Enantiospecific Total Synthesis of l-2‘,3‘-Dideoxyisonucleosides via Regioselective Opening of Optically Active C2-Symmetric 1,4-Pentadiene Bis-epoxide1
journal contributionposted 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 4a−c, 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., 28−9 and 32−3. Unfortunately, the tetrols, their simple derivatives, and the final sulfonates and epoxides could not be readily separated by any simple means.