Enantioselective total synthesis of idesolide via NaHCO3- promoted dimerization

Article abstract of DOI:10.1016/j.tet.2010.05.034

The enantioselective total synthesis of idesolide has been accomplished in 20% overall yield from a known allylic alcohol by a nine-step sequence involving the Sharpless asymmetric epoxidation as the source of chirality and an efficient NaHCO₃-promoted dimerization of the monomeric form of idesolide as the key transformation.

Full text of DOI:10.1016/j.tet.2010.05.034

Tetrahedron 66 (2010) 4965e4969
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Enantioselective total synthesis of idesolide via NaHCO3-promoted dimerization
*
Tomohiro Nagasawa, Naoyuki Shimada, Munefumi Torihata, Shigefumi Kuwahara
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University, Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective total synthesis of idesolide has been accomplished in 20% overall yield from
a known allylic alcohol by a nine-step sequence involving the Sharpless asymmetric epoxidation as the
source of chirality and an efficient NaHCO3-promoted dimerization of the monomeric form of idesolide
as the key transformation.
Received 28 April 2010
Received in revised form 9 May 2010
Accepted 10 May 2010
Available online 13 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Idesolide
Antiinflammatory
Total synthesis
Dimerization
Spiro compounds
1. Introduction
or found as a component of more complex natural products produced
by willows and poplars.4 Recently, Snider and co-workers achieved
In their search for antiinflammatory substances from natural
sources, Kim and co-workers isolated an inhibitor of lipopolysac-
charide-induced nitric oxide (NO) production in BV2 microglial cells
fromthe fresh fruits of Idesia polycarpa, a deciduous treenative to East
Asian countries.1 Based on extensive spectroscopic analyses coupled
with X-ray crystallography, they determined the structure of the NO
production inhibitor as 1, albeit without assignment of its absolute
configuration, and named it idesolide (Fig. 1). Recently, idesolide (1)
was also shown to improve hippocampus-dependent recognition
memory in rodents, indicating its potential as a therapeutic drug for
memory-related brain anomalies such as mild cognitive impairment
(MIC) and Alzheimer’s disease.2 From a structural viewpoint, ideso-
lide (1) characterized by a unique spirocyclic architecture embedded
with a tetrahydrobenzodioxole ring is an unsymmetrical dimer of its
monomeric form 2,3 which has also been isolated as a naturalproduct
the first synthesis of the monomer 2 in both racemic and optically
enriched forms and attempted its dimerization to idesolide (1).5 All of
their efforts to dimerize 2 into 1 were, however, unsuccessful, sug-
gesting the presence of a significant kinetic barrier to the formation/
decomposition of idesolide (1). This difficulty was overcome by
Iwabuchi and co-workers’ serendipitous discovery that the di-
merization of 2 was significantly promoted by AZADO6 and some
tertiary amines, which enabled them to complete the first total syn-
thesis of 1anddetermineitsabsoluteconfiguration.7 Prompted by the
unique structure and the interesting biological activity of 1, we also
embarked on its total synthesis. The present article describe a new
enantioselective total synthesis of 1 using the Sharpless asymmetric
epoxidation as the source of chirality and an efficient NaHCO3-pro-
moted dimerization of 2 into 1 as the key transformation.
2. Results and discussion
HO CO2Me
O
MeO2C
MeO2C
OH
O
Our retrosynthetic analysis of 1 is shown in Scheme 1. Assuming
that idesolide (1) should be formed from two molecules of its mo-
nomeric form 2 via unsymmetrical acetal/hemiacetal formation,8 we
set the preparation of the monomer 2 as our first task. Compound 2
O
OH
1
2
would be obtainable by b-eliminative epoxide ring opening of 3,
Figure 1. Idesolide (1) and its monomeric form (2).
which inturncould bederived fromepoxyalcohol 4 viaoxidationand
subsequent methyl esterification. To obtain 4, we planned to use the
Sharpless asymmetric epoxidation of known allylic alcohol 5.
