Letter Cite This: Org. Lett. 2018, 20, 1031−1033
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Enantioselective, Protecting-Group-Free Total Synthesis of Boscartin F Akinobu Matsuzawa, Junya Shiraiwa, Akihiko Kasamatsu, and Kazuyuki Sugita* Department of Synthetic Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan S Supporting Information *
ABSTRACT: In this work, the protecting-group-free total synthesis and stereochemical assignment of (−)-boscartin F have been reported. The key steps, including Sharpless asymmetric epoxidation, I2-mediated iodoetherification, aldol reaction, and ring-closing metathesis, allowed for rapid and highly stereoselective access to boscartin F. In addition, single-crystal X-ray crystallographic analysis of the semicarbazone derivative 22 confirmed the stereochemistry of boscartin F.
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NOESY and X-ray crystallographic analyses. However, the twodimensional drawing of boscartin A in the same paper has an (R) configuration at C-11 (Figure 1, 1 vs 6), and the same inconsistency also appears for other members of boscartins, such as boscartin C and F. We assume that the stereochemistry deduced from NOESY and/or X-ray analyses is more likely to be correct; therefore, the structures of 1−4 in Figure 1 were drawn based on these experimental data. One of the structural characteristics of boscartins is an oxygen bridge at C-1 and C-12 to form a tetrahydrofuran (THF) ring. Incensole (5) is the first cembranoid of this type to have been isolated from the same genus in 1967.3 Although several other incensole derivatives have been isolated since,4 to the best of our knowledge, no total synthesis of this type of natural products has been reported to date.5 We were particularly interested in the total synthesis of boscartin F because it was reported to exhibit one of the highest x-boxbinding protein 1 transcriptional activity among boscartins.2 Herein, we report a concise and protecting-group-free total synthesis of boscartin F (4). X-ray crystallographic analysis of a derivative of a synthetic intermediate not only clarified the stereochemistry at C-11 but also enabled us to assign the absolute configuration of 4. Our retrosynthetic strategy for 4 is depicted in Scheme 1. The macrocyclic skeleton of boscartin F (4) can be accessed via ring-closing metathesis (RCM) of triene 7, whose βhydroxyketone moiety can be constructed via a diastereoselective aldol reaction of aldehyde 8. In order to construct the chiral THF ring skeleton of aldehyde 8, we decided to utilize oxidant-induced cyclization of olefinic alcohol 9. Preparation of
embranoids are diterpenes that share a common 14membered ring skeleton. Hundreds of different cembranoids have been isolated and reported to exhibit a wide range of bioactivities.1 In 2015, Qin and co-workers reported the isolation of a series of new cembranoids, boscartins A−H, from the gum resin of Boswellia carterii (Figure 1, 1−4).2 The
Figure 1. Structures of selected boscartins (1−4) and incensole (5). The incorrectly drawn structure of boscartin A from ref 2 (6).
structures of these natural products, including the relative configurations, were deduced from HRMS, IR, and NMR analyses. In addition, the absolute configurations of boscartins A, B, and C were determined by X-ray crystallographic analysis, although the absolute configurations of boscartins D−H are yet to be assigned. Unfortunately, the article describing the isolation of these boscartins is inconsistent with respect to the stereochemistry at C-11. For example, the stereochemistry at C-11 for boscartin A was determined to be (S) based on © 2018 American Chemical Society
Received: December 22, 2017 Published: January 23, 2018 1031
DOI: 10.1021/acs.orglett.7b03979 Org. Lett. 2018, 20, 1031−1033
Letter
Organic Letters
instead resulted in the isolation of epoxide 14. Following these unsuccessful results, we tried haloetherification for the ring closure. To our delight, treatment of 9 with I2 and K2CO3 in THF at −78 °C produced the cyclized product 16 in 86% yield with a 7:1 diastereomeric ratio, in favor of the desired diastereomer.7 Although the origin of diastereoselectivity under these reaction conditions is not clear at this stage, we tentatively assume that the reversible nature of the formation of iodonium ion is key to the observed diastereoselectivity. As expected, the conversion of neopentyl-type iodide 16 to alcohol 15 was difficult to achieve. For example, poor yields of 15 were obtained upon treatment of 16 with an alkaline aqueous solution