Enantioselective synthesis of the natural product (S)-rugulactone

Article abstract of DOI:10.1002/hlca.201200668

A simple and efficient enantioselective synthesis of (6S)-5,6-dihydro-6- [(2E)-4-oxo-6-phenylhex-2-en-1-yl]-2H-pyran-2-one (=(S)-rugulactone) has been accomplished. The synthesis started from commercially available propane-1,3-diol and ethyl 3-phenylpropa

Full text of DOI:10.1002/hlca.201200668

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Helvetica Chimica Acta – Vol. 96 (2013)
Enantioselective Synthesis of the Natural Product (S)-Rugulactone
by Burea Nagaiah and Akkirala Venkat Narsaiah*
Organic and Biomolecular Chemistry Division, Indian Institute of Chemical Technology, Hyderabad
500007, India (fax: þ 91-40-27160387; e-mail: vnakkirala2001@yahoo.com)
A simple and efficient enantioselective synthesis of (6S)-5,6-dihydro-6-[(2E)-4-oxo-6-phenylhex-2-
en-1-yl]-2H-pyran-2-one (¼(S)-rugulactone) has been accomplished. The synthesis started from
commercially available propane-1,3-diol and ethyl 3-phenylpropanoate and involve the Hor-
nerꢀWadsworthꢀEmmons (HWE) and Stillꢀs modified HWE olefinations, and Sharpless asymmetric
epoxidation.
Introduction. – Natural products possessing pyranone moieties exhibit a variety of
pharmacological properties, which include antifungal, antitumor, antibacterial, anti-
diabetic, anti-inflammatory, antiviral, anti-Alzheimer, antioxidant, antigrowth effects.
The broad range of biological activities reported for this class of compounds has been
ascribed to their inherent tendency to act as Michael acceptors. In accord with their
biological importance, the syntheses of naturally occurring pyranones have been the
subject of intense research [1]. The (arylalkyl)-substituted a,b-unsaturated d-lactones
are omnipresent metabolites of the evergreen trees of genus Cryptocarya, which are
well-known for their potential medicinal properties [2]. Rugulactone (1), a 6-
(arylalkyl)-5,6-dihydro-2H-pyran-2-one, is a natural product, isolated for the first time
in 2009 from the plant Cryptocarya rugulosa by Cardellina and co-workers [13].
Rugulactone (1) was found to inhibit the nuclear factor-kB (NF-kB) activation
pathway and is active against many types of cancer, exhibiting up to fivefold induction
of IkB at 25 mg/ml concentration in human lymphoma cell lines [3]. The biological
activity of 1 has attracted many researchers and led to its synthesis in different ways
[4][5]. The majority of the previous synthetic pathways involved the use of costly
reagents and resulted in low yields. Our synthetic route involves the use of
commercially available reagents, is highly enantioselective, and leads to the product
in high yield.
Results and Discussion. – As part of our research program on asymmetric synthesis
of biologically active natural and synthetic compounds [6], herein we report a simple
ꢁ 2013 Verlag Helvetica Chimica Acta AG, Zꢂrich

Helvetica Chimica Acta – Vol. 96 (2013)
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and efficient enantioselective synthesis of (S)-rugulactone (1). Our synthetic strategy
started from commercially available propane-1,3-diol (2) and ethyl 3-phenylpropa-
noate (Scheme 1).
Scheme 1
Desymmetrization of propane-1,3-diol (2) was achieved by the known method to
afford the mono benzylated compound, 3-(benzyloxy)propan-1-ol in 75% yield [7]
(Scheme 2). The OH group was subjected to oxidation under Swern [8] conditions at
low temperature to afford 3-(benzyloxy)propanal, and thus obtained crude aldehyde
was further subjected to Wittig [9] reaction to yield ethyl (2E)-5-(benzyloxy)pent-2-
enoate (3) in very good yield. The olefin 3 was reduced with diisobutylaluminum
hydride (DIBAL-H) [10] in CH2Cl2 at low temperature to give (2E)-5-(benzylox-
y)pent-2-en-1-ol (4) in excellent yield. Thus obtained alcohol 4 was subjected to a well-
known Sharpless asymmetric epoxidation [11] using ( þ )-diethyl tartrate, Ti(OiPr)4,
and tBuOOH in the presence of molecular sieves in CH2Cl2 at ꢀ 208 to furnish {(2S,3S)-
3-[2-(benzyloxy)ethyl]oxiran-2-yl}methanol (5) in excellent yield and with excellent
enantioselectivity ([a]2D9 ¼ ꢀ29.2, c ¼ 1, CHCl3). Epoxy alcohol 5 was reacted with
sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) for regioselective ring
Scheme 2
t
a) [12]; b) Me3CCOCl, pyridine, CH2Cl2, 08 – r.t., 81%; c) BuMe2SiCl (TBSCl), 1H-imidazole, 4-
(dimethylamino)pyridine, CH2Cl2, 08 – r.t., 6 h, 95%; d) 10% Pd/C, H2, MeOH, r.t., 8 h, 92%; e)
(COCl)2, Me2SO, Et3N, CH2Cl2, ꢀ 788, 3 h.

