Stereoselective synthesis of malyngic acid and fulgidic acid

Article abstract of DOI:10.1016/j.tet.2011.01.005

A new stereoselective total synthesis of malyngic acid has been achieved from a known oxazolidinone derivative via eight steps involving the Evans asymmetric alkylation as the chirality-inducing step and chelation-controlled Zn(BH₄)₂

Full text of DOI:10.1016/j.tet.2011.01.005

Tetrahedron 67 (2011) 1649e1653
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Stereoselective synthesis of malyngic acid and fulgidic acid
*
Yusuke Kurashina, Ayako Miura, Masaru Enomoto, 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:
A new stereoselective total synthesis of malyngic acid has been achieved from a known oxazolidinone
derivative via eight steps involving the Evans asymmetric alkylation as the chirality-inducing step and
Received 20 December 2010
Received in revised form 28 December 2010
Accepted 4 January 2011
chelation-controlled Zn(BH4)2 reduction of an
a-hydroxy ketone intermediate for the installation of the
12,13-anti stereochemistry. Fulgidic acid, the C12-epimer of malyngic acid, has also been synthesized in
eight steps from the same starting material by using syn-selective K-Selectride reduction of an a-alkoxy
Available online 9 January 2011
ketone intermediate.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Malyngic acid
Fulgidic acid
Oxylipin
Total synthesis
Diastereoselective reduction
1. Introduction
and co-workers from the rice plant Oryza sativa along with its
15,16-dihydro analog 3. Both 2 and 3 were found to play an es-
sential role in the self defense of the rice plant by exhibiting anti-
fungal activity against the rice blast fungus Pyricularia oryzae.3
Compound 3 was later reisolated by Nagai and co-workers from
the medicinal plant Pinelliae tuber as an effective oral adjuvant for
nasal influenza vaccine, and named pinellic acid.4 The interesting
arrangement of hydroxyls on the unsaturated fatty acid chains of
1e3 as well as the agriculturally and medicinally important bio-
activities of 2 and 3, respectively, prompted a considerable number
of synthetic studies on these natural products.5e7 From the view-
point of methodology to install the C12,13-stereochemistry, those
syntheses could be classified into four groups: (1) ring opening of
a cis-substituted epoxide with oxygen nucleophiles;3 (2) the
Sharpless asymmetric oxidations;4b,5a,6e,7d,e,g,h (3) derivation from
natural products with an appropriate vicinal diol unit;5b,6b,c,7b,i,j,l
Malyngic acid (1), which belongs to the oxylipin family of nat-
ural products, was isolated by Cardellina and Moore from the
marine blue-green alga Lyngbya majuscula, and characterized as
a trihydroxy unsaturated fatty acid on the basis of spectroscopic
analyses coupled with chemical degradation to known compounds
(Fig. 1).1 Fulgidic acid (2), on the other hand, was first isolated by
Herz and Kulanthaivel from the terrestrial higher plant Rudbeckia
fulgida, and identified as the C12-epimer of 1 from the comparison
of its NMR data with those of malyngic acid (1).2 Soon after the
isolation from R. fulgida, the fatty acid 2 was also isolated by Kato
and (4) diastereoselective addition of organometallics to
a-oxy-
genated aldehydes.7f,k We describe herein a new stereodivergent
approach to 1 and 2 using two types of diastereoselective re-
ductions of chiral a-oxygenated ketone intermediates for the es-
tablishment of the C12,13-anti and cis stereochemistries embedded
in 1 and 2, respectively.
2. Results and discussion
Fig. 1. Structures of malyngic acid (1), fulgidic acid (2), and pinellic acid (3).
Our retrosynthetic analysis of 1 and 2 is shown in Scheme 1. We
envisaged that malyngic acid 1 with C12,13-anti stereochemistry
would be obtainable from 4 via a diastereoselective reduction un-
der chelation-controlled conditions, while fulgidic acid 2, the
* 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 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.005

1650
Y. Kurashina et al. / Tetrahedron 67 (2011) 1649e1653
C12,13-syn epimer of 1, could be synthesized from the common
intermediate 4 by means of a syn-selective reduction according to
of the oxazolidinone moiety of 10 with alkaline hydrogen peroxide
afforded carboxyallic acid 11, which was then converted into the
corresponding Weinreb amide 12 in 78% overall yield from 10.
Treatment of 12 with the carbanion prepared from dimethyl
methylphosphonate and n-BuLi gave keto phosphonate 5 in 94%
yield.11 In order to transform 10 into 5 in a single step, we also
attempted the direct treatment of 10 with the phosphonate carb-
anion in THF. This reaction, however, resulted in the formation of
a mixture containing the desired product 5 (35% isolated yield) and
amide 13 (24% isolated yield) stemming from the undesired nu-
cleophilic attack of the carbanion at the ring carbonyl.12
the FelkineAnh transition state model. The
a-alkoxy ketone in-
termediate 4 would be traced back to phosphonate 5 and aldehyde
6 by dissecting the double bond conjugated to the ketone function.
The PMBO-bearing chiral center of 5 was considered to be installed
by the Evans asymmetric alkylation of known oxazolidinone de-
rivative 7, and the
a-acetoxy aldehyde 6 would be prepared by the
oxidative cleavage of the double bond of known allylic alcohol 8.
