Synthesis of 3,5-diazabicyclo [5.1.0] octenes. A new platform to mimic glycosidase transition states

All-cis 1-hydroxymethyl 2,3 bis-aminomethyl cyclopropane was used to construct the first 3,5-diazabicyclo [5.1.0]-3-octenes. This system has the interesting ability to exist in a conformation that resembles a snapshot of a glycoside hydrolysis reaction with respect to charge and geometric analogy to an oxocarbenium ion, and the positioning of the departing aglycon. The cis-configured cyclopropane core was synthesized by Cu-catalyzed intramolecular cyclopropanation of benzyl protected cis-2-butene-1,4-diol diazoacetate ester. Serial functionalization to bis-aminomethyl cyclopropanes and subsequent cyclization to amidines lead to the target bicyclic compounds in good overall yields. Several glycosidases were surveyed for the inhibitory potential of these transition state analogs, and amongst them, selective competitive inhibitors with micromolar Ki values were identified.

Graphical abstract3,5-diazabicyclo [5.1.0] octenes have been synthesized as charge and shape mimics of glycosyl transfer transition states.Figure optionsDownload full-size imageDownload as PowerPoint slide