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Organic Chemistry
At the University of Pittsburgh
The Department of Chemistry at the University of Pittsburgh has a long and lustrous record in organic chemistry. Our traditional strengths are in organic synthesis, molecular recognition, and physical organic chemistry. Newly added research fields include chemical biology, catalysis, combinatorial and polymer chemistry. The following paragraphs give a short overview of our faculty and some of our research topics. Please feel free to contact us anytime for more information. An overview of departmental activities and infrastructure can also be found on our web pages at http://www.chem.pitt.edu.
NATURAL PRODUCTS TOTAL SYNTHESIS
The Brummond, Cohen, Curran, Floreancig, Koide, Nelson and Wipf research groups are actively pursuing the total synthesis of biologically active natural products. Examples of natural product targets recently synthesized or currently studied are:
The Koide group is pursuing chemical and biological studies of FR901464, a natural product that is known to activate DNA transcription. This compound also exhibits antitumor activity in vivo at low concentrations. During the synthetic endeavor, tandem formations of a C-C bond and a C-O bond will be attempted to construct the pyrane ring. A convergent synthetic strategy provides many analogs of the natural product in order to study the biological action of FR901464. Determination of the target biomacro-molecule(s) and kinetic studies of transcription induced by FR901464 may elucidate the mechanism of transcription.
In many cases, the completion of a total synthesis represents the starting point for further medicinal or bioorganic studies on the natural product. For example, a recent tandem radical approach to the camptothecin class of natural products in the Curran group has led to the discovery of “silatecans”, a new class of highly active anti-tumor agents.
The Wipf group has elucidated the solution conformation of lissoclinamide 7, and discovered novel macrocyclic silver complexes.
The Floreancig group aims at understanding the molecular basis for the inhibition of P-glycoprotein (P-gp) mediated drug efflux by members of the dihydro-b-agarofuran family of natural products. Overexpression of P-gp has been implicated as the cause of one form of multidrug resistance in several forms of cancer. The rigid dihydro-b-agarofuran ring system is expected to provide an excellent foundation for the development of synthetic strategies and for the rational design of analogs designed to elucidate the molecular features required for P-gp inhibition.
Synthetic Methodology
The Brummond group develops new methods in organic synthesis, particularly in the area of organo-metallic chemistry. The allenic Pauson-Khand reaction developed in the Brummond lab affords a-methylene or 4-alkylidene cyclopentenones. The scope of this method has been successfully applied to the synthesis of hydroxymethyl-acylfulvene (HMAF), an anticancer compound soon to enter Phase III clinical trials. A silicon-tethered version of this reaction is currently being applied to the synthesis of 15-deoxy-D12,14 PGJ2, a natural ligand for the PPAR-a receptor that has been linked to Type II diabetes and obesity.
Cohen's group develops novel synthetic methods, based on new reactions, and showcases these by efficient syntheses of natural and unnatural products. Current methods involve the first synthetic uses of lithium metallo-ene cyclizations. An exciting example is a novel tandem lithium-ene cyclization - cyclopropanation leading to useful vinylcyclopropanes. An allylic oxyanionic function, while not required, greatly accelerates the reaction and completely controls the stereochemistry; the same concept greatly increases the utility of the magnesium-ene cyclization. The most efficient syntheses of two terpenes, starting from the same readily available alcohol, are shown below.
The Floreancig Group is working on the initiation of cyclization reactions by single electron oxidation. Radical cations, the highly reactive intermediates in this process, are generated under neutral conditions - a feature that is expected to be useful in the synthesis of acid or base sensitive products of biochemical significance. In addition to exploiting the synthetic utility of this reaction, efforts will be directed toward understanding the fine details of its mechanism.
In the Nelson group, asymmetric metal-based catalysis constitutes the foundation of a reaction invention program that encompasses synthetic and mechanistic organometallic chemistry. They have elucidated the solid-state structure of an optically active Al(III) cyclocondensation catalyst, which expresses a unique form of distortion-enhanced Lewis acidity. These structures provide inspiration for the synthesis and evaluation of unique cationic Si(IV) and Sn(IV) complexes as new Lewis acid catalysts.
