Synthesis of the (9R,13R)-isomer of LDS1, a flower-inducing oxylipin isolated from Lemna paucicostata

Article abstract of DOI:10.1080/09168451.2016.1166935

The first synthesis of the (9R,13R)-stereoisomer of LDS1, a flower-inducing oxylipin isolated from Lemna paucicostata, has been achieved from a known allylic alcohol by a seven-step sequence that involves the Horner-Wadsworth-Emmons olefination to constru

Full text of DOI:10.1080/09168451.2016.1166935

Bioscience, Biotechnology, and Biochemistry
ISSN: 0916-8451 (Print) 1347-6947 (Online) Journal homepage: http://www.tandfonline.com/loi/tbbb20
Synthesis of the (9R,13R)-isomer of LDS1, a
flower-inducing oxylipin isolated from Lemna
paucicostata
Yuki Takayasu, Yusuke Ogura, Ryo Towada & Shigefumi Kuwahara
To cite this article: Yuki Takayasu, Yusuke Ogura, Ryo Towada & Shigefumi Kuwahara
(
2016): Synthesis of the (9R,13R)-isomer of LDS1, a flower-inducing oxylipin isolated
from Lemna paucicostata, Bioscience, Biotechnology, and Biochemistry, DOI:
0.1080/09168451.2016.1166935
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Date: 30 May 2016, At: 03:27

Bioscience, Biotechnology, and Biochemistry, 2016
Synthesis of the (9R,13R)-isomer of LDS1, a flower-inducing oxylipin isolated
from Lemna paucicostata
Yuki Takayasu, Yusuke Ogura, Ryo Towada and Shigefumi Kuwahara*
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai,
Japan
Received March 1, 2016; accepted March 9, 2016
http://dx.doi.org/10.1080/09168451.2016.1166935
The first synthesis of the (9R,13R)-stereoisomer of
LDS1, a flower-inducing oxylipin isolated from
Lemna paucicostata, has been achieved from a
known allylic alcohol by a seven-step sequence that
involves the Horner–Wadsworth–Emmons olefina-
tion to construct its full carbon framework and an
enzymatic hydrolysis of a penultimate methyl ester
intermediate to provide the target molecule.
structure, LDS1 or its analogs are expected to be used as
a flowering inducer in agricultural and horticultural pro-
duction. Despite the potential usefulness, the total syn-
thesis of LDS1 has never been reported so far. As part of
our ongoing efforts toward the total synthesis of bioac-
6
−10)
tive oxylipins,
we describe herein the first total syn-
thesis of the (9R,13R)-LDS1 (1), the most abundant
stereoisomer of LDS1.
Key words: LDS1; oxylipin; flower induction;
Experimental
enzymatic hydrolysis; total synthesis
IR spectra were recorded by a Jasco FT/IR-4600
spectrometer using an ATR (ZnSe) attachment. NMR
spectra were recorded with TMS as an internal standard
In the course of studies to find flower-inducing sub-
stances from the free-floating aquatic plant Lemna pauci-
costata, Watanabe and co-workers isolated three
oxylipins from the plant pre-exposed to drought stress
and named them LDS1, LDS2, and LDS3. Among the
three compounds, LDS1 was found to induce flowering
in L. paucicostata at a very low concentration of 10 nM,
while LDS2 exhibited much lower activity than LDS1
in CDCl by a Varian MR-400 spectrometer (400 MHz
3
1
13
for H and 100 MHz for C). Optical rotation values
were measured with a Jasco P-2200 polarimeter. Mass
spectra were obtained with a Jeol JMS-700 spectrome-
ter operated in the FAB mode. Merck silica gel 60
1
)
(70–230 mesh) was used for column chromatography.
Solvents for reactions were distilled prior to use: THF
(
ca. 1/100) and LDS3 had no such effect. Based on spec-
and Et O from Na and benzophenone; EtOH from Na
troscopic analyses including the modified Mosher
method coupled with some additional experiments,
LDS1 was revealed to be a mixture of 1 [(9R,13R)-iso-
mer] and its three possible stereoisomers [1/(9R,13S)-iso-
mer/(9S,13R)-isomer/(9S,13S)-isomer = 9:3:3:1] (Fig. 1).
