Protecting-Group-Free Total Synthesis and Biological Investigation of Cabucine Oxindole A†
Shengling Xie
Department of Chemistry and Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis and Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Southern University of Science and Technology, Shenzhen, Guangdong, 518055 China
These authors contributed equally.
Search for more papers by this authorChengqing Ning
Department of Chemistry and Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis and Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Southern University of Science and Technology, Shenzhen, Guangdong, 518055 China
These authors contributed equally.
Search for more papers by this authorQingzhen Yu
Department of Chemistry and Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis and Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Southern University of Science and Technology, Shenzhen, Guangdong, 518055 China
These authors contributed equally.
Search for more papers by this authorJieping Hou
Department of Chemistry and Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis and Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Southern University of Science and Technology, Shenzhen, Guangdong, 518055 China
Search for more papers by this authorCorresponding Author
Jing Xu
Department of Chemistry and Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis and Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Southern University of Science and Technology, Shenzhen, Guangdong, 518055 China
E-mail: [email protected]Search for more papers by this authorShengling Xie
Department of Chemistry and Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis and Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Southern University of Science and Technology, Shenzhen, Guangdong, 518055 China
These authors contributed equally.
Search for more papers by this authorChengqing Ning
Department of Chemistry and Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis and Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Southern University of Science and Technology, Shenzhen, Guangdong, 518055 China
These authors contributed equally.
Search for more papers by this authorQingzhen Yu
Department of Chemistry and Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis and Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Southern University of Science and Technology, Shenzhen, Guangdong, 518055 China
These authors contributed equally.
Search for more papers by this authorJieping Hou
Department of Chemistry and Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis and Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Southern University of Science and Technology, Shenzhen, Guangdong, 518055 China
Search for more papers by this authorCorresponding Author
Jing Xu
Department of Chemistry and Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis and Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Southern University of Science and Technology, Shenzhen, Guangdong, 518055 China
E-mail: [email protected]Search for more papers by this authorDedicated to Department of Chemistry, SUSTech, on the occasion of her 10th founding anniversary.
Main observation and conclusion
Owing to their challenging structures and promising biological profiles, spirooxindole alkaloids have long attracted much attention from the synthetic community. Herein, we wish to describe a concise, protecting-group-free total synthesis of cabucine oxindole A, a putative natural spirooxindole alkaloid and a possible biosynthetic congener of cabucine and palmirine. Key transformations of our approach include a one-step, organocatalytic and enantioselective construction of the spiro[pyrrolidine-3,3’-oxindole] moiety and a Korte rearrangement to furnish the final dihydropyran motif. Biological investigation of 1 and its synthetic intermediates revealed lactone 2 as a mild MOLT-4 and MCF7 cell line inhibitor.
Supporting Information
| Filename | Description |
|---|---|
| cjoc202000460-sup-0001-Supinfo.pdfPDF document, 753 KB |
Appendix S1: Supporting Information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1(a) Rottmann, M.; McNamara, C.; Yeung, B. K. S.; Lee, M. C. S.; Zou, B.; Russell, B.; Seitz, P.; Plouffe, D. M.; Dharia, N. V.; Tan, J.; Cohen, S. B.; Spencer, K. R.; Gonzalez-Paéz, G. E.; Lakshminarayana, S. B.; Goh, A.; Suwanarusk, R.; Jegla, T.; Schmitt, E. K.; Beck, H.-P.; Brun, R.; Nosten, F.; Renia, L.; Dartois, V.; Keller, T. H.; Fidock, D. A.; Winzeler, E. A.; Diagana, T. T. Spiroindolones, a potent compound class for the treatment of malaria. Science 2010, 329, 1175–1180; (b) Ye, N.; Chen, H.; Wold, E. A.; Shi, P.-Y.; Zhou, J. Therapeutic potential of spirooxindoles as antiviral agents. ACS Infect Dis. 2016, 2, 382–392; (c) Yu, B.; Zheng, Y.-C.; Shi, X.-J.; Qi, P.-P.; Liu, H.-M. Natural product-derived spirooxindole fragments serve as privileged substructures for discovery of new anticancer agents. Anti-Cancer Agents Med. Chem. 2016, 16, 1315–1324; (d) Zhou, L.-M.; Qu, R.-Y.; Yang, G.-F. An overview of spirooxindole as a promising scaffold for novel drug discovery. Expert. Opin. Drug Discov. 2020, 15, 603–625.
