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Catalyst-controlled oligomerization for the collective synthesis of polypyrroloindoline natural products

Abstract

In nature, many organisms generate large families of natural product metabolites that have related molecular structures as a means to increase functional diversity and gain an evolutionary advantage against competing systems within the same environment. One pathway commonly employed by living systems to generate these large classes of structurally related families is oligomerization, wherein a series of enzymatically catalysed reactions is employed to generate secondary metabolites by iteratively appending monomers to a growing serial oligomer chain. The polypyrroloindolines are an interesting class of oligomeric natural products that consist of multiple cyclotryptamine subunits. Herein we describe an iterative application of asymmetric copper catalysis towards the synthesis of six distinct oligomeric polypyrroloindoline natural products: hodgkinsine, hodgkinsine B, idiospermuline, quadrigemine H and isopsychotridine B and C. Given the customizable nature of the small-molecule catalysts employed, we demonstrate that this strategy is further amenable to the construction of quadrigemine H-type alkaloids not isolated previously from natural sources.

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Figure 1: Nature's method for the construction of polypyrroloindoline oligomers.
Figure 2: Design of orthogonal monomers and catalyst-controlled oligomerization.
Figure 3: Synthesis of hodgkinsine and hodgkinsine B, quadrigemine H and isopsychotridine B and C.
Figure 4: Synthesis of two putatively unnatural quadrigemines.

References

  1. 1

    Hodson, H. F., Robinson, B. & Smith, S. F. Chimonanthine, a new calycanthaceous alkaloid. Proc. Chem. Soc. 465–466 (1961).

  2. 2

    Anet, E. F. L. J., Hughes, G. K. & Ritchie, E. Hodgkinsine, the alkaloid of Hodgkinsonia frutescens F. Muell. Aust. J. Chem. 14, 173–174 (1961).

    CAS  Article  Google Scholar 

  3. 3

    Fridrichsons, J., Mackay, M. F. & Mathieson, A. McL . The molecular structure of hodgkinsine, C33H38N6 . Tetrahedron Lett. 8, 3521–3524 (1967).

    Article  Google Scholar 

  4. 4

    Fridrichsons, J., Mackay, M. F. & Mathieson, A. McL . The absolute molecular structure of hodgkinsine. Tetrahedron 30, 85–92 (1974).

    CAS  Article  Google Scholar 

  5. 5

    Roth, A., Kuballa, B., Cabalion, P. & Anton, R. Preliminary study of the alkaloids of Psychotria forsteriana. Planta Med. 51, 289 (1985).

    Article  Google Scholar 

  6. 6

    Beretz, A. et al. Polyindolic alkaloids from Psychotria forsteriana. Potent inhibitors of the aggregation of human platelets. Planta Med. 51, 300–303 (1985).

    CAS  Article  Google Scholar 

  7. 7

    Saad, H.-E. A. Contribution à l'Étude des Alcaloïdes d'Espéces Nouvelles de Rubiacées: Calycodendron milnei (A. Gray) A.C. Smith et de Lindenia Austro-caledonica Brongn. et de Quelques Propriétés Pharmacologiques PhD thesis, Univ. Louis Pasteur de Strasbourg (1986).

  8. 8

    Libot, F. et al. Plants of New Caledonia: rubiaceae of oceania: alkaloids of Psychotria oleoides from New Caledonia and Calycodendron milnei from Vanuatu (New Hebrides). J. Nat. Prod. 50, 468–473 (1987).

    CAS  Article  Google Scholar 

  9. 9

    Adjibadé, Y. et al. In vitro cytotoxicity of polyindolenine alkaloids on rat hepatoma cell lines. Structure activity relationships. J. Ethnopharmacol. 29, 127–136 (1990).

    Article  Google Scholar 

  10. 10

    Guéritte-Voegelein, F. et al. Alkaloids from Psychotria oleoides with activity on growth hormone release. J. Nat. Prod. 55, 923–930 (1992).

    Article  Google Scholar 

  11. 11

    Saad, H.-E. A., Sharkawy, S. H. & Shier, W. T. Biological activities of pyrrolidinoindoline alkaloids from Calycodendron milnei. Planta Med. 61, 313–316 (1995).

