The protecting-group free selective 3'-functionalization of nucleosides
Jamie M McCabe Dunn1, Mikhail Reibarkh1, Edward C Sherer2
1Department of Process Research & Development , MRL , Merck & Co., Inc. , Rahway , NJ 07065 , USA . Email: Jamie.mccabe.dunn@merck.com ;
Abstract:
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.
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