Synthesis of (-)-pinellic acid and its (9R,12S,13S)-diastereoisomer

Article abstract of DOI:10.1002/hlca.200900095

The total synthesis of (-)-pinellic acid with (9S,12S,13S)-configuration and its (9R,12S,13S)-diastereoisomer was achieved in high overall yields from a common intermediate derived from (+)-L-diethyl tartrate.

Full text of DOI:10.1002/hlca.200900095

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Helvetica Chimica Acta – Vol. 92 (2009)
Synthesis of (ꢀ)-Pinellic Acid and Its (9R,12S,13S)-Diastereoisomer
by Gowravaram Sabitha*, Martha Bhikshapathi, Erigala Venkata Reddy, and Jhillu S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500007, India
(phone: þ 91-40-27160512; fax: þ 91-40-27160512; e-mail: gowravaramsr@yahoo.com)
The total synthesis of (ꢀ)-pinellic acid with (9S,12S,13S)-configuration and its (9R,12S,13S)-
diastereoisomer was achieved in high overall yields from a common intermediate derived from (þ)-l-
diethyl tartrate.
Introduction. – Kampo medicine, ꢀSho-seiryu-toꢁ, was found to possess potent
adjuvant activity by oral administration on nasal influenza infection and nasal influenza
vaccination [1]. (ꢀ)-Pinellic acid (1) was responsible for its adjuvant activity, isolated
from pinelliae tuber, one of the component herbs of the Kampo formula, ꢀSho-seiryu-
toꢁ (SST) [2]. The absolute configuration of (ꢀ)-1 was determined as (9S,12S,13S)
(Fig.) by its total synthesis [3].
Figure. All stereoisomers of pinellic acid (1)
Influenza is an infectious respiratory disease caused by specific influenza viruses
(RNA virus of the orthomyxoviridae family) leading to both worldwide pandemics and
local outbreaks. Influenza virus infection is critical for patients having respiratory
ꢂ 2009 Verlag Helvetica Chimica Acta AG, Zꢃrich

Helvetica Chimica Acta – Vol. 92 (2009)
2053
diseases such as asthma, AIDS, or cardiopulmonary disease. The characteristic
symptoms of influenza in humans are fever, severe headache, coughing, and malaise.
Influenza vaccine is useful as prophylaxis of influenza virus infection [4]. Pinellic acid
(1) is a novel and potentially useful oral adjuvant when used in conjunction with
intranasal inoculation of influenza HA vaccines [2a]. Among the series of pinellic acid
isomers, the (9S,12S,13S)-compound, i.e., the natural pinellic acid (1), exhibited the
most potent adjuvant activity [5].
Recently, we reported the synthesis of the (9S,12R,13S)-isomer 3 [6]. Now, we
herein disclose our reports on the synthesis of pinellic acid (1, (9S,12S,13S)-
configuration) and its (9R,12S,13S)-diastereoisomer 6 starting from a single chiral
building block derived from l-(þ)-diethyl tartrate ((þ)-DET). Only few syntheses of
these acids have been reported in the literature [3][6 – 8].
Results and Discussion. – The known chiral aldehyde 9 derived from (þ)-DET [9]
was subjected to the Wittig olefination reaction with butyltriphenylphosphonium
bromide in the presence of potassium tert-butoxide in THF to provide the
corresponding olefinic compound 10 in a 9 :1 (E)/(Z) ratio in 70% yield. Removal
of the Bn protecting group with concomitant hydrogenation of the C¼C bond was
easily performed at atmospheric pressure, in AcOEt in the presence of 10% Pd/C as the
catalyst to afford the saturated alcohol 11 in 94% yield. Oxidation of the primary OH
group and subsequent Wittig reaction with the stable ylide Ph3PCHCO2Et furnished the
unsaturated ester 12 (80% yield over two steps). Reduction of the ester group with
DIBAL-H in CH2Cl2 afforded an unstable enal, which, without isolation, was subjected
to a Grignard reaction with THP protected bromo derivative 13. The reaction yielded a
diastereoisomeric mixture of secondary alcohols 14a and 14b in a 1.5 :1 ratio. These two
isomers were separated by column chromatography and their configurational assign-
ments were confirmed on a later stage. Compound 14b was converted into 14a by
inversion of the configuration of the alcohol under standard Mitsunobu conditions
(diisopropyl azodicarboxylate, Ph3P, and p-nitrobenzoic acid) (Scheme 1). On the other
hand, 14b was also used for the synthesis of the isomer 6 as shown in Scheme 2.
