Letter pubs.acs.org/OrgLett
Synthesis of Spiromamakone A Benzo Analogues via Double OxaMichael Addition of 1,8-Dihydroxynaphthalene Hirokazu Tsukamoto,† Shogo Hanada,† Koichi Kumasaka,† Noritaka Kagaya,§ Miho Izumikawa,‡ Kazuo Shin-ya,§ and Takayuki Doi*,† †
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan Japan Biological Informatics Consortium (JBIC), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan § National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan ‡
S Supporting Information *
ABSTRACT: Two benzo analogues of cytotoxic spiromamakone A, comprising carbon atoms with the same oxidation state and unsaturation degree as those of the natural products, are synthesized and biologically evaluated. Substitution of α,α′-dioxoketene dithioacetals, derived from 1,3-cyclopentanediones with protected (2-formylphenyl)magnesium bromide and 1,8-dihydroxynaphthalene, followed by deprotection, generated these analogues via an intramolecular aldol reaction. The cytotoxicity of benzo analogues and synthetic intermediates against cervical carcinoma HeLa cells shows the necessity of the 4-cyclopentene-1,3dione moiety for biological activity.
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synthesis. Although Munro also reported a synthesis of the carbon skeleton of spiromamakone A, functional groups on the B ring (4-cyclopentene-1,3-dione) were neither properly arranged nor fully evaluated in biological testing.5 As a part of our ongoing research to find more potent anticancer agents,6 we independently initiated a synthetic study toward spiromamakone A. The synthesis of 1 requires an efficient method to build the naphthalene acetal located on the congested position next to the spiro carbon. Although several methods for constructing naphthalene acetals derived from acetone,7 tetralone,8 and quinone9 have been developed, they are not applicable to the acetalization of cyclopentenone.5 The ineffective acetal formation under conventional acidic conditions is ascribed to the competing oxidative autopolymerization of 1,8-dihydroxynaphthalene, leading to a black tar.10 Hence, an alternative method for constructing a naphthalene acetal under basic conditions was developed. Prior to the synthesis of the natural product 1, benzannulated spiromamakones 2 and 3, which comprise carbon atoms in the same oxidation state and with the same degree of unsaturation
piromamakone A (1), exhibiting potent cytotoxicity (IC50 0.33 μM against the murine leukemia cell line P388) and antimicrobial activity, was isolated by Munro and co-workers from an endophytic fungus of the native New Zealand tree Knightia excelsa (rewarewa) (Figure 1).1 Spiromamakone A (1)
Figure 1. Spiromamakone A and its benzo analogues.
belongs to the spirobisnaphthalene class of compounds wherein two naphthalene-derived C10 units are bridged by a spiroacetal linkage;2 however, it has a unique spiro[4,4]nonadiene skeleton resulting from the loss of one carbon atom during biosynthesis.3,4 The highly oxidized structure, which has one naphthalene acetal at C-1, one hydroxyl group at C-4, two ketones at C-6 and C-9, and two double bonds between C-2− C-3 and C-7−C-8, may not be readily accessible by means of © 2016 American Chemical Society
Received: August 5, 2016 Published: September 20, 2016 4848
DOI: 10.1021/acs.orglett.6b02328 Org. Lett. 2016, 18, 4848−4851
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Organic Letters
