Inotilone and related phenylpropanoid polyketides from Inonotus sp. and their identification as potent COX and XO inhibitors

By bioassay-guided isolation, phenylpropanoid-derived polyketides, including an unusual 5-methyl-3(2H)-furanone derivative (inotilone) with potent cyclooxygenase (COX) and xanthone oxidase (XO) inhibitory activities were obtained from the fruiting body of the mushroom Inonotus sp.     

Convergent synthesis of potent COX-2 inhibitor inotilone

The first synthesis of potent COX-2 inhibitor inotilone is reported. The convergent route features a Mukaiyama aldol condensation that generates the target without the use of protecting groups or a separate dehydration step. The approach also highlights a superior regioselective preparation of 1-bromo-2,4-pentanedione involving a bis(silyl enol ether) and NBS.     

Synthesis of 6-substituted 3-cyano-5-nitropyridine-2(1H)-thiones

The reactions of 1-substituted 2-nitro-3-phenylaminoprop-2-en-1-ones with cyanothioacetamide afforded the corresponding 6-substituted 3-cyano-5-nitropyridine-2(1H)-thiones, which were used for the synthesis of 6-substituted 3-cyano-2-methylthio-5-nitropyridines and 7-substituted 4-hydroxy-8-nitropyrido[2",3":4,5]thieno[2,3-b]pyridin-2(1H)-ones.     

Synthesis of (4Z)‐4‐(Arylmethylidene)‐5‐ethoxy‐1,3‐oxazolidine‐2‐thiones by the Reaction of Ethyl (2Z)‐3‐Aryl‐2‐isothiocyanatoprop‐2‐enoates with Organolithium Compounds

A convenient one‐pot method for the preparation of (4Z)‐4‐(arylmethylidene)‐5‐ethoxy‐1,3‐oxazolidine‐2‐thiones 2 and 3 from ethyl (2Z)‐3‐aryl‐2‐isothiocyanatoprop‐2‐enoates 1 , which can be easily prepared from ethyl 2‐azidoacetate and aromatic aldehydes, has been developed. Thus, these α‐isothiocyanato α,β‐unsaturated esters were treated with organolithium compounds, including lithium enolates of acetates, to provide 5‐substituted (4Z)‐4‐(arylmethylidene)‐5‐ethoxy‐1,3‐oxazolidine‐2‐thiones, 2 , and 2‐[(4Z)‐(4‐arylmethylidene)‐5‐ethoxy‐2‐thioxo‐1,3‐oxazolidin‐5‐yl]acetates, 3 .     

Synthesis of 2-Arylthiopyrano[2, 3-d]Pyrimidines and Thieno[2, 3-D]Pyrimidines

Diethyl thiopyrano[2,3-d]pyrimidine-6,7-dicarboxylates 2a, b ; thiopyrano[23-d]pyrimidines 3a-c and 4a-c thieno[2,3-d]pyrimidine-6-carbonitriles 5a-c and thieno[2, 3-d]pyrimidine-6-carboxamides 5d-f have been prepared.     

Stereoselective Synthesis and Alkylation of N-Methylmorpholinium 4,5-trans-4-(2-chlorophenyl)-3-cyano-6-hydroxy-5-(2-thenoyl)-6-trifluoromethyl-1,4,5,6-tetrahydropyridine-2-thiolate. Molecular and Crystal Structure of 4,5-trans-4-(2-chlorophenyl)-3-cyano-6-hydroxy-2-methallylthio-5-(2-thenoyl)-6-trifluoromethyl-1,4,5,6-tetrahydropyridine

The condensation of 2-chlorobenzaldehyde with cyanothioacetamide and 2-thenoyltrifluoroacetone in the presence of N-methylmorpholine takes place stereoselectively and leads to the formation of N-methylmorpholinium 4,5-trans-4-(2-chlorophenyl)-3-cyano-6-hydroxy-5-(2-thenoyl)-6-trifluoromethyl-1,4,5,6-tetrahydropyridine-2-thiolate. The latter was used to synthesize the corresponding 2-alkylthiotetrahydropyridines. The structure of 4,5-trans-4-(2-chlorophenyl)-3-cyano-6-hydroxy-2-methallylthio-5-(2-thenoyl)-6-trifluoromethyl-1,4,5,6-tetrahydropyridine was determined by X-ray crystallographic analysis.     

