Diastereoselective Synthesis of the Hydroperoxide–Keto Form of

Letter Cite This: Org. Lett. 2018, 20, 4153−4156

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Diastereoselective Synthesis of the Hydroperoxide−Keto Form of (±)-Steenkrotin B Jun Xuan,† An Zhu,† Binjie Ma, and Hanfeng Ding* Department of Chemistry, Zhejiang University, Hangzhou 310058, P. R. China

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ABSTRACT: A diastereoselective approach for the synthesis of the hydroperoxide−keto form of (±)-steenkrotin B (2′) is described. The key features of the strategy involve a Diels− Alder cycloaddition, a titanium(III)-catalyzed reductive annulation, and a regio- and diastereoselective hydroperoxidation.

I

intramolecular aldol/vinylogous retro-aldol/aldol process.4 Herein, we report a diastereoselective total synthesis of the claimed structure of steenkrotin B in its hydroperoxide−keto form, which calls into question the assigned structure. Our retrosynthetic analysis for (±)-steenkrotin B is depicted in Scheme 1. We reasoned that the endoperoxide in (±)-2

solation studies with Croton plants for the discovery of potential medicinal leads have provided a variety of structurally appealing and biologically active diterpenoids.1 With the common name of “Marsh Fever-berry” or “Tonga Croton” for centuries, species of the Croton steenkampianus Gerstner (Euphorbiaceae) were widely employed as traditional medicine for the treatment of a broad spectrum of diseases owing to their remarkable curative ability.2 In 2008, steenkrotins A (1) and B (2) bearing two unprecedented skeletons, which exhibit moderate antiplasmodial activities, were isolated by Hussein and co-workers from this genus (Figure 1).3

Scheme 1. Retrosynthetic Analysis of (±)-Steenkrotin B (2)

Figure 1. Steenkrotins A and B and their common tricyclic steenkrotane core.

The relative configuration of steenkrotin A (1) was unambiguously established by X-ray diffraction analysis, featuring a compact [3,5,5,6,7] pentacyclic carbon framework containing a sterically congested tetrahydrofuran moiety. The structure of steenkrotin B (2) was originally assigned through a combination of one- and two-dimensional NMR experiments, which apparently revealed an unusual and highly oxygenated [5,6,6,7] tetracyclic skeleton embedded with an endoperoxide subunit. Both molecules share a common [5,6,7] tricyclic steenkrotane core that consists of eight stereogenic centers, six of which are contiguous including one quaternary. The unique architectures, potentially important bioactivities, and interesting biogenetic pathways of steenkrotins A and B have prompted us to launch their chemical synthesis. Very recently, we achieved the first asymmetric total synthesis of steenkrotin A in a concise and efficient manner based on a cascade © 2018 American Chemical Society

might be constructed from tricycle 3 through a regio- and diastereoselective Schenck ene reaction.5 A new titanium(III)catalyzed reductive annulation reaction6 on the vinyl epoxide− aldehyde 5 was expected to yield 3 via the intermediacy of 4, which is analogous to our concise total synthesis of pepluanol A.7 The preparation of 5 could be traced back to the Received: June 16, 2018 Published: June 27, 2018 4153

