Letter pubs.acs.org/OrgLett
Formal Total Synthesis of (±)-Lycojaponicumin C Nan Zheng,† Lijie Zhang,† Jianxian Gong,*,† and Zhen Yang*,†,‡ †
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China ‡ Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National Laboratory for Molecular Science (BNLMS), and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China S Supporting Information *
ABSTRACT: The formal total synthesis of (±)-lycojaponicumin C has been accomplished. Key transformations include a Rh-catalyzed formal [3 + 2] cycloaddition reaction to construct the bicyclic [3.3.0] scaffold bearing two vicinal quaternary carbon centers, a stereoselective γ-hydroxyl directed Michael addition to introduce the vinyl group at a bulky position, and a late-stage ring-closing metathesis reaction to form the cyclohexanone ring.
O
ver the past decade, the Lycopodium alkaloids have provided a large number of interesting bioactive natural products, which have attracted significant attention from both chemical and biological communities.1,2 Lycojaponicumin C (1), a fawettimine-type Lycopodium alkaloid, was isolated from the traditional Chinese medicine, Lycopodium japonicum, along with lycojaponicumin A and B, by Yu et al. in 2012 (Figure 1).3
Bicyclic [3.3.0] and [4.3.0] ring systems with two vicinal stereogenic quaternary carbon centers at the ring junction have been observed in a wide variety of intriguing natural products exhibiting important biological activities.4 Given the significance of these structures, considerable progress has been made over the past two decades, allowing for the development of new therapeutic agents and drugs.5 Our group has been interested in the syntheses of natural products bearing vicinal quaternary carbon centers, and we have developed a Rh-catalyzed formal [3 + 2] cycloaddition reaction of an enyne precursor to access this synthetically challenging structure. We have successfully applied this method to the synthesis of (+)-lingzhiol and the tetracyclic core structure of retigeranic acid A.6 Based on our previous studies, the retrosynthetic analysis of the total synthesis of lycojaponicumin C (1) is delineated in Scheme 1. We envisioned that the D ring of 1 could be formed through ring-closing metathesis (RCM) and a subsequent double bond migration from diene 4. The vinyl group in 4 could be generated through an OHdirected Michael addition of enone 5. We planned to install the
Figure 1. Lycojaponicums A−C and the [3.3.0] core skeleton.
Scheme 1. Retrosynthetic Analysis
In vitro biological testing shows that lycojaponicumin C exhibits moderate inhibition toward lipopolysaccharide (LPS)induced pro-inflammatory factors, but is inactive against acetylcholinesterase, which is the most common bioactivity of the majority of Lycopodium alkaloids.3 Structurally, Lycojaponicumin C (1) features a fused 6/5/5/ 6 tetracyclic skeleton composing a bicyclic [3.3.0] core with four continuous stereocenters, two of which are unprecedented vicinal quaternary carbon centers (Figure 1). These features make 1 an interesting and challenging target for total synthesis. In 2013, Tu and co-workers reported the first enantioselective total synthesis of Lycojaponicumin C (1) starting from (R)(+)-pulegone using a Cu-induced intramolecular carbene addition/cyclization and Truji−Trost type allylation as key reactions.2g © 2017 American Chemical Society
Received: April 17, 2017 Published: May 22, 2017 2921
DOI: 10.1021/acs.orglett.7b01154 Org. Lett. 2017, 19, 2921−2924
Letter
Organic Letters protected piperidine ring A via a cascade Staudinger−reductive amination of keto-azide 6. Finally, the functionalized core 7 bearing the bicyclic [3.3.0] ring system (B, C rings) could be synthesized through our previously developed Rh-catalyzed formal [3 + 2] cycloaddition reaction from enyne 8, which could be synthesized from commercially available starting material ethyl 9. The synthesis starts with the preparation of enyne 8 as described in Scheme 2.
