Unified route to asymmetrically substituted butenolide, maleic anhydride, and maleimide constituents of Antrodia camphorata

Article abstract of DOI:10.1016/j.tet.2012.09.064

The first synthesis of antrocinnamomin D and a new synthesis of antrodins A and B have been achieved in 6-8 steps and high overall efficiency (51, 46, and 43%, respectively) from commercially available methyl 4-hydroxyphenylacetate. Key steps include Fuerstner-Kochi iron-catalyzed sp²-sp ³ cross-coupling and 2-silyloxyfuran oxyfunctionalization.

Full text of DOI:10.1016/j.tet.2012.09.064

Tetrahedron 68 (2012) 9592e9597
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Unified route to asymmetrically substituted butenolide, maleic anhydride, and
maleimide constituents of Antrodia camphorata
*
€
John Boukouvalas , Vincent Albert, Richard P. Loach, Raphael Lafleur-Lambert
ꢀ
ꢀ
ꢀ
Departement de Chimie, Pavillon Alexandre-Vachon, Universite Laval, 1045 Avenue de la Medecine, Quebec City, Quebec G1V 0A6, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 August 2012
Received in revised form 7 September 2012
Accepted 11 September 2012
Available online 18 September 2012
The first synthesis of antrocinnamomin D and a new synthesis of antrodins A and B have been achieved
in 6e8 steps and high overall efficiency (51, 46, and 43%, respectively) from commercially available
methyl 4-hydroxyphenylacetate. Key steps include FurstnereKochi iron-catalyzed sp2esp3 cross-
€
coupling and 2-silyloxyfuran oxyfunctionalization.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cross-coupling
Dimethyldioxirane
Furan
g-Hydroxybutenolide
Oxidation
1. Introduction
R
O
N
O
O
O
O
Antrodia camphorata is a renown parasitic fungus used in
traditional Chinese medicine for the treatment of liver cancer, drug
intoxication, hypertension, and a host of other conditions.1 The
fungus can only be found in Taiwan where it grows slowly in the
wild on the inner heartwood of the endangered native tree Cin-
namomun kanehirai. Because the fungus is difficult to cultivate for
commercial purposes and its fruiting body is hardly noticeable
unless the host tree has fallen down, fruiting bodies are extremely
rare and precious retailing at V10,000e28,000/kg.2
O
O
2 R = H (antrodin B)
3 R = OH (antrodin C)
1 (antrodin A)
R
N
Extensive investigation of A. camphorata over the past decade
has led to the isolation and characterization of an impressive array
of natural products.1 Of these, a small family of maleic anhydrides
and relatives,3e5 represented by antrodins AeC 1e33,6 and antro-
cinnamomin D 44 (Fig. 1), have garnered particular attention on
account of their diverse pharmacological effects including antitu-
mor,3,7 antiviral,8 and anti-inflammatory activities.4,5,9 For exam-
ple, anhydride 1 is a noncytotoxic, potent, and selective inhibitor of
O
OH
O
O
O
O
4 (antrocinnamomin D)
O
5 R = H (himanimide A)
6 R = OH (himanimide C)
hepatitis C virus (HCV) protease (IC50¼0.9
m
g/mL),8 whereas its
Fig. 1. Antrodins and related natural products.
maleimide counterpart 2 is devoid of anti-HCV activity but displays
strong cytotoxicity against Lewis lung carcinoma (LLC) cells.4,10
Furthermore, recent studies have revealed that 2 suppresses the
growth of estrogen-independent, highly invasive MDA-MB-231
breast cancer cells in nude mice at a dose of 3 mg/kg (ꢀ3/week,
ip) without side-effects.11 Newer members of this family, such as 4,
have been shown to inhibit the production of pro-inflammatory
mediators in macrophages (e.g., NO and IL-6),4,5 although their
limited availability has prevented more comprehensive screening.9
* Corresponding author. Tel.: þ1 418 656 5473; fax: þ1 418 656 7916; e-mail
address: john.boukouvalas@chm.ulaval.ca (J. Boukouvalas).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.064

J. Boukouvalas et al. / Tetrahedron 68 (2012) 9592e9597
9593
Understandably, the therapeutic potential and scarcity of these
2. Results and discussion
compounds have stimulated considerable interest in their synthe-
sis. Antrodins AeC have been synthesized by the groups of Argade,
Stewart, and Lee.12e14 A number of antrodin analogues have also
been prepared.13b Included in this group are the antimicrobial/
fungicidal himanimides (e.g., 5e6, Fig.1), obtained from the Chilean
fungus Serpula himantoides, and their unnatural analogues.14,15
Whereas all of the previous syntheses have targeted the anhy-
drides and maleimides, we were interested in a de novo synthetic
Our synthetic study commenced with the preparation of ester
14 from commercially available methyl 4-hydroxyphenylacetate 13
(Scheme 3). Crafting 14 into tetronic acid 15 was conveniently ac-
complished in a single operation by adaptation of a recently con-
veyed method by Le Gall.22 Thus, treatment of 14 with methyl
glycolate and t-BuOK in DMF for 50 h at rt cleanly effected tandem
transesterification/Dieckmann condensation to furnish after a sim-
ple work-up crystalline 15 in essentially quantitative yield. The next
task entailed activation of 15 for the ensuing cross-coupling re-
approach that would also provide the
g-hydroxybutenolide
antrocinnamomin D (4). The difficulties associated with the latter
target are illustrated by Clive’s synthesis of a related natural
product, namely, microperfuranone 10 (Scheme 1).16,17 Besides the
low-yielding preparation of anhydride 8 from phenylsuccinic acid
7, earlier described by Momose and Muraoka,18,19 and the equally
low-yielding transformation of 8 to furan 9, eventual oxidation of
the latter using either sodium chlorite or the Faulkner method
afforded 10 as a 1:1 mixture with its regiomer 11 (Scheme 1).16
Evidently, the lack of regioselectivity in the all-important oxida-
tion step reflects the absence of significant steric/electronic bias in
both furan 9 and its endoperoxide 12 from which 10 and 11 derive
via KornblumeDeLaMare rearrangement20 under the Faulkner
conditions.21
action. Although both
b
-tetronic acid bromides23 and triflates24
generally perform well as electrophiles, the bromides are usually
preferred since they are more robust and often highly crystalline.
