Synthesis of topsentolides A2 and C2, and non-enzymatic conversion of the former to the latter

Article abstract of DOI:10.1016/j.tet.2014.04.040

The first total synthesis of the marine-derived cytotoxin topsentolide A₂, which eventually culminated in its stereochemical determination, was accomplished in 17 steps from a known chiral alcohol. An improved synthesis of its congener, topsentolide C₂, from a synthetic intermediate of topsentolide A₂ was also performed by utilizing the Yamaguchi lactonization to construct its nine-membered lactone ring. Treatment of epoxide ring-containing topsentolide A₂ with HCl/MeOH brought about its quantitative conversion into topsentolide C₂.

Full text of DOI:10.1016/j.tet.2014.04.040

Tetrahedron 70 (2014) 3774e3781
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of topsentolides A2 and C2, and non-enzymatic conversion
of the former to the latter
*
Ryo Towada, 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 first total synthesis of the marine-derived cytotoxin topsentolide A2, which eventually culminated in
its stereochemical determination, was accomplished in 17 steps from a known chiral alcohol. An im-
proved synthesis of its congener, topsentolide C2, from a synthetic intermediate of topsentolide A2 was
also performed by utilizing the Yamaguchi lactonization to construct its nine-membered lactone ring.
Treatment of epoxide ring-containing topsentolide A2 with HCl/MeOH brought about its quantitative
conversion into topsentolide C2.
Received 22 March 2014
Received in revised form 9 April 2014
Accepted 11 April 2014
Available online 18 April 2014
Keywords:
Topsentolide
Oxylipin
Ó 2014 Elsevier Ltd. All rights reserved.
Cytotoxic
Artifact
Marine natural product
1. Introduction
O
11
12
O
O
8
R
R S
1
In the search for cytotoxic substances from the marine sponge
Topsentia sp., Jung and co-workers isolated seven oxylipins con-
taining a nine-membered lactone ring and named them top-
sentolides A1, A2, B1eB3, C1, and C2.1,2 The marine natural products
were all shown to exhibit significant cytotoxicity against five hu-
1 (topsentolide A1)
OMe
O
man solid tumor cell lines with ED50 values of 2.4e17.5 mg/mL. The
O
O
O
S
O
S
12
OH
planar structures of the topsentolides were determined based on
extensive spectroscopic analyses, while their stereochemistry was
not assigned conclusively except for the relative configuration be-
tween the C11 and C12 stereogenic centers of topsentolides A1, A2,
and B1eB3 as well as the absolute configuration at the hydroxy-
bearing C12 position of topsentolide C2, which was determined to
be S by the modified Mosher method (see compound 2 in Fig. 1).1
The naturally rare nine-membered lactone unit embedded in
common in the topsentolides and their medicinally important bi-
ological activity attracted considerable attention from organic
chemists, and thereby six synthetic studies on topsentolides have
been reported so far.3e7 Among them, the one reported by Wata-
nabe and co-workers led to the determination of the absolute
stereochemistry of topsentolide A1 as 8R, 11R, and 12S (structure 1,
Fig. 1) by comparison of the 1H NMR spectra and specific rotations
of two synthetic stereoisomers of topsentolide A1 with those of
R
2 (topsentolide C2)
3
(tentative stereochemistry
of topsentolide A2)
Fig. 1. Absolute configuration of topsentolides A1 (1) and C2 (2), and assumed ste-
reochemistry of topsentolide A2 (3).
natural topsentolide A1.3 We also conducted a stereodivergent
synthesis of all of the four diastereomers of topsentolide C2 bearing
a methoxy group at the C11 position and established its stereo-
chemistry as 8R, 11S, and 12S (structure 2).7
As part of our ongoing efforts toward the total synthesis of
bioactive oxylipins,7,8 we set about the first synthesis and stereo-
chemical determination of topsentolide A2 (17,18-dihydro de-
rivative of 1). Although the stereochemistry of topsentolide A2 was
not established by Jung et al. except for the relative configuration of
the epoxide ring moiety as cis, we tentatively assumed its
* 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 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.040

R. Towada, S. Kuwahara / Tetrahedron 70 (2014) 3774e3781
3775
stereochemistry to be 8R, 11R, and 12S as depicted in 3 based on
their speculation that topsentolide C2 (2) might be an artifact de-
rived non-enzymatically from topsentolide A2 during the extrac-
tion of the latter with MeOH from the marine sponge as well as by
analogy to the absolute configuration of topsentolide A1 (1).3 We
describe herein the total synthesis of the tentative structure of
topsentolide A2 (3), determination of the stereochemistry of top-
sentolide A2, improved synthesis of topsentolide C2 (2), and non-
enzymatic conversion of 3 into 2.
the resulting diol 12a afforded 12b almost quantitatively from 11.
Treatment of 12b with HF$Py effected selective unmasking of the
primary hydroxy group,12 furnishing 12c (70% yield), which, on
exposure to the Swern oxidation conditions, afforded the aldehyde
5 quantitatively.
c
d
X
O
O
O
Et
O
Et
Et
CO2Me
11
Et
2. Results and discussion
7: X = OH
10a: X = I
a
b
10b X = PPh3·I
2.1. Retrosynthetic analysis of 2 and 3
CHO
OTBS
g
OR1
Scheme 1 delineates our retrosynthetic analysis of topsentolides
C2 (2) and A2 (3) that features the use of appropriately protected
seco acid 4 as a common precursor. The nine-membered lactone
ring contained in 2 and 3 would be installable by the Yamaguchi
lactonization of a seco acid intermediate generated by deprotection
of the methyl ester and TBS ether functionalities of 4, while the
epoxide ring in 3 would be constructed by properly manipulating
the oxygen-containing functional groups at the C11 and C12 posi-
tions. With a view to establishing the E-geometry at the C9eC10
double bond of 4 by the HornereWadswortheEmmons olefination,
the pivotal intermediate 4 was traced back to two building blocks 5
and 6. The aldehyde 5 would readily be accessible from known
alcohol 7, and the phosphonate 6 via the Evans asymmetric alkyl-
ation of oxazolidinone derivative 8 with allylic iodide 9.
OR2
CO2Me
CO2Me
5
12a: R1 = R2 = H
e
f
12b: R1 = R2 = TBS
12c: R1 = H, R2 = TBS
Scheme 2. Preparation of aldehyde 5. Reagents and conditions: (a) I2, Ph3P, imidazole,
CH2Cl2; (b) Ph3P, MeCN, 83% from 7; (c) NaHMDS, methyl 5-oxopentanoate, THF, 73%;
(d) Amberlite IR-120 Plus, MeOH/H2O; (e) TBSCl, imidazole, DMF, 99% from 11; (f)
HF$Py, THF/Py, 70%; (g) DMSO, (COCl)2, Et3N, CH2Cl2, quant.
2.3. Preparation of phosphonate 6
The preparation of the phosphonate segment 6 commenced
with the Evans asymmetric alkylation of 88b,13 with iodide 98b,14 to
give 13 in 73% yield after chromatographic purification (Scheme
3).15 The N-acyl oxazolidinone 13 was hydrolyzed with aq LiOH
and the resulting carboxylic acid 14a was converted into the cor-
responding Weinreb’s amide 14b in 80% yield over the two steps.
Finally, treatment of 14b with dimethyl lithiomethylphosphonate
gave 6 in 94% yield.
OMe
O
O
O
O
R
O
R
OH
2
3
R = n-C5H11
O
I
O
O
O
OH
a
12
R
O
N
+
O
N
11
OPMB
O
OPMB
OTBS
OPMB
Bn
Bn
CO2Me
8
9
13
4
O
b
d
O
O
X
CHO
R
+
OPMB
14a: X = OH
14b: X = NMe(OMe)
(MeO)2P
OPMB
O
OTBS
(MeO)2P
OPMB
6
CO2Me
HO
6
c
5
7
Scheme 3. Preparation of phosphonate 6. Reagents and conditions: (a) NaHMDS, THF,
73%; (b) LiOH$H2O, H2O2, THF/H2O; (c) MeNH(OMe)$HCl, DCC, DMAP, CH2Cl2, 80% from
13; (d) MePO(OMe)2, n-BuLi, THF, 94%.
