Enantioselective preparation of asymmetrically protected 2-propanoyl-1,3-propanediol derivatives: Toward the total synthesis of Kazusamycin A

Article abstract of DOI:10.1016/j.tetasy.2004.01.007

The preparation of enantiomerically pure 2-propanoyl-1,3-propanediol derivatives, key intermediates in our studies on total synthesis of the potent antitumor compound Kazusamycin A are described. After various enzymatic protocols for desymmetrization of t

Full text of DOI:10.1016/j.tetasy.2004.01.007

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 733–741
Enantioselective preparation of asymmetrically protected
2-propanoyl-1,3-propanediol derivatives: toward the total
synthesis of Kazusamycin A
b
Noriyoshi Arai, Noriko Chikaraishi, Mitsuhiro Ikawa, Satoshi Omura
b
c
a
ꢀ
and Isao Kuwajimaa,b,
*
aKitasato Institute for Life Science, Kitasato University, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan
bCreation and Function of New Molecules and Molecular Assemblies, Core Research for Evolutional Science and
Technology (CREST), Japan Science and Technology Agency (JST), 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan
cDepartment of Chemistry, Faculty of Science, Kitasato University, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan
Received 28 November 2003; accepted 5 January 2004
Abstract—The preparation of enantiomerically pure 2-propanoyl-1,3-propanediol derivatives, key intermediates in our studies on
total synthesis of the potent antitumor compound Kazusamycin A are described. After various enzymatic protocols for desym-
metrization of the prochiral diol were studied, it was found that these compounds could be prepared in 97–98% ee by means of an
enzymatic kinetic resolution.
ꢀ 2004 Published by Elsevier Ltd.
1. Introduction
However, there was no enzymatic preparative method
available for enantiomerically pure 2-acyl(or acyl
equivalent)-1,3-propanediol derivatives, in contrast to
the widely developed protocols of enantioselective
enzymatic transesterification of prochiral simple 2-alkyl-
or 2-aryl-1,3-propanediols.4 To the best of our knowl-
edge, enzymatic transesterification of 2-dialkoxymethyl-
1,3-propanediol reported by Poppe et al. is the only
example of enantioselective preparation of 2-acylequiv-
alent-3-acyloxypropanol, though the best enantiomeric
excess of the product was 71% ee.5 Herein, we describe
the details of our investigation into the preparation of
enantiomerically pure 3 and the first example, which
gives 2-acyl-1,3-propanediol in up to 98% ee.
Enantioselective transesterification of prochiral 2-
substituted-1,3-propanediols catalyzed by an enzyme is
well known as an effective tool to obtain enantiomeri-
cally pure synthetic building blocks, and much attention
has been focused on this field in past decades.1 In the
course of our study on the total synthesis of Kazusa-
mycin A 1, a potent antitumor compound isolated from
a culture broth of actinomycete sp. 81-484,2 we planned
to construct the four contiguous stereogenic centers
employing a stereoselective aldol reaction between a
homochiral aldehyde 2 and asymmetrically protected 1-
hydroxy-2-hydroxymethyl-3-butanone 3, according to
the protocol reported by Paterson et al. (Scheme 1).3
For the preparation of 3, we intended to employ the
above mentioned enzymatic transesterification, since
this method would allow the reaction to be performed
on a large scale and thus supply sufficient amounts of
the enantiomerically pure 3 at an early stage in our total
synthesis. In addition, it seemed to require significant
work to derive enantiomerically pure 3 from readily
available enantiomerically pure synthetic intermediates.
2. Results and discussion
2.1. Preparation of the prochiral diol 8
The prochiral diol, 1-hydroxy-2-hydroxymethyl-3-buta-
none 8, was prepared in five steps starting from diol 4 as
reported by Poppe et al.5 Benzylation of the diol 4
afforded 5, which was converted to alcohol 6 through
hydrolysis of the diethylacetal moiety followed by the
addition of ethylmagnesium bromide. The desired
* Corresponding author. Tel.: +81-42-778-9932; fax: +81-42-778-9931;
e-mail: kuwajima@lisci.kitasato-u.ac.jp
0957-4166/$ - see front matter ꢀ 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2004.01.007

734
N. Arai et al. / Tetrahedron: Asymmetry 15 (2004) 733–741
OH
O
HO
O
HO
1
O
Paterson's Aldol Reaction
Kazusamycin A
O
O
CHO
BnO
+
OPMB
3
2
OTBDPS
Scheme 1. Synthetic plan for Kazusamycin A (stereochemistry is speculative).
Table 1. Enantioselective desymmetrization of the prochiral diol 8 by
enzymatic transesterification
compound 8 was obtained by the oxidation of the
alcohol 6 and subsequent deprotection (Scheme 2).
Run
Enzyme
Yield/%
Ee of 9/% Major
configuration
9
10
2.2. Enantioselective desymmetrization of the prochiral
diol 8 by enzymatic transesterification
1
2
3
4
5
6
Lipase AK
Lipase PSC
Lipase PSA
Lipase OF
CAL-B
32
11
75
39
14
20
62
85
0
35
32
24
11
59
9
S
S
S
S
S
R
To obtain compound 3 in enantiomerically pure form,
we first adopted desymmetrization of the prochiral diol
8 by enzymatic acetylation. When the diol 8 was treated
with excess amounts (ca. 10-fold) of vinyl acetate in the
presence of Lipase AK in isopropyl ether at room
temperature, monoacetate 9 was obtained in 32% yield
accompanied by diacetate 10 (62%) (Scheme 3, Table 1,
Run 1). The enantiomeric excess of the monoacetate 9
was determined as 35% by HPLC analysis of its tert-
butyldiphenylsilylated derivative. Determination of the
absolute configuration of 9 is discussed in the next sec-
tion. In the same manner, diol 8 was subjected to
transesterification with Lipase PSC, PSA, OF (Runs 2–
4). Though the reactions were to be stopped at
approximately 50% conversion of the available
hydroxyls, the yield of 9 and 10 showed some variation
depending on the difference of the catalytic activity of
these enzymes. Unfortunately, none of these enzymes
gave an acceptable ee of 9 (11–32%). Polymer supported
CAL-B afforded 9 in much modified ee (Run 5). In
0
86
0
PPL
contrast to these examples, PPL gave mainly the oppo-
site enantiomer (Run 6).
