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Total synthesis of bryostatin 16 using atom-economical and chemoselective approaches

Abstract

Of the concepts used to improve the efficiency of organic syntheses, two have been especially effective: atom economy1 (the use of routes in which most of the atoms present in the reactants also end up in the product) and chemoselectivity2 (the use of reactions that take place only at desired positions in a molecule). Synthesis of complex natural products is the most demanding arena in which to explore such principles. The bryostatin family of compounds are especially interesting targets, because they combine structural complexity with promising biological activity3,4,5,6,7. Furthermore, synthetic routes to some bryostatins have already been reported9,10,11,12, providing a benchmark against which new syntheses can be measured. Here we report a concise total synthesis of bryostatin 16 (1), a parent structure from which almost all other bryostatins could in principle be accessed. Application of atom-economical and chemoselective reactions currently under development provides ready access to polyhydropyran motifs in the molecule, which are common structural features of many other natural products. The most notable transformations are two transition-metal-catalysed reactions. The first is a palladium-catalysed reaction of two different alkynes to form a large ring. The product of this step is then converted into a dihydropyran (the ‘C ring’ of bryostatins) in the second key reaction, which is catalysed by a gold compound. Analogues of bryostatin that do not exist in nature could be readily made by following this route, which might allow the biological activity of bryostatins to be fine-tuned.

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Figure 1: Structures of bryostatins 1–20.
Figure 2: Retrosynthetic analysis.
Figure 3: Synthesis of alkene 7 and alkyne 8.
Figure 4: Synthesis of acid 5 and alcohol 4.
Figure 5: Synthesis of bryostatin 16.

References

  1. Trost, B. M. The atom economy–a search for synthetic efficiency. Science 254, 1471–1477 (1991)

    ADS  CAS  Article  Google Scholar 

  2. Trost, B. M. Selectivity: a key to synthetic efficiency. Science 219, 245–250 (1983)

    ADS  CAS  Article  Google Scholar 

  3. Hale, K. J., Hummersone, M. G., Manaviazar, S. & Frigerio, M. The chemistry and biology of the bryostatin antitumour macrolides. Nat. Prod. Rep. 19, 413–453 (2002)

    CAS  Article  Google Scholar 

  4. Newman, D. J. & Cragg, G. M. Marine natural products and related compounds in clinical and advanced preclinical trials. J. Nat. Prod. 67, 1216–1238 (2004)

    CAS  Article  Google Scholar 

  5. Dowlati, A. et al. Phase I and correlative study of combination bryostatin 1 and vincristine in relapsed B-cell malignancies. Clin. Cancer Res. 9, 5929–5935 (2003)

    CAS  PubMed  Google Scholar 

  6. Hongpaisan, J. & Alkon, D. L. A structural basis for enhancement of long-term associative memory in single dendritic spines regulated by PKC. Proc. Natl Acad. Sci. USA 104, 19571–19576 (2007)

    ADS  CAS  Article  Google Scholar 

  7. Dell’Aquilla, M. L., Harold, C. L., Kamano, Y., Pettit, G. R. & Blumberg, P. M. Differential effects of bryostatins and phorbol esters on arachidonic acid metabolite release and epidermal growth factor binding in C3H 10T1/2 cells. Cancer Res. 48, 3702–3708 (1988)

    Google Scholar 

  8. Schaufelberger, D. E. et al. The large-scale isolation of bryostatin 1 from Bugula neritina following current good manufacturing practices. J. Nat. Prod. 54, 1265–1270 (1991)

    CAS  Article  Google Scholar 

  9. Kageyama, M. et al. Synthesis of bryostatin 7. J. Am. Chem. Soc. 112, 7407–7408 (1990)

    CAS  Article  Google Scholar 

  10. Evans, D. A. et al. Total synthesis of bryostatin 2. J. Am. Chem. Soc. 121, 7540–7552 (1999)

    CAS  Article  Google Scholar 

  11. Ohmori, K. et al. Total synthesis of bryostatin 3. Angew. Chem. Int. Ed. 39, 2290–2294 (2000)

    CAS  Article  Google Scholar 

  12. Manaviazar, S. et al. Enantioselective formal total synthesis of the antitumor macrolide bryostatin 7. Org. Lett. 8, 4477–4480 (2006)

    CAS  Article  Google Scholar 

  13. Wender, P. A. & Verma, V. A. The design, synthesis and evaluation of C7 diversified bryostatin analogs reveals a hot spot for PKC affinity. Org. Lett. 10, 3331–3334 (2008)

    CAS  Article  Google Scholar 

  14. Wender, P. A., DeChristopher, B. A. & Schrier, A. J. Efficient synthetic access to a new family of highly potent bryostatin analogues via a Prins-driven macrocyclization strategy. J. Am. Chem. Soc. 130, 6658–6659 (2008)

    CAS  Article  Google Scholar 

  15. Keck, G. E. et al. Convergent assembly of highly potent analogues of bryostatin 1 via pyran annulation: bryostatin look-alikes that mimic phorbol ester function. J. Am. Chem. Soc. 130, 6660–6661 (2008)