Unfortunately, however, they are also notoriously difficult to pre-
pare from the corresponding tetronic acids.25e27 Accordingly we
opted for triflate 16, whose preparation from 15 proved uneventful
when carried out using Tf2O/i-Pr2NEt.28
Among the plethora of cross-coupling regimens extant, that
reported by Furstner and co-workers29 appeared best suited to our
€
needs. Notwithstanding the steric bulk of the aryl substituent po-
sitioned adjacent to the triflate group in 16, iron-catalyzed29,30
coupling with i-BuMgBr proceeded smoothly at ꢁ30 ꢂC in 15 min
to provide butenolide 17 in a reproducible yield of 67% after flash
chromatography. For the sake of comparison, we also tried the
somewhat delicate SuzukieMiyaura coupling of 16 with commer-
cial isobutylboronic acid.31,32 The best yield of 17 (55%) was realized
under Falck’s conditions33 necessitating the use of a 2.5-fold excess
of Ag2O in addition to the Pd-catalyst and a strong base (Scheme 3).
With a viable route to the antrodin skeleton, we turned our
attention to the conversion of 17 into the initial synthetic target,
antrocinnamomin D 4. Prompted by a literature report describing
O
O
O
3 steps
22%
HO C CO H
2
2
Ph
Ph
Ph
8
7
2 steps
12%
O
O
O
O
NaClO
OH
Ph
HO
O
2
+
an ostensibly simple and efficient autoxidation of the
a,b-diary-
69%
Ph
Ph
Ph
Ph
10
Ph
lbutenolide rofecoxib (VioxxÔ) to -hydroxyrofecoxib (O2/char-
g
9
11
1 : 1
coal/EtOAc, 92% yield),34 we set out to explore the possibility of
directly converting 17 to 4 under similar conditions. However, ex-
posure of an ethyl acetate solution of 17 to oxygen in the presence
of activated charcoal at rt for several days failed to give 4 in any
detectable amounts. Inclusion of DBU, known to facilitate such re-
actions,35 was to no avail. Clearly, the capacity of butenolides to
undergo autoxidation is dictated to a considerable degree by the
nature of their substitution.
(microperfuranone)
O
O
Kornblum-DeLaMare
rearrangement
O
1
H
H
O
i-Pr NEt
2
2
78%
Ph
Ph
12
Scheme 1. Clive’s synthesis of microperfuranone.16
At this point, we decided to deploy our two-step oxy-
functionalization method,36 which has displayed remarkable gen-
erality and scope.37,38 Thus, silylation of 17 with TIPSOTf/Et3N,
followed by sequential treatment of the resulting 2-silyloxyfuran 18
with dimethyldioxirane (DMDO) and a few drops of water/Amber-
lyst 15, led uniquely toantrocinnamomin D 4 (84%, two steps) whose
spectral properties were in good agreement with those reported for
As indicated in Scheme 2, our approach to such
g-hydrox-
ybutenolides (cf. H) completely eliminates this challenge. Regiospe-
cificaccessto Hwouldbegainedbyinstallingthehydroxyl grouponto
butenolideB, which would in turn arise from Ebycross-couplingwith
the appropriate nucleophile. Subsequent conversion of H to anhy-
dride (A) and then to maleimides (M) would swiftly extend the route
to the full gamut of fungal metabolites. Reported herein is the suc-
cessful implementation of this strategy to the first synthesis of
antrocinnamomin D and a new synthesis of antrodins A and B.
the natural product.4,39 Subsequent oxidation of
4
with
DesseMartin periodinane40 cleanly provided antrodin A 1 (90%),
thereby setting the stage for easy access to maleimides (cf. antrodins
B and C 2 and 3, Fig.1). Even though the latter have been synthesized
from 1 on several occasions,12e14 the reported procedures for pre-
paring 2 were deemed overly harsh (urea/135e140 ꢂC or AcONH4/
AcOH/120 ꢂC, 60e88%).12e14 Pleasingly, we were able to convert 1 to
antrodin B 2 in excellent yield (93%) by rt reaction with hexame-
thyldisilazane (HMDS) in MeOH/DMF41 (Scheme 3).