The results of desymmetrization of 8 with several
enzymes at 0 ꢁC are shown in Table 2. Whereas Lipase
AK gave superior eeꢀs compared to the reaction at room
temperature, Lipase PSC and CAL-B afforded some-
what inferior results. Though it is expected that the
enantioselectivity should increase at lower tempera-
tures,6 this was no the case here. The reason was not
clear at this stage, however, the effect of the reaction
temperature was marginal in our case. The possibility of
racemization during the operation was completely
excluded as described in the next section. These results
led us to carry out the following preliminary studies at
EtO
EtO
EtO
EtO
O
O
OH
a
b, c
d
e
OH
OH
OBn
OBn
OBn
OBn
OH
OH
OBn
OBn
4
5
6
7
8
Scheme 2. Preparation of prochiral diol 8. Reagents and conditions: (a) NaH, BnBr, THF, rt, 73%; (b) TFA, CHCl3–H2O, 0 ꢁC; (c) EtMgBr, THF,
0 ꢁC, 72% in two steps; (d) Dess–Martin periodinane, CH2Cl2, rt, 85%; (e) H2, Pd/C, EtOH, rt, 95%.
O
O
O
enzyme
vinyl acetate
OH
OH
OH
OAc
OAc
OAc
+
i-Pr2O
8
9
10
Scheme 3.

N. Arai et al. / Tetrahedron: Asymmetry 15 (2004) 733–741
735
Table 2. Enantioselective desymmetrization of the prochiral diol 8 at
0 ꢁC
however, the ee in each case was far from acceptable
(Runs 1–4). CAL-B gave a better result than the previ-
ously mentioned enzymes (Run 5). Unexpectedly, PPL,
which had given a poor result in the transesterification,
hydrolyzed 10–9 in the best yield and ee (Run 6).
Run
Enzyme
Yield/%
Major
configuration
Ee of 9/%
9
10
1
2
3
Lipase AK
Lipase PSC
CAL-B
67
53
64
22
27
8
49
25
39
S
S
S
The absolute configuration of monoacetate 9 was
determined as follows: Monoacetate 9 prepared by
hydrolysis of 10 with PPL was transformed to the
known benzyl ether 12 as shown in Scheme 5. The ether
room temperature. Though vinyl benzoate and vinyl
pivalate were also tested as acyl donors in place of vinyl
acetate, neither of them gave modified results (with
Lipase AK, vinyl benzoate: 76% yield, 28% ee, very
retarded reaction, vinyl pivalate: no reaction).
12 thus prepared showed a negative optical rotation,
26
D
specific rotation of (R)-12 was reported by Paterson
½aꢀ ¼ )11.0 (c 0.55, CHCl3). On the other hand, the
20
D
et al. as ½aꢀ ¼ )25.8 (c 9.0, CHCl3).7 These facts indi-
cated that monoacetate 9 prepared here had the same
configuration as (R)-12, that is, its absolute configura-
tion was S. Absolute configurations in other examples
shown in tables were deduced from this result.
From these results of the initial study, it seemed to be
difficult to realize high yield and high ee simultaneously
in the desymmetrization of 8, and these results prompted
us to investigate other enzymatic methods to obtain
enantiomerically pure 9 or an equivalent, before the
transesterification with CAL-B was fully optimized,
which gave the best result in Table 1.
The possibility of racemization of 9 during reaction,
work-up, and purification was checked as shown in
Scheme 6. The PMB ether 14, the ee of which was
known (14% ee), was transformed to 15 by usual syn-
thetic methods. The ee of 15 was determined as 14% by
HPLC analysis. This result shows no racemization
occurred during the operations.
2.3. Enantioselective desymmetrization of the prochiral
diacetate 10 by enzymatic hydrolysis
Monoester 9, which was prepared as described above
(14% ee), was subjected to the approximate conditions
of the transesterification (with Lipase AK, without vinyl
acetate, in diisopropylether at rt), and recovered in the
usual manner. The ee of the recovered material was
determined as 14% by the same method described above.
This shows no racemization had occurred in the solution
in the presence of lipase.
Hydrolytic desymmetrization of prochiral diacetate 10
was next investigated. The results were shown in Scheme
4 and Table 3. Hydrolysis of 10 with Lipase AK, PSA,
PSC, OF afforded monoacetate 9 in moderate yield,
O
O
enzyme
OAc
OAc
OH
OAc
pH7 phosphate buffer
- i-Pr2O
10
Scheme 4.
9
2.4. Kinetic resolution of monoprotected diol 13
As mentioned in the previous two sections, enzymatic
desymmetrization of prochiral diol 8 or diacetate 10 did
not seem to be the method of choice to obtain the
asymmetric building unit 3 in highly enantiomerically
enriched form. So next we turned our attention to the
kinetic resolution of the monoprotected diol. On the
initial stage of the study, we chose compound 13 (one
hydroxyl group in diol 8 was protected with PMB) as a
substrate due to the preparative simplicity of 3. The
results are summarized in Scheme 7 and Table 4. Among
the enzymes tried here, Lipase AK gave the best results
(Run 1). Though the ee of esterified 14 was not so high,
the ee of recovered alcohol 13 was found to be 97%. The
Table 3. Enantioselective desymmetrization of the prochiral diacetate
10 by enzymatic hydrolysis
Run
Enzyme
Yield of 9/% Ee of 9/%
Major
configuration
1
2
3
4
5
6
Lipase AK
Lipase PSC
Lipase PSA
Lipase OF
CAL-B
31
38
51
63
17
66
11
11
12
6
R
R
R
R
R
S
49
57
PPL
O
O
O
O
a
b, c
d, e, f
OAc
OAc
OH
OBn
OH
OBn
OAc
10
9
11
12
Scheme 5. Transformation of diacetate 10. Reagents and conditions: (a) PPL, pH 7 phosphate buffer–i-Pr2O, rt, 66%; (b) CCl3C(@NH)OBn, cat.
CF3SO3H, CH2Cl2–cyclohexane, rt, 86%; (c) PPL, pH 7 phosphate buffer–i-Pr2O, rt, 76%; (d) CH3SO2Cl, Et3N, CH2Cl2, 0 ꢁC; (e) LiAlH4, THF,
0 ꢁC; (f) Dess–Martin periodinane, CH2Cl2, rt, 33% in three steps.

736
N. Arai et al. / Tetrahedron: Asymmetry 15 (2004) 733–741
O
O
O
TBDPSCl
imidazole
H2, Pd/C
OPMB
OAc
OH
OAc
(R)-9
OTBDPS
OAc
DMF, rt
82%
EtOH, rt
92%
(R)-14
(S)-15
14%ee
14%ee
Lipase AK
i-Pr2O, rt
quant.
O
O
TBDPSCl
imidazole
OH
OTBDPS
DMF, rt
70%
OAc
OAc
(R)-9
(recovered)
(S)-15
14%ee
Scheme 6.
