Synthesis of a hydroxyethylene isostere of the tripeptide Arg-Gly-Leu via a convergent acyl-like radical addition strategy

[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.