Linear and cyclic phosphoramidate and phosphonate prodrugs are of growing importance in the development of novel HCV, HIV and oncology pro-nucleotide (ProTides) therapies. Much research in this area has focused on the development of direct, chemoselective or enantioselective reactions to provide 5’-ProTides. However, the development of a direct and efficient synthesis of 3’-ProTides, which was a key feature of our design to synthesize cyclic prodrugs, remained relatively unexplored. In an effort to develop an efficient, robust and scalable route to support Phase 1 clinical studies, we discovered a direct and chemoselective 3’-phosphoramidation that enabled the direct functionalization of the secondary hydroxyl group at the nucleoside 3’-position in the presence of the unprotected 5’-primary hydroxyl group. In addition to the successful application of this chemistry in GMP campaigns, the investigation of this rare selectivity was explored through a combination of NMR spectroscopy and computational studies. The findings of these studies allowed us to develop a predictive computational model that accurately assesses the potential for 3’-functionalization for a broad range of nucleosides and nucleoside mimetics. The discovery, development and delivery of a cyclic ProTide, as well as the understanding the selectivity and demonstration of the method on a broad scope of nucleosides and electrophiles will be presented.

Accessing novel phosphoramidate prodrugs via the protecting-group free selective 3’-functionalization of nucleosides

255th National Meeting (2018)

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