Synthesis and Measurements of New Fluorous Reagents

Recently developed techniques for "fluorous synthesis" unite the reaction and separation processes in organic reactions (Refs. 1,2). Molecules bearing fluorous (highly fluorinated) tags can be separated from organic (non-tagged) molecules by fluorous liquid-liquid or solid-liquid extraction. And molecules bearing different fluorous tags can be separated from each other by fluorous chromatography. However, because the field is very young, there are relatively few fluorous reagents available to pair with the new separation techniques. Last year, undergraduate coworkers developed new fluorous carbobenzyloxy  (^FCbz) groups, protected both natural and unnatural amino acids with these groups, and used the protected amino acids in innovative new techniques like quasiracemic synthesis. That work is now being readied for publication. This year’s project will involve the synthesis of a new fluorous reagent or protecting group and the study of its use in representative organic transformations.
(1) A. Studer; S. Hadida; R. Ferritto; S. Y. Kim; P. Jeger; P. Wipf; D. P. Curran, Science 1997, 275, 823-826.  (2) Luo, Z. Y.; Zhang, Q. S.; Oderaotoshi, Y.; Curran, D. P. "Fluorous mixture synthesis: A fluorous-tagging strategy for the synthesis and separation of mixtures of organic compounds" Science 2001, 291, 1766-1769  [11/04]

Professor Joseph J. Grabowski

Measuring Relative Rates of Microwave-Accelerated and Conventional Organic Synthesis

In recent years, powerful single-mode microwaves have found an increasing number of applications in organometallic chemistry and drug discovery. Many organic solvents are transparent for microwave radiation, and in these cases that dipolar starting materials and intermediates are directly responsible for absorption of microwave energy, and a dielectric heating mechanism is operative.  Rate acceleration is particularly effective when the polarity is enhanced from ground to transition state.  We have found that transition metals such as alkenylzirconocene and -zinc species are surprisingly stable in the microwave environment under elevated temperature and pressure and thus offer an attractive opportunity for a synthetically advantageous use of this technology.  Carbon-carbon bond formations of the type shown below will be studied and new experimental applications of microwave reactors will be developed.  [2/04]

For more information about the Wipf research group and projects, see their website:  http://ccc.chem.pitt.edu/wipf/index.html.

Measuring the Structure of the Phenol Dimer:  High Resolution Electronic Spectroscopy Compared to ab initio Calculations.

Molecules can interact together leading either to the formation of a new molecule or to a molecular cluster.  In the former, covalent bonds are formed while in the latter, weaker noncovalent interactions come into play.  Noncovalent interactions are very important in chemistry and physics, and are of key importance in biology.  In this project, high resolution electronic spectroscopy in the gas phase (1)  will be used to determine the structure of the phenol dimer, a species in which two different types of noncovalent bonding play a role, hydrogen bonding between the OH groups of the two molecules, and dispersive interactions between the two aromatic rings.  The final, equilibrium structure of the dimer is determined by a competition between these two types of interactions.  Previously, the structure of this dimer has been measured by the low resolution rotational coherence technique (2).  Our experiments will provide a refined structure, which will further be compared to the results of  recent ab initio calculations (3)  [2/04]
(1) W.A. Majewski, et al., Laser Techniques in Chemistry, ed. A.B. Myers and T.R. Rizzo, John Wiley and Sons, 1995, p.101.  (2) L.L. Connell, et al., J. Chem. Phys. 96 (1992) 2585.  (3) P. Hobzda, et al., Chem. Phys. 283 (2002) 331.

The Effect of Current on the Degradation Rate of a Drug-Delivery Polymer.

The synthesis of biologically compatible materials is key to many potential medical advances including the development of artificial organs, controlled drug delivery, and the use of stem cells for regeneration of diseased tissue.  In some cases it is desirable to make durable materials that will resist attacks by the bodies defense systems while in others the goal is to prepare a material that will gradually degrade to non-toxic molecules.  One class of materials that exhibits slow degradation in the body, is poly(lactic acid).  This FDA-approved polymer can be formulated in various ways to give materials that hydrolyze in vivo in periods ranging from minutes to years.  Unfortunately, once such a material is placed in the body, there is no way to change the rate of degradation.  We are interested in exploring whether the incorporation of a small amount of a conducting polymer (polypyrrole) as a blend with poly(lactic acid) will allow us to use electric current to accelerate the decomposition.  This blended material would be particularly suitable for drug delivery applications where the drug is encapsulated in the degradable polymer.  The student on this project would be involved in the preparation of polypyrrole/poly(lactic acid) blends and measurement of the rates of degradation in simulated body fluids, as a function of current applied.  [2/04]

