Multicyclic Polypeptide Model Compounds. 1. Synthesis of a Tricyclic Amphiphilic α-Helical Peptide Using an Oxime Resin, Segment-Condensation Approach

An idealized model amphiphilic α-helical peptide, cyclo(3-7,10-14,17-21) H-[LysLeuLysGluLeuLysGlu]₃-OH (peptide 1-1-1), comprising three repeats of a Lys³-Glu⁷ side-chain bridged heptapeptide, has been synthesized by a generally applicable segment-condensation approach that involves a novel solid-phase cyclization reaction. The linear heptapeptide, Boc-Lys-(2Cl-Z)LeuLys(Trt)Glu(OBzl)LeuLys(2Cl-Z)Glu(oxime resin)-OPac, was built on a p-nitrobenzophenone oxime derivatized polystyrene solid support by standard methods. After selective detritylation with TFA, the Lys³ ϵ-amino group was liberated with DIEA, and then intrachain cyclization in the presence of AcOH released the protected cyclic heptapeptide precursor to peptide 1-1-1 into the solvent in 61% yield and high purity. Selective N^α-and C^α-group deprotection, followed by two solution-phase segment-condensation reactions and then complete deprotection with trimethylsilyl triflate, yielded peptide 1-1-1. Circular dichroism spectra indicated that peptide 1-1-1 adopted mostly disordered conformations in aqueous solution, but a high α-helix content was induced in 50% TFE and upon adsorption of peptide 1-1-1 from aqueous solution onto siliconized quartz slides.