O. Varela

Michael Addition of Thiols to Sugar Enones. Synthesis of 3-Deoxy-4-Thiohexopyranosid-2-uloses as Key Precursors of 3-Deoxy- and C-2 Branched-Chain 4-Thiosugars

Benzyl and 2-propyl 6-O-acetyl-3,4-dideoxy-α -D-glycero-hex-3-enopyranosid-2-uloses (2) and (3) were readily prepared by the tin(IV) chloride-promoted glycosylation of glycal (1). The enone system of (2) and (3) underwent a highly diastereoselective Michael addition of thiols (ethanethiol, propane-2-thiol, and benzenemethanethiol) to afford the sulfur-containing hexopyranosid-2-ulose derivatives (4a-c) and (5a-c) in good yields. Sodium borohydride reduction of the carbonyl functionalities of (4b,c) and (5b) led to the corresponding 3-deoxy-4-thiohexopyranosides having the D-xylo (6b), (6c), and (8b) or the D-lyxo (7b), (7c), and (8c) configuration. Standard acetylation of these compounds gave the corresponding per-O-acetyl derivatives (10b), (10c), and (12b) and (11b), (11c), and (13b), useful for confirming all the previous configurational assignments by means of their 1H and 13C nuclear magnetic resonance spectra. Furthermore the 2-ulose (5b) proved to be a key intermediate for the synthesis of C-2 branched-chain 4-thiopyranosides, such as (16). The latter was synthesized by a good yielding ammonium acetate-catalysed Knoevenagel-type condensation of malononitrile with (5b).

β-Elimination in aldonolactones. the conversion of l-rhamnono-1-5-lactone into 3-benzoyloxy-6-methylpyran-2-one

Abstract Benzoylation of l -rhamnono-1,5-lactone ( 1 ) for 90 min at room temperature afforded 2,3,4-tri- O -benzoyl- l -rhamnono-I,5-Iactone ( 2 ). When an excess of benzoyl chloride and pyridine was used for 20 h, with subsequent sublimation of benzoic acid from the mixture at 120° in vacua , a double elimination took place and 3-benzoyloxy-6-methylpyran-2-one ( 4 ) was isolated as the main product. The conversion of 1, 2, and 2,4.-di- O -benzoyl-3,6-dideoxy- l - erythro -hex-2-enono-l,5-lactone ( 3 ) into the pyran-one derivative 4 under different conditions was monitored chromatographically.

Synthesis of Furanose Glycosides of Abequose (3, 6-Dideoxy-D-Xylo-Hexose)

ABSTRACT Hydrogenolysis of 2,3,5-tri-O-benzoyl-6-O-trityl-D-galactono-1,4-lactone (2) gave the corresponding 3-deoxy-D-xylo-hexono-1,4-lactone derivative (3), which on treatment with HBr in acetic acid afforded 2,5-di-O-benzoyl-6-bromo-3,6-dideoxy-D-xylo-hexono 1,4-lactone (4). Hydrogenation of 4 led to 3,6-dideoxy-D-xylo-hexono-1,4-lactone dibenzoate (6). The overall yield of 6 from D-galactono-1, 4-lactone (1) was about 59%. Alternatively, compound 6 was prepared (67% overall yield from 1) by hydrogenolysis of 6-bromo-6-deoxy-D-galactono-1,4-lactone tribenzoate (5), obtained by treatment of 2 with HBr in dry dichloromethane. Diisoamylborane reduction of 6 gave an anomeric mixture of 2,5-di-O-benzoyl-3,6-dideoxy-α, β-D-xylo-hexofuranose (7), which on O-debenzoylation afforded 3,6-dideoxy-D-xylo-hexose (abequose, 8) whose tautomeric equilibrium was studied by 13C NMR spectroscopy. Acetylation of 7 gave the 1-O-acetyl derivative (9) mainly in the β anomeric configuration. Tin (IV) chloride promoted glycosy...

Convenient synthesis of 4-thiolactose, 3,4-dithiolactose and related thiooligosaccharides and disulfides. Inhibitory activity of the glycomimetics against a β-galactosidase

The ring-opening reaction of sugar 3,4-epoxides by 2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranose (7) as a nucleophile led to (1 → 3)- and (1 → 4)-thiodisaccharides. High regio- and diastereoselectivities were achieved in the synthesis of the per-O-acetyl derivative of the β-D-Galp-S-(1 → 4)-4-thio-α-D-Glcp-O-iPr (10). Analogues of the 4-thiolactoside 10 have been prepared, with the β-D-Galp non-reducing end S-linked to D-Glcp, D-Gulp and D-Idop. A similar regioselective attack of 7 on C-4 of 2-propyl 3,6-di-O-acetyl-3,4-epithio-α-D-galactopyranoside (6) led to 2-propyl 3,4-dithiolactoside derivative 15. During this reaction the free 3-SH group of 15 underwent oxidative dimerization or oxidative coupling with the SH function of 7 to give the respective disulfides. Glycosylation of the thiol group of 15 using trichloroacetimidate derivatives of β-D-Galp or β-D-Galf afforded the corresponding branched dithiotrisaccharides. The free compounds were evaluated as inhibitors of the E. coli β-galactoside. The bis(2-propyl 3,4-dithiolactosid-3-yl)-disulfide, obtained from 15, displayed the strongest inhibitory activity in these series of glycomimetics and proved to be a non-competitive inhibitor (K(i) = 95 μM).

Synthesis of 3,4-Di-O-benzyl-1-O-methyl-L-galactitol, a key precursor of the C33-C37 fragment of calyculins

3,4-Di-O-benzyl-1-O-methyl-L-galactitol (3) has been synthesized in a seven step sequence starting from 1,2:3,4-di-O-isopropylidene-a-D-galactopyranose (4). The synthesis involves the methyllation of HO-6 of 4, followed by methanolysis to the mixture of the corresponding methyl 6-O-methyl-a-D-galactopyranoside (6, major product) and the b-furanoside analog (8). Compound 6 was converted into the 3,4-O-isopropylidene derivative 9, and the free HO-group was protected as the methoxyethoxymethyl (MEM) ether. Chemoselective removal of the acetonide by hydrolysis, followed by benzylation gave the methyl 3,4-di-O-benzyl-2-O-methoxyethoxymethyl-6- O-methyl-a-D-galactopyranoside (12). Simultaneous acid hydrolysis of the methyl glycoside and MEM group of 12 led to 13, which was then reduced with sodium borohydride to the target molecule 3.