A concise synthesis of pinellic acid using a cross-metathesis approach

Article abstract of DOI:10.1016/j.tet.2009.02.063

A new enantioselective synthesis of pinellic acid, a trihydroxy unsaturated fatty acid exhibiting oral adjuvant activity for nasally administered influenza vaccine, has been accomplished using a cross-metathesis reaction between two terminal olefin interm

Full text of DOI:10.1016/j.tet.2009.02.063

Tetrahedron 65 (2009) 3364–3368
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A concise synthesis of pinellic acid using a cross-metathesis approach
*
Ayako Miura, 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 enantioselective synthesis of pinellic acid, a trihydroxy unsaturated fatty acid exhibiting oral
adjuvant activity for nasally administered influenza vaccine, has been accomplished using a cross-me-
tathesis reaction between two terminal olefin intermediates as the key step. This synthesis is the shortest
to date, furnishing pinellic acid in 17% overall yield via only seven steps from a readily available known
dihydroxy ester.
Received 24 October 2008
Received in revised form 24 February 2009
Accepted 25 February 2009
Available online 3 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Pinellic acid
Influenza
Total synthesis
Cross-metathesis
Fatty acid
1. Introduction
Pinellia ternata as an effective oral adjuvant for nasally admin-
istered influenza HA vaccine and given the trivial name pinellic
(9S,10E,12S,13S)-(ꢀ)-9,12,13-Trihydroxy-10-octadecenoic acid
(1) was first isolated by Kato and co-workers from a rice cultivar
(Sasanishiki) suffering from the rice blast disease, and shown to
exhibit clear inhibitory activity against the rice blast fungus
(Fig. 1).1 The gross structure of 1 was assigned spectroscopically,
and the stereochemistry was determined through its synthetic
studies coupled with CD spectral analysis of a p-bromobenzoate
derivative prepared from a natural sample of 1.1,2 The agricul-
turally important biological activity of 1 prompted its total
synthesis, and one synthesis of the methyl ester of 1 using
(þ)-dimethyl tartrate as the starting material as well as a syn-
thesis of stereoisomers of 1 from a sugar derivative was repor-
ted.3,4 The trihydroxy fatty acid (1) was later reisolated by
Yamada and co-workers from the tuber of the medicinal plant
acid.5 Soon after the rediscovery, Omura and co-workers
reported a series of synthetic works on 1 and its stereoisomers,
in which they confirmed the stereochemistry of 1 and elucidated
the stereochemistry–activity relationship including the findings
that the natural stereoisomer 1 exhibited the most potent ad-
juvant activity and, interestingly, the activity of its C12-epimer
was comparable to that of 1.6–8 Inspired by the medicinally in-
triguing biological activity of 1, four additional syntheses of 1 or
its stereoisomers have recently been reported.9–12 The previous
syntheses employed dithiane chemistry,6–8 acetylenic coupling
methodology including the Sonogashira reaction,9–11 or the
Wittig olefination12 to construct the carbon skeleton of the
target molecules. In this paper, we describe a new concise ap-
proach to 1 via a cross-metathesis reaction, which has led to the
shortest synthesis of 1 among those reported so far.
OH
9
chain
OH
CO2Et
OR
12
elongation
CO2H
n-C5H11
n-C5H11
OH
OH
OH
4
OR
2
1
cross-
metathesis
Figure 1. Structure of pinellic acid (1).
+
1
kinetic
resolution
(CH2)7
(CH2)7
CO2Me
CO2Me
OR
OH
( )-3
3
* Corresponding author. Tel./fax: þ81 22 717 8783.
Scheme 1. Synthetic plan for pinellic acid (1).
E-mail address: skuwahar@biochem.tohoku.ac.jp (S. Kuwahara).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.063

A. Miura, S. Kuwahara / Tetrahedron 65 (2009) 3364–3368
3365
TBSOTf
OTBS
CO2Et
OTBS
6
With terminal olefins 2 and 3 in hand, we moved on to the final
stage of the synthesis (Scheme 4). Since preliminary experiments
using the first generation Grubbs catalyst revealed that the cross-
OR
CO2Et
2,6-lutidine
DIBAL
CH2Cl2
96%
n-C5H11
n-C5H11
CH2Cl2
98%
OR
4: R = H
OTBS
5: R = MTPA
( )-3a or ( )-3b
n-C5H11
(CH2)7
DMSO
(COCl)2, Et3N
CO2Me
2a
OTBS
OTBS
CHO
OTBS
Grubbs-II
CH2Cl2
OTBS
OR
n-C5H11
OH
n-C5H11
CH2Cl2
99%
10a: R = H
OTBS
7
10b: R = TBS
8
OR
OR
(CH2)7
MeO2C
Tebbe reagent
CO2Me
(CH2)7
n-C5H11
toluene/THF/Py
71%
OR
11a: R = H
11b: R = TBS
OR
2a: R = TBS
2b: R = H
TBAF, THF
88%
OH
( )-3a or ( )-3b
Scheme 2. Preparation of 2a and 2b.
