Asymmetric Total Synthesis of (−)-Psychotriadine Featuring [3,3]-Rearrangement and Stereo-Controllable Ring-Contraction

The first asymmetric total syntheses of (−)-psychotriadine
(1) and its putative congener tetrahydropsychotriadine
(2) were accomplished in 12 and 13 steps, respectively,
featuring Meerwein–Eschenmoser–Claisen rearrangement
and Fischer indolization/Plancher rearrangement cascade. A stereochemically
controllable dearomative ring contraction was utilized to create the
vicinal quaternary stereocenters. The absolute configuration was confirmed
through X-ray crystallography and >200 mg of 1 (90%
enantiomeric
excess (ee)) was obtained. Biological studies revealed that natural
product precursor S-10 acts as an agonist toward liver
X receptors (LXRs, KD = 1.22/0.79 μM),
which upregulates protein levels of ABCA1 and APOE, exhibiting potential
as a drug lead in developing medicine for Alzheimer’s disease.