Synthesis of 5-(7-hydroxyhept-3-enyl)-1,2-dithiolan-3-one 1-oxide, a core functionality of antibiotic leinamycin

5-(7-Hydroxyhept-3-enyl)-1,2-dithiolan-3-one 1-oxide 1 possessing both the 1,2-dithiolan-3-one 1-oxide five-membered ring and the double bond at the gamma position of the heterocycle, characteristic of the antibiotic leinamycin, was synthesized. In addition, the activated ester form of 1 was prepared that may be useful for coupling 1 to certain DNA-binding agents.     

Activation of leinamycin by thiols: a theoretical study

Reaction of thiols with the 1,2-dithiolan-3-one 1-oxide heterocycle found in leinamycin (1) results in the conversion of this antitumor antibiotic to a DNA-alkylating episulfonium ion (5). While the products formed in this reaction have been rationalized by a mechanism involving initial attack of thiol on the central sulfenyl sulfur (S2') of the 1,2-dithiolan-3-one 1-oxide ring, the carbonyl carbon (C3') and the sulfinyl sulfur (S1') of this heterocycle are also expected to be electrophilic. Therefore, it is important to consider whether nucleophilic attack of thiol at these sites might contribute either to destruction of the antibiotic or conversion to its episulfonium ion form. To address this question, we have used computational methods to examine the attack of methyl thiolate on each of the three electrophilic centers in a simple analogue of the 1,2-dithiolan-3-one 1-oxide heterocycle found in leinamycin. Calculations were performed at the MP2/6-311+G(3df,p)//B3LYP/6-31G level of theory with inclusion of solvent effects. The results indicate that the most reasonable mechanism for thiol-mediated activation of leinamycin involves initial attack of thiolate at the S2'-position of the antibiotic's 1,2-dithiolan-3-one 1-oxide heterocycle, followed by conversion to the 1,2-oxathiolan-5-one intermediate (3).     

Incorporation of the bioactive moiety of leinamycin into thymidine

A simple synthesis of 1,2-dithiolan-3-ones from α,β-unsaturated thiophenyl esters has been elaborated. With the aim of introducing the biologically active 1,2-dithiolan-3-one-1-oxide moiety of leinamycin into a nucleoside, the method was successfully applied to thymidine-5^′-aldehyde.     

Entering the leinamycin rearrangement via 2-(trimethylsilyl)ethyl sulfoxides

Attack of cellular thiols on the antitumor natural product leinamycin is believed to generate a sulfenate intermediate that undergoes subsequent rearrangement to a DNA-alkylating episulfonium ion. Here, 2-(trimethylsilyl)ethyl sulfoxides were employed in a fluoride-triggered generation of sulfenate anions related to the putative leinamycin-sulfenate. The resulting sulfenates enter smoothly into a leinamycin-type rearrangement reaction to afford an episulfonium ion alkylating agent. The results provide evidence that the sulfenate ion is, indeed, a competent intermediate in the leinamycin rearrangement. Further, the molecules examined here may provide a foundation for the design of functional leinamycin analogues that bypass the unstable and synthetically challenging 1,2-dithiolan-3-one 1-oxide moiety found in the natural product.     

Attractive through-space S-O interaction in the DNA-cleaving antitumor antibiotic leinamycin

We describe here a study on the intramolecular nonbonded 1, 5-sulfur-oxygen (S-O) interaction in the antitumor antibiotic leinamycin 1. The results from density-functional theoretical and semiempirical calculations on leinamycin 1 and model systems 2-5 provide evidence for the 1,5-S-O nonbonded interaction. Our results are used to explain previous experimental data on the X-ray structure of leinamycin 1 (Hirayama, N.; Matsuzawa, E. S. Chem. Lett. 1993, 1957). The amide oxygen (O5) alters the thiosulfinate ester conformation and stabilizes the 1,2-dithiolan-3-one 1-oxide heterocycle. The attractive interaction induces S1 of leinamycin to adopt a distorted trigonal bipyramidal geometry. The magnitude of this stabilizing interaction is approximately 6 kcal/mol.     