Quite interestingly, each of the four stereoisomers
showed almost the same activity as the naturally occur-
ring stereoisomeric mixture, which was ascribed to con-
formational flexibility of the molecules in their binding
2
and diethyl phthalate; MeOH from Mg(OMe)2;
CH Cl , and CH CN from CaH . All air- or moisture-
2
2
3
2
sensitive reactions were conducted under a nitrogen
atmosphere.
(
S)-4-Benzyl-3-[(R,Z)-2-[(4-methoxybenzyl)oxy]hept-
-enoyl]oxazolidin-2-one (8). To a stirred solution of
NaHMDS (1.9 M in THF, 1.1 mL, 2.1 mmol) in THF
4 mL) was added dropwise a solution of 6 (0.590 g,
4
1
)
to a receptor for flower induction. Biosynthetically,
(
LDS1 was proved to be produced by the action of an
1
)
1.66 mmol) in THF (3.4 mL) at –78 °C. After 30 min,
a solution of 5 (0.820 g, 4.18 mmol) in THF (4 mL)
was added and the resulting mixture was stirred at the
same temperature for 8 h. The mixture was gradually
warmed to −40 °C and stirred for 9 h. The mixture was
enzyme (probably, 13-lipoxygenase) on KODA (2),
which had previously been isolated from L. paucicostata
and known to induce flowering only when mixed with
catecholamines such as norepinephrine or epinephr-
2
−5)
ine.
It is worth mentioning that, unlike KODA (2)
quenched with saturated aq NH Cl and extracted with
4
which necessitates pre-incubation with a catecholamine
Et O. The extract was washed with brine, dried over
2
to exhibit its flower-inducing activity, LDS1 exerts the
1
)
MgSO
4
, and concentrated in vacuo after filtration. The
effect by itself without any additives. From the interest-
ing biological activity as well as the considerably simple
residue was purified by silica gel column chromatogra-
*Corresponding author. Email: skuwahar@biochem.tohoku.ac.jp
Abbreviations: CAN, cerium(IV) ammonium nitrate; DDQ, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; NaHMDS, sodium hexamethyldisilazide;
PMB, p-methoxybenzyl.
©
2016 Japan Society for Bioscience, Biotechnology, and Agrochemistry

2
Y. Takayasu et al.
1
9
O
EtOAc = 3:1) to give 3 (27.4 mg, 64%). [α]
+ 24.9
D
1
3
9
(
(
c = 0.555, CHCl ); IR ν : 3009 (w), 1734 (m), 1613
m), 1514 (s), 1250 (s); H NMR δ: 0.95 (3H, t,
J = 7.6 Hz), 1.99–2.08 (2H, m, J5,6 = J6,7 = 7.6 Hz),
.43–2.46 (2H, m, J2,3 = J3,4 = 6.4 Hz), 3.77 (1H, ddd,
J = 6.4, 6.4, 2.4 Hz), 3.81 (3H, s), 4.53 (1H, d,
J = 11.2 Hz), 4.59 (1H, d, J = 11.2 Hz), 5.32–5.40 (1H,
m), 5.49–5.56 (1H, m), 6.87–6.91 (2H, m,
Jvic = 8.8 Hz), 7.26–7.30 (2H, m, J = 8.8 Hz), 9.62
1H, d, J = 2.4 Hz); C NMR δ: 13.9, 20.6, 28.1,
3 max
CO2H
CO2H
1
OH
OH
(
9R,13R)-LDS1 (1)
2
O
1
3
OH
vic
KODA (2)
1
3
(
5
1
5.1, 72.1, 82.8, 113.8 (2C), 122.1, 129.3, 129.6 (2C),
Fig. 1. Structures of LDS1 and KODA.
35.0, 159.4, 203.4; HRMS m/z: calcd. for
+
C H O Na, 271.1311; found, 271.1310 ([M + Na] ).
1
5 20 3
phy (hexane/EtOAc = 3:1) to give 8 (0.580 g, 82%).
