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Synthesis of macrocyclic natural products by catalyst-controlled stereoselective ring-closing metathesis

Abstract

Many natural products contain a C = C double bond through which various other derivatives can be prepared; the stereochemical identity of the alkene can be critical to the biological activities of such molecules. Catalytic ring-closing metathesis (RCM) is a widely used method for the synthesis of large unsaturated rings1,2; however, cyclizations often proceed without control of alkene stereochemistry2. This shortcoming is particularly costly when the cyclization reaction is performed after a long sequence of other chemical transformations2. Here we outline a reliable, practical and general approach for the efficient and highly stereoselective synthesis of macrocyclic alkenes by catalytic RCM; transformations deliver up to 97% of the Z isomer owing to control induced by a tungsten-based alkylidene. Utility is demonstrated through the stereoselective preparation of epothilone C (refs 3–5) and nakadomarin A (ref. 6), the previously reported syntheses of which have been marred by late-stage, non-selective RCM7,8,9,10,11,12. The tungsten alkylidene can be manipulated in air, delivering the products in useful yields with high stereoselectivity. As a result of efficient RCM and re-incorporation of side products into the catalytic cycle with minimal alkene isomerization, desired cyclizations proceed in preference to alternative pathways, even under relatively high substrate concentration.

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Figure 1: Two cases in natural product total synthesis where catalytic RCM with commonly used complexes (1, 2b–d) delivers the macrocyclic alkene with minimal stereoselectivity.
Figure 2: Total synthesis of nakadomarin A realized through late-stage tungsten-catalysed RCM of pentacyclic 13, and comparison with results delivered by Ru catalysts.

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Acknowledgements

This work was supported by the United States National Institutes of Health, Institute of General Medical Sciences (grant GM-59426 to A.H.H. and R.R.S.). M. Y. is a John LaMattina graduate fellow, A.F.K. the recipient of an EPSRC-GlaxoSmithKline synthesis studentship, and P.J. an EPSRC postdoctoral fellow. D.J.D. is grateful for an EPSRC leadership fellowship. We thank S. J. Meek, S. J. Malcolmson, R. V. O’Brien, T. J. Mann and E. T. Kiesewetter for discussions; A. R. Zhugralin, S. Torker and D. L. Silverio for DFT calculations; K. Wu for experimental assistance; and Boston College for providing access to computational facilities. The X-ray facilities at Boston College are supported by the United States National Science Foundation (CHE-0923264).

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Contributions

M.Y. and C.W. were involved in the discovery, design and development of the Z-selective macrocyclic ring-closing metathesis strategies and applications to the natural product syntheses. A.F.K., P.J. and D.J.D. devised routes for and performed enantioselective syntheses of precursors 5 and 13. R.R.S. and A.H.H. were involved in the discovery and development of the catalysts used in the study; A.H.H. conceived and directed the investigations and composed the manuscript with revisions provided by M.Y. and C.W.

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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 the catalysts and the resulting technology used in the submitted manuscript.

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The file contains Supplementary Text and Data (see contents list for more details) and Supplementary Tables 1-7. (PDF 8584 kb)

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Yu, M., Wang, C., Kyle, A. et al. Synthesis of macrocyclic natural products by catalyst-controlled stereoselective ring-closing metathesis. Nature 479, 88–93 (2011). https://doi.org/10.1038/nature10563

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