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opening [12]. This reaction was very clean and completed within 4 h to afford (3R)-5-
(benzyloxy)pentane-1,3-diol exclusively in very good yield. The latter was reacted with
pivaloyl chloride in the presence of pyridine in CH2Cl2 to selectively protect the
primary alcohol [13].
t
The secondary alcohol group was protected by treatment with BuMe2SiCl in the
presence of 1H-imidazole and a catalytic amount of 4-(dimethylamino)pyridine
(DMAP) in CH2Cl2 to give (3S)-5-(benzyloxy)-3-{[(tert-butyl)(dimethyl)silyl]oxy}-
pentyl 2,2-dimethylpropanoate (6) [14] in 95% yield ([a]2D9 ¼ ꢀ27.0, c ¼ 1, CHCl3). The
fully protected compound 6 was subjected to debenzylation under H2 using Pd/C in
MeOH to afford (3S)-3-{[(tert-butyl)(dimethyl)silyl]oxy}-5-hydroxypentyl 2,2-dime-
thylpropanoate (7; [a]2D9 ¼ ꢀ17.0, c ¼ 1, CHCl3).
Compound 7 was oxidized under Swern conditions to give (3R)-3-{[(tert-butyl)(di-
methyl)silyl]oxy}-5-oxopentyl 2,2-dimethylpropanoate (8) in very good yield. The
latter was subjected to HornerꢀWadsworthꢀEmmons reaction to afford (3S,5E)-3-
{[(tert-butyl)(dimethyl)silyl]oxy}-7-oxo-9-phenylnon-5-en-1-yl 2,2-dimethylpropano-
ate (9) in 80% yield [15] ([a]2D9 ¼ ꢀ29.5, c ¼ 1, CHCl3) (Scheme 3). The (E)-con-
figuration was evidenced by the coupling constant (J ¼ 16.0 Hz) of the olefinic H-
atoms. The optimized conditions were evaluated as 1:1 ratio of aldehyde and phos-
phonate1) in the presence of Ba(OH)2 in THF/H2O at room temperature. Compound 9
was subjected to reduction with (DIBAL-H) in CH2Cl2 at low temperature to yield
(3S,5E)-3-{[(tert-butyl)(dimethyl)silyl]oxy}-9-phenylnon-5-ene-1,7-diol (10).
Scheme 3
a) Dimethyl (2-oxo-4-phenylbutyl)phosphonate, Ba(OH)2 · 8 H2O, THF/H2O, r.t., 78% (2 steps); b)
diisobutylaluminum hydride (DIBAL-H), CH2Cl2, ꢀ 788, 3 h, 92%; c) (COCl)2, Me2SO, Et3N, CH2Cl2,
ꢀ 788, 3 h; d) (F3CCH2O)2POCH2CO2Me, NaH, THF, ꢀ 788, 2 h, 86% (2 steps); e) TsOH acid,
benzene, r.t., 15 h, 91%.
In this reaction, the keto group was reduced to the secondary alcohol, and the
pivaloyl group was deprotected to give the primary alcohol. Thus obtained diol 10 was
treated under Swern condition with oxalyl chloride, Me2SO at low temperature to
1
)
The phosphonate was prepared by Claisen condensation of methyl 3-phenylpropanoate with the Li
salt of dimethyl methylphosphonate [16].

