Alkaloids Overman pyrrolidine synthesis

The Overman pyrrolidine synthesis, or aza-Cope-Mannich reaction, was developed while troubleshooting a stereochemical challenge encountered by the Overman group as they pursued the amphibian alkaloid. 

The synthetic utility of the Overman pyrrolidine synthesis has been demonstrated in various approaches to a range of alkaloids the Amaryllidaceae alkaloids, Aspidosperma alkaloids, Strychnos alkaloids, and Melodinus alkaloids are several types. 

Other academic groups have used the Overman pyrrolidine synthesis en route to complex alkaloids and other medicinally relevant compounds. The Brummond group at the University of Pittsburgh has reported the formal synthesis of (-)-FR901483 (48), an immunosuppressant isolated by researchers at Fujisawa Pharmaceuticals. In this report, Brummond incorporated a tandem cationic aza-Cope rearrangement/Mannich cyclization that proceeds via a bridgehead iminium ion. Treatment of intermediate 44... 

A process that has been popularized and utilized extensively by Overman and coworkers involves a tandem 2-aza-Cope rearrangement followed by trapping of the resultant isomer by a Mannich reaction. First demonstrated in 1979, this has become a powerful methodology that has found substantial utility in alkaloid synthesis. " The reaction between 215 and benzaldehyde results in formation of iminium ion 217, which undergoes the 2-azonia-Cope rearrangement to give iminium ion 218. Trapping of 218 by the enol functionality results in pyrrolidine 219. 

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