Enantioselective formal total synthesis of aplysin utilizing a palladium-catalyzed addition of an arylboronic acid to an allenic alcohol - Eschenmoser/Claisen rearrangement

Article abstract of DOI:10.1016/j.tet.2010.04.134

The enantioselective formal total synthesis of aplysin has been achieved utilizing a palladium-catalyzed addition of arylboronic acid to the allenic alcohol followed by the Eschenmoser/Claisen rearrangement as the key steps.

Full text of DOI:10.1016/j.tet.2010.04.134

Tetrahedron 66 (2010) 5053e5058
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Enantioselective formal total synthesis of aplysin utilizing a palladium-catalyzed
addition of an arylboronic acid to an allenic alcoholdEschenmoser/Claisen
rearrangement
*
Masahiro Yoshida , Yasunobu Shoji, Kozo Shishido
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 April 2010
Received in revised form 29 April 2010
Accepted 29 April 2010
Available online 6 May 2010
The enantioselective formal total synthesis of aplysin has been achieved utilizing a palladium-catalyzed
addition of arylboronic acid to the allenic alcohol followed by the Eschenmoser/Claisen rearrangement as
the key steps.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
would potentially provide valuable building blocks for the syn-
theses of natural products having a quaternary carbon center,6 we
Aplysin (1), isolated from the sea hare Aplysia kurodai,1 is rep-
resentative of a class of halogenated sesquiterpenoids, which
exhibits antifeedant properties to protect the host mollusks from
raptorial advances. The sterically congested structure of 1, con-
taining two consecutive quaternary carbon stereocenters, has
attracted considerable synthetic interest (Fig. 1).2
envisioned such an application of this methodology for the syn-
thesis of aplysin (1). Herein, we describe the enantioselective for-
mal total synthesis of 1, utilizing the palladium-catalyzed addition
of an arylboronic acid to an allene followed by the Eschenmoser/
Claisen rearrangement.
2. Results and discussion
Our strategy for aplysin (1) is shown in the retrosynthetic
analysis in Scheme 2. We expected that the dihydrobenzofuran 2,
Fukumoto’s intermediate for the synthesis of 1,2d could be syn-
thesized from the cyclopentenone 3 via an intramolecular oxy-
mercuration. Compound 3 would be obtained by the formation of
a five-membered ring from the amide 4, which would be prepared
by the palladium-catalyzed addition of the arylboronic acid 6 to the
optically active allenic alcohol 5 followed by the Eschenmoser/
Claisen rearrangement.
O
Br
aplysin (1)
Figure 1. Structure of aplysin (1).
The synthesis of the intermediate 4 was carried out as shown in
Scheme 3. Enantioselective reduction of the alkynyl ketone 7 with
the (S)-CBS reagent7 and BH3 followed by the reaction of the
resulting alcohol 8 with LiAlH4 gave the optically active allenic
alcohol 5 in 83% yield with 99% ee.8 When compound 5 was treated
Recently, we have developed an addition of arylboronic acids to
allenic alcohols using
a
palladium catalyst,3 in which aryl-
substituted allylic alcohols having an E-olefin were obtained regio-
and stereoselectively. Furthermore, it was found that a quaternary
carbon center can be stereospecifically created by the Claisen-type
rearrangement4 of the resulting allylic alcohol (Scheme 1), and the
methodology was successfully applied to the enantioselective
synthesis of the enokipodins A and B.5 Since our methodology
with the arylboronic acid
6 in the presence of 5 mol % of
[Pd2(OH)2(PPh3)4][BF4]2 and 5 equiv of Et3N in dioxane/H2O (20:1)
at 80 ꢀC,3 the desired aryl-substituted allylic alcohol 9 was pro-
duced in 74% yield with 95% ee.9 We next examined the Eschen-
moser/Claisen rearrangement of 9 to construct the quaternary
asymmetric center. The reaction successfully proceeded to afford
the corresponding amide 4 having a quaternary asymmetric center
in 84% yield. The enantiomeric excess of 4 was 95%, which indicates
* Corresponding author. Tel./fax: þ81 88 6337294; e-mail address: yoshida@ph.
tokushima-u.ac.jp (M. Yoshida).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.134

5054
M. Yoshida et al. / Tetrahedron 66 (2010) 5053e5058
OH
*
·
O
X
Claisen-type
OH
R
cat. Pd(II)
Rearrangement
+
R
Ar
R
Ar
*
*
ArB(OH)2
Scheme 1. Palladium-catalyzed addition of an arylboronic acid to an allenic alcoholdEschenmoser/Claisen rearrangement.
