Letter pubs.acs.org/OrgLett
Total Syntheses of (±)-Rhodonoids C, D, E, F, and G and Ranhuadujuanine B Hao Wu,† Richard P. Hsung,‡ and Yu Tang*,†,§,∥ †
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P. R. China Division of Pharmaceutical Sciences, University of Wisconsin, Madison, Wisconsin 53705, United States § Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, P. R. China ∥ Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, P. R. China ‡
S Supporting Information *
ABSTRACT: Here we describe the divergent, biosynthetically inspired syntheses of (±)-rhodonoids C−G and (±)-ranhuadujuanine B. The key steps of the syntheses include the construction of the chromene unit through a formal oxa-[3 + 3] annulation and a biomimetic acid-catalyzed ring cyclization. Cationic [2 + 2] cycloaddition is accomplished to form the cyclobutane core of (±)-rhodonoids E and F.
R
ecently, Hou1,2 reported the isolation of (±)-rhodonoids A−G (Figure 1) from Rhododendron capitatum Maxim, a
synthesize (±)-rhodonoids C−G. In particular, annulations of resorcinols with vinyliminium salts would lead to facile construction of the chromene nucleus via a sequence of a Knoevenagel-type condensation and a six-π-electron electrocyclic ring closure (Scheme 1). Biosynthetically, as shown in Scheme 1. An Oxa-[3 + 3] Cycloaddition of Resorcinols
Figure 1. (±)-Rhodonoids A−G and (±)-ranhuadujuanine B.
Scheme 2, we envisioned that (±)-rhodonoids C, D, and G could be derived from chromene 9, which could be prepared via our oxa-[3 + 3] annulation.12,13 Oxidation of chromene 9 led to epoxide 11, which could provide (±)-rhodonoids C and D through catalysis with acid (path a). In an alternative biogenetic pathway (path b), hydration of the double bond of chromene 9
shrub found in the Qinghai province of China, which is used in Tibetan medicine. In addition to their unique motifs, these novel meroterpenoids possess anti-HSV-1 activity (1) and inhibitory effects on PTP1B (8). Although synthesized as early as 1984, ranhuadujuanine B was not isolated until 2011 from Rhododendron anthopogonoides.3,4 This unique structural motif has attracted an array of synthetic efforts.5,6 Our long-standing interests in oxa-[3 + 3] annulation7,8 and the biomimetic total synthesis of meroterpenoids9−13 led us to © 2017 American Chemical Society
Received: May 17, 2017 Published: June 12, 2017 3505
DOI: 10.1021/acs.orglett.7b01463 Org. Lett. 2017, 19, 3505−3507
Letter
Organic Letters
endo-tet or 5-exo-tet) may be affected by the identity of the acid (see the Supporting Information for details). We reported an oxa-[3 + 3] annulation in tandem with a cationic [2 + 2] cycloaddition as a bioinspired strategy for the facile total synthesis of clusiacyclol A and B.11 In this study, we uncovered an unexpected a tetracyclic citran byproduct, which has a similar construction as rhodoniod G. We therefore examined whether the protic-acid-catalyzed cyclization could give (±)-rhodoniod G (3) directly (Table 1). Initial
Scheme 2. Proposed Biosyntheses of Rhodonoids C−G
Table 1. Acid-Catalyzed Cyclization of 9
would give (±)-rhodonoid G via acid-catalyzed cyclization. The cyclobutane core 12 of (±)-rhodonoids E and F is similar to that of C12-epi-rhodonoid B, an analogue recently synthesized by our group.13 In this work, 12 was efficiently prepared through an oxa-[3 + 3] annulation and a subsequent diastereoselective cationic [2 + 2] annulation that is biosynthetic in origin.14 Oxidation of cyclobutane 12 provided epoxide 13. The further biosynthetic transformation of epoxide 13, involving ring opening of the epoxy group, provided (±)-rhodonoids E and F. During the course of our studies, George and co-workers reported an elegant total synthesis of (±)-rhodonoids C and D in which the precise biogenetic origin was proposed.15 Here we report divergent, biosynthetically inspired total syntheses of (±)-rhodonoids C (1), D (2), E (4), F (5), and G (3) and (±)-ranhuadujuanine B (6). The total synthesis of (±)-rhodonoids C and D was expeditiously achieved from chromene 9 as shown in Scheme 3. Acetylation of the phenol within 9 generated 14 in a robust
yields (%)a entry
acid
6
3
16
17
1 2 3 4
CSAb MsOHc NosOH·xH2Od TsOH·H2Oe
30 30 11 8
0 0 8 40
31 0 13 8
22 36 60 36
a Isolated yields. bCSA: camphorsulfonic acid. cMsOH: methanesulfonic acid. dNosOH·xH2O: p-nitrobenzenesulfonic acid hydrate. e TsOH·H2O: p-toluenesulfonic acid monohydrate.
