Synthesis of N′-substituted Ddz-protected hydrazines and their application in solid phase synthesis of aza-peptides

Hydrazine derivatives are of considerable scientific and industrial value. Substituted hydrazines are precursors for many compounds of great interest and importance, among them aza-peptides. (Aza-peptides are peptide analogues in which one or more of the α-carbons, bearing the side chain residues, has been replaced by a nitrogen atom.) Aza-amino acid residues conserve the pharmacophores necessary for biological activity while inducing conformational changes and increased resistance to proteolytic degradation. These properties make aza-peptides attractive tools for structure-activity relationship studies and drug design. We describe the synthesis of N′-substituted 2-(3,5-dimethoxyphenyl)propan-2-yloxycarbonyl (Ddz) protected hydrazines. A general approach for solid phase synthesis of aza-peptides has been developed based on the in-situ activation of the N-Ddz,N′-substituted hydrazines with phosgene, followed by introduction to the N-terminus of a resin-bound peptide. The Ddz-aza-amino building units include aliphatic, aromatic and functionalized side chains, protected for synthesis by the Fmoc strategy. Solid phase aza-peptide synthesis is demonstrated including selective mild deprotection of Ddz with Mg(ClO4)2 and coupling of the next amino acid with triphosgene. Ddz deprotection is orthogonal with the Fmoc and Boc protecting groups, making the solid phase Ddz-aza-peptide synthesis compatible with both the Fmoc and the Boc strategies. The Ddz-protected hydrazines have wide applications in the synthesis of substituted hydrazines and in the synthesis of aza containing peptidomimetics.

Graphical abstractSubstituted hydrazines are precursors for many compounds of considerable scientific and industrial value. We describe the synthesis of N′-substituted 2-(3,5-dimethoxyphenyl)propan-2-yloxycarbonyl (Ddz) protected hydrazines. A general approach for solid phase synthesis of aza-peptides has been developed based on the in-situ activation of the N-Ddz,N′-substituted hydrazines with phosgene, followed by introduction to the N-terminus of resin-bound peptide. Ddz-protected hydrazines have wide applications in the synthesis of substituted hydrazines and in the synthesis of aza containing peptidomimetics.Download full-size image