    CAS  Article  Google Scholar 

  12. 12

    Duke, R. K. et al. Idiospermuline, a trimeric pyrrolidinoindoline alkaloid from the seed of Idiospermum australiense. J. Nat. Prod. 58, 1200–1208 (1995).

    CAS  Article  Google Scholar 

  13. 13

    Jannic, V. et al. Pyrrolidinoindoline alkaloids from Psychotria oleoides and Psychotria lyciiflora. J. Nat. Prod. 62, 838–843 (1999).

    CAS  Article  Google Scholar 

  14. 14

    Amador, T. A., Verotta, L., Nunes, D. S. & Elisabetsky, E. Antinociceptive profile of hodgkinsine. Planta Med. 66, 770–772 (2000).

    CAS  Article  Google Scholar 

  15. 15

    Steven, A. & Overman, L. E. Total synthesis of complex cyclotryptamine alkaloids: stereocontrolled construction of quaternary carbon stereocenters. Angew. Chem. Int. Ed. 46, 5488–5508 (2007).

    CAS  Article  Google Scholar 

  16. 16

    Robinson, R. & Teuber, H. J. Reactions with nitrosodisulfonate. IV. Calycanthine and calycanthidine. Chem. Ind. 783–784 (1954).

  17. 17

    Scott, A. I., McCapra, F. & Hall, E. S. Chimonanthine. One-step synthesis and biosynthetic model. J. Am. Chem. Soc. 86, 302–303 (1964).

    CAS  Article  Google Scholar 

  18. 18

    Lebsack, A. D., Link, J. T., Overman, L. E. & Stearns, B. A. Enantioselective total synthesis of quadrigemine C and psycholeine. J. Am. Chem. Soc. 124, 9008–9009 (2002).

    CAS  Article  Google Scholar 

  19. 19

    Kodanko, J. J. & Overman, L. E. Enantioselective total syntheses of the cyclotryptamine alkaloids hodgkinsine and hodgkinsine B. Angew. Chem. Int. Ed. 42, 2528–2531 (2003).

    CAS  Article  Google Scholar 

  20. 20

    Overman, L. E. & Peterson, E. A. Enantioselective total synthesis of the cyclotryptamine alkaloid idiospermuline. Angew. Chem. Int. Ed. 42, 2525–2528 (2003).

    CAS  Article  Google Scholar 

  21. 21

    Overman, L. E. & Peterson, E. A. Enantioselective synthesis of (–)-idiospermuline. Tetrahedron 59, 6905–6919 (2003).

    CAS  Article  Google Scholar 

  22. 22

    Foo, K., Newhouse, T., Mori, I., Takayama, H. & Baran, P. S. Total synthesis guided structure elucidation of (+)-psychotetramine. Angew. Chem. Int. Ed. 50, 2716–2719 (2011).

    CAS  Article  Google Scholar 

  23. 23

    Snell, R. H., Woodward, R. L. & Willis, M. C. Catalytic enantioselective total synthesis of hodgkinsine B. Angew. Chem. Int. Ed. 50, 9116–9119 (2011).

    CAS  Article  Google Scholar 

  24. 24

    Snell, R. H., Durbin, M. J., Woodward, R. L. & Willis, M. C. Catalytic enantioselective desymmetrization as a tool for the synthesis of hodgkinsine and hodgkinsine B. Chem. Eur. J. 18, 16754–16764 (2012).

    CAS  Article  Google Scholar 

  25. 25

    Sung, L. Studies Towards the Enantioselective Total synthesis of Quadrigemine H PhD thesis, Univ. California (2008).

    Google Scholar 

  26. 26

    Kodanko, J. J. et al. Synthesis of all low-energy stereoisomers of the tris(pyrrolidinoindoline) alkaloid hodgkinsine and preliminary assessment of their antinociceptive activity. J. Org. Chem. 72, 7909–7914 (2007).

