title: Synthesis of a hydroxyethylene isostere of the tripeptide Arg-Gly-Leu via a convergent acyl-like radical addition strategy.
abstract: [reaction: see text] A hydroxyethylene isostere of the tripeptide Arg-Gly-Leu, representing an important fragment of a novel cyclic-peptide-based uPA inhibitor, was synthesized in few steps employing as the key step a samarium diiodide promoted coupling of either the 4-thiopyridyl ester of N(alpha)-Fmoc- or N(alpha)-Cbz-protected L-ornithine with the N-acryloyl derivative of L-leucine methyl ester. Epimerization under the coupling conditions at the chiral center in the alpha-position to the ketone was demonstrated not to take place. A stereoselective reduction of the Cbz-protected aminoketone obtained from this radical reaction was promoted by the same single-electron reducing agent in the presence of methanol providing the syn-amino alcohol with a diastereoselectivity of 85:15. With the use of lithium tri-tert-butoxyaluminum hydride in methanol, the corresponding anti-isomer was obtained almost exclusively. Subsequent elaboration of the ornithine moiety in the anti-isomer by introduction of the guanidine group followed by hydrolysis of the C-terminal ester bond and protection of the alcohol as its tert-butyldimethylsilyl ether provided the desired tripeptide mimic. The long reaction times required for the radical addition reactions with N(delta)-Boc-L-ornithine (up to 5 days) led to a short study where a series of 4-thiopyridyl esters of Cbz-protected amino acids were reacted with two acrylates. Whereas N(delta)-Boc-L-ornithine, alanine, phenylalanine, proline, and leucine all provided the aminoketone in 43-79% yield, valine only afforded traces of the coupling product.
authors.affiliation: Department of Chemistry, University of Aarhus, Langelandsgade 140, 8000 Aarhus C, Denmark.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Jensen
authors.forename: Karl B
authors.initials: KB
authors.lastname: Lindsay
authors.forename: Peter
authors.initials: P
authors.lastname: Andreasen
authors.forename: Troels
authors.initials: T
authors.lastname: Skrydstrup
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D005030:Ethylenes / Q000138:chemical synthesis; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D005030:Ethylenes; D009842:Oligopeptides; C067254:hydroxyethylene; D014568:Urokinase-Type Plasminogen Activator