A multifunctional catalyst that stereoselectively assembles prodrugs

• Published in: Science (American Association for the Advancement of Science) Vol. 356; no. 6336; pp. 426 - 430
• Main Authors: DiRocco, Daniel A., Ji, Yining, Sherer, Edward C., Klapars, Artis, Reibarkh, Mikhail, Dropinski, James, Mathew, Rose, Maligres, Peter, Hyde, Alan M., Limanto, John, Brunskill, Andrew, Ruck, Rebecca T., Campeau, Louis-Charles, Davies, Ian W.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 28.04.2017; The American Association for the Advancement of Science
• Subjects: Amides - chemical synthesis; Antineoplastic Agents - chemical synthesis; Antiviral Agents - chemical synthesis; Cancer; Catalysis; Catalysts; Chemical compounds; Chemical synthesis; Computer applications; Computer Simulation; Critical components; Drugs; Mathematical models; Nucleoside analogs; Nucleosides; Nucleosides - chemical synthesis; Phosphates; Phosphoric Acids - chemical synthesis; Phosphorus; Prodrugs; Prodrugs - chemical synthesis; Selectivity; Stereoisomerism; Stereoselectivity
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aam7936

The catalytic stereoselective synthesis of compounds with chiral phosphorus centers remains an unsolved problem. State-of-the-art methods rely on resolution or stoichiometric chiral auxiliaries. Phosphoramidate prodrugs are a critical component of pronucleotide (ProTide) therapies used in the treatment of viral disease and cancer. Here we describe the development of a catalytic stereoselective method for the installation of phosphorus-stereogenic phosphoramidates to nucleosides through a dynamic stereoselective process. Detailed mechanistic studies and computational modeling led to the rational design of a multifunctional catalyst that enables stereoselectivity as high as 99:1.