then achieved by treatment with MsCl/Et3N, and the resultant mesylate was reacted with sodium azide via an SN2 substitution reaction to finish 15 in 90% yield over two steps. Subsequent DMP oxidation of 15 afforded the corresponding ketone derivative 6 in 84% yield. We then investigate the formation of the piperidine ring adopting a strategy developed by Tu’s group,2g featuring a Staudinger−reductive amination.9 To this end, the azide in 6 was reduced with Ph3P (Scheme 4), and resultant iminophos-
Scheme 2. Synthesis of the Bicyclic Framework 7 with Two Vicinal Quaternary Carbon Centers
Scheme 4. Synthesis of Compound 20
Based on our previous procedure in the total synthesis of (+)-lingzhiol, enyne 10 was generated from 9 in decagram scale through Waser alkynylation and Luche reduction.6a Riley oxidation of 10 gave diol 11 in 60% yield as a single diastereomer, which can be rationalized using transition state 10a.7 After a selective TBS protection, the key reaction precursor 8 was prepared in gram scale. With precursor 8 in hand, the stage was set to test the ability of the Rh-catalyzed formal [3 + 2] cycloaddition to stereospecifically forge two vicinal stereogenic quaternary carbon centers and generate the BC rings in compound 7. To our delight, when 8 was treated with [RhCl(CO)2]2 (5 mol %) under a balloon pressure of CO at 85 °C for 20 h, the desired bicyclic [3.3.0] aldehyde 7 was obtained in 88% yield as a single diastereomer. This single operation successfully built up the congested part of the molecule and retained functional groups for further transformations. With the key intermediate 7 in hand, we started to prepare compound 13 via a double-Wittig reaction8 (Scheme 3). Thus, after reaction of 7 with a Wittig reagent followed by hydrolysis twice, aldehyde 13 was obtained in 57% yield over the two steps. Further treatment of aldehyde 13 with NaBH4 in MeOH followed by desilylation afforded diol 14 in 90% yield over two steps. Selective mesylation of the primary alcohol in diol 14 was
phorane10 was then condensed with its ketone at C9, followed by reduction with NaBH3CN, in which the hydride might approach from the less hindered bottom-face to give amine 16 as a single diastereomer.2k The amine, which was not purified due to its instablility on silica gel, was protected with TsCl/ Et3N to give 17 in 70% yield over three steps. We next focused on the installation of the C5-carbonyl group in substrate 5 (Scheme 4). An earlier effort attempting a direct installation of an oxygen at the C5 position of 17 via an allylic oxidation failed, and several oxidative agents (such as SeO2, CrO3, TBHP)11 were tested. To achieve this allylic oxidation, the ester in 17 was reduced to its corresponding primary alcohol using LiAlH4, and the resultant primary alcohol was protected as its silyl ether 18 in 88% yield over two steps. Using Thomson’s one-pot allylic bromination−Kornblum oxidation conditions,12 silyl ether 18 was first subjected to treatment of NBS followed by AgBF4 to introduce the C5 oxygen. The resulting product then underwent a desilylation to afford compound 5 in 65% yield over three steps. With 5 in hand, we then investigated the stereoselective synthesis of the challenging intermediate 20. Aside from the obvious difficulties posed by the high steric demand of the C ring bearing two vicinal quaternary bridged-head carbons in 20, the unique challenge associated with the stereoselective formation of 19 bearing a sterically hindered C7 stereogenic center had to be addressed. Initial attempts to construct 19 from 5 through a conventional Lewis acid mediated vinylcopper reagent13 failed to afford the desired product. However, application of a γ-OH directed 1,4-addition developed by White’s group gave the desired product 19 in 60% yield (74% brsm).14 The observed stereochemical outcome of 19 could be
Scheme 3. Introduction of the Nitrogen Functionality
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Letter
Organic Letters
center; and (iv) RCM and double bond migration to afford the core structure of lycojaponicumin C. On the basis of the current research, the asymmetric total syntheses of 1 and other related natural products are currently underway in our laboratory.
attributed to the formed reactive ternary ate complex 5a, which delivers the vinyl group to C7 from its top face. Thus, aldehyde 20 was obtained in 77% yield after oxidation of the resultant primary alcohol via Ley oxidation.15 The structure of 20 was unambiguously identified by X-ray crystallographic analysis.16 Having established all four continuous stereocenters, we began to develop an approach for the construction of the cyclohexanone D ring of Lycopodium alkaloids via the RCM reaction. Aldehyde 20 was reacted with (2-methylallyl)magnesium chloride to afford diene 4 as a pair of diastereomers (Scheme 5), which underwent an RCM reaction catalyzed by
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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.7b01154. Experimental procedures, characterization for new compounds including 1H and 13C NMR spectra (PDF) X-ray crystallographic data for 20 (CIF)
Scheme 5. Formal Synthesis of (±)-Lycojaponicumin C
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Zhen Yang: 0000-0001-8036-934X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the NSF of China (Grant Nos. 21372016 and 21402002), National 863 Program (2013AA090203), 973 Program (2012CB722602), and NSFC-Shandong Joint Fund for Marine Science Research Centers (U1406402).