The secondary OH group in 14a was protected as a methoxymethyl (MOM) ether,
and subsequent removal of the THP group with catalytic pyridinium p-toluene
sulphonate (PPTS) in MeOH at room temperature led to the formation of 16a. This
alcohol was oxidized with iodoxybenzoic acid (IBX) reagent in DMSO and dry CH2Cl2
to afford aldehyde 17a, which, on subsequent oxidation with NaClO2, NaH2PO4 in
DMSO and H2O, afforded the corresponding acid 18a in 75% yield. Finally, the
acetonide and MOM groups were removed under acidic conditions (HCl in MeOH) to
afford the target molecule 1 in 66% yield. The physical and spectroscopic data of 1 were
identical with those reported [3][6].
Similarly, compound 14b was submitted to all steps described above leading to the
formation of 6 (Scheme 2). The structure of 6 was confirmed by spectral and analytical
data.
In summary, a facile, practical, and efficient synthesis was accomplished in high
overall yields from a common chiral building block derived from l-(þ)-diethyl tartrate.
M. B. and E. V. thank CSIR, New Delhi, for the award of fellowships.

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Helvetica Chimica Acta – Vol. 92 (2009)
Scheme 1
a) BuPPh3Br, t-BuOK, THF, 08 – r.t., 3 h, 70%. b) H2/Pd-C, AcOEt, 8 h, 94%. c) 1. oxalyl chloride,
DMSO, CH2Cl2, ꢀ 788, 45 min; 2. Ph3PCHCO2Et, C6H6, r.t., 3 h (80% two steps). d) 1. DIBAL-H,
CH2Cl2, ꢀ 788, 30 min; 2. Mg, 13, THF, 66%. e) 1. diisopropyl azodicarboxylate, Ph3P, 4-nitrobenzoic
acid; 2. K2CO3, MeOH, 08, 1 h, 66%. f) MOM-Cl, DIPEA, 08 – r.t., 2 h, 90%. g) Pyridinium p-
toluenesulfonate (PPTS), MeOH, r.t., 6 h, 80%. h) Iodoxybenzoic acid, DMSO, CH2Cl2, 3 h. i) NaClO2,
NaH2PO4, DMSO, H2O, 6 h, 75%. j) HCl (cat.), MeOH, r.t., 10 h, 66%.
Scheme 2
a) MOM-Cl, DIPEA, 08 – r.t., 2 h, 90%. b) PPTS, MeOH, r.t., 6 h, 78%. c) IBX, DMSO, CH2Cl2, 3 h. d)
NaClO2, NaH2PO4, DMSO, H2O, 6 h, 75%. e) HCl (cat.), MeOH, r.t., 10 h, 66%.
Experimental Part
General. Reactions were conducted under N2 using anh. solvents such as CH2Cl2 and THF. All
reactions were monitored by thin layer chromatography (TLC) using silica-coated plates (Merck 60 F-
254 silica gel plates) and visualizing under UV light. Light petroleum ether (60 – 808; PE) was used.
Column chromatography (CC): silica gel (SiO2; 60 – 120 mesh) supplied by Acme Chemical Co., India.
Yields refer to chromatographically and spectroscopically (1H, 13C) homogeneous material. Air sensitive
reagents were transferred by syringe or with a double-ended needle. Evaporation of solvents was

Helvetica Chimica Acta – Vol. 92 (2009)
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performed at reduced pressure, using a Bꢀchi rotary evaporator. Optical rotations: Jasco DIP-370
polarimeter at 208. 1H-NMR Spectra: Varian FT-200 MHz (Gemini) and Bruker UXNMR FT-300 MHz
(Avance) spectrometers in CDCl3; chemical shift values were reported in ppm rel. to TMS (d ¼ 0.0) as an
internal standard. EI-MS: at 70 eV on LC-MSD (Agilent Technologies).
