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October 9, 2006
Volume 84, Number 41
p. 12

Organic Chemistry

First Synthesis Of Platensimycin

Work could ease way to improved analogs of unique antibiotic natural product

Stu Borman

Academic researchers have completed the first total synthesis of a racemic version of platensimycin, an antibiotic with a unique mechanism of action, only four months after its discovery was reported.

Platensimycin is the first antibiotic natural product with a new mechanism of action discovered in over 40 years, and the total synthesis could ease access to analogs with improved drug properties.

The discovery of platensimycin was reported just this May by biologist Jun Wang, structural biologist Stephen M. Soisson, and Director of Natural Products Chemistry Sheo B. Singh of Merck Research Laboratories, in Rahway, N.J., and coworkers (Nature 2006, 441, 358; C&EN, May 22, page 7). "Most antibiotics used today fall into four different categories in terms of how they kill bacteria," Singh says, "and platensimycin uses a fifth mechanism-inhibition of fatty acid biosynthesis."

Now, chemistry professor K. C. Nicolaou, grad student Ang Li, and postdoc David J. Edmonds of Scripps Research Institute and the University of California, San Diego, have achieved the first total synthesis of racemic platensimycin (Angew. Chem. Int. Ed., DOI: 10.1002/anie.200603892). The synthesis was carried out by making two key precursors, a carboxylic acid and an aromatic amine, and combining them. Racemic platensimycin would have to be resolved to render the active enantiomeric version of the natural product, but the synthesis nevertheless sets the stage for synthesizing designed analogs with better characteristics than the native compound.

Stitched Up Racemic platensimycin (shown here as the enantiomeric natural product) was constructed by amide bond formation between two key components, an aromatic amine and an enyne-derived carboxylic acid. TBS is tert-butyldimethylsilyl; MOM is methoxymethyl.

"This expedient total synthesis opens an important chapter in antibiotic research," says assistant professor of chemistry Martin J. Lear of the National University of Singapore, whose group also has been trying to synthesize platensimycin. "The synthetic approach is cleverly planned, and routes to asymmetric variants and designed analogs for drug development look conceivable."

"The approach is very concise," Singh says. "It confirms the structure we proposed, and it provides avenues for building in modifications that couldn't be made by chemically modifying the natural product."

Chemical & Engineering News
ISSN 0009-2347
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