O
O
O
O
O
OH
R
O
O
R
R
Ar
B
Ar
Ar
A
H
3. Conclusion
R'
N
O
The first synthesis of antrocinnamomin D and a new synthesis of
O
O
O
+
RCH M
2
antrodins
A
and
B
have been achieved from methyl
X
Ar
4-hydroxyphenylacetate in 6e8 steps and overall yields of 51, 46,
and 43%, respectively. Besides establishing a unified, modular, and
efficient pathway to this family of fungal metabolites, the foregoing
R
Ar
E
M
Scheme 2. Unified synthetic strategy.

9594
J. Boukouvalas et al. / Tetrahedron 68 (2012) 9592e9597
CO Me
CO Me
2
2
O
O
O
O
c
O
TIPSO
O
d
e
a
b
OR
OH
13
O
O
O
14
15 R = H
16
17
18
R = Tf
O O
(DMDO)
f
H
N
+
O O
g
H O
3
h
O
O
O
OH
O
O
O
O
TIPSO
O
H
O
O
O
2
1
4
(antrodin B)
(antrodin A)
(antrocinnamomin D)
Scheme 3. Reagents and conditions: (a) Me2C]CHCH2Br, K2CO3, acetone, reflux, 17 h (97%); (b) HOCH2CO2Me, t-BuOK, DMF, rt, 50 h; (c) Tf2O, i-Pr2NEt, CH2Cl2, ꢁ40 ꢂC, 40 min (93%,
two steps); (d) method A: i-BuMgBr, Fe(acac)3 (5 mol %), NMP, THF, ꢁ30 ꢂC, 15 min (67%), method B: i-BuB(OH)2, Pd(dppf)Cl2 (10 mol %), Ag2O (2.5 equiv), K2CO3 (3.0 equiv), THF,
80 ꢂC, 16 h (55%); (e) TIPSOTf/Et3N, CH2Cl2, 0 ꢂC/rt, 1 h (86%); (f) DMDO in acetone, CH2Cl2, ꢁ78/ꢁ20 ꢂC; ca. 1 h, then Amberlyst 15/water, rt, 30 min (98%, one-pot procedure);
(g) DesseMartin periodinane, CH2Cl2, rt, 1 h (90%); (h) HMDS, MeOH/DMF, rt, 14 h (93%).
€
work highlights: (i) the value of Furstner’s iron-catalyzed cross-
coupling protocol as a practical, greener alternative to the more
mainstream Pd-catalyzed cross-coupling reactions, and (ii) the
serviceability of our oxyfunctionalization method for constructing
electrospray ionization (ESI) high-resolution mass spectra were
recorded on an Agilent 6210 TOF LC/MS instrument. Infra-red
spectra were recorded on a Bomem Arid Zone MB-series FTIR in-
strument, with samples prepared on single NaCl plates, as either
a pure film if in liquid form, or a neat layer if solid.
g
-hydroxybutenolides of predetermined substitution.
4.2. Methyl 4-prenyloxyphenylacetate (14)
4. Experimental
A
mixture of methyl 4-hydroxyphenylacetate 13 (6.83 g,
4.1. General methods
41.1 mmol, 1.0 equiv) and potassium carbonate (8.86 g, 64.1 mmol,
1.6 equiv) was stirred in freshly distilled acetone (62 mL) for 5 min,
and prenyl bromide (7.96 g, 6.17 mL, 53.8 mmol, 1.3 equiv) was
added dropwise over the course of 10 min. The resulting mixture
was refluxed for 17 h. Once TLC had indicated complete disap-
pearance of starting material, the solvent was removed under re-
duced pressure. The residue was dissolved in water and extracted
with ethyl acetate (3ꢀ100 mL). The organic layer was dried with
sodium sulfate, filtered, and concentrated in vacuo to leave a brown
oil, which was purified by flash column chromatography (15%
EtOAc/hexanes) to yield 14 as a colorless oil (9.37 g, 97% yield).
Unless otherwise indicated, all air- and/or moisture-sensitive
reactions were carried out under an argon or nitrogen atmo-
sphere in glassware that had been flame-dried under a stream of
the same inert gases. Glass syringes and stainless steel needles or
cannulae were used to transfer air- and moisture-sensitive liquids/
solutions. Sealed tube reactions were performed in Kimble KimaxÒ
thick-walled screw-cap tubes measuring 13ꢀ100 mm. Prior to use,
ꢁ
DMF was left to stand at rt for 24 h over 4 A molecular sieves that
had previously been oven-dried at 200e300 ꢂC for 3e4 days;
dichloromethane and methanol were distilled from calcium hy-
dride, acetone from calcium sulfate, and THF from sodium/aceto-
phenone. Commercial reagents were used as received except for
Rf¼0.40 (20% EtOAc/hexanes); IR (NaCl, film):
1733, 1612, 1512, 1435, 1239, 1157, 1004, 818 cmꢁ1
(400 MHz, CDCl3):
7.19 (d, J¼8.5 Hz, 2H), 6.88 (d, J¼8.5 Hz, 2H),
5.50 (t, J¼6.6 Hz, 1H), 4.49 (d, J¼6.6 Hz, 2H), 3.67 (s, 3H), 3.56 (s,
2H), 1.80 (s, 3H), 1.74 (s, 3H); 13C NMR (100 MHz, CDCl3):
172.2,
n
2975, 2952, 2873,
;
1H NMR
d
€
Hunig’s base that was distilled from KOH pellets. Reactions were
monitored by thin layer chromatography (TLC) carried out using
Merck 0.2 mm silica gel 60 F254 aluminum-backed plates. These
plates were visualized by UV light and either cerium ammonium
molybdate (CAM) or a potassium permanganate solution was used
as developing agent. Flash column chromatography was performed
using SilicycleÒ silica gel 60 (230e400 mesh). The term ‘neutralized
silica gel’ is used to describe silica gel that has been flushed three
times in the chromatography column with a mixture of hexanes/
triethylamine (95:5) before use. NMR spectra were recorded on
either an Agilent DDR spectrometer operating at 500 MHz for 1H
and 125 MHz for 13C nuclei, or a Varian Inova spectrometer oper-
ating at 400 MHz for 1H and 100 MHz for 13C nuclei; 1H and 13C
spectra are reported in parts per million (ppm) from tetrame-
thylsilane with the solvent resonance as the internal standard (1H
NMR: dH 7.260 in CDCl3, 2.050 in acetone-d6; 13C NMR: dC 77.00 in
CDCl3, 39.52 in acetone-d6). Melting points were recorded on
d
157.9, 137.8, 130.1, 125.8, 119.7, 114.6, 64.6, 51.8, 40.1, 25.7, 18.0;
HRMS (ESI): m/z calcd for C14H18O3: 234.1256; found: 234.1268.
