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 #
2R01GM031332-29
Application #
8504608
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
2013-04-01
Budget End
2014-02-28
Support Year
29
Fiscal Year
2013
Total Cost
$359,186
Indirect Cost
$126,186
Name
California Institute of Technology
Department
None
Type
Schools of Engineering
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
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
Liu, Yiyang; Kim, Kelly E; Herbert, Myles B et al. (2014) Palladium-Catalyzed Decarbonylative Dehydration of Fatty Acids for the Production of Linear Alpha Olefins. Adv Synth Catal 356:130-136
Hartung, John; Grubbs, Robert H (2014) Catalytic, enantioselective synthesis of 1,2-anti-diols by asymmetric ring-opening/cross-metathesis. Angew Chem Int Ed Engl 53:3885-8
Hartung, John; Dornan, Peter K; Grubbs, Robert H (2014) Enantioselective olefin metathesis with cyclometalated ruthenium complexes. J Am Chem Soc 136:13029-37
Schwaid, Adam G; Shannon, D Alexander; Ma, Jiao et al. (2014) Correction to "chemoproteomic discovery of cysteine-containing human short open reading frames. J Am Chem Soc 136:820
Cannon, Jeffrey S; Zou, Lufeng; Liu, Peng et al. (2014) Carboxylate-assisted C(spĀ³)-H activation in olefin metathesis-relevant ruthenium complexes. J Am Chem Soc 136:6733-43
Pribisko, Melanie A; Ahmed, Tonia S; Grubbs, Robert H (2014) Z-Selective Ruthenium Metathesis Catalysts: Comparison of Nitrate and Nitrite X-type Ligands. Polyhedron 84:144-149
Mangold, Shane L; O'Leary, Daniel J; Grubbs, Robert H (2014) Z-Selective olefin metathesis on peptides: investigation of side-chain influence, preorganization, and guidelines in substrate selection. J Am Chem Soc 136:12469-78
Rosebrugh, Lauren E; Herbert, Myles B; Marx, Vanessa M et al. (2013) Highly active ruthenium metathesis catalysts exhibiting unprecedented activity and Z-selectivity. J Am Chem Soc 135:1276-9
Cannon, Jeffrey S; Grubbs, Robert H (2013) Alkene chemoselectivity in ruthenium-catalyzed Z-selective olefin metathesis. Angew Chem Int Ed Engl 52:9001-4

Showing the most recent 10 out of 44 publications