According to our synthetic plan, the starting material 5,
obtained by the Morita/Baylis/Hillman reaction of 2-cyclohexenone
* Corresponding author. Tel./fax: þ81 22 717 8783; e-mail address: skuwahar@
biochem.tohoku.ac.jp (S. Kuwahara).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.034

4966
T. Nagasawa et al. / Tetrahedron 66 (2010) 4965e4969
methyl salicylate, in most cases. Exposure of TBS enol ether 7, pre-
HO CO2Me
O
MeO2C
MeO2C
OH
O
dimerization
pared by treating 3 with NaHMDS/TBSOTf in THF, to basic conditions
(LHMDS/THF, LTMP/THF, or LDA/t-BuOK/THF14) followed by desily-
O
lation was also unsuccessful. Faced with the difficulty in the
b-
OH
1
2
eliminative epoxide ring opening, we next attempted two-step
procedures consisting of epoxide ring opening of 3 with a nucleo-
philic species (Xꢀ) and subsequent base-induced
b-elimination of
O
O
CO2Me
O
HX. The ring opening of the epoxide 3 proceeded smoothly by its
treatment with TiCl4 in CH2Cl215 and TMSI in CH2Cl2,16 giving 8a and
8b, respectively, the former of which was then further transformed
quantitatively into the corresponding TMS ether 8a0. Treatment of
8a, 8a0, and 8bwith DBU in CH3CN, CH2Cl2, or toluene in the presence
orabsence of AgClO4, however, yielded neither the desired product 2
nor its TMS ether derivative 9; substrates 8a and 8a0 merely afforded
3, and a mixture of 3 and 8a, respectively, as identifiable products,
while 8b gave methyl salicylate when treated with DBU in CH3CN at
OH
OH
O
O
5
4
3
Scheme 1. Retrosynthetic analysis of 1.
with formaldehyde,9 was subjected to the Sharpless asymmetric
epoxidation to give 4 in 87% yield and 92% enantiomeric excess
(Scheme 2). The epoxy alcohol 4 was then oxidized with Jones re-
agent, and the resulting carboxylic acid 6 was esterified with
diazomethane to afford the epoxy keto ester 3.
70 ꢁC. Oxidative elimination (aq H2O2/NaHCO3 in THF) of
selenide 8c obtained in low yield by treating 3 with PhSeH and SnCl4
b-hydroxy
17,18
in CH2Cl2
also resulted in the formation of a complex mixture
CrO3
L-(+)-DIPT
containing only a trace amount of 2. Although the transformation of
3 into 2 was found to be troublesome, the isolation of methyl salic-
ylate in the Lewis acid-promoted isomerization of 3 as well as in the
O
O
CO2H
O
H2SO4
Ti(O-iPr)4
OH
5
acetone
TBHP, MS 4Å
CH2Cl2
O
b-elimination of 8b led us to suspect that the generation of methyl
4
6
87%
(92% ee)
salicylate might have proceeded via initial formation of 2 or 9 by
b
-
elimination of 3 or 8b, followed by undesired enolization of the
ketone function and subsequent 1,4-elimination of H2O or TMSOH
from the resulting skipped diene 10.19 These considerations made us
take an alternative approach to 2 using an alcohol intermediate in-
stead of the ketone intermediates 3 and 8.
O
CO2Me
O
CH2N2
ether
71% from 4
3
Scheme 2. Preparation of intermediate 3.
In line with the discussion described above, the ketone 3 was
reduced with LiB(s-Bu)3H to give epoxy alcohols 11
yields of 83% and 16%, respectively (Scheme 4).20 The major epimer
11 was then protected as its TBS ether and the product 12 was
treated with PhSeSePh and NaBH4 in EtOH to give -hydroxy sel-
enide 13b 18a
The selenide was subjected, in one pot, to oxidative
elimination conditions to afford allylic alcohol 14 in 89% yield
b and 11a in
To obtain the idesolide monomer 2 from3 in a single step, wefirst
attempt the -eliminative ring opening of the epoxide 3 using LDA,
b
b
b
LHMDS, or LTMP as the base (2 equiv) in the presence or absence of
HMPA at a wide range of temperatures (ꢀ78 to 0 ꢁC) in THF
(Scheme 3). All of the attempts were, however, unsuccessful,
resulting in the formation of complex mixtures. Lewis acid-pro-
moted direct isomerization of 3 into 2 (or its TMS ether) using such
reaction conditions as LiClO4/toluene,10 Bu2BOTf/DBU/CH2Cl2,11
TMSOTf/2,6-lutidine/CH2Cl2,12 and Mg(ClO4)2/toluene13 also
brought no fruitful outcome, affording the aromatization product,
b
.
