Short and efficient synthesis of rubrolide E

Article abstract of DOI:10.1080/00397910701575665

Short and efficient synthesis of rubrolide E from commercially available 4-methoxyacetophenone, employing ring-closing metathesis, Knoevenagel condensation, and Reformatsky reactions, are the key steps are described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701575665

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Short and Efficient Synthesis of Rubrolide E
Subhash P. Chavan a , Ashok B. Pathak a , Ankur Pandey a & Uttam R. Kalkote
a
a Division of Organic Chemistry: Technology , National Chemical Laboratory ,
Pune, 411008, India
Published online: 10 Dec 2007.
To cite this article: Subhash P. Chavan , Ashok B. Pathak , Ankur Pandey & Uttam R. Kalkote (2007) Short
and Efficient Synthesis of Rubrolide E, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:23, 4253-4263, DOI: 10.1080/00397910701575665
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Synthetic Communicationsw, 37: 4253–4263, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701575665
Short and Efficient Synthesis of Rubrolide E
Subhash P. Chavan, Ashok B. Pathak, Ankur Pandey,
and Uttam R. Kalkote
Division of Organic Chemistry: Technology, National Chemical Laboratory,
Pune, India
Abstract: Short and efficient synthesis of rubrolide E from commercially available
4-methoxyacetophenone, employing ring-closing metathesis, Knoevenagel conden-
sation, and Reformatsky reactions, are the key steps are described.
Keywords: antibiotics, antitumor, epoxide, natural products, total synthesis
INTRODUCTION
Rubrolides 1 (A–F, I–N) are the family of biologically active marine ascidian
tunicate metabolites. Rubrolides A–F were isolated in 1991 by Miao and
Andersen from the colonial tunicate Ritterella rubra.[1] They exhibit potent
in vitro antibiotic activity and moderate but selective inhibition of protein
phosphatases. Rubrolides I–N were isolated in 2000 by Ortega and
coworkers from tunicate Synoicum blochmannii,[2] which possess significant
cytotoxic activity against different kind of cancer cells. Some analogs and
related drugs show antitumor properties and biological activity in congestive
heart failure and inhibition of cholesterol biosynthesis.[3] A common structural
feature of rubrolide is the presence of central butenolide nucleus and two
para-hydroxyphenyl moieties at the fourth and fifth carbon atom with or
without halogen atoms.
Even though several syntheses of rubrolide and its analogs are reported in
the literature,[3a–h] because of its broad spectrum of action against different
Received in India May 8, 2007
Address correspondence to Subhash P. Chavan, Division of Organic Chemistry:
Technology, National Chemical Laboratory, Pune 411008, India. E-mail: sp.chavan@
ncl.res.in
4253

4254
S. P. Chavan et al.
kinds of diseases and limited supply from natural sources, many organic and
medicinal chemists shifted their attention toward the synthesis of this
molecule (Figure 1). The first synthesis of rubrolide E was reported by
Kotara and Negishi in 1997[3a] involving aromatic halide and coupling with
ethynylzinc bromide using Pd (0) as the key step. The literature survey
revealed that most of the syntheses start from appropriately substituted
formed five-membered heterocyclic moiety (i.e., furanone and maleimide
coupling involving Suzuki, Stille, Heck, and Meerwein couplings reactions)
and their manipulation into the desired molecules.
Ring-closing metathesis (RCM) protocol provides a unique entry into
cyclic structures, and its usage is increasing in ring construction from small
to large size. In connection with an ongoing program in our group on utiliz-
ation of RCM for the synthesis of biologically active molecules, natural
products, and butenolides,[4] we have accomplished the syntheses of a
variety of natural products employing RCM as the pivotal step (viz., camp-
tothecin,[4a] microcarpalide,[4b] parvifoline,[4c] and mitralactonine[4d]). Refor-
matsky reaction is also mild, inexpensive, efficient, facile, and a powerful
reaction for the C-C bond formation. Taking advantage of the Reformatsky
reaction, we have synthesized naturally occurring compounds, which
include butenolides as the end products or intermediates molecules (viz.,
heritol[5a] mintlactone,[5b] laevigatin,[5c] and lipoic acid[5d]). In keeping with
this continued interest, we decided to explore RCM, Reformatsky reaction,
and Knoevenagel condensation for the construction of a furanone ring in
the synthesis of rubrolide E 1 and some related compounds.
