A formal total synthesis of (-)-FR901483, using a tandem cationic aza-Cope rearrangement/Mannich cyclization approach |
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Authors: | Brummond Kay M Hong Sang-phyo |
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Affiliation: | Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA. kbrummon@pitt.edu |
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Abstract: | A formal total synthesis of the immunosuppressant FR901483 has been accomplished. The key step in the synthesis utilizes a tandem cationic aza-Cope rearrangement/Mannich cyclization reaction for accessing the unprecedented bridging tricyclic azaspirane substructure of this compound. The tandem reaction proceeds through a bridgehead iminium ion, a functionality that has rarely been explored in the context of natural product syntheses. Improved stereoselectivity was observed in an aldol reaction when using a Boc-protected amino aldehyde and zinc chloride as an additive. A stereoselective epimerization of the aldehyde-containing stereocenter was achieved with l-phenylalanine upon completion of the Mannich cyclization. Finally, this synthesis is the only one to date that controls the stereochemistry of the oxygen-bearing stereocenters. All other synthetic routes required late stage adjustments to at least one of these stereocenters. |
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