1
2
The preparation of the other building block 6 was achieved in
two steps consisting of the acetylation of the known chiral allylic
alcohol 8 and ozonolysis of the resulting acetate 14 (Scheme 3);
compound 8 in turn was obtained in 80% yield with >98% enan-
tiomeric excess by the Sharpless kinetic resolution of the corre-
sponding racemate according to our previous procedure.7j The
HornereWadswortheEmmons (HWE) olefination between 5 and 6
proceeded smoothly to give 4 in 96% yield after chromatographic
removal of a minute amount of its Z-siomer contained in the crude
reaction product.
OPMB
OAc
CO2Me
O
4
O
PMBO
P(OMe)2
OAc
CO2Me
CO2Me
+
OHC
O
O
5
6
OR
CO2Me
OH
O3, CH2Cl2, Me2S
Bn
Ac2O, Py
93%
8: R = H
14: R = Ac
PMBO
86%
N
O
OAc
8
CO2Me
O
7
OHC
6
5, LiBr, Et3N, THF
Scheme 1. Retrosynthetic analysis of 1 and 2.
96%
OPMB
OAc
According to our synthetic plan, the starting material 78 was
subjected to the Evans asymmetric alkylation with (Z)-1-iodo-2-
pentene 99 to give 10 in 89% yield (Scheme 2).10 Hydrolytic removal
CO2Me
O
4
Scheme 3. Preparation of key intermediate 4.
Bn
NaHMDS
PMBO
THF
H2O2, LiOH
THF/H2O
With the key intermediate 4 in hand, we went on to the final
stage of the synthesis of 1 and 2 (Scheme 4). Oxidative removal of
the PMB group of 4 with DDQ gave hydroxy ketone 15, which was
then subjected to reduction with Zn(BH4)2.13 As was predicted from
many precedents, this chelation-controlled reduction proceeded
highly diastereoselectively to afford 12,13-anti diol 16 in 88% yield
after chromatographic purification. Finally, hydrolysis of the two
ester groups with aq LiOH furnished malyngic acid 1 as a white
solid, the spectral and physical properties of which showed good
agreement with those of the natural product.1 To synthesize the
other target molecule, fulgidic acid (2), the PMB-protected ketone 4
was reduced with K-Selectride in THF to give a 16:1 diastereomeric
mixture of 12,13-syn diol 17 and its C12-epimer.14 Reduction of 4
with L-Selectride/THF,15 NaBH4/CeCl3/MeOH,16 and NaBH4/MeOH
also gave the FelkineAnh product 17 preferentially in yields of 75%,
94%, and 98%, respectively, but the diastereoselectivities of these
conditions were lower (9:1, 5.7:1, 2.3:1, respectively) than that of
N
O
7
I
O
O
9
10
89%
MeNH(OMe)·HCl
DCC, DMAP
PMBO
PMBO
OMe
N
OH
CH2Cl2
O
O
78% from 10
11
12
MePO(OMe)2
n-BuLi, THF
94%
O
O
PMBO
H
N
O
P(OMe)2
PMBO
P(OMe)2
O
O
Bn
O
5
13
Scheme 2. Preparation of phosphonate intermediate 5.
OH
OAc
(CH2)7
OH
OAc
(CH2)7
Zn(BH4)2
DDQ
LiOH
CO2Me
CO2Me
1
4
CH2Cl2/H2O
96%
THF
88%
THF/H2O
49%
O
OH
16
15
TFA
OPMB
OAc
(CH2)7
OH
OAc
(CH2)7
K-Selectride
anisole
LiOH
CO2Me
CO2Me
2
THF
89%
THF/H2O
64%
CH2Cl2
70%
OH
17
OH
12-epi-16
Scheme 4. Stereodivergent conversion of 4 into 1 and 2.

Y. Kurashina et al. / Tetrahedron 67 (2011) 1649e1653
1651
the K-Selectride conditions. Deprotection of the PMB group of 17
with TFA in CH2Cl2 in the presence of anisole followed by chro-
matographic removal of a small amount of 16 originating from 12-
epi-17 afforded 12-epi-16,17 which was then hydrolyzed to give
fulgidic acid 2 as a white solid. The 1H and 13C NMR data of 2 were
identical with those of natural fulgidic acid.18
dd, J¼13.3, 3.3 Hz), 3.79 (3H, s), 4.12e4.17 (2H, m), 4.48 (1H, d,
J¼11.2 Hz), 4.53 (1H, d, J¼11.2 Hz), 4.56e4.62 (1H, m), 5.12 (1H, dd,
J¼7.1, 5.0 Hz), 5.43e5.56 (2H, m), 6.84e6.88 (2H, m), 7.18e7.21 (2H,
m), 7.27e7.35 (5H, m); 13C NMR:
d 14.1, 20.7, 30.8, 37.9, 55.0, 55.3,
66.7, 72.4, 76.5, 113.6 (2C), 122.8, 127.4, 128.9 (2C), 129.4 (2C), 129.7,
130.0 (2C), 134.8, 135.0, 153.0, 159.3, 172.7; HRMS (FAB): m/z calcd
for C25H29NO5Na, 446.1944; found, 446.1944 ([MþNa]þ).
