A facile chemoenzymatic approach to natural cytotoxic ellipsoidone A and natural ellipsoidone B

Article abstract of DOI:10.1016/j.tet.2005.12.020

Starting from citraconic anhydride (3) a facile four-step synthesis of deoxyellipsoidone 8 has been reported with 37% overall yield. An elegant six-step access to naturally occurring cytotoxic ellipsoidone A (1) and ellipsoidone B (2) has been reported with good overall yields, via the conversion of itaconic anhydride (9) to the acetoxymethylmaleic anhydride (11), regioselective sodium borohydride reduction of anhydride 11 to acetoxymethylbutyrolactone 12, Knoevenagel condensation of lactone 12 with 5-methylfurfural, selenium dioxide induced oxidation of the formed butenolide 13 and an Amano PS catalyzed deacylation of the formed diacetoxybutenolide 14 as a pathway.

Full text of DOI:10.1016/j.tet.2005.12.020

Tetrahedron 62 (2006) 2715–2720
A facile chemoenzymatic approach to natural cytotoxic
ellipsoidone A and natural ellipsoidone B
*
Sanjib Gogoi and Narshinha P. Argade
*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Received 22 August 2005; revised 21 November 2005; accepted 9 December 2005
Available online 28 December 2005
Abstract—Starting from citraconic anhydride (3) a facile four-step synthesis of deoxyellipsoidone 8 has been reported with 37% overall yield.
An elegant six-step access to naturally occurring cytotoxic ellipsoidone A (1) and ellipsoidone B (2) has been reported with good overall yields,
via the conversion of itaconic anhydride (9) to the acetoxymethylmaleic anhydride (11), regioselective sodium borohydride reduction of
anhydride 11 to acetoxymethylbutyrolactone 12, Knoevenagel condensation of lactone 12 with 5-methylfurfural, selenium dioxide induced
oxidation of the formed butenolide 13 and an Amano PS catalyzed deacylation of the formed diacetoxybutenolide 14 as a pathway.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
H
HOCH2
OCH2
O
O
Plants of the genus Hemsleya are distributed throughout the
southwest region of China and the tubers of these plants
OH
O
1
have been used in Chinese folk medicine system. As a part
HO
of survey of Chinese medicinal resources, Nomura et al. in
collaboration with group of researchers from China isolated
the new compounds ellipsoidones A (1) and B (2) along
with the known glucosidyl butenolide, siphonoside from the
OH
- 3H O
-
3H O
2
2
Siphonoside (C11H16O ) (Cytotoxic
against Walker-256-sarcoma cells)
8
O
O
2
H
H
tubers of Hemsleya ellipsoidea (Fig. 1). One can easily
make out that siphonoside is a biological precursor of 1 and 2.
3
O
OH
O
OH
Siphonoside on loss of three water molecules would
generate 1 and 2 via an intramolecular condensation and
dehydrative ring contraction pathway. The structural
O
O
H
HO
H
OH
1
assignment of 1 and 2 was done on the basis of UV, H
H
H
H
H
1
3
NMR, C NMR, 2D NMR, NOE and HRFABMS data. The
two new acetogenins 1 and 2 are geometric stereoisomers of
each other and ellipsoidone A (1) possesses cytotoxic
Ellipsoidone A (1) (C11H10O5)
Ellipsoidone B (2)
(C11H10O5)
(
Cytotoxic against P-388 cells)
2
Figure 1. Bioactive natural products from Hemsleya ellipsoidea.
activity against P-388 cells [IC50 47 mg/mL]. A large
number of structurally interesting butenolides have been
isolated previously as bioactive natural products and several
elegant methods for synthesis of this class of compounds are
known in the literature. Synthesis of these two geometric
isomers 1 and 2 with two hydroxymethyl moieties is a
bioactive natural and unnatural products, now herein, we
report a facile chemoenzymatic route to 1 and 2 using
acetoxymethylmaleic anhydride (11) as a precursor
(Schemes 1 and 2).
4
,5
4
challenging task as Nature derives them from the sugar,
siphonodin 6-O-b-D-glycopyranoside. In continuation of
our studies on cyclic anhydrides to structurally interesting
3
2. Results and discussion
Selenium dioxide oxidation of the b-methyl group of a,b-
unsaturated esters and several types of allylic/benzylic methyl
*
NCL communication no. 6689.
6
–8
groups are known in the literature.
We felt that the
Keywords: Butyrolactone; Knoevenagel condensation; Selenium dioxide
oxidation; Enzymatic hydrolysis; Natural ellipsoidones A and B; Synthesis.