(4S,5S)-4-[(Benzyloxy)methyl]-2,2-dimethyl-5-[(1E)-pent-1-en-1-yl]-1,3-dioxolane (10). To the sus-
pension of butyltriphenylphosphonium bromide (13.5 g, 33.8 mmol) in THF was added dropwise a soln.
of tert-BuOK (3.1 g, 27.6 mmol) in THF at 08 followed by a soln. of aldehyde 9 [9] (3.3 g, 13.2 mmol) in
THF. The mixture was stirred for 3 h, then quenched with aq. NH4Cl, extracted with Et2O (2 ꢁ 10 ml),
and washed with brine and H2O. The combined org. layer was dried (anh. Na2SO4), concentrated under
reduced pressure to give the crude product, which was purified by flash CC using hexane/AcOEt 95 :5 to
afford 10 (9 :1 (E)/(Z), 70% yield). Colorless oil. IR (neat): 2928, 2858, 1610, 1420. 1H-NMR (CDCl3,
300 MHz): 7.31 – 7.27 (m, 5 H); 5.66 – 5.56 (m, 1 H); 5.40 – 5.30 (m, 1 H); 4.61 (t, J ¼ 8.3, 1 H); 4.57 (s,
2 H); 3.81 – 3.74 (m, 1 H); 3.60 – 3.46 (m, 2 H); 2.16 – 1.94 (m, 2 H); 1.41 (s, 3 H); 1.39 – 1.32 (m, 5 H);
0.89 (t, J ¼ 7.3, 3 H). LC-MS: 313 ([M þ Na]þ).
[(4S,5S)-2,2-Dimethyl-5-pentyl-1,3-dioxolan-4-yl]methanol (11). To a soln. of olefin 10 (2.4 g,
8.3 mmol) in anh. AcOEt was added a cat. amount of Pd/C, and the mixture stirred under H2 atmosphere
for 8 h. Then, the mixture was filtered through a Celite pad, washed with AcOEt, and the filtrate was
concentrated under reduced pressure. The crude product was subjected to flash CC (hexane/AcOEt
70 :30) to give pure 11 (94%). Viscous liquid. IR (neat): 3440, 2930, 2858, 1420. 1H-NMR (CDCl3,
300 MHz): 3.87 – 3.80 (m, 1 H); 3.79 – 3.71 (m, 1 H); 3.68 – 3.62 (m, 1 H); 3.57 – 3.48 (m, 1 H); 1.71 (dd,
J ¼ 5.2, 2.2, 1 H); 1.57 – 1.47 (m, 2 H); 1.37 (s, 6 H); 1.35 – 1.29 (m, 4 H); 0.90 (t, J ¼ 6.7, 3 H). LC-MS: 225
([M þ Na]þ).
Ethyl (2E)-3-[(4S,5S)-2,2-Dimethyl-5-pentyl-1,3-dioxolan-4-yl]prop-2-enoate (12). To a soln. of
DMSO (3.3 ml, 46.5 mmol) in CH2Cl2 was added dropwise at ꢀ 788 oxalyl chloride (2.0 ml, 23.3 mmol),
followed by a soln. of 11 (2.2 g, 10.9 mmol) in CH2Cl2. The mixture was stirred for 45 min at ꢀ 788, and
the reaction was quenched with Et3N (9.8 ml, 70.3 mmol). To this mixture were added 5 ml of benzene
followed by the Wittig ylide Ph3PCHCO2Et (6.1 g, 17.5 mmol) and stirred at r.t. for 3 h. After completion
of the reaction, the mixture was diluted with CH2Cl2, washed with brine and H2O. The combined org.
layer was dried (Na2SO4) and concentrated under vacuum. The crude compound eluted on CC (SiO2;
hexane/AcOEt 95 :5) afforded pure 12 (80%). Colorless liquid. IR (neat): 2928, 2858, 1725, 1602, 1453.
1H-NMR (CDCl3, 200 MHz): 6.81 (dd, J ¼ 15.4, 5.1, 1 H); 6.07 (dd, J ¼ 15.4, 1.5, 1 H); 4.27 – 4.04 (m,
3 H); 3.75 – 3.62 (m, 1 H); 1.60 – 1.49 (m, 2 H); 1.42 – 1.25 (m, 15 H); 0.90 (t, J ¼ 6.6, 3 H). LC-MS: 293
([M þ Na]þ).
