Enantioselective dearomative prenylation of indole derivatives

Abstract

Prenylation is a ubiquitous process common to almost all living organisms, and a key transformation in organic synthesis. Dearomative prenylation reactions of tryptophan derivatives lead to various prenylated indoline alkaloids with diverse biological activities. However, enantioselective dearomative prenylations without a pre-installed stereogenic centre in the substrate have not been reported. Here, we show that a small molecule-based catalytic system derived from a commercially available palladium precursor and a chiral phosphoramidite ligand (allylphos) can catalyse the enantioselective dearomative prenylation of indole derivatives, which tolerates a much broader substrate scope than those of known enzymatic dearomative prenylation processes. Enantioselective dearomative geranylation and farnesylation reactions also proceed smoothly under the standard conditions. The concise total or formal syntheses of a series of natural products can be realized using this catalytic system. The mechanistic investigations provide deep insights for the further design of chiral ligands and catalysts for asymmetric reactions.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Structures and syntheses of prenylated molecules.
Fig. 2: Substrate scope of the dearomative prenylation reaction.
Fig. 3: Total syntheses of (−)-flustramine B, pseudophrynaminol and mollenine A.
Fig. 4: Substrate scope for the cascade approach towards the preparation of prenylated indole alkaloids.
Fig. 5: Mechanistic studies.

References

  1. 1.

    Sacchettini, J. C. & Poulter, C. D. Creating isoprenoid diversity. Science 277, 1788–1789 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    Walsh, C. T., Garneau-Tsodikova, S. & Gatto, G. J. Jr. Protein posttranslational modifications: the chemistry of proteome diversifications. Angew. Chem. Int. Ed. 44, 7342–7372 (2005).

    Article  CAS  Google Scholar 

  3. 3.

    Chang, W.-C., Song, H., Liu, H.-W. & Liu, P. Current development in isoprenoid precursor biosynthesis and regulation. Curr. Opin. Chem. Biol. 17, 571–579 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Zhang, H., Boghigian, B. A., Armando, J. & Pfeifer, B. A. Methods and options for the heterologous production of complex natural products. Nat. Prod. Rep. 28, 125–151 (2011).

    Article  PubMed  Google Scholar 

  5. 5.

    Oldfield, E. & Lin, F.-Y. Terpene biosynthesis: modularity rules. Angew. Chem. Int. Ed. 51, 1124–1137 (2012).

    Article  CAS  Google Scholar 

  6. 6.

    Williams, R. M., Stocking, E. M. & Sanz-Cervera, J. F. Biosynthesis of prenylated alkaloids derived from tryptophan. Top. Curr. Chem. 209, 97–173 (2000).

    Article  CAS  Google Scholar 

  7. 7.

    Li, S.-M. Prenylated indole derivatives from fungi: structure diversity, biological activities, biosynthesis and chemoenzymatic synthesis. Nat. Prod. Rep. 27, 57–78 (2010).

    Article  PubMed  Google Scholar 

  8. 8.

    Lindel, T., Marsch, N. & Adla, S. K. Indole prenylation in alkaloid synthesis. Top. Curr. Chem. 309, 67–129 (2011).

    Article  CAS  Google Scholar 

  9. 9.

    Carlé, J. S. & Christophersen, C. Bromo-substituted physostigmine alkaloids from a marine Bryozoa Flusta foliacea. J. Am. Chem. Soc. 101, 4012–4013 (1979).

    Article  Google Scholar 

  10. 10.

    Holst, P. B., Anthoni, U., Christophersen, C. & Nielsen, P. H. Marine alkaloids, 15. Two alkaloids, flustramine E and debromoflustramine B, from the marine Bryozoan Flustra foliacea. J. Nat. Prod. 57, 997–1000 (1994).