*
butenolide 5 would be a potential starting material for the
synthesis of ellipsoidones A (1) and B (2) and selenium
dioxide oxidation of both the allylic methyl groups in 5 would
Corresponding author. Tel.: C91 20 25902333; fax: C91 20 25893153;
e-mail: np.argade@ncl.res.in
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.020

2716
S. Gogoi, N. P. Argade / Tetrahedron 62 (2006) 2715–2720
O
O
the monoacetate 7 on base catalyzed deacylation gave the
deoxyellipsoidone 8 (E:ZZ12:88, by H NMR) in68and 61%
yields, respectively. Most of the naturally occurring buteno-
1
i
O
O
(
87%)
lides of such type exist as the thermodynamically more stable
Z-isomer and herein, we could assign the Z-geometry to the
4
O
3
4
ii (76%)
exocyclic carbon–carbon double bonds in compounds 5 to 8
onthebasisof HNMRdata. Asexpected, incompounds5to8
1
O
O
O
1
the lactone methyl group signals for the minor E-isomersin H
iii
O
NMRspectra were more deshielded (ca. d2.51)than the corres-
ponding major Z-isomer signals (ca. d 2.22), due to the aniso-
tropic effect of the furan ring. All our attempts to oxidize the
allylic methyl group ofthe lactonemoiety in 5 met with failure.
Wefeel that, ontheformation of new exocyclic carbon–carbon
double bond in 5, the allylic methyl group hydrogens lose the
sacrificial hyperconjugation with the lactone carbonyl group
(
26%)
O
OHC
O
6
(E:Z = 1:9)
5(E:Z = 1:9)
v
(68%)
O
iv (92%)
O
and hence it becomes inactive to the SeO -oxidation. There-
2
fore, wealteredourstrategyanddecidedtostartthesynthesisof
1 and 2 from acetoxymethylbutenolide 12.
vi
61%)
O
O
(
O
O
HO
AcO
7
(E:Z = 1:9)
We envisaged the preparation of acetoxymethyllactone 12
from itaconic anhydride (9). The bromination of itaconic
8
(E:Z = 12:88)
1
0
Scheme 1. Reagents, conditions and yields: (i) (a) NaBH
4
, THF, 0 8C, 2 h,
b) H /HCl (87%); (ii) 5-methylfurfural, piperidine, CH OH, rt, 15 h
76%); (iii) SeO , CH COOH, reflux, 2 h (26%); (iv) SeO , CH COOH
anhydrous), reflux, 1.5 h (92%); (v) (a) NaBH , C OH, rt, 1 h, (b) H
CO , CH OH, 0 8C to rt, 2 h (61%).
anhydride (9) furnished the dibromodiacid 10 in 98% yield
Scheme 2). The diacid 10 on treatment with Ac O/NaOAc
C
(
(
(
3
(
2
2
3
2
3
C
mixture at room temperature for 6 h followed by removal of
acetic anhydride in vacuo gave the crude acetoxymethylma-
leic anhydride (11). Herein all the three-steps, the ring closure
of acid 10 to the intermediate succinic anhydride derivative,
dehydrobromination to form the second intermediate bromo-
methylmaleic anhydride and the allylic substitution of the
bromide with the acetoxy group took place in one pot. The
acetoxymethylmaleic anhydride (11) was very unstable and
we were unable to purify it. The structure of the anhydride 11
4
2
H
5
/
HCl (68%); (vi) K
2
3
3
provide a simple and efficient access to these natural products.
In this context, for the preparation of 5, we performed the
sodium borohydride reduction of citraconic anhydride (3) and
obtainedtheknown butyrolactone4in87%yield (Scheme 1).
Piperidine catalyzed Knoevenagel condensation of lactone 4
with 5-methylfurfural gave the desired butenolide 5 in 76%
9
1
1
yield (E:ZZ1:9, by H NMR). The butenolide 5 was strongly
resistant to selenium dioxide oxidation in refluxing ethanol
was established on the basis of IR, H NMR data of crude 11.
