Syntheses and Reactions of 1′,2′-Unsaturated 2′,3′-Seconucleoside Analogues

The 1′,2′-unsaturated 2′,3′-secoadenosine and 2′,3′-secouridine analogues were synthesized by the regioselective elimination of the corresponding 2′,3′-ditosylates, 2 and 18 , respectively, under basic conditions. The observed regioselectivity may be explained by the higher acidity and, hence, preferential elimination of the anomeric H–C(1′) in comparison to H? C(4′). The retained (tol-4-yl)sulfonyloxy group at C(3′) of 3 allowed the preparation of the 3′-azido, 3′-chloro, and 3′-hydroxy derivatives 5–7 by nucleophilic substitution. ZnBr₂ in dry CH₂Cl₂ was found to be successful in the removal (85%) of the trityl group without any cleavage of the acid-sensitive, ketene-derived N,O-ketal function. In the uridine series, base-promoted regioselective elimination (→ 19 ), nucleophilic displacement of the tosyl group by azide (→ 20 ), and debenzylation of the protected N(3)-imide function gave 1′,2′-unsaturated 5′-O-trityl-3′-azido-secouridine derivative 21 . The same compound was also obtained by the elimination performed on 2,2′-anhydro-3′-azido-3′-azido-3′-deoxy-5′-O-2′,3′-secouridine ( 22 ) that reacted with KO(t-Bu) under opening of the oxazole ring and double-bond formation at C(1′).     

5-(α-Fluorovinyl)tryptamines and 5-(α-Fluorovinyl)-3-(N-methyl-1′,2′,5′,6′,-tetrahydropyridin-3′- and -4′-yl)indoles—5-(α-Fluorovinyl)tryptamines

5-(α-Fluorovinyl)tryptamines 4a, 4b and 5-(α-fluorovinyl)-3-(N-methyl-1′,2′,5′,6′-tetrahydropyridin-3′- and -4′-yl) indoles 5a, 5b were synthesized using 5-(α-fluorovinyl)indole ( 7 ). The target compounds are bioisosteres of 5-carboxyamido substituted tryptamines and their tetrahydropyridyl analogs.     

Synthesis of 5-benzyl and 5-benzyloxybenzyl-3′-azido-2′,3′-dideoxyuridine and their analogues as potential anti-AIDS agents

5-Benzyl and 5-benzyloxybenzyl-substituted 3′-azido-2′,3′-dideoxyuridine, ( 8a and 8b ), 3′-halogeno-2′,3′-dideoxyuridine, 9a, 9b, 10a, 10b, 11a and 11b , and 2′,3′-dideoxyuridine, 12a and 12b , of Scheme I were synthesized as potential anti AIDS agents. Synthesis of epimers of 8a and 8b , 5-benzyl- and 5-benzyloxybenzyl-1-(3′-azido-2′,3′-dideoxy-β-D-threo-pentafuranosyl)uracil, 15a and 15b , and 5-benzyl- and 5-benzyloxy-5′-azido-2′,5′-dideoxyuridine, 16a and 16b , shown in Scheme II, were also reported.     

New heterocyclic derivatives of 1′- and 3′-amino-5′,6′,7′,8′-tetrahydro-2′-acetonaphthones

The preparation of 1′-and 3′-amino-5′,6′,7′,8′-tetrahydro-2′-acetonaphthones (IIIa and IIIb) is described, by reduction of the low temperature nitration products of 5′,6′,7′,8′-tetrahydro-2′-acetonaphtone (I). The structures of the nitro isomers (IIa and IIb), and the reduction products, IIIa and IIIb, were elucidated spectroscopically. By known reactions, a series of new heterocyclic compounds prepared from the o-aminoketones, IIIa and IIIb, resulted in two series of new heterocyclic compounds.     

