A new strategy applied to the synthesis of an α-helical bicyclic peptide constrained by two overlapping i, i+7 side-chain bridges of novel design

Article abstract of DOI:10.1016/0040-4039(96)00121-9

A conformationally constrained, bicyclic, 14-residue peptide containing two overlapping i, i+7 side-chain bridges has been synthesized. The design of the side-chain linkage, which is built around a p-substituted benzene ring for rigidity, and the solid-phase approach applied to the peptide synthesis, are both new. A Boc/Benzyl peptide chain assembly method was combined with Fmoc/OFm orthogonal side-chain deprotection and solid-phase cyclization to form the first side-chain lactam bridge. A 2-(2-pyridyl)ethyl group (2-Pet), activated by methylation with CH₃I in DMF, was then used in combination with Fmoc to allow a second orthogonal side-chain deprotection and solid-phase cyclization to form the second bridge. The circular dichroism spectrum of the product indicates that it is highly helical.