Stereoselective total synthesis of Oxylipins: (6S,7E,9R,10S)-6,9,10- trihydroxyoctadec-7-enoic acid and (6z,8r,9r,10s)-8,9,10-trihydroxyoctadec-6- enoic acid

Article abstract of DOI:10.1002/hlca.201300223

The stereoselective total syntheses of oxylipins 1b and 1c are described starting from readily accessible natural sugars via the Grubbs cross-metathesis, Wittig olefination, and Zn-mediated reductive elimination as key steps. Copyright

Full text of DOI:10.1002/hlca.201300223

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Stereoselective Total Synthesis of Oxylipins: (6S,7E,9R,10S)-6,9,10-
Trihydroxyoctadec-7-enoic Acid and (6Z,8R,9R,10S)-8,9,10-
Trihydroxyoctadec-6-enoic Acid
by Jhillu Singh Yadav*, Kattela Shiva Shankar, Anugu Srinivas Reddy, and Basi V. Subba Reddy
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad – 500
007, India (fax: 91-40-27160512; e-mail: yadavpub@iict.res.in)
The stereoselective total syntheses of oxylipins 1b and 1c are described starting from readily
accessible natural sugars via the Grubbs cross-metathesis, Wittig olefination, and Zn-mediated reductive
elimination as key steps.
Introduction. – Oxylipins are saturated and unsaturated fatty acids that are widely
distributed in nature as constituents of various complex lipids or as free carboxylic acids
[1][2]. Plant oxylipins are polyunsaturated fatty acid derivatives, which are involved in
plant defense responses to pest and pathogen attack. Indeed, some of these molecules
show antimicrobial properties, and a few of them act as regulators of plant defense gene
expression [3]. In particular, Dracotium loretense, a plant belonging to the Araceae
family, is widely distributed in Peruvian Amazon and has been extensively used
traditionally in Peruvian folk medicine to boost immune function [4 – 6]. Oxylipins 1a –
1d, isolated from the BuOH extract of the corms of D. loretense, are known to exhibit
potent immunostimulatory effects at 10 mm concentration on human peripheral blood
mononuclear cells (PBMCs) proliferation (Fig.) [7].
However, there are no reports on the total synthesis of 1c, despite a recent report on
oxylipin 1b [8]. In continuation of our long-lasting interest on the total synthesis of
bioactive natural products [9] by establishing novel synthetic routes, we herein report a
Figure. Examples of oxylipins (trihydroxy fatty acids)
ꢀ 2014 Verlag Helvetica Chimica Acta AG, Zꢁrich

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concise synthetic strategy for the most active oxylipins 1b and 1c, employing simple
sugars as chiral starting materials. Our strategy involves mainly the retention of sugar
stereogenic centers in the target molecules.
Results and Discussion. – Synthesis of Oxylipin 1b. Retrosynthesis of 1b is based on
a convergent approach, wherein two fragments 2 and 3 could be coupled by olefin
cross-metathesis in analogy to [8]. The fragment 2 was proposed to be obtained from d-
ribose, while fragment 3 (chiral vinyl alcohol) could be prepared from hexane-1,6-diol
(Scheme 1). The synthesis of fragment 2 started from d-ribose acetonide [10].
Treatment of 2,3-O-isopropylidene-d-ribose (4) with heptyltriphenylphosphonium
bromide ((Me(CH2)6)Ph3PþBrꢀ) [11] in the presence of BuLi in THFat 08 [12] gave the
olefin 5 as a (E)/(Z)-mixture (2 :8) in 90% yield, which was inseparable by column
chromatography. The (E)/(Z) ratio was determined by 1H-NMR spectroscopy.
Hydrogenation of 5 using Pd/C under H2 in EtOH afforded the diol 6 in 98% yield.
Treatment of 6 with MsCl in the presence of Et3N in CH2Cl2 gave the bis(methanesul-
fonate) 7 in 89% yield. Reductive elimination of 7 using Zn powder in DMF [13] led to
the olefin 2 in 95% yield (Scheme 2).
The second fragment 3 was prepared from the commercially available hexane-1,6-
diol as outlined in Scheme 2. Oxidation of the benzyloxy alcohol 8 [14] under Swern
conditions afforded the aldehyde, which was then subjected to Wittig olefination with
ethyl 2-(triphenylphosphoranylidene)acetate (Ph3P¼CHCOOEt) to give the a,b-
unsaturated ester 9 [15] in 92% yield over two steps. Reduction of the ester 9 with
DIBAL-H gave the allylic alcohol 10 [16], which was then subjected to Sharpless
t
asymmetric epoxidation [17] employing (þ)-DET, Ti(OiPr)4, and BuOOH to afford
the chiral epoxy alcohol 11 in 88% yield. Treatment of 11 with I2 in the presence of Ph3P
in THF gave the epoxy iodide, which was then subjected to Zn-mediated reductive
elimination [18] to give the chiral allylic alcohol 3 [19] in 96% yield (Scheme 2).