Reaction of 2-(5-aminopyrazol-1-yl)quinoxaline 4-oxides with dimethyl acetylenedicarboxylate

The reaction of 6-chloro-2-hydrazinoquinoxaline 4-oxide 6 with ethyl 2-(ethoxymethylene)-2-cyanoacetate or (1-ethoxyethylidene)malononitrile gave 2-(5-amino-4-ethoxycarbonylpyrazol-1-yl)-6-chloroquinoxaline 4-oxide 7a or 2-(5-amino-4-cyano-3-methylpyrazol-1-yl)-6-chloroquinoxaline 4-oxide 7b , respectively. The reaction of compound 7a or 7b with dimethyl acetylenedicarboxylate resulted in the 1,3-dipolar cycloaddition reaction and then ring transformation to afford 4-(5-amino-4-ethoxycarbonylpyrazol-1-yl)-8-chloro-1,2,3-trismethoxycarbonylpyrrolo[1,2-α]quinoxaline 8a or 4-(5-amino-4-cyano-3-methylpyrazol-1-yl)-8-chloro-1,2,3-trismethoxycarbonylpyrrolo[1,2-α]quinoxaline 8b , respectively.     

Sulfur-containing heterocycles 14. New synthesis of cyclic anhydrides of 3-sulfinocarboxylic acids

3-Chlorosulfinylalkanoyl chlorides undergo cyclization into the corresponding five-membered mixed anhydrides (1,2-oxathiolan-5-one 2-oxides) under the action of sodium or mercury acetates. 2-Chlorosulfinylbenzoyl chloride gives 3H-2,1-benzoxathiol-3-one 1-oxide in high yield.     

Synthesis of 1-Amino-6,7-dihydro-7-(hydroxymethyl)-4-nitro-pyrrolo[1,2-f]pyrimidin-3-(5H)-one from 2-Amino-6-methylpyrimidin-3-one

The synthesis of previously unreported 1-amino-6,7-dihydro-7-(hydroxymethyl)-4-nitropyrrolo[1,2-f]pyrimidin-3-(5H)-one starting from 2-amino-6-methylpyrimidin-3-one is described.     

Substituent effects on the reactivity of benzo-1,2-dithiolan-3-one 1-oxides and their possible application to the synthesis of DNA-targeting drugs

The efficiency of polysulfane product generation has been investigated for n-propyl thiol reactions with ortho- and para-substituted benzo-1,2-dithiolan-3-one 1-oxides in acetonitrile-water (7:3) mixtures. The reaction is facilitated by reducing the electron density at the para position or by placing substituents bearing lone pair electrons ortho to the dithiolanone-oxide (S1) reaction center. Through-space and through-bond effects both contribute to the conversion of polysulfane products.     

Condensed isoquinolines. 37.* Heterocyclization using 3-(arylamino)- and 3-(hetarylamino)isoquinolin-1(2H)-ones

The reaction of 3-NHR-isoquinolin-1(2H)-ones (R = Ar) with aromatic aldehydes in the presence of Me3SiCl or in acetic acid leads to the formation of derivatives of dibenzo[b,f][1, 8]naphthyridin-5(6H)- one and benzo[f]isoquino[3,4-b][1, 8]naphthyridine-5,9(6H,7H)-dione. The reaction for R = Het in the presence of Me3SiCl gives derivatives of 5H-pyrido[1',2':1,2]pyrimido[4,5-c]isoquinolin-5-one, benzo[f]isoquinoline[3,4-b][1,8]naphthyridine-5,9[6H,7H]-dione, and derivatives of new heterocyclic systems, 5H-pyrazino[1',2':1,2]pyrimido[4,5-c]isoquinolin-5-one, 5H-[1,3]thiazolo[3',2':1,2]pyrimido- [4,5-c]isoquinolin-5-one, 5-H-benzo[f]pyrazolo[3,4-b][1,8]naphthyridin-5-one, and isoquino[3,4-b]- [1,5]naphthyridin-5(6H)-one. The effect of the structure of substituent R and nature of the substituent in the benzaldehydes on the structure of the reaction products was studied.     

Microbiological synthesis of 7-bromo-5-(o-chlorophenyl)-3-hydroxy-1,2-dihydro-3H-1,4-benzodiazepin-2-one by immobilized actinomycetes

It has been shown that the highest yields (15%) of 7-bromo-5-(o-chlorophenyl)-3-hydroxy-1,2-dihydro-3H-1,4-benzodiazepin-2-one are obtained by the use of the cells of actinomycetes immobilized in poly(vinyl alcohol) in the presence of the cosubstrate 7-bromo-5-(o-chlorophenyl)-3-methyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one.     

Cyclisation of 4-[2-Cyclofentenyl]-3-Hydroxy [1] Benzopypan-2-One

4-[2-cyclopentenyl]-3-hydroxy [1] bonzopyran-2-one(3) was cyclised to the bicyclie coumar in-1,3-ethano-2-bromo-1,2-dihydro-3H-pyrano [2,3-c] [1] benzopyran-5-one (6) by a sequence of reactions viz. acetylation of 3, addition of bromine to cyclopenteny double bond and treating the resulting acetyldibromo compound (5) with 4% alcoholic KOH, Cyclisation of compound (3) with mercuric acetate in methanol gave condensed furan derivative 7 which on reductive demercuration with zinc borohydride in dimethoxyethane gave the 1,3-propano-1,2-dihydrofuro [2,3-c] [1] benzopyran-4-one, 8. Cyclisation of compound 2 with come. H₂SO₄ furnished a mixture of bicyclic derivative 9 ad furo coumarin derivative 8.     

