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A concise synthesis of (+)-batzelladine B from simple pyrrole-based starting materials

Nature volume 525, pages 507–510 (2015)Cite this article

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Abstract

Alkaloids, secondary metabolites that contain basic nitrogen atoms, are some of the most well-known biologically active natural products in chemistry and medicine1. Although efficient laboratory synthesis of alkaloids would enable the study and optimization of their biological properties2, their preparation is often complicated by the basicity and nucleophilicity of nitrogen, its susceptibility to oxidation, and its ability to alter reaction outcomes in unexpected ways—for example, through stereochemical instability and neighbouring group participation. Efforts to address these issues have led to the invention of a large number of protecting groups that temper the reactivity of nitrogen3; however, the use of protecting groups typically introduces additional steps and obstacles into the synthetic route. Alternatively, the use of aromatic nitrogen heterocycles as synthetic precursors can attenuate the reactivity of nitrogen and streamline synthetic strategies4. Here we use such an approach to achieve a synthesis of the complex anti-HIV alkaloid (+)-batzelladine B in nine steps (longest linear sequence) from simple pyrrole-based starting materials. The route uses several key transformations that would be challenging or impossible to implement using saturated nitrogen heterocycles and highlights some of the advantages of beginning with aromatic reagents.

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Figure 1: Structure and synthetic analysis of (+)-batzelladine B (1).
Figure 2: Synthesis of the vessel fragment of (+)-batzelladine B (1) and determination of its stereochemistry.
Figure 3: Synthesis of the anchor fragment of (+)-batzelladine B (1).
Figure 4: Coupling of 17 and 27 and completion of the synthesis of (+)-batzelladine B (1).

References

  1. Roberts, M.F. & Wink, M. (eds) Alkaloids: Biochemistry, Ecology, and Medicinal Applications (Plenum, 1998)

    Book  Google Scholar 

  2. Wender, P. A. & Miller, B. L. Synthesis at the molecular frontier. Nature 460, 197–201 (2009)

    Article  CAS  ADS  Google Scholar 

  3. Greene, T. W. & Wuts, P. G. M. Protective Groups in Organic Synthesis 3rd edn, Ch. 7 (Wiley, 1999)

    Book  Google Scholar 

  4. Lipshutz, B. H. Five-membered heteroaromatic rings as intermediates in organic synthesis. Chem. Rev. 86, 795–819 (1986)

    Article  CAS  Google Scholar 

  5. Crampton, R. M. & Robotham, I. A. Acidities of some substituted ammonium ions in dimethyl sulfoxide. J. Chem. Res. Synop. 22–23 (1997)

  6. Mayr, H. & Ofial, A. R. Kinetics of electrophile-nucleophile combinations: a general approach to polar organic reactivity. Pure Appl. Chem. 77, 1807–1821 (2005)

    Article  CAS  Google Scholar 

  7. Bordwell, F. G. Equilibrium acidities in dimethyl sulfoxide solution. Acc. Chem. Res. 21, 456–463 (1988)

    Article  CAS  Google Scholar 

  8. Chen, K. & Baran, P. S. Total synthesis of eudesmane terpenes by site-selective C–H oxidations. Nature 459, 824–828 (2009)

    Article  CAS  ADS  Google Scholar 

  9. Patil, A. D. et al. Novel alkaloids from the sponge Batzella sp.: inhibitors of HIV gp120-human CD4 binding. J. Org. Chem. 60, 1182–1188 (1995)

    Article  CAS  Google Scholar 

  10. Patil, A. D. et al. Batzelladines F−I, novel alkaloids from the sponge Batzella sp.: inducers of p56lck-CD4 dissociation. J. Org. Chem. 62, 1814–1819 (1997)

    Article  CAS  Google Scholar 

  11. Hua, H.-M. et al. Batzelladine alkaloids from the Caribbean sponge Monanchora unguifera and the significant activities against HIV-1 and AIDS opportunistic infectious pathogens. Tetrahedron 63, 11179–11188 (2007)

    Article  CAS  Google Scholar 

  12. Laville, R. et al. Bioactive guanidine alkaloids from two Caribbean marine sponges. J. Nat. Prod. 72, 1589–1594 (2009)

    Article  CAS  Google Scholar 

  13. Franklin, A. S., Ly, S. K., Mackin, G. H., Overman, L. E. & Shaka, A. J. Application of the tethered Biginelli reaction for enantioselective synthesis of batzelladine alkaloids. Absolute configuration of the tricyclic guanidine portion of batzelladine B. J. Org. Chem. 64, 1512–1519 (1999)

    Article  CAS  Google Scholar 

  14. Duron, S. G. & Gin, D. Y. Synthesis and determination of absolute configuration of the bicyclic guanidine core of batzelladine A. Org. Lett. 3, 1551–1554 (2001)

    Article  CAS  Google Scholar 

  15. Snider, B. B., Chen, J., Patil, A. D. & Freyer, A. J. Synthesis of the tricyclic portions of batzelladines A, B and D. Revision of the stereochemistry of batzelladines A and D. Tetrahedron Lett. 37, 6977–6980 (1996)

    Article  CAS  Google Scholar 

  16. Shimokawa, J., Shirai, K., Tanatani, A., Hashimoto, Y. & Nagasawa, K. Enantioselective total synthesis of batzelladine A. Angew. Chem. Int. Ed. 43, 1559–1562 (2004)

