New picropodophyllin analogs via palladium-catalyzed allylic alkylation-Hiyama cross-coupling sequences

J Org Chem. 2008 Aug 1;73(15):5795-805. doi: 10.1021/jo800707q. Epub 2008 Jun 25.


Unsaturated malonyl esters underwent Pd-catalyzed intramolecular allylic alkylation to give 4-vinyl-substituted gamma-lactones. In contrast to the formerly studied cyclization of malonamides, this reaction could be achieved only with a substrate incorporating a suitably positioned silicon moiety, which directs the ionization toward the desired eta(3)-allylpalladium complex. The resulting 4-[dimethyl-(2-thienyl)silylvinyl]lactone could be subsequently engaged into Hiyama couplings with various iodoarenes, to give the corresponding 4-(alpha-styryl)-gamma-lactones. The use of a specifically substituted iodoarene generated an advanced tetracyclic lactone intermediate incorporating rings A-D of lignans belonging to the podophyllotoxin family. Subsequent electrophilic aromatic substitution with a variety of electron-rich arenes afforded the target picropodophyllin analogs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylation
  • Allyl Compounds / chemistry*
  • Benzhydryl Compounds / chemistry
  • Catalysis
  • Cross-Linking Reagents / chemistry*
  • Cyclization
  • Ions / chemistry
  • Ketones / chemistry
  • Lactones / chemistry
  • Molecular Structure
  • Oxidation-Reduction
  • Palladium / chemistry*
  • Podophyllotoxin / analogs & derivatives*
  • Podophyllotoxin / chemical synthesis
  • Podophyllotoxin / chemistry


  • Allyl Compounds
  • Benzhydryl Compounds
  • Cross-Linking Reagents
  • Ions
  • Ketones
  • Lactones
  • picropodophyllin
  • Palladium
  • Podophyllotoxin