The direct regioselective NaBH4 reduction of the crude
anhydride 11 in THF furnished the desired lactone 12 in 37%
yield (two-steps), without deacylation of the acetate moiety in
and 1,4-dioxane solutions and the starting material was
recovered after 12 h reflux time. The SeO oxidation of 5 in
2
9
8% acetic acid directly furnished the aldehyde 6, but only in
11/12. Alternately, the desired lactone 12 can also be obtained
from dihydroxy acetone in four-steps with 38% overall
26% yield, wherein both the hydroxylation and further
oxidation of the alcohol to the aldehyde took place in one
1
yield. The Knoevenagel condensation of lactone 12 with
1
pot. To arrest the SeO oxidation of 5 at the alcohol stage, we
2
performed the reaction in a freshly dried anhydrous acetic acid
and exclusivelyobtained the monoacetoxymethylbutenolide7
5-methylfurfural gave the required monoacetoxymethyl-
1
butenolide 13 (E:ZZ7:93, by H NMR) in 75% yield. Herein,
the regioselective carbanion formation on an internal
butyrolactone methylene group, rather than the external
in 92% yield. The aldehyde 6 on NaBH reduction as well as
4
O
O
O
O
O
HO
HO
i
ii
iii
O
O
O
(37%)
H
(
98%)
Br
OAc
OAc
Br
10
O
O
H
11
12
9
iv (75%)
O
O
O
O
O
O
vi
95%)
v
O
+
O
(
(92%)
HO
OH
AcO
O
O
O
O
OH
H
OAc
OAc
H
OH
Ellipsoidone A (1)
Ellipsoidone B (2)
14 (E:Z = 2:8)
13 (E:Z = 7:93)
C
2 4
O, AcONa, rt, 6 h; (iii) (a) NaBH , THF, 0 8C, 2 h, (b) H /HCl (two steps,
, AcOH (anhydrous), reflux, 6 h (92%); (vi) Amano PS, hexane–benzene (2/1), phosphate
Scheme 2. Reagents, conditions and yields: (i) Br
7%); (iv) 5-methylfurfural, piperidine, rt, 15 h (75%); (v) SeO
buffer pH 7.0, rt, 40 h (95%, 1:2Z86:14).
2
, CCl
4
, rt, 24 h (98%); (ii) Ac
3
2

S. Gogoi, N. P. Argade / Tetrahedron 62 (2006) 2715–2720
2717
acetoxymethyl moiety is noteworthy and could be due to the
generation of the stable oxyfurananion in the former case. As
expected, here too the methylene proton signals from the
groups with the reactive enol-lactone. Finally, we carried out
the Amano PS catalyzed double deacylation of 14 at pH 7 and
obtained the mixture of desired products 1 and 2 (1:2Z86:14,
1
–
CH OAc groups on lactone moieties for the minor E-isomers
2
by H NMR) in 95% yield. All our attempts to obtain the pure
in compounds 13 and 14 appeared more downfield than the
corresponding signals for their major Z-isomers. The SeO2
oxidation of 13 in anhydrous acetic acid gave the desired
diacetoxymethylbutenolide 14 in 92% yield. To obtain the
natural products 1 and 2, we systematically studied the
deacylation of 14, both under acidic and basic conditions and
observed that the starting material 14 and formed products 1
and 2 are not very stable under these conditions. In our hands,
wealways got a complex mixture ofproductsand thiscould be
due to the intermolecular reactions of the two hydroxymethyl
major isomer 1 from the 1 plus 2 mixture by recrystallization
were unsuccessful. Finally, we did the HPLC separation of 1
plus 2 mixture using the known procedure and obtained pure
2
1 and 2 with quantitative recovery. The analytical and spectral
data obtained for 1 and 2 were in complete agreement with the
reported data. In the present six-step synthesis, starting from
2
itaconic anhydride (9), the overall yield of ellipsoidone A (1)
and ellipsoidone B (2) were 20.4 and 3.3%, respectively. The
photochemical conversion of ellipsoidone B to ellipsoidone A
2
is known.
Chloroform-d
O
O
O
OAc
13
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10
0
O
O
O
OAc
13
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10
0

2718
S. Gogoi, N. P. Argade / Tetrahedron 62 (2006) 2715–2720
3. Conclusion
using a mixture of ethyl acetate and petroleum ether
0.5:9.5) furnished 5 as a yellow crystalline solid.
(
In summary, we have demonstrated the first total synthesis
of isomeric natural cytotoxic ellipsoidone A (1) and natural
ellipsoidone B (2) using regioselective reduction of
acetoxymethylmaleic anhydride (11), selenium dioxide
hydroxylation of butenolide 13 and an enzymetic deacyla-
tion of diacetoxybutenolide 14 as key reactions. In the
present stepwise approaches, we could design the acetyl
derivatives of both the unnatural deoxyellipsoidone regioi-
somers. In the present synthesis, the enzymatic hydrolysis of
diacetate 14 to obtain the labile multifunctional ellipsoi-
dones A and B in 95% yield is noteworthy. We feel that the
present approach to 1 and 2 is general in nature and it would
be useful to design the analogs and congeners of these
bioactive natural products for the structure–activity
relationship studies.