- 2For selected, recent synthesis, see: (a) Shimokawa, J.; Harada, T.; Yokoshima, S.; Fukuyama, T. Total synthesis of gelsemoxonine. J. Am. Chem. Soc. 2011, 133, 17634–17637; (b) Zhou, X.; Xiao, T.; Iwama, Y.; Qin, Y. Biomimetic total synthesis of (+)-gelsemine. Angew. Chem. Int. Ed. 2012, 51, 4909–4912; (c) Diethelm S.; Carreira, E. M. Total synthesis of (±)-gelsemoxonine. J. Am. Chem. Soc. 2013, 135, 8500–8503; (d) Bian, Z.; Marvin, C. C.; Martin, S. F. J. Am. Chem. Soc. 2013, 135, 10886–10889; (e) Kong, K.; Enquist Jr. J. A.; McCallum, M. E.; Smith, G. M.; Matsumaru, T.; Menhaji-Klotz, E.; Wood, J. L. J. Am. Chem. Soc. 2013, 135, 10890–10893; (f) Mercado-Marin, E. V.; Garcia-Reynaga, P.; Romminger, S.; Pimenta, E. F.; Romney, D. K.; Lodewyk, M. W.; Williams, D. E.; Andersen, R. J.; Miller, S. J.; Tantillo, D. J.; Berlinck, R. G. S.; Sarpong, R. Total synthesis and isolation of citrinalin and cyclopiamine congeners. Nature 2014, 509, 318–324; (g) Bian, Z.; Marvin, C. C.; Pettersson, M.; Martin, S. F. J. Am. Chem. Soc. 2014, 136, 14184–14192; (h) Chen, X.; Duan, S.; Tao, C.; Zhai, H.; Qiu, F. G. Total synthesis of (+)-gelsemine via an organocatalytic Diels-Alder approach. Nat. Commun. 2015, 6, 7204–7210; (i) Diethelm, S.; Carreira, E. M. Total synthesis of gelsemoxonine through a spirocyclopropane isoxazolidine ring contraction. J. Am. Chem. Soc. 2015, 137, 6084–6096; (j) Mercado-Marin, E. V.; Sarpong, R. Unified approach to prenylated indole alkaloids: Total syntheses of (–)-17-hydroxycitrinalin B, (+)-stephacidin A, and (+)-notoamide I. Chem. Sci. 2015, 6, 5048–5052; (k) Huang, Y.-M.; Liu, Y.; Zheng, C.-W.; Jin, Q.-W.; Pan, L.; Pan, R.-M.; Liu, J.; Zhao, G. Total synthesis of gelsedilam by means of a thiol-mediated diastereoselective conjugate addition-aldol reaction. Chem.-Eur. J. 2016, 22, 18339–18342; (l) Newcomb, E. T.; Knutson, P. C.; Pedersen, B. A.; Ferreira, E. M. Total synthesis of gelsenicine via a catalyzed cycloisomerization strategy. J. Am. Chem. Soc. 2016, 138, 108–111; (m) Wang, P.; Gao, Y.; Ma, D. Divergent entry to gelsedine-type alkaloids: Total syntheses of (–)-gelsedilam, (–)-gelsenicine, (–)-gelsedine, and (–)-gelsemoxonine. J. Am. Chem. Soc. 2018, 140, 11608–11612. For a recent review, see: (n) Santos, M. M. M. Recent advances in the synthesis of biologically active spirooxindoles. Tetrahedron 2014, 70, 9735–9757.
