Carsten M. Nielsen

Synthesis of 2′,3′-dideoxynucleosides from 5-alkoxymethyluracils

SummaryA modified synthesis of protected 2,3-dideoxyribose5 starting fromL-glutamic acid (1) is described. Reaction of5 with silylated 5-hydroxymethyluracil7 a and 5-alkoxymethyluracils7 b–e in the presence of trimethylsilyl triflate afforded an anomeric mixture of 2′,3′-dideoxyuridine derivatives8 a–e and9 a–e. Deprotection with methanolic ammonia and separation by chromatography gave the corresponding nucleosides10 a–e and11 a–e. Treatment of9 b–e with tri(1H-1,2,4-triazol-1-yl)phosphine oxide and subsequent reaction of12 b–e with ammonia in dioxane afforded the cytosine derivatives13 b–e which on treatment with methanolic ammonia gave the corresponding 2′,3′-dideoxycytidine derivatives14 b–e and15 b–e. In contrast with the parent compounds, these alkoxymethyl derivatives had no appreciable activity against human immunodeficiency virus (HIV-1).ZusammenfassungAusgehend vonL-Glutaminsäure (1) wird eine modifizierte Synthese von geschützter 2,3-Dideoxyribose (5) beschrieben. Reaktion von5 mit silyliertem 5-Alkoxymethyluracilen7 b–e in Gegenwart von Trimethylsilyltriflat ergab anomere Mischungen der 2′,3′-Dideoxyuridinderivate8 a–e und9 a–e. Abspaltung der Schutzgruppe mit methanolischen Ammoniak und chromatographische Trennung ergab die entsprechenden Nucleoside10 a–e und11 a–e. Behandlung von9 b–e mit Tri(1H-1,2,4-triazol-1-yl)phosphinoxid und nachfolgende Reaktion von12 b–e mit Ammoniak in Dioxan ergab die Cytosinderivate13 b–e, welche nach Behandlung mit methanolischem Ammoniak die entsprechenden 2′,3′-Dideoxycytidinderivate14 b–e und15 b–e ergaben. Im Gegensatz zur Stammverbindung hatten diese Alkoxymethylderivate keine nennenswerte Wirksamkeit gegen den menschlichen Immunschwächevirus (HIV-1).

Synthesis of 2',3'-dideoxy-D-erythro-hex-2'-enopyranosyl nucleosides from 5-aminouracils and 3,4,6-tri-O-acetyl-D-glucal

Condensation of silylated N,N-disubstituted aminouracils (4) and 3,4,6-tri-O-acetyl-D-glucal (3) in the presence of TMS triflate as catalyst gave anomeric mixtures of 2,3-dideoxy-D-erythro-hex-2-enopyranosylnucleosides (5) and (6). The pure β- and α-anomers were separated by chromatography and deprotected with a saturated solution of ammonia in methanol to give 1-(2,3-dideoxy-β-D-erythro-hex-2-enopyranosyl)-5-aminouracils (7) and their corresponding α-anomers (8), respectively. The anomeric configurations of these nucleosides were assigned by nmr analysis of the dihydroderivatives 9 and 10 obtained by hydrogenation of 7a and 8a, respectively. No significant activity against HIV-1 was found

5-Amino Derivatives of 2',3'-Dedeoxynucleosides for Evaluation of Anti-HIV Activity

Reaction of protected 2,3-dideoxy-D-ribose (2) with silylated 5-amino derivatives of uracil using trimethylsilyl trifluoromethanesulfonate as catalyst afforded the 2,3-dideoxynucleosides (3a-d) which were deprotected with methanolic ammonia and separated by chromatography to give α-anomers (4a-d) and β-anomers (5a-d). Compounds (3a-c) were converted to 4-(1,2.4-triazol-1-yl) derivatives (6a-c). Ammonia in dioxane converted the 4-(1,2,4-triazole-1-yl)pyrimidin-2(1H)-one moiety into cytosin-1-yl. In case of 6b, 4-methoxypyrimidin-2-one 2,3-dideoxyriboside was accomplished via transformation of the 4-triazolyl moiety with methanol on silica. Methanolic ammonia was used for deprotection of the sugar moiety to afford 7-10

5-Alkoxymethyl-1-hydroxyalkyluracils with Potential Anti-HIV Activity

Acid catalyzed etherification of 5-hydroxymethyluracil (3) afforded the corresponding 5-alkoxymethyluracils (4a-h). Treatment of the sodium salt of compounds (4a-g) with 4-bromobutyl acetate afforded 1,3-bis-(4-acetyloxybutyl)- (5a-g) and 1,4-acetyloxybutyluracil derivetives -6a-g). Alkylation of 4h with 5-chloropentyl benzoate gave 1,3-bis-(5-benzoyloxypentyl)- (8) and 1-(5-benzoyloxypentyl)-5-b-butyloxymethyluracil (9). Ammonolysis of 6a-g and 9 at room temperature gave the corresponding hydroxyalkyl derivatives (7a-g and 10)

SYNTHESIS AND INVESTIGATION OF ANTIVIRAL ACTIVITY OF 3'-O-(AMINOALKYL)-THYMIDINES AND THEIR QUATERNARY AMMONIUM SALTS

SummaryAlkylation of 5′-O-tritylthymidine with dialkylaminoalkyl chlorides in the presence of sodium hydride yields 3′-O-dialkylaminoalkyl-5′-O-tritylthymidine derivatives2 which were treated with an excess of iodomethane to afford the corresponding quaternary ammonium derivatives3. Deprotected nucleosides4 and6 were obtained by refluxing3 and2, respectively, in 80% acetic acid. When the compounds2–4 and6 were investigated for activity against HSV and HIV, the trityl derivatives2a and2c were found active against HSV.ZusammenfassungAlkylierung von 5′-O-Tritylthymidin mit Dialkylaminoalkylchloriden in Gegenwart von Natriumhydrid ergab 3′-O-Dialkylaminoalkyl-5′-O-tritylthymidinderivate2, die mit einem Überschuß an Iodmethan zu den entsprechenden quartären Ammoniumderivaten3 umgesetzt wurden. Die entschützten Nucleoside4 und6 wurden durch Kochen von3 bzw.2 in 80% iger Essigsäure unter Rückfluß erhalten. Bei der Untersuchung von2–4 und6 im Hinblick auf ihre Wirksamkeit gegen HSV und HIV wurde bei den Tritylderivaten2a und2c Aktivität gegen HSV festgestellt.