Liquid-phase combinatorial synthesis of 1,4-benzodiazepine-2,5-diones as the candidates of endothelin receptor antagonism

A library of 1,4-benzodiazepine-2,5-dione dicarboxylate derivatives containing aryl substituents at N(1)- and N(4)-positions to mimic the amino acid residues of Try-13, Phe-14, and Asp-18 in endothelin-1 is established by using the starting materials of alpha-amino esters, hydroxybenzaldehydes, nitrobenzoyl chlorides, and benzyl bromides in a polyethylene resin-bound liquid-phase synthesis. All of the six synthetic steps are conducted under mild conditions to give the desired products with reasonable yields and purity. The poly(ethylene glycol) support plays as a part of ester linkage that is released at the final step.     

Synthesis of 1,4-benzodiazepine-3,5-diones

Even though benzodiazepines have a strong position in medicinal chemistry, very few synthetic routes to 1H-1,4-benzodiazepine-3,5(2H,4H)-diones have ever been published and the claimed products have often been poorly characterized. Through the present work several 1H-1,4-benzodiazepine-3,5(2H,4H)-diones have become available from N-carbamoylmethylanthranilic acids. The required ring closures were achieved only when the amino groups of the starting materials were substituted with electron withdrawing groups such as acetyl, alkyloxycarbonyl, or nitroso. During the synthetic work a novel ring contraction rearrangement from a 1-nitroso-1H-1,4-benzodiazepine-3,5(2H,4H)-dione to a 3H-quinazoline-4-one was observed. The proposed mechanism involves elimination of HNO followed by a proton-mediated loss of CO. The 1-nitrosated 1,4-benzodiazepinediones could be separately denitrosated to the corresponding amino compounds.     

Palladium- and copper-catalyzed synthesis of medium- and large-sized ring-fused dihydroazaphenanthrenes and 1,4-benzodiazepine-2,5-diones. control of reaction pathway by metal-switching

Methods for the synthesis of dihydroazaphenanthrene fused to macrocycles (2) and medium-ring heterocycles (4), as well as 1,4-benzodiazepine-2,5-diones (5), are developed. A distinctly different catalytic property of palladium and copper catalysts was uncovered that leads to the development of a divergent synthesis of two different heterocyclic scaffolds from the same starting materials, simply by metal-switching. Thus, starting from linear amide 3, palladium acetate triggers a domino intramolecular N-arylation/C-H activation/aryl-aryl bond-forming process to provide 4, while copper iodide promotes only the intramolecular N-arylation reaction leading to 5. In combination with the Ugi multicomponent reaction (Ugi-4CR) for the preparation of the linear amides, a two-step synthesis of either the 5,6-dihydro-8H-5,7a-diazacyclohepta[jk]phenanthrene-4,7-dione (4) or 1,4-benzodiazepine-2,5-diones (5), by appropriate choice of metal catalyst, is subsequently developed from very simple starting materials.     

Fluorous synthesis of sclerotigenin-type benzodiazepine-quinazolinones

A new synthetic protocol for sclerotigenin-type benzodiazepine-quinazolinone library scaffold is introduced. A fluorous benzyl protecting group is used for the synthesis of 4-benzodiazepine-2,5-dione intermediate and also as a phase tag for fluorous solid-phase extraction (F-SPE).     

Enantioselective synthesis of diversely substituted quaternary 1,4-benzodiazepin-2-ones and 1,4-benzodiazepine-2,5-diones

Benzodiazepines are privileged scaffolds in medicinal chemistry, but enantiopure examples containing quaternary stereogenic centers are extremely rare. We demonstrate that installation of the di(p-anisyl)methyl (DAM) group at N1 of 1,4-benzodiazepin-2-ones and 1,4-benzodiazepine-2,5-diones derived from enantiopure proteinogenic amino acids allows retentive replacement of the C3-proton via a deprotonation/trapping protocol. A wide variety of carbon and nitrogen electrophiles function well in this reaction, providing the corresponding quaternary benzodiazepines with excellent enantioselectivity. Deprotonation/trapping experiments on a pair of diastereomeric 1,4-benzodiazepine-2,5-diones provide evidence for a key role of conformational chirality in these enantioselective reactions. Acidic removal of the DAM group is fast and high-yielding and can be performed selectively in the presence of a N-Boc indole. Thus the synthesis of quaternary benzodiazepines with diverse N1 functionality can now be accomplished.     

