Stereoselective total synthesis of stagonolide E

Article abstract of DOI:10.1002/hlca.201400265

Abstract An efficient and highly stereoselective synthesis of stagonolide E (1) starting from the readily available hexane-1,6-diol (8) was accomplished, employing MacMillan α-hydroxylation, Horner-Wadsworth-Emmons olefination, (Z)-selective Still-Gennari

Full text of DOI:10.1002/hlca.201400265

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Helvetica Chimica Acta – Vol. 98 (2015)
Stereoselective Total Synthesis of Stagonolide E
by Singanaboina Rajaram, Udugu Ramulu, Seema Aravind, and Katragadda Suresh Babu*
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500 007, India
(phone: þ 91-40-27191881; fax: þ 91-40-27160512; e-mail: suresh@iict.res.in)
An efficient and highly stereoselective synthesis of stagonolide E (1) starting from the readily
available hexane-1,6-diol (8) was accomplished, employing MacMillan a-hydroxylation, HornerÀ
WadsworthÀEmmons olefination, (Z)-selective StillÀGennari olefination, and Yamaguchi lactonization
as key steps.
Introduction. – Macrolides containing a ten-membered ring are known to exhibit
several biological activities [1]. Stagonolide E (1; Fig.) was isolated from Stagonospora
crisii, which is a fungal pathogen of Cirsium arvense and known to produce phytotoxic
metabolites [2]. The main metabolite, stagonolide A, exhibits phytotoxic activity [3],
stagonolide B (2) shows cytotoxic and antimicrobial activities [2], and stagonolide F (3)
displays antimicrobial activity [2][4]. Intrigued by the biological properties of
stagonolides B – F (Fig.) and their scarce availability, and due to our continuing
interest in the total synthesis of lactone-containing molecules [5], we studied the
synthesis of 1. The total synthesis of stagonolide E (1) [6][7] employing Jacobsen
kinetic resolution and Yamaguchi lactonization was reported by Sabitha et al., while
Das and Nanda applied a chemoenzymatic method. Bernd Schmidt et al. reported the
synthesis of 1 from (3R,4R)-hexa-1,5-diene-3,4-diol using a key bidirectional olefin-
metathesis functionalization of the terminal C¼C bonds. Chattopadhyay et al. also
reported stagonolide E from hept-6-ene-2,5-diol by two lipase-catalyzed acylations to
obtain useful chiral intermediates, followed by HoveydaÀGrubbsꢀ II catalysis and (Z)-
selective WittigÀHorner reaction as key steps. Herein, we describe a concise synthesis
of 1 by using proline-catalyzed MacMillan a-hydroxylation, HornerÀWadsworthÀ
Emmons (HWE) olefination, (Z)-selective StillÀGennari olefination, and Yamaguchi
lactonization reactions.
Figure. Structures of stagonolides E, B, F, C, and D, 1 – 5, respectively
ꢁ 2015 Verlag Helvetica Chimica Acta AG, Zürich

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Results and Discussion. – The retrosynthetic analysis of stagonolide E (1) is
depicted in Scheme 1. The target molecule, 1, can be easily obtained by Yamaguchi
lactonization of unsaturated acid 6, which, in turn, can be derived from ester 7 by (Z)-
selective StillÀGennari olefination, and other reactions. Compound 7 can be prepared
from hexane-1,6-diol (8) using l-proline-catalyzed MacMillan a-hydroxylation and
HWE olefination.
