Total synthesis of a novel antiulcer agent via a modification of the intramolecular Wadsworth-Emmons-Wittig reaction

Abstract

7967mL of 4 M HCI was added, followed by 1.0 mL of 0.37 M FeCI, solution.The absorbance of the resulting solution was then measured.(c) Ester Assay. A 1.0-mL volume of NaOH solution was placed in a 15" test tube to which 1.0 mL of 28% N H 2 0 H solution was also added. The absorbance of the resulting solution was then measured.(d) Amide Assay. A 0.5-mL volume of NaOH solution was placed in a 15-mL test tube to which 1.0 mL of reaction mixture was added. After 20 min, 1 .O mL of 40% NH20H.HC1 solution was added. This mixture was heated for 90 min at 90 OC and then allowed to cool to room temperature, after which 1.0 mL of 4 M HCI, 1.0 mL of 0.37 M FeCI,, and 0.5 mL of water were added. The absorbance of the resulting solution was then measured.Kinetic Measurements. Solutions for kinetic studies were prepared immediately before use. A 25-mL solution containing all the ingredients except acetyl phosphate was equilibrated at 40 OC in a water-jacketed beaker. The pH of the solution was monitored continuously with a pH meter standardized at 40 OC. The pH of the solution was adjusted to the desired level by adding a few drops of 1.0 N NaOH (for pH 9-11) or 0.1 N N a O H (for pH 7-9). An accurately weighed sample (ca. 2.3 mg) of dilithium acetyl phosphate was added to the solution, and aliquots were taken at 30-s to 3-min intervals, depending on the anticipated rate of the reaction. The course of the reaction was followed by means of the acetyl phosphate assay. Ester assays were performed whenever the possibility of ester formation existed, and amide assays were carried out when amines were present. The reactions were followed for a period of 10 min to 6 h. T, aliquots were taken at 6-24 h, depending on the reaction rate. In all cases, the plot of the log values of the concentrations vs. time yielded a straight line. Rate constants were determined graphically and by a least-squares computer program. The rate constants for each reaction were determined 3 times from three separte runs, and a 5-7% range in the rate constant was generally observed.Abstract: A convergent synthesis of the novel, potent antiulcer agent U-68,215 (3), a benzindene prostacyclin analogue, is described. U-68,215 is prepared via a cyclopentane annulation sequence in optically pure form in 14 steps and 12% yield from 5-methoxy-2-tetralone (Sa). The key step in the synthesis involves the coupling of the phosphonate reagent 6 (the chirality of which was derived from a Sharpless resolution of a n allylic alcohol precursor) with the enol lactone 7a (prepared in 50% overall yield from Sa) to produce enone 5 via a modified intramolecular Wadsworth-Emmons-Wittig reaction. Hydrogenation of 5 followed by an unusual one-pot equilibration-reduction sequence generates the four centers around the cyclopentane ring with complete stereocontrol.Several years ago, w e first reported t h e synthesis a n d initial biological evaluation of t h e benzindene prostaglandins, chemically stable potent prostacyclin (PGI,, la) mimics.' T h e parent 6 H iiH ijH Research"; Samuel...

Synthetic studies with Pinus elliottiis rosin derivatives. Oxidation of maleopimaric anhydride methyl ester and trimethyl fumaropimarate

“…18-crown-6; CH 2 Cl 2 ; 25 o C; 24 h; b) 20 KMnO 4 supported on silica gel; CH 2 Cl 2 ; 25 o C; c) 21,22 KMnO 4 (cat.) with NaIO 4 ; K 2 CO 3 ; H 2 O/t-BuOH; 70 o C; 160 h, in hope to obtain a better yield of 13.…”

Stereoselective Alkylations of Chiral Nitro Imine and Nitro Hydrazone Dianions. Synthesis of Enantiomerically Enriched 3-Substituted 1-Nitrocyclohexenes

“…The synthesis of 21 began with the nitration of 5-methoxy-2-tetralone 44 using the anionic nitration method of Feuer. 45 Treatment of the tetralone with potassium t -butoxide in THF at −50 °C produced a green anion that was treated with isoamyl nitrate to afford the solid potassium nitronate salt 20 in 85% yield.…”

Design, synthesis and docking studies of new furobenzopyranones and pyranobenzopyranones as photoreagent towards DNA and as antimicrobial agents

“…4,9-Dimethoxy-7-oxo-5-methyl-7H-furo [3,2-g]benzopyrane-6-carbonitrile 2 was synthesized directly, in good yield, by refluxing 1-(6-hydroxy-4,7-dimethoxybenzofuran-5-yl) ethanone 1 with ethyl cyanoacetate in sodium ethoxide [38,39]. Compound 2 was routinely hydrolyzed to the corresponding 4,9-Dimethoxy-7-oxo-5-methyl-7H-furo[3,2-g]benzopyrane-6-carboxylic acid 3 by refluxing with 15% sodium hydroxide for three hours then acidified [40]. Esterification of 3 in methanol using thionyl chloride afforded methyl 4,9-dimethoxy-7-oxo-5-methyl-7H-furo[3,2-g]benzopyrane-6-carboxylate 4 [40].…”

“…Compound 2 was routinely hydrolyzed to the corresponding 4,9-Dimethoxy-7-oxo-5-methyl-7H-furo[3,2-g]benzopyrane-6-carboxylic acid 3 by refluxing with 15% sodium hydroxide for three hours then acidified [40]. Esterification of 3 in methanol using thionyl chloride afforded methyl 4,9-dimethoxy-7-oxo-5-methyl-7H-furo[3,2-g]benzopyrane-6-carboxylate 4 [40]. Reaction of 4 with hydrazine hydrate yielded the hydrazone 5 in good yield [19,41].…”

“…2(1H)-oxo-4-methyl-(2(1H)oxo-4-phenyl-pyrano)[2,3-f]benzopyran-3-carbonitrile 9 was synthesized through refluxing 8-Acetyl-7-hydroxy-4-phenyl-2H-1-benzopyran-2-one 8 with ethyl cyanoacetate in sodium ethoxide [38,39], followed by its hydrolysis to give 2(1H)-oxo-4-methyl-(2(1H)oxo-4-phenyl-pyrano)[2,3-f] benzopyran -3-car boxylic acid 10 [40]. It was then estrified to afford Methyl-2(1H)-oxo-4-methyl-(2(1H)oxo-4-phenyl-pyrano) [2,3-f] [1]benzopy ran-3-carboxylate 11 [40]. Its hydrazone derivative (1H)-oxo-4-methyl-(2(1H)oxo-4-phenyl-pyrano)[2,3-f]benzopyran-3-carbohydrazide 12 was formed by its reaction with hydrazine hydrate in ethanol [19,41].…”