New concise and efficient synthesis of rubrolides C and e via intramolecular Wittig reaction

Article abstract of DOI:10.1002/hlca.201100351

A short total synthesis of rubrolides C and E has been achieved in four steps, using readily available 4-methoxyacetophenone, 2-bromoacetic acid, and the appropriate aromatic aldehyde, in 46 and 45% yield, respectively. Key reactions involved are α-tosyloxylation of the aryl methyl ketone, intramolecular Wittig reaction, Knoevenagel condensation, and demethylation. Copyright

Full text of DOI:10.1002/hlca.201100351

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Helvetica Chimica Acta – Vol. 95 (2012)
New Concise and Efficient Synthesis of Rubrolides C and E via
Intramolecular Wittig Reaction
by Nilesh P. Tale, Amol V. Shelke, Girdharilal B. Tiwari, Prerana B. Thorat, and Nandkishor N. Karade*
Department of Chemistry, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, Maharashtra
4
40033, India
(
e-mail: nnkarade@gmail.com)
A short total synthesis of rubrolides C and E has been achieved in four steps, using readily available
-methoxyacetophenone, 2-bromoacetic acid, and the appropriate aromatic aldehyde, in 46 and 45%
4
yield, respectively. Key reactions involved are a-tosyloxylation of the aryl methyl ketone, intramolecular
Wittig reaction, Knoevenagel condensation, and demethylation.
Introduction. – The g-benzylidenebutenolide motif with two 4-hydroxyphenyl
moieties, with or without halogen atoms, is a common structural feature of a novel
family of biologically active marine ascidian metabolites called rubrolides (Fig.) [1].
The rubrolides without halogen atoms at C(3) of the butenolide framework are A, C,
D, E, and J. The presence of a Cl-atom at C(3) of the furan-2(5H)-one is found in the
rubrolides B, I, K, L, M, and O, while 3-Br substitution occurs in rubrolide N only.
Rubrolides A to H were isolated in 1991 from the colonial tunicate Ritterella rubra. It is
noteworthy that only minute amounts of rubrolide A (132 mg), B (68 mg), C (48 mg),
D (4 mg), E (3 mg), G (8 mg), and H (11 mg) could be obtained from 400 g of the
frozen specimens of Ritterella rubra after multiple purification steps. The rubrolides are
potent non-nitrogenous antibiotics and were also found to possess moderate but
selective inhibition of protein phosphatases 1 and 2A. Rubrolides I, K, L, and M have
been isolated from the red colonial tunicate Synoicum blochmanni and found to display
significant cytotoxicities against four different cancer cells lines [2]. Moreover,
rubrolide L has recently been shown to be a potent inhibitor of human aldose
Figure. Naturally occuring bioactive rubrolides
ꢀ
2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 95 (2012)
853
reductase, thereby representing a novel lead in the search of new drugs for the
treatment of diabetic complications [2a].
Owing to their useful biological activities and limited supply from the natural
source, the rubrolides have attracted considerable attention from the synthesis
community. The first synthesis of diacetates of rubrolides A, C, D, and E was reported
by Kotora and Negishi in 1997 by the Pd-catalyzed cross-couplingꢀlactonization
tandem reaction of arylalkyne with b-iodocinnamic acid with Cl Pd(Ph P) and CuI as
2
3
2
catalysts [3]. The Pd-catalyzed Suzuki cross-coupling reaction between 4-bromo- or 4-
tosylfuran-2(5H)-one and arylboronic acid has been demonstrated for four step
syntheses of rubrolides C and E [4][5]. The requisite 4-bromofuran-2(5H)-one was in
turn obtained from Vilsmeier bromination of b-tetronic acid (¼4-hydroxyfuran-2(5H)-
one), while 4-tosylfuran-2(5H)-one was provided by the reaction of TsCl/Et N with b-
3
tetronic acid. A six-step synthesis of rubrolide E with 30% overall yield can be achieved
by Meerwein coupling reaction of 4-anisyldiazonium chloride with N-phenylmaleimide
as a key step for installation of aryl substituent at C(4) of the furanone ring [6].