O
O
I
O
+
O
N
R
O
Et
OPMB
Et
2.4. Synthesis of topsentolide C2
Bn
8
9
With the two building blocks, 5 and 6, in hand, we proceeded to
their connection followed by transformation of the resulting
product into topsentolide C2 (2) (Scheme 4). The E-selective Hor-
nereWadswortheEmmons reaction between 5 and 6 under the
RousheMasamune conditions gave an 85% yield of enone 15,16
which was then subjected to Luche’s reduction conditions, de-
livering FelkineAhn product 4 as a single diastereomer in 98%
yield.8b O-Methylation of 4 was efficiently performed by its treat-
ment with NaHMDS and MeI in HMPA/THF and exposure of the
resulting product 16a to TBAF in THF furnished alcohol 16b in 80%
yield for the two steps. Saponification of the methyl ester 16b with
aq LiOH gave seco acid 17 almost quantitatively, which set the stage
for the Yamaguchi lactonization to install the nine-membered
Scheme 1. Retrosynthetic analysis of 2 and 3.
2.2. Preparation of aldehyde 5
The preparation of the aldehyde segment 5 is depicted in
Scheme 2.9 The starting alcohol 7, which was prepared from
-malic
D
acid in two steps according to the literature procedure,10 was
converted into phosphonium salt 10b via iodide 10a in 83% yield for
the two steps. The Wittig olefination of 10b with methyl 5-
oxopentanoate proceeded in a highly Z-selective manner, afford-
ing 11 in 73% yield. Acidic hydrolysis of its acetal protecting group
with Amberlite IR-120 Plus11 followed by bis-TBS etherification of

3776
R. Towada, S. Kuwahara / Tetrahedron 70 (2014) 3774e3781
lactone ring.17 The ring forming reaction of 17 was effected in an
excellent yield of 95%, and subsequent removal of the PMB pro-
tecting group of the cyclization product 18 gave topsentolide C2 (2)
quantitatively. The 1H and 13C NMR spectra of 2 were identical with
those of natural topsentolide C2 and, of course, with those of our
synthetic sample of 2 previously obtained in a lower overall yield
due to poor efficiency (56% yield) in the Mitsunobu lactonization
OH
OTBS
OPMB
CO2Me
4
a
OR1
employed for the formation of the lactone ring.7 The specific ro-
OR3
OPMB
CO2R2
21
tation value of 2 {[
a
]
D
þ77.2 (c 0.820, MeOH)} showed good
19a: R1 = EE, R2 = Me, R3 = TBS
19b: R1 = EE, R2 = Me, R3 = H
19c: R1 = EE, R2 = R3 = H
d
þ86.8 (c 1.33, MeOH)}.7
29
b
c
agreement with our previous data {[a]
D
OR1
OR2
O
O
O
a
b
5 + 6
h
OTBS
OPMB
CO2Me
15
20a: R1 = EE, R2 = PMB
20b: R1 = H, R2 = PMB
20c: R1 = Ms, R2 = PMB
20d: R1 = Ms, R2 = H
O
e
O
OH
O
f
g
OTBS
OPMB
CO2Me
3
c
4
OR1
Scheme 5. Synthesis of 3. Reagents and conditions: (a) EtOCH]CH2, PPTS, CH2Cl2; (b)
TBAF, THF; (c) LiOH$H2O, THF/H2O, 94% from 4; (d) Cl3C6H2COCl, DIPEA, THF, then
DMAP, toluene, 88%; (e) PPTS, EtOH; (f) Ms2O, DIPEA, DMAP, CH2Cl2; (g) DDQ, CH2Cl2/
phosphate buffer (pH 7); (h) K2CO3, MeOH, 16% from 20a.
OR3
OPMB
CO2R2
16a: R1 = R2 = Me, R3 = TBS
16b: R1 = R2 = Me, R3 = H
e
d
concluded that the absolute configuration of topsentolide A2
should be represented by structure 3.
OMe
OH
OPMB
2.6. Methanolytic epoxide ring-opening of 3 into 2 under
acidic conditions
CO2H
f
17
OMe
O
To demonstrate the speculation by Jung and co-workers that
topsentolide C2 (2) might be an artifact derived non-enzymatically
from topsentolide A2 (3) during the extraction of 3 from Topsentia
sp. with MeOH,1 we tried exposing 3 to a mixture of MeOH and
CH2Cl2 at room temperature; both the solvents were employed in
their extraction process. Under these neutral conditions, compound
3 was quite stable and did not change at all after 3 h of stirring. On
the other hand, refluxing the solution of 3 in MeOH/CH2Cl2 brought
about gradual decomposition of 3 and finally led to its disappear-
ance and the formation of a mixture of unidentified products after
overnight stirring, none of which was found to be identical with
topsentolide C2 (2) by TLC analysis. Quite interestingly, however,
treatment of 3 with hydrogen chloride in MeOH at room temper-
ature for a few hours effected complete consumption of 3 and
generated topsentolide C2 (2) almost quantitatively with inversion
of configuration at the allylic C11 position (see Supplementary data
for the NMR spectra of the crude reaction product) (Scheme 6).18
These results would support the above-mentioned speculation by
Jung et al. that topsentolide C2 (2) might be an artifact formed from
topsentolide A2 (3), although, at present, we have no way of
knowing whether their sponge extract was acidic or not.
O
OR
18: R = PMB
2: R = H
g
Scheme 4. Synthesis of 2. Reagents and conditions: (a) Et3N, LiBr, THF, 80%; (b) NaBH4,
CeCl3$7H2O, MeOH, 98%; (c) NaHMDS, MeI, HMPA, THF, 82%; (d) TBAF, THF, 98%; (e)
LiOH$H2O, THF/H2O, 99%; (f) Cl3C6H2COCl, DIPEA, THF, then DMAP, toluene, 95%; (g)
DDQ, CH2Cl2/H2O, 99%.
2.5. Synthesis of topsentolide A2
Scheme 5 outlines the transformation of the intermediate 4 into
the tentative structure of topsentolide A2 (3). Protection of the al-
cohol 4 as its 1-ethoxyethyl ether followed by deprotection of the
TBS group of the resulting product 19a afforded hydroxy ester 19b,
which was then subjected to basic hydrolysis conditions, providing
seco acid 19c (94% yield from 4) as a mixture of diastereomers due
to the newly formed stereocenter in the EE group. Lactonization of
19c under the Yamaguchi conditions furnished nine-membered
lactone derivative 20a in 88% yield. Removal of the EE group of
20a with PPTS in EtOH and subsequent mesylation of alcohol in-
termediate 20b gave 20c. Treatment of the PMB ether 20c with
DDQ in CH2Cl2/phosphate buffer (pH 7) afforded a very unstable
hydroxy mesylate 20d, which was, after quick purification by silica
gel column chromatography to remove p-methoxybenzaldehyde
generated as a by-product, exposed to K2CO3 in MeOH, providing
epoxy lactone 3, albeit in a modest overall yield of 16% for the four
steps (mainly due to the instability of 20d). The 1H and 13C NMR
3. Conclusion
In conclusion, the first total synthesis of topsentolide A2 (3) was
accomplished in 4.4% overall yield from the known alcohol 7 by
a 17-step sequence (or 5.7% yield from the allylic iodide 9 through
14 steps) involving the Evans asymmetric alkylation as a source of
chirality and the highly diastereoselective reduction of the a-alkoxy
spectral data of 3 were identical with those reported for natural
ketone 15 to install the C12 stereogenic center. We also achieved an
improved synthesis of topsentolide C2 (2) by exploiting the Yama-
guchi lactonization for the formation of the nine-membered lac-
tone ring instead of the Mitsunobu lactonization previously
21
topsentolide A2,1 and the specific rotation of 3 {[
a
]
þ73 (c 0.22,
D
MeOH)} was in good accord with that of natural topsentolide A2
{[a
]
D
24 þ84.6 (c 0.27, MeOH)}.1 Based on these results as well as by
analogy to the stereochemistry of topsentolide A1 (1), we
employed in our first synthesis of 2. Treatment of 3 with

R. Towada, S. Kuwahara / Tetrahedron 70 (2014) 3774e3781
3777
mixture was concentrated in vacuo and filtered. The filtrate was
extracted with hexane/EtOAc (4:1), and the extract was washed
with brine, dried (MgSO4), and concentrated in vacuo. The residue
was purified by silica gel column chromatography (hexane/
O
O
O
EtOAc¼10:1) to give 11 (880 mg, 73%) as a pale yellow oil. [
a] D
27
3
3); IR: nmax 3015 (w), 1738 (s), 1160 (m), 1077 (m); 1H
ꢁ23.0 (c 1.06, CHCl
HCl, MeOH
quant
NMR:
d
0.89 (3H, t, J¼7.4 Hz), 0.91 (3H, t, J¼7.4 Hz), 1.58e1.75 (6H,
m), 2.10 (2H, q, J¼7.2 Hz), 2.22e2.29 (1H, m), 2.32 (2H, t, J¼7.6 Hz),
2.38e2.47 (1H, m), 3.50 (1H, dd, J¼7.6, 6.5 Hz), 3.67 (3H, s), 4.04
(1H, dd, J¼7.6, 6.5 Hz), 4.10 (1H, quint, J¼6.5 Hz), 5.37e5.53 (2H, m);
OMe
O
O
13C NMR:
d 8.14, 8.40, 24.8, 26.9, 29.8, 30.0, 31.5, 33.6, 51.7, 69.8,
OH
75.9, 113.0, 125.3, 131.5, 174.2; HRMS (FAB): m/z calcd for C15H27O4
2
([MþH]þ) 271.1909, found 271.1910.
