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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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).
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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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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