The thio-Mitsunobu reaction: a useful tool for the preparation of 2,5-anhydro-2-thio- and 3,5-anhydro-3-thiopentofuranosides.
The unprotected methyl L-arabinofuranosides, D-ribofuranosides and D-xylofuranosides are transformed into the corresponding S-acetyl-5-thio derivatives by the thio-Mitsunobu reaction. Mesylation and subsequent reaction with sodium hydrogen carbonate led, depending on the configuration of the intermediate, to 2,5-anhydro-2-thio- or 3,5-anhydro-3-thiopentofuranosides. Due to inversion at C-3 or C-2 during the intramolecular nucleophilic displacement the products exhibit L-lyxo-, D-arabino- or D-lyxo-configuration. Analogously, the methyl 2,3-anhydro-D-ribofuranosides yielded 5-thio-S-acetates with intact 2,3-oxirane groups, which were cyclised with sodium hydrogen carbonate by epoxide ring opening and concomitant ring closure to form exclusively 3,5-anhydro-3-thio-D-xylofuranosides. A related 3,5-anhydro-3-seleno-D-lyxofuranoside was obtained by reaction of a 3,5-di-O-mesyl-D-arabinofuranoside with sodium hydrogen selenide. Several X-ray diffraction analyses proved the structures of the products.
Synthesis of [4,5-Bis(hydroxymethyl)-1,3-oxathiolan-2-yl]nucleosides as Potential Inhibitors of HIV via Stereospecific Base-Induced Rearrangement of a 2,3-Epoxy Thioacetate(1).
The synthesis of [4,5-bis(hydroxymethyl)-1,3-oxathiolan-2-yl]nucleosides is described. 2,3-Epoxy alcohol 10 was converted in one pot into thioacetate 11. Treatment of 11 under mild alkaline conditions gave thiirane 12 with inversion of configuration at C-2. We also found that thioacetate 11 rearranges into thiirane 14 under mild acidic conditions. This rearrangement reaction was shown by independent synthesis to proceed with net retention of configuration at C-2. We have proposed a tentative mechanism which may explain the results obtained. Opening of thiiranes 12 and 14 followed by deprotection gave (2R,3R)-2-thiothreitol (23) and (2S,3R)-2-thioerythritol (25), respectively. Regioselective silylation of the primary hydroxyl groups of 23 followed by treatment with trimethyl orthoformate gave 2-methoxy-1,3-oxathiolanes 26 and 27. Condensation with silylated bases followed by deprotection and separation of the anomers gave the oxathiolanylnucleosides. Compounds 29-31, 34, and 35 were found to be inactive when tested for inhibition of HIV-1 activity in vitro.
Some aspects of the formation of hex-2-enopyranosides from methyl 2,3-di-O-methanesulfonyl-α-D-glucopyranosides
The elimination of vicinal sulfonyloxy groups from methyl 2,3-di-O-methanesulfonyl-α-D-glucopyranosides with the formation of hex-2-enopyranosides using potassium iodide, and zinc in refluxing dry dimethyl formamide has been investigated. The specific use of a zinc–copper couple has been found to be highly advantageous to the yield and reproducibility of the reaction, and the elimination proceeds successfully whether acid or base labile groups are present at carbon-4 or -6. Both the 4,6-di-O-benzoyl (3b) and the 6-O-benzoyl (3d) precursors give methyl 6-O-benzoyl-α-D-erythro-hex-2-enopyranoside (4d) as the major product, the latter also being obtainable by selective benzoylation of methyl α-D-erythro-hex-2-enopyranoside (4c). The reaction of the dibenzoate therefore occurs with some deacylation at carbon-4, but it is noteworthy that this is not accompanied by any epimerization. A similar pattern of reaction apparently occurs with the 4,6-di-O-acetyl derivative (3a). The conformations of the starting di-O-...