Synthesis of Myrocin G, the Putative Active Form of the Myrocin Antitumor Antibiotics

The antiproliferative antimicrobial
fungal metabolites known as
the myrocins have been proposed to cross-link DNA by double nucleotide
addition. However, the nature of the DNA-reactive species is ambiguous,
as myrocins have been isolated as functionally distinct 5-hydroxy-γ-lactone
and diosphenol isomers. Based on literature precedent, we hypothesized
that the diosphenol 7 (assigned here the trivial name
myrocin G) is the biologically active form of the representative isolate
(+)-myrocin C (1). To probe this, we developed a short
enantioselective route to 7. A powerful fragment-coupling
reaction that forms the central ring of the target in 38% yield and
in a single step was developed. In support of our hypothesis, 7 was efficiently transformed to the bis­(sulfide) 6, a product previously isolated from reactions of 1 with
excess benzenethiol. This work provides the first direct access
to the diosphenol 7, sets the stage for elucidating the
mode of interaction of the myrocins with DNA, and provides a foundation
for the synthesis of other pimarane diterpenes.