Stereochemistry Of Cancer Drugs

¿-Tartaric acid

COOH rnfio-tartaric acid

/-tartaric acid

Figure 12 Wisticenus.

isomers. In a lecture, held much later in Utrecht on May 16,1904, van't Hoff said the following:

Students, let me give you a recipe for making discoveries. In connexion with what has just been said about libraries, I might remark that they have always had a mind-deadening effect on me. When Wislicenus' paper on lactic add appeared and I was studying it in the Utrecht library, I therefore broke off my study half-way through, to go for a walk; and it was during this walk, under the influence of the fresh air, that the idea of asymmetric carbon first struck me.

These proposals of van't Hoff's came as a breath of fresh air to Wislicenus. No wonder that he was the first to welcome it enthusiastically, or that he sponsored the German translation that made it widely known, or that he was the first to make significant further use of the hypothesis, in his work on geometrical isomers of unsaturated compounds (13).

The other example of note is the optically active tartaric acids (Fig. 11). Tartaric acid contains two asymmetric carbon atoms. The dextro- and levo-tartaric acids are enantiomers. However, a third isomer is possible in which the two rotations due to the two asymmetric carbon atoms compensate and the molecule is optically inactive as a whole. That is, the molecule contains a plane of symmetry. This form, meso-tartaric acid, was also discovered by P&steur, differs from the two optically active tartaric acids in being internally compensated, and is not resolvable. Thus, the tetrahedral model for carbon and the asymmetric carbon atom proposed by van't Hoff were able to completely explain the observations of Pasteur relating to the three isomers of tartaric acid.

Le Bel published his stereochemical ideas two months later, in November 1874, under the title, "The relations that exist between the atomic formulas of organic compounds and the rotatory power of their solutions" (14). An English translation is presented in Le Bel (15). Le Bel approached the problem from a different direction from van't Hoff. His hypothesis was based on neither the tetrahedral model of the carbon atom nor the concept of fixed valences between the atoms. He proceeded purely from symmetry arguments; he spoke of the asymmetry, not of individual atoms, but of the entire molecule, so that his views would nowadays be classed under the heading of molecular asymmetry. Only once does he mention the tetrahedral carbon atom, which he regarded as not a general principle but a special case. Today, substituted allenes, spiranes, and biphenyls are but a few examples of asymmetric molecules that do not contain any asymmetric carbons, thus confirming Le Bel's views on molecular asymmetry. The reason for the different approaches by van't Hoff and le Bel is easy to understand, van't Hoff came from the camp of structural chemists, and he wished his hypothesis to be understood as an extension of the structural theory to spatial relationships. The tetravalent atomic models used by Kekule in his lectures presumably also prompted his pupil van't Hoff, possibly unconsciously, in the conception of the asymmetric carbon atom. Le Bel, on the other hand, was trained in the tradition of Pasteur (whose investigations he also mentioned expressly in his article), that is, he started out from Pasteur's considerations of the connections between optical rotation and molecular structure.

In 1877 Hermann Kolbe, one of the most distinguished of the older German chemists, published a diatribe in the Journal fur Praktische Chemie after reading the work of van't Hoff {which had been translated into German by Felix Herrmann at the suggestion of Wislicenus). An English translation of this abusive attack is presented completely in Riddell and Robinson (3). Those individuals interested in seeing an example of the great personal attacks by editors that appeared in journals of the nineteenth century should read this translation. Although defamatory, this criticism served a useful purpose, since it made a decisive contribution to the dissemination of these ideas of van't Hoff. This was fortunate, since van't Hoff soon turned his genius away from stereochemistry to physical chemistry, for which he received the Nobel Prize.

We can now end this historical journey. We have walked through the early days of stereochemistry in the company of giants. In 1949, almost exactly 100 years after the first resolution of d,¿-tartaric acid by Pasteur, the Dutchman Bijvoet (16), using x-ray diffraction, determined the actual arrangement in space of the atoms of the sodium rubidium salt of {+)-tartaric acid, and thus made the first determination of the absolute configuration about an asymmetric carbon. To further complete the link with the past, Bijvoet did this work while the Director-of the van't Hoff Laboratory at the University of Utrecht.

In the intervening years since the first resolution of a racemate by Pasteur, many chromatographic and nonchromatographic methods have been developed for the resolution of racemic compounds. These methods are the subjects of many of the other chapters in this book.

+2 0

Post a comment