1
Compound 5: 442 mg (76% yield); mp 103–105 8C; H
NMR (CDCl , 200 MHz), major Z-isomer: d 2.19 (d, JZ
3
1 Hz, 3H), 2.35 (s, 2.7H), 5.91 (br s, 1H), 6.04 (s, 0.9H),
6.15 (d, JZ4 Hz, 0.9H), 6.94 (d, JZ4 Hz, 0.9H), [the
following four signals for the minor E-isomer showed
splitting and appeared at d 2.49 (d, JZ1 Hz, 0.3H), 6.10 (d,
JZ4 Hz, 0.1H), 6.44 (s, 0.1H), 6.49 (d, JZ4 Hz, 0.1H)];
1
3
C NMR (CDCl , 50 MHz), major Z-isomer: d 11.5, 13.7,
3
98.9, 109.6, 114.8, 116.6, 146.7, 147.5, 154.5, 154.7,
169.2; IR (CHCl ) n 1773, 1751, 1651, 1520,
1215 cm . Anal. Calcd for C H O : C, 69.46; H, 5.30.
3
max
K1
1
1 10 3
Found: C, 69.22; H, 5.51.
4.1.3. 5-(3-Methyl-5-oxo-5H-furan-2-ylidenemethyl)-
furan-2-carbaldehyde (6). To a stirred solution of lactone
5
SeO (117 mg, 1.05 mmol) and the reaction mixture was
refluxed for 2 h. The reaction mixture was filtered through
Celite and acetic acid was removed in vacuo. The residue
was purified by silica gel column chromatography using a
mixture of ethyl acetate and petroleum ether (1:4) to furnish
(100 mg, 0.53 mmol) in acetic acid (5 mL) was added
2
4. Experimental
4
.1. General
Melting points are uncorrected. Column chromatographic
separations were carried out on ACME silica gel (60–120
mesh). Commercially available citraconic anhydride,
sodium borohydride, 5-methylfurfural, piperidine, selenium
dioxide, bromine, sodium acetate, and Amano PS-1310 U
from Amano Pharmaceuticals, Japan were used. The
activity of the lipase powder used is expressed in terms
of units, 1 unit corresponding to micromoles of butyric acid
liberated (estimation by GC) from glyceryl tributyrate per
minute per milligram of enzyme powder. Dry acetic acid
6
as a yellow crystalline solid.
1
Compound 6: 28 mg (26% yield); mp 187–190 8C; H NMR
(
(
CDCl , 200 MHz), major Z-isomer: d 2.26 (s, 2.7H), 6.10
3
s, 1H), 6.19 (s, 0.9H), 7.23 (d, JZ4 Hz, 1H), 7.34 (d, JZ
4
minor E-isomer showed splitting and appeared at d 2.58 (s,
0
Hz, 0.9H), 9.65 (s, 1H), [the following three signals for the
1
2
13
.3H), 6.53 (s, 0.1H), 6.71 (d, JZ4 Hz, 0.1H)]; C NMR
(
1
CDCl , 50 MHz), major Z-isomer: d 11.6, 97.2, 116.1,
17.3, 123.5, 151.7, 152.0, 153.8, 154.9, 168.0, 177.3; IR
3
was obtained by refluxing it over active CuSO for 12 h,
4
followed by distillation.
K1
(CHCl ) n
C H O : C, 64.71; H, 3.95. Found: C, 64.67; H, 4.04.
1782, 1676, 1215 cm . Anal. Calcd for
max
3
1
1 8 4
4
.1.1. 4-Methyl-5H-furan-2-one (4). To a stirred solution
of citraconic anhydride 3 (800 mg, 7.14 mmol) in THF
15 mL), was added NaBH (675 mg, 17.85 mmol) at 0 8C
4
.1.4. Acetic acid 5-(3-methyl-5-oxo-5H-furan-2-ylidene
methyl)-furan-2-ylmethyl ester (7). To a stirred solution of
lactone 5 (100 mg, 0.53 mmol) in dry acetic acid (5 mL) was
added SeO (117 mg, 1.05 mmol) and the reaction mixture
was refluxed for 1.5 h. The reaction mixture was filtered
through Celite and acetic acid was removed in vacuo. The
residue was purified by silica gel column chromatography
using a mixture of ethyl acetate and petroleum ether (1:9) to
furnish 7 as a yellow crystalline solid.