    CAS  Article  Google Scholar 

  27. 27

    Canham, S. M. et al. Stereocontrolled enantioselective total synthesis of the [2+2] quadrigemine alkaloids. Tetrahedron 71, 6424–6436 (2015).

    CAS  Article  Google Scholar 

  28. 28

    Zhu, S. & MacMillan, D. W. C. Enantioselective copper-catalyzed construction of aryl pyrroloindolines via an arylation-cyclization cascade. J. Am. Chem. Soc. 134, 10815–10818 (2012).

    CAS  Article  Google Scholar 

  29. 29

    Overman, L. E., Paone, D. V. & Stearns, B. A. Direct stereo- and enantiocontrolled synthesis of vicinal stereogenic quaternary carbon centers. Total synthesis of meso- and (–)-chimonanthine and (+)-calycanthine. J. Am. Chem. Soc. 121, 7702–7703 (1999).

    CAS  Article  Google Scholar 

  30. 30

    Ishikawa, H., Takayama, H. & Aimi, N. Dimerization of indole derivatives with hypervalent iodines(III): a new entry for the concise total synthesis of rac- and meso-chimonanthines. Tetrahedron Lett. 43, 5637–5639 (2002).

    CAS  Article  Google Scholar 

  31. 31

    Menozzi, C., Dalko, P. I. & Cossy, J. Concise synthesis of the (±)-Nb-desmethyl-meso-chimonanthine. Chem. Commun. 93, 4638–4640 (2006).

    Article  Google Scholar 

  32. 32

    Movassaghi, M. & Schmidt, M. A. Concise total synthesis of (–)-calycanthine, (+)-chimonanthine, and (+)-folicanthine. Angew. Chem. Int. Ed. 46, 3725–3728 (2007).

    CAS  Article  Google Scholar 

  33. 33

    Burke, A. J. et al. Cu(I) catalysed cyclopropanation of olefins: stereoselectivity studies with arylid-BOX and isbut-BOX ligands. J. Organomet. Chem. 692, 4863–4874 (2007).

    CAS  Article  Google Scholar 

  34. 34

    Fuchs, J. R. & Funk, R. L. Total synthesis of (±)-perophoramidine. J. Am. Chem. Soc. 126, 5068–5069 (2004).

    CAS  Article  Google Scholar 

  35. 35

    Hinman, R. L. & Bauman, C. P. Reactions of N-bromosuccinimide and indoles. Simple synthesis of 3-bromooxindoles. J. Org. Chem. 29, 1206–1215 (1964).

    CAS  Article  Google Scholar 

  36. 36

    Fuchs, J. R. & Funk, R. L. Indol-2-one intermediates: mechanistic evidence and synthetic utility. Total syntheses of (±)-flustramines A and C. Org. Lett. 7, 677–680 (2005).

    CAS  Article  Google Scholar 

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Acknowledgements

We are grateful for the financial support provided by the NIHGMS (RO1 GM103558-04) and kind gifts from Merck. We are also grateful to L. Verotta for providing extracts from P. muscosa, C. Kraml, N. Byrne and L. Wilson (Lotus Separations) and E. Rowley (Chiromics) for compound purification, P. Jeffrey for assistance with X-ray structure determination and I. Pelczer and K. Conover for assistance with NMR sspectroscopy.

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C.R.J., J.J.B., J.M.L. and R.J.C. performed and analysed the experiments. C.R.J., J.J.B., J.M.L., R.J.C. and D.W.C.M. designed the experiments. C.R.J., J.J.B., J.M.L. and D.W.C.M. prepared this manuscript.

Corresponding author

Correspondence to David W. C. MacMillan.

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The authors declare no competing financial interests.

Supplementary information

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Supplementary information (PDF 18333 kb)

Supplementary information

Crystallographic data for compound 2. (CIF 30 kb)

Supplementary information

Crystallographic data for compound Quadrigemine H tetramethiodide salt. (CIF 955 kb)

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Jamison, C., Badillo, J., Lipshultz, J. et al. Catalyst-controlled oligomerization for the collective synthesis of polypyrroloindoline natural products. Nature Chem 9, 1165–1169 (2017). https://doi.org/10.1038/nchem.2825

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