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.