- 3(a) Lerchner A.; Carreira, E. M. First Total synthesis of (±)-strychnofoline via a highly selective ring-expansion reaction. J. Am. Chem. Soc. 2002, 124, 14826–14827; (b) Lerchner, A.; Carreira, E. M. Synthesis of (±)-strychnofoline via a highly convergent selective annulation reaction. Chem.-Eur. J. 2006, 12, 8208–8219; (c) Yu, Q.; Guo, P.; Jian, J.; Chen, Y.; Xu, J. Nine-step total synthesis of (–)-strychnofoline. Chem. Commun. 2018, 54, 1125–1128.
- 4(a) Edmonson, S. D.; Danishefsky, S. J. The total synthesis of spirotryprostatin A. Angew. Chem. Int. Ed. 1998, 37, 1138–1140;
10.1002/(SICI)1521-3773(19980504)37:8<1138::AID-ANIE1138>3.0.CO;2-N PubMed Web of Science® Google Scholar(b) Edmonson, S. D.; Danishefsky, S. J. Total synthesis of spirotryprostatin A, leading to the discovery of some biologically promising analogues. J. Am. Chem. Soc. 1999, 121, 2147–2155; (c) von Nussbaum, F.; Danishefsky, S. J. A Rapid total synthesis of spirotryprostatin B: Proof of its relative and absolute stereochemistry. Angew. Chem. Int. Ed. 2000, 39, 2175–2178;10.1002/1521-3773(20000616)39:12<2175::AID-ANIE2175>3.0.CO;2-J PubMed Web of Science® Google Scholar(d) Overman, L. E.; Rosen, M. D. Total synthesis of (−)-spirotryprostatin B and three stereoisomers. Angew. Chem. Int. Ed. 2000, 39, 4596–4599;10.1002/1521-3773(20001215)39:24<4596::AID-ANIE4596>3.0.CO;2-F CAS PubMed Web of Science® Google Scholar(e) Wang, H.; Ganesan, A. A biomimetic total synthesis of (−)-spirotryprostatin B and related studies. J. Org. Chem. 2000, 65, 4685–4693; (f) Sebahar, P. R.; Williams, R. M. The asymmetric total synthesis of (+)- and (−)-spirotryprostatin B. J. Am. Chem. Soc. 2000, 122, 5666–5667; (g) Sebahar, P. R.; Osada, H.; Usui, T.; Williams, R. M. Asymmetric, stereocontrolled total synthesis of (+) and (−)-spirotryprostatin B via a diastereoselective azomethine ylide [1,3]-dipolar cycloaddition reaction. Tetrahedron 2002, 58, 6311–6322; (h) Bagul, T. D.; Lakshmaiah, G.; Kawabata, T.; Fuji, K. Total synthesis of spirotryprostatin B via asymmetric nitroolefination. Org. Lett. 2002, 4, 249–251; (i) Meyers, C.; Carreira, E. M. Total synthesis of (−)-spirotryprostatin B. Angew. Chem. Int. Ed. 2003, 42, 694–696; (j) Onishi, T.; Sebahar, P. R.; Williams, R. M. Concise, asymmetric total synthesis of spirotryprostatin A. Org. Lett. 2003, 5, 3135–3137; (k) Onishi, T.; Sebahar, P. R.; Williams, R. M. Concise, asymmetric total synthesis of spirotryprostatin A. Tetrahedron 2004, 60, 9503–9515; (l) Miyake, F. Y.; Yakushijin, K.; Horne, D. A. Preparation and synthetic applications of 2-halotryptophan methyl esters: Synthesis of spirotryprostatin B. Angew. Chem. Int. Ed. 2004, 43, 5357–5360; (m) Miyake, F. Y.; Yakushijin, K.; Horne, D. A. A concise synthesis of spirotryprostatin A. Org. Lett. 2004, 6, 4249–4251; (n) Marti, C.; Carreira, E. M. Total synthesis of (−)-spirotryprostatin B: synthesis and related studies. J. Am. Chem. Soc. 2005, 127, 11505–11515; (o) Trost, B. M.; Stiles, D. T. Total synthesis of spirotryprostatin B via diastereoselective prenylation. Org. Lett. 2007, 9, 2763–2766; (p) Kitahara, K.; Shimokawa, J.; Fukuyama, T. Stereoselective synthesis of spirotryprostatin A. Chem. Sci. 2014, 5, 904–907; (q) Xi, Y.-K.; Zhang, H.; Li, R.-X.; Kang, S.-Y.; Li, J.; Li, Y. Total synthesis of spirotryprostatins through organomediated intramolecular umpolung cyclization. Chem.-Eur. J. 2019, 25, 3005–3009.