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Wang, H.-J., Gloer, J. B., Wicklow, D. T. & Dowd, P. F. Mollenines A and B: new dioxomorpholines from the ascostromata of Eupenicillium molle. J. Nat. Prod. 61, 804–807 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Spande, T. F. et al. Pseudophrynamine A: an unusual prenyl pyrrolo[2,3-b]indole ester from an Australian frog, Pseudophryne coriacea (Myobatrachidae). J. Org. Chem. 53, 1222–1226 (1988).

    Article  CAS  Google Scholar 

  13. 13.

    Badio, B., Garraffo, H. M., Padgett, W. L., Greig, N. H. & Daly, J. W. Pseudophrynaminol: a potent noncompetitive blocker of nicotinic receptor-channels. Biochem. Pharmacol. 53, 671–676 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Skiredj, A., Beniddir, M. A., Evanno, L. & Poupon, E. Mimicking the main events of the biosynthesis of drimentines: synthesis of Δ8’-isodrimentine A and related compounds. Eur. J. Org. Chem. 2016, 2954–2958 (2016).

    Article  CAS  Google Scholar 

  15. 15.

    Tanner, M. E. Mechanistic studies on the indole prenyltransferases. Nat. Prod. Rep. 32, 88–101 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Austin, J. F., Kim, S.-G., Sinz, C. J., Xiao, W.-J. & MacMillan, D. W. C. Enantioselective organocatalytic construction of pyrroloindolines by a cascade addition–cyclization strategy: synthesis of (−)-flustramine B. Proc. Natl Acad. Sci. USA 101, 5482–5487 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Trost, B. M., Malhotra, S. & Chan, W. H. Exercising regiocontrol in palladium-catalyzed asymmetric prenylations and geranylation: unifying strategy toward flustramines A and B. J. Am. Chem. Soc. 133, 7328–7331 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Pape, A. R., Kaliappan, K. P. & Kündig, E. P. Transition-metal-mediated dearomatization reactions. Chem. Rev. 100, 2917–2940 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Davies, H. M. L. & Hedley, S. J. Intermolecular reactions of electron-rich heterocycles with copper and rhodium carbenoids. Chem. Soc. Rev. 36, 1109–1119 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Roche, S. P. & Porco, J. A. Jr. Dearomatization strategies in the synthesis of complex natural products. Angew. Chem. Int. Ed. 50, 4068–4093 (2011).

    Article  CAS  Google Scholar 

  21. 21.

    Zhuo, C.-X., Zhang, W. & You, S.-L. Catalytic asymmetric dearomatization reactions. Angew. Chem. Int. Ed. 51, 12662–12686 (2012).

    Article  CAS  Google Scholar 

  22. 22.

    Zhuo, C.-X., Zheng, C. & You, S.-L. Transition-metal-catalyzed asymmetric allylic dearomatization reactions. Acc. Chem. Res. 47, 2558–2573 (2014).

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Repka, L. M., Ni, J. & Reisman, S. E. Enantioselective synthesis of pyrroloindolines by a formal [3+2] cycloaddition reaction. J. Am. Chem. Soc. 132, 14418–14420 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Jones, S. B., Simmons, B., Mastracchio, A. & MacMillan, D. W. C. Collective synthesis of natural products by means of organocascade catalysis. Nature 475, 183–188 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Spangler, J. E. & Davies, H. M. L. Catalytic asymmetric synthesis of pyrroloindolines via a rhodium(II)-catalyzed annulation of indoles. J. Am. Chem. Soc. 135, 6802–6805 (2013).

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Xiong, H., Xu, H., Liao, S., Xie, Z. & Tang, Y. Copper-catalyzed highly enantioselective cyclopentannulation of indoles with donor−acceptor cyclopropanes. J. Am. Chem. Soc. 135, 7851–7854 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Nelson, H. M., Reisberg, S. H., Shunatona, H. P., Patel, J. S. & Toste, F. D. Chiral anion phase transfer of aryldiazonium cations: an enantioselective synthesis of C3-diazenated pyrroloindolines. Angew. Chem. Int. Ed. 53, 5600–5603 (2014).

    Article  CAS  Google Scholar 

  28. 28.

