Synfacts 2017; 13(08): 0867
DOI: 10.1055/s-0036-1590687
Organo- and Biocatalysis
© Georg Thieme Verlag Stuttgart · New York

Catalytic Stereoselective Synthesis of Pronucleotides

Benjamin List
Lucas Schreyer
DiRocco DA. * Ji Y. Sherer EC. Klapars A. Reibarkh M. Dropinski J. Mathew R. Maligres P. Hyde AM. Limanto J. Brunskill A. Ruck RT. Campeau L.-C. Davies IW. Merck & Co., Inc., Rahway, USA
A Multifunctional Catalyst that Stereoselectively Assembles Prodrugs.

Science 2017;
356: 426-430
Further Information

Publication History

Publication Date:
18 July 2017 (online)



DiRocco and co-workers report a diastereoselective synthesis of pronucleotides from the corresponding nucleosides by a dynamic kinetic resolution of chlorophosphoramidate 1. Whereas the reaction with N-methylimidazole as catalyst proceeds with almost no stereoselectivity toward the newly formed stereogenic center on phosphorus, a dimeric, chiral, imidazole-based catalyst with additional hydrogen-bonding sites furnished a series of pronucleotides in good yields and good to excellent stereoselectivities.



Pronucleotides are important compounds for the treatment of viral diseases and cancer. The derivative MK-3682, for instance, is a hepatitis C viral RNA polymerase inhibitor, currently undergoing late-stage clinical trials. Because different absolute configurations of the P-based stereogenic center can significantly alter the drug’s potency and toxicity, stereoselective generation thereof is of great importance. Herein, the authors report the first catalytic, stereoselective access to compounds bearing P-based stereogenic centers.