Zeolites steer photoreactions to precise products

By confining reactants to a particularly shaped space, zeolites can direct photo­chemical reactions to specific products, according to work by chemists at Tulane University, New Orleans. Their findings may be useful for fine chemical synthe­ses and could lead to a new approach to "clean" chemistry.

Chemistry professor Vaidhyanathan Ramamurthy, postdoctoral fellow Kasi Pitchumani, and graduate student Manoj

Ramamurthy: create chiral space In zeolite

V. Warrier have shown that the interior of a zeolite can control selectivity in the photochemical rearrangements of aryl es­ters \J. Am. Chem. Soc, 118, 9428 (1996)]. Some products of such rear­rangements are important precursors of pharmaceutical compounds. For exam­ple, conversion of phenyl acetate top-hy-droxyacetophenone is a key step in pre­paring the analgesic acetaminophen.

Aryl ester rearrangements usually are done in solution, using catalysts like alu­minum trichloride and mineral acids such as hydrofluoric or sulfuric acid. This generates large amounts of toxic wastes, Ramamurthy notes. The reactions form phenol and both ortho and para isomers of a second product. Because of the poor selectivity, controlling product distribu­tions is difficult.

The Tulane study shows there is more selectivity when the rearrangements oc­cur photochemically in zeolites. Ortho isomers, which have a more rounded shape, are formed in great excess within zeolites with spherical cavities, such as faujasites X and Y. But para isomers—

which are more linear than spherical— predominate when zeolites have tubular cavities, like pentasils ZSM-5 and ZSM-11.

Commenting on the research, chemis­try professor Galen D. Stucky of the Uni­versity of California, Santa Barbara, points out that although the reactions were carried out to only about 30% con­version, "in some cases, the selectivity is excellent, and the work represents a sig­nificant achievement."

The Tulane work is an excellent ex­ample of how noncovalent interactions can be used to direct nonselective reac­tions to specific products, adds Columbia University chemistry professor Nicholas J. Turro, who pioneered the concept of

shape selectivity for con­trolling photochemical reactions. "It provides in­sight to the mechanism of size and shape selec­tivity of porous solid cat­alysts under mild condi­tions," he says.

In these reactions, the zeolite is merely a medium, not a catalyst, Ramamurthy stresses. Its shape and the cat­ions within the cavity constrain the transition state, forcing the reac­tion to form the product with a shape similar to that of the cavity.

He hopes the work will spur interest in photochemical reactions for industrial processes, very few of which are used at present. Earlier, his group and a team led by chemistry professor John R. Scheffer at the University of British Columbia, Vancouver, used zeolites as a medium for photochemical asymmetric synthesis \J. Am. Chem. Soc, 118, 1219 (1996)].

"The ideal would have been to use chiral zeolites. But those are not avail­able," Ramamurthy notes. So the re­searchers inserted optically active com­pounds to create the chiral space in the zeolite. For photochemical conversion of c/s-4-ter£-butylcyclohexyl ketones to cy-clobutanols, ephedrine was the best chiral inductor, yielding 25 to 30% enan­tiomeric excesses. These yields are poor, he says, but they suggest an important role for zeolites in photochemical asym­metric synthesis.

"There is a perception that photo­chemical reactions are messy and diffi­cult to control," he says. "Our work is showing that the scene is changing."

Maureen Rouhi

Genomics-based drug discovery venture Genetics Institute has launched a gene-based protein drug discovery platform and signed on two major biopharmaceu-tical firms as its first licensees.

The Cambridge, Mass.-based company calls its DiscoverEase program "function­al genomics"—designed to isolate and rapidly determine not only genes but also the related functions of critical pro­teins. Other genomics programs se­quence vast amounts of human genetic information. But Genetics Institute sug­gests the race is not to uncover the most genes, but rather the most valuable ones to speed up gene-based drug discovery.

Chiron, of Emeryville, Calif., and Gen-entech, of South San Francisco, have joined the program to increase their sources for drug leads. Genetics Institute is offering broad access by multiple part­ners for what it calls "low up-front fees." It retains an option to codevelop and co-commercialize any resulting products based on individual proteins selected by partners for exclusive licensing.

It is not surprising that the first licens­ees are biopharmaceutical companies that have successfully developed and marketed several recombinant protein-based drugs. Genetics Institute's technol­ogy targets similar "secreted proteins" produced by cells to mediate biological functions and interactions. The company says it has used its "signal sequence trap" technology, which identifies and isolates fragments of genes encoding for secreted proteins, to identify 5,000 se­creted gene fragments. To date, it has identified 250 of the associated proteins.

Genetics Institute—in which American Home Products holds a majority share—is entering the competitive and lucrative field of genomics research. Large pharma­ceutical firms have eagerly promised sig­nificant sums to access gene sequence li­braries to find potential drug targets.

More than 15 major drug firms al­ready have licensing deals with three leading genomics firms: Human Genome Sciences, Rockville, Md.; Millennium Pharmaceuticals, Cambridge, Mass.; and Incyte Pharmaceuticals, Palo Alto, Calif. Not including all possible R&D milestone and royalty payments, these deals are val­ued at more than $600 million com­bined. Genetics Institute anticipates sign­ing additional partners in the U.S., Eu­rope, and Japan by the end of the year.

Ann Thayer

OCTOBER 7, 1996 C&EN 7