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Catalytic Z-selective olefin cross-metathesis for natural product synthesis

Nature volume 471, pages 461–466 (2011)Cite this article

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Abstract

Alkenes are found in many biologically active molecules, and there are a large number of chemical transformations in which alkenes act as the reactants or products (or both) of the reaction. Many alkenes exist as either the E or the higher-energy Z stereoisomer. Catalytic procedures for the stereoselective formation of alkenes are valuable, yet methods enabling the synthesis of 1,2-disubstituted Z alkenes are scarce. Here we report catalytic Z-selective cross-metathesis reactions of terminal enol ethers, which have not been reported previously, and of allylic amides, used until now only in E-selective processes. The corresponding disubstituted alkenes are formed in up to >98% Z selectivity and 97% yield. These transformations, promoted by catalysts that contain the highly abundant and inexpensive metal molybdenum, are amenable to gram-scale operations. Use of reduced pressure is introduced as a simple and effective strategy for achieving high stereoselectivity. The utility of this method is demonstrated by its use in syntheses of an anti-oxidant plasmalogen phospholipid, found in electrically active tissues and implicated in Alzheimer’s disease, and the potent immunostimulant KRN7000.

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Figure 1: A catalytic CM reaction can afford as many as six alkenes, so the challenge is designing an efficient process that favours formation of the cross products.
Figure 2: Z -selective CM reactions of enol ethers with terminal alkenes and application to stereoselective synthesis of C18 (plasm)-16:0 (PC).
Figure 3: Z -selective CM reactions of allylic amides with terminal alkenes and application to stereoselective synthesis of KRN7000.

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Acknowledgements

This research was supported by the US National Institutes of Health, Institute of General Medical Sciences (GM-59426 to A.H.H. and R.R.S.) and the National Science Foundation (CHE-0715138 to A.H.H.). R.V.O. and J.L. were LaMattina and Spanish government Visiting Scholar Fellows, respectively. We thank S. Castillón, S. J. Malcolmson and M. Yu for discussions. Mass spectrometry facilities at Boston College are supported by the US National Science Foundation (DBI-0619576).

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Authors and Affiliations

  1. Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, 02467, Massachusetts, USA

    Simon J. Meek, Robert V. O’Brien, Josep Llaveria & Amir H. Hoveyda

  2. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Richard R. Schrock

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Contributions

S.J.M., R.V.O. and J.L. were involved in the discovery, design and development of the new Z-selective cross-metathesis strategies and applications to the natural product syntheses. A.H.H. and R.R.S. conceived the research programme. A.H.H. directed the investigations and composed the manuscript, with revisions provided by S.J.M. and R.V.O.

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Correspondence to Amir H. Hoveyda.

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Competing interests

A.H.H. and R.R.S. are founders of a company that utilizes Mo-based olefin metathesis catalysts for commercial purposes.

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Supplementary Information

The file contains Supplementary Methods, Text and Figures (see table of contents on page 1). This file was replaced on 17 October 2011 as pages 30-92 were missing from the original file posted on line. (PDF 4549 kb)

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Meek, S., O’Brien, R., Llaveria, J. et al. Catalytic Z-selective olefin cross-metathesis for natural product synthesis. Nature 471, 461–466 (2011). https://doi.org/10.1038/nature09957

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