry 18 (2007) 2454–2461
73.2, 72.9, 66.6, 51.1, 46.1, 27.9, 21.1; MS (ESI): 666.4
(2M+Na)+, 345.0 (M+Na)+.
(70 mL) contained in a 250 mL autoclave. The autoclave
was purged with H2 and then filled with H2 (20 atm). The
mixture was stirred at constant pressure with heating at
32 ꢁC inner temperature for 16 h. TLC (EtOAc/hexane,
1:4) indicated quantitative clean reaction. The catalyst
4.3.3. tert-Butyl (5S)-6-(4-methybenzyloxy)-3,5-dihydroxy-
hexanoate syn/anti-9. Compound 8 (11.0 g, 34.2 mmol),
isopropanol (60 mL), and H2O (10 mL) were added to a
150 mL flask and cooled to 0 ꢁC. NaBH4 (1.5 g, 40.5 mmol)
dissolved in H2O (5 mL) solution was added dropwise for
30 min. After 4 h, 3 M HCl was added to neutrality. Isopro-
panol was removed and the remaining mixture was
extracted with ethyl acetate (2 · 60 mL). The separated
organic layer was dried with magnesium sulfate and concen-
trated to yield syn/anti-9 (9.4 g, 85%) as a colorless oil;
drs:a = 4.0:1. The value of drs:a was determined by GC after
9 was converted to 10; IR (film): 3445, 1731, 1153 cmꢀ1; 1H
NMR (400 MHz, CDCl3): d 7.23 (d, J = 8.4 Hz, 2H), 7.17
(d, J = 7.6 Hz, 2H), 4.51 (s, 2H), 4.23–4.29 (m, 1H), 4.06–
4.12 (m, 1H), 3.61, 3.90 (br s, 1H), 3.46–3.51 (m, 1H),
3.37–3.43 (m, 1H), 2.11, 3.05 (br s, 1H), 2.42 (d,
J = 6.4 Hz, 2H), 2.35 (s, 3H), 1.64 (dt, J = 16.0 Hz,
4.8 Hz, 1H), 1.46 (s, 9H); MS (ESI): 347 (M+Na)+.
was filtered and the solvent was evaporated. The residue
20
was dried to give a colorless oil 5 (1.9 g, 90%). ½aꢁD
¼
þ9:9 (c 2.0, CHCl3); ꢀ6.8 (c 1.5, MeOH), {lit.
20
½aꢁD ¼ ꢀ7:57 (c 2.0, MeOH)5d}; IR (film): 3446, 1731,
1154 cmꢀ1; H NMR (400 MHz, CDCl3): d 4.19–4.26 (m,
1
1H), 3.91–3.97 (m, 1H), 3.54 (dd, J = 11.6 Hz, 3.6 Hz,
1H), 3.46 (dd, J = 11.6 Hz, 6.4 Hz, 1H), 2.56 (br s, 1H),
2.40 (dd, J = 15.2 Hz, 7.2 Hz, 1H), 2.28 (dd, J = 15.2 Hz,
6.0 Hz, 1H), 1.46 (dt, J = 12.8 Hz, 2.4 Hz, 1H), 1.41 (s,
3H), 1.38 (s, 9H), 1.32 (s, 3H), 1.29 (d, J = 12.4 Hz, 1H);
13C NMR (100 Hz, CDCl3): d 170.0, 98.7, 80.5, 69.5,
65.68, 65.64, 42.5, 31.7, 29.8, 27.9, 19.6; MS (70 eV, EI)
m/z (%): 260 (M+, trace), 245 (3), 229 (1), 189 (100), 173
(34), 147 (6), 129 (93), 111 (81), 87 (24), 57 (66).
Acknowledgments
4.3.4. tert-Butyl (5S)-6-(4-methybenzyloxy)-3,5-O-isopropyl-
idene-3,5-dihydroxyhexanoate syn/anti-10. To a stirred
solution of syn/anti-9 (9.0 g, 27.8 mmol) in 2,2-dimethoxy-
propane (20 mL) was added camphorsulfonic acid (0.1 g).
The mixture was stirred for 4 h at room temperature. After
the reaction was completed, the mixture washed with satu-
rated sodium hydrogen carbonate to neutrality. The organ-
ic phase was dried with magnesium sulfate, filtered,
and distilled to yield syn/anti-9 (9.6 g, 95%, drs:a = 4.0:1).
We thank the Chinese National Natural Science Founda-
tion (No. 20606030 and 20336010), Key Project of Chinese
National Programs for Fundamental Research and Devel-
opment (No. 2003CB716008), and Hi-Tech Research and
Development Program of China (No. 2006AA02Z238).
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