Saturated heterocycles. 242. Synthesis of 2-substituted-6-(6′,7′-dimethoxy-3′,4′-dihydro-1′-isoquinolyl)-5,6,7,8-tetrahydro- quinazolin-4(3H)-one Derivatives

In the reactions of the recently synthesized β-ketoesters 1-[(3′-methoxycarbonyl- and 1-[(3′-ethoxycarbonyl-4′-oxo)-1′-cyclohexyl]-3,4-dihydroisoquinoline 4, 5 with amidines or cyclic guanidines, a number of 2-substituted-6-(6′,7′-dimethoxy-3′,4′-dihydro-1′-isoquinolyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one derivatives 6–8 were prepared. The new compounds possess various pharmacological actions.     

The structure of new cis and trans 3′-phenyl-3′,3a′,4′,5′,6′,7a′-hexahydro-2,1-benzisoxazole-7a′-spiro-2-(3-phenylaziridine)

The reaction of dibenzalcyclohexanone with hydroxylamine hydrochloride afforded three compounds 1–3 including the aziridine 3 showing a 3′,3a′-trans configuration. Now we report on the isolation of a new aziridine 4 , possessing a 3′,3a′-cis configuration. Its structure was deduced by 2D nmr and single crystal X-ray diffraction studies.     

A method for the synthesis of racemic and optically active 2-substituted 9-(2′,3′-dihydroxypropyl)-8-azahypoxanthines and 8-azaadenines

Several 9-(2′,3′-O-isopropylidene)- and 9-(2′,3′-dihydroxypropyl)-8-azahypoxanthines and 8-azaadenines were synthesized by a “one pot” method starting from the acetonide of racemic or (S)-1-azido-2,3-dihydroxypropane, obtained from D-mannitol. 9-(2′,3′-Dihydroxypropyl)-8-azapurines were tested as adenosine deaminase inhibitors.     

Angiotensin-II Analogues. I: Synthesis and incorporation of the halogenated amino acids 3-(4′-iodophenyl)alanine, 3-(3′,5′-dibromo-4′-chlorophenyl)alanine, 3-(3′,4′,5′-tribromophenyl)alanine,and 3-(2′,3′,4′,5′,6′-pentabromophenyl)alanine

The synthesis of the polyhalogenated phenylalanines Phe(3′,4′,5′-Br₃) ( 3 ), Phe(3′,5′-Br₂-4′-Cl) ( 4 ) and DL -Phe (2′,3′,4′,5′,6′-Br₅) ( 9 ) is described. The trihalogenated phenylalanines 3 and 4 are obtained stereospecifically from Phe(4′-NH₂) by electrophilic bromination followed by Sandmeyer reaction. The most hydrophobic amino acid 9 is synthesized from pentabromobenzyl bromide and a glycine analogue by phase-transfer catalysis. With the amino acids 4, 9 , Phe(4′-I) and D -Phe, analogues of [1-sarcosin]angiotensin II ([Sar¹]AT) are produced for structure-activity studies and tritium incorporation. The diastereomeric pentabromo peptides L - and D - 13 are separated by HPLC. and identified by catalytic dehalogenation and comparison to [Sar¹]AT ( 10 ) and [Sar¹, D -Phe⁸]AT ( 14 ).     

Synthesis and Properties of 2′-Deoxy-1′,2′-seco-D-ribosyl (5′ → 3′)oligonucleotides (= 1′,2′-seco-DNA) containing adenine and thymine