The cross-coupling of fragments 2 and 3 was achieved using Grubbs 2nd-generation
catalyst in CH2Cl2 [8]. In this cross-metathesis, the trans-isomer 12 was formed
exclusively in 70% yield [20]. Protection of the OH group of 12 with TBSOTf in the
presence of 2,6-lutidine afforded the silyl ether 13 in 80% yield. Removal of the Bn
group in 13 with DDQ gave the primary alcohol 14 in 70% yield, which was then
Scheme 1. Retrosynthetic Analysis of Oxylipin 1b

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Scheme 2
a) BuLi, THF, (Me(CH2)6)Ph3PþBrꢀ, ꢀ 408 to r.t.; 90%. b) H2, 10% Pd/C, EtOH, 2 h; 98%. c) MsCl,
Et3N, CH2Cl2, r.t., 1 h; 89%. d) Zn, DMF, reflux, 7 h; 95%. e) NaH, BnBr, dry THF, r.t., 4 h; 95%. f) 1)
(COCl)2, DMSO, Et3N, CH2Cl2, ꢀ 788. 2) Ph3P¼CHCO2Et, benzene, reflux, 8 h; overall yield for two
steps, 92%. g) Diisobutylaluminium hydride (DIBAL-H), CH2Cl2, 08, 4 h; 95%. h) (2R,3R)-Diethyl
tartrate ((þ)-DET), Ti(OiPr)4, tBuOOH (TBHP), CH2Cl2, 4-ꢂ molecular sieves, 16 h, ꢀ 258; 88%. i) 1)
I2, Ph3P, 1H-imidazole, toluene, 1 h. 2) Zn/EtOH, reflux, 6 h; overall yield for two steps 96%. j) Grubbs-
II catalyst, CH2Cl2, r.t., 30 min; 70%. k) (tert-Butyl)(dimethyl)silyl trifluoromethanesulfonate
(TBSOTf), 2,6-lutidine, CH2Cl2, 10 min; 80%. l) 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ),
CH2Cl2/H2O 19 :1, 4 h, r.t.; 70%. m) (Diacetoxyiodo)benzene, 2,2,6,6-tetramethylpiperidin-1-oxyl
(TEMPO), MeCN/H2O 4 :1, 4 h, r.t., then, 3n HCl, THF, 608, 10 h; 50%.
converted to the carboxylic acid using TEMPO/(diacetoxyiodo)benzene in MeCN/H2O
(4 :1) [21]. Global deprotection of TBS and acetonide groups with 3n HCl in THF
under reflux conditions furnished the target molecule 1b in 50% yield (Scheme 2). The
spectroscopic data for 1b were in agreement with those reported in the literature [8].
Synthesis of Oxylipin 1c. Our retrosynthetic analysis of 1c is depicted in Scheme 3.
The internal (Z)-C¼C bond was assumed to be attained through Wittig olefination, and
the three stereogenic centers of 15 could be obtained from d-xylose. The (tBu)Me2Si
(TBS)-protected Wittig salt 16 could be prepared from 6-bromohexan-1-ol.

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Scheme 3. Retrosynthetic Analysis of Oxylipin 1c
The synthesis of aldehyde 15 was initiated from d-xylose. Compound 17 was
prepared in four steps as described in [22]. Wittig olefination of 17 with
(Me(CH2)6)Ph3PþBrꢀ in presence of BuLi at 08 afforded the ene-diol 18 in 90% yield
with a 9 :1 (E)/(Z) ratio. Protection of 18 (92%) as acetonide, followed by hydro-
genation, gave compound 20 in 95% yield. Selective oxidation of 20 with TEMPO/
(diacetoxyiodo)benzene in CH2Cl2 afforded the aldehyde 15 in 70% yield (Scheme 4)
[23]. The Wittig salt 16 was prepared as described in [24]. The coupling of fragments 15
and 16 through Wittig reaction using NaHMDS in THF at ꢀ 788 gave the en-ol 21 in
70% yield with high diastereoselectivity ((E)/(Z) 1:9) favoring the (Z)-isomer, which
Scheme 4
a) BuLi, dry THF, (Me(CH2)6)Ph3PþBrꢀ, ꢀ 408 to r.t.; 90%. b) 2,2-Dimethoxypropane/PPTS (cat.),
CH2Cl2, 30 min, r.t.; 92%. c) H2, 10% Pd/C, EtOH, 3 h; 95%. d) (Diacetoxyiodo)benzene, TEMPO,
CH2Cl2, r.t., 2 h; 70%. e) Sodium bis(trimethylsilyl)amide (NaHMDS), dry THF, compound 16, ꢀ 788,
3 h; 70%. f) Bu4NF, THF, 30 min, r.t.; 80%. g) (Diacetoxyiodo)benzene, TEMPO, MeCN/H2O 4 :1, r.t.,
2 h then 3n HCl, THF, 608, 6 h; 60%.

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was separated by column chromatography. Deprotection of 21 with Bu4NF in THF
gave the diol 22 in 80% yield. Compound 22 was then converted to the acid using
TEMPO/(diacetoxyiodo)benzene [25] in MeCN/H2O 4 :1, followed by deprotection of
the acetonide with 3n HCl in THF under reflux conditions to give the target molecule
1c in 60% yield (Scheme 4). The spectroscopic data and optical rotation of the synthetic
compound were identical to those reported for the natural product [7].
Conclusions. – We have reported an efficient and cost-effective synthetic procedure
for the total synthesis of oxylipins 1b and 1c starting from d-ribose and d-xylose,
respectively. The key steps involved were Grubbs cross-metathesis, Wittig olefination,
Zn-mediated elimination, and selective oxidation.
K. S. S and A. S. R. thank CSIR, New Delhi, India, for the award of fellowships. B. V. S. thanks CSIR,
New Delhi, for financial support as a part of XII Five Year Plan under the title DENOVA (CSC-0205).
Experimental Part
General. Solvents were dried over standard drying agents and freshly distilled prior to use. The
reagents were purchased from Aldrich and Acros, and were used without further purification unless
otherwise stated. All moisture-sensitive reactions were carried out under N2. Org. solns. were dried
(Na2SO4) and concentrated in vacuo below 408. Column chromatography (CC): silica gel (Acmeꢃs, 60 –
120 mesh and 100 – 200 mesh). Optical rotations: Horiba high-sensitive polarimeter SEPA-300 at 258. IR
.
Spectra: PerkinElmer IR-683 spectrophotometer with NaCl optics; ˜n in cmꢀ1 1H- (300 MHz) and
13C-NMR (75 MHz) spectra: Bruker Avance 300 instrument; d in ppm rel. to Me4Si as internal standard, J
in Hz. MS: Agilent Technologies 1100 Series (Agilent ChemStation software); in m/z.