(1E,3S)-1-[(4S,5S)-2,2-Dimethyl-5-pentyl-1,3-dioxolan-4-yl]-11-(tetrahydro-2H-pyran-2-yloxy)un-
dec-1-en-3-ol (14a) and (1E,3R)-1-[(4S,5S)-2,2-Dimethyl-5-pentyl-1,3-dioxolan-4-yl]-11-(tetrahydro-2H-
pyran-2-yloxy)undec-1-en-3-ol (14b). To a stirred soln. of ester 12 (2.0 g, 7.4 mmol) in CH2Cl2 was added
dropwise at ꢀ 788 DIBAL-H (7.4 ml, 7.4 mmol), and the mixture was allowed to stir at the same temp. for
30 min. After monitoring with TLC, the reaction was quenched with aq. MeOH at 08. Then was added
sat. soln. of sodium potassium tartrate, and extracted with CH2Cl2. The org. layer was washed with brine
and H2O. The combined org. layer was dried over anh. Na2SO4, concentrated under vacuum to obtain the
aldehyde which was used without further purification. A soln. of bromide 13 (4.3 g, 14.7 mmol) in THF
was added to a suspension of Mg (0.35 g, 14.4 mmol) in THF, refluxed for 20 min, then it was cooled to 08
and was added to the soln. of aldehyde in THF. The mixture was stirred for 1 h. After monitoring TLC,
the reaction was quenched with aq. NH4Cl, filtered through a Celite pad using AcOEt. The filtrate was
dried (Na2SO4), concentrated under vacuum, and purified by CC (SiO2; hexane/AcOEt 80 :20), to afford
pure 14a and 14b in a 1.5 :1 ratio (66%).
Data of 14a. Pale yellow oil. IR (neat): 3444, 2930, 2857, 1460. 1H-NMR (CDCl3, 300 MHz): 5.81 (dd,
J ¼ 15.1, 6.0, 1 H); 5.61 (dd, J ¼ 15.1, 7.5, 1 H); 4.59 – 4.55 (m, 1 H); 4.15 – 4.07 (m, 1 H); 3.95 (t, J ¼ 7.5,
1 H); 3.88 – 3.80 (m, 1 H); 3.75 – 3.59 (m, 2 H); 3.54 – 3.44 (m, 1 H); 3.39 – 3.31 (m, 1 H); 1.91 – 1.80 (m,
1 H); 1.75 – 1.48 (m, 8 H); 1.40 (s, 6 H); 1.38 – 1.28 (m, 20 H); 0.93 (t, J ¼ 6.8, 3 H). LC-MS: 463 ([M þ
Na]þ).
1
Data of 14b. Pale yellow oil. IR (neat): 3446, 2930, 2857, 1742, 1460. H-NMR (CDCl3, 300 MHz):
5.82 (dd, J ¼ 15.8, 5.3, 1 H); 5.62 (dd, J ¼ 15.8, 6.8, 1 H); 4.57 (t, J ¼ 3.7, 1 H); 4.20 – 4.10 (m, 1 H); 3.95

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Helvetica Chimica Acta – Vol. 92 (2009)
(t, J ¼ 7.5, 1 H); 3.84 (dt, J ¼ 8.3, 3.0, 1 H); 3.76 – 3.59 (m, 2 H); 3.54 – 3.44 (m, 1 H); 3.39 – 3.31 (m, 1 H);
1.91 – 1.27 (m, 34 H); 0.93 (t, J ¼ 6.0, 3 H). LC-MS: 463 ([M þ Na]þ).
2-{[(9S,10E)-11-[(4S,5S)-2,2-Dimethyl-5-pentyl-1,3-dioxolan-4-yl]-9-(methoxymethoxy)undec-10-
en-1-yl]oxy}tetrahydro-2H-pyran (15a). To the soln. of alcohol 14a (0.7 g, 1.6 mmol) in CH2Cl2 was added
Hunigꢁs base (DIPEA) (1.08 ml, 6.4 mmol) and cooled to 08, and then MOM-Cl (0.27 ml, 3.6 mmol) was
added in dropwise manner, and the mixture was allowed to stir for 2 h. After monitoring TLC, the
mixture was diluted with CH2Cl2, washed with H2O, combined org. layer was dried (Na2SO4),
concentrated under vacuum and purified by CC (SiO2; hexane/AcOEt 85 :15) to afford pure 15a (90%).
