Synthesis of naturally occurring bioactive butyrolactones: Maculalactones A-C and nostoclide I

Article abstract of DOI:10.1016/j.tet.2005.03.065

Starting from citraconic anhydride (13), a simple multistep (9-10 steps) synthesis of naturally occurring butyrolactones maculalactone A (3), maculalactone B (1), maculalactone C (2) and nostoclide I (4) have been described with good overall yields via di

Full text of DOI:10.1016/j.tet.2005.03.065

Tetrahedron 61 (2005) 5297–5302
Synthesis of naturally occurring bioactive butyrolactones:
maculalactones A–C and nostoclide I*
*
Anirban Kar, Sanjib Gogoi and Narshinha P. Argade
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Received 20 January 2005; revised 1 March 2005; accepted 18 March 2005
Available online 11 April 2005
Abstract—Starting from citraconic anhydride (13), a simple multistep (9–10 steps) synthesis of naturally occurring butyrolactones
maculalactone A (3), maculalactone B (1), maculalactone C (2) and nostoclide I (4) have been described with good overall yields via
dibenzylmaleic anhydride (20) and benzylisopropylmaleic anhydride (27). The two anhydrides 20 and 27 were prepared by SN20 coupling
reactions of appropriate Grignard reagents with dimethyl bromomethylfumarate (14), LiOH-induced hydrolysis of esters to acids,
bromination of carbon–carbon double bond, in situ dehydration followed by dehydrobromination and chemoselective allylic substitution of
bromoatom in disubstituted anhydrides 19 and 26 with appropriate Grignard reagents. The NaBH4 reduction of these anhydrides 20 and 27
furnished the desired lactones 21 and 29, respectively. The lactone 21 on Knoevenagel condensation with benzaldehyde, furnished
maculalactone B (1), which on isomerization gave maculalactone C (2). Selective catalytic hydrogenation of 1 gave maculalactone A (3).
The conversion of lactone 29 to nostoclide I (4) is known.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
several bioactive natural products in our group.14 We felt
that the synthesis of suitably disubstituted maleic anhy-
drides, followed by their reductive conversion to the
respective lactones, and then the Knoevenagel condensation
with different aldehydes will provide an easy access to these
novel butenolide skeletons. In continuation of our ongoing
studies on cyclic anhydrides to bioactive natural products,14
now we herein report the synthesis of naturally occurring
maculalactones A–C (3,1,2) and nostoclide I (4), starting
from citraconic anhydride (13) via the unsymmetrical
bromomethylmaleic anhydrides 19 and 26 (Schemes 1 and 2).
A very large number of natural and unnatural butyrolactones
are known in the literature.1 Recently several diverse
skeletons with butyrolactone as a core unit have been
isolated as bioactive natural products2–11 and some of them
have been depicted in Figure 1. These butyrolactones
possess cytotoxic, antibiotic and antimicrobial activities.3,6,8
Maculalactones A–C have been isolated from the epilithic-
encrusting cyanobacterium Kyrtuthrix maculans from Hong
Kong island and they possess marine anti-fouling activity.2,12
The natural (C)-maculalactone A has been assigned S-
configuration. To date only one synthesis of these
butyrolactones 1-3 has been reported in the literature.12
Nostoclide I (4) has been isolated from the culture of a
symbiotic blue-green alga, Nostoc sp., from the lichen
Peltigera canina and it has cytotoxic activity.3 To date two
syntheses of 4 are known in the literature.13 These
butyrolactones are generally synthesized via Stobbe con-
densation,12 Stille coupling reaction13b and conversion of
furan to the required lactone.13a Since 1997, using cyclic
anhydrides as potential precursors, we have designed
2. Results and discussion
Recently, we studied the NBS-allylic bromination of
dimethyl methylmaleate,15 chemoselective SN20 coupling
reactions of Grignard reagents prepared from primary alkyl
halides with dimethyl bromomethylfumarate (14) in
absence of CuI,16–18 and chemoselective allylic substitution
of bromide in (bromomethyl)methylmaleic anhydride with
Grignard reagents prepared from primary alkyl halides in
presence of CuI,19 to design the bioactive natural products.