b
from 12
b. The intermediate 13
b
was stable enough to be isolated
O
O
CO2Me
OH
CO2Me
LiB(s-Bu)3H
+
3
THF
OH
LiNR2 (2 eq)
O
MeO2C
11 (83%)
11 (16%)
CO2Me
O
OH
O
or Lewis acids
PhSe
6
OH
CO2Me
TBSOTf
Et3N
O
PhSeSePh
CO2Me
OTBS
3
2
NaBH4
NaHMDS
TBSOTf
94%
LiNR2
11
then F–
2
CH2Cl2
96%
EtOH
a) TiCl4
b) TMSI
or
c) PhSeH
SnCl4
OTBS
12
13
O
CO2Me
OTBS
OH
OH
NaIO4
NaHCO3
DMP
NaHCO3
CO2Me
CO2Me
aq HF
7
2
CH2Cl2
89%
CH3CN
X
OTBS
OH
OR
DBU
or H2O2
MeO2C
76% from 14
14
15
OR
O
CO2Me
O
OH
OH
DMP
NaHCO3
2
CH2Cl2
ca. 25%
CO2Me
TMSOTf
Et3N
8a: X = Cl, R = H (96%)
8a': X = Cl, R = TMS
8b: X = I, R = TMS (70%)
8c: X = PhSe, R = H (12%)
2: R = H
9: R = TMS
CO2Me
OH
11
PhSe
6
quant
60%
15
OTBS
2
H
OR
H2, Pd/C
EtOAc
H
OH
CO2Me
CO2Me
13
CO2Me
3
2
NOE
or 8b
or 9
OH
OH
ROH
OH
10
methyl salicylate
16
Scheme 4. Successful transformation of 3 into 2.
Scheme 3. Attempts for the conversion of 3 into 2.

T. Nagasawa et al. / Tetrahedron 66 (2010) 4965e4969
4967
and analyzed by 1H NMR, enabling us to determine the 2,6-cis
3. Conclusion
stereochemistry by observing a NOE correlation between the hy-
drogens at the C2 and C6 positions (see the conformational diagram
in Scheme 4). Finally, removal of the TBS protecting group and
The enantioselective total synthesis of (ꢀ)-idesolide (1), fea-
turing the Sharpless asymmetric epoxidation as the chirality-
inducing step and the use of NaHCO3 as an efficient dimerization
promoter of the idesolide monomer 2, has been accomplished from
the known allylic alcohol 5 in 20% overall yield through a nine-step
sequence.
subsequent oxidation of the resulting trans diol 15
Martin periodinane furnished the idesolide monomer 2. The minor
epimer 11 formed in the reduction of 3 could also be transformed
into 2 via 15 by following the same reaction sequence as used for
the conversion of 11 into 2, although the final oxidation step for
the conversion of the cis diol 15 into 2 resulted in a low yield of
25%, presumably due to the CeC bond cleavage of the vicinal diol
moiety.21 The absolute configuration of 15
was confirmed by re-
b with the Dess/
a
a
b
a
4. Experimental
4.1. General
a
ducing it into known dihydroxy ester 16 and comparing its specific
rotation with a reported value.22,23
IR spectra were recorded by a Jasco FT/IR-4100 spectrometer
using an ATR (ZnSe) attachment. NMR spectra were recorded with
TMS as an internal standard in CDCl3 by a Varian MR-400 spec-
trometer (400 MHz for 1H and 100 MHz for 13C). Optical rotation
values were measured with a Jasco DIP-371 polarimeter, and the
mass spectra were obtained with Jeol JMS-700 spectrometer op-
erated in the EI or FAB mode. Melting points were determined with
a Yanaco MP-J3 apparatus and are uncorrected. Merck silica gel 60
(7e230 mesh) was used for column chromatography unless oth-
erwise stated. Solvents for reactions were distilled prior to use: THF
from Na and benzophenone; CH2Cl2 and CH3CN from CaH2; EtOH
from Na and diethyl phthalate. All air- or moisture-sensitive
reactions were conducted under a nitrogen atmosphere.