    Romano, C., Jia, M., Monari, M., Manoni, E. & Bandini, M. Metal-free enantioselective electrophilic activation of allenamides: stereoselective dearomatization of indoles. Angew. Chem. Int. Ed. 53, 13854–13857 (2014).

    Article  CAS  Google Scholar 

  29. 29.

    Zhao, X. et al. Asymmetric dearomatization of indoles through a Michael/Friedel–Crafts-type cascade to construct polycyclic spiroindolines. Angew. Chem. Int. Ed. 54, 4032–4035 (2015).

    Article  CAS  Google Scholar 

  30. 30.

    Jamison, C. R., Badillo, J. J., Lipshultz, J. M., Comito, R. J. & MacMillan, D. W. C. Catalyst-controlled oligomerization for the collective synthesis of polypyrroloindoline natural products. Nat. Chem. 9, 1165–1169 (2017).

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Bera, S., Daniliuc, C. G. & Studer, A. Oxidative N-heterocyclic carbene catalyzed dearomatization of indoles to spirocyclic indolenines with a quaternary carbon stereocenter. Angew. Chem. Int. Ed. 56, 7402–7406 (2017).

    Article  CAS  Google Scholar 

  32. 32.

    Trost, B. M. & Crawley, M. L. Asymmetric transition-metal-catalyzed allylic alkylations: applications in total synthesis. Chem. Rev. 103, 2921–2944 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Lu, Z. & Ma, S. Metal-catalyzed enantioselective allylation in asymmetric synthesis. Angew. Chem. Int. Ed. 47, 258–297 (2008).

    Article  CAS  Google Scholar 

  34. 34.

    Trost, B. M. & Quancard, J. Palladium-catalyzed enantioselective C-3 allylation of 3-substituted-1H-indoles using trialkylboranes. J. Am. Chem. Soc. 128, 6314–6315 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Liu, Y. & Du, H. Pd-catalyzed asymmetric allylic alkylations of 3-substituted indoles using chiral P/olefin ligands. Org. Lett. 15, 740–743 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Kaiser, T. M. & Yang, J. Catalytic enantioconvergent decarboxylative allylic alkylation of allyl indolenin-3-carboxylates. Eur. J. Org. Chem. 2013, 3983–3987 (2013).

    Article  CAS  Google Scholar 

  37. 37.

    Ruchti, J. & Carreira, E. M. Ir-catalyzed reverse prenylation of 3-substituted indoles: total synthesis of (+)-aszonalenin and (−)-brevicompanine B. J. Am. Chem. Soc. 136, 16756–16759 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    Zhang, X., Han, L. & You, S.-L. Ir-catalyzed intermolecular asymmetric allylic dearomatization reaction of indoles. Chem. Sci. 5, 1059–1063 (2014).

    Article  CAS  Google Scholar 

  39. 39.

    Trost, B. M. Designing a receptor for molecular recognition in a catalytic synthetic reaction: allylic alkylation. Acc. Chem. Res. 29, 355–364 (1996).

    Article  CAS  Google Scholar 

  40. 40.

    Trost, B. M., Machacek, M. R. & Aponick, A. Predicting the stereochemistry of diphenylphosphino benzoic acid (DPPBA)-based palladium-catalyzed asymmetric allylic alkylation reactions: a working model. Acc. Chem. Res. 39, 747–760 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. 41.

    Helmchen, G. & Pfaltz, A. Phosphinooxazolines—a new class of versatile, modular P,N-ligands for asymmetric catalysis. Acc. Chem. Res. 33, 336–345 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. 42.

    Noyori, R. & Takaya, H. BINAP: an efficient chiral element for asymmetric catalysis. Acc. Chem. Res. 23, 345–350 (1990).

    Article  CAS  Google Scholar 

  43. 43.

    Wang, M.-Z. et al. Total synthesis and absolute configuration reassignment of mollenines A and B. Org. Chem. Front. 5, 954–957 (2018).

