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.