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

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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.

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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) doi:10.1038/nature07543

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