As outlined in Scheme 2, stagonolide E (1) was synthesized from hexane-1,6-diol
(8). Initially, 8 was protected as its p-methoxybenzyl (PMB) ether (9), obtained in 83%
yield, with NaH and p-methoxybenzyl bromide (PMBBr) [8c] in THF. The primary
alcohol 9 was oxidized to the aldehyde using 2-iodoxybenzoic acid (IBX)/DMSO,
Scheme 1. Retrosynthetic Analysis
Scheme 2
a) NaH, THF, p-Methoxybenzyl bromide (PMBBr), Bu4NI, 08 to r.t., 1.5 h; 83%. b) 1) 2-Iodoxybenzoic
acid (IBX), DMSO, CH2Cl2, 3 h; 2) PhNO, d-proline, CHCl3, 08, 2 h; NaBH4, EtOH, 08, 2 h; AcOH, Zn,
12 h; 65%. c) 1) Bu2SnO, Et3N, CH2Cl2, TsCl, 08 to r.t., 12 h; 2) LiAlH4, THF, reflux, 3 h; 79%. d) 1) 1H-
Imidazole, CH2Cl2, (tBu)Me2SiCl (TBSCl), r.t., 6 h; 92%; 2) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ), CH2Cl2/H2O 10 :1, r.t., 2 h; 93%. e) 1) IBX, DMSO, CH2Cl2, 08, 3 h; 90%; 2) PhNO, l-proline,
DMSO, 208, 25 min; (EtO)2P(O)CH2COOEt, 1,8-diazabicycloundec-7-ene (DBU), LiCl, r.t., 1 h;
MeOH, CuSO4 · 5 H2O, r.t., overnight; 60%. f) 1) Diisobutylaluminium hydride (DIBAL-H), CH2Cl2,
À 788, 2 h; 79%; 2) (CF3CH2O)2P(O)CH2COOMe, 18-crown-6, potassium hexamethyldisilazide
(KHMDS), anh. THF, À 788, 4 h; 86%. g) TsOH, MeOH, 08, 0.5 h; 89%. h) 1) LiOH · H2O, THF/
H2O 1:1, r.t., 8 h; 86%; 2) Et3N, 2,4,6-trichlorobenzoyl chloride, toluene, DMAP, 808, 12 h; 58.3%.

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which was further subjected to MacMillan a-aminoxylation [8d] by using PhNO and d-
proline in CHCl3, followed by reduction with NaBH4 in EtOH, to furnish an unstable
anilinoxy compound, which was further treated with AcOH and Zn to provide diol 10
in 65% yield. The primary OH group in diol 10 was selectively protected with TsCl and
Et3N in the presence of a catalytic amount of Bu2SnO in anhydrous CH2Cl2, and the Ts-
protected intermediate was further treated with LiAlH4 [8e] in anhydrous THF to
furnish the secondary alcohol 11 [8] in 79% yield. Protection of the secondary OH
group in 11 with (tert-butyl)(dimethyl)silyl chloride (TBSCl) and 1H-imidazole in
CH2Cl2 gave the corresponding TBS ether in 92% yield, which was then subjected
to PMB deprotection with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in
CH2Cl2/H2O at room temperature to give 12 in 93% yield.
The primary alcohol 12 was oxidized with IBX in CH2Cl2 to afford the
corresponding aldehyde, which was further subjected to sequential a-aminoxylation
[9] by using PhNO and l-proline in DMSO, followed by HWE reaction to furnish the
O-amino-substituted allylic alcohol, which was further treated with 20 mol-% of
CuSO4 · 5 H2O in MeOH at room temperature to cleave the OÀN bond to provide g-
hydroxy-a,b-unsaturated ester 7 in 60% yield [10] with high diastereoselectivity (98%
de; MacMillan a-hydroxylation; Scheme 2).
Ethyl ester 7 was reduced with DIBAL-H (1m in toluene) at À 788 to afford
an aldehyde, which was further subjected to (Z)-selective StillÀGennari olefination
by employing bis(2,2,2-trifluoroethyl) [(methoxycarbonyl)methyl]phosphonate
((CF3CH2O)2P(O)CH2COOMe), 18-crown-6, potassium bis(trimethylsilyl)amide
(KHMDS) in anhydrous THF to furnish (Z)-olefinic ester 13 in 86% yield [11].
Then, the TBS protecting group in 13 was removed with TsOH in MeOH to give
secondary alcohol 14 in 89% yield. Further, the (Z)-configured a,b-unsaturated ester
14 was hydrolyzed with LiOH · H2O to afford the corresponding acid 6 in 86% yield.
Finally, intramolecular lactonization of 6 by employing Yamaguchi protocol by using
2,4,6-trichlorobenzoyl chloride in toluene at 808 [12] gave the target natural product,
stagonolide E (1), in 58.3% yield (Scheme 2). The [a]2D5 value (À182.4 (c ¼ 0.5, CHCl3);
À186 (c ¼ 0.2, CHCl3) [2]) and spectral data were found to be identical with those of
the reported natural product in [2].
Conclusions. – In conclusion, we have achieved a stereoselective total synthesis of
stagonolide E (1) in a highly concise manner, using easily accessible starting materials.