- 5
Borges, J.; Manresa, M. T.; Martín Ramón, J. L.; Pascual, C.; Rumbero, A. Two new oxindole alkaloids isolated from Hamelia Patens Jacq. Tetrahedron Lett. 1979, 20, 3197–3200.
10.1016/S0040-4039(01)95361-4 Google Scholar
- 6(a) Sigaut-Titeux, F.; Le Men-Olivier, L.; Le Men, J. Partial synthesis of oxindole derivatives of cabucine and tetraphylline. Bull. Soc. Chim. Fr. 1976, 9–10, 1473–1475; (b) Sigaut-Titeux, F.; Le Men-Olivier, L.; Le Men, J. Heteroyohimbines and their corresponding oxindoles. III. A chemical correlation through seco-oxindoles. Heterocycles 1977, 6, 1129–1132.
- 7(a) Korte, F.; Büchel, K. H. Neuere Methoden der präparativen organischen Chemie II. 15. Die Acyl–lacton–Umlagerung, ein Verfahren zur Darstellung heterocyclischer Ringsysteme. Angew. Chem. 1959, 71, 709–722; (b) For a recent application, see: Younai, A.; Zeng, B.-S.; Meltzer, H. Y.; Scheidt, K. A. Enantioselective syntheses of heteroyohimbine natural products: A unified approach through cooperative catalysis. Angew. Chem. Int. Ed. 2015, 54, 6900–6904; (c) For a recent, related study, see: Wang, X.; Xia, D.; Qin, W.; Zhou, R.; Zhou, X.; Zhou, Q.; Liu, W.; Dai, X.; Wang, H.; Wang, S.; Tan, L.; Zhang, D.; Song, H.; Liu, X.-Y.; Qin, Y. A radical cascade enabling collective syntheses of natural products. Chem 2017, 2, 803–816.
- 8(a) Franzén, J.; Fisher, A. Asymmetric alkaloid synthesis: A one-pot organocatalytic reaction to quinolizidine derivatives. Angew. Chem. Int. Ed. 2009, 48, 787–791; (b) Zhang, W.; Franzén, J. Diverse asymmetric quinolizidine synthesis: A stereodivergent one-pot approach. Adv. Synth. Catal. 2010, 352, 499–518; (c) Zhang, W.; Bah, J.; Wohlfarth, A.; Franzén, J. A stereodivergent strategy for the preparation of corynantheine and ipecac alkaloids, their epimers, and analogues: Efficient total synthesis of (−)-dihydrocorynantheol, (−)-corynantheol, (−)-protoemetinol, (−)-corynantheal, (−)-protoemetine, and related natural and nonnatural compounds. Chem.-Eur. J. 2011, 17, 13814–13824.
