STUDIES ON THE SYNTHESIS OF AUREOLIC ACID ANTIBIOTICS - HIGHLY STEREOSELECTIVE SYNTHESIS OF ARYL 2-DEOXY-BETA-GLYCOSIDES VIA THE MITSUNOBU REACTION AND SYNTHESIS OF THE OLIVOMYCIN A-B DISACCHARIDE

The Mitsunobu reaction of phenols and 1,2-cis-2-thiophenyl-alpha-D-glycopyranoses or 1,2-cis-2-selenophenyl-alpha-D-glycopyranoses is a very effective method for the highly stereoselective synthesis of aryl 2-deoxy-beta-D-glycosides. The equatorial 2-thiophenyl or 2-selenophenyl- substituents are easily removed by Bu(3)SnH reduction following the glycosidation reaction to provide the aryl 2-deoxy-beta-D-glycosides in good to excellent yield. The aryl beta-D-glycosides are obtained with 6.5:1 selectivity in the least selective case(Table 1) and up to >20:1 selectivity in others. The reaction appears to be S-N(2)-like in character (see 30), in that the beta:alpha reaction stereoselectivity correlates well with the alpha:beta anomeric composition of the pyranose starting material. The equatorial 2-thiophenyl or 2-selenophenyl substituents play an important role by increasing the alpha:beta anomer ratio of the pyranose starting materials. The reactions do not appear to proceed by way of free oxonium ions such as 17, since several reactions in which 17 was deliberately generated (e.g., TMS-OTf promoted reactions of glycosyl acetate 14, BF3 . Et(2)O catalyzed reactions of imidate 15) gave at best 1:1 mixtures of alpha- and beta-glycosides, and in several cases gave alpha-glycosides with >10:1 selectivity. These data also rule out the involvement of episulfonium ion 18 as a kinetically significant intermediate in reactions that proceed by way of oxonium ion 17. A short and highly effective synthesis of reducing disaccharide 53 from D-fucal was developed. This functionalized disaccharide readily undergoes Mitsunobu glycosidation with 2-naphthol, providing the model naphthyl A-B disaccharide 5 with 11:1 beta,alpha:alpha,alpha selectivity. Finally, olivin precursor 63 has also been glycosylated with 53, providing the advanced synthetic intermediate 6 with excellent diastereoselectivity.