With the idesolide monomer 2 in hand, we proceeded to its di-
merization to complete the total synthesis of 1. Unlike previous in-
vestigations by Iwabuchi and co-workers, which focused mainly on
the use of amines as the dimerization promoter,7 we examined the
effect of inorganic salts on the dimerization reaction. As shown in
Table 1, no product was produced without additives (entry 1). The
use of finely-powdered NH4Cl as an acid catalyst also did not induce
the dimerization, which is comprised of two consecutive hemi-
acetalizations (entry 2). Gratifyingly, however, when 2 was mixed
with NaHCO3 powder as a base catalyst and stirred (or left to stand)
Table 1
Dimerization of 2 into idesolide (1)
HO CO2Me
OH
4.1.1. (1S,6S)-1-(Hydroxymethyl)-7-oxabicyclo[4.1.0]heptan-2-one
(4). To a stirred suspension of pulverized 4 Å molecular sieves
MeO2C
CO2Me
O
R
additive
S
S
S
(12.0 g),
L
-(þ)-diisopropyl tartrate (9.00 mL, 42.8 mmol) and Ti(Oi-
no solvent
O
O
Pr)4 (13.0 mL, 41.7 mmol) in CH2Cl2 (100 mL) was added a solution
of 5 (3.59 g, 28.5 mmol) in CH2Cl2 (35 mL) at ꢀ20 ꢁC. After 30 min,
the mixture was cooled to ꢀ30 ꢁC and a solution of TBHP (5.60 M in
toluene, 15.5 mL, 86.8 mmol) was added dropwise. The mixture
was gradually warmed to ꢀ17 ꢁC and stirred for 20 h before being
quenched with FeSO4$7H2O (24.0 g) and 10% aq tartaric acid
(150 mL). The resulting mixture was filtered and the filtrate was
extracted with CHCl3. The extract was washed with brine, dried
(MgSO4), and concentrated in vacuo. The residue was purified by
OH
2
1
Entry
Additive
Temp
Time
Calcd yielda (%)
1
epi-1
17
1
2
3
4
5
None
5
ꢁC
C
C
2 d
0
0
39
51
65
0
0
3
5
4
0
0
7
8
7
NH4Cl (1 equiv)
NaHCO3 (1 equiv)
NaHCO3 (1 equiv)
NaHCO3 (2 equiv)
5 ꢁ
5 ꢁ
rt
20 h
20 h
20 h
20 h
rt
silica gel column chromatography (hexane/EtOAc¼2:1e1:1) to give
a
Determined by 1H NMR.
21
3.52 g (87%) of 4 as a colorless oil. [
a]
ꢀ87.4 (c 1.23, CHCl3); IR:
D
nmax 3418 (br s), 2881 (m), 1699 (vs), 1045 (s), 878 (w); 1H NMR:
1.65e1.76 (1H, m), 1.89e2.03 (2H, m), 2.07e2.17 (1H, m),
at 5 ꢁC for 20 h,24 the formation of a substantial amount of 1 (39%,
calculated fromthe 1H NMR spectrum of the crude reaction mixture)
as well as small amounts of epi-1, and heterodimer 17 [originating
fromthe incomplete enantiomericexcess(92% ee)of thesubstrate2]
was observed (entry 3, Fig. 2).25 Raising the reaction temperature
from 5 ꢁC to room temperature (ca. 15e20 ꢁC) was found to be
effective to promote the dimerization, furnishing 1 in 51% yield,
(entry 4). Furthermore, addition of an increased amount of NaHCO3
(2 equiv) gave a better yield of 65% (entry 5), which enabled us to
isolate 1 in 60% yield by flash column chromatography.26 The im-
provement in the yield may be ascribable to the increase in the in-
terfacial area between the liquid substrate and solid NaHCO3, which
d
2.22e2.33 (1H, m), 2.58 (1H, dm, J¼17.6 Hz), 2.63e2.68 (br m, OH),
3.66 (1H, br s), 3.86 (1H, dd, J¼12.9, 5.2 Hz), 3.93 (1H, dd, J¼12.9,
7.8 Hz); 13C NMR:
d 17.4, 22.9, 36.8, 59.6, 60.0, 60.5, 207.5; HRMS
(FAB): m/z calcd for C7H11O3, 143.0708; found, 143.0702 ([MþH]þ).
