Chiral Route to a Privileged Class

SYNTHESIS

The first highly enantioselective synthesis of dihydropyrimidones could ease access to this family of bioactive compounds.

Dihydropyrimidones--one of the so-called privileged compound classes because of their affinity for diverse biological targets--have been closely investigated as potential drugs by several groups. A notable example is monastrol. Discovered in 1999 by a Harvard University group, monastrol was the first small molecule found to inhibit mitosis by interacting with a novel target, the kinesin motor protein Eg5.

The asymmetric construction of monastrol and other dihydropyrimidones has been a challenge for some time. The compounds are generally produced as racemates by the Biginelli reaction, developed in 1893, and single enantiomers are obtained by chiral resolution.

Assistant professor of chemistry Scott E. Schaus and coworkers at Boston University's Center for Chemical Methodology & Library Development have now devised the first highly asymmetric synthesis of Biginelli reaction products (J. Am. Chem. Soc. 2005, 127, 11256). The addition reaction provides a direct catalytic route to highly enantiopure chiral dihydropyrimidones.

In the reaction, cinchona alkaloids catalyze the condensation of ß-keto esters and acyl aryl imines to form highly functionalized chiral building blocks, which can then be elaborated into asymmetric dihydropyrimidones and ß-amino alcohols.

Reaction products are obtained in good yields and high enantioselectivities (80-96% enantiomeric excess), compared with 20-30% enantioselectivities for the best previous methods. The reaction is an adaptation of cinchona alkaloid-catalyzed enantioselective reactions developed earlier by groups such as those of chemistry professors Thomas Lectka at Johns Hopkins University and Karl Anker Jørgensen at Aarhus University, in Denmark, and that of associate professor of chemistry Li Deng at Brandeis University, Waltham, Mass.

The study "constitutes a significant breakthrough in the long-sought preparation of highly enantio-enriched chiral dihydropyrimidones," says chemistry professor Eusebio Juaristi of National Polytechnic Institute, Mexico City.

"This first asymmetric version of the Biginelli reaction represents a breakthrough," says associate professor of chemistry C. Oliver Kappe of Karl-Franzens University of Graz, in Austria, an expert in dihydropyrimidone synthesis. "We tried to do this ourselves a couple of years ago and failed. The application for the synthesis of enantiomerically pure pyrimidines is certainly a first."

The reaction is "a great advance over previous methods, which usually involved resolution of enantiomers or the use of chiral auxiliaries," adds John Tallarico, head of chemogenetics at the Novartis Institutes for Biomedical Research, Cambridge, Mass. "Although the method is not as elegant or general a solution toward synthesizing this type of compound as the original multicomponent Biginelli reaction, it offers very concise access to the enantioselective synthesis of dihydropyrimidones."