He. Blackwell et al., Ring-closing metathesis of olefinic peptides: Design, synthesis, and structural characterization of macrocyclic helical peptides, J ORG CHEM, 66(16), 2001, pp. 5291-5302
Heptapeptides containing residues with terminal olefin-derivatized side cha
ins (3 and 4) have been treated with ruthenium alkylidene 1 and undergone f
acile ring-closing olefin metathesis (RCM) to give 21- and 23-membered, mac
rocyclic peptides (5 and 6). The primary structures of peptides 3 and 4 wer
e based upon a previously studied heptapeptide (2), which was shown to adop
t a predominantly 3(10)-helical conformation in CDCl3 solution and an alpha
-helical conformation in the solid state. Circular dichroism, IR, and solu
tion-phase H-1 NMR studies strongly suggested that acyclic precursors 3 and
4 and the fully saturated macrocyclic products 7 and 8 also adopted helica
l conformations in apolar organic solvents. Single-crystal X-ray diffractio
n of cyclic peptide 8 showed it to exist as a right-handed 3(10)-helix up t
o the fifth residue. Solution-phase NMR structures of both acyclic peptide
4 and cyclic peptide 8 in CD2Cl2 indicated that the acyclic diene assumes a
loosely 3(10)-helical conformation, which is considerably rigidified upon
macrocyclization. The relative ease of introducing carbon-carbon bonds into
peptide secondary structures by RCM and the predicted metabolic stability
of these bonds renders olefin metathesis an exceptional methodology for the
synthesis of rigidified peptide architectures.