(
4
and the reaction mixture was further stirred at 0 8C for 2 h.
The reaction was quenched with water, acidified with dilute
HCl and extracted with ethyl acetate (50 mL!3). The
organic layer was washed with water, brine and dried over
2
Na SO . Concentration of the organic layer in vacuo
4
2
followed by silica gel column chromatographic purification
of the residue using a mixture of ethyl acetate and petroleum
ether (3:7) furnished pure 4.
9
1
Compound 7: 120 mg (92% yield); mp 84–86 8C; H NMR
(
(
CDCl , 200 MHz), major Z-isomer: d 2.10 (s, 2.7H), 2.22
3
d, JZ2 Hz, 3H), 5.08 (s, 2H), 5.97 (s, 1H), 6.09 (s, 1H),
1
Compound 4: 609 mg (87% yield); thick oil; H NMR
(
2
1
CDCl , 200 MHz) d 2.16 (s, 3H), 4.76 (s, 2H), 5.83 (q, JZ
3
13
6.55 (d, JZ4 Hz, 0.9H), 7.02 (d, JZ4 Hz, 1H), [the
following two signals for the minor E-isomer showed
splitting and appeared at d 2.48 (s, 0.3H), 6.50 (d, JZ4 Hz,
0.1H)]; C NMR (CDCl , 50 MHz), major Z-isomer: d
1
1
Hz, 1H); C NMR (CDCl , 50 MHz) d 13.5, 73.5, 115.5,
3
K1
66.4, 173.8; IR (CHCl ) n 1782, 1751, 1647, 1215 cm
3
.
max
1
3
Anal. Calcd for C H O : C, 61.22; H, 6.17. Found:
5
6
2
3
C, 61.37; H, 6.21.
1.6, 20.8, 57.9, 98.4, 113.7, 115.6, 115.7, 148.1, 149.4,
50.6, 154.8, 168.9, 170.5; IR (CHCl ) n 1774, 1751,
3
max
K1
4.1.2. 4-Methyl-5-(5-methyl-furan-2-ylmethylene)-5H-
furan-2-one (5). To a stirred solution of lactone 4
1651, 1601, 1234 cm . Anal. Calcd for C13
62.90; H, 4.87. Found: C, 63.03; H, 4.62.
H O : C,
12 5
(
(
3
300 mg, 3.06 mmol) in methanol were added piperidine
0.21 mL, 2.14 mmol) and 5-methylfurfural (0.30 mL,
.06 mmol) at room temperature and the reaction mixture
4.1.5. 5-(5-Hydroxymethyl-furan-2-ylmethylene)-4-
methyl-5H-furan-2-one (8). To a stirred solution of lactone
7 (70 mg, 0.28 mmol) in methanol (5 mL) was added
K CO (5 mg, 0.04 mmol) and the reaction mixture was
was stirred for 15 h. Removal of solvent in vacuo followed
by column chromatographic purification of the residue
2
3

S. Gogoi, N. P. Argade / Tetrahedron 62 (2006) 2715–2720
2719
1
Compound 12: 400 mg (37% yield); thick oil; H NMR
stirred at room temperature for 1 h. Methanol was removed
in vacuo at room temperature and water (10 mL) was added
to the reaction mixture. The reaction mixture was acidified
to pH 4 using 2 N HCl and immediately extracted with ethyl
acetate (15 mL!4). The combined organic layer was
washed with water, brine and dried over Na SO .
(CDCl , 200 MHz) d 2.11 (s, 3H), 4.81 (d, JZ2 Hz, 2H), 4.93
3
1
3
(d, JZ2 Hz, 2H), 6.01 (quintet, JZ2 Hz, 1H); C NMR
(CDCl , 50 MHz) d 20.3, 59.2, 71.0, 116.6, 163.6, 170.0,
3
K1
172.7; IR (neat) nmax 1782, 1747, 1651, 1229 cm . Anal.
Calcdfor C H O : C, 53.85;H, 5.16. Found:C, 53.77;H, 5.04.
7 8 4
2
4
Concentration of the organic layer in vacuo followed by
silica gel column chromatographic purification of the
residue using a mixture of ethyl acetate and petroleum
ether (2:8) as an eluent gave 8.