(1R)-1-{(4R,5S)-2,2-Dimethyl-5-[(E/Z)-oct-1-en-1-yl]-1,3-dioxolan-4-yl}ethane-1,2-diol (5). To a
pre-cooled (08) soln. of the Wittig salt (Me(CH2)6)Ph3PþBrꢀ (23.15 g, 52.64 mmol) in anh. THF
(300 ml) was added BuLi (1.6m in hexane, 24.29 ml, 39.48 mmol) slowly under N2. The orange-red soln.
was stirred under the above conditions for 30 min, and then a soln. of 4 (5 g, 26.32 mmol) in dry THF
(50 ml) was added dropwise under N2. The mixture was stirred at this temp. for another 30 min and then
allowed to warm to r.t. The reaction was monitored by TLC (petroleum ether/AcOEt 3 :1), until all
starting materials disappeared. The reaction was then quenched with sat. aq. NH4Cl (50 ml), and the
mixture was extracted with AcOEt (3 ꢁ 250 ml). The combined org. phase was dried (Na2SO4) and
concentrated. Purification of the residue by CC gave 5 (6.44 g, 90%). Syrup. Rf (30% AcOEt/hexane)
1
0.40. IR (KBr): 3451, 2952, 2921, 2836, 1458, 1376. H-NMR (300 MHz, CDCl3): 6.01 – 5.72 (m, 1 H);
5.66 – 5.52 (m, 1 H); 4.15 – 4.03 (m, 1 H); 3.86 – 3.67 (m, 4 H); 2.22 – 2.02 (m, 2 H); 1.47 (s, 3 H); 1.36 (s,
3 H); 1.33 – 1.21 (m, 8 H); 0.88 (t, J ¼ 6.7, 3 H). 13C-NMR (75 MHz, CDCl3): 136.6; 136.2; 124.9; 124.6;
108.6; 78.4; 78.1; 69.9; 64.2; 32.3; 31.5; 28.9; 28.8; 27.7; 25.1; 22.5; 14.0. ESI-MS: 295 ([M þ Na]þ). HR-
ESI-MS: 295.22437 (C15H28NaOþ4 ; calc. 295.22473).
(1R)-1-[(4R,5S)-2,2-Dimethyl-5-octyl-1,3-dioxolan-4-yl]ethane-1,2-diol (6). To a soln. of 5 (3.0 g,
11.02 mmol) in MeOH (30 ml) was added 10% Pd/C (100 mg), and the mixture was stirred for 4 h under
H2 with 55 psi pressure. After filtering the catalyst, the solvent was removed and the resulting residue was
purified by CC to afford 6 (2.96 g, 98%). Colorless oil. Rf (30% AcOEt/hexane) 0.5. [a]3D0 ¼ ꢀ15.2 (c ¼
1.5, CHCl3). IR (CHCl3): 3445, 2932, 2844, 1642, 1205, 1076. 1H-NMR (300 MHz, CDCl3): 4.27 – 4.10 (m,
1 H); 4.04 – 3.92 (m, 1 H); 3.89 – 3.70 (m, 3 H); 1.79 – 1.51 (m, 4 H); 1.49 – 1.18 (m, 18 H); 0.88 (t, J ¼ 6.7,
3 H). 13C-NMR (75 MHz, CDCl3): 107.9; 77.9; 77.6; 69.6; 64.6; 31.8; 29.6; 29.5; 29.3; 29.2; 28.0; 26.5; 25.5;
22.6; 14.0. ESI-MS: 297 ([M þ Na]þ). HR-ESI-MS: 297.20363 (C15H30NaOþ4 ; calc. 297.20373).
(1R)-1-[(4S,5S)-2,2-Dimethyl-5-octyl-1,3-dioxolan-4-yl]-2-[(methylsulfonyl)oxy]ethyl Methanesul-
fonate (7). To a soln. of 6 (2.0 g, 7.30 mmol) in dry CH2Cl2 (50 ml) was added Et3N (2.16 ml,
21.89 mmol); and the mixture was stirred at 08 under N2. After 10 min, MsCl (1.75 ml, 15.84 mmol) was
added, and the mixture was stirred at r.t. for 4 h. The reaction was quenched with H2O, and the mixture

Helvetica Chimica Acta – Vol. 97 (2014)
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extracted with CH2Cl2 (2 ꢁ 25 ml). The org. extract was washed with H2O (10 ml), followed by brine
(5 ml). The org. layer was dried (Na2SO4) and concentrated in vacuo to give the crude product, which
was purified by CC (10% AcOEt/hexane) to provide 7 (2.78 g, 89%). Colorless oil. Rf (10% AcOEt/
hexane) 0.6. [a]2D5 ¼ ꢀ21.0 (c ¼ 0.5, CHCl3). IR (KBr) : 2928, 2857, 1443, 1372, 1218, 772. 1H-NMR
(300 MHz, CDCl3): 4.87 (td, J ¼ 2.2, 5.2, 1 H); 4.61 (dd, J ¼ 2.2, 12.0, 1 H); 4.44 (dd, J ¼ 5.2, 12.0, 1 H);
4.31 – 4.19 (m, 2 H); 3.13 (s, 3 H); 3.09 (s, 3 H); 1.71 – 1.50 (m, 4 H); 1.43 (s, 3 H); 1.34 (s, 3 H); 1.31 – 1.23
(m, 10 H); 0.87 (t, J ¼ 7.5, 3 H). 13C-NMR (75 MHz, CDCl3): 108.6; 77.0; 76.7; 75.4; 68.2; 39.3; 37.6; 31.7;
29.3; 29.3; 29.1; 28.1; 27.2; 26.7; 24.9; 22.6; 14.0. ESI-MS: 453 ([M þ Na]þ). HR-ESI-MS: 453.15873
(C17H34NaO8Sþ2 ; calc. 453.15895).
(4R,5S)-4-Ethenyl-2,2-dimethyl-5-octyl-1,3-dioxolane (2). A mixture of 7 (2 g, 4.65 mmol), NaI
(4.2 g, 28.02 mmol), and Zn dust (1.82 g, 28.95 mmol) in DMF (20 ml) was heated at 908 for 8 h (TLC).
