Evolution of a Strategy for the Total Synthesis of (+)‐Cornexistin. Issue 47 (7th July 2021)

• Record Type: Journal Article
• Authors: Wildermuth, Raphael E.; Steinborn, Christian; Barber, David M.; Mühlfenzl, Kim S.; Kendlbacher, Mario; Mayer, Peter; Wurst, Klaus; Magauer, Thomas
• Is Part Of: Chemistry. Volume 27:Issue 47(2021)
• Page Start: 12181
• Page End: 12189
• Publication Date: 2021-07-07
• Subjects: herbicides -- natural products -- nine-membered carbocycles -- nonadrides -- total synthesis; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.202101849
• Languages: English
• ISSNs: 0947-6539

Abstract

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. Abstract : Cycle tricks : The evolution of the first total synthesis of (+)‐cornexistin is reported. Highlights of the successful chiral‐pool strategy are an intermolecular Nozaki–Hiyama–Kishi coupling to install the Z alkene, a syn ‐Evans‐aldol reaction to construct the C2/C3 stereocenters, an intramolecular allylic alkylation to close the nine‐membered carbocycle and the stepwise hydrolysis of a β‐keto nitrile, which furnished the maleic anhydride.