Thus, it was revealed that the kinetic resolution of 13 by
lipase AK catalyzed transesterification afforded opti-
cally active 13 in high ee, the absolute configuration of
which was correct for the preparation of the synthetic
unit 3. This is the first example that giving nearly
enantiomerically pure 2-acyl-1,3-propanediol deriva-
tives. Accordingly, this key intermediate 3 was success-
fully prepared in 98% ee as shown in Scheme 9.
O
O
enzyme
vinyl acetate
OPMB
OAc
OPMB
OH
i-Pr2O
13
Scheme 7.
14
E value8 of this reaction was calculated as 5.5. Some
investigations on solvent effects were also carried out.
Other than isopropyl ether, ethyl acetate, chloroform,
THF, and tert-butylmethyl ether were tested, however,
none of them improved the results. Expecting that the
more bulky protecting group would give the higher
enantioselectivity, kinetic resolution of mono TBDPS
ether of 8 was investigated. The investigation revealed
that the TBDPS ether afforded a comparable result to 13
(24% recovery, 92% ee, when using Lipase AK).
Hydrolytic kinetic resolution was also tried, however, it
turned out to show much less selectivity.
3. Conclusion
In summary, we have studied the enantioselective
preparation of asymmetrically protected 2-propanoyl-
1,3-propanediol derivatives by means of enzymatic
methods for the total synthesis of Kazusamycin A. After
screening various protocols and enzymes, it was even-
tually found that the kinetic resolution of monopro-
tected diol 13 with Lipase AK afforded nearly
enantiomerically pure 13 (up to 98% ee) as recovered
material at approximately 80% conversion. The deriva-
tives of enantiomerically pure 13 seem to be very useful
chiral synthetic units for combination with Patersonꢀs
stereoselective aldol reactions, and applicable to natural
The absolute configuration of recovered 13 was deter-
mined by comparing the specific rotation of ketone 189
derived from 13 to the same ketone prepared from com-
mercially available optically active ester 19 (Scheme 8).
Table 4. Kinetic resolution of half-protected diol 13 by enzymatic transesterification
Run
Enzyme
13
14
E valuea
Major configu-
ration of 13
Recovered/%
Ee/%b
Yield/%
Ee/%c
1
2
Lipase AK
Lipase PSC
Lipase PSA
Lipase OF
Lipase MY
CCL
20
13
76
92
30
79
78
10
26
67
57
97
70
9
76
83
20
6
24
4
5.5
1.7
2.6
1.2
1.2
1.2
1.1
1.3
1.6
1.6
1.8
R
R
R
R
R
R
R
S
3
40
5
4
3
5
12
3
65
15
16
86
72
33
38
3
6
8
7
CRL
PSL
3
5
8
17
37
8
8
9
CAL
CAL-B
PPL
10
20
26
R
R
S
10
11
8
a E ¼ ln½1 ꢁ cð1 þ eeð14ÞÞꢀ= ln½1 ꢁ cð1 ꢁ eeð14ÞÞꢀ, c ¼ eeð13Þ=ðeeð13Þ þ eeð14ÞÞ. See Ref. 7.
b The ee of 13 was determined by HPLC analysis of its TBDPS ether.
c The ee of 14 was determined by HPLC analysis.

N. Arai et al. / Tetrahedron: Asymmetry 15 (2004) 733–741
OH
737
O
O
O
a
b
c
OPMB
OH
OPMB
OMs
OPMB
OPMB
17
18
[α]D27 -21.1 (c 0.605, CHCl3)
13
16
O
O
O
d
e
OPMB
[α]D26 -21.9 (c 1.41, CHCl3)
MeO
OPMB
MeO
OH
18
19
20
Scheme 8. Transformation of 13. Reagents and conditions: (a) CH3SO2Cl, Et3N, CH2Cl2, 0 ꢁC; (b) LiAlH4, THF, 0 ꢁC; (c) Dess–Martin period-
inane, CH2Cl2, rt, 94% in three steps; (d) CCl3C(@NH)OPMB, cat. CSA, CH2Cl2, rt, 83%; (e) MeONHMeÆHCl, EtMgBr, THF, )20 ꢁC to rt, 55%.
Lipase AK
TBDPSCl
imidazole
O
O
O
vinyl acetate
OPMB
OPMB
OPMB
DMF, rt
76%
i-Pr2O, rt
21%
OH
13
OH
(R)-13 98%ee
(recovered material)
OTBDPS
3
Scheme 9. Preparation of the key intermediate 3.
product syntheses especially of highly functionalized
polyketides.
temperature for 1 h, followed by the addition of benzyl
bromide (43 mL, 0.36 mol). The reaction mixture was
stirred for 4 h at room temperature, before quenching
with saturated aqueous ammonium chloride. The mix-
ture was extracted with ethyl acetate, dried over anhy-
drous sodium sulfate, filtered, and concentrated at
reduced pressure. The crude product was purified by
silica gel column chromatography (eluent, hexane–ethyl
acetate ¼ 20:1 to 10:1) to afford dibenzylated compound
5 (26.9 g, 73%). IR (KBr, neat, cmꢁ1) 3031, 2975, 1779,
1454, 1364, 1094, 737, 697; 1H NMR (500 MHz, CDCl3)
d 1,17 (distorted t, 6H), 2.23–2.29 (m, 1H), 3.46–3.52 (m,
2H), 3.60–3.71 (m, 6H), 4.49 (d, J ¼ 11:9 Hz, 2H), 4.52
(d, J ¼ 11:9 Hz, 2H), 4.63 (d, J ¼ 6:4 Hz, 1H), 7.27–7.37
(m, 10H). 13C NMR (125 MHz, CDCl3) d 15.28, 43.72,
62.88, 67.29, 73.09, 101.90, 127.34, 127.49, 128.21,
138.66. HRMS(FAB), m=z (M+Naþ) calcd 381.2042,
obsd 381.2060.
4. Experimental
4.1. General
NMR spectra were obtained on a JEOL ECP500 spec-
trometer. IR spectra were recorded on JASCO FT/IR-
420 spectrophotometer. Mass spectra were taken on
JEOL JMS-700 instrument. Optical rotations were
taken on JASCO P-1010 polarimeter. Silica gel column
chromatography was performed with Kanto Chemical
Co., Inc. Silica Gel 60N (63–210 lm). Preparative thin
layer chromatography was carried out with Wako Gel
B-5F (Wako Pure Chemical Industries, Ltd.). GPC was
performed on Japan Analytical Industry Co., Ltd. LC-
918 with JAIGEL 1H and 2H columns. Enzymes used in
this study were obtained from the following suppliers:
Lipase AK, Lipase PSC, Lipase PSA: Amano Pharma-
ceutical Co., Ltd.; Lipase OF, Lipase MY: Meito San-
gyo Co., Ltd.; CAL-B (carrier-fixed): Boehringer
Mannheim; CCL, CRL, PSL, CAL, PPL: Sigma-
Aldrich.