1-Oxa-3-azapentalen-2-ones as Precursors of cis-2-Amino Alcohols: Synthesis from Propargyl Alcohols, CO2, and Amines Using an Intramolecular Amidoalkylation Reaction of Oxazolidin-2-ones

The reaction of 5-methyl-5-(4-methyl-3-pentenyl)-4-methylene-1,3-dioxolan-2-one with primary amines gives the corresponding 4-hydroxy-4-methyloxazolidin-2-ones. These undergo an intramolecular amidoalkylation reaction to form 1-oxa-3-azapentalen-2-ones which are potential precursors of cyclopentanyl cis-2-amino alcohols.     

A new stereoselective synthesis of 2-amino-4,5-dihydrothiophene-3-carbonitrile derivatives

A new stereoselective method for the synthesis of trans-isomers of 2-amino-4-aryl-5-benzoyl-4,5-dihydrothiophene-3-carbonitriles was proposed. The method involves base-catalyzed reactions of phenacyl thiocyanate with 3-(het)aryl-2-cyanoprop-2-enethioamides. (4R,5S/4S,5R)-2-Amino-5-benzoyl-4-(2-chlorophenyl)-4,5-ihydrothiophene-3-carbonitrile was structurally characterized by X-ray diffraction analysis. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1379–1383, July, 2007.     

Fluorinated 1,3-diketones, 2-trifluoroacetyl phenols and their derivatives: versatile reactants in phosphorus chemistry