HO
O
O
O
OMOM
Br
2
aplysin (1)
3
NMe2
OMOM
OMOM
O
OH
(HO)2B
·
+
Ph
Ph
4
5
6
Scheme 2. Retrosynthetic analysis of aplysin (1).
that a highly enantiospecific [3,3]-sigmatropic rearrangement had
proceeded.
using LDA and benzotriazole/methanol,10 the resulting product was
successively hydrogenated to give the -hydroxy ketone 12 (74%
b
The synthetic sequence toward the key intermediate 2 from 4 is
outlined in Scheme 4. Transformation of the amide 4 to the methyl
ketone 10 with MeLi followed by the oxidative cleavage of the
double bond successfully afforded the ketoaldehyde 11. The cyclo-
pentenone 3 was obtained in 94% yield by the intramolecular aldol
condensation of 11 with K2CO3. After hydroxymethylation of 3
yield, two steps). Treatment of 12 with TsCl in pyridine caused the
dehydration to afford the methylenecyclopentanone 13 (83% yield),
which was subjected to the reaction with MeLi in the presence of
CeCl3 leading to the methylated product 14 in 81% yield. The final
stage of the synthesis involves the deprotection of the MOM group
of 14 followed by the cyclization. However, mainly decomposition
(S)-CBS reagent
O
OH
LiAlH4
Ph
BH3
Ph
Ph
THF, –42 ºC
0.5 h, quant
Et2O, 0.5 h
OTHP
OTHP
83%, 99% ee
7
8
OMOM
(HO)2B
OH
OMOM
OH
6
Ph
·
5 mol % [Pd2(OH)2(PPh3)4][BF4]2
5 equiv Et3N, dioxane/H2O (20/1)
80 ºC, 0.5 h, 74%
5
9
NMe2
O
OMOM
MeC(OMe)2NMe2
toluene, reflux, 10 h
84%, 95% ee
Ph
4
Scheme 3. Synthesis of the intermediate 4.

M. Yoshida et al. / Tetrahedron 66 (2010) 5053e5058
5055
NMe2
OMOM
1) OsO4, NMO
acetone-H2O
rt, 10 h
O
O
OMOM
MeLi
Et2O, –78 ºC
1.5 h, 83%
Ph
2) Pb(OAc)4
CH2Cl2, 0 ºC
1 h
Ph
10
4
88% (2 steps)
N
1) LDA;
N
O
N
O
OH
OMOM
OMOM
K2CO3
THF, –78 ºC, 1 h
H
t
2) H2, Pd-C, AcOEt, rt
1 h
BuOH, reflux
10 h, 94%
O
74% (2 steps)
3
11
OH
O
O
TsCl
pyridine, 60 ºC
7 h, 83%
MeLi, CeCl3
OMOM
OMOM
THF, –78 ºC to rt
1 h, 81% (brsm 92%)
13
12
Hg(OCOCF3)2;
HO
HO
NaBH4, NaOH
OH
3
N
HCl
PrOH, 0 ºC, 10 h
40% (80% brsm)
OMOM
i
THF, rt, 4 h, 66%
15
14
HO
O
2
Scheme 4. Synthesis of the dihydrobenzofuran 2.
of 14 was observed in most of the acidic deprotective conditions,
presumably due to the instability of the tertiary allylic alcohol
moiety. After several attempts, the desired product 15 was obtained
in 40% yield (80% yield based on recovered starting material) when
3 N HCl was used in iPrOH at 0 ꢀC for 10 h. The cyclization of 15 was
conducted by the oxymercuration/reduction procedure producing
the dihydrobenzofuran 2 in 66% yield. The spectroscopic data of our
sample of synthetic 2 were completely identical with those pre-
viously reported.2d
4. Experimental
4.1. General
All nonaqueous reactions were carried out under a positive at-
mosphere of argon in dried glassware unless otherwise indicated.
Materials were obtained from commercial suppliers and used
without further purification except when otherwise noted. Solvents
were dried and distilled according to standard protocols. The phrase
‘residue upon workup’ refers to the residue obtained when the
organic layer was separated and dried over anhydrous MgSO4, and
the solvent was evaporated under reduced pressure. Column chro-
matography was performed on silica gel, and flash column chro-
matography was performed on silica gel using the indicated solvent.
3. Conclusion
In conclusion, we have completed the enantioselective formal
total synthesis of aplysin, in which the enantioselective construc-
tion of the quaternary carbon center using a palladium-catalyzed
addition of an arylboronic acid to an allene followed by an
Eschenmoser/Claisen rearrangement has been successfully applied.
4.1.1. (S)-1-Phenyl-4-(tetrahydropyran-2-yloxy)-but-2-yn-1-ol (8).