4.3. 1-Benzyloxy-2-(benzyloxymethyl)-3-pentanol 6
To a solution of diethylacetal 5 (23.5 g, 65.9 mmol) in
chloroform (88 mL) was added a 50% aqueous solution
of TFA (44 mL) at 0 ꢁC. The reaction mixture was stir-
red for 15 h at 0 ꢁC, then quenched with saturated
aqueous NaHCO3. The mixture was extracted with
chloroform (100 mL · 2), dried over anhydrous sodium
sulfate, filtered, and concentrated at reduced pressure,
giving the aldehyde. IR (KBr, neat, cmꢁ1) 3031, 2862,
1726, 1496, 1454, 1363, 1099, 738, 698; 1H NMR
(500 MHz, CDCl3) d 2.83–2.88 (m, 1H), 3.80 (dd,
J ¼ 9:6, 5.5 Hz, 2H), 3.86 (dd, J ¼ 9:6, 6.0 Hz, 2H), 4.53
(s, 4H), 7.29–7.37 (m, 10H), 9.80 (d, J ¼ 1:4 Hz, 1H).
4.2. 3-Benzyloxy-2-(benzyloxymethyl)-propanal diethyl-
acetal 5
Diol 4 (18.4 g, 0.104 mol) was treated with NaH (60% oil
dispersion, 12.4 g, 0.31 mol) in THF (150 mL) at room

738
N. Arai et al. / Tetrahedron: Asymmetry 15 (2004) 733–741
13C NMR (125 MHz, CDCl3) d 52.75, 66.22, 73.35,
127.59, 127.70, 128.37, 137.82, 202.28. HRMS(FAB),
m=z (M+Hþ) calcd 285.1491, obsd 285.1489. This
material was used in the next reaction without further
purification.
2888, 1704, 1461, 1408, 1378, 1038; 1H NMR (500 MHz,
CDCl3) d 1.05 (t, J ¼ 7:3 Hz, 3H), 2.59 (q, J ¼ 7:3 Hz,
2H), 2.78–2.82 (m, 1H), 3.09 (br s, 2H), 3.89–3.91 (br m,
2H), 3.95–3.98 (br m, 2H). 13C NMR (125 MHz, CDCl3)
d 7.29, 35.58, 54.76, 61.85, 213.78. HRMS(FAB), m=z
(M+Naþ) calcd 155.0684, obsd 155.0697.
The aldehyde was dissolved in THF (95 mL), and this
solution was treated with ethylmagnesium bromide
(0.89 M in THF, 89 mL, 79 mmol) at 0 ꢁC. After stirring
for 1.5 h at the temperature, the reaction was quenched
with saturated aqueous ammonium chloride, and
extracted with ether (200 mL · 3). The extracts were
dried over anhydrous magnesium sulfate, filtered,
evaporated at reduced pressure. The crude product was
purified by silica gel column chromatography (eluent,
hexane–ethyl acetate ¼ 2:1) to afford the alcohol 6
(14.9 g, 72%). IR (KBr, neat, cmꢁ1) 3501 (br), 3031,
2871, 1496, 1454, 1364, 1093, 737, 698; 1H NMR
(500 MHz, CDCl3) d 0.97 (distorted t, 3H), 1.47–1.61
(m, 2H), 1.96–2.01 (m, 1H), 3.12 (d, J ¼ 5:5 Hz, 1H),
3.66–3.77 (m, 5H), 4.48–4.54 (m, 4H), 7.28–7.38 (m,
10H). 13C NMR (125 MHz, CDCl3) d 10.46, 27.90,
43.34, 68.43, 70.49, 73.41, 73.47, 74.60, 127.63, 128.39,
137.98, 138.15. HRMS(FAB), m=z (M+Naþ) calcd
337.1780, obsd 337.1771.
4.6. 2-(1-Oxopropyl)propan-1,3-diyl diacetate 10
To a solution of 8 (52.0 mg, 0.393 mmol) in dichloro-
methane (2 mL) were added acetic anhydride (120 mL,
1.27 mmol), pyridine (105 mL, 1.30 mmol), and DMAP
(1.7 mg, 0.014 mmol), successively. After stirring for 1 h,
the reaction was quenched with water, and the mixture
was extracted with ether (10 mL · 3). Combined organic
layer was washed with water then brine, and dried over
anhydrous magnesium sulfate. After filtration, the
solution was concentrated under reduced pressure. The
crude product was purified by silica gel column chro-
matography (eluent, hexane–ethyl acetate ¼ 2:1) to
afford the diacetate 10 (81.3 mg, 96%). IR (KBr, neat,
cmꢁ1) 2979, 1743, 1718, 1461, 1368, 1042; 1H NMR
(500 MHz, CDCl3) d 1.03 (t, J ¼ 7:3 Hz, 3H), 2.00 (s,
3H), 2.52 (q, J ¼ 7:3 Hz, 2H), 3.07–3.12 (m, 1H), 4.22
(dd, J ¼ 11:5, 6.0 Hz, 2H), 4.27 (dd, J ¼ 11:5, 6.4 Hz,
2H). 13C NMR (125 MHz, CDCl3) d 7.27, 20.63, 35.85,
49.64, 61.49, 170.51, 208.63. HRMS(FAB), m=z
(M+Hþ) calcd 217.1076, obsd 217.1095.
