New isomers of 4,1-benzothiazepines. The first evidence for the desmotropy of seven-membered heterocycles

A novel procedure was developed for the preparation of 2,3-disubstituted 4,1-benzothiazepines, via the ring transformation of (2R^∗,2aS^∗)-2-chloro-2a-phenyl-2,2a-dihydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one (1) with sodium ethoxide in ethanol. The tautomeric products (R^∗)-3-ethoxycarbonyl-2-phenyl-3,5-dihydro-4,1-benzothiazepine (4) and 3-ethoxycarbonyl-2-phenyl-1,5-dihydro-4,1-benzothiazepine (5) exhibit the rare phenomenon of desmotropy of the condensed seven-membered heterocycles. Surprisingly, these desmotropes could be separated by column chromatography. The products are unexpectedly stable in solution and their structures were proved by means of NMR and mass spectrometry.     

Diastereoselective synthesis of (2S)-2-[(R)-1H-indol-3-yl(phenyl)methyl]-2,3-dihydro-1H-inden-1-one

Double asymmetric induction in Michael reactions has been studied. Enantioselective alkylation of a cyclic ketone (1-indanone) with α-phenyl-nor-gramine was carried out. The relative configuration of (2S^∗)-2-[(R^∗)-1H-indol-3-yl(phenyl)methyl]-2,3-dihydro-1H-inden-1-one was established by X-ray diffraction. The relative configuration of (R^∗,R^∗,S^∗)- and (S^∗,R^∗,S^∗)-2-1H-indol-3-yl(phenyl)methyl]-2,3-dihydro-1H-inden-1-ols was established by ¹H NMR studies.     

Photochemistry synthesis. Part 1: Syntheses of xanthine derivatives by photolysis of 1-(5′-oxohexyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (pentoxifylline): an ambident chromophore

We investigated the use of photochemistry to make novel derivatives of pentoxifylline. Under conditions that favour singlet excited states, we obtained 1-allyl-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione, (R^∗,R^∗)-(±)-1-{[2-hydroxy-2-methylcyclobutyl]methyl}-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione and 1-(5-hydroxyhexyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione. Naphthalene or molecular oxygen increases the yields and triplet sensitisers (acetophenone, benzophenone and acetone) decrease the yields. Efficient intramolecular triplet energy transfer from the carbonyl to the xanthine moiety allows the carbonyl moiety to react from a singlet excited state only. In solvents with an α-hydroxyalkyl hydrogen under conditions that favour triplet excited states, we obtained 8-substituted pentoxifylline derivatives: 8-(1-hydroxy-1-methylethyl)-3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione in isopropanol, 8-(1-hydroxymethyl)-3,7-dimethyl-1-(5-oxo-hexyl)-3,7-dihydro-1H-purine-2,6-dione in methanol and 8-(1-hydroxyethyl)-3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione in ethanol. The xanthine moiety reacts from a triplet state via a radical mechanism and yields are considerably improved by the addition of catalytic amounts of di-tert-butyl peroxide.     

Stereoselective cycloadditions of (1Z,4R,5R)-1-arylmethylidene-4-benzoylamino-5-phenylpyrazolidin-3-on-1-azomethine imines to maleimides

A library of 15 1,6,7,9-tetrasubstituted 6,7,9,9a-tetrahydro-5H-pyrazolo[1,2-a]pyrrolo[3,4-c]pyrazole-1,3,5(2H,3aH)-triones was prepared by combinatorial stereoselective cycloadditions of (1Z,4R^∗,5R^∗)-1-arylmethylidene-4-benzoylamino-5-phenylpyrazolidin-3-on-1-azomethine imines to N-substituted maleimides. Stereochemistry was controlled by the stereodirecting phenyl group at position-3 and by the ortho-substituents at the aromatic ring at position-1′ in azomethine imines. Consequently, two sets of diastereomeric cycloadducts were obtained, one set from the ortho-unsubstituted dipoles and the other set from the ortho-disubstituted dipoles.     

