Letter pubs.acs.org/OrgLett
Toward the Total Synthesis of Eurifoloid A Xin Liu,†,‡,§ Junyang Liu,‡,§ Jing Zhao,*,† Shaoping Li,*,† and Chuang-Chuang Li*,†,‡ †
Institute of Chinese Medical Sciences, University of Macau, Macao, China Department of Chemistry, South University of Science and Technology of China, Shenzhen 518055, China
‡
S Supporting Information *
ABSTRACT: Construction of the [5−7−7] tricyclic core of eurifoloid A, which contains an unusual and highly strained bicyclo[4.4.1]undecane ring system with trans-bridgehead, was attempted using a type II intramolecular [5 + 2] cycloaddition reaction and a Meinwald rearrangement reaction of the epoxide as key synthetic steps. The reported chemistry illustrates the feasibility of constructing the 8-epi-eurifoloid A framework by type II intramolecular [5 + 2] cycloaddition.
E
C5, and a tigloyloxy group at C17, which also pose considerable synthetic challenges. Besides their structural complexity, various esters of ingenane diterpenes have shown remarkable biological activity,5 ranging from antitumor5b to anti-HIV activity.5c In particular, ingenol mebutate (3, commercially available as Picato), which has an angeloyloxy group located at C3, was approved as a first-in-class topical treatment for actinic keratosis by the FDA in 2012.6 However, the relative scarcity of eurifoloid A (1), which also contains an angeloyloxy group, in natural sources has impeded a more systematic evaluation of its biological activity, and the development of an efficient synthetic process for the construction of this complex molecule is therefore highly desired. Owing to its unusual structural motifs and promising pharmacological properties, ingenol (2) has attracted considerable attention from synthetic chemists, and this has resulted in four elegant total syntheses of 2,7 one total synthesis of 13oxyingenol,8 and many synthetic approaches to the tricyclic skeleton.9 However, there are no reports in the literature to date pertaining to the synthetic study or total synthesis of eurifoloid A (1). Figure 2a shows the bond disconnections in eurifoloid A (1) that lead to the concise strategy employed in our synthetic program. It was envisioned that eurifoloid A (1) could be generated from tricyclic core 4 through a cyclopropanation reaction10 followed by a series of functional group transformations. Compound 4, which has in/out intrabridgehead stereochemistry, could be synthesized by Meinwald rearrangement11,12 of epoxide 5, which would be activated for opening with inversion of stereochemistry through a concerted [1,2]hydrogen migration, thus transferring the stereochemical configuration from the starting material to the product.12 In turn, compound 5 could be formed from 6 by stereoselective reduction and epoxidation. Compound 6, with an all-carbon
urifoloid A (1), a highly oxygenated tetracyclic diterpenoid natural product of the phorboid family, was isolated from Euphorbia neriifolia and characterized by Yue’s group in 2014 (Figure 1).1 Like that of ingenol (2),2 the structure of eurifoloid
Figure 1. Structures of eurifoloid A and ingenol.
A contains several synthetically challenging features that are found in numerous oxygenated terpenoid natural products.3 These include a congested stereogenic cis-triol segment located on the upper face from C3 to C5, two adjacent quaternary stereocenters at C4 and C10, a functionalized cyclopropane, and an unusual and highly strained bicyclo[4.4.1]undecane ring system with trans-bridgehead, which is known as in/out intrabridgehead stereochemistry4 of the BC ring system. Slightly different from ingenol, however, eurifoloid A contains an allcarbon quaternary stereocenter at C15, an angeloyloxy group at © 2017 American Chemical Society
Received: April 12, 2017 Published: May 8, 2017 2742
DOI: 10.1021/acs.orglett.7b01102 Org. Lett. 2017, 19, 2742−2745
Letter
Organic Letters
more stable E-olefin prior to cycloaddition on heating under basic conditions makes this reaction particularly challenging. In our continuing efforts toward the synthesis of biologically active natural products,15 we herein report a concise synthetic approach to the construction of the tricyclic core of eurifoloid A, which contains a bicyclo[4.4.1]undecane ring system, based on type II intramolecular [5 + 2] cycloaddition. Our synthesis began with the preparation of 9 and 14 (Scheme 1). Sequential 1,2-addition of the bromide Grignard reagent of Scheme 1. Synthesis of 6
Figure 2. (a) Retrosynthetic analysis of eurifoloid A and (b) type II intramolecular [5 + 2] cycloaddition reaction.
