Biomimetic synthesis of antrodia maleimides and maleic anhydrides

Article abstract of DOI:10.3987/COM-13-S(S)92

A simple and efficient biomimetic synthesis of Antrodia maleimides and maleic anhydrides, including the HCV protease inhibitor antrodin A, is described. The key step is a Perkin-type condensation performed under exceptionally mild conditions.

Full text of DOI:10.3987/COM-13-S(S)92

HETEROCYCLES, Vol. 88, No. 2, 2014
939
HETEROCYCLES, Vol. 88, No. 2, 2014, pp. 939 - 944. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 16th July, 2013, Accepted, 1st August, 2013, Published online, 5th August, 2013
DOI: 10.3987/COM-13-S(S)92
BIOMIMETIC SYNTHESIS OF ANTRODIA MALEIMIDES AND
MALEIC ANHYDRIDES‡
John Boukouvalas* and Vincent Albert
Département de Chimie, Pavillon Alexandre-Vachon, 1045 Avenue de la
Médecine, Université Laval, Quebec City, Quebec G1V 0A6, Canada
*E-mail: john.boukouvalas@chm.ulaval.ca
‡Dedicated to Professor Victor Snieckus on the occasion of his 77th birthday and
in recognition of his significant contributions to heterocyclic chemistry
Abstract – A simple and efficient biomimetic synthesis of Antrodia maleimides
and maleic anhydrides, including the HCV protease inhibitor antrodin A, is
described. The key step is a Perkin-type condensation performed under
exceptionally mild conditions.
The development of practical methods for constructing 3,4-disubstituted maleic anhydrides and
maleimides continues to attract a great deal of attention due to the important biological properties of
many such compouds.1 In 2004, Hattori and co-workers reported the isolation of a small family of closely
related natural products, exemplified by antrodins A-C (1-3),2 from the treasured Taiwanese medicinal
fungus Antrodia camphorata (a.k.a. Antrodia cinnamomea).3 Subsequently, in 2008 and 2013, additional
members of the antrodin family were reported (e.g. 4-7, Figure 1).4-6 Despite their simple structures, the
antrodins display a range of highly sought biological activities. Anhydride 1 is a non-cytotoxic, potent
and selective inhibitor of hepatitis C virus (HCV) protease (IC50 = 0.9 µg/mL).7 In contrast, maleimide 2
is devoid of HCV-protease inhibitory activity7 but suppresses the growth of estrogen-independent, highly
metastatic MDA-MB-231 breast cancer cells in nude mice at a dose as low as 3 mg/kg (x3/week, i.p.).8
Furthermore, newer members of this family, including 5-7, have been shown to inhibit the production of
pro-inflammatory mediators such as IL-64a and NO.5,6
So far, antrodins 1-3 have been synthesized by four groups including our own.9-12 The shortest available
route10 requires a total of six steps to assemble anhydride 1 from which the maleimides 2-3 are derived.9-12

