Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis of (+)-Nivetetracyclate A Michel Blitz,† Robert C. Heinze,‡ Klaus Harms,† and Ulrich Koert*,†,§ †
Fachbereich Chemie, Philipps- Universität Marburg, Hans-Meerwein-Strasse 4, D-35043 Marburg, Germany Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany
‡
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S Supporting Information *
ABSTRACT: A stereoselective synthetic approach to the natural product (+)-nivetetracyclate A is reported. The tetracyclic skeleton was assembled in a convergent manner by an alkylation to a diarylmethane and subsequent Friedel−Crafts acylation. Further key steps are an asymmetric Sharpless epoxidation and the boron trifluoride-mediated diastereoselective rearrangement of an epoxy alcohol to a β-hydroxy aldehyde. Optimized timing for the deprotection step and the chemo- and stereoselective Noyori-transfer hydrogenation of a 1,4-diketone allowed the late stage introduction of the C4 stereocenter.
A
Scheme 1. Retrosynthetic Analysis of Nivetetracyclate A (1)
nthracyclines are an important and well-studied class of natural products.1 Their significant bioactivity makes them an interesting and important subject for chemical and pharmaceutical studies.2 In 2013, Zhang et al. reported two novel tetracyclic compounds from Streptomyces niveus.3 On the basis of NMR spectroscopic data, the structures of nivetetracyclate A (1) and B (2) were proposed (Figure 1). The absolute configuration
Figure 1. Structures of nivetetracyclate A (1) and B (2).
was attributed by comparison of the calculated CD spectra with experimental spectra. Both nivetratacyclates have a unique and novel tetracyclic scaffold, which relates them to the class of anthracyclines and tetracyclines. Nivetetracylate A (1) and B (2) show moderate activity against human HeLa cells (IC50 11.22 μM and 7.57 μM) and weak activity against MRSA with a MIC value of 64 μM. Our synthetic plan for nivetetracyclate A (1) schedules the introduction of the C 4 stereocenter to the final stage of synthesis. One key step would be the chemo- and stereoselective reduction of the diketone 3 (Scheme 1). A benzohydroquinone dimethyl ether substructure is a promising precursor for the 1,4-diketone motif in 3 and the β-hydroxy ester and the stereocenters at C9 and 10 could be developed from an allylic alcohol. This makes tetracylic compound 4 a key intermediate. Anthracene 4 might be built up by a © XXXX American Chemical Society
Friedel−Crafts cyclization of the carboxylic acid 5. Intermediate 5 should be accessible in a convergent manner from the benzylic bromide 6 and the anisole 7 via ortho-metalation and subsequent intermolecular alkylation. The building block 6 was synthesized based on the work of Shair.4 Starting point for the synthesis was the benzaldehyde 8 (Scheme 2). Methylation in ortho-position following Comin’s protocol gave aldehyde 9.5 After Pinnick oxidation of 9, the carboxylic acid 10 could be converted into the methyl ester 11. Wohl-Ziegler bromination of the benzylic methyl group gave building block 6 in good yield. Received: December 19, 2018
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DOI: 10.1021/acs.orglett.8b04044 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Synthesis of Building Block 61
Scheme 4. Friedel−Crafts Acylation of Acid 161
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(a) ZnCl2 (0.10 equiv), AcOH, Ac2O, 120 °C, 30 min; (b) Ghosez’s Reagent (5.0 equiv), ZnCl2 (2.0 equiv), DMAP (cat.), Ac2O, pyridine, CH2Cl2, 0 °C to rt, 16 h; (c) TFAA (2.0 equiv), CH2Cl2, 0 °C, 15 min; (d) DMAP (0.10 equiv), pyridine, Ac2O, 0 °C to rt, 16 h. 1
(a) N,N,N′-Trimethylethylendiamine (1.1 equiv), n-BuLi (1.05 equiv), toluene, 0 °C to rt, 1 h; (b) PhLi (3.0 equiv) toluene, rt, 8 h; (c) MeI (6.0 equiv), THF, −78 °C to rt 16 h; (d) NaClO2 (2.0 equiv), NaH2PO4 (5.0 equiv), 2-methyl-2-butene (8.0 equiv), H2O, tBuOH, rt, 1 h; (e) oxalyl chloride (1.2 equiv), DMF (cat.), CH2Cl2, 0 °C to rt, 1 h; (f) Et3N (3.0 equiv), MeOH (20 equiv), 0 °C to rt, 15 h; (g) NBS (1.01 equiv), AIBN (0.02 equiv), cyclohexane, 90 °C, 4 h.
