Efficient convergent synthesis of 1,3-diazepinone nucleosides by ring-closing metathesis and direct glycosylation

Abstract

A new and highly efficient ring-closing metathesis-based strategy was developed for the synthesis of the cyclic urea 1,3-diazepinone, presenting significant improvement upon previous methods. Using a direct glycosylation approach, analogues of the potent cytidine deaminase (CDA) inhibitor diazepinone riboside were then synthesized including 2′-deoxyribo-, 2′-deoxy-2′-fluoroarabino-, and 2′-deoxy-2′,2′-difluoro-diazepinone nucleosides, all with moderate to good yield and excellent anomeric selectivity. Crucially, in contrast to the previous multistep linear synthesis of 2′-deoxyribo- and 2′-deoxy-2′-fluoroarabino-diazepinone nucleosides, this is the first report of direct glycosylation to access these nucleosides. Overall, we report efficient convergent routes to multiple 2′-modified-diazepinone nucleosides for further evaluation as CDA and potential APOBEC3 inhibitors.