Design and Synthesis of Building Blocks for PPII‐Helix Secondary‐Structure Mimetics: A Stereoselective Entry to 4‐Substituted 5‐Vinylprolines

In the course of our studies towards the synthesis of proline‐based secondary‐structure mimetics, we developed a straightforward methodology for the diastereoselective preparation of 4‐alkyl‐5‐vinyl‐substituted proline derivatives. Starting from N ‐Boc‐protected tert ‐butyl pyroglutamate, α‐alkylation, lactam reduction and acid‐catalyzed methanolysis afforded 4‐alkyl‐5‐methoxyproline derivatives. After BF 3 ‐induced formation of an N ‐acyl‐iminium intermediate, the introduction of the 5‐vinyl side chain was achieved with high diastereoselectivity by using vinylmagnesium bromide in the presence of AlCl 3 or CuBr · SMe 2 to afford either the cis ‐ or the trans ‐product, respectively. The utility of the method was demonstrated in the rapid and efficient construction of new diproline mimetics rigidified in a polyproline‐type II helix (PPII) conformation.