Scheme 6. Methanolytic epoxide ring-opening of 3 into 2.
4.3. Methyl (5Z,8R)-8,9-bis[(tert-butyldimethylsilyl)oxy]-5-
nonenoate (12b)
methanolic HCl brought about methanolytic opening of the epox-
ide ring at the C11 allylic position with inversion of configuration
and afforded 2 quantitatively, which supported the speculation by
Jung et al. that topsentolide C2 (2) might be an artifact derived from
topsentolide A2 (3).
To a stirred solution of 11 (650 mg, 2.40 mmol) in MeOH/H2O
(20:1, 8.4 mL) was added Amberlite IR-120 Plus (500 mg) at room
temperature. After 15 h, the mixture was filtered and the filtrate
was concentrated in vacuo. The residue was diluted with Et2O,
dried (Na2SO4), and concentrated in vacuo to give crude 12a
(480 mg), which was taken up in DMF (5 mL). To the solution were
successively added imidazole (975 mg, 14.3 mmol) and TBSCl
(1.09 g, 7.23 mmol) at 0 ꢀC. After 12 h, the mixture was quenched
with H2O at 0 ꢀC and extracted with EtOAc. The extract was washed
with brine, dried (MgSO4), and concentrated in vacuo. The residue
was purified by silica gel column chromatography (hexane/
4. Experimental section
4.1. General
IR spectra were recorded by a Jasco FT/IR-4100 spectrometer
using an ATR (ZnSe) attachment. 1H NMR spectra were recorded
with TMS as an internal standard in CDCl3 by a Varian MR-400
spectrometer (400 MHz) unless otherwise stated. 13C NMR were
recorded in CDCl3 by the same spectrometer (100 MHz) and
chemical shifts were reported with reference to the solvent peak
(CDCl3, 77.16 ppm) unless otherwise stated. Optical rotation values
were measured with a Horiba Septa-300 polarimeter, and the mass
spectra were obtained with Jeol JMS-700 spectrometer operated in
the EI or FAB mode. Merck silica gel 60 (70e230 mesh) was used for
column chromatography. Solvents for reactions were distilled prior
to use: THF from Na and benzophenone; CH2Cl2, MeCN, DMF, and
HMPA from CaH2; MeOH from Mg(OMe)2; toluene from LiAlH4;
EtOH from Na and diethyl phthalate. All air- or moisture-sensitive
reactions were conducted under a nitrogen atmosphere.
EtOAc¼50:1) to give 12b (1.02 g, 99% from 11) as a pale yellow oil.
23
[a
]
þ1.73 (c 1.42, CHCl3); IR: nmax 3014 (w), 1742 (s), 1252 (m),
D
1098 (m), 832 (s); 1H NMR:
d 0.04 (6H, s), 0.05 (6H, s), 0.88 (9H, s),
0.89 (9H, s), 1.69 (2H, quint, J¼7.5 Hz), 2.08 (2H, q, J¼7.5 Hz),
2.11e2.19 (1H, m), 2.26e2.34 (1H, m), 2.31 (2H, t, J¼7.7 Hz), 3.41
(1H, dd, J¼10.0, 6.3 Hz), 3.49 (1H, dd, J¼10.0, 5.5 Hz), 3.64e3.71 (4H,
m), 5.37e5.52 (2H, m); 13C NMR:
18.5, 25.0, 26.0 (3C), 26.1 (3C), 26.9, 32.3, 33.7, 51.6, 67.1, 73.3, 127.1,
130.3, 174.3; HRMS (FAB): m/z calcd for C22H46O4Si2Na ([MþNa]þ)
453.2833, found 453.2837.
d
ꢁ5.22, ꢁ5.16, ꢁ4.5, ꢁ4.2, 18.3,
4.4. Methyl (5Z,8R)-8-[(tert-butyldimethylsilyl)oxy]-9-
hydroxy-5-nonenoate (12c)
To a solution of 12b (418 mg, 0.970 mmol) in THF (5 mL) was
added dropwise a solution of HF$Py (40% HF$Py/Py/THF¼1:2:5,
4.0 mL) at ꢁ10 ꢀC. After 24 h, the mixture was quenched with
saturated aq NaHCO3 and extracted with Et2O. The extract was
successively washed with saturated aq CuSO4 and brine, dried
(MgSO4), and concentrated in vacuo. The residue was purified by
silica gel column chromatography (hexane/EtOAc¼50:1e4:1) to
4.2. Methyl (Z)-7-[(R)-2,2-diethyl-1,3-dioxolan-4-yl]-5-
heptenoate (11)
To a stirred solution of 7 (5.78 g, 33.2 mmol) in CH2Cl2 (150 mL)
were successively added imidazole (6.82 g, 100.0 mmol), Ph3P
(11.5 g, 43.8 mmol), and I2 (10.8 g, 42.6 mmol) at 0 ꢀC. The resulting
mixture was gradually warmed to room temperature and stirred
overnight. The mixture was quenched with saturated aq Na2S2O3
and extracted with hexane. The extract was washed with brine,
dried (MgSO4), and concentrated in vacuo to give crude 10a
(8.40 g), which was taken up in MeCN (100 mL). To the solution was
added Ph3P (9.34 g, 35.6 mmol) while stirring at room temperature,
and the mixture was then heated under reflux for 17 h. The mixture
was cooled to room temperature and concentrated in vacuo to give
a solid, which was suspended in Et2O and filtered to give 10b
(15.0 g, 83% from 7). To a stirred suspension of 10b (2.44 g,
4.46 mmol) in THF (10 mL) was added dropwise a solution of
NaHMDS (1.0 M in THF, 6.70 mL, 6.70 mmol) at 0 ꢀC, and the
resulting solution was stirred at the same temperature for 1 h. To
give 12c (215 mg, 70%) as a yellow oil. [
a
]
24 ꢁ17.5 (c 1.06, CHCl3); IR:
D
nmax 3477 (m), 1739 (s), 834 (s), 775 (s). 1H NMR:
d
0.09 (6H, s), 0.90
(9H, s), 1.69 (2H, quint, J¼7.4 Hz), 1.90 (1H, t, J¼6.3 Hz), 2.08 (2H, q,
J¼7.4 Hz), 2.19e2.29 (2H, m), 2.32 (2H, t, J¼7.4 Hz), 3.40e3.47 (1H,
m), 3.51e3.58 (1H, m), 3.67 (3H, s), 3.72e3.79 (1H, m), 5.36e5.49
(2H, m); 13C NMR:
d
ꢁ4.5, e4.3, 18.2, 24.9, 26.0 (3C), 26.8, 32.1, 33.6,
51.7, 66.0, 72.8, 126.0, 131.1, 174.2; HRMS (FAB): m/z calcd for
C
16H33O4Si ([MþH]þ) 317.2148, found 317.2152.