To a stirred solution of 1-phenyl-4-(tetrahydropyran-2-yloxy)-but-
2-yn-1-one 7 (6.34 g, 25.8 mmol) in THF (100 mL) was added

5056
M. Yoshida et al. / Tetrahedron 66 (2010) 5053e5058
dropwise 1.0 M solution of (S)-2-methyl-CBS-oxazaborolidine in
toluene (25.8 mL, 25.8 mmol) at rt. After stirring was continued for
10 min at ꢁ42 ꢀC, 1.0 M solution of BH3 in THF (118 mL, 129 mmol)
was added dropwise to the reaction mixture at the same temper-
ature. After stirring was continued for 30 min, the reaction mixture
was quenched with EtOH. The residue upon evaporation was
chromatographed on silica gel with hexane/AcOEt (75:25 v/v) as
eluent to give (S)-propargylic alcohol 8 (6.35 g, quant) as a yellow
isopropanol/hexane, 0.5 mL/min,
17.7 min (R), and 20.9 min (S)].
l
¼254 nm, retention times
4.1.5. (S)-3-(2-Methoxymethoxy-4-methylphenyl)-3-methyl-5-phe-
nylpent-4-enoic acid dimethylamide (4). To a stirred solution of al-
lylic alcohol 9 (2.50 g, 8.38 mmol) in toluene (90 mL) was added N,
N-dimethylacetamide dimethylacetal (12.3 mL, 83.8 mmol) at rt.
After being refluxed for 10 h, the solvent was removed in vacuo. The
residue was chromatographed on silica gel with hexane/AcOEt
oil; [
a
]
D
27 ꢁ9.67 (c 1.0 in CHCl3). Other spectral data coincides with
those of the enantiomer of 8.5
(75:25 v/v) as eluent to give amide 4 (2.55 g, 84%, 95% ee) as
27
a yellow oil; [
a
]
ꢁ13.0 (c 1.0 in CHCl3); IR (neat): 2933, 1649,
D
4.1.2. (R)-1-Phenyl-2,3-butadiene-1-ol (5). To a stirred suspension
of LiAlH4 (1.17 g, 30.7 mmol) in Et2O (150 mL) was added dropwise
a solution of (S)-propargylic alcohol 8 (6.31 g, 25.6 mmol) in Et2O
(50 mL) at 0 ꢀC. After being refluxed for 30 min, the reaction
mixture was treated with minimum amount of cold water and
filtered through a pad of Celite. The residue upon workup was
chromatographed on silica gel with hexane/AcOEt (85:15 v/v) as
1014 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
1.71 (3H, s), 2.31 (3H, s),
2.85 (3H, s), 2.92 (3H, s), 3.06 (1H, d, J¼14.4 Hz), 3.14 (1H, d,
J¼14.4 Hz), 3.39 (3H, s), 5.11 (1H, d, J¼6.8 Hz), 5.14 (1H, d, J¼6.8 Hz),
6.24 (1H, d, J¼16.4 Hz), 6.80 (1H, dd, J¼0.8 and 8.0 Hz), 6.84 (1H, d,
J¼16.4 Hz), 6.92 (1H, d, J¼0.8 Hz), 7.16 (1H, t, J¼7.2 Hz), 7.20e7.30
(3H, m), 7.34 (2H, d, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3)
d 21.1
(CH3), 25.8 (CH3), 35.4 (CH3), 37.7 (CH3), 41.9 (CH2), 42.6 (Cq), 56.1
(CH3), 94.6 (CH2), 115.6 (CH), 122.4 (CH), 125.9 (CH), 126.0 (CH),
126.7 (CH), 127.9 (CH), 128.4 (CH), 132.3 (Cq), 137.7 (Cq), 138.0 (Cq),
139.1 (CH), 155.2 (Cq), 171.3 (Cq); HRMS (ESI) m/z calcd for
C23H30NO3 [MþH]þ 368.2226, found 368.2223. Enantiomeric
excess was determined by HPLC analysis [CHIRALCEL AS-H column,
eluent to give allenic alcohol 5 (3.12 g, 83%, 99% ee) as a colorless
27
oil;
[
a]
ꢁ34.1 (c 1.2 in CHCl3). Enantiomeric excess was
D
determined by HPLC analysis [CHIRALCEL OD-H column, 10% iso-
propanol/hexane, 0.5 mL/min,
l¼254 nm, retention times 16.9 min
(R), and 20.3 min (S)]. Other spectral data coincides with those of
the enantiomer of 5.5
10% isopropanol/hexane, 0.5 mL/min,
33.1 min (R), and 44.5 min (S)].