generated naphthalene acetal 4 in 78% yield. Bisacetal 4 underwent chemoselective hydrolysis of a 2-aryl-1,3-dioxolane moiety upon exposure to aqueous hydrochloric acid to afford dibenzo spiromamakone A (2) via an intramolecular aldol reaction in 73% yield. The structure of 2 was established by NMR experiments (see the Supporting Information). Next, the synthesis of monobenzo spiromamakone A (3) (Figure 1) was investigated. Simple substitution of the starting 1,3-indanedione in Scheme 2 with 4-cyclopentene-1,3-dione would not be appropriate for the above route as a result of the latter compound’s high susceptibility to Michael addition. Thus, dioxoketene dithioacetal 11, derived from 1,3-cyclopentanedione (10), was chosen as the starting material; this compound could be oxidized to 4-cyclopentene-1,3-dione in the later stages of the synthesis (Scheme 3). The cyclic dioxoketene
as those of 1, were chosen as the target molecules (Figure 1). The retrosynthesis of dibenzo analogue 2 is shown in Scheme 1. This analogue should be in equilibrium with the ring-opened Scheme 1. Retrosynthesis of Dibenzo Analogue 2
Scheme 3. Synthesis of Spiromamakone A Monobenzo Analogue 3
isomer 2′,1 which can be prepared by acid-catalyzed chemoselective hydrolysis of 1,3-dioxolane 4. The naphthalene acetal moiety in 4 can be generated by the double oxa-Michael addition11 of 1,8-dihydroxynaphthalene (5) to the vinylogous thioester 6 under basic conditions. Sulfide 6 can be prepared by an addition−elimination reaction12 between cyclic α,α′dioxoketene dithioacetal 813 and arylmagnesium bromide 7.14 Oxidation of the sulfide group in 6 may help the oxa-Michael reaction with 5. Our preliminary synthetic study on spiromamakone A commenced with preparation of dibenzo analogue 2 (Scheme 2). The addition−elimination reaction between Grignard Scheme 2. Synthesis of Spiromamakone A Dibenzo Analogue 2
dithioacetal 11 readily underwent an addition−elimination reaction with arylmagnesium bromide 7 to give the vinylogous thioester 12 in excellent yield. Again, the following double oxaMichael addition of 5 necessitated oxidation of the sulfide in 12. However, oxidation of 12 with m-CPBA led to the formation of a triketone via hydrolysis of the resulting sulfone. In order to realize the reactivity between sulfide and sulfone, sulfoxide 13 was employed as the Michael acceptor. Oxidation of 12 to sulfoxide 13 was achieved by treatment with Selectfluor in aqueous acetonitrile in the presence of sodium bicarbonate.16 Owing to its instability, sulfoxide 13 was immediately used for the next oxa-Michael addition of 5 after aqueous workup and subsequent short-path silica gel column chromatography. The oxa-Michael addition of 5 to 13 under the same reaction conditions used for the conversion of 9 to 4 (Scheme 2) and acid hydrolysis of 1,3-dioxolane provided aldol
reagent 7 and dioxoketene dithioacetal 8, derived from 1,3indanedione, proceeded well to afford sulfide 6 in high yield. The vinylogous thioester 6 was found to be inert to the next double oxa-Michael addition of 1,8-dihydroxynaphthalene (5). Oxidation of sulfide 6 to sulfone 9 with m-CPBA was required to generate a suitable Michael acceptor.15 The double oxaMichael addition of 5 in the presence of potassium carbonate 4849
DOI: 10.1021/acs.orglett.6b02328 Org. Lett. 2016, 18, 4848−4851
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Organic Letters 15 in moderate yield. Among several reagents investigated for oxidation of 1,3-cyclopentanedione to 4-cyclopentene-1,3dione (CuBr2, PdCl2, PhSeCl, DDQ, Bobbitt’s salt, NBS, Br2, and PhNMe3Br3),17 only trimethylphenylammonium tribromide transformed 15 into 3. Unfortunately, the reproducibility of the reaction was low. Eventually, we found that protection of the hydroxyl group in 15 with an acetyl group and deprotection under acidic conditions before and after the oxidation, respectively, were necessary to ensure good reproducibility. The cytotoxicity of authentic spiromamakone A (1) isolated from the extract of cultured spiromamakone producing strain, its benzo analogues 2 and 3, and their synthetic intermediates 15, 16, and 17 against cervical carcinoma HeLa cells was evaluated (Table 1). While dibenzo anaologue 2 was