Special features of the alkylation of 7-bromo-5-(2-chlorophenyl)- 3-hydroxy-1,2-dihydro-3h-1,4-benzo- diazepin-2-one with alkyl tosylates

On interacting 7-bromo-5-(2-chlorophenyl)-3-hydroxy-1,2-dihydro-3H-1,4-benzodiazepin-2-one with methyl, hexyl, dodecyl, and cetyl tosylates, 1-alkyl-7-bromo-5-(2-chlorophenyl)-1,2,4,5-tetrahydro-3H-1,4-benzodiazepin-2,3-diones, and 1-alkyl-7-bromo-5-(2-chlorophenyl)-3-hydroxy-1,2-dihydro-3H-1,4-benzodiazepin- 2-ones were obtained. Only the dione was formed in the case of hexyl tosylate. On alkylating with methyl tosylate only the 3-hydroxy derivative was formed. It was shown that at pH 14 the 1-cetyl and 1-dodecyl-3-hydroxy derivatives were completely converted into the corresponding diones. The molecular and crystal structures of the compounds were established by X-ray structural analysis.     

Synthesis of 2-(2′,3′-dihydroxypropyl)-5-amino-2H-1,2,4-thiadiazol-3-one and 3-(2′,3′-dihydroxypropyl)-5-amino-3H-1,3,4-thiadiazol-2-one

The synthesis of two new acyclic nucleoside analogs, 2-(2′,3′-dihydroxypropyl)-5-amino-2H-1,2,4-thiadiazol-3-one (1) and 3-(2′,3′-dihydroxypropyl)-5-amino-3H-1,3,4-thiadiazol-2-one (2), is reported. The first compound, 1, was obtained by reaction of 3-chloro-1,2-propanediol with the sodium salt of 5-amino-2H-1,2,4-thiadiazol-3-one (3) in anhydrous dimethylformamide. Similarly, 5-amino-3H-1,3,4-thiadiazol-2-one (4) reacted with 3-chloro-1,2-propanediol to give 2. The thiadiazole 4 was prepared by condensation-cyclization of hydrazothiodicarbonamide (9).     

Quinazolines and 1,4-benzodiazepines. XLVI. Photochemistry of nitrones and oxaziridines

The cyclic nitrones 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide ( 5a ) and 1,3-dihydro-7-methylthio-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide ( 5b ) are photoisomerized to readily isolable oxaziridines, 7-chloro-4,5-epoxy-5-phenyl-1,3,4–5-tetrahydro-2H-1,4-benzodiazepin-2-one ( 6a ) and 4,5-epoxy-5-phenyl-1,3,4,5-tetrahydro-7-methylthio-2H-1,4-benzo-diazepin-2-one ( 6b ). Oxaziridine 6b upon further irradiation gave ring expansion and ring contraction products, 4,6-dihydro-2-phenyl-9-methylthio-5H-1,3,6-benzoxadiazocin-5-one ( 7b ) and 4-benzoyl-3,4-dihydro-6-methylthioquinoxalin-2(1H)-one ( 8b ) respectively. The ring contraction product, 4-benzoyl-6-chloro-3,4-dihydroquinoxalin-2(1H)-one ( 8a ), was obtained from irradiation of oxaziridine 6a .     

Microbiological synthesis of 7-bromo-5-(o-chlorophenyl)-3-hydroxy-1,2-dihydro-3H-1,4-benzodiazepin-2-one by immobilized actinomycetes

It has been shown that the highest yields (15%) of 7-bromo-5-(o-chlorophenyl)-3-hydroxy-1,2-dihydro-3H-1,4-benzodiazepin-2-one are obtained by the use of the cells of actinomycetes immobilized in poly(vinyl alcohol) in the presence of the cosubstrate 7-bromo-5-(o-chlorophenyl)-3-methyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one.Physicochemical Institute, Academy of Sciences of the Ukrainian SSR, Odessa. Translated from Khimiya Prirodnykh Soedinenii, No. 6, pp. 779–783, November–December, 1981.     

