Application of sequential proline-catalyzed α-chlorination and aldol reactions in the total synthesis of 1-deoxygalactonojirimycin

Meanwell, Michael; Sutherland, Mathew; Britton, Robert

doi:10.1139/cjc-2017-0318

Cited by 6 publications

(2 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have reported several methods for the concise synthesis of polyhydroxylated pyrrolidines and piperidines starting from α‐chloroaldehydes [12] . Most pertinent to the preparation of DGJNAc analogues, we have developed a concise de novo asymmetric synthesis of DGJ starting from commercially available Cbz‐protected β‐aminopropanal 5 that required only 5‐steps (Scheme 1A) [12c] . Thus, we envisioned that the readily prepared epoxide 7 could be selectively opened to generate a valuable intermediate for the preparation of DGJNAc and analogues.…”

Section: Resultsmentioning

confidence: 99%

Potent and Selective Cell‐Active Iminosugar Inhibitors of Human α‐N‐Acetylgalactosaminidase (α‐NAGAL)

Ashmus

Wang

González-Cuesta

et al. 2023

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

Glycoside hydrolases (GHs) are a class of enzymes with emerging roles in a range of disease. Selective GH inhibitors are sought to better understand their functions and assess the therapeutic potential of modulating their activities. Iminosugars are a promising class of GH inhibitors but typically lack the selectivity required to accurately perturb biological systems. Here, we describe a concise synthesis of iminosugar inhibitors of N‐acetyl‐α‐galactosaminidase (α‐NAGAL), the GH responsible for cleaving terminal α‐N‐acetylgalactosamine residues from glycoproteins and other glycoconjugates. Starting from non‐carbohydrate precursors, this modular synthesis supported the identification of a potent (490 nM) and α‐NAGAL selective (∼200‐fold) guanidino‐containing derivative DGJNGuan. To illustrate the cellular activity of this new inhibitor, we developed a quantitative fluorescence image‐based method to measure levels of the Tn‐antigen, a cellular glycoprotein substrate of α‐NAGAL. Using this assay, we show that DGJNGuan exhibits excellent inhibition of α‐NAGAL within cells using patient derived fibroblasts (EC50=150 nM). Moreover, in vitro and in cell assays to assess levels of lysosomal β‐hexosaminidase substrate ganglioside GM2 show that DGJNGuan is selective whereas DGJNAc exhibits off‐target inhibition both in vitro and within cells. DGJNGuan is a readily produced and selective tool compound that should prove useful for investigating the physiological roles of α‐NAGAL.

show abstract

Section: Resultsmentioning

confidence: 99%

Potent and Selective Cell‐Active Iminosugar Inhibitors of Human α‐N‐Acetylgalactosaminidase (α‐NAGAL)

Ashmus

Wang

González-Cuesta

et al. 2023

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although recent progress in their de novo preparation through the diversity oriented synthetic approach by elegant asymmetric organocatalyzed processes [38,39,40] have been reported, one of the best methods remains the addition of C -Nu to N -glycosylamines.…”

Section: Introductionmentioning

confidence: 99%

Glycoside Mimics from Glycosylamines: Recent Progress

Nicolas

Martin

2018

Molecules

View full text Add to dashboard Cite

Glycosylamines are valuable sugar derivatives that have attracted much attention as synthetic intermediates en route to iminosugar-C-glycosyl compounds. Iminosugars are among the most important glycomimetics reported to date due to their powerful activities as inhibitors of a wide variety of glycosidases and glycosyltransferases, as well as for their use as pharmacological chaperones. As they provide ready access to these important glycoside mimics, we have reviewed the most significant glycosylamine-based methodologies developed to date, with a special emphasis on the literature reported after 2006. The groups of substrates covered include N-alkyl- and N-benzyl-glycosylamines, N-glycosylhydroxylamines, N-(alkoxycarbonyl)-, and N-tert-butanesulfinyl-glycosylamines.

show abstract