The synthesis of complex molecules such as those used in pharmaceuticals depends heavily on the ability to rapidly and efficiently construct carbon-carbon bonds. Over the past decades, olefin metathesis has become a key tool for such a process. Olefin metathesis has been used widely in drug discovery and is now moving into process chemistry. A number of pharmaceutical agents that are made possible by the metathesis reaction have proceeded through Phase II trials and a number are now entering into Phase III. Although the olefin metathesis reaction has been known for a number of decades, it has only become useful in organic synthesis with the discovery of highly active and stable catalysts that are tolerant of most functional groups and are easily used by organic chemists. The modification of ligands on the basic ruthenium-based metathesis complexes has resulted in highly efficient catalysts that are used in a wide array of applications, from pharmaceutical synthesis to the construction of high end composites. Each advance in catalyst efficiency and selectivity has opened a variety of new applications. One of the final deficiencies in catalyst design has been the lack of control of double bond geometry. In most cases, the reactions produce a majority of the more stable E geometric isomer. During the last granting period, major breakthroughs have been made in the design of catalyst that will produce Z-olefins in high yields from simple terminal olefins. These catalysts open many new applications. During the next granting period, efforts will be made to increase their efficiency and selectivity, and to develop applications that exploit their capabilities. Building on the lessons from the discovery of a Z-selective catalyst, new systems will be designed that will be focused on the synthesis of purely E-olefins. The results from the next granting period will further enhance the utility of the powerfl olefin metathesis reaction in the synthesis of new pharmaceuticals and bioactive molecules.

Public Health Relevance

Key to the discovery of new pharmaceuticals is the availability of efficient synthetic methods for the rapid creation of complex structures. Olefin metathesis has emerged as a powerful method for this application and has become an important tool for drug discovery and synthesis. Efficient and selective catalysts open up possibilities for the formation of novel compounds. New catalysts that control the geometry and methods of coupling olefins will further enhance the capabilities of this reaction with ever expanding applications.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM031332-30
Application #
8635353
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
1994-10-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
30
Fiscal Year
2014
Total Cost
$424,762
Indirect Cost
$163,624
Name
California Institute of Technology
Department
None
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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