The role of fluorinated β-diketones, their tautomers (keto–enols) and their derivatives as reagents towards λ³P compounds is reviewed, including 2-trifluoroacetyl phenols, possessing formally a keto–enol system, and their derivatives. In an ‘insertion’ reaction phosphine and the keto–enol tautomers of 1,1,1,5,5,5-hexafluoro- and 1,1,1-trifluoropentan-2,4-dione furnished primary (S) or (R) α-hydroxy phosphines, whose enol functions probably isomerized the corresponding keto compounds. Further addition and isomerisation furnished 1,3α,5,7β-tetrakis(trifluoromethyl)-2-phospha-6-oxa-9-oxabicyclo[3.3.1]-nonan-3β,7α-diol and 1,7-trifluoromethyl-3,5-methyl-2,4,8-trioxa-6-phophaadamantane, exclusively one diastereomer in each case. The main mechanistic feature of these reactions is a consecutive diastereoselective hemiketal cyclization. 1,1,1,5,5,5-Hexafluoro- and 1,1,1-trifluoropentan-2,4-dione, as well as 2-trifluoroacetyl phenol and its imino derivatives reacted diastereospecifically with phosphonous acid dichlorides, RPCl₂ to give in a concerted mechanism thermally stable tricyclic λ⁵σ⁵P phosphoranes containing two five-membered rings and one six-membered ring. Surprisingly, the two CF₃ groups bonded to an sp³-hybridized carbon were in a cisoid arrangement having closest non-bonding FF distances of 301.4 or 273.5 pm. These findings reflect the ‘through space’ F---F coupling constants of the tricyclic phosphoranes (J_FF=4.0–7.0 Hz), in solution. 4,4,4-Trifluoro-3-hydroxy-1-phenyl-butan-1-one and methyl or phenyl phosphonous acid dichlorides gave similar tricyclic phosphoranes decomposing at ambient temperature to furnish 1,2λ⁵σ⁴-oxaphospholanes and (E)-1,1,1-trifluoro-4-phenyl-but-2-en-4-one. Dialkylphosphites and 1,1,1,5,5,5-hexafluoropentan-2,4-dione reacted to give either the (Z)-enol phosphonates or the respective γ-ketophosphonates from which in two cases four diastereomeric 2-oxo-2,5-dialkoxy-3,5-bis(trifluoromethyl)-3-hydroxy-1,2λ⁵σ⁴-oxa-phospholanes were obtained. 2-Trifluoroacetyl cyclohexanone, 4,4,4-trifluoro-3-trimethylsiloxy-1-phenylbutan-1-one, 1-benzoyl-2-trifluormethyloxirane, 1-benzoyl-2-trifluoro-methylaziridine, 2-trifluoroacetyl-1-trimethylsiloxybenzene and (trifluoroacetyl-1-phenyl) diethyl phosphate reacted with tris(trimethylsilyl) phosphite to give functionalized α-trimethylsiloxy phosphonates, which could easily be transferred into the respective phosphonic acids. In the case of an oxirane and an aziridine ketone no ring cleavage was observed. For 1,1′-(2-hydroxy-5-methyl-m-phenylene)-bis-ethanone and 1,1′-(2-trimethylsiloxy-5-methyl-m-phenylene)-bis-ethanone benzoxaphospholanes were obtained. Trialkyl phosphites and 1,1,1,5,5,5-hexafluoropentan-2,4-dione furnished cyclic phosphoranes containing the 3-hydroxy-3,5-bis(trifluoromethyl)-1,2λ⁵σ⁵-oxaphospholene structural element, stable at ambient temperature only in the case of one cyclic phosphite precursor. (E)-1,1,1-Trifluoro-4-phenyl-but-2-en-4-one and trimethylphosphite reacted to form 1,2λ⁵σ⁵-oxaphosphol-4-ene as the sole product. Results similar to the reaction of 1,1′-(2-hydroxy-5-methyl-m-phenylene)-bis-ethanone with diethyltrimethylsilylphosphite were obtained for trimethylphosphite and 2-trifluoroacetyl phenol where a deoxygenated phosphorane was found, easily hydrolyzed to give the respective phosphonic acid. With dialkylisocyanato phosphites and the keto components, 1,1,1,5,5,5-hexafluoro- and 1,1,1-trifluoropentan-2,4-dione, 4,4,4-trifluoro-1-phenyl-1,3-butandione, 2-trifluoroacetyl cyclohexanone, 2-trifluoroacetyl phenol and 1,1′-(2-hydroxy-5-methyl-m-phenylene)-bis-ethanone reacted in a ‘double’ cycloaddition to form bicyclic phosphoranes containing the 4,8-dioxa-2-aza-1λ⁵σ⁵-phosphabicyclo[3.3.0]-oct-6-en-3-one ring system; for the imino derivatives of 2-trifluoroacetyl phenol a corresponding 8-oxa-2,4-diaza- system was generated. For (E)-1,1,1,5,5,5-hexafluoro-4-trimethylsiloxy-3-penten-2-one however, a cyclic spiroimino phosphorane was obtained which underwent a [2+2] cyclodimerization to form a diazadiphosphetidine. Dimethylpropynyl phosphonite and 1,1,1,5,5,5-hexafluoropentan-2,4-dione yielded diastereoselectively a bisphosphorane, namely 1,4-bis(trifluoromethyl)-3,6-dioxa-2,2,7,7-tetramethoxy-2,7-di(1-propynyl)-2,7-diphosphabicyclo[2.2.1] heptane. When trimethylsilanyl–phosphenimidous acid bis-trimethylsilanyl–amide, Me₃SiN=PN(SiMe₃)₂, was allowed to react with 1,1,1,5,5,5-hexafluoro- and 1,1,1-trifluoropentan-2,4-dione, (E)-1,1,1,5,5,5-hexafluoro-4-trimethylsiloxy-3-penten-2-one, 2-trifluoroacetyl cyclopentanone, 2-trifluoroacetyl phenol and its imino derivatives, 2-imino-1,2λ⁵σ⁴-oxaphospholenes were found containing two diastereomers in each case, which added hexafluoroacetone across the P=N bond to give 1,3,2λ⁵σ⁵-oxazaphosphetanes.     

Synthesis of 5-Hydroxymethyl-8-methyl-3-(3-aryl-[1,2,4]oxadiazol-5-yl)-2H-pyrano[2,3-c]pyridin-2-ones and Their Esters

New 5-hydroxymethyl-8-methyl-3-(3-aryl-[1,2,4]oxadiazol-5-yl)-2H-pyrano-[2,3-c]pyridin-2-ones and their esters were synthesized. The structure of obtained compounds was determined through a complete ¹H NMR analysis.     