ZnCl2 or in a two-step procedure9 via the corresponding acid chloride gave complex reaction mixtures and were unsatisfying. Therefore, a two-step reaction sequence was applied. In the first step, the mixed anhydride was formed using TFAA, which undergoes Friedel−Crafts acylation to anthracenol 17. Because of its oxidative instability, the latter was directly acetylated to produce the desired tetracyclic product 18 in 72% overall yield. Deprotection of silyl ether 18 using HF led to allylic alcohol 19 in good yield (Scheme 5). Asymmetric Sharplessepoxidation of 19 provided the epoxide 20.10
Starting point for the synthesis of the type-5 intermediate was the tetralone 12, which was converted into the allylic alcohol 13 in a known three-step procedure using a Shapiro reaction (Scheme 3).6 Protection of the alcohol using TIPSCl Scheme 3. Synthesis of Carboxylic Acid 161
Scheme 5. Asymmetric Synthesis of Epoxide 201
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(a) TIPSCl (1.5 equiv), imidazole (2.0 equiv), DMF, rt, 20 h; (b) tBuLi (1.3 equiv), TMEDA (1.1 equiv), pentane 0 °C, 1 h; (c) CuI (1.0 equiv), nBu3P (2.2 equiv), THF, 0 °C, 30 min; (d) benzylic bromide 6 (1.0 equiv), THF, −78 °C to rt, 3 h; (e) KOH (20 equiv), EtOH/H2O 9:1, 90 °C, 4 h.
1
(a) HF (48%, 10 equiv), MeCN, rt, 1 h; (b) (−)-DET (1.5 equiv), Ti(Oi-Pr)4 (1.0 equiv), t-BuOOH (2.0 equiv), 4 Å MS, CH2Cl2, −20 °C to −40 °C, 22 h.
and imidazole gave silyl ether 15 in excellent yield. With protected building block 14 in hand, its ortho-metalation and subsequent alkylation with benzyl bromide 6 to obtain the diarylmethane 15 was investigated. Using t-butyl lithium, ortho-lithiation was achieved at 0 °C, and after transmetalation to Cu(I) at −78 °C using bis(tri-n-butylphosphine)copper(I) iodide,7 the reaction with bromide 6 led to the diarylmethane 15. The subsequent saponification of the ortho,ortho′disubstituted methyl ester 15 to the carboxylic acid 16 required higher reaction temperatures, which caused side reaction (e.g., silyl ether cleavage). Screening of different bases such as NaOH, LiOH, KOH as well as temperatures, solvents, and reaction times showed that the best results were obtained with KOH at 90 °C for 4 h. A Friedel−Crafts acylation of the carboxylic acid 16 was hampered by oxidative side reactions of the electron rich trimethoxyanthracenol 17 (Scheme 4). Attempts to obtain the more stable acylated anthracenol 18 directly8 using Ac2O/
The next synthetic task consisted of the conversion of the epoxy alcohol into the trans-β-hydroxy ester of the C9 and 10 substructure. The structurally simpler epoxy alcohol rac-21 was used first as a model system to investigate this case (Scheme 6). Kende reported a trans-selective epoxide opening using a palladium catalyzed hydrogenolysis for a related example.6 In contrast, the hydrogenolysis of our epoxy alcohol rac-21 gave the cis product rac-22 only, whose structure was confirmed by X-ray.11 We were able to synthesize the trans-alcohol using boron trifluoride and triethyl silane as hydrogen source but only in 20% yield. Fortunately, we observed that epoxide rac21 rearranges with Lewis acids such as boron trifluoride or TMSOTf to the trans-aldehyde rac-23 via a 1,2-hydride shift (24 → 25).12 The relative configuration of rac-23 was confirmed after DIBAH-reduction to the corresponding literature known trans-diol (not shown).13 B
DOI: 10.1021/acs.orglett.8b04044 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 6. Diastereoselective Opening of Epoxide 211
Scheme 8. Chemo- and Stereoselective Reduction of 1,4Diketone1
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(a) H2 (1 atm), Pd/C (10% w/w), KOH (0.20 equiv), EtOH, rt, 4 h; (b) BF3·OEt2 (1.00 equiv), CH2Cl2, − 78 °C, 20 min; (c) X-ray crystal structure of rac-22.
