5a-Carba-β-D-, 5a-Carba-β-L- and 5-Thio-β-L-xylopyranosides as New Orally Active Venous Antithrombotic Agents

Mitsunobu displacement of (−)-(1S,4R,5S,6S)-4,5,6-tris{[(tert-butyl)dimethylsilyl]oxy}cyclohex-2-en-1-ol ((−)- 12 ; a (−)-conduritol-F derivative) with 4-ethyl-7-hydroxy-2H-1-benzopyran-2-one ( 16 ) provided a 5a-carba-β-D -pyranoside (+)- 17 that was converted into (+)-4-ethyl-7-[(1′R,4′R,5′S,6′R)-4′,5′,6′-trihydroxycyclohex-2′-en-1′-yloxy]-2H-1-benzopyran-2-one ((+)- 5 ) and (+)-4-ethyl-7-[(1′R,2′R,3′S,4′R)-2′,3′,4′-trihydroxycyclohexyloxy]-2H-1-benzopyran-2-one ((+)- 6 ). The 5a-carba-β-D -xyloside (+)- 6 was an orally active antithrombotic agent in the rat (venous Wessler's test), but less active than racemic carba-β-xylosides (±)- 5 and (±)- 6 . The 5a-carba-β-L -xyloside (−)- 6 was derived from the enantiomer (+)- 12 and found to be at least 4 times as active as (+)- 6 . (+)-4-Cyanophenyl 5-thio-β-L -xylopyranoside ((+)- 3 ) was synthesized from L -xylose and found to maintain ca. 50% of the antithrombotic activity of its D -enantiomer. Compounds (±)- 5 , (±)- 6 , and (−)- 6 are in vitro substrates for galactosyltransferase 1.     

Substituted γ-Lactones. 35 . Reduction of 4-aroyl-3-hydroxy-2(5H)-furanones

The reduction of 4-aroyl-3-hydroxy-2(5H)-furanons 1a-c was investigated using different reducing agents. Sodium borohydride reacts with type 1 compounds by loss of water to yield 4-(arylmethylene)-2,3(4H,5H)-furandiones 2a-c . Platinum or charcoal supported by pallodium chloride transforms 1a to 4-benzyl-3-hydroxy-2(5H)-furanone ( 3). Compounds 2a and 2b react with o-phenylenediamine to give 3-(E-(1′-hydroxymethyl-2′-aryl)ethenyl]-2-quinoxalinones 4a and 4b . The lactone 3 under the same conditions splits out formaldehyde and forms 3-(2′-phenylethyl)-2-quinoxalinone ( 6 ). The structure assignments of the novel compounds are based on elemental analysis and nmr as well as ir spectroscopic data.     

Muricatetrocins A and B and Gigantetrocin B: Three New Cytotoxic Monotetrahydrofuran-Ring Acetogenins from Annona muricata

Extracts from the seeds of Annona muricata yielded three new Annonaceous acetogenins: muricatetrocin A (= (5S)-3-{(2R)-2-hydroxy-9-{(2R,5S)-tetrahydro-5-[(1S,4S,5S)-1,4,5-trihydroxyheptadecyl]furan-2-yl}nonyl}-5-methylfuran-2(5H)-one; 1 ), muricatetrocin B (= (5S)-{(2R)-2-hydroxy-9-{(2S,5S)-tetrahydro-5-[(1S,4S,5S)-1,4,5-trihydroxyheptadecyl]furan-2-yl}nonyl}-5-methylfuran-2(5H)-one; 2 ), and gigantetrocin B (= (5S)-3-{(2R)-2-hydroxy-7-{(2S,5S)-tetrahydro-5-[(1S,4R,5R)-1,4,5-trihydroxynonadecyl]furan-2-yl}heptyl}-5-methyl-furan-2(5H)-one; 3 ). Their C-skeletons were deduced by mass spectrometry. Configurations were determined by ¹H-NMR of ketal derivatives and 2D-NMR experiments utilizing Mosher esters. A previously described compound, gigantetrocin A (= (5S)-3-{(2R)-2-hydroxy-7-{(2S,5S)-tetrahydro-5-[(1S,4S,5S)-1,4,5-trihydroxynonadecyl]furan-2-yl}heptyl}-5-methylfuran-2-(5H)one; 4 ), was also isolated and is new to this species. Compounds 1–4 were all selectively cytotoxic for the HT-29 human colon-tumor cell line with potencies at least 10 times that of adriamycin.     