l¼254 nm, retention times
4.1.3. 2-Methoxymethoxy-4-methylphenylboronic acid (6). To a stir-
red solution of 1-(methoxymethoxy)-3-methylbenzene (484 mg,
3.18 mmol) in Et2O (20 mL) and TMEDA (0.57 mL, 3.82 mmol) was
added dropwise 0.45 M solution of sBuLi in hexane (8.5 mL,
3.82 mmol) at ꢁ78 ꢀC. After stirring was continued for 2 h, tri-
methyl borate (0.71 mL, 6.36 mmol) was added dropwise to this
reaction mixture at the same temperature and stirring was con-
tinued for 21 h at rt. The reaction mixture was quenched with 2 N
HCl to pH 6 and extracted with AcOEt. The combined extracts were
washed with brine, and the residue upon workup was recrystal-
lized from hexane/AcOEt to give boronic acid 6 (268 mg, 43%) as
white needles; mp 77.6e80.1 ꢀC (recrystallized from AcOEt/hex-
4.1.6. (S)-4-(2-Methoxymethoxy-4-methylphenyl)-4-methyl-6-phe-
nylhex-5-en-2-one (10). To a stirred solution of amide 4 (656 mg,
1.79 mmol) in Et2O (20 mL) was added dropwise 2.5 M solution of
MeLi in diethoxymethane (0.86 mL, 2.14 mmol) at ꢁ78 ꢀC. After
stirring was continued for 1.5 h at the same temperature, the
reaction mixture was quenched with saturated aqueous NH4Cl
solution and extracted with Et2O. The combined extracts were
washed with brine, and the residue upon workup was chromato-
graphed on silica gel with hexane/AcOEt (91:9 v/v) as eluent to give
27
ketone 10 (500 mg, 83%) as a colorless oil; [
a
]
D
ꢁ44.5 (c 1.0 in
CHCl3); IR (neat): 2916,1703,1503 cmꢁ1; 1H NMR (400 MHz, CDCl3)
ane); IR (KBr): 3398, 1609, 1157, 820 cmꢁ1
;
1H NMR (400 MHz,
d
1.62 (3H, s), 1.91 (3H, s), 2.31 (3H, s), 3.08 (1H, d, J¼14.8 Hz), 3.38
CDCl3)
d
2.37 (3H, s), 3.51 (3H, s), 5.29 (2H, s), 6.04 (2H, s), 6.90 (1H,
(1H, d, J¼14.8 Hz), 3.42 (3H, s), 5.13 (1H, d, J¼6.4 Hz), 5.16 (1H, d,
J¼6.4 Hz), 6.26 (1H, d, J¼16.4 Hz), 6.68 (1H, d, J¼16.4 Hz), 6.79 (1H,
dd, J¼0.8 and 7.6 Hz), 6.93 (1H, d, J¼0.8 Hz), 7.15e7.21 (1H, m), 7.18
(1H, t, J¼7.2 Hz), 7.27 (2H, t, J¼7.2 Hz), 7.34 (2H, d, J¼7.2 Hz); 13C
d, J¼7.6 Hz), 6.95 (1H, s), 7.73 (1H, d, J¼7.6 Hz); 13C NMR (100 MHz,
CDCl3)
d 21.9 (CH3), 56.5 (CH3), 94.6 (CH2), 114.1 (CH), 123.1 (CH),
136.6 (CH), 142.8 (Cq), 143.6 (Cq), 162.5 (Cq); HRMS (ESI) m/z calcd
for C9H13O4NaB [MþNa]þ 219.0805, found 219.0806.
NMR (100 MHz, CDCl3) d 21.1 (CH3), 25.8 (CH3), 31.5 (CH3), 42.1 (Cq),
52.7 (CH2), 56.2 (CH3), 94.5 (CH2), 115.6 (CH), 122.4 (CH), 126.1 (CH),
126.2 (CH), 126.9 (CH), 127.9 (CH), 128.5 (CH), 131.2 (Cq), 137.8 (Cq),
138.0 (Cq), 138.7 (CH), 155.3 (Cq), 208.0 (Cq); HRMS (ESI) m/z calcd
for C22H27O3 [MþH]þ 339.1960, found 339.1962.