DOI: 10.1021/acs.orglett.8b01875 Org. Lett. 2018, 20, 4153−4156

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Organic Letters

cross-coupling12 in 72% yield over two steps. Although in hemiketal form, the inversion of the configuration at C-11 proceeded smoothly with concomitant removal of the benzoyl group upon exposure to NaOMe at 65 °C (12 → 13a → 13b). Dess−Martin oxidation of the resultant 13b delivered diketone 14 in 85% yield. The zinc enolate of the ketone at C-14, prepared by transmetalation of the lithium enolate, reacted with acetone to furnish adduct 15 in 75% yield as a single diastereomer.13 After a further regioselective epoxidation at the Δ6,7 olefin upon subjection to DMDO solution, the remaining terminal alkene moiety was then cleaved via a Lemieux− Johnson oxidation to afford vinyl epoxide−aldehyde 5 in 56% yield, setting the stage for the anticipated reductive annulation. To our delight, by treatment with Cp2TiCl2 (cat.)/Zn/ collidine·HCl over 2 h, the desired tricyclic diol 16 was obtained in 89% yield as a pair of inconsequential isomers (dr = 1.3:1 at C-3). As a comparison, the ketyl−olefin radical couplings in the presence of n-Bu3SnH/AIBN, n-Bu3SnH/ Et3B/O 2, and SmI2/HMPA only afforded dramatically decreased yields. The subsequent regioselective oxidation of the alcohol at C-3 was achieved by TEMPO/NCS14 and provided ketone 3 in 86% yield. It should be mentioned that the allylic alcohol at C-7 was more reactive toward various other oxidants such as PCC, Dess−Martin periodinane, (COCl)2/DMSO, SO3·pyridine/DMSO, and n-Pr4RuO4/ NMO. The structure of 3 was unambiguously determined by X-ray crystallographic analysis of its derivative 18, which was prepared from the former in 82% yield over two steps. Having assembled the [5,6,7] tricyclic skeleton, we turned our attention to completing the synthesis of (±)-steenkrotin B (Scheme 3). Due to the liability of 3 to undergo a retro−aldol side reaction, protection of its two hydroxyl groups prior to further core modification was required. However, conventional conditions such as TBSCl/Et3N/DMAP or TBSOTf/2,6lutidine resulted in the exclusive formation of tetracycle 20 in excellent yields (for details, see the Supporting Information). Pleasingly, treatment of 3 with NaH and TBSCl in THF at reflux afforded the desired product 19 in 75% yield. The efficient enolization of the ketone at C-3, which would inhibit the intramolecular ketal formation, was presumably responsible for this outcome. To our disappointment, under standard Schenck ene reaction conditions, the expected endoperoxide 21 was not detected in spite of exhaustive screening of the commonly used photosensitizers [meso-tetraphenylporphyrin, methylene blue, rose bengal, Ru(bpy)3Cl2·6H2O, etc.] and solvents (MeOH, CH2Cl2, and MeCN et al.). On the other hand, attempts at reacting 19 with the chemical source of singlet oxygen generated by NaClO/H2O215 and Na2MoO4/ H2O216 only led to recovery of the starting material. Moreover, the Δ5,6 olefin of 19 was also found to be inert toward Mukaiyama hydroperoxidation [Co(acac)2, Et3SiH, O2, DCE, rt or Co(thd)2, Et3SiH, O2, TBHP, DCE, rt] even upon prolonged reaction time. As an alternative, dienone 26 bearing a more reactive Δ6,20 exo-double bond was envisioned for realizing this transformation. Thus, 19 was treated with mCPBA to give the β-epoxide 23 in 67% yield. By exposure to LiHMDS/MeI, the methylation at C-2 occurred to provide 24. Without isolation, the epimerization of 24 took place rapidly under elevated temperature, accompanied by spontaneous ring-opening of the epoxide to deliver 25 in 65% yield in one operation. Dehydration was next achieved uneventfully with the aid of Burgess reagent and afforded 26 in 78% yield. Other conditions such as MsCl/DBU, SOCl2/pyridine, p-TsOH, and

cycloheptenone 7 and Rawal’s diene 8 by taking advantage of a Diels−Alder reaction8 and global functionalization of the corresponding adduct 6. Our synthesis commenced with construction of the [5,6,7] tricycle 3 (Scheme 2). Iodination of the readily available Scheme 2. Construction of the [5,6,7] Tricycle 3

cycloheptenone 9 9 by employing a modified method developed by Danishefsky and co-workers10 gave α-iodoenone 10 in 88% yield. Under the Negishi cross-coupling conditions [Pd(dba)2, P(o-furyl)3, DMF, rt],11 the union of 10 and homoallylzinc bromide 11 afforded enone 7 in 74% yield. After extensive optimization, the anticipated Diels−Alder cycloaddition between 7 and Rawal’s diene 8 was found to toke place readily at 40 °C. By quenching the reaction at low temperature with 2 N aqueous hydrochloric acid, the desired cis-[6,7] bicyclic diketone 6 was formed with generation of the quaternary carbon at C-9 in 83% yield as a single diastereomer. The regioselective enol−triflation successfully occurred on the ketone at C-6, which was then converted into 12 by installation of the methyl group through a CuI-catalyzed 4154

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Table 1. Optimization on the Hydroperoxidation of 26a

Scheme 3. Total Synthesis of the Hydroperoxide−Keto Form of (±)-Steenkrotin B (2′)

yieldb (%) entry

metal precatalyst

hydride source

27

25

1c 2c 3 4 5 6d 7e 8d−f 9g 10g 11g

Co(tdcpp) Co(tdcpp) Co(tfa)2 Co(dpm)2 Co(acac)2 Co(acac)2 Mn(dpm)3 Mn(dpm)3 Fe(acac)3 Fe(ox)3·6H2O Fe(Pc)2

