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

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 ß-keto nitrile to furnish the maleic anhydride.

Total Synthesis of (+)-Cornexistin.

Herein, we describe the first total synthesis of (+)-cornexistin as well as its 8-epi-isomer starting from malic acid. The robust and scalable route features a Nozaki-Hiyama-Kishi reaction, an auxiliary-controlled syn-Evans-aldol reaction, and a highly efficient intramolecular alkylation to form the nine-membered carbocycle. The delicate maleic anhydride moiety of the nonadride skeleton was constructed from a ß-keto nitrile. The developed route enabled the synthesis of 165 mg (+)-cornexistin.

9-Membered Carbocycles: Strategies and Tactics for their Synthesis.

Many natural products comprising a nine-membered carbocyclic core structure exhibit interesting biological effects. However, only a minority have succumbed to their synthesis in the past. The synthesis of functionalized nine-membered carbocycles still remains a challenging goal for synthetic chemists, mainly due to their high ring strain. Different strategies to overcome the unfavorable enthalpic and entropic factors associated with their formation are highlighted in this Concept article. The presented methods are classified into two different categories: (1) the ring-expansion of smaller rings or the ring-contraction of larger rings and (2) the direct cyclization of acyclic precursors.