As shown in retrosynthesis (Scheme 1), rubrolide 1 can be readily
obtained from arylbutenolide 6 by Knoevenagel condensation and deprotec-
tion of methyl groups. The butenolide 6 can be accessed from alcohol 9 by
two routes employing Knoevenagel condensation and Reformatsky reaction
as the key steps. The alcohol 9 could be accessed from 4-methoxyacetophe-
none 8. The butenolide 6 can also be prepared from compound 5 employing
RCM as a key step. Compound 5 can be readily obtained from ester 2 as a
starting material.
Figure 1. Naturally occurring rubrolides.

Short and Efficient Synthesis of Rubrolide E
4255
Scheme 1. Retrosynthetic analysis.
Our synthesis commenced from ester 2, which was prepared from
commercially available 4-methoxyphenylacetonitrile by Vogel’s procedure.
Further treatment of the ester 2 with paraformaldehyde using potassium
carbonate as the base and TBAHSO4 as a phase-transfer catalyst gave a,b-
unsaturated ester 3 in 89% yield.[6] The reduction of the ester 3 to alcohol
was accomplished using diisobutylaluminium hydride (DIBAL-H) at
2788C to furnish the corresponding allyl alcohol 4 in 97% yield. The
alcohol 4 was reacted with acryloyl chloride using triethyl amine as a base
in anhydrous dichloromethane at 08C to furnish corresponding ester 5 in
92% yield. Initially, ring-closing metathesis reaction was carried out on
compound 5 using Grubbs’s first-generation catalyst. Different solvents
(viz., dichloromethane, benzene, toluene, and usage of titanium isopropoxide
as the Lewis acid) could not render the product at all,[7] whereas Grubbs’s
second-generation catalyst in anhydrous toluene at 808C for 3 days
furnished very poor yields of cyclized product in 5–7% yield. This is may
be attributed to the quenching of the catalytic cycle by complexation of
olefin. Gratifyingly, this problem could be circumvented by addition of
titanium isopropoxide as the Lewis acid and by performing RCM in
refluxing dichloromethane for 12 h, which furnished butenolide 6[8] in 83%
yield (Scheme 2).
In an another approach involving Knoevenagel condensation, the
synthesis started from cheap and commercially available 4-methoxyacetophe-
none 8, which was treated with TMSCl to give enol ether, which on treatment
with m-chloroperbenzoic acid followed by acid, furnished alcohol 9 in 87%
yield over three steps (Scheme 3).
Alcohol 9 was reacted with ethyl malonyl chloride to furnish ester 10 in
97% yield. The Knoevenagel condensation on 10 was accomplished by

4256
S. P. Chavan et al.
Scheme 2. Reagents and conditions: (a) (CH2O)n (1.5 eq.), K2CO3 (1.5 eq.),
TBAHSO4 (0.1 eq.), toluene, 808C, 6 h, 89%; (b) DIBAL-H (2.1 eq.), dry DCM,
2788C, 3 h, 97%; (c) Et3N (1.5 eq.), acryloyl chloride (1.2 eq.), dry DCM, 08C, 1 h,
92%; (d) 7 (10 mol%), titanium isopropoxide (1.2 eq.), dry DCM, reflux, 12 h, 83%.
sodium hydride treatment to give a,b-unsaturated lactone 11 in 95% yield.
Further decarboxylation under Krapcho’s condition afforded the desired
butenolide 6 in 91% yield.
After RCM and Knoevenagel condensation reactions employed for the
successful synthesis of aryl butenolide 6 (Scheme 4), we thought that 6
could be prepared employing the Reformatsky reaction as a key step.
Alcohol 9 was reacted, with ethyl bromoacetate and zinc powder in
refluxing benzene–diethyl ether (1:1) to furnish the diol 12, which was
subjected to a catalytic amount of p-toluenesulphonic acid in refluxing
benzene to furnish the desired butenolide 6 in 89% yield over two steps.[5d]
Still, we felt that both the steps could be performed in one pot. Accordingly,
the Reformatsky reaction was carried out under the conditions depicted in
Scheme 5 and monitored by thin-layer chromatography (TLC). After the dis-
appearance of the starting material, a catalytic amount of p-toluenesulphonic
acid was added, and the reaction mixture was refluxed for additional 3–4 h to
afford butenolide 6 in 78% yield. In this way, we achieved tandem three
reactions (viz., Reformatsky reaction, dehydration, and lactonization) in one
pot in good overall yields.