The key steps involved were are MacMillan a-hydroxylation, HWE olefination, (Z)-
selective StillÀGennari olefination, and Yamaguchi lactonization.
S. R., U. R., and S. A. are grateful to CSIR-UGC, New Delhi, India, for financial support, and to
Dr. M. Lakshmi Kantam, Director, CSIR-IICT, for her encouragement.
Experimental Part
General. All solvents and reagents were purified by standard techniques. Column chromatography
(CC): silica gel (SiO2; 60 – 120 mesh). Optical rotations: Horiba high sensitive polarimeter; cell length,
1
1 cm. FT-IR Spectra: Thermo Nicolet NEXUS 670 spectrometer; n˜ in cmÀ1. H- and 13C-NMR spectra:
Varian Gemini 500 and Bruker Avance 300 instrument; d in ppm rel. to Me4Si as internal standard, J in

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Hz. ESI-MS: Micromass Quattro micro API mass spectrometer (Waters); in m/z. HR-MS: QSTAR XL
Hybrid MS/MS system (Applied Biosystems, USA); in m/z.
6-[(4-Methoxybenzyl)oxy]hexan-1-ol (9) [8c]. To a soln. of hexane-1,6-diol (8; 8.0 g, 67.79 mmol) in
anh. THF (100 ml) was added NaH (60%, 2.44 g, 45.76 mmol) at 08, and the mixture was stirred for
30 min at the same temp. Then, PMBBr (9.55 g, 61.01 mmol) was added slowly at 08, followed by Bu4NI
(cat.), and the mixture was stirred at r.t. for 1 h. After completion of the reaction, cold H2O was added at
08, the two layers were separated, and the aq. phase was extracted with AcOEt (3 Â 100 ml). The
combined org. layers were washed with H2O and brine, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by CC (hexanes/AcOEt 7:3) to furnish 9 (13.08 g, 83%). Colorless oil. IR (neat):
3385, 2952, 1720, 1493, 1454, 1220, 1096. 1H-NMR (500 MHz, CDCl3): 7.26 (d, J ¼ 8.5, 2 H); 6.87 (d, J ¼
8.5, 2 H); 4.43 (s, 2 H); 3.80 (s, 3 H); 3.62 (t, J ¼ 6.7, 2 H); 3.44 (t, J ¼ 6.5, 2 H); 1.64 – 1.53 (m, 4 H); 1.42 –
1.32 (m, 4 H). 13C-NMR (75 MHz, CDCl3): 158.6; 130.5; 129.1; 113.6; 72.4; 69.9; 62.6; 55.1; 32.5; 29.5;
25.8; 25.4. ESI-MS: 261 ([M þ Na]þ).
(2S)-6-[(4-Methoxybenzyl)oxy]hexane-1,2-diol (10) [8d]. To a stirred soln. of IBX (7.05 g,
25.21 mmol) in anh. DMSO (7 ml) was added a soln. of 9 (4 g, 16.80 mmol) in anh. CH2Cl2 (30 ml) at
r.t., and the mixture was stirred for 3 h at r.t. After completion of the reaction, the mixture was filtered,
diluted with H2O (10 ml), and extracted with CH2Cl2 (2 Â 30 ml). The combined org. extracts were
washed with brine (20 ml), dried (Na2SO4), and concentrated in vacuo to give a crude aldehyde, which
was directly used in the next step.
The aldehyde (3.6 g, 15.25 mmol) was added dropwise to a soln. of PhNO (1.63 g, 15.25 mmol) and
d-proline (0.70 g, 6.101 mmol) in CHCl3 (9 ml) at 08, and the soln. was vigorously stirred at 08 for 2 h. The
mixture was transferred dropwise to a soln. of NaBH4 (0.58 g, 15.25 mmol) in EtOH (90 ml) at 08, and the
soln. was stirred at 08 for 2 h, and then concentrated. Sat. NaHCO3 soln. (90 ml) was added, and the
mixture was extracted with AcOEt (3 Â 50 ml). The combined org. extracts were dried (Na2SO4) and
concentrated. The residue was dissolved in EtOH/AcOH 3 :1 (40 ml) and treated with Zn powder (3.3 g,
50.72 mmol), and the mixture was stirred at r.t. for 12 h, then filtered through Celite, and concentrated.
