Recent Advances in Charge-Accelerated Aza-Claisen Rearrangements

Abstract

Aza-Claisen rearrangements (3-aza-Cope rearrangements) have gained an increasing interest in synthetic organic chemistry. Originally, the exceptionally high reaction temperatures of this hetero variant of the well-known 3,3-sigmatropic reaction limited their applicability to selected molecules. Since about 1970, charge acceleration enabled a significant reduction of the reaction temperature to be achieved, and cation- and anion-promoted rearrangements found their way into the syntheses of more complex molecules. The first total syntheses of natural products were reported. The development of zwitterionic aza-Claisen rearrangements allowed the reactions to be run at room temperature or below, and the charge neutralization served as the highly efficient driving force. After overcoming several teething troubles, the method was established as a reliable conversion displaying various stereochemical advantages. The first successful total syntheses of natural products incorporating the aza-Claisen rearrangement as a key step emphasized the synthetic potential. To date the aza-Claisen rearrangements are far from being exhausted. Still, an enantioselectively catalyzed variant has to be developed. This review summarizes one decade of investigation efforts in this area.