With butenolide 6 by three different strategies in hand, Knoevenagel con-
densation was carried out with p-anisaldehyde, furnishing exclusively (Z)
Scheme 3. Reagents and conditions: (a) Et3N (2.0 equiv.), TMSCl (1.5 equiv.), dry
CH3CN, reflux, 12 h; (b) 5% NaHCO3 solution (2.0 equiv.), MCPBA (1.2 equiv.),
CH2Cl2, rt, 3 h; (c) 10% HCl solution (1.5 equiv.), CH2Cl2, rt, 12 h, 87% over three
steps.

Short and Efficient Synthesis of Rubrolide E
4257
Scheme 4. Reagents and conditions: (a) Et3N (2.0 equiv.), ethyl malonyl chloride
(1.2 equiv.), dry CH2Cl2, 08C, 1 h, 97%; (b) NaH (1.2 equiv.), dry THF, 08C, 1 h,
95%; (c) NaCl (4.0 equiv.), DMSO-H2O (3:1), 120–1308C, 6 h, 91%.
Scheme 5. Reagents and conditions: (a) zinc powder (3.0 equiv.), ethyl bromoacetate
(1.5 equiv.), C6H6–Et2O (1:1), reflux, 6 h; (b) PTSA (cat.), C6H6, reflux, 3 h, 89% over
two steps; (c) zinc powder (3.0 equiv.), ethylbromoacetate (1.5 equiv.), C6H6–Et2O
(1:1), reflux, 6 h, PTSA (cat.), reflux, 3–4 h, 78%.
butenolide 13 in 81% yield (Scheme 6). Lastly, the demethylation of aromatic
methoxy groups using BBr3 provided the desired rubrolide E 1 in 95% yield.
The spectral data of rubrolide E 1 were in good agreement with those reported
in the literature.
In conclusion, we have successfully completed a practical, facile, and efficient
total synthesis of rubrolide E 1 employing ring-closing metathesis in seven steps
with 50% overall yield, Knoevenagel condensation in eight steps with 56%
Scheme 6. Reagents and conditions: (a) piperidine (0.7 equiv.), anisaldehyde (1.0 equiv.),
dry MeOH, rt, 81%; (b) BBr3 (3.0 equiv.), dry CH2Cl2, 2788C, 15 min, rt, 24 h, 95%.

4258
S. P. Chavan et al.
overall yield, and Reformatsky reaction in six steps with 52% overall yield and in
situ dehydration and lactonization. Also, formal synthesis of rubrolide C was
accomplished. The salient feature of the present approach is mild, simple, and
high yielding as well as a one-pot version of a three-reaction sequence.
EXPERIMENTAL
All solvents were freshly distilled before use. IR spectra were recorded on a
Perkin-Elmer infrared spectrophotometer model 68B or on Perkin-Elmer
1
1615 FT infrared spectrophotometer. H NMR spectra were recorded on a
Bruker AC-200 (200 MHz). 13C spectra were recorded on a Bruker AC-200
(50 MHz). The carbon spectra were assigned using dimentionless enhanced
polarization transfer (DEPT) experiment. Coupling constants (J) were
recorded in hertz. Mass spectra were recorded at ionization energy of 70 eV
on Finnigan MAT-1020 and on API Q Starpulsar using electron spray ionization
(ESI). Microanalytical data were obtained using a Carlo-Erba CHNS-O EA
1108 elemental analyzer. Progress of the reactions were monitored by TLC
using Merck silica-gel 60 F254 precoated plates, and compounds were visualized
by fluorescence quenching, or using iodine, or charring after treatment with the
mixture of p-anisaldehyd þ AcOH þ H2SO4 in ethanol. Column chromato-
graphy was performed using flash silica gel (230 to 400-mesh size).