n-C5H11
(CH2)7
CO2Me
CO2Me
2b
Grubbs-II
CH2Cl2
OH
OR
2. Results and discussion
12a: R = H
12b: R = TBS
Our retrosynthetic analysis of 1 is shown in Scheme 1. We
planned to construct the C10–C11 double bond of 1 by the cross-
metathesis reaction between oxygen-containing terminal olefins 2
and 3. Compound 2 would be obtainable via one-carbon elongation
of known dihydroxy ester 4, while the other component of the
cross-metathesis reaction (3) should readily be prepared by the
Sharpless kinetic resolution of racemic alcohol (ꢁ)-3, which is also
a known compound.
OH
3a or 3b
n-C5H11
(CH2)7
OR
Grubbs-II
CH2Cl2
OH
13a: R = H (35%)
13b: R = TBS (24%)
NaOH, H2O/MeOH
85%
1
The preparation of the TBS-protected and unprotected forms of 2
(i.e., 2a and 2b) is shown in Scheme 2. The known dihydroxy ester
4,13 which was obtained from commercially available ethyl (E)-2-
octenoate in 98% yield by the Sharpless asymmetric dihydroxylation
Scheme 4. Completion of the synthesis of pinellic acid (1).
metathesis reactions between 2a and (ꢁ)-3a, and between 2a and
(ꢁ)-3b as well, gave neither the desired cross-metathesis products
(10a and 10b, respectively) nor the undesired self-metathesis
(homodimerization) products of (ꢁ)-3a and 3b (11a and 11b, re-
spectively) in detectable amounts, all of subsequent metathesis
experiments were conducted using the second generation Grubbs
catalyst (5 mol % Grubbs-II, 3 equiv of (ꢁ)-3a or (ꢁ)-3b, CH2Cl2,
40 ꢂC, 5 h).19,20 As shown in Scheme 4, even the use of Grubbs-II did
not lead to the successful formation of the desired cross-coupling
products 10a and 10b (resulting only in the recovery of 2a), but we
could observe the formation of a large amount of 11a in the reaction
of 2a and (ꢁ)-3a by changing the metathesis catalysts from the first
generation to the second generation; a small amount of 11b was
also generated when the reaction between 2a and (ꢁ)-3b was
continued overnight. To overcome the inertness of 2a to the me-
tathesis reaction, we also tried the reaction with use of its un-
protected form (2b), since it had sometimes been documented that
the protection of allylic alcohols exerted an adverse effect on cross-
metathesis reaction.21 To our delight, exposure of 2b to (ꢁ)-3a and
also to (ꢁ)-3b under the above-mentioned metathesis conditions
furnished the desired cross-metathesis products 12a (ca. 40% yield)
and 12b (ca. 25% yield),22 respectively. From the product yields
obtained, we could also find that the unprotected olefin (ꢁ)-3a was
better than the protected olefin (ꢁ)-3b as the coupling partner of
2b in the present case.23,24 Indeed, the cross-metathesis reaction of
2b with optically active olefin 3a afforded, after complete con-
sumption of 2b, the desired cross-metathesis product 13a in 35%
isolated yield along with the homodimers of 2b and 3a as well as
the starting material 3a employed in excess (see the Experimental
section for each yield), while the metathesis with the other opti-
cally active olefin (3b) bearing the TBS protecting group gave 13b in
a lower yield of 24% together with the homodimer of 2b and a trace
amount of the homodimer of 3b in addition to the starting material
3b (see the Experimental section for each yield). The 1H and 13C
NMR spectra of 13a and 13b indicated that both of the compounds
were produced with complete E-geometrical selectivity. Finally,
using AD-mix-a
and estimated to be >98% ee by 1H NMR analysis of
the corresponding (R)- and (S)-MTPA esters 5, was protected as its
bis-TBS ether 6 by treatment with TBSOTf and 2,6-lutidine in
dichloromethane. The product 6, obtained in 98% yield, was reduced
with DIBAL to give alcohol 7 in 96% yield, which was then oxidized
under the Swern oxidation conditions to afford aldehyde 8 in almost
quantitative yield. Installation of a terminal double bond in 8 leading
to 2a proved to be more problematic than expected. When 8 was
subjected to two kinds of Wittig reaction conditions, Ph3PCH3Br/n-
BuLi/ether and Ph3PCH3Br/NaHMDS/THF, the desired product 2a
was obtained in only 23% yield in the former case, and none of the
desired olefin was produced in the latter case, affording merely
a complex mixture. Exposure of 8 to CH2I2/Zn/Al(CH3)3/THF was also
unsuccessful, resulting only in the recovery of the starting alde-
hyde.14 Fortunately, this olefination was finally found to be achiev-
able by treating 8 with the Tebbe reagent [Cp2TiCH2AlCl(CH3)2] in
toluene/THF/Py, giving 2a in a good yield of 71%.15,16 Deprotection of
2a with TBAF in THF afforded the olefinic diol 2b in 88% yield.
