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A SYNTHETIC TOUR DE FORCE
After a 12-year effort, chemists achieve total synthesis of a ciguatoxin
Every year, more than 20,000 people become sick from eating any of 400 species of warm-water fish that accumulate ciguatoxins. These large and complex, ladderlike polyethers are structurally similar to but far more lethal than the red-tide toxins called brevetoxins.
Ciguatoxins cause gastrointestinal, neurological, and cardiovascular disturbances that can lead to paralysis and death. Lacking a supply of the natural product, researchers have been hampered in studying their action and in developing methods for their detection.
PHOTO BY PAMELA ZURER
A solution to the supply problem is at hand. Researchers at Tohoku University, Sendai, Japan, led by chemistry professor Masahiro Hirama, have made the ciguatoxin called CTX3C in the lab [Science, 294, 1904 (2001)]. This synthesis, Hirama and coworkers write, "will provide a practical supply of ciguatoxins for further studies."
István E. Markó, a chemistry professor at the Catholic University of Louvain, Belgium, summarizes the synthetic challenge in an accompanying Science commentary: The molecule has 30 stereogenic centers and 13 rings ranging in size from five to nine members; 12 rings are trans fused; one ring belongs to a spiroketal function.
The Tohoku chemists have synthesized "an impressively complex target, one of the more complex of this class of cyclic ethers, possessing significant--albeit adverse--biological activity that could teach us much about our marine world," comments Paul A. Wender, a chemistry professor at Stanford University.
The researchers applied a highly convergent strategy. They separately prepared two parts of CTX3C--rings AE and HM--and joined them. With 11 rings in place, they next used carefully manipulated reactions, including ring-closing metathesis, to construct rings F and G.
"The strategy works quite well," Hirama says. "The synthesis was executed by two graduate students--Hisatoshi Uehara and Megumi Maruyama--without the help of postdocs. That proves how efficient our approach is."
Also, the penultimate intermediate, a protected CTX3C, has no detectable toxicity. This suggests that "the route is nontoxic until the final deprotection step."
The size of the molecule--3 nm long--posed some complications. "Some reactions in the later stages--after the two large fragments had been coupled--failed even though the model reactions with small fragments worked well," Hirama comments. "The 3-nm-long molecules showed unexpected reactivity. I like to name this phenomenon 'nanoscale effects in organic synthesis.' "
Looking at individual bond-forming steps, Wender notes how the synthesis "reaches back" to now-common reactions--from Wittig olefinations to the almost ubiquitous ring-closing metathesis reaction. To a casual observer, these series of steps may not amount to anything new. But for anyone who has mounted a major complex synthesis effort, he says, "there is considerable appreciation of the tactical and strategic challenges that must be met for success in this type of project."
Hirama first became involved with ciguatoxins in 1989, after the structure of one was determined by NMR by Takeshi Yasumoto, a former professor in the agriculture faculty at Tohoku University. Yasumoto "asked me to help define the absolute stereochemistry of the ciguatoxin through synthesis," Hirama says. The amount of natural material was not enough to do so by crystallography or chemical transformation. The collaboration drew Hirama's attention to the formidable synthetic challenge the compounds pose and the public health problems the compounds cause. "I thought that organic chemists, by taking up this synthetic challenge, could help solve a human health problem and advance biological, medical, and pharmacological studies of these compounds," he says.
5 + 6 = 13 CTX3C is built by coupling the AE ring to the HM ring and constructing rings G and F in sequence, the latter through a ring-closing metathesis reaction using a Grubbs catalyst.
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Copyright © 2001 American Chemical Society