title: Exercises in pyrrolidine chemistry: gram scale synthesis of a Pro-Pro dipeptide mimetic with a polyproline type II helix conformation.
abstract: A practical and scalable synthesis of a Fmoc-protected tricyclic dipeptide mimetic (6), that is, a 1,4-diaza-tricyclo-[8.3.0(3,7)]-tridec-8-ene derivative resembling a rigidified di-L-proline in a polyproline type II (PPII) helix conformation, was developed. The strategy is based on a Ru-catalyzed ring-closing metathesis of a dipeptide (4) prepared by PyBOP coupling of cis-5-vinylproline tert-butylester (2) and trans-N-Boc-3-vinylproline (rac-3) followed by chromatographic diastereomer separation. Building block 2 was prepared from L-proline in six steps via electrochemical C5-methoxylation, cyanation and conversion of the nitrile into a vinyl substituent. Building block rac-3 was prepared in five steps exploiting a Cu-catalyzed 1,4-addition of vinyl-MgBr to a 2,3-dehydroproline derivative in the key step. In the course of the investigation subtle dependencies of protecting groups on the reactivity of the 2,3- and 2,5-disubstituted pyrrolidine derivatives were observed. The configuration and conformational preference of several intermediates were determined by X-ray crystallography. The developed synthesis allows the preparation of substantial amounts of 6, which will be used in the search for new small molecules for the modulation of protein-protein interactions involving proline-rich motifs (PRDs).
authors: Department of Chemistry, Institute of Organic Chemistry, University of Cologne, Greinstrasse 4, 50939 Köln, Germany.
authors: Cédric
authors: C
authors: Reuter
authors: Peter
authors: P
authors: Huy
authors: Jörg-Martin
authors: JM
authors: Neudörfl
authors: Ronald
authors: R
authors: Kühne
authors: Hans-Günther
authors: HG
authors: Schmalz
mesh_terms: D002384:Catalysis; D003300:Copper / Q000737:chemistry; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry*; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D013237:Stereoisomerism
chemical_list: D004151:Dipeptides; D010455:Peptides; C448039:prolyl-proline; C011083:polyproline; D003300:Copper