The preparation of the unprotected form of 3 (i.e., 3a in Scheme 3)
was performed in 80% yield by simply subjecting the racemic alcohol
(ꢁ)-3 to the Sharpless kinetic resolution conditions;17 the starting
material (ꢁ)-3 in turn was obtained in ca. 60% yield by allylic oxida-
tion of commercially available methyl 10-undecenoate with SeO2/
TBHP according to a literature procedure.18 The enantiomeric excess
of 3a was determined to be >98% by 1H NMR analysis of the corre-
sponding (R)- and (S)-MTPA esters 9. The allylic alcohol 3a was con-
verted into the corresponding TBS-protected form (3b) in 91% yield.
D-DIPT, TBHP
Ti(Oi-Pr)4, MS4A
(CH2)7
CO2Me
( )-3
CH2Cl2, 80%
OR
3a: R = H
3b: R = TBS
9: R = MTPA
TBSCl, imidazole
DMF, 91%
Scheme 3. Preparation of 3a and 3b.

3366
A. Miura, S. Kuwahara / Tetrahedron 65 (2009) 3364–3368
saponification of 13a afforded in 85% yield the target molecule 1,
4.1.3. (2S,3S)-2,3-Bis(tert-butyldimethylsilyloxy)-1-octanol (7)
To a stirred solution of 6 (308 mg, 0.711 mmol) in CH2Cl2 (6 ml)
was added dropwise a solution of DIBAL (1.02 M in hexane, 1.53 ml,
1.56 mmol) at ꢀ70 ꢂC. After 1.5 h, the mixture was quenched with
satd Rochelle’s salt aq and extracted with EtOAc. The extract was
successively washed with water and brine, dried (MgSO4), and
concentrated in vacuo. The residue was chromatographed over SiO2
the 1H and 13C NMR spectral data of which were identical with
25
those previously reported.2,5–8,11 The specific rotation ([
a
]
D
ꢀ9.5 (c
0.30, MeOH)) and melting point (mp 103.5–104.0 ꢂC) of 1 also
showed good agreement with those reported in the literature.5–8,11
3. Conclusion
(hexane/EtOAc¼30:1) to give 7 (266 mg, 96%) as a colorless oil.
25
[a
]
ꢀ28.0 (c 1.05, CHCl3); IR
n
3476 (br w), 1254 (m), 1097 (m), 833
D
The enantioselective synthesis of pinellic acid 1 was accom-
plished in 17% overall yield from known dihydroxy ester 4 via only
seven steps involving the cross-metathesis reaction between ter-
minal olefins 2b and 3a as the key step. Although we needed to use
a threefold excess of the hydroxy olefin 3a in the cross-metathesis
step to increase the yield of the desired product 13a, the ready
availability of 3a in only two steps from the cheap commercially
available ester, methyl 10-dodecenoate, is considered to alleviate
the problem. Efforts to improve the efficiency of the cross-me-
tathesis step as well as synthetic studies on structurally related
polyhydroxy fatty acids with various biological activities are now
underway and will be reported in due course.