4.4. 1-Benzyloxy-2-(benzyloxymethyl)-3-pentanone 7
To a solution of alcohol 6 (6.56 g, 20.9 mmol) in di-
chloromethane (100 mL) was added Dess–Martin peri-
odinane10 (9.75 g, 23.0 mmol) at room temperature, and
the mixture was stirred for 1 h. The suspension was
diluted with ether (100 mL), then quenched with aque-
ous NaHCO3 and Na2S2O3. The mixture was extracted
with ether (100 mL · 3), and extracts were dried over
anhydrous magnesium sulfate, filtered, evaporated at
reduced pressure. The crude product was purified by
silica gel column chromatography (eluent, hexane–ethyl
acetate ¼ 2:1) to afford the ketone 7 (5.51 g, 85%). IR
(KBr, neat, cmꢁ1) 3031, 2863, 1714, 1496, 1454, 1364,
4.7. Enzymatic transesterification of 8 (typical procedure)
To a solution of diol 8 (34.2 mg, 0.260 mmol) and vinyl
acetate (119 lL, 1.30 mmol) in diisopropyl ether
(2.6 mL) was added Lipase AK (52 mg) in one portion at
room temperature. After stirring vigorously for 30 min,
the mixture was filtered through a Celite pad, and the
filtrate was evaporated at reduced pressure. The crude
product was purified by silica gel column chromato-
graphy (eluent, hexane–ethyl acetate ¼ 3:1) to afford the
monoacetate 9 (14.2 mg, 32%) and diacetate 10 (34.6 mg,
1
1095, 738, 698; H NMR (500 MHz, CDCl3) d 1.05 (t,
J ¼ 7:3 Hz, 3H), 2.56 (q, J ¼ 7:3 Hz, 2H), 3.11–3.17 (m,
1H), 3.62 (dd, J ¼ 9:2, 5.5 Hz, 2H), 3.70 (dd, J ¼ 9:2,
6.9 Hz, 2H), 4.46 (d, J ¼ 11:9 Hz, 2H), 4.49 (d,
J ¼ 11:9 Hz, 2H), 7.27–7.36 (m, 10H). 13C NMR
(125 MHz, CDCl3) d 7.32, 36.53, 52.41, 68.41, 73.25,
127.52, 127.61, 128.33, 137.96, 211.66. HRMS(FAB),
m=z (M+Hþ) calcd 313.1804, obsd 313.1788.
62%).
2-Hydroxymethyl-3-oxopentyl
acetate
9:
27
½aꢀ ¼ +7.8 (c 0.660, CHCl3), 35% ee (S major); IR
D
(KBr, neat, cmꢁ1) 3438 (br), 2941, 1740, 1714, 1462,
1370, 1246, 1040; 1H NMR (500 MHz, CDCl3) d 1.04 (t,
J ¼ 7:3 Hz, 3H), 2.02 (s, 3H), 2.55 (q, J ¼ 7:3 Hz, 2H,
involving br s, 1H), 2.95–2.99 (m, 1H), 3.76–3.78 (br m,
1H), 3.82–3.84 (br m, 1H), 4.30 (d, J ¼ 6:4 Hz, 2H). 13C
NMR (125 MHz, CDCl3) d 7.26, 20.72, 36.01, 52.64,
60.37, 61.80, 179.96, 211.45. HRMS(FAB), m=z
(M+Hþ) calcd 175.0970, obsd 175.0971.
4.5. 1-Hydroxy-2-(hydroxymethyl)-3-pentanone 8
To a solution of ketone 7 (5.51 g, 17.7 mmol) in ethanol
(55 mL) was added Pd on activated carbon (10%, ca.
0.3 g), and the mixture was stirred under an atmospheric
pressure of hydrogen at room temperature until the
starting material disappeared on TLC. The suspension
was filtered through a Celite pad, and the filtrate was
evaporated at reduced pressure. The crude product was
purified by silica gel column chromatography (eluent,
hexane–ethyl acetate ¼ 2:1) to afford the ketone 8
(2.23 g, 95%). IR (KBr, neat, cmꢁ1) 3374 (br), 2942,
4.8. Enzymatic hydrolysis of 10 (typical procedure)
To a solution of diacetate 10 (333.4 mg, 1.54 mmol) in a
mixed solvent of diisopropyl ether (2.4 mL), pH 7
phosphate buffer (1.2 mL), and water (12 mL) was added
PPL (0.3 g) in one portion at room temperature. After
stirring vigorously for 20 min, the mixture was filtered
through a Celite pad, and the filtrate was evaporated at
reduced pressure. The crude product was purified by

N. Arai et al. / Tetrahedron: Asymmetry 15 (2004) 733–741
739
silica gel column chromatography (eluent, hexane–ethyl
acetate ¼ 3:1) to afford the monoacetate 9 (176.3 mg,
66%).
imidazole (40 mg, 0.59 mmol) in DMF (0.5 mL) was
added TBDPSCl (115 lL, 0.441 mmol). After stirring for
25 min, cold water was added, and the resulting mixture
was extracted with hexane–ethyl acetate (1:1)
(20 mL · 1). The extract was washed with water, brine,
then dried over anhydrous sodium sulfate. After filtra-
tion, the solution was evaporated at reduced pressure.
The crude product was purified by silica gel thin layer
4.9. Determination of the absolute configuration of 9
Monoacetate
9
(3.46 g, 19.9 mmol) prepared as
described in the former section was dissolved in dichlo-
romethane–cyclohexane (1:2 (v/v), 200 mL). To this
solution was added benzyl trichloroimidate11
(2.3 mol dmꢁ3 in hexane, 17 mL, 40 mmol) and trifluo-
romethanesulfonic acid (0.17 mL, 2 mmol) successively,
and the mixture was stirred for 4 h at room temperature.
The reaction mixture was filtered through a cotton plug,
and the filtrate was washed with saturated sodium
hydrogen carbonate, dried over anhydrous sodium sul-
fate, filtered again, and then evaporated at reduced
pressure. The crude product was purified by silica gel
column chromatography (eluent, hexane–ethyl ace-
tate ¼ 5:1) to afford the corresponding benzyl ether
(4.53 g, 86%). Acetoxy moiety of this compound (4.34 g,
16.5 mmol) was hydrolyzed under neutral condition
according to the procedure described in Section 4.8 to
avoid epimerization or elimination, affording b-hy-
droxyketone 11 (2.76 g, 76%).
chromatography (hexane–ethyl acetate ¼ 6:1, developed
26
D
three times) to afford (S)-15 (98.9 mg, 82%). ½aꢀ ¼ +2.8
(c 1.09, CHCl3). IR (KBr, neat, cmꢁ1) 2934, 1745, 1716,
1472, 1428, 1364, 1239, 1113, 1040, 704; 1H NMR
(500 MHz, CDCl3) d 1.04 (s, 9H), 1.06 (t, J ¼ 7:3 Hz,
3H), 1.97 (s, 3H), 2.46–2.61 (m, 2H), 3.02–3.07 (m, 1H),
3.82 (dd, J ¼ 11:1, 5.5 Hz, 1H), 3.86 (dd, J ¼ 11:1,
6.0 Hz, 1H), 4.25 (dd, J ¼ 11:0, 6.0 Hz, 1H), 4.32 (dd,
J ¼ 11:0, 6.9 Hz, 1H), 7.37–7.46 (m, 6H), 7.62–7.64 (m,
4H). 13C NMR (125 MHz, CDCl3) d 7.29, 19.11, 20.73,
26.68, 36.42, 52.86, 61.83, 61.93, 127.74, 129.82, 132.88,
135.48, 170.61, 210.34. HRMS(FAB), m=z (M+Hþ)
calcd 413.2148, obsd 413.2160.
