Facile preparation of methyl 5-aryl-4-hydroxyhex-2(E)-enoate, chiral synthon of bisabolane-type sesquiterpenes, based on lipase-catalyzed kinetic resolution and rearrangement of an aryl group

Article abstract of DOI:10.1016/j.tetasy.2009.04.015

The lipase-catalyzed enantioselective acetylation of racemic methyl (4S^*,5S^*)-4-aryl-5-hydroxyhex-2(E)-enoates 1a-h was performed and efficient resolutions were achieved (E >400) by using CAL-B. After brosylation of the obtained opti

Full text of DOI:10.1016/j.tetasy.2009.04.015

Tetrahedron: Asymmetry 20 (2009) 1286–1294
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Facile preparation of methyl 5-aryl-4-hydroxyhex-2(E)-enoate, chiral synthon
of bisabolane-type sesquiterpenes, based on lipase-catalyzed kinetic
resolution and rearrangement of an aryl group
*
*
Mikio Fujii , Sumie Yasuhara, Hiroyuki Akita
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 247-8510, Japan
a r t i c l e i n f o
a b s t r a c t
The lipase-catalyzed enantioselective acetylation of racemic methyl (4S*,5S*)-4-aryl-5-hydroxyhex-2(E)-
enoates 1a–h was performed and efficient resolutions were achieved (E >400) by using CAL-B. After bro-
sylation of the obtained optically active 1a–h, solvolysis of brosylates 13a–h afforded the corresponding
methyl (4S*,5S*)-5-aryl-4-hydroxyhex-2(E)-enoates 3a–h (26–94% yield). The yields of 3a and 3c on the
solvolysis of the corresponding 13 were 92% and 40%, respectively, while solvolysis of the corresponding
tosylate was reported at 70% and 17%, respectively. This procedure is a facile and practical route to the
synthesis of bioactive and optically active bisabolane-type sesquiterpenes.
Article history:
Received 31 March 2009
Accepted 27 April 2009
Available online 8 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
tive hydrolysis by lipase P to give (4S,5S)-11 and (4R,5R)-12. Then,
recovered (4S,5S)-11 was hydrolyzed to (4S,5S)-12. Both enantio-
Optically active methyl (4S*,5S*)-4-aryl-5-hydroxyhex-2(E)-
enoates 1 are considered as important chiral building blocks for
the synthesis of natural products, especially bisabolane-type ses-
quiterpene, since the stereoselective rearrangement of the aryl
group of tosylate 2 to optically active methyl (4S*,5S*)-5-aryl-4-
hydroxyhex-2(E)-enoates 3 via a phenonium ion has been devel-
oped (Scheme 1).1–3 Due to the antifungal and antitumor activity
of bisabolane-type sesquiterpenes, such as xanthorrizol 4,4,5 curcu-
quinone 5, curcuphenol 6, curcudiol 7,6 and curcumene 8,7 much
attention has been paid to their synthesis (Fig. 1). For example,
Fuganti and Serra reported the synthesis of (+)-xanthorrizol (+)-4,
(+)-curcuquinone (+)-5, and (+)-curcuphenol (+)-6 based on bakers’
mers of 12 were converted to corresponding optically active 10,
after which 10 was treated with aromatic compounds bearing an
electron-donating group in the presence of boron trifluoride ether
complex to afford optically active 1. Furthermore, in the synthetic
application of 1, both enantiomers of bisabolane-type sesquiter-
penes such as curcudiol 7 and curcumene 8 were synthesized from
optically active 1. However, direct resolution of rac-1 is desired for
the practical and efficient synthesis of the bisabolane-type
sesquiterpenes.
Herein we report the direct resolution of rac-1 by Candida ant-
arctica lipase B (CAL-B) and improvements in the rearrangement
of optically active 1 via phenonium ion to chiral synthon 3 for
the synthesis of bisabolane-type sesquiterpenes.
yeast reduction of
a
,b-unsaturated aldehyde.8 Manatti and Döts
demonstrated the asymmetric synthesis of (ꢀ)-curcuquinone
(ꢀ)-5 involving a regioselective [3+2+1]-benzannulation reaction
and Sharpless epoxidation.9 Kamal et al. reported the chemoenzy-
matic syntheses of curcuphenol and curcumene using lipase-cata-
lyzed optical resolution of ethyl 3-arylbutanoate.10
2. Results and discussion
2.1. Preparation of 1
Previously, we reported the lipase-catalyzed enantioselective
hydrolysis of (4S*,5S*)-methyl 5-acetyl-4-arylhex-2(E)-enoate 9,
but failed to resolve the enantiomers effectively.11 To obtain opti-
cally active 1, synthetic methods by way of optically active
(4S*,5S*)-methyl 4,5-epoxyhex-2(E)-enoate 10 as a chiral synthon
from rac-10 were developed (Scheme 2).12,13 Acetate rac-11 ob-
tained from rac-10 was subjected to lipase-catalyzed enantioselec-
Substrates 1a–h for the lipase-catalyzed kinetic resolution were
prepared from rac-10 and anisole derivatives in the presence of
BF3ꢁEt2O by following the reported procedure;3 the yields of 1a–
h are shown in Scheme 3.
2.2. Kinetic resolution of 1
Initially several lipases were investigated for stereoselectivity in
the transesterification against rac-1a since normally sterically hin-
dered substrates around the active site of the lipase were not found
to be suitable. As a result, CAL-B was found to convert (4R,5R)-1a to
* Corresponding authors. Tel./fax: +81 47 472 1825 (M.F.).
E-mail addresses: mfujii@phar.toho-u.ac.jp (M. Fujii), akita@phar.toho-u.ac.jp (H.
Akita).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.04.015

M. Fujii et al. / Tetrahedron: Asymmetry 20 (2009) 1286–1294
1287
OH
O
OTs
O
H2O-MeNO2
OMe
OMe
Ar
(4S,5S)-1
Ar
(4S,5S)-2
O
Ar
O
OMe
OMe
OH
OTs
(4S,5S)-3
phenonium ion intermediate
Scheme 1.
OH
O
OH
O
(R)-Xanthorrizol (R)-4
(R)-Curcuphenol (R)-5
(R)-Curcuquinone (R)-6
OH
OH
(R)-Curcudiol (R)-7
(R)-Curcumene (R)-8
Figure 1. Structures of typical bisabolane-type sesquiterpenes.
O
OAc
O
OAc
O
OH
O
O
Lipase PS
H2O
+
OMe
OMe
OMe
OMe
OBn
rac-11
OBn
OBn
rac-10
(4S,5S)-11
(4R,5R)-12
O
O
O
O
OMe
OMe
(4S,5S)-10
(4R,5R)-10
OH
O
OH
O
OMe
OMe
Ar
Ar
(4S,5S)-1
(4R,5R)-1
Scheme 2.
the corresponding acetate (4R,5R)-9a stereoselectively. CAL-B
(200 mg) and rac-1a (1.0 g) in vinyl acetate (10 mL) were stirred
for 3 days at 25 °C, after which (4R,5R)-9a was obtained in 49%
yield and 99.8% ee; recovered (4S,5S)-1a was obtained in 50% yield
and >99.9% ee (Table 1, entry 1). While lipases Amano AK and Ama-
no PS catalyzed the reaction, the conversions after 2 weeks were
only 23% and 6.8%, respectively. The absolute configuration of
(4S,5S)-1a from the CAL-B-catalyzed reaction was determined by

1288
M. Fujii et al. / Tetrahedron: Asymmetry 20 (2009) 1286–1294
was reused for the next reaction and similar results were obtained
as shown in Table 1 (entry 2).
OH
O
O
ArH
BF3 Et2O
O
OMe
The reaction was then demonstrated on a large scale. When
40.5 g of rac-1a was treated with 3.0 g of lipase CAL-B in 400 mL
of vinyl acetate for 7 days, 20.1 g (49.6%) of (4S,5S)-1a was recov-
ered in >99.9% ee and 22.5 g (48%) of (4R,5R)-9a was obtained in
99.9% ee. Methanolysis of (4R,5R)-9a by CAL-B in diisopropylether
and methanol afforded (4R,5R)-1a in 93% yield and >99.9% ee
(Scheme 4).
.
OMe
Ar
rac-1
rac-10
Ar = 4-MeOPh 1a: 72%
Ar = 2-MeO-4-MePh 1b: 34%,
1c
: 45%
2-Me-4-MeOPh
Next, several methyl 4-aryl-5-hydroxyhex-2(E)-enoates 1b–h
were subjected to enzymatic resolution, and the corresponding
acetates 9b–h and remaining alcohols 1a–h were obtained in high
yields with excellent ees as shown in Table 1. The E-values of the
kinetic resolution in Table 1 were over 417 in every case.
The preparation of optically active 1 from rac-10 had required
seven steps for (4R,5R)-1 and eight steps for (4S,5S)-1 in the previ-
ous method, but the present method shortened the procedure to
three and two steps, respectively.15
Ar = 3-Me-4-MeOPh 1d: 64%
1e
Ar = 2-MeO-5-MePh
1f
: 80%
Ar = 2,5-(MeO)2Ph : 72%
1g
Ar = 3,4-(MeO)2Ph
: 92%
Ar = 2,5-(MeO)2-4-Me-Ph 1h: 71%
Scheme 3.
2.3. Rearrangement of 1 to 3
comparison of the specific rotation ([
value ([a]
a]D = +21.2) with the reported
D = +21.3);2 the E-value of the reaction was over 1000.