Ethyl 2-(4-Methoxyphenyl) Acrylate (3)
Toasolutionofethyl2-(4-methoxyphenyl)acetate 2(5.0 g, 25 mmol)inanhydrous
toluene (50 ml), K2CO3 (5.37 g, 37 mmol), TBAHSO4 (0.875 g, 2.5 mmol), and
(CH2O)n (1.125 g, 37 mmol) were added. The reaction mixture was heated at
808C for 12 h. After completion of the reaction (TLC), H2O (25 ml) was added
and extracted with EtOAc (3 ꢀ 25 ml). The combined organic layers were dried
over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash-column chromatography (SiO2) using 2% EtOAc/
pet. ether as eluent, giving 5.3 g of compound 3 as a colorless oil (89% yield). IR
1
(CHCl3): 1716, 1610, 1513, 1251, 1216, 1177, 836 cm21. H NMR (CDCl3,
200 MHz) d: 1.33 (t, J ¼ 7.2 Hz, 3H), 3.81 (s, 3H), 4.28 (q, J ¼ 7.2 Hz, 2H),
5.82 (d, J ¼ 1.3 Hz, 1H), 6.25 (d, J ¼ 1.3 Hz, 1H), 6.88 (d, J ¼ 9.0 Hz, 2H),
7.37 (d, J ¼ 9.0 Hz, 2H). 13C NMR (CDCl3, 50 MHz) d: 14.0, 55.0, 59.8, 113.3,
124.6, 129.0, 129.3, 140.7, 159.4, 166.9. ESI-MS: m/z 207 (Mþ þ 1). Anal.
calcd. for C12H14O3: 69.88; H, 6.84. Found: C, 69.74; H, 7.02.
2-(4-Methoxyphenyl) Prop-2-en-1-ol (4)
To the solution of ethyl 2-(4-methoxyphenyl) acrylate 3 (3.0 g, 14.5 mmol) in
anhydrous CH2Cl2 (20 ml) at 2788C, 2 M DIBAL-H (4.34 g, 15.3 ml,

Short and Efficient Synthesis of Rubrolide E
4259
30.5 mmol) was added dropwise. The reaction mixture stirred for 1 h at
2788C, gradually warmed up to room temperature, and further stirred for
2 h. The progress of reaction was monitored by TLC and then reaction was
quenched with methanol. The organic layer was separated, and aqueous
layer was extracted with CH2Cl2 (3 ꢀ 15 ml). The combined organic layers
were washed with brine solution, dried over anhydrous Na2SO4, and
filtered, and solvent was removed on a rotary evaporator under reduced
pressure. The resulting residue was purified by flash-column chromatography
(SiO2) with EtOAc/pet. ether (2:3) as the eluent to provide compound 4 as a
thick colorless oil (2.31 g, 97% yield). IR (CHCl3): 3443, 1609, 1513, 1249,
.
1216, 1034 cm21 1H NMR (CDCl3, 200 MHz): d 3.88 (s, 1H), 4.58
(s, 2H), 5.32 (s, 1H), 5.45 (s, 1H), 6.95 (d, J ¼ 8.97 Hz, 2H), 7.46
(d, J ¼ 8.97 Hz, 2H). ESI-MS: m/z 165 (Mþ þ 1). Anal. calcd. for
C10H12O2: C, 73.14; H, 7.36. Found: C, 72.91; H, 7.07.
2-(4-Methoxyphenyl) Allyl Acrylate (5)
To the stirred solution of alcohol 4 (2.0 g, 12.19 mmol) in anhydrous CH2Cl2
(25 ml), Et3N (1.85 g, 18.28 mmol) was added at 08C. The reaction mixture
was allowed to stirr for 15 min, and then acryloyl chloride (1.32 g, 14.6 mmol)
was added dropwise over 10 min. The reaction mixture was allowed to stir for
a further 1 h at 08C. After the completion of the reaction (TLC), H2O (20 ml)
was added and extracted with CH2Cl2 (3 ꢀ 15 ml). The combined organic
layers were washed with brine (20 ml), dried over anhydrous Na2SO4, filtered,
and concentrated in vacuo. Residue was purified by flash-column chromato-
graphy with a mixture of ethyl acetate/pet. ether (1:4) as the eluent to give
ester 5 as a viscous colorless liquid (2.44 g, 92% yield). IR (CHCl3): 1721,
1
1608, 1514, 1215, 758 cm21. H NMR (CDCl3, 200 MHz) d: 3.83 (s, 3H),
5.05 (d, J ¼ 1.1 Hz, 2H), 5.30 (d, J ¼ 1.1 Hz, 1H), 5.50 (s, 1H), 5.81–5.87
(dd, J ¼ 10.2 & 1.65 Hz, 1H), 6.08–6.22 (dd, J ¼ 17.2 & 10.2 Hz, 1H), 6.39–
6.48 (dd, J ¼ 17.2 & 1.65 Hz, 1H), 6.89 (d, J ¼ 9.0 Hz, 2H), 7.40
(d, J ¼ 9.0 Hz, 2H). 13C NMR (CDCl3, 50 MHz) d: 55.1, 65.8, 113.5, 113.8,
127.0, 128.2, 130.4, 131.0, 141.6, 159.5, 165.8. MS ESI: m/z 218 (Mþ). Anal.