Synthesis of perfluoroalkyl-substituted 4,5-dihydro-3H-pyrazolo[4,3-a]phenazines and tetrahydroimidazo[4,5-e]indazoles

Oxidation of 1-aryl-3-perfluoroalkyl-6,7-dihydro-1H-indazol-4(5H)-ones with selenium dioxide in the presence of sulfuric acid in glacial acetic acid, followed by treatment of 6,7-dihydro-1H-indazole-4,5-diones thus obtained with an equimolar amount of o-phenylenediamine in ethanol or with a mixture of 4-fluorobenzaldehyde and ammonium acetate in acetic acid, gave 3-aryl-1-perfluoroalkyl-4,5-dihydro-3H-pyrazolo-[4,3-a]phenazines and 6-aryl-2-(4-fluorophenyl)-8-perfluoroalkyl-1(3),4,5,6-tetrahydroimidazo[4,5-e]indazoles, respectively.     

Synthesis of tricyclic isoindoles and thiazolo[3,2-c][1,3]benzoxazines

The thermolysis of (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylic acids in Ac₂O led to novel 3-methylene-2,5-dioxo-3H,9bH-oxazolo[2,3-a]isoindoles and chiral (9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindoles were obtained on FVP. Starting from l-cysteine methyl ester (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazines were obtained as single stereoisomers. The thermolysis of (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazine-3-carboxylic acid in Ac₂O gave 5-acetyl-2-phenyl-2,3-dihydrothiazole. The structures of methyl (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylate 1a and methyl (2R,4R)-N-chlorocarbonyl-2-(2-hydroxyphenyl)thiazolidine-4-carboxylate 9 were determined by X-ray crystallography.     

Five-membered 2,3-dioxo heterocycles: XCVII. Reaction of 3-aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones with Fischer’s base

3-Aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones reacted with 1,3,3-trimethyl-2-methylidene-2,3-dihydro-1H-indole (Fischer’s base) to give (2Z)-1-aryl-2-[3-oxo-3,4-dihydroquinoxalin-2(1H)-ylidene]-5-(1,3,3-trimethyl-2,3-dihydro-1H-indol-2-ylidene)pentane-1,3,4-triones.     

Unexpected cleavage of the N-N bond in the reactions of 3-pyrazolidinone-1-azomethine imines with HCN

Treatment of (1Z,4R^∗,5R^∗)-1-arylmethylidene-4-benzamido-5-phenylpyrazolidin-3-one 1-azomethine imines 4a-d with potassium cyanide in the presence of acetic acid resulted in addition of HCN to the exocyclic CN double bond followed by β-eliminative N-N single bond cleavage (ring opening) to give the N-[(1R^∗,2R^∗)-3-amino-2-benzamido-3-oxo-1-phenylpropyl]benzimidoyl cyanides 6a-d in 28-85% yields. Reaction of dipole 4e with HCN furnished stable intermediate, (1′S^∗,4R^∗,5R^∗)-4-benzamido-1-[cyano(mesityl)methyl]-5-phenylpyrazolidin-3-one (5e), in 76% yield. The structure of compound 6c was determined by X-ray diffraction.     

Regio- and stereoselective cycloadditions of (1Z,4R,5R)-1-arylmethylidene-4-benzoylamino-3-oxo-5-phenylpyrazolidin-1-ium-2-ides to methyl methacrylate

[3+2] Cycloadditions of (1Z,4R^∗,5R^∗)-1-arylmethylidene-4-benzoylamino-3-oxo-5-phenylpyrazolidin-1-ium-2-ides 1a-e to methyl methacrylate gave the 1-CO₂Me regioisomers 3/3′, exclusively, in 1-67% yields. Stereocontrol was dependent on the ortho-substituents at the 1′-aryl group in dipole 1: ortho-unsubstituted dipoles 1a-c gave the major (1R^∗,3R^∗,5R^∗,6R^∗)-isomers 3a-c, whilst ortho-disubstituted dipoles gave the major (1R^∗,3S^∗,5R^∗,6R^∗)-isomers 3′d,e. The structures of cycloadducts were determined by NMR and X-ray diffraction.     

Synthesis and stereochemical studies of 1- and 2-phenyl-substituted 1,3-oxazino[4,3-a]isoquinoline derivatives

Starting from the 1′- or 2′-phenyl-substituted 1-(2′-hydroxyethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline diastereomers 3 and 6, 4-unsubstituted and 4-(p-nitrophenyl)- and 4-oxo-substituted 1-phenyl- and 2-phenyl-9,10-dimethoxy-2H,4H-1,6,7,11b-tetrahydro-1,3-oxazino[4,3-a]isoquinolines (7-12) were prepared. The relative configurations and the predominant conformations of the products were determined by NMR spectroscopy, by quantum chemical calculations and, for (2R^∗,4S^∗,11bR^∗)-9,10-dimethoxy-4-(p-nitrophenyl)-2-phenyl-2H,4H-1,6,7,11b-tetrahydro-1,3-oxazino[4,3-a]isoquinoline (11), by X-ray diffraction.     

