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Constructing Dideoxyverticillin

Total synthesis of cytotoxic alkaloid could provide insight into its biosynthesis

by Bethany Halford
April 13, 2009 | A version of this story appeared in Volume 87, Issue 15

ALTHOUGH THEY were first identified nearly 40 years ago, no members of the densely functionalized family of dimeric epidithiodiketopiperazine natural products have succumbed to total synthesis—until now. Scientists at MIT report that they have chemically constructed the fungal metabolite (+)-11,11'-dideoxyverticillin A in just 11 steps from commercially available starting materials (Science 2009, 324, 238).

The synthetic strategy used to tackle the complex structure aims to mimic a plausible biosynthetic pathway and could offer a road map for synthesizing other molecules in this family, according to Mohammad Movassaghi, Justin Kim, and James A. Ashenhurst, who synthesized the compound.

Movassaghi tells C&EN that the challenge of making dideoxyverticillin A—a sterically congested molecule packed with stereogenic centers, as well as acid-, base-, and redox-sensitive groups—first attracted him to the project. It also offered the opportunity to develop a laboratory synthesis inspired by a plausible biogenic pathway for the natural product. “We have attempted to capture the power of biosynthetic considerations as a guiding principle for synthetic planning and as an inspiration for the development of new reactions,” he says.

The key reactions Movassaghi, Kim, and Ashenhurst employ “lead to barely stable structures that might otherwise only be seen under the auspices of biosynthetic enzymes,” writes Yale University chemistry professor Scott J. Miller in a commentary that accompanies the report. The questions raised and insights gained by this synthesis, Miller adds, may assist the annotation of the biosynthetic gene cluster connected to this family of alkaloids.

“It is an exceptionally beautiful piece of synthetic chemistry,” comments Brian M. Stoltz, a chemistry professor at Caltech. “The paper vividly captures not only the trials and tribulations of complex-molecule synthesis, but also the highly sophisticated and creative nature of the problem-solving process in our field.”

Stoltz says he is particularly impressed with how the MIT team managed to stereoselectively install four hydroxyl groups in the molecule in one step. Although this process could have generated many different diastereomers, Movassaghi, Kim, and Ashenhurst manage to get a single diastereomer in 63% yield via use of the oxidizing agent bis(pyridine)silver(I) permanganate.

William Fenical, a pharmaceutical science professor at the University of California, San Diego’s Scripps Institution of Oceanography, first determined the structure of the cytotoxic alkaloid dideoxyverticillin A 10 years ago. Simply figuring out the molecule’s structure was a long and laborious process because of its complex three-dimensional architecture; even attempting to synthesize it, he says, required considerable scientific boldness. This synthesis, Fenical adds, “facilitates entry into a wider variety of related structures, thus supporting the potential development of this previously unattainable class of alkaloids for the treatment of cancer.”



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