Other projects in the Nelson group currently involve (1) the synthesis of optically active lanthanide complexes as catalysts for the transfer of cyanide from commercially available acetone cyanohydrin to imines as a route to optically active a-amino acids and (2) the investigation of optically active transition metal catalysts for the asymmetric ene reactions of simple, commercially available olefins (2-butene) and aldehydes.
In the radical area, Professor Curran is continuing studies on mechanism, synthetic methods, and control of relative and absolute stereochemistry.
The Wipf group pursues synthetic methodology programs in heterocyclic and organometallic chemistry. In the latter field, they have applied organozirconocenes for a wide range of asymmetric C-C and C-O bond forming reactions.
Chemical Biology
Biologists learn the functions of proteins in biological systems by modifying those protein functions and observing the effect on the organism. Classical genetics uses mutations in protein gene sequences to modify protein function. The approach of "chemical genetics" seeks to probe the functions of proteins through the use of small molecule ligands that will bind to proteins and modify their functions. The Schafmeister group uses synthetic chemistry to develop new classes of small molecule ligands that are shaped like flat disks presenting at least four diversity elements on one side of the molecule. This shape is designed to bind the surfaces of proteins to disrupt protein/protein interactions and probe the biological roles of those interactions in vivo. The Schafmeister lab uses combinatorial chemistry to generate large libraries of these compounds and match them to proteins that they bind. These compounds are subsequently used to probe the functions of their target proteins.
Transcriptional activity is measured by a rather indirect method where the enzymatic activity is monitored. For more direct and accurate measurements, the concentration of transcribed RNA must be quantified without disrupting cells. The Koide group is interested in developing a new transcriptional activity screening system in which a catalytic RNA converts a masked fluorophore to an active fluorophore. Techniques in combinatorial chemistry and combinatorial biology are used to establish the system. This direct method will lead to a means to quantify transcriptional activity in vivo, and will also allow the study of transcription in real-time. It is amenable to high-throughput and therefore applicable to screening of libraries of small molecules to identify a specific regulator of transcription. Shown below is the concept of a novel screening system for transcription. The fluorescent intensity of the dye is proportional to DNA transcription.
Polymer and Materials Chemistry
The Chapman group studies interfacial properties of polymers, from coatings with very hydrophobic or hydrophilic surfaces to surfactants and tissue engineering. The polymer coatings are polyurethane-based and are candidates for such uses as blood-compatible coatings and the prevention of marine fouling. The surfactants are hybrid dendrimer and linear polymer conjugates and have demonstrated potential in such diverse areas as green chemistry, controlled drug delivery, tissue engineering, and the development of an artificial blood substitute. Another area of research is the creation of dendrimers with interesting photophysical and photocatalytic properties, the latter as a model of photosynthesis.
Cohen's group has discovered a Lewis-acid induced titanium-ene cyclization. This concept is being used for the cyclopolymerization of conjugated dienes to ladder polymers instead of the conventional polymerization to polyunsaturated linear polymers.
Working on a new frontier for synthesis, the Wilcox group seeks to create micro-structured materials and assemblies through nanosynthesis. The scale of nanosynthesis lies between molecular synthesis and macro-assembly. Their goal is to create anisotropic nanometer to micron sized particles that can be assembled with complete control.
Current work is focused on making chemically anisotropic polystyrene particles. Chemically anisotropic 10 mm polystyrene spheres can be assembled to make new devices. Here, a 1 mm fluorescent patch has been created on the sphere.
Physical Organic Chemistry
The Curran, Grabowski, Wilcox, and Wipf groups are active in mechanistic and physical organic studies. In collaboration with the Beratan group, the Wipf group has devised exciting new methods to assign the stereochemistry of natural products based on ab initio quantum mechanical calculations. The Wilcox group is exploring the effects of ion pairs on chemical reactions and using these effects to control the stereochemical outcome of reactions.
Research in the Grabowski group centers on developing and exploiting state-of-the-art approaches for defining the paradigms of organic reactivity. In the gas-phase, novel ions are synthesized and studied to address fundamental issues of reactivity. For example, cyclopentadienylidene radical anions and cycloheptatrienylidene radical cations are models for phenyl radicals. Experiment and theory are used to quantitatively characterize reaction coordinate diagrams as exemplified by the base-sensitive deprotonation/ring-opening competition of heteroaromatic compounds. Photochemical techniques establish the energetic parameters for liquid-phase reactions including B12-dependent rearrangements. Modern mass spectrometric techniques are being developed or pushed to their limit in order to characterize biologically active macromolecules as in the case of proteins that function in neuron-specific exon selection.
