Angewandte Chemie International Edition
© WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
For full article and contact information, see Angew. Chem. Int. Ed. 2003, 42 (14), 1648 - 1652
Image or Mirror Image?
Determining the configuration of peloruside A,
a potential new antitumor agent
About three years ago, scientists led by Peter Northcote isolated a previously unknown compound, a potential cancer-fighting agent, from a New Zealand sea sponge. Peloruside A works in a fashion similar to Taxol, and could be a complementary chemotherapy drug. American chemists working with Jef De Brabander at the University of Texas Southwestern Medical Center at Dallas have now achieved the first total synthesis of Peloruside A -- but in a form that is the mirror image of the natural product. By means of the synthetic route together with additional analytical data, the team was able to contribute the last puzzle pieces to the determination of the configuration of natural peloruside A.
Natural products are often carbon molecules with complex structures. Whereas it is possible to analyze their overall structure quite well, the determination of the exact spatial relationships often turns out to be extremely difficult. One reason for this is the spatial arrangement of the four "bonding arms" of carbon atoms, which point toward the four corners of a tetrahedron. Four different bonding partners can thus be arranged in two different ways, which are mirror images of each other. Peloruside A contains ten such chiral centers, as they are called. It had previously been possible to determine the the orientation of the individual chiral centers toward each other, however, the absolute configuration of these centers remained unclear -- because a single "relative structure" can manifest itself in two molecules that are mirror images of each other but are otherwise identical.
But is it the right mirror image? Unfortunately not, according to De Brabander's team; the synthetic compound rotates plane-polarized light to the left, which is opposite to the right-rotating natural product. At least the configuration of natural peloruside A has now been unequivocally determined. It is also clear what the Texan group is now feverishly working on -- the total synthesis of the other mirror image, since only this form is pharmacologically active.