Some 2′-deoxy-1′,2′-seco-D-ribosyl (5′→3′)oligonucleotides (= 1′,2′-seco-DNA), differing from natural DNA only by a bond scission between the centers C(1′) and C(2′), were synthesized and studied in order to compare their structure properties and pairing behavior with those of corresponding natural DNA and homo-DNA oligonucleotides (2′,3′-dideoxy-β-D-glucopyranosyl oligonucleotides). Starting from (?)-D-tartaric acid, 2′-deoxy-1′,2′-secoadenosine derivative 9a and 1′,2′-secothymidine ( 9b ) were obtained in pure crystalline form. Using the phosphoramidite variant of the phosphite-triester method, a dinucleotide monophosphate 1′,2′-seco-d(T₂) was synthesized in solution, while oligonucleotides 1′,2′-seco-d[(AT)₆], 1′,2′-seco-d(A₁₀) and 1′,2′-seco-d(T₁₀) were prepared on solid phase with either automated or manual techniques. Results of UV- and CD-spectroscopic as well as gel-electrophoretic studies indicated that neither adenine-thymine base pairing (as observed in natural DNA and homo-DNA), nor the adenine-adenine base pairing (as observed in homo-DNA) was effective in 1′,2′-seco-DNA, Furthermore, hybrid pairing was observed neither between 1′.2′-seco-DNA and natural DNA nor between 1′,2′-seco-DNA and homo-DNA.     

1,1-Disubstituted-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolecarboxylic acid esters and ketones. The base catalyzed transformation of 1-(2′,3′,4′,9′-tetrahydrospiro[cyclohexane-1,1′-[1H]pyrido[3,4-b]indol]-2-yl)alkanones into 2-(4,9-dihydro-3H-pyrido[3,4-b]indol-1-yl)-1 -alkylcyclohexanols

Condensation of 1H-indole-3-ethanamines 1 with cyclic β-keto esters 2 under azeotropic conditions followed by acid-catalyzed ring closure of the resulting enamines 3 gave 2′,3′,4′,9′-tetrahydrospiro[piperidine-3,1′,-[1H]pyrido[3,4-b]indole] -4-carboxylic acid alkyl esters 4 . Condensation of 1 with 2-acylcycloalkanones 8 gave two types of enamines, 10 and 11 , respectively. Enamines 10 on treatment with acid gave 1-(2′,3′,4′,9′-tetrahydro-3H-pyrido[3,4-b]indol-1-yl)-1-alkylcyclohexanols 17 . Compounds 17 were further dehydrated to give cycloalkane derivatives 19.     

Isomerisierung bei der Komplexbildung von 3-Acetyl-tetramsäure: Struktur und magnetische Eigenschaften des CuII- und NiII-Komplexes von 2,7-Bis(1′, 5′, 5′-trimethylpyrrolidin-2′, 4′-dion-3′ -yl)-3, 6-diazaocta-2, 6-dien

Isomerization at the Complexation of 3-Acetyltetramic Acid: Structure and Magnetic Properties of the Cu^II- and Ni^II-Complex of 2,7-Bis (1′, 5′, 5′ -trimethylpyrrolidin-2′,4′ -dion-3′ -yl)-3,6-diazaocta-2,6-dien 2,7-Bis(1′, 5′, 5′ -trimethylpyrrolidin-2′, 4′ -dion-3′ -yl)-3,6-diazaoctadien formes Cu^II and Ni^II complexes with different constitutions (because of the Z/E isomerization). Results of X-ray analysis of N,N′ -ethylenbis(1′, 5′, 5′ -trimethylpyrrolidin-2′, 4′ -dion-3′ -acetiminato)nickel(II) 1 respectively -copper(II) 2 shows, that the complexing agent in 1 occurs in the E-form, whereas the ligand of the Cu^II complex forms the Z-form. Magnetic susceptibility and shift effects of the ¹³C-NMR signals point to a weak paramagnetism of the Ni^II complex. ESR-spectra are obtained from 2 only. Furthermore, the Cu^II complex reduces the relaxation times T₁ and T₂ of ¹H and ¹⁷O nuclei spins from water. From the temperature dependence of the shortening of the relaxation times an activation energy is calculated which describes the reorientation of the copper complex in the “water matrix”.     