4.5. Methyl (5Z,8R)-8-[(tert-butyldimethylsilyl)oxy]-9-oxo-5-
nonenoate (5)
To a stirred solution of (COCl)2 (0.130 mL, 1.58 mmol) in CH2Cl2
(2.6 mL) was added dropwise a solution of DMSO (0.220 mL,
3.15 mmol) in CH2Cl2 (4 mL) at ꢁ78 ꢀC. After 5 min, a solution of 12c
(400 mg, 1.26 mmol) in CH2Cl2 (2.5 mL) was added and the
resulting mixture was stirred at ꢁ78 ꢀC for 30 min. To the mixture
the solution was added dropwise
a solution of methyl 5-
oxopentanoate (700 mg, 5.35 mmol) in THF (5 mL) at ꢁ78 ꢀC. Af-
ter 3 h, the mixture was gradually warmed to room temperature,
stirred overnight, and then quenched with saturated aq NH4Cl. The

3778
R. Towada, S. Kuwahara / Tetrahedron 70 (2014) 3774e3781
was added dropwise Et3N (0.880 mL, 6.30 mmol) and the mixture
was gradually warmed to ꢁ30 ꢀC. The mixture was quenched with
saturated aq NaHCO3, gradually warmed to room temperature, and
extracted with CH2Cl2. The extract was washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
silica gel column chromatography (hexane/EtOAc¼10:1) to give 5
NMR: d 13.9, 22.4, 27.1, 29.1, 30.2, 31.3, 32.1, 55.0, 61.1, 70.9, 74.8,
113.5 (2C), 124.0, 129.4 (2C), 129.7, 132.5, 159.1, 172.7; HRMS (FAB):
m/z calcd for C20H32NO4 ([MþH]þ) 350.2331, found 350.2329.
4.8. Dimethyl [(3S,5Z)-3-(4-methoxyphenyl)methoxy-2-oxo-
5-undecenyl]phosphonate (6)
(400 mg, quant) as a pale yellow oil. [
a
]
22 þ13.4 (c 1.04, CHCl3); IR:
D
nmax 3020 (w), 1738 (s), 1252 (m), 836 (m), 777 (m); 1H NMR:
d
0.07
To a stirred solution of MePO(OMe)2 (2.0 mL, 18.7 mmol) in THF
(110 mL) was added dropwise a solution of n-BuLi (1.59 M in hex-
ane, 11.0 mL, 17.5 mmol) at ꢁ78 ꢀC. After 1 h, a solution of 14b
(1.27 g, 3.63 mmol) in THF (30 mL) was added, and the resulting
mixture was stirred at ꢁ78 ꢀC for 6 h. The mixture was quenched
with saturated aq NH4Cl, gradually warmed to room temperature,
and extracted with EtOAc. The extract was washed with brine, dried
(MgSO4), and concentrated in vacuo. The residue was purified by
silica gel column chromatography (hexane/EtOAc¼1:1) to give 6
(3H, s), 0.09 (3H, s), 0.92 (9H, s), 1.69 (2H, quint, J¼7.5 Hz),
2.03e2.13 (2H, m), 2.31 (2H, t, J¼7.5 Hz), 2.39 (2H, t, J¼6.4 Hz), 3.67
(3H, s), 4.00 (1H, dt, J¼1.3, 6.4 Hz), 5.40e5.53 (2H, m), 9.60 (1H, d,
J¼1.3 Hz); 13C NMR:
d
ꢁ4.7, e4.6, 18.3, 24.8, 25.9 (3C), 26.8, 31.0,
33.6, 51.7, 77.6, 124.6, 131.9, 174.1, 204.0; HRMS (FAB): m/z calcd for
C
16H31O4Si ([MþH]þ) 315.1992, found 315.1994.
4.6. (R)-4-Benzyl-3-[(2S,4Z)-2-(4-methoxyphenyl)methoxy-4-
decenoyl]-2-oxazolidinone (13)
(1.41 g, 94%). [
a
]
23 ꢁ19.7 (c 1.00, CHCl3); IR: nmax 1720 (w), 1612 (w),
D
1514 (m), 1248 (s), 1027 (s); 1H NMR:
d
0.88 (3H, t, J¼6.8 Hz),
To a stirred solution of NaHMDS (1.0 M in THF, 7.60 mL,
7.60 mmol) in THF (10 mL) was added dropwise a solution of 8
(1.80 g, 5.06 mmol) in THF (15 mL) at ꢁ78 ꢀC. After 30 min, a so-
lution of 9 (2.86 g, 12.0 mmol) in THF (10 mL) was added and the
resulting mixture was stirred at ꢁ78 ꢀC for 30 min. The mixture was
gradually warmed to ꢁ40 ꢀC and stirred overnight. The mixture
was quenched with saturated aq NH4Cl and extracted with Et2O.
The extract was washed with brine, dried (MgSO4), and concen-
trated in vacuo. The residue was purified by silica gel column
1.21e1.37 (6H, m), 2.00 (2H, q, J¼7.2 Hz), 2.38e2.53 (2H, m), 3.16
(1H, dd, J¼21.8, 14.7 Hz), 3.32 (1H, dd, J¼21.8, 14.7 Hz), 3.76 (3H, d,
J¼5.9 Hz), 3.79 (3H, d, J¼5.9 Hz), 3.81 (3H, s), 3.96 (1H, t, J¼6.0 Hz),
4.46 (1H, d, J¼11.1 Hz), 4.57 (1H, d, J¼11.1 Hz), 5.35 (1H, dt, J¼10.8,
7.2 Hz), 5.51 (1H, dt, J¼10.8, 7.2 Hz), 6.88 (2H, d, J¼8.6 Hz), 7.28 (2H,
d, J¼8.6 Hz); 13C NMR:
d 14.2, 22.7, 27.5, 29.3, 29.6, 31.6, 36.3 (d,
J¼132.4 Hz), 53.1 (2C), 55.4, 72.4, 84.2, 114.0 (2C), 123.3, 129.6, 129.8
(2C), 133.6, 159.6, 204.1 (d, J¼7.5 Hz); HRMS (FAB): m/z calcd for
C
21H34O6P ([MþH]þ) 413.2093, found 413.2093.
chromatography (hexane/EtOAc¼4:1) to give 13 (1.72 g, 73%) as
24
a colorless oil. [
a]
ꢁ71.2 (c 0.960, CHCl3); IR: nmax 1778 (s), 1708
4.9. Methyl (5Z,8R,9E,12S,14Z)-8-(tert-butyldimethylsilyl)oxy-
12-(4-methoxyphenyl)methoxy-11-oxo-5,9,14-icosatrienoate
(15)
D
(m), 1612 (w), 1513 (m), 1248 (s); 1H NMR:
d
0.87 (3H, t, J¼7.1 Hz),
1.22e1.38 (6H, m), 2.05 (2H, q, J¼6.8 Hz), 2.48e2.65 (2H, m), 2.70
(1H, dd, J¼13.3, 9.6 Hz), 3.23 (1H, dd, J¼13.3, 3.2 Hz), 3.79 (3H, s),
4.12e4.18 (2H, m), 4.48 (1H, d, J¼11.2 Hz), 4.53 (1H, d, J¼11.2 Hz),
4.55e4.63 (1H, m), 5.12 (1H, dd, J¼7.0, 5.2 Hz), 5.44e5.57 (2H, m),
A mixture of 6 (576 mg, 1.40 mmol) and LiBr (243 mg,
2.80 mmol) in THF (14 mL) was stirred at room temperature for
30 min. To the mixture was added Et3N (0.260 mL, 1.90 mmol) and
the mixture was stirred for 1 h. Then a solution of 5 (400 mg,
1.27 mmol) in THF (12 mL) was added, and the resulting mixture
was stirred overnight at room temperature. The mixture was
quenched with saturated aq NH4Cl and extracted with Et2O. The
extract was washed with brine, dried (MgSO4), and concentrated in
vacuo. The residue was purified by silica gel column chromatog-
raphy (hexane/EtOAc¼10:1 to 1:1) to give 15 (668 mg, 80%) as
6.86 (2H, d, J¼8.6 Hz), 7.19 (2H, d, J¼6.8 Hz), 7.24e7.35 (5H, m); 13
C
NMR:
d 14.2, 22.7, 27.5, 29.4, 31.1, 31.6, 38.0, 55.1, 55.4, 66.8, 72.5,
76.6, 113.8 (2C), 123.5, 127.5, 129.1 (2C), 129.6 (2C), 129.8, 130.1 (2C),
133.5, 135.2, 153.1, 159.5, 172.8; HRMS (FAB): m/z calcd for
C
28H35NO5Na ([MþNa]þ) 488.2413, found 488.2413.
