ORGN 83 |
Palladium mediated Ferrier rearrangement type glycosidation with aromatization prone xylo-furanoid glycals for the synthesis of biologically active nucleosides
| Anusuya Choudhury, Michael E. Pierce, Dieu Nguyen, Louis Storace, and Pat Confalone. Chemical Process R&D, DuPont Pharmaceuticals, Deepwater, NJ 08023 |
| A short and concise synthesis of the nucleoside D-D4FC (1), a known anti-HIV agent (Pharmasset, Inc.), would preferably invoke a Ferrier type of rearrangement on a furanoid glycal to fix the position of the double bond in the sugar ring and to direct the approach of the nucleophile during concomitant formation of the anomeric carbon center. Though the Ferrier rearrangement is a well known reaction for pyranoid glycals as substrates (cf. 2 -> 4), the similar strategy using furanoid counterparts was reported to be unsuccessful due to the inherent instability of such systems. Moreover, the acidic reaction conditions required for the rearrangement also cause undesired aromatization in furanoid glycals bearing leaving groups at C-3. We developed conditions for the synthesis and isolation of furanoid glycals with the requisite xylo-configuration in reasonable chemical purities. These precursors were utilized in palladium (0) mediated Ferrier rearrangements with a fluorocytocine nucleophile to synthesize D-D4FC (1) in a highly stereoselective fashion (cf. 5 -> 7). Synthesis of the xylo-configuration furanoid glycals, optimal reaction conditions for glycal formation and glycosidation, and extension of this Pd(0) mediated coupling protocol with other nucleophiles will be presented.  |
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