Pale yellow oil. IR (neat): 2930, 2858, 1460. 1H-NMR (CDCl3, 300 MHz): 5.59 – 5.56 (m, 2 H); 4.65 – 4.47
(m, 3 H); 3.96 – 3.87 (m, 2 H); 3.84 (m, 1 H); 3.60 – 3.54 (m, 2 H); 3.35 – 3.30 (m, 2 H); 3.34 (m, 3 H);
1.67 – 1.42 (m, 10 H); 1.37 (s, 6 H); 1.34 – 1.24 (m, 18 H); 0.89 (t, J ¼ 7.5, 3 H). LC-MS: 507 ([M þ Na]þ).
2-{[(9R,10E)-11-[(4S,5S)-2,2-Dimethyl-5-pentyl-1,3-dioxolan-4-yl]-9-(methoxymethoxy)undec-10-
en-1-yl]oxy}tetrahydro-2H-pyran (15b). Yield 90%. Pale yellow oil. IR (neat): 2930, 2857, 1460. 1H-NMR
(CDCl3, 300 MHz): 5.62 – 5.58 (m, 2 H); 4.65 – 4.47 (m, 3 H); 4.04 – 3.93 (m, 2 H); 3.84 (dt, J ¼ 11.3, 2.2,
1 H); 3.75 – 3.59 (m, 2 H); 3.53 – 3.44 (m, 1 H); 3.40 – 3.33 (m, 5 H); 2.10 – 1.79 (m, 2 H); 1.75 – 1.49 (m,
8 H); 1.44 – 1.27 (m, 24 H); 0.93 (t, J ¼ 6.8, 3 H). LC-MS: 507 ([M þ Na]þ).
(9S,10E)-11-[(4S,5S)-2,2-Dimethyl-5-pentyl-1,3-dioxolan-4-yl]-9-(methoxymethoxy)undec-10-en-1-
ol (16a). Compound 15a (0.6 g, 1.2 mmol) was dissolved in MeOH, to which was added cat. amount of
pyridinium p-toluene sulfonate (PPTS) at 08, the mixture was stirred at r.t. for 6 h. After monitoring
TLC, the reaction was quenched with NaHCO3, and MeOH was removed under vacuum, the crude
compound was purified through CC (SiO2; hexane/AcOEt 70 :30) to afford pure 16a. Colorless oil
(80%). [a]2D5 ¼ þ31.7 (c ¼ 0.5, CHCl3). IR (neat): 3439, 2927, 2857, 1632, 1460. 1H-NMR (CDCl3,
200 MHz): 5.61 – 5.54 (m, 2 H); 4.56 (AB, J ¼ 6.8, 2 H); 4.05 – 3.88 (m, 2 H); 3.61 (t, J ¼ 6.2, 2 H); 3.59 –
3.54 (m, 1 H); 3.33 (s, 3 H); 1.62 – 1.25 (m, 28 H); 0.91 (t, J ¼ 6.2, 3 H). 13C-NMR (CDCl3, 75 MHz):
134.6; 130.1; 108.5; 93.8; 81.7; 80.8; 80.7; 76.0; 63.0; 55.4; 35.8; 32.7; 31.9; 31.5; 29.5; 29.4; 29.3; 27.3; 26.9;
25.7; 25.2; 22.5; 14.0. LC-MS: 423 ([M þ Na]þ).
(9R,10E)-11-[(4S,5S)-2,2-Dimethyl-5-pentyl-1,3-dioxolan-4-yl]-9-(methoxymethoxy)undec-10-en-1-
ol (16b). Yield 78%. Colorless oil. [a]2D5 ¼ ꢀ75.8 (c ¼ 1.0, CHCl3). IR (neat): 3444, 2930, 2859, 1640, 1461.