4.7. (2S,4Z)-N-Methoxy-2-(4-methoxyphenyl)methoxy-N-
methyl-4-decenamide (14b)
a pale yellow oil. [
a]
22 ꢁ37.0 (c 1.10, CHCl3); IR: nmax 1739 (s), 1696
D
To a stirred solution of 13 (0.320 g, 0.687 mmol) in THF/H2O (3:1,
12 mL) were successively added 30% aq H2O2 (0.270 g, 2.35 mmol)
and LiOH$H2O (60.4 mg, 1.44 mmol) at 0 ꢀC. After 3 h, the mixture
was quenched with 1.5 M aq Na2SO3 and gradually warmed to room
temperature over 2 h. The mixture was concentrated in vacuo, and
the residue was diluted with saturated aq NaHCO3 and extracted
with Et2O. The aqueous layer was acidified with 2 M aq HCl and
extracted with CH2Cl2. The extract was washed with brine, dried
(MgSO4), and concentrated in vacuo to give crude 14a (197 mg),
which was taken up in CH2Cl2 (4 mL). To the solution were suc-
cessively added MeNH(OMe)$HCl (94.2 mg, 96.6 mmol), DMAP
(118 mg, 96.7 mmol), and DCC (199 mg, 96.7 mmol) while stirring at
0 ꢀC. The mixture was gradually warmed to room temperature over
3 h and filtered through a pad of Celite. The filtrate was successively
washed with saturated aq NH4Cl, saturated NaHCO3, and brine,
dried (MgSO4), and concentrated in vacuo. The residue was purified
(w), 1630 (w), 1514 (m), 1249 (s); 1H NMR:
d
0.03 (3H, s), 0.06 (3H,
s), 0.87 (3H, t, J¼7.0 Hz), 0.90 (9H, s), 1.20e1.35 (6H, m), 1.68 (2H,
quint, J¼7.4 Hz), 1.98 (2H, q, J¼7.4 Hz), 2.05 (2H, q, J¼6.9 Hz),
2.23e2.36 (4H, m), 2.36e2.50 (2H, m), 3.66 (3H, s), 3.80 (3H, s), 3.92
(1H, t, J¼6.6 Hz), 4.32 (1H, d, J¼11.5 Hz), 4.32e4.37 (1H, m), 4.53
(1H, d, J¼11.5 Hz), 5.31e5.52 (4H, m), 6.69 (1H, dd, J¼15.6, 1.3 Hz),
6.86 (2H, d, J¼8.6 Hz), 6.99 (1H, dd, J¼15.6, 4.4 Hz), 7.24 (2H, d,
J¼8.6 Hz); 13C NMR:
d
ꢁ4.7, ꢁ4.5, 14.2, 18.3, 22.7, 24.8, 25.9 (3C),
26.9, 27.5, 29.3, 30.5, 31.6, 33.6, 35.5, 51.6, 55.4, 71.8, 72.0, 83.8,113.9
(2C), 123.2, 123.5, 125.5, 129.5 (2C), 129.8, 131.4, 133.2, 150.1, 159.4,
174.1, 201.0; HRMS (FAB): m/z calcd for C35H56O6SiNa ([MþNa]þ)
623.3743, found 623.3741.
4.10. Methyl (5Z,8R,9E,11S,12S,14Z)-8-(tert-butyldimethylsilyl)
oxy-11-hydroxy-12-(4-methoxyphenyl)methoxy-5,9,14-
icosatrienoate (4)
by silica gel column chromatography (hexane/EtOAc¼5:1) to give
24
14b (192 mg, 80% from 13) as a yellow oil. [
a
]
ꢁ53.4 (c 1.00,
A mixture of 15 (145 mg, 0.241 mmol) and CeCl3$7H2O (98.2 mg,
0.264 mmol) in MeOH (4 mL) was stirred at room temperature for
5 min. To the mixture was added dropwise a solution of NaBH4
(9.03 mg, 0.239 mmol) in MeOH (0.8 mL) at ꢁ78 ꢀC and the
resulting mixture was stirred for 1 h. The mixture was quenched
with saturated aq NH4Cl, gradually warmed to room temperature,
D
CHCl3); IR: nmax 1672 (s), 1613 (m),1513 (s), 1247 (s); 1H NMR:
d 0.87
(3H, t, J¼7.0 Hz), 1.20e1.36 (6H, m), 2.01 (2H, q, J¼6.9 Hz),
2.46e2.52 (2H, m), 3.21 (3H, s), 3.57 (3H, s), 3.80 (3H, s), 4.28 (1H, br
t J¼5.5 Hz), 4.35 (1H, d, J¼11.7 Hz), 4.62 (1H, d, J¼11.7 Hz),
5.39e5.53 (2H, m), 6.86 (2H, d, J¼8.6 Hz), 7.28 (2H, d, J¼8.6 Hz); 13
C

R. Towada, S. Kuwahara / Tetrahedron 70 (2014) 3774e3781
3779
and extracted with Et2O. The extract was washed with brine, dried
(MgSO4), and concentrated in vacuo. The residue was purified by
silica gel column chromatography (hexane/EtOAc¼10:1e4:1) to
113.7 (2C), 125.6, 125.8, 128.2, 129.7 (2C), 131.0, 132.1, 132.2, 136.4,
159.2, 174.2; HRMS (FAB): m/z calcd for C30H46O6Na ([MþNa]þ)
525.3192, found 525.3191.
give 4 (142 mg, 98%) as a pale yellow oil. [
a]
23 þ3.45 (c 1.00, CHCl3);
D
IR: nmax 3529 (w), 3006 (w), 1739 (m), 1613 (w), 1513 (m), 1248 (s);
4.13. (5Z,8R,9E,11S,12S,14Z)-8-Hydroxy-11-methoxy-12-(4-
methoxyphenyl)methoxy-5,9,14-icosatrienoic acid (17)
1H NMR:
d
0.03 (3H, s), 0.05 (3H, s), 0.86e0.91 (12H, m), 1.22e1.39
(6H, m),1.68 (2H, quint, J¼7.5 Hz),1.97e2.10 (4H, m), 2.17e2.34 (5H,
m), 2.36e2.44 (1H, m), 2.56 (1H, br s, OH), 3.33 (1H, q, J¼5.6 Hz),
3.66 (3H, s), 3.80 (3H, s), 4.04 (1H, br s), 4.11e4.19 (1H, m), 4.45 (1H,
d, J¼11.0 Hz), 4.62 (1H, d, J¼11.0 Hz), 5.37e5.53 (4H, m), 5.64 (1H,
dd, J¼15.3, 6.2 Hz), 5.76 (1H, dd, J¼15.3, 5.3 Hz), 6.87 (2H, d,
To a stirred mixture of 16b (78.0 mg, 0.155 mmol) in THF/H2O
(3:1, 2 mL) was added LiOH$H2O (64.5 mg, 1.54 mmol) at room
temperature and the resulting mixture was stirred at 40 ꢀC for 16 h.