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afford the oxidized product, (3S,5E)-3-{[(tert-butyl)(dimethyl)silyl]oxy}-7-oxo-9-phe-
nylnon-5-enal (11) in very good yield. The latter was subjected to Stillꢀs modified
HornerꢀWadsworthꢀEmmons reaction [17] with methyl [bis(2,2,2-trifluoroethoxy)-
phosphoryl]acetate in the presence of NaH in THFat low temperature to furnish a (Z)-
olefine, i.e., methyl (2Z,5R,7E)-5-{[(tert-butyl)(dimethyl)silyl]oxy}-9-oxo-11-phenyl-
undeca-2,7-dienoate (12) in very good yield, and the optical rotation of this compound
was [a]2D9 ¼ 27 (c ¼ 1, CHCl3). The (Z)-configuration of the C(2)¼C(3) bond is
confirmed by the coupling constant (J ¼ 12.0 Hz). Finally, 12 was reacted with TsOH
in benzene at room temperature to remove the TBS group, followed by lactonization to
afford the desired target molecule (S)-rugulactone (1; [a]2D9 ¼ þ79, c ¼ 1, CHCl3) in
excellent yield. In the literature, different optical-rotation values of the natural product
rugulactone have been reported, but our value agrees with that reported by Pietruszka
and co-workers ([a]2D9 ¼ 78.9 (c ¼ 0.53, CHCl3)) [5b]. The structures of all the
1
compounds were established by their H- and 13C-NMR, IR and MS data.
Conclusions. – A new stereoselective synthesis of 1 has been accomplished using a
Sharpless asymmetric epoxidation protocol, Stillꢀs modified olefination to afford a (Z)-
olefinic ester, and HornerꢀWadsworthꢀEmmons reaction to afford the (E)-olefinic
compound. All the reactions were very clean, and the products were obtained in very
good yields.
Experimental Part
General. All the reactions were carried out under N2 in anh. solvents and were monitored by TLC
(silica-coated plates Merck 60 F254 ; visualization with a-naphthol charring). Org. solns. were dried
(Na2SO4), and crude products were purified by column chromatography (CC; silica gel (SiO2)); Acmes
60 – 120 mesh; AcOEt and hexane). Moisture-sensitive reagents were transferred through syringe.
Optical rotations: JASCO P-1020 instrument. IR Spectra: Perkin-Elmer FT-IR 240-c spectrophotometer.
1H-NMR Spectra: Bruker-300 spectrometer, in CDCl3; TMS as internal standard. MS: Finnigan MAT
1020 mass spectrometer operating at 70 eV.
3-(Benzyloxy)propan-1-ol [7]. To stirred propane-1,3-diol (5 g, 65.8 mmol) was added powdered
KOH (3.3 g, 59.2 mmol) and PhCH2Br (BnBr; 9 g, 52.6 mmol) in four intervals over a period of 1 h, and
stirring was continued for another 1 h at r.t. Then, H2O (30 ml) was added, and the mixture was extracted
with Et2O (2 ꢁ 20 ml). The combined org. layer was washed with brine, dried (anh. Na2SO4), and
concentrated. The crude product was purified by CC (SiO2 (60 – 120 mesh); AcOEt/hexane 3 :7). Pure 3-
(benzyloxy)propan-1-ol was obtained as yellow liquid (8.2 g, 75%).
3-(Benzyloxy)propanal [7]. To a stirred soln. of (COCl)2 (7.65 g, 60 mmol) in dry CH2Cl2 (30 ml)
was added Me2SO (9.4 g, 120 mmol) under N2 at ꢀ 788, and, after 45 min stirring, a soln. of 3-
(benzyloxy)propan-1-ol (5 g, 30 mmol) in CH2Cl2 (20 ml) was added. Stirring was continued for 2 h, then
Et3N (18 g, 180 mmol) was added, and stirring was continued for further 1 h at the same temp. Progress of
the reaction was monitored by TLC. After completion of the reaction, the mixture was cooled to 08 and
stirred for 30 min, and then H2O (30 ml) was added, followed by CH2Cl2 (30 ml). The mixture was stirred
for 10 min at r.t. The org. layer was separated, washed with brine, dried (Na2SO4), and concentrated
under reduced pressure. The obtained crude product was used for the Wittig reaction without
purification.
Ethyl (2E)-5-(Benzyloxy)pent-2-enoate (3) [7]. To a stirred soln. of 3-(benzyloxy)propanal (5 g,
30.5 mmol) in benzene (30 ml) was added (ethoxycarbonyl)(triphenylphosphonio)methanide (12.7 g,
36.6 mmol) at r.t., and stirring was continued for 3 h. After completion of the reaction (TLC), the
mixture was extracted with AcOEt (2 ꢁ 25 ml). The combined org. layer was washed with brine, dried

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Helvetica Chimica Acta – Vol. 96 (2013)
(Na2SO4), and concentrated under reduced pressure. The crude product was purified by CC (SiO2 (60 –
120 mesh); AcOEt/hexane 1:9) to yield pure 3 (6.15 g, 86%). Yellow liquid.