(a) CAN (2.00 equiv), MeCN, H2O, 0 °C, 15 min; (b) H2 (1 atm), Rh(PPh3)3Cl (0.10 equiv), toluene, rt, 3 h; (c) RuCl(p-cymene)[(S,S)-Ts-DPEN] (0.10 equiv), HCO2H/Et3N (5:2, 7.50 equiv).
With this procedure in hand, we were able to apply it on tetracyclic epoxy alcohol 20 leading to the corresponding transaldehyde 26 with an excellent diastereoselectivity of >20:1 (Scheme 7). Because of the instability of aldehyde 26, it was
Conversion of compound 30 into the target molecule 1 required the cleavage of the acetate and the methyl ether, which proved to be problematic. Lewis acidic conditions (e.g., BBr3, AlBr3, TMSI) and nucleophilic conditions (e.g., NaSEt, LiBr) led to complex reaction mixtures and (mainly) decomposition. The lability of the benzylic alcohol at C4 may be the main reason for this failure. Therefore, the deprotection was examined at the stage of the 1,4-diketone 29 (Scheme 9). AlCl3 at 50 °C allowed the cleavage of both
1
Scheme 7. Rearrangement of Epoxyalcohol 20 and Synthesis of Ester 271
Scheme 9. Deprotection and Final Reduction1
(a) BF3·OEt2 (1.00 equiv), CH2Cl2, − 78 °C, 5 min; (b) NaClO2 (2.00 equiv), NaH2PO4 (5.00 equiv), 2-methyl-2-butene (8.00 equiv), H2O, tBuOH, THF, rt, 1 h; (c) K2CO3 (10.0 equiv), MeI (10.0 equiv), DMF, 100 °C, 1 h. 1
(a) AlCl3 (5.00 equiv), CH2Cl2, 50 °C, 19 h; (b) RuCl(pcymene)[(S,S)-Ts-DPEN] (0.10 equiv), HCO2H/Et3N (5:2, 7.50 equiv).
1
directly oxidized under Pinnick-conditions to the corresponding acid, which was subjected to a nucleophilic esterification to yield ester 27 in 55% over three steps. The final challenge of the synthesis consisted of the conversion of the hydroquinone dimethyl ether into the γhydroxyketone of nivetetracyclate A (1) (Scheme 8). CAN oxidation of 27 gave the p-benzoquinone 28, which could be hydrogenated to the 1,4-diketone 29. Monoreduction of diketone 29 by Noyori transfer hydrogenation14 produced alcohol 30 as a single diastereomer. The relative configuration of 30 was postulated by Noyori’s results and supported by comparison with X-ray data from a related derivative.15 The deactivation of the C1 ketone by the C12 substituent could explain the chemoselective reduction of the C4 ketone.16
protective groups in moderate yield. The resulting diketone 31 was subjected directly to the Noyori reduction to yield (+)-nivetetracyclate A (1), which was identical with respect to the NMR-data of the natural product. CD-spectroscopy proved the fit of the absolute configuration. In conclusion, the first enantioselective synthesis of nivetetracyclate A (1) was achieved. Key steps are a copper mediated coupling to a diarylmethane followed by a Friedel− Crafts acylation to construct the tetracyclic skeleton. Asymmetric Sharpless epoxidation followed by a trans-selective epoxide rearrangement allowed us to build up the trans-βhydroxyester. Removal of the protective groups at the 1,4C
DOI: 10.1021/acs.orglett.8b04044 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters diketone stage and final highly regio- and stereoselective Noyori transfer hydrogenation delivered (+)-nivetetracyclate A (1). This synthesis should be adaptable for the synthesis of nivetetracyclate B (2) and related natural products as well.
