Article | Published:

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

Nature Chemistry volume 9, pages 11651169 (2017) | Download Citation

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.

  • Compound

    2-(1H-indol-3-yl)-N-methylacetamide

  • Compound

    mesityl(3-(2-(methylamino)-2-oxoacetyl)-1H-indol-7-yl)iodonium perchlorate

  • Compound

    N-methyl-2-(7-((3aR,8aR)-1-methyl-2-oxo-2,3,8,8a-tetrahydropyrrolo[2,3-b]indol-3a(1H)-yl)-1H-indol-3-yl)-2-oxoacetamide

  • Compound

    N-methyl-2-(7-((3aR,8aR)-1-methyl-2-oxo-2,3,8,8a-tetrahydropyrrolo[2,3-b]indol-3a(1H)-yl)-1H-indol-3-yl)acetamide

  • Compound

    2-(7-((3aR,3'aS,8aR,8'aR)-1,1'-dimethyl-2,2'-dioxo-2,2',3,3',8,8a,8',8'a-octahydro-1H-[3a,7'-bipyrrolo[2,3-b]indol]-3'a(1'H)-yl)-1H-indol-3-yl)-N-methylacetamide

  • Compound

    N-methyl-2-(7-((3aR,3'aR,3''aS,8aR,8'aR,8''aR)-1,1',1''-trimethyl-2,2',2''-trioxo-2,2',2'',3,3',3'',8,8a,8',8'a,8'',8''a-dodecahydro-1H,1'H-[3a,7':3'a,7''-terpyrrolo[2,3-b]indol]-3''a(1''H)-yl)-1H-indol-3-yl)acetamide

  • Compound

    copper(I) (4S,4'S)-2,2'-(2-methylprop-1-ene-1,1-diyl)bis(4-phenyl-4,5-dihydrooxazole) perchlorate

  • Compound

    copper(I) (4R,4’R)-2,2’-(2-methylprop-1-ene-1,1-diyl)bis(4-phenyl-4,5-dihydrooxazole) perchlorate

  • Compound

    methyl (3aS,8aS)-8-benzyl-3a-((R)-7-((3aR,8aR)-1-methyl-2-oxo-2,3,8,8a-tetrahydropyrrolo[2,3-b]indol-3a(1H)-yl)-3-(2-(methylamino)-2-oxoethyl)-2-oxoindolin-3-yl)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate

  • Compound

    methyl (3aR,8aR)-8-benzyl-3a-((S)-7-((3aR,8aR)-1-methyl-2-oxo-2,3,8,8a-tetrahydropyrrolo[2,3-b]indol-3a(1H)-yl)-3-(2-(methylamino)-2-oxoethyl)-2-oxoindolin-3-yl)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate

  • Compound

    methyl (3aS,8aS)-8-benzyl-3a-((R)-7-((3aR,3'aR,8aR,8'aR)-1,1'-dimethyl-2,2'-dioxo-2,2',3,3',8,8a,8',8'a-octahydro-1H-[3a,7'-bipyrrolo[2,3-b]indol]-3'a(1'H)-yl)-3-(2-(methylamino)-2-oxoethyl)-2-oxoindolin-3-yl)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate

  • Compound

    methyl (3aS,8aS)-8-benzyl-3a-((R)-3-(2-(methylamino)-2-oxoethyl)-2-oxo-7-((3aR,3'aR,3''aR,8aR,8'aR,8''aR)-1,1',1''-trimethyl-2,2',2''-trioxo-2,2',2'',3,3',3'',8,8a,8',8'a,8'',8''a-dodecahydro-1H,1'H-[3a,7':3'a,7''-terpyrrolo[2,3-b]indol]-3''a(1''H)-yl)indolin-3-yl)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate

  • Compound

    methyl (3aR,8aR)-8-benzyl-3a-((S)-3-(2-(methylamino)-2-oxoethyl)-2-oxo-7-((3aR,3'aR,3''aR,8aR,8'aR,8''aR)-1,1',1''-trimethyl-2,2',2''-trioxo-2,2',2'',3,3',3'',8,8a,8',8'a,8'',8''a-dodecahydro-1H,1'H-[3a,7':3'a,7''-terpyrrolo[2,3-b]indol]-3''a(1''H)-yl)indolin-3-yl)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate

  • Compound

    2-(7-((3aR,3'aR,8aR,8'aS)-1,1'-dimethyl-2,2'-dioxo-2,2',3,3',8,8a,8',8'a-octahydro-1H-[3a,7'-bipyrrolo[2,3-b]indol]-3'a(1'H)-yl)-1H-indol-3-yl)-N-methylacetamide

  • Compound

    methyl (3aS,8aS)-8-benzyl-3a-((R)-7-((3aR,3'aS,8aR,8'aS)-1,1'-dimethyl-2,2'-dioxo-2,2',3,3',8,8a,8',8'a-octahydro-1H-[3a,7'-bipyrrolo[2,3-b]indol]-3'a(1'H)-yl)-3-(2-(methylamino)-2-oxoethyl)-2-oxoindolin-3-yl)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate

  • Compound

    methyl (3aR,8aR)-8-benzyl-3a-((S)-7-((3aR,3'aS,8aR,8'aS)-1,1'-dimethyl-2,2'-dioxo-2,2',3,3',8,8a,8',8'a-octahydro-1H-[3a,7'-bipyrrolo[2,3-b]indol]-3'a(1'H)-yl)-3-(2-(methylamino)-2-oxoethyl)-2-oxoindolin-3-yl)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate

  • Compound

    unnatural quadrigemine

  • Compound

    unnatural quadrigemine

  • Compound

    (3-(2-(methylamino)-2-oxoacetyl)-1H-indol-7-yl)boronic acid

  • Compound

    copper(I) bis(pivalonitrile) perchlorate

  • Compound

    2-(3-chloro-7-((3aR,8aR)-1-methyl-2-oxo-2,3,8,8a-tetrahydropyrrolo[2,3-b]indol-3a(1H)-yl)-2-oxoindolin-3-yl)-N-methylacetamide

  • Compound

    2-(7-((3aR,3'aS,8aR,8'aR)-1,1'-dimethyl-2,2'-dioxo-2,2',3,3',8,8a,8',8'a-octahydro-1H-[3a,7'-bipyrrolo[2,3-b]indol]-3'a(1'H)-yl)-1H-indol-3-yl)-N-methyl-2-oxoacetamide

  • Compound

    2-(3-chloro-7-((3aR,3'aR,8aR,8'aR)-1,1'-dimethyl-2,2'-dioxo-2,2',3,3',8,8a,8',8'a-octahydro-1H-[3a,7'-bipyrrolo[2,3-b]indol]-3'a(1'H)-yl)-2-oxoindolin-3-yl)-N-methylacetamide

  • Compound

    N-methyl-2-oxo-2-(7-((3aR,3'aR,3''aS,8aR,8'aR,8''aR)-1,1',1''-trimethyl-2,2',2''-trioxo-2,2',2'',3,3',3'',8,8a,8',8'a,8'',8''a-dodecahydro-1H,1'H-[3a,7':3'a,7''-terpyrrolo[2,3-b]indol]-3''a(1''H)-yl)-1H-indol-3-yl)acetamide

  • Compound

    2-(7-((3aR,3'aR,8aR,8'aS)-1,1'-dimethyl-2,2'-dioxo-2,2',3,3',8,8a,8',8'a-octahydro-1H-[3a,7'-bipyrrolo[2,3-b]indol]-3'a(1'H)-yl)-1H-indol-3-yl)-N-methyl-2-oxoacetamide

  • Compound

    2-(3-chloro-7-((3aR,3'aS,8aR,8'aS)-1,1'-dimethyl-2,2'-dioxo-2,2',3,3',8,8a,8',8'a-octahydro-1H-[3a,7'-bipyrrolo[2,3-b]indol]-3'a(1'H)-yl)-2-oxoindolin-3-yl)-N-methylacetamide

  • Compound

    N-Bn unnatural quadrigemine

  • Compound

    2-((R)-3-((3aR,3'aS,8aR,8'aS)-1,1'-dimethyl-2,2'-dioxo-2,2',3,3',8,8a,8',8'a-octahydro-1H-[3a,7'-bipyrrolo[2,3-b]indol]-3'a(1'H)-yl)-7-((3aR,8aR)-1-methyl-2-oxo-2,3,8,8a-tetrahydropyrrolo[2,3-b]indol-3a(1H)-yl)-2-oxoindolin-3-yl)-N-methylacetamide

  • Compound

    2-(7-((3aR,8aS)-1,8-dimethyl-2-oxo-2,3,8,8a-tetrahydropyrrolo[2,3-b]indol-3a(1H)-yl)-1H-indol-3-yl)-N-methyl-2-oxoacetamide

  • Compound

    2-(7-((3aR,8aS)-1,8-dimethyl-2-oxo-2,3,8,8a-tetrahydropyrrolo[2,3-b]indol-3a(1H)-yl)-1H-indol-3-yl)-N-methylacetamide

  • Compound

    methyl (3aR,3'aR,3''aR,8aR,8'aR,8''aS)-1',1'',8,8''-tetramethyl-2',2''-dioxo-2,2',2'',3,3',3'',8,8a,8',8'a,8'',8''a-dodecahydro-1H,1'H,1''H-[3a,3'a:7',3''a-terpyrrolo[2,3-b]indole]-1-carboxylate

  • Compound

    methyl (3aS,3'aR,3''aR,8aS,8'aR,8''aS)-1',1'',8,8''-tetramethyl-2',2''-dioxo-2,2',2'',3,3',3'',8,8a,8',8'a,8'',8''a-dodecahydro-1H,1'H,1''H-[3a,3'a:7',3''a-terpyrrolo[2,3-b]indole]-1-carboxylate

