Homophthalic Anhydride Research Articles

Cis/trans‐Isochromanones. DMAP Induced Cycloaddition of Homophthalic Anhydride and Aldehydes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Cis/ trans-Isochromanones. DMAP induced cycloaddition of homophthalic anhydride and aldehydes

Homophthalic anhydride ( 1 ) reacts with wide variety of aromatic aldehydes, in the presence of chloroform and DMAP ( N, N-dimethyl-4-amino-pyridine) at room temperature, to give in high yields cis- and trans-1-oxo-isochroman-4-carboxylic acids. Under these conditions, the trans-isomer is predominant and formation of Perkin-type products was not observed in contrast to the reaction carried out in the presence of pyridine. The unexpected trans-6-oxo-11-thiophen-2-yl-11,12-dihydro-6 H-dibenzo[ c, h]chromene-12-carboxylic acid methyl ester ( 8 ) was isolated when the reaction between 1 and thiophene-2-carbaldehyde was carried out in pyridine.

Design, synthesis, and biological evaluation of indenoisoquinoline topoisomerase I inhibitors featuring polyamine side chains on the lactam nitrogen.

The indenoisoquinolines are a class of noncamptothecin topoisomerase I inhibitors that display significant cytotoxicity in human cancer cell cultures. They offer a number of potential advantages over the camptothecins, including greater chemical stability, formation of more persistent cleavage complexes, and induction of a unique pattern of DNA cleavage sites. Molecular modeling has suggested that substituents on the indenoisoquinoline lactam nitrogen would protrude out of the DNA duplex in the ternary cleavage complex through the major groove. This indicates that relatively large substituents in that location would be tolerated without compromising biological activity. As a strategy for increasing the potencies and potential therapeutic usefulness of the indenoisoquinolines, a series of compounds was synthesized containing polyamine side chains on the lactam nitrogen. The rationale for the synthesis of these compounds was that the positively charged ammonium cations would increase DNA affinity through electrostatic binding to the negatively charged DNA backbone, and the polyamines might also facilitate cellular uptake by utilization of polyamine transporters. The key step in the synthesis involved the condensation of Schiff bases, containing protected amine side chains, with substituted homophthalic anhydrides, to afford cis-3-aryl-4-carboxy-1-isoquinolones. These isoquinolones were then converted to indenoisoquinolines with thionyl chloride. Although monoamines were much more potent than the lead compound, no significant increase in potency was observed through incorporation of additional amino groups in the side chain. However, one of the monoamine analogues, which features a bis(2-hydroxyethyl)amino group in the side chain, proved to be one of the most cytotoxic indenoisoquinoline synthesized to date, with a GI50 mean-graph midpoint (MGM) of 0.07 microM in the NIH human cancer cell culture screen, and topoisomerase I inhibitory activity comparable to that of camptothecin.

New trans/cis tetrahydroisoquinolines. 2. trans‐ and cis‐3‐(1‐methyl‐1h‐pyrrol‐2‐yl)‐1‐(2H)‐oxo‐2‐phenethyl‐1,2,3,4‐tetrahydroisoquino‐lin‐4‐carboxylic acids and subsequent transformations

AbstractStereochemical course of the reaction of homophthalic anhydride and N‐(1‐methyl‐1H‐pyrrol‐2‐yl‐methylidene)‐phenethylamine was studied. Mixtures of the expected trans‐ and cis‐1,2,3,4‐tetrahydroiso‐quinoline‐4‐carboxylic acids trans‐4 and cis‐4 were obtained along with by‐products 5 and 6. The ratios of all products and the diastereomers, obtained under different reaction conditions, were established by pmr. THF as a solvent and ultrasonic treatment are applied for the first time in the reaction of this type. The reaction was made diastereoselective towards any isomer. The carboxylic group of trans‐4 was transformed in four steps into various cyclic amino‐methyl groups yielding numerous new tetrahydroisoquinolinones trans‐10a‐i incorporating a given fragment of pharmacological interest. Reduction of 10a‐i was studied.