Combinatorial Chemistry
Combinatorial chemistry is actively pursued in the Brummond, Curran, Koide, Schafmeister, Wilcox, and Wipf groups. The Curran group develops new sample purification schemes. Fluorous techniques for strategic separation capitalize on the fact that highly fluorinated species will partition out of an organic phase and into a fluorous (highly fluorinated) phase in a liquid-liquid or solid-liquid extraction. This forms the basis for effective separation methods that can be used in both traditional and combinatorial applications.
The Wilcox group has invented a new strategy for reaction product isolation. This approach is based on “precipitons” – protecting groups that have controllable solubility states. After a homogeneous reaction is complete, the chemist adds a catalyst or exposes the reaction mixture to soft UV light and pure product precipitates from the reaction mixture. The method may allow fully automated preparation of high-value molecules in milligram to kilogram scales.
The Wipf group prepares natural product-derived inhibitors of tubulin assembly, protein phosphatases, and kinases. For the development of a discovery library, they have designed a very efficient synthesis of alkene peptide isosteres that provides pure compounds over ten consecutive steps without the need for a single chromatographic purification.
The new Combinatorial Chemistry Center (ccc.chem.pitt.edu) further increases opportunities for research with cutting-edge instrumentation in the Department. The highly interactive environment in the CCC forms the focal point for significant advances in the design and application of novel combinatorial chemistry strategies for academic and industrial organic synthesis.
Interdisciplinary Research
Most groups in the organic division have attractive collaborations with physical and analytical chemists, engineers, pharmacologists, the Medical School, and chemical companies. Visit Pittsburgh to learn more about these exciting projects at the interface of chemistry, biology, medicine, physics and material sciences!
Representative References
- Brummond, K.M.; Lu, J. "A Rapid Synthesis of Hydroxymethylacylfulvene (HMAF) Using the Allenic Pauson-Khand Reaction. A Synthetic Approach to Either Enantiomer of the Illudane Structure." J. Am. Chem. Soc. 2000, 122, 4915.
- Chapman, T. M.; Hillyer, G. L.; Mahan, E.; Shaffer, K. A., "Hydraamphiphiles: Novel Linear-Dendritic Block Copolymer Surfactants." J. Am. Chem. Soc. 1994, 116, 11195.
- Liu, H.; Shook, C. A.; Thiruvazhi, M., Jamison, J. A., Cohen, T., "The Cyclopropylalkylidenecyclopro-pane Thermal Double Ring Expansion. A Novel Route to the Bicyclo[5.3.1]undecane Skeleton of the AB Ring System of Taxanes." J. Am. Chem. Soc. 1998, 120, 605.
- Grabowski, J. J., "The Aqueous-Phase pKa of the methyl group in acetic acid." Chem. Commun. 1997, 255.
- Studer, A.; Hadida, S.; Ferritto, R.; Kim, S.; Jeger, P.; Wipf, P.; Curran, D. P., "Fluorous synthesis: A fluorous-phase strategy for improving separation efficiency in organic synthesis." Science 1997, 275, 823.
- Ribe, S.; Kondru, R. K.; Beratan, B. N.; Wipf, P., "Optical rotation computation, total synthesis and stereochemistry assignment of the marine natural product pitiamide A." J. Am. Chem. Soc. 2000, 122, 4608.
- Lewis Acidity Expressed in Neutral Electron-Rich Aluminum(III) Complexes: An Example of Ligand-Defined Catalysis,” Nelson, S. G.; Kim, B.-K.; Peelen, T. J. J. Am. Chem. Soc. 2000, 122, 9318.
- Tamura, K., Southwick, E. C., Kerns, J., Rosi, K., Carr, B. I., Wilcox, C. S., Lazo, John S. "Cdc25 Inhibition and Cell Cycle Arrest by a Synthetic Thioalkyl Vitamin K Analogue" Cancer Res. 2000, 60, 1317.