The mixture was brought to r.t., then poured into H2O (30 ml), and extracted with Et2O (3 ꢁ 15 ml). The
combined org. extracts were washed successively with 10% aq. Na2S2O3 (1 ꢁ 10 ml) soln., H2O (3 ꢁ
10 ml), and brine (1 ꢁ 10 ml), and dried (Na2SO4). The org. layer was concentrated in vacuo to give a
crude product, which was purified by CC to provide 2. (1.06 g, 95%) Colorless oil. Rf (10% AcOEt/
hexane) 0.5. [a]D25 ¼ ꢀ5.4 (c ¼ 0.8, CHCl3). IR (KBr): 2981, 2949, 2942, 2837, 1632, 1212, 1055. 1H-NMR
(300 MHz, CDCl3): 5.86 – 5.77 (m, 1 H); 5.29 (dd, J ¼ 1.0, 16.8, 1 H); 5.22 (dd, J ¼ 1.0, 9.8, 1 H); 4.47 (t,
J ¼ 6.9, 1 H); 4.16 – 4.10 (m, 1 H); 1.48 (s, 3 H); 1.36 (s, 3 H); 1.33 – 1.21 (m, 14 H); 0.88 (t, J ¼ 6.9, 3 H).
13C-NMR (75 MHz, CDCl3): 134.5; 117.9; 107.9; 79.8; 78.2; 31.7; 30.2; 29.5; 29.4; 28.6; 28.1; 26.0; 25.5;
22.6; 14.0. ESI-MS: 263 ([M þ Na]þ). HR-ESI-MS: 263.07910 (C15H28NaOþ2 ; calc. 263.07912).
6-(Benzyloxy)hexan-1-ol (8) [14]. To a stirred suspension of NaH (2.03 g, 84.74 mmol, 60% (w/v)
dispersion in mineral oil) in THF (100 ml) was added a soln. of hexane-1,6-diol (5 g, 42.37 mmol) in THF
(20 ml) at 08. After stirring for 30 min at r.t. Bu4NF (0.5 g) and BnBr (5.5 ml, 46.60 mmol) were added
subsequently, and stirring was continued overnight at r.t. The reaction was then quenched with H2O
(8 ml) at 08, and the mixture was extracted with AcOEt (2 ꢁ 50 ml). The combined org. layers were
washed with H2O (50 ml) and brine (50 ml), and dried (Na2SO4). The solvent was removed in vacuo, and
the residue was purified by CC to afford 8 (8.37 g, 95% yield). Colorless liquid. Rf (10% AcOEt/hexane)
0.2.
Ethyl (2E)-8-(Benzyloxy)oct-2-enoate (9) [15]. To a soln. of Ph3P¼CHCOOEt (3.9 g, 11.52 mmol) in
benzene (50 ml), was added the aldehyde (2.0 g, 9.6 mmol) derived from 8 at reflux temp., and the
mixture was stirred for another 30 min at the same temp. The solvent was evaporated under reduced
pressure, and the product was purified by CC to afford 9 (2.44 g, 92%). Colorless oil. Rf (20% AcOEt/
hexane) 0.40.
(2E)-8-(Benzyloxy)oct-2-en-1-ol (10) [16]. To a soln. of 9 (2.0 g, 7.25 mmol) in THF (20 ml) was
added DIBAL-H (6.17 ml, 10.8 mmol, 25% in toluene) at ꢀ 108, and the resulting soln. was stirred for
30 min at 08. The soln. was diluted with sodium potassium tartarate and extracted with AcOEt (2 ꢁ
50 ml). The org. extracts were washed with H2O (2 ꢁ 25 ml), followed by brine (25 ml), and dried
(Na2SO4). Evaporation of the solvent, followed by purification, afforded 10 (1.61 g, 95%). Colorless oil.
Rf (30% AcOEt/hexane) 0.5.
{(2R,3R)-3-[5-(Benzyloxy)pentyl]oxiran-2-yl}methanol (11). A mixture of Ti(OiPr)4 (0.22 ml,
0.76 mmol), (þ)-diethyl d-tatrate ((þ)-DET; 0.15 ml, 0.89 mmol) and 3.0 g of activated 4-ꢂ molecular
sieves was stirred in 20 ml of anh. CH2Cl2 at ꢀ 308 for 30 min. To this mixture was added 10 (1.5 g,
6.41 mmol) in CH2Cl2 (5 ml), and the resulting mixture was stirred at ꢀ 308 for another 30 min. It was
t
then treated with BuOOH (1.26 ml, 3.5m in toluene) and stirred for 4 h at the same temp. Upon
completion of the reaction, the mixture was allowed to warm to 08 and poured into freshly prepared cold
soln. of FeSO4 and tartaric acid (1.2 g and 0.4 g resp.) in deionized H2O (1.5 ml). The resulting mixture
was stirred for 30 min, and the aq. phase was separated and then extracted with Et2O. The combined org.
layers were treated with 30% aq. NaOH soln. The mixture was then stirred for 1 h at r.t., and the aq. layer
was separated and extracted with Et2O. The combined org. extracts were dried (Na2SO4) and
concentrated under reduced pressure. The resulting crude product was purified by CC to give 11 (1.41 g,
88%). Colorless liquid. Rf (30% AcOEt/hexane) 0.30. [a]2D5 ¼ ꢀ44.8 (c ¼ 0.8, CHCl3). IR (KBr): 3413,
2920, 2867, 1455, 1295, 1124. 1H-NMR (300 MHz, CDCl3): 7.34 – 7.26 (m, 5 H); 5.22 – 5.08 (m, 2 H); 4.40
(d, J ¼ 6.7, 2 H); 3.61 (t, J ¼ 6.7, 1 H); 3.44 (t, J ¼ 6.7, 1 H); 3.03 – 3.01 (m, 2 H); 1.67 – 1.49 (m, 2 H); 1.46 –

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1.24 (m, 6 H). 13C-NMR (75 MHz, CDCl3): 138.3; 128.2; 127.5; 127.3; 72.7; 70.0; 61.6; 58.4; 55.8; 31.3;
29.4; 25.8; 25.6. ESI-MS: 273 ([M þ Na]þ). HR-ESI-MS: 273.14612 (C15H22NaOþ3 ; calc. 273.14582).
