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Ring-Closing Metathesis of Olefinic Peptides: Design, Synthesis, and Structural Characterization of Macrocyclic Helical Peptides

Blackwell, Helen E. and Sadowsky, Jack D. and Howard, Rebecca J. and Sampson, Joshua N. and Chao, Jeffery A. and Steinmetz, Wayne E. and O'Leary, Daniel J. and Grubbs, Robert H. (2001) Ring-Closing Metathesis of Olefinic Peptides: Design, Synthesis, and Structural Characterization of Macrocyclic Helical Peptides. Journal of Organic Chemistry, 66 (16). pp. 5291-5302. ISSN 0022-3263. http://resolver.caltech.edu/CaltechAUTHORS:20170427-083244053

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Abstract

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 α-helical conformation in the solid state. Circular dichroism, IR, and solution-phase ^1H 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_2Cl_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.


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http://dx.doi.org/10.1021/jo015533kDOIArticle
http://pubs.acs.org/doi/abs/10.1021/jo015533kPublisherArticle
http://pubs.acs.org/doi/suppl/10.1021/jo015533kPublisherSupporting Information
ORCID:
AuthorORCID
Grubbs, Robert H.0000-0002-0057-7817
Additional Information:© 2001 American Chemical Society. Received 20 January 2001. Published online 11 May 2001. Published in print 1 August 2001. Work at Caltech was generously supported by the National Institutes of Health (NIH) and AstraZeneca. Work at Pomona College was supported by the National Science Foundation (NSF). H.E.B. thanks the ACS Division of Organic Chemistry for a predoctoral graduate fellowship (supported by Pfizer, Inc.). Dr. Saeed Khan (UCLA) is gratefully acknowledged for X-ray crystallographic analyses. Prof. Andrew T. Morehead, Jr. is acknowledged for assistance in preliminary molecular modeling studies. We thank Dr. Isabella L. Karle, Prof. Barbara Imperiali, Prof. Scott J. Miller, and Dr. Keith Russell for helpful discussions. We are grateful to Jack Sadowsky for his creative artwork featured on the cover of this journal.
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Funding AgencyGrant Number
NIHUNSPECIFIED
AstraZenecaUNSPECIFIED
NSFUNSPECIFIED
PfizerUNSPECIFIED
American Chemical Society Organic DivisionUNSPECIFIED
Record Number:CaltechAUTHORS:20170427-083244053
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20170427-083244053
Official Citation:Ring-Closing Metathesis of Olefinic Peptides:  Design, Synthesis, and Structural Characterization of Macrocyclic Helical Peptides Helen E. Blackwell, Jack D. Sadowsky, Rebecca J. Howard, Joshua N. Sampson, Jeffery A. Chao, Wayne E. Steinmetz, Daniel J. O'Leary, and Robert H. Grubbs The Journal of Organic Chemistry 2001 66 (16), 5291-5302 DOI: 10.1021/jo015533k
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:76981
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:27 Apr 2017 16:33
Last Modified:27 Apr 2017 16:33

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