4.3. 4-Hydroxy-3-(4-prenyloxyphenyl)-furan-2(5H)-one (15)
To a solution of ester 14 (4.00 g,17.1 mmol,1.0 equiv) and methyl
glycolate (1.60 mL, 1.87 g, 20.7 mmol, 1.2 equiv) in 80 mL of anhy-
drous DMF was slowly added 40 mL of a THF solution of potassium
tert-butoxide (1 M, 40.0 mmol, 2.3 equiv). The resulting light yel-
low suspension was stirred under argon at rt for 50 h. The reaction
mixture was then poured in one portion into 200 mL of ice cold aq
1 M HCl. The resulting suspension was subsequently kept in an ice
bath for 20 min, filtered, and the filter cake washed with ice cold aq
1 M HCl. The filter cake was then dissolved in ethyl acetate and
washed with water then brine, dried over sodium sulfate, filtered,
a
Barnstead/Thermolyne MelTempÒ Electrothermal Apparatus,

J. Boukouvalas et al. / Tetrahedron 68 (2012) 9592e9597
9595
and concentrated in vacuo. The resulting beige crystals of tetronic
acid 15 (4.44 g, 99% yield) were pure enough for utilization in the
next step. Mp 121e122.5 ꢂC; Rf¼0.38 (10% MeOH/CH2Cl2þ0.2%
0.1 equiv), powdered potassium carbonate (211.5 mg, 1.530 mmol,
3.0 equiv), and Ag2O (295.5 mg, 1.275 mmol, 2.5 equiv) in THF
(8 mL) was degassed with a flow of bubbling argon, sealed, and
then stirred under argon at 80 ꢂC. After 16 h, the mixture was
cooled to rt, then concentrated in vacuo and purified by flash col-
umn chromatography (10% EtOAc/hexanes) to afford 17 as a yellow
oil (84.8 mg, 55% yield), whose 1H and 13C NMR data were identical
to those just described (method A).
AcOH); IR (NaCl, film):
n 2925, 2871, 2696, 1695, 1652, 1608, 1425,
1394, 1293, 1253, 1172, 1052, 1003, 834, 738 cmꢁ1
(400 MHz, acetone-d6):
7.90 (d, J¼9.2 Hz, 2H), 6.92 (d, J¼9.0 Hz,
2H), 5.44 (t, J¼7.2 Hz, 1H) 4.73 (s, 2H), 4.54 (d, J¼6.8 Hz, 2H), 1.74 (s,
3H), 1.72 (s, 3H); 13C NMR (100 MHz, acetone-d6):
172.8, 171.4,
;
1H NMR
d
d
158.0, 137.0, 128.4, 123.0, 120.5, 114.3, 99.5, 65.9, 64.6, 25.1, 17.5;
HRMS (ESI): m/z calcd for C15H16O4: 260.1049; found: 260.1059.
4.6. 4-Isobutyl-3-(4-prenyloxyphenyl)-2-
triisopropylsilyloxyfuran (18)
4.4. 3-(4-Prenyloxyphenyl)-4-trifluoromethanesulfonyl-fu-
ran-2(5H)-one (16)
To a solution of butenolide 17 (61.9 mg, 0.206 mmol, 1.0 equiv) in
anhydrous dichloromethane (4 mL) that had been cooled to 0 ꢂC,
Tetronic acid 15 (30.7 mg, 0.118 mmol, 1.0 equiv) was dissolved
were added sequentially triethylamine(37.3
1.3 equiv) and triisopropylsilyl trifluoromethanesulfonate (66.5
m
L, 27.1 mg, 0.268 mmol,
in 2 mL of anhydrous dichloromethane and cooled to ꢁ40 ꢂC, at
mL,
€
which point 41.1
mL
of Hunig’s base (30.5 mg, 0.236 mmol,
75.7 mg, 0.247 mmol, 1.2 equiv). After 1 h, the mixture was poured
into aq 10% sodium bicarbonate (10 mL). The aqueous layer was
extracted twice using dichloromethane (2ꢀ15 mL) and the combined
organic layers were dried with magnesium sulfate. The mixture was
concentrated in vacuo and purified by flash column chromatography
on neutralized silica gel (100% hexanes), furnishing 18 as a colorless
oil (80.5 mg, 86% yield). Rf¼0.65 (100% hexanes); IR (NaCl, film):
2.0 equiv) was added, followed by a slow dropwise addition of
25.9 of trifluoromethanesulfonic anhydride (43.4 mg,
mL
0.154 mmol, 1.3 equiv). After 40 min at this same temperature, TLC
indicated complete disappearance of starting material, at which
point 5 mL of water was added and the temperature allowed to rise
to rt. Once the water had melted the organic layer was separated
and the aqueous layer extracted with dichloromethane (3ꢀ10 mL).