(3R)-8-(Benzyloxy)oct-1-en-3-ol (3) [19]. To a soln. of 11 (1.20 g, 4.8 mmol) in anh. THF (20 ml)
were added 1H-imidazole (0.39 g, 5.76 mmol), Ph3P (1.38 g, 5.28 mmol), and I2 (0.67 g, 5.28 mmol) at 08.
After 5 min, the cooling bath was removed, and the mixture was stirred for 1 h at r.t. During this period,
the color was changed from brown to bright yellow and the mixture became highly viscous. The reaction
was then quenched with sat. Na2S2O3 soln. (10 ml), and the mixture was extracted with Et2O (3 ꢁ 10 ml).
The combined org. layers were washed with brine (10 ml), dried (Na2SO4), and concentrated under
reduced pressure. Purification of the crude product by CC afforded the iodo compound, which was
simultaneously treated with Zn (1.44 g, 24.0 mmol ) in refluxing MeOH (20 ml) for 6 h. The mixture was
filtered through Celite pad and washed with MeOH. The combined MeOH layers were dried (Na2SO4)
and concentrated under reduced pressure. The residue was purified by CC to give 3 (1.07 g, 96%).
Colorless syrup. Rf (10% AcOEt/hexane) 0.2.
(1E,3S)-8-(Benzyloxy)-1-[(4R,5S)-2,2-dimethyl-5-octyl-1,3-dioxolan-4-yl]oct-1-en-3-ol (12). Com-
pounds 2 (1g, 4.1 mmol) and 3 (1.07g, 4.5 mmol) were mixed in anh. CH2Cl2 (2 ml) under N2. It was then
treated with Grubbs 2nd-generation catalyst (22 mg, 0.82 mmol) at r.t. After consumption of the starting
materials, the reaction was quenched and the solvent was removed under reduced pressure to give a
brown residue, which was then purified by CC to afford pure 12 (1.08 g, 70%). Colorless syrup. Rf (20%
AcOEt/hexane) 0.5. [a]2D5 ¼ þ0.9 (c ¼ 0.9, CHCl3). IR (KBr): 3428, 2928, 2902, 1654, 1476, 1079, 1012.
1H-NMR (300 MHz, CDCl3): 7.43 – 7.28 (m, 5 H); 5.73 (dd, J ¼ 6.0, 15.4, 1 H); 5.62 (dd, J ¼ 7.5, 15.4, 1 H);
4.58 – 4.44 (m, 3 H); 4.20 – 4.07 (m, 2 H); 3.46 (t, J ¼ 6.4, 2 H); 1.69 – 1.56 (m, 2 H); 1.48 (s, 3 H); 1.36 (s,
3 H); 1.32 – 1.19 (m, 20 H); 0.87 (t, J ¼ 6.0, 3 H). 13C-NMR (75 MHz, CDCl3): 138.5; 137.1; 128.3; 127.5;
127.4; 127.0; 108.0; 78.9; 78.3; 72.8; 72.3; 70.2; 36.9; 31.8; 30.3; 29.6; 29.5; 29.2; 28.2; 26.1; 26.1; 25.8; 25.6;
25.2; 22.6; 14.0. ESI-MS: 469 ([M þ Na]þ). HR-ESI-MS: 469.32883 (C28H46NaOþ4 ; calc. 469.32897).
({(1E,3S)-8-(Benzyloxy)-1-[(4R,5S)-2,2-dimethyl-5-octyl-1,3-dioxolan-4-yl]oct-1-en-3-yl}oxy)(tert-
butyl)(dimethyl)silane (13). To a soln. of 12 (0.5 g, 1.12 mmol) in dry CH2Cl2 (10 ml) was added EtNiPr2
(0.38 ml, 2.24 mmol), and the mixture was stirred at 08 under N2. After 5 min, (tert-butyl)(dimethyl)silyl
trifluoromethanesulfonate (TBDMSOTf; 0.28 ml, 1.12 mmol) was added and the mixture was stirred at
the same temp. for 10 min. Then, sat. aq. NaHCO3 soln. (10 ml) was added, and the mixture was extracted
with CH2Cl2 (3 ꢁ 12 ml). The org. extract was washed with H2O and brine, and the org. layer was dried
(Na2SO4) and concentrated under reduced pressure to give a crude product, which was then purified by
CC to provide 13. (0.5 g, 80%). Colorless oil. Rf (10% AcOEt/hexane) 0.8. [a]2D5 ¼ ꢀ0.8 (c ¼ 0.45,
CHCl3). IR (KBr): 2942, 2867, 1454, 1361, 1255, 1019. 1H-NMR (300 MHz, CDCl3): 7.39 – 7.29 (m, 5 H);
5.67 (dd, J ¼ 5.4, 15.4, 1 H); 5.56 (dd, J ¼ 7.5, 15.4, 1 H); 4.53 – 4.43 (m, 3 H); 4.16 4.05 (m, 2 H); 3.46 (t,
J ¼ 6.6, 2 H); 1.69 – 1.54 (m, 2 H); 1.47 (s, 3 H); 1.35 (s, 3 H); 1.32 – 1.21 (m, 20 H); 0.96 – 0.83 (m, 12 H);
0.04 (s, 3 H); 0.03 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 137.4; 128.3; 127.5; 127.4; 125.5; 123.7; 101.9; 79.1;
78.4; 72.8; 72.5; 70.3; 38.1; 31.8; 30.5; 29.7; 29.4; 29.2; 28.3; 26.17; 26.16; 25.8; 25.7; 25.0; 24.8; 22.0; 18.1;
14.0; ꢀ 4.3; ꢀ 4.8. ESI-MS: 583 ([M þ Na]þ). HR-ESI-MS: 583.32414 (C34H60NaO4Siþ; calc. 583.32414).
(6S,7E)-6-{[(tert-Butyl)(dimethyl)silyl]oxy}-8-[(4R,5S)-2,2-dimethyl-5-octyl-1,3-dioxolan-4-yl]oct-
7-en-1-ol (14). To a stirred soln. of 13 (0.5g, 0.89 mmol), in CH2Cl2/H2O 19 :1 (5 ml) was added DDQ
(0.24 g, 0.97 mmol) and the mixture was stirred for 4 h. The reaction was then quenched with solid
NaHCO3, and the mixture was extracted with CH2Cl2 (3 ꢁ 10 ml). The org. extract was washed with H2O
and brine, and the org. layer was dried (Na2SO4) and concentrated in vacuo to give a crude product,
which was then purified by CC to afford 14 (0.32 g, 70%). Colorless oil. Rf (20% AcOEt/hexane) 0.5.