The mixture was cooled to room temperature, quenched with 1 M
oxalic acid, and extracted with CH2Cl2. The extract was washed
with brine, dried (MgSO4), and concentrated in vacuo. The residue
was purified by silica gel column chromatography (hexane/
J¼8.2 Hz), 7.25 (2H, d, J¼8.2 Hz); 13C NMR:
d
ꢁ4.6, ꢁ4.2, 14.2, 18.4,
22.7, 24.9, 26.0 (3C), 26.9, 27.6, 28.5, 29.4, 31.7, 33.6, 36.4, 51.6, 55.4,
72.3, 72.6, 73.5, 82.2, 114.0 (2C), 124.7, 126.7, 128.8, 129.6 (2C), 130.5
(2C), 132.6, 135.9, 159.4, 174.2; HRMS (FAB): m/z calcd for
EtOAc¼1:1) to give 17 (75.2 mg, 99%) as a colorless oil. [
a
]
19 þ5.50
D
C
35H58O6SiNa ([MþNa]þ) 625.3901, found 625.3896.
(c 1.07, CHCl3); IR: nmax 3397 (m), 3005 (m), 1709 (s), 1614 (w), 1514
(s), 1248 (s); 1H NMR:
d
0.88 (3H, t, J¼6.7 Hz), 1.20e1.38 (6H, m),
4.11. Methyl (5Z,8R,9E,11S,12S,14Z)-8-(tert-Butyldimethylsilyl)
oxy-11-methoxy-12-(4-methoxyphenyl)methoxy-5,9,14-
icosatrienoate (16a)
1.70 (2H, quint, J¼7.1 Hz), 2.01 (2H, q, J¼6.7 Hz), 2.11 (2H, q,
J¼7.1 Hz), 2.17e2.26 (1H, m), 2.26e2.42 (5H, m), 3.29 (3H, s), 3.39
(1H, q, J¼5.7 Hz), 3.63 (1H, dd, J¼6.6, 4.9 Hz), 3.79 (3H, s), 4.18 (1H,
q, J¼5.7 Hz), 4.53 (1H, d, J¼11.7 Hz), 4.56 (1H, d, J¼11.7 Hz),
5.34e5.56 (4H, m), 5.64 (1H, dd, J¼15.6, 7.2 Hz), 5.73 (1H, dd,
J¼15.6, 5.4 Hz), 6.85 (2H, d, J¼8.3 Hz), 7.26 (2H, d, J¼8.3 Hz); 13C
To a stirred solution of 4 (142 mg, 0.236 mmol) and HMPA
(0.140 mL, 0.826 mmol) in THF (2.4 mL) was added dropwise a so-
lution of NaHMDS (1.0 M in THF, 0.230 mL, 0.230 mmol) at ꢁ78 ꢀC.
After 1 h, MeI (0.23 mL, 0.230 mmol) was added, and the resulting
mixture was stirred at ꢁ78 ꢀC for 5 h. The mixture was gradually
warmed to room temperature and stirred overnight. The mixture
was quenched with saturated aq NH4Cl and extracted with Et2O.
The extract was washed with brine, dried (MgSO4), and concen-
trated in vacuo. The residue was purified by silica gel column
NMR:
d 14.2, 22.7, 24.6, 26.7, 27.5, 28.7, 29.4, 31.7, 33.4, 35.3, 55.4,
57.0, 71.8, 72.5, 81.0, 83.2, 113.7 (2C), 125.6, 125.9, 128.1, 129.7 (2C),
130.9, 131.9, 132.2, 136.4, 159.2, 178.8; HRMS (FAB): m/z calcd for
C
29H44O6Na ([MþNa]þ) 511.3036, found 511.3038.
4.14. (6Z,9R)-4,5,8,9-Tetrahydro-9-[(1E,3S,4S,6Z)-3-methoxy-
4-(4-methoxyphenyl)methoxy-1,6-dodecadienyl]-2(3H)-ox-
oninone (18)
chromatography (hexane/EtOAc¼10:1 to 4:1) to give 16a (119 mg,
20
82%) as a colorless oil. [
a]
ꢁ7.72 (c 0.950, CHCl3); IR: nmax 3008
D
(w), 1740 (s), 1613 (w), 1514 (m), 1248 (s), 1081 (s); 1H NMR:
d
0.04
To a stirred solution of 17 (57.5 mg, 0.118 mmol) and DIPEA
(3H, s), 0.06 (3H, s), 0.88 (3H, t, J¼7.3 Hz), 0.89 (9H, s), 1.20e1.37
(6H, m), 1.67 (2H, quint, J¼7.4 Hz), 1.96e2.09 (4H, m), 2.13e2.24
(2H, m), 2.24e2.39 (4H, m), 3.28 (3H, s), 3.33e3.39 (1H, m), 3.60
(1H, dd, J¼7.6, 5.1 Hz), 3.66 (3H, s), 3.79 (3H, s), 4.16 (1H, q,
J¼5.8 Hz), 4.52 (1H, d, J¼11.4 Hz), 4.59 (1H, d, J¼11.4 Hz), 5.34e5.49
(4H, m), 5.55 (1H, dd, J¼15.7, 7.6 Hz), 5.66 (1H, dd, J¼15.7, 5.8 Hz),
(145
m
L, 0.833 mmol) in THF (2.4 mL) was added 2,4,6-
trichlorobenzoyl chloride (92.0
m
L, 0.589 mmol) at 0 ꢀC. After
30 min, the mixture was warmed to room temperature and stirred
for 1.5 h. The mixture was filtered and the filtrate was concentrated
in vacuo. The residue was diluted with toluene (8 mL) and added
dropwise to a solution of DMAP (360 mg, 2.95 mmol) in toluene
(100 mL) at 90 ꢀC over 8 h. After being stirred at 90 ꢀC for an ad-
ditional 1 h, the mixture was cooled to room temperature and di-
luted with EtOAc. The resulting solution was successively washed
with 0.5 M aq HCl, saturated aq NaHCO3, and brine, dried (MgSO4),
and concentrated in vacuo. The residue was purified by silica gel
column chromatography (hexane/EtOAc¼10:1) to give 18 (52.7 mg,
6.85 (2H, d, J¼8.3 Hz), 7.26 (2H, d, J¼8.3 Hz); 13C NMR:
ꢁ4.6, ꢁ4.3,
d
14.2, 18.3, 22.7, 24.9, 26.0 (3C), 26.9, 27.5, 28.9, 29.4, 31.7, 33.6, 36.4,
51.6, 55.4, 56.8, 72.7, 72.9, 81.4, 83.9, 113.7 (2C), 125.7, 126.6, 127.2,
129.5 (2C), 130.4, 131.2, 132.1, 137.7, 159.1, 174.1; HRMS (FAB): m/z
calcd for C36H60O6SiNa ([MþNa]þ) 639.4057, found 639.4053.
4.12. (5Z,8R,9E,11S,12S,14Z)-8-Hydroxy-11-methoxy-12-(4-
methoxyphenyl)methoxy-5,9,14-icosatrienoate (16b)
95%) as a colorless oil. [
a
]
D
19 þ57.0 (c 1.40, CHCl3); IR: nmax 3009 (w),
1740 (s), 1612 (w), 1513 (m), 1247 (m), 1079 (s); 1H NMR:
d
0.88 (3H,
t, J¼6.7 Hz), 1.20e1.38 (6H, m), 1.75e1.86 (1H, m), 1.97e2.13 (5H,
m), 2.18e2.55 (6H, m), 3.30 (3H, s), 3.37 (1H, q, J¼5.7 Hz), 3.60e3.65
(1H, m), 3.79 (3H, s), 4.53 (1H, d, J¼11.6 Hz), 4.58 (1H, d, J¼11.6 Hz),
5.29 (1H, br d, J¼10.8 Hz), 5.35e5.56 (4H, m), 5.69e5.79 (2H, m),
TBS ether 16a (97.4 mg, 0.158 mmol) and a solution of TBAF
(1.0M in THF, 0.470 mL, 0.470 mmol) was mixed at 0 ꢀC, and the
mixture was stirred at the same temperature for 30 min. The
mixture was warmed to room temperature and stirred for an ad-
ditional 3 h. The mixture was quenched with saturated aq NH4Cl
and extracted with Et2O. The extract was washed with brine, dried
(MgSO4), and concentrated in vacuo. The residue was purified by
silica gel column chromatography (hexane/EtOAc¼2:1) to give 16b
6.85 (2H, d, J¼8.4 Hz), 7.26 (2H, d, J¼8.4 Hz); 13C NMR:
d 14.2, 22.7,
25.4, 26.6, 27.5, 28.6, 29.4, 31.7, 33.6, 34.6, 55.4, 57.1, 72.36, 72.42,
80.7, 83.0, 113.7 (2C), 124.5, 125.4, 129.5, 129.7 (2C), 130.9, 131.7,
132.3, 135.2, 159.2, 173.9; HRMS (FAB): m/z calcd for C29H42O5Na
([MþNa]þ) 493.2929, found 493.2928.
