During the last 30 years, various biological active peptides have been discovered and characterized. Thus, these peptides are focused by the biomedical field, and the number of natural and modified peptides that are used as therapeutics is still increasing. It is highly important to enhance the activity of peptidic compounds by changing a part or whole of these molecules. Alkene-type dipeptide isosteres (ADIs) are expected as “peptidomimetics” due to a high structural homology with natural dipeptides (1). Among them, chloroalkene dipeptide isosteres (CADIs) are considered to be ideal peptide bond mimetics because of their steric and electronic mimicking. We have developed a synthetic methodology for CADIs as chemical equivalents of peptides. Recently, we have reported that chloroalkene structures can be constructed by treatment of γ,γ-dichloro-α,β-unsaturated carbonyl compounds with organocopper reagents (2).
In this study, based on this reaction we have developed a synthetic strategy for the CADIs (3). The synthesis of L-Xaa-Gly-type CADIs from γ,γ-dichloro-α-β-unsaturated esters using a higher-order organocopper reagent was succeeded (4). In addition, treatment of the substrates having the (E)- or (Z)-olefin geometry with lower-order organocopper reagents provided the corresponding (L,D)- or (L,L)-type CADIs in high yield and diastereoselectivity. Furthermore, successful formation of Boc- or Fmoc-protected carboxylic acids of CADIs from the common intermediates was performed for peptide synthesis. Utilizing this methodology, a CADI was incorporated into a bioactive cyclic RGD peptide to find that the synthesized CADI-containing cyclic RGD peptidomimic showed higher inhibitory activity than the parent cyclic peptide.