1H-NMR (CDCl3, 300 MHz): 5.63 – 5.58 (m, 2 H); 4.56 (AB, J ¼ 6.2, 2 H); 4.05 – 3.92 (m, 2 H); 3.67 – 3.59
(m, 3 H); 3.36 (s, 3 H); 1.62 – 1.28 (m, 28 H); 0.93 (t, J ¼ 6.8, 3 H). 13C-NMR (CDCl3, 75 MHz): 134.9;
130.0; 108.5; 93.7; 81.9; 80.8; 76.0; 63.0; 55.4; 35.5; 32.7; 31.9; 29.5; 29.4; 29.3; 27.3; 26.9; 25.7; 25.2; 22.5;
14.0. LC-MS: 423 ([M þ Na]þ).
(9S,10E)-11-[(4S,5S)-2,2-Dimethyl-5-pentyl-1,3-dioxolan-4-yl]-9-(methoxymethoxy)undec-10-enoic
Acid (18a). To an ice-cold soln. of iodoxybenzoic acid (0.33 g, 1.18 mmol) in DMSO (1 ml) was added a
soln. of alcohol 16a (0.3 g, 0.75 mmol) in CH2Cl2 and stirred for 3 h at r.t. The mixture was filtered
through a Celite pad, washed with CH2Cl2, the filtrate was washed with H2O, and the combined org. layer
was dried (Na2SO4) and concentrated under reduced pressure. The crude aldehyde was dissolved in
DMSO, at 08, aq. solns of NaH2PO4 (0.07 g, 0.58 mmol) and NaClO2 (0.12 g, 1.33 mmol) were added
dropwise and stirred for 6 h at r.t. The mixture was extracted with Et2O, washed with brine and H2O. The
combined org. layer was dried (Na2SO4), concentrated, and purified to afford 18a (70%). Pale yellow oil.
1
[a]2D5 ¼ þ22.8 (c ¼ 0.5, CHCl3). IR (neat): 3439, 2930, 2858, 1711, 1461. H-NMR (CDCl3, 300 MHz):
5.62 – 5.58 (m, 2 H); 4.56 (AB, J ¼ 6.8, 2 H); 4.03 – 3.92 (m, 2 H); 3.65 – 3.56 (m, 1 H); 3.36 (s, 3 H); 2.34
(t, J ¼ 7.5, 2 H); 1.71 – 1.27 (m, 26 H); 0.91 (t, J ¼ 6.8, 3 H). 13C-NMR (CDCl3, 75 MHz): 134.5; 130.0;
108.5; 93.7; 81.7; 80.8; 80.7; 75.9; 63.0; 55.4; 35.4; 33.9; 31.9; 31.8; 29.2; 29.0; 28.9; 27.2; 26.9; 25.7; 25.2;
22.5; 14.0. LC-MS: 437 ([M þ Na]þ).
(9R,10E)-11-[(4S,5S)-2,2-Dimethyl-5-pentyl-1,3-dioxolan-4-yl]-9-(methoxymethoxy)undec-10-enoic
1
Acid (18b). Yield 75% over two steps. Colorless oil. IR (neat): 2930, 2857, 1739, 1710, 1461. H-NMR
(CDCl3, 300 MHz): 5.62 – 5.58 (m, 2 H); 4.56 (AB, J ¼ 6.8, 2 H); 4.04 – 3.93 (m, 2 H); 3.68 – 3.58 (m, 1 H);
3.36 (s, 3 H); 2.35 (t, J ¼ 7.5, 2 H); 1.70 – 1.27 (m, 26 H); 0.93 (t, J ¼ 6.8, 3 H). LC-MS: 437 ([M þ Na]þ).
(ꢀ)-Pinellic Acid (¼(9S,10E,12S,13S)-9,12,13-Trihydroxyoctadec-10-enoic Acid; 1). To a soln. of
acid 18a (0.25 g, 0.6 mmol) in MeOH was added a cat. amount of HCl and stirred for 10 h at r.t. The
reaction was quenched with NaHCO3, MeOH was removed under vacuum, and the crude product was
purified to afford 1 (66%). White powder. M.p. 102 – 1048 ([3]: 104 – 1068). [a]2D5 ¼ ꢀ9.2 (c ¼ 0.5, MeOH)

Helvetica Chimica Acta – Vol. 92 (2009)
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1
([3]: [a]2D2 ¼ ꢀ8.0 (c ¼ 0.3, MeOH)). IR (KBr): 3440, 2930, 2858, 1710, 1620. H-NMR (CDCl3/DMSO,
200 MHz): 5.76 – 5.56 (m, 2 H); 4.45 – 4.27 (m, 1 H); 4.17 – 3.90 (m, 1 H); 3.56 – 3.22 (m, 4 H); 2.21 (t, J ¼
7.0, 2 H); 1.63 – 1.23 (m, 20 H); 0.90 (t, J ¼ 7.0, 3 H). 13C-NMR (CDCl3/DMSO, 75 MHz): 178.2; 134.5;
130.0; 76.8; 75.9; 72.9; 37.6; 33.9; 32.8; 29.8; 29.2; 29.0; 28.8; 26.2; 26.1; 25.8; 23.9; 14.0. LC-MS: 453
([M þ Na]þ).