(s), 808 (m), 773 (s); 1H NMR
d 0.07 (s, 3H), 0.08 (s, 3H), 0.09 (s, 6H),
0.87–0.91 (m, 21H), 1.18–1.38 (m, 6H), 1.43–1.50 (m, 1H), 1.65–1.71
(m, 1H), 2.34 (t, J¼5.4 Hz, 1H, OH), 3.55–3.60 (m, 1H), 3.64–3.67 (m,
1H), 3.72–3.79 (m, 2H); 13C NMR
18.0, 22.5, 25.7 (3C), 25.8 (3C), 26.2, 30.4, 31.8, 63.2, 73.7, 75.4;
HRMS (FAB) m/z calcd for C20H47O3Si2 ([MþH]þ) 391.3064, found
391.3068.
d
ꢀ4.7 (2C), ꢀ4.6, ꢀ4.3, 14.0, 17.9,
4.1.4. (2R,3S)-2,3-Bis(tert-butyldimethylsilyloxy)octanal (8)
To a stirred solution of (COCl)2 (0.11 ml, 1.28 mmol) in CH2Cl2
(8 ml) was added dropwise DMSO (0.18 ml, 2.56 mmol) at ꢀ70 ꢂC.
After 20 min, a solution of 7 (333 mg, 0.85 mmol) in CH2Cl2 (9 ml)
was added, and the mixture was stirred for 1 h. The mixture was
gradually warmed to ꢀ60 ꢂC, quenched with water, and then
extracted with CH2Cl2. The extract was washed with brine, dried
(MgSO4), and concentrated in vacuo. The residue was chromato-
4. Experimental
4.1. General
graphed over SiO2 (hexane/EtOAc¼50:1) to give 8 (328 mg, 99%) as
23
a pale yellow oil. [
a]
ꢀ39.8 (c 0.500, CHCl3); IR
n 1738 (m), 1254
D
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 UNITY plus-500
spectrometer (500 MHz for 1H and 125 MHz for 13C) unless other-
wise 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. Merck silica
gel 60 (7–230 mesh) was used for column chromatography. Sol-
vents for reactions were distilled prior to use: THF from Na and
benzophenone; CH2Cl2 from CaH2; toluene from LiAlH4. All air- or
moisture-sensitive reactions were conducted under a nitrogen
atmosphere.
(m), 1106 (m), 835 (s), 774 (s); 1H NMR
d 0.04 (s, 3H), 0.07 (s, 6H),
0.08 (s, 3H), 0.88 (t, J¼6.8 Hz, 3H), 0.89 (s, 9H), 0.92 (s, 9H), 1.20–
1.34 (m, 6H),1.36–1.42 (m,1H),1.69–1.75 (m), 3.86 (dt, J¼7.8, 4.4 Hz,
1H), 4.02 (d, J¼4.4 Hz, 1H), 9.76 (d, J¼1.0 Hz, 1H); 13C NMR
d
ꢀ5.2,
ꢀ4.57, ꢀ4.55, ꢀ4.51, 14.0, 18.0, 18.2, 22.5, 25.5, 25.70 (3C), 25.72
(3C), 31.7, 32.6, 74.6, 80.0, 203.9; HRMS (EI) m/z calcd for
C20H44O3Si2 (Mþ) 388.2829, found 388.2832.
4.1.5. (3S,4S)-Bis(tert-butyldimethylsilyloxy)-1-nonene (2a)
To a stirred solution of 8 (76.8 mg, 0.197 mmol) in toluene/THF/
pyridine (3:1:0.03, 4.03 ml) was added dropwise the Tebbe reagent
(0.5 M in toluene, 0.47 ml, 0.237 mmol) at ꢀ70 ꢂC. The mixture was
gradually warmed to ꢀ10 ꢂC over 3 h, and quenched with succes-
sive addition of Et3N (0.4 ml) and satd NaHCO3 aq. The mixture was
extracted with ether, and the extract was washed with brine, dried
(MgSO4), and concentrated in vacuo. The residue was chromato-
4.1.1. Determination of the enantiomeric excess of 4
25
Compound 4 ([
a
]
ꢀ14.4 (c 1.00, EtOH)) was converted into the
D
corresponding (R)- and (S)-MTPA esters (5) by treating with (S)-
and (R)-MTPACl, respectively, in pyridine. The 1H NMR signal for the
methine proton at the C3 position of the (R)-MTPA ester was ob-
served at 5.55 ppm (dt, J¼2.0, 7.1 Hz), while that of the (S)-MTPA
ester appeared at 5.61 ppm (dt, J¼2.0, 7.3 Hz). In each spectrum of
the diastereomeric MTPA esters, no signal due to the corresponding
diastereomer was observed. Therefore, compound 4 was estimated
to be optically pure within the limit of NMR detection.
