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October 31, 2006

ORGANIC SYNTHESIS

Elusive Natural Product Is Synthesized

Kinamycin C, an antibiotic with unusual diazo group, is created from scratch

Stu Borman

Kinamycin C, a bioactive natural product whose structure was misinterpreted when it was discovered in the early 1970s and wasn't corrected until over two decades later, has succumbed to total synthesis (J. Am. Chem. Soc., DOI: 10.1021/ja066621v).

Kinamycin C is one of several compounds in the kinamycin family with strong antibiotic and anticancer activity. Its enantioselective total synthesis, by graduate student Xiaoguang Lei and chemistry professor John A. Porco Jr. of Boston University, could facilitate the creation of interesting variants for drug discovery and other applications. The work also represents a potential first step toward the assembly of related dimeric compounds, the lomaiviticins, whose synthesis is being ardently pursued by several groups.

A key step in kinamycin C's synthesis was the use of an asymmetric nucleophilic epoxidation developed earlier by Porco's group to establish the correct configuration and stereochemistry of a cyclic fragment that became the natural product's highly oxygenated D ring. The compound's diazo group, which also presented a great synthetic challenge because of its high reactivity, was installed very late in the synthesis.

The presence in kinamycin C of a diazo group, instead of what had earlier been believed to be an N-cyano group, was discovered independently by two research teams in 1994. Apart from the 1996 synthesis of a biosynthetic precursor, progress on the synthesis of kinamycin C "has been relatively slow," says associate professor of chemistry Gary Dmitrienko of the University of Waterloo, Ontario, who led one of the teams that recognized the compound's diazo group.

BOSTON UNIVERSITY
CONSTRUCTION TEAM Porco (left) and Lei achieved the first total synthesis of kinamycin C.

The stereocontrolled construction of the D ring and the problem of introducing the delicate diazo group have proven to be nontrivial issues, Dmitrienko says. This first total synthesis in the kinamycin series "is a promising initial step toward the generation of analogs of the kinamycins to optimize their potential therapeutic properties and to probe their mode of action," which recent biological and biochemical studies suggest is unlike that of other known antibiotics.

The kinamycins are already accessible by fermentation, so the new synthesis is not necessarily needed to produce them, says Guy T. Carter, assistant vice president of chemical technologies in Chemical & Screening Sciences at Wyeth Pharmaceuticals, Pearl River, N.Y. "Nevertheless, the total synthesis would allow for modifications to be made so you could probe structure-activity relationships more easily than would be possible with a biosynthetic approach. And people who are trying to synthesize the lomaiviticins will benefit from this study" because the lomaiviticins contain kinamycin-like units.

"This is a beautifully instructive synthesis of a challenging natural product that has been hotly pursued by several groups over the past decade," comments associate professor of chemistry Phil S. Baran of Scripps Research Institute. It "will pave the way for syntheses of other members of the family and allow access to kinamycin analogs inaccessible from nature."

Chemical & Engineering News
ISSN 0009-2347
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