[Note: the following text differs somewhat from that in the original print version, containing minor corrections made for the sake of accuracy.] It comes as a shock, then, to discover that quite a simple molecule is capable of acting as a catalyst for key organic reactions. Paper #4 describes one for the formation of carbon-carbon bonds, which not only works well but selectively, so that a high yield of only one enantiomer is produced. The perfect catalyst would give a 100% yield of 100% of the required enantiomer, but a yield of 97% of 96% is enough to bring this remarkable discovery to the attention of the chemical world. In paper #4, Benjamin List, Richard A. Lerner, and Carlos Barbas at the Scripps Research Institute, La Jolla, California, have achieved this for the asymmetric aldol condensation of acetone and isobutyraldehyde to form the "ee" enantiomer of 5-methyl-4-hydroxy-hexan-2-one. And the catalyst? Nothing more complex than the simple amino acid proline, C4H6NHCO2H, which consists of a 5-membered pyrrolidine ring with an acid group attached. Proline is particularly abundant in wheat proteins and gelatin, where it comprises more than 10% of their amino acid makeup. In 1996, Barbas and Lerner developed what became the commercially available catalytic antibody 38C2 for making enantiomers, via a reaction that involved an aldol step. Early work in the 1970s by Zoltan Hajos and David Parrish had shown that proline would catalyze a ring-forming aldol reaction, and Barbas reasoned that it might well do the same for the reactions he was interested in. Ben List, lead author of paper #4, found that proline was also highly effective in various intermolecular reactions involving benzaldehyde. The Scripps colleagues, intrigued that such a simple chemical reagent could act this way, tried other amino acids and amines to see if they performed as well, but most failed miserably, although the related amino acid, 4-hydroxy-proline was also active. Further work with proline showed that its catalytic activity was not specific only to aromatic aldehydes such as benzaldehyde and its derivatives, but that it would work with simple aliphatic aldehydes, provided these were branched. Thus, while isobutyraldehyde gave the 97% yield mentioned above, its straight chain version, pentanal, gave virtually none of the desired product. So how does proline work its magic? Paper #4 proposes a simple mechanism in which it first reacts with acetone, and then forms an active intermediate enamine species. This uses hydrogen bonding to position the incoming aldehyde, so that it not only forms the desired carbon-carbon bond, but invests it with the desired enantiomeric configuration. In the meantime, List and colleagues have extended the proline-catalyzed asymmetric intermolecular aldol reaction to other substrates (see W. Notz & B. List, et al., J. Amer. Chem. Soc., 122[30]: 7386-7, 2000; Org. Lett., 3[4]: 573-5, 2001) and invented several new related reactions. These include the first proline-catalyzed asymmetric Mannich, intermolecular Michael-, and alpha-amination reactions (see B. List, et al., J. Amer. Chem. Soc., 122[38]: 9336-7, 2000; J. Amer. Chem. Soc., 124: 827-33, 2002; Org. Lett., 3[16]: 2423-5, 2001; J. Amer. Chem. Soc., 124[20]: 5656-7, 2002). The full paper, of which #4 was the preliminary communication, appeared in Journal of the American Chemical Society, (see K. Sakthivel, et al., 123[22]:5260-7, 2001). Two related papers have also appeared in the same journal (both under A. Cordova, et al., in issue 124[9], 2001; pp. 1842-3 and 1866-7), and these are devoted to preparing enantiomers of amino acids derivatives, again using proline as the catalyst. "A recent major advance in our studies has been the application of our approach to aldehyde addition reactions," says Barbas, explaining that such reactions used to be regarded as particularly difficult to control in terms of producing specific enantiomers. Now all that has changed, which not only explains why #4 is being heavily cited, but why List and colleagues’ discovery is being hailed as a "greener" way of carrying out key reactions because it involves environmentally benign materials (see Chemical & Engineering News, 80[8]:33, 25 February 2002). The "green" credentials of proline as a catalyst are summarized in #4. It is non-toxic (indeed it is an essential component of the human body), non-metallic, readily available, cheap, reactive at room temperature, water soluble (so easily removed at the end of the reaction), and it has the ability to be scaled up to industrial use. What more could one ask of any catalyst? Dr. John Emsley is
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nzymes are superbly efficient catalysts, converting one molecule into another, and with total specific stereochemistry. For chemists, the challenge is to find other materials that will perform equally well, and much work has gone into making genetically modified enzymes or sophisticated organometallic compounds. Ideally these catalysts should have the robustness to be used in industrial processes, or maybe even to replace existing processes with "greener" alternatives.
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