Synthesis of p-phenylthio- peri-hydroxy polyaromatic compounds by strong-base-induced [4+2] cycloaddition of 4-(phenylthio)homophthalic anhydrides with phenylsulfinyl- dienophiles

Synthesis of p-phenylthio- peri-hydroxy polyaromatic compounds by strong-base-induced [4+2] cycloaddition of 4-(phenylthio)homophthalic anhydrides with phenylsulfinyl- dienophiles

Room Temperature Ionic Liquids Promoted Three‐Component Coupling Reactions: A Facile Synthesis of cis‐Isoquinolonic Acids.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Formal synthesis of angiogenesis inhibitor NM-3.

We report the formal synthesis of angiogenesis inhibitor NM-3 (1) in six steps from either of the 2,4-dimethoxyhalobenzenes 13a,b or 3,5-dimethoxychlorobenzene (13c). The first key reaction is the regiospecific alkylation/rearrangement between the aryne derived from 13a-c with sodium diethylmalonate in THF to produce diester 11, which after hydrolysis and cyclization affords homophthalic anhydride 3. The second is the reaction of anhydride 3 with either ethyl 2-methylmalonate (28a), in the presence of 1,1'-carbonyldiimidazole, or ethyl-2-methylmalonyl chloride (28b) under basic conditions to afford key isocoumarin 27. The conversion of 27 constitutes a formal synthesis of NM-3.

Room temperature ionic liquids promoted three-component coupling reactions: a facile synthesis of cis-isoquinolonic acids

Room temperature ionic liquids are found to catalyze efficiently the three component-coupling reactions of aldehydes, amines and homophthalic anhydride under mild and convenient conditions to afford the corresponding cis-isoquinolonic acids in excellent yields with high cis-selectivity.

New trans/cis tetrahydroisoquinolines. 1. trans‐2‐benzyl‐3‐(l‐methyl‐1h‐pyrrol‐2‐yl)‐4‐substituted‐1,2,3,4‐tetrahydroisoquinolin‐1‐ones and corresponding tetrahydroisoquinolines

AbstractThe reaction of homophthalic anhydride and N‐(1‐methyl‐1H‐pyrrol‐2‐yl‐methylidene)‐benzylamine in boiling benzene afforded as a main product the expected substituted trans‐1,2,3,4‐tetrahydroisoquinoline‐4‐carboxylic acid 5. The carboxylic group of 5 was transformed in four steps into cyclic amino‐methyl groups yielding numerous new tetrahydroisoquinolinones 11a‐j incorporating a given fragment of pharmacological interest. Reduction of 11a‐j was studied.

Synthesis and cytotoxic activity of tetracenomycin d and of saintopin analogues

Regiospecific synthesis of title compounds is based either on cycloaddition of ketene acetals derived from Hagemann's ester or of homophthalic anhydrides. Thus, tetracenomycin D and 3,8-di- O-methyl saintopin have been prepared in few steps. New derivatives of 10-deoxysaintopin have been also obtained. Evaluation of their cytotoxicity against L1210 leukemia cells are reported.

Enantioselective total synthesis of a potent antitumor antibiotic, fredericamycin A.

The asymmetric total synthesis of both enantiomers of the potent antitumor antibiotic fredericamycin A (1) is detailed based on the protocol for the construction of its peri-hydroxy polyaromatic skeleton bearing the chirality at the spiro carbon via a strong base-induced cycloaddition of suitably substituted homophthalic anhydrides (AB-ring unit) with an optically active CDEF-ring unit. Particular attention has been given to the novel synthesis of the optically active spiro carbon center by a stereospecific rearrangement of optically active benzofuzed-trans-epoxy acylates leading to spirocyclopentane-1,1'-indane systems. This method is quite useful for the construction of an optically active spiro compound and was applied to the synthesis of the optically pure CDEF-ring unit of 1. Cycloaddition of the optically pure CDEF-ring unit to AB-ring units prepared via benzyne afforded two natural and unnatural-type hexacyclic compounds, which were converted to natural and unnatural enantiomers of synthetic 1, and the absolute configuration of natural 1 was determined as S.

