SmI2 reduced thioesters as synthons of unstable acyl radicals:: Direct synthesis of potential protease inhibitors via intermolecular radical addition

Aromatic α-heterosubstituted thioesters were found to undergo radical 1,4-addition reactions to a series of α,β-unsaturated amides and one ester when subjected to the single electron reducing agent, samarium diiodide, at -78 °C. These thioesters derived from α-amino acids represent a synthetically useful synthon of unstable acyl radicals. This reaction conveniently provides access to γ-ketoamides and esters in yields up to 90%, structures that are common in various protease inhibitors derived from peptides. Examples with acryloyl and methacryloyl derivatives of α-amino acids and dipeptides lead directly to tri- and tetrapeptide mimetics possessing the γ-ketoamide functionality. No epimerization was observed with the mild conditions used for these reactions. Copyright © 2003 American Chemical Society.