Synthesis of gymnoascolide A

Article abstract of DOI:10.1055/s-2007-990901

Recently isolated 4-benzyl-3-phenylfuran-2,5-dione and antifungal gymnoascolide A have been synthesized using the chemoselective S _N2′ coupling of phenylmagnesium bromide with dimethyl 2-(bromomethyl)fumarate, chemoselective allylic substitution of bromide in 3-(bromomethyl)-4-phenylfuran-2,5-dione with phenylmagnesium bromide and regioselective N-Selectride-induced reduction of 3-benzyl-4-phenylfuran-2,5- dione as the key reactions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990901

26
SHORT PAPER
Synthesis of Gymnoascolide A
Synthesisof
Gymnoas
d
colide
A
. Merajuddin Baag, Narshinha P. Argade*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
E-mail: np.argade@ncl.res.in
Received 14 September 2007; revised 1 October 2007
Abstract: Recently isolated 4-benzyl-3-phenylfuran-2,5-dione and
antifungal gymnoascolide A have been synthesized using the
chemoselective SN2¢ coupling of phenylmagnesium bromide with
dimethyl 2-(bromomethyl)fumarate, chemoselective allylic substi-
tution of bromide in 3-(bromomethyl)-4-phenylfuran-2,5-dione
with phenylmagnesium bromide and regioselective N-Selectride-
induced reduction of 3-benzyl-4-phenylfuran-2,5-dione as the key
reactions.
O
O
O
O
OH
Key words: dimethyl (bromomethyl)fumarate, SN2¢ Grignard cou-
pling reaction, functionalized maleic anhydrides, regioselective re-
duction, gymnoascolide A
eutypoid A (3)4
gymnoascolide A (1)1
X
HO
O
Recently, gymnoascolides A–C (1, 2a, 2b) were isolated
from the Australian soil ascomycete Gymnoascus reessii1
and Malbranchea filamentosa IFM41300.2 3-Benzyl-4-
phenylfuran-2,5-dione was isolated from Aspergillus nid-
ulans.3 Gymnoascolides A–C possess moderate activity
against the pathogenic plant fungus Septoria nodorum.1
Gymnoascolide A also possesses vasodilatory activity
and it inhibits Ca2+-induced vasocintraction in aortic rings
pretreated with high K+ or norepinephrine.2 3-Benzyl-4-
phenylfuran-2,5-dione possesses plant growth regulatory
activity and it effectively accelerates the root elongation
of radish seedlings.3 The gymnoascolides possess a rare
structural motif, only a few examples are known in the lit-
erature such as eutypoid A (3), isolated from a south
China sea marine fungus of the genus Eutypa4 and mi-
croperfuranone (4), isolated from terrestrial fungi Anixiel-
la micropertusa5 (Figure 1).
Y
O
O
O
OH
microperfuranone (4)5
gymnoascolide B (2a, X = β-OMe, Y = OH)1
gymnoascolide C (2b, X = α-OMe, Y = OH)1
Figure 1 Naturally occurring bioactive butenolactones 1–4
tive SN2¢ coupling reaction of phenylmagnesium bromide
with 5 exclusively gave the desired dimethyl 2-methyl-
ene-3-phenylsuccinate (6) in 73% yield. The base-cata-
lyzed hydrolysis of diester 6 to diacid 7 (92%) followed
by acetic anhydride induced ring closure gave the expect-
ed anhydride 8 in nearly 100% yield. In this reaction, both
the formation of the succinic anhydride intermediate and
carbon–carbon double-bond migration took place in one
pot. The N-bromosuccinimide bromination of the allylic
carbon in the anhydride 8 furnished the required bromo
anhydride 9 in 80% yield. We did not observe any bromi-
nation of the phenyl ring under our reaction conditions.
