Structure determination by synthesis
Chemical & Engineering News, 30 August 2004, 27-29
It can be difficult to determine the structure of a complex natural product; the way structures are proven is to synthesize the structure you think it is, then compare the properties to the authentic material.
In the case of azaspiracid-1, a toxin derived from the blue mussel Mytilus edulis, this led to a whole lot of work for K.C. Nicolau's group at the Scripps Research Institute.
The structure had been proposed by Takeshi Yasumoto and Masayuki Satake and their coworkers at Tohoku University, Sendai, Japan, in 1998. The Nicolau group synthesized the first structure suggested by Yasumoto et al, but found that it was not the same as the natural toxin. So, since the original paper had expressed some uncertainty about certain areas of the structure , Nicolau and coworkers tried the other suggested structure. It still wasn't right.
After a great deal of thought, and of laboratory and library work, Nicolau's group settled on two possible structures (shown below), and synthesized both of them, in 96 steps each! Notice how different their shapes are. Can you spot the stereochemical differences between the two?
It can be painfully frustrating to discover that you have been chasing 'phantom molecules' and not the true natural product structure. The azaspiracid saga represents an intriguing detective story as well as a classic adventure in complex target molecule synthesis and structural elucidation, relying throughout on the combination of chemical insight; flexible synthetic planning; and, above all, sheer perseverance.
For the full story, see the article cited above.