Using these reactions we designed natural products 1,7 (Z)-
nonadecadiene-2,3-dicarboxylic acid,16 chaetomellic acid
A,16 2-(b-carboxyethyl)-3-hexylmaleic, 2-(b-carboxy-
ethyl)-3-octylmaleic and 2-carboxymethyl-3-hexylmaleic
anhydrides17,18 and unnatural products isochaetomellic acid
B, 2,3-dihexylmaleic anhydride and 2,3-dioctylmaleic
* NCL Communication No. 6678.
Keywords: Dimethyl bromomethylfumarate; SN20 Grignard couplings;
Disubstituted maleic anhydrides; NaBH4 reductions; Maculalactone A–C;
Nostoclide I; Synthesis.
Corresponding author. Tel.: C91 20 25893153; fax: C91 20 25893153;
e-mail: argade@dalton.ncl.res.in
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.065

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A. Kar et al. / Tetrahedron 61 (2005) 5297–5302
Figure 1. Naturally occurring bioactive butyrolactones and analogs.
anhydride.16–18 Herein, we planned to study the above two
coupling reactions with Grignard reagents from secondary
alkyl halides, benzyl halides and aryl halides to design the
desired substituted maleic anhydrides 20 and 27. Citraconic
anhydride (13) was converted to bromodiester 14 in 2-steps
with 64% overall yield using known procedure16 (Scheme
1). The SN20 coupling reaction of benzylmagnesium
bromide with 14 furnished the diester 15 in 70% yield,
with an exo carbon–carbon double bond. Lithium hydroxide
hydrolysis of diester 15 at room temperature, followed by
acidification with hydrochloric acid gave the desired
dicarboxylic acid 16 in 92% yield, without isomerization
of carbon–carbon double bond. The addition of molecular
bromine to the carbon–carbon double bond in 16 gave a
mixture of all possible isomers of dibromodicarboxylic acid
17 in w100% yield. The dibromodicarboxylic acid 17
underwent a very smooth in situ dehydration followed by
dehydrobromination reaction in presence of acetic anhy-
dride at reflux to give unsymmetrical (bromomethyl)ben-
zylmaleic anhydride (19) in w100% yield via the unisolable
intermediate dibromosuccinic anhydride 18. The chemo-
selective allylic substitution of the bromide in anhydride 19
with phenylmagnesium bromide furnished dibenzylmaleic
anhydride (20) in 45% yield. Sodium borohydride reduction
Scheme 1. Reagents, conditions and yields: (i) PhCH2MgBr (1.5 equiv), THF, HMPA, K20 8C, 0.5 h (70%); (ii) (a) LiOH (10 equiv), THFCH2O (3:1), rt,
18 h, (b) HC/HCl (92%); (iii) Br2 (1.5 equiv), CCl4, rt, 6 h (w100%); (iv) Ac2O, reflux, 1.5 h (w100%); (v) C6H5MgBr (5 equiv) CuI (0.1 equiv), Et2O,
HMPA, K5 to 0 8C (45%); (vi) NaBH4 (2.5 equiv), THF, 0 8C, 2 h (91%); (vii) Piperidine (0.7 equiv), PhCHO (1 equiv), MeOH, rt, 16 h (77%); (viii) CHCl3,
rt, 8 days (50%); (ix) H2, Pd/C, EtOAc, 12 h (75%); (x) 6, 200 8C, 3 h (100%).