Reactions of 2,2′,5′,2′-terfuran

Formylation of 2,2′,5′,2′-terfuran ( 1 ) with N-methylformanilide and phosphorus oxychloride gave 5-formyl-2,2′,5′,2′-terfuran ( 2 ) and 5,5′-diformyl-2,2′5′,2′-terfuran ( 3 ). Reduction of 2 and 3 afforded 5-hydroxymethyl-2,2′,5′,2′-terfuran ( 4 ) and 5,5′ dihydroxymethyl-2,2′,5′,2′-terfuran ( 5 ), respectively. Terfuran 1 reacted with phenylmagnesium bromide to give 5-(phenylhydroxymethyl)-2,2′,5′,2′-terfuran ( 6 ), and was carbonated to 5-carboxy 2,2′,5′,2′-terfuran ( 7 ) and 5,5′-dicarboxy-2,2′,5′,2′-terfuran ( 8 ). Bromination of 1 with N-bromosuccinimide gave 5,5′-dibromo 2,2′,5′,2′-terfuran ( 9 ).     

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).     

Studies of phosphazenes. Aminolysis reactions of pentachloro(2′, 2′, 2′-triphenyl-phosphazen-1′-yl) cyclotriphosphazene,N3P3Cl5(NPPh3)

The reactions of pentachloro(2′, 2′, 2′-triphenylphosphazen-1′-yl)cyclotriphosphazene, N₃P₃Cl₅(NPPh₃), with primary and secondary amines have been investigated using diethyl ether, methyl cyanid or benzene as the solvent. The structures of the products obtained, N₃P₃Cl_5minus;nR_n(NPPh₃) [n = 1, R = NHMe, NHBu^t, NMe₂, NC₅H₁₀, NEt₂; n = 2, R = NMe₂, NC₅H₁₀, NEt₂; n = 3, R = NMe₂, NHBu^t; n = 5, R = NMe₂] are elucidated by ¹H and ³¹P NMR spectroscopy. The ? NPPh₃ substituent exerts a pronounced geminal directing influence on incoming secondary amino nucleophiles; compounds containing a ≡ PCl(NPPh₃) group are not formed at the bis and subsequent stages of chlorine replacement. The reactions that involve primary amines follow the pattern established for the analogous reactions of hexachlorocyclotriphosphazene. The effect of solvent and possible mechanism(s) are discussed.     

The synthesis and spectroscopic properties of 3-(2′,4′-Xylyl)-1H,3H-quinazoline-2,4-diones

The synthesis of 3-(2′,4′-xylyl)-1H,3H-quinazoline-2,4-diones ( 1a, 9a-j ) has been accomplished. Their pmr and ir spectra data for all compounds are presented.     

Nucleosides 4: Synthesis of 2′,3′-Didehydro-2′,3′-dideoxydoridosine and 2′,3′-Dideoxydoridosine as Potential Antihypertensive Agents

To measure the hydrophobic character of the ribose moiety of doridosine on the adenosine receptors, 2′,3′-didehydro-2′,3′-dideoxydoridosine (2) and 2′,3′-dideoxydoridosine (3) were prepared. Initial treatment of doridosine with N,N-dimethylformamide diethylacetal, and subsequently with tert-butyldimethylsilyl chloride gave 5. Compound 5 was then reacted with 1,1′-thiocarbonyldiimidazole and the resulting thionocarbonate 6 was heated with triethyl phosphite at 135°C to afford 7. Treatment of compound 7 with tetrabutylammonium fluoride and methanolic ammonia furnished compound 2 in good yield. Compound 2 was subjected to catalytic hydrogenation affording compound 3 in 85% yield.     

Facile synthesis of novel spiro[azetidine-2,4′(1′H)-isoquinoline-1′,3′,4(2′H)-triones]

A convenient general method for the synthesis of a new heterocycle, spiro[azetidine-2,4′(1′H)-iso-quinoline-1′,3′,4(2′H)-trione] is described. The key intermediate 2 was prepared by direct halogenation of position-4 of acid 3 with thionyl chloride, and subsequent treatment of the generated 4-Cl, 4-acetyl chloride 11 with a THF/NH₃ solution at low temperature.