4.1.8. Acetic acid 2-(5-methyl-furan-2-ylmethylene)-5-
oxo-2,5-dihydro-furan-3-ylmethyl ester (13). To a stirred
solution of lactone 12 (300 mg, 1.92 mmol) in methanol was
added piperidine (0.13 mL, 1.35 mmol) and 5-methyl-
furfural (0.19 mL, 1.92 mmol) at room temperature and the
reaction mixture was stirred for 15 h. Removal of solvent in
vacuo followed by column chromatographic purification of
the residue using a mixture of ethyl acetate and petroleum
ether (1:9) furnished 13 as a faint yellow solid.
Butenolide 6 (25 mg, 0.12 mmol) on NaBH4 (5 mg,
0
.14 mmol) reduction in EtOH (3 mL) at room temperature
for 1 h followed by acidification with 2 N HCl gave 8 in
8% yield as a yellow crystalline solid.
6
1
Compound 8: 35 mg (61% yield); mp 95–96 8C; H NMR
1
Compound 13: 358 mg (75% yield); mp 83–85 8C; H NMR
(CDCl , 200 MHz) d 2.16 (s, 2.79H), 2.23 (s, 0.21H), 2.35
3
(
(
CDCl , 200 MHz), major Z-isomer: d 2.20 (s, 2.64H), 4.64
3
s, 3H), 5.94 (s, 1H), 6.07 (s, 1H), 6.43 (d, JZ4 Hz, 0.88H),
6
minor E-isomer showed splitting and appeared at d 2.49
.95 (d, JZ4 Hz, 1H), [the following two signals for the
(s, 2.79H), 2.43 (s, 0.21H), 5.06 (d, JZ2 Hz, 1.86H), 5.43
(d, JZ2 Hz, 0.14H), 6.08 (s, 0.93H), 6.11 (s, 0.93H), 6.17
(d, JZ4 Hz, 0.93H), 6.23 (s, 0.07H), 6.26–6.31 (m, 0.07H),
6.50 (br s, 0.07H), 6.53 (d, JZ4 Hz, 0.07H), 6.97 (d, JZ
1
3
(
s, 0.36H), 6.53 (d, JZ4 Hz, 0.12H)]; C NMR (CDCl3,
5
1
3
0 MHz), major Z-isomer: d 11.6, 57.5, 98.6, 111.0, 115.4,
15.8, 147.7, 148.8, 154.9, 155.6, 169.1; IR (CHCl ) n
1
3
3
max
4 Hz, 0.93H); C NMR (CDCl , 50 MHz), major Z-isomer:
3
K1
449, 1780, 1755, 1649, 1599, 1217 cm . Anal. Calcd for
d 13.8, 20.6, 57.3, 100.3, 109.9, 114.8, 117.6, 143.1, 147.0,
1773, 1751,
max
C H O : C, 64.07; H, 4.89. Found: C, 63.91; H, 4.99.
1
152.5, 155.2, 168.4, 170.0; IR (CHCl ) n
3
1
10
4
K1
1
653, 1597, 1215 cm . Anal. Calcd for C H O : C,
13 12 5
62.90; H, 4.87. Found: C, 63.02; H, 4.95.
4
.1.6. 2-Bromo-2-(bromomethyl)succinic acid (10). To a
stirred solution of itaconic anhydride 9 (4.0 g, 35.70 mmol)
in carbon tetrachloride (30 mL) was added a solution of
bromine (3.60 mL, 71.40 mmol) in carbon tetrachloride
4
5
.1.9. Acetic acid 2-(5-acetoxymethyl-furan-2-ylmethylene)-
-oxo-2,5-dihydro-furan-3-ylmethyl ester (14). To a
stirred solution of lactone 13 (300 mg, 1.21 mmol) in dry
acetic acid (10 mL) was added SeO (268 mg, 2.42 mmol)
(
20 mL) at room temperature over a period of 20 min. The
2
reaction mixture was further stirred for 24 h and then it was
concentrated in vacuo. The obtained crude residue was
recrystallized from petroleum ether plus ethyl acetate (1:1)
and the reaction mixture was refluxed for 6 h. The reaction
mixture was filtered through Celite and acetic acid was
removed in vacuo. The residue was purified by silica gel
column chromatography using a mixture of ethyl acetate
and petroleum ether (0.5:9.5) to furnish 14 as a faint yellow
solid.
1
0
mixture to obtain pure 10 as a white crystalline solid.
1
0
Compound 10: 10.13 g (98% yield); mp 163–165 8C (lit.
