Potential glycosidase inhibitors: synthesis of 1,4-dideoxy-1,4-imino derivatives of D-glucitol, D- and L-xylitol, D- and L-allitol, D- and L-talitol, and D-gulitol

Abstract

Conversion of 2,3,5,6-tetra-O-benzyl-~-galactofuranose (1 9) into its oxime and subsequent treatment with methanesulphonyl chloride gave 2,3,5,6-tetra-O-benzyl-4-O-rnethylsulphonyl-~galactonitrile (21 ). Reductive cyclization by sodium borohydride/cobalt( 11) chloride, followed by hydrogenolysis under acidic conditions yielded 1,4-dideoxy-l,4-imino-~-glucitol hydrochloride (11). A similar reaction sequence was used to convert 2,3,5-tri-O-benzyl L-arabinofuranose (23) via the nitrile (25) into 1,4-dideoxy-I ,4-imino-~-xylitol hydrochloride (1 2), and the corresponding Darabinose derivative (27) gave 1,4-dideoxy-I ,4-imino-~-xylitol hydrochloride (1 3), using the same chemistry. Treatment of 2,3: 5,6-di-~-isopropylidene-~-~-gu~ofuranose (31 ) with hydroxylamine and then methanesulphonyl chloride in pyridine gave 4-0methylsul phony1 -2,3 : 5,6-di -0isopropylidene-Dgulononitrile (32), which was converted by treatment with lithium aluminium hydride and subsequent acid hydrolysis into 1,4-dideoxy-l,4-imino-~-allitol hydrochloride (1 4); similar chemistry in the enantiomeric series gave the L-allitol derivative (1 5). An analogous reaction sequence was used to convert 2,3: 5,6-di-O-isopropylidene-~-~-rnannofuranose into 4 -0methylsulphonyl-2,3: 5,6-di-O-isopropyIidene D-mannononitrile (38) and thence into 1,4-dideoxy-1,4-imino-~-talitol hydrochloride (1 6); L-mannonolactone was converted via 2,3 : 5,6-di-0isopropylidene-a-L-mannofuranose (41 ) into 1,4-dideoxy-I ,4-imino-~-talitol hydrochloride (1 7). 2,3: 5,6-Di-O-isopropylidene-~-~-allofuranose (45) was converted via its oxime (46) into 4 -0methylsulphonyl-2,3:5,6-di-0-isopropylidene-~-allononitrile (47), which on reductive cyclization with lithium aluminium hydride, and subsequent acid hydrolysis, gave 1,4-dideoxy-l,4-imino-~gulitol hydrochloride (1 8).

A fast, efficient and stereoselective synthesis of hydroxy-pyrrolidines

“…Alkenylamine 8 was then subjected to our iodine-mediated carbamate annulation methodology, which gave carbamate 10 in an excellent yield (93%) and as the major product (>20:1 d.s., as determined by 1 H NMR of the crude reaction mixture). Hydrolysis of the carbamate and comparison of the NMR spectral data and optical rotation values of the hydrolysed product with those in the literature 21,22 confirmed the identity of the resulting pyrrolidine to be that of 1,4-dideoxy-1,4-imino-L-xylitol (2). With an overall yield of 54%, this five-step synthesis is remarkably efficient.…”

3,4-Dihydroxypyrrolidine as Glycosidase Inhibitor

“…The inhibitory activity of 64 towardsgalactosidase and -mannosidase is quite similar to that of A powerful inhibitior 85 against -fucosidase is similar to that of compound 63 [77,104]. Compounds with (2R,3R,4S)-configuration (86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97) showed moderate inhibitory activities against -mannosidase [89], and those with a (2R,3S,4R)-configuration (98)(99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109) tend to inhibitglucosidase and -galactosidase [88,89,93,109,110]. The specificity of these compounds was explained based on the similarity with substrate structures of individual enzymes where it was considered that a flexible pyrrolidine structure could adopt a 4 E conformation and 2-and 3-OH groups might mimic the hydroxyl groups of glucopyranosyl cation species (Fig.…”

“…Trans-diol (D~F-type) [32,38,86,88,109,111,112] Among the D-type compounds, 1,4-dideoxy-imino-Dxylitol (111) inhibited -galactosidase rather weakly, but it was noted that the inhibition was non-specific [86,111]. Compound 112 having an L-iditol configuration inhibitedgalactosidase (95% inhibition at 1mM) [109] Compound 113 having a configuration mimicking glucofuranose was found to be a competitive inhibitor of -and -glucosidase and a non-competitive inhibitor of -galactosidase [86,88,109,112]. The 2,5-disubstituted compounds 114 and 115 were inhibitors of fucosidase [32,111].…”

Ti‐Mediated Synthesis of Aminocyclopropyl‐Substituted Carbohydrates

“…We have found that the dehydration can be achieved in higher yield by use of methanesulfonyl chloride in pyridine (Entry 2). [16] Accordingly, treatment of -arabino-aldoxime 6 with pivaloyl chloride as the dehydrating agent gave nitrile 2 in quantitative yield (Entry 3). The nitrile 3 has been prepared by dehydration of the corresponding aldoxime 7 with ruthenium salts.…”