| Abstract
| - A hydroxyethylene isostere of the tripeptide Arg-Gly-Leu, representing an important fragment ofa novel cyclic-peptide-based uPA inhibitor, was synthesized in few steps employing as the key stepa samarium diiodide promoted coupling of either the 4-thiopyridyl ester of Nα-Fmoc- or Nα-Cbz-protected l-ornithine with the N-acryloyl derivative of l-leucine methyl ester. Epimerization underthe coupling conditions at the chiral center in the α-position to the ketone was demonstrated notto take place. A stereoselective reduction of the Cbz-protected aminoketone obtained from this radicalreaction was promoted by the same single-electron reducing agent in the presence of methanolproviding 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 almostexclusively. Subsequent elaboration of the ornithine moiety in the anti-isomer by introduction ofthe guanidine group followed by hydrolysis of the C-terminal ester bond and protection of the alcoholas its tert-butyldimethylsilyl ether provided the desired tripeptide mimic. The long reaction timesrequired for the radical addition reactions with Nδ-Boc-l-ornithine (up to 5 days) led to a shortstudy where a series of 4-thiopyridyl esters of Cbz-protected amino acids were reacted with twoacrylates. Whereas Nδ-Boc-l-ornithine, alanine, phenylalanine, proline, and leucine all providedthe aminoketone in 43−79% yield, valine only afforded traces of the coupling product.
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