MULTICYCLIC POLYPEPTIDE MODEL COMPOUNDS .1. SYNTHESIS OF A TRICYCLIC AMPHIPHILIC ALPHA-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 Nα-and Cα-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. © 1990, American Chemical Society. All rights reserved.