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.