Previously, we reported the solvolysis of tosylate 2 to afford
rearranged product 3 via phenonium ion.3 However, the reaction
took an extended period of time (3–12 days) and gave low yield
The recognition of the stereocenter at the 50-position of the reac-
tion against 1a was similar to the empirical rule for the kinetic res-
olution of the secondary alcohols (Fig. 2).14 The recovered lipase
(15–70%).
In
order
to
shorten
the
reaction
time,
Table 1
Kinetic resolution of rac-1 by Candida antarctica lipase B (CAL-B)
OAc
O
OH
O
OH
O
CAL-B
+
OMe
OMe
OMe
vinyl acetate
Ar
(4R,5R)-9
Ar
rac-1
Ar
(4S,5S)-1
Substrate
(4S,5S)-1
(4R,5R)-9
E
Yield (%)
Ee (%)
Yield (%)
Ee (%)
1a (Ar = 4-MeOPh)
50
50
46
50
49
50
52
48
49
>99.9
99.9
>99.9
>99.9
99.3
98.2
95.2
98.6
99.8
49
49
50
50
46
48
46
50
46
99.8
99.9
98.5
99.8
98.2
99.8
98.2
98.0
99.8
>1000
>1000
>1000
>1000
622
>1000
417
492
1aa
1b (Ar = 2-MeO-4-MePh)
1c (Ar = 4-MeO-2-MePh)
1d (Ar = 4-MeO-3-MePh)
1e (Ar = 2-MeO-5-MePh)
1f (Ar = 2,5-(MeO)2Ph)
1g (Ar = 3,4-(MeO)2Ph)
1h (Ar = 2,5-(MeO)2-4-MePh)
>1000
Conditions: rac-1; 1 g, lipase CAL-B; 200 mg, vinyl acetate 20 mL, at 25 °C for 3–4 days.
a
CAL-B was reused for the reaction.
OH
OAc
Lipase
M
M
acetyl donor
L
L
OAc
O
OH
O
CAL-B
OMe
OMe
vinyl acetate
M
Ar
(4R,5R)-9
Ar
L
1
(4R,5R)-
Figure 2. Empirical rule of enantiopreference for lipase-catalyzed reaction of secondary alcohol.

M. Fujii et al. / Tetrahedron: Asymmetry 20 (2009) 1286–1294
1289
OAc
O
OH
O
OH
O
+
OMe
OMe
OMe
CAL-B
vinyl acetate
OMe
(4R,5R)-9a
48 %, 99.9% ee
(22.5g)
OMe
(4S,5S)-1a
50 %, >99% ee
(20.1g)
OMe
rac-1a (40.5g)
CAL-B
MeOH / i-Pr2O
OH
O
OMe
OMe
(4R,5R)-1a
93 %, >99% ee
17.1 g from 21.5 g of (4R,5R)-9
Scheme 4.
4-bromobenzenesulfonyl (brosyl) group was employed as a better
leaving group. The obtained optically active (4S,5S)-1a (>99% ee)
was converted to the corresponding brosylate (4S,5S)-13a in 89%
yield. Rearrangement of (4S,5S)-13a in water saturated nitrometh-
ane gave a rearranged product (4S,5S)-3a in 92% yield and an unre-
arranged (4S,5S)-1a in 7.2% yield (Table 2, entry 1). Optical purity
of the product (4S,5S)-3a was retained as that of starting material
(4S,5S)-1a (>99% ee). The enantiomer (4R,5R)-13a from (4R,5R)-1a
was converted to (4R,5R)-3a by the same procedure in 94% yield
(Table 2, entry 2).
In contrast, the rearrangement of tosylate (4S,5S)-2a was re-
ported to afford (4S,5S)-3a in 70% yield. Considering the mecha-
nism by way of the phenonium ion shown in Scheme 1, the
regioselectivity of the reaction seemed not to be affected by the
type of leaving group. However, the ratio of products 3a/1a of
the reaction increased. To ensure this phenomenon, solvolysis of
(4S*,5S*)-2a and (4S*,5S*)-13a was investigated several times. The
ratio of the products (3a /1a) on the reaction of 2a was 7.0 0.8,
while that of 13a was 11.5 0.7. The results showed that the reg-
ioselectivity of the reaction was clearly affected by the leaving
group. Rearrangement of the aryl group via the phenonium ion
was well studied by Cram et al. and Schreiber et al.16 As the reac-
tion involved an SN2-type concerted mechanism, the regioselectiv-
ity was affected by the leaving group. The reason for the
regioselectivity by the leaving group is still unclear, so further
study on the mechanism is currently underway.
Optically active (4S,5S)-1b–h were converted to corresponding
brosylates(4S,5S)-13b–h, which were then subjected to a rearrange-
ment reaction to afford the corresponding compounds 3b–h. The
results are summarized in Table 2. The rearrangement of
Table 2
The yield on the conversion from (4S,5S)-1 to (4S,5S)-3
OBrs
Ar
O
Ar
O
OH
O
+ (4S,5S)-1
OMe
OMe
OMe
OH
(4S,5S)-3
Ar
(4S,5S)-1
(4S,5S)-13
Substrate
Isolated yield (%)
(4S,5S)-13
(4S,5S)-3
(4S,5S)-1
(4S,5S)-1a (Ar = 4-MeOPh)
(4R,5R)-1a
89
85
69
94
89
92
71
73
84
92 (70)a
94
7.2
5.5
73
58
0.3
26
62
11
42
(4S,5S)-1b (Ar = 2-MeO-4-MePh)
(4S,5S)-1c (Ar = 4-MeO-2-MePh)
(4S,5S)-1d (Ar = 4-MeO-3-MePh)
(4S,5S)-1e (Ar = 2-MeO-5-MePh)
(4S,5S)-1f (Ar = 2,5-(MeO)2Ph)
(4S,5S)-1g (Ar = 3,4-(MeO)2Ph)
26 (47)a
40 (17)a
94 (51)a
61 (19)a
37
87
45 (19)
a
(4S,5S)-1h (Ar = 2,5-(MeO)2-4-MePh)
Conditions: see experimental.
a
Reported yield (%) on reaction of the corresponding tosylate in parentheses.3

1290
M. Fujii et al. / Tetrahedron: Asymmetry 20 (2009) 1286–1294
H2O
H2O
OBrs
Ar
O
a
O
b
O
H2O-MeNO2
OMe
OMe
OBrs
+
OMe
OBrs
MeO
O
X
Me
(4S,5S)-13
phenonium ion intermediate
path a
X
Brs: Brosyl
oxonium ion intermediate
path b
path c
OH
O
Ar
O
OMe
OMe
Ar
(4S,5S)-1
OH
(4S,5S)-3
Scheme 5.
(4S,5S)-13a–h afforded the corresponding (4S,5S)-3a–h (26–94%
yield). The yields of (4S,5S)-3c, (4S,5S)-3d, (4S,5S)-3e, and (4S,5S)-
3h were higher than those of the reaction of the corresponding tos-
ylate 2. The reaction of (4S,5S)-13b exhibited a lower yield than that
of (4S,5S)-2b. This might be dependenton the stabilityof (4S,5S)-13b
(reaction time of (4S,5S)-13b: 6 h, 2b: 3 days). In the case of the reac-
tions of 13 possessing an ortho-substituent, the rearrangement
afforded a considerable amount of corresponding 1. The proposed
reaction pathways are shown in Scheme 5.3 The formation of 3a
and 1a was explained by way of the phenonium ion (path a and path
b, respectively). A substituent at the 20-position on the aromatic ring
prevented production of 3 by forming an oxonium intermediate
(path c) and/or by preferable nucleophilic attack of water to the 50-
position of phenonium intermediate (path b) as described in a previ-
ous report.3 As a result, solvolysisof 13b, 13c, 13e, 13f, and 13hcould
afford the corresponding 3 in low yield.
ried out on JASCO FT/IR 4100 using ATR method (neat). Specific
rotation was measured on JASCO P-2200. HPLC analysis was per-
formed on SSC-3210 pump equipped with chiral column, SSC-
5200 UV detector, and SIR Chromatocordor 21.
Chemicals were purchased from Tokyo Kasei Industry Co., Ltd,
Wako Chemicals or Aldrich Inc. otherwise indicated. Candida ant-
arctica lipase B (CAL-B) supported on acrylic resin was purchased
from Sigma–Aldrich Inc. and was used in this study. Racemic 1a–
e were synthesized by following the reported procedure from
rac-methyl 4,5-epoxyhex-(2E)-enoate and the corresponding ani-
sole derivatives. The absolute configurations of 1d, 1e, and 1h were
determined by comparison with the retention time of the corre-
sponding authentic sample prepared from optically active epoxide
10 on HPLC analysis.
4.2. General procedure for CAL-B-catalyzed kinetic resolution
of 1
3. Conclusion
To a solution of rac-1 (1.0 g) in vinyl acetate (50 mL) was added
lipase CAL-B (200 mg) and the resulting mixture was stirred at
25 °C. The ee of 1 and/or 9 was monitored by HPLC, and the reaction
was stopped by filtration through a pad of Celite 545. The reaction
time for 1a, 1d, 1e, and 1g was 3 days and that for 1b, 1c, and 1f
was 4 days. The residue was washed with ethyl acetate and then
the filtrate was evaporated under reduced pressure and afforded
the mixture of the substrate and the corresponding product. The res-
idue was purified by silica gel column chromatography (silica gel
30 g, n-hexane/AcOEt = 6/1) to afford 1 and 9. The ees of 1 and 9 were
determined by HPLC analysis and the results are shown in Table 1.