The ee of this sample was determined as 14% (S major)
by HPLC analysis (DAICEL CHIRALCEL OD-H,
hexane–2-propanol ¼ 99.7:0.3 (v/v), at a flow rate of
0.5 mL minꢁ1). The
R
isomer was eluted first
(tR ¼ 35:2 min), followed by S isomer (tR ¼ 42:2 min).
To a solution of 11 (55.7 mg, 0.251 mmol) in dichlo-
romethane (2.5 mL) was added triethylamine (84 lL,
0.60 mmol) and methanesulfonyl chloride (23 lL,
0.30 mmol) at 0 ꢁC. After stirring at the temperature for
1.5 h, the reaction was quenched with pH 7 phosphate
buffer. The mixture was extracted with dichloromethane
(20 mL · 2), and the extracts were dried over anhydrous
sodium sulfate, filtered, and then evaporated at reduced
pressure, to afford a crude mesylate (70.8 mg). This
mesylate was dissolved in THF (2.3 mL), and the solu-
tion was added to a suspension of LiAlH4 (21.9 mg,
0.578 mmol) in THF (0.6 mL) at room temperature with
stirring. After 20 min, water was added to the reaction
mixture at 0 ꢁC, and the mixture was extracted with
ether (20 mL · 2), dried over anhydrous magnesium
sulfate. Concentration of the extracts gave a crude
reduced compound (49.4 mg). This compound was
dissolved in dichloromethane (2.4 mL) and treated with
Dess–Martin periodinane (150.8 mg, 0.356 mmol) at
room temperature for 15 min. After conventional work-
4.11. 2-Hydroxymethyl-1-(4-methoxybenzyloxy)-3-pen-
tanone 13
To a solution of 8 (294.8 mg, 2.23 mmol) in dichloro-
methane (9 mL) was added 4-methoxybenzyl trichloro-
imidate12 (0.51 mL, 2.5 mmol), followed by addition of a
catalytic amount of (1S)-(+)-10-camphorsulfonic acid
(25.9 mg, 0.224 mmol). Stirring was continued for 1 day,
then the reaction was quenched with saturated aqueous
NaHCO3. The mixture was extracted with dichloro-
methane (20mL·3), and extracts were dried over anhy-
drous sodium sulfate, filtered, evaporated at reduced
pressure. The crude product was purified by silica gel
column chromatography (eluent, hexane–ethyl ace-
tate ¼ 10:1 gradually to 3:1) to afford the monoprotected
compound 13 (371.8 mg, 66%). IR (KBr, neat, cmꢁ1
)
3450 (br), 2938, 1708, 1612, 1514, 1461, 1363, 1302,
1248, 1175, 1091, 1034, 821; 1H NMR (500 MHz,
CDCl3) d 1.03 (t, J ¼ 7:3 Hz, 3H), 2.48–2.61 (m, 2H),
2.92–2.97 (m, 1H), 3.66 (dd, J ¼ 9:6, 6.0 Hz, 1H), 3.69
(dd, J ¼ 9:6, 6.0 Hz, 1H), 3.77–3.79 (br dd, 1H), 3.79 (s,
3H), 3.87–3.90 (br dd, 1H), 4.42 (s, 2H), 6.87 (d,
J ¼ 8:7 Hz, 2H), 7.21 (d, J ¼ 8:7 Hz, 2H). 13C NMR
(125 MHz, CDCl3) d 7.30, 36.04, 53.66, 55.20, 61.73,
68.51, 73.06, 113.79, 129.24, 129.69, 159.25, 212.72.
HRMS(FAB), m=z (M+Naþ) calcd 275.1259, obsd
275.1263.
up, the resulting mixture was purified by GPC to afford
27
D
the ketone 12 (16.9 mg, 33% based on 11). ½aꢀ ¼ )11.0
20
(c 0.550, CHCl3), lit.7 ½aꢀ ¼ )25.8 (c 9.0, CHCl3).
D
4.10. Stereochemical stability of 9
A solution of (R)-14 (530.4 mg, 1.81 mmol, obtained by
kinetic resolution of 13) in ethanol was stirred for 2 h at
room temperature under atmospheric pressure of
hydrogen in the presence of Pd/C. After removal of the
catalyst by filtration, the solution was concentrated
under reduced pressure. The crude product was purified
by silica gel column chromatography (eluent, hexane–
ethyl acetate ¼ 1:1) to afford (R)-9 (290.9 mg, quant.).
To a solution of this (R)-9 (51.1 mg, 0.294 mmol) and
4.12. Kinetic resolution of 13 by enzymatic transesterifi-
cation (typical procedure)
To a solution of 13 (761.7 mg, 3.02 mmol) and vinyl
acetate (2.8 mL, 30.2 mmol) in diisopropyl ether (50 mL)

740
N. Arai et al. / Tetrahedron: Asymmetry 15 (2004) 733–741
was added Lipase AK (0.6 g) at room temperature. After
stirring vigorously for 35 min, the mixture was filtered
through a Celite pad, washed thoroughly with ether, and
the filtrate was concentrated at reduced pressure. The
crude product was purified by silica gel column chro-
matography (eluent, hexane–ethyl acetate ¼ 3:1) to af-
55.26, 66.63, 67.52, 73.09, 113.86, 129.37 (overlapped),
159.43, 208.92. To a cooled solution (0 ꢁC) of the mes-
ylate 16 in THF (4 mL) was added LiAlH4 (assay: >80%,
85.7 mg, 1.8 mmol) in one portion. After stirring for 1 h
at room temperature, the reaction was quenched with
3 M NaOH at 0 ꢁC. The mixture was extracted with
ether (10 mL · 3), and extracts were dried over anhy-
drous magnesium sulfate, filtered, evaporated at reduced
pressure, to give the reduced material 17 (170.7 mg) as a
mixture of diastereomers (approx. 1:1).
ford the acetate 14 (670.8 mg, 76%). Unreacted 13
26
(155.4 mg, 20%) was recovered. ½aꢀ ¼ +18.4 (c 0.710,
D
CHCl3).