1-(Organosulfonyloxy)-3(1H)-1,2-benziodoxoles: Preparation and Reactions with Alkynyltrimethylsilanes

Organosulfonyloxy derivatives of 1,2-benziodoxol-3(1H)-one (3a-c) and 3,3-bis(trifluoromethyl)-3(1H)-1,2-benziodoxole (5a-c) can be prepared in high yield by the reaction of 1-hydroxybenziodoxoles 1 or 4 and the corresponding sulfonic acids or Me(3)SiOTf in the form of stable, but moderately hygroscopic, microcrystalline solids. Reaction of the triflate derivatives 3a and 5a with alkynyltrimethylsilanes affords either alkynyliodonium triflates 6, or (E)-beta-(trifluoromethanesulfonyloxy)alkenyliodonium triflates 7, while the same reaction in the presence of pyridine selectively gives the respective 1-alkynylbenziodoxoles 8 and 9 in 82-90% yield.     

Synthesis of 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide

The reaction of methyl 2-bromo-6-(trifluoromethyl)-3-pyridinecarboxylate ( 1 ) with methanesulfonamide gave methyl 2-[(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridine-carboxylate ( 2 ). Alkylation of compound 2 with methyl iodide followed by cyclization of the resulting methyl 2-[methyl(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridinecarboxylate ( 3 ) yielded 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 4 ). The reaction of compound 4 with α,2,4-trichlorotoluene, methyl bromopropionate, methyl iodide, 3-trifluoromethylphenyl isocyanate, phenyl isocyanate and 2,4-dichloro-5-(2-propynyloxy)phenyl isothiocyanate gave, respectively, 4-[(2,4-dichlorophenyl)methoxy]-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazine 2,2-dioxide ( 5 ), methyl 2-[[1-methyl-2,2-dioxido-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4-yl]oxy]propanoate ( 6 ), 1,3,3-trimethyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 7 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-[3-(trifluoromethyl)phenyl]-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 8 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-phenyl-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 9 ) and N-[2,4-dichloro-5-(2-propynyloxy)phenyl]-4-hydroxy-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2] thiazine-3-carboxamide 2,2-dioxide ( 10 ).     

Novel pyrrolo[1,2-a][3.1.6]benzothiadiazocine ring synthesis. Unusual Truce-Smiles type rearrangement of 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfonyl(or sulfinyl)}acetone

Reaction of 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfonyl}acetone with sodium hydroxide with or without zinc gave 1-(2-nitrophenyl)(1H-pyrrol-2-ylsulfonyl)methane by a Truce-Smiles type of transformation and 1-(2-nitrophenyl)-2-methylsulfonylpyrrole by deacetylation. Similar treatment of 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfinyl}acetone gave only 1-(2-nitro-phenyl)(1H-pyrrol-2-ylsulfinyl)methane. 1-{[1-(2-Nitrophenyl)-1H-pyrrol-2-yl]sulfanyl}acetone, 2-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfanyl}-1-phenyl-ethan-1-one or 2-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfanyl}acetonitrile were reductively cyclised with sodium borohydride and 5% palladium-on-carbon into 6-methyl(or phenyl)-5,6-dihydro-7H-pyrrolo[1,2-a][3.1.6]benzothiadiazocin-7-ol or 6-amino-5H-pyrrolo[1,2-a][3.1.6]benzothiadiazocine-7-oxide, respectively.     

Reaction of perfluorinated 1-ethyl-, 1,1-diethyl-, and 1,2-diethylcyclobutabenzenes with pentafluorobenzene in SbF<Subscript>5</Subscript>

Perfluoro(1-ethyl-1,2-dihydrocyclobutabenzene) reacts with pentafluorobenzene in SbF5 to give perfluoro(1-ethyl-2-phenyl-1,2-dihydrocyclobutabenzene). Analogous reaction of a mixture of perfluoro(1,1-diethyl-1,2-dihydrocyclobutabenzene) and perfluoro(1,2-diethyl-1,2-dihydrocyclobutabenzene) leads to the formation (after hydrolysis of the reaction mixture) of perfluorinated 7-phenyl-8,8-diethylbicyclo[4.2.0]octa-1,4,6-trien-3-one, 1,1-diethyl-2-(4-oxocyclohexa-2,5-dienylidene)-1,2-dihydrocyclobutabenzene, and 2-(pent-2-en-3-yl)benzophenone (from the 1,1-isomer) and perfluorinated (E)-1,2-diethyl-1-phenyl-1,2-dihydrocyclobutabenzene, 7,8-diethyl-8-phenylbicyclo[4.2.0]octa-1,4,6-trien-3-one, and 1-[2-(1-phenylprop-1-en-1-yl)-phenyl]propan-1-one (from the 1,2-isomer).