Format

Send to

Choose Destination
J Am Chem Soc. 2018 Nov 28;140(47):16058-16061. doi: 10.1021/jacs.8b10891. Epub 2018 Nov 16.

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

Author information

1
Department of Chemistry , Yale University , New Haven , Connecticut 06520 , United States.
2
Department of Pharmacology , Yale School of Medicine , New Haven , Connecticut 06520 , United States.

Abstract

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-ő≥-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.

PMID:
30415540
DOI:
10.1021/jacs.8b10891

Supplemental Content

Full text links

Icon for American Chemical Society
Loading ...
Support Center