A multifunctional catalyst that stereoselectively assembles prodrugs
Daniel A DiRocco1, Yining Ji2, Edward C Sherer2
1Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA. daniel.dirocco@merck.com.
Abstract:
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.
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