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, K D = 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.