Collective synthesis of natural products by means of organocascade catalysis

Abstract

Organic chemists are now able to synthesize small quantities of almost any known natural product, given sufficient time, resources and effort. However, translation of the academic successes in total synthesis to the large-scale construction of complex natural products and the development of large collections of biologically relevant molecules present significant challenges to synthetic chemists. Here we show that the application of two nature-inspired techniques, namely organocascade catalysis and collective natural product synthesis, can facilitate the preparation of useful quantities of a range of structurally diverse natural products from a common molecular scaffold. The power of this concept has been demonstrated through the expedient, asymmetric total syntheses of six well-known alkaloid natural products: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine.

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Figure 1: Cascade catalysis in biosynthesis.
Figure 2: Collective natural product synthesis: nature-inspired application of cascade catalysis.
Figure 3: Proposed mechanism of organocascade cycles for the generation of a common tetracyclic intermediate ( 1).
Figure 4: Twelve-step enantioselective total synthesis of (−)-strychnine.
Figure 5: Ten-step enantioselective synthesis of (−)-akuammicine.
Figure 6: Enantioselective total syntheses of (+)-aspidospermidine and (+)-vincadifformine.
Figure 7: Enantioselective total syntheses of (−)-kopsinine and (−)-kopsanone.

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Acknowledgements

Financial support was provided by NIHGMS (R01 GM078201-05) and gifts from Merck, Bristol-Myers Squibb and Abbott. S.B.J. and B.S. thank Bristol-Myers Squibb and Merck, respectively, for graduate fellowships.

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S.B.J., B.S. and A.M. participated in the performance and analysis of the experiments. S.B.J., B.S., A.M. and D.W.C.M. designed the experiments. S.B.J. and D.W.C.M. wrote the paper.

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Correspondence to David W. C. MacMillan.

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Jones, S., Simmons, B., Mastracchio, A. et al. Collective synthesis of natural products by means of organocascade catalysis. Nature 475, 183–188 (2011). https://doi.org/10.1038/nature10232

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