Abstract
Hydroxymethyl isodideoxynucleosides, designed as potential antiviral agents, have been synthesized through development of a multi-step procedure starting from furan and cyanovinyl acetate. Key steps in the synthesis include a Diels-Alder reaction, oxidative cleavage of alkene, a Mitsunobu reaction, stereospecific introduction of amino group and nucleobase construction.
Highlights
Isomeric dideoxynucleosides as antiviral agents have been the subject of intense investigation in our laboratory 4 and have been studied by others
5 Work in our laboratory led to the discovery of 4 (S)-(adenin-9-yl)-2(S)-hydroxymethyltetrahydrofuran [(S,S)-isoddA] (1, Figure 1) which exhibits potent anti-HIV activity against HIV-1, HIV-2, and HIV-resistant strains
Introduction of an additional hydroxymethyl group was of interest, because of the observation of anti-HIV activity associated with isomeric nucleosides in which the adenine ring and the –CH2OH have cis-1,3- and 1,2-relationships (2, Figure 1),6,7 and because of the known antiviral activity of natural oxetanocin and its ring expanded analog which bear an additional –CH2OH group
Summary
Isomeric dideoxynucleosides as antiviral agents have been the subject of intense investigation in our laboratory 4 and have been studied by others. 5 Work in our laboratory led to the discovery of 4 (S)-(adenin-9-yl)-2(S)-hydroxymethyltetrahydrofuran [(S,S)-isoddA] (1, Figure 1) which exhibits potent anti-HIV activity against HIV-1, HIV-2, and HIV-resistant strains. 6 Its triphosphate is among the strongest known inhibitors of HIV reverse transcriptase. The resulting residue (compound 9) was dissolved in methanol (20 mL), to which was added sodium borohydride (1.6 g, 42.29 mmol) over 20 min at 0 °C (internal temperature), and the resulting reaction mixture was stirred for 1h and concentrated under reduced pressure at 31 °C.
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