Grantee Research Project Results
Final 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 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 objectives of the research project were to: (1) develop catalysts that imitate the selectivity and effectiveness of enzymes; and (2) operate in water to perform selective oxidations of important substrates and other useful transformations under environmentally benign conditions.
Summary/Accomplishments (Outputs/Outcomes):
This is a description of what has been achieved under this grant in the past 3 years. Work continues on the project, with the hope that a new grant, which has been applied for, will be approved.
In previous work, we had prepared a catalyst 1 carrying cyclodextrins. We had shown that catalyst 1 was able to perform the selective hydroxylation of an androstane 2 derivative 3 in water solution at carbon 6, producing only the equatorial alcohol 5 after hydrolysis of the ester groups in 4. However, only about five turnovers were achieved before the catalyst itself was oxidatively destroyed. Our specific proposals were built on this prior finding.
The following are the objectives of the project, along with what we have achieved so far:
- Modify the catalysts so that they are stable, permitting higher turnovers. This has been very successful. We prepared catalyst 7 with fluorinated phenyl groups (Figure 1), as we had proposed, and by both the original pathway and a later improved very short synthetic path. We found that this catalyst was able to perform the selective hydroxylations with almost 400 turnovers, instead of the 5 turnovers of catalyst 1. Again, the reaction was performed in environmentally benign water solution. We have found that 8, an analog of 7 with one nitrophenyl group and only three attached cyclodextrins, performs the processes with 3,000 turnovers?a huge improvement.
Furthermore, the catalysts made so far have beta-cyclodextrin linked para to a phenyl group on the meso position of the porphyrin. We need to modify the catalysts to change the binding geometry of substrates, both to understand the geometric control possible and to help in the design of catalysts for specific functions.
- Prepare new catalysts with modified binding geometry of various substrates. This also has been quite successful. We prepared an analog of catalyst 1 with the cyclodextrins linked to the meta positions of the phenyl rings and saw that for many processes, it was not different from the original 1, but for a specific hydroxylation at C-9 with a novel substrate, it was completely selective while 1 was not.
In the work to date, the metalloporphyrins have incorporated either Mn(III) or, less effectively, Fe(III). Other metals can have different and better properties, such as ruthenium and rhodium.
- Incorporate other metals into the porphyrin system to compare the properties with those of the existing catalysts. We have done this; so far, nothing exciting has been achieved with these new catalysts, but it is too early to know all their potential.
H2O2 also is a practical candidate. In previous work, we even showed that a nitrogen analog 16 of iodosobenzene can be used to transfer a nitrogen atom. The oxidant used so far is iodosobenzene, which is known to transfer oxygen atoms to some metalloporphyrins.
However, the literature has examples in which other, and cheaper, oxidants are used for such processes. The most attractive is O2 itself, and catalytic amination with geometric control could be very attractive.
- Generalize the oxidizing reagents that are used along with the catalysts. We have examined a number of other oxidizing agents, but, so far, iodosobenzene is still the best. We hope to examine this situation further, if our new grant proposal is funded.
The substrates examined so far are not the limit of the possibilities. In the first work, we need to clarify the products formed with those substrates that gave mixtures of products, so we can understand the nature of the freedom in the molecular complex. Then we need to examine other substrates that can be of equal or greater interest.
- Generalize the substrates to be oxidized or aminated. This has been pursued quite extensively. By extending the linkers in the substrates such as 3, we have been able to move the position of hydroxylation around in a predictable fashion, in particular, moving it to ring D of the steroid.
Most exciting is the finding with a substrate 9 in which we attach binding ester groups to all three of the hydroxyls in compound 5. Molecular models show that this tilts the steroid so that the hydrogen on carbon 9 is presented to the Mn=O group in catalyst 7. We find that this is indeed the case, and that we can hydroxylate this position and thus have direct entry into medicinally useful corticosteroids. Until now, the only practical way to achieve this hydroxylation was using microbiological fermentation, which is not an environmentally clean process. Other substrates also can be used with our catalysts to achieve this very important selective hydroxylation. This is part of what we hope to pursue in the grant currently being considered.
Journal Articles on this Report : 17 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. Biomimetic chemistry: A frontier at the chemistry/biology interface. Chemistry & Biology 1998;5(2):R27-R28. |
R826653 (Final) |
not available |
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Breslow R, Dong SD. Biomimetic reactions catalyzed by cyclodextrins and their derivatives. Chemistry Review 1998;98(5):1997-2011. |
R826653 (Final) |
not available |
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Breslow R. Bioorganic chemistry: A natural and unnatural science. Journal of Chemical Education 1998;75(6):705-718. |
R826653 (Final) |
not available |
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Breslow R, Gabriele B, Yang J. Geometrically directed selective steroid hydroxylation with high turnover by a fluorinated artificial cytochrome P-450. Tetrahedron Letters 1998;39(19):2887-2890. |
R826653 (Final) |
not available |
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Breslow R. Studies in biomimetic chemistry. Pure and Applied Chemistry 1998;70(2):267-270. |
R826653 (Final) |
not available |
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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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Breslow R. Biomimetic selectivity. Chemical Record 2001;1(1):3-11. |
R826653 (Final) |
not available |
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Dong SD, Breslow R. Bifunctional cyclodextrin metalloenzyme mimics. Tetrahedron Letters 1998;39(51):9343-9346. |
R826653 (Final) |
not available |
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Fasella E, Dong SD, Breslow R. Reversal of optical induction in transamination by regioisomeric bifunctionalized cyclodextrins. Bioorganic & Medicinal Chemistry 1999;7(5):709-714. |
R826653 (Final) |
not available |
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Liu L, Breslow R. Selective racemization in preference to transamination catalyzed by pyridoxal enzyme analogs. Tetrahedron Letters 2001;42(15):2775-2777. |
R826653 (Final) |
not available |
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Sprecher M, Breslow R, Philosof-Oppenheimer R, Chavet E. Steroid phosphate esters. Tetrahedron 1999;55(17):5465-5482. |
R826653 (Final) |
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 |
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Yang J, Weinberg R, Breslow R. The hydroxylation and amidation of equilenin acetate catalyzed by chloro[5,10,15,20-tetrakis(pentafluorophenyl)porphyrinato]manganese(III). Chemical Communications 2000;7:531-532. |
R826653 (Final) |
Exit |
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Yang J, Gabriele B, Belvedere S, Huang Y, Breslow R. Catalytic oxidations of steroid substrates by artificial cytochrome P-450 enzymes. Journal of Organic Chemistry 2002;67(15):5057-5067. |
R826653 (Final) |
not available |
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Yuan DQ, Dong SD, Breslow R. Cyclodextrin-based class I aldolase enzyme mimics to catalyze crossed aldol condensations. Tetrahedron Letters 1998;39(42):7673-7676. |
R826653 (Final) |
not available |
Supplemental Keywords:
cytochrome P-450, environmentally benign solvents., 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:
Welcome to Professor Breslow's labs, Department of Chemistry, Columbia University 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.