3 years ago

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

Design and Synthesis of Building Blocks for PPII-Helix Secondary-Structure Mimetics: A Stereoselective Entry to 4-Substituted 5-Vinylprolines
Jörg-Martin Neudörfl, Judith Bruns, Arne Soicke, Robert Opitz, Slim Chiha, Matthias Müller, Matthias Barone, Hans-Günther Schmalz, Ronald Kühne
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.Starting from pyroglutamic acid, 4-substituted-5-vinylprolines were stereoselectively prepared and used as building blocks for the synthesis of conformationally well-defined diproline analogs, which are of interest as proline-derived modules (ProMs) for the construction of PPII-helix secondary-structure mimetics acting as inhibitors of relevant protein-protein interactions.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/ejoc.201701584

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