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 (4), the putative active form of the metabolite myrocin C (1), that featured a carefully orchestrated tandem fragment coupling–annulation cascade. Herein, we describe the evolution of our synthetic strategy toward 4 and report the series of discoveries that prompted the design of this cascade coupling. Efforts to convert the diosphenol (−)-myrocin G (4) to the corresponding 5-hydroxy-γ-lactone isomer myrocin C (1) are also detailed. We present a preliminary evaluation of the antiproliferative activities of (−)-myrocin G (4) 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.