The protecting-group free selective 3′-functionalization of nucleosidesElectronic supplementary information (ESI) available. CCDC 1525736-1525737. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6sc05081f

• Main Authors: McCabe Dunn, Jamie M, Reibarkh, Mikhail, Sherer, Edward C, Orr, Robert K, Ruck, Rebecca T, Simmons, Bryon, Bellomo, Ana
• Format: Article
• Language: English
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/c6sc05081f

The direct and chemoselective 3′-phosphoramidation, phosphorylation and acylation of nucleosides are described. Upon the discovery of a novel 3′-phosphorylamidation of therapeutic nucleoside analogues with DBU, we explored the mechanism of this rare selectivity through a combination of NMR spectroscopy and computational studies. The NMR and computational findings 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 synthetic utility of this model was exemplified by demonstration on a broad scope of nucleosides and electrophiles yielding targets that were previously only accessible via a protection/deprotection sequence or an enzymatic approach. The direct and chemoselective 3′-phosphoramidation, phosphorylation and acylation of nucleosides are described.