A. Kar et al. / Tetrahedron 61 (2005) 5297–5302
5299
Scheme 2. Reagents, conditions and yields: (i) C3H7MgBr (1.5 equiv), THF, HMPA, K20 8C, 0.5 h (79%); (ii) (a) LiOH (10 equiv), THFCH2O (3:1), rt, 18 h,
(b) HC/HCl (91%); (iii) Br2 (1.5 equiv), CCl4, rt, 6 h (w100%); (iv) Ac2O, reflux, 1.5 h (w100%); (v) C6H5MgBr (5 equiv), CuI (0.1 equiv), Et2O, HMPA,
K5 to 0 8C (43%); (vi) NaBH4 (2.5 equiv), THF, 0 8C, 4 h (70%).
of dibenzylmaleic anhydride (20) in THF at room
temperature gave the desired lactone 21 in 91% yield. The
Knoevenagel condensation of lactone 21 with benzaldehyde
furnished the naturally occurring maculalactone B (1) in
77% yield. The maculalactone B (1) on palladium–charcoal
catalyzed chemoselective hydrogenation gave the (G)-
maculalactone A (3) in 75% yield. The photochemical
conversion of maculalactone B (1) to the maculalactone C
(2) is known in 80% yield.12 The maculalactone B (1) is
thermodynamically more stable than the maculalactone C
(2), but due to the presence of associated p-stacking
interaction between the two phenyl groups,2 it slowly
transforms to maculalactone C (2). The maculalactone B (1)
in chloroform at room temperature underwent nearly 50%
conversion to maculalactone C (2) in 8 days (by 1H NMR).
We isolated and heated the neat 50:50 mixture of
maculalactones B and C at 200 8C for 3 h and obtained
exclusively the maculalactone B (1) proving that it is
thermodynamically more stable than maculalactone C (2).
The maculalactones B plus C mixture on catalytic
hydrogenation also gave the maculalactone A (3) in same
75% yield. The analytical and spectral data obtained for
maculalactones A–C were in complete agreement with
reported data.2,12
3. Conclusion
In summary, starting from readily available citraconic
anhydride we have demonstrated the multi-step synthesis of
novel bioactive natural products maculalactone A (10-steps,
10%), maculalactone B (9-steps, 13%), maculalactone C
(10-steps, 7%) via the three different types of carbon–
carbon coupling reactions. In the synthesis of these unusual
natural products with three phenyl rings, the first phenyl ring
unit was loaded by SN20 Grignard reaction, the second
phenyl ring was coupled via allylic substitution reaction,
while the third phenyl ring unit was attached using
Knoevenagel condensation reaction. Similarly, we have
also completed the formal synthesis of bioactive natural
product nostoclide I (4), the desired precursor 29 was
obtained in 8-steps with 14% overall yield. We feel that our
present approach is general in nature and can be used to
design diverse butyrolactone skeletons for the structure–
activity relationship studies.
4. Experimental
4.1. General
1
Melting points are uncorrected. The H NMR spectra were
Our next plan was to design the bioactive natural product
nostoclide I (4). Starting from diester 14, we similarly
prepared the benzylisopropylmaleic anhydride (27) in 5-
steps with 20% overall yield via SN20 Grignard coupling,
hydrolysis, bromination, in situ dehydration followed by
dehydrobromination and allylic substitution pathway
(Scheme 2). The sodium borohydride induced regioselec-
tive reduction of unsymmetrical maleic anhydride 27 in
THF at 0 8C gave the separable mixture of desired and
undesired lactones 29 and 28 with 70% yield in 3:2 ratio,
respectively. The analytical and spectral data obtained for
lactone 29 was in complete agreement with reported data.
The conversion of lactone 29 to nostoclide I (4) is well
known in the literature.13
recorded on Bruker AC 200 NMR spectrometer and Bruker
MSL 300 NMR spectrometer with TMS as an internal
standard. The 13C NMR spectra were recorded on Bruker
AC 200 NMR spectrometer (50 MHz) and Bruker MSL 300
NMR spectrometer (75 MHz). IR spectra were recorded on
Shimadzu FTIR instrument. Microanalytical data were
obtained using a Carlo-Erba CHNS-O EA 1108 elemental
analyzer. Column chromatographic separations were carried
out on silica gel (60–120 mesh) and flash chromatographic
separation was carried out using 230–400 mesh size silica
gel. Commercially available citraconic anhydride, benzyl
bromide, 2-bromopropane, bromobenzene, magnesium
turnings, HMPA, CuI, lithium hydroxide, piperidine, acetic
anhydride, NaBH4 and benzaldehyde were used.

