Stereoselective Synthesis of 2-Acetamido-1,2-dideoxyallonojirimycin (DAJNAc), a New Potent Hexosaminidase Inhibitor

Abstract

A practical synthesis of the previously unreported N-acetyl-d-allosamine glycomimetic DAJNAc is described. The reaction sequence involves Pd-catalyzed allylic substitution by phthalimide in an azaheterobicyclic scaffold as the key step. The new iminosugar resulted in being a stronger β-N-acetylglucosaminidase (human placenta) competitive inhibitor than the d-gluco (DNJNAc) and d-galacto (DGJNAc) stereoisomers.

Stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc) and ureido-DNJNAc derivatives as new hexosaminidase inhibitors

“…[32][33][34] Most synthetic approaches to iminosugars are based on the chiral pool thus making these processes rather long. [35][36][37][38][39] This is also the case for acetamido iminosugars, 13,16,40,41 with a few exceptions limited to the stereoselective synthesis of 2-acetamido-1,2-dideoxyallonojirimycin (DAJNAc, 9) 42 and the manno diastereomer DMJNAc (5). 17 Herein, we report a new stereoselective total synthesis of the gluco counterpart DNJNAc (4) and its regioisomer 3-acetamido-1,3-dideoxyaltronojirimycin (29).…”

The Lysozyme Inhibitor Thionine Acetate Is Also an Inhibitor of the Soluble Lytic Transglycosylase Slt35 from Escherichia coli

“…Iminosugars, alkaloids and their synthetic analogues ( Figure 1 ) can act as glycosidase inhibitors by mimicking the glycosyloxocarbenium ion intermediate and related transition states in enzymatic glycoside hydrolysis [ 26 ]. 1-Deoxynojirimycin, a D-glucose analogue, is the best known iminosugar.…”

Stereodivergent Syntheses of altro and manno Stereoisomers of 2‐Acetamido‐1,2‐dideoxynojirimycin

“…Following this approach we have reported efficient stereoselective procedures to obtain (2 S )‐2‐acetamido iminosugars 4 , 5 , and 6 . [14f], In our previous work, the ( S ) configuration of the acetamide substituent at the 2‐position was secured by substitution reactions that took place with complete inversion of configuration.…”

“…Natural products of this family, such as siastatin B ( 1 ), nagstatin ( 2 ), and pochonicine ( 3 ), have been reported to show inhibitory activities that range from low micromolar to nanomolar. Among the synthetic compounds that have been reported, N ‐acetylglucosamine analogues such as 2‐acetamido‐1,2‐dideoxynojirimycin ( 4 ), and their galacto ( 5 ) and allo ( 6 ) isomers, have received special attention (Figure ). Most procedures for the synthesis of iminosugars that have been described to date are based on the chiral pool, starting from sugars or amino acids .…”