quaternary stereocenter, could be synthesized diastereoselectively from 7 by type II intramolecular [5 + 2] cycloaddition.13 Compound 7 could be derived from acetoxypyranone tin reagent 8 and vinyl iodide 9 by Stille coupling.14 Lastly, compounds 8 and 9 could be prepared from commercially available 4-bromofuran2-carbaldehyde (10) and 3-methoxycyclopent-2-en-1-one (11), respectively, by simple functional group transformations. The key step in our current strategy is the type II intramolecular [5 + 2] cycloaddition reaction, which was developed by our group in 2014 (Figure 2b).13 The reaction involves the oxidopyrylium ylide and simple alkene in B, which allow the efficient, diastereoselective, and direct construction of various highly functionalized and synthetically challenging bridged cycloheptane bicyclic skeletons, such as C. The acetoxy group at the allylic position of the dienophile alkene group (as in A) was found to be crucial for the high diastereoselectivity (>20:1 dr). However, the presence of the additional C13−C14 double bond within the bicyclo[4.4.1]undecane ring system of 6 will bring about more strain to the molecule, which has not previously been reported. It would be difficult to control the diastereoselectivity of the reaction of compound 7 with a methyl group at C11. Furthermore, the potential isomerization of the Zolefin at C13−C14, which is conjugated with the enone, to the
1216 to 11, followed by treatment of the resulting product with aqueous HCl, provided aldehyde 13 in 50% overall yield (25.8 g scale). Aldehyde 13 reacted cleanly with Wittig reagent Ph3PCH2I2 and KHMDS17 to give Z-vinyl iodide 9 in 70% yield (7.6 g scale). Sequential reduction and protection of 10, followed by Br−Sn exchange, gave tin reagent 14 in 80% overall yield (>20.0 g scale). Stille coupling of vinyl iodide 9 with 14 and subsequent deprotection of the TBS group in one pot gave 15 in 70% yield (5.9 g scale). Oxidative rearrangement of 15 using V(acac)2 and TBHP in DCM, followed by one-pot Bocprotection of the anomeric hydroxyl group and type II intramolecular [5 + 2] cycloaddition of 16 under 2,2,6,6tetramethylpiperidine and heating conditions, gave [5−7−7] tricyclic core-containing 6 in 30% yield over two steps, which was confirmed by X-ray crystallography (see the Supporting Information (SI) for details). Having successfully prepared tricyclic core structure 6, which contains the bicyclo[4.4.1]undecane ring system, we were eager 2743
DOI: 10.1021/acs.orglett.7b01102 Org. Lett. 2017, 19, 2742−2745
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Organic Letters
analysis of its derivative 20. Substrate-controlled stereoselective epoxidation of 19 with m-CPBA in DCM provided desired epoxide 5 in 79% yield. The structure of 5 was determined by two-dimensional NMR spectroscopy. With 5 in hand, we proceeded to investigate our proposed Meinwald rearrangement reaction for the synthesis of 4 through stereospecific intramolecular hydrogen transfer. To the best of our knowledge, there are no literature reports of a Meinwald rearrangement reaction within the bicyclo[4.4.1]undecane ring system. Moreover, under Lewis acid conditions, compound 5, which contains an α-hydroxy epoxide moiety, would potentially undergo a competitive semipinacol rearrangement19 to give unexpected products. These factors make this Meinwald rearrangement reaction particularly challenging. After extensive experimentation, we found that treatment of 5 with BF3−Et2O in DCM afforded product 4a in 60% yield as well as some unidentified byproducts (Scheme 2). At this stage, one of the remaining issues was how to establish the stereochemistry of 4a. At the beginning, we attempted to use crystallography