1
8
[
(
(
α]
+ 71 (c = 0.43, CHCl ); IR ν : 3011 (w), 1781
D 3 max
1
vs), 1708 (m), 1514 (m), 1249 (s); H NMR δ: 0.96
3H, t, J = 7.5 Hz), 2.07 (2H, quint, J = 7.5 Hz), 2.50–
Methyl
(R)-9-[(4-methoxybenzyl)oxy]-10-oxode-
canoate (12).
To a stirred solution of 7 (4.32 g,
2
.65 (2H, m), 2.70 (1H, dd, J = 13.3, 9.8 Hz), 3.23
20.2 mmol), MgO (1.87 g, 46.4 mmol) and 10 (12.9 g,
46.2 mmol) in PhCF3 (250 mL) was added MeOTf
(5.10 mL, 45.1 mmol) at 0 °C. The reaction mixture
was warmed to room temperature over 4 h and filtered.
The filter cake was washed with EtOAc, and the com-
bined filtrate and washings were successively washed
with water and brine, dried over Na SO , and concen-
(
(
1H, dd, J = 13.3, 3.2 Hz), 3.79 (3H, s), 4.13–4.18
2H, m), 4.48 (1H, d, J = 11.2 Hz), 4.54 (1H, d,
J = 11.2 Hz), 4.55–4.62 (1H, m), 5.12 (1H, dd, J = 6.8,
5
7
.2 Hz), 5.43–5.57 (2H, m), 6.86 (2H, d, J = 8.4 Hz),
1
3
.20 (2H, d, J = 7.2 Hz), 7.25–7.36 (5H, m); C NMR
δ:14.0, 20.5, 30.7, 37.7, 54.8, 55.1, 66.5, 72.2, 76.4,
13.5 (2C), 122.8, 127.2, 128.8 (2C), 129.3 (2C),
29.6, 129.8 (2C), 134.6, 134.9, 152.8, 159.2, 172.5;
HRMS m/z: calcd. for C H O NNa, 446.1944; found,
2
4
1
1
trated in vacuo after filtration. The residue was diluted
with CH Cl and filtered through a short pad of silica
2
2
2
5 29 5
gel with hexane/EtOAc (8:1) as eluent. The filtrate was
concentrated in vacuo to give crude 11 (4.69 g,
ca.70%), which was then dissolved in CH Cl
+
4
46.1942 ([M + Na] ).
2
2
(
7
1400 mL). Ozone was bubbled into the solution at –
8 °C while stirring until complete consumption of 11
(
R,Z)-2-[(4-methoxybenzyl)oxy]hept-4-en-1-ol (9).
To a stirred solution of 8 (0.30 g, 0.708 mmol) in a
mixed solvent of EtOH (46 μL) and Et O (2.3 mL) was
was observed by TLC monitoring. After the removal of
excess O by a stream of O , the mixture was treated
with Me S and gradually warmed to room temperature.