Recently, a Heck coupling reaction of arenediazonium tetrafluoroborates with 4-
hydroxybut-2-enoate in the presence of catalytic amounts of Pd(OAc) has been
2
utilized for the synthesis of rubrolide E [7]. Apart from these metal-catalyzed cross-
coupling reactions, an eight-step synthesis of rubrolide E has been accomplished from
4-methoxyacetophenone, employing ring-closing metathesis, Knoevenagel condensa-
tion, and Reformatsky reactions [8].
Results and Discussion. – Here, we report a short and efficient synthesis of
rubrolide E in four steps with 45% overall yield using readily available starting
materials such as 4-methoxyacetophenone, 2-bromoacetic acid, and anisaldehyde. The
methodology was also extended to the synthesis of rubrolide C in an overall yield of
46%. Key reactions involved in the synthesis of rubrolides C and E were a-
tosyloxylation of aryl methyl ketone, intramolecular Wittig reaction, Knoevenagel
condensation, and demethylation.
The retrosynthetic analysis (Scheme 1) for rubrolides C and E reveals that the 4-(4-
methoxyphenyl)furan-2(5H)-one (3) is the common key intermediate which can be
constructed via intramolecular Wittig reaction [9]. The synthesis of rubrolide E,
therefore, commenced with the preparation of 2-(4-methoxyphenyl)-2-oxoethyl 2-
bromoacetate (4). [Hydroxy(tosyloxy)iodo]benzene (HTIB), popularly known as
Koser reagent, is a versatile hypervalent iodine(III) reagent, used for a-tosyloxylation
of enolizable ketones [10]. Because it is generally not necessary to isolate the a-
tosyloxy ketone, it is utilized in situ as a strategic precursor for the one-pot synthesis of
a wide range of a-functionalized ketones [11]. In our study, we have utilized this
strategy for the one-pot synthesis of 2-(4-methoxyphenyl)-2-oxoethyl 2-bromoacetate.
Thus, the reaction of 4-methoxyacetophenone with PhI(OH)OTs in refluxing
MeCN resulted, in 1.2 h, in the formation of a-tosyloxy-4-methoxyacetophenone
(
TLC), which was subsequently trapped with 2-bromoacetic acid in the presence of
K CO to form 4 in 69% yield (Scheme 2). The intramolecular Wittig reaction of 4 with
2
3
Ph P/Et N in THF afforded 4-(4-methoxyphenyl)furan-2(5H)-one (3) in 89% yield.
3
3
The Knoevenagel condensation of 3 with anisaldehyde by using piperidine as a base in
MeOH led exclusively to (5Z)-5-(4-methoxybenzylidene)-4-(4-methoxyphenyl)furan-

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Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 1. Retrosynthetic Analysis for Rubrolides C and E
2(5H)-one (2a) in 79% yield. Finally, 2a underwent the demethylation reaction with
6
equiv. of BBr in CH Cl at ꢀ 108 to room temperature, by stirring for 4 h, to form
3
2
2
rubrolide E (1a) in 93% yield. Rubrolide E was thus obtained in four steps in 45%
overall yield.
Similarly, the Knoevenagel condensation of 3,5-dibromo-4-methoxybenzaldehyde
with 3 by using piperidine as a base in MeOH afforded 2b in 79% yield. Subsequent
demethylation of 2b with BBr resulted in the formation of rubrolide C in 91% yield.
3
Thus, the total synthesis of rubrolide C was accomplished in four steps in a 46% overall
yield. All the intermediates involved in the four-step reaction sequence have been well
characterized by IR and NMR spectroscopy, and mass spectrometry, and the data
obtained are well in agreement with those reported in the literature.