3. Conclusion
4.1.3. (2S,4Z)-N-Methoxy-2-(4-methoxybenzyloxy)-N-methyl-4-hep-
tenamide (12). To a stirred solution of 10 (1.02 g, 2.41 mmol) in THF/
H2O (3:1, 48 mL) were added dropwise 30% aq H2O2 (930 mg,
8.20 mmol) and LiOH$H2O (200 mg, 4.77 mmol) at 0 ꢀC. After 1.5 h,
the mixture was quenched with 1.5 M aq Na2SO3 and gradually
warmed to room temperature over 1.5 h. The mixture was concen-
trated in vacuo, and the residue was diluted with EtOAc and
extracted with satd aq NaHCO3. The aqueous solution was acidified
with 2 M aq HCl to pH ca. 2, and extracted with CH2Cl2. The extract
was washed with brine, dried (MgSO4), and concentrated in vacuo to
give 11 (548 mg). To a stirred solution of 11 (539 mg, 2.04 mmol) in
CH2Cl2 (10 mL) were added MeNH(OMe)$HCl (300 mg, 3.08 mmol),
DMAP (429 mg, 3.51 mmol), and DCC (724 mg, 3.51 mmol) at 0 ꢀC
under N2. The mixture was gradually warmed to room temperature
over 3 h and filtered through a pad of Celite. The filtrate was suc-
cessively washed with satd aq NH4Cl, satd aq NaHCO3 and brine,
dried (MgSO4), and concentrated in vacuo. The residue was purified
by SiO2 column chromatography (hexane/EtOAc) to give 12 (570 mg,
An enantioselective total synthesis of malygic acid (1) was ach-
ieved in 26% overall yield from known oxazolidinone derivative 7 via
eight steps. The new synthetic route utilized the Evans asymmetric
alkylation as the chirality-inducing step and established the
12,13-anti stereochemistry of 1 by chelation-controlled Zn(BH4)2
reduction of a-hydroxy ketone intermediate 15 prepared from its
PMB-protected form 4. Fulgidic acid (2), the C12-epimer of 1, was
also synthesized from 7 in 25% overall yield via eight steps involving
syn-selective K-Selectride reduction of the common intermediate 4
as the pivotal transformation.
4. Experimental
4.1. General
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) unless otherwise
stated. Optical rotation values were measured with a Jasco DIP-371
polarimeter, and the mass spectra were obtained with Jeol JMS-700
spectrometer operated in the EI or FAB mode. Melting points were
determined with a Yanaco MP-J3 apparatus and are uncorrected.
Column chromatography was conducted with Merck silica gel 60
(7e230 mesh) or Kanto Kagaku silica gel 60 N (spherical neutral,
78% from 10). [
a
]
D
27 þ46.8 (c 1.10, CHCl3); IR: nmax 1670 (s), 1612 (m),
1513 (s),1246 (s); 1H NMR:
d
0.93 (3H, t, J¼7.6 Hz),1.99e2.08 (2H, m),
2.43e2.55 (2H, m), 3.20 (3H, s), 3.58 (3H, s), 3.80 (3H, s), 4.28 (1H, br
t, J¼5.7 Hz), 4.35 (1H, d, J¼11.5 Hz), 4.62 (1H, d, J¼11.5 Hz), 5.37e5.53
(2H, m), 6.84e6.88 (2H, m), 7.26e7.30 (2H, m); 13C NMR:
d 14.1, 20.5,
30.1, 32.3, 55.2, 61.3, 71.0, 75.0, 113.6 (2C), 123.6, 129.5 (2C), 129.9,
134.2, 159.2, 172.9; HRMS (FAB): m/z calcd for C17H26NO4, 308.1862;
found, 308.1865 ([MþH]þ).
particle size 100e210
mm). Solvents for reactions were distilled
prior to use: THF from Na and benzophenone; CH2Cl2 and CH3CN
from CaH2.
4.1.4. Dimethy [(S)-3-(4-methoxybenzyloxy)-2-oxo-5-octenyl]phos-
phonate (5). To a stirred solution of MeP(O)(OMe)2 (0.903 mL,
8.33 mmol) in THF (50 mL) was added dropwise a solution of n-BuLi
(1.59 M in hexane, 5.00 mL, 7.59 mmol) at ꢂ78 ꢀC under N2. After
1 h, a solution of 12 (513 mg, 1.67 mmol) in THF (10 mL) was added,
and the resulting mixture was stirred for 5 h. The mixture was
quenched with satd aq NH4Cl and extracted with EtOAc. The extract
was washed with brine, dried (MgSO4), and concentrated in vacuo.