unsuccessful attempts involved CSA and MsOH, as highlighted entries 1 and 2. Although elimination products 16 and 17 and the citran natural product (±)-ranhuadujuanine B (6) were isolated instead, we were still encouraged, as hydration of the isopropenyl group in 16 and 17 could possibly afford the desired product 3 via a biomimetic transformation.16 Treating chromene 9 with a protic acid hydrate, such as p-nitrobenzenesulfonic acid hydrate, changed the outcome, and 3 was isolated as a single diastereomer (entry 3). After a few conditions were screened, p-toluenesulfonic acid monohydrate proved to be the optimal acid, leading to 3 in 40% yield at room temperature (entry 4). It is noteworthy that the maximum yield of 3 in this reaction was just 40%, as the reverse conversions of these four products (3, 6, 16, and 17) were feasible. To prove the equilibrium, compounds 3, 6, 16, and 17 were separately exposed to 2 equiv of TsOH·H2O in toluene at room temperature. Each reaction provided a mixture of the other three products along with the starting material (see the Supporting Information for details). Our total syntheses of (±)-rhodonoids E and F (Scheme 4) commenced with chromene 12, which was readily prepared from (2E,6E)-farnesol via oxa-[3 + 3] annulation followed by cationic [2 + 2] cycloaddition.12,13 Silylation using TBDPSCl to protect the phenol hydroxyl group provided 18 smoothly. Compound 18 was converted into a mixture of diastereomers 19 and 20 by oxidation with m-CPBA in CH2Cl2 followed by refluxing with aluminum isopropoxide in toluene. Compounds 19 and 20 were separated by flash column chromatography. Successful removal of the TBDPS group with TBAF efficiently
Scheme 3. Total Syntheses of (±)-Rhodonoids C and D
and scalable fashion. Oxidation of 14 with m-chloroperoxybenzoic acid (m-CPBA) and subsequent deacetylation of the phenolic hydroxyl group afforded epoxide 11 as an inseparable mixture of diastereomers. After refluxing in toluene with silica gel for 2 h, 11 was converted to (±)-rhodonoid C (1) in 14% yield, (±)-rhodonoid D (2) in 8% yield, and undesired 15 in 26% yield. While the yield of 1 was lower than that achieved in George’s work (32%), SiO2 provided a higher ratio of 2 to 1 (1:1.75 vs 1:6.5), which suggests that the ring-opening path (63506
DOI: 10.1021/acs.orglett.7b01463 Org. Lett. 2017, 19, 3505−3507
Letter
Organic Letters
(3) Kane, V. V.; Martin, A. R.; Peters, J. A.; Crews, P. J. Org. Chem. 1984, 49, 1793. (4) Iwata, N.; Kitanaka, S. Chem. Pharm. Bull. 2011, 59, 1409. (5) Li, X.; Lee, Y. R. Org. Biomol. Chem. 2014, 12, 1250. (6) Riveira, M. J.; La-Venia, A.; Mischne, M. P. J. Org. Chem. 2016, 81, 7977. (7) For reviews, see: (a) Xu, X.; Doyle, M. P. Acc. Chem. Res. 2014, 47, 1396. (b) Harrity, J. P. A.; Provoost, O. Org. Biomol. Chem. 2005, 3, 1349. (c) Deng, J.; Wang, X.