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compd
IC50 (μM)
1 2 3 4 5 6
1 2 3 15 16 17
0.77 >25 0.56 >25 18.4 4.4
*E-mail:
[email protected]. Fax: +81 22 795 6864. Tel: +81 22 795 6865. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was partly supported by the Suntry Foundation for Life Sciences and Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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REFERENCES
(1) van der Sar, S. A.; Blunt, J. W.; Munro, M. H. G. Org. Lett. 2006, 8, 2059−2061. (2) Cai, Y.-S.; Guo, Y.-W.; Krohn, K. Nat. Prod. Rep. 2010, 27, 1840− 1870. (3) After isolation of 1, natural products with a naphthalene acetal on a cyclopentene or benzocyclopentene ring were found in natural produts: (a) Chen, X.; Shi, Q.; Lin, G.; Guo, S.; Yang, J. J. Nat. Prod. 2009, 72, 1712−1715. (b) Shan, T.; Tian, J.; Wang, X.; Mou, Y.; Mao, Z.; Lai, D.; Dai, J.; Peng, Y.; Zhou, L.; Wang, M. J. Nat. Prod. 2014, 77, 2151−2160. (4) van der Sar, S. A.; Lang, G.; Mitova, M. I.; Blunt, J. W.; Cole, A. L. J.; Cummings, N.; Ellis, G.; Munro, M. H. G. J. Org. Chem. 2008, 73, 8635−8638. (5) Murphy, A. C.; Devenish, S. R. A.; Muscroft-Taylor, A. C.; Blunt, J. W.; Munro, M. H. G. Org. Biomol. Chem. 2008, 6, 3854−3862. (6) Fuse, S.; Inaba, K.; Takagi, M.; Tanaka, M.; Hirokawa, T.; Johmoto, K.; Uekusa, H.; Shin-ya, K.; Takahashi, T.; Doi, T. Eur. J. Med. Chem. 2013, 66, 180−184. (7) Maiti, B. C.; Musgrave, O. C.; Skoyles, D. Tetrahedron 2005, 61, 1765−1771. See also ref 3. (8) (a) Ragot, J. P.; Alcaraz, M.-L.; Taylor, R. J. K. Tetrahedron Lett. 1998, 39, 4921−4924. (b) Ragot, J. P.; Steeneck, C.; Alcaraz, M.-L.; Taylor, R. J. K. J. Chem. Soc., Perkin Trans. 1 1999, 1073−1082. (c) Barrett, A. G. M.; Hamprecht, D.; Meyer, T. Chem. Commun. 1998, 809−810. (d) Barrett, A. G. M.; Blaney, F.; Campbell, A. D.; Hamprecht, D.; Meyer, T.; White, A. J. P.; Witty, D.; Williams, D. J. J. Org. Chem. 2002, 67, 2735−2750. (e) Inoue, M.; Nabatame, K.; Hirama, M. Heterocycles 2003, 59, 87−92. (9) (a) Wipf, P.; Jung, J.-K. J. Org. Chem. 1999, 64, 1092−1093. (b) Wipf, P.; Jung, J.-K. J. Org. Chem. 2000, 65, 6319−6337. (c) Wipf, P.; Jung, J.-K.; Rodríguez, S.; Lazo, J. S. Tetrahedron 2001, 57, 283− 296. (d) Wipf, P.; Lynch, S. M. Org. Lett. 2003, 5, 1155−1158. (e) Wipf, P.; Lynch, S. M.; Birmingham, A.; Tamayo, G.; Jiménez, A.; Campos, N.; Powis, G. Org. Biomol. Chem. 2004, 2, 1651−1658. (f) Coutts, I. G. C.; Allcock, R. W.; Scheeren, H. W. Tetrahedron Lett. 2000, 41, 9105−9107. (g) Krohn, K.; Wang, S.; Ahmed, I.; Altun, S.; Aslan, A.; Flörke, U.; Kock, I.; Schlummer, S. Eur. J. Org. Chem. 2010, 4476−4481. (10) (a) Allport, D. C.; Bu’Lock, J. D. J. Chem. Soc. 1958, 4090− 4094. (b) Allport, D. C.; Bu’Lock, J. D. J. Chem. Soc. 1960, 654−662. (11) Nising, C. F.; Bräse, S. Chem. Soc. Rev. 2012, 41, 988−999. (12) (a) Yugandar, S.; Misra, N. C.; Parameshwarappa, G.; Panda, K.; Ila, H. Org. Lett. 2013, 15, 5250−5253. (b) Huang, X.; Chen, B. Synthesis 1987, 1987, 480−481. (13) (a) Hirano, M.; Kawaminami, E.; Toyoshima, A.; Moritomo, H.; Seki, N.; Wakayama, R.; Okada, M.; Kusayama, T. Patent US2003/ 191164 A1, 2003. (b) Verma, R. K.; Ila, H.; Singh, M. S. Tetrahedron 2010, 66, 7389−7398.