calcd. for C13H14O3: C, 71.54; H, 6.47. Found: C, 71.48; H, 6.42.
2-Hydroxy-1-(4-Methoxyphenyl) Ethanone (9)
(a) To a stirred solution of 4-methoxyacetophenone 8 (1.0 g, 6.6 mmol) in
anhydrous CH3CN (20 ml), Et3N (1.34 g, 13.2 mmol) and TMSCl (1.07 g,
9.9 mmol) were added dropwise at room temperature and refluxed for 12 h.
The progress of the reaction was monitored (TLC); the reaction mixture
was quenched by saturated sodium bicarbonate and extracted with CH2Cl2
(3 ꢀ 15 ml). The combined organic layers were dried over anhydrous

4260
S. P. Chavan et al.
sodium sulfate and filtered, and solvent was removed under reduced pressure
to furnish enol ether as a crude product.
(b) To a stirred solution of crude enol ether (1.48 g, 6.6 mmol) in
CH2Cl2 (20 ml), 5% NaHCO3 (1.11 g, 13.2 mmol) and MCPBA (1.38 g,
7.92 mmol) were added. The reaction mixture was stirred at room temper-
ature for 3 h. After the disappearance of starting material (TLC), the
organic phase was separated, and aqueous phase was extracted with CH2Cl2
(3 ꢀ 10 ml). The combined organic layers were dried over anhydrous
sodium sulfate, and filtered, and concentrated in vacuo afforded epoxide as
a crude product.
(c) To a stirred solution of crude epoxide (1.58 g, 6.6 mmol) in CH2Cl2
(10 ml), 10% HCl solution (0.36 g, 3.6 ml, 9.9 mmol) was added, and the
reaction mixture was allowed to stir at room temperature for 12 h. The
progress of the reaction was monitored by TLC. The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2 (3 ꢀ 10 ml).
The combined organic layers were dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure. Residue was purified by
flash-column chromatography (SiO2) using ethyl acetate/pet. ether (3:7) as
the eluent to furnish hydroxy compound 9 (0.96 g, 87% yield). IR (CHCl3)
1
3467, 1677, 1602, 1264, 1215, 759, 669 cm21. H NMR (CDCl3, 200 MHz)
d: 3.59 (t, J ¼ 4.3 Hz, 1H), 3.89 (s, 3H), 4.82 (d, J ¼ 3.9 Hz, 2H), 6.97
(d, J ¼ 9.0 Hz, 2H), 7.90 (d, J ¼ 9.0 Hz, 2H). 13C NMR (CDCl3, 50 MHz)
d: 55.7, 65.1, 114.3, 126.5, 130.15, 164.5, 196.9. ESI-MS: m/z 166
(Mþ þ 1). Anal. calcd. for C9H10O3: C, 65.05; H, 06.06. Found: C, 65.19;
H, 05.90.
