Cyclooligomerization of a helix-bearing template into macrocycles bearing multiple helices

Cyclooligomerization was investigated for separating and spatially arranging helical peptides as discontinuous surfaces. Tetrapeptide H-Ile-Ser-Lys(Ox)]-OH, containing a turn-inducing oxazole constraint, was connected through its lysine side chain via a beta-alanine linker to the C-terminus of a two-turn helical nonapeptide Ac-(cyclo-4,8)-LRL KARAD](Aib). The resulting helix-appended template was self-condensed and cyclized to a library of macrocycles ( n = 2-6) containing multiple (2-6) helices. An NMR structure shows retention of alpha helicity in the cyclotrimer ( n = 3).