The mixture was concentrated in vacuo, and the residue
was purified by silica gel column chromatography (hex-
ane/EtOAc = 4:1) to give 12 (2.36 g, ca. 50%) (35%
from 7). [α]
1
1
2
3
2
added a solution of LiBH (3.0 M in THF, 0.28 mL,
.84 mmol) at 0 °C. After 5 h, the reaction mixture was
quenched with 1 M aq NaOH, diluted with Et O, and
washed with water. The resulting ethereal solution was
dried over Na SO and concentrated in vacuo after fil-
tration. The residue was purified by silica gel column
chromatography (hexane/EtOAc = 3:2) to give
0.150 g, 85%). [α]
440 (m, br), 3007 (w), 1613 (m), 1514 (s), 1249 (s);
H NMR δ: 0.96 (3H, t, J = 7.5 Hz), 2.05 (2H, quint,
J = 7.5 Hz), 2.17 (1H, br s, OH), 2.23–2.32 (1H, m),
.32–2.40 (1H, m), 3.47–3.54 (2H, m), 3.59–3.66 (1H,
m), 3.79 (3H, s), 4.46 (1H, d, J = 11.2 Hz), 4.60 (1H,
d, J = 11.2 Hz), 5.30–5.38 (1H, m), 5.44–5.52 (1H, m),
.88 (2H, d, J = 8.8 Hz), 7.27 (2H, d, J = 8.8 Hz);
NMR δ: 14.1, 20.6, 28.6, 55.3, 64.2, 71.2, 79.2, 113.9
2C), 123.7, 129.4 (2C), 130.4, 134.3, 159.3; HRMS
m/z: calcd. for C H O Na, 273.1467; found,
4
2
0
2
1
9
2
4
+ 30.7 (c = 0.600, CHCl ); IR νmax:
D 3
1
737 (s), 1612 (w), 1514 (m), 1250 (s); H NMR δ:
.22–1.48 (8H, m), 1.56–1.68 (4H, m), 2.29 (2H, t,
9
1
9
(
–25 (c = 0.38, CHCl ); IR νmax:
D 3
J = 7.6 Hz), 3.66 (3H, s), 3.72 (1H, ddd J = 6.4, 6.4,
.4 Hz), 3.81 (3H, s), 4.47 (1H, d, J = 11.6 Hz), 4.59
1H, d, J = 11.6 Hz), 6.87–6.91 (2H, m, Jvic = 8.6 Hz),
.25–7.29 (2H, m, Jvic = 8.6 Hz), 9.61 (1H, d,
3
2
(
7
1
1
3
2
J = 2.4 Hz); C NMR δ: 24.6, 24.8, 28.92, 28.94,
2
1
m/z: calcd. for C H O Na, 359.1834; found,
3
9.1, 29.9, 34.0, 51.4, 55.2, 72.2, 83.0, 113.8 (2C),
29.3, 129.7 (2C), 159.5, 174.2, 204.0; HRMS (FAB)
1
3
6
C
1
9 28 5
+
59.1832 ([M + Na] ).
(
1
5 22 3
+
2
73.1467 ([M + Na] ).
Methyl (R)-11-(dimethoxyphosphoryl)-9-[(4-methoxy-
benzyl)oxy]-10-oxoundecanoate (4). To a stirred
solution of MeP(O)(OMe)2 (2.30 mL, 2.12 mmol) in
THF (12.8 mL) was added dropwise a solution of n-
BuLi (2.6 M in hexane, 0.90 mL, 2.34 mmol) at –
(
R,Z)-2-[(4-methoxybenzyl)oxy]hept-4-enal (3).
To
a stirred solution of 9 (43.0 mg, 0.172 mmol) and
Et N (0.12 mL, 0.86 mmol) in CH Cl (0.57 mL) was
3
2
2
78 °C. After 30 min, anhydrous CeCl was added, and
3
added dropwise
a
solution of SO ·Py (82 mg,
3
the resulting mixture was stirred at the same tempera-
ture for 15 min. To the mixture was added a solution
of 12 (0.600 g, 1.78 mmol) in THF (11.0 mL) while
stirring. After 14 h, the mixture was quenched with sat-
0
.52 mmol) in DMSO (0.19 mL) at room temperature.