4.1.4. (R)-3-(2-Methoxymethoxy-4-methylphenyl)-1-phenylbut-2-
en-1-ol (9). To a stirred solution of allenic alcohol 5 (2.00 g,
13.7 mmol) in 1,4-dioxane/water (20:1) (105 mL) were added
arylboronic acid 6 (3.49 g, 17.8 mmol), Et3N (9.53 mL, 68.4 mmol),
and [Pd2(OH)2(PPh3)4][BF4]2 (1.01 g, 0.684 mmol) at rt. After stir-
ring was continued for 30 min at 80 ꢀC, the reaction mixture was
diluted with AcOEt and dried over MgSO4. After filtration of the
mixture through a pad of silica gel, the residue upon evaporation of
the solvent was chromatographed on silica gel with hexane/AcOEt
4.1.7. (R)-2-(2-Methoxymethoxy-4-methylphenyl)-2-methyl-4-ox-
opentanal (11). To
a stirred solution of ketone 10 (499 mg,
1.47 mmol) in acetone/water (6:1) (21 mL) were added a catalytic
amount of OsO4 and NMO (181 mg, 1.62 mmol) at rt. After stirring
was continued for 10 h, the reaction mixture was quenched with
saturated aqueous Na2S2O3 solution and extracted with AcOEt. The
combined extracts were washed with brine, and the residue upon
workup was chromatographed on silica gel with hexane/AcOEt
(20:80 v/v) as eluent to give diol (549 mg) as a colorless oil. To
a stirred solution of this diol (549 mg) in CH2Cl2 (15 mL) was added
Pb(OAc)4 (654 mg, 1.47 mmol) at 0 ꢀC. After stirring was continued
for 1 h at the same temperature, the reaction mixture was filtrated
through a pad of Celite. The residue upon evaporation of the solvent
was chromatographed on silica gel with hexane/AcOEt (86:14 v/v)
(85:15 v/v) as eluent to give allylic alcohol 9 (3.03 g, 74%, 95% ee) as
27
a yellow oil; [
a
]
þ7.08 (c 1.1 in CHCl3); IR (neat): 3388, 3028,
D
1610 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.90 (1H, d, J¼2.4 Hz), 2.14
(3H, d, J¼0.8 Hz), 2.32 (3H, s), 3.42 (3H, s), 5.11 (1H, d, J¼6.8 Hz),
5.14 (1H, d, J¼6.8 Hz), 5.63 (1H, dd, J¼2.4 and 8.8 Hz), 5.71 (1H, dd,
J¼0.8 and 8.8 Hz), 6.77 (1H, d, J¼7.6 Hz), 6.89 (1H, s), 7.03 (1H, d,
J¼7.6 Hz), 7.28 (1H, t, J¼7.6 Hz), 7.36 (2H, t, J¼7.6 Hz), 7.47 (2H, d,
J¼7.6 Hz); 13C NMR (100 MHz, CDCl3)
d 17.8 (CH3), 21.3 (CH3), 56.1
(CH3), 70.7 (CH), 94.6 (CH2), 115.5 (CH), 122.5 (CH), 126.1 (CH), 127.4
(CH), 127.4 (Cq), 128.4 (CH), 129.3 (CH), 131.7 (CH), 137.2 (Cq), 138.5
(Cq), 143.7 (Cq), 154.0 (Cq); HRMS (ESI) m/z calcd for C19H23O3
[MþH]þ 299.1647, found 299.1643. Enantiomeric excess was de-
termined by HPLC analysis [CHIRALCEL AS-H column, 10%
as eluent to give ketoaldehyde 11 (342 mg, 88%, two steps) as
27
a colorless oil; [
a
]
ꢁ116 (c 1.1 in CHCl3); IR (neat): 2937, 1715,
D
1612 cmꢁ1; 1H NMR (400 MHz, CDCl3)
(3H, s), 3.08 (1H, d, J¼16.4 Hz), 3.17 (1H, d, J¼16.4 Hz), 3.46 (3H, s),
d 1.51 (3H, s),1.97 (3H, s), 2.33

M. Yoshida et al. / Tetrahedron 66 (2010) 5053e5058
5057
5.13 (1H, d, J¼6.4 Hz), 5.16 (1H, d, J¼6.4 Hz), 6.85 (1H, dd, J¼0.8 and
7.6 Hz), 6.96 (1H, d, J¼0.8 Hz), 7.13 (1H, d, J¼7.6 Hz), 9.61 (1H, s); 13C
J¼6.8 Hz), 5.97 (1H, s), 6.77 (1H, dd, J¼0.8 and 8.0 Hz), 6.92 (1H, d,
J¼0.8 Hz), 7.20 (1H, d, J¼8.0 Hz); 13C NMR (100 MHz, CDCl3)
d 21.1
NMR (100 MHz, CDCl3)
d
20.1 (CH3), 21.3 (CH3), 31.2 (CH3), 48.6
(CH3), 28.0 (CH3), 34.0 (CH2), 36.2 (CH2), 45.5 (Cq), 56.1 (CH3), 93.9
(CH2), 115.2 (CH), 115.6 (CH2), 121.6 (CH), 126.6 (CH), 133.2 (Cq),
138.0 (Cq), 154.4 (Cq), 155.0 (Cq), 207.7 (Cq); HRMS (ESI) m/z calcd
for C16H21O3 [MþH]þ 261.1491, found 261.1492.
(CH2), 50.0 (Cq), 56.4 (CH3), 94.3 (CH2), 114.8 (CH), 122.8 (CH), 126.6
(Cq), 127.9 (CH), 139.3 (Cq), 154.2 (Cq), 202.7 (Cq), 207.0 (Cq); HRMS
(ESI) m/z calcd for C15H21O4 [MþH]þ 265.1440, found 265.1435.