[a]2D5 ¼ ꢀ5.0 (c ¼ 0.05, CHCl3). IR (KBr): 3467, 2983, 2959, 2932, 2873, 1642, 1217, 1065. 1H-NMR
(300 MHz, CDCl3): 5.68 (dd, J ¼ 5.4, 15.4, 1 H); 5.57 (dd, J ¼ 7.5, 15.4, 1 H); 4.52 – 4.44 (m, 1 H); 4.17 –
4.05 (m, 2 H); 3.63 (t, J ¼ 6.4, 2 H); 1.64 – 1.51 (m, 4 H); 1.47 (s, 3 H); 1.36 (s, 3 H); 1.31 – 1.19 (m, 18 H);
0.95 – 0.81 (m, 12 H); 0.05 (s, 3 H); 0.03 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 137.3; 125.5; 107.8; 79.1;
78.4; 72.4; 62.9; 38.1; 32.7; 31.8; 30.5; 29.6; 29.4; 29.2; 28.3; 26.1; 25.8; 25.7; 25.7; 24.8; 22.6; 18.2; 14.1; ꢀ
4.3; ꢀ 4.8. ESI-MS: 493 ([M þ Na]þ). HR-ESI-MS: 493.36836 (C27H54NaO4Siþ; calc. 493.36889).
(6S,7E,9R,10S)-6,9,10-Trihydroxyoctadec-7-enoic Acid (1b) [8]. To a stirred soln. of 22 (0.1g,
0.21 mmol) in MeCN/H2O 4 :1 (5 ml) were added (diacetoxyiodo)benzene (0.14 g, 0.46 mmol) and
TEMPO (0.006 g, 0.04 mmol) at 08, and stirring was continued at r.t. for 4 h. After completion of the

Helvetica Chimica Acta – Vol. 97 (2014)
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reaction, the solvent was removed under reduced pressure, and the crude mixture was dissolved in
AcOEt, and sat. aq. Na2S2O3 soln. (3 ml) was added. The combined org. layers were washed with H2O
(5 ml), followed by brine (3 ml), and dried (Na2SO4). The crude residue was dissolved in THF (5 ml),
and aq. 3n HCl (0.5 ml) was added at r.t. The resulting mixture was heated at 608 for 10 h. Upon
completion, the mixture was neutralized with aq. NaHCO3 soln., and then extracted with CHCl3. The org.
layer was washed with H2O (5 ml), followed by brine (3 ml), and then dried (Na2SO4). Removal of the
solvent, followed by CC, gave 1b (0.035g, 50% overall yield). White solid. Rf (5% MeOH/CHCl3) 0.2.
[a]2D5 ¼ þ6.0 (c ¼ 0.25, MeOH) ([a]D24 ¼ þ6.3 (c ¼ 0.980, MeOH [8]). 1H-NMR (300 MHz, CD3OD): 5.70
(dd, J ¼ 14.9, 4.0, 1 H); 5.57 (dd, J ¼ 14.9, 5.9, 1 H); 4.08 (q, J ¼ 5.9, 1 H); 3.99 (dd, J ¼ 6.9, 3.0, 1 H);
3.54 – 3.52 (m, 1 H); 2.30 (t, 6.9 Hz, 2 H); 1.68 – 1.59 (m, 2 H); 1.46 – 1.41 (m, 6 H); 1.34 – 1.20 (m, 12 H);
0.88 (t, 6 H). 13C-NMR (75 MHz, CD3OD): 177.3; 137.0; 130.8; 76.5; 75.0; 73.1; 37.7; 34.2; 33.7; 31.2; 30.8;
30.7; 30.4; 28.3; 27.0; 26.4; 23.8; 14.2. ESI-MS: 353 ([M þ Na]þ). HR-ESI-MS: 353.22985 (C18H34NaO5þ ;
calc. 353.22937).
(2R,3R,4S,5E/Z)-1,3-Bis(benzyloxy)dodec-5-ene-2,4-diol (18). To a pre-cooled (08) soln. of the
Wittig salt (Me(CH2)6)Ph3PþBrꢀ (10.66 g, 24.24 mmol) in anh. THF (100 ml) was slowly added BuLi
(1.6m in hexane, 11.18 ml, 18.18 mmol) under N2. The orange red soln. was stirred for 30 min, and then a
soln. of 17 (336 mg, 1.12 mmol) in dry THF (15 ml) was added dropwise under N2. The mixture was
stirred at the same temp. for another 30 min and then allowed to warm to r.t. The reaction was monitored
by TLC until all starting materials disappeared. The reaction was then quenched by sat. aq. NH4Cl
(50 ml), and the mixture was extracted with AcOEt (3 ꢁ 100 ml). The combined org. phases were dried
(Na2SO4) and concentrated. Purification of the residue by CC gave 18 (4.49 g, 90%). Syrup. IR (KBr):
1
3405, 2955, 2932, 1655, 1455, 1365. H-NMR (300 MHz, CDCl3): 7.39 – 7.28 (m, 10 H); 4.76 – 4.46 (m,
5 H); 3.98 – 3.85 (m, 3 H); 3.62 – 3.46 (m, 3 H); 2.24 – 1.98 (m, 2 H); 1.43 – 1.19 (m, 8 H); 0.87 (d, J ¼ 6.9,
3 H). 13C-NMR (75 MHz, CDCl3): 137.8; 137.7; 134.6; 134.2; 128.9; 128.47; 128.40; 128.3; 128.0; 127.9;
127.86; 127.80; 82.0; 81.7; 75.3; 75.1; 73.4; 73.0; 71.2; 71.0; 70.4; 70.1; 68.2; 31.6; 29.4; 28.9; 27.8; 25.5; 14.0.