(2E)-5-(Benzyloxy)pent-2-en-1-ol (4) [7]. To a stirred soln. of 3 (5 g, 21.4 mmol) in CH2Cl2 (30 ml)
under N2 at ꢀ 788 was added DIBAL-H (6 g, 42.7 mmol) slowly over a period of 15 min, and stirring was
continued for 3 h under similar conditions. After completion of the reaction (TLC), aq. sat. soln. of
potassium sodium tartrate at ꢀ 788, and stirring was continued for 1 h at r.t. Then, the mixture was
extracted with CH2Cl2 (2 ꢁ 25 ml). The combined org. layer was washed with brine, dried (Na2SO4), and
concentrated. The crude 4 was purified by CC (SiO2 (60 – 120 mesh); AcOEt/hexane 2 :8) to afford 3.7 g
(90%) of yellow liquid.
{(2S,3S)-3-[2-(Benzyloxy)ethyl]oxiran-2-yl}methanol (5). See [7].
(3R)-5-(Benzyloxy)pentane-1,3-diol. See [12].
(3S)-5-(Benzyloxy)-3-hydroxypentyl 2,2-Dimethylpropanoate. To a stirred soln. of (3R)-5-(benzyl-
oxy)pentane-1,3-diol (3.5 g, 16.7 mmol) in CH2Cl2 (30 ml) was added pyridine (1.6 g, 20 mmol) at 08, and
after 15 min stirring was added pivaloyl chloride (2.2 g, 18.3 mmol) under the same condition. After
10 min stirring, cooling was removed, and stirring was continued at r.t. for 3 h. After completion of the
reaction (TLC), the mixture was extracted with CH2Cl2 (2 ꢁ 25 ml). The combined org. layer was washed
with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by
CC (SiO2 (60 – 120 mesh); AcOEt/hexane 3 :7). Pure (3S)-5-(benzyloxy)-3-hydroxypentyl 2,2-dime-
thylpropanoate (3.97 g, 81%) was obtained as colorless liquid. [a]2D9 ¼ þ10.5 (c ¼ 1, CHCl3). IR (neat):
3457, 3031, 2965, 2931, 2869, 1726, 1479, 1457, 1399, 1364, 1287, 1163, 1099, 1034, 742, 698. 1H-NMR
(CDCl3): 1.19 (s, 9 H); 1.69 – 1.79 (m, 4 H); 3.59 – 3.64 (m, 1 H); 3.67 – 3.72 (m, 1 H); 3.82 – 3.88 (m, 1 H);
4.10 – 4.16 (m, 1 H); 4.25 – 4.31 (m, 1 H); 4.51 (s, 2 H); 7.23 – 7.33 (m, 5 H). EI-MS: 295 (100, [M þ 1]þ),
277 (45), 242 (10), 207 (15), 187 (25), 176 (20), 145 (20), 129 (15).
(3S)-5-(Benzyloxy)-3-{[(tert-butyl)(dimethyl)silyl]oxy}pentyl 2,2-Dimethylpropanoate (6). To a
stirred soln. of (3S)-5-(benzyloxy)-3-hydroxypentyl 2,2-dimethylpropanoate (3.7 g, 12.6 mmol) in
CH2Cl2 (30 ml) was added 1H-imidazole (3.42 g, 50.3 mmol), followed by tBuMe2SiCl (TBS-Cl;
2.83 g, 18.9 mmol) and 4-(dimethylamino)pyridine (DMAP; 50 mg) at 08. The resulting mixture was
stirred at r.t. for 8 h. After completion of the reaction (TLC), the mixture was extracted with CH2Cl2
(2 ꢁ 30 ml). The combined org. layer was washed with brine, dried (Na2SO4), and concentrated under
reduced pressure. The crude 6 was purified by CC (SiO2 (60 – 120 mesh); AcOEt/hexane 2 :8) to afford
pure 6 (4.88g, 95%). Colorless liquid. [a]2D9 ¼ ꢀ27.0 (c ¼ 1, CHCl3). IR (neat): 3167, 2957, 2929, 2857,
1729, 1462, 1399, 1364, 1284, 1254, 1159, 1102, 1055, 837, 773, 698. 1H-NMR (CDCl3): 0.10 (s, 6 H); 0.88 (s,
9 H); 1.18 (s, 9 H); 1.71 – 1.81 (m, 4 H); 3.45 – 3.53 (m, 2 H); 3.95 – 4.20 (m, 3 H); 4.45 (s, 2 H); 7.22 – 7.32
(m, 5 H). 13C-NMR (CDCl3): 178.4; 138.4; 120.2; 127.5; 127.4; 72.9; 66.6; 66.4; 61.1; 37.2; 36.1; 27.1; 25.8;
18.0; ꢀ 4.67; ꢀ 4.62. EI-MS: 426 (100, [M þ 18]þ), 409 (50, [M þ 1]þ), 370 (15), 358 (10), 277 (15), 267
(15), 193 (40), 167 (20).