4.1.2. Determination of the enantiomeric excess of 4. The enantio-
meric excess of 4 was determined to be 92% by analyzing the 1H
NMR spectra of the (R)-and (S)-MTPA esters derived form 4. The
hydroxyl-bearing methylene protons of the (R)-MTPA ester
appeared at
d
4.61 ppm (1H, d, J¼12.2 Hz) and
d
4.75 ppm (1H d,
4.68 ppm (1H,
is considered to be the site for the reaction to occur. The 1H and 13
NMR spectra of 1 were identical with those previously reported, and
the specific rotation and melting point of 1 also showed good
agreement with reported data.1,7
C
J¼12.2 Hz) as the major peaks (96% in total) and at
d
d, J¼12.7 Hz) and 4.70 ppm (1H, d, J¼12.7 Hz) as the minor peaks
d
(4% in total). These assignments were confirmed by the 1H NMR of
the (S)-MTPA ester.
4.1.3. Methyl (1S,6S)-2-oxo-7-oxabicyclo[4.1.0]heptane-1-carboxyl-
ate (3). To a stirred solution of 4 (383 mg, 2.70 mmol) in acetone
(40 mL) was added dropwise a solution of Jones reagent (2.70 mL,
7.21 mmol) at 0 ꢁC. The mixture was stirred at 0 ꢁC for 30 min and
at room temperature for an additional 2.5 h. The mixture was
quenched with i-PrOH and concentrated in vacuo. The residue was
diluted with water and extracted with EtOAc. The extract was
successively washed with water and brine, dried (MgSO4), and
HO CO2Me
HO CO2Me
MeO2C
MeO2C
O
S
O
R*
S
R*
S
S*
O
O
OH
OH
17
epi-1
Figure 2. Minor products in the dimerization of 2.

4968
T. Nagasawa et al. / Tetrahedron 66 (2010) 4965e4969
22
concentrated in vacuo to give 6 as a yellow oil, which was then
dissolved in Et2O (10 mL). To the solution was added dropwise
a freshly prepared solution of CH2N2 in Et2O at 0 ꢁC until the gas
evolution ceased. The resulting mixture was quenched with AcOH
and concentrated in vacuo. The residue was purified by silica gel
EtOAc¼20:1) to give 513 mg (89%) of 14
ꢀ130 (c 1.14, CHCl3); IR: nmax 3512 (w), 3032 (w), 1731 (s), 1095 (s),
776 (m); 1H NMR:
0.056 (3H, s), 0.077 (3H, s), 0.86 (9H, s),1.75e1.84
b as a pale yellow oil. [a]
D
d
(1H, m), 2.07e2.16 (1H, m), 2.17e2.29 (2H, m), 3.77 (1H, s, OH), 3.79
(3H, s), 4.45 (1H, dd, J¼11.1, 4.5 Hz), 5.45 (1H, ddd, J¼9.9, 2.3,1.7 Hz),
column chromatography (toluene/EtOAc¼30:1) to give 328 mg
5.94 (1H, ddd, J¼9.9, 4.7, 2.8 Hz); 13C NMR:
d
ꢀ4.9, ꢀ4.6, 17.8, 23.9,
23
(71%) of 3 as a white solid. Mp 55.5e56.0 ꢁC; [
a
]
ꢀ115 (c 1.25,
25.6 (3C), 28.3, 52.8, 75.4, 77.6, 126.3, 131.7, 174.2; HRMS (FAB): m/z
calcd for C14H27O4Si, 287.1679; found, 287.1682 ([MþH]þ).