  • Compound

    methyl (3aR,3'aS,3''aR,8aR,8'aS,8''aS)-1',1'',8,8''-tetramethyl-2',2''-dioxo-2,2',2'',3,3',3'',8,8a,8',8'a,8'',8''a-dodecahydro-1H,1'H,1''H-[3a,3'a:7',3''a-terpyrrolo[2,3-b]indole]-1-carboxylate

  • Compound

    methyl (3aS,3'aS,3''aR,8aS,8'aS,8''aS)-1',1'',8,8''-tetramethyl-2',2''-dioxo-2,2',2'',3,3',3'',8,8a,8',8'a,8'',8''a-dodecahydro-1H,1'H,1''H-[3a,3'a:7',3''a-terpyrrolo[2,3-b]indole]-1-carboxylate

  • Compound

    3a,8a,3a,8a'-tetra-epiidiospermuline

  • Compound

    bis-epiidiospermuline

  • Compound

    bis-epiidiospermuline

  • Compound

    N-Bn hodgkinsine

  • Compound

    N-Bn hodgkinsine B

  • Compound

    hodgkinsine

  • Compound

    hodgkinsine B

  • Compound

    quadrigemine H

  • Compound

    quadrigemine H tetramethiodide salt

  • Compound

    idiospermuline

  • Compound

    isopsychotridine B

  • Compound

    isopsychotridine C

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References

  1. 1.

    , & Chimonanthine, a new calycanthaceous alkaloid. Proc. Chem. Soc. 465–466 (1961).

  2. 2.

    , & Hodgkinsine, the alkaloid of Hodgkinsonia frutescens F. Muell. Aust. J. Chem. 14, 173–174 (1961).

  3. 3.

    , & . The molecular structure of hodgkinsine, C33H38N6. Tetrahedron Lett. 8, 3521–3524 (1967).

  4. 4.

    , & . The absolute molecular structure of hodgkinsine. Tetrahedron 30, 85–92 (1974).

  5. 5.

    , , & Preliminary study of the alkaloids of Psychotria forsteriana. Planta Med. 51, 289 (1985).

  6. 6.

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

  7. 7.

    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.

    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).

  9. 9.

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

  10. 10.

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

  11. 11.

    , & Biological activities of pyrrolidinoindoline alkaloids from Calycodendron milnei. Planta Med. 61, 313–316 (1995).

  12. 12.

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

  13. 13.

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

  14. 14.

    , , & Antinociceptive profile of hodgkinsine. Planta Med. 66, 770–772 (2000).

  15. 15.

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

  16. 16.

    & Reactions with nitrosodisulfonate. IV. Calycanthine and calycanthidine. Chem. Ind. 783–784 (1954).

  17. 17.

    , & Chimonanthine. One-step synthesis and biosynthetic model. J. Am. Chem. Soc. 86, 302–303 (1964).

  18. 18.

    , , & Enantioselective total synthesis of quadrigemine C and psycholeine. J. Am. Chem. Soc. 124, 9008–9009 (2002).

  19. 19.

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

  20. 20.

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

  21. 21.

    & Enantioselective synthesis of (–)-idiospermuline. Tetrahedron 59, 6905–6919 (2003).

  22. 22.

    , , , & Total synthesis guided structure elucidation of (+)-psychotetramine. Angew. Chem. Int. Ed. 50, 2716–2719 (2011).

  23. 23.

    , & Catalytic enantioselective total synthesis of hodgkinsine B. Angew. Chem. Int. Ed. 50, 9116–9119 (2011).

  24. 24.

    , , & Catalytic enantioselective desymmetrization as a tool for the synthesis of hodgkinsine and hodgkinsine B. Chem. Eur. J. 18, 16754–16764 (2012).

  25. 25.

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

  26. 26.

    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).

  27. 27.

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

  28. 28.

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

  29. 29.

    , & 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).

  30. 30.

    , & 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).

  31. 31.

    , & Concise synthesis of the (±)-Nb-desmethyl-meso-chimonanthine. Chem. Commun. 93, 4638–4640 (2006).

  32. 32.

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

  33. 33.

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

  34. 34.

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

  35. 35.

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

  36. 36.

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

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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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  1. Department of Chemistry, Princeton University, 192 Frick Laboratory, Princeton, New Jersey 08540, USA

    • Christopher R. Jamison
    • , Joseph J. Badillo
    • , Jeffrey M. Lipshultz
    • , Robert J. Comito
    •  & David W. C. MacMillan

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David W. C. MacMillan.

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    Supplementary information

    Crystallographic data for compound 2.

  2. 2.

    Supplementary information

    Crystallographic data for compound Quadrigemine H tetramethiodide salt.

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https://doi.org/10.1038/nchem.2825

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