Ring-closing metathesis of olefinic peptides: design, synthesis, and structural characterization of macrocyclic helical peptides.
Heptapeptides containing residues with terminal olefin-derivatized side chains (3 and 4) have been treated with ruthenium alkylidene 1 and undergone facile ring-closing olefin metathesis (RCM) to give 21- and 23-membered macrocyclic peptides (5 and 6). The primary structures of peptides 3 and 4 were based upon a previously studied heptapeptide (2), which was shown to adopt a predominantly 3(10)-helical conformation in CDCl(3) solution and an alpha-helical conformation in the solid state. Circular dichroism, IR, and solution-phase (1)H NMR studies strongly suggested that acyclic precursors 3 and 4 and the fully saturated macrocyclic products 7 and 8 also adopted helical conformations in apolar organic solvents. Single-crystal X-ray diffraction of cyclic peptide 8 showed it to exist as a right-handed 3(10)-helix up to the fifth residue. Solution-phase NMR structures of both acyclic peptide 4 and cyclic peptide 8 in CD(2)Cl(2) 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.
Blackwell
H E
HE
The Arnold and Mabel Beckman Laboratory of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
Sadowsky
J D
JD
Howard
R J
RJ
Sampson
J N
JN
Chao
J A
JA
Steinmetz
W E
WE
O'Leary
D J
DJ
Grubbs
R H
RH
D000475:Alkenes / Q000138:chemical synthesis* / Q000737:chemistry; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D017433:Protein Structure, Secondary; D013055:Spectrophotometry, Infrared
D000475:Alkenes; D010456:Peptides, Cyclic