Protecting-Group-Free Total Synthesis of (−)-Jiadifenolide: Development of a [4 + 1] Annulation toward Multisubstituted Tetrahydrofurans

A concise,
protecting-group-free total synthesis of (−)-jiadifenolide,
a synthetically challenging seco-prezizaane sesquiterpene
with potent neurotrophic activity, is reported. The convergent route
features a SmI2/H2O-mediated stereoselective
reductive cyclization, an unprecedented formal [4 + 1] annulative
tetrahydrofuran-forming reaction and programmed redox manipulations.
The newly developed annulation of β-hydroxy aldehydes or ketones
with lithium trimethylsilyldiazomethane provides access to a diverse
array of multisubstituted tetrahydrofurans. The synthetic jiadifenolide
exhibited weak cytotoxicity against five human cancer cell lines.