The lipase-catalyzed enantioselective acetylation of racemic
1a–h was performed and efficient optical resolutions were
achieved (E >400). The procedure for the preparation of optically
active 1 was shortened by direct enzymatic resolution of rac-1
when compared to a previously reported procedure. After the bro-
sylation of optically active 1a–h, the rearrangement of 13a–h affor-
ded the corresponding 3a–h (26–94% yield). Compounds 3a, 3d,
and 3g without a substituent at the 2’-position were obtained in
over 87% yield, and the yield of the reaction was improved by
the use of brosylate 13 in comparison with tosylate 2. The obtained
optically active (4S,5S)-3a can be expanded to optically active xan-
thorrizol 4 and curcumene 8; (4S,5S)-3e also can be expanded to
curcuphenol by our reported procedure.1,2 This present procedure
is useful for the synthesis of bisabolane-type sesquiterpenes from
methyl sorbate. Moreover, 1 and 3 are well-functionalized com-
4.2.1. Kinetic resolution of (4S*,5S*)-methyl 5-hydroxy-4-(4-
methoxyphenyl)-hex-2(E)-enoate rac-1a
From rac-1a (1.00 g, 4.00 mmol) to (4S,5S)-1a (500 mg,
2.00 mmol, 50%) and (4R,5R)-methyl 5-acetoxy-4-(4-methoxy-
phenyl)hex-2(E)-enoate (4R,5R)-9a (575 mg, 1.97 mmol, 49%).
pounds possessing a hydroxyl group and
a,b-unsaturated ester
(4S,5S)-1a: ½a 2D3
ꢂ
¼ þ21:2 (c 2.07, CHCl3); Lit.2
½
a 2D5
ꢂ
¼ þ21:3 (c
moiety; these compounds could be important chiral building
blocks for natural product synthesis.
2.12, CHCl3); 1H NMR: d 1.10 (3H, d, J = 6.0 Hz), 2.04 (1H, brs)
3.32 (1H, dd, J = 8.8, 7.2 Hz), 3.71 (3H, s), 3.79 (3H, s), 4.05 (1H,
qd, J = 6.0, 7.2 Hz), 5.89 (1H, dd, J = 1.2, 15.6 Hz), 6.78 (2H, d,
J = 6.4 Hz), 7.11 (2H, d, J = 6.4 Hz), 7.26 (1H, dd, J = 8.8, 15.6 Hz);
13C NMR: d 21.2, 51.5, 55.2, 56.0, 70.5, 114.2 (2C), 122.8, 129.1
(2C), 131.9, 148.7, 158.6, 166.8; HR-EI-MS calcd for C14H18O4:
250.1205; found: 250.1210; HPLC analysis: Chiralcel OD-H, n-hex-
ane/EtOH = 20/1, flow rate; 1.0 mL/min, detection; 254 nm,
(4R,5R)-1a; tR = 17.3 min, (4S,5S)-1a; tR = 22.0 min.
4. Experimental
4.1. General
The NMR spectra were recorded in CDCl3 on JEOL-AL-400 spec-
trometer (400 MHz for 1H NMR and 100 MHz for 13C NMR). Mass
spectra were measured by JEOL JMS-AM II 50. IR spectra were car-

M. Fujii et al. / Tetrahedron: Asymmetry 20 (2009) 1286–1294
1291
(4R,5R)-9a: ½a 2D1
ꢂ
¼ ꢀ5:5 (c 2.44, CHCl3); 1H NMR: d 1.11 (3H, d,
½
a 2D3
ꢂ
¼ ꢀ12:9 (c 2.27, CHCl3); 1H NMR (CDCl3, 400 MHz): d 1.11
J = 6.4 Hz), 2.03 (3H, s) 3.47 (1H, t, 8.4 Hz), 3.71 (3H, s), 3.79 (3H, s),
5.16–5.23 (1H, m), 5.82 (1H, dd, J = 1.2, 15.6 Hz), 6.86 (2H, d,
J = 8.4 Hz), 7.13 (2H, d, J = 8.4 Hz), 7.16 (1H, dd, J = 8.4, 15.6 Hz);
13C NMR: d 18.4, 21.1, 51.5, 53.2, 55.2, 72.4, 114.3 (2C), 122.5,
129.2 (2C), 130.8, 147.8, 158.8, 166.8, 170.4; IR: 1721, 1654,
1611, 1512, 1235 cmꢀ1; HR-EI-MS calcd for C15H20O4: 292.1311;
found: 292.1313; HPLC analysis: Chiralcel OD-H, n-hexane/
EtOH = 20/1, flow rate; 0.5 mL/min, detection; 254 nm, (4R,5R)-
9a; tR = 17.5 min, (4S,5S)-9a; tR = 14.7 min.
(3H, d, J = 6.4 Hz), 1.81 (1H, br s) 2.33 (3H, s), 3.71 (3H, s), 3.71–
3.81 (1H, m), 3.81 (3H, s), 4.14–4.22 (1H, m), 5.90 (1H, d,
J = 15.6 Hz), 6.70 (1H, s), 6.74 (1H, d, J = 7.9 Hz), 7.01 (1H, d,
J = 7.9 Hz), 7.34 (1H, dd, J = 8.8, 15.6 Hz); 13C NMR (CDCl3,
100 MHz): d 21.1, 21.4, 50.5, 51.4, 55.4, 69.6, 112.0, 121.5, 122.8,
125.3, 129.0, 138.2, 148.4, 156.6, 166.9. IR: 3445, 1722, 1650,
1611, 1579, 1506, 1267, 1039 cmꢀ1; HR-EI-MS calcd for C15H20O4:
264.1362, Found: 264.1352; The ee of 1c was determined by HPLC
analysis after acetylation of 1c–9c by acetic anhydride and pyridine.
HPLC analysis: Chiralcel OD-H, n-hexane/EtOH = 50/1, flow rate;
0.3 mL/min, detection; 254 nm, (4R,5R)-9c; tR = 22.6 min, (4S,5S)-
4.2.2. Large-scale preparation of optically active 1
To a solution of rac-1a (40.5 g, 0.162 mol) in vinyl acetate
(400 mL) was added lipase CAL-B (3.0 g) and the resulting mixture
was stirred at 25 °C for 7 days. The reaction was stopped by filtra-
tion through a glass filter. The residue was washed with ethyl ace-
tate and then the filtrate and ether solution were combined, and
evaporated under reduced pressure to afford the mixture of the
substrate and the corresponding product. The residue was purified
by silica gel column chromatography (silica gel 500 g, n-hexane/
AcOEt = 6/1) to afford (4R,5R)-1a (20.1 g, 80.4 mmol, 50%, >99.9%
ee) and (4R,5R)-9a (22.5 g, 77.1 mmol, 48%, 99.8% ee).
9c; tR = 21.6 min. (4R,5R)-9c: ½a D29
ꢂ
¼ þ18:6 (c 1.11, CHCl3); 1H
NMR: d 1.13 (3H, d, J = 6.4 Hz), 2.04 (3H, s), 2.35 (3H, s), 3.72 (3H,
s), 3.83 (3H, s), 3.95 (1H, dd, J = 8.0, 8.4 Hz), 5.35 (1H, dq, J = 6.4,
8.0 Hz), 5.84 (1H, d, J = 15.8 Hz), 6.71 (1H, s), 6.75 (1H, d,
J = 7.6 Hz), 7.03 (1H, d, J = 7.6 Hz), 7.20 (1H, dd, J = 8.0, 15.8 Hz);
13C NMR: d 18.5, 21.2, 21.4, 47.5, 51.4, 55.3, 71.9, 111.9, 121.3,
122.3, 129.0, 138.4, 148.0, 146.7, 156.7, 166.9, 170.5; IR: 1726,
1654, 1508, 1235 cmꢀ1; HR-EI-MS calcd for C17H22O5: 306.1467;
found: 306.1476.
(4R,5R)-1a: To the solution of (4R,5R)-9a (21.5 g, 73.7 mmol) in
diisopropylether (400 mL) and methanol (100 mL) was added the
CAL-B (3 g) that was recovered from the above-mentioned reac-
tion. The mixture was stirred for 4 days at rt, after which it was fil-
tered by glass filter and the residue was washed with ether. The
filtrate and the ethereal solution were combined and evaporated
under reduced pressure. The residue was purified by silica gel col-
umn chromatography (silica gel 100 g, n-hexane/AcOEt = 7/1) to
afford (4R,5R)-1a (17.1 g, 68.3 mmol 93%, >99.9% ee).
4.2.5. Resolution of (4S*,5S*)-methyl 5-hydroxy-4-(4-methoxy-
3-methylphenyl)hex-2(E)-enoate rac-1d
From rac-1d (1.11 g. 4.02 mmol) to (4S,5S)-1d (547 mg,
2.07 mmol, 49%) and (4R,5R)-methyl 5-acetoxy-4-(4-methoxy-3-
methylphenyl)hex-2(E)-enoate (4R,5R)-9d (594 mg, 1.94 mmol,
46%).
½
a 2D7
ꢂ
¼ þ17:6 (c 1.01, CHCl3); 1H NMR: d 1.11 (3H, d, J = 6.6 Hz),
1.81 (1H, br) 2.20 (3H, s), 3.28 (1H, dd, J = 8.0, 8.4 Hz), 3.72 (3H, s),
3.81 (3H, s), 4.01–4.09 (1H, m), 5.90 (1H, d, J = 15.6 Hz), 6.77 (1H, d,
J = 7.6 Hz), 6.96 (1H, s), 6.97 (1H, d, J = 7.6 Hz), 7.34 (1H, dd, J = 8.4,
15.6 Hz); 13C NMR: d 16.3, 21.2, 51.5, 55.3, 56.1, 70.6, 110.1, 122.7,
126.3, 127.1, 130.3, 131.3, 148.8, 156.8, 166.8; IR: 3443, 1714,
1650, 1504, 1258, 1038 cmꢀ1; HR-EI-MS calcd for C15H20O4:
264.1362; found: 264.1363; HPLC analysis: Chiralcel OD-H, n-hex-
ane/EtOH = 50/1, flow rate; 1.0 mL/min, detection; 254 nm,
(4R,5R)-1d; tR = 40.0 min, (4S,5S)-1d; tR = 29.8 min.