The chemoselective allylic substitution of the bromo atom
in anhydride 9 with phenylmagnesium bromide gave 3-
benzyl-4-phenylfuran-2,5-dione (10) in 45% yield. In an-
hydride 10, one of the carbonyl groups is in conjugation
with the phenyl ring, while the other one is sterically hin-
dered because of an adjacent phenyl ring. Hence the re-
gioselective reduction of one of the carbonyls to obtain 1
is a challenging task. In our hands sodium borohydride re-
duction of anhydride 10 was not selective and we obtained
an inseparable mixture of both regioisomers in 74% yield
(ratio desired/undesired = 1:2, by 1H NMR). Fortunately,
N-Selectride regioselectively reduced the unhindered car-
bonyl in anhydride 10 at –78 °C and exclusively furnished
the natural product gymnoascolide A (1) in 90% yield.
Earlier, 3-benzyl-4-phenylfuran-2,5-dione was synthe-
sized by Momose and co-workers.6 In order to study the
structure–activity relationship of these types of natural
and unnatural molecules, a flexible synthetic approach
that will allow mono, dialkyl, allyl, benzyl, or aryl func-
tionalization of both the vinylic carbons, with the pres-
ence of several types of heteroatom in the five-membered
ring needs to be developed. In continuation of our studies
on the synthesis of structurally interesting and biological-
ly important natural and unnatural products using cyclic
anhydrides as potential precursors,7 we herein report the
synthesis of gymnoascolide A (Scheme 1).
We planned to use dimethyl (bromomethyl)fumarate (5)7d
as a potential starting material for the stepwise construc-
tion of natural product gymnoascolides. The chemoselec-
SYNTHESIS 2008, No. 1, pp 0026–0028
x
x
.
x
x
.2
0
0
7
Advanced online publication: 15.11.2007
DOI: 10.1055/s-2007-990901; Art ID: Z21407SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Synthesis of Gymnoascolide A
27
Br
O
O
O
O
OH
OMe
OMe
i
ii
MeO
HO
Ph
MeO
92%
73%
Ph
O
O
7
5
6
iii
>99%
Ph
Ph
Ph
Br
O
O
O
vi
90%
iv
v
O
O
O
O
O
80%
45%
Ph
Ph
Ph
O
O
O
1
10
9
8
Scheme 1 Reagents and conditions: (i) PhMgBr (1.50 equiv), THF, HMPA, 0 °C, 0.5 h; (ii) (a) LiOH (10.00 equiv), THF–H2O (3:1), r.t., 18
h; (b) H+/HCl; (iii) Ac2O, reflux, 1.5 h; (iv) NBS (1.50 equiv), (BzO)2 (10 mol%), CCl4, reflux, 12 h; (v) PhMgBr (5.00 equiv), THF, HMPA,
CuI, 0 °C, 8 h; (vi) N-Selectride (3.00 equiv), THF, –78 °C, 1 h.
1H NMR (200 MHz, CDCl3): d = 3.71 (s, 3 H), 3.78 (s, 3 H), 4.84
The analytical and spectral data obtained for these natural
(s, 1 H), 5.40 (s, 1 H), 6.41 (s, 1 H), 7.20–7.45 (m, 5 H).
products 10 and 1 were in complete agreement with the re-
ported data.1–3,6
13C NMR (50 MHz, CDCl3): d = 52.2, 52.4, 53.0, 127.8, 128.1,
128.8, 129.0, 135.7, 138.8, 166.7, 172.2.
In summary, we have demonstrated the synthesis of natu-
ral 3-benzyl-4-phenylfuran-2,5-dione (10) (5 steps, 24%)
and the first synthetic approach to bioactive natural prod-
uct gymnoascolide A (1) (6 steps, 22%). In the present
synthesis, the selective Grignard reagent coupling reac-
tions and N-Selectride reduction are noteworthy. We feel
that our present approach is general and will be useful to
design congeners of gymnoascolides in the search for new
lead molecules with better activity.
Anal. Calcd for C13H14O4: C, 66.65; H, 6.02. Found: C, 66.49; H,
5.88.
2-Methylene-3-phenylsuccinic Acid (7)
A soln of LiOH (2.40 g) in H2O (20 mL) was added to a soln of 6
(2.34 g, 10.00 mmol) in THF (30 mL) at r.t. and the mixture was
stirred for 18 h. The mixture was concentrated in vacuo and EtOAc
(50 mL) was added and then it was acidified to pH 2 with 2 M HCl.