The residue was purified by SiO2 column chromatography (hexane/
4.1.1. (Z)-1-Iodo-2-pentene (9). To
a stirred solution of (Z)-2-
penten-1-ol (0.500 mL, 4.95 mmol) and NaI (1.50 g, 10.0 mmol) in
CH3CN (15 mL) was added BF3$OEt2 (1.30 mL, 10.3 mmol) at 0 ꢀC
under N2. The mixture was stirred at room temperature for 1.25 h
and quenched with satd aq NaHCO3 and Na2S2O3. The mixture was
extracted with pentane and the extract was successively washed
with water (ꢁ2) and brine, dried (MgSO4), and concentrated in
vacuo to give 9 (694 mg, 71%). IR: nmax 3016 (m), 1640 (w), 1146 (s),
EtOAc) to give 5 (580 mg, 94%). [
a]
25 ꢂ17.3 (c 1.13, CHCl3); IR: nmax
D
1718 (w), 1612 (w), 1514 (m), 1247 (s), 1025 (vs); 1H NMR:
d 0.95
742 (m); 1H NMR:
(2H, d, J¼8.8 Hz), 5.48 (1H, dt, J¼10.6, 7.4 Hz), 5.68e5.77 (1H, m);
d
1.03 (3H, t, J¼7.6 Hz), 2.07e2.16 (2H, m), 3.92
(3H, t, J¼7.6 Hz), 1.99e2.08 (2H, m), 2.40e2.53 (2H, m), 3.16 (1H, dd,
J¼21.9, 14.6 Hz), 3.32 (1H, dd, J¼21.7, 14.6 Hz), 3.76 (3H, d, J¼5.7 Hz),
3.79 (3H, d, J¼5.5 Hz), 3.81 (3H, s), 4.46 (1H, d, J¼11.2 Hz), 4.57 (1H,
d, J¼11.2 Hz), 5.29e5.37 (1H, m), 5.47e5.54 (1H, m), 6.86e6.90 (2H,
13C NMR:
d 0.5, 13.0, 20.1, 126.0, 136.4; HRMS (EI): m/z calcd for
C5H9I, 195.9749; found, 195.9751 (Mþ). This compound was
chemically and isomerically pure enough to enable its direct use in
the next step without chromatographic purification.
m), 7.26e7.30 (2H, m); 13C NMR:
d 14.0, 20.6, 29.3, 36.2 (d,
J¼133.1 Hz), 52.9 (d, J¼5.3 Hz), 53.0 (d, J¼5.3 Hz), 55.2, 72.2, 84.0 (d,
J¼2.9 Hz), 113.8 (2C), 122.6, 129.4, 129.6 (2C), 134.9, 159.4, 203.9 (d,
J¼6.9 Hz); HRMS (FAB): m/z calcd for C18H28O6P, 371.1623; found,
371.1625 ([MþH]þ).
4.1.2. (R)-4-Benzyl-3-[(S)-2-(4-methoxybenzyloxy)-4-heptenoyl]-2-
oxazolidinone (10). To a stirred solution of NaHMDS (1.07 M in THF,
1.65 mL, 1.77 mmol) in THF (10 mL) was added dropwise a solution
of 7 (420 mg,1.18 mmol) in THF (5 mL) at ꢂ78 ꢀC under N2. After 1 h,
a solution of 9 (688 mg, 3.51 mmol) in THF (5 mL) was added, and
the resulting mixture was stirred at the same temperature for 3 h.
The mixture was quenched with satd aq NH4Cl and extracted with
hexane/EtOAc (1:1). The extract was washed with brine, dried
(MgSO4), and concentrated in vacuo. The residue was purified by
4.1.5. Methyl (S)-9-acetoxy-10-undecenoate (14). To a stirred solu-
tion of 8 (112 mg, 0.523 mmol) in pyridine (0.26 mL) was added
Ac2O (0.15 mL, 1.59 mmol) at room temperature. After 6.5 h, the
mixture was quenched with satd aq NaHCO3, stirred for 35 min, and
then extracted with ether. The extract was successively washed
with cold 1 M HCl (ꢁ2), satd aq NaHCO3, water and brine, dried
(MgSO4), and concentrated in vacuo. The residue was purified by
SiO2 column chromatography (hexane/EtOAc) to give 14 (124 mg,
SiO2 column chromatography (hexane/EtOAc) to give 10 (447 mg,
25
89%). [
a
]
ꢂ80.5 (c 1.10, CHCl3); IR: nmax 1775 (vs), 1705 (s), 1612
D
(w), 1513 (m), 1245 (s); 1H NMR:
(2H, m), 2.50e2.64 (2H, m), 2.70 (1H, dd, J¼13.3, 9.7 Hz), 3.23 (1H,
d
0.95 (3H, t, J¼7.6 Hz), 2.03e2.11
93%). [
a
]
25 ꢂ7.25 (c 1.02, CHCl3); IR: nmax 1736 (vs), 1650 (w), 1235
D
(s); 1H NMR:
d 1.25e1.34 (8H, m), 1.56e1.66 (4H, m), 2.06 (3H, s),

1652
Y. Kurashina et al. / Tetrahedron 67 (2011) 1649e1653
2.30 (2H, t, J¼7.7 Hz), 3.67 (3H, s), 5.13e5.25 (3H, m), 5.77 (1H, ddd,
temperature, and then re-cooled to 0 ꢀC. To the mixture was added
dropwise a solution of 15 (50.0 mg, 0.131 mmol) in THF (5 mL). After
30 min, the mixture was quenched with satd aq NH4Cl and
extracted with CH2Cl2. The extract was washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
SiO2 column chromatography (hexane/EtOAc) to give 16 (44.1 mg,
J¼17.3, 10.5, 6.3 Hz); 13C NMR:
d 21.2, 24.8, 24.9, 28.97, 29.04, 29.1,
34.0, 34.1, 51.4, 74.8, 116.5, 136.6, 170.3, 174.2; HRMS (FAB): m/z
calcd for C14H25O4, 257.1753; found, 257.1758 ([MþH]þ).