½
a 2D3
ꢂ
¼ ꢀ21:8 (c 1.00, CHCl3).
4.2.3. Kinetic resolution of (4S*,5S*)-methyl 5-hydroxy-4-(4-me-
thoxy-2-methylphenyl)hex-2(E)-enoate rac-1b
From rac-1b (1.10 g, 4.17 mmol) to (4S,5S)-1b (546 mg,
2.07 mmol, 50%) and (4R,5R)-methyl 5-acetoxy-4-(4-methoxy-2-
methylphenyl)hex-2(E)-enoate ((4R,5R)-9b) (590 mg, 1.97 mmol,
46%). (4S,5S)-1b: ½a D23
ꢂ
¼ þ2:0 (c 1.10, CHCl3). Lit.1
½
a 2D3
ꢂ
¼ þ5:8 (c
(4R,5R)-9d: ½a 2D7
ꢂ
¼ ꢀ10:0 (c 1.01, CHCl3); 1H NMR: d 1.08 (3H, d,
1.17, CHCl3); 1H NMR: d 1.11 (3H, d, J = 6.2 Hz), 1.75 (1H, br) 2.30
(3H, s), 3.57 (1H, dd, J = 8.0, 8.4 Hz), 3.71 (3H, s), 3.78 (3H, s),
4.06–4.13 (1H, m), 5.85 (1H, d, J = 15.6 Hz), 6.70–6.78 (2H, m),
6.97 (1H, d, J = 8.4 Hz), 7.22 (1H, dd, J = 8.0, 15.6 Hz); 13C NMR: d
20.4, 21.7, 52.0, 52.1, 55.8, 71.1, 112.3, 116.9, 123.1, 128.9, 131.1,
138.0, 149.7, 158.7, 167.5; IR: 3445, 1714, 1651, 1608, 1577,
1504, 1272, 1048 cmꢀ1; HR-EI-MS calcd for C15H20O4: 264.1362;
found: 264.1365; HPLC analysis: Chiralcel OD-H, n-hexane/
EtOH = 50/1, flow rate; 1.0 mL/min, detection; 254 nm, (4R,5R)-
1b; tR = 29.8 min, (4S,5S)-1b; tR = 40.0 min.
J = 6.4 Hz), 2.01 (3H, s), 2.17 (3H, s), 3.39 (1H, t, J = 8.4 Hz), 3.68
(3H, s), 3.78 (3H, s), 5.35 (1H, dq, J = 8.4, 6.4 Hz), 5.84 (1H, d,
J = 15.6 Hz), 6.73 (1H, d, J = 7.6 Hz), 6.93 (1H, d, J = 2.0 Hz), 6.94
(1H, dd, J = 2.0, 7.6 Hz), 7.09 (1H, dd, J = 8.4, 15.6 Hz); 13C NMR: d
16.2, 18.5, 21.2, 51.5, 53.5, 55.3, 72.5, 110.1, 122.3, 126.4, 127.1,
130.3 (2C), 148.8, 157.0, 166.7, 170.4; IR: 1726, 1655, 1508,
1235, 1051 cmꢀ1; HR-EI MS calcd for C17H22O5: 306.1467; found:
306.1465. HPLC analysis: Chiralcel OD-H, n-hexane/EtOH = 50/1,
flow rate; 1.0 mL/min, detection; 254 nm, (4R,5R)-9d;
tR = 10.0 min, (4S,5S)-9d; tR = 7.2 min.
(4R,5R)-9b: ½a 2D3
ꢂ
¼ þ1:8 (c 1.12, CHCl3); 1H NMR: d 1.06 (3H, d,
J = 6.4 Hz), 1.98 (3H, s), 2.25 (3H, s), 3.61 (3H, s), 3.63–3.72 (1H, m)
3.70 (3H, s), 5.20 (1H, dq, J = 8.4, 6.4 Hz), 5.71 (1H, dd, J = 0.8,
15.6 Hz), 6.65–6.70 (2H, m), 6.98–7.06 (2H, m); 13C NMR: d 18.2,
19.9, 21.0, 48.5, 51.2, 54.9, 72.3, 111.6, 116.2, 121.9, 128.4, 129.0,
137.2, 148.0, 156.1, 166.5, 170.2; IR: 1730, 1654, 1608, 1577,
1504, 1245, 1044 cmꢀ1; HR-EI-MS calcd for C17H22O5: 306.1467;
found: 306.1475; HPLC analysis: Chiralcel OD-H, n-hexane/
EtOH = 50/1, flow rate; 1.0 mL/min, detection; 254 nm, (4R,5R)-
9b; tR = 9.7 min, (4S,5S)-9b; tR = 8.7 min.
4.2.6. Resolution of (4S*,5S*)-methyl 5-hydroxy-4-(2-methoxy-
5-methylphenyl)hex-2(E)-enoate rac-1e
From rac-1e (1.01 g, 3.83 mmol) to (4S,5S)-1e (507 mg,
1.92 mmol, 50%) and (4R,5R)-methyl 5-acetoxy-4-(2-methoxy-5-
methylphenyl)hex-2(E)-enoate (4R,5R)-9e (560 mg, 1.83 mmol,
48%). (4S,5S)-1e: ½a D28
ꢂ
¼ ꢀ1:7 (c 1.08, CHCl3); 1H NMR: d 1.11 (3H,
d, J = 6.4 Hz), 1.92 (1H, br s) 2.27 (3H, s), 3.72 (3H, s), 3.71–3.81
(1H, m), 3.80 (3H, s), 4.14–4.21 (1H, m), 5.92 (1H, d, J = 15.6 Hz),
6.78 (1H, d, J = 7.8 Hz), 6.94 (1H, s), 7.01 (1H, d, J = 7.8 Hz), 7.34
(1H, dd, J = 8.8, 15.6 Hz); 13C NMR: d 23.5, 24.2, 53.8, 54.5, 58.6,
72.6, 114.0, 126.0, 131.1, 131.4, 132.8, 133.1, 151.3, 157.6, 169.9;
IR: 3444, 1714, 1650, 1504, 1241, 1034 cmꢀ1; HR-EI-MS calcd for
C15H20O4: 264.1362; found: 264.1358; HPLC analysis: Chiralcel
OD-H, n-hexane/EtOH = 50/1, flow rate; 0.3 mL/min, detection;
254 nm; (4R,5R)-1e; tR = 24.0 min, (4S,5S)-1e; tR = 20.9 min.
4.2.4. Resolution of (4S*,5S*)-methyl 5-hydroxy-4-(2-methoxy-
4-methylphenyl)hex-2(E)-enoate rac-1c
From rac-1c (1.10 g, 4.17 mmol) to (4S,5S)-1c (547 mg,
2.07 mmol, 50%) and (4R,5R)-methyl 5-acetoxy 4-(2-methoxy-4-
methylphenyl)hex-2(E)-enoate (4R,5R)-9c (635 mg, 2.08 mmol,
50%). 1c:
½
a 2D9
ꢂ
¼ ꢀ14:2 (c 1.00, CHCl3). Lit.1 (4S,5S)-1c
(4R,5R)-9e: ½a 2D3
ꢂ
¼ þ12:5 (c 1.07, CHCl3); 1H NMR: d 1.13 (3H, d,

1292
M. Fujii et al. / Tetrahedron: Asymmetry 20 (2009) 1286–1294
J = 6.4 Hz), 2.05 (3H, s), 2.29 (3H, s), 3.73 (3H, s), 3.82 (3H, s), 3.97
(1H, t, J = 6.4 Hz), 5.36 (1H, dq, J = 8.4, 6.4 Hz), 5.84 (1H, d,
J = 15.6 Hz), 6.78 (1H, d, J = 8.4 Hz), 6.96 (1H, d, J = 2.0 Hz), 7.04
(1H, dd, J = 2.0, 8.4 Hz), 6.94 (1H, dd, J = 8.4, 15.6 Hz); 13C NMR:
d 18.5, 20.4, 21.2, 47.7, 51.4, 55.5, 71.9, 110.9, 122.4, 126.9,
128.6, 129.8, 129.9, 147.9, 154.8, 166.9, 170.5; IR: 1731, 1655,
1504, 1241 cmꢀ1; HR-EI-MS calcd for C17H22O5: 306.1467; found:
306.1476. HPLC analysis: Chiralcel OD-H, n-hexane/EtOH = 50/1,
flow rate; 1.0 mL/min, detection; 254 nm, (4R,5R)-9e; tR = 7.4 min,
(4S,5S)-9e; tR = 6.3 min.
4.2.9. Resolution of rac-methyl 5-hydroxy 4-(30,40-dimethoxy-
phenyl)hex-2(E)-enoate 1h
From rac-1h (940 mg, 3.16 mmol) to (4S,5S)-1h (460 mg, 50%)
and (4R,5R)-methyl 5-acetoxy-4-(2-methoxy-5-methylphenyl)
hex-2(E)-enoate
(4R,5R)-9h
(498 mg,
46%).
