Design, synthesis, and preliminary immunopotentiating activity of new analogues of nojirimycin

Stereoselective Synthesis of Nojirimycin α-C-Glycosides from a Bicyclic Acyliminium Intermediate: A Convenient Entry to N,C-Biantennary Glycomimetics

“… 49 − 51 An apparent reason is the complexity in accessing the C -glycoside precursors in pure diastereoisomeric form. Most of the current protocols involve intramolecular reductive amination 47 , 52 or aza-Wittig cyclization reactions, 47 , 50 , 53 with variable diastereoselectivity outcomes, or the use of 1- C -activated precursors that are themselves obtained as mixtures of diastereomers ( Figure 2 , left panel). 47 , 54 Sharply different, the 5 N ,6 O -oxomethylidenenojirimycin derivative 3 ( 55 , 56 ) (ONJ), a member of the sp 2 -iminosugar subgroup, 57 is a chemically stable and configurationally defined compound that can be functionalized at the pseudoanomeric position via the corresponding acyliminium cation with total α-stereoselectivity ( Figure 2 , right panel).…”

“…The combination of N -substitution and C -branching in the same iminosugar scaffold appears to be an obvious strategy for finely tuning the biological activity . Surprisingly, the reported examples of biantennary N -substituted iminosugar C -glycosides are rather limited. − An apparent reason is the complexity in accessing the C -glycoside precursors in pure diastereoisomeric form. Most of the current protocols involve intramolecular reductive amination , or aza-Wittig cyclization reactions, ,, with variable diastereoselectivity outcomes, or the use of 1- C -activated precursors that are themselves obtained as mixtures of diastereomers (Figure , left panel). , Sharply different, the 5 N ,6 O -oxomethylidenenojirimycin derivative 3 , (ONJ), a member of the sp 2 -iminosugar subgroup, is a chemically stable and configurationally defined compound that can be functionalized at the pseudoanomeric position via the corresponding acyliminium cation with total α-stereoselectivity (Figure , right panel). − Since the cyclic carbamate ring can be considered as a protecting group of the vicinal amino alcohol fragment, we conceived that 3 could provide a reliable access to iminosugar α- C -glycosides and then to N -substituted-α- C -glycosides, in both the classical and sp 2 -iminosugar series, thereby offering opportunities for molecular diversity.…”

“…Surprisingly, the reported examples of biantennary N -substituted iminosugar C -glycosides are rather limited. − An apparent reason is the complexity in accessing the C -glycoside precursors in pure diastereoisomeric form. Most of the current protocols involve intramolecular reductive amination , or aza-Wittig cyclization reactions, ,, with variable diastereoselectivity outcomes, or the use of 1- C -activated precursors that are themselves obtained as mixtures of diastereomers (Figure , left panel). , Sharply different, the 5 N ,6 O -oxomethylidenenojirimycin derivative 3 , (ONJ), a member of the sp 2 -iminosugar subgroup, is a chemically stable and configurationally defined compound that can be functionalized at the pseudoanomeric position via the corresponding acyliminium cation with total α-stereoselectivity (Figure , right panel). − Since the cyclic carbamate ring can be considered as a protecting group of the vicinal amino alcohol fragment, we conceived that 3 could provide a reliable access to iminosugar α- C -glycosides and then to N -substituted-α- C -glycosides, in both the classical and sp 2 -iminosugar series, thereby offering opportunities for molecular diversity. As a proof of concept, here we report (a) an optimized synthesis of 3 on a gram scale, (b) its transformation into NJ α- C -glycosides ( I ) by allylation–carbamate hydrolysis–cross-metathesis sequences, (c) the synthesis of N -alkyl ( II ) and N -( N’ -alkylthiocarbamoyl) ( III ) biantennary derivatives via an intermolecular reductive amination or a thiourea-forming reaction, respectively, and (d) the cyclization of the last two species to access bicyclic isothiourea analogues ( IV ; Figure , right panel).…”