Many therapeutic agents are macrocyclic trisubstituted alkenes but preparation of these structures is typically inefficient and non-selective. A possible solution would entail catalytic macrocyclic ring-closing metathesis, but these transformations require high catalyst loading, conformationally rigid precursors and are often low yielding and/or non-stereoselective. Here we introduce a ring-closing metathesis strategy for synthesis of trisubstituted macrocyclic olefins in either stereoisomeric form, regardless of the level of entropic assistance. The goal was achieved by addressing several unexpected difficulties, including complications arising from pre-ring-closing metathesis alkene isomerization. The power of the method is highlighted by two examples. The first is the near-complete reversal of substrate-controlled selectivity in the formation of a macrolactam related to an antifungal natural product. The other is a late-stage stereoselective generation of an E-trisubstituted alkene in a 24-membered ring, en route to the cytotoxic natural product dolabelide C.
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Financial support was provided by the National Institutes of Health (GM-130395). F.W.W.H. was supported as a Deutsche Forschungsgemeinschaft postdoctoral fellow. K.E.L. was supported by a Complex Systems Chemistry (CSC) graduate fellowship funded by the French National Research Agency (CSC-IGS ANR-17-EURE-0016). We thank T. Koengeter, C. Qin and S. Xu for helpful discussions and suggestions.
The authors declare no competing interests.
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The file contains an extended bibliography regarding preparation of trisubstituted macrocyclic natural products. It also contains the experimental procedures for preparation of organometallic complexes, substrates, reagents and products and all the corresponding analytical/characterization data (tabulated and reproductions of 1H and 13C NMR spectra).
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Mu, Y., Hartrampf, F.W.W., Yu, E.C. et al. E- and Z-trisubstituted macrocyclic alkenes for natural product synthesis and skeletal editing. Nat. Chem. 14, 640–649 (2022). https://doi.org/10.1038/s41557-022-00935-y
Nature Chemistry (2022)