The construction of pharmaceutical and bioactive molecules relies on methods for the formation of carbon-carbon bonds. Over the past decade olefin metathesis has emerged as a powerful means by which to form these bonds in applications ranging from, but not limited to, small organic molecules, complex natural products, and well-controlled polymer architectures. The availability of robust catalysts that are highly active, efficient, stable, and selective is key to the further development of these wide-ranging applications. Over the last granting period catalysts were prepared that facilitate metathesis (a) in aqueous solutions, (b) with sterically hindered substrates, (c) at lower catalyst loadings, and (d) with higher levels of enantioselectivity. A powerfully simple method for the construction of N-heterocyclic carbene ligands was developed. This method will be exploited over the next granting period for the development of stereoselective metathesis catalysts (controlling the trans:cis ratio of the carbon-carbon double bonds), and improvement of catalyst stability (to lower catalyst loadings), among other proposed improvements. The design and preparation of such catalysts would further enable the rapid and selective formation of biologically-relevant chemical compounds.

Public Health Relevance

The preparation of bioactive molecules remains a significant challenge in the study of human health and related fields. Olefin metathesis is now routinely used for the constructions of such molecules. Development of catalysts for this reaction is key to the advancement of this powerful carbon-carbon bond forming technology.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM031332-28
Application #
8231281
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
1994-10-01
Project End
2013-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
28
Fiscal Year
2012
Total Cost
$351,264
Indirect Cost
$120,940
Name
California Institute of Technology
Department
Chemistry
Type
Schools of Engineering
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Rosebrugh, L E; Ahmed, T S; Marx, V M et al. (2016) Probing Stereoselectivity in Ring-Opening Metathesis Polymerization Mediated by Cyclometalated Ruthenium-Based Catalysts: A Combined Experimental and Computational Study. J Am Chem Soc 138:1394-405
Dornan, Peter K; Lee, Daniel; Grubbs, Robert H (2016) Tandem Olefin Metathesis/Oxidative Cyclization: Synthesis of Tetrahydrofuran Diols from Simple Olefins. J Am Chem Soc 138:6372-5
Martin, David; Marx, Vanessa M; Grubbs, Robert H et al. (2016) A Ruthenium Catalyst for Olefin Metathesis Featuring an Anti-Bredt N-Heterocyclic Carbene Ligand. Adv Synth Catal 358:965-969
Endo, Koji; Grubbs, Robert H (2016) Cationic ruthenium alkylidene catalysts bearing phosphine ligands. Dalton Trans 45:3627-34
Dornan, Peter K; Wickens, Zachary K; Grubbs, Robert H (2015) Tandem Z-Selective Cross-Metathesis/Dihydroxylation: Synthesis of anti-1,2-Diols. Angew Chem Int Ed Engl 54:7134-8
Wickens, Zachary K; Guzmán, Pablo E; Grubbs, Robert H (2015) Aerobic palladium-catalyzed dioxygenation of alkenes enabled by catalytic nitrite. Angew Chem Int Ed Engl 54:236-40
Mangold, Shane L; Grubbs, Robert H (2015) Stereoselective synthesis of macrocyclic peptides via a dual olefin metathesis and ethenolysis approach. Chem Sci 6:4561-4569
Liu, Yiyang; Virgil, Scott C; Grubbs, Robert H et al. (2015) Palladium-Catalyzed Decarbonylative Dehydration for the Synthesis of α-Vinyl Carbonyl Compounds and Total Synthesis of (-)-Aspewentins A, B, and C. Angew Chem Int Ed Engl 54:11800-3
Marx, Vanessa M; Sullivan, Alexandra H; Melaimi, Mohand et al. (2015) Cyclic alkyl amino carbene (CAAC) ruthenium complexes as remarkably active catalysts for ethenolysis. Angew Chem Int Ed Engl 54:1919-23
Bronner, Sarah M; Herbert, Myles B; Patel, Paresma R et al. (2014) Ru-Based Z-Selective Metathesis Catalysts with Modified Cyclometalated Carbene Ligands. Chem Sci 5:4091-4098

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