4.1.6. Methyl (S)-9-acetoxy-10-oxodecanoate (6). Ozone was bub-
bled into a stirred solution of 14 (124 mg, 0.484 mmol) in CH2Cl2
(6 mL) at ꢂ78 ꢀC until the disappearance of 14 was observed by TLC
monitoring. Me2S (excess) was then added, and the mixture was
gradually warmed to room temperature. The mixture was con-
88%). [
a
]
D
25 ꢂ20.1 (c 1.17, CHCl3); IR: nmax 3468 (m), 1736 (s), 1237 (s),
1020 (m); 1H NMR:
d
0.97 (3H, t, J¼7.6 Hz), 1.24e1.34 (8H, m),
1.52e1.69 (4H, m), 2.01e2.10 (2H, m), 2.05 (3H, s), 2.11e2.19 (1H,
m), 2.21e2.29 (1H, m), 2.30 (2H, t, J¼7.5 Hz), 2.48 (1H, br s, OH),
3.67 (3H, s), 3.66e3.72 (1H, m), 4.16 (1H, dd, J¼5.5, 3.9 Hz), 5.22
(1H, q, J¼6.5 Hz), 5.33e5.41 (1H, m), 5.52e5.59 (1H, m), 5.70 (1H,
centrated in vacuo, and the residue was purified by SiO2 column
25
chromatography (hexane/EtOAc) to give 6 (107 mg, 86%). [a]
D
ꢂ23.5 (c 1.15, CHCl3); IR: nmax 2725 (w), 1734 (s), 1230 (m); 1H NMR:
dd, J¼15.8, 6.5 Hz), 5.78 (1H, dd, J¼15.8, 6.0 Hz); 13C NMR:
d 14.2,
d
1.28e1.36 (6H, m),1.36e1.45 (2H, m),1.57e1.66 (2H, m),1.67e1.87
20.7, 21.3, 24.8, 25.0, 28.9, 29.00, 29.04, 29.8, 34.0, 34.3, 51.4, 73.8,
74.3 (2C), 124.1, 130.5, 131.5, 135.1, 170.5, 174.3; HRMS (FAB): m/z
calcd for C21H37O6, 385.2590; found, 385.2595 ([MþH]þ).
(2H, m), 2.18 (3H, s), 2.30 (2H, t, J¼7.5 Hz), 3.67 (3H, s), 4.98 (1H, br
dd, J¼8.3, 4.8H), 9.51 (1H, d, J¼0.8 Hz); 13C NMR:
d 20.6, 24.8, 28.5
(2C), 28.9 (2C), 29.0, 34.0, 51.4, 78.2, 170.6, 174.2, 198.3; HRMS
(FAB): m/z calcd for C13H23O5, 259.1545; found, 259.1550 ([MþH]þ).
4.1.10. (9S,10E,12R,13S,15Z)-9,12,13-Trihydroxy-10,15-octadecadie-
noate (1). A mixture of 16 (36.0 mg, 0.0936 mmol), water (0.05 mL),
and LiOH$H2O (43.6 mg,1.04 mmol) in THF (0.15 mL) was stirred for
3 h at room temperature and for an additional 1 h at 40 ꢀC. The
mixture was concentrated in vacuo, diluted with water, and then
extracted with ether. The aq solution was acidified with 0.9 M citric
acid to pH 3 and extracted with CH2Cl2. The extract was washed
with brine, dried (MgSO4), and concentrated in vacuo. The residue
was purified by SiO2 column chromatography (CH2Cl2/MeOH) to
give 1 (15.2 mg, 49%) as a white solid. Mp: 48.7e49.8 ꢀC (lit.1 mp
4.1.7. Methyl (9S,13S)-9-acetoxy-13-(4-methoxybenzyloxy)-12-oxo-
10,15-octadecadienoate (4). A mixture of 5 (821 mg, 2.22 mmol)
and LiBr$H2O (465 mg, 4.43 mmol) in THF (27 mL) was stirred at
room temperature for 30 min under N2. To the mixture was added
dropwise Et3N (0.37 mL, 2.65 mmol) and the mixture was stirred
for 1 h. A solution of 6 (601 mg, 2.33 mmol) in THF (22 mL) was then
added, and the resulting mixture was stirred overnight at room
temperature. The mixture was quenched with satd aq NH4Cl,
concentrated in vacuo, diluted with water, and then extracted with
ether. The extract was successively washed with water and brine,
dried (MgSO4), and concentrated in vacuo. The residue was purified
by SiO2 column chromatography (hexane/EtOAc) to give 4 (1.07 g,
22
24.5
48.5e51 ꢀC); [
MeOH), lit.5a
a
]
þ7.4 (c 0.730, MeOH) [lit.1
[
a
]
þ7.5 (c 1.2,
D
[
a]
Dþ7.7 (MeOH)]; IR: nmax 3316 (m), 1696 (s), 1434
D
(m), 1073 (s); 1H NMR (CD3CN):
d
0.94 (3H, t, J¼7.5 Hz), 1.24e1.34
(8H, m), 1.39e1.48 (2H, m), 1.50e1.59 (2H, m), 2.03 (2H, quint,
J¼7.3 Hz), 2.03e2.12 (1H, m), 2.14e2.22 (1H, m), 2.25 (2H, t,
J¼7.5 Hz), 3.50 (1H, dt, J¼8.4, 4.3 Hz), 3.91e3.95 (1H, m), 3.98e4.03