Ethyl 2-(4-Methoxyphenyl)-2-oxoethyl Malonate (10)
To a stirred solution of compound 9 (0.5 g, 3.0 mmol), Et3N (0.608 g,
6.0 mmol) in CH2Cl2 (25 ml) was added. The solution was cooled at 08C,
and ethyl malonyl chloride (0.54 g, 3.6 mmol) was added dropwise at 08C
and stirred for 1 h. After the completion of reaction (TLC), H2O (50 ml)
was added, the organic layer was separated, and the aqueous layer was
extracted with CH2Cl2 (3 ꢀ 15 ml). Combined organic layers were washed
with brine, dried over anhydrous sodium sulfate, filtered, and concentrated
in vacuo. Residue was purified by flash-column chromatography using ethyl
acetate/pet. ether (1:3) as the eluent to provide ester 10 as a thick colorless
oil (0.815 g, 97% yield). IR (CHCl3): 1758, 1736, 1695, 1602, 1264, 1242,
1
756, 667 cm21. H NMR (CDCl3, 200 MHz) d: 1.30 (t, J ¼ 7.2 Hz, 3H),
3.57 (s, 2H), 3.88 (s, 3H), 4.24 (q, J ¼ 7.2 Hz, 2H), 5.37 (s, 2H), 6.96
(d, J ¼ 9.0 Hz, 2H), 7.89 (d, J ¼ 9.0 Hz, 2H). 13C NMR (CDCl3, 50 MHz)
d: 14.3, 41.4, 55.75, 61.9, 66.7, 114.3, 127.3, 130.3, 164.4, 166.4, 166.5,
190.0. ESI-MS: m/z 280 (Mþ). Anal. calcd. for C14H16O6: C, 59.99; H,
5.75. Found: C, 60.11; H, 5.67.

Short and Efficient Synthesis of Rubrolide E
4261
Ethyl 4-(4-Methoxyphenyl)-2-oxo-2,5-dihydrofuran-3-carboxylate (11)
NaH (60%, 0.102 g, 2.57 mmol) was washed by dry pet. ether (10 ml). Dry
THF (10 ml) was added and cooled to 08C. Compound 10 (0.6 g,
2.14 mmol) in THF was added dropwise at 08C. The reaction mixture was
stirred for 1 h at 08C. After the completion of the reaction (TLC), the
reaction mixture was quenched by saturated ammonium chloride solution.
Organic layer was separated, and the aqueous layer was extracted with
CH2Cl2 (3 ꢀ 10 ml). The combined organic layers were washed with brine,
dried over anhydrous sodium sulfate, and filtered, and the solvent was
removed on a rotary evaporator under reduced pressure. The resulting crude
product was purified by flash-column chromatography using ethyl acetate/
pet. ether (1:2) as the eluent, furnishing compound 11 as a pale yellow
solid (0.533 g, 95% yield). IR (CHCl3): 1763, 1722, 1606, 1516, 1216,
1
1038, 758, 668 cm21. H NMR (CDCl3, 200 MHz) d: 1.35 (t, J ¼ 7.2 Hz,
3H), 3.88 (s, 3H), 4.40 (q, J ¼ 7.2 Hz, 2H), 5.16 (s, 2H), 6.97
(d, J ¼ 9.0 Hz, 2H), 7.55 (d, J ¼ 9.0 Hz, 2H). 13C NMR (CDCl3, 50 MHz)
d: 47.2, 55.7, 62.0, 70.4, 114.7, 117.15, 121.6, 130.1, 163.0, 163.1, 163.6,
170.25. ESI-MS: m/z 263 (Mþ þ 1), 285 (Mþ þ 23). Anal. calcd. for
C14H14O5: C, 64.11; H, 5.38. Found: C, 64.19; H, 5.11.
4-(4-Methoxyphenyl) Furan-2-(5H)-one (6)
(a) To a solution of allyl acrylate 5 (2.0 g, 9.17 mmol) in anhydrous CH2Cl2
(50 ml), titanium isopropoxide (3.12 g, 11.0 mmol) and Grubbs’s second-
generation catalyst (0.77 g, 0.91 mmol) were added. The reaction mixture
was degassed under an argon atmosphere and refluxed for 12 h. After the dis-
appearance of starting material (TLC), the solvent was removed on a rotary
evaporator under diminished pressure, and the resultant residue was purified
by flash-column chromatography using ethyl acetate/pet. ether (30:70) as
eluent, affording the butenolide 6 as a pale yellow solid (1.44 g, 83% yield).
(b) To a solution of ester 11 (0.5 g, 1.9 mmol) in DMSO–H2O (3:1)
(20 ml), NaCl (0.442 g, 7.6 mmol) was added, and the reaction mixture was
heated at 120–1308C for 6 h. After the disappearance of starting material
(TLC), H2O (20 ml) was added and extracted with EtOAc (3 ꢀ 20 ml). The
combined organic layers were dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo, and the residue was purified by flash-column
chromatography using the ethyl acetate/pet. ether (30:70) as eluent,
affording butenolide 6 as a pale yellow solid (0.329 g, 91% yield).