The organic layers were combined, dried over sodium sulfate, fil-
tered, and concentrated in vacuo to yield a brown oil. Purification
by flash column chromatography (10% EtOAc/hexanes) yielded
triflate 16 as a bright orange oil, which solidified when stored in the
freezer (43.8 mg, 94% yield). Mp 44 ꢂC; Rf¼0.35 (5% EtOAc/hex-
n
2946, 2868, 1651, 1609, 1575, 1516, 1464, 1404, 1289, 1238, 1174, 1035,
991, 883, 831, 688 cmꢁ1 1H NMR (400 MHz, CDCl3):
;
d
7.30 (d,
J¼9.0 Hz, 2H), 6.90(d, J¼8.8 Hz, 2H), 6.65(s,1H), 5.52(t, J¼6.8 Hz,1H),
4.52 (d, J¼7.0 Hz, 2H), 2.31 (d, J¼6.8 Hz, 2H), 1.81 (s, 3H), 1.76 (s, 3H),
1.69e1.62 (m, 1H), 1.23e1.14 (m, 3H), 1.02 (d, J¼8.0 Hz, 18H), 0.84 (d,
J¼6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3):
d 157.0, 153.1, 138.2, 129.9,
anes); IR (NaCl, film):
1248, 1224, 1142, 1002, 951, 836, 810, 764 cmꢁ1; 1H NMR (400 MHz,
CDCl3):
7.77 (d, J¼9.0 Hz, 2H), 6.99 (d, J¼9.2 Hz, 2H), 5.49 (t,
J¼6.8 Hz,1H), 5.06 (s, 2H), 4.56 (d, J¼6.8 Hz, 2H), 1.81 (s, 3H), 1.76 (s,
3H); 13C NMR (100 MHz, CDCl3):
168.9, 160.5, 157.6, 139.0, 130.0,
n
3356, 2975, 2918, 1780, 1609, 1513, 1436,
128.3, 126.1, 125.0, 120.1, 114.5, 99.1, 64.9, 34.6, 27.8, 26.1, 22.8, 18.4,
17.8, 12.5; HRMS (ESI): m/z calcd for C28H44O3Si: 456.3060; found:
456.3063.
d
d
4.7. Antrocinnamomin D (4)
119.3, 118.5 (q, JCeF¼319.7 Hz), 117.9, 117.2, 115.3, 66.1, 65.1, 26.1,
18.5; HRMS (ESI): m/z calcd for C16H15O6SF3: 392.0541; found:
392.0546.
Furan 18 (80.5 mg, 0.176 mmol, 1.0 equiv) was dissolved in an-
hydrous dichloromethane (1 mL) and cooled to ꢁ78 ꢂC, whereupon
dimethyldioxirane in acetone (6.5 mL, ca. 0.05e0.07 M)42 was
added dropwise. After 30 min, the mixture was allowed to warm to
ca. ꢁ20 ꢂC, at which point TLC (on silica plates pre-neutralized with
10% triethylamine in hexanes, elution with hexanes) showed that
all starting material was consumed. The volatiles were removed
under reduced pressure at ca. ꢁ20 ꢂC and the residue was dissolved
in acetone (3 mL), to which 10 drops of water were added along
with 15 mg of Amberlyst 15. After stirring for 30 min at rt, the so-
lution was concentrated under reduced pressure and diethyl ether
(25 mL) was added. After drying with MgSO4, filtration and removal
of the volatiles under reduced pressure, purification by flash
chromatography (30% EtOAc/hexanes) gave 4 as a white solid
(54.4 mg, 98% yield). Mp 66e68 ꢂC; Rf¼0.25 (30% EtOAc/hexanes);
4.5. 4-Isobutyl-3-(4-prenyloxyphenyl)-furan-2(5H)-one (17)
Method A: A solution of isobutylmagnesium bromide (2 M in
THF, 300 mL, 0.154 mmol, 1.2 equiv) was rapidly added to a solution
of triflate 16 (50 mg, 0.128 mmol, 1.0 equiv) and Fe(acac)3 (2.1 mg,
0.0064 mmol, 0.05 equiv) in THF (2 mL) and 1-methyl-2-
pyrrolidinone (NMP, 0.1 mL) at ꢁ30 ꢂC. There was an immediate
color change from orange-red to brown/black. The mixture was left
stirring for 15 min at that temperature before it was quenched with
aq saturated ammonium chloride (1 mL). The mixture was parti-
tioned between water (15 mL) and diethyl ether (15 mL) and was
repeatedly extracted with diethyl ether (3ꢀ15 mL). The combined