Synthesis of the (2<Emphasis Type="Italic">S</Emphasis>,4<Emphasis Type="Italic">S</Emphasis>)-stereoisomers of 4-(indol-1-yl) and 4-arylamino derivatives of 5-oxoproline,proline, and 2-hydroxymethylpyrrolidine

Nucleophilic substitution of the halogen atom in dimethyl (S)-4-bromoglutamate followed by removal of the protecting groups and closure of a lactam ring afforded (2S,4S)-4-(indolin-1-yl)-5-oxoproline. The indoline fragment was oxidized into the indole fragment to give (2S,4S)-4-(indol-1-yl)-5-oxoproline; reduction of the carbonyl groups with BH3 yielded (2S,4S)-4-(indol-1-yl)prolines and (2S,4S)-2-hydroxymethyl-4-(indol-1-yl)pyrrolidines. Reduction of (2S,4S)-4-arylamino-5-oxoprolines with BH3 to the corresponding (2S,4S)-4-arylaminoprolines and (2S,4S)-4-arylamino-2-hydroxymethylpyrrolidines was studied.     

Chiral [2H]-Labelled Methylene Groups in Trienoic- and Dienoic Fatty Acids: A Facile Approach via Asymmetric Epoxidation of [2H] Allyl Alcohols

Chiral [²H] -labelled methylene groups flanked by two double bonds within (poly)unsaturated fatty acids are readily available from trans-2,3-epoxy[2,3-²H₂] alk-4-yn-l-ols, obtained in their turn by asymmetric epoxidation of the corresponding (E)-[2,3-²H₂] alk-2-en-4-yn-l-ols (see Scheme 3). The procedure is exemplified for (8S,3Z,6Z,9Z)-[7,8-²H₂] trideca-3,6,9-trienoic acid ((8S)- 11 ) and (8R)- 11 (Scheme 4) as well as for (5S,3Z,6Z)-[4,5^?2H₂]deca-3,6-dienoic acid ((5S)- 13 ) and (5R)- 13 (Scheme 5).     

Total Asymmetric Synthesis of Doubly Branched Carba-hexopyranoses and Amino Derivatives Starting from the Diels-Alder Adducts of Maleic Anhydride to Furfuryl Esters

The Diels-Alder adducts of maleic anhydride to furfuryl esters were reduced into 7-oxabicyclo[2.2.1]hept-5-ene-1,2-exo,3-exo-trimethanol (±)- 15 and enantiomerically pure (−)- 15 (Scheme 1). The tripivalate of (±)- 15 was converted into (1RS,2RS,3RS,4RS,5SR,6SR)-1,5,6-tris(hydroxymethyl)cyclohexane-1,2,3,4-tetrol ((±)- 23 ; Scheme 2). Reaction of BBr₃ with the triacetate (±)- 30 of (±)- 15 gave (1RS,2RS,5RS,6RS)-5-bromo-6-hydroxycyclohex-3-ene-1,2,3-trimethyl triacetate ((±)- 31 ) at −78°, and (1RS,2RS,5SR,8SR)-2-endo-hydroxy-6-oxabicylo[3.2.1]oct-3-ene-5,8-dimethyl diacetate ((±)- 32 ) at 0° (Scheme 3). Single-crystal X-ray diffraction of (1RS,2RS,5SR,8SR)-2-acetoxy-6-oxabicyclo[3.2.1]oct-3-ene-5,8-dimethyl diacetate ((±)- 33 ) was carried out. Displacement of bromide (+)- 31 (derived from (−)- 15 ) with azide anion gave (+)- 38 which was transformed into (+)-(1R,2R,5S,6S)-5-amino-6-hydroxycyclohex-3-ene-1,2,3-trimethanol ((+)- 40 ) (Scheme 4). Reaction of (±)- 31 with BBr₃ at 0°, followed by azide disubstitution led to (1RS,2RS,5SR,6SR)-5-amino-3-(aminomethyl)-6-hydroxycyclohex-3-ene-1,2-dimethanol ((±)- 45 ). Dihydroxylation of (±)- 38 and further transformations gave (1RS,2RS,3SR,4RS,5SR,6RS)-5-amino-1,4,6-trihydroxycyclohexane-1,2,3-trimethanol ((±)- 49 ) and (1RS,2RS,3SR,4RS,5SR,6RS)-2,3-dihydroxy-7-oxabicyclo[4.1.0]heptane-2,3,4-trimethanol ((±)- 55 ) (Schemes 5 and 6). Expoxidation of the 4-nitrobenzoate (±)- 61 of (±)- 38 allowed the preparation of (1RS,2RS,3SR,4RS,5RS)-5-amino-1,4-dihydroxycyclohexane-1,2,3-trimethanol ((±)- 65 ) and of (1RS,2RS,3SR,4RS,5SR,6RS)-5-amino-4-hydroxy-7-oxabicyclo[4.1.0]heptane-1,2,3-trimethanol ((±)- 67 ) (Scheme 7). The new unprotected polyols and aminopolyols were tested for their inhibitory activity toward commercially available glycohydrolases. At 1 mM concentration, 34, 30, and 31% inhibition of β-galactosidase from bovine liver was observed for (+)- 40 , (±)- 65 , and (±)- 67 , respectively.     