The organic layer was separated and the aqueous layer was further
extracted with EtOAc (3 × 20 mL). The combined organic extracts
were washed with H2O and brine, dried (Na2SO4), and concentrated
in vacuo. The residue was chromatographed (silica gel, PE–EtOAc,
6:4) to give 7 (1.89 g, 92%) as a white solid; mp 145 °C.
IR (Nujol): 2700–2500, 1713, 1693, 1634, 1463, 1304 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.78 (s, 1 H), 5.36 (s, 1 H), 6.54
(s, 1 H), 7.25–7.50 (m, 5 H), 11.12 (br s, 2 H).
Melting points are uncorrected. 1H NMR spectra were recorded on
a Bruker AC 200 NMR spectrometer using TMS as an internal stan-
dard. 13C NMR spectra were recorded on Bruker AC 200 (50 MHz),
Bruker AC 300 (75 MHz). or Bruker AC 500 NMR spectrometers
(125 MHz). FT-IR spectra were recorded on a FT-IR-8300 Shimad-
zu spectrophotometer. Column chromatographic separations were
carried out on silica gel (60–120 mesh) eluting with petroleum ether
(PE; bp 60–80 °C) and EtOAc. Commercially available citraconic
anhydride, bromobenzene, Mg turnings, HMPA, NBS, (BzO)2,
Ac2O, and N-Selectride were used.
13C NMR (50 MHz, CDCl3): d = 53.4, 128.2, 129.1, 129.2, 130.8,
134.4, 138.6, 172.2, 178.5.
Anal. Calcd for C11H10O4: C, 64.07; H, 4.89. Found: C, 63.92; H,
5.02.
Dimethyl 2-Methylene-3-phenylsuccinate (6)
3-Methyl-4-phenylfuran-2,5-dione (8)
A fresh soln of PhMgBr in THF was prepared as follows. A soln of
bromobenzene (3.76 g, 24.00 mmol) in anhyd THF (30 mL) was
added in 3 equal portions at 10 min intervals to Mg turnings (1.73
g, 72.00 mmol) in THF (10 mL) under argon at r.t. with constant
stirring. The mixture was further stirred at r.t. for 4 h. This freshly
generated Grignard reagent was added dropwise to a soln of 5 (3.79
g, 16.00 mmol) and HMPA (14.34 g, 80.00 mmol) in anhyd THF
(30 mL) under argon at 0 °C and the mixture was stirred at this tem-
perature for 30 min. The reaction was quenched by the addition of
sat. NH4Cl soln (30 mL). EtOAc (50 mL) was added to the mixture
and the organic layer was separated. The aqueous layer was extract-
ed with EtOAc (3 × 20 mL). The combined EtOAc extracts were
washed with H2O and brine, dried (Na2SO4), and concentrated in
vacuo. The residue was chromatographed (silica gel, PE–EtOAc,
9:1) to give 6 (2.73 g, 73%) as a thick oil.
A soln of 7 (1.65 g, 8.00 mmol) in Ac2O (15 mL) was gently re-
fluxed for 1.5 h and the mixture was concentrated under vacuo at 50
°C. The residue was diluted with EtOAc (40 mL) and the organic
layer was washed with H2O and brine, dried (Na2SO4), and concen-
trated in vacuo to give 8 (1.50 g, ~100%) as a yellow solid; mp 100
°C (Lit.8 94.5 °C).
IR (Nujol): 1774, 1759, 1643, 1460, 1377 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.33 (s, 3 H), 7.50–7.58 (m, 3 H),
7.62–7.71 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 10.8, 127.4, 129.0, 129.4, 131.0,
138.7, 139.9, 164.8, 166.2.
Anal. Calcd for C11H8O3: C, 70.21; H, 4.28. Found: C, 70.10; H,
4.37.
IR (neat): 1738, 1724, 1634, 1448, 1250 cm–1.