organic layers were dried over magnesium sulfate and concen-
trated in vacuo to give a brown residue. Purification by flash column
chromatography on silica gel (25% EtOAc/hexanes) gave butenolide
17 as a yellow oil (25.5 mg, 67% yield). Rf¼0.30 (15% EtOAc/hex-
IR (NaCl, film):
n
3393, 2958, 2870, 1761, 1733, 1608, 1512, 1464,
1H NMR (400 MHz, CDCl3):
1291, 1243, 1178, 1115, 994, 835 cmꢁ1
;
d
7.36 (d, J¼8.8 Hz, 2H), 6.96 (d, J¼9.2 Hz, 2H), 6.08 (s, 1H), 5.50 (t,
J¼6.4 Hz, 1H), 4.54 (d, J¼6.8 Hz, 2H), 4.33 (br s, 1H), 2.49 (d,
J¼7.6 Hz, 2H), 2.03e1.96 (m, 1H), 1.81 (s, 3H), 1.76 (s, 3H), 0.97 (d,
J¼6.8 Hz, 3H), 0.86 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
anes); IR (NaCl, film):
1385, 1290, 1242, 1178, 1127, 1037, 986, 955, 834, 780, 628 cmꢁ1; 1H
NMR (400 MHz, CDCl3):
n 2958, 2927, 2870, 1752, 1608, 1511, 1465,
d
7.37 (d, J¼8.8 Hz, 2H), 6.97 (d, J¼9.0 Hz,
d 171.9, 159.5, 159.1, 138.8, 130.6, 129.7, 121.7, 119.6, 114.9, 97.3, 65.0,
2H), 5.51 (t, J¼6.8 Hz, 1H), 4.80 (s, 2H), 4.54 (d, J¼6.8 Hz, 2H), 2.49
35.6, 27.3, 26.1, 23.6, 22.5, 18.5. HRMS (ESI): m/z calcd for C19H24O4:
316.1675; found: 316.1694.
(d, J¼7.6 Hz, 2H), 1.91e184 (m, 1H), 1.81 (s, 3H), 1.76 (s, 3H), 0.93 (d,
J¼6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3):
d 174.2, 160.3, 159.2,
138.7,130.5, 127.4,122.5, 119.7, 114.9, 71.6, 65.0, 36.9, 27.8, 26.1, 22.9,
18.5. HRMS (ESI): m/z calcd for C19H24O3: 300.1725; found:
300.1727.
4.8. Antrodin A (1)
Antrocinnamomin D 4 (37.3 mg, 0.118 mmol, 1.0 equiv) was
stirred in a glass screw-cap vial in dichloromethane (1.5 mL) at rt.
DesseMartin periodinane (0.3 M in THF, 0.472 mL, 0.142 mmol,
1.2 equiv) was added and the reaction was monitored by TLC. After
Method B: In a screw-cap sealed tube, a suspension of iso-
butylboronic acid (78.0 mg, 0.765 mmol, 1.5 equiv), triflate 16
(200 mg, 0.510 mmol, 1.0 equiv), Pd(dppf)Cl2 (41.7 mg, 0.051 mmol,

9596
J. Boukouvalas et al. / Tetrahedron 68 (2012) 9592e9597
6. Antrodins AeC are also known as camphorataanhydride A (1) and camphor-
ataimides B and C (2) and (3).
1 h, the mixture was partitioned between a saturated solution of
sodium sulfite (15 mL) and dichloromethane (20 mL). The organic
layer was then washed successively with aq saturated sodium bi-
carbonate (15 mL), then brine (15 mL) and was dried with magne-
sium sulfate. The mixture was concentrated in vacuo and the residue
subjected to flash column chromatography (8% EtOAc/hexanes) to
give 1 as a fluorescent yellow oil (33.2 mg, 90% yield). Rf¼0.50 (20%
7. Wen, C.-L.; Teng, C.-L.; Chiang, C.-H.; Chang, C.-C.; Hwang, W.-L.; Hsu, S.-L.;
Denge, J.-S.; Huang, G.-J.; Kuo, C.-L.; Hsu, S.-L. Phytomedicine 2012, 19, 424e435.
8. Phuong, D. T.; Ma, C.-M.; Hattori, M.; Jin, J. S. Phytother. Res. 2009, 23, 582e584.
9. Wen, C.-L.; Chang, C.-C.; Huang, S.-S.; Kuo, C.-L.; Hsu, S.-L.; Deng, J.-S.; Huang,
G.-J. J. Ethnopharmacol. 2011, 137, 575e584.
10. For a pharmacokinetic study of antrodins B and C, see: Liu, Y.; Di, X.; Liu, X.;
Shen, W.; Leung, K. S.-Y. J. Pharm. Biomed. Anal. 2010, 53, 781e784.
11. Lin, E.-L.; Lee, Y.-J.; Wang, S.-M.; Huang, P.-Y.; Tseng, T.-H. Eur. J. Pharmacol. 2012,
680, 8e15.