Synthesis of 2′-deoxyribofuranosyl indole nucleosides related to the antibiotics SF-2140 and neosidomycin

The 2′-deoxyribofuranose analog of the naturally occurring antibiotics SF-2140 and neosidomycin were prepared by the direct glycosylation of the sodium salts of the appropriate indole derivatives, with 1-chloro-2- deoxy-3,5-di-O-p-toluoyl-α-D-erythropentofuranose ( 5 ). Thus, treatment of the sodium salt of 4-methoxy-1H- indol-3-ylacetonitrile ( 4a ) with 5 provided the blocked nucleoside, 4-methoxy-1-(2-deoxy-3,5-di-O-p-toluoyl-β- D-erythropentofuranosyl)-1H-indol-3-ylacetonitrile ( 6a ), which was treated with sodium methoxide to yield the SF-2140 analog, 4-methoxy-1-(2-deoxy-β-D-erythropentofuranosyl)-1H-indol-3- ylacetonitrile ( 7a ). The neosidomycin analog ( 8 ) was prepared by treatment of the sodium salt of 1H-indol-3-ylacetonitrile ( 4b ) with 5 to obtain the blocked intermediate 1-(2-deoxy-3,5-di-O-p-toluoyl-β-D-erythropentofuranosyl) ?1H-indol-3-ylace-tonitrile ( 6b ) followed by sodium methoxide treatment to give 1-(2-deoxy-β-D-erythropentofuranosyl)-1H- indol-3-ylacetonitrile ( 7b ) and finally conversion of the nitrile function of 7b to provide 1-(2-deoxy-β-D- erythropentofuranosyl)-1H-indol-3-ylacetamide ( 8 ). In a similar manner, indole ( 9a ) and several other substituted indoles including 1H-indole-4-carbonitrile ( 9b ), 4-nitro-1H-indole ( 9c ), 4-chloro-1H-indole-2-carboxamide ( 9d ) and 4-chloro-1H-indole-2-carbonitrile ( 9e ) were each glycosylated and deprotected to provide 1-(2-deoxy-β-D-erythropentofuranosyl)-1H-indole ( 11a ), 1-(2-deoxy-β-D-erythropentofuranosyl)-1H-indole-4- carbonitrile ( 11b ), 4-nitro-1-(2-deoxy-β-D-erythropentofuranosyl)-1H-indole ( 11c ), 4-chloro-1-(2-deoxy-β-D- erythropentofuranosyl)-1H-indole-2-carboxamide ( 11d ) and 4-chloro-1-(2-deoxy-β-D-erythropentofuranosyl)- 1H-indole-2-carbonitrile ( 11e ), respectively. The 2′-deoxyadenosine analog in the indole ring system was prepared for the first time by reduction of the nitro group of 11c using palladium on carbon thus providing 4-amino-1-(2-deoxy-β-D-erythropentofuranosyl)- 1H-indole ( 16 , 1,3,7-trideaza-2′-deoxyadenosine).     