Nouvelle Synthese Des 2-Thioxoethylphosphonates, 2- mercaptovinylphosphonates, 2-Phosphoryl-3-thioxopropanoates, 2-Thiomethylvinylphosphonates, 2-Thioethoxycarbonylmethylvinylphosphonates

The cyanomethylphosphonates 1 and the ethyl phosphoacetates 2 were reacted with some fluorophenylisothiocyanates to give the 2-thioxoethylphosphonates 3 in tautomeric equilibrium with the corresponding 2-mercaptovinylphosphonates 3 ′ and the 2-phosphoryl-3-thioxopropanoates 4 , respectively. Reaction of the cyanomethylphosphonates 1 with fluorophenylisothiocyanates in presence of methyliodide furnished the 2- thiometylvinylphosphonates 5 . The 2-mercaptovinylphosphonates 3 ′ reacted with ethyl chloroacetate in refluxing ethanol in the presence of triethylamine to give S-substitued derivatives 6 .     

Die Bildung von [(tBu)2P]2P?P[P(tBu)2]2 aus LiP[P(tBu)2]2 und 1,2-Dibromethan. Die Thermolyse von tBu2P?PP(Br)tBu2

[(tBu)₂P]₂P? P[P(tBu)₂]₂ from LiP[P(tBu)₂]₂ and 1,2-Dibromomethane. Pyrolysis of tBu₂P? P?P(Br)tBu₂ All products of the reaction of [tBu₂P]₂PLi 1 with 1,2-dibromoethane 2 were investigated. Already at ?70°C tBu₂P? P?P(Br)tBu₂ 3 as main product and [tBu₂P]₂PBr 4 are formed. Only with an excess of 1 also [tBu₂P]P? P[P(tBu)₂]₂ 5 is obtained. Warming of a pure solution of 3 in toluene from ?70°C to ?30°C leads to 4 , and at 20°C tBu₂PBr and the cyclophosphanes P₄[P(tBu)₂]₄ and P₃[P(tBu)₂]₃ are observed. 5 does not result from 3 , it's rather a byproduct from the reaction of 1 with 4 . Also the ylide 3 and 1 yields 5 .     

Synthesis of New 2-[(Substituted-pyrazol-1-yl)carbonyl]-thieno[2,3b]pyridine Derivatives Using 1,3-Diketones,Alkylethoxymethylenes and Ketene Dithioacetals

The reaction of 3-amino-4,6-dimethyl-2-thieno[2,3-b]pyridine carbohydrazide ( 1 ) with appropriate 1,3-diketones 2a-2d in glacial acetic acid afforded 3-amino-2-[(3,5-disubstituted-pyrazo)-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 3a-3d. 3-Amino-2-[(5-amino-3,4-disubstituted-pyrazol-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 5a-5h were also prepared by treatment of carbohydrazide 1 with appropriate alkylethoxymethylenes and ketene dithioacetals 4a-4h , respectively.     

Synthesis and anticancer activity evaluation of 3-(4-oxo-2-thioxothiazolidin-5-yl)-1H-indole-carboxylic acids derivatives

Abstract

A mild and efficient method for the synthesis of 1-oxo-9H-thiopyrano[3,4-b]indole-3-carboxylic acids and dimerized 3-(4-carboxy-1H-3-indolyl)-2-propenoic acids via alkaline hydrolysis of 3-(rhodanin-5-yl)-1H-indole-2-carboxylic acids derivatives was elaborated. Anticancer activity screening in NCI60-cell lines assay allowed identification of 5-fluoro-3-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)-1H-indole-2-carboxylic acid methyl ester 2a with significant antimitotic activity at micromolar and submicromolar concentrations.     