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REFERENCES
(1) For reviews of the Lycopodium alkaloids, see: (a) Ma, X.; Gang, D. R. Nat. Prod. Rep. 2004, 21, 752. (b) Kobayashi, J.; Morita, H. The Lycopodium Alkaloids. In The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.; Academic Press: New York, 2005; Vol. 61, pp 1− 57. (c) Hirasawa, Y.; Kobayashi, J.; Morita, H. Heterocycles 2009, 77, 679. (d) Siengalewicz, P.; Mulzer, J.; Rinner, U. Lycopodium Alkaloids: Synthetic Highlights and Recent Developments. In The Alkaloids: Chemistry and Biology; Knölker, H.-J., Ed.; Academic Press: New York, 2013; Vol. 72, pp 1−151. (e) Murphy, R. A.; Sarpong, R. Chem. - Eur. J. 2014, 20, 42. (2) For recent reports of total synthesis of the fawcettimine-type Lycopodium alkaloids, see: (a) Kozak, J. A.; Dake, G. R. Angew. Chem., Int. Ed. 2008, 47, 4221. (b) Jung, M. E.; Chang, J. Org. Lett. 2010, 12, 2962. (c) Ramharter, J.; Weinstabl, H.; Mulzer, J. J. Am. Chem. Soc. 2010, 132, 14338. (d) Nakayama, A.; Kogure, N.; Kitajima, M.; Takayama, H. Angew. Chem., Int. Ed. 2011, 50, 8025. (e) Pan, G.; Williams, R. M. J. Org. Chem. 2012, 77, 4801. (f) Li, H.; Wang, X.; Lei, X. Angew. Chem., Int. Ed. 2012, 51, 491. (g) Hou, S.-H.; Tu, Y.-Q.; Liu, L.; Zhang, F.-M.; Wang, S.-H.; Zhang, X.-M. Angew. Chem., Int. Ed. 2013, 52, 11373. (h) Ochi, Y.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2016, 18, 1494. (i) Williams, B. M.; Trauner, D. Angew. Chem., Int. Ed. 2016, 55, 2191. (j) Hartrampf, F. W. W.; Furukawa, T.; Trauner, D. Angew. Chem., Int. Ed. 2017, 56, 893. (k) Ge, M. H.; Zhang, L.-D.; Tan, R. X.; Yao, Z. J. J. Am. Chem. Soc. 2012, 134, 12323. (3) (a) Wang, X.-J.; Zhang, G.-J.; Zhuang, P.-Y.; Zhang, Y.; Yu, S.-S.; Bao, X.-Q.; Zhang, D.; Yuan, Y.-H.; Chen, N.-H.; Ma, S.-G.; Qu, J.; Li, Y. Org. Lett. 2012, 14, 2614. (b) Wang, X.-J.; Liu, Y. B.; Li, L.; Yu, S.S.; Lv, H. N.; Ma, S.-G.; Bao, X. Q.; Zhang, D.; Qu, J.; Li, Y. Org. Lett. 2012, 14, 5688. (4) (a) Anke, T.; Heim, J.; Knoch, F.; Mocek, D.-C. U.; Steffan, b.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1985, 24, 709. (b) Boeckman,
Grubbs’ second generation catalyst17 followed by a DMPoxidation to afford product 21 as a single diastereoisomer in 63% yield over two steps. To complete the total synthesis of lycojaponicumin C, 21 was subjected to a double bond migration under acidic conditions18 to give product 22 in 92% yield. However, the selective removal of the Ts in substrate 22 in the presence of an α,β-unsaturated double bond proved to be problematic. Various conditions were attempted, including conventional Nanaphthalene and Mg-methanol detosylation conditions; however, only decomposition of 22 was observed. To solve this issue, we used 21 as the substrate for the Nanaphthalene-mediated detosylation.19 To this end, 21 was treated with Na in the presence of naphthalene in DME, and the resulting piperidine anion was