(3S)-3-{[(tert-Butyl)(dimethyl)silyl]oxy}-5-hydroxypentyl 2,2-Dimethylpropanoate (7). To a stirred
soln. of 6 (4.5 g, 11 mmol) in MeOH (30 ml) was added 10% Pd/C (100 mg), and the resulting mixture
was stirred under H2 for 10 h at r.t. After the completion of the reaction (TLC), the mixture filtered
through Celite. The filtrate was concentrated, and the crude compound 7 was purified by CC (SiO2 (60 –
120 mesh); AcOEt/hexane 2 :8) to furnish pure 7 (3.2 g, 92%). Colorless liquid. [a]2D9 ¼ ꢀ17.0 (c ¼ 1,
CHCl3). IR (neat): 3447, 2957, 2933, 2860, 1728, 1472, 1392, 1367, 1287, 1255, 1161, 1107, 1058, 838, 776,
721. 1H-NMR (CDCl3): 0.10 (s, 6 H); 0.90 (s, 9 H); 1.19 (s, 9 H); 1.56 – 1.72 (m, 1 H); 1.74 – 1.94 (m, 3 H);
3.60 – 3.88 (m, 2 H); 3.96 – 4.20 (m, 3 H). 13C-NMR (CDCl3): 178.4; 68.1; 61.0; 59.6; 38.6 38.3; 35.6; 27.1;
25.7; 17.8; ꢀ 4.7. EI-MS: 341 (50, [M þ Na]þ), 242 (20), 221 (20), 198 (25), 187 (100), 169 (10), 157 (15).
(3R)-3-{[(tert-Butyl)(dimethyl)silyl]oxy}-5-oxopentyl 2,2-Dimethylpropanoate (8). The procedure
described for 3-(benzyloxy)propanal from 3-(benzyloxy)propan-1-ol was applied on 7 (3 g, 9.42 mmol).
The crude product was used for further reaction without any purification.
(3S,5E)-3-{[(tert-Butyl)(dimethyl)silyl]oxy}-7-oxo-9-phenylnon-5-en-1-yl 2,2-Dimethylpropanoate
(9). To a stirred soln. of dimethyl (2-oxo-4-phenylbutyl)phosphonate (4.13 g, 16.13 mmol) in THF
(30 ml) was added Ba(OH)2 · 8 H2O (5.39 g, 17 mmol), and stirring was continued for 30 min. Then, a
soln. of 8 (3 g, 9.49 mmol) in THF/H2O 40 :1 (10 ml) was added, and stirring was continued for 30 min at
r.t. After completion of the reaction (TLC), sat. NH4Cl soln. was added, and the mixture was extracted

Helvetica Chimica Acta – Vol. 96 (2013)
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with AcOEt (2 ꢁ 25 ml). The combined org. layer was washed with brine, dried (Na2SO4), and
concentrated under reduced pressure. The crude 9 was purified by CC (SiO2 (60 – 120 mesh); AcOEt/
hexane 2 :8) to give pure 9 (3.28 g, 78% for 2 steps). Colorless liquid. [a]2D9 ¼ ꢀ29.5 (c ¼ 1, CHCl3). IR
(neat): 3028, 2928, 2858, 1730, 1675, 1633, 1467, 1367, 1284, 1255, 1157, 1109, 935, 838, 775, 700. 1H-NMR
(CDCl3): 0.10 (s, 6 H); 0.88 (s, 9 H); 1.18 (s, 9 H); 1.68 – 1.76 (m, 2 H); 2.28 – 2.44 (m, 2 H); 2.81 (t, J ¼ 7.5,
2 H); 2.91 (t, J ¼ 6.0, 2 H); 3.88 – 3.94 (m, 1 H); 4.01 – 4.07 (m, 1 H); 4.11 – 4.17 (m, 1 H); 6.09 (d, J ¼ 16.0,
1 H); 6.72 – 6.80 (m, 1 H); 7.11 – 7.26 (m, 5 H). 13C-NMR (CDCl3): 199.1; 159.1; 143.1; 141.1 132.5; 128.4;
128.2; 126.0; 67.9; 60.9; 41.6; 40.5; 36.0; 30.0; 27.1; 25.7; 18.0; ꢀ 4.4; ꢀ 4.7. EI-MS: 469 (40, [M þ Na]þ),
458 (100), 446 (15), 348 (10), 315 (20).