    Article  CAS  Google Scholar 

  44. 44.

    Wollinsky, B., Ludwig, L., Xie, X. & Li, S.-M. Breaking the regioselectivity of indole prenyltransferases: identification of regular C3-prenylated hexahydropyrrolo[2,3-b]indoles as side products of the regular C2-prenyltransferase FtmPT1. Org. Biomol. Chem. 10, 9262–9270 (2012).

    Article  CAS  PubMed  Google Scholar 

  45. 45.

    Alqahtani, N. et al. Synergism between genome sequencing, tandem mass spectrometry and bio-inspired synthesis reveals insights into nocardioazine B biogenesis. Org. Biomol. Chem. 13, 7177–7192 (2015).

    Article  CAS  PubMed  Google Scholar 

  46. 46.

    Caballero, E., Avendaño, C. & Menéndez, J. C. Brief total synthesis of the cell cycle inhibitor tryprostatin B and related preparation of its alanine analogue. J. Org. Chem. 68, 6944–6951 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. 47.

    Defieber, C., Grützmacher, H. & Carreira, E. M. Chiral olefins as steering ligands in asymmetric catalysis. Angew. Chem. Int. Ed. 47, 4482–4502 (2008).

    Article  CAS  Google Scholar 

  48. 48.

    Feng, C.-G., Xu, M.-H. & Lin, G.-Q. Development of bicyclo[3.3.0]octadiene- or dicyclopentadiene-based chiral diene ligands for transition-metal-catalyzed reactions. Synlett 2011, 1345–1356 (2011).

    Article  CAS  Google Scholar 

  49. 49.

    Hegedus, L. S., Åkermark, B., Olsen, D. J., Anderson, O. P. & Zetterberg, K. π-Allyl)palladium complex ion pairs containing two different, mobile π-allyl groups: NMR and X-ray crystallographic studies. J. Am. Chem. Soc. 104, 697–704 (1982).

    Article  CAS  Google Scholar 

  50. 50.

    De Munno, G. et al. Crystal structure of [Pd(η3-2-propenyl)(dps)] [Pd(η3-2-propenyl)Cl2]. NMR evidence of binuclear η3-ally1 palladium(II) species with bridging dps. Inorg. Chim. Acta 208, 67–75 (1993).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the National Key Research and Development Program of China (2016YFA0202900), National Basic Research Program of China (973 Program 2015CB856600), National Natural Science Foundation of China (21332009 and 21572252), Strategic Priority Research Program (XDB20000000) and Key Research Program of Frontier Sciences (QYZDYSSWSLH012) of the Chinese Academy of Sciences, and the Science and Technology Commission of Shanghai Municipality (16XD1404300) for generous financial support, and X. Leng and J. Sun (SIOC) for X-ray crystallographic analysis.

Author information

Affiliations

Authors

Contributions

H.-F.T. and X.Z. were involved in the discovery, design and development of the enantioselective dearomative prenylation of indole derivatives. X.Z. synthesized allylphos. H.-F.T. performed the total syntheses of the natural products. H.-F.T. and C.Z. performed the mechanistic studies. M.Z. was involved in the synthesis of substrates. S.-L.Y. conceived and supervised the project. H.-F.T., C.Z. and S.-L.Y. wrote the manuscript with revisions suggested by all authors.

Corresponding author

Correspondence to Shu-Li You.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Methods, Supplementary Figures 1–3, Supplementary Tables 1–17, Supplementary References

Crystallographic data

CIF for compound C1; CCDC reference: 1822391

Crystallographic data

CIF for compound C2; CCDC reference: 1822392

Crystallographic data

CIF for compound 22; CCDC reference: 1822393

Crystallographic data

CIF for compound (R)-L1; CCDC reference: 1822394

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tu, H., Zhang, X., Zheng, C. et al. Enantioselective dearomative prenylation of indole derivatives. Nat Catal 1, 601–608 (2018). https://doi.org/10.1038/s41929-018-0111-8

Download citation

Further reading