D
CHCl3); IR: nmax 1753 (s), 1707 (s), 1227 (s), 1061 (s), 770 (m); 1H
NMR:
d
1.71e1.91 (2H, m), 2.04 (1H, dddd, J¼15.4, 11.0, 5.5, 1.4 Hz),
2.17 (1H, ddd, J¼17.1, 11.7, 5.8 Hz), 2.35 (1H, dm, J¼15.4 Hz), 2.57
4.1.7. Methyl (S)-1-hydroxy-6-oxo-2-cyclohexene-1-carboxylate (2).
To a stirred solution of 14b (376 mg, 1.42 mmol) in MeCN (2 mL) was
added dropwise a solution of HF (48% aq solution, 1.0 mL) at room
temperature. After 45 min, the mixture was quenched with NaHCO3
and stirred for 1 h. The resulting mixture was diluted with water and
extracted with EtOAc. The extract was washed with brine, dried
(1H, dt, J¼17.1, 4.3 Hz), 3.69e3.70 (1H, br m), 3.83 (3H, s); 13C NMR:
d
16.4, 22.8, 37.2, 52.8, 58.6, 60.0, 166.5, 199.3; HRMS (FAB): m/z
calcd for C8H11O4, 171.0657; found, 171.0657 ([MþH]þ).
4.1.4. Methyl (1R,2S,6S)-2-hydroxy-7-oxabicyclo[4.1.0]heptane-1-car-
boxylate (11b). To a stirred solution of 3 (827 mg, 4.86 mmol) in THF
(MgSO4), and concentrated in vacuo to give 15b (229 mg) as a yellow
(40 mL) was added dropwise a solution of L-SelectrideÒ (1.0 M inTHF,
5.0 mL, 5.0 mmol) at ꢀ78 ꢁC. After 1 h, the mixture was quenched
with satd NH4Cl aq and extracted with EtOAc. The extract was suc-
cessively washed with water and brine, dried (Na2SO4), and concen-
trated in vacuo. The residue was purified by silica gel column
chromatography (hexane/EtOAc¼5:1e1:2) to give 693 mg (83%) of
oil, which was then dissolved in CH2Cl2 (6 mL). To the solution was
successively added NaHCO3 (342 mg, 4.07 mmol) and Dess/Martin
periodinane (851 mg, 2.01 mmol) at room temperature. The mixture
was stirred for 45 min, quenched with half satd Na2S2O3 aq, and then
extracted with CH2Cl2. The extract was washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
11b
as a colorless oil and 137 mg (16%) of 11
a
as a white solid. Com-
silica gel column chromatography (hexane/EtOAc¼2:1) to give
24
pound 11
b
: [
a
]
22 ꢀ71.5 (c 1.25, CHCl3); IR: nmax 3618 (br m), 1741 (s),
183 mg (76%) of 2 as a colorless oil. [
a
]
ꢀ252 (c 1.16, CHCl3) (lit.7
D
D
1265 (s), 1044 (s); 1H NMR:
d
1.25e1.36 (1H, m), 1.56e1.77 (3H, m),
[a]
ꢀ274.8 (c 1.01, CHCl3)); IR: nmax 3616 (m), 3039 (w), 1746 (s),
27
D
1.87e1.97 (1H, m), 1.99e2.07 (1H, m), 3.59 (1H, dm, J¼4.3 Hz), 3.63
1720 (vs), 1136 (m); 1H NMR:
d 2.52e2.63 (1H, m), 2.64e2.79 (2H,
(1H, br s, OH), 3.79 (3H, s), 4.48 (1H, br s); 13C NMR:
d
13.3, 22.4, 26.1,
m), 3.00 (1H, dt, J¼14.3, 8.0 Hz), 3.80 (3H, s), 4.26 (1H, s, OH), 5.79
52.7, 57.3, 58.6, 64.6, 172.2; HRMS (FAB): m/z calcd for C8H13O4,
(1H, ddd, J¼9.8, 2.1, 1.7 Hz), 6.13 (1H, ddd, J¼9.8, 4.1, 3.9 Hz); 13C
173.0814; found, 173.0818 ([MþH]þ). Compound 11
a:
mp
NMR: d 26.8, 35.1, 53.4, 77.9,127.5,131.8,170.3, 205.4; HRMS (EI): m/z
55.0e56.0 ꢁC; [
a]
D
24 ꢀ48.8 (c 1.23, CHCl3); IR: nmax 3488 (m), 1742 (s),
calcd for C8H10O4, 170.0579; found, 170.0579 (Mþ).
