Process Safety Assessment of the Iron-Catalyzed 1,2-cis-Selective Glycal Aminoglycosylation

Complex glycans are directly involved in numerous disease processes, and these structural motifs are increasingly incorporated in pharmaceuticals and biological probes. Therefore, the development of highly stereoselective and broadly effective glycosylation processes that are safe and readily scalable has been of great value in both academia and industry. We report herein a process safety assessment of an iron-catalyzed, entirely 1,2-cis-selective, glycosylation process for the synthesis of a broad range of biologically important 1,2-cis-aminoglycosides. Differential scanning calorimetry analysis of the corresponding catalyst, amination reagents, and an array of representative 1,2-cis-aminoglycosides revealed that all of them are thermally stable at temperatures at least 100 °C above the glycosylation temperature. Accelerating rate calorimetry analysis of the amination reagents confirmed the high exothermic decomposition temperatures of these amination reagents and concluded that they present modest maximum self-heat rates and are thereby safe for storage and use in bulk. Drop weight test of the amination reagents suggested that they are impactstable. Guided by this assessment, we have developed a multigram-scale synthesis of stereochemically pure Tn antigen via the iron-catalyzed 1,2-cis-selective glycal aminoglycosylation.