(78.0 mg, 98%) as a colorless oil. [
a
]
D
20 þ4.17 (c 1.27, CHCl3); IR: nmax
3459 (m), 3006 (w), 1737 (s), 1613 (m), 1514 (s), 1247 (s); 1H NMR:
4.15. (6Z,9R)-4,5,8,9-Tetrahydro-9-[(1E,3S,4S,6Z)-4-hydroxy-3-
methoxy-1,6-dodecadienyl]-2(3H)-oxoninone (2)
d
0.88 (3H, t, J¼6.6 Hz), 1.21e1.38 (6H, m), 1.70 (2H, quint, J¼7.4 Hz),
1.77 (1H, d, J¼3.9 Hz, OH), 2.01 (2H, q, J¼6.8 Hz), 2.09 (2H, q,
J¼7.2 Hz), 2.16e2.26 (1H, m), 2.26e2.42 (5H, m), 3.29 (3H, s),
3.34e3.41 (1H, m), 3.63 (1H, dd, J¼7.2, 4.9 Hz), 3.66 (3H, s), 3.79
(3H, s), 4.14e4.22 (1H, m), 4.55 (2H, s), 5.35e5.56 (4H, m), 5.64 (1H,
dd, J¼15.5, 7.2 Hz), 5.73 (1H, dd, J¼15.5, 5.5 Hz), 6.85 (2H, d,
To a stirred mixture of 18 (50.0 mg, 0.106 mmol) in CH2Cl2/H2O
(10:1, 1.1 mL) was added DDQ (72.3 mg, 0.319 mmol) at 0 ꢀC. After
2 h, the mixture was quenched with saturated aq NaHCO3 and
extracted with CH2Cl2. The extract was washed with brine, dried
(MgSO4), and concentrated in vacuo. The residue was purified by
silica gel column chromatography (hexane/EtOAc¼4:1) to give 2
J¼8.4 Hz), 7.26 (2H, d, J¼8.4 Hz); 13C NMR:
d 14.2, 22.7, 24.8, 26.8,
27.5, 28.7, 29.4, 31.7, 33.5, 35.4, 51.7, 55.4, 57.0, 71.7, 72.6, 81.0, 83.3,

3780
R. Towada, S. Kuwahara / Tetrahedron 70 (2014) 3774e3781
21
(36.7 mg, 99%) as a colorless oil. [
a
]
þ77.2 (c 0.820, MeOH); IR:
purified by silica gel column chromatography (hexane/
D
19
nmax 3476 (m), 3012 (m), 1742 (s), 1138 (m), 1080 (m); 1H NMR
EtOAc¼10:1) to give 20a (97.4 mg, 88%) as a pale yellow oil. [
þ62.0 (c 0.900, CHCl3); IR: nmax 1741 (m), 1613 (w), 1513 (m), 1247
(m), 1079 (s); 1H NMR:
0.88 (3H, t, J¼6.7 Hz), 1.15 (3H, t, J¼7.0 Hz),
a]
D
(CD3OD):
d
0.90 (3H, t, J¼6.6 Hz), 1.24e1.40 (7H, m), 1.70e1.83 (1H,
m), 1.99e2.25 (7H, m), 2.29e2.58 (4H, m), 3.29 (3H, s), 3.47e3.53
(2H, m), 5.24e5.30 (1H, m), 5.41e5.53 (4H, m), 5.69 (1H, dd, J¼15.6,
7.4 Hz), 5.86 (1H, dd, J¼15.6, 5.4 Hz); 13C NMR (CD3OD,
d
1.20e1.37 (9H, m), 1.74e1.86 (1H, m), 1.96e2.13 (5H, m), 2.13e2.54
(6H, m), 3.36e3.53 (2H, m), 3.53e3.66 (1H, m), 3.80 (3H, s), 4.08
(0.4ꢂ1H, t, J¼5.8 Hz), 4.16e4.20 (0.6ꢂ1H, m), 4.49e4.62 (2H, m),
4.70 (0.6ꢂ1H, q, J¼5.4 Hz), 4.75 (0.4ꢂ1H, q, J¼5.4 Hz), 5.24e5.31
(1H, m), 5.39e5.56 (4H, m), 5.70e5.88 (2H, m), 6.85 (0.6ꢂ2H, d,
J¼8.4 Hz), 6.86 (0.4ꢂ2H, d, J¼8.4 Hz), 7.26 (2H, d, J¼8.4 Hz); 13C
d
49.00 ppm): d 14.4, 23.6, 26.3, 27.6, 28.4, 30.4, 31.8, 32.7, 34.4, 35.5,
57.0, 73.9, 74.8, 85.7, 125.6, 126.6, 130.1, 132.7, 134.0, 136.2, 175.6;
HRMS (FAB): m/z calcd for C21H34O4Na ([MþNa]þ) 373.2355, found
373.2354.
NMR:
d 14.2, 15.3/15.5, 20.4/20.6, 22.7, 25.4, 26.6, 27.5/27.6, 28.4/
4.16. (5Z,8R,9E,11S,12S,14Z)-11-[(R/S)-1-Ethoxyethoxy]-8-
hydroxy-12-(4-methoxyphenyl)methoxy-5,9,14-icosatrienoic
aicd (19c)
28.6, 29.4, 31.7, 33.6, 34.55/34.61, 55.3/55.4, 59.4/60.7, 72.5, 77.8,
81.0, 81.1 97.8/100.2, 113.69/113.74 (2C), 124.5, 125.6/125.8, 129.55/
129.64 (2C), 130.2/130.3, 130.8/130.9, 131.5, 131.9/132.0, 135.1,
159.21/159.23, 173.8/173.9; HRMS (FAB): m/z calcd for C32H48O6Na
([MþNa]þ) 551.3349, found 551.3347.
To a stirred mixture of 4 (134 mg, 0.222 mmol) and ethyl vinyl
ether (32.0
mL, 0.334 mmol) in CH2Cl2 (2 mL) was added PPTS
(7.4 mg, 0.029 mmol) at room temperature. After being stirred
overnight, the solution was poured into saturated aq NaHCO3 and
extracted with CH2Cl2. The extract was washed with brine, dried
(MgSO4), and concentrated in vacuo to give crude 19a, which was
dissolved in THF (0.7 mL). To the solution was added a solution of
TBAF (1 M in THF, 0.70 mL, 0.70 mmol) at 0 ꢀC, and the mixture was
stirred for 1 h. The mixture was warmed to room temperature,
stirred for an additional 3 h, and quenched with saturated aq NH4Cl.
The mixture was extracted with Et2O, and the extract was washed
with brine, dried (MgSO4), and concentrated in vacuo to give crude
19b, which was then taken up in a THF/H2O (3:1, 4.4 mL). To the
solution was added LiOH$H2O (37.6 mg, 0.896 mmol) at room
temperature and the mixture was stirred overnight at 40 ꢀC. The
mixture was quenched with saturated aq NH4Cl and extracted with
CH2Cl2. The extract was washed with brine, dried (Na2SO4), and
concentrated in vacuo. The residue was purified by silica gel column
4.18. (6Z,9R)-9-[(1E,3R,4S,6Z)-3,4-Epoxy-1,6-dodecadienyl]-
4,5,8,9-tetrahydro-2(3H)-oxoninone (3)
To a stirred solution of 20a (66.0 mg, 0.125 mmol) in EtOH
(1.2 mL) was added PPTS (94.1 mg, 0.375 mmol) at room temper-
ature. After being stirred overnight, the solution was quenched
with saturated aq NaHCO3 and extracted with CH2Cl2. The extract
was washed with brine, dried (MgSO4), and concentrated in vacuo
to give crude 20b, which was dissolved in CH2Cl2 (1.2 mL). To the
solution were successively added DIPEA (0.110 mL, 0.632 mmol),
DMAP (76.3 mg, 0.625 mmol), and Ms2O (76.2 mg, 0.437 mmol)
while stirring at 0 ꢀC. After 5 h, the solution was quenched with
saturated aq NH4Cl and extracted with CH2Cl2. The extract was
washed with brine, dried (Na2SO4), and concentrated in vacuo to
give crude 20c, which was taken up in CH2Cl2/pH 7 phosphate
buffer (10:1, 2.2 mL). To the solution was added DDQ (90.4 mg,
0.396 mmol) while stirring at 0 ꢀC, and the mixture was stirred
overnight at the same temperature. The mixture was quenched
with saturated aq NaHCO3 and extracted with CH2Cl2. The extract
was washed with brine, dried (Na2SO4), and concentrated in vacuo.
