Synthesis of E- and Z-trisubstituted alkenes by catalytic cross-metathesis

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Abstract

Catalytic cross-metathesis is a central transformation in chemistry, yet corresponding methods for the stereoselective generation of acyclic trisubstituted alkenes in either the E or the Z isomeric forms are not known. The key problems are a lack of chemoselectivity—namely, the preponderance of side reactions involving only the less hindered starting alkene, resulting in homo-metathesis by-products—and the formation of short-lived methylidene complexes. By contrast, in catalytic cross-coupling, substrates are more distinct and homocoupling is less of a problem. Here we show that through cross-metathesis reactions involving E- or Z-trisubstituted alkenes, which are easily prepared from commercially available starting materials by cross-coupling reactions, many desirable and otherwise difficult-to-access linear E- or Z-trisubstituted alkenes can be synthesized efficiently and in exceptional stereoisomeric purity (up to 98 per cent E or 95 per cent Z). The utility of the strategy is demonstrated by the concise stereoselective syntheses of biologically active compounds, such as the antifungal indiacen B and the anti-inflammatory coibacin D.

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Figure 1: The challenge of developing stereoselective trisubstituted alkene cross-metathesis.
Figure 2: Synthesis of Z- and E-trisubstituted alkenyl chlorides.
Figure 3: Synthesis of Z- and E-trisubstituted alkenyl bromides.
Figure 4: Synthesis of E- or Z-trisubstituted non-halogenated alkenes.
Figure 5: Synthesis of biologically active compounds.

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Acknowledgements

This research was supported by the United States National Institutes of Health, Institute of General Medical Sciences (GM-59426 and, in part, CHE-1362763). M.J.K. and T.J.M. are grateful for support in the form of a Bristol Myers-Squibb Fellowship in Organic Chemistry and a John LaMattina Graduate Fellowship, respectively.

Author information

T.T.N. and M.J.K. were involved in the discovery, design and development of the cross-metathesis strategies and their applications. T.J.M. carried out the initial exploratory studies with 1,1-disubstituted alkenes. A.H.H. designed and directed the investigations. A.H.H. and R.R.S. conceived the studies that led to the development of molybdenum complexes used in this study. A.H.H. wrote the manuscript with revisions provided by T.T.N., M.J.K. and T.J.M.

Correspondence to Amir H. Hoveyda.

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Extended data figures and tables

Extended Data Figure 1 Non-productive olefin metathesis pathways.

Cross-metathesis between v and 1a via symmetrical metallacyclobutane iv′ (right, in black) is more likely than one involving complex iv″ as an intermediate (left, in red). This is as a result of greater steric pressure between the Cα substituent and the sizeable aryloxide ligand27. Cycloreversion of iv′ would then regenerate v and afford 1a (a non-productive process).

Extended Data Figure 2 Distinctive pathways for cross-metathesis of 22 and vinyl–B(pin) with Mo-1 and Mo-2.

a, Cross-metathesis between 25 and vinyl–B(pin) in the presence of Mo-1 and Mo-2 results in different product distribution and stereoselectivity profiles. b, The reactions proceed via mcbIMe because of severe steric repulsion between the larger Cβ aryl group in mcbIIMe and the Me units of the aryloxide ligand in Mo-3. By-product 33 may react with vinyl–B(pin) to furnish Z-32. c, There is less steric pressure at Cβ in mcbIt- Bu and mcbIIt- Bu; consequently, steric repulsion between the Cα metallacyclobutane substituent and an ortho fluorine substituent of the arylimido becomes more of a factor. Therefore, cross-metathesis probably proceeds via mcbIIt- Bu to afford the corresponding alkenyl–B(pin) compound (E-32). The resulting reaction of xiv with vinyl–B(pin) probably affords 34, which may then react with vinyl–B(pin) to furnish E-3n.

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Nguyen, T., Koh, M., Mann, T. et al. Synthesis of E- and Z-trisubstituted alkenes by catalytic cross-metathesis. Nature 552, 347–354 (2017) doi:10.1038/nature25002

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