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Communication | Special issue | Vol. 88, No. 2, 2014, pp. 939-944
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

Pavillon Alexandre-Vachon, Department of Chemistry, Laval University, 1045 Avenue de la Médecine, Quebec City, Quebec G1V 0A6, Canada

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

On the other hand, γ−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 α−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.

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 α−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. each) and the free α−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

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,

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 γ−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.

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.


1. For some recent syntheses of maleic anhydrides and maleimides, see: (a) D. Basavaiah, B. Devendar, K. Aravindu, and A. Veerendhar, Chem. Eur. J., 2010, 16, 2031; CrossRef (b) T. Yoshimitsu, Y. Arano, T. Kaji, T. Ino, H. Nagaoka, and T. Tanaka, Heterocycles, 2009, 77, 179; CrossRef (c) S. Prateeptongkum, K. M. Driller, R. Jackstell, and M. Beller, Chem. Asian J., 2010, 5, 2173; CrossRef (d) L. Bouissane, J. P. Sestelo, and L. A. Sarandeses, Org. Lett., 2009, 11, 1285; CrossRef (e) P. S. Deore and N. P. Argade, J. Org. Chem., 2012, 77, 739; CrossRef (f) A. Cornia, F. Felluga, V. Frenna, F. Ghelfi, A. F. Parsons, M. Pattarozzi, F. Roncaglia, and D. Spinelli, Tetrahedron, 2012, 68, 5863. CrossRef
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(a) S.-C. Chien, M.-L. Chen, H.-T. Kuo, Y.-C. Tsai, B.-F. Lin, and Y.-H. Kuo, J. Agric. Food Chem., 2008, 56, 7017; CrossRef Maleimides 2 and 5 were also isolated from Antrodia salmonea: (b) C.-C. Shen, C.-F. Lin, Y.-L. Huang, S.-T. Wan, C.-C. Chen, S.-J. Sheu, Y.-C. Lin, and C.-C. Chen, J. Chin. Chem. Soc., 2008, 55, 854.
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Data for homovalencic acid (8): white powder, mp 73-75 °C (lit.15 brown powder); IR (NaCl, film): v 3030 (br), 2965, 2915, 2865, 1694, 1614, 1514, 1442, 1423, 1407, 1385, 1300, 1251, 1179, 1011, 925, 816 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.18 (d, J = 9.0 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 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); 13C NMR (125 MHz, CDCl3): δ = 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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Synthesis of Antrodin A (General Procedure): To a solution of 8 (100.7 mg, 0.457 mmol, 1.0 equiv) and α−ketoisocaproic acid (65.4 mg, 0.503 mmol, 1.1 equiv) in THF (2.5 mL), acetic anhydride (216 μL, 233.4 mg, 2.286 mmol, 5 equiv) and triethylamine (318 μL, 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 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 a fluorescent yellow oil (113.7 mg, 79 %) whose 1H and 13C NMR spectra were identical to those described in the literature12.
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 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.51 (d, J = 9.0 Hz, 2H), 7.25 (br s, 1H), 6.98 (d, J = 9.0 Hz, 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); 13C NMR (125 MHz, CDCl3): δ = 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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