Synthesis 2008, No. 1, 26–28 © Thieme Stuttgart · New York

28
M. M. Baag, N. P. Argade
SHORT PAPER
4-Benzyl-3-phenylfuran-2(5H)-one (Gymnoascolide A, 1)
3-(Bromomethyl)-4-phenylfuran-2,5-dione (9)
A mixture of 8 (940 mg, 5.00 mmol), NBS (1.34 g, 7.50 mmol), and
a catalytic amount of (BzO)2 (122 mg, 10 mol%) in CCl4 (50 mL)
was gently refluxed for 12 h. The mixture was left overnight at r.t.
and then filtered. The residue was washed with CCl4 (25 mL) and
the combined organic layers were washed with H2O and brine, dried
(Na2SO4), and concentrated in vacuo. The crude product was puri-
fied by column chromatography (silica gel, PE–EtOAc, 9:1) to give
9 (1.07 g, 80%) as a yellow solid; mp 72 °C.
IR (Nujol): 1761, 1636, 1601, 1512, 1460 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.35 (s, 2 H), 7.50–7.70 (m, 3 H),
7.75–7.90 (m, 2 H).
To a stirred soln of 10 (50 mg, 0.19 mmol) in anhyd THF (10 mL)
at –78 °C, was added 1 M N-Selectride in THF (0.60 mL, 0.60
mmol) over a period of 10 min. The mixture was maintained at this
temperature for 1 h. The reaction was quenched with H2O (5 mL) at
–78 °C and allowed to reach to r.t. The organic layer was separated
and the aqueous layer was extracted with EtOAc (3 × 15 mL). The
combined organic extracts were washed with H2O and brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, PE–EtOAc, 9:1) to give gym-
noascolide A (1) (42 mg, 90%) as a thick oil.
IR (CHCl3): 1751, 1655, 1522, 1215, 768 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.97 (s, 2 H), 4.70 (s, 2 H), 7.10–
7.20 (m, 2 H), 7.25–7.35 (m, 3 H), 7.40–7.60 (m, 5 H).
13C NMR (125 MHz, CDCl3): d = 34.0, 71.1, 127.4, 127.6, 128.5,
128.7, 128.8, 128.9, 129.2, 129.6, 136.1, 159.7, 173.3.
13C NMR (125 MHz, CDCl3): d = 17.9, 126.6, 129.4, 129.7, 132.1,
136.2, 141.2, 163.9 (2 C).
Anal. Calcd for C11H7O3Br: C, 49.47; H, 2.64. Found: C, 49.39; H,
2.55.
Anal. Calcd for C17H14O2: C, 81.58; H, 5.64. Found: C, 81.62; H,
5.49.
3-Benzyl-4-phenylfuran-2,5-dione (10)
A fresh soln of PhMgBr in THF was prepared as follows. A soln of
bromobenzene (785 mg, 5.00 mmol) in anhyd THF (20 mL) was
added in 3 equal portions at 10 min intervals to Mg turnings (600
mg, 25.00 mmol) in THF (5 mL) under argon at r.t. with constant
stirring. The mixture was further stirred at r.t. for 4 h. This freshly
generated Grignard reagent was added dropwise to a soln of 9 (267
mg, 1.00 mmol) and CuI (19 mg, 0.10 mmol) in THF (10 mL) and
HMPA (1 mL) under argon at 0 °C over 15–20 min with stirring.
The mixture was allowed to reach r.t. and stirred for 8 h. The mix-
ture was diluted with EtOAc (10 mL) and acidified with 2 M H2SO4
(20 mL) and the aqueous layer was further extracted with EtOAc (3
× 30 mL). The combined organic extracts were washed with H2O
and brine, dried (Na2SO4), and concentrated in vacuo. The residue
was chromatographed (silica gel, PE–EtOAc, 9.5:0.5) to give 10
(118 mg, 45%) as a white solid; mp 65 °C (Lit.3 67–68 °C).
IR (CHCl3): 1769, 1656, 1508, 1215, 758 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.04 (s, 2 H), 7.15–7.35 (m, 5 H),
7.45–7.70 (m, 5 H).
13C NMR (125 MHz, CDCl3): d = 30.4, 127.1, 127.3, 128.4, 129.0,
129.1, 129.3, 131.2, 135.4, 140.6, 141.1, 164.8, 165.8.
References
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Anal. Calcd for C17H12O3: C, 77.26; H, 4.57. Found: C, 77.13; H,
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Synthesis 2008, No. 1, 26–28 © Thieme Stuttgart · New York