Et3SiH PhSiH3 Et3SiH Et3SiH Et3SiH Et3SiH PhSiH3 PhSiH3 PhSiH3 NaBH4 NaBH4

28 13 46 58 72 87 52 63 nd nd nd

nd 20 nd nd nd nd 34 25 nd nd nd

a Reaction conditions: 26 (0.02 mmol), metal precatalyst (0.2 equiv), hydride source (1.3 equiv), and O2 (1 atm) in DCE (1 mL) at rt for 1 h. bIsolated yields. ci-PrOH/CH2Cl2 (1:1 v/v) instead of DCE. d TBHP (1.5 equiv) was added. ei-PrOH instead of DCE. fReaction was performed at −10 °C. gEtOH instead of DCE, 24 h. nd = not detected. acac = acetylacetonate, dpm = dipivaloylmethanato, ox = oxalate, Pc = phthalocyanine, tdcpp = 5,10,15,20-tetrakis(2,6dichlorophenyl)porphinato.

tion from the pioneering work of Mukaiyama,18 Isayama,19 and Magnus,20 a systematic screening of the metal precatalysts was conducted. To our pleasure, Co(acac)2 quickly emerged as superior to other common metal hydride generating systems, affording 27 in 72% yield as a single isomer (entry 5). By further addition of stoichiometric amounts of TBHP serving as a replacement activator and/or reoxidant, the yield was improved to 87% (entry 6). In the case of manganese hydride (entries 7 and 8), 27 was obtained in diminished yields, along with the formation of significant quantity of 25 due to premature reduction of the corresponding peroxy radical by PhSiH3. Other hydroperoxidation processes based on iron21 were also investigated but, unfortunately, led to the recovery of 26. Desilylation of 27 with HF·pyridine eventually furnished 2′ in 74% yield. To our surprise, the spectroscopic data of 2′ were inconsistent with those reported for natural steenkrotin B.3 Although its structure has been verified by a two-step transformation into 27 in 62% yield, the presence of the endoperoxide subunit in 2′ was not detected (δC 214.1 vs 110.1 for C-14). This outcome indicated that 2′ is a hydroperoxide−keto form of (±)-steenkrotin B (2). However, both attempts on the conversion of 2′ to (±)-2 and 27 to 28 under various acidic or basic conditions were met with failures. On the other hand, following the exact procedure for preparation of the triacetyl derivative by Hussein and coworkers,3 treatment of 2′ with Ac2O and pyridine only caused decomposition of the starting material. At this stage, the structure of steenkrotin B remains elusive to us owing to the inaccessibility of natural samples for further analysis. In summary, we have developed a diastereoselective approach for the synthesis of the hydroperoxide−keto form of (±)-steenkrotin B (2′). The key steps of the strategy entail a

Martin’s sulfurane were employed as well but caused complete decomposition of the starting material. The regio- and diastereoselective hydroperoxidation of dienone 26 was now investigated (Table 1). Based on elegant studies by Matsushita and Sugamoto,17 cobalt(II) porphyrin was first employed in the presence of Et3SiH and PhSiH3 as hydride sources. However, both trials gave low yields of 27 (entries 1 and 2), whose structure was unambiguously confirmed by X-ray crystallographic analysis. Taking inspira4155

