Evolution of a Strategy for the Total Synthesis of (+)‐Cornexistin

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.

Total Syntheses of (+)-Waixenicin A, (+)-9-Deacetoxy-14,15-deepoxyxeniculin, and (−)-Xeniafaraunol A

“…Our retrosynthetic analysis aimed for maximum side chain flexibility to access different xenicin natural products at a late stage and was initially guided by the 9-membered ring for which several disconnections were evaluated (Scheme ). Inspiration came from the intramolecular Pd-catalyzed Tsuji–Trost reaction that Corey has employed in the synthesis of antheliolide A ( 3 ) as well as the intramolecular alkylation developed by us to install the 9-membered ring of cornexistin . For the adaption of this maneuver to 1 , we dissected 1 into two fragments: the linear and functionalized side chain attached to C4 and the 6,9- trans -fused building block 7 with a triflate functionality which was foreseen to serve a dual purpose.…”

Total Synthesis of Isoxeniolide A**

“…For the latter type of substrates, Magauer has reported the cyclization of a disubstituted Z vinyl iodide in 28 % yield, in the context of studies towards the synthesis of cornexitin [40] . To the best of our knowledge, the only examples for the cyclization of E ‐configured vinyl (pseudo)halides have been described by Procter and co‐workers [41] as well as Takao, Tadano and co‐workers [42] for the formation of the nine‐membered ring in pestalotiopsin A through intramolecular NHK reactions in yields between 45 % and 92 % [43] .…”

“…[40] To the best of our knowledge, the only examples for the cyclization of E-configured vinyl (pseudo)halides have been described by Procter and coworkers [41] as well as Takao, Tadano and co-workers [42] for the formation of the nine-membered ring in pestalotiopsin A through intramolecular NHK reactions in yields between 45 % and 92 %. [43] As in Magauer's case, [40] these latter cyclizations were found to be highly stereoselective; while this was encouraging, it needs be noted that the cyclization precursors in the pestalotiopsin case incorporated a stereo-center adjacent to the aldehyde group, which may have been beneficial for the stereochemical outcome of the cyclization. It was thus uncertain at the planning stage, if the conversion of vinyl (pseudo)halides of type R-3 into carbocycle R-1 would be stereoselective and, if so, to what degree and in favor of which isomer.…”

Die Totalsynthese von Isoxeniolid A**

“…[39] Die zweite Variante wurde von Magauer im Kontext seiner Synthese des Cornexitins beschrieben, bei der ein disubstituiertes Z-Vinyliodid in 28 %-iger Ausbeute zyklisiert werden konnte. [40] Die einzigen bisher publizierten Beispiele von Zyklisierungen E-konfigurierter Vinyl(pseudo)halogenide stammen unseres Wissens von Procter und Mitarbeitenden, [41] sowie von Takao, Tadano und Mitarbeitenden. [42] Es handelt sich in beiden Fällen um den Aufbau des 9-gliedrigen Rings in Pestalotiopsin A via intramoleku-lare NHK-Reaktionen, die in Ausbeuten zwischen 45 % und 92 % abliefen.…”