Novel synthesis of N(4)-substituted 1,4-benzodiazepine-2,5-diones using poly(ethylene glycol) as soluble polymer support

An efficient method for the liquid-phase combinatorial synthesis of N4-substituted 1,4-benzodiazepine-2,5-diones has been developed. Poly(ethylene glycol) (PEG) stepwise reacted with bromoacetyl bromide, a primary amine and 2-azidobenzoic acid to give a potential PEG-bound dipeptide, which was reduced by NaI / acetic acid, along with concurrent cyclization and cleavage of the seven-membered heterocycle from the PEG support.     

Highly enantioselective synthesis of rigid, quaternary 1,4-benzodiazepine-2,5-diones derived from proline

[reaction: see text] Proline-derived 1,4-benzodiazepine-2,5-diones are extremely useful scaffolds in medicinal chemistry. In this paper, we describe a protocol for retentive C3 alkylation of these materials, thus accomplishing the direct synthesis of enantiopure quaternary 1,4-benzodiazepine-2,5-diones. The high enantioselectivities (up to 99.5%) are attributed to memory of chirality.     

Synthesis and Antioxidant Activity of N -Aminomethyl Derivatives of Ethosuximide and Pufemide Anticonvulsants

Aminomethylation of 3-methyl-3-ethylpyrrolidin-2,5-dione (ethosuximide) and 3-(4-isopropoxyphenyl)pyrrolidine-2,5-dione (pufemide) with a 25% aqueous formalin solution and alkyl(aryl)amines yielded corresponding N-aminomethyl derivatives. The antioxidant activity of the synthesized compounds and their effect on some parameters of the blood coagulation system were studied.     

Phytogrowth-inhibitory and antibacterial activities of 2,5-dihydroxy-1,4-dithiane and its derivatives

2,5-Dihydroxy-1,4-dithiane (I) and its derivatives (II-IV) showed rather marked inhibitory activities on the growth of the roots of two plant species. All compounds tested had phytogrowth-inhibitory activities. These compounds markedly inhibited the growth of the two plant species at the concentration of 1.0 x 10(-3) M. Seeds of Brassica rapa treated with 2,5-dihydroxy-2,5-dimethyl-1,4-dithiane (III) and its diacetate (IV) at the same concentration failed to germinate. Among these compounds, IV showed the most potent inhibitory activity on the two plant species. The radicles of both plant species treated with these compounds at concentrations higher than 1.0 x 10(-4) M showed negative geotropism, even though germination occurred. The compounds except for 2,5-diacetoxy-1,4-dithiane (II) also had antibacterial activities. In particular, III had rather marked antibacterial activity and its minimal inhibitory concentration (MIC) for Staphylococcus aureus IFO-3060 and Escherichia coli IFO-12734 was 4.0 micrograms/ml.     

A simple route to tetrahydro-1,4-benzodiazepin-3-ones bearing diverse N1, N4, and C10 functionalization

We describe an efficient synthesis of enantiopure tetrahydro-1,4-benzodiazepine-3-ones derived from l-alanine. Diverse substitution at N1, N4, and C10 can be achieved by coupling various N-alkyl derivatives of l-alanine and N-allyl-(2-fluoro-5-nitro)benzylamine. Cyclization of this intermediate proceeds in high yield and without racemization, providing diversity at N1. The NO₂ group was easily transformed into other functional groups or removed, providing diversity at C10. Finally, oxidative deallylation allows diverse substitution to be installed at N4.     

海洋放线菌Streptomyces sp.124092中的细胞毒活性成分

对海洋放线菌Streptomyces sp.发酵液的提取物进行柱层析分离, 得到5个化合物. 经MS, NMR, 1H-1H COSY, HSQC和HMBC等数据鉴定, 其结构分别为3-氨基-丙酸对甲苯酯(1)、6-Amino-3-(4-hydroxybenzyl)-1,4-diazonane-2,5-dione(2)、正丁基-α-D-吡喃甘露糖苷(3)、大豆苷元(4)和1H-3-吲哚甲酸(5). 其中化合物1和2为新化合物, 细胞毒活性测试结果表明, 化合物1~4对人肝癌细胞(SMMC-7721)具有不同程度的生长抑制活性.     

