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Enantiospecific Total Synthesis of l-2‘,3‘-Dideoxyisonucleosides via Regioselective Opening of Optically Active C2-Symmetric 1,4-Pentadiene Bis-epoxide1

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journal contribution
posted on 02.04.1998, 00:00 by Michael E. Jung, Oliver Kretschik
A new method for the synthesis of l-2‘,3‘-dideoxyisonucleosides is described. The readily available, optically active C2-symmetric bis-epoxide (2S,4S)-1,2:4,5-diepoxypentane (5) was prepared by a short route from readily available starting materials. The key step of the new synthesis is the opening of 5 with nucleophiles, which proceeds highly regioselectively; e.g., reaction with sodium sulfide affords a 5:1 mixture of the tetrahydrothiophenediol 9a and the tetrahydrothiopyrandiol 14, and reaction with sodium hydroxide gives exclusively the tetrahydrofurandiol 9b via a preferred 5-exo cyclization. These five-membered diols 9a,b can be converted in only four steps into the modified dideoxyuridine and adenosine isonucleosides 4ac, one of which (4c) has shown good antiviral activity. In addition, we have examined the opening of the analogous six-carbon bis-epoxide, (2S,5S)-1,2:5,6-diepoxyhexane (23), which affords a 3:1 mixture of the hexahydrothiepinediol 24 and the tetrahydrothiopyrandiol 25 with sodium sulfide via a preferred 7-endo cyclization. An alternate route to these two optically active bis-epoxides 5 and 23 was also examined, namely the asymmetric dihydroxylation of 1,4-pentadiene and 1,5-hexadiene followed by selective sulfonylation and epoxide formation. The asymmetric reaction produces a nearly 1:1 mixture of optically active and meso tetrols, e.g., 289 and 323. Unfortunately, the tetrols, their simple derivatives, and the final sulfonates and epoxides could not be readily separated by any simple means.

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