(1H, m), 5.39 (1H, dtt, J¼10.8, 6.8, 1.4 Hz), 5.46 (1H, dtt, J¼10.8, 6.8,
96%) as a single geometrical isomer. [
a]
25 ꢂ33.2 (c 1.16, CHCl3); IR:
D
nmax 1737 (s), 1698 (m), 1514 (m), 1232 (s); 1H NMR:
d 0.92 (3H, t,
J¼7.5 Hz), 1.26e1.36 (8H, m), 1.56e1.69 (4H, m), 1.93e2.05 (2H, m),
2.10 (3H, s), 2.30 (2H, t, J¼7.6 Hz), 2.44 (2H, t, J¼6.9 Hz), 3.66 (3H, s),
3.81 (3H, s), 3.92 (1H, t, J¼6.6 Hz), 4.36 (1H, d, J¼11.2 Hz), 4.49 (1H,
d, J¼11.2 Hz), 5.28e5.36 (1H, m), 5.38e5.44 (1H, m), 5.44e5.52 (1H,
m), 6.61 (1H, dd, J¼15.7, 1.5 Hz), 6.84e6.91 (3H, m), 7.22e7.27 (2H,
1.4 Hz), 5.59e5.68 (2H, m); 13C NMR (CD3OD):
d 14.6, 21.7, 26.1,
26.5, 30.2, 30.4, 30.5, 31.7, 35.0, 38.3, 73.3, 75.96, 76.02, 126.35,
130.6, 134.4, 136.8, 177.8; HRMS (FAB): m/z calcd for C18H32O5Na,
351.2148; found, 351.2151 ([MþNa]þ).
m); 13C NMR:
d 14.0, 20.6, 21.0, 24.8, 24.9, 28.96, 29.01, 29.1, 30.2,
33.8, 34.0, 51.4, 55.2, 72.0, 72.8, 83.8, 113.8 (2C), 122.6, 124.0, 129.4,
129.7 (2C), 134.7, 144.9, 159.4, 170.0, 174.2, 200.7; HRMS (EI): m/z
calcd for C29H42O7Na, 525.2829; found, 525.2830 ([MþNa]þ).
4.1.11. (9S,10E,12S,13S,15Z)-9-Acetoxy-12-hydroxy-13-(4-methox-
ybenzyloxy)-10,15-octadecadienoate (17). To a stirred solution of 4
(106 mg, 0.211 mmol) in THF (2.1 mL) was added K-Selectride (1 M
in THF, 0.220 mL, 0.220 mmol) at ꢂ78 ꢀC under N2. After 80 min, the
mixture was quenched with satd aq NH4Cl and extracted with
CH2Cl2. The extract was washed with brine, dried (Na2SO4), and
concentrated in vacuo. The residue was purified by SiO2 column
4.1.8. Methyl (9S,10E,13S,15Z)-9-acetoxy-13-hydroxy-12-oxo-10,15-
octadecadienoate (15). To
a stirred mixture of 4 (206 mg,
0.410 mmol) and water (0.4 mL) in CH2Cl2 (4.1 mL) was added DDQ
(280 mg, 1.23 mmol) at 0 ꢀC. The mixture was warmed to room
temperature and stirred overnight. The mixture was diluted with
water and extracted with CH2Cl2. The extract was successively
washed with water and brine, dried (MgSO4), and concentrated in
vacuo. The residue was purified by SiO2 column chromatography
chromatography (hexane/EtOAc) to give 17 (94.2 mg, 89%) as a 16:1
20
diastereomeric mixture. [
a]
ꢂ3.4 (c 2.57, CHCl3); IR: nmax 3508
D
(w), 1735 (s), 1613 (w), 1514 (m), 1240 (s); 1H NMR:
d 0.97 (3H, t,
J¼7.6 Hz), 1.24e1.33 (8H, m), 1.55e1.65 (4H, m), 2.00e2.08 (2H, m),
2.04 (3H, s), 2.24e2.32 (1H, m), 2.29 (2H, t, J¼7.5 Hz), 2.36e2.44
(1H, m), 2.54 (1H, d, J¼4.5 Hz, OH), 3.32e3.37 (1H, m), 3.66 (3H, s),
3.81 (3H, s), 4.01e4.07 (1H, m), 4.42 (1H, d, J¼11.0 Hz), 4.62 (1H, d,
J¼11.0 Hz), 5.21e5.27 (1H, m), 5.36e5.52 (2H, m), 5.66e5.75 (2H,
(hexane/EtOAc) to give 15 (151 mg, 96%). [
a]
25 þ4.5 (c 1.02, CHCl3);
D
IR: nmax 3481 (w), 1737 (s), 1697 (m), 1635 (m), 1231 (s); 1H NMR:
d
0.95 (3H, t, J¼7.5 Hz), 1.26e1.37 (8H, m), 1.57e1.70 (4H, m),
1.98e2.07 (2H, m), 2.11 (3H, s), 2.30 (2H, t, J¼7.6 Hz), 2.37e2.45 (1H,
m), 2.54e2.62 (1H, m), 3.48 (1H, br s, OH), 3.67 (3H, s), 4.43 (1H, t,
J¼5.5 Hz), 5.28e5.36 (1H, m), 5.39e5.45 (1H, m), 5.50e5.58 (1H, m),
6.36 (1H, dd, J¼15.6, 1.4 Hz), 6.90 (1H, dd, J¼15.6, 5.3 Hz); 13C NMR:
m), 6.86e6.90 (2H, m), 7.23e7.27 (2H, m); 13C NMR:
d 14.1, 20.7,
21.2, 24.8, 25.0, 28.0, 28.99, 29.04, 29.1, 34.0, 34.3, 51.4, 55.2, 72.1,
72.9, 74.1, 81.5, 113.8 (2C), 123.7, 129.5 (2C), 130.1, 130.9, 132.3, 134.1,
159.3, 170.3, 174.2; HRMS (FAB): m/z calcd for C29H44O7Na,
527.2985; found, 527.2985 ([MþNa]þ).
