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Published September 3, 2014 | Supplemental Material + Published
Journal Article Open

Z-Selective Olefin Metathesis on Peptides: Investigation of Side-Chain Influence, Preorganization, and Guidelines in Substrate Selection


Olefin metathesis has emerged as a promising strategy for modulating the stability and activity of biologically relevant compounds; however, the ability to control olefin geometry in the product remains a challenge. Recent advances in the design of cyclometalated ruthenium catalysts has led to new strategies for achieving such control with high fidelity and Z selectivity, but the scope and limitations of these catalysts on substrates bearing multiple functionalities, including peptides, remained unexplored. Herein, we report an assessment of various factors that contribute to both productive and nonproductive Z-selective metathesis on peptides. The influence of sterics, side-chain identity, and preorganization through peptide secondary structure are explored by homodimerization, cross metathesis, and ring-closing metathesis. Our results indicate that the amino acid side chain and identity of the olefin profoundly influence the activity of cyclometalated ruthenium catalysts in Z-selective metathesis. The criteria set forth for achieving high conversion and Z selectivity are highlighted by cross metathesis and ring-closing metathesis on diverse peptide substrates. The principles outlined in this report are important not only for expanding the scope of Z-selective olefin metathesis to peptides but also for applying stereoselective olefin metathesis in general synthetic endeavors.

Additional Information

© 2014 American Chemical Society. ACS AuthorChoice Received: July 15, 2014; Published: August 7, 2014. This work was financially supported by the NIH (NIH R01-GM031332). Research at Pomona College was funded in part by the Gordon and Betty Moore Foundation. NMR spectra were obtained on instruments supported by the NIH (RR027690). Materia, Inc., is acknowledged for the generous donation of catalysts 1 and 2. The authors also thank Scott Virgil (Caltech Center for Catalysis and Chemical Synthesis), Samir Das, and Arundhati Nag for helpful discussions.

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Published - ja507166g.pdf

Supplemental Material - ja507166g_si_001.pdf


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