Development of a Convergent Enantioselective Synthetic Route to (-)-Myrocin G.

Myrocins are a family of antiproliferative antibiotic fungal metabolites possessing a masked electrophilic cyclopropane. Preliminary chemical reactivity studies imputed the bioactivity of these natural products to a DNA cross-linking mechanism, but this hypothesis was not confirmed by studies with native DNA. We recently reported a total synthesis of (-)-myrocin G (), the putative active form of the metabolite myrocin C (), that featured a carefully orchestrated tandem fragment coupling-annulation cascade. Herein, we describe the evolution of our synthetic strategy toward and report the series of discoveries that prompted the design of this cascade coupling. Efforts to convert the diosphenol (-)-myrocin G () to the corresponding 5-hydroxy-γ-lactone isomer myrocin C () are also detailed. We present a preliminary evaluation of the antiproliferative activities of (-)-myrocin G () and related structures, as well as DNA cross-linking studies. These studies indicate that myrocins do not cross-link DNA, suggesting an alternative mode of action potentially involving a protein target.