After 1 h, the reaction mixture was quenched with
water and extracted with CH Cl . The extract was
washed with brine, dried over Na SO , and concen-
trated in vacuo after filtration. The residue was purified
2
2
2
4
urated aq NH Cl and extracted with EtOAc. The
4
extract was successively washed with water and brine,
by silica gel column chromatography (hexane/
dried over Na SO , and concentrated in vacuo after
2
4

Synthesis of LDS1
3
O
after filtration. The residue was purified by silica gel
column chromatography (hexane/EtOAc = 4:1) to give
2
0
14 (47.7 mg, 75%). [α]
+ 42.7 (c = 1.09, CHCl3);
D
OH
OH
HO2C
O
IR νmax: 3010 (w), 1737 (m), 1694 (w), 1613 (m),
1
1
1514 (s), 1250 (s), 758 (s); H NMR δ: 0.93 (3H, t,
J = 7.4 Hz), 1.20–1.36 (7H, m), 1.36–1.48 (1H, m),
1.56–1.72 (4H, m), 2.00 (2H, br quint, J = 7.4 Hz),
CHO
+
2.29 (2H, t, J = 7.4 Hz), 2.31–2.46 (2H, m), 3.66 (3H,
OPMB
(MeO)2P
O
OPMB
MeO2C
s), 3.79 (3H, s), 3.80 (3H, s), 3.88 (1H, dd, J = 8.0,
5.2 Hz), 3.98 (1H, br q, J = 6.3 Hz), 4.33 (1H, d,
J = 12.0 Hz), 4.36 (1H, d, J = 12.0 Hz), 4.51 (2H, d,
J = 12.0 Hz), 5.27–5.35 (1H, m), 5.43–5.51 (1H, m),
3
4
I
O
N
O
6.68 (1H, dd, J = 16.0, 1.2 Hz), 6.86 (4H, d,
+
O
J = 8.4 Hz), 6.92 (1H, dd, J = 16.0, 6.2 Hz), 7.23 (2H,
OH
PMBO
MeO C
13
5
2
d, J = 8.4 Hz), 7.24 (2H, d, J = 8.4 Hz); C NMR δ:
Bn
7
1
3
4.1, 20.7, 24.9, 25.2, 29.01, 29.04, 29.1, 32.4, 32.7,
4.0, 51.4, 55.22, 55.24, 70.8, 71.9, 77.9, 84.0, 113.78
6
Scheme 1. Retrosynthetic analysis of 1.
(2C), 113.80 (2C), 123.2, 124.9, 129.3 (2C), 129.6
3C), 130.1, 134.4, 147.6, 159.2, 159.4, 174.2, 201.5;
HRMS m/z: calcd. for C H O Na, 603.3298; found,
(
3
5 48 7
filtration. The residue was diluted with Et O and fil-
+
2
603.3301 ([M + Na] ).
tered through a short pad of silica gel with EtOAc as
eluent. The filtrate was concentrated in vacuo to give
crude 13 (0.520 g, ca. 63%), which was the taken up
in CH Cl (8.4 mL). The solution was added dropwise
(9R,11E,13R,15Z)-9,13-dihydroxy-10-oxooctadeca-
2
2
11,15-dienoic acid (1) (LDS1). To a stirred solution
of 14 (10.0 mg, 17.2 μmol) in a mixed solvent of
CH Cl (0.17 mL) and water (17 μL) was added DDQ
to a stirred suspension of the Dess–Mertin periodinane
0.530 g, 1.25 mmol) in CH Cl2 (4.7 mL) at 0 °C.
(
2
2
2
After 1 h, the mixture was quenched with saturated aq
NaHCO and extracted with CH Cl . The extract was
successively washed with saturated aq NaHCO3 and
(9.0 mg, 40 μmol) at 0 °C. After 30 min, the mixture
3
2
2
was diluted with water and extracted with CH Cl . The
2
2
extract was successively washed with water and brine,
brine, dried over Na SO , and concentrated in vacuo
dried over Na SO , and concentrated in vacuo after fil-
2
4
2
4
after filtration. The residue was purified by silica gel
tration. The residue was diluted with CH Cl and fil-
2 2
column chromatography (hexane/EtOAc = 1:1) to give
tered through a short pad of silica gel with hexane/
EtOAc (2:1) as eluent. The filtrate was concentrated in
vacuo to give crude diol 16 (6.3 mg, quant). A mixture
