Grantee Research Project Results
2000 Progress Report: Biomimetic Chemistry in Water Solution
EPA Grant Number: R826653Title: Biomimetic Chemistry in Water Solution
Investigators: Breslow, Ronald
Institution: Columbia University in the City of New York
EPA Project Officer: Aja, Hayley
Project Period: August 3, 1998 through August 2, 2001
Project Period Covered by this Report: August 3, 1999 through August 2, 2000
Project Amount: $376,747
RFA: Exploratory Research - Environmental Chemistry (1998) RFA Text | Recipients Lists
Research Category: Air , Safer Chemicals , Land and Waste Management , Sustainable and Healthy Communities
Objective:
The objective of this research project is to develop catalysts that imitate the selectivity and effectiveness of enzymes, and operate in water to perform selective oxidations of important substrates and other useful transformations.
Progress Summary:
At the time of the grant application, we had a selective catalyst that hydroxylated a saturated steroid in water solution, but with only 5 turnovers. We proposed to synthesize a related catalyst carrying perfluorinated phenyl rings, to stabilize the catalyst to oxidation, and this was achieved in the first year and described in the first year report.
The new stabilized catalyst then performed the same selective oxidation as did the previous unfluorinated catalyst, but now with 187 turnovers instead of the previous 5. When chlorine atoms were placed on the pyrrole rings as well, the resulting catalyst now performed selective oxidations with almost 400 turnovers.
We find that this fluorinated catalyst is easy to make, and other chemists have duplicated our synthesis and developed selective reactions related to ours, also performed in water solution. We have used it as the basis for the second year work, generalizing the substrates to be oxidized, the metal ions to be incorporated in the porphyrin, and the oxidants used with the catalyst. In particular, we have examined metal ions other than the manganese of our published work, and find some useful differences. Some work related to this is described in reference 8.
We have some evidence on the process that eventually kills the catalysts--the cyclodextrin rings are apparently eventually oxidized. Thus, our indication in the original proposal that we would replace the cyclodextrins with other more stable binding groups is especially important, and work on this is underway, but not yet completed.
We also proposed to adjust the geometry of the catalyst-substrate complex so as to direct the oxidations to positions other than those attacked in our first system. This has had some success, but more is needed. As hoped, we can move the point of functionalization from ring B of the steroid into ring D with a rationally designed change in geometry.
The most striking advance is described in reference 5. We had proposed to learn how to carry out the selective hydroxylation of C-9 in a steroid, to replace fermentation reactions in the commercial synthesis of corticosteroids. We have succeeded in this, by changing the mode of binding of the substrate to our catalyst. Specifically, we use three point binding of the substrate into the catalyst, which rotates the substrate so as to present the important C-9 hydrogen. We find exclusive hydroxylation at this otherwise inaccesible position. The resulting 9-hydroxy steroid can be dehydrated to introduce a 9(11) double bond, which is currently used in the manufacture of corticosteroids. However, current manufacturing procedures are not environmentally friendly.
Also, we had proposed to try to account for our findings using computer modeling. Again this has been successful. Our computer model accounts for the reaction at C-6 of the steroid in the original work, and the change to reaction at C-9 in the new work.
We also proposed to examine substrates other than androstane derivatives, and some of this has been done. Perhaps the most exciting finding is that it is apparently possible to oxidize an unactivated carbon atom in a lithocholenic acid derivative even in the presence of the normally more reactive double bond. This is the geometric control we have hoped for, that completely reverses normal selectivities, and if the results can be confirmed and amplified they will be a real advance. Since this was first reported we have found that indeed our reported findings are correct.
We also proposed to use reagents other than iodosobenzene along with our catalysts. Several have been tried, but none has any yield advantage yet. However, some of them are more environmentally benign than is iodosobenzene, so they may be of importance and will be pursued.
Some novel catalysts have been prepared. As we proposed, we have replaced the manganese of our oxidation catalyst with ruthenium and rhodium. The ruthenium catalyst performs some novel oxidations not well done by the original manganese catalyst, while the rhodium catalyst has the potential to perform carbon-carbon bond formation. This has been further examined in the second year.
The general description of our catalysts is a combination of binding groups?preferably at least two?and metal catalyst groups that will hold a substrate in a well defined position and carry out selective chemistry in water solution. We have described a catalyst system that does not use a porphyrin as the metal coordinating group, but instead uses a derivative of bipyridyl. The result is a catalyst that binds some substrates strongly in water and then performs a catalytic hydrolysis promoted by the metal ion of the catalyst. Now we have started an examination of this system as an oxidation catalyst, which will have very different geometric aspects than does the porphyrin-based system we have concentrated on so far. This work will be pursued vigorously in year 3 of the grant.
The funds for the first and second year have been fully expended, and we are now operating on funding for the third year. We expect that it will be sufficient, but that there will be no excess.
Future Activities:
We will continue our efforts to achieve truly important selective functionalizations that can be used in the manufacture of medicinal compounds such as corticosteroids, and vitamins D and A. We hope to show that such manufacturing is better done in water solution with our enzyme mimic catalysts. We will be examining catalysts with different active groups than the metalloporphyrins used to date, and binding groups other than cyclodextrins. We will also be examining new substrates, including those for which selective oxidations will be of great practical interest as they have been for the steroids we have examined to date.
Journal Articles on this Report : 5 Displayed | Download in RIS Format
| Other project views: | All 24 publications | 20 publications in selected types | All 18 journal articles |
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Breslow R, Belvedere S, Gershell L, Leung D. The chelate effect in binding, catalysis, and chemotherapy. Pure and Applied Chemistry 2000;72(3):333-342. |
R826653 (2000) R826653 (Final) |
not available |
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Nesnas N, Lou JH, Breslow R. The binding of cocaine to cyclodextrins. Bioorganic & Medicinal Chemistry Letters 2000;10(17):1931-1933. |
R826653 (2000) |
not available |
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Yan J, Breslow R. An enzyme mimic that hydrolyzes an unactivated ester with catalytic turnover. Tetrahedron Letters 2000;41(13):2059-2062. |
R826653 (2000) R826653 (Final) |
Exit |
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Yang J, Breslow R. Regioselective oxidations of equilenin derivatives catalyzed by a rhodium (III) porphyrin complex-contrast with the manganese (III) porphyrin. Tetrahedron Letters 2000;41(42):8063-8067. |
R826653 (2000) R826653 (Final) |
Exit |
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Yang J, Breslow R. Selective hydroxylation of a steroid at C-9 by an artificial cytochrome P-450. Angewandte Chemie-International Edition 2000;39(15):2692-2694. |
R826653 (2000) R826653 (Final) |
Exit Exit |
Supplemental Keywords:
water, chemicals, green chemistry, innovative technology, clean technologies, environmentally conscious manufacturing, environmental chemistry., Sustainable Industry/Business, Air, Scientific Discipline, Chemical Engineering, Environmental Chemistry, Engineering, Chemistry, & Physics, cleaner production/pollution prevention, water solution, catalysts, pharmaceutical industry, pollution prevention, biometric chemistry, enzymes, cyclodextrin, pharmaceuticals, medicinal compounds, biomimetic synthesis, cleaner production, geometric catalytic selectivity, green chemistryRelevant Websites:
http://www.columbia.edu/cu/chemistry/breslow/boss.html Exit
Progress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.