4.1.8. (S)-4-(2-Methoxymethoxy-4-methylphenyl)-4-methyl-2-cyclo-
pentenone (3). To a stirred solution of ketoaldehyde 11 (342 mg,
1.29 mmol) in tBuOH (30 mL) was added K2CO3 (894 mg, 6.47 mmol)
at rt. After being refluxed for 10 h, the reaction mixture was diluted
with Et2O and filtered through a pad of Celite. The residue upon
evaporation of the solvent was chromatographed on silica gel with
4.1.11. (1S,3R)-3-(2-Methoxymethoxy-4-methylphenyl)-1,3-di-
methyl-2-methylenecyclopentanol (14). To a stirred suspension of
CeCl3 (142 mg, 0.576 mmol) in THF (6 mL) was added dropwise
1.0 M solution of MeLi in Et2O (0.58 mL, 0.576 mmol) at ꢁ78 ꢀC.
After stirring was continued for 1 h, enone 13 (30.0 mg,
0.115 mmol) in THF (4 mL) was added dropwise at the same tem-
perature. After stirring was continued for 1 h at the same temper-
ature, the reaction mixture was quenched with water and extracted
with Et2O. The combined extracts were washed with brine, and the
residue upon workup was chromatographed on silica gel with
hexane/AcOEt (88:12 v/v) as eluent to give alcohol 14 (25.7 mg,
hexane/AcOEt(87:13v/v)aseluenttogivecyclopentenone 3(298 mg,
27
94%) as a colorless oil; [
a
]
ꢁ65.3 (c 1.1 in CHCl3); IR (neat): 2922,
D
1714, 1015 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.59 (3H, s), 2.32 (3H, s),
2.58(1H, d, J¼18.8 Hz), 2.78(1H, d, J¼18.8 Hz), 3.46(3H, s), 5.15 (1H, d,
J¼6.8 Hz), 5.18 (1H, d, J¼6.8 Hz), 6.17 (1H, d, J¼5.6 Hz), 6.77 (1H, d,
J¼8.0 Hz), 6.95 (1H, s), 7.06 (1H, d, J¼8.0 Hz), 7.79 (1H, d, J¼5.6 Hz);
81%) as a colorless oil and some starting material was recovered
28
13C NMR (100 MHz, CDCl3)
d
21.0 (CH3), 27.2 (CH3), 46.8 (Cq), 50.1
(3.7 mg, 12%); [
a]
ꢁ66.1 (c 0.85 in CHCl3); IR (neat): 3558, 2966,
D
(CH2), 56.1 (CH3), 93.7 (CH2), 115.0 (CH), 121.8 (CH), 126.3 (CH), 130.1
(Cq), 131.0 (CH), 138.2 (Cq), 154.9 (Cq), 170.7 (CH), 209.8 (Cq); HRMS
(ESI) m/z calcd for C15H19O3 [MþH]þ 247.1334, found 247.1336.
927 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 1.42 (3H, s), 1.47 (3H, s),
1.52e1.64 (1H, m), 1.88e1.99 (2H, m), 2.32 (3H, s), 2.44e2.53 (1H,
m), 3.34 (1H, s), 3.47 (3H, s), 4.66 (1H, s), 5.14 (1H, d, J¼6.8 Hz), 5.18
(1H, s), 5.22 (1H, d, J¼6.8 Hz), 6.81 (1H, dd, J¼0.8 and 8.0 Hz), 6.92
(1H, d, J¼0.8 Hz), 7.35 (1H, d, J¼8.0 Hz); 13C NMR (100 MHz, CDCl3)
4.1.9. (2R,3R) and (2S,3R)-2-Hydroxymethyl-3-(2-methoxymethoxy-
4-methylphenyl)-3- methylcyclopentanone (12) (ratio of 1:1). To
d 21.1 (CH3), 27.0 (CH3), 28.5 (CH3), 36.7 (CH2), 40.1 (CH2), 48.8 (Cq),
i
a stirred solution of Pr2NH (0.085 mL, 0.609 mmol) in THF (3 mL)
56.7 (CH3), 78.7 (Cq), 94.5 (CH2), 106.8 (CH2), 115.4 (CH), 122.1 (CH),
127.83 (CH), 133.4 (Cq), 137.6 (Cq), 154.2 (Cq), 166.4 (Cq); HRMS
(ESI) m/z calcd for C17H24O3 [M]þ 276.1725, found 276.1728.