1255 (s), 1039 (s), 938 (m), 735 (m); 1H NMR:
d 1.25e1.38 (1H, m),
1.45e1.63 (2H, m), 1.64e1.72 (1H, m), 1.82e1.97 (2H, m), 2.28e2.35
(1H, brm, OH), 3.55(1H, brd, J¼3.3 Hz), 3.80(3H, s), 4.58e4.66(1H, br
4.1.8. Dimethyl
(10R,20S,3aS,7aR)-3a,6,7,7a-tetrahydro-20,7a-dihy-
droxyspiro[1,3-benzodioxole-2,10-[3]cyclohexene]-20,3a-dicarboxylate
[Idesolide (1)]. A mixture of 2 (20.5 mg, 0.121 mmol) and NaHCO3
powder (20.5 mg, 0.244 mmol) was stirred at room temperature for
8 h and then left to stand for an additional 12 h at the same tem-
perature. The mixture was diluted with CHCl3, filtered, and con-
centrated in vacuo. The residue was purified by flash column
m); 13C NMR:
d 17.8, 22.9, 28.2, 52.7, 59.9, 61.0, 66.0, 170.6; HRMS
(FAB): m/z calcd for C8H13O4, 173.0814; found, 173.0818 ([MþH]þ).
4.1.5. Methyl (1S,2S,6S)-2-(tert-butyldimethylsilyloxy)-7-oxabicyclo
[4.1.0]heptane-1-carboxylate (12b). To a stirred solution of 11b
(1.30 g, 7.58 mmol) in CH2Cl2 (40 mL) was successively added Et3N
(1.60 mL, 11.5 mmol) and TBSOTf (2.20 mL, 9.39 mmol) at 0 ꢁC, and
the mixture was stirred at 0 ꢁC for 30 min. The mixture was
quenched with satd NH4Cl aq and extracted with CH2Cl2. The ex-
tract was washed with brine, dried (MgSO4), and concentrated in
vacuo. The residue was purified by silica gel column chromatog-
chromatography [Merck, silica gel 60 (spherical), 40e50 mm; hex-
ane/EtOAc¼2:1] to give 12.2 mg (60%) of 1 as a colorless solid. Mp:
25
139.5e141.0 ꢁC (lit.1 mp 141.0e143.0 ꢁC; lit.7 mp 138e140 ꢁC); [
a
a
]
]
D
25
25
D
ꢀ248 (c 1.06, CHCl3) [lit.1
[
a]
ꢀ230.0 (c 1.0, CHCl3); lit.7
[
D
ꢀ238.9 (c 0.27, CHCl3)]; IR: nmax 3411 (w), 3370 (w), 1761 (s), 1728
(s), 1251 (s), 1095 (s), 1075 (s), 800 (m); 1H NMR:
d 1.80e1.88 (1H,
raphy (hexane/EtOAc¼100:1e25:1) to give 2.07 g (96%) of 12
b
as
m), 2.08e2.47 (7H, m), 3.77 (3H, s), 3.91 (3H, s), 4.86 (1H, br s, OH),
5.46 (1H, ddd, J¼10.2, 2.4, 1.5 Hz), 5.59 (1H, ddd, J¼10.2, 2.4, 1.2 Hz),
24
a colorless oil. [
a]
D
þ7.87 (c 1.15, MeOH); IR: nmax 3008 (w), 1746
(vs), 1256 (s), 833 (s); 1H NMR:
d
0.076 (3H, s), 0.092 (3H, s), 0.87
5.96e6.02 (2H, m), 6.00 (1H, s, OH); 13C NMR:
d 22.4, 24.3, 29.7,
(9H, s), 1.21e1.30 (1H, m), 1.39e1.47 (1H, m), 1.57e1.74 (2H, m),
1.85e2.02 (2H, m), 3.65 (1H, br d, J¼3.7 Hz), 3.74 (3H, s), 4.45 (1H,
31.0, 52.7, 54.2, 76.6, 86.4, 102.1, 110.9, 126.1, 126.4, 130.6, 132.4,
169.0, 173.1; HRMS (FAB): m/z calcd for C16H21O4, 341.1236; found,
341.1241 ([MþH]þ).