1
mp 167–168 8C); H NMR (D O, 200 MHz) d 3.27 (dd, JZ
2
1
8, 4 Hz, 2H), 4.03 (s, 2H); C NMR (D O, 50 MHz)
3
1
d 40.0, 44.7, 59.5, 173.5, 174.8; IR (Nujol) n
1
Compound 14: 341 mg (92% yield); mp 93–96 8C; H NMR
(CDCl , 200 MHz) d 2.10 (s, 3H), 2.18 (s, 3H), 5.07 (d, JZ
1
0
2
2700–2500,
max
K1
3
1
720, 1713, 1462 cm
.
Hz, 1.6H), 5.08 (s, 1.6H), 5.11 (s, 0.4H), 5.42 (d, JZ1 Hz,
.4H), 6.13 (s, 0.8H), 6.19 (d, JZ2 Hz, 0.8H), 6.30–6.35
4.1.7. Acetic acid 5-oxo-2,5-dihydro-furan-3-ylmethyl
ester (12). To a stirred solution of acid 10 (2.0 g,
(m, 0.2H), 6.50–6.60 (m, 0.6H), 6.56 (d, JZ4 Hz, 0.8H),
13
7.05 (d, JZ4 Hz, 0.8H); very clean two sets of C carbon
13
6
.90 mmol) in Ac O (15 mL) was added NaOAc (1.70 g,
2
signals were obtained for the major and minor isomers,
C
NMR (CDCl , 125 MHz), major isomer: d 20.6, 20.8, 57.2,
20.70 mmol) and the reaction mixture was stirred at room
temperature for 6 h. Acetic anhydride was removed in vacuo
3
57.9, 99.8, 113.8, 116.1, 116.6, 144.9, 149.0, 151.3, 152.7,
167.9, 170.0, 170.4, minor isomer: d 20.6, 20.7, 57.7, 60.8,
103.5, 113.3, 117.2, 118.4, 145.4, 147.6, 152.0, 152.1,
to obtain crude 11. To the stirred solution of this residue in
THF (20 mL) was added NaBH (522 mg, 13.80 mmol) at
4
0
8C. The reaction mixture was further stirred at 0 8C for 2 h
167.6, 169.9, 170.5; IR (CHCl ) nmax 1776, 1746, 1676,
3
K1
and then quenched with water and acidified with dilute HCl
and extracted with ethyl acetate (50 mL!3). The organic
layer was washed with water, brine and dried over Na SO .
1653, 1605, 1219 cm . Anal. Calcd for C15
58.83; H, 4.61. Found: C, 58.72; H, 4.80.
H O : C,
14 7
2
4
Concentration of the organic layer in vacuo followed by the
silica gel column chromatographic purification of the
residue using a mixture of ethyl acetate and petroleum
4.1.10. 4-Hydroxymethyl-5-(5-hydroxymethyl-furan-2-
ylmethylene)-5H-furan-2-one (ellipsoidone A, 1 and
ellipsoidone B, 2). A solution of diacetate 14 (100 mg,
0.33 mmol) in petroleum ether–benzene (2/1) mixture
1
1
ether (3:7) furnished 12.
(
12 mL) was added to a suspension of Amano PS lipase
1
Compound 11 (crude): H NMR (CDCl , 200 MHz) d 2.19
(40 mg) in aqueous sodium phosphate (0.01 M, 4 mL) at
pH 7. The reaction mixture was stirred at room temperature
for 40 h. The reaction mixture was filtered through Celite
3
(
s, 3H), 5.05 (d, JZ2 Hz, 2H), 6.83 (t, JZ2 Hz, 1H); IR
K1
(
neat) nmax 1771, 1738, 1730 cm
.

2720
S. Gogoi, N. P. Argade / Tetrahedron 62 (2006) 2715–2720
and the aqueous layer was extracted with ethyl acetate
20 mL!4). The combined organic layer was washed with
water, brine and dried over Na SO . The organic layer was
References and notes
(
2
4
1. Wu, C.-Y. Acta Phytotaxonomica Sinica 1985, 23, 121.
2. Hano, Y.; Shi, Y.-Q.; Nomura, T.; Yang, P.-Q.; Chang, W.-J.
Phytochemistry 1997, 46, 1447.
concentrated in vacuo and the residue was purified by silica
gel column chromatography using a mixture of ethyl acetate
and petroleum ether (1:1) as an eluent to furnish
ellipsoidone A (1) plus ellipsoidone B (2) in 95% yield.
HPLC separation of 1 plus 2 mixture was done using the
3. (a) Wagner, H.; Flitsch, K. Planta Med. 1981, 43, 245. (b)
Wagner, H.; Flitsch, K.; Jurcic, K. Planta Med. 1981, 43, 249.