The crude residue was purified by CC (hexanes/AcOEt 4 :6) to give 10 (2.5 g, 65%). Colorless oil. The
enantiomeric excess (ee) was determined by chiral HPLC (CHIRALPAK IA; 250 Â 4.6 mm, 5 mm;
i
mobile phase, 15% PrOH in hexane; flow rate, 1 ml minÀ1; detection, 210 nm; tR 17.326 min): 98% ee.
1
[a]2D5 ¼ þ6.8 (c ¼ 1.0, CHCl3). IR (neat): 3390, 2934, 2861, 1610, 1513, 1249, 1093, 1033, 821. H-NMR
(300 MHz, CDCl3): 7.25 (d, J ¼ 8.6, 2 H); 6.87 (d, J ¼ 8.6, 2 H); 4.42 (s, 2 H); 3.80 (s, 3 H); 3.72 – 3.52 (m,
2 H); 3.49 – 3.32 (m, 3 H); 2.97 (br. s, 1 H); 1.70 – 1.33 (m, 6 H). 13C-NMR (75 MHz, CDCl3): 159.1;
130.4; 129.2; 113.7; 72.5; 72.0; 69.8; 66.6; 55.2; 32.7; 29.5; 22.2. ESI-MS: 277 ([M þ Na]þ).
(2R)-6-[(4-Methoxybenzyl)oxy]hexan-2-ol (11) [8e]. To a cooled (08) soln. of 10 (2.4 g,
9.523 mmol), a cat. amount of Bu2SnO (5 mg) and Et3N (2.64 ml, 21.046 mmol) in CH2Cl2 (15 ml),
and TsCl (1.81 g, 9.523 mmol) were added portionwise at 08, and the mixture was stirred at r.t. for 4 h.
After completion of the reaction, the mixture was diluted with H2O and extracted with CH2Cl2 (3 Â
50 ml). The org. layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to give the
crude residue which was purified by CC (hexanes/AcOEt 75 :25) to afford the monotosylated product
(3.1 g, 80%) as viscous liquid.
To a stirred suspension of LiAlH4 (0.56 g, 14.705 mmol) in anh. THF (30 ml), a soln. of the
monotosylated compound (3.0 g, 7.35 mmol) in anh. THF (30 ml) was added dropwise at 08 under N2,
and the mixture was stirred under reflux for 12 h. The mixture was cooled to 08, treated with sat. aq.
Na2SO4 soln. (25 ml), filtered, dried (Na2SO4), and concentrated in vacuo. The crude residue was
purified by CC (hexanes/AcOEt 8 :2) to give 11 (1.38 g, 79%). Colorless liquid. [a]2D5 ¼ À3.0 (c ¼ 2.0,
1
CHCl3). IR (neat): 3421, 2934, 2860, 1612, 1513, 1247, 1095, 819. H-NMR (300 MHz, CDCl3): 7.28 (d,
J ¼ 8.3, 2 H); 6.90 (d, J ¼ 8.3, 2 H); 4.45 (s, 2 H); 3.81 (s, 3 H); 3.79 – 3.68 (m, 1 H); 3.47 (t, J ¼ 6.4, 2 H);
1.70 – 1.55 (m, 2 H); 1.52 – 1.33 (m, 4 H); 1.18 (d, J ¼ 6.0, 3 H). 13C-NMR (75 MHz, CDCl3): 158.8; 130.3;
129.0; 113.5; 72.2; 69.7; 67.4; 54.9; 38.7; 29.3; 23.1; 22.2. ESI-MS: 261 ([M þ Na]þ).
(5R)-5-{[(tert-Butyl)(dimethyl)silyl]oxy}hexan-1-ol (12) [8e]. To a soln. of 11 (1.3 g, 5.46 mmol) in
anh. CH2Cl2 (15 ml) was added 1H-imidazole (0.743 g, 10.92 mmol), and the mixture was stirred for
10 min at 08. To this soln., TBSCl (0.983 g, 6.55 mmol) was added at 08, and the mixture was stirred at r.t.