br dd, J¼4.7, 3.7 Hz); 13C NMR:
d
ꢀ5.2, ꢀ4.6, 13.7, 17.9, 22.7, 25.6
(3C), 28.2, 52.1, 57.7, 60.3, 66.0, 169.5; HRMS (FAB): m/z calcd for
C14H27O4Si, 287.1679; found, 287.1676 ([MþH]þ).
4.1.9. Methyl (1S,2R)-1,2-dihydroxycyclohexane-1-carboxylate (16).
This known compound showed the following properties: colorless
þ3.55 (c 1.30, 95% EtOH) (lit.22
[
a]
þ2.5 (c 1.1, 95%
23
24
4.1.6. Methyl (1S,6S)-6-(tert-butyldimethylsilyloxy)-1-hydroxy-2-cy-
oil; [
a
]
D
D
clohexene-1-carboxylic acid (14
b). To a stirred suspension of PhSe-
EtOH)); IR: nmax 3470 (br s), 1730 (s), 1238 (s), 1148 (m); 1H NMR:
SePh (502 mg, 1.54 mmol) in EtOH (6 mL) was added portionwise
NaBH4 (138 mg, 3.34 mmol) at room temperature. After 30 min,
d
1.25e1.38 (1H, m), 1.48e1.61 (3H, m), 1.65e1.87 (4H, m), 2.23 (1H,
br s, OH), 3.40 (1H, br s, OH), 3.80e3.86 (1H, m), 3.82 (3H, s); 13C
a solution of 12
b
(575 mg, 2.01 mmol) in EtOH (4 mL) was added,
NMR: d 19.8, 24.0, 30.2, 34.3, 53.0, 72.2, 76.8, 176.6; HRMS (FAB): m/
andthe resulting mixturewasstirredfor 8 h. Themixturewascooled
to 0 ꢁC and diluted with EtOH (5 mL) and water (5 mL). NaHCO3
(1.10 g, 13.0 mmol) and NaIO4 (2.39 g, 11.2 mmol) was then added,
and the resulting mixture was stirred at room temperature for 1 h
and then at 60 ꢁC for an additional 3 h. The mixture was diluted with
water and extracted with Et2O. The extract was successively washed
with waterand brine, dried (MgSO4), and concentrated in vacuo. The
residue was purified by silica gel column chromatography (hexane/
z calcd for C8H15O4, 175.0970; found, 175.0976 ([MþH]þ).
Acknowledgements
This work was financially supported, in part, by a Grant-in-Aid
for Scientific Research (B) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan (No. 16380075).

T. Nagasawa et al. / Tetrahedron 66 (2010) 4965e4969
4969
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Supplementary data associated with this article can be found in
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MOL files and InChiKeys of the most important compounds de-
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24. Several hours after the start of the reaction, the spinning of the magnetic
stirring bar stopped, because the viscosity of the reaction mixture increased as
the dimerization proceeded. Therefore, the mixture was, actually, left to stand
for the rest of the reaction time.
25. The calculated yields would probably have some margin of error, especially for the
minor products (epi-1 and 17), because they were determined by 1H NMR in-
tegration. The structural assignments of epi-1 and 17 were based on their authentic
1H and 13C NMR spectra previously reported by Iwabuchi and co-workers; see Ref. 7.
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€
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