(3S,5E)-3-{[(tert-Butyl)(dimethyl)silyl]oxy}-9-phenylnon-5-ene-1,7-diol (10). To a stirred soln. of 9
(1 g, 2.24 mmol) in dry CH2Cl2 (10 ml) was added DIBAL-H (1m in toluene, 0.7 g, 4.93 mmol) at ꢀ 788
under N2, and stirring was continued for 30 min. After completion of the reaction (TLC), sat. potassium
sodium tartrate soln. at ꢀ 788, and then the temp. was raised to r.t., and stirring was continued for 1 h.
The mixture was extracted with CH2Cl2 (2 ꢁ 20 ml), and the combined org. layer was washed with brine,
dried (Na2SO4), and concentrated under reduced pressure. The crude 10 was purified by CC (SiO2 (60 –
120 mesh); AcOEt/hexane 3 :7) to furnish pure 10 (0.74 g, 92%). Colorless liquid. [a]2D9 ¼ þ3.5 (c ¼ 1,
CHCl3). IR (neat): 3421, 3028, 2932, 2858, 1632, 1460, 1253, 1062, 974, 836, 775, 741, 698. 1H-NMR
(CDCl3): 0.30 (s, 6 H); 0.90 (s, 9 H); 1.52 – 1.90 (m, 4 H); 2.26 (t, J ¼ 6.0, 2 H); 2.60 – 2.80 (m, 2 H); 3.62 –
3.81 (m, 2 H); 3.88 – 3.98 (m, 1 H); 4.01 – 4.12 (m, 1 H); 5.48 – 5.67 (m, 2 H); 7.10 – 7.27 (m, 5 H).
13C-NMR (CDCl3): 141.8; 135.6; 128.3; 127.4 127.3; 125.7; 72.0; 70.9; 59.9; 39.6; 38.6; 37.6; 31.7; 25.7; 17.9;
ꢀ 4.4. EI-MS: 365 (100, [M þ 1]þ), 363 (30), 351 (90), 341 (40), 337 (85), 332 (40), 327 (50), 320 (30),
313 (20), 311 (25).
(3S,5E)-3-{[(tert-Butyl)(dimethyl)silyl]oxy}-7-oxo-9-phenylnon-5-enal (11). To a stirred soln. of
(COCl)2 (0.69 g, 5.5 mmol) in dry CH2Cl2 (10 ml) was added Me2SO (0.86 g, 11 mmol) under N2 at ꢀ 788.
After 45 min stirring under the same condition, a soln. of 10 (0.5 g, 1.37 mmol) in dry CH2Cl2 (5 ml) was
added. The resulting mixture was stirred for 2 h, then Et3N (1.67 g, 16.5 mmol) was added, and stirring
was continued for 1 h at ꢀ 788. After completion of the reaction (TLC), the temp. was raised to 08, and
H2O (10 ml) was added, followed by CH2Cl2 (10 ml). The mixture was extracted with CH2Cl2 (2 ꢁ 10 ml),
and the combined org. layer was washed with brine, dried (Na2SO4), concentrated under reduced
pressure, and the obtained crude product was used for further reaction without purification. Crude
1
compound. H-NMR (CDCl3): 0.10 (s, 6 H); 0.91 (s, 9 H); 2.15 – 2.35 (m, 4 H); 2.90 – 3.01 (m, 4 H);
4.10 – 4.20 (m, 1 H); 6.10 (d, J ¼ 15.5, 1 H); 6.62 – 6.80 (m, 1 H); 7.05 – 7.15 (m, 5 H); 9.80 (s, 1 H).