(c) To a solution of compound 9 (0.5 g, 3.0 mmol) in C6H6–Et2O (1:1)
(20 ml), zinc power (0.587 g, 9.0 mmol) and ethylbromoacetate (0.75 g,
4.5 mmol) were added. The reaction mixture was refluxed for 3–4 h, and
the progress of the reaction was monitored by TLC. After the disappearance
of the starting material, a catalytic amount of PTSA was added and further

4262
S. P. Chavan et al.
refluxed for additional 3 h, monitored by TLC. The reaction mixture was
quenched with 10% HCl and extracted with Et2O (3 ꢀ 10 ml). The
combined organic layers were washed with NaHCO3 solution and brine,
dried over anhydrous sodium sulfate, filtered, and concentrated under dimin-
ished pressure. The residue was purified by flash-column chromatography
eluting with (3:7) ethyl acetate/pet. ether, furnishing butenolide 6 as a pale
yellow solid (0.446 g, 78% yield). Mp 1388C (lit. 138–1398C). IR (CHCl3):
1
1745, 1620, 1609, 1514, 1215 cm21. H NMR (CDCl3, 200 MHz) d: 3.87
(s, 3H), 5.2 (d, J ¼ 1.6 Hz, 2H), 6.24 (t, J ¼ 1.6 Hz, 1H), 6.97
(d, J ¼ 9.0 Hz, 2H), 7.46 (d, J ¼ 9.0 Hz, 2H). 13C NMR (CDCl3, 50 MHz)
d: 55.4, 70.9, 110.5, 114.6, 122.2, 128.1, 162.3, 163.55, 174.3. ESI-MS:
m/z 191 (Mþ þ 1), 213 (Mþ þ 23). Anal. calcd. for C11H10O3: C, 69.46; H,
5.30. Found: C, 69.38; H, 5.16.
(Z)-5-(4-Methoxybenzylidene)-4-(4-methoxyphenyl) Furan-2(5H)-
one (13)
To a stirred solution of lactone 6 (1.90 g, 10 mmol) in MeOH, piperidine
(595 mg, 7 mmol) and para-anisaldehyde (1.36 g, 10 mmol) were added at
room temperature, and the mixture was stirred for 15 h. Removal of solvent
in vacuo followed by flash-column chromatographic purification of the
residue using ethyl acetate/pet. ether (1:9) furnished Z-butenolide 13 as a
yellow solid (2.4 g, 78% yield). Mp 136–1408C (lit. 136–1408C). IR
(CHCl3): 1754, 1732, 1604, 1511, 1256, 1176, 1032 cm21 1H NMR
.
(CDCl3, 200 MHz) d: 3.85 (s, 3H), 3.89 (s, 3H), 6.10 (s, 1H), 6.17 (s, 1H),
6.92 (d, J ¼ 9.0 Hz, 2H), 7.04 (d, J ¼ 9.0 Hz, 2H), 7.46 (d, J ¼ 8.8 Hz,
2H), 7.78 (d, J ¼ 8.8 Hz, 2H). 13C NMR (CDCl3, 50 MHz) d: 55.2, 55.35,
112.1, 113.6, 114.2, 114.4, 122.8, 125.8, 129.9, 132.4, 146.5, 158.3, 160.3,
161.3, 169.2. ESI-MS: m/z 308 (Mþ þ 1). Anal. calcd. for C19H16O4: C,
74.01; H, 5.23. Found: C, 73.87; H, 5.12.