EtOAc/hexanes); IR (NaCl, film):
1506,1422,1350,1233, 1170, 994, 926, 901, 838, 824, 752, 616 cmꢁ1
1H NMR (400 MHz, CDCl3):
n 2959, 2917, 2872,1838,1764,1605,
;
12. Baag, M. M.; Argade, N. P. Synthesis 2006, 1005e1008.
d
7.62 (d, J¼8.8 Hz, 2H), 7.02 (d, J¼9.2 Hz,
13. (a) Stewart, S. G.; Polomska, M. E.; Lim, R. W. Tetrahedron Lett. 2007, 48,
2241e2244; (b) Stewart, S. G.; Ho, L. A.; Polomska, M. E.; Percival, A. T.; Yeoh, G.
C. T. ChemMedChem 2009, 4, 1657e1667.
2H), 5.50 (t, J¼6.8 Hz, 1H), 4.56 (d, J¼7.0 Hz, 2H), 2.60 (d, J¼7.2 Hz,
2H), 2.18e2.08 (m, 1H), 1.82 (s, 3H), 1.77 (s, 3H), 0.95 (d, J¼6.4 Hz,
14. Cheng, C.-F.; Lai, Z.-C.; Lee, Y.-J. Tetrahedron 2008, 64, 4347e4353.
6H); 13C NMR (100 MHz, CDCl3):
d
166.6, 165.7, 161.2, 140.4, 140.0,
ꢂ
15. (a) Selles, P. Org. Lett. 2005, 7, 605e608; (b) Basavaiah, D.; Devendar, B.; Ara-
vindu, K.; Veerendhar, A. Chem.dEur. J. 2010, 16, 2031e2035; (c) Pra-
teeptongkum, S.; Driller, K. M.; Jackstell, R.; Beller, M. Chem. Asian J. 2010, 5,
2173e2176.
139.3,131.3,120.1,119.1,115.4, 65.2, 33.8, 28.2, 26.1, 22.9,18.5; HRMS
(ESI): m/z calcd for C19H22O4: 314.1518; found: 314.1527.
16. Clive, D. L. J.; Minaruzzaman; Ou, L. J. Org. Chem. 2005, 70, 3318e3320 and
Supporting information.
17. For the isolation of microperfuranone and related fungal g-hydroxybutenolides
4.9. Antrodin B (2)
see:(a)Fujimoto, H.;Satoh, Y.;Yamaguchi, K.;Yamazaki, M.Chem.Pharm. Bull.1998,
46,1506e1510; (b) Fujimoto, H.; Asai, T.; Kim, Y.-P.; Ishibashi, M. Chem. Pharm. Bull.
2006, 54, 550e553; (c) Clark, B.; Capon, R. J.; Lacey, E.; Tennant, S.; Gill, J. H.;
Bulheller, B.; Bringmann, G. J. Nat. Prod. 2005, 68, 1226e1230 and cited refs.
18. Momose, T.; Tanabe, G.; Tsujimori, H.; Muraoka, O. Chem. Pharm. Bull. 1992, 40,
2525e2530.
19. For recent syntheses of anhydride 8, which is also a fungal metabolite, see
Ref. 15b and the following article: Baag, M. M.; Argade, N. P. Synthesis 2008,
26e28.
A solution of antrodin A 1 (23.6 mg, 0.075 mmol, 1.0 equiv) in
DMF (0.6 mL) was treated with methanol (16
mL, 12.7 mg,
0.395 mmol, 5.3 equiv) and hexamethyldisilazane (158
mL,
122.3 mg, 0.758 mmol, 10.1 equiv). After 16 h at rt, the mixture was
poured into water (50 mL) and extracted with ethyl acetate
(2ꢀ30 mL). The combined extracts were washed with water
(25 mL) and dried with magnesium sulfate. After filtration and
concentration in vacuo, the residue was purified by flash column
chromatography (15% EtOAc/hexanes), to furnish 2 as bright yellow
crystals (21.9 mg, 93% yield) that fluoresced under a UV lamp. Mp
104e105 ꢂC (lit.3 110e111 ꢂC, lit.14 104.5e105 ꢂC). Rf¼0.21 (15%
20. (a) Kornblum, N.; DeLaMare, H. E. J. Am. Chem. Soc. 1951, 73, 880e881; For
diverse synthetic applications see: (b) Jefford, C. W.; Kohmoto, S.; Rossier, J.-C.;
Boukouvalas, J. J. Chem. Soc., Chem. Commun. 1985, 1783e1784; (c) Jefford, C. W.;
Rossier, J.-C.; Boukouvalas, J. J. Chem. Soc., Chem. Commun. 1986, 1701e1702; (d)
Staben, S. T.; Linghu, X.; Toste, F. D. J. Am. Chem. Soc. 2006, 126, 12658e12659;
ꢂ
(e) Nicolaou, K. C.; Totokotsopoulos, S.; Giguere, D.; Sun, Y.-P.; Sarlah, D. J. Am.