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A. Kar et al. / Tetrahedron 61 (2005) 5297–5302
4.1.1. Dimethyl 1-buten-4-phenyl-2,3-dicarboxylate (15).
A fresh solution of benzylmagnesium bromide in ether was
prepared as follows. A solution of benzyl bromide (4.10 g,
24 mmol) in LAH–dried ether (20 mL) was added at room
temperature to magnesium turnings (1.73 g, 72 mmol) in
ether (20 mL) under argon with constant stirring in three
equal portions at an interval of 10 min. The reaction mixture
was stirred at room temperature for a further 4 h. This
freshly generated Grignard reagent was added drop wise to a
solution of HMPA (14.34 g, 80 mmol) and 14 (3.79 g,
16 mmol) in anhydrous ether (40 mL) under argon at
K20 8C and the reaction mixture was stirred at the same
temperature for a further 30 min. The reaction was
quenched by the addition of a saturated ammonium chloride
solution (50 mL). An additional quantity of ether (50 mL)
was added to the reaction mixture and the organic layer was
separated. The aqueous layer was extracted with ether
(30 mL!3), the combined ether extract was washed with
water and brine, dried with Na2SO4 and concentrated in
vacuo. The residue was chromatographed over silica gel
using petroleum ether/ethyl acetate (9.5:0.5) to give 15:
2.78 g (70% yield); thick oil; 1H NMR (CDCl3, 200 MHz) d
2.96 (dd, JZ14, 6 Hz, 1H), 3.25 (dd, JZ14, 8 Hz, 1H), 3.63
(s, 3H), 3.76 (s, 3H), 3.75–3.90 (m, 1H), 5.67 (s, 1H), 6.31
(s, 1H), 7.10–7.40 (m, 5H); 13C NMR (CDCl3, 50 MHz) d
37.3, 48.6, 51.9, 52.0, 126.3, 127.3, 128.2, 128.8, 137.5,
138.6, 166.2, 172.8; IR (CHCl3) nmax 1730, 1725,
1630 cmK1. Anal. Calcd for C14H16O4: C, 67.73; H, 6.50.
Found: C, 67.81; H, 6.44.
4.1.4. 1-Penten-4-methyl-2,3-dicarboxylic acid (23). It
was prepared similarly from 22 (2.00 g, 10 mmol) and
aqueous lithium hydroxide solution (2.40 g in 18 mL water)
as described above to obtain the corresponding dicarboxylic
1
acid 23: 1.57 g (91% yield); thick oil; H NMR (CDCl3,
200 MHz) d 0.92 (d, JZ6 Hz, 3H), 1.06 (d, JZ6 Hz, 3H),
2.05–2.35 (m, 1H), 3.40 (d, JZ10 Hz, 1H), 6.07 (s, 1H),
6.62 (s, 1H), 10.16 (bs, 2H); 13C NMR (CDCl3, 75 MHz) d
19.9, 20.8, 31.1, 52.3, 130.3, 136.7, 172.0, 179.3; IR
(CHCl3) nmax 3020, 2968, 2700–2500, 1703, 1701,
1624 cmK1. Anal. Calcd for C8H12O4: C, 55.81; H, 7.02.
Found: C, 55.73; H, 7.00.