Methyl (2Z,5S,7E)-5-{[(tert-Butyl)(dimethyl)silyl]oxy}-9-oxo-11-phenylundeca-2,7-dienoate (12).
To a stirred soln. of NaH (0.053 g, 2.22 mmol) in dry THF (5 ml) was added a soln. of methyl
[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate (0.35 g, 1.11 mmol) in THF (5 ml) at 08 under N2, and the
mixture was stirred for 30 min. The soln. was cooled to ꢀ 788, a soln. of 11 (0.5 g, 1.39 mmol) in dry THF
(5 ml) was added, and stirring was continued for 2 h. After completion of the reaction (TLC), sat. NH4Cl
soln. was added at ꢀ 788, the temp. was raised to r.t., and stirring was continued for 20 min. The solvent
was removed from the mixture under reduced pressure, and the residue was extracted with AcOEt (2 ꢁ
20 ml), the combined org. layer was washed with brine, dried (Na2SO4), and concentrated. The crude 12
was purified by CC (SiO2 (60 – 120 mesh); AcOEt/hexane 2 :8) to furnish pure 12 (0.5 g, 86%). Colorless
liquid. [a]2D9 ¼ þ27 (c ¼ 1, CHCl3). IR (neat): 2925, 2856, 1717, 1639, 1510, 1456, 1366, 1206, 1093, 829,
766, 698. 1H-NMR (CDCl3): 0.10 (s, 6 H); 0.88 (s, 9 H); 2.34 (t, J ¼ 7.5, 2 H); 2.71 – 2.97 (m, 6 H); 3.66 (s,
3 H); 3.90 – 3.99 (m, 1 H); 5.86 (d, J ¼ 12.0, 1 H); 6.06 (d, J ¼ 15.0, 1 H); 6.26 – 6.36 (m, 1 H); 6.73 – 6.89
(m, 1 H); 7.13 – 7.25 (m, 5 H). 13C-NMR (CDCl3): 199.7; 166.3; 145.6; 143.5; 132.4; 128.4; 128.3; 126.1;
125.9; 121.1; 70.5; 56.8; 51.0; 47.3; 41.3; 36.3; 29.6; 25.7; ꢀ 4.63; ꢀ 4.68. EI-MS: 439 (100, [M þ Na]þ), 427
(20), 409 (15), 408 (50), 352 (20), 301 (18), 285 (22), 243 (30), 211 (25).
(S)-Rugulactone (¼(6S)-5,6-Dihydro-6-[(2E)-4-oxo-6-phenylhex-2-en-1-yl]-2H-pyran-2-one; 1). To
a stirred soln. of 12 (0.25 g, 0.595 mmol) in benzene (5 ml) was added TsOH (25 mg) under N2, and the
mixture was stirred for 15 h at r.t. After the completion of reaction (TLC), the mixture was extracted
with AcOEt (2 ꢁ 20 ml), and the combined org. layer was washed with NaHCO3 soln., brine, dried
(Na2SO4), concentrated under reduced pressure. The crude 1 was purified by CC (SiO2 (60 – 120 mesh);
AcOEt/hexane 2 :8) to give pure 1 (0.15 g, 92%). Colorless liquid. [a]2D9 ¼ þ79 (c ¼ 1, CHCl3). IR (neat):

1954
Helvetica Chimica Acta – Vol. 96 (2013)
1
3027, 2923, 2855, 1720, 1632, 1493, 1450, 1381, 1249, 1148, 1039, 976, 811, 751, 700. H-NMR (CDCl3):
2.27 – 2.34 (m, 2 H); 2.54 – 2.68 (m, 2 H); 2.83 – 2.95 (m, 4 H); 4.46 – 4.53 (m, 1 H); 6.01 (d, J ¼ 10.0, 1 H);
6.15 (d, J ¼ 16.0, 1 H); 6.71 – 6.78 (m, 1 H); 6.80 – 6.85 (m, 1 H); 7.12 – 7.27 (m, 5 H). 13C-NMR (CDCl3):
198.9; 163.6; 144.6; 140.8; 140.2; 133.3; 128.2; 125.9; 121.2; 75.9; 41.6; 37.3; 29.8; 29.5; 28.8. EI-MS: 293
(100, [M þ Na]þ), 271 (40), 253 (15).
B. N. is grateful to University Grants Commission, New Delhi, for providing a fellowship.
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Received December 31, 2012