Eine überraschende Ringerweiterung von 3-(Dimethylamino)-2,2-dimethyl-2H-azirin zu 4,5-Dihydropyridin-2(3H)-on-Derivaten

An Unexpected Ring Enlargement of 3-(Dimethylamino)-2,2-dimethyl-2H-azirine to 4,5-Dihydropyridin-2(3H)-one Derivatives The reaction of 3-(dimethylamino)-2,2-dimethyl-2H-azirine ( 1a ) and 4,4-disubstituted 2-(trifluoromethyl)-1,3-oxazol-5(4H)-ones 7 in MeCN at 70° afforded 5-(dimethylamino)-3,6-dihydropyrazin-2(1H)-ones 10 (Scheme 4), whereas no reaction could be observed between 1a and 2-allyl-4-phenyl-2-(trifluoromethyl)-1,3-oxazol-5(2H)-one ( 8a ) or 4,4-dibenzyl-2-phenyl-1,3-oxazol-5(4H)-one ( 9 ). The formation of 10 is rationalized by a mechanism via nucleophilic attack of 1a onto 7 . The failure of a reaction with 9 shows that only activated 1,3-oxazol-5(4H)-ones bearing electron-withdrawing substituents do react as electrophiles with 1a . The amino-azirine 1a and 2,4-disubstituted 1,3-oxazol-5(4H)-ones 2b – e in refluxing MeCN undergo a novel ring enlargement to 4,5-dihydropyridin-2(3H)-ones 11 (Scheme 5). Several side products were observed in these reactions. Two different reaction mechanisms for the formation of 11 are proposed: either 1a undergoes a nucleophilic addition onto the open-chain ketene tautomer of 2 (Scheme 6), or 2 reacts as CH-acidic compound (Scheme 7).     

Bildung von 5,6-Dihydro-1,3(4H)-thiazin-4-carbonsäure-estern aus 4-Allyl-1,3-thiazol-5(4H)-onen

Formation of Methyl 5,6-Dihydro-l, 3(4H)-thiazine-4-carboxyiates from 4-Allyl-l, 3-thiazol-5(4H)-ones . The reaction of N-[1-(N, N-dimethylthiocarbamoyl)-1-methyl-3-butenyl]benzamid ( 1 ) with HCl or TsOH in MeCN or toluene yields a mixture of 4-allyl-4-methyl-2-phenyl-1,3-thiazol-5(4H)-one ( 5a ) and allyl 4-methyl-2-phenyl-1,3-thiazol-2-yl sulfide ( 11 ; Scheme 3). Most probably, the corresponding 1,3-oxazol-5(4H)-thiones B are intermediates in this reaction. With HCl in MeOH, 1 is transformed into methyl 5,6-dihydro-4,6-dimethyl-2-phenyl-1,3(4H)-thiazine-4-carboxylate ( 12a ). The same product 12a is formed on treatment of the 1,3-thiazol-5(4H)-one 5a with HCl in MeOH (Scheme 4). It is shown that the latter reaction type is common for 4-allyl-substituted 1,3-thiazol-5(4H)-ones.     

Stereoselective Synthesis of 2,4,6-Trimethylcyclohex-4-ene-1,3-diol Derivatives and of polypropionate fragments with four contiguous stereogenic centers

