ABSTRACT
We report herein a newly developed domino reaction that facilitates the synthesis of new 1,5-dideoxy-1,5-iminoribitol iminosugar C-glycosides 7a-e and 8. The key intermediate in this approach is a six-membered cyclic sugar nitrone that is generated in situ and trapped by an alkene dipolarophile via a [2 + 3] cycloaddition reaction to give the corresponding isooxazolidines 10a-e in a "one-pot" protocol. The iminoribitol C-glycosides 7a-e and 8 were found to be modest ß-galactosidase (bGal) inhibitors. However, compounds 7c and 7e showed "pharmacological chaperone" activity for mutant lysosomal bGal activity and facilitated its recovery in GM1 gangliosidosis patient fibroblasts by 2-6-fold.
Subject(s)
Alkenes/chemistry , Fibroblasts/chemistry , Gangliosidosis, GM1/drug therapy , Lysosomes/chemistry , Molecular Chaperones/pharmacology , Molecular Chaperones/therapeutic use , Monosaccharides/chemical synthesis , Nitrogen Oxides/chemistry , beta-Galactosidase/antagonists & inhibitors , beta-Galactosidase/chemistry , Cycloaddition Reaction , Gangliosidosis, GM1/enzymology , Gangliosidosis, GM1/metabolism , Glycosides , Humans , Lysosomes/metabolism , Monosaccharides/chemistryABSTRACT
The Baylis-Hillman reaction of 3-O-allyl-alpha-d-xylo-pentodialdo-1,4-furanose 3 afforded a diastereomeric mixture of d-gluco- and l-ido-configured alpha-methylene-beta-hydroxy esters 4a and 4b, respectively, in a ratio of 2:3. Reduction of the ester functionality in 4a/4b gave alcohols 5a/5b. The diene thus formed in 5a/5b was subjected to ring-closing metathesis (Grubbs' second-generation catalyst) to afford oxa-bicyclic ring system 6a/6b in high yield. Further manipulation of the acetonide functionality in 6a and 6b afforded new polyhydroxylated oxepines 1a/2a and 1b/2b, respectively. The (1)H NMR of oxepines 1a and 1b in D(2)O showed doubling of signals indicating their existence in two different rotamers/conformers. This fact was substantiated by calculating energetics of 1 and 2 conformers using the density functional theory and correlating the calculated (1)H NMR chemical shift pattern with that of the experimental spectra.
ABSTRACT
Synthesis of catechuic acid (1) and ethyl 2,4,5-trihydroxybenzoate (2) from D-glucose-derived beta-ketoester is described. The polyhydroxylated beta-ketoester obtained from the hydrolysis of sugar beta-ketoester 3 was subjected to an aldol-type condensation to get 4 that on enolization, dehydration, and hydrogenation afforded ethyl 2,4,5-trihydroxybenzoate (2). On the other hand, hydrogenation of aldol product 4 afforded polyhydroxylated keto-carbasugar 6, which on mild acid treatment and ester hydrolysis in basic media led to catechuic acid 1. Intermediate 4 is co-related to 3-dehydroshikimic acid, a biochemical intermediate from D-glucose in the synthesis of pro-catechuic acid.