Conclusions. – An efficient and concise four-step synthesis of rubrolide C (four
steps; 46% overall yield) and E (four steps; 45% overall yield) has been accomplished
from readily available inexpensive starting materials by an intramolecular Wittig
reaction as a key step for the facile construction of 4-arylfuran-2(5H)-one. The
possibility of varying the substituents on acetophenones and aromatic aldehydes
renderes this methodology as general approach for the synthesis of related compounds.
The authors are thankful to the Department of Science and Technology, New Delhi, India (No. SR/
S1/OC-72/2009) for the financial support. The authors are also grateful to Mr. Avtar Singh, Punjab
University, Chandigarh, India, for recording the NMR spectra.

Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 2. Synthesis of Rubrolides C and E
855
i) PhI(OH)OTs, MeCN, reflux, 1.2 h, then BrCH COOH/K CO reflux, 4 h; 69%. ii) Ph P/Et N, THF,
2
2
3
3
3
reflux 2 h; 89%. iii) Anisaldehyde, piperidine, MeOH, 15 h, r.t.; 79%. iv) Br B, dry CH Cl , ꢀ 108 to r.t.,
3
2
2
2
4 h; 93%. v) 3,5-Dibromo-4-methoxybenzaldehyde, piperidine, MeOH, 15 h, r.t.; 79%. vi) Br B, dry
3
CH Cl , ꢀ 108 to r.t., 24 h; 91%.
2
2
Experimental Part
General. All of the org. solvents used were dried on appropriate drying agents and distilled prior to
use. All chemicals were commercially available. TLC: Merck Kieselgel 60 F254. Column chromatography
(
CC): silica gel 230 – 400 mesh. M.p.: Electro thermal melting apparatus; uncorrected. IR Spectra:
ꢀ
1
1
13
Shimadzu FTIR-8300 spectrophotometer; ˜n in cm
. H- and C-NMR spectra: Bruker FT NMR
spectrometer operating at 400 and 100 MHz, resp.; d in ppm rel. to Me Si as internal standard, J in Hz.
4
LC/MS: Shimadzu 2010; in m/z.
Synthesis of 2-(4-Methoxyphenyl)-2-oxoethyl 2-Bromoacetate (4) [9b]. To a soln. of 4-methoxya-
cetophenone (7.5 g, 50 mmol) in MeCN (75 ml) was added [hydroxy(tosyloxy)iodo]benzene (23.52 g,
6
0 mmol), and the mixture was heated to reflux for 1.5 h. After the successful formation of the a-tosyloxy
ketone (as monitored by TLC), BrCH COOH (7.64 g, 55 mmol) and K CO (8.97 g, 65 mmol) were
2
2
3
added, and the mixture was again heated to reflux for 4 – 5 h until the consumption of a-tosyloxy ketone.
After completion of the reaction, the mixture was diluted with H O and extracted with AcOEt (70 ml ꢁ
2
2
). The org. layer was dried (anh. Na SO ) and concentrated under reduced pressure to give crude
2 4
product, which was purified by CC (petroleum ether/AcOEt 9 :1) to afford pure 4 (9.9 g, 69% yield).
1
M.p. 62 – 648. IR (KBr): 1759, 1718, 1686, 1603, 1508, 1425, 1260, 1169, 1026, 929, 944, 773. H-NMR
(
CDCl
3
): 3.88 (s, MeO); 4.03 (s, CH
2
Br); 5.44 (s, CH
2
O); 6.95, 7.89 (AA’BB’, J ¼ 8.8, 4 arom. H).
1
3
C-NMR (CDCl ): 25.33; 55.59; 67.00; 114.23; 126.85; 130.13; 164.25; 166.93; 189.55. ESI-MS: 286.75
[M þ H] , C H BrO ; calc. 286.99).