(c) Fung, S. Y.; Herrebout, W. M.; Verpoorte, R.; Fischer, F. C.
J. Chem. Ecol. 1988, 14, 1099.
2
known literature procedure.
4
. Kar, A.; Gogoi, S.; Argade, N. P. Tetrahedron 2005, 61, 5297
and references cited therein.
. (a) Mhaske, S. B.; Argade, N. P. Tetrahedron 2004, 60, 3417.
Compound 1: 59 mg (81.4% yield); yellow crystalline solid;
mp 141–143 8C; H NMR (acetone-d , 500 MHz) d 4.57 (s,
1
5
6
(
b) Kar, A.; Argade, N. P. Tetrahedron 2003, 59, 2991.
(c) Kar, A.; Argade, N. P. J. Org. Chem. 2002, 67, 7131.
d) Mhaske, S. B.; Argade, N. P. Synthesis 2002, 323. (e)
2
5
1
1
1
5
H), 4.73 (s, 2H), 6.20 (s, 1H), 6.31 (s, 1H), 6.49 (d, JZ
13
Hz, 1H), 6.90 (d, JZ5 Hz, 1H); C NMR (acetone-d6,
25 MHz) d 57.1, 57.3, 99.8, 111.0, 114.2, 116.4, 145.7,
49.3, 158.5, 161.5, 169.2; IR (Nujol) nmax 3329, 3211,
(
Mhaske, S. B.; Argade, N. P. J. Org. Chem. 2001, 66, 9038. (f)
Deshpande, A. M.; Natu, A. A.; Argade, N. P. Synthesis 2001,
K1
749, 1638, 1462 cm . Anal. Calcd for C H O : C,
1
1 10 5
7
02. (g) Argade, N. P.; Balasubramaniyan, V. Heterocycles
000, 53, 475. (h) Deshpande, A. M.; Natu, A. A.; Argade, N. P.
9.46; H, 4.54. Found: C, 59.52; H, 4.63.
2
J. Org. Chem. 1998, 63, 9557. (i) Desai, S. B.; Argade, N. P.
J. Org. Chem. 1997, 62, 4862 and references cited therein 5a–i.
. Rabjohn, N. Org. React. 1949, 5, 331.
Compound 2: 9.6 mg (13.2% yield); yellow crystalline
solid; mp 159–161 8C; H NMR (acetone-d , 500 MHz) d
1
6
6
4
.63 (s, 2H), 4.97 (d, JZ2 Hz, 2H), 6.41 (m, 1H), 6.46 (d,
13
7. Rabjohn, N. Org. React. 1976, 24, 261.
JZ1 Hz, 1H), 6.62 (s, 1H), 6.74 (d, JZ2 Hz, 1H); C NMR
acetone-d , 125 MHz) d 57.3, 60.0, 103.6, 110.5, 117.8,
8
. Curley, R. W., Jr.; Ticoras, C. J. J. Org. Chem. 1986, 51, 256.
. (a) Scheiper, B.; Bonnekessel, M.; Krause, H.; Furstner, A.
J. Org. Chem. 2004, 69, 3943. (b) Wel, H. V. D.; Nibbering,
N. M. M.; Kayser, M. M. Can. J. Chem. 1988, 66, 2587.
(
6
9
1
3
17.9, 146.1, 147.8, 159.0, 160.5, 168.4; IR (Nujol) n
max
K1
331, 3302, 1736, 1638, 1460 cm . Anal. Calcd for
C H O : C, 59.46; H, 4.54. Found: C, 59.31; H, 4.60.
11 10 5
1
0. (a) Laursen, R. A.; Shen, W.-C.; Zahka, K. G. J. Med. Chem.
971, 14, 619. (b) Nokami, J.; Tamaoka, T.; Ogawa, H.;
Wakabayashi, S. Chem. Lett. 1986, 541.
1
1
1. (a) Lattmann, E.; Hoffmann, H. M. R. Synthesis 1996, 155. (b)
Bentley, P. H.; McCrae, W. J. Org. Chem. 1970, 35, 2082. (c)
Gadir, S. A.; Smith, Y.; Taha, A. A.; Thaller, V. J. Chem. Res.
Acknowledgements
S.G. thanks CSIR, New Delhi, for the award of a research
fellowship. We thank Amano Pharmaceuticals Co., Japan
for a generous gift of the enzyme Amano PS.
(
S) 1986, 222.
2. Dupuis, C.; Corre, C.; Boyaval, P. Appl. Environ. Microbiol.
993, 59, 4004.
1
1