for 6 h. After completion of the reaction, the mixture was diluted with H2O and extracted with CH2Cl2

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(3 Â 20 ml). The combined org. extracts were washed with brine, dried (Na2SO4), and concentrated
under reduced pressure. The crude residue was purified by CC (hexanes/AcOEt 95 :5) to give the pure
TBS-protected product (1.76 g, 92%) as colorless liquid. Then, to a cooled (08) soln. of the above TBS-
protected compound (1.7 g, 4.83 mmol) in CH2Cl2 (15 ml) and H2O (1.5 ml) was added DDQ (2.2 g,
9.71 mmol), and the mixture was stirred at r.t. for 2 h. After completion of the reaction, sat. NaHCO3
soln. was added, and the aq. layer was extracted with CH2Cl2 (2 Â 20 ml). The combined org. extracts
were dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by CC (hexanes/AcOEt
7:3) to give 12 (1.04 g, 93%). Colorless liquid. [a]2D5 ¼ À5.5 (c ¼ 1.0, CHCl3). IR (neat): 3430, 1263.
1H-NMR (300 MHz, CDCl3): 3.83 – 3.75 (m, 1 H); 3.64 (t, J ¼ 6.2, 2 H); 1.60 – 1.52 (m, 2 H); 1.50 – 1.30
(m, 4 H); 1.12 (d, J ¼ 6.6, 3 H); 0.88 (s, 9 H); 0.04 (s, 6 H). 13C-NMR (75 MHz, CDCl3): 68.5; 62.6; 39.3;
32.6; 25.8; 23.7; 21.8; 18.0; À 4.4; À 4.7. ESI-MS: 255 ([M þ Na]þ).
Ethyl (2E,4R,7R)-7-{[(tert-Butyl)(dimethyl)silyl]oxy}-4-hydroxyoct-2-enoate (7) [5a]. To a stirred
soln. of IBX (1.80 g, 6.46 mmol) in anh. DMSO (2 ml) was added a soln. of 12 (1.0 g, 4.31 mmol) in anh.
CH2Cl2 (20 ml) at r.t., and the mixture was stirred for 3 h at r.t. After completion of the reaction, the
mixture was filtered, diluted with H2O (10 ml), and extracted with CH2Cl2 (2 Â 30 ml). The combined
org. extracts were washed with brine (20 ml), dried (Na2SO4), and concentrated in vacuo to give a crude
aldehyde, which was directly used in the next step.
To a soln. of the obtained aldehyde (1.2 g, 5.20 mmol) were added PhNO (0.557 g, 5.20 mmol) and l-
proline (0.24 g, 2.08 mmol) in anh. DMSO (17.4 ml) at 208. The mixture was vigorously stirred for 25 min
under N2 and then cooled to 08. Thereafter, a cooled (08), premixed soln. of (EtO)2P(O)CH2COOEt
(3.09 ml, 15.02 mmol), DBU (2.33 ml, 15.02 mmol), and LiCl (0.663 g, 15.02 mmol) in MeCN (17.4 ml)
was added quickly (1 – 2 min). The resulting mixture was allowed to warm to r.t. within 1 h, and the
reaction was quenched by addition of ice pieces. MeCN was evaporated under reduced pressure, and the
mixture was diluted with H2O (100 ml) and extracted with Et2O (3 Â 100 ml). The combined org. layers
were washed with brine, dried (Na2SO4), and concentrated in vacuo to give a crude product, which was
dissolved in MeOH (20 ml) and reacted with CuSO4 · 5 H2O (0.26 g, 1.04 mmol), the mixture was stirred
at r.t. overnight, and the reaction was quenched with cold sat. NH4Cl soln. (15 ml). The mixture was
filtered through a Celite pad, washed thoroughly with AcOEt (100 ml), concentrated, and extracted with
AcOEt (3 Â 75 ml). The combined org. layers were washed with brine, dried (Na2SO4), filtered, and
concentrated in vacuo. The crude product was then purified by CC (hexane/AcOEt 85 :15) to give 7
(0.988 g, 60%). Brown liquid. [a]2D5 ¼ À13.1 (c ¼ 0.8, CHCl3). IR (neat): 3432, 2956, 2932, 2858, 1720,
1657, 1467, 1370, 1256, 1174, 1044, 834, 775. 1H-NMR (300 MHz, CDCl3): 6.93 (dd, J ¼ 15.6, 4.6, 1 H); 6.06
(dd, J ¼ 15.6, 2.4, 1 H); 4.30 – 4.24 (m, 1 H); 4.20 (q, J ¼ 7.0, 2 H); 3.97 – 3.89 (m, 1 H); 1.78 – 1.52 (m,
4 H); 1.29 (t, J ¼ 7.0, 3 H); 1.16 (d, J ¼ 6.2, 3 H); 0.9 (s, 9 H); 0.08 (s, 6 H). 13C-NMR (75 MHz, CDCl3):
166.5; 150.2; 120.1; 71.1; 68.4; 60.3; 35.3; 32.2; 25.9; 23.0; 14.3; À 4.4; À 4.7. ESI-MS: 339 ([M þ Na]þ).
