Development of Methods for Convergent Synthesis of Chloroalkene Dipeptide Isosteres and Its Application

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-beta aggregation than the parent peptide.

Automated summary

This study reports improved methods for convergent synthesis using a chloroalkene dipeptide isostere (CADI), demonstrating the direct application of Fmoc-protected CADI in solid-phase peptide synthesis and the discovery of a CADI-containing peptidomimetic with superior inhibitory effects on amyloid-beta aggregation compared to the parent peptide.