Ytterbium Catalyst for Asymmetric Biginelli Reaction

ASYMMETRIC SYNTHESIS

A new chiral catalyst based on ytterbium enables the room-temperature formation of optically active dihydropyrimidines through multicomponent Biginelli condensation with good to excellent enantioselectivities.

In the Biginelli reaction, an aldehyde, a 1,3-ketoester, and a urea or thiourea condense in one pot to form polyfunctionalized dihydropyrimidines. Many of these heterocyclic compounds possess potent biological activities, and researchers have long sought an asymmetric version of the atom-economical reaction. Yijun Huang, Fengyue Yang, and Chengjian Zhu of Nanjing University, in China, now have developed an asymmetric version catalyzed by ytterbium triflate [Yb(OTf)₃] with a chiral hexadentate ligand (J. Am. Chem. Soc. 2005, 127, 16386).

They applied the optimized protocol to monastrol, the only small molecule known to inhibit mitosis by interacting with the kinesin motor protein Eg5, and to (R)-SQ 32,926, a potent orally active antihypertensive agent. The reaction of m-hydroxybenzaldehyde, acetoacetate, and thiourea yielded (R)-monastrol in 99% enantiomeric excess. (R)-SQ 32,926 was obtained in more than 99% enantiomeric excess. The catalyst can be reused several times without significant loss of activity after recovery by extraction, the authors report.

“Accomplishing a direct enantiocontrolled route to dihydropyrimidines has been a challenge for synthetic chemists for many years, and this work will benefit ongoing efforts in drug discovery in industry and academe,” comments chemistry professor Peter Wipf of the University of Pittsburgh. Wipf also points out that the new study complements a recent one by Scott E. Schaus at Boston University. Schaus and coworkers obtained similar polyfunctionalized heterocycles in good enantiomeric excess by cyclizing chiral Mannich addition products (J. Am. Chem. Soc. 2005, 127, 11256).