Solid phase synthesis of peptide aldehydes

Abstract

For the last few years, we have been involved in the synthesis of peptide aldehydes on solid support. Peptide aldehydes are excellent starting material for many chemistries (formation of reduced bond, Wittig reactions, ligation...) and have been found to be potential inhibitors of several classes of enzymes such as serine proteases [1, 2], prohormone convertases [3], cysteyl proteases [4, 5] and aspartyl proteases [6, 7]. These inhibitory properties result from the tetrahedral hydrated C-terminus aldehyde function, which mimics the transition state of the substrate during hydrolysis. Various methods for the synthesis of peptide aldehydes in solution have been described, for example, the peptide alcohol can be oxidized into the corresponding aldehyde [8, 9]. Another widely used strategy is the diisobutylaluminium hydride reduction of the corresponding methyl esters [10]. The synthesis of argininal analogues, due to their significant activities for anticoagulant and antithrombotic properties, has been often reported using s-lactam [2, 11, 12] and semicarbazone derivatives [1] The synthesis of an interleukin-1 s converting enzyme inhibitor having an aspartyl residue at the C-terminal was described by Chapman [4]. The aspartyl aldehyde moiety was protected as its corresponding O-benzylacylal which could be coupled and then hydrogenolyzed to afford the desired compound. Recent reports have mentioned the use of thiazolidines [ 13] or oxazolidine [ 14] as aldehyde precursors. However there are very few publications concerning the solid phase synthesis of peptide aldehydes [ 15, 16].