Mechanism of Alkaline Hydrolysis of Diazepam

Diazepam (1) is a frequently prescribed hypnotic/anxiolytic drug in worldwide use. Compound 1 is hydrolyzed in alkaline medium to form 2-methylamino-5-chlorobenzophenone imine (2) and 2-methylamino-5-chlorobenzophenone (3) ; the ratio of 2:3 increases with increasing NaOH concentration (J. Pharm. Sci. 85, 745–748, 1996). The mechanism in the conversion of 1 to 2 and 3 via various intermediates is the subject of this report. Results of hydrolysis kinetics and structural identification of some intermediate products indicated an initial hydroxide attack at the C2-carbonyl carbon of 1 , resulting in the formation of a dioxide ( 7 , 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2,2-dioxide). Compound 7 was characterized by proton NMR spectroscopy and via its monomethyl ether ( 8 , 7-chloro-1,3-dihydro-2-hydroxy-2-methoxy-l-methyl-5-pheny]-2H-1,4-benzodiazepine). The seven-member diazepine ring of 7 opened at the N1-C2 bond to form a glycinate [ 5 , 2-methylamino-5-chloro-α-(phenylhenzylidene)glycinate]. Compound 7 (and/or 5 ) underwent an additional hydroxide attack at the C5-N4 imine bond to form a tetrahedral intermediate, which decomposed to form 2 and 3 .     

Three-component condensation of pyridin-2-one, bis(2-chloroethyl)amine hydrochloride, and K2CO3 in DMF as a new method for oxazolidinylethylation

Three-component condensation of pyridin-2-one, bis(2-chloroethyl)amine hydrochloride, and K₂CO₃ in DMF unexpectedly gave N-and O-oxazolidinylethylation products of pyridin-2-one in the ratio 3: 2. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1047–1048, May, 2007.     

Reaction of 5-aryl-2-tosylmethylimino-2,3-dihydro-3-furanones with substitutedN-(benzylidene)benzylamines. Crystal structure of 1-benzyl-5-p-methoxyphenyl-2-(p-chlorobenzoyl)acetylimidazole

5-Aryl-2-aroylacetyl-1-benzylimidazoles were synthesized by treatment of 5-aryl-2-tosylmethylimino-2, 3-dihydro-3-furanones withN-(benzylidene)benzylamines containing electron-donating substitutents in the benzylidene moiety. The structure of 1-benzyl-5-p)-methoxyphenyl-2-(p-chlorobenzoyl)acetylimidazole was studied by X-ray diffraction.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2013–2016, October, 1995.     

An Efficient Synthesis of 3‐(1H‐Tetrazol‐5‐yl)coumarins (=3‐(1H‐Tetrazol‐5‐yl)‐2H‐1‐benzopyran‐2‐ones) via Domino Knoevenagel Condensation,Pinner Reaction,and 1,3‐Dipolar Cycloaddition in Water

A novel straightforward synthesis of 3‐(1H‐tetrazol‐5‐yl)coumarins (=3‐(1H‐tetrazol‐5‐yl)‐2H‐1‐benzopyran‐2‐ones) 6 via domino Knoevenagel condensation, Pinner reaction, and 1,3‐dipolar cycloaddition of substituted salicylaldehydes (=2‐hydroxybenzaldehydes), malononitrile (propanedinitrile), and sodium azide in H₂O is reported (Scheme 1 and Table 2). This general protocol provides a wide variety of 3‐(1H‐tetrazol‐5‐yl)coumarins in good yields under mild reaction conditions.     

Phase-transfer catalysis in reactions of 5-alkyl-3H-furan-2-ones with dichlorocarbene

Treatment of 5-alkyl-3H-furan-2-ones and 5-alkyl-3H-thiophen-2-ones with dichlorocarbene under conditions of phase-transfer catalysis at 20–90 °C results in insertion of the carbene at the C=C bond followed by skeletal rearrangement.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1995–1997, October, 1995.     

Synthesis and crystal structure of ethyl 1-benzyl-2-hydroxy-5-methyl-3-oxo-2-phenacyl-2,3-dihydropyrrole-4-carboxylate

Reaction of 5-phenyl-2,3-dihydro-2,3-furandione with ethyl 3-benzylamino-2-butenoate, resulting in ethyl 1-benzyl-2-hydroxy-5-methyl-3-oxo-2-phenacyl-2,3-dihydropyrrole-4-carboxylate and benzylamide ofN-benzoylpyruvic acid, was studied. The structure of the pyrrole derivative was confirmed by X-ray analysis.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1552–1555, August, 1995.