A multifunctional catalyst that stereoselectively assembles prodrugs

• Autores: Daniel A. DiRocco, Yining Ji, Edward C. Sherer
• Localización: Science, ISSN 0036-8075, Vol. 356, Nº 6336, 2017, págs. 426-430
• Idioma: inglés
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• Resumen

  • 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.