(4S,5S)-1h:
½
a 1D4
ꢂ
¼ þ10:5 (c 1.36, CHCl3); 1H NMR: d 1.12 (3H, d, J = 6.0 Hz),
2.20 (3H, s), 3.70(3H, s), 3.72–3.78 (1H, m), 3.78 (3H, s), 4.18 (1H,
qd, J = 6.0, 8.4 Hz), 5.90 (1H, d, J = 15.6 Hz), 6.64 (1H, s), 6.71 (1H,
s), 7.36 (1H, dd, J = 8.4, 15.6 Hz); 13C NMR: d 16.0, 21.2, 50.8,
51.3, 55.5, 56.1, 69.5, 111.6, 114.4, 122.6, 126.0, 126.1, 148.6,
150.4, 151.7, 166.9; IR: 1722, 1654, 1622, 1517, 1237 cmꢀ1; HR-
EI-MS calcd for C16H22O5: 294.1467; found: 294.1460; Chiralcel
AD-H, n-hexane/i-PrOH = 20/1, flow rate; 1.0 mL/min, detection;
254 nm, (4R,5R)-1h; tR = 27.5 min, (4S,5S)-1h; tR = 33.5 min.
4.2.7. Resolution of rac-methyl 5-hydroxy-4-(20,50-dimethoxy-
phenyl)hex-2(E)-enoate 1f
From rac-1f (1.01 g, 3.60 mmol) to (4S,5S)-1f (528 mg,
1.89 mmol, 52%) and (4R,5R)-methyl 5-acetoxy-4-(2-methoxy-5-
methylphenyl)hex-2(E)-enoate (4R,5R)-9f (538 mg, 1.67 mmol,
(4R,5R)-9h: ½a 1D4
ꢂ
¼ ꢀ5:6 (c 0.36, CHCl3); 1H NMR: d 1.12 (3H,
d, J = 7.2 Hz), 2.03 (3H, s), 2.20 (3H, s), 3.70 (3H, s), 3.77 (6H, s),
3.95 (1H, t, J = 8.4 Hz), 5.32 (1H, qd, J = 7.2, 8.4 Hz), 5.84 (1H, d,
J = 15.6 Hz), 6.60 (1H, s), 6.70 (1H, s), 7.18 (1H, dd, J = 8.4,
15.6 Hz); 13C NMR: d 16.1, 18.4, 21.1, 47.5, 51.3, 56.0, 56.0,
71.9, 111.4, 114.4, 122.3, 124.7, 126.4, 147.8, 150.6, 151.7,
166.7, 170.4; IR: 1725, 1655, 1505, 1237, 1210 cmꢀ1. HR-EI-MS
calcd for C18H24O6: 336.1573; found: 336.1575; HPLC analysis:
Chiralcel AD-H, n-hexane/i-PrOH = 20/1, flow rate; 1.0 mL/min,
detection; 254 nm, (4R,5R)-9h; tR = 8.5 min, (4S,5S)-9h; tR =
10.5 min.
46%). (4S,5S)-1f: ½a D24
ꢂ
¼ þ4:1 (c 1.10, CHCl3); Lit.11
½
a 1D8
ꢂ
¼ ꢀ3:55
(c 1.52, CHCl3, (4R,5R)-1f, 90%ee); 1H NMR:
d 1.12 (3H, d,
J = 6.0 Hz), 1.94 (1H, br s) 3.72 (3H, s), 3.74–3.80 (1H, m), 3.76
(3H, s), 3.78 (3H, s), 4.14–4.21 (1H, m), 5.92 (1H, dd, J = 1.2,
15.6 Hz), 6.70–6.77 (2H, m), 6.82 (1H, d, J = 8.0 Hz), 7.31 (1H, dd,
J = 8.8, 15.6 Hz); 13C NMR: d 21.2, 50.8, 51.6, 55.7, 56.0, 69.6,
111.9, 112.0, 115.8, 123.1, 129.6, 148.0, 151.0, 153.7, 166.8; IR:
3471, 1717, 1650, 1497, 1225, 1043 cmꢀ1; HR-EI-MS calcd for
C15H20O5: 280.1311; found: 280.1315. HPLC analysis: Chiralcel
OD-H, n-hexane/EtOH = 30/1, flow rate; 1.0 mL/min, detection;
254 nm, (4R,5R)-1f; tR = 46.8 min, (4S,5S)-1f; tR = 34.0 min.
4.3. Brosylation of 1
(4R,5R)-9f: ½a 2D5
ꢂ
¼ þ6:5 (c 1.03, CHCl3). Lit.11
½
a 1D8
ꢂ
¼ ꢀ4:9 (c 3.28,
CHCl3, (4S,5S)-9f, 67%ee); 1H NMR: d 1.12 (3H, d, J = 6.4 Hz), 2.03
(3H, s), 3.71 (3H, s), 3.75 (3H, s), 3.78 (3H, s), 3.95 (1H, dd,
J = 8.4, 8.8 Hz), 5.32 (1H, dq, J = 8.4, 6.4 Hz), 5.84 (1H, d,
J = 15.6 Hz), 6.71 (1H, d, J = 2.8 Hz), 6.96 (1H, d, J = 2.8, 8.8 Hz),
6.80 (1H, dd, J = 8.8 Hz), 7.18 (1H, dd, J = 8.8, 15.6 Hz); 13C NMR:
d 18.5, 21.2, 47.7, 51.5, 55.7, 56.0, 71.8, 110.9, 112.3, 115.7,
122.7, 128.3, 147.5, 151.1, 153.6, 166.8, 170.5; IR: 1729, 1653,
4-Bromobenzenesulfonylchloride (2.5 equiv) was added to a
solution of 1 (1.2 mmol) in pyridine (1.5 mL) at 0 °C and the mix-
ture was stirred for 6 h at rt. The mixture was poured into water
and extracted with ethyl acetate. The organic layer was evaporated
under reduced pressure. The residue was purified by silica gel col-
umn chromatography (silica gel 30 g, n-hexane/AcOEt = 6/1) to af-
ford 13.
1594, 1497, 1231, 1042 cmꢀ1
. HR-EI-MS calcd for C17H22O6:
322.1416; found: 322.1411. Ee of 9f was determined by HPLC anal-
ysis after 9f was converted to 1f by methanolysis using K2CO3.
4.3.1. (4S,5S)-Methyl 5-(4-bromobenzenesulfonyloxy)-4-(4-
methoxyphenyl)hex-2(E)-enoate (4S,5S)-13a
From (4S,5S)-1a (5.00 g, 20.0 mmol) to (4S,5S)-13a (8.31 g,
4.2.8. Resolution of rac-methyl 5-hydroxy-4-(30,40-dimethoxy-
phenyl)hex-2(E)-enoate 1g
17.8 mmol, 89%). ½a D23
ꢂ
¼ þ22:1 (c 1.13, CHCl3); 1H NMR: d 1.29
(3H, d, J = 6.2 Hz), 3.48 (1H, t, J = 8.2 Hz), 3.72 (3H, s), 3.75 (3H,
s), 4.86 (1H, qd, J = 8.2, 6.2 Hz), 5.76 (1H, d, J = 15.4 Hz), 6.79 (2H,
d, J = 8.7 Hz), 6.95 (1H, dd, J = 8.2, 15.4 Hz), 6.98 (2H, d,
J = 8.7 Hz), 7.60 (2H, d, J = 8.4 Hz), 7.65 (2H, d, J = 8.4 Hz); 13C
NMR: d 19.9, 51.6, 53.3, 55.2, 82.2, 114.3 (2C), 123.7, 128.6, 129.1
(2C), 129.1 (2C), 129.6, 132.4 (2C), 135.8, 145.8, 159.0, 166.1; IR:
1732, 1657, 1610, 1575, 1515, 1274, 1185, 904 cmꢀ1; HR-EI-MS
calcd for C20H21O6SBr: 468.0242, 470.0222; found: 468.0223
(100%), 470.0234 (99.2%).
From rac-1g (920 mg) to (4S,5S)-1g (452 mg, 50%) and (4R,5R)-
methyl 5-acetoxy-4-(2-methoxy-5-methylphenyl)hex-2(E)-enoate
(4R,5R)-9g (501 mg, 48%). (4S,5S)-1g: ½a D27
¼ þ15:1 (c 1.26, CHCl3);
ꢂ
Lit.11
½
a 2D4
ꢂ
¼ ꢀ8:2 (c 2.10, CHCl3, (4R,5R)-1g, 62%ee); 1H NMR: d
1.12 (3H, d, J = 6.4 Hz), 2.15 (1H, br s) 3.31 (1H, dd, J = 7.2,
8.8 Hz), 3.73 (3H, s), 3.86 (3H, s), 3.88 (3H, s), 4.04–4.11 (1H, m),
5.92 (1H, d, J = 15.6 Hz), 6.71(1H, d, J = 1.6 Hz), 6.75 (1H, dd,
J = 8.4, 1.6 Hz), 6.83 (1H, d, J = 8.4 Hz), 7.27 (1H, dd, J = 8.8,
15.6 Hz); 13C NMR: d 23.5, 24.2, 53.8, 54.5, 58.6, 72.6, 114.0,
126.0, 131.1, 131.4, 132.8, 133.1, 151.3, 157.6, 169.9; IR: 3500,
1714, 1652 1621, 1261, 1241, 1027 cmꢀ1. HR-EI-MS calcd for
C15H20O5: 280.1311; found: 280.1312; HPLC analysis: Chiralcel
OD-H, n-hexane/EtOH = 20/1, flow rate; 1.0 mL/ min, detection;
254 nm, (4R,5R)-1g; tR = 32.4 min, (4S,5S)-1g; tR = 28.1 min.
