Synthesis of Chlorinated Oligopeptides via & gamma;- and & delta;-Selective Hydrogen Atom Transfer Enabled by the N-Chloropeptide Strategy

The introduction of a chlorine atom could potentiallyendow peptidederivatives with notable bioactivity and applicability. However, despiteconsiderable recent progress in C(sp(3))-H functionalizationchemistry, a general method for the site-selective chlorination ofinert aliphatic C-H bonds in peptides still remains elusive.Herein, we report a site-selective C(sp(3))-H chlorinationof oligopeptides based on an N-chloropeptide strategy. N-chloropeptides, which are easily prepared from the correspondingnative oligopeptides, are smoothly degraded in the presence of anappropriate copper catalyst, and a subsequent 1,5-hydrogen atom transferaffords & gamma;- or & delta;-chlorinated peptides in excellent yield.A wide variety of amino acid residues can thus be site-selectivelychlorinated in a predictable manner. This method hence enables theefficient synthesis of otherwise less accessible, chlorine-containingpeptide fragments of natural peptides. We moreover demonstrate herethe successful estimation of the stereochemistry of the chlorinatedcarbon atom in aquimarin A. Furthermore, we reveal that side-chain-chlorinatedpeptides can serve as highly useful substructures with a fine balancebetween stability and reactivity, which renders them promising targetsfor synthetic and medicinal applications.