of crude 16 (6.0 mg) and PPL (Sigma–Aldrich, 8.8 mg)
in a mixture of acetone (35 μL) and 0.5 M phosphate
buffer (pH 7, 88 μL) was stirred vigorously at room
temperature for 25 min. The reaction mixture was
diluted with 1.8 M acetate buffer (pH 4) and extracted
with EtOAc. The extract was dried over Na SO and
1
9
4
(0.230 g, 44%) (28% from 12). [α]
+ 19 (c = 0.26,
D
CHCl ); IR ν : 1733 (s), 1613 (w), 1514 (m), 1250
3
max
1
(
1
s), 1032 (s); H NMR δ: 1.22–1.42 (8H, m), 1.55–
.69 (4H, m), 2.29 (2H, t, J = 7.6 Hz), 3.22 (2H, d,
J = 22.0 Hz), 3.66 (3H, s), 3.77 (3H, d, J = 3.6 Hz),
.80 (3H, d, J = 4.0 Hz), 3.81 (3H, s), 3.88 (1H, dd,
J = 7.2, 5.2 Hz), 4.38 (1H, d, J = 11.4 Hz), 4.56 (1H,
d, J = 11.4 Hz), 6.87–6.91 (2H, m, J = 8.6 Hz),
3
ortho
2
4
1
3
7
2
.26–7.30 (2H, m, Jortho = 8.6 Hz); C NMR δ: 24.8,
5.0, 28.97, 28.99, 29.1, 31.3, 34.0, 35.6 (d,
concentrated in vacuo after filtration. The residue was
purified by silica gel column chromatography (CHCl3/
MeOH = 6:1) to give LDS1 (1) (3.2 mg, 60% from
J = 132.7 Hz), 51.4, 53. (2C, d, J = 6.1 Hz), 55.3, 72.2,
1
9
8
1
4.4 (d, J = 3.0 Hz), 113.8 (2C), 129.4, 129.7 (2C),
59.4, 174.2, 204.5 (d, J = 6.8 Hz); HRMS m/z: calcd.
14). [α]
–33 (c = 0.46, CHCl ); IR νmax: 3446 (m,
D 3
br), 3015 (m), 1713 (s), 1633 (m), 1280 (m), 759 (vs);
1
for C H O PNa, 481.1967; found, 481.1966
H NMR δ: 0.98 (3H, t, J = 7.4 Hz), 1.24–1.40 (7H,
2
2 35 8
+
(
[M + Na] ).
m), 1.40–1.58 (2H, m), 1.58–1.67 (2H, m), 1.77–1.87
(1H, m), 2.06 (2H, dquint, J = 1.6, 7.4 Hz), 2.34 (2H,
t, J = 7.4 Hz), 2.34–2.46 (2H, m), 4.37 (1H, dd,
J = 7.2, 3.6 Hz), 4.39–4.45 (1H, m), 5.30–5.38 (1H,
Methyl (9R,11E,13R,15Z)-9,13-bis[(4-methoxybenzyl)
oxy]-10-oxooctadeca-11,15-dienoate (14). To a flask
charged with anhydrous LiCl (5.0 mg, 0.12 mmol) was
added a solution of 4 (60.0 mg, 0.131 mmol) in
m), 5.60–5.68 (1H, m), 6.51 (1H, dd, J = 15.6,
13
1
1
3
2
.6 Hz), 7.04 (1H, dd, J = 15.6, 4.0 Hz); C NMR δ:
4.1, 20.7, 24.3, 24.5, 28.6, 28.7, 28.9, 33.7, 33.8,
4.4, 70.6, 75.6, 122.4, 122.7, 136.7, 149.5, 178.7,
00.7; HRMS m/z: calcd. for C H O Na, 344.1991;
CH CN (0.53 mL) at room temperature. DIPEA
3
(
20 μL, 0.11 mmol) was then added and the resulting
1
8 30 5
mixture was stirred for 15 min. To the mixture was
added a solution of 3 (27.1 mg, 0.109 mmol) in
CH CN (57 μL) via a syringe. Additional CH CN
+
found, 349.1990 ([M + Na] ).
3
3
(
2 × 57 μL) was used to rinse the container of 3 and
Results and discussion
the syringe. After 3.5 h, the mixture was concentrated
in vacuo, and the residue was diluted with water and
Scheme 1 outlines our synthetic plan for 1. Com-
pound 1 was retrosynthetically dissected into two build-
ing blocks, aldehyde 3 and phosphonate 4, with a view
extracted with Et O. The extract was washed with
2
brine, dried over NaSO , and concentrated in vacuo
4

4
Y. Takayasu et al.
LiBH
iodide 5. The phosphonate 4, on the other hand, would
O
4
NaHMDS
, THF
O
EtOH, Et O
5
2
be readily prepared from known allylic alcohol 7.