and this method lacked reproducibility. Furthermore, the treatment of 16 with silver salts promoted cationic rearrangement and led to the formation of a tetrahydropyran ring. After a literature survey, we found that clean conversion could be achieved by treating 16 with KO2/ 18-crown-6.8 Finally, IBX oxidation of 15 completed the stereoselective synthesis of chiral aldehyde 8. The endgame of the total synthesis of boscartin F is depicted in Scheme 4. Ester 17, which was easily prepared from βmethallyl alcohol in one step,9 was reduced by DIBAL.10 The resulting volatile aldehyde was not isolated and directly subjected to Horner−Wadsworth−Emmons olefination,11 affording α,β-unsaturated ketone 19 in 68% yield over two steps. This ketone was then deprotonated by LHMDS and
Scheme 1. Retrosynthetic Plan of Boscartin F (4)
9 can be achieved by attaching hydrocarbon chains to epoxy alcohol 10. Our synthesis commenced with the Sharpless asymmetric epoxidation of the known allylic alcohol 116 to prepare the chiral epoxy alcohol 10 (Scheme 2). In the presence of 15 mol Scheme 2. Synthesis of Chiral Alcohol 9
Scheme 4. Enantioselective Total Synthesis of Boscartin F (4)
% of Ti(OiPr)4 and 30 mol % of L-diethyl tartrate (L-DET), epoxide 10 was obtained in 72% yield and 92% ee. The thusformed epoxide was treated with vinylmagnesium bromide in the presence of a copper catalyst to afford diol 12 in 73% yield. The diol was then converted into epoxide 13 via a mesylation/ cyclization sequence, and ring opening of the resulting epoxide by methallyl magnesium bromide/CuI delivered tertiary alcohol 9. After the synthesis of alcohol 9, we investigated the diastereoselective construction of the THF ring (Scheme 3). An initial attempt to this end involved treating 9 with mCPBA at room temperature. Under these reaction conditions, cyclization proceeded smoothly via the intermediary epoxide 14, affording alcohol 15 in 64% yield as an equimolar mixture of diastereomers. Attempts at improving the diastereoselectivity by lowering the reaction temperature were unsuccessful and Scheme 3. Diastereoselective Construction of the THF Ring
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DOI: 10.1021/acs.orglett.7b03979 Org. Lett. 2018, 20, 1031−1033
Letter
Organic Letters Notes
reacted with aldehyde 8 to give the aldol adduct 7. Remarkably, the aldol reaction proceeded with essentially complete diastereoselectivity.12 Next, RCM of 7 was examined under various reaction conditions. Initially, we utilized Grubbs or Hoveyda−Grubbs second generation catalysts for RCM, but these catalysts led to low conversions and dimer formation. We assumed that a sterically less demanding catalyst would overcome the steric hindrance posed by the isopropyl group. Our assumption proved to be correct because Stewart−Grubbs catalyst 20,13 which is sterically less crowded than a Hoveyda− Grubbs second generation catalyst, showed superior reactivity. After extensive experimentation, the optimal reaction conditions were found to be 60 °C in toluene (5 mM) in the presence of catalyst 20, and desired macrocycle 21 was obtained in 55% yield.14 Fortunately, the stereochemistry of 21 could be unambiguously determined by X-ray crystallographic analysis after conversion to the corresponding semicarbazone 22 (CCDC 1810771).15 This X-ray structure confirmed that all stereogenic centers had the desired stereochemistry. Finally, epoxidation of 21 was carried out. As can be expected from the X-ray structure of 22, epoxidation of 21 by mCPBA proceeded exclusively from the β-face, and boscartin F (4) was obtained in 74% yield. Similar diastereoselectivity has been reported for the epoxidation of incensole (5), a structurally related natural product.16 All of the spectroscopic data of synthetic boscartin F were in agreement with those reported for natural boscartin F. In conclusion, an enantioselective and protecting-group-free total synthesis of boscartin F was achieved in a longest linear sequence of 10 steps from the known alcohol 11. Sharpless asymmetric epoxidation of 11 allowed for enantioselective preparation of epoxy alcohol 10, and subsequent transformations constructed the other stereogenic centers with excellent diastereoselectivity. X-ray crystallographic analysis of semicarbazone 22 not only confirmed the stereochemistry at C11 but also identified the absolute configuration of boscartin F. Total syntheses of other members of boscartins and medicinal chemistry using the established synthetic routes are ongoing in our laboratory and will be reported in due course.