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Topics in Current Chemistry; Krische, M. J., Ed.; Springer-Verlag: Berlin, 2007; Vol. 279, p 25. (c) Morcillo, S. P.; Miguel, D.; Campaña, A. G.; de Cienfuegos, L. Á .; Justicia, J.; Cuerva, J. M. Org. Chem. Front. 2014, 1, 15. (7) Xuan, J.; Liu, Z.; Zhu, A.; Rao, P.; Yu, L.; Ding, H. Angew. Chem., Int. Ed. 2017, 56, 8898. (8) (a) Diels, O.; Alder, K. Liebigs Ann. Chem. 1928, 460, 98. (b) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668. (9) Pearson, A. J.; Bansal, H. S. Tetrahedron Lett. 1986, 27, 283. (10) Angeles, A. R.; Waters, S. P.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, 13765. (11) (a) Baba, S.; Negishi, E. J. Am. Chem. Soc. 1976, 98, 6729. (b) Negishi, E.; Tan, Z.; Liou, S.-Y.; Liao, B. Tetrahedron 2000, 56, 10197. (12) Jonasson, C.; Rönn, M.; Bäckvall, J.-E. J. Org. Chem. 2000, 65, 2122. (13) (a) Hagiwara, H.; Uda, H.; Kodama, T. J. Chem. Soc., Perkin Trans. 1 1980, 963. (b) Witschel, M. C.; Bestmann, H. J. Synthesis 1997, 1997, 107. (14) (a) Lebelev, O. L.; Kazarnovskii, S. N. Zh. Obshch. Khim. 1960, 30, 1631. (b) Lin, S.-C.; Chein, R.-J. J. Org. Chem. 2017, 82, 1575. (15) (a) Foote, C. S.; Wexler, S. J. Am. Chem. Soc. 1964, 86, 3879. (b) Foote, C. S.; Wexler, S.; Ando, W. Tetrahedron Lett. 1965, 6, 4111. (16) (a) Böhme, K.; Brauer, H.-D. Inorg. Chem. 1992, 31, 3468. (b) Niu, Q. J.; Foote, C. S. Inorg. Chem. 1992, 31, 3472. (c) Aubry, J.M.; Bouttemy, S. J. Am. Chem. Soc. 1997, 119, 5286. (17) (a) Matsushita, Y.-i.; Sugamoto, K.; Nakama, T.; Matsui, T. J. Chem. Soc., Chem. Commun. 1995, 567. (b) Sugamoto, K.; Matsushita, Y.-I.; Matsui, T. J. Chem. Soc., Perkin Trans. 1 1998, 3989. (18) (a) Isayama, S.; Mukaiyama, T. Chem. Lett. 1989, 18, 1071. (b) Mukaiyama, T.; Isayama, S.; Inoki, S.; Kato, K.; Yamada, T.; Takai, T. Chem. Lett. 1989, 18, 449. (c) Inoki, S.; Kato, K.; Takai, T.; Isayama, S.; Yamada, T.; Mukaiyama, T. Chem. Lett. 1989, 18, 515. (19) Isayama, S. Bull. Chem. Soc. Jpn. 1990, 63, 1305. (20) (a) Magnus, P.; Payne, A. H.; Waring, M. J.; Scott, D. A.; Lynch, V. Tetrahedron Lett. 2000, 41, 9725. (b) Magnus, P.; Waring, M. J.; Scott, D. A. Tetrahedron Lett. 2000, 41, 9731. (c) Magnus, P.; Scott, D. A.; Fielding, M. R. Tetrahedron Lett. 2001, 42, 4127. (d) Magnus, P.; Fielding, M. R. Tetrahedron Lett. 2001, 42, 6633. (21) (a) Barker, T. J.; Boger, D. L. J. Am. Chem. Soc. 2012, 134, 13588. (b) Leggans, E. K.; Barker, T. J.; Duncan, K. K.; Boger, D. L. Org. Lett. 2012, 14, 1428. (c) Lo, J. C.; Yabe, Y.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 1304.

Diels−Alder reaction, a titanium(III)-catalyzed reductive annulation as well as a regio- and diastereoselective hydroperoxidation. With high efficiency in building structural complexity, the described strategy and methods should have broad application in synthesizing other related natural products.

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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.8b01875. General experimental procedures, characterization data, and 1H and 13C NMR spectra of new compounds (PDF) Accession Codes

CCDC 1846113−1846114 contain 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 [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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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Hanfeng Ding: 0000-0002-1781-4604 Author Contributions †

J.X. and A.Z. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the National Natural Science Foundation of China (21622205, 21472167) and the Fundamental Research Funds for the Central Universities (2017XZZX002-02) is gratefully acknowledged. We thank Prof. Xiaoli Zhao (East China Normal University) for the Xray diffraction analysis.

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REFERENCES

(1) (a) Gupta, M.; Mazumder, U. K.; Vamsi, M. L. M.; Sivakumar, T.; Kandar, C. C. J. Ethnopharmacol. 2004, 90, 21. (b) Cai, Y.; Evans, F. J.; Roberts, M. F.; Phillipson, J. D.; Zenk, M. H.; Gleba, Y. Y. Phytochemistry 1991, 30, 2033. (2) Pooley, E. In The Complete Field Guide to Trees of Natal, Zululand and Transkei; Natal Flora Publications Trust: Durban, 1993; p 222. (3) Adelekan, A. M.; Prozesky, E. A.; Hussein, A. A.; Ureña, L. D.; van Rooyen, P. H.; Liles, D. C.; Meyer, J. J. M.; Rodríguez, B. J. Nat. Prod. 2008, 71, 1919. (4) (a) Pan, S.; Xuan, J.; Gao, B.; Zhu, A.; Ding, H. Angew. Chem., Int. Ed. 2015, 54, 6905. (b) Pan, S.; Gao, B.; Hu, J.; Xuan, J.; Xie, H.; Ding, H. Chem. - Eur. J. 2016, 22, 959. (5) For reviews, see: (a) Wasserman, H. H.; Ives, J. L. Tetrahedron 1981, 37, 1825. (b) Prein, M.; Adam, W. Angew. Chem., Int. Ed. Engl. 1996, 35, 477. (6) For reviews, see: (a) Barrero, A. F.; del Moral, J. F. Q.; Sánchez, E. M.; Arteaga, J. F. Eur. J. Org. Chem. 2006, 2006, 1627. (b) Gansäuer, A.; Justicia, J.; Fan, C.-A.; Worgull, D.; Piestert, F. In 4156

DOI: 10.1021/acs.orglett.8b01875 Org. Lett. 2018, 20, 4153−4156