Rubrolide E (1)
To a stirred solution of 13 (1.54 g, 5 mmol) in anhydrous CH2Cl2 (25 ml) at
2788C, a 1 M solution of BBr3 in CH2Cl2 (15 ml, 15 mmol) was added
over a period of 15 min. The mixture was then allowed to warm up to room
temperature and stirred for a further 24 h. The reaction was quenched with
H2O (25 ml). The organic layer was separated, and the aqueous layer was
extracted with EtOAc (3 ꢀ 50 ml). The combined organic layers were
washed with H2O and brine, dried over anhydrous Na2SO4, filtered, and con-
centrated in vacuo. The residue thus obtained was purified by flash silica-gel
column chromatography using ethyl acetate/pet. ether (2:3) as the eluant to
obtain the natural product rubrolide 1 E as a yellow solid (1.33 g, 95%

Short and Efficient Synthesis of Rubrolide E
4263
yield). Mp 278–2818C (lit. 282–2838C). IR (CHCl3): 3418, 1728, 1604, 1461,
1
1279, 1170, 830 cm21. H NMR (CDCl3 þ DMSO-d6, 200 MHz) d: 6.30
(s, 1H), 6.31 (s, 1H), 6.84 (d, J ¼ 8.6 Hz, 2H), 6.93 (d, J ¼ 8.6 Hz, 2H), 7.47
(d, J ¼ 8.6 Hz, 2H), 7.66 (d, J ¼ 8.6 Hz, 2H), 10.33 (bs, 1H), 10.38 (bs, 1H).
13C NMR (CDCl3 þ DMSO-d6, 50 MHz) d: 111.4, 114.4, 116.7, 116.75,
121.5, 125.0, 131.1, 133.3, 146.1, 158.9, 159.3, 160.3, 169.8. ESI-MS: m/z,
280 (Mþ). Anal. calcd. for C17H12O4: C, 72.85; H, 4.32. Found: C, 72.73; H,
4.25.
ACKNOWLEDGMENTS
A. B. P. thanks Council of Scientific and Industrial Research (CSIR), New
Delhi, India, for a fellowship, and S. P. C. thanks Department of Science
and Technology (DST), New Delhi, India, for funding.
REFERENCES
1. Miao, S.; Andersen, R. J. J. Org. Chem. 1991, 56, 6275.
2. Ortega, M. J.; Zubia, E.; Ocana, J. M.; Naranjo, S.; Salva, J. Tetrahedron 2000, 56,
3963.
3. (a) Kotora, M.; Negishi, E. Synthesis 1997, 121; (b) Boukouvalas, J.;
Lachance, N.; Ouellet, M.; Trudeau, M. Tetrahedron Lett. 1998, 39, 7665;
(c) Prim, D.; Fuss, A.; Krisch, G.; Silva, A. M. S. J. Chem. Soc., Perkin
Trans. 2 1999, 1175; (d) Bellina, F.; Anselmi, C.; Stephane, V.; Mannina, L.;
Rossi, R. Tetrahedron 2001, 57, 9997; (e) Bellina, F.; Anselmi, C.; Rossi, R.
Tetrahedron Lett. 2002, 43, 2023; (f) Bellina, F.; Anselmi, C.; Martina, F.;
Rossi, R. Eur. J. Org. Chem. 2003, 2290; (g) Boukouvalas, J.; Pouliot, M.
Synlett 2005, 343; (h) Argade, N. P.; Kar, A. Synthesis 2005, 14, 2284.
4. (a) Chavan, S. P.; Pasupathy, K.; Venkatraman, M. S.; Kale, R. R. Tetrahedron
Lett. 2004, 45, 6879; (b) Chavan, S. P.; Praveen, C. Tetrahedron Lett. 2005, 46,
1939; (c) Chavan, S. P.; Thakkar, M.; Jogadand, G. F. J. Org. Chem. 2006, 71,
8986; (d) Chavan, S. P.; Sharma, P. S.; Sivappa, R.; Kalkote, U. R. Tetrahedron
Lett. 2006, 47, 9301.
5. (a) Chavan, S. P.; Zubaidha, P. K.; Dhondge, V. D. Tetrahedron Lett. 1992, 33,
4605; (b) Chavan, S. P.; Zubaidha, P. K.; Dhondge, V. D. Tetrahedron 1993,
49, 6429; (c) Chavan, S. P.; Rao, Y. T. S.; Govande, C. A.; Zubaidha, P. K.;
Dhondge, V. D. Tetrahedron Lett. 1997, 38, 6429; (d) Chavan, S. P.;
Shivshankar, K.; Pasupathy, K. Synthesis 2005, 8, 1297.
6. Serelis, A. K.; Simpson, G. W. Tetrahedron Lett. 1997, 38, 4277.
7. Nakagawa, M.; Arisawa, M.; Theeraladanon, C.; Nishida, A. Tetrahedron Lett.
2001, 42, 8029.
8. Ghosh, A. K.; Cappiello, J.; Shin, D. Tetrahedron Lett. 1998, 39, 4651.