(4R,5R)-13a: From (4R,5S)-1a (14.0 g, 56.0 mmol) to (4R,5R)-
13a (22.3 g, 47.7 mmol, 85.2%). ½a D23
¼ ꢀ19:4 (c 1.04, CHCl3).
ꢂ
4.3.2. (4S,5S)-Methyl 5-(4-bromophenylsulfonyloxy)-4-(4-
methoxy-2-methylphenyl)hex-2(E)-enoate (4S,5S)-13b
From (4S,5S)-1b (300 mg, 1.14 mmol) to (4S,5S)-13b (377 mg,
(4R,5R)-9g: ½a 2D7
ꢂ
¼ ꢀ11:2 (c 1.07, CHCl3); Lit.11
½
a 2D4
ꢂ
¼ þ10:5 (c
0.782 mmol, 69%). ½a D23
ꢂ
¼ þ16:4 (c 4.80, CHCl3); 1H NMR: d 1.31
1.77, CHCl3, (4S,5S)-9g, 99%ee); 1H NMR:
d 1.13 (3H, d,
(3H, d, J = 6.0 Hz), 2.03 (3H, s), 3.70 (3H, s), 3.70–3.78 (1H, m),
3.76 (3H, s), 4.89 (1H, dq, J = 8.0, 6.0 Hz), 5.70 (1H, d,
J = 15.6 Hz), 6.65–6.70 (2H, m), 6.85–6.92 (2H, m), 7.62 (2H, d,
J = 8.0 Hz) 7.68 (2H, d, J = 8.0 Hz); 13C NMR: d 19.8, 19.9, 48.7,
51.5, 55.1, 82.0, 111.9, 116.4, 123.1, 128.0, 128.4, 128.6, 129.1
(2C), 132.3 (2C), 135.7, 137.1 146.3, 158.4, 166.1; IR: 1719,
1655, 1608, 1576, 1504, 1185, 1173, 894 cmꢀ1; HR-EI-MS calcd
for C21H23O6SBr: 482.0399, 484.0378; found: 482.0353 (97.4%),
484.0377 (100%).
J = 6.4 Hz), 2.05 (3H, s), 3.47 (1H, dd, J = 8.0, 8.4 Hz), 3.72 (3H, s),
3.86 (3H, s), 3.88 (3H, s), 5.22 (1H, qd, J = 6.4, 8.0 Hz), 5.84 (1H, d,
J = 15.6 Hz), 6.70 (1H, d, J = 2.0 Hz), 6.76 (1H, dd, J = 2.0, 8.0 Hz),
6.84 (1H, d, J = 8.0 Hz), 7.14 (1H, dd, J = 8.4, 15.6 Hz); 13C NMR: d
18.4, 21.0, 51.3, 53.6, 55.7, 55.7, 72.2, 110.9, 111.3, 120.3, 122.4,
131.1, 147.5, 148.1, 149.1 166.4, 170.2; IR: 1722, 1654, 1622,
1517, 1237 cmꢀ1; HR-EI-MS calcd for C17H22O6: 322.1416; found:
322.1421. Ee of 9g was determined by HPLC analysis after 9g
was converted to 1g by methanolysis using K2CO3.

M. Fujii et al. / Tetrahedron: Asymmetry 20 (2009) 1286–1294
1293
4.3.3. (4S,5S)-Methyl 5-(4-bromobenzenesulfonyloxy)-4-(2-me-
thoxy-4-methylphenyl)hex-2(E)-enoate (4S,5S)-13c
8.2 Hz), 6.75 (1H, d, J = 8.2 Hz), 6.98 (1H, dd, J = 9.2, 15.6 Hz),
7.61 (2H, d, J = 8.8 Hz) 7.65 (2H, d, J = 8.8 Hz); 13C NMR: d 20.6,
52.3, 54.4, 57.5, 57.6, 82.8, 111.8, 112.1, 120.9, 124.5, 129.4,
129.7 (2C), 130.8, 133.0 (2C), 137.5, 146.3, 149.3, 149.9, 166.8.
IR: 1720, 1655, 1518, 1244, 1186 cmꢀ1; HR-EI-MS calcd for
C21H23O7SBr: 498.0348, 500.0327; found: 498.0338 (100%),
500.0323 (98.1%).
From (4S,5S)-1c (140 mg, 0.56 mmol) to (4S,5S)-13c (252 mg,
0.525 mmol, 94%). ½a D23
ꢂ
¼ þ3:7 (c 2.96, CHCl3); 1H NMR: d 1.35
(3H, d, J = 6.0 Hz), 2.32 (3H, s), 3.71 (6H, s), 3.71–3.81 (1H, m),
5.01 (1H, dq, J = 6.4, 6.0 Hz), 5.77 (1H, d, J = 15.8 Hz), 6.55 (1H, s),
6.63 (1H, d, J = 8.0 Hz), 6.85 (1H, d, J = 8.0 Hz), 7.04 (1H, dd,
J = 8.2, 15.8 Hz), 7.53 (2H, d, J = 8.4 Hz), 7.66 (2H, d, J = 8.4 Hz);
13C NMR: d 20.1, 21.4, 48.5, 51.5, 55.1, 81.0, 111.6, 121.2, 123.1,
123.8, 128.3, 129.0, 129.1 (2C), 132.0 (2C), 135.4, 138.9, 145.3,
156.0, 166.2. IR: 1732, 1657, 1610, 1575, 1515, 1274, 1185,
904 cmꢀ1. HR-EI-MS calcd for C21H23O6SBr: 482.0399, 484.0378;
found: 482.0226 (94.7%), 484.0234 (100%).
4.3.8. (4S,5S)-Methyl 5-(4-bromobenzenesulfonyloxy)-4-(2,
5-dimethoxy-4-methylphenyl)hex-2(E)-enoate (4S,5S)-13h
From (4S,5S)-1h (4.33 g, 14.7 mmol) to (4S,5S)-13h (6.32 mg,
12.3 mmol, 84%). ½a D23
ꢂ
¼ ꢀ0:6 (c 1.03, CHCl3) 1H NMR: d 1.35 (3H,
d, J = 6.4 Hz), 2.19 (3H, s), 3.69 (3H, s), 3.72 (3H, s), 3.73 (3H, s),
3.72–3.80 (1H, m), 5.04 (1H, dq, J = 7.2, 6.4 Hz), 5.79 (1H, d,
J = 15.6 Hz), 6.42 (1H, s), 6.57 (1H, s), 6.98 (1H, dd, J = 9.2,
15.6 Hz), 7.54 (2H, d, J = 9.2 Hz) 7.57 (2H, d, J = 9.2 Hz); 13C NMR:
d 16.3, 20.2, 51.6, 55.8, 56.1, 81.3, 113.7, 114.0, 123.8, 124.0,
126.9, 128.5, 129.1 (2C), 132.1 (2C), 135.7, 145.3, 150.0, 151.7,
166.3; IR: 1721, 1656, 1576, 1508, 1212, 1187 cmꢀ1 HR-EI-MS
calcd for C22H25O7SBr: 512.0504, 514.0484; found: 512.0518
(100%), 514.0490 (99.2%).
4.3.4. (4S,5S)-Methyl 5-(4-bromobenzenesulfonyloxy)-4-(4-me-
thoxy-3-methylphenyl)hex-2(E)-enoate (4S,5S)-13d
From (4S,5S)-1d (350 mg, 1.33 mmol) to (4S,5S)-13d (452 mg,
1.18 mmol, 89%). ½a D23
ꢂ
¼ þ22:6 (c 1.62, CHCl3); 1H NMR: d 1.31
(3H, d, J = 6.4 Hz), 2.15 (3H, s), 3.44 (1H, dd, J = 9.0, 8.4 Hz), 3.71
(3H, s), 3.79 (3H, s), 4.86 (1H, dq, J = 8.4, 6.4 Hz), 5.76 (1H, d,
J = 15.4 Hz), 6.68 (1H, d, J = 8.0 Hz), 6.81 (1H, d, J = 2.0 Hz), 6.85
(1H, dd, J = 2.0, 8.0 Hz), 6.96 (1H, dd, J = 9.0, 15.4 Hz), 7.58 (2H, d,
J = 8.4 Hz), 7.63 (2H, d, J = 8.4 Hz); 13C NMR: d 16.2, 19.9, 51.5,
53.3, 55.2, 82.3, 110.0, 123.4, 126.3, 137.2, 128.5, 129.0 (2C),
129.2, 130.0, 132.2 (2C), 135.7, 146.0, 157.1, 166.1; IR: 1720,
1655, 1609, 1576, 1505, 1254, 1186, 1174, 904 cmꢀ1; HR-EI-MS
calcd for C21H23O6SBr: 482.0399, 484.0378; found: 482.0296
(97.7%), 484.0249 (100%).
4.4. Solvolysis of 13
A solution of 13 (0.6 mmol) in water-saturated nitromethane
(30 mL) was stirred for 2 days [6 h for (4S,5S)-13b, 35 h for
(4S,5S)-13c] at 50 °C. To the reaction mixture was added saturated
aq NaHCO3 (1 mL) and the resulting mixture was evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (silica gel 15 g, n-hexane/AcOEt = 4/1) to afford
3. The results are listed in Table 2.
4.3.5. (4S,5S)-Methyl 5-(4-bromobenzenesulfonyloxy)-4-(2-me-
thoxy-5-methylphenyl)hex-2(E)-enoate (4S,5S)-13e
From (4S,5S)-1e (382 mg, 1.25 mmol) to (4S,5S)-13e (555 mg,
1.15 mmol, 92%). ½a D23
ꢂ
¼ ꢀ5:5 (c 1.23, CHCl3); 1H NMR: d 1.31
4.4.1. (4S,5S)-Methyl 4-hydroxy-5-(4-methoxyphenyl)hex-2(E)-
enoate (4S,5S)-3a
From (4S,5S)-13a (311 mg, 0.665 mmol) to (4S,5S)-3a (153 mg,
0.613 mmol, 92%) and (4S,5S)-1a (12.0 mg, 0.048 mmol, 7.2%).