graphed over SiO2 (hexane/EtOAc¼50:1) to give 2a (54.5 mg, 71%)
24
as a pale yellow oil. [
a
]
D
ꢀ67.9 (c 0.45, CHCl3); IR
n 3095 (w), 3025
d 0.04 (s, 3H), 0.05 (s, 3H),
(w), 1254 (m), 832 (s), 772 (s); 1H NMR
0.06 (s, 3H), 0.07 (s, 3H), 0.87 (t, J¼7.3 Hz, 3H), 0.90 (s, 9H), 0.91 (s,
9H), 1.14–1.31 (m, 6H), 1.37–1.43 (m, 1H), 1.52–1.57 (m, 1H), 3.55–
3.58 (m,1H), 4.12–4.15 (m, 1H), 5.13 (dt, J¼10.3, 2.0 Hz,1H), 5.25 (dt,
J¼17.1, 2.0 Hz, 1H), 5.98 (ddd, J¼3.9, 10.3, 17.1 Hz, 1H); 13C NMR
d
ꢀ4.9, ꢀ4.7, ꢀ4.6, ꢀ4.2, 14.0, 18.0, 18.2, 22.6, 25.8, 25.8 (3C), 25.9
4.1.2. Ethyl (2R,3S)-2,3-bis(tert-butyldimethylsilyloxy)octanoate (6)
To a stirred solution of 4 (388 mg, 1.90 mmol) and 2,6-lutidine
(1.32 ml, 11.4 mmol) in CH2Cl2 (40 ml) was added TBSOTf (1.30 ml,
5.68 mmol) at 0 ꢂC. The mixture was stirred at room temperature for
4 h, quenched with brine, and then extracted with water. The ex-
tract was washed with brine, dried (Na2SO4), and concentrated in
vacuo. The residue was chromatographed over SiO2 (hexane/
(3C), 30.7, 31.9, 75.31, 75.34, 114.5, 137.1; HRMS (EI) m/z calcd for
C21H46O2Si2 (Mþ) 386.3036, found 386.3040.
4.1.6. (3S,4S)-1-Nonene-3,4-diol (2b)
To 2a (neat, 47.1 mg, 0.121 mmol) was added a solution of TBAF
(1.0 M in THF, 0.27 ml, 0.27 mmol) at 0 ꢂC with stirring, and the
mixture was gradually warmed to 10 ꢂC over 3 h. The mixture was
diluted with satd NH4Cl aq, and extracted with ether. The extract
was washed with brine, dried (Na2SO4), and concentrated in vacuo.
EtOAc¼100:1 to 20:1) to give 6 (804 mg, 98%) as a pale yellow oil.
25
[
a]
ꢀ2.86 (c 1.10, CHCl3); IR
n 1755 (m), 1252 (s), 1106 (s), 835 (vs),
D
774 (vs); 1H NMR
d
0.04 (s, 6H), 0.05 (s, 3H), 0.07 (s, 3H), 0.87 (s, 9H),
The residue was chromatographed over SiO2 (hexane/EtOAc¼3:1)
23
0.88 (t, J¼6.8 Hz, 3H), 0.91 (s, 9H),1.22–1.40 (m, 7H),1.27 (t, J¼7.3 Hz,
to give 2b (17.0 mg, 88%) as a pale yellow oil. [
a
]
D
ꢀ25.5 (c 1.02,
3H), 1.68–1.75 (m, 1H), 3.81–3.84 (m, 1H), 4.11–4.21 (m, 3H); 13C
CHCl3); IR
n 3374 (br s), 3082 (w), 1650 (w), 1049 (m), 991 (m), 923
NMR
d
ꢀ5.1, ꢀ4.8, ꢀ4.4, ꢀ4.36, 14.0, 14.2, 18.0, 18.3, 22.6, 25.4, 25.7,
(m); 1H NMR
d
0.89 (t, J¼6.8 Hz, 3H), 1.25–1.56 (m, 8H), 2.23 (br s,
25.7 (3C), 25.8 (3C), 31.9, 32.5, 60.5, 74.6, 74.8, 172.3; HRMS (FAB)
2H, OH), 3.46–3.52 (m, 1H), 3.92–3.96 (m, 1H), 5.25 (d, J¼10.7 Hz,
m/z calcd for C22H49O4Si2 ([MþH]þ) 433.3169, found 433.3170.