was added dropwise 1.5 M solution of nBuLi in hexane (0.41 mL,
0.609 mmol) at ꢁ78 ꢀC. After stirring was continued for 1.5 h,
cyclopentenone 3 (50.0 mg, 0.203 mmol) in THF (2 mL) was added
dropwise to this reaction mixture at the same temperature. After
stirring was continued for 2 h, benzotriazole/methanol (150 mg,
1.02 mmol) was added to this reaction mixture, and further stirring
was continued for 1 h at the same temperature. The reaction mix-
ture was quenched with water and extracted with Et2O. The com-
bined extracts were washed with brine, and the residue upon
workup was diluted with AcOEt (5 mL) and treated with Pd/C
(5.6 mg, 10%) at rt. After stirring was continued under a hydrogen
atmosphere for 1 h, the reaction mixture was filtered through a pad
of Celite. The residue upon evaporation was chromatographed on
4.1.12. (1S,3R)-3-(2-Hydroxy-4-methylphenyl)-1,3-dimethyl-2-meth-
ylidenecyclopentanol (15). To a stirred solution of MOM ether 14
i
(5.4 mg, 0.020 mmol) in PrOH (2 mL) was added 3 N HCl (0.5 mL)
at 0 ꢀC. After stirring was continued for 30 h at the same temper-
ature, the reaction mixture was extracted with Et2O and washed
with brine. The residue upon workup was chromatographed on
silica gel with hexane/AcOEt (88:12 v/v) as eluent to give phenol 15
(1.8 mg, 40%) as a colorless oil and some starting material was
28
recovered (2.7 mg, 50%); [
a
]
D
ꢁ66.1 (c 0.85 in CHCl3); IR (neat):
3354, 2966, 910 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d 1.44 (3H, s),
silica gel with hexane/AcOEt (80:20 v/v) as eluent to give
b
-hydroxy
1.50e2.35 (3H, m), 1.57 (3H, s), 2.28 (3H, s), 2.44e2.55 (1H, m), 4.83
(1H, s), 5.23 (1H, s), 6.68 (1H, s), 6.69 (1H, d, J¼8.0 Hz), 7.26 (1H, d,
ketone 12 (42.0 mg, 74% as a 1:1 mixture, two steps) as a colorless
oil; [
a
]
27 þ50.3 (c 1.1 in CHCl3); IR (neat) 3458, 2953, 1731 cmꢁ1; 1H
J¼8.0 Hz); 13C NMR (100 MHz, CDCl3)
d 20.7 (CH3), 26.2 (CH3), 28.9
D
NMR (400 MHz, CDCl3)
d
1.29 (1.5H, s), 1.44 (1.5H, s), 2.04 (0.5H, br
(CH3), 36.1 (CH2), 39.4 (CH2), 47.8 (Cq), 80.2 (Cq), 108.9 (CH2), 118.5
(CH), 120.1 (CH), 126.9 (CH), 129.9 (Cq), 138.0 (Cq), 153.9 (Cq), 164.0
(Cq); HRMS (ESI) m/z calcd for C15H21O2 [MþH]þ 233.1542, found
233.1543.
s), 2.11e2.18 (0.5H, m), 2.28e2.57 (3.5H, m), 2.33 (3H, s), 2.76 (0.5H,
dd, J¼4.0 and 8.4 Hz), 2.93 (0.5H, br s), 3.20 (0.5H, dd, J¼4.0 and
8.4 Hz), 3.35e3.43 (0.5H, m), 3.49 (1.5H, s), 3.50 (1.5H, s), 3.45e3.55
(0.5H, m), 3.72 (0.5H, ddd, J¼2.4, 8.4, and 11.2 Hz), 3.90 (0.5H, ddd,
J¼2.8, 8.4, and 11.2 Hz), 5.16 (0.5H, d, J¼6.8 Hz), 5.20 (0.5H, d,
J¼6.8 Hz), 5.25 (1H, s), 6.80 (0.5H, dd, J¼0.8 and 8.0 Hz), 6.82 (0.5H,
dd, J¼0.8 and 8.0 Hz), 6.95 (0.5H, d, J¼0.8 Hz), 6.98 (0.5H, d,
J¼0.8 Hz), 7.13 (0.5H, d, J¼8.0 Hz), 7.16 (0.5H, d, J¼8.0 Hz); HRMS
(ESI) m/z calcd for C16H23O4 [MþH]þ 279.1596, found 279.1594.
