Development of Methods for Convergent Synthesis of Chloroalkene Dipeptide Isosteres and Its Application
Takuya Kobayakawa, Chika Azuma, Yuki Watanabe, Shunsuke Sawamura, Atsuhiko Taniguchi, Yoshio Hayashi, Kohei Tsuji, Hirokazu Tamamura
Abstract
Improved methods of convergent synthesis for peptidomimetic utilizing a chloroalkene dipeptide isostere (CADI) are reported. In this synthesis, Fmoc- or Boc-protected carboxylic acids can be produced from N- and C-terminal analogues corresponding to each amino acid starting material via an Evans syn aldol reaction, followed by a [3.3] sigmatropic rearrangement utilizing the Ichikawa allylcyanate rearrangement reaction. With this strategy, an Fmoc-protected CADI can be directly applied for solid-phase peptide synthesis. Using this approach, we have also identified the CADI-containing cyclo[-Lys-Leu-Val-Phe-Phe-] peptidomimetic, which is a superior inhibitor of amyloid-β aggregation than the parent peptide.