Organocatalytic Enantioselective Addition of Malonates to Cyclic Imines: A Short Total Synthesis of Tetraponerine T-1.

Cyclic imines are common intermediates in the biosynthesis of alkaloids, but their use in enantioselective organic synthesis is limited by their high reactivity and tendency to trimerize. Here, we present a mild organocatalytic method for the stereoselective addition of malonates to cyclic imines. Under carefully optimized conditions that suppress background reactivity, cinchona alkaloid-derived catalysts enabled access to α-functionalized pyrrolidines and 5-6-5 and 6-6-5 tricycles in high yields and stereoselectivity. Mechanistic studies revealed that the catalyst controls the stereochemistry of the initial addition, while subsequent reactions are governed by the substrate. The total synthesis of the alkaloid Tetraponerine T-1, the shortest route reported to date, highlights the synthetic utility of the methodology.