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Evolution of a Strategy for the Total Synthesis of (+)-Cornexistin |
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| Authors: | Dr Raphael E Wildermuth Christian Steinborn Dr David M Barber Kim S Mühlfenzl Mario Kendlbacher Dr Peter Mayer Dr Klaus Wurst Prof Dr Thomas Magauer |
| Affiliation: | 1. Institute of Organic Chemistry and Center for Molecular Biosciences, Leopold-Franzens-University Innsbruck, Innrain 80–82, 6020 Innsbruck, Austria
Department of Chemistry and Pharmacy, Ludwig-Maximilians-University Munich, Butenandtstrasse 5–13, 81377 Munich, Germany These authors contributed equally to this work.;2. Institute of Organic Chemistry and Center for Molecular Biosciences, Leopold-Franzens-University Innsbruck, Innrain 80–82, 6020 Innsbruck, Austria These authors contributed equally to this work.;3. Research & Development, Weed Control Chemistry, Bayer AG Crop Science Division Industriepark Höchst, 65926 Frankfurt am Main, Germany;4. Department of Chemistry and Pharmacy, Ludwig-Maximilians-University Munich, Butenandtstrasse 5–13, 81377 Munich, Germany;5. Institute of Organic Chemistry and Center for Molecular Biosciences, Leopold-Franzens-University Innsbruck, Innrain 80–82, 6020 Innsbruck, Austria;6. Institute of General, Inorganic & Theoretical Chemistry, Leopold-Franzens-University Innsbruck, Innrain 80–82, 6020 Innsbruck, Austria |
| Abstract: | Herein is given a full account of the evolution of the first total synthesis of (+)-cornexistin. Initial efforts were based on masking the reactive maleic anhydride moiety as a 3,4-substituted furan and on forming the nine-membered carbocycle in an intramolecular Conia-ene or Nozaki–Hiyama–Kishi (NHK) reaction. Those strategies suffered from low yields and were jeopardized by a late-stage installation of the Z-alkene, as well as the stereocenters along the eastern periphery. These issues were addressed by employing a chiral-pool strategy that involved construction of the crucial stereocenters at C2, C3 and C8 at an early stage with installation of the maleic anhydride as late as possible. The successful approach featured an intermolecular NHK coupling to install the Z-alkene, a syn-Evans-aldol reaction to forge the stereocenters along the eastern periphery, an intramolecular allylic alkylation to close the nine-membered carbocycle, and a challenging stepwise hydrolysis of a β-keto nitrile to furnish the maleic anhydride. |
| Keywords: | herbicides natural products nine-membered carbocycles nonadrides total synthesis |
