Copper-Catalyzed Double Additions and Radical Cyclization Cascades in the Re-Engineering of the Antibacterial Pleuromutilin.

A general synthetic sequence involving simply prepared starting materials provides rapid access to diverse, novel tricyclic architectures inspired by pleuromutilin. Sm(II) -mediated radical cyclization cascades of dialdehydes, prepared using a new, one-pot, copper-catalyzed double organomagnesium addition to β-chlorocyclohexenone, proceed with complete sequence selectivity and typically with high diastereocontrol to give analogues of the target core. Our expedient approach (ca. 7 steps) allows non-traditional, de novo synthetic access to analogues of the important antibacterial that can't be prepared from the natural product by semisynthesis.