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(11) CCDC 1884679 contain the supplementary crystallographic data for 22. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif. (12) The rearrangement (24 → 25) can be described as a semipinacol rearrangement of an α-hydroxy epoxide with hydride migration to a benzylic position. The stereoselectivity for this process is not presently understood. Leading references for the semi-pinacol rearrangement: Snape, T. J. Chem. Soc. Rev. 2007, 36, 1823−1842. (b) Macias, F. A.; Velasco, R. F.; Alvarez, J. A.; Castellano, D.; Galindo, J. C. G. Tetrahedron 2004, 60, 8477−8488. (13) Meyers, A. I.; Higashiyama, K. J. J. Org. Chem. 1987, 52, 4592− 4597. (14) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521−2522. (15) Heinze, R. C. Studien zur Totalsynthese von Nivetetracyclat A. M.S. Thesis, Philipps-Universität Marburg, Marburg, March 2015. (16) For an enantioselective reduction of tetraline-1,4-dione: Kündig, E. P.; Enriquez-Garcia, A. Beilstein J. Org. Chem. 2008, 4, 37 DOI: 10.3762/bjoc.4.37.
ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b04044. Experimental details, spectroscopic and analytical data of all new compounds (PDF) Accession Codes
CCDC 1884679 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 e-mailing
[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
Robert C. Heinze: 0000-0002-3431-816X Ulrich Koert: 0000-0002-4776-8549 Present Address §
Fachbereich Chemie, Philipps-Universität Marburg, HansMeerwein-Strasse, 35032 Marburg, Germany.
Author Contributions
Experimental work was accomplished by M.B. and R.C.H.; the X-ray crystal structure was performed by K.H. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support by the Deutsche Forschungsgemeinschaft is gratefully acknowledged. REFERENCES
(1) Anthracycline Chemistry and Biology I; Krohn, K., ed; Springer: Berlin, Germany, 2008. (2) Minotti, G.; Menna, P.; Salvatorelli, E.; Cairo, G.; Gianni, L. Pharmacol. Rev. 2004, 56, 185−229. (3) Chen, C.; Liu, X.; Abdel-Mageed, W. M.; Guo, H.; Hou, W.; Jaspars, M.; Li, L.; Xie, F.; Ren, B.; Wang, Q.; Dai, H.; Song, F.; Zhang, L. Org. Lett. 2013, 15, 5762. (4) Lee, H. G.; Ahn, J. Y.; Lee, A. S.; Shair, M. D. Chem. - Eur. J. 2010, 16, 13058−13062. (5) (a) Comins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49, 1078− 1083. (b) Comins, D. L.; Brown, J. D. J. Org. Chem. 1989, 54, 3730− 3732. (6) Rizzi, J. P.; Kende, A. S. Tetrahedron 1984, 40, 4693−4700. (7) Suzuki, M.; Suzuki, T.; Kawagishi, T.; Noyori, R. Tetrahedron Lett. 1980, 21, 1247. (8) Platt, K. L.; Oesch, F. J. Org. Chem. 1982, 47, 5321−5326. (9) Wehlan, H.; Jezek, E.; Lebrasseur, N.; Pavé, G.; Roulland, E.; White, A. J. P.; Burrows, J. N.; Barrett, A. G. M. J. Org. Chem. 2006, 71, 8151−8158. (10) Katsuki, T.; Martin, V. Org. React. 1996, 48, 1. D
DOI: 10.1021/acs.orglett.8b04044 Org. Lett. XXXX, XXX, XXX−XXX