2-(4-Methoxybenzyloxymethyl)-3-oxopentyl acetate 14:
27
D
½aꢀ ¼ +2.6 (c 1.56, CHCl3). IR (KBr, neat, cmꢁ1) 2939,
The alcohol 17 was dissolved in dichloromethane (3 mL)
and treated with Dess–Martin periodinane (382.7 mg,
0.902 mmol) at room temperature for 1 h. Saturated
aqueous NaHCO3 was then added and the mixture was
extracted with ether (10 mL · 3). The extracts were
washed with saturated aqueous NaHCO3, then brine,
and dried over anhydrous magnesium sulfate. After fil-
tration, the solution was concentrated under reduced
pressure to give the crude ketone. The crude material
was purified by silica gel column chromatography (elu-
1742, 1715, 1613, 1514, 1462, 1366, 1247, 1174, 1098,
1036, 821; 1H NMR (500 MHz, CDCl3) d 1.04 (t,
J ¼ 7:3 Hz, 3H), 1.99 (s, 3H), 2.45–2.58 (m, 2H), 3.05–
3.11 (m, 1H), 3.57 (dd, J ¼ 9:6, 6.0 Hz, 1H), 3.61 (dd,
J ¼ 9:6, 6.9 Hz, 1H), 3.79 (s, 3H), 4.23 (dd, J ¼ 11:0,
5.5 Hz, 1H), 4.29 (dd, J ¼ 11:0, 7.3 Hz, 1H), 4.38 (d,
J ¼ 11:5 Hz, 1H), 4.41 (d, J ¼ 11:5 Hz, 1H), 6.86 (d,
J ¼ 8:7 Hz, 2H), 7.19 (d, J ¼ 8:7 Hz, 2H). 13C NMR
(125 MHz, CDCl3) d 7.29, 20.72, 36.17, 51.02, 55.18,
62.16, 67.52, 72.94, 113.76, 129.19, 129.72, 159.23,
170.61, 210.23. HRMS(FAB), m=z (M+Naþ) calcd
317.1365, obsd 317.1383.
ent, hexane–ethyl acetate ¼ 4:1) to afford the ketone 18
27
(153.6 mg, 94% based on 13). ½aꢀ ¼ )21.1 (c 0.605,
D
CHCl3). IR (KBr, neat, cmꢁ1) 2974, 1714, 1613, 1513,
1460, 1362, 1248, 1173, 1092, 1035, 821; 1H NMR
(500 MHz, CDCl3) d 1.04 (t, J ¼ 7:3 Hz, 3H), 1.06 (d,
J ¼ 7:3 Hz, 3H), 2.50 (q, J ¼ 7:3 Hz, 2H), 2.82–2.89 (m,
1H), 3.42 (dd, J ¼ 9:2, 5.5 Hz, 1H), 3.59 (dd, J ¼ 9:2,
7.8 Hz, 1H), 3.80 (s, 3H), 4.39 (d, J ¼ 11:5 Hz, 1H), 4.42
(d, J ¼ 11:5 Hz, 1H), 6.86 (d, J ¼ 8:7 Hz, 2H), 7.21 (d,
J ¼ 8:7 Hz, 2H). 13C NMR (125 MHz, CDCl3) d 7.49,
13.58, 35.21, 46.18, 55.19, 72.04, 72.85, 113.69, 129.11,
130.19, 159.14, 213.70. HRMS(FAB), m=z (M+Naþ)
calcd 259.1310, obsd 259.1314.
The ee of 14 was determined as 24% (R major) by HPLC
analysis (DAICEL CHIRALPAK AD-H, hexane–2-
propanol ¼ 96:4 (v/v), at a flow rate of 0.5 mL minꢁ1).
The R isomer [corresponding to acetylated (S)-13] was
eluted first (tR ¼ 30:8 min), followed by S isomer
(tR ¼ 33:3 min). On the other hand, the ee of recovered
13 was determined after transformation to silylated
form 3. HPLC analysis (DAICEL CHIRALCEL
OD-H, hexane–2-propanol ¼ 99:1 (v/v), at a flow rate of
0.5 mL minꢁ1) of 3 disclosed that the ee was 97% (S).
The R isomer (corresponding to silylated (S)-13) was
eluted first (tR ¼ 17:0 min), followed by S isomer
(tR ¼ 19:2 min).
4.14. Preparation of authentic 2-methyl-1-(4-methoxy-
benzyloxy)-3-pentanone 18
To a solution of (R)-())-methyl 3-hydroxy-2-methyl-
propanoate 19 (359.2 mg, 3.04 mmol) and 4-methoxy-
benzyl trichlroimidate12 (2 M in hexane, 2.5 mL, 5 mmol)
in dichloromethane (6 mL) was added (1S)-(+)-10-cam-
phorsulfonic acid (66.7 mg, 0.287 mmol) in one portion
at room temperature. After stirring for 29 h, saturated
aqueous NaHCO3 was added, and the mixture was
extracted with ether (20 mL · 2). The extracts were
washed with water, then brine, dried over anhydrous
sodium sulfate. Concentration of the solution after fil-
tration gave the crude product. The crude product was
purified by silica gel column chromatography (eluent,
hexane–ethyl acetate ¼ 15:1 to 9:1) to afford the PMB
ether 19 (601.0 mg, 83%).
4.13. Absolute configuration of 13
To a cooled solution (0 ꢁC) of 13 (174.4 mg, 0.691 mmol)
in dichloromethane (3 mL) was added triethylamine
(120 lL, 0.86 mmol), followed by the addition of meth-
anesulfonyl chloride (64 lL, 0.83 mmol). After stirring
for 30 min, the reaction was quenched with pH 7 phos-
phate buffer. The mixture was separated and the aque-
ous phase was extracted with ether (10 mL · 2). The
combined organic phase was washed with water, then
brine, and dried over anhydrous magnesium sulfate.
After filtration, the solution was concentrated under
reduced pressure to give almost pure mesylate 15
(227.2 mg, 0.688 mmol), which was used in the next
reaction without further purification. IR (KBr, neat,
cmꢁ1) 2938, 1715, 1612, 1514, 1461, 1357, 1248, 1175,
To a cooled suspension ()23 ꢁC) of the PMB ether 20
(459.4 mg, 1.93 mmol) and N-methylhydroxylamine
hydrochloride (280.5 mg, 2.88 mmol) in THF (4 mL) was
added EtMgBr (0.9 M in THF, 16.8 mmol) dropwise
over 30 min.13 After stirring at the temperature for
10 min, the reaction was allowed to warm to room
temperature and stirring was continued for 4 h. The
reaction was quenched with 1 M HCl at 0 ꢁC and pH of
the mixture was adjusted around 2. The mixture was
1
1099, 1033, 959, 834; H NMR (500 MHz, CDCl3) d
1.05 (t, J ¼ 7:3 Hz, 3H), 2.44–2.60 (m, 2H), 2.98 (s, 3H),
3.12–3.17 (m, 1H), 3.63 (d, J ¼ 5:5 Hz, 2H), 3.81 (s, 3H),
4.36 (dd, J ¼ 9:6, 5.5 Hz, 1H), 4.39 (d, J ¼ 11:5 Hz, 1H),
4.44 (d, J ¼ 11:5 Hz, 1H), 4.51 (dd, J ¼ 9:6, 7.3 Hz, 1H),
6.87 (d, J ¼ 8:7 Hz, 2H), 7.20 (d, J ¼ 8:7 Hz, 2H). 13C
NMR (125 MHz, CDCl3) d 7.31, 35.73,36.98, 51.29,

N. Arai et al. / Tetrahedron: Asymmetry 15 (2004) 733–741
741
extracted with ethyl acetate (20 mL · 3) and the extracts
were washed successively with saturated aqueous
NaHCO3, and brine, then dried over anhydrous sodium
sulfate. Concentration of the solution after filtration
gave the crude product, which was purified by silica gel
column chromatography (eluent, hexane–ethyl ace-
tate ¼ 9:1 to 7:1) to afford 18 (250.5 mg, 55%).