4.1.5. 1,2-Dibromobutan-4-phenyl-2,3-dicarboxylic acid
(17). A solution of bromine (1.92 g, 12 mmol) in CCl4
(20 mL) was added dropwise to a solution of 16 (1.76 g,
8 mmol) in CCl4 (30 mL) at room temperature and the
reaction mixture was stirred for 6 h. The reaction mixture
was then concentrated in vacuo, and the residue was
dissolved in ethyl acetate (50 mL). The organic layer was
washed with saturated sodium metabisulphite, water and
brine, dried over Na2SO4 and concentrated in vacuo, to
obtain 17: 3.03 g (w100% yield); thick oil; 1H NMR
(CDCl3, 200 MHz) d 3.00–3.40 (m, 2H), 3.64 (t, JZ6 Hz,
1H), 3.85–4.25 (m, 2H), 7.00–7.60 (m, 5H), 11.01 (bs, 2H);
IR (Nujol) nmax 2700–2500, 1757, 1713, 1605 cmK1. Anal.
Calcd for C12H12Br2O4: C, 37.93; H, 3.18. Found: C, 37.97;
H, 3.11.
4.1.6. 1,2-Dibromopentan-4-methyl-2,3-dicarboxylic
acid (24). It was prepared similarly from 23 (1.38 g,
8 mmol) and bromine (1.92 g, 12 mmol) as described above
to obtain the corresponding diacid 24: 2.65 g (w100%
4.1.2. Dimethyl 1-penten-4-methyl-2,3-dicarboxylate
(22). Repetition of above procedure using 2-propylmagne-
sium bromide (prepared from 2-bromopropane (2.95 g,
24 mmol) and magnesium (1.73 g, 72 mmol)) and 14
(3.79 g, 16 mmol) gave the corresponding diester 22:
1
yield); thick oil; H NMR (CDCl3, 200 MHz) d 0.80–1.40
(m, 6H), 2.00–2.45 (m, 1H), 3.30–3.55 (m, 1H), 3.80–4.50
1
2.53 g (79% yield); thick oil; H NMR (CDCl3, 200 MHz)
(m, 2H), 8.76 (bs, 2H); IR (CHCl3) nmax 1714, 1711 cmK1
.
d 0.87 (d, JZ7 Hz, 3H), 0.97 (d, JZ7 Hz, 3H), 2.10–2.50
(m, 1H), 3.41 (d, JZ10 Hz, 1H), 3.66 (s, 3H), 3.76 (s, 3H),
5.92 (s, 1H), 6.41 (s, 1H); 13C NMR (CDCl3, 50 MHz) d
19.8, 20.7, 31.2, 51.4, 51.9, 52.3, 127.0, 137.6, 166.8, 173.3;
IR (neat) nmax 2961, 1736, 1726, 1626 cmK1. Anal. Calcd
for C10H16O4: C, 59.98; H, 8.06. Found: C, 59.93; H, 8.11.
Anal. Calcd for C8H12Br2O4: C, 28.94; H, 3.64. Found: C,
29.01; H, 3.66.
4.1.7. 2-Bromomethyl-3-benzylmaleic anhydride (19). A
solution of 17 (3.03 g, 8 mmol) in acetic anhydride (20 mL)
was gently heated at reflux for 1.5 h and the reaction
mixture was concentrated under vacuo at 50 8C. The residue
was diluted with ethyl acetate (40 mL) and the organic layer
was washed with water and brine, dried with Na2SO4 and
concentrated in vacuo to obatin 19: 2.24 g (w100% yield);
4.1.3. 1-Buten-4-phenyl-2,3-dicarboxylic acid (16). A
solution of lithium hydroxide (2.40 g in 18 mL water) was
added to a solution of 15 (2.48 g, 10 mmol) in tetrahy-
drofuran (54 mL) at room temperature and the reaction
mixture was stirred for 18 h. The reaction mixture was then
concentrated in vacuo. To the residue was added ethyl
acetate (100 mL) and then acidified to pH 2 with 2 M
hydrochloric acid. The organic layer was separated and the
aqueous layer was further extracted with ethyl acetate
(30 mL!3). The combined organic layer was washed with
water and brine, dried over Na2SO4 and concentrated in
vacuo. The residue was chromatographed over silica gel
using petroleum ether/ethyl acetate (6:4) to give 16: 2.02 g
1
thick oil; H NMR (CDCl3, 200 MHz) d 3.91 (s, 2H), 4.05
(s, 2H), 7.15–7.50 (m, 5H); 13C NMR (CDCl3, 50 MHz) d
15.9, 30.7, 127.6, 128.9, 129.1, 133.6, 139.0, 144.7, 163.6,
164.6; IR (CHCl3) nmax 1828, 1773, 1705, 1638 cmK1
.
