Soth Samreth

Towards a new type-of HMG-COA reductase inhibitor

Abstract In an attempt to design a novel class of HMG-Co A reductase inhibitors, we have synthesized compound as a reaction intermediate analogue of the enzymatic reduction of mevaldic acid by NADPH. A 15 steps, enantioselective sequence allowed us, from commercial R-(+)-malic acid to prepare aldehyde in an optically pure form and to couple it with the nicotinamide moiety affording the target molecule.

The crystal and molecular structures of 4-cyanophenyl 1,5-dithio-β-d-xylopyranoside S-5 oxide and 4-ethyl-2-oxo-2H- 1-benzopyran-7-yl 5-thio-β-d-xylopyranoside S-5 oxide

Abstract Crystals of 4-cyanophenyl 1,5-dithio-β- d -xylopyranoside S-5 oxide (1) and 4-ethyl-2-oxo-2H-1-benzopyran-7-yl 5-thio-β- d -xylopyranoside S-5 oxide (2) are monoclinic, space group P21, with two independent thioxylosides molecules in the asymmetric unit. The unit cell dimensions are α = 26.385, b = 5.934, c = 8.902 A, and β = 109.90 ° for 1 and α = 16.033, b = 16.676, c = 6.459 A, and β = 91.26 ° for 2. The present work provides structural information on the influence of substitution of intracyclic and glycosidic oxygen atoms by sulfur atoms, as well as on the influence of aromatic rings and of sulfoxide groups on the carbohydrate moiety. In both molecules, the xylopyranosides rings have the classical4C1 conformation. For 1, the orientation of the phenyl substituent with respect to the xylopyranose is very similar in the two independent molecules: the φ and ψ torsion angles are respectively: (−99.5°, 153.8°) and (−102.1°, 154.2°). This is not the case for 2, for which these values are strikingly different: (− 79.4°, 172.1°) and (− 130.2°, −178.4°). In each structure, the molecules are hydrogen bonded within a network of infinite chains.

Synthetic studies in the 5-thio-d-xylopyranose seriespart 3: Preparations ofO-phenyl andC-(4-hydroxyphenyl) 5-thio-d-xylopyranosides

Abstract Treatment of the tri- O -acetyl 5-thio-α- d -xylopyranosyl 1- O -trichloroacetimidate 1 and phenol in the presence of BF 3 · OEt 2 at low temperature led to the corresponding O -phenyl (4: ∼30 % yield) and C -(4-hydroxyphenyl) 5-thio- d -xylopyranosides (5: ∼40 % yield) as a result of competitive O -glycosidation and aromatic electrophilic substitution. At higher temperatures, O -phenyl 5-thio-β- d -xylopyranoside was shown to rearrange readily to give C -(4-hydroxyphenyl) 5-thio-β- d -xylopyranoside as the thermodynamically favoured product. In the presence of zinc oxide, the sugar α-bromide 2 and phenol led also to a mixture of 4 (∼20 % yield) and 5 (∼40 % yield). Compound 5 was produced from 2 on treatment with dibutyltin diphenoxide and from the 1- O -trimethylsilyl sugar derivative 3 and trimethylsilyloxybenzene, when reacted in the presence of trimethylsilyl triflate in dichloromethane (35 % yield). Under these conditions, a tetrahydrothiophene derivative was observed ( 6 : ∼5 % yield). However, the sulfur transannular participation pathway which accounted for its formation became predominant when the α-bromide 2 and phenol were treated for several hours with zinc chloride, thus affording 6 in a 42 % yield.

Synthesis of the 2- and 4-monomethyl ethers and the 4-deoxy-4-fluoro derivative of 4-cyanophenyl 1,5-dithio-β-d-xylopyranoside as potential antithrombotic agents

Abstract The title glycoside undergoes acetonation with 2-methoxypropene to give a 2:1 mixture of the crystalline 2,3- and 3,4-isopropylidene acetals in 94% yield, which upon methylation under controlled conditions followed by deacetonation afforded the respective 4- and 2-monomethyl ethers. The 2,3-acetal underwent reaction with diethylaminosulfur trifluoride to introduce fluorine at C-4 with net retention of stereochemistry, but the 3,4-acetal under comparable conditions underwent migration of the arylthio group to C-2 and fluorination at C-1, with stereochemical retention at both positions.

Synthesis of the 3-methyl ether and 4-deoxy derivatives of 4-cyanophenyl 1,5-dithio-β-d-xylopyranoside (Beciparcil)

Treatment of the 2,3-isopropylidene acetal of the title dithioxyloside with 2,4,5-triiodoimidazole-PPh3 caused replacement of the 4-hydroxyl group by iodine to afford 82% of the 4-axial iodide 6, converted by base into 4-cyanophenyl 2,3-O-isopropylidene-1,5-dithio-beta-D-glycero-pent-3-enopyranoside++ + (8). Acid treatment of 8 gave 87% of the deacetonated glycos-3-ulose, borohydride reduction of which afforded 63% of 4-cyanophenyl 4-deoxy-1,5-dithio-alpha-L-threo-pentopyranoside (3), together with 27% of the 3-axial epimer. The 3-methyl ether of the title dithioxyloside was satisfactorily prepared via 2,4-protection as the cyclic phenylboronate, methylation, and deprotection; alternative strategy via the 2,4-bis(triisopropylsilyl) ether was complicated because of silyl-group migration under methylation conditions.

New efficient electrochemical synthesis of 1,5-dithioxylopyranosides in the presence of a sacrificial anode.

Electroreduction of the disulfide derivative RSSR (5, R= [bond]C(6)H(4)[bond]CO[bond]C(6)H(4)[bond]CN) on a mercury pool or a carbon gauze electrode in the presence of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide (1), using a sacrificial zinc anode gave an alpha,beta anomeric mixture of [4-(4-cyanobenzoylphenyl)] 2,3,4-tri-O-acetyl-1,5-dithio-D-xylopyranoside (6) in 40-70% yield, according to the experimental conditions used (nature of solvent, electrolyte salt, and temperature). High selectivity favouring the alpha anomer of 6 is observed starting from the alpha anomer of 1. Mechanistic aspects are discussed.

Chemical interconversions of 4-cyanophenyl 1,5-dithio-β-d-xylopyranoside (Beciparcil®): structural modification at the C-4 position

Abstract The title dithioxyloside 1 , an orally active antithrombotic agent, as its 2,3-isopropylidene acetal, was converted into the corresponding glycos-4-ulose, which served as precursor via reduction to the 4-epimer of 1 and via oximation–reduction to the 4-acetamido-4-deoxy 4-epimer of 1 .

Efficient electrochemical synthesis of thioxylal

Reduction elimination of acetylated thioxylopyranosyl bromide or acetylated thioxylopyranosyl chloride affording thioxylal is easily performed by direct electroreduction or using niobocene dichloride as catalyst.