    CAS  Article  Google Scholar 

  16. Trost, B. M., Yang, H., Thiel, O. R., Frontier, A. J. & Brindle, C. S. Synthesis of a ring-expanded bryostatin analogue. J. Am. Chem. Soc. 129, 2206–2207 (2007)

    CAS  Article  Google Scholar 

  17. Ball, M. et al. A preliminary evaluation of a metathesis approach to bryostatins. Tetrahedr. Lett. 47, 2223–2227 (2006)

    CAS  Article  Google Scholar 

  18. Pettit, G. R. et al. Antineoplastic agents. 340. Isolation and structural elucidation of bryostatins 16–18. J. Nat. Prod. 59, 286–289 (1996)

    CAS  Article  Google Scholar 

  19. Sudek, S. et al. Identification of the putative bryostatin polyketide synthase gene cluster from “Candidatus Endobugula sertula”, the uncultivated microbial symbiont of the marine ryozoan Bugula neritina. J. Nat. Prod. 70, 67–74 (2007)

    CAS  Article  Google Scholar 

  20. Trost, B. M., Matsubara, S. & Caringi, J. J. Cycloisomerization of α,ω-diynes to macrocycles. J. Am. Chem. Soc. 111, 8745–8746 (1989)

    CAS  Article  Google Scholar 

  21. Trost, B. M., Yang, H. & Wuitschik, G. A. Ru-catalyzed tandem alkyne-enone coupling/Michael addition: synthesis of 4-methylene-2,6-cis-tetrahydropyrans. Org. Lett. 7, 4761–4764 (2005)

    CAS  Article  Google Scholar 

  22. Brown, H. C. & Jadhav, P. K. Asymmetric carbon-carbon bond formation via β-allyldiisopinocampheylborane. Simple synthesis of secondary homoallylic alcohols with excellent enantiomeric purities. J. Am. Chem. Soc. 105, 2092–2093 (1983)

    CAS  Article  Google Scholar 

  23. Lin, M. & Loh, T. Indium-mediated reaction of trialkylsilyl propargyl bromide with aldehydes: highly regioselective synthesis of allenic and homopropargylic alcohols. J. Am. Chem. Soc. 125, 13042–13043 (2003)

    CAS  Article  Google Scholar 

  24. Dess, D. B. & Martin, J. C. A useful 12-I-5 triacetoxyperiodinane (the Dess-Martin periodinane) for the selective oxidation of primary or secondary alcohols and a variety of related 12-I-5 species. J. Am. Chem. Soc. 113, 7277–7287 (1991)

    CAS  Article  Google Scholar 

  25. Corey, E. J. & Helal, J. C. Reduction of carbonyl compounds with chiral oxazaborolidine catalysts: A new paradigm for enantioselective catalysis and a powerful new synthetic method. Angew. Chem. Int. Ed. 37, 1986–2012 (1998)

    CAS  Article  Google Scholar 

  26. Roth, G. J., Liepold, B., Müller, S. G. & Bestmann, H. J. Further improvements of the synthesis of alkynes from aldehydes. Synthesis 59–62 (2004)

  27. Nicolaou, K. C., Estrada, A. A., Zak, M., Lee, S. H. & Safina, B. S. A mild and selective method for the hydrolysis of esters with trimethyltin hydroxide. Angew. Chem. Int. Ed. 44, 1378–1382 (2005)

    CAS  Article  Google Scholar 

  28. Inanaga, J., Hirata, K., Saeki, H., Katsuki, T. & Yamaguchi, M. A rapid esterification by mixed anhydride and its application to large-ring lactonization. Bull. Chem. Soc. Jpn 52, 1989–1993 (1979)

    CAS  Article  Google Scholar 

  29. Liu, Y., Song, F., Song, Z., Liu, M. & Yan, B. Gold-catalyzed cyclization of (Z)-2-en-4-yn-1-ols: highly efficient synthesis of fully substituted dihydrofurans and furans. Org. Lett. 7, 5409–5412 (2005)

    CAS  Article  Google Scholar 

  30. Pettit, G. R., Sengupta, D., Herald, C. L., Sharkey, N. A. & Blumberg, P. M. Antineoplastic agents. 192. Synthetic conversion of bryostatin 2 to bryostatin 1 and related bryopyrans. Can. J. Chem. 69, 856–860 (1991)

    CAS  Article  Google Scholar 

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Acknowledgements

We acknowledge the National Institutes of Health (GM 13598) for their support of our programs. G.D. is a Stanford Graduate Fellow. We thank H. Yang for discussions and for help characterizing compound 21, and we additionally thank him and C. S. Brindle for providing synthetic intermediates. Palladium and ruthenium salts were supplied by Johnson Matthey. We acknowledge S. R. Lynch for his help with two-dimensional nuclear magnetic resonance analysis. We also thank the Wender group’s assistance with reverse-phase high-performance liquid chromatography.

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Correspondence to Barry M. Trost.

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Trost, B., Dong, G. Total synthesis of bryostatin 16 using atom-economical and chemoselective approaches. Nature 456, 485–488 (2008). https://doi.org/10.1038/nature07543

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