Anal. Calcd for C12H9BrO3: C, 51.27; H, 3.23. Found: C,
51.33; H, 3.18.
4.1.8. 2-Bromomethyl-3-isopropylmaleic anhydride (26).
It was prepared similarly from 24 (2.65 g, 8 mmol) and
acetic anhydride (20 mL) as described above to obtain the
corresponding anhydride 26: 1.86 g (w100% yield); thick
1
(92% yield); thick oil; H NMR (CDCl3, 200 MHz) d 3.03
1
(dd, JZ14, 10 Hz, 1H), 3.38 (dd, JZ14, 6 Hz, 1H), 3.60–
3.75 (m, 1H), 5.61 (s, 1H), 6.42 (s, 1H), 7.00–7.40 (m, 5H),
10.6 (bs, 2H); 13C NMR (CDCl3, 50 MHz) d 36.6, 48.8,
126.6, 128.5, 128.9, 131.0, 136.4, 138.3, 171.7, 179.0; IR
(Nujol)nmax 2700–2500,1709, 1705, 1628 cmK1. Anal. Calcd
for C12H12O4: C, 65.45; H, 5.49. Found: C, 65.52; H, 5.43.
oil; H NMR (CDCl3, 300 MHz) d 1.36 (d, JZ9 Hz, 6H),
3.09 (sept, JZ9 Hz, 1H), 4.21 (s, 2H); 13C NMR (CDCl3,
75 MHz) d 15.8, 19.5, 26.7, 137.7, 151.2, 163.6, 163.7; IR
(CHCl3) nmax 1850, 1832, 1773, 1707, 1655 cmK1. Anal.
Calcd for C8H9BrO3: C, 41.23; H, 3.89. Found: C, 41.17; H,
3.85.

A. Kar et al. / Tetrahedron 61 (2005) 5297–5302
5301
4.1.9. 2,3-Dibenzylmaleic anhydride (20). A fresh solution
of phenylmagnesium bromide in ether was prepared as
follows. A solution of bromobenzene (3.93 g, 25 mmol) in
LAH–dried ether (20 mL) was added at room temperature to
magnesium turnings (1.80 g, 75 mmol) in ether (20 mL)
under argon with constant stirring in three equal portions at
an interval of 10 min. The reaction mixture was stirred at
room temperature for a further 4 h. This freshly generated
Grignard reagent was added dropwise to a solution of 19
(1.41 g, 5 mmol) and copper (I) iodide (95 mg, 0.5 mmol) in
ether (30 mL) and HMPA (10 mL) under argon at K5 to
0 8C over 15–20 min with stirring. The reaction mixture was
allowed to reach room temperature and stirred for a further
8 h. It was diluted with ether (30 mL) and acidified with 4 M
H2SO4 (30 mL), and the aqueous layer was further extracted
with ether (30 mL!3). The combined organic layer was
washed with water, brine and dried over Na2SO4 and
concentrated in vacuo. The residue was chromatographed
over silica gel using petroleum ether/ethyl acetate (9.5:0.5)
to give 20: 626 mg (45% yield); thick oil; 1H NMR (CDCl3,
200 MHz) d 3.78 (s, 4H), 7.05–7.20 (m, 4H), 7.20–7.35 (m,
6H); 13C NMR (CDCl3, 50 MHz) d 29.9, 127.1, 128.6,
chromatography using a mixture of ethyl acetate and
petroleum ether (1:17) to furnish 28 (65 mg) and 29
1
(98 mg). 28: thick oil; H NMR (CDCl3, 300 MHz) d 1.30
(d, JZ9 Hz, 6H), 2.97 (sept, JZ9 Hz, 1H), 3.77 (s, 2H),
4.49 (s, 2H), 7.15 (dd, JZ9, 3 Hz, 2H), 7.25–7.45 (m, 3H);
IR (CHCl3) nmax 1746, 1665, 1603 cmK1. Anal. Calcd for
C14H16O2: C, 77.75; H, 7.46. Found: C, 77.67; H, 7.52.