ESI-MS: 435 ([M þ Na]þ).
(4R,5R,6S)-5-(Benzyloxy)-4-[(benzyloxy)methyl]-2,2-dimethyl-6-[(E/Z)-oct-1-en-1-yl]-1,3-dioxane
(19). To a stirred soln. of 18 (4.0 g, 9.71 mmol) in dry CH2Cl2 (50 ml) at 08 was added 2,2-
dimethoxypropane (2.37 ml, 19.42 mmol), followed by catalytic amount of pyridinium p-toluenesulfo-
nate (PPTS). After stirring at r.t. for 4 h, the reaction was quenched with solid NaHCO3. The mixture
was diluted with H2O and extracted with CH2Cl2 (3 ꢁ 50 ml). The combined org. layers were washed with
brine, dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by CC to
afford 19 (4.03 g, 92%). Colourless liquid. Rf (10% AcOEt/hexane) 0.6. IR (KBr): 2932, 2850, 1452, 1372,
1208. 1H-NMR (300 MHz, CDCl3): 7.76 – 7.65 (m, 5 H); 7.53 – 7.40 (m, 5 H); 5.91 – 5.67 (m, 2 H); 5.62 –
5.48 (m, 2 H); 5.02 – 4.93 (m, 0.5 H); 4.61 (t, J ¼ 6.7, 1.5 H); 4.05 – 3.95 (m, 2 H); 3.80 – 3.58 (m, 3 H);
2.17 – 2.01 (m, 2 H); 1.44 (s, 3 H); 1.42 – 1.24 (m, 11 H); 0.9 (t, J ¼ 6.2, 3 H). 13C-NMR (75 MHz, CDCl3):
138.2; 137.2; 133.4; 128.3; 128.1; 127.7; 127.5; 127.2; 126.8; 98.7; 74.6; 73.4; 72.6; 71.2; 69.4; 68.7; 31.6; 29.7;
29.4; 28.9; 28.0; 22.5; 19.1; 14.0. ESI-MS: 475 ([M þ Na]þ).
(4R,5R,6S)-4-(Hydroxymethyl)-2,2-dimethyl-6-octyl-1,3-dioxan-5-ol (20). To a soln. of 19 (4.0 g,
8.85 mmol) in EtOH (20 ml) was added 10% Pd/C (100 mg), and the mixture was stirred for 4 h under H2
at 55 psi pressure. After filtering the catalyst, the solvent was evaporated, and the resulting residue was
purified by CC to afford 20 (2.30 g, 95%). White solid. Rf (40% AcOEt/hexane) 0.5. [a]2D5 ¼ ꢀ5.4 (c ¼
1
0.9, CHCl3). IR (KBr): 3442, 2986, 2952, 13751, 1220, 1056. H-NMR (300 MHz, CDCl3): 4.16 – 4.07
(m, 1 H); 3.91 (td, J ¼ 1.5, 6.0, 1 H); 3.85 – 3.69 (m, 3 H); 1.61 – 1.50 (m, 2 H); 1.46 (s, 3 H); 1.43 (s, 3 H);
1.32 – 1.22 (m, 12 H); 0.87 (t, J ¼ 7.5, 3 H). 13C-NMR (75 MHz, CDCl3): 99.3; 73.2; 72.8; 65.6; 63.7; 31.8;
30.8; 29.7; 29.4; 29.4; 29.2; 24.8; 22.6; 19.0; 14.0. ESI-MS: 297 ([M þ Na]þ). HR-ESI-MS: 297.20363
(C15H30NaOþ4 ; calc. 297.20373).
(4S,5R,6S)-5-Hydroxy-2,2-dimethyl-6-octyl-1,3-dioxane-4-carbaldehyde (15). To a soln. of 20 (2.0 g,
7.30 mmol) in dry CH2Cl2 (30 ml), (diacetoxyiodo)benzene (2.82 g, 8.76 mmol) and TEMPO (0.22,
1.46 mmol) were added at 08 under N2 and stirred for 2 h at r.t. Then, the reaction was quenched by sat.
aq. Na2S2O3 soln. (10 ml). The combined org. layers were washed with brine, dried (Na2SO4), and
concentrated in vacuo. The crude residue was purified by CC to give 15 (1.4 g, 70%). Colorless liquid.
Rf (20% AcOEt/hexane) 0.6. [a]2D5 ¼ꢀ 2.1 (c ¼ 0.5, CHCl3). IR (KBr): 3405, 2955, 2932, 1720, 1695,

554
Helvetica Chimica Acta – Vol. 97 (2014)
1365. 1H-NMR (300 MHz, CDCl3): 8.97 (s, 1 H); 4.20 – 4.12 (m, 1 H); 3.95 – 4.01 (m, 1 H); 3.85 – 3.72 (m,
1 H); 1.60 – 1.49 (m, 2 H); 1.48 (s, 3 H); 1.45 (s, 3 H); 1.35 – 1.22 (m, 12 H); 0.90 (t, J ¼ 7.2, 3 H). 13C-
NMR (75 MHz, CDCl3): 200.5; 99.7; 74.1; 73.5; 69.5; 32.1; 30.7; 30.4; 29.9; 29.5; 29.5; 29.1; 23.4; 19.8;
14.2. ESI-MS: 295 ([M þ Na]þ).
(4R,5R,6S)-4-[(1Z)-7-{[(tert-Butyl)(dimethyl)silyl]oxy}hept-1-en-1-yl]-2,2-dimethyl-6-octyl-1,3-di-
oxan-5-ol (21). To a pre-cooled soln. of 16 (4.05 g, 7.30 mmol) in anh. THF (50 ml) was added NaHMDS
(7.29 ml, 1m in hexane, 7.30 mmol) slowly under N2. The orange red soln. was stirred for ca. 30 min at the
same temp., and then a soln. of 15 (1 g, 3.65 mmol) in dry THF (10 ml) at ꢀ 788 was added dropwise
under N2. The resulting mixture was stirred at this temp. for another 30 min and then allowed to warm to
r.t. The reaction was monitored by TLC until all starting materials disappeared. It was then quenched
with sat. aq. NH4Cl (20 ml), and the mixture was extracted with AcOEt (3 ꢁ 20 ml). The combined org.
