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Temporal separation of catalytic activities allows anti-Markovnikov reductive functionalization of terminal alkynes

Nature Chemistry volume 6, pages 22–27 (2014)Cite this article

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Abstract

There is currently great interest in the development of multistep catalytic processes in which one or several catalysts act sequentially to rapidly build complex molecular structures. Many enzymes—often the inspiration for new synthetic transformations—are capable of processing a single substrate through a chain of discrete, mechanistically distinct catalytic steps. Here, we describe an approach to emulate the efficiency of these natural reaction cascades within a synthetic catalyst by the temporal separation of catalytic activities. In this approach, a single catalyst exhibits multiple catalytic activities sequentially, allowing for the efficient processing of a substrate through a cascade pathway. Application of this design strategy has led to the development of a method to effect the anti-Markovnikov (linear-selective) reductive functionalization of terminal alkynes. The strategy of temporal separation may facilitate the development of other efficient synthetic reaction cascades.

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Figure 1: Comparison of previous auto-tandem catalytic reactions and tandem reactions exhibiting temporal separation of catalytic activities.
Figure 2: Optimization and spectroscopic studies of the reductive hydration reaction.
Figure 3: Triple-cascade anti-Markovnikov hydration, olefination and enone reduction.

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Acknowledgements

The authors acknowledge financial support from the David and Lucile Packard Foundation. The authors thank J.A. Ellman for helpful discussions. S.B.H. is a fellow of the David and Lucile Packard and Alfred P. Sloan Foundations, a Camille Dreyfus Teacher–Scholar, and a Cottrell Scholar of the Research Corporation for Science Advancement.

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Authors and Affiliations

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

    Le Li & Seth B. Herzon

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  1. Le Li
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L.L. and S.B.H. designed the research, analysed the data and wrote the manuscript. L.L. performed the experiments.

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Correspondence to Seth B. Herzon.

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The authors declare no competing financial interests.

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Li, L., Herzon, S. Temporal separation of catalytic activities allows anti-Markovnikov reductive functionalization of terminal alkynes. Nature Chem 6, 22–27 (2014). https://doi.org/10.1038/nchem.1799

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