De novo asymmetric synthesis of milbemycin beta3 via an iterative asymmetric hydration approach.

The enantioselective synthesis of the spiroketal/macrolide natural product milbemycin beta3 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 beta3 was introduced by two Sharpless asymmetric dihydroxylations, two pi-allylpalladium-catalyzed reductions, and an iridium-catalyzed hydrogen migration/Claisen rearrangement to install the C-12 stereocenter.