Stereoselective Synthesis of 3‐Deoxy‐4‐S‐(1→4)‐Thiodisaccharides and Their Inhibitory Activities Towards β‐Glycoside Hydrolases

Abstract

The sulfur linkage of β‐(1→4)‐thiodisaccharides was constructed with excellent diastereoselectivity by Michael addition of 2,3,4,6‐tetra‐O‐acetyl‐1‐thio‐β‐D‐galactose (2) or its β‐D‐glucose isomer (3) to sugar‐derived (2S, 6S)‐6‐acetoxymethyl‐2‐(2‐propyloxy)‐2H‐pyran‐3(6H)‐one (1). These reactions led to the per‐O‐acetyl glycosides of 3‐deoxy‐4‐S‐glycopyranosyl‐4‐thiohexopyranosid‐2‐ulose (4 and 5, respectively). Similar conjugated addition to the enone 1 of the isothiouronium salts 6 or 7, precursors in the synthesis of 2 or 3, also afforded the thiodisaccharides 4 or 5, respectively, with exclusive formation of the isomer that has an R configuration for the C‐4 stereocenter of the reducing‐end. The carbonyl function of 4 and 5 was reduced, and the resulting products were O‐deacetylated to give the free 4‐S(1→4)‐thiodisaccharides 10, 11, 14, and 15, which have a deoxy functionality adjacent to the thio group. These compounds were tested as inhibitors of glycoside hydrolases. Thus 11, the 3‐deoxy‐4‐thiomimetic of Galβ(1→4)Gal, proved to be a competitive inhibitor of the β‐galactosidase from E. coli (Ki = 0.16 mM). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Two Straightforward Strategies for the Synthesis of Thiodisaccharides with a Furanose Unit as the Nonreducing End

“…[12,14] Witczak [15] and Thiem [16] employed this methodology for the synthesis of a number of thiodisaccharides starting from levoglucosenone, or other enones, and 1-thiopyranoses as S-glycosyl donors. To apply this procedure, we tried unsuccessfully to prepare tri-O-benzoyl-1-thio--arabinofuranose by the methods described for pyranoses, [17] as the disulfide was mainly produced.…”

“…[6] However, we have described that 1-thiosugars generated in situ from Sglycosyl isothiourea derivatives can be trapped by a sugar enone to yield the corresponding thiodisaccharide. [12] Glycosyl isothiourea derivatives may be readily prepared start-ing from 1,2-trans-glycopyranosyl acetates. [18] As 1,2,3,5-tetra-O-benzoyl-α--arabinofuranose (1a) is easily obtained by direct benzoylation of -arabinose at high temperature, [19] we studied the glycosylation of this compound with thiourea by using BF 3 ·OEt 2 as a catalyst.…”

“…[10] Recently, thioimidoyl α--arabinofuranosides have been described as the first potent inhibitors of an arabinofuranosidase. [11] In view of the previous considerations and in connection with our studies on the synthesis and inhibitory activity of S-linked saccharides, [12][13][14] we explored the construction of thiodisaccharides containing a pentofuranose unit as potential inhibitors of pentofuranosidases. We report here two successful approaches for the synthesis of such thiodisaccharides starting from readily available per-O-acylated pentofuranoses.…”

Design, synthesis and biological evaluation of sulfur-containing 1,1-bisphosphonic acids as antiparasitic agents

“…Based on the ability of mercaptane derivatives to undergo 1,4-conjugate Michael-type addition reactions on a number of α,β-unsaturated carbonyl compounds [52–55], the synthetic precursors of the sulfur-containing 1,1-bisphosphonic acids ( 22 – 30 ) were successfully prepared via this 1,4-conjugated addition among commercial n -alkyl mercaptanes and the acceptor 16 , in the presence of triethylamine. Reaction yields ranged 68–94%.…”

Internal asymmetric induction by the C-6 substituent on the oxidation reaction of interglycosidic sulfur atom of thiodisaccharides

“…However, the sulfoxides were obtained as diastereomeric mixtures and the absolute conguration of the SO group has not been established. In connection with our work on the synthesis of thiodisaccharides and their inhibitory activity of specic glycosidases, [15][16][17][18][19] we have studied the oxidation of these substrates to their respective diastereomeric sulfoxides. These compounds could be successfully separated in many cases and the absolute conguration of the sulfur stereocenter was determined by a procedure developed by us.…”