An Efficient and Accessible Hectogram-Scale Synthesis for the Selective O-GlcNAcase Inhibitor Thiamet-G

Altered levels of intracellular protein glycosylation with O-linked β-N-acetylglucosamine (O-GlcNAc) have emerged as being involved in various cancers and neurodegenerative diseases. OGA inhibitors have proven critically useful as tools to help understand the roles of O-GlcNAc, yet accessing large quantities of inhibitors necessary for many animal studies remains a challenge. Herein is described a scalable method to produce Thiamet-G, a potent, selective, and widely used brain-permeable OGA inhibitor. This synthetic route begins with inexpensive precursor, requires no column chromatography, employs simple nontoxic reagents, and in a single campaign can furnish several hundred grams of crystalline Thiamet-G in an overall yield of 44% over six steps.