to determine the relative stereochemistry, but we failed to obtain good quality crystals for an X-ray study. We then decided to use two-dimensional NMR spectroscopy for the structure determination (see the SI for details). Very surprisingly, the relative stereochemistry at C8 in 4a was determined to be that shown for 4b, which is the opposite of the stereochemistry of desired compound 4 (Scheme 2). This result indicates that the Meinwald rearrangement probably proceeded through an unusual stepwise mechanism instead of the expected concerted pathway. We reasoned that complex formation between BF320 and substrate 5 was critical for this rearrangement reaction. The epoxide was activated and opened to give a carbenium ion, which was stabilized by the olefin at C13−C14. The carbenium ion was subsequently quenched by a hydride from the reaction system to give 4b, which contains a less strained bicyclo[4.4.1]undecane ring system with cis-bridgehead. Also, a pathway involved an initial inversion proceeding through a Payne-type rearrangement could present an alternative possibility (see the SI for details). Further studies utilizing this reaction in total synthesis, as well as a mechanistic study, are currently underway in our laboratory. In summary, a concise synthetic approach to the construction of the [5−7−7] tricyclic core of eurifoloid A (1), which contains a bicyclo[4.4.1]undecane ring system, has been developed. This approach features a diastereoselective type II intramolecular [5 + 2] cycloaddition reaction. In particular, the four continuous stereocenters (C3, C4, C10, and C11) in 1, including a synthetically challenging bridgehead all-carbon quaternary stereocenter, have been addressed. Although the Meinwald rearrangement reaction of epoxide 5 gave the core of 8-epieurifoloid A with undesired stereochemistry, the generated information eventually allowed us to work out a new approach to the construction of the highly strained bicyclo[4.4.1]undecane ring system with trans-bridgehead of eurifoloid A, and the total synthesis of eurifoloid A is currently underway in our laboratory.
Scheme 2. Synthesis of 4b
to investigate the installation of the desired trans-intrabridgehead hydrogen at C8 in eurifoloid A (Scheme 2). We initially tried 1,4conjugated addition of 6 with Stryker’s reagent ([(PPh3)CuH]6).18 However, an inseparable 4:1 mixture of 17 and 18 was obtained, and this mixture underwent further hydrogenation to provide 18 as a single product in 98% yield. Unfortunately, the configuration of the bridgehead hydrogen at C8 in 17 was the undesired configuration; this was confirmed by X-ray crystallographic analysis of 18. Diastereoselective reduction of compound 6 with Dibal-H provided diol 19 in excellent yield (Scheme 2). The structure of 19 was unambiguously confirmed by X-ray crystallographic
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01102. Detailed experimental procedure and 1H and 13C NMR spectra (PDF) X-ray data for 6 (CIF) X-ray data for 18 (CIF) 2744
DOI: 10.1021/acs.orglett.7b01102 Org. Lett. 2017, 19, 2742−2745
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Organic Letters
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A.; Slattery, C. N.; Maguire, A. R.; McKervey, M. A. Chem. Rev. 2015, 115, 9981. (d) Chanthamath, S.; Iwasa, S. Acc. Chem. Res. 2016, 49, 2080. For cyclopropanation of olefins with disubstituted metal carbenes, see: (e) Goudreau, S. R.; Marcoux, D.; Charette, A. B. J. Org. Chem. 2009, 74, 470. (f) DeAngelis, A.; Dmitrenko, O.; Yap, G. P. A.; Fox, J. M. J. Am. Chem. Soc. 2009, 131, 7230. (g) Zhu, S. F.; Xu, X.; Perman, J. A.; Zhang, X. P. J. Am. Chem. Soc. 2010, 132, 12796. (h) Nishimura, T.; Maeda, Y.; Hayashi, T. Angew. Chem., Int. Ed. 2010, 49, 7324. (i) Lindsay, V. N. G.; Nicolas, C.; Charette, A. B. J. Am. Chem. Soc. 2011, 133, 8972. (j) Deng, C.; Wang, L. J.; Zhu, J.; Tang, Y. Angew. Chem., Int. Ed. 2012, 51, 11620. (k) Xu, X.; Zhu, S. F.; Cui, X.; Wojtas, L.; Zhang, X. P. Angew. Chem., Int. Ed. 2013, 52, 11857. (l) Xu, X.; Wang, Y.; Cui, X.; Wojtas, L.; Zhang, X. P. Chem. Sci. 2017, DOI: 10.1039/ C7SC00658F. (11) For reviews, see: (a) Rickborn, B. Acid-Catalyzed Rearrangements of Epoxides. