University-Industry Focus: Licensing Chiral Technologies for Drug Manufacturing

The announcement on Feb. 11 of an exclusive licensing agreement between Catalytica Pharmaceuticals, Inc. (Mountain View, Calif.) and Pennsylvania State University (University Park, Pa.) was the latest in a series of licensing deals between companies and academics for industrial-grade chiral technology. The need for chiral processes, which produce drugs as single optical isomers (enantiomers) in high chemical yield, is becoming critical as two thirds of new drugs are being developed as pure enantiomers. The Catalytica-Penn State deal involves the license of a "chiral toolbox" of asymmetric catalytic reactions, invented by Penn State chemistry professor Xumu Zhang, for human and animal drugs.

Companies in need of such technology have been lining up at the doors of leading universities. About twenty firms approached Zhang, who has signed non-exclusive agreements with several agrochemical firms as well as the exclusive agreement with Catalytica. Such licenses give companies the right to produce commercial quantities of single-isomer compounds using novel, efficient processes such as reductions, hydrogenations, alkylations, and kinetic resolutions.

For Catalytica, Zhang's chiral processes are essential for its pharmaceutical division's continued growth. Catalytica Pharmaceuticals had all essential capabilities for becoming a leading contract manufacturer except for proprietary chiral technologies. Although the company can boast of such customers as Eli Lilly, Pfizer, Merck, Glaxo-Wellcome, and Pharmacia & Upjohn, and a multi-year, $800 million agreement with Glaxo, "Chiral drugs were not very big for us," said Catalytica spokesman Lloyd Baylis. "Now it will be."

Zhang's Chiral Toolbox
Xumu Zhang has invented a wide variety of proprietary chiral processes with application to a very broad range of pharmaceutical intermediates (Figure 1). His catalysts use active transition metals complexed to a variety of phosphorus, nitrogen, and sulfur ligands. Some of the more advanced processes involve:

Figure 1: Some drugs which could benefit from Zhang's chiral toolchest

Tridentate ligands of transition metals
These reagents address the problem of achieving asymmetric hydrogenation (reduction) of ketones, imines, and olefins which are not highly substituted. These are very desirable substrates because of their simplicity and low cost, but reducing them is difficult because the lack of functional groups on the substrate limits the amount and type of discriminatory interaction between the substrate and the catalyst. With Zhang's tridentate ligands, all the discriminatory capability is built into the catalyst. The ligands are accessible in large quantities through new synthetic schemes outline by Zhang.

Bidentate phosphine ligands for transition metal catalysts
Zhang has produced what are recognized as the most innovative bidentate phosphine ligands in a generation (Figure 2). The common feature of these ligands is a rigid aromatic backbone which limits the flexibility of the ligands, thus achieving efficient chiral transfer from ligand to substrate and the incipient product. These catalysts have been used to reduce N-acylaminoacrylic acids, enamides, allylic alcohols, hetero ketones, keto carboxylic acids, simple olefins, ketones, and imines, as well as for making new carbon-carbon bonds (Figure 3).

Monophosphine catalysts
Transition metal complexes with novel chiral phosphabicyclo[2.2.1]heptanes are excellent catalysts for asymmetric allylic alkylation (using palladium) and hydrovinylation (nickel). These reactions are important because they transfer functionalized carbon-carbon double bonds into new molecules. Zhang has also demonstrated ruthenium-catalyzed asymmetric olefin metathesis and palladium-catalyzed ene reactions.

Heterobicyclo heptanes
These catalysts, which contain phosphorus in a bicyclic carbon backbone, are used to make chiral cyclopentenes and other compounds through selective carbon-carbon bond formation.

For more information, contact: Lloyd Baylis, Catalytica Pharmaceuticals, Inc., 430 Ferguson Dr., Mountain View, CA 94043. Tel: 650-940-6356.

By Angelo DePalma