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

TL;DR

This paper assesses the safety of an iron-catalyzed glycosylation process for making biologically important compounds, showing it is stable and scalable.

Contribution

The study provides a process safety assessment of an iron-catalyzed glycosylation method, enabling multigram-scale synthesis of stereochemically pure Tn antigen.

Findings

The catalyst, amination reagents, and 1,2-cis-aminoglycosides are thermally stable above 200°C.

Amination reagents are impact-stable based on Drop Weight Test results.

A multigram-scale synthesis of stereochemically pure Tn antigen was successfully developed.

Abstract

Complex glycans are directly involved in numerous disease processes and their structural motifs are increasingly incorporated in pharmaceuticals and biological probes. Therefore, the development 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 thermal stable at temperatures at least 200°C above the glycosylation temperature. Drop Weight Test of the amination reagents suggested that they are impact-stable. 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.