phases were dried (Na2SO4) and concentrated. Purification of the residue by CC gave 21 (1.2 g, 70%; (Z)/
(E) 9 :1, determined by 1H-NMR). Colorless syrup. Rf (20% AcOEt/hexane) 0.5. [a]2D5 ¼ ꢀ24.5 (c ¼ 1.0,
CHCl3). IR (neat): 3455, 2986, 2935, 1365, 1221, 1155, 1056. 1H-NMR (300 MHz, CDCl3): 5.67 – 5.62 (m,
2 H); 4.61 (dd, J ¼ 5.5, 14.5, 1 H); 3.81 (td, J ¼ 1.1, 6.6, 1 H); 3.78 – 3.71 (m, 1 H); 3.60 (t, J ¼ 6.6, 2 H);
2.17 – 2.02 (m, 2 H); 1.88 – 182 (m, 2 H); 1.51 (s, 3 H); 1.44 (s, 3 H); 1.40 – 1.22 (m, 18 H); 0.91 – 0.85 (m,
12 H); 0.05 (s, 6 H). 13C-NMR (75 MHz, CDCl3): 134.3; 126.3; 91.1; 72.9; 69.4; 67.7; 63.0; 32.6; 31.8; 31.2;
29.9; 29.5; 29.2; 28.0; 25.9; 25.5; 25.4; 24.9; 22.6; 19.0; 18.3; 14.0; ꢀ 5.2. ESI-MS: 493 ([M þ Na]þ). HR-
ESI-MS: 493.36836 (C27H54NaO4Siþ; calc. 493.36889).
(4R,5R,6S)-4-[(Z)-7-Hydroxyhept-1-en-1-yl]-2,2-dimethyl-6-octyl-1,3-dioxan-5-ol (22). To a stirred
soln. of 21 (0.5 g, 1.06 mmol) in dry THF (5 ml) at 08 was added Bu4NF (0.27 ml, 1.06 mmol). After
stirring at r.t. for 2 h, the mixture was diluted with H2O (5 ml) and extracted with AcOEt (3 ꢁ 10 ml).
The combined org. layers were washed with brine, dried (Na2SO4), and concentrated under reduced
pressure. The crude residue was purified by CC to afford 22 (0.3 g, 80%). Colorless oil. Rf (20% AcOEt/
hexane) 0.6. [a]D25 ¼ ꢀ15.6 (c ¼ 0.5, CHCl3). IR (neat): 3446, 2972, 2951, 1368, 1219, 1165, 1054. 1H-NMR
(300 MHz, CDCl3): 5.69 – 5.60 (m, 2 H); 4.61 (dd, J ¼ 5.4, 12.0, 1 H); 3.81 (td, J ¼ 1.0, 7.6, 1 H); 3.67 – 3.62
(m, 3 H); 2.18 – 2.06 (m, 2 H); 1.64 – 1.54 (m, 4 H); 1.51 (s, 3 H); 1.44 (s, 3 H); 1.37 – 1.24 (m, 16 H); 0.88
(t, J ¼ 6.5, 3 H). 13C-NMR (75 MHz, CDCl3): 134.1; 126.4; 99.2; 72.9; 69.5; 67.6; 62.8; 32.4; 31.8; 31.2;
29.9; 29.6; 29.5; 29.2; 27.9; 27.1; 25.3; 24.9; 22.6; 19.0; 14.0. ESI-MS: 379 ([M þ Na]þ). HR-ESI-MS:
379.24550 (C21H40NaOþ4 ; calc. 379.24607).
(6Z,8R,9R,10S)-8,9,10-Trihydroxyoctadec-6-enoic Acid (1c) [7]. To a stirred soln. of 22 (0.2 g,
10.56 mmol) in MeCN/H2O 4 :1 (10 ml) were added (diacetoxyiodo)benzene (0.39 g, 1.2 mmol) and
TEMPO (0.017 g, 0.11 mmol) at 08 and the stirring was continued for 4 h at r.t. After completion of the
reaction, the solvent was removed under reduced pressure, and the crude mixture was dissolved in
AcOEt, and sat. aq. Na2S2O3 soln. (3 ml) was added. The combined org. layers were washed with H2O
(5 ml), brine (5 ml) and dried (Na2SO4), and concentrated in vacuo. The crude residue was dissolved in
THF and treated with aq. 3n HCl (0.5 ml), and the mixture was heated at 608 for 10 h. The mixture was
then neutralized with sat. aq. NaHCO3 and extracted with CHCl3. The org. layer was washed with H2O
(5 ml), brine (5 ml) and dried (Na2SO4), and concentrated in vacuo. The residue was purified by CC to
provide 1c (0.11 g, 60%). White solid. Rf (5% MeOH/CHCl3) 0.2. [a]2D5 ¼ ꢀ16.8 (c ¼ 0.9, MeOH); [7]:
[a]2D4 ¼ ꢀ17.4 (c ¼ 0.2, MeOH). 1H-NMR (300 MHz, CDCl3): 5.61 (dt, J ¼ 10.9, 6.7, 1 H); 5.49 (ddt, J ¼
10.9, 9.8, 1.3, 1 H); 4.50 (dd, J ¼ 7.1, 6.7, 1 H); 3.75 (m, 1 H); 3.30 (dd, J ¼ 6.7, 1.5, 1 H); 2.27 (t, J ¼ 8.3,
2 H); 1.73 – 1.50 (m, 6 H); 1.49 – 1.19 (m, 14 H); 0.94 (t, J ¼ 6.6, 3 H). 13C-NMR (75 MHz, CDCl3): 178.3;
135.1; 131.0; 76.8; 71.7; 69.0; 35.0; 34.7; 33.0; 30.3; 30.2; 29.9; 29.7; 28.5; 26.3; 25.8; 23.7; 14.3. ESI-MS: 353
([M þ Na]þ). HR-ESI-MS: 353.22985 (C18H34NaOþ5 ; calc. 353.22912).
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Received May 30, 2013