Four-Step Synthesis of the Antimalarial Cardamom Peroxide via an Oxygen Stitching Strategy

A four-step synthesis
of the antimalarial terpene cardamom peroxide,
a 1,2-dioxepane-containing natural product, is reported from (−)-myrtenal
and molecular oxygen. This highly concise route was guided by biosynthetic
logic and enabled by an unusual manganese-catalyzed, tandem hydroperoxidation
reaction. The absolute configuration of the cardamom peroxide is reported,
and its mode of fragmentation following Fe­(II)-mediated endoperoxide
reduction is established. These studies reveal the generation of reactive
intermediates distinct from previously studied endoperoxide natural
products.