De Novo Asymmetric Synthesis of Milbemycin β₃ via an Iterative Asymmetric Hydration Approach

The enantioselective synthesis of the spiroketal/macrolide natural product milbemycin β₃ has been achieved in 22 steps and 2.8% overall yield from an achiral dienoate. The spiroketal ring system was installed by three sequential asymmetric hydrations followed by sprioketalization. Both the absolute and relative stereochemistry of milbemycin β₃ was introduced by two Sharpless asymmetric dihydroxylations, two π-allylpalladium-catalyzed reductions, and an iridium-catalyzed hydrogen migration/Claisen rearrangement to install the <i>C</i>-12 stereocenter.