d
14.1, 20.7, 20.9, 24.77, 24.84, 28.9, 28.95, 29.01, 31.8, 33.7, 33.9, 51.4,
72.5, 75.3, 122.0, 123.9, 135.4, 145.7, 170.0, 174.2, 199.9; HRMS (FAB):
m/z calcd for C21H35O6, 383.2433; found, 383.2435 ([MþH]þ).
4.1.12. Methyl (9S,10E,12S,13S,15Z)-9-acetoxy-12,13-dihydroxy-10,15-
octadecadienoate (12-epi-16). To a stirred solution of 17 (25.8 mg,
4.1.9. Methyl (9S,10E,12R,13S,15Z)-9-acetoxy-12,13-dihydroxy-10,15-
octadecadienoate (16). To a stirred solution of ZnCl2 (71.2 mg,
0.522 mmol) in THF (1 mL) was added NaBH4 (40.0 mg, 1.06 mmol)
at 0 ꢀC under Ar. The mixture was stirred overnight at room
0.0511 mmol) and anisole (54
was added a solution of TFA (36
m
m
L, 0.50 mmol) in CH2Cl2 (4.7 mL)
L, 0.47 mmol) in CH2Cl2 (0.4 mL) at
0 ꢀC. After being stirred at room temperature for 30 h, the mixture
was quenched with satd aq NH4Cl and extracted with CH2Cl2. The

Y. Kurashina et al. / Tetrahedron 67 (2011) 1649e1653
1653
extract was washed with brine, dried (Na2SO4), and concentrated in
vacuo. The residue was purified by SiO2 column chromatography
(hexane/EtOAc) to give 12-epi-16 (13.7 mg, 70%) as a 16:1 di-
astereomeric mixture. This could be further purified by SiO2 col-
umn chromatography to afford diastereomerically pure 12-epi-16.
with this article can be found in the online version, at doi:10.1016/
j.tet.2011.01.005. These data include MOL files and InChiKeys of the
most important compounds described in this article.
[
a]
25 ꢂ36 (c 0.48, CHCl3); IR: nmax 3444 (w), 1736 (s), 1237 (s), 1019
References and notes
D
(m); 1H NMR:
d
0.97 (3H, t, J¼7.5 Hz), 1.24e1.34 (8H, m), 1.55e1.66
1. Cardellina, J. H., II; Moore, R. E. Tetrahedron 1980, 36, 993e996.
2. Herz, W.; Kulanthaivel, P. Phytochemistry 1985, 24, 89e91.
(4H, m), 1.69 (1H, s, OH), 2.01e2.11 (2H, m), 2.05 (3H, s), 2.20e2.32
(2H, m), 2.30 (3H, t, J¼7.6 Hz), 2.45 (1H, s, OH), 3.47e3.54 (1H, m),
3.67 (3H, s), 3.95e4.02 (1H, m), 5.20e5.26 (1H, m), 5.35e5.44 (1H,
3. (a) Kato, T.; Yamaguchi, Y.; Abe, N.; Uyehara, T.; Namai, T.; Kodama, M.; Shio-
bara, Y. Tetrahedron Lett. 1985, 26, 2357e2360; (b) Kato, T.; Yamaguchi, Y.;
Hirukawa, T.; Hoshino, N. Agric. Biol. Chem. 1991, 55, 1349e1357.