- 9(a) Wu, X. Y.; Dai, X. Y.; Nie, L. L.; Fang, H. H.; Chen, J.; Ren, Z. J.; Cao, W. G.; Zhao, G. Organocatalyzed enantioselective one-pot three- component access to indoloquinolizidines by a Michael addition- Pictet-Spengler sequence. Chem. Commun. 2010, 46, 2733–2735; (b) Fang, H. H.; Wu, X. Y.; Nie, L. L.; Dai, X. Y.; Chen, J.; Cao, W. G.; Zhao, G. Diastereoselective syntheses of indoloquinolizidines by a Pictet- Spengler/lactamization cascade. Org. Lett. 2010, 12, 5366–5369; (c) Jin, Z. C.; Wang, X.; Huang, H. C.; Liang, X. M.; Ye, J. X. Diastereo- and enantioselective synthesis of oxazine and oxazolidine derivatives with a chiral quaternary carbon center under multifunctional catalysis. Org. Lett. 2011, 13, 564–567; (d) Zhou, S. L.; Li, J. L.; Dong, L.; Chen, Y. C. Organocatalytic sequential hetero-Diels-Alder and Friedel-Crafts reaction: Constructions of fused heterocycles with scaffold diversity. Org. Lett. 2011, 13, 5874–5877; (e) Wu, X. Y.; Dai, X. Y.; Fang, H. H.; Nie, L. L.; Chen, J.; Cao, W. G.; Zhao, G. One-pot three-component syntheses of indoloquinolizidine derivatives using an organocatalytic Michael addition and subsequent Pictet-Spengler cyclization. Chem.-Eur. J. 2011, 17, 10510–10514; (f) Sun, X.; Ma, D. Organocatalytic approach for the syntheses of corynantheidol, dihydrocorynantheol, protoemetinol, protoemetine, and mitragynine. Chem.-Asian J. 2011, 6, 2158–2165; (g) Jin, Z. C.; Huang, H. C.; Li, W. J.; Luo, X. Y.; Liang, X. M.; Ye, J. X. Enantioselective organocatalytic synthesis of oxazolidine derivatives through a one-pot cascade reaction. Adv. Synth. Catal. 2011, 353, 343–348; (h) Rueping, M.; Volla, C. M. R.; Bolte, M.; Raabe, G. General and efficient organocatalytic synthesis of indoloquinolizidines, pyridoquinazolines and quinazolinones through a one-pot domino Michael addition-cyclization-Pictet- Spengler or 1,2-amine addition reaction. Adv. Synth. Catal. 2011, 353, 2853–2859; (i) Jin, Z.; Yu, F.; Wang, X.; Huang, H.; Luo, X.; Liang, X.; Ye, J. A one-pot asymmetric organocatalytic tandem reaction for the synthesis of oxazine derivatives. Org. Biomol. Chem. 2011, 9, 1809–1816; (j) Rueping, M.; Volla, C. M. R. Brønsted-acid catalyzed condensation-Michael reaction-Pictet-Spengler cyclization-highly stereoselective synthesis of indoloquinolizidines. RSC Adv. 2011, 1, 79–82; (k) Dai, X. Y.; Wu, X. Y.; Fang, H. H.; Nie, L. L.; Chen, J.; Deng, H. M.; Cao, W. G.; Zhao, G. Enantioselective organocatalyzed cascade reactions to highly functionalized quinolizidines. Tetrahedron 2011, 67, 3034–3040; (l) Wu, X. Y.; Fang, H. H.; Liu, Q.; Nie, L. L.; Chen, J.; Cao, W. G.; Zhao, G. Diastereoselective cascade reactions toward substituted diazaindeno[2,1-α]phenanthrenes. Tetrahedron 2011, 67, 7251–7257; (m) Wu, X. Y.; Zhang, Y.; Dai, X. Y.; Fang, H. H.; Chen, J.; Cao, W. G.; Zhao, G. Enantioselective cascade sequence to indoloquinolizidines and its application in the synthesis of epi-geissochizol. Synthesis 2011, 3675–3679; (n) Wu, X. Y.; Liu, Q.; Fang, H. H.; Chen, J.; Cao, W. G.; Zhao, G. Enantioselective organocatalyzed cascade reactions to highly functionalized spirotetracyclic indolenines and oxindoles. Chem.