The preparation of the aldehyde segment 3 is
depicted in Scheme 2. According to our synthetic plan,
the known allylic iodide 5 was subjected to the Evans
6
N
O
–
78 °C to rt
2%
0 °C to rt
85%
8
PMBO
Bn
8
7
)
asymmetric alkylation with 6 to give 8. Reduction of
the oxazolidione 8 with LiBH4 afforded alcohol 9,
which was then exposed to Parikh–Doering’s oxidation
conditions to provide 3.
SO ·Py, Et N
3
3
CHO
OH
CH Cl , rt
2
2
PMBO
PMBO
6
4%
The other coupling partner 4 in the HWE reaction
was prepared by a four-step sequence shown in
Scheme 3 from the optically active allylic alcohol 7,
which in turn was readily obtained in 98% enan-
tiomeric excess by the Sharpless kinetic resolution of
9
3
Scheme 2. Preparation of aldehyde segment 3.
10
the corresponding racemic alcohol (±)-7 according to
MeOTf, MgO
6,11)
our previous protocol.
The alcohol 7 was first pro-
OH
PhCF
OPMB
3
tected as its PMB ether 11 by treatment with lepidine
MeO2C
MeO2C
0
°C to rt
12)
ether 10 under Dudley’s conditons. The double bond
7
11
7
0%
of 11 was then oxidatively cleaved by ozonolysis to
give 12, which on exposure to the lithium anion
derived from dimethyl methylphosphonate in the pres-
ence of CeCl3 afforded 13. Finally, oxidation of the
alcohol 13 with the Dess–Martin periodinane furnished
the phosphonate 4.
O
O3
MeOH/CH2Cl2
OHC
(MeO) PMe
2
–
78 °C
then Me2S
0%
OPMB
n-BuLi, CeCl3
THF, –78 °C to rt
63%
MeO2C
5
12
X
The final stage of our total synthesis of (9R,13R)-1
is shown in Scheme 4. The HWE olefination between
3
and 4 was performed according to the Masamune–
(
MeO)2P
OPMB
MeO2C
N
OPMB
Roush procedure, giving rise to 14 as a single geomet-
O
10
1
3)
1
3: X = H, OH DMP, CH2Cl2
rical isomer. With the enone 14 having the full car-
bon skeleton and functionalities for the target molecule
in hand, the remaining tasks to be performed were the
deprotection of the two PMB groups and the hydrolysis
of the ester group. We first hydrolyzed the ester func-
tion of 14 with LiOH in aqueous THF to give the cor-
responding carboxylic acid 15 in 57% yield.
Deprotection of the PMB groups of 15 by treatment
with DDQ in aqueous CH Cl was, however, problem-
atic, resulting in the formation of a complex mixture.
Although we were unable to characterize any reaction
products, the H NMR spectrum of the crude product
mixture indicated the disappearance of the signals for
the 11E double bond. An analogous unsuccessful out-
come was obtained in the deprotection using CAN in
4
: X = O 0 °C, 44%
Scheme 3. Preparation of phosphonate segment 4.
O
i-Pr2NEt, LiCl
3
+ 4
CH3CN, rt
5%
2
2
OPMB
OPMB
7
2
MeO C
1
4
LiOH, aq THF
DDQ
CH Cl , H O
rt, quant
1
4
0°C, 57%
OPMB
2
2
2
O
OPMB
aqueous CH CN. Then, we changed the order of reac-
3
HO2C
1
5
tions and conducted, at first, the removal of the PMB
groups in 14 with DDQ, which proceeded smoothly to
furnish 16 quantitatively. Subjection of the dihydroxy
ester 16 to basic hydrolysis conditions (LiOH in aque-
ous THF) did not afford the desired product 1 at all.
Fortunately, however, this hydrolysis could be achieved
successfully by treatment of 16 with PPL (porcine pan-
creatic lipase) in a mixture of acetone and a phosphate
buffer (pH 7), providing (9R,13R)-LDS1 (1) in 60%
yield from 14. The H and C NMR spectra of 1
showed good agreement with those reported for
(9R,13R)-LDS1 of natural origin.