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Y.; Yamada, H. Int. Immunopharmacol. 2002, 2, 1183e1193; (b) Sunazuka, T.;
Shirahata, T.; Yoshida, K.; Yamamoto, D.; Harigaya, Y.; Nagai, T.; Kiyohara, H.;
Yamada, H.; Kuwajima, I.; Omura, S. Tetrahedron Lett. 2002, 43, 1265e1268; (c)
Nagai, T.; Shimizu, Y.; Shirahata, T.; Sunazuka, T.; Kiyohara, H.; Omura, S.; Ya-
mada, H. Int. Immunopharmacol. 2010, 10, 655e661.
m), 5.53e5.61 (1H, m), 5.68e5.77 (2H, m); 13C NMR:
d 14.2, 20.7,
21.3, 24.8, 24.9, 28.9, 28.99, 29.03, 30.8, 34.0, 34.2, 51.5, 73.97, 74.04,
74.5, 123.7, 131,4, 131.9, 135.2, 170.4, 174.3; HRMS (FAB): m/z calcd
for C21H37O6, 385.2590; found, 385.2591 ([MþH]þ).
5. For synthetic studies on 1, see: (a) Gurjar, M. K.; Reddy, A. S. Tetrahedron Lett.
1990, 31, 1783e1784; (b) Sharma, G. V. M.; Rao, S. M. Tetrahedron Lett. 1992, 33,
2365e2368.
4.1.13. (9S,10E,12S,13S,15Z)-9,12,13-Trihydroxy-10,15-octadecadie-
noate (2). A mixture of 12-epi-16 (53.5 mg, 0.139 mmol), water
(0.07 mL), and LiOH$H2O (35.0 mg, 0.834 mmol) in THF (0.21 mL)
was stirred for 2.5 h at room temperature and for an additional 1.5 h
at 40 ꢀC. The mixture was acidified with 1 M aq citric acid and
extracted with CH2Cl2. The extract was washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
6. For synthetic studies on 2, see: (a) Ref. 3; (b) Suemune, H.; Harabe, T.; Sakai, K.
ꢀ
ꢀ
Chem. Pharm. Bull. 1988, 36, 3632e3637; (c) Gosse-Kobo, B.; Mosset, P.; Gree, R.
Tetrahedron Lett. 1989, 30, 4235e4236; (d) Ref. 5b; (e) Sharma, P. K. Chem. Lett.
1994, 1825e1826.
7. For synthetic studies on 3, see: (a) Ref. 6b; (b) Quinton, P.; Le Gall, T. Tetrahedron
Lett. 1991, 32, 4909e4912; (c) Ref. 4b; (d) Shirahata, T.; Sunazuka, T.; Yoshida,
K.; Yamamoto, D.; Harigaya, Y.; Nagai, T.; Kiyohara, H.; Yamada, H.; Kuwajima, I.;
Omura, S. Bioorg. Med. Chem. Lett. 2003, 13, 937e941; (e) Shirahata, T.; Suna-
zuka, T.; Yoshida, K.; Yamamoto, D.; Harigaya, Y.; Kuwajima, I.; Nagai, T.;
Kiyohara, H.; Yamada, H.; Omura, S. Tetrahedron 2006, 62, 9483e9496; (f) Sa-
bitha, G.; Reddy, E. V.; Bhikshapathi, M.; Yadav, J. S. Tetrahedron Lett. 2007, 48,
313e315; (g) Naidu, S. V.; Kumar, P. Tetrahedron Lett. 2007, 48, 2279e2282; (h)
Naidu, S. V.; Gupta, P.; Kumar, P. Tetrahedron 2007, 63, 7624e7633; (i) Prasad, K.
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wahara, S. Tetrahedron 2009, 65, 3364e3368; (k) Sharma, A.; Mahato, S.;
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SiO2 column chromatography (CH2Cl2/MeOH) to give 2 (29.3 mg,
23
64%) as a white solid. Mp 71.5e72.3 ꢀC; [
a]
ꢂ12 (c 0.705, CHCl3)
D
[lit.18
[
a
]
D
ꢂ7.1 (c 1.0, CHCl3)]; IR: nmax 3536 (w), 3322 (m), 3013
25
(w), 1694 (s); 1H NMR (CD3OD):
d
0.97 (3H, t, J¼7.6 Hz), 1.29e1.38
(8H, m), 1.46e1.55 (2H, m), 1.55e1.64 (2H, m), 2.02e2.16 (3H, m),
2.28 (3H, t, J¼7.5 Hz), 2.35 (1H, dt, J¼14.6, 4.9 Hz), 3.43e3.48 (1H,
m), 3.96 (1H, t, J¼4.9 Hz), 4.05 (1H, q, J¼5.1 Hz), 5.41e5.50 (2H, m),
5.67e5.77 (2H, m); 13C NMR (CD3OD):
d 14.6, 21.7, 26.1, 26.5, 30.2,
30.4, 30.6, 31.5, 35.1, 38.3, 73.0, 75.8, 75.9, 126.4, 131.1, 134.3, 136.5,
177.9; HRMS (FAB): m/z calcd for C18H31O5, 327.2172; found,
327.2169 ([MꢂH]ꢂ).
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Acknowledgements
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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. 22380064).
€
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15512e15520.
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8, 5737e5740.
Supplementary data
17. Enomoto, M.; Kuwahara, S. Angew. Chem., Int. Ed. 2009, 48, 1144e1148.
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1H and 13C NMR spectra of compounds 9, 10, 12, 5, 14, 6, 4, 15, 16,
1, 17, 12-epi-16, and 2 can be found. Supplementary data associated