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Published June 6, 2007 | Supplemental Material
Journal Article Open

Facile and E-Selective Intramolecular Ring-Closing Metathesis Reactions in 3_(10)-Helical Peptides: A 3D Structural Study


The ring-closing metathesis reaction can be used to cross-link allylated serine residues situated at the i and i + 3 positions in 3_(10)-helical peptides containing the helicogenic amino acid, α-aminoisobutyric acid (Aib). An octapeptide with the sequence Boc-Aib-Aib-Aib-Ser(Al)-Aib-Aib-Ser(Al)-Aib-OMe was found to undergo a facile and >20:1 E-selective ring-closing metathesis (RCM) reaction catalyzed by the Grubbs second-generation catalyst to yield an 18-membered macrocycle. The formation of this cross-link does not significantly disturb the peptide's native 3_(10)-helicity, as judged by an X-ray diffraction study of the acyclic diene, the E-olefin RCM product, and its hydrogenated derivative. A heptapeptide system with the sequence Boc-Val-Ser(Al)-Leu-Aib-Ser(Al)-Val-Leu-OMe also underwent an efficient RCM reaction, albeit with diminished E-selectivity. It is apparent from these studies that a minimal, RCM-derived, macrocyclic constraint can be readily incorporated into 3_(10)-helical peptides.

Additional Information

© 2007 American Chemical Society. Received February 16, 2007. Publication Date (Web): May 11, 2007. D.J.O. thanks the Mellon Foundation and Susan and David Hirsch for financial support. Work at Caltech was supported by the National Institutes of Health. We thank Lawrence M. Henling and Dr. Michael W. Day (Caltech) for providing the X-ray crystallographic analysis of peptide 2, and Professor Helen Blackwell (University of Wisconsin) for helpful discussions.

Attached Files

Supplemental Material - ja071148msi20070216_112538.pdf

Supplemental Material - ja071148msi20070216_112607.cif

Supplemental Material - ja071148msi20070216_112625.cif

Supplemental Material - ja071148msi20070216_112644.cif


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