    Article  CAS  Google Scholar 

  17. Arnold, M. A., Day, K. A., Durón, S. G. & Gin, D. Y. Total synthesis of (+)-batzelladine A and (−)-batzelladine D via [4 + 2]-annulation of vinyl carbodiimides with N-alkyl imines. J. Am. Chem. Soc. 128, 13255–13260 (2006)

    Article  CAS  Google Scholar 

  18. Cohen, F. & Overman, L. E. Evolution of a strategy for the synthesis of structurally complex batzelladine alkaloids. Enantioselective total synthesis of the proposed structure of batzelladine F and structural revision. J. Am. Chem. Soc. 128, 2594–2603 (2006)

    Article  CAS  Google Scholar 

  19. Cohen, F. & Overman, L. E. Enantioselective total synthesis of batzelladine F and definition of its structure. J. Am. Chem. Soc. 128, 2604–2608 (2006)

    Article  CAS  Google Scholar 

  20. Evans, P. A., Qin, J., Robinson, J. E. & Bazin, B. Enantioselective total synthesis of the polycyclic guanidine-containing marine alkaloid (−)-batzelladine D. Angew. Chem. Int. Ed. 46, 7417–7419 (2007)

    Article  CAS  Google Scholar 

  21. Butters, M. et al. Synthesis and stereochemical determination of batzelladine C methyl ester. Org. Biomol. Chem. 7, 5001–5009 (2009)

    Article  CAS  Google Scholar 

  22. Babij, N. R. & Wolfe, J. P. Asymmetric total synthesis of (+)-merobatzelladine B. Angew. Chem. Int. Ed. 51, 4128–4130 (2012)

    Article  CAS  Google Scholar 

  23. Aron, Z. D. & Overman, L. E. The tethered Biginelli condensation in natural product synthesis. Chem. Commun. 253–265 (2004)

  24. Reddy, R. P. & Davies, H. M. L. Asymmetric synthesis of tropanes by rhodium-catalyzed [4 + 3] cycloaddition. J. Am. Chem. Soc. 129, 10312–10313 (2007)

    Article  CAS  Google Scholar 

  25. Tang, T. P. & Ellman, J. A. Asymmetric synthesis of β-amino acid derivatives incorporating a broad range of substitution patterns by enolate additions to tert-butanesulfinyl imines. J. Org. Chem. 67, 7819–7832 (2002)

    Article  CAS  Google Scholar 

  26. Davies, H. M. L., Ahmed, G. & Churchill, M. R. Asymmetric synthesis of highly functionalized 8-oxabicyclo[3.2.1]octene derivatives. J. Am. Chem. Soc. 118, 10774–10782 (1996)

    Article  CAS  Google Scholar 

  27. Masamune, S., Choy, W., Petersen, J. S. & Sita, L. R. Double asymmetric synthesis and a new strategy for stereochemical control in organic synthesis. Angew. Chem. Int. Ed. 24, 1–30 (1985)

    Article  Google Scholar 

  28. Fernández González, D., Brand, J. P. & Waser, J. Ethynyl-1,2-benziodoxol-3(1 H)-one (EBX): an exceptional reagent for the ethynylation of keto, cyano, and nitro esters. Chem. Eur. J. 16, 9457–9461 (2010)

    Article  Google Scholar 

  29. Gainer, M. J., Bennett, N. R., Takahashi, Y. & Looper, R. E. Regioselective rhodium(II)-catalyzed hydroaminations of propargylguanidines. Angew. Chem. Int. Ed. 50, 684–687 (2011)

    Article  CAS  Google Scholar 

  30. Zeng, M., Li, L. & Herzon, S. B. A highly active and air-stable ruthenium complex for the ambient temperature anti-Markovnikov reductive hydration of terminal alkynes. J. Am. Chem. Soc. 136, 7058–7067 (2014)

    Article  CAS  Google Scholar 

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Acknowledgements

Financial support from the National Institutes of Health (NRSA fellowship GM110898-01A1 to B.T.P, Chemistry Biology Interface Training Program T32GM067543 to C.E.) and Yale University is acknowledged. We thank B. Mercado for X-ray crystallographic analysis of 19 and K.-p. Wang for assistance with HPLC purification of 1.

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Authors and Affiliations

  1. Department of Chemistry, Yale University, New Haven, 06520, Connecticut, USA

    Brendan T. Parr, Christos Economou & Seth B. Herzon

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  1. Brendan T. Parr
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  2. Christos Economou
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  3. Seth B. Herzon
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Contributions

B.T.P. and C.E. performed and analysed the experiments. All authors contributed to the design of experiments and composition of the manuscript.

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Correspondence to Seth B. Herzon.

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The authors declare no competing financial interests.

Additional information

Crystallographic data for 19 have been deposited at the Cambridge Crystallographic Data Centre as CCDC 1400311.

Supplementary information

Supplementary Information

This file contains Supplementary Tables 1-8, Supplementary Text and Data and a Supplementary Bibliography – see contents page for details. (PDF 8756 kb)

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Parr, B., Economou, C. & Herzon, S. A concise synthesis of (+)-batzelladine B from simple pyrrole-based starting materials. Nature 525, 507–510 (2015). https://doi.org/10.1038/nature14902

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