Design and Stereoselective Synthesis of ProM-2: A Spirocyclic Diproline Mimetic with Polyproline Type II (PPII) Helix Conformation

• Published in: Chemistry : a European journal 2015-06, Vol.21 (23), p.8464-8470
• Main Authors: Reuter, Cédric, Opitz, Robert, Soicke, Arne, Dohmen, Stephan, Barone, Matthias, Chiha, Slim, Klein, Marco Tobias, Neudörfl, Jörg-Martin, Kühne, Ronald, Schmalz, Hans-Günther
• Format: Article
• Language: English
• Subjects: amino acids; Binding; Chemistry; conformation analysis; Decomposition reactions; Dipeptides - chemistry; Esters; helical structures; Modulation; Peptides; Peptides - chemistry; Peptidomimetics; Proline; Protein Conformation; protein-protein interactions; Proteins; Proteins - chemistry; RCM; Scaffolds; Stereoisomerism
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201406493

With the aim of developing polyproline type II helix (PPII) secondary‐structure mimetics for the modulation of prolin‐rich‐mediated protein–protein interactions, the novel diproline mimetic ProM‐2 was designed by bridging the two pyrrolidine rings of a diproline (Pro–Pro) unit through a Z‐vinylidene moiety. This scaffold, which closely resembles a section of a PPII helix, was then stereoselectively synthesized by exploiting a ruthenium‐catalyzed ring‐closing metathesis (RCM) as a late key step. The required vinylproline building blocks, that is, (R)‐N‐Boc‐2‐vinylproline (Boc=tert‐butyloxycarbonyl) and (S,S)‐5‐vinylproline‐tert‐butyl ester, were prepared on a gram scale as pure stereoisomers. The difficult peptide coupling of the sterically demanding building blocks was achieved in good yield and without epimerization by using 2‐(1H‐7‐azabenzotriazol‐1‐yl)‐1,1,3,3‐tetramethyluronium hexafluorophosphate (HATU)/N,N‐diisopropylethylamine (DIPEA). The RCM proceeded smoothly in the presence of the Grubbs II catalyst. Stereostructural assignments for several intermediates were secured by X‐ray crystallography. As a proof of concept, it was shown that certain peptides containing ProM‐2 exhibited improved (canonical) binding towards the Ena/VASP homology 1 (EVH1) domain as a relevant protein interaction target. ProMoting proline: The spiro‐tricyclic scaffold ProM‐2, which is designed to be a diproline analogue locked in a polyproline type II (PPII) conformation, can be synthesized from vinylproline building blocks. ProM‐2 serves as a module for the development of small molecules that specifically interfere with PPII helix‐mediated protein–protein interactions (see figure).