O
6
1
OH
OH
OH
MeO2C
1
PPL
phosphate buffer (pH 7)
acetone, rt, 60%
O
14)
1
13
OH
HO2C
1
)
1
In conclusion, the first enantioselective total synthe-
sis of (9R,13R)-LDS1 (1) was accomplished in 4.4%
overall yield through 7 steps from 7 (or 20% overall
yield from 6 in 6 steps). Since the enantiomers of the
starting materials, 6 and 7, are both readily available,
the synthetic route described in this paper should also
be applicable to the synthesis of other stereoisomers of
LDS1.
Scheme 4. Completion of the synthesis of (9R,13R)-LDS1 (1).
to installing the 11E-double bond by the Horner–Wads-
worth–Emmons (HWE) olefination. The aldehyde 3
would be obtainable by the Evans asymmetric alkyla-
tion of (S)-4-benzyl-2-oxazolidinone derivative 6 with

Synthesis of LDS1
5
[
3] Yamaguchi S, Yokoyama M, Iida T, et al. Identification of a
component that induces flowering of Lemna among the reaction
products of α-ketol linolenic acid (FIF) and norepinephrine. Plant
Cell Physiol. 2001;42:1201–1209.
Authors contribution
Y.O. and S.K. designed the synthetic route and wrote
the manuscript. Y.T. conducted the synthetic experi-
ments with the aid of R.T. and Y.O.
[
[
4] Kai K, Takeuchi J, Kataoka T, et al. Structure and biological
activity of novel FN analogs as flowering inducers. Bioorg.
Med. Chem. 2008;16:10043–10048.
5] Kai K, Oba Y, Akaike R, et al. Insight into the chemistry of
cycloaddition between α-ketol oxylipin and epinephrine: isolation
and structure elucidation of a new reaction product. Tetrahedron
Lett. 2013;54:2247–2250.
Acknowledgments
The authors appreciate the help received from Ms.
Yuka Taguchi (Tohoku University) with NMR and MS
measurements.
[
6] Miura A, Kuwahara S. A concise synthesis of pinellic acid using
a cross-metathesis approach. Tetrahedron. 2009;65:3364–3368.
7] Kurashina Y, Miura A, Enomoto M, et al. Stereoselective syn-
thesis of malyngic acid and fulgidic acid. Tetrahedron.
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011;67:1649–1653.
Disclosure statement
[8] Kurashina Y, Kuwahara S. Stereoselective synthesis of a pro-
tected form of (6 R ,7 E ,9 S ,10 R ,12 Z )-6,9,10-trihydroxy-
7,12-hexadecadienoic acid. Biosci. Biotechnol. Biochem.
No potential conflict of interest was reported by the authors.
2
012;76:605–607.
9] Towada R, Kurashina Y, Kuwahara S. Stereochemical assign-
ment of topsentolide C by stereodivergent synthesis of its four
diastereomers. Tetrahedron Lett. 2013;54:6878–6881.
2 2
10] Towada R, Kuwahara S. Synthesis of topsentolides A and C ,
and non-enzymatic conversion of the former to the latter. Tetra-
hedron. 2014;70:3774–3781.
11] Perlikowska W, Mikolajczyk M. A concise approach to both
[
2
Funding
This work was supported by JSPS KAKENHI [grant num-
ber 15J02009 (R.T.)], [grant number 26292056 (S.K.)].
[
[
[
[
Supplemental materials
1
enantiomers of phytoprostane B type II. Tetrahedron: Asymme-
try. 2011;22:1767–1771.
12] Nwoye EO, Dudley GB. Synthesis of para-methoxybenzyl
PMB) ethers under neutral conditions. Chem. Commun.
007;1436–1437.
The supplemental material for this paper is available
at http://dx.doi.org/10.1080/09168451.2016.1166935.
(
2
13] Blanchette MA, Choy W, Davis JT, et al. Horner-Wadsworth-
Emmons reaction: Use of lithium chloride and an amine for
base-sensitive compounds. Tetrahedron Lett. 1984;25:2183–
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