The residue was roughly purified by silica gel column chromatog-
raphy to remove p-methoxybenzaldehyde (hexane/EtOAc¼4:1) to
give crude 20d. The hydroxy mesylate 20d just obtained was dis-
solved in MeOH (1 mL) and mixed with K2CO3 (17.3 mg,
0.125 mmol) while stirring at ꢁ15 ꢀC. After 1 h, the mixture was
filtered into a stirred solution of Et2O/saturated aq NH4Cl at 0 ꢀC
and extracted with ether. The extract was washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
silica gel column chromatography (hexane/EtOAc¼8:1) to give 3
chromatography (hexane/EtOAc¼1:1) to give 19c (as a ca. 3:2 di-
19
astereomeric mixture, 115 mg, 94% from 4) as a colorless oil. [
a
]
D
þ11.2 (c 1.57, CHCl3); IR: nmax 1709 (m), 1514 (m), 1246 (s), 1037 (s);
1H NMR:
d
0.878 (0.6ꢂ3H, t, J¼6.8 Hz), 0.884 (0.4ꢂ3H, t, J¼6.8 Hz),
1.15 (0.6ꢂ3H, t, J¼7.0 Hz), 1.16 (0.4ꢂ3H, t, J¼7.0 Hz), 1.22e1.37 (9H,
m), 1.71 (2H, quint, J¼7.2 Hz), 2.00 (2H, q, J¼6.4 Hz), 2.12 (2H, q,
J¼7.2 Hz), 2.16e2.23 (1H, m), 2.25e2.37 (5H, m), 3.37e3.68 (3H, m),
3.80 (3H, s), 4.05e4.21 (2H, m), 4.52e4.61 (2H, m), 4.73 (0.6ꢂ1H, q,
J¼5.3 Hz), 4.75 (0.4ꢂ1H, q, J¼5.3 Hz), 5.40e5.56 (4H, m), 5.61e5.76
(2H, m), 6.85 (0.6ꢂ2H, d, J¼8.7 Hz), 6.86 (0.4ꢂ2H, d, J¼8.7 Hz), 7.26
(2H, d, J¼8.7 Hz); 13C NMR:
d 14.2, 15.3/15.4, 20.4/20.6, 22.7, 24.5,
26.7, 27.50/27.53, 28.5/28.6, 29.4, 31.0/33.3, 31.7, 35.2/35.3, 55.3,
59.2/61.0, 71.7/71.8, 72.6, 77.4/77.7, 81.2/81.4, 97.4/100.0, 113.69/
113.74 (2C), 125.8/125.9, 126.0, 128.0/128.8, 129.6/129.7 (2C), 130.8/
130.9, 131.75/131.78, 131.84/131.9, 134.9/136.2, 159.19/159.21, 178.5/
178.6; HRMS (FAB): m/z calcd for C32H50O7Na ([MþNa]þ) 569.3454,
found 569.3453.
(6.4 mg, 16% from 20a) as a colorless oil. [
a]
21 þ73 (c 0.22, MeOH);
D
IR: nmax 3011 (w), 1741 (s), 1257 (m), 1218 (m), 1136 (m); 1H NMR
(CD3OD):
d
0.90 (3H, t, J¼6.6 Hz), 1.26e1.41 (6H, m), 1.69e1.82 (1H,
m), 1.98e2.27 (7H, m), 2.32e2.58 (4H, m), 3.11 (1H, dt, J¼4.3,
6.4 Hz), 3.47 (1H, dd, J¼6.9, 4.3 Hz), 5.29 (1H, dd, J¼10.9, 5.6 Hz),
5.40 (1H, dt, J¼10.8, 7.3 Hz), 5.45e5.56 (3H, m), 5.75 (1H, dd, J¼15.5,
6.9 Hz), 6.03 (1H, dd, J¼15.5, 5.7 Hz); 13C NMR (CD3OD,
4.17. (6Z,9R)-9-{(1E,3S,4S,6Z)-3-[(R/S)-1-Ethoxyethoy]-4-(4-
methoxyphenyl)methoxy-1,6-dodecadienyl}-4,5,8,9-
tetrahydro-2(3H)-oxoninone (20a)
d
49.00 ppm): d 14.4, 23.7, 26.3, 27.0, 27.6, 28.4, 30.4, 32.7, 34.4, 35.4,
57.3, 59.5, 73.8, 124.7, 125.5, 127.3, 133.8, 135.2, 136.2, 175.6; HRMS
(FAB): m/z calcd for C20H30O3Na ([MþNa]þ) 341.2093, found
341.2092.
To a stirred solution of 19c (115 mg, 0.209 mmol) and DIPEA
(260
m
L,1.49 mmol) in THF (4 mL) was added 2,4,6-trichlorobenzoyl
chloride (163
m
L, 1.04 mmol) at 0 ꢀC. After 30 min, the mixture was
warmed to room temperature and stirred for 1.5 h. The mixture was
filtered and the filtrate was concentrated in vacuo. The residue was
diluted with toluene (6 mL) and added dropwise to a solution of
DMAP (638 mg, 5.23 mmol) in toluene (205 mL) at 90 ꢀC over 8 h.
After being stirred at 90 ꢀC for an additional 1 h, the mixture was
cooled to room temperature and diluted with EtOAc. The resulting
solution was successively washed with saturated aq NaHCO3 and
brine, dried (MgSO4), and concentrated in vacuo. The residue was
4.19. Conversion of topsentolide A2 (3) into topsentolide C2 (2)
To a stirred solution of 3 (1.5 mg, 4.7
m
mol) in MeOH (1 mL) was
added a solution of HCl in MeOH (0.125 M, 5.0
m
L, 0.63
m
mol) at 0 ꢀC.
The mixture was stirred at 0 ꢀC for 1 h and then at room temper-
ature for an additional 1 h. To the mixture was added again the
methanolic HCl solution (10
mL, 1.3 mmol) at room temperature and
the resulting solution was stirred for 1.5 h. The mixture was

R. Towada, S. Kuwahara / Tetrahedron 70 (2014) 3774e3781
3781
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extract was washed with brine, dried (Na2SO4), and concentrated in
vacuo to give 2 (1.7 mg, quant) as a virtually pure compound, as
judged by its 1H and 13C NMR spectra.
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Acknowledgements
This work was financially supported, in part, by a Grant-in-Aid
for Scientific Research (B) from the MEXT (No. 24658105).
Supplementary data
1H and 13C NMR spectra of 2, 3, key synthetic intermediates, and
the crude ring-opening product of 3. Supplementary data associ-
ated with this article can be found in the online version, at http://
dx.doi.org/10.1016/j.tet.2014.04.040. These data include MOL file
and InChiKeys of the most important compounds described in this
article.
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References and notes
18. No signal assignable to 11-epi-2,7 the product formed by the attack of MeOH at
the C11 position of 3 with retention of configuration, was observed in the 1H
and 13C NMR spectra of the crude reaction product. This means that the ep-
oxide ring-opening reaction took place with complete (or almost complete)
inversion of configuration, which might be in accord with the fact that 11-epi-2
was not isolated from the MeOH extract of Topsentia sp.
1. Luo, X.; Li, F.; Hong, J.; Lee, C.-O.; Sim, C. J.; Im, K. S.; Jung, J. H. J. Nat. Prod. 2006,
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Prog. Lipid Res. 2009, 48, 148e170; (b) Bottcher, C.; Pollmann, S. FEBS J. 2009,
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€