-Eur. J. 2012, 18, 12196–12201; (o) Muratore, M. E.; Shi, L.; Pilling, A. W.; Storer, R. I.; Dixon, D. J. Exploiting a novel size exclusion phenomenon for enantioselective acid/base cascade catalysis. Chem. Commun. 2012, 48, 6351–6353; (p) Lin, S. Z.; Deiana, L.; Tseggai, A.; Córdova, A. Concise total synthesis of dihydrocorynanthenol, protoemetinol, protoemetine, 3-epi-protoemetinol and emetine. Eur. J. Org. Chem. 2012, 398–408; (q) Hong, B.-C.; Liao, W.-K.; Dange, N. S.; Liao, J.-H. One-pot organocatalytic enantioselective domino double-Michael reaction and Pictet-Spengler-lactamization reaction. A facile entry to the “inside yohimbine” system with five contiguous stereogenic centers. Org. Lett. 2013, 15, 468–471; (r) Aillaud, I.; Barber, D. M.; Thompson, A. L.; Dixon, D. J. Enantioselective Michael addition/iminium ion cyclization cascades of tryptamine-derived ureas. Org. Lett. 2013, 15, 2946–2949; (s) Suryavanshi, P. A.; Sridharan, V.; Menéndez, J. C. A β-enaminone-initiated multicomponent domino reaction for the synthesis of indoloquinolizines and benzoquinolizines from acyclic precursors. Chem.-Eur. J. 2013, 19, 13207–13215; (t) Zhang, H.; Ma, X.; Kang, H.; Hong, L.; Wang, R. The enantioselective formal synthesis of rhynchophylline and isorhynchophylline. Chem.-Asian J. 2013, 8, 542–545; (u) Tan, Y.; Luan, H.-L.; Lin, H.; Sun, X.-W.; Yang, X.-D.; Dong, H.-Q.; Lin, G.-Q. One-pot enantioselective construction of indoloquinolizidine derivatives bearing five contiguous stereocenters using aliphatic aldehydes, nitroethylenes, and tryptamine. Chem. Commun. 2014, 50, 10027–10030; (v) Du, H.; Rodriguez, J.; Bugaut, X.; Constantieux, T. Organocatalytic enantioselective multicomponent synthesis of pyrrolopiperazines. Adv. Synth. Catal. 2014, 356, 851–856; (w) Li, L.; Aibibula, P.; Jia, Q.; Jia, Y. Total syntheses of naucleamides A–C and E, geissoschizine, geissoschizol, (E)-isositsirikine, and 16-epi-(E)-iso-sitsirikine. Org. Lett. 2017, 19, 2642–2645; (x) He, W.-X.; Xing, X.; Yang, Z.-J.; Yu, Y.; Wang, N.; Yu, X.-Q. Biocatalytic one-pot three-component synthesis of indoloquinolizines with high diastereoselectivity. Catal. Lett. 2019, 149, 638–643; (y) Maity, P.; Adhikari, D.; Jana, A. K. An overview on synthetic entries to tetrahydro-β-carbolines. Tetrahedron 2019, 75, 965–1028; (z) Usman, M.; Hu, X.-D.; Liu, W.-B. Recent Advances and Perspectives in the Synthesis and Applications of Tetrahydrocarbazol-4-ones. Chin. J. Chem. 2020, 38, 737–752.
- 10 CCDC 2010560 (Compound 2) 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.
- 11(a) Hoffmann, R. W. Protecting-group-free synthesis. Synthesis 2006, 3531–3541; (b) Young, I. S.; Baran, P. S. Protecting-group-free synthesis as an opportunity for invention. Nat. Chem. 2009, 1, 193–205; (c) Saicic, R. N. Protecting group-free syntheses of natural products and biologically active compounds. Tetrahedron 2014, 70, 8183–8218; (d) Hui, C.; Chen, F.; Pu, F.; Xu, J. Innovation in protecting- group-free natural product synthesis. Nat. Rev. Chem. 2019, 3, 85–107.