1H), 5.36 (d, J¼17.1 Hz, 1H), 5.87 (ddd, J¼6.3, 10.7, 17.1 Hz); 13C NMR

A. Miura, S. Kuwahara / Tetrahedron 65 (2009) 3364–3368
3367
25
d
14.0, 22.6, 25.3, 31.8, 32.8, 74.3, 76.2, 117.4, 137.7; HRMS (FAB) m/z
[
a
]
ꢀ7.03 (c 1.28, CHCl3)); IR
n
3542 (m), 3314 (br m), 1729 (s),
D
calcd for C9H18NaO2Na ([MþNa]þ) 181.1204, found 181.1212.
1250 (m), 1175 (m), 975 (m); 1H NMR (CDCl3/D2O)
d 0.89 (t,
J¼6.8 Hz, 3H), 1.26–1.56 (m, 18H), 1.58–1.64 (m, 2H), 2.30 (t,
J¼7.3 Hz, 2H), 3.45–3.49 (m, 1H), 3.67 (s, 3H), 3.94 (t, J¼6.3 Hz,
1H), 4.14 (q, J¼5.9 Hz, 1H), 5.71 (dd, J¼6.3, 15.6 Hz, 1H), 5.82 (dd,
4.1.7. Methyl (S)-9-hydroxy-10-undecenoate (3a)
To a stirred mixture of powdered 4 Å molecular sieves (10 g) in
CH2Cl2 (40 ml) was successively added diisopropyl
D
-tartrate
J¼5.9, 15.6 Hz, 1H); 13C NMR
d 14.0, 22.6, 24.8, 25.2, 25.3, 28.9,
(1.60 ml, 7.56 mmol), Ti(Oi-Pr)4 (1.86 ml, 6.30 mmol), and a solu-
tion of TBHP (ca. 5 M in toluene, 2.52 ml, 12.6 mmol) at ꢀ20 ꢂC.
After 30 min, a solution of (ꢁ)-3 (1.35 g, 6.30 mmol) in CH2Cl2
(30 ml) was added, and the resulting mixture was stirred at ꢀ20 ꢂC
for 3 days. The mixture was quenched with an ice-cooled solution
of FeSO4 (4.4 g) in 10% aq tartaric acid (15 ml), stirred for an addi-
tional 30 min, and then gradually warmed to room temperature.
After being stirred for 1 h, the mixture was filtered, and the filtrate
was concentrated in vacuo. The residue was chromatographed over
SiO2 (hexane/EtOAc¼6:1 to 2:1) to give 3a (541 mg, 80% of the
theoretical amount) as a pale yellow oil together with an epoxi-
29.1, 29.2, 31.8, 32.9, 34.0, 37.1, 51.5, 72.0, 74.6, 75.3, 129.7, 136.2,
174.4; HRMS (FAB) m/z calcd for C19H37O5 ([MþH]þ) 345.2641,
found 345.2641.
