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.