Synthesis of new indeno[1,2-c]isoquinolines: cytotoxic non-camptothecin topoisomerase I inhibitors.

In an attempt to design and synthesize potential anticancer agents acting by inhibition of topoisomerase I (top1), a new series of indenoisoquinolines was prepared and tested for cytotoxicity in human cancer cell cultures and for activity against top1. The synthesis relied on the condensation of substituted Schiff bases with homophthalic anhydrides to produce cis-3-aryl-4-carboxyisoquinolones that were cyclized to indenoisoquinolines in the presence of thionyl chloride. Both top1 inhibitory activity and cytotoxicity maximized in a single compound, 6-[3-(2-hydroxyethyl)aminopropyl]-5,6-dihydro-2,3-dimethoxy-8, 9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline hydrochloride (19a), which proved to be a very potent top1 inhibitor having a 110 nM mean graph midpoint (MGM) when tested for cytotoxicity in 55 human cancer cell cultures. A number of structurally related indenoisoquinolines were also obtained that had both potent cytotoxicity as well as top1 inhibitory activity. The key feature of the more potent compounds was the presence of an aminoalkyl side chain on the indenoisoquinoline nitrogen atom. The DNA cleavage patterns induced by top1 in the presence of the indenoisoquinolines were different from those seen with camptothecin. Some of the cleavage sites induced by the indenoisoquinolines were different from those seen with camptothecin, and conversely, camptothecin induced unique cleavage sites not apparent with the indenoisoquinolines. However, both camptothecin and the indenoisoquinolines also induced DNA cleavage sites that were the same in both series but varied in intensity. In addition, some of the DNA cleavages seen with the free base of 19a (compound 18c) in the presence of top1 were inhibited at higher drug concentrations, suggesting either a direct inhibition of the enzyme or an alternative mechanism involving DNA intercalation. Consistent with intercalation, compound 18c did unwind DNA.

A Facile and Convenient Synthesis of 3-Alkylamino-5-arylthiophenes with a Variety of Substituents at C-2 and Studies of Reaction Mechanisms

Thioaroylketene S,N-acetals were treated with active methylene compounds including beta-keto ester, nitromethane, cyanoacetic acid, p-toluenesulfonylacetone, 4-nitrophenylacetic acid, and diethyl (2-oxopropyl)phosphonate in the presence of mercury(II) acetate in CH(2)Cl(2) at room temperature. These reactions gave 3-alkylamino-5-arylthiophenes containing various substituents, which comprised, respectively, alkoxycarbonyl, nitro, cyano, p-toluenesulfonyl, 4-nitrophenyl, and diethylphosphono groups at C-2 in good yields. The reaction of 3-methylamino-3-methylthio-1-phenylthioxopropene with malonic acid or Meldrum's acid under the same conditions gave 3-methylamino-5-phenylthiophene. Similarly, treatment of 3-methylamino-3-methylthio-1-phenylthioxopropene with various enolizable cyclic ketones such as 4-hydroxy-6-methyl-2-pyrone, homophthalic anhydride, 2-hydroxy-1,4-benzoquinone, and 1, 3-diethyl-2-thiobarbituric acid gave thieno[3,2-b]pyridin-4-one, thieno[3,2-c]isoquinolin-5-one, thieno[3,2-c]benzazepine-1,6-dione, and thieno[3,2-d]pyrimidine-2,4-dione, respectively.