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was financially supported by JSPS KAKENHI Grant Numbers JP24590136 and JP16K08180. (1) (a) Duh, C.; Wang, S.; Tseng, H.; Sheu, J.; Chiang, M. Y. J. Nat. Prod. 1998, 61, 844. (b) Su, J.; Yang, R.; Kuang, Y.; Zheng, L. J. Nat. Prod. 2000, 63, 1543. (c) Moussaieff, A.; Shohami, E.; Kashman, Y.; Fride, E.; Schmitz, M. L.; Renner, F.; Fiebich, B. L.; Munoz, E.; BenNeriah, Y.; Mechoulam, R. Mol. Pharmacol. 2007, 72, 1657. (d) Wen, T.; Ding, Y.; Deng, Z.; van Ofwegen, L.; Proksch, P.; Lin, W. J. Nat. Prod. 2008, 71, 1133. (e) Al-Lihaibi, S. S.; Alarif, W. M.; Abdel-Lateff, A.; Ayyad, S. E. N.; Abdel-Naim, A. B.; El-Senduny, F. F.; Badria, F. A. Eur. J. Med. Chem. 2014, 81, 314. (f) Martins, A. H.; Hu, J.; Xu, Z.; Mu, C.; Alvarez, P.; Ford, B. D.; El Sayed, K.; Eterovic, V. A.; Ferchmin, P. A.; Hao, J. Neuroscience 2015, 291, 250. (2) Ren, J.; Wang, Y. G.; Wang, A. G.; Wu, L. Q.; Zhang, H. J.; Wang, W. J.; Su, Y. L.; Qin, H. L. J. Nat. Prod. 2015, 78, 2322. (3) Corsano, S.; Nicoletti, R. Tetrahedron 1967, 23, 1977. (4) (a) Nicoletti, R.; Forcellese, M. L. Tetrahedron 1968, 24, 6519. (b) Forcellese, M. L.; Nicoletti, R.; Petrossi, U. Tetrahedron 1972, 28, 325. (c) Forcellese, M. L.; Nicoletti, R.; Santarelli, C. Tetrahedron Lett. 1973, 14, 3783. (d) Ma, X.; Yu, X.; Zheng, Z.; Mao, J. Chromatographia 1991, 32, 40. (5) For semisyntheses of incensole and its derivative, see: (a) Kato, T.; Yen, C. C.; Kobayashi, T.; Kitahara, Y. Chem. Lett. 1976, 5, 1191. (b) Kato, T.; Yen, C. C.; Uyehara, T.; Kitahara, Y. Chem. Lett. 1977, 6, 565. (c) Strappaghetti, G.; Proietti, G.; Corsano, S.; Grgurina, I. Bioorg. Chem. 1982, 11, 1. (6) Faulkner, A.; Scott, J. S.; Bower, J. F. J. Am. Chem. Soc. 2015, 137, 7224. (7) The stereochemistry of 16 was determined by NOE experiment. See Supporting Information for details. (8) Brimble, M.; Williams, G. M.; Baker, R.; James, M. Tetrahedron Lett. 1990, 31, 3043. (9) Green, J. C.; Brown, E. R.; Pettus, T. R. R. Org. Lett. 2012, 14, 2929. (10) Qian, H.; Han, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 9536. (11) For the synthesis of phosphonate 18, see: Tao, X.; Li, W.; Ma, X.; Li, X.; Fan, W.; Zhu, L.; Xie, X.; Zhang, Z. J. Org. Chem. 2012, 77, 8401. (12) In the literature, the stereoselectivity for the aldol reaction of αalkoxy aldehydes was rationalized by the modified Cornforth model: Evans, D. A.; Cee, V. J.; Siska, S. J. J. Am. Chem. Soc. 2006, 128, 9433. See Supporting Information for a detailed discussion. (13) (a) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs, R. H.; Schrodi, Y. Org. Lett. 2007, 9, 1589. (b) Stewart, I. C.; Douglas, C. J.; Grubbs, R. H. Org. Lett. 2008, 10, 441. (c) Stewart, I. C.; Benitez, D.; O’Leary, D. O.; Tkatchouk, E.; Day, M. W.; Goddard, W. A., III; Grubbs, R. H. J. Am. Chem. Soc. 2009, 131, 1931. (14) At higher temperatures, lower yields of 21 were obtained, most likely due to fast decomposition of catalyst 20. (15) In the ORTEP diagram of 22 (ellipsoids at the 50% probability level), most hydrogen atoms were omitted for clarity. (16) Hasegawa, T.; Kikuchi, A.; Saitoh, H.; Yamada, H. J. Essent. Oil Res. 2012, 24, 593.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03979. Detailed experimental procedures, analytical and spectral data for all new compounds (PDF) Accession Codes
CCDC 1810771 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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REFERENCES
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Kazuyuki Sugita: 0000-0001-6490-7259 1033
DOI: 10.1021/acs.orglett.7b03979 Org. Lett. 2018, 20, 1031−1033