Central-to-axial chirality transfer and induced circular dichroism in 6,7-dihydro-5H-dibenz[c,e]azepine derivatives of α- and β-amino esters

DAZ-Xaa^∗-OMe amino ester derivatives with Xaa^∗ = d/l-Ala, d/l-Val, l-Leu, l-Ile, l-Ser, l-β³-HAla, l-β³-HVal, l-β³-HLeu, (1S,2S)/(1R,2R)-ACHC (2-aminocyclohexanecarboxylic acid) and (1S,2S)/(1R,2R)-ACPC (2-aminocyclopentanecarboxylic acid), N-blocked as 6,7-dihydro-5H-dibenz[c,e]azepines (DAZ), have been synthesized and evaluated for the determination of the absolute configuration of α- and β-amino esters through the induced circular dichroism of the biphenyl chromophore.     

Extremely high regio- and stereoselective C-C bond formation of substituted γ-hydroxylactams: synthesis of macronecines based on their structural duality

With a view to develop a new synthetic entry for the necine bases, treatment of functionalized γ-hydroxylactams was found to undergo quite high regio- and diastereoselective carbon-carbon bond formation reactions, affording the corresponding structurally dualistic alkylated lactams in satisfactory yields. The reaction was further applied to the practical and efficient synthesis of (±)-macronecine [(1S^∗,2R^∗,7aR^∗)-1-hydroxymethyl-2-hydroxypyrrolizidine] and (±)-2-epi-macronecine [(1S^∗,2S^∗,7aR^∗)-1-hydroxymethyl-2-hydroxypyrrolizidine].     

Convenient method for synthesis of thiazolo[3,2-a]pyrimidine derivatives in a one-pot procedure

An efficient one-pot method to synthesize thiazolo[3,2-a]pyrimidine derivatives has been developed. The method involves the temperature controlled functionalization-annulation of 5-ethoxycarbonyl-6-methyl-4-aryl-3,4-dihydro-2(1H)-pyrimidin-2-thione (DHPM) derivatives with in-situ generated bromo-ketones received by reaction of different α-H carbonyl compounds with bromine.     

Enantioselective addition of methyl group to aldehydes catalyzed by titanium complex of fluorous ligand

Titanium complex of fluorous axially dissymmetric ligand ((Ra^∗)-2,2′-bis[(R^∗)-perfluoro-1H-1-hydroxyoctyl]biphenyl, ((Ra^∗)-(R^∗)₂-1)) having perfluoroheptyl carbinol moieties catalyzed enantioselective addition of a methyl group to aldehydes. Dimethylzinc prepared in situ by mixing ZnCl₂ and methyl magnesium bromide without removal of magnesium salt was more reactive for addition of methyl group than dimethylzinc without magnesium salt, and gave up to 99% ee of the products. The high fluorine content of 1 enables it to be recoverable by the selective extraction with perfluorohexane.     

Oxidative ring-opening of rel-(2R,3R,5S)-5-aryl-2-benzoylamino-6,7-bis(methoxycarbonyl)-2,3-dihydro-1-oxo-3-phenyl-1H,5H-pyrazolo[1,2-a]-pyrazoles. Synthesis of rel-(2R,3R)-3-phenyl-3-[5-aryl-3,4-bis(methoxycarbonyl)pyrazolyl-1]alanine esters

rel-(2R,3R)-N-Benzoylamino-6,7-bis(methoxycarbonyl)-2,3-dihydro-1-oxo-1H,5H-pyrazolot[1,2-a]-pyrazoles 5 , accesible by cycloaddition of dimethyl acetylenedicarboxylate ( 3 ) to (1Z)-rel-(4R,5R)-1-aryl-methylidene-4-benzoylamino-5-phenyl-3-pyrazolidinone-1-azomethine imines 4 , undergo oxidative ring cleavage with methanolic bromine giving rel-(2R,3R)-N-benzoyl-3-phenyl-3-[5-aryl-3,4-bis(methoxy-carbonyl)pyrazolyl-1]alanine methyl esters 6 as products.     

