Efforts toward the Total Synthesis of Thuggacin A

Thuggacin A (<b>1</b>) is a 17-membered-ring-polyketide antibiotic compound with excellent antituberculosis activity. The total synthesis of thuggacin A has not yet been reported so far. Herein, we disclose our efforts toward the convergent total synthesis of thuggacin A. The key synthetic features include our own one-pot cascade thiazole formation, Evans <i>syn</i>-aldol, Mukaiyama asymmetric aldol reaction, organosilicon-promoted selective alkyne reduction, Shiina macrolactonization, and a nucleophilic ring-opening of epoxide with alkyne to assemble the main framework of thuggacin A. The enantioselective synthesis of trimethylsilyl ethoxymethyl (SEM) derived thuggacin A analogue <b>2</b> was achieved in 18 longest linear steps with 2.0% overall yield, and the bioassay of <b>2</b> exhibited moderate antituberculosis activity with minimum inhibitory concentration (MIC) of 320 μg/mL.