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HETEROCYCLES, Vol. 88, No. 2, 2014
O
O
OH
O
O
O
O
O
O
O
R
N
O
X
O
HO N
O
O
O
HO
6 (antrocinnamomin D)
O
1 (antrodin A)
2 R = H (antrodin B)
3 R = OH (antrodin C)
4 X = O
5 X = NH
7 (antrocinnamomin E)
Figure 1. Representative members of the antrodin family
On the other hand, !"hydroxybutenolide 6 has only been prepared once12 through oxyfunctionalization13
of the corresponding butenolide. Our quest for a shorter route to 1-7 led us to consider the biosynthesis of
these compounds,14 thought to arise via Perkin-type condensation of #"ketoisocaproic acid (KIC) with 8
(Scheme 1). Interestingly, the only mention of 8 in the literature pertains to its isolation from a fungus,15
which somewhat increases the likelihood of being a biosynthetic precursor of 1. We now report that this
biomimetic pathway is not only realizable but provides a remarkably short and efficient synthesis of 1-3
and their congeners.
tyrosine
O
O
O
O
O
O
O
O
O
8
HO
H
HO
HO
O
O
-2 H O
2
O
O
HO
6
HO
1
OH
O
KIC
leucine
Scheme 1. Proposed biosynthesis of 1 and 6
Gram-quantities of the requisite homovalencic acid 8 were easily obtained from commercial phenol 9 by
prenylation12 and subsequent ester hydrolysis (Scheme 2).16 In a seminal study of the Perkin condensation,
Fields and co-workers have shown that this process works well for preparing 3,4-diarylmaleic anhydrides
but rather poorly when one of the aryl groups is replaced by an alkyl.17 Furthermore, a literature survey
revealed that all documented applications of the Fields method pertain to the synthesis of
diaryl-substituted maleic anhydrides.18 Unsurprisingly, initial attempts at condensing 8 with commercial
#"ketoisocaproic acid (or its potassium salt) using the Fields conditions (Ac2O, 140 °C) led only to traces
of 1 (<10%). To our delight, however, a systematic investigation of various reaction parameters enabled
an optimal procedure to be found, which consists in the use of triethylamine and acetic anhydride (5 equiv.

HETEROCYCLES, Vol. 88, No. 2, 2014
941
each) and the free !"keto acid in THF at room temperature. Under these mild conditions, antrodin A (1)
was obtained in a respectable yield of 79% after flash chromatography.19 Since the conversion of 1 to
antrodins B-C (2-3) has been reported,11,12 our route also delivers the latter in step-economical fashion.
The usefulness of this chemistry is further demonstrated by the first synthesis of the anti-inflammatory
norprenyl antrodin 5 and an exceptionally short formal synthesis9 of antrodin 4 (Scheme 2). Thus,
commercial p-methoxyphenylacetic acid (10) was transformed in a single step (72%) to anhydride 11,
which had previously been prepared by a 7-step route from citraconic anhydride (15.4% overall).9
Conversion of 11 to maleimide 1220 followed by demethylation afforded antrodin 5 (mp 202-205 °C, lit.4a
199-201 °C) whose NMR data were in good agreement with those reported for the natural product.4
O
O
1) Me2C=CHCH2Br
K2CO3 (ref. 12)
97%
OH
O
O
O
i-BuCOCO2H
aminolysis
ref. 11-12
R
N
O
2) LiOH, aq.MeOH/THF
95%
Ac2O, Et3N
THF, rt, 4 h
OMe
OH
OR
O
O
9
8
1
79%
O
O
2
3
R = H (93%)12
R = OH (82%)11
OMe
OH
OMe
O
O
O
i-BuCOCO2H
HMDS
Ac2O, Et3N
MeOH, DMF, rt
BBr3, CH2Cl2
O
HN
HN
THF, rt, 4 h
72%
-78 °C to rt
97%
92%
OH
O
O
O
10
12
5
O
11 R = Me
BBr3 (91%)9
4
R = H
Scheme 2. Short synthesis of antrodins 1-5 from commercial chemicals
With easy access to anhydride 1, its reduction to antrocinnamomin D (6) was also explored (Eq. 1). The
contrasting steric and electronic effects operating on either of the two carbonyl groups of 1 suggested that
the task of attaining good regioselectivity would be challenging.21 After screening several metal hydrides,
O
O
O
O
O
HO
O
H
(1)
O
O
+
THF, -78 °C
O
HO
O
6
13
1
NaBH
1
1
4
: 1.5 (35%)
: 2 (42%)
: 1 (43%)
4
LiAlH(t-BuO)
3
L-selectride