4.1.13. (3S,3aR,8bS)-(ꢁ)-2,3,3a,8b-Tetrahydro-3-hydroxy-3,3a,6,8b-
tetramethyl-1H-cyclopenta[b]benzofuran (2). To a stirred solution of
phenol 15 (10 mg, 0.044 mmol) in THF (5 mL) was added Hg
(OCOCF3)2 (19 mg, 0.044 mmol) at rt. After stirring was continued
for 4 h, the reaction mixture was treated with aqueous 10% NaOH
(0.6 mL) and NaBH4 (8.8 mg, 0.23 mmol) successively, and satu-
rated with NaCl. This mixture was diluted with AcOEt and filtrated
through silica gel. The residue upon evaporation of the solvent was
chromatographed on silica gel with hexane/AcOEt (90:10 v/v) as
eluent to give dihydrobenzohuran 2 (6.7 mg, 66%) as a colorless oil;
4.1.10. (S)-3-(2-Methoxymethoxy-4-methylphenyl)-3-methyl-2-
methylenecyclopentanone (13). To a stirred solution of b-hydroxy
ketone 12 (453 mg, 1.63 mmol) in pyridine (20 mL) was added TsCl
(1.55 g, 8.14 mmol) at rt. After stirring was continued for 7 h at
60 ꢀC, the reaction mixture was diluted with water and extracted
with AcOEt. The combined extracts were washed with brine, and
the residue upon workup was chromatographed on silica gel with
hexane/AcOEt (90:10 v/v) as eluent to give enone 13 (353 mg, 83%)
28
25
[a
]
ꢁ8.0 (c 0.60 in CHCl3) [lit., [
a]
ꢁ6.6 (c 0.56 in CHCl3)];2d IR
D
D
(neat): 3568, 2954, 1500 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 1.23
(3H, s), 1.25 (3H, s), 1.36 (3H, s), 1.52e1.79 (4H, m), 2.30 (3H, s), 2.77
(1H, d, J¼0.8 Hz), 6.57 (1H, t, J¼0.8 Hz), 6.71 (1H, dq, J¼0.8 and
as a colorless oil; [
a
]
27 ꢁ156 (c 1.0 in CHCl3); IR (neat): 2960, 1722,
7.6 Hz), 6.93 (1H, d, J¼7.6 Hz); 13C NMR (100 MHz, CDCl3)
d 15.5
D
928 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.60 (3H, s), 1.79e1.88 (1H,
(CH3), 21.4 (CH3), 22.0 (CH3), 23.6 (CH3), 37.7 (CH2), 39.9 (CH2), 51.8
(Cq), 80.9 (Cq), 99.4 (Cq), 109.8 (CH), 121.7 (CH), 122.5 (CH), 133.9
(Cq), 138.3 (Cq), 157.2 (Cq); HRMS (ESI) m/z calcd for C15H20O2Na
m), 2.31 (3H, s), 2.45 (2H, t, J¼8.0 Hz), 2.51e2.60 (1H, m), 3.40 (3H,
s), 5.01 (1H, d, J¼0.8 Hz), 5.04 (1H, d, J¼6.8 Hz), 5.12 (1H, d,

5058
M. Yoshida et al. / Tetrahedron 66 (2010) 5053e5058
[MþNa]þ 255.1361, found 255.1365. The spectroscopic data of our
sample of synthetic 2 were completely identical with those pre-
viously reported.2d
References and notes
1. Yamamura, S.; Hirata, Y. Tetrahedron 1963, 19, 1485e1496.
2. For
a synthesis of racemic aplysin and debromoaplysins, see: (a) Har-
rowven, D. C.; Lucas, M. C.; Howes, P. D. Tetrahedron Lett. 1999, 40,
4443e4444; Tetrahedron 2001, 57, 791e804 and references cited therein;
For a synthesis of optically active aplysin via optical resolution, see: (b)
Ronald, R. C.; Gewali, M. B.; Ronald, B. P. J. Org. Chem. 1980, 45, 2224e2229
For an enantioselective synthesis of (ꢁ)-aplysins, see: (c) Takano, S.; Mor-
iya, M.; Ogasawara, K. Tetrahedron Lett. 1992, 33, 329e332; (d) Nemoto, H.;
Nagamochi, M.; Ishibashi, H.; Fukumoto, K. J. Org. Chem. 1994, 59, 74e79;
(e) Srikrishna, A.; Chandrasekhar Babu, N. Tetrahedron Lett. 2001, 42,
4913e4914.
3. Yoshida, M.; Matsuda, K.; Shoji, Y.; Gotou, T.; Ihara, M.; Shishido, K. Org. Lett.
2008, 10, 5183e5186.
4. (a) Ziegler, F. E. Chem. Rev. 1988, 88, 1423e1452; (b) Martín Castro, A. M. Chem.
Rev. 2004, 104, 2939e3002.
Acknowledgements
This study was supported in part by a Grant-in-Aid for the En-
couragement of Young Scientists (B) from the Japan Society for the
Promotion of Science (JSPS), Uehara Memorial Foundation and the
Program for Promotion of Basic and Applied Research for In-
novations in the Bio-oriented Industry (BRAIN).
5. Yoshida, M.; Shoji, Y.; Shishido, K. Org. Lett. 2009, 11, 1441e1443.
6. (a) Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105e10146; (b) Corey, E. J.;
Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 389e401.
7. Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986e2012.
8. The enantiomer of 5 was previously synthesized by the same method. See Ref. 5.
9. It is expected that the resulting optically active allylic alcohol 9 was partially
racemized by the palladium catalyst.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.04.134.
10. Deguest, G.; Bischoff, L.; Fruit, C.; Marsais, F. Org. Lett. 2007, 9, 1165e1167.