3
þ
79
þ
4
(
11
12

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Helvetica Chimica Acta – Vol. 95 (2012)
Synthesis of 4-(4-Methoxyphenyl)furan-2(5H)-one (3). To a soln. of 4 (9.6 g, 33.4 mmol) in THF
(
50 ml), Ph P (9.98 g, 37.9 mmol) and Et N (5.57 ml, 40.1 mmol) were added, and the mixture was heated
3 3
to reflux for 2 h. The progress of the reaction was monitored by TLC. After the completion of the
reaction, the mixture was concentrated under vacuum, and the residue was purified by CC (petroleum
ether/AcOEt 4 :1) to afford 3 (5.6 g, 89%). Pale yellow solid. M.p. 134 – 1368 ([6] 136 – 1398). IR (KBr):
1
2
6
1
1
928, 1735, 1604, 1512, 1425, 1263, 1165, 1047, 895, 835. H-NMR (CDCl ): 3.77 (s, MeO); 5.09 (s, CH O);
3
1
2
3
.14 (s, CH); 6.88 (d, J ¼ 8.9, 2 arom. H); 7.37 (d, J ¼ 8.9, 2 arom. H). C-NMR (CDCl ): 55.53; 70.98;
3
þ
þ
10.43; 114.67; 122.19; 128.24; 162.39; 163.71; 174.39. ESI-MS: 190.80 ([M þ H] , C H O
3
; calc.
11
11
91.07).
Synthesis of (5Z)-5-(4-Methoxybenzylidene)-4-(4-methoxyphenyl)furan-2(5H)-one (2a). To a stirred
soln. of 3 (2.75 g, 14.4 mmol) in MeOH (20 ml), piperidine (1.42 ml, 14.4 mmol) and 4-anisaldehyde
1.92 ml, 15.9 mmol) were added at r.t., and the mixture was stirred for 15 h. Removal of the solvent in
(
vacuo followed by CC (petroleum ether/AcOEt 9 :1), furnished 2a (3.52 g, 79% yield). Yellow solid.
M.p. 137 – 1388 ([6] 136 – 1408). IR (KBr): 2924, 2843, 1763, 1606, 1504, 1427, 1253, 1180, 1020, 922, 823.
1
H-NMR (CDCl ): 3.84 (s, MeO), 3.88 (s, MeO); 6.08 (s, CH); 6.15 (s, CH); 6.91 (d, J ¼ 8.8, 2 arom. H);
3
13
7
5
1
.03 (d, J ¼ 8.3, 2 arom. H); 7.45 (d, J ¼ 8.7, 2 arom. H); 7.76 (d, J ¼ 8.8, 2 arom. H). C-NMR (CDCl ):
3
5.41; 55.49; 106.27; 114.40; 114.45; 114.57; 121.25; 125.52; 130.68; 132.69; 146.20; 153.48; 160.75; 161.24;
þ
þ
4
65.49. ESI-MS: 308.80 ([M þ H] , C H O ; calc. 309.11).
19
17
Synthesis of (5Z)-5-(4-Hydroxybenzylidene)-4-(4-hydroxyphenyl)furan-2(5H)-one (Rubrolide E;
a). To a stirred soln. of 2a (3.4 g, 11 mmol) in anh. CH Cl (35 ml) at ꢀ 108, BBr (3.12 ml, 33 mmol)
1
2
2
3
was added dropwise. The resulting mixture was then allowed to warm to r.t. and stirred further for 4 h.