1
29: thick oil; H NMR (CDCl3, 300 MHz) d 1.11 (d, JZ
9 Hz, 6H), 3.08 (sept, JZ9 Hz, 1H), 3.63 (s, 2H), 4.73 (s,
2H), 7.10–7.40 (m, 5H); 13C NMR (CDCl3, 75 MHz) d 20.9,
27.3, 29.4, 68.7, 124.5, 126.5, 128.4, 128.6, 138.2, 166.9,
175.1; IR (CHCl3) nmax 1753, 1666, 1603 cmK1. Anal.
Calcd for C14H16O2: C, 77.75; H, 7.46. Found: C, 77.81; H,
7.53.
4.1.13. 3,4-Dibenzyl-5Z-benzylidine-5H-furan-2-one
(maculalactone B, 1). To a stirred solution of lactone 21
(200 mg, 0.76 mmol) in methanol, piperidine (0.05 mL,
0.53 mmol) and benzaldehyde (0.08 mL, 0.76 mmol) were
added at room temperature and the reaction mixture was
stirred for another 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 1: 206 mg (77% yield); mpZ102–103 8C;
1H NMR (CDCl3, 200 MHz) d 3.74 (s, 2H), 3.93 (s, 2H),
5.97 (s, 1H), 7.05–7.40 (m, 13H), 7.71 (dd, JZ6, 2 Hz, 2H);
13C NMR (CDCl3, 75 MHz) d 29.8, 30.6, 110.4, 126.7,
127.0, 127.7, 127.9, 128.2, 128.4, 128.6, 128.7, 128.8,
128.9, 129.3, 130.5, 133.1, 136.6, 137.5, 148.3, 150.7,
170.2; IR (CHCl3) nmax 1755, 1649, 1603 cmK1. Anal.
Calcd for C25H20O2: C, 85.20; H, 5.72. Found: C, 85.27; H,
5.66.
128.8, 134.9, 142.7, 165.6; IR (CHCl3) nmax 1769 cmK1
.
Anal. Calcd for C18H14O3: C, 77.68; H, 5.07. Found: C,
77.75; H, 5.14.
4.1.10. 2-Benzyl-3-isopropylmaleic anhydride (27). Rep-
etition of above procedure using phenylmagnesium bromide
(prepared from bromobenzene (3.93 g, 25 mmol) and
magnesium (1.80 g, 75 mmol)), 26 (1.17 g, 5 mmol), copper
(I) iodide (95 mg, 0.5 mmol) and HMPA (10 mL) gave
the corresponding anhydride 27: 495 mg (43% yield);
1
thick oil; H NMR (CDCl3, 300 MHz) d 1.28 (d, JZ9 Hz,
6H), 3.06 (sept, JZ9 Hz, 1H), 3.81 (s, 2H), 7.15–7.45 (m,
5H); 13C NMR (CDCl3, 75 MHz) d 20.0, 26.4, 29.8, 126.2,
127.3, 127.9, 128.6, 129.0, 135.7, 141.2, 149.1, 164.4,
165.8; IR (neat) nmax 1773, 1703, 1605 cmK1. Anal.
Calcd for C14H14O3: C, 73.03; H, 6.13. Found: C, 72.96; H,
6.07.
4.1.14. 3,4-Dibenzyl-5E-benzylidine-5H-furan-2-one
(maculalactone C, 2). A solution of 1 (100 mg) in CHCl3
(10 mL) was kept at room temperature for 8 days.
