| METHOD |
It's now possible to determine enantiomeric selectivities of thousands of compounds simultaneously, solving a critical problem that has impeded the discovery of new enantioselective catalysts via high-throughput screening of compound libraries. Several methods are already available for determining the catalytic reactivity of compounds in such studies. But there has been no rapid and convenient technique for determining a catalyst's enantioselectivity—the extent to which it favors the synthesis of one enantiomeric product over the product with opposite chirality. The ability to determine gene expression ratios en masse with DNA microarrays has "revolutionized our view of biology. "We wondered if we could use that same approach and focus it on organic chemistry." They've apparently succeeded in reaching this goal, although the "reaction microarrays" technique has not yet been fully tested in real high-throughput catalyst-discovery experiments. The researchers tested it initially with -amino acids as stand-ins for chiral products of enantioselective catalysts. "But our long-term goal is to expand the scope to include the high-throughput analysis of any product from any asymmetric catalysis experiment," In the new technique, a contact printer is used to deposit spots of chiral product onto a glass slide. A coupling reagent is included in the spotting solution so that the enantiomeric products become covalently attached to surface groups on the slide. Two fluorescent chiral probe reagents—a green one for one enantiomeric product and a red one for the other—are added to each spot simultaneously. The two probe reagents react with the enantiomers at different rates, a process known as kinetic resolution. Fluorescence from each spot on the slide is measured with a laser scanner to determine the degree of incorporation of chiral product. These data are then entered into an equation developed by the late French chemist Alain Horeau of the Collège de France in Paris that calculates enantiomeric excess from kinetic resolution data. The red-green ratio also can indicate the absolute configuration of a product if a study on the reactivity of the enantiomers with the red and green probes has been carried out in advance.The area of enantioselective catalyst discovery is actually rather contentious at the moment. "One school of people likes to design catalysts," he says. "Another group thinks that design is possible but that screening is another very powerful approach because we don't understand all the forces involved in asymmetric catalysis. "What we're hoping is to make the screening approach so powerful that we start to find things you would not have seen by doing single experiments," FINDING FAVORITISM On this microarray of 15,552 proline samples, all but two had low (0-20%) enantiomeric excess, one had a 99% excess of D-proline, and another had a 99% excess of L-proline. located those two spots in about 48 hours using their new technique, but now have it down to less than 24 hours. With chiral high-performance liquid chromatography, the same experiment would take several months, |
| UPDATE | 01.01 |
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