A New Class of Glycosidase Inhibitor:  Synthesis of Salacinol and Its Stereoisomers

Abstract

Salacinol (4) is one of the active principles in the aqueous extracts of Salacia reticulata that are traditionally used in Sri Lanka and India for the treatment of diabetes. The syntheses of salacinol (4), the enantiomer of salacinol (5), and a diastereomer (7) are described. The synthetic strategy relies on the selective nucleophilic attack of 2,3,5-tri-O-benzyl-1,4-anhydro-4-thio-D- or L-arabinitol at C-1 of 2,4-O-benzylidene D- or L-erythritol-1,3-cyclic sulfate. The work serves to resolve the ambiguity about the exact structure of salacinol and establishes conclusively the structure of the natural product.

Synthesis of a novel class of sulfonium ions as potential inhibitors of UDP-galactopyranose mutase

“…The compounds for alkylation could either be the open-chain sulfate or the cyclic sulfate derivatives. 29; 30 We proposed the use of cyclic sulfate derivatives as alkylation reagents, specifically 2,4-Obenzylidene-D D -(5) and L L -(6) erythritol-1,3-cyclic sulfates. 29;30 Methyl a-D D -glucopyranoside was converted to 1,2,3,5,6-penta-O-acetyl-4-thio-a-D D -galactofuranose, as described previously.…”

“…26 We argue that the protonation of the nitrogen atom in the active site provides electrostatic stabilization with carboxylate residues, and that the permanent positive charge on the sulfonium ion would serve to mimic this interaction. There is precedent for such mimicry with glycosidase enzymes, namely the glycosidase inhibitory activities of salacinol (3) [27][28][29] and the corresponding nitrogen analogue, ghavamiol (4). 30 We reasoned further that the biologically important side chain of salacinol containing an internal sulfate counterion would be advantageous in stabilizing the compound, as is the case with salacinol (3).…”

Recent knowledge and innovations related to hexofuranosides: structure, synthesis and applications

“…They reasoned that (i) the permanent positive charge on the sulfonium or the selenium ions would serve to mimic this interaction, and (ii) an erythritol side chain containing an internal sulfate counterion would be advantageous in stabilizing the compound, as in the case of the biologically important salacinol. 209,210 Consequently, they prepared a series of ammonium, sulfonium and selenium salts analogs of galactofuranose (Fig. 21).…”

Synthesis of phosphate derivatives related to the glycosidase inhibitor salacinol

“…The required dimesylated compound (18) was prepared from commercially available L L-xylose in five steps following a literature procedure. 31 (20) in 76% yield. Finally, hydrogenolysis of 20 using 10% Pd on carbon afforded the desired product (11) as a white solid in 79% yield.…”

“…This potential reaction is patterned after our earlier syntheses of salacinol (1) and its analogues by opening of cyclic sulfates. [18][19][20][21][22][23][24][25][26][27][28][29][30] In order to check the general reactivity of cyclic phosphates, the cyclic phosphates (14,15) derived from D Derythritol were synthesized, in turn, from the less expensive D D-glucose using a similar protocol as for the synthesis of the corresponding cyclic sulfate (Scheme 2). 20 The diol (16) O six steps using a procedure developed by Satoh et al 31 Various conditions were tried to couple the D D-cyclic phosphates (14, 15) with either compound 17 or tetrahydrothiophene, but the reactions did not proceed as planned (Table 1).…”