Concentration of above CHCl3 solution in vacuo furnished
1
100 mg of 50:50 mixture of 1 and 2. In H NMR (CDCl3),
the vinylic proton in 2 appeared at d 6.84. The preparative
HPLC separation of mixture of 1 and 2 is known.12
4.1.11. 3,4-Dibenzyl-5H-furan-2-one (21). To a stirred
solution of 20 (300 mg, 1.08 mmol) in THF, NaBH4
(102 mg, 2.70 mmol) was added at 0 8C and the reaction
mixture was further stirred at 0 8C for 2 h and then quenched
with water and acidified with dilute HCl and extracted with
ethyl acetate (50 mL!3). The organic layer was washed
with brine, dried with Na2SO4, concentrated in vacuo. The
residue was purified by silica gel column chromatography
using a mixture of ethyl acetate and petroleum ether (1:4) to
furnish 21: 259 mg (91% yield); thick oil; 1H NMR (CDCl3,
200 MHz) d 3.72 (s, 2H), 3.74 (s, 2H), 4.53 (s, 2H), 6.95–
7.10 (m, 2H), 7.15–7.50 (m, 8H); 13C NMR (CDCl3,
50 MHz) d 29.6, 33.5, 71.2, 126.6, 126.8, 127.2, 128.6,
128.7, 129.0, 130.1, 135.8, 138.0, 159.7, 174.6; IR (CHCl3)
nmax 1755, 1672, 1601 cmK1. Anal. Calcd for C18H16O2: C,
81.79; H, 6.10. Found: C, 81.83; H, 6.05.
4.1.15. 3,4,5-Tribenzyl-5H-furan-2-one (maculalactone
A, 3). A mixture of 1 (100 mg, 0.28 mmol) and a catalytic
amount of Pd/C in ethyl acetate (8 mL) was subjected to
hydrogenation at 65-psi hydrogen pressure for 16 h at room
temperature. The reaction mixture was filtered through
celite and the filtrate was concentrated in vacuo. The residue
was purified by silica gel column chromatography using a
mixture of ethyl acetate and petroleum ether (1:4) to furnish
3: 75 mg (75% yield); thick oil; 1H NMR (CDCl3,
300 MHz) d 2.82 (dd, JZ12, 6 Hz, 1H), 3.23 (dd, JZ12,
3 Hz, 1H), 3.48 (d, JZ15 Hz, 1H), 3.57 (d, JZ15 Hz, 1H),
3.64 (d, JZ15 Hz, 1H), 3.92 (d, JZ15 Hz, 1H), 4.94 (dd,
JZ6, 3 Hz, 1H), 6.88 (m, 2H), 7.02 (m, 2H), 7.05–7.40 (m,
11H); 13C NMR (CDCl3, 50 MHz) d 29.3, 33.1, 37.9, 81.5,
126.3, 127.1, 127.3, 128.1, 128.5 (3-carbons), 128.6, 129.0,
129.4, 134.8, 135.9, 137.6, 161.7, 173.5; IR (neat) nmax
1755, 1668, 1603 cmK1. Anal. Calcd for C25H22O2: C,
81.06; H, 5.98. Found: C, 80.93; H, 5.86.
4.1.12. 3-Isopropyl-4-benzyl-5H-furan-2-one (28) and 3-
benzyl-4-isopropyl-5H-furan-2-one (29). Repetition of
above procedure using 27 (248 mg, 1.08 mmol) and
NaBH4 (102 mg, 2.70 mmol) gave the mixture of both the
corresponding lactones (28:29Z40:60) 163 mg (70%
yield). The mixture was separated by flash column

5302
A. Kar et al. / Tetrahedron 61 (2005) 5297–5302
Tetrahedron Lett. 1977, 18, 37. (b) Pettus, J. A., Jr.; Wing,
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A. K. and S. G. thank CSIR, New Delhi, for the award of a
research fellowship. N. P. A. thanks Department of Science
and Technology, New Delhi, for financial support.
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