Five-membered 2,3-dioxo heterocycles: LXXIV. Recyclization of 3-aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones by the action of benzohydrazides. Crystalline and molecular structure of N-[2,4-dihydroxy-5-oxo-3-(3-oxo-3,4-dihydroquinoxalin-2-yl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]benzamide

Recyclization of 3-aroyl-1H-pyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones by the action of benzoic acid hydrazides gave N-[2,4-dihydroxy-5-oxo-3-(3-oxo-3,4-dihydroquinoxalin-2-yl)-2-aryl-2,5-dihydro-1H-pyrrol-1-yl]benzamides whose structure was proved by X-ray analysis.     

Synthesis of ent-ambrox® from (−)-nidorellol

Using ozonolysis of the acid-catalyzed cyclized products of (−)-nidorellol and air-autoxidation as the key steps, (+)-ambrox was obtained in 53% overall yield. In the course of our synthesis, we discovered that (−)-nidorellol provided (+)-ambrox instead of the expected product, (−)-ambrox. Thus the absolute configuration of (−)-nidorellol was proved to be trans-(5R^∗,7R^∗,8R^∗,9S^∗,10R^∗)-labda-12,14-diene-7α,8β-diol, which is opposite to that illustrated in a previous report.     

Lipase-catalyzed synthesis of a tri-substituted cyclopropyl chiral synthon: a practical method for preparation of chiral 1-alkoxycarbonyl-2-oxo-3-oxabicyclo[3.1.0]hexane

An efficient method for the preparation of optically active enantiomers of 1-ethoxycarbonyl-2-oxo-3-oxabicyclo[3.1.0]hexane 1 has been developed. Treatment of 1 with lipase Amano PS gave (1S,5R)-1-carboxy-2-oxo-3-oxabicyclo[3.1.0]hexane 4a which was converted to (1S,5R)-1-ethoxycarbonyl-2-oxo-3-oxabicyclo[3.1.0]hexane 1a with high enantiomeric purity (98.0% ee, 75% yield), while the (1R,5S)-lactone ester 1b remained intact. A simple procedure for the recovery of 4a from the reaction mixture was also established.     

A mechanistic study on the intramolecular ionic Diels-Alder reaction of 2-methyl-3,9,11-tridecatriene-2-ol and 2,11-dimethyl-1,3,9,11-dodecatetraene

Intramolecular ionic Diels-Alder reaction of 2-methyl-3,9,11-tridecatriene-2-ol (1) was studied under acidic conditions. Treatment of 2-methyl-3,9,11-tridecatriene-2-ol (1) with trifluoromethanesulfonic acid yielded 7-methyl-8-isopropenyl-1,2,3,4,4aR^∗,7R^∗,8R^∗,8aS^∗-octahydronaphthalene (4) and (1Z)-1-((E)-but-2-enylidene)-2-(2-methylpropenyl)cyclohexane (5) through regioselective intramolecular ionic Diels-Alder reaction. The reaction appeared to proceed partly through a stepwise mechanism involving a carbocation intermediate. However, a concerted pathway rather than a stepwise one is suggested to be involved in the acid-catalyzed intramolecular Diels-Alder reaction of 2,11-dimethyl-1,3,9,11-dodecatetraene (13).     

Synthesis,Antibacterial and Antifungal Activity of New 3-Aryl-5H-pyrrolo[1,2-a]imidazole and 5H-Imidazo[1,2-a]azepine Quaternary Salts

A series of novel 3-aryl-5H-pyrrolo[1,2-a]imidazole and 5H-imidazo[1,2-a]azepine quaternary salts were synthesized in 58–85% yields via the reaction of 3-aryl-6, 7-dihydro-5H-pyrrolo[1,2-a]imidazoles or 3-aryl-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepines and various alkylating reagents. All compounds were characterized by ¹H NMR, ¹³C NMR, and LC-MS. The conducted screening studies of the in vitro antimicrobial activity of the new quaternary salts derivatives established that 15 of the 18 newly synthesized compounds show antibacterial and antifungal activity. Synthesized 3-(3,4-dichlorohenyl)-1-[(4-phenoxyphenylcarbamoyl)-methyl]-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-1-ium chloride 6c possessed a broad activity spectrum towards Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Cryptococcus neoformans, with a high hemolytic activity against human red blood cells and cytotoxicity against HEK-293. However, compound 6c is characterized by a low in vivo toxicity in mice (LD₅₀ > 2000 mg/kg).