Rearrangement of 1,4-benzodiazepin-2,4-diones to 3,l-benzoxazin-4-ones

Treatment of 7-chloro-3,4-dihydro-1H-1,4-benzodiazepin-2,5-dione (Ia) with refluxing acetic anhydride in the presence of pyridine afforded 6-chloro-2-methyl-4H-3,1-benzoxazin-4-one (IIa). A plausible reaction path for this novel rearrangement reaction is described: Ia → 4-acetyl-7-chloro-3,4-dihydro-lH-1,4-benzodiazepin-2,5-dione → 7-chloro-1,4-diacetyl-3,4-dihydro-lH-1,4-benzodiazepin-2,4-dione → IIa. When 7-chloro-3,4-dihydro-4-methyl-lH-1,4-benzodiazepin-2,5-dione (Ib), 3,4-dihydro-4-methyl-1H-1,4-benzodiazepin-2,5-dione (Id) and 3,4-dihydro-1-methyl-1H-1,4-benzodiazepin-2,5-dione (Ie) were allowed to react with acetic anhydride under conditions similar to those used for the rearrangement reaction, only acetylation occurred.     

Condensation of 1,4-diacetylpiperazine-2,5-dione with aldehydes

Condensation of 1,4-diacetylpiperazine-2,5-dione with aldehydes has been applied to the synthesis of albonoursin and unsymmetrical 3,6-diarylidenepiperazine-2,5-diones. The reaction has been extended to 1,4-diacetyl-3,6-dimethylpiperazine-2,5-dione, which gives derivatives of 2-methyl-3- phenylserine. The mechanism and stereochemistry are discussed; cis 1-acetyl-3-isobutylidene- piperazine-2,5-dione has been isolated.     

Synthesis of 4-unsubstituted dihydropyrimidines having acyl and alkoxycarbonyl groups at 5- and 6-positions by cyclization–elimination reactions using 1,3-diaza-1,3-butadienes

A synthetic method for novel 4-unsubstituted 2-phenyldihydropyrimidines having acyl and alkoxycarbonyl groups at the 5- and 6-positions was developed. The cyclization of 4-dimethylamino-1,3-diaza-1,3-butadiene having N-protecting groups (Boc, Cbz) with 1,2-disubstituted ethylenes, such as diethyl maleate, diethyl fumarate, (Z)-hex-3-ene-2,5-dione, (E)-1,4-diphenylbut-2-ene-1,4-dione, and unsymmetrical (E)-ethyl 4-oxo-4-phenylbut-2-enoate, following the elimination of a dimethylamino group proceeded smoothly, producing the corresponding dihydropyrimidines in good overall yield. The N-protecting group (Boc) could be easily removed to obtain N-unsubstituted dihydropyrimidines as a mixture of tautomers, and their tautomeric behavior was analyzed by ¹H NMR spectroscopy.     

A Remarkable Two-Step Synthesis of Diverse 1,4-Benzodiazepine-2,5-diones Using the Ugi Four-Component Condensation

A two-step, general synthesis of 1,4-benzodiazepine-2,5-diones (BZDs) is presented. This synthesis employs an Ugi four-component condensation using a convertible isocyanide (1-isocyanocyclohexene), followed by an acid-activated cyclization reaction. This synthesis represents a dramatically improved route to BZDs over those currently in the literature. In addition, since amino acids are not used as inputs, the potential for molecular diversity is much greater than that with existing syntheses. It was also found that BZDs substituted with methylenes at the C-3 and N-4 positions display conformational isomerism in the NMR spectra at room temperature. Variable-temperature NMR experiments support this observation and offer the interesting conclusion that the BZD core structure, in certain examples, might not be as rigid as previously supposed.     

Determination of the anxiolytic agent 8-chloro-6-(2-chlorophenyl)-4H-imidazo-[1,5-alpha] [1,4]-benzodiazepine-3-carboxamide in whole blood, plasma or urine by high-performance liquid chromatography

A rapid, sensitive and specific high-performance liquid chromatographic (HPLC) assay was developed for the determination of 8-chloro-6-(2-chlorophenyl)-4H-imidazo-[1,5-alpha]-[1,4]-benzodiazepine-3-carboxamide [I] and its 4-hydroxy metabolite, 8-chloro-6-(2-chlorophenyl)-4-hydroxy-4H-imidazo-[1,5-alpha] [1,4]-benzodiazepine-3-carboxamide [II] in whole blood, plasma or urine. The assay for both compounds involves extraction into diethyl ether-methylene chloride (70:30) from blood, plasma, or urine buffered to pH 9.0. The overall recoveries of [I] and [II] are 92.0 +/- 5.4% (S.D.) and 90.3 +/- 4.9% (S.D.), respectively. The sensitivity limit of detection is 50 ng/ml of blood, plasma, or urine using a UV detector at 254 nm. The HPLC assay was used to monitor the blood concentration-time fall-off profiles, and urinary excretion profiles in the dog following single 1 mg/kg intravenous and 5 mg/kg oral doses, and following multiple oral doses of 100 mg/kg/day of compound [I].     

