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Evolution of a Strategy for the Total Synthesis of (+)‐Cornexistin
Author(s) -
Wildermuth Raphael E.,
Steinborn Christian,
Barber David M.,
Mühlfenzl Kim S.,
Kendlbacher Mario,
Mayer Peter,
Wurst Klaus,
Magauer Thomas
Publication year - 2021
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202101849
Subject(s) - stereocenter , intramolecular force , maleic anhydride , moiety , alkene , allylic rearrangement , chemistry , total synthesis , stereochemistry , enantioselective synthesis , organic chemistry , catalysis , polymer , copolymer
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.