(3H, d, J = 6.4 Hz), 2.17 (3H, s), 2.29 (3H, s), 3.69 (6H, s), 3.71–
3.77 (1H, m), 5.02 (1H, dq, J = 6.4, 6.8 Hz), 5.74 (1H, d,
J = 15.6 Hz), 6.62 (1H, d, J = 8.0 Hz), 6.72 (1H, d, J = 2.0 Hz), 6.95
(1H, dd, J = 2.0, 8.0 Hz), 7.21 (1H, dd, J = 8.8, 15.6 Hz), 7.51 (2H,
d, J = 8.4 Hz) 7.53 (2H, d, J = 8.4 Hz); 13C NMR: d 20.2, 21.0,
48.9, 51.5, 55.3, 81.2, 110.7, 123.9, 125.9 128.5, 128.9, 129.0
(2C), 129.9, 130.0, 132.1 (2C), 135.6, 146.0, 154.2, 166.3; IR:
½
a 2D3
ꢂ
¼ ꢀ12:9 (c 1.01, CHCl3); Lit.2
½
a 2D0
ꢂ
¼ ꢀ14:7 (c 1.00, CHCl3,
(4S,5S)-3a); 1H NMR: d 1.26 (3H, d, J = 7.2 Hz), 2.90 (1H, dq,
J = 6.4,, 7.2 Hz), 3.68 (3H, s), 3.76 (3H, s), 4.31 (1H, br) 4.33 (1H,
ddd, J = 1.6, 4.8, 6.4 Hz), 5.97 (1H, dd, J = 1.6, 15.6 Hz), 6.83 (2H,
d, J = 8.6 Hz), 6.87 (1H, dd, J = 4.8, 15.8 Hz), 7.10 (2H, d,
J = 8.6 Hz); 13C NMR: d 15.5, 44.3, 51.5, 55.2, 75.3, 113.9 (2C),
120.5, 128.8 (2C), 134.4, 148.8, 158.4, 166.9; IR: 3473, 1723,
1658, 1611, 1583, 1513, 1248 cmꢀ1; HPLC analysis: Chiralcel OD-
H, n-hexane/EtOH = 50/1, flow rate; 0.3 mL/min, detection;
254 nm, (4S,5S)-3a; tR = 39.0 min, (4R,5R)-3a; tR = 47.2 min.
1723, 1654, 1576, 1505, 1187 cmꢀ1
. HR-EI-MS calcd for
C21H23O6SBr: 482.0188, 484.0378; found: 482.0321 (96.7%),
484.0187 (100%).
4.3.6. (4S,5S)-Methyl 5-(4-bromobenzenesulfonyloxy)-4-(2,
4-dimethoxyphenyl)hex-2(E)-enoate (4S,5S)-13f
From (4S,5S)-1f (366 mg, 1.20 mmol) to (4S,5S)-13f (425 mg,
0.853 mmol, 71%). ½a D24
ꢂ
¼ ꢀ0:5 (c 2.26, CHCl3); 1H NMR: d 1.33
4.4.2. (4R,5R)-Methyl 4-hydroxy-5-(4-methoxyphenyl)hex-2(E)-
enoate (4R,5R)-3a
(3H, d, J = 6.4 Hz), 3.69 (3H, s), 3.70 (3H, s), 3.70 (3H, s), 3.76
(1H, dd, J = 6.8, 9.6 Hz), 5.02 (1H, dq, J = 6.4, 6.8 Hz), 5.76 (1H, d,
J = 15.6 Hz), 6.50 (1H, d, J = 2.8 Hz), 6.66 (1H, d, J = 8.8 Hz), 6.69
(1H, dd, J = 2.8, 8.8 Hz), 6.98 (1H, dd, J = 9.6, 15.6 Hz), 7.53 (2H,
d, J = 8.8 Hz) 7.56 (2H, d, J = 8.8 Hz); 13C NMR: d 20.3, 48.8, 51.6,
55.6, 55.8, 81.1, 111.6, 112.3, 116.0, 124.2, 127.3, 128.5, 129.1
(2C), 132.2 (2C), 135.6, 144.9, 150.5, 153.5, 166.2. IR: 1720,
From (4R,5R)-13a (312 mg, 0.667 mmol) to (4R,5R)-3a (157 mg,
0.626 mmol, 94%) and (4R,5R)-1a (9.2 mg, 0.037 mmol, 5.5%).
½
a 2D3
ꢂ
¼ þ13:2 (c 1.01, CHCl3).
4.4.3. (4S,5S)-Methyl 4-hydroxy-5-(4-methoxy-2-methylphenyl)
hex-2(E)-enoate (4S,5S)-3b
1655, 1577, 1499, 1225, 1186 cmꢀ1
.
HR-EI-MS calcd for
From (4S,5S)-13b (294 mg, 0.61 mmol) to (4S,5S)-3b (42.0 mg,
0.159 mmol, 26%) and (4S,5S)-1b (119 mg, 0.451 mmol, 74%).
C21H23O7SBr: 498.0348, 500.0327; found; 498.0342 (100%),
500.0321 (99.7%).
½
a 2D0
ꢂ
¼ ꢀ11:7 (c 1.40, CHCl3); 1H NMR: d 1.24 (3H, d, J = 7.2 Hz),
1.92 (1H, br), 2.27 (3H, s), 3.15 (1H, dq, J = 6.0, 7.2 Hz), 3.70 (3H,
s), 3.75 (3H, s), 4.31–4.36 (1H, m), 6.02 (1H, dd, J = 1.6, 15.8 Hz),
6.67–6.73 (2H, m), 6.89 (1H, dd, J = 4.4, 15.8 Hz), 7.12 (1H, d,
J = 8.2 Hz); 13C NMR: d 15.4, 20.0, 39.2, 51.5, 55.1, 74.4, 111.3,
116.2, 120.3, 127.5, 133.1, 137.1, 149.0, 157.9, 166.9; IR: 3446,
1720, 1654, 1608, 1577, 1558, 1504, 1253 cmꢀ1; HR-EI-MS calcd
for C15H20O4: 264.1362; found: 264.1363.
4.3.7. (4S,5S)-Methyl 5-(4-bromobenzenesulfonyloxy)-4-(2,
4-dimethoxyphenyl)hex-2(E)-enoate (4S,5S)-13g
From (4S,5S)-1g (303 mg, 0.99 mmol) to (4S,5S)-13g (360 mg,
0.722 mmol, 73%). ½a D23
ꢂ
¼ þ19:2 (c 1.04, CHCl3); 1H NMR: d 1.31
(3H, d, J = 6.0 Hz), 3.47 (1H, dd, J = 7.2, 9.2 Hz), 3.80 (3H, s), 3.84
(3H, s), 3.86 (3H, s), 4.88 (1H, dq, J = 7.2, 6.0 Hz), 5.79 (1H, d,
J = 15.6 Hz), 6.57 (1H, d, J = 1.6 Hz), 6.62 (1H, dd, J = 1.6,

1294
M. Fujii et al. / Tetrahedron: Asymmetry 20 (2009) 1286–1294
4.4.4. (4S,5S)-Methyl 4-hydroxy-5-(2-methoxy-4-methylphenyl)
hex-2(E)-enoate (4S,5S)-3c
4.4.8. (4S,5S)-Methyl 4-hydroxy-5-(3,4-dimethoxyphenyl)hex-
2(E)-enoate (4S,5S)-3g
From (4S,5S)-13c (252 mg, 0.52 mmol) to (4S,5S)-3c (55.2 mg,
0.209 mmol, 40%) and (4S,5S)-1c (80.0 mg, 0.303 mmol, 58%).
From (4S,5S)-13g (266 mg, 0.534 mmol) to (4S,5S)-3g (130 mg,
0.484 mmol, 87%) and (4S,5S)-1g (15.7 mg, 0.056 mmol, 11%).
½
a 2D0
ꢂ
¼ þ25:1 (c 0.53, CHCl3); Lit ½a D22
ꢂ
¼ þ18:5 (c 0.5, CHCl3); 1H
½
a 2D3
ꢂ
¼ ꢀ12:1 (c 1.21, CHCl3); 1H NMR: d 1.30 (3H, d, J = 7.2 Hz),
NMR: d 1.22 (3H, d, J = 7.2 Hz), 2.15 (1H, br s), 2.32 (3H, s), 3.43
(1H, dq, J = 4.4, 7.2 Hz), 3.70 (3H, s), 3.80 (3H, s), 4.46–4.48 (1H,
m), 6.01 (1H, d, J = 15.6 Hz), 6.68 (1H, s), 6.70 (1H, d, J = 8.0 Hz),
6.39 (1H, dd, J = 4.2, 15.6 Hz), 7.03 (1H, d, J = 8.0 Hz); 13C NMR: d
13.6, 21.4, 37.7, 51.5, 55.3, 74.1, 111.5, 120.1, 121.3, 127.6, 128.0,
137.8, 149.2, 156.6, 167.0; IR: 3464, 1721, 1654, 1612, 1507,
1.98 (1H, br s), 2.94 (1H, dq, J = 5.6, 7.2 Hz), 3.72 (3H, s), 3.86
(3H, s), 3.87 (3H, s), 4.36–4.42 (1H, m), 6.01 (1H, dd, J = 1.6,
15.6 Hz), 6.74 (1H, d, J = 2.0 Hz), 6.77 (1H, dd, J = 2.0, 8.4 Hz), 6.83
(1H, d, J = 8.4 Hz), 6.93 (1H, dd, J = 5.6, 15.6 Hz); 13C NMR: d 15.4,
44.8, 51.5, 55.8, 55.8, 75.2, 111.2, 111.2, 119.8, 120.6, 134.8,
147.9, 148.6, 148.9, 166.8; IR: 3493, 1720, 1516, 1261, 1237,
1145, 1026 cmꢀ1; HR-EI-MS calcd for C15H20O5: 280.1311; found:
280.1321.
