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

Abstract

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 BF3-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 AlCl3 or CuBr·SMe2 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.