NEWS OF THE WEEK ORGANIC
LADDER POLYETHERS IN A SNAP
CASCADE Ladder polyether forms by regioselective epoxide opening that is sequentially directed by trimethylsilyl groups, which are not retained in the final product.
Q, ^
Directing group governs regioselective epoxide opening, then is jettisoned
B
Q.
Me3Si
Me3Si
Me = methyl
H
H
SYNTHESIS
H
ECAUSE THEY ARE BIOACTIVE
and difficult to synthesize, the marine natural products known as ladder polyethers—so called because oftheir extended structure of fused heterocycles— have intrigued synthetic chemists for decades. Now, chemists at MIT have reported the shortest route yet to the tetrahydropyran tetrad common to the majority of these compounds {J. Am. Chem.Soc. 2006,128, 1056). The efficient syn-
B I O I N O R G A N I C
thesis, developed by chemistry professor Timothy F. Jamison, postdoctoral fellow Graham L. Simpson, and graduate students Timothy P. Heffron and Estibaliz Merino, employs an epoxide-opening cascade reaction that zips the structure in one step. Chemists have hypothesized for 20 years that ladder polyethers are biosynthesized via this type of cascade. But until now, Jamison says, no one had been able to use this route to make tetrahydropyran tetrads. The M I T group's approach relies on a "disappearing" trimethylsilyl (TMS) group. This moiety regioselectively directs the epoxide
C H E M I S T R Y
CLOT PLOT THICKENS A phosphate polymer emerges as an unsung player in blood chemistry
CIRCULAR CLUES The dark round structures in these electron micrographs of a platelet (left) and a trypanosome (right) contain polyphosphate.
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CLUE T H A T I N O R G A N I C
polymers made of tens to hundreds of phosphate units might serve previously unrecognized roles in blood clotting showed up as dark circles in two seemingly unconnected electron micrographs that cell biologist Roberto Docampo had on his desk a fewyears ago at the University of Illinois, UrbanaChampaign (UIUC).
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One micrograph shows a singlecelled parasite known as a trypanosome. The other depicts blood plasma components called platelets. To Docampo, now at the University of Georgia, Athens, the dark circles in both appeared too similar to leave uninvestigated. Now Docampo, UIUC biochemist James H. Morrissey, and their colleagues have carried out a raft of experiments indicating that polyphosphate is no bit player in blood clotting. This discovery, the researchers say, could lead to new ways of controlling bleeding. "We have this idea that we have found all of the major players in blood clotting, so this is a surprise," Morrissey says.
opening so that a six-membered tetrahydropyran forms, rather than a five-membered tetrahydrofuran. After cyclization, the TMS group leaves the molecule before the next epoxide-opening reaction in the cascade. Jamison and colleagues discovered the departing directing group while tweaking cyclization conditions. The strong Lewis acids typically used to open epoxides failed to give them the desired product. When the chemists used Cs 2 C0 3 and methanol, however, not only did they achieve the desired cyclization, but to their surprise, the TMS groups were not retained in the final product. "That was a 'jumping up and down in the lab' result," Jamison says. After a bit more fine-tuning, the group was able to make the tetrad in just one step. These and related tetrads, Jamison notes, may serve as building blocks for making relatively large amounts of these rare, bioactive ladder polyethers.-BETHANY HALFORD
In platelets, polyphosphate is largely sequestered in so-called dense granules, but it's released when the platelets are stimulated with clot-promoting factors such as thrombin. When that happens, the researchers found in benchtop studies, the polyphosphate activates the complex biochemical cascade behind clotting, interferes with an anticlotting protein, and helps delay the busting of the clot that forms by boosting the effectiveness of a clot-preserving protein in the blood (Proc. Natl. Acad. Sci. USA 2006,103, 903). "The net effect is accelerating the rate at which blood clots form and then prolonging how long they last," Morrissey says. The work has attracted seed money from the Roy J. Carver Charitable Trust to set up the U I U C Center for Hemostasis Research, where researchers will work toward such goals as developing new treatments for otherwise uncontrollable bleeding.-IVAN AMATO
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