The Diels-Alder adduct (±)- 3 of 2,4-dimethylfuran and 1-cyanovinyl acetate was converted stereoselectively into benzyl 6-(4-chlorophenylsulfonyl)-1,3-exo,5-trimethyl-7-oxabicyclo[2.2.1]hept-5-en-2-exo-yl ( 26 ) and -2-endo-yl ether ( 36 ). Addition of LiAlH₄ to the latter led to the 3-O-benzyl derivatives 28 and 37 of (1RS,2SR,3SR,6SR)- and (1RS,2SR,3RS,6SR)-5-(4-chlorophenylsulfonyl)-2,4,6-trimethylcyclohex-4-ene-1,3-diol, respectively. Methylenation of 6-exo-(4-chlorophenylthio)-1-methyl-5-methylidene-7-oxabicyclo[2.2.1]heptan-2-one ( 16 ), obtained by reaction of (±)- 3 with 4-Cl-C₆H₄SCl and saponification gave, 6-exo-(4-chlorophenylthio)-1-methyl-3,5-dimethylidene-7-oxabicyclo [2.2.1]heptan-2-one ( 43 ), the reduction of which with K-Selectride afforded 6-exo-(4-chlorophenylthio)-1,3-endo-dimethyl-5-methylidene-7-oxabicyclo[2.2.1]heptan-2-endo-ol ( 44 ). The 3-O-benzyl derivative 48 of (1RS,2RS,3RS,6SR)-5-(4-chlorophenylsulfonyl)- 2,4,6-trimethylcyclohex-4-ene-1,3-diol was derived from 44 via based-induced oxa-ring opening of benzyl 6-endo-(4-chlorophenylsulfonyl)-1,3-endo-5-endo-trimethyl-7-oxabicyclo[2.2.1]hept-2-endo-yl ether ( 49 ). Benzylation of 28 , followed by reductive desulfonylation and oxidative cleavage of the cyclohexene moiety afforded (2RS,3SR,4RS,5RS)-3,5-bis(benzyloxy)-2,4-dimethyl-6-oxoheptanal ( 32 ).     

Synthesis of isomeric 2-oxazolidinones from (1<Emphasis Type="Italic">R</Emphasis>,2<Emphasis Type="Italic">R</Emphasis>)-and (1<Emphasis Type="Italic">S</Emphasis>,2<Emphasis Type="Italic">S</Emphasis>)-2-amino-1-(4-nitrophenyl)-1,3-propanediols

A synthesis is reported for (4R,5R)-and (4S,5S)-4-hydroxymethyl-5-(4-nitrophenyl)oxazolidin-2-ones and (1′R,4R)-and (1′S,4S)-4-[hydroxy(4-nitrophenyl)methyl]oxazolidin-2-ones from (1R,2R)-and (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediols. The effect of the experimental conditions on the formation of these compounds was studied. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1562–1570, October, 2007.     

Borohydride reduction of acetophenone and esters of dehydrocarboxylic acids in the presence of chiral cobalt(<Emphasis Type="SmallCaps">II</Emphasis>) diamine complexes

The catalytic reduction of acetophenone, methyl α-acetamidocinnamate, and dimethyl itaconate with alcohol-modified sodium borohydride was studied in the presence of complexes CoCl₂·L₂ (L₂ are chiral C ₂-symmetric diamines: (4S,5S)-2,2-dimethyl-4,5-bis(aminomethyl)-1,3-dioxolane, (4S, 5S)-2,2-dimethyl-4,5-bis(methylaminomethyl)-1,3-dioxolane, (4S, 5S)-2,2-dimethyl-4,5-bis(dimethylaminomethyl)-1,3-dioxolane, and (4S, 5S)-2,2-dimethyl-4,5-bis(diphenylaminomethyl)-1,3-dioxolane). The maximum enantiomeric excess of (S)-1-phenylethanol was 24%, that of dimethyl α-methylsuccinate was 38%.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 342–347, February, 2005.     

Synthese von 4-Benzylthio- und 4-(Arylthio)-1,3-oxazol-5(2H)-onen

Synthesis of 4-(Benzylthio)-and 4-(Arylthio)-1,3-oxazole-5(2H)-ones Following a known procedure, 4-(benzylthio)-1,3-oxazol-5(2H)-one ( 4a ) was synthesized starting from sodium cyanodithioformate ( 1 ) and cyclohexanone (Scheme 1). The structure of the intermediate 4-(benzylthio)-1,3-thiazol-5(2H)-one ( 3a ) was established by X-ray crystallography. An alternative route was developed for the synthesis of 4-(arylthio)-1,3-oxazol-5(2H)-ones which are not accessible by the former reaction. Treatment of ethyl cyanoformate ( 5 ) with a thiophenol in the presence of catalytic amounts of Et₂NH and TiCl₄, followed by addition of a ketone and BF₃.Et₂O in a one-pot-reaction, gave 4f–i in low-to-fair yields (Scheme 3). Both synthetic pathways-complementary as for benzyl–S and aryl-S derivatives–seem to be limited with respect to variation of substituents of the ketone.     