4.1.11. Methyl (9S,10E,12S,13S)-9-(tert-butyldimethylsilyl)oxy-
12,13-dihydroxy-10-octadecenoate (13b)
To a stirred solution of 2b (13.0 mg, 82.2
(81.1 mg, 0.246 mmol) in CH2Cl2 (6.5 ml) was added the second
generation Grubbs catalyst (1.7 mg, 2.0 mol) at room tempera-
ture, and the mixture was stirred at 40 ꢂC. After 2.5 h, additional
mmol) and 3b
m
catalyst (1.7 mg, 2.0 mmol) was added, and resulting mixture was
dized product (660 mg, 92% of the theoretical amount) as a color-
stirred at 40 ꢂC for another 2.5 h. The mixture was filtered, and the
filtrate was concentrated in vacuo. The residue was chromato-
graphed over SiO2 (hexane/EtOAc¼10:1 to 3:1) to give 13b (9.1 mg,
25
less oil. [
a
]
þ5.75 (c 1.00, CHCl3); IR
n
3449 (br m), 3080 (w), 1738
D
(s), 1199 (m), 1172 (m); 1H NMR
d 1.28–1.43 (m, 7H), 1.47–1.57 (m,
3H), 1.57–1.65 (m, 3H), 2.30 (t, J¼7.3 Hz, 2H), 3.67 (s, 3H), 4.09 (q,
24%) as a yellow oil together with the homodimer of 2b (6.7 mg),
22
J¼6.3 Hz, 1H), 5.10 (d, J¼10.7 Hz, 1H), 5.22 (d, J¼17.1 Hz, 1H), 5.87
and the starting material 3b (72.7 mg). [
IR
835 (m), 775 (m); 1H NMR (CDCl3/D2O)
a]
ꢀ11.9 (c 0.13, CHCl3);
D
(ddd, J¼6.3, 10.7, 17.1 Hz, 1H); 13C NMR
d
24.9, 25.2, 29.0, 29.1, 29.3,
n
3410 (br m), 1742 (s), 1251 (m), 1198 (w), 1172 (w), 971 (w),
0.03 (s, 3H), 0.05 (s, 3H),
34.1, 37.0, 51.5, 73.2, 114.6, 141.3, 174.3; HRMS (FAB) m/z calcd for
C12H23O3 ([MþH]þ) 215.1647, found 215.1644.
d
0.89 (s, 9H), 0.89 (t, J¼6.6 Hz, 3H), 1.25–1.53 (m, 20H), 1.60–1.62
(m, 2H), 2.30 (t, J¼7.3 Hz, 2H), 3.43 (dt, J¼2.4, 6.8 Hz, 1H), 3.67 (s,
3H), 3.90 (t, J¼6.8 Hz, 1H), 4.12 (dt, J¼5.9, 6.3 Hz, 1H), 5.59 (dd,
J¼6.8, 15.6 Hz, 1H), 5.75 (dd, J¼5.9, 15.6 Hz, 1H); 13C NMR (CDCl3)
4.1.8. Determination of the enantiomeric excess of 3a
Compound 3a was converted into the corresponding (R)- and
(S)-MTPA esters (9) by treating with (S)- and (R)-MTPACl, re-
spectively, in pyridine. The 1H NMR signal for the olefinic proton at
the C10 position of the (R)-MTPA ester was observed at 5.72 ppm
(ddd, J¼6.8,10.7,17.6 Hz), while that of the (S)-MTPA ester appeared
at 5.82 ppm (ddd, J¼7.3, 10.3, 17.6 Hz). In each spectrum of the di-
astereomeric MTPA esters, no signal due to the corresponding di-
astereomer was observed. Therefore, compound 3a was estimated
to be optically pure within the limit of NMR detection.
d
ꢀ4.8, ꢀ4.4, 14.0, 18.2, 22.6, 24.8, 25.0, 25.2, 25.9, 29.0, 29.1, 29.3,
31.9, 32.9, 34.1, 38.1, 51.5, 72.6, 74.7, 75.7, 128.4, 137.2, 174.4; HRMS
(FAB) m/z calcd for C25H50O5SiNa ([MþNa]þ) 481.3325, found
481.3324.