An Efficient Synthesis of peri-Hydroxy Aromatic Compounds via a Strong-Base-Induced [4+2] Cycloaddition of Homophthalic Anhydrides with Enolizable Enones

An efficient synthesis of peri-hydroxy aromatic compounds has been accomplished via a strong-base-induced [4+2] cycloaddition of homophthalic anhydrides with alpha-sulfinyl-substituted derivatives of enolizable enones. The unsubstituted enones did not undergo an efficient [4+2] cycloaddition reaction with homophthalic anhydrides, presumably due to their enolization under the basic reaction conditions. The sulfinyl group not only promotes the cycloaddition reaction but also undergoes in situ elimination under the reaction conditions to afford the peri-hydroxy aromatic compounds in a single step. The application of this methodology for the synthesis of a key intermediate of antitumor antibiotic fredericamycin A is described. PM3 calculations of various 2-substituted cyclopentenones as well as the mechanism of the cycloaddition are also discussed.

Cycloaddition of homophthalic anhydrides with aldehydes and ketones: a route to 3,4-dihydroisocoumarin-4-carboxylic acid derivatives

Homophthalic anhydride reacts with benzaldehyde in the presence of boron trifluoride-diethyl ether complex to give the cycloadduct 3-phenyl-3,4-dihydroisocoumarin-4-carboxylic acid in good to excellent yield. Under these conditions we did not observe the formation of Perkin-type products. The reaction can be extended to a wide variety of aldehydes and to some ketones in synthetically useful yields. Amides can be obtained in good yields after activation of the carboxylic function with DCC at O°C.

Synthesis of new5-alkylidene-4-chloro-5H-1,2,3-dithiazoles and their stereochemistry

A variety of5-alkylidene-4-chloro-5H-1,2,3-dithiazoles ( 9–25) have been prepared from4-chloro-5H-1,2,3-dithiazolium chloride, active methylene compounds, and pyridine. The reactions with ethyl nitroacetate ((Z) > (E)), ethyl 3-nitrobenzoylacetate ((E) > (Z)), ethyl 2-fluorobenzoylacetate ((E) > (Z)), and tetronic acid ((Z) > (E)) gave a mixture of(E)-and(Z)-isomers, whereas those of benzoylnitromethane (Z),5,6-dihydro-4-hydroxy-6-methyl-2H-pyran-2-one (E), 4-hydroxy-6-methyl-2-pyrone (E), 4-hydroxycoumarin (E), 6-chloro-4-hydroxycoumarin (E), and 6-bromo-4-hydroxycoumarin (E) afforded only single stereoisomers. The reactions with4-hydroxy-1-methyl-2(1H)-quinolone, 2-hydroxy-1,4-naphthoquinone and homophthalic anhydride gave only single stereoisomers whose stereochemistry is uncertain. It appears that geometrically more rigid cyclic 1,3-dicarbonyl compounds give better yields of dithiazol-5-ylidenes than the corresponding acyclic compounds. [Display omitted]

ChemInform Abstract: A Strong‐Base Induced [4 + 2] Cycloaddition of Homophthalic Anhydrides with Enolizable Enones: A Direct and Efficient Synthesis of peri‐Hydroxy Aromatic Compounds.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of Homophthalates from Allenic Diesters: Conversion into Viocristin and Analogues, and Application to 6-Methylpretetramid.

Oxy-substituted homophthalic anhydrides have been synthesized by cycloaddition of di- and tri-oxy butadienes to the allenic diester (1). By base-catalysed cycloaddition to appropriate benzoquinones they have afforded new syntheses of viocristin (19), isoviocristin (20) and analogous 1,4-anthraquinones. Related chemistry has led to the naphthalene (34) and the anhydride (35), intermediates in published syntheses of semivioxanthin and 6- methylpretetramid respectively.

Total synthesis of decumbenine B

Decumbenine B, a 3-arylisoquinoline alkaloid isolated from Corydalis decumbens, has been first synthesized from piperonal via 18 steps. The key step was condensation of 5,6-(methylenedioxy)-homophthalic anhydride 5 with Schiff base 6.

ChemInform Abstract: An Efficient Synthesis of peri‐Hydroxy Aromatic Compounds: A Strong Base‐Induced [4 + 2] Cycloaddition of 4‐Phenylthio‐Substituted Homophthalic Anhydrides with Various Sulfinyl‐Substituted Dienophiles.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.