Modular Total Synthesis of Lasalocid Acid A through Direct C(sp ³ )–C(sp ³ ) Attached Ring Construction

Lasalocid acid A is a natural product polyether antibiotic used in veterinary medicine to prevent parasitic infections which also displays potent inhibitory activity against drug-resistant Gram-positive bacteria and bacterial biofilms. The possibilities for improving the therapeutic potential of lasalocid acid A, through structural optimization, are restricted by the current, prohibitively lengthy syntheses required to construct the complex scaffold. Here, we report a highly concise and module-based synthesis of lasalocid acid A in 11 steps in the longest linear sequence, which is enabled by a new Tsuji-Trost <i>C</i>-glycosylation reaction to directly access the hindered, attached oxacyclic rings constituting the most challenging structural motif. This new reaction accomplishes the chemo-, regio-, and stereoselective C-C coupling of silyloxyfurans with acetoxy-dihydropyranones, affording a hindered C(sp³)-C(sp³) bond, including a quaternary stereocenter, and we demonstrate compatibility with multiple substrate variations. Overall, our results have afforded a new method allowing access to complex chiral scaffolds of relevance for medicinal chemistry and have unlocked the potential for conducting deep structural exploration of lasalocid acid A.