Chem. Soc. 2011, 133, 8150e8153; (f) Buchanan, G. S.; Cole, K. P.; Tang, Y.; Hsung,
R. P. J. Org. Chem. 2011, 76, 7027e7039; (g) Tan, H.; Chen, X.; Liu, Z.; Wang, D. Z.
EtOAc/hexanes); IR (NaCl, film):
1605, 1511, 1349, 1247, 1176, 988, 837 cmꢁ1
CDCl3):
n
3287 (br), 2959, 2926, 1770, 1709,
;
1H NMR (500 MHz,
€
Tetrahedron 2012, 68, 3952e3955; (h) Palframan, M. J.; Kociok-Kohn, G.; Lewis,
S. E. Chem.dEur. J. 2012, 18, 4766e4774.
d
7.51 (d, J¼8.7 Hz, 2H), 7.37 (br s,1H), 7.00 (d, J¼8.7 Hz, 2H),
21. Kernan, M. R.; Faulkner, D. J. J. Org. Chem. 1988, 53, 2773e2776.
22. (a) Mallinger, A.; Le Gall, T.; Mioskowski, C. J. Org. Chem. 2009, 74, 1124e1129;
(b) Mallinger, A.; Le Gall, T.; Mioskowski, C. Synlett 2008, 386e388.
23. (a) Boukouvalas, J.; Lachance, N.; Ouellet, M.; Trudeau, M. Tetrahedron Lett.
1998, 39, 7665e7668; (b) Bellina, F.; Anselmi, C.; Rossi, R. Tetrahedron Lett.
2001, 42, 3851e3854; (c) Zhang, J.; Blazecka, P. G.; Belmont, D.; Davidson, J. G.
Org. Lett. 2002, 4, 4559e4561; (d) Williams, D. R.; Nold, A. L.; Mullins, R. J. J. Org.
Chem. 2004, 69, 5374e5382; (e) Boukouvalas, J.; Pouliot, M. Synlett 2005,
5.51 (t, J¼6.6 Hz, 1H), 4.56 (d, J¼6.6 Hz, 2H), 2.53 (d, J¼7.3 Hz, 2H),
2.02e2.10 (m, 1H), 1.82 (s, 3H), 1.77 (s, 3H), 0.91 (d, J¼6.7 Hz, 6H);
13C NMR (100 MHz, CDCl3):
131.1, 121.3, 119.3, 115.0, 65.0, 33.0, 29.9, 28.2, 26.0, 22.9, 18.4; HRMS
d
¼171.9, 171.2, 160.2, 139.3, 138.9, 138.8,
(ESI): m/z calcd for C19H23NO3: 313.1678; found: 313.1689.
ꢀ
€
343e345; (f) Le Vezouet, R.; White, A. J. P.; Burrows, J. N.; Barrett, A. G. M.
Acknowledgements
Tetrahedron 2006, 62, 12252e12263; (g) Chen, S.; Williams, R. W. Tetrahedron
ˇ
ꢀ
2006, 62, 11572e11579; (h) Boukouvalas, J.; Cote, S.; Ndzi, B. Tetrahedro
ˇ
n Lett.
ꢀ
ꢀ
2007, 48, 105e107; (i) Boukouvalas, J.; Beltran, P. P.; Lachance, N.; Cote, S.;
Maltais, F.; Pouliot, M. Synlett 2007, 219e222; (j) De Simone, R.; Andres, R. M.;
We thank the Natural Sciences and Engineering Research
Council of Canada (NSERC) and the FQRNT/Quebec Centre in Green
Chemistry and Catalysis (CGCC) for financial support. We also thank
NSERC and FQRNT for doctoral scholarships to R.P.L. and V.A.
respectively.
ꢀ
Aquino, M.; Bruno, I.; Guerrero, M. D.; Terencio, M. C.; Paya, M.; Riccio, R. Chem.
Biol. Drug Des. 2010, 76, 17e24; (k) Boukouvalas, J.; Albert, V. Synlett 2011,
2541e2544; (l) Zhang, R.; Iskander, G.; da Silva, P.; Chan, D.; Vignevich, V.;
Nguyen, V.; Bhadbhade, M. M.; Black, D. S.; Kumar, N. Tetrahedron 2011, 67,
~
3010e3016; (m) Barbosa, L. C. A.; Varejao, J. O. S.; Petrollino, D.; Pinheiro, P. F.;
Demuner, A. J.; Maltha, C. R. A.; Forlani, G. Arkivoc 2012, 5, 15e32.
24. (a) Grigg, R.; Kennewell, P.; Savic, V. Tetrahedron 1994, 50, 5489e5494; (b)
Honda, T.; Mizutani, H.; Kanai, K. J. Org. Chem. 1996, 61, 9374e9378; (c) Yao, M.-
L.; Deng, M.-Z. J. Org. Chem. 2000, 65, 5034e5036; (d) Molander, G. A.; St. Jean,
D. J., Jr. J. Org. Chem. 2002, 67, 3861e3865; (e) Zorn, N.; Lett, R. Tetrahedron Lett.
2006, 47, 4325e4330; (f) Clark, J. S.; Northall, J. M.; Marlin, F.; Nay, B.; Wilson,
C.; Blake, A. J.; Waring, M. J. Org. Biomol. Chem. 2008, 6, 4012e4025; (g) Bou-
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Supplementary data
1H NMR and 13C NMR spectra for all compounds synthesized (1,
2, 4, 13e18). Supplementary data associated with this article can be
found in the online version, at http://dx.doi.org/10.1016/
j.tet.2012.09.064.
27. A notable exception is the parent
-tetronic acid in >80% yield (e.g., Refs. 23a and f) by the method of Jas: Jas, G.
Synthesis 1991, 965e966.
b-bromobutenolide, routinely prepared from
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