A simple and efficient approach for the synthesis of a novel class aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives via intramolecular nucleophilic substitution reaction

In this study, we synthesized a new series of substituted aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives (6-24) in yields ranging from 42 to 70% with an interesting mechanism that involves internal nucleophilic substitution followed by an S_N2-type nucleophilic substitution. First, 1-(4-chlorophenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanone (3) was synthesized from the reaction of 5-methyl-1,3,4-thiadiazole-2-thiol (1) with 2-bromo-1-(4-chlorophenyl)ethanone (2) in the presence of potassium hydroxide. Then, 1-(4-chlorophenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanol (4) was synthesized by a reduction reaction of this compound using NaBH₄. Finally, 5-methyl-3-alkyl-1,3,4-thiadiazol-2(3H)-one derivatives (6-24), which are the target compounds, were synthesized from the reaction of this compound (4), which is a secondary alcohol with various alkyl halides (5a-n) in the presence of sodium hydride (NaH). This study presents an interesting reaction mechanism related to the synthesis of aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives that is not recorded in the literature.     

Synthesis of (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles

Abstract  

An efficient synthesis method for the preparation of a series of new (Z)- and (E)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles was developed. The reaction of (Z)- and (E)-3-styrylchromones with hydrazine hydrate afforded the corresponding (Z)- and (E)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles, except for nitro derivatives, where both (Z)- and (E)-4′-nitro-3-styrylchromones afforded (E)-3(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)pyrazoles. The reaction mechanism for these transformations is discussed and the stereochemistries of all products were established by NMR experiments.     

New Furano-sesquiterpenoids from Mediterranean Sponges

A mixture of sponges of the East Pyrenean Mediterranean is shown to contain the known sponge products longifolin ( 1 ), avarol ((+)- 3 ), and avarone ( 4 ) and the terrestrial-plant product sesquirosefuran ( 2 ), besides to the new furano-sesquiterpenoids tavacfuran (= 3-methyl-2-[(3′Z)-3′-methyl-4″-methyl-2″-furyl-3′-butenyl]furan; ( 5 ) and tavacpallescensin (= 5,10-dihydro-6,9-dimethyl-4H-benzo[5,6]cyclohepta[1,2-b]furan; 6 ) and the new furano-butenolide sesquiterpenoids tavacbutenolide-1 (= (±-4-ethoxy-2-methyl-4-)[(2′E)-2′-methyl-4′-(3″-methyl-2″-furyl)-2′-butenyl]-2-buten-4-olide; (±)- 7 ) and tavacbutenolide-2 (= (±)-4-ethoxy-3-methyl-4-[2′E)-3′-methyl-4′-(4″-methyl-2″-furyl)-2′-butenyl]-2-buten-4-olide; (±)- 8 ). Structural assignments are based on NMR data and on the synthesis of the (E)-isomer of 5 . The sponge Dysidea tupha of the same area is also shown to contain the two sesquiterpenoids ent-furodysinin ((?)- 14 ), which is enantiomeric to a product of a Dysidea sp. of Australian waters, and tuphabutenolide ((+)- 15 ).     

Synthesis and antimicrobial testing of 2-amino-6-hydroxymethyl-4-(3H)pyrido[3,2-d]pyrimidinone

Synthesis of 2-amino-6-hydroxymethyl-4-(3H)pyrido[3,2-d]pyrimidinone ( 5 ) from 2-amino-6-methyl-4-(3H)-pyrido[3,2-d]pyrimidinone ( 2 ) was accomplished by selenium dioxide oxidation of 2 to the aldehyde 4 followed by sodium borohydride reduction. Compound 2 was available in four steps from 5-aminouracil or in two steps from 5-nitroisocytosine ( 3a ). Catalytic reduction of 4 or 5 gave a mixture of 2-amino-6-methyl-5,6,7,8-tetrahydro-4-(3H)pyrido[3,2-d]pyrimidinone ( 6a ) and the 6-hydroxymethyl compound 6b . These compounds showed only weak inhibitory activity in the coupled reactions catalyzed by 7,8-dihydro-6-hydroxymethylpterin pyrophosphokinase and 7,8-dihydropteroate synthetase from E. Coli. No significant antibacterial activity was observed.     

