A formal total synthesis of (-)-FR901483, using a tandem cationic aza-Cope rearrangement/Mannich cyclization approach.
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.
Brummond
Kay M
KM
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA. kbrummon@pitt.edu
Hong
Sang-phyo
SP
D001372:Aza Compounds / Q000138:chemical synthesis; D002412:Cations; D003500:Cyclization; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000737:chemistry; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
D001372:Aza Compounds; D002412:Cations; C098358:FR 901483; D007166:Immunosuppressive Agents; D009943:Organophosphorus Compounds