南海红树林内生真菌cephalosporium sp.代谢产物

红树林内生真菌;代谢产物;cephalosporium sp.     

Synthese von Plectranthonen,diterpenoiden Phenanthren-1,4-chinonen

Synthesis of Plectranthons, Diterpenoid Phenanthrene-1,4-diones The following phenanthrene-1,4-diones have been synthesized by using the photocyclization of the corresponding highly substituted stilbenes as the key step: 3-hydroxy-5,7,8-trimethyl-2-(prop-2-enyl)phenanthrene-1,4-dione ( 1 ), (RS)-, (R)-, and (S)-2-[3-hydroxy-5,7,8-trimethyl-1,4-dioxophenanthren-2-yl]-1-methylethyl acetate ( 2 , 31 , and 32 , resp.), 3-hydroxy-7,8-dimethyl-2-(prop-2-enyl)phenanthrene-1,4-dione ( 3 ), 3-hydroxy-7,8,10-tri-methyl-2-(prop-2-enyl)phenanthrene-1,4-dione ( 4 ), 5,7,8-trimethyl-2-(prop-2-enyl)phenanthrene-1,4-dione ( 17 ), and 3-hydroxy-2-methylphenanthrene-1,4-dione ( 42 ). The quinones 1 and 3 proved to be identical with the recently isolated plectranthons A and C. Compounds 2 , 31 , and 32 exhibited the same UV/VIS, IR, ¹H-NMR and mass spectra as natural plectranthon B , but had different melting points. This might be due either to crystal modifications or to diastereoisomerism caused by the helical structure of the phenanthrene-1,4-dione skeleton. The spectral data of synthetic 4 were not compatible with those of natural plectranthon D for which structure 4 had been proposed based mainly on ¹H-NMR arguments concerning the chemical shifts of H? C(9) and H? C(10) in 1–3. Extensive ¹H-NMR investigations have now revealed that the currently stated assignments of the H? C(9)/ H? C(10) AB system have to be reversed for highly substituted phenanthrene-1,4-diones: in the model compounds 2-methylphenanthrene-1,4-dione (41) and 2, H? C(10) resonates al lower field as expected (peri-position), whereas in the highly substituted congeners 1 , 2 , 3 , 31 , and 32 , H? C(9) is shifted paramagnetically, a fact which had lead to the erroneous assignment of structure 4 for natural plectranthon D .     

Synthesis of some new biologically active coumarin derivatives

The reaction of 4-hydroxycoumarin in toluene with a variety of aromatic binucleophilic compounds has been studied. 3-(Dimethylaminomethylene)chromane-2,4-dione was used as a key intermediate for the preparation of bis[N-(4-oxocoumarinylmethylene)]-1,4-diamines. Alternative synthetic procedures and antibacterial activity data of some of the new compounds are given. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 361–366, March, 2006.     

Catalytic enantioselective synthesis of (-)-prostaglandin E1 methyl ester based on a tandem 1,4-addition-aldol reaction

Catalytic enantioselective 1,4-additions and tandem 1,4-addition-aldol reactions of dialkylzinc reagents to cyclopentene-3,5-dione monoacetals in the presence of an in situ generated Cu(OTf)(2)/chiral phosphoramidite catalyst result in highly functionalized cyclopentane building blocks with ee's up to 97%. A new synthesis of cyclopentene-3,5-dione monoacetals is presented as well as its use in a tandem 1,4-addition-aldol protocol for the catalytic asymmetric total synthesis of (-)-PGE(1) methyl ester. This synthesis represents a new approach to this class of natural products. By using only 3 mol % of an enantiomerically pure catalyst in the key step, the absolute configurations at three stereocenters of the basic structure of the PGE(1) are established at once.