Stereoselective Synthesis of Iminosugar 2-Deoxy(thio)glycosides from Bicyclic Iminoglycal Carbamates Promoted by Cerium(IV) Ammonium Nitrate and Cooperative Brønsted Acid-Type Organocatalysis

Abstract

The first examples of iminosugar-type 2-deoxy(thio)glycoside mimetics are reported. The key step is the activation of a bicyclic iminoglycal carbamate to generate a highly reactive acyliminium cation. Cerium(IV) ammonium nitrate efficiently promoted the formation of 2-deoxy S-glycosides in the presence of thiols, probably by in situ generation of catalytic HNO3, with complete α-stereoselectivity. Cooperative phosphoric acid/Schreiner's thiourea organocatalysis proved better suited for generating 2-deoxy Oglycosides, significantly broadening the scope of the approach.

Synthesis of sp2-Iminosugar Selenoglycolipids as Multitarget Drug Candidates with Antiproliferative, Leishmanicidal and Anti-Inflammatory Properties

“…The ensemble of data collected on the immunomodulatory behavior of sp 2 -IGLs [45][46][47][48][49][50][51][52][53][54][55] instils that linear aliphatic tails with a length equal or higher than C 8 are required to elicit significant anticancer, antiparasitic and/or anti-inflammatory responses. Accordingly, we focused on n-octyl and n-docecyl aglycone lipid tails in this study.…”

“…1 H NMR (300 MHz, CD 3 OD): δ 4.63 (d, 1 H, J 1,2 = 5.1 Hz, H-1), 4.48 (t, 1 H, J 6a,6b = J 5,6a = 8.5 Hz, H-6a), 4.27 (dd, 1 H, J 5,6b = 4.8 Hz, H-6b), 3.82 (ddd, 1 H, J 4,5 = 9.5 Hz, H-5), 3.61 (t, 1 H, J 2,3 = J 3,4 = 9.5 Hz, H-3), 3.47 (dd, 1 H, H-2), 3.26 (t, 1 H, H-4), 2.63-2.53 (m, 2 H, NHCH 2 ), 1.58-1.20 (m, 20 H, CH 2 ), 0.90 (t, 3 H, 3 J H,H = 6.9 Hz, CH 3 ). 13 C NMR (75.5 MHz, CD 3 OD): δ 159.2 (CO), 75.6 (C-4), 74.5 (C-3), 72.3 (C-2), 69.6 (C-1), 67.9 (C-6), 54 To a stirred solution of (1R)-1,2,3,4-tetra-O-acetyl-5N,6O-oxomethylidenenojirimycin (16) (150 mg, 0.40 mmol) in anhydrous DCM (8 mL) under Ar atmosphere, the corresponding selenol (0.84 mmol, 2.1 equiv.) and BF 3 .Et 2 O (0.18 mL, 1.41 mmol, 3.5 equiv.)…”

“…Conjugates conjoining a sp 2 -minosugar glycone and an α-oriented lipid aglycone, generically termed sp 2 -iminosugar glycolipids (sp 2 -IGLs), have also shown promising abilities as innate immune system regulators with anti-inflammatory [45][46][47], anticancer [48,49] and antiparasitic [50,51] behaviors. A variety of sp 2 -IGLs with C-, N-, Oand S-pseudoglycosidic bonds are already on record [52][53][54]. Structure-activity relationship studies have shown that (i) the lipid aglycone plays an essential role in the therapeutic effect of the sp 2 -IGLs; and (ii) the nature of the glycosidic functionality bridging the aglycone and lipid moieties is also critical for activity.…”

sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease

“…We and others have previously shown that replacing the amine-type endocyclic nitrogen atom in iminosugar frameworks by a pseudoamide-type nitrogen (sp 2 -iminosugars) represents a versatile strategy to achieve highly selective glycosidase ligands for fundamental studies on enzyme mechanisms 40–43 and drug discovery, with applications ranging from cancer 44–46 and inflammation 47 to antiparasitic agents 48 . sp 2 -iminosugars are very well adapted to molecular diversity schemes, including modifications in the configurational pattern, the heterocycle framework and the nature of substituents 49–53 . Their outstanding chemical flexibility is ideally suited for structure-activity relationship studies, which has allowed optimising candidates capable of restoring the correct folding and trafficking of several LSD-causative mutant glycosidases.…”

Tandem Radical Fragmentation/Cyclization of Guanidinylated Monosaccharides Grants Access to Medium-Sized Polyhydroxylated Heterocycles

“…Notwithstanding, the successful preparation of these medium-sized guanidines demonstrates the robust versatility and novelty of the β-ARF/cyclization protocol, enabling the synthesis of polyhydroxylated nitrogen-containing cyclic structures otherwise difficult to access by any reported method to date. It should also be noted that the methodology described herein is one of the few general existing methods for the formation of exo- and endoguanidine sugars presenting oxidation at the pseudoanomeric position, which gives these compounds a greater degree of sugar character and could potentially permit subsequent derivatization through this hemiaminal-like center …”