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, U.K., 1991; p 733. (b) Wang, Z. Meinwald Rearrangement. Comprehensive Organic Name Reactions and Reagents; Wiley: Hoboken, NJ, 2010; p 1880. (c) Meinwald, J.; Labana, S. S.; Chadha, M. S. J. Am. Chem. Soc. 1963, 85, 582. For recent examples, see: (d) Robinson, M. W. C.; Davies, A. M.; Buckle, R.; Mabbett, I.; Taylor, S. H.; Graham, A. E. Org. Biomol. Chem. 2009, 7, 2559. (e) Srirambalaji, R.; Hong, S.; Natarajan, R.; Yoon, M.; Hota, R.; Kim, Y.; Ko, Y. H.; Kim, K. Chem. Commun. 2012, 48, 11650. (f) Lamb, J. R.; Jung, Y.; Coates, G. W. Org. Chem. Front. 2015, 2, 346. (g) Pandey, A. K.; Ghosh, A.; Banerjee, P. Eur. J. Org. Chem. 2015, 2015, 2517. (h) Tiddens, M. R.; Klein Gebbink, R. J. M.; Otte, M. Org. Lett. 2016, 18, 3714. (12) For representative examples of stereospecific hydride migrations, see: (a) McMurry, E.; Musser, J. H.; Ahmad, M. S.; Blaszczak, L. C. J. Org. Chem. 1975, 40, 1829. (b) Hecker, S. J.; Heathcock, C. H. J. Am. Chem. Soc. 1986, 108, 4586. (c) Trost, B. M.; Hipskind, P. A. Tetrahedron Lett. 1992, 33, 4541. (d) Mateos, A. F.; Barba, A. L.; Coca, G. P.; Gonzalez, R. R.; Hernandez, C. T. Synthesis 1997, 1997, 1381. (e) Fernandez-Mateos, A.; Martin de la Nava, E.; Pascual Coca, G.; Rubio Gonzalez, R.; Ramos Silvo, A. I.; Simmonds, M. S. J.; Blaney, W. M. J. Org. Chem. 1998, 63, 9440. (f) Suda, K.; Kikkawa, T.; Nakajima, S. i.; Takanami, T. J. Am. Chem. Soc. 2004, 126, 9554. (g) Behenna, D. C.; Stockdill, J. L.; Stoltz, B. M. Angew. Chem., Int. Ed. 2007, 46, 4077. (h) Hrdina, R.; Müller, C. E.; Wende, R. C.; Lippert, K. M.; Benassi, M.; Spengler, B.; Schreiner, P. R. J. Am. Chem. Soc. 2011, 133, 7624. (i) Paterson, I.; Xuan, M.; Dalby, S. M. Angew. Chem., Int. Ed. 2014, 53, 7286. (13) Mei, G. J.; Liu, X.; Qiao, C.; Chen, W.; Li, C. C. Angew. Chem., Int. Ed. 2015, 54, 1754. (14) (a) Stille, J. K. Angew. Chem., Int. Ed. 1986, 25, 508. (b) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J. Org. Chem. 1994, 59, 5905. (c) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748. (d) Lu, G. P.; Voigtritter, K. R.; Cai, C.; Lipshutz, B. H. Chem. Commun. 2012, 48, 8661. (15) (a) Qiao, C.; Zhang, W.; Han, J.; Li, C. C. Org. Lett. 2016, 18, 4932. (b) Han, J. C.; Li, F.; Li, C. C. J. Am. Chem. Soc. 2014, 136, 13610. (c) Liu, G.; Mei, G. J.; Chen, R.; Yuan, H.; Yang, Z.; Li, C. C. Org. Lett. 2014, 16, 4380. (d) Wei, H.; Qiao, C.; Liu, G.; Yang, Z.; Li, C. C. Angew. Chem., Int. Ed. 2013, 52, 620. (16) For preparation of 12, see: Doran, R.; Duggan, L.; Singh, S.; Duffy, C. D.; Guiry, P. J. Eur. J. Org. Chem. 2011, 2011, 7097. (17) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173. (18) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem. Soc. 1988, 110, 291. (19) (a) Kurti, L.; Czako, B. In Strategic Applications of Named Reactions in Organic Synthesis; Elsevier Academic Press: Burlington, MA, 2005; p 350. For reviews, see: (b) Coveney, D. J. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, U.K., 1991; p 777. (c) Song, Z. L.; Fan, C. A.; Tu, Y. Q. Chem. Rev. 2011, 111, 7523. (d) Wang, B. M.; Tu, Y. Q. Acc. Chem. Res. 2011, 44, 1207. (20) Fraile, J. M.; Mayoral, J. A.; Salvatella, L. J. Org. Chem. 2014, 79, 5993.