Kind gifts of enzymes from Amano Pharmaceutical Co.,
Ltd., Boehringer Mannheim, and Meito Sangyo Co.,
Ltd. were gratefully acknowledged.
References and notes
26
1
½aꢀ ¼ )21.9 (c 1.41, CHCl3). H NMR spectrum was
D
1. (a) Theil, F. Chem. Rev. 1995, 95, 2203; (b) Schoffers, E.;
Golebiowski, A.; Johnson, C. R. Tetrahedron 1996, 52,
3769; (c) Sugai, T. Curr. Org. Chem. 1999, 3, 373.
2. (a) Umezawa, I.; Komiyama, K.; Oka, H.; Okada, K.;
Tomisaka, S.; Miyano, T.; Takano, S. J. Antibiot. 1984,
37, 706; (b) Komiyama, K.; Okada, K.; Oka, H.; Tomi-
saka, S.; Miyano, T.; Funayama, S.; Umezawa, I. J.
Antibiot. 1985, 38, 220; (c) Wang, Y.; Ponelle, M.;
Sanglier, J.-J.; Wolff, B. Helv. Chim. Acta 1997, 80, 2157.
3. (a) Paterson, I.; Tillyer, R. D. Tetrahedron Lett. 1992, 33,
4233; (b) Paterson, I.; Norcross, R. D.; Ward, R. A.;
Romea, P.; Lister, M. A. J. Am. Chem. Soc. 1994, 116,
11287.
4. (a) Grisenti, P.; Ferraboschi, P.; Manzocchi, A.; Santan-
iello, E. Tetrahedron 1992, 48, 3827; (b) Fadel, A.; Arzel,
P. Tetrahedron: Asymmetry 1997, 8, 283; (c) Lundhaug,
K.; Overbeeke, A.; Jongejan, J. A.; Anthonsen, T.
Tetrahedron: Asymmetry 1998, 9, 2851; (d) Akai, S.;
Naka, T.; Fujita, T.; Takabe; Kita, Y. Chem. Commun.
2000, 1461; (e) Yadav, J. S.; Nanda, S. Tetrahedron:
Asymmetry 2001, 12, 3223.
identical to that of 18 derived from 13.
4.15. Preparation of (S)-1-(tert-butyldiphenylsiloxy)-2-(4-
methoxybenzyloxymethyl)-3-pentanone 3
To a solution of kinetically resolved 13 (98.4 mg,
0.390 mmol) prepared as described in Section 4.11 and
imidazole (53.2 mg, 0.781 mmol) in DMF (4 mL) was
added TBDPSCl (152 lL, 0.586 mmol). After stirring for
3 h, saturated aqueous ammonium chloride was added,
and the resulting mixture was extracted with hexane–
ethyl acetate (1:1) (20 mL · 2). The extracts were washed
with brine, then dried over anhydrous sodium sulfate,
filtered, evaporated at reduced pressure. The crude
product was purified by silica gel column chromato-
graphy (eluent, hexane–ethyl acetate ¼ 10:1) to afford 3
27
(145.2 mg, 76%). ½aꢀ ¼ +6.8 (c 1.06, CHCl3) (98% ee,
D
S). IR (KBr, neat, cmꢁ1) 2933, 1715, 1613, 1513, 1248,
1
ꢁ
5. Egri, G.; Fogassy, E.; Novak, L.; Poppe, L. Tetrahedron:
1112, 703; H NMR (500 MHz, CDCl3) d 1.01 (s, 9H),
Asymmetry 1997, 8, 547.
6. Sakai, T.; Kawabata, I.; Kishimoto, T.; Ema, T.; Utaka,
M. J. Org. Chem. 1997, 62, 4906.
7. Paterson, I.; Lister, M. A.; Ryan, G. R. Tetrahedron Lett.
1991, 32, 1749.
8. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J.
Am. Chem. Soc. 1982, 104, 7294.
9. Paterson, I.; Cowden, C. J.; Woodrow, M. D. Tetrahedron
Lett. 1998, 39, 6037. The optical rotation is not reported in
the literature.
1.04 (t, J ¼ 7:3 Hz, 3H), 2.50–2.58 (m, 2H), 3.03–3.08
(m, 1H), 3.55 (dd, J ¼ 9:2, 6.0 Hz, 1H), 3.64 (dd,
J ¼ 9:2, 7.8 Hz, 1H), 3.78 (dd, J ¼ 10:1, 6.0 Hz, 1H),
3.79 (s, 3H), 3.86 (dd, J ¼ 10:1, 6.9 Hz, 1H), 4.34 (d,
J ¼ 11:5 Hz, 1H), 4.38 (d, J ¼ 11:5 Hz, 1H), 6.84 (d,
J ¼ 8:3 Hz, 2H), 7.16 (d, J ¼ 8:3 Hz, 2H), 7.36–7.38 (m,
4H), 7.41–7.44 (m, 2H), 7.60–7.62 (m, 4H). 13C NMR
(125 MHz, CDCl3) d 7.30, 19.14, 26.71, 36.89, 54.38,
55.21, 62.39, 67.80, 72.89, 113.71, 127.69, 129.14,
129.71, 130.10, 133.09, 133.20, 135.50, 135.53, 159.14,
211.98. HRMS(FAB), m=z (M+Naþ) calcd 513.2437,
obsd 513.2418.
10. (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277; (b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58,
2899; (c) Frigerio, M.; Santagostino, M.; Sputore, S.
J. Org. Chem. 1999, 64, 4537.
11. Wessel, H.-P.; Iversen, T.; Bundle, D. R. J. Chem. Soc.,
Perkin Trans. 1 1985, 2247.
12. Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O.
Tetrahedron Lett. 1988, 29, 4139.
Acknowledgements
13. Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini,
G.; Dolling, U.-H.; Grabowski, E. J. J. Tetrahedron Lett.
1995, 36, 5461.
We thank Associate Prof. Takeshi Sugai in Department
of Chemistry, Keio University, for helpful discussion.