Highly Stereodivergent Synthesis of Chiral C4-Ester-Quaternary Pyrrolidines: A Strategy for the Total Synthesis of Spirotryprostatin A

In this work, we disclose two sets of highly diastereo-and enantioselective [3 + 2] cycloadditions of iminoesters with various alpha-substituted acrylates, especially for sterically hindered and weakly activated alpha-aryl or alkyl-substituted acrylates and alkenal, alkynal, or unstable aliphatic aldehyde-derived iminoesters, catalyzed by the AgHMDS/DTBM-Segphos or Ag2O/ CA-AA-Amidphos catalytic system, achieving the stereodivergent synthesis of chiral C4-ester-quaternary exo-or endo-pyrrolidines with high yields and excellent diastereo-and enantioselectivities (up to >99:1 dr and >99% ee). More importantly, the gram-scale synthetic exo-adduct displays significant applications in the aspect of realizing the total synthesis of the spirotryprostatin A alkaloid via nine steps in a 36% overall yield.

Automated summary

In this study, we report the highly diastereo- and enantioselective [3 + 2] cycloadditions of iminoesters with various alpha-substituted acrylates. The reactions are catalyzed by AgHMDS/DTBM-Segphos or Ag2O/CA-AA-Amidphos, and result in the stereodivergent synthesis of chiral C4-ester-quaternary exo- or endo-pyrrolidines with high yields and excellent diastereo- and enantioselectivities (up to >99:1 dr and >99% ee). The gram-scale synthetic exo-adduct is particularly significant, as it enables the total synthesis of the spirotryprostatin A alkaloid in nine steps with a 36% overall yield.