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HETEROCYCLES, Vol. 88, No. 2, 2014
including NaBH4, LiAlH(t-BuO)3, and K, N and L-selectride, it was found that the three selectrides gave
some selectivity in favor of 6, with the best ratio (ca. 4:1) obtained using the L-version (Eq. 1).
Nonetheless, the difficulties encountered in separating the two isomers from each other and the modest
yields of the so obtained 6/13 mixtures (35-50%) led us to abandon this approach, especially when
considering the availability of a highly efficient, regiospecific method for constructing 6 and related
#"hydroxybutenolides.12,13
In conclusion, we have described a remarkably short, biomimetic synthesis of the potent HCV protease
inhibitor antrodin A (3 steps, 73% overall), which represents a significant improvement over the previous
synthetic routes.9-12 The approach is modular, amenable to scale-up and demonstrates the serviceability of
Perkin condensation for assembling 3-alkyl-4-aryl substituted maleic anhydrides.
ACKNOWLEDGEMENTS
We thank the Natural Sciences and Engineering Research Council of Canada (NSERC) and the
Quebec-FQRNT Centre in Green Chemistry and Catalysis (CGCC) for financial support. We also thank
FQRNT for a doctoral scholarship to V.A.
REFERENCES AND NOTES
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943
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3030 (br), 2965, 2915, 2865, 1694, 1614, 1514, 1442, 1423, 1407, 1385, 1300, 1251, 1179, 1011,
1
925, 816 cm-1; H NMR (500 MHz, CDCl3): ! 7.18 (d, J = 9.0 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H),
13
5.49 (t, J = 7.0 Hz, 1H), 4.48 (d, J = 7.0 Hz, 2H), 3.58 (s, 2H), 1.79 (s, 3H), 1.74 (s, 3H); C NMR
(125 MHz, CDCl3): ! = 178.0, 158.3, 138.4, 130.5, 125.3, 119.8, 114.9, 64.9, 40.2, 26.0, 18.3;
HRMS (ESI): m/z calcd for C13H17O3 [M + H]+: 221.1172; found: 221.1172.
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19. Synthesis of Antrodin A (General Procedure): To a solution of 8 (100.7 mg, 0.457 mmol, 1.0
equiv) and !"ketoisocaproic acid (65.4 mg, 0.503 mmol, 1.1 equiv) in THF (2.5 mL), acetic
anhydride (216 "L, 233.4 mg, 2.286 mmol, 5 equiv) and triethylamine (318 "L, 231.3 mg, 2.286
mmol, 5 equiv) were successively added. After 4 h at rt, the mixture was partitioned between 40 mL
of ethyl acetate and 40 mL of water. The organic layer was separated and the aq. phase was extracted

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HETEROCYCLES, Vol. 88, No. 2, 2014
with ethyl acetate (2 x 40 mL). The combined organic phases were dried (MgSO4) and concentrated.
Purification by flash chromatography (CombiFlash, 10% EtOAc/hexanes) afforded antrodin A (1) as
1
13
a fluorescent yellow oil (113.7 mg, 79 %) whose H and C NMR spectra were identical to those
described in the literature.12
20. Data for maleimide 12: fluorescent yellow solid, mp 134-136 °C; IR (NaCl, film): v 3247 (br), 2961,
2933, 2871, 2847, 1764, 1710, 1606, 1513, 1464, 1353, 1336, 1297, 1253, 1177, 1029, 841, 825
1
cm-1; H NMR (500 MHz, CDCl3): ! 7.51 (d, J = 9.0 Hz, 2H), 7.25 (br s, 1H), 6.98 (d, J = 9.0 Hz,
13
2H), 3.86 (s, 3H), 2.51 (d, J = 7.5 Hz, 2H), 2.05 (m, 1H), 0.90 (d, J = 7.0 Hz, 6H); C NMR (125
MHz, CDCl3): ! = 171.7, 171.1, 160.8, 139.4, 138.9, 131.1, 121.4, 114.3, 55.5, 33.0, 28.3, 22.9;
HRMS (ESI): m/z calcd for C15H18NO3 [M + H]+ : 260.1281; found: 260.1280.
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