Synthesis of 2-(β-D-ribofuranosyl)[1,3,5]triazines

The synthesis of the first [1,3,5]triazine carbon linked nucleosides are reported. 4-Amino-6-(β-D-ribofuranosyl)[1,3,5]triazin-2(1H)-one ( 8 ), an analog of 5-azacytidine and pseudoisocytidine was prepared. 2,5-Anhydro-D-allonamidine hydrochloride ( 3 ) was condensed with dimethyl cyanoiminodithiocarbonate ( 4 ) to give 4-methylthio-6-(β-D-ribofuranosyl)[1,3,5]triazin-2-amine ( 5 ). Compound 5 was reacted with m-chloroperbenzoic acid to give 4-methylsulfinyl-6-(β-D-ribofuranosyl)[1,3,5]triazin-2-amine ( 6 ). Displacement of the methyl sulfinyl with the appropriate nucleophile gave 6-(β-D-ribofuranosyl)[1,3,5]triazine-2,4-diamine ( 7 ), 4-amino-6-(β-D-ribofuranosyl)[1,3,5]triazin-2(1H)-one ( 8 ), and 4-amino-6-(β-D-ribofuranosyl)[1,3,5]triazine-2(1H)-thione ( 9 ). Dethiation of compound 5 with Raney nickel gave 4-(β-D-ribofuranosyl)[1,3,5]triazin-2-amine ( 10 ). The crystal structure of 7 was determined by single crystal X-ray.     

A facile and novel synthesis of 1,6-naphthyridin-2(1H)-ones

A new and convenient procedure for the synthesis of 1,6-naphthyridin-2(1H)-ones and their derivatives is described. In the first scheme 5-acetyl-6-[2-(dimethylamino)ethenyl]-1,2-dihydro-2-oxo-3-pyridinecarbonitrile ( 4 ) obtained by the reaction of N,N-dimethylformamide dimethyl acetal with 5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile ( 3 ) was cyclized to 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile ( 5 ) by the action of ammonium acetate. Thermal decarboxylation of acid 7 obtained from the hydrolysis of nitrile 5 led to a mixture of 5-methyl-1,6-naphthyridin-2(1H)-one ( 8 ) and its dimer 9 . Hydrazide 11 obtained from nitrile 5 in two steps was converted to 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one ( 12 ) by the Curtius rearrangement. The amino group of 12 was readily replaced by treatment with aqueous sodium hydroxide to yield 3-hydroxy-5-methyl-1,6-naphthyridin-2(1H)-one ( 13 ). In the second scheme, Michael reaction of enamines of type 20 with methyl propiolate, followed by ring closure gave 5-acyl(aroyl)-6-methyl-2(1H)-pyridinones ( 21 ) which in turn were treated with Bredereck's reagent to produce 5-acyl(aroyl)-6-[2-(dimethylamino)ethenyl]-2(1H)-pyridinones ( 22 ). Treatment of 22 with ammonium acetate led to the formation of 1,6-naphthyridin-2(1H)-ones 23 .     

Synthesis of (+)-1,3:2,5-dianhydroviburnitol ((+)-(1R,2R,3S,5R,6S)-4,7-dioxatricyclo[3.2.1.03,6]octan-2-ol)

Epoxidation of (?)-(1R,2R,4R)-2-endo-cyano-7-oxabicyclo[2.2.1]hept-5-en-2-exo-yl acetate ((?)-5) followed by saponification afforded (+)-(1R,4R,5R,6R)-5,6-exo-epoxy-7-oxabicyclo[2.2.1]heptan-2-one ((+)-7). Reduction of (+)-7 with diisobutylaluminium hydride (DIBAH) gave (+)-1,3:2,5-dianhydroviburnitol ( = (+)-(1R,2R,3S,4R,6S)-4,7-dioxatricyclo[3.2.1.0^3,6]octan-2-ol; (+)-3). Hydride reductions of (±)-7 were less exo-face selective than reductions of bicyclo[2.2.1]heptan-2-one and its derivatives with NaBH₄, AlH₃, and LiAlH₄ probably because of smaller steric hindrance to endo-face hydride attack when C(5) and C(6) of the bicyclo-[2.2.1]heptan-2-one are part of an exo oxirane ring.