protected with Cbz by treatment with Z-OSU (N-(benzyloxycarbonyloxy)succinimide) to give product 23 with in situ double bond isomerization. The overall yield for this one-pot reaction was 51% yield. Compound 23 is the key intermediate in the total synthesis of lycojaponicumin C by Tu’s group.2g In conclusion, we have completed a formal total synthesis of (±)-lycojaponicumin C (1). The key features include (i) a Rhcatalyzed formal [3 + 2] cycloaddition reaction to build the bicyclic [3.3.0] framework with two vicinal quaternary carbon centers; (ii) a Staudinger−reductive amination cascade to construct the piperidine ring A; (iii) OH-directed intramolecular Michael addition to furnish the continuous stereo2923
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Organic Letters R. K., Jr; Blum, D. M.; Arnold, E. V.; Clardy, J. Tetrahedron Lett. 1979, 20, 4609. (5) For reviews, see: (a) Long, R.; Huang, J.; Gong, J.; Yang, Z. Nat. Prod. Rep. 2015, 32, 1584. (b) Buschleb, M.; Dorich, S.; Hanessian, S.; Tao, D.; Schenthal, K. B.; Overman, L. E. Angew. Chem., Int. Ed. 2016, 55, 4156. (c) Peterson, E. A.; Overman, L. E. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 11943. For recent synthetic examples, see: (d) Zhang, Y.; Danishefsky, S. J. J. Am. Chem. Soc. 2010, 132, 9567. (e) Kikushima, K.; Holder, J. C.; Gatti, M.; Stoltz, B. M. J. Am. Chem. Soc. 2011, 133, 6902. (f) Levin, S.; Nani, R. R.; Reisman, S. E. J. Am. Chem. Soc. 2011, 133, 774. (g) Weiss, M. E.; Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50, 11501. (h) Jeker, O. F.; Carreira, E. M. Angew. Chem., Int. Ed. 2012, 51, 3474. (i) Michels, T. D.; Dowling, M. S.; Vanderwal, C. D. Angew. Chem., Int. Ed. 2012, 51, 7572. (j) Belmar, J.; Funk, R. L. J. Am. Chem. Soc. 2012, 134, 16941. (k) Lu, P.; Gu, Z.; Zakarian, A. J. Am. Chem. Soc. 2013, 135, 14552. (l) King, S. M.; Calandra, N. A.; Herzon, S. B. Angew. Chem., Int. Ed. 2013, 52, 3642. (m) Trost, B. M.; Osipov, M. Angew. Chem., Int. Ed. 2013, 52, 9176. (n) Goetz, A. E.; Silberstein, A. E.; Corsello, M. A.; Garg, N. K. J. Am. Chem. Soc. 2014, 136, 3036. (o) Zou, Y.; Melvin, J. E.; Gonzales, S. S.; Spafford, M. J.; Smith, A. B., III J. Am. Chem. Soc. 2015, 137, 7095. (p) Ellerbrock, P.; Armanino, N.; Ilg, M. K.; Webster, R.; Trauner, D. Nat. Chem. 2015, 7, 879. (q) Ting, C. P.; Xu, G.; Zeng, X.; Maimone, T. J. J. Am. Chem. Soc. 2016, 138, 14868. (r) Hou, S.-H.; Tu, Y.-Q.; Wang, S.-H.; Xi, C.-C.; Zhang, F.-M.; Wang, S.-H.; Li, Y.-T.; Liu, L. Angew. Chem., Int. Ed. 2016, 55, 4456. (s) Li, Y.; Zhu, S.; Li, J.; Li, A. J. Am. Chem. Soc. 2016, 138, 3982. (t) Cernijenko, A.; Risgaard, N.; Baran, P. S. J. Am. Chem. Soc. 2016, 138, 9425. (u) Gong, J.; Chen, H.; Liu, X.-Y.; Wang, Z.-X.; Nie, W.; Qin, Y. Nat. Commun. 2016, 7, 12183. (v) Liang, X.; Zhang, T.-Y.; Zeng, X.-Y.; Zheng, Y.; Wei, K.; Yang, Y.