completely inactive, monobenzo analogue 3 was equipotent to spiromamakone A (entries 1−3). The importance of the enedione moiety in 1 and 3 for cytotoxicity was also supported by the observation that saturation of the olefin in 3 caused a significant drop in activity (entry 3 vs 4). Their acetates showed a similar tendency, with 4-cyclopentene-1,3-dione 17 exhibiting greater potency than 1,3-cyclopentanedione 16 (entry 5 vs 6); both were equal or inferior in cytotoxicity to the parent alcohols 3 and 15. These results indicate that the 4cyclopentene-1,3-dione moiety (B ring) in 1 is much more important for cytotoxicity than the 2-cyclopenten-1-ol unit (A ring). In summary, we have demonstrated the synthesis of two benzo analogues of spiromamakone A (1), which consist of carbon atoms in the same oxidation state and with the same degree of unsaturation as those of 1. Construction of the naphthalene acetals was achieved by double oxa-Michael addition of 1,8-dihydroxynaphthalene to appropriately oxidized vinylogous thioesters 6 and 12, which were readily prepared by addition−elimination reactions between Grignard reagent 7 and cyclic α,α′-dioxoketene dithioacetals 8 and 11, respectively. A structure−activity relation study of the synthesized compounds proved that the readily accessible monobenzo analogue 3 was equipotent to natural product 1 and that the 4cyclopentene-1,3-dione moiety was essential for the cytotoxicity. Furthermore, spiromamakone A analogues can be obtained by substitution of the nucleophiles, i.e., Grignard reagent and diol, in the short-step synthesis. The synthesis of spiromamakone A using an acrolein β-anion equivalent18 instead of 7 is underway.
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AUTHOR INFORMATION
Corresponding Author
Table 1. Cytotoxicity of Compounds 1−3 and 15−17 against Cervical Carcinoma HeLa Cells entry
Detailed experimental procedures, spectroscopic data, and NMR spectra (PDF)
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.6b02328. 4850
DOI: 10.1021/acs.orglett.6b02328 Org. Lett. 2016, 18, 4848−4851
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Organic Letters (14) Tomcufcik, A. S.; Wright, W. B., Jr.; Meyer, W. E. U.S. Patent 4,892,885, Jan 9, 1990. (15) The sulfoxide variant of 6 reluctantly underwent the double oxaMichael addition of 5 to give 4 in 26% yield. The conjugated benzene ring in the sulfoxide variant would lower the electron-withdrawing property of the adjacent carbonyl groups. See the Supporting Information. (16) (a) Vincent, S. P.; Burkart, M. D.; Tsai, C.-Y.; Zhang, Z.; Wong, C.-H. J. Org. Chem. 1999, 64, 5264−5279. Also see reviews on Selectfluor: (b) Stavber, S. Molecules 2011, 16, 6432−6464. (c) Stavber, S.; Zupan, M. Acta Chim. Slov. 2005, 52, 13−26. (d) Nyffeler, P. T.; Durón, S. G.; Burkart, M. D.; Vincent, S. P.; Wong, C.-H. Angew. Chem., Int. Ed. 2005, 44, 192−212. (e) Singh, R. P.; Shreeve, J. M. Acc. Chem. Res. 2004, 37, 31−44. (f) Banks, R. E. J. Fluorine Chem. 1998, 87, 1−17. (17) CuBr2: (a) Kreiser, W.; Wiggermann, A.; Krief, A.; Swinnen, D. Tetrahedron Lett. 1996, 37, 7119−7122. PdCl2: (b) Parker, K. A.; Koziski, K. A.; Breault, G. Tetrahedron Lett. 1985, 26, 2181−2182. PhSeCl: (c) Billington, S.; Mann, J.; Quazi, P.; Alexander, R.; Eaton, M. A. W.; Millar, K.; Millican, A. Tetrahedron 1991, 47, 5231−5236. DDQ: (d) Liu, P.-Y.; Wu, Y.-J; Pye, C. C.; Thornton, P. D.; Poirier, R. A.; Burnell, D. J. Eur. J. Org. Chem. 2012, 2012, 1186−1194. Bobbitt’s salt: (e) Eddy, N. A.; Kelly, C. B.; Mercadante, M. A.; Leadbeater, N. E.; Fenteany, G. Org. Lett. 2012, 14, 498−501. NBS: (f) Agosta, W. C.; Smith, A. B., III J. Org. Chem. 1970, 35, 3856−3860. Br2: (g) Evans, J. C.; Klix, R. C.; Bach, R. D. J. Org. Chem. 1988, 53, 5519− 5527. PhNMe3Br3: (h) Schultz, A. G.; Motyka, L. A.; Plummer, M. J. Am. Chem. Soc. 1986, 108, 1056−1064. (18) (a) Chinchilla, R.; Nájera, C. Chem. Rev. 2000, 100, 1891−1928. (b) Katritzky, A. R.; Piffl, M.; Lang, H.; Anders, E. Chem. Rev. 1999, 99, 665−722.
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