Methyl (2Z,4E,6R,9R)-9-{[(tert-Butyl)(dimethyl)silyl]oxy}-6-hydroxydeca-2,4-dienoate (13). To a
cooled (À 788), stirred soln. of 7 (0.6 g, 1.89 mmol) in anh. CH2Cl2 (20 ml) was added DIBAL-H (1.0m,
2.08 ml, 2.08 mmol), and the mixture was stirred at the same temp. for 2 h. After completion, the reaction
was quenched with sat. potassium sodium tartrate (10 ml), and the mixture was stirred for 0.5 h. The
mixture was extracted with CH2Cl2 (3 Â 40 ml). The combined org. phases were washed with brine and
dried (Na2SO4). The solvent was removed under reduced pressure. The crude product was purified by CC
(hexane/AcOEt 82 :18) to give an aldehyde (0.408 g, 79%) as brown liquid.
To a cooled (À 788) soln. of (CF3CH2O)2P(O)CH2COOMe (0.06 ml, 1.92 mmol) and 18-crown-6
(1.69 g, 6.42 mmol) in anh. THF (15 ml) was added KHMDS (1.54 ml, 1.54 mmol), and the mixture was
stirred for 0.5 h. The previously prepared aldehyde (0.35 g, 1.28 mmol) in anh. THF (4 ml) was added,
and the mixture was stirred for 4 h at the same temp. After completion, the reaction was quenched with
sat. NH4Cl, and the mixture was extracted with AcOEt. The combined org. layers were washed with
brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by CC (hexane/AcOEt
83 :17) to give 13 (362 mg, 86%). Colorless liquid. [a]2D5 ¼ À10.2 (c ¼ 0.44, CHCl3). IR (neat): 3449, 2931,
1
2857, 1715, 1641, 1604, 1439, 1251, 1176, 999, 964, 830, 770. H-NMR (300 MHz, CDCl3): 7.48 (dd, J ¼
16.0, 12.0, 1 H); 6.55 (t, J ¼ 11.0, 1 H); 6.02 (dd, J ¼ 16.0, 7.0, 1 H); 5.65 (d, J ¼ 12.0, 1 H); 4.26 – 4.19
(m, 1 H); 3.93 – 3.85 (m, 1 H); 3.72 (s, 3 H); 1.71 – 1.48 (m, 4 H); 1.16 (d, J ¼ 6.0, 3 H); 0.90 (s, 9 H); 0.07

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(s, 6 H). 13C-NMR (75 MHz, CDCl3): 166.2; 146.4; 144.3; 125.5; 116.8; 71.8; 68.4; 50.8; 35.3; 32.8; 25.8;
23.4; 18.0; À 4.5; À 4.7. ESI-MS: 351 ([M þ Na]þ).
Methyl (2Z,4E,6R,9R)-6,9-Dihydroxydeca-2,4-dienoate (14). To a cooled (08) soln. of 13 (250 mg,
0.76 mmol) in MeOH (10 ml) was added TsOH (131 mg, 0.76 mmol), and the mixture was stirred at the
same temp. for 0.5 h. After completion, the reaction was quenched with solid NaHCO3, the mixture was
filtered, and MeOH was evaporated under reduced pressure to afford a crude product, which was
purified by CC (hexane/AcOEt 40 :60) to give 14 (145 mg, 89%). Colorless liquid. [a]2D5 ¼ À38.4 (c ¼
1
0.33, CHCl3). IR (neat): 3383, 2924, 2856, 1711, 1642, 1602, 1440, 1201, 1177, 1002, 968, 820. H-NMR
(300 MHz, CDCl3): 7.49 (dd, J ¼ 15.8, 11.3, 1 H); 6.58 (t, J ¼ 11.3, 1 H); 6.06 (dd, J ¼ 15.1, 6.0, 1 H); 5.69
(d, J ¼ 11.3, 1 H); 4.37 – 4.30 (m, 1 H); 3.91 – 3.82 (m, 1 H); 3.73 (s, 3 H); 1.78 – 1.47 (m, 4 H); 1.21 (d, J ¼
6.0, 3 H).13C-NMR (75 MHz, CDCl3): 166.8; 146.2; 144.4; 125.5; 116.9; 71.4; 67.5; 51.2; 34.3; 32.7; 23.1.
