Preparation of 1,6-di-deoxy-d-galacto and 1,6-di-deoxy-l-altro nojirimycin derivatives by aminocyclization of a 1,5-dicarbonyl derivative

Abstract

Iminosugars are known glycosidase inhibitors which are the subject of drug development efforts against several diseases. The access to structurally-related families of iminosugars is of primary importance for running structure-activity relationship studies. In this work, the double reductive amination (aminocyclization) reaction of a dicarbonyl derivative of the Larabino series, in turn obtained from lactose, is reported. Different ratios of 1,6-di-deoxy-Dgalacto and 1,6-di-deoxy-L-altro nojirimycin derivatives were obtained depending on the amine employed in this transformation which provided an insight into the effects of their structure on the outcome of the reaction. Of particular interest were the results obtained when two enantiomeric amino acids (D-Phe-OMe and L-Phe-OMe) were used, which resulted in the inversion of the reaction stereoselectivity.

Synthesis and investigation of polyhydroxylated pyrrolidine derivatives as novel chemotypes showing dual activity as glucosidase and aldose reductase inhibitors

“…To a solution of either 5 or 6 and the selected ammonium salt (1 eq) in MeOH, NaBH3CN (2.2 eq) was added and the mixture was stirred at 60 °C for 24-48 hours (Scheme 2). Overall, the yields of the aminocyclization reactions were quite satisfactory, spanning from 37% to 50% (Table 1-SI, Supporting Information), although somewhat lower than those usually obtained in the D-xylohexos-5-ulose series [11,18,19]. Particularly frustrating were instead the difficulties encountered when trying to purify the pyrrolidine diastereoisomers via chromatography on silica gel.…”

Oxy-imino saccharidic derivatives as a new structural class of aldose reductase inhibitors endowed with anti-oxidant activity

“…Aldohexos-5-uloses (type 2) are versatile platform chemicals for accessing biologically relevant targets such as iminosugars 15,16,19 and cyclitols 20 . As a continuation of our recent results aimed at searching new potential ALR2 inhibitors 15 from these 1,5-dicarbonyl substrates, we studied their reaction with O-(arylmethyl)hydroxylamines hydrochlorides (Figure 3).…”

“…Derivative 6a was also reacted with O-(arylmethyl)hydroxylamine hydrochloride 7a bearing an electron-donor group (methoxy group) (Scheme 3), in the condition of the intramolecular double reductive amination (aminocyclisation) following a protocol previously reported by us (NaBH 3 CN, MeOH, 60 C, 96 h) 15,19,26 or performed in presence of AcOH (pH 5-6) 27 .In both cases the purification of the crude products by flash chromatography on silica gel afforded the pure azasugar 12 (D-galacto) in a rather low yield (15-20%), together with the mixture of E/Z-8 oxime (10-12%) and the corresponding 6-O-deprotected E/Z-10 isomers (40-43%).…”

Developments in Carbohydrate-Based Metzincin Inhibitors

“…Azasugars or iminosugars, whether of natural or synthetic origin, are hydroxylated carbohydrate mimics, where a basic nitrogen substitutes the classic endocyclic oxygen [ 85 ]. This modification appears simple and not significant but provides important biological properties and also gives rise to many synthetic challenges [ 86 , 87 , 88 , 89 , 90 , 91 , 92 ]. Historically, iminosugars are known as inhibitors of glycosidases, enzymes involved in the glycosidic bond hydrolysis in different biological processes, such as intestinal digestion, post-translational processing of the sugar chain of glycoproteins, and lysosomal catabolism of glycoconjugates [ 93 ].…”