Total Synthesis and SARS-CoV‑2 3CLpro Inhibition Activities of (±)-Tuaimenal A and Its Derivatives

The first total synthesis of (±)-tuaimenal A was
achieved
in six steps starting from sesamol, with an overall yield of 26.4%.
The key transformation was a tandem pyridine-catalyzed condensation/6π-electrocyclization
sequence, which efficiently constructed the 2H-benzopyran
core. Chiral resolution of the racemate was accomplished by using
Boc-d-Phe-OH as a chiral auxiliary. Enzymatic inhibition
assays revealed that both (+)-tuaimenal A and its enantiomer exhibited
comparable inhibitory activity against SARS-CoV-2 3CLpro (the viral
main protease). Furthermore, 20 analogues were synthesized, and the
preliminary structure–activity relationship (SAR) was discussed.