ESI-MS: 237 ([M þ Na]þ).
(2Z,4E,6R,9R)-6,9-Dihydroxydeca-2,4-dienoic Acid (6). To a soln. of 14 (60 mg, 0.28 mmol) in THF
(1 ml) and H2O (1 ml) was added LiOH · H2O (58 mg, 1.4 mmol). The mixture was stirred for 8 h at r.t.,
then concentrated, the residue was diluted with H2O (3 ml) and acidified with 2n HCl, and the aq. layer
was extracted with AcOEt (3 Â 15 ml). The combined org. layers were washed with brine, dried
(Na2SO4), and concentrated in vacuo. The crude product was purified by CC (CH3Cl/MeOH 90 :10) to
give 6 (48.2 mg, 86%). Colorless gummy liquid. [a]2D5 ¼ À48.3 (c ¼ 1.5, MeOH). IR (neat): 3421, 2922,
2853, 1702, 1640, 1602, 1434, 1378, 1203, 1075, 1007, 969. 1H-NMR (300 MHz, CD3OD): 7.46 (dd, J ¼ 15.1,
11.3, 1 H); 6.56 (t, J ¼ 11.3, 1 H); 6.00 (dd, J ¼ 15.1, 6.0, 1 H); 5.67 (d, J ¼ 11.3, 1 H); 4.20 – 4.10 (m, 1 H);
3.76 – 3.66 (m, 1 H); 1.74 – 1.38 (m, 4 H); 1.15 (d, J ¼ 6.8, 3 H). 13C-NMR (75 MHz, CD3OD): 171.6;
145.8; 143.4; 127.5; 121.3; 73.0; 68.6; 36.0; 34.4; 23.5. ESI-MS: 223 ([M þ Na]þ).
(3Z,5E,7R,10R)-7,8,9,10-Tetrahydro-7-hydroxy-10-methyl-2H-oxecin-2-one (¼ Stagonolide E; 1). To
a soln. of 6 (20 mg, 0.10 mmol) and Et3N (0.08 ml, 0.60 mmol) in anh. THF (3 ml) was added 2,4,6-
trichlorobenzoyl chloride (0.08 ml, 0.50 mmol). The resulting mixture was stirred at r.t. for 3 h and was
then diluted in toluene (15 ml). The resulting soln. was added dropwise (2 ml hÀ1) to a diluted soln. of 4-
(dimethylamino)pyridine (DMAP; 244 mg, 1.99 mmol) in toluene (110 ml) at 808. Once the addition was
complete, the mixture was stirred for further 12 h at 808. The mixture was filtered, and the org. layer was
washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by CC
(hexane/AcOEt 80 :20) to give 1 (10.6 mg, 58.3%). Colorless liquid. [a]2D5 ¼ À182.4 (c ¼ 0.5, CHCl3;
À 186 (c ¼ 0.2, CHCl3) [2]). IR (neat): 3440, 2927, 2855, 1703, 1601, 1250, 960. 1H-NMR (300 MHz,
CDCl3): 6.62 (br. d, J ¼ 11.6, 1 H); 6.12 (br. d, J ¼ 15.4, 1 H); 5.85 (d, J ¼ 11.6, 1 H); 5.74 (dd, J ¼ 15.3,
9.4, 1 H); 5.03 – 4.93 (m, 1 H); 4.25 (td, J ¼ 9.0, 4.0, 1 H); 1.94 – 1.57 (m, 4 H); 1.22 (d, J ¼ 6.6, 3 H).
13C-NMR (75 MHz, CDCl3): 168.1; 140.2; 139.4; 126.5; 125.6; 73.5; 73.2; 37.4; 30.3; 21.3. ESI-MS: 205
([M þ Na]þ).
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Received August 13, 2014