-N.; Hsung, R. P. In Methods and Applications of Cycloaddition Reactions in Organic Syntheses; Nishiwaki, N., Ed.; John Wiley & Sons: Hoboken, NJ, 2014; Chapter 12. (d) Hsung, R. P.; Kurdyumov, A. V.; Sydorenko, N. Eur. J. Org. Chem. 2005, 2005, 23. (8) For recent development of oxa-[3 + 3] annulations, see: (a) Song, L. Y.; Yao, H. L.; Zhu, L. Y.; Tong, R. B. Org. Lett. 2013, 15, 6. (b) Wang, S.; Zhang, Y.; Dong, G.; Wu, S.; Zhu, S.; Miao, Z.; Yao, J.; Li, H.; Li, J.; Zhang, W.; Sheng, C.; Wang, W. Org. Lett. 2013, 15, 5570. (c) Tan, H.; Liu, H.; Chen, X.; Yuan, Y.; Chen, K.; Qiu, S. Org. Lett. 2015, 17, 4050. (d) Xiao, Y.; Lin, J.-B.; Zhao, Y.-N.; Liu, J.-Y.; Xu, P.-F. Org. Lett. 2016, 18, 6276. (e) Dong, S.; Fang, C.; Tang, W.; Lu, T.; Du, D. Org. Lett. 2016, 18, 3882. (f) Yu, J.; Cai, C. Mol. Diversity 2017, DOI: 10.1007/s11030-017-9741-z. (9) Kurdyumov, A. V.; Hsung, R. P.; Ihlen, K.; Wang, J. Org. Lett. 2003, 5, 3935. (10) Kurdyumov, A. V.; Hsung, R. P. J. Am. Chem. Soc. 2006, 128, 6272. (11) Yeom, H.-S.; Li, H.; Tang, Y.; Hsung, R. P. Org. Lett. 2013, 15, 3130. (12) Luo, G. Y.; Wu, H.; Tang, Y.; Li, H.; Yeom, H. S.; Yang, K.; Hsung, R. P. Synthesis 2015, 47, 2713. (13) Wu, H.; Hsung, R. P.; Tang, Y. J. Org. Chem. 2017, 82, 1545. (14) Thulasiram, H. V.; Erickson, H. K.; Poulter, C. D. Science 2007, 316, 73. (15) Day, A. J.; Lam, H. C.; Sumby, C. J.; George, J. H. Org. Lett. 2017, 19, 2463. (16) Hesse, R.; Gruner, K. K.; Kataeva, O.; Schmidt, A. W.; Knölker, H.-J. Chem. - Eur. J. 2013, 19, 14098.
Scheme 4. Total Syntheses of (±)-Rhodonoids E and F
afforded (±)-rhodonoids E (4) and F (5). The spectroscopic data for (±)-rhodonoids C−G and ranhuadujuanine B matched those reported in the literature.2,4 In conclusion, we have completed divergent, biomimetic total syntheses of (±)-rhodonoids C, D, E, F, and G and ranhuadujuanine B featuring a formal [3 + 3] annulation and acid-induced cyclization. The biosynthetic relationship among these natural products is further strengthened by our direct biomimetic pathway.
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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.7b01463. Experimental procedures and NMR spectra and characterizations for all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Yu Tang: 0000-0001-8224-4639 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Y.T. and R.P.H. thank the National Natural Science Foundation of China for financial support (21572154). R.P.H. thanks the Laura and Edward Kremers Family Foundation for a generous endowed chair in natural products chemistry. Y.T. thanks the Fundamental Research Funds for the Central Universities (201612013) and the NSFC−Shandong Joint Fund for Marine Science Research Centers (U1606403) for financial support.
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REFERENCES
(1) Liao, H.-B.; Lei, C.; Gao, L.-X.; Li, J.-Y.; Li, J.; Hou, A.-J. Org. Lett. 2015, 17, 5040. (2) Liao, H.-B.; Huang, G.-H.; Yu, M.-H.; Lei, C.; Hou, A.-J. J. Org. Chem. 2017, 82, 1632. 3507
DOI: 10.1021/acs.orglett.7b01463 Org. Lett. 2017, 19, 3505−3507