(9R,10E,12S,13S)-9,12,13-Trihydroxyoctadec-10-enoic Acid (6). Yield 66%. White powder. M.p.
66 – 708 ([5]: 69 – 748). [a]2D5 ¼ ꢀ24.2 (c ¼ 0.5, MeOH) ([5]: [a]2D2 ¼ ꢀ24.0 (c ¼ 0.3, MeOH)). IR (KBr):
1
3362, 2928, 2850, 1695. H-NMR (CDCl3/DMSO, 200 MHz): 5.64 – 5.56 (m, 2 H); 3.99 – 3.90 (m, 1 H);
3.78 – 3.71 (m, 1 H); 3.36 – 3.21 (m, 4 H); 2.18 (t, J ¼ 7.4, 2 H); 1.63 – 1.23 (m, 20 H); 0.90 (t, J ¼ 6.6, 3 H).
13C-NMR (CDCl3/DMSO, 75 MHz): 180.4; 133.8; 128.8; 75.0; 74.0; 70.0; 36.2; 33.0; 31.6; 31.0; 28.2; 28.0;
27.7; 24.4; 24.2; 23.9; 21.5; 13.2. LC-MS: 453 ([M þ Na]þ).
REFERENCES
[1] T. Miyamoto, Asian Med. J. 1992, 35, 30; T. Nagai, H. Yamada, Int. J. Immunopharmacol. 1994, 16,
605; T. Nagai, M. Urata, H. Yamada, Immunopharmacol. Immunotoxicol. 1996, 18, 193.
[2] a) T. Kato, Y. Yamaguchi, S. Ohnuma, T. Uyehara, T. Namai, M. Kodama, Y. Shiobara, Chem. Lett.
1986, 577; b) C. D. Funk, W. S. Powell, Biochem. Biophys. Acta 1983, 754, 57; c) M. Hanberg, Lipids
1991, 26, 407; d) N. Harada, J. Iwabuchi, Y. Yokota, N. Uda, K. Nakanishi, J. Am. Chem. Soc. 1981,
103, 5590.
[3] T. Sunazuka, T. Shirahata, K. Yoshida, D. Yamamoto, Y. Harigaya, T. Nagai, H. Kiyohara, H.
¯
Yamada, I. Kuwajima, S. Omura, Tetrahedron Lett. 2002, 43, 1265; T. Shirahata, T. Sunazuka, K.
¯
Yoshida, D. Yamamoto, Y. Harigaya, T. Nagai, H. Kiyohara, H. Yamada, I. Kuwajima, S. Omura,
Bioorg. Med. Chem. Lett. 2003, 13, 937.
[4] B. R. Murphy, R. G. Webster, ꢀOrthomixovirusesꢁ, in ꢀVirologyꢁ, 2nd Edn., Eds. B. N. Fields, D. M.
Knipe, Raven, New York, 1990, pp. 1091 – 1152.
[5] T. Shirahata, T. Sunazuka, K. Yoshida, D. Yamamoto, Y. Harigaya, I. Kuwajima, T. Nagai, H.
¯
Kiyohara, H. Yamada, S. Omura, Tetrahedron 2006, 62, 9483.
[6] G. Sabitha, E. V. Reddy, M. Bhikshapathi, J. S. Yadav, Tetrahedron Lett. 2007, 48, 313.
[7] S. V. Naidu, P. Kumar, Tetrahedron Lett. 2007, 48, 2279.
[8] K. R. Prasad, B. Swain, Tetrahedron: Asymmetry 2008, 19, 1134.
[9] W. Lu, G. Zheng, Haji, A. Aisa, J. Cai, Tetrahedron Lett. 1998, 39, 9521.
Received March 17, 2009