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Kinetically E-selective macrocyclic ring-closing metathesis

Nature volume 541, pages 380–385 (2017)Cite this article

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Abstract

Macrocyclic compounds are central to the development of new drugs, but preparing them can be challenging because of the energy barrier that must be surmounted in order to bring together and fuse the two ends of an acyclic precursor such as an alkene (also known as an olefin)1. To this end, the catalytic process known as ring-closing metathesis (RCM)2,3,4 has allowed access to countless biologically active macrocyclic organic molecules, even for large-scale production5. Stereoselectivity is often critical in such cases: the potency of a macrocyclic compound can depend on the stereochemistry of its alkene; alternatively, one isomer of the compound can be subjected to stereoselective modification (such as dihydroxylation6). Kinetically controlled Z-selective RCM reactions have been reported7,8,9,10, but the only available metathesis approach for accessing macrocyclic E-olefins entails selective removal of the Z-component of a stereoisomeric mixture by ethenolysis10, sacrificing substantial quantities of material if E/Z ratios are near unity. Use of ethylene can also cause adventitious olefin isomerization—a particularly serious problem when the E-alkene is energetically less favoured. Here, we show that dienes containing an E-alkenyl–B(pinacolato) group, widely used in catalytic cross-coupling11, possess the requisite electronic and steric attributes to allow them to be converted stereoselectively to E-macrocyclic alkenes. The reaction is promoted by a molybdenum monoaryloxide pyrrolide complex and affords products at a yield of up to 73 per cent and an E/Z ratio greater than 98/2. We highlight the utility of the approach by preparing recifeiolide (a 12-membered-ring antibiotic)12,13 and pacritinib (an 18-membered-ring enzyme inhibitor)14,15, the Z-isomer of which is less potent than the E-isomer16. Notably, the 18-membered-ring moiety of pacritinib—a potent anti-cancer agent that is in advanced clinical trials for treating lymphoma and myelofibrosis—was prepared by RCM carried out at a substrate concentration 20 times greater than when a ruthenium carbene was used.

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Figure 1: The strategy and the optimal substituent.
Figure 2: Kinetically E-selective macrocyclic RCM.
Figure 3: Application to stereoselective synthesis of recifeiolide.
Figure 4: Application to synthesis of pacritinib.

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Acknowledgements

This research was supported by grants from the National Institutes of Health (GM-59426) and the National Science Foundation (CHE-1362763). M.J.K. was supported as a LaMattina Graduate Fellow in Chemical Synthesis. We thank S. Torker for many helpful discussions, and L. Ondi, J. Balazs Czirok and G. Mate Nagy for their support and advice on paraffin tablets, which were gifts from XiMo, AG.

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Authors and Affiliations

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

    Xiao Shen, Thach T. Nguyen, Ming Joo Koh, Dongmin Xu, Alexander W. H. Speed & Amir H. Hoveyda

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

    Richard R. Schrock

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Contributions

X.S., T.T.N. and M.J.K. developed the catalytic method and analysed the results regarding various catalysts and substrates. A.W.H.S. first suggested the possibility of controlling RCM stereoselectivity with an appropriate electronically deficient alkene substituent. X.S. carried out the synthesis of recifeiolide, and X.S. and D.X. performed the investigations in connection to synthesis of pacritinib. R.R.S. and A.H.H. developed the molybdenum MAP complexes used in these studies. A.H.H. directed the investigations and composed the manuscript, with revisions provided by the other authors.

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Correspondence to Amir H. Hoveyda.

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A.H.H. and R.R.S. are co-founders of a company that has licensed the technology reported here.

Extended data figures and tables

Extended Data Figure 1 By-products from RCM with an E-β-substituted styrene.

Although pathway i represents the desired route, pathways ii and ii are competitive and can lead to the formation of a variety of undesired byproducts. Mass-spectrometry analysis of the unpurified mixture resulting from the reaction of compound 1c confirmed the existence of by-products A, E, H and I and the desired RCM product. 1H-NMR analysis of the mixture confirmed the existence of stilbene (F). A, High-resolution mass spectrometry (HRMS) mass of [M+H]+, calculated for C23H35O2: 343.26370; found: 343.26277; E, HRMS[M+H]+, calculated for C44H65O4: 657.48828; found: 657.48808; H, HRMS[M+H]+, calculated for C38H61O4: 581.45730; found: 581.45698; I, HRMS[M+H]+, calculated for C29H39O2: 419.29500; found: 419.29383; RCM product, HRMS[M+H]+, calculated for C15H27O2: 239.20110; found: 239.20019.

Extended Data Figure 2 Performance of other catalyst types.

Examination of alternative Mo MAP complexes shows that the precise identity of the aryloxide ligand is crucial for achieving optimal efficiency and E selectivity. Furthermore, with two widely used achiral complexes (Mo-4 and Ru-4), efficiency and E/Z selectivity are low. Two of the more recently introduced Z-selective Ru complexes (Ru-5 and Ru-6) afford only homocoupling products. Mes, 2,4,6-(Me)3C6H2; ND, not determined; R, functional group. Reactions were performed under atmospheric nitrogen. Conversion values and E/Z ratios were determined by analysis of 1H-NMR spectra of unpurified product mixtures (± 2%). See Supplementary Information for all experimental and analytical details.

Extended Data Figure 3 Reported RCM reactions with bis(α-olefin) compounds and promoted by ruthenium complexes.

See refs 13, 25, 26, 43, 44, 45.

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Supplementary Information

This file contains Supplementary Text and Data and the NMR Spectra (see Contents for details). (PDF 4269 kb)

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Shen, X., Nguyen, T., Koh, M. et al. Kinetically E-selective macrocyclic ring-closing metathesis. Nature 541, 380–385 (2017). https://doi.org/10.1038/nature20800

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