The reaction was quenched with NH Cl soln. (25 ml). The org. layer was separated, and the aq. layer was
4
extracted with CHCl (3 ꢁ 50 ml). The combined org. layers were washed with H O, dried (anh. Na SO ),
3
2
2
4
filtered, and concentrated in vacuo. The residue thus obtained was purified by CC (petroleum ether/
1
AcOEt 4 :1) to give 1a (2.8 g, 93%). Yellow solid. M.p. 281 – 2828 ([6] 282 – 2838). H-NMR (DMSO):
6
.06 (s, CH); 6.14 (s, CH); 6.77 (d, J ¼ 8.72, 2 arom. H); 6.87 (d, J ¼ 6.8, 2 arom. H); 7.34 (d, J ¼ 6.8 Hz, 2
13
arom. H); 7.59 (d, J ¼ 8.6, 2 arom. H); 9.71 (s, 1 H, ArOH); 9.79 (s, 1 H, ArOH). C-NMR (DMSO):
1
10.49; 113.41; 115.65; 115.75; 120.67; 124.06; 129.82; 132.25; 145.38; 158.21; 158.58; 159.57; 168.56. ESI-
þ
þ
4
MS: 280.90 ([M þ H] , C H O ; calc. 281.08).
17
13
Synthesis of (5Z)-5-(3,5-Dibromo-4-methoxybenzylidene)-4-(4-methoxyphenyl)furan-2(5H)-one
2b). To a stirred soln. of 3 (2.75 g, 14.4 mmol) in MeOH (20 ml), piperidine (1.42 ml, 14.4 mmol) and
(
3
,5-dibromo-4-methoxybenzaldehyde (4.67 g, 15.9 mmol) were added at r.t., and the mixture was stirred
for 15 h. Removal of the solvent in vacuo followed by FC (petroleum ether/AcOEt 4 :1), furnished 2b
(
5.3 g, 79% yield). Yellow solid. M.p. 268 – 2708. IR (KBr): 2926, 2852, 1768, 1608, 1508, 1467, 1251, 1176,
1
9
6
1
20, 819, 744. H-NMR (CDCl ): 3.84 (s, MeO); 3.89 (s, MeO); 6.01 (s, CH); 6.18 (s, CH); 7.04 (d, J ¼
3
1
3
.72, 2 arom. H); 7.44 (d, J ¼ 6.68, 2 arom. H); 7.94 (s, 2 arom. H). C-NMR (CDCl
3
): 55.53; 60.83;
09.90; 113.89; 114.69; 118.52; 130; 134.35; 149.05; 154.69; 158.45; 161.58; 168.47. ESI-MS: 466.90 ([M þ
þ
79
81
þ
4
H] , C H Br BrO ; calc. 466.93).
19
15
Synthesis of (5Z)-5-(3,5-Dibromo-4-hydroxybenzylidene)-4-(4-hydroxyphenyl)furan-2(5H)-one
Rubrolide C; 1b). To a stirred soln. of 2b (5.1 g, 10.9 mmol) in anh. CH Cl (35 ml) at ꢀ 108, BBr
(
(
2
2
3
3.12 ml, 33 mmol) was added dropwise. The resulting mixture was then allowed to warm to r.t. and
stirred further for 4 h. The reaction was quenched with NH Cl soln. (25 ml). The org. layer was separated,
4
and the aq. layer was extracted with CHCl (3 ꢁ 50 ml). The combined org. layers were washed with H O,
3
2
dried (anh. Na SO ), filtered, and concentrated in vacuo. The residue thus obtained was purified by FC
2
4
1
(
petroleum ether/AcOEt 9 :1) to give 1b (4.3 g, 91%). Yellow solid. M.p. 232 – 2348. H-NMR (DMSO):
.24 (s, CH); 6.28 (s, CH); 6.87 (d, J ¼ 8.6, 2 arom. H); 7.40 (d, J ¼ 8.56, 2 arom. H); 7.95 (s, 2 arom. H);
6
9
1
13
.73 (s, OH); 9.92 (s, OH). C-NMR (DMSO): 110.01; 111.68; 115.83; 120.17; 127.38; 130.17; 133.96;
þ
79
81
þ
47.01; 151.36; 157.89; 159.86; 168.02. ESI-MS: 438.80 ([M þ H] , C H Br BrO ; calc. 438.90).
17
11
4

Helvetica Chimica Acta – Vol. 95 (2012)
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Received September 6, 2011