-R. J. Am. Chem. Soc. 2017, 139, 3364. For recent developed methodologies: (w) Hernández-Linares, M. G.; Guerrero-Luna, G.; Pérez-Estrada, S.; Ellison, M.; Ortin, M. M.; Garcia-Garibay, M. A. J. Am. Chem. Soc. 2015, 137, 1679. (x) Yu, X.; Hu, J.; Shen, Z.; Zhang, H.; Gao, J. M.; Xie, W. Angew. Chem., Int. Ed. 2017, 56, 350. (6) (a) Long, R.; Huang, J.; Shao, W.; Liu, S.; Lan, Y.; Gong, J.; Yang, Z. Nat. Commun. 2014, 5, 5707. (b) Zhang, J.; Wang, X.; Li, S.; Li, D.; Liu, S.; Lan, Y.; Gong, J.; Yang, Z. Chem. - Eur. J. 2015, 21, 12596. (c) Qi, X.; Liu, S.; Zhang, T.; Long, R.; Huang, J.; Gong, J.; Yang, Z.; Lan, Y. J. Org. Chem. 2016, 81, 8306. (7) Shi, H.; Tan, C.; Zhang, W.; Zhang, Z.; Long, R.; Luo, T.; Yang, Z. Org. Lett. 2015, 17, 2342. (8) Xu, W.; Wu, S.; Zhou, L.; Liang, G. Org. Lett. 2013, 15, 1978. (9) Sha, C.-K.; Chiu, R.-T.; Yang, C.-F.; Yao, N.-T.; Tseng, W.-H.; Liao, F.-L.; Wang, S.-L. J. Am. Chem. Soc. 1997, 119, 4130. (10) (a) Jiang, B.; Yang, C.-G.; Wang, J. J. Org. Chem. 2002, 67, 1396. (b) White, J. D.; Cammack, J. H.; Sakuma, K. J. Am. Chem. Soc. 1989, 111, 8970. (11) (a) Jin, Y.; Yeh, C.-H.; Kuttruff, C. A.; Jørgensen, L.; Dünstl, G.; Felding, J.; Natarajan, S. R.; Baran, P. S. Angew. Chem., Int. Ed. 2015, 54, 14044. (b) Kawamura, S.; Chu, H.; Felding, J.; Baran, P. S. Nature 2016, 532, 90. (c) Brill, Z. G.; Grover, H. K.; Maimone, T. J. Science 2016, 352, 1078. (12) (a) Gong, J.; Lin, G.; Sun, W.; Li, C.-C.; Yang, Z. J. Am. Chem. Soc. 2010, 132, 16745. (b) Zheng, C.; Dubovyk, I.; Lazarski, K. E.; Thomson, R. J. J. Am. Chem. Soc. 2014, 136, 17750. (13) (a) Zhang, Y.; Danishefsky, S. J. J. Am. Chem. Soc. 2010, 132, 9567. (b) Yue, G.; Yang, L.; Yuan, C.; Jiang, X.; Liu, B. Org. Lett. 2011, 13, 5406. (c) Goetz, A. M.; Silberstein, A. l.; Corsello, M. A.; Garg, N. K. J. Am. Chem. Soc. 2014, 136, 3036. (d) Huang, B.; Guo, L.; Jia, Y. Angew. Chem., Int. Ed. 2015, 54, 13599. (e) Martinez, L. P.; Umemiya, S.; Wengryniuk, S. E.; Baran, P. S. J. Am. Chem. Soc. 2016, 138, 7536. (14) (a) White, J. D.; Shin, H.; Kim, T. S.; Cutshall, N. S. J. Am. Chem. Soc. 1997, 119, 2404. (b) Solomon, M.; Jamison, C. L.; McCormick, M.; Liotta, D. C.; Cherry, D. A.; Mills, J. E.; Shah, R. D.; Rodgers, J. D.; Maryanoff, C. A. J. Am. Chem. Soc. 1988, 110, 3702. (c) Swiss, K. A.; Liotta, D. C.; Maryanoff, C. A. J. Am. Chem. Soc. 1990, 112, 9393.
(15) He, S.; Yang, W.; Zhu, L.; Du, G.; Lee, C.-S. Org. Lett. 2014, 16, 496. (16) CCDC 1534783 (20) contains the supplementary crystallographic data for this paper. These data are available free of charge from the Cambridge Crystallographic Data Centre. (17) Nicolaou, K. C.; Jennings, M. P.; Dagneau, P. Chem. Commun. 2002, 21, 2480. (18) (a) Lee, H. J.; Deng, L. J. Am. Chem. Soc. 2012, 134, 18209. (b) Zhao, N.; Xie, S.; Chen, G.; Xu, J. Chem. - Eur. J. 2016, 22, 12634. (19) McGee, P.; Betournay, G.; Barabe, F.; Barriault, L. Angew. Chem., Int. Ed. 2017, 56, 6280.
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