1264 cmꢀ1
264.1357.
; HR-EI-MS calcd for C15H20O4: 264.1362; found:
4.4.5. (4S,5S)-Methyl 4-hydroxy-5-(4-methoxy-3-methylphenyl)
hex-2(E)-enoate (4S,5S)-3d
4.4.9. (4S,5S)-Methyl 4-hydroxy-5-(2,5-dimethoxy-4-methyl-
phenyl)hex-2(E)-enoate (4S,5S)-3h
From (4S,5S)-13d (300 mg, 0.623 mmol) to (4S,5S)-3d (155 mg,
From (4S,5S)-13h (315 mg, 0.615 mmol) to (4S,5S)-3h (81.5 mg,
0.554 mmol, 45%) and (4S,5S)-1h (75.5 mg, 0.514 mmol, 42%).
0.589 mmol, 94%) and (4S,5S)-1d (1.6 mg, 0.6 lmol, 0.3%).
½
a 2D1
ꢂ
¼ ꢀ8:4 (c 1.00, CHCl3); 1H NMR: d 1.25 (3H, d, J = 6.4 Hz),
½
a 2D3
ꢂ
¼ ꢀ5:8 (c 1.22, CHCl3); 1H NMR: d 1.25 (3H, d, J = 7.6 Hz),
2.18 (3H, s), 2.25 (1H, br s), 2.86 (1H, dq, J = 6.0, 6.4 Hz), 3.69
(3H, s), 3.80 (3H, s), 4.31–4.35 (1H, m), 6.01 (1H, dd, J = 1.6,
15.6 Hz), 6.74 (1H, d, 7.2 Hz), 6.89 (1H, dd, J = 4.4, 15.6 Hz), 6.95–
6.99 (2H, m); 13C NMR: d 15.4, 16.2, 44.3, 51.4, 55.2, 75.2, 109.9,
120.4, 125.9, 126.6, 130.1, 134.0, 148.9, 156.6, 166.9; IR: 3502,
1719, 1654, 1609, 1545, 1506, 1254 cmꢀ1; HR-EI-MS calcd for
C15H20O4: 264.1362; found: 264.1366.
2.24 (3H, s) 2.34 (1H, d, J = 4.0 Hz), 2.94 (1H, dq, J = 5.6, 7.2 Hz),
3.72 (3H, s), 3.86 (3H, s), 3.87 (3H, s), 4.36–4.42 (1H, m), 6.01
(1H, dd, J = 1.6, 15.6 Hz), 6.74 (1H, d, J = 2.0 Hz), 6.77 (1H, dd,
J = 2.0, 8.4 Hz), 6.83 (1H, d, J = 8.4 Hz), 6.93 (1H, dd, J = 5.6,
15.6 Hz); 13C NMR: d 13.9, 16.1, 38.2, 51.4, 56.1, 56.1, 74.2, 111.2,
114.1, 120.2, 125.7, 128.4, 149.1, 150.1, 151.8, 167.0; IR: 3467,
2951, 1722, 1658, 1505, 1209, 1046 cmꢀ1; HR-EI-MS calcd for
C16H22O5: 294.1467; found: 294.1460.
4.4.6. (4S,5S)-Methyl 4-hydroxy 5-(2-methoxy-5-methylphenyl)
hex-2(E)-enoate (4S,5S)-3e
References
From (4S,5S)-13e (299 mg, 0.62 mmol) to (4S,5S)-3e (43.3 mg,
0.164 mmol, 26%) and (4S,5S)-1e (99.5 mg, 0.377 mmol, 61%).
1. Ehara, T.; Yokoyama, H.; Ono, M.; Akita, H. Heterocycles 2007, 71, 627–634.
2. Ehara, T.; Tanikawa, S.; Ono, M.; Akita, H. Chem. Pharm. Bull. 2007, 55, 1361–
1364.
3. Ono, M.; Ehara, T.; Yokoyama, H.; Ohtani, N.; Hoshino, Y.; Akita, H. Chem.
Pharm. Bull. 2005, 53, 1259–1265.
4. Rompler, H.; Hansel, R.; Kochendoerfer, L. Z. Naturforsch., B 1970, 25, 995.
5. Itokawa, H.; Hirayama, F.; Funakoshi, K.; Takeya, K. Chem. Pharm. Bull. 1985, 33,
3488–3491.
6. McEnroe, F. J.; Fenical, W. Tetrahedron 1978, 34, 1661.
7. Wright, A. E.; Pomponi, S. A.; McConnell, O. J.; Kohmoto, S.; McCarthy, P. J.
J. Nat. Prod. 1987, 50, 976–978.
8. Fuganti, C.; Serra, S. J. Chem. Soc., Perkin Trans. 1 2000, 3764–3785.
9. Minatti, A.; Dötz, K. H. J. Org. Chem. 2005, 70, 3745–3748.
10. Kamal, A.; Malik, M. S.; Shaik, A. A.; Azeeza, S. Tetrahedron: Asymmetry 2007, 18,
2547–2553.
11. Akita, H.; Umezawa, I.; Takano, M.; Ohyama, C.; Matsukura, H.; Oishi, T. Chem.
Pharm. Bull. 1993, 41, 55–63.
12. Akita, H.; Umezawa, I.; Takano, M.; Oishi, T. Chem. Pharm. Bull. 1993, 41, 680–
684.
13. Akita, H.; Umezawa, I.; Takano, M.; Matsukura, H.; Oishi, T. Chem. Pharm. Bull.
1991, 39, 3094–3096.
½
a 2D1
ꢂ
¼ 0 (c 0.78, CHCl3); 1H NMR: d 1.22 (3H, d, J = 7.2 Hz), 2.15
(1H, br s), 2.26 (3H, s), 3.42 (1H, dq, J = 4.4, 7.2 Hz), 3.70 (3H, s),
3.78 (3H, s), 4.49 (1H, dt, J = 2.0, 4.4 Hz), 6.02 (1H, dd, J = 2.0,
15.6 Hz), 6.75 (1H, d, J = 8.2 Hz), 6.93 (1H, dd, J = 4.4, 15.6 Hz),
6.96 (1H, d, 2.0 Hz), 6.99 (1H, dd, J = 2.0, 8.2 Hz); 13C NMR: d
13.5, 20.6, 38.1, 51.4, 55.5, 74.0, 110.6, 120.1, 128.0, 129.0, 129.9,
130.5, 149.2, 154.7, 167.0; IR: 3481, 1719, 1654, 1504,
1242 cmꢀ1
264.1363.
; HR-EI-MS calcd for C15H20O4: 264.1362; found:
4.4.7. (4S,5S)-Methyl 4-hydroxy-5-(2,5-dimethoxyphenyl)hex-
2(E)-enoate (4S,5S)-3f
From (4S,5S)-13f (423 mg, 0.848 mmol) to (4S,5S)-3f (101 mg,
0.313 mmol, 37%) and (4S,5S)-1f (168 mg, 0.522 mmol, 67%).
½
a 2D1
ꢂ
¼ ꢀ4:1 (c 0.60, CHCl3); 1H NMR: d 1.24 (3H, d, J = 7.2 Hz),
14. Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in Organic Synthesis; Wiley-VCH,
2006.
2.34 (1H, br s), 3.54 (1H, dq, J = 4.4, 7.2 Hz), 3.72 (3H, s), 3.76
(3H, s), 3.79 (3H, s), 4.48–4.52 (1H, m), 6.04 (1H, dd, J = 1.6,
15.6 Hz), 6.73 (1H, dd, J = 2.8, 8.8 Hz), 6.77 (1H, d, J = 2.8 Hz), 6.81
(1H, d, J = 8.8 Hz), 6.94 (1H, dd, J = 4.4, 15.6 Hz); 13C NMR: d 13.6,
38.1, 51.5, 55.6, 55.9, 74.0, 111.4, 111.4, 115.0, 120.3, 132.1,
149.0, 151.0, 153.7, 167.0; IR: 3481, 1721, 1657, 1498, 1282,
1217, 1175 cmꢀ1; HR-EI-MS calcd for C15H20O5: 280.1311; found:
280.1313.
15. Ono, M.; Saotome, C.; Akita, H. Tetrahedron: Asymmetry 1996, 7, 2595–2602.
16. (a) Cram, D. J. J. Am. Chem. Soc. 1949, 71, 3871–3875; (b) Cram, D. J. J. Am. Chem.
Soc. 1952, 74, 2159–2165; (c) Cram, D. J. J. Am. Chem. Soc. 1952, 74, 2152–2159;
(d) Cram, D. J.; Elhafez, F. A. A.; Nyquist, H. L. J. Am. Chem. Soc. 1954, 76, 22–28;
(e) Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1954, 76, 28–33; (f) Winstein,
S.; Schereiber, K. C. J. Am. Chem. Soc. 1952, 74, 1113–1120; (g) Winstein, S.;
Morse, B. K.; Grunwald, E.; Schereiber, K. C.; Corse, J. J. Am. Chem. Soc. 1952, 74,
2165–2170.