4.1.12. (9S,10E,12S,13S)-9,12,13-Trihydroxy-10-
octadecenoic acid (1)
To a stirred solution of 13a (10.5 mg, 30
(0.140 ml) was added 1 M NaOH aq (35 l, 35
mixture was stirred at 40 ꢂC for 5 h. The mixture was quenched
with 1 M HCl aq (35
l) at 0 ꢂC and extracted with EtOAc. The
mmol) in MeOH
m
mmol) and the
4.1.9. Methyl (S)-9-(tert-butyldimethylsilyl)oxy-10-
undecenoate (3b)
m
To a stirred solution of 3a (63.1 mg, 0.294 mmol) in DMF (0.5 ml)
were added imidazole (60.1 mg, 0.883 mmol) and TBSCl (66.5 mg,
0.442 mmol) at 0 ꢂC. The mixture was gradually warmed to room
temperature over 4 h, quenched with brine, and then extracted
with ether. The extract was washed with water, dried (MgSO4), and
concentrated in vacuo. The residue was chromatographed over SiO2
extract was washed with brine, dried (MgSO4), and concentrated
in vacuo. The residue was chromatographed over SiO2 (CHCl3/
MeOH¼10:1) to give 1 (8.5 mg, 85%) as a white solid. Mp 103.5–
25
104.0 ꢂC (lit.8 mp 104–106 ꢂC, lit.11 mp 104–106 ꢂC); [
a
]
D
ꢀ9.8 (c
28
25
0.30, MeOH) (lit.5 [
a
]
ꢀ8.1 (c 0.32, MeOH), lit.8 [
a
]
ꢀ8.0 (c 0.30,
D
D
25
MeOH), lit.11
[
a
]
ꢀ7.9 (c 0.30, MeOH)); IR
n 3543 (m), 3317 (br m),
D
(hexane/EtOAc¼100:1) to give 3b (82.8 mg, 86%) as a pale yellow
2954 (w), 2921 (s), 2846 (s), 1693 (s), 1461 (w), 1070 (w), 974 (w);
23
oil. [
a]
ꢀ6.00 (c 1.00, CHCl3); IR
n
1742 (s), 1252 (m), 1199 (w), 1171
1H NMR (CD3OD)
d
0.91 (t, J¼6.8 Hz, 3H), 1.25–1.43 (m, 14H), 1.44–
D
(w), 836 (m), 775 (m); 1H NMR (CDCl3)
d
0.03 (s, 3H), 0.05 (s, 3H),
1.63 (m, 6H), 2.26 (t, J¼7.3 Hz), 3.38–3.43 (m, 1H), 3.90 (t, J¼5.4 Hz,
1H), 4.04 (q, J¼5.4 Hz, 1H), 5.67 (dd, J¼5.4, 15.6 Hz, 1H), 5.71 (dd,
0.89 (s, 9H), 1.29 (m, 8H), 1.40–1.50 (m, 2H), 1.62 (m, 2H), 2.30 (t,
J¼7.3 Hz, 2H), 3.67 (s, 3H), 4.09 (dt, J¼5.9, 6.3 Hz, 1H), 5.01 (d,
J¼10.3 Hz, 1H), 5.12 (d, J¼17.1 Hz, 1H), 5.79 (ddd, J¼6.3, 10.3, 17.1 Hz,
J¼5.4, 15.6 Hz, 1H); 13C NMR (CD3OD)
d 14.5, 23.8, 26.3, 26.5, 26.7,
30.3, 30.5, 30.6, 33.2, 33.6, 35.5, 38.4, 73.1, 75.8, 76.6, 131.1, 136.6,
178.4; HRMS (FAB) m/z calcd for C18H35O5Na ([MþNa]þ) 353.2304,
found 353.2307.
1H); 13C NMR
d
ꢀ4.8, ꢀ4.4,18.3, 24.9, 25.1, 25.9 (3C), 29.1, 29.2, 29.4,
34.1, 38.0, 51.4, 73.8, 113.4, 141.9, 174.3; HRMS (FAB) m/z calcd for
C18H36O3SiNa ([MþNa]þ) 351.2331, found 351.2334.
Acknowledgements
4.1.10. Methyl (9S,10E,12S,13S)-9,12,13-trihydroxy-10-
octadecenoate (13a)
To a stirred solution of 2b (20.0 mg, 0.126 mmol) and 3a
(81.2 mg, 0.379 mmol) in CH2Cl2 (2.5 ml) was added the second
We thank Ms. Yamada (Tohoku University) for measuring NMR
and mass spectra. This work was supported, in part, by a Grant-in-
Aid for Scientific Research (B) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan (No. 19380065).
generation Grubbs catalyst (5.4 mg, 6.3 mmol) at room tempera-
ture, and the mixture was stirred at 40 ꢂC for 5 h. The mixture was
filtered, and the filtrate was concentrated in vacuo. The residue
was chromatographed over SiO2 (hexane/EtOAc¼1:1) to give 13a
(14.8 mg, 35%) as a white solid together with the homodimer of 2b
Supplementary data
1H and 13C NMR spectra of compounds 4–8, 2a, 2b, 3a, 3b, 9, 13a,
13b, and 1. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2009.02.063.
(9.6 mg), the homodimer of 3a (32.3 mg), and the starting mate-
26
rial 3a (26.0 mg). Mp 92.5–93.0 ꢂC; [
a]
ꢀ9.00 (c 0.60, CHCl3) (lit.3
D

3368
A. Miura, S. Kuwahara / Tetrahedron 65 (2009) 3364–3368
14. Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. Bull. Chem. Soc. Jpn.1980, 53,1698–1702.
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