X-ray data for 20 (CIF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Chuang-Chuang Li: 0000-0003-4344-0498 Author Contributions §
X.L. and J.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank one of the reviewers for helpful discussion about the mechanism of the product 4b. This work was supported by the Natural Science Foundation of China (Grant Nos. 21672095, 21602100, 21522204, and 21472081), Guangdong Science and Technology Department (2016A050503011), the Shenzhen Science and Technology Innovation Committee (JSGG20160301103446375 and KQTD2015071710315717).
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REFERENCES
(1) Zhao, J. X.; Liu, C. P.; Qi, W. Y.; Han, M. L.; Han, Y. S.; Wainberg, M. A.; Yue, J. M. J. Nat. Prod. 2014, 77, 2224. (2) (a) Hecker, E. Cancer Res. 1968, 28, 2338. (b) Zechmeister, K.; Brandl, F.; Hoppe, W.; Hecker, E.; Opferkuch, H. J.; Adolf, W. Tetrahedron Lett. 1970, 11, 4075. (3) Hecker, E. Pure Appl. Chem. 1977, 49, 1423. (4) Winkler, J. D.; Hong, B. C.; Hey, J. P.; Williard, P. G. J. Am. Chem. Soc. 1991, 113, 8839. and references cited therein For a review of in/out isomerism, see: Alder, R. W.; East, S. P. Chem. Rev. 1996, 96, 2097. (5) (a) Hasler, C. M.; Acs, G.; Blumberg, P. Cancer Res. 1992, 52, 202. (b) Ogbourne, S. M.; Suhrbier, A.; Jones, B.; Cozzi, S. J.; Boyle, G. M.; Morris, M.; McAlpine, D.; Johns, J.; Scott, T. M.; Sutherland, K. P.; Gardner, J. M.; Le, T. T. T.; Lenarczyk, A.; Aylward, J. H.; Parsons, P. G. Cancer Res. 2004, 64, 2833. (c) Fujiwara, M.; Ijichi, K.; Tokuhisa, K.; Katsuura, K.; Shigeta, S.; Konno, K.; Wang, G. Y.; Uemura, D.; Yokota, T.; Baba, M. Antimicrob. Agents Chemother. 1996, 40, 271. (6) U.S. Food and Drug Administration, 2012 Novel New Drugs Summary (FDA, Washington, DC, 2013); www.fda.gov/downloads/ Drugs/DevelopmentApprovalProcess/DrugInnovation/UCM337830. pdf. (7) (a) Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124, 9726. (b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498. (c) Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P. D.; Greene, B.; Yusuff, N.; Wood, J. L. J. Am. Chem. Soc. 2004, 126, 16300. (d) Jørgensen, L.; McKerrall, S. J.; Kuttruff, C. A.; Ungeheuer, F.; Felding, J.; Baran, P. S. Science 2013, 341, 878. (e) McKerrall, S. J.; Jørgensen, L.; Kuttruff, C. A.; Ungeheuer, F.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 5799. (8) Ohyoshi, T.; Funakubo, S.; Miyazawa, Y.; Niida, K.; Hayakawa, I.; Kigoshi, H. Angew. Chem., Int. Ed. 2012, 51, 4972. (9) For thorough reviews of the approaches to and syntheses of ingenol, see: (a) Kim, S.; Winkler, J. D. Chem. Soc. Rev. 1997, 26, 387. (b) Kuwajima, I.; Tanino, K. Chem. Rev. 2005, 105, 4661. (c) Cha, J. K.; Epstein, O. L. Tetrahedron 2006, 62, 1329. (10) For cyclopropanation reaction reviews, see: (a) Davies, H. M. L.; Antoulinakis, E. G. Intermolecular Metal-Catalyzed Carbenoid Cyclopropanations In Organic Reaction; Overman, L. E., Ed.; John Wiley & Sons Inc., 2001; Vol. 57, p 1. (b) Lebel, H.; Marcoux, J. F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977. (c) Ford, A.; Miel, H.; Ring, 2745
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