Examining Molecular Transprot in Lung Surfactant Monolayers

Measuring Local Rotational Dynamics in Peptides

Measuring electron transfer between electrodes and biomolecules

Measuring electron tunneling between molecules

Electron transfer reactions constitute a fundamental chemical process and are of intrinsic importance in biology, chemistry, and the emerging field of nanotechnology.  Biological processes such as photosynthesis and respiration rely on electron transfer between molecular subsystems that interact through a collection of covalent and noncovalent linkages. Our group is using supermolecules that contain electron donor and electron acceptor units to investigate how electrons tunnel from one side of a molecule to another and between two molecules.  The diagram illustrates the architecture of such a molecule in which the electron tunnels from the donor to the acceptor through a pendant moiety.  We are probing how the electron tunneling probability depends the motion of the pendant group in the cleft and the rotation of dipolar solvent molecules.  An REU student will investigate how the electron transfer rate constant depends on the frictional coupling between the tunneling barrier and the solvent.  [2/04]  [A.M. Napper, N. J.Head, A.M. Oliver, M. J. Shephard, M. N. Paddon-Row, I. Read, and D. H. Waldeck “Use of U-shaped Donor-Bridge-Acceptor Molecules to Study Electron Tunneling Through Non-bonded Contacts” J. Am. Chem. Soc, 2002, 124, 10171-10181.]

Professor Kenneth D. Jordan

The participating student will use quantum mechanical methods to characterize the local minima and transition states of small conformationally flexible biomolecules, both in isolation and in the presence of water solvent molecules. These results will be used to test new polarizable force fields for describing these systems.      [2/04]

Novel Cyclizations to Nitrogen Heterocycles and Measurement of Their Enantioselectivities

Recently, we have demonstrated two major advances in the construction of 5-membered rings by intramolecular carbometallation of alkenes.  1. Reductive lithiation of phenyl thioethers by aromatic radical-anions is the most versatile method of generating the organolithiums for that purpose.  2. An oxyanionic function allylic or homoallylic to the alkene has a powerful accelerating effect on the cyclization and controls the stereochemistry.  The project is to apply these two findings to the development of novel enantioselective syntheses of 5·5 fused ring nitrogen heterocycles.  A number of biologically important alkaloids contain these general ring structures.  In the following schemes, LDMAN and LDBB are aromatic radical-anions.  Reasonable assumptions are made about some of the steps.  The deprotonation step in Scheme 1 is well established by Peter Beak.  The reductive lithiation in the absence of THF in Scheme 1 has recently been pioneered in our lab.  It is necessary because of the ability of alkyllithiums to deprotonate THF at room temperature.  The first goal is to prepare 6 and measure its enantiomeric excess.  We have compound 3 in hand.  If time permits, a start on the preparation of 10 may be made.  [2/04]

Anticancer compound libraries using a (–)-laulimalide template

Probing protein structure & function through b-peptide models

New, Activated Scaffolds for Tissue Engineering

Our current research has involved exploring the use of the highly branched, dendritic polymer based on the natural amino acid lysine.  This polymer has the lysine residues joined via amide bonds at both the a- and e- amino groups. It’s rate of biodegradation is somewhat slow.  We wish to explore similar dendritic polymers  where the monomer is a lysine esterified to the natural metabolite glycolic acid.  This polymer will contain ester groups between residues and its rate of biodegradation should be correspondingly faster.  If too fast, lactic acid can be substituted.  The potential uses of the polymer will range from drug delivery, to tissue engineering, to gene therapy.  [2/04]

Measuring Cellular Proteome Changes in Microtubule Stabilizer-Treated Cancer Cells

We are exploring how an important class of anticancer drugs, microtubule stabilizers (the clinically used Taxol and Taxotere, and investigational agents, e.g., (+)-discodermolide, (-)-laulimalide and their derivatives) alters the proteome in cancer cells. Proteomics, a multi-method analytical chemistry platform for measuring changes in protein levels and post-translational modifications, has recently been implemented in our labs. The methods and tools to be used include cell culture, difference 2D gel electrophoresis (a.k.a. DiGE), fluorescence image analysis, solution-phase isoelectric focusing, liquid and sample handling robotics, multidimensional nanoflow HPLC, isotope-coded affinity tagging, electrospray ionization ion trap mass spectrometry (MDLC-ESI-MS), matrix-assisted laser desorption time of flight mass spectrometry (MALDI-TOF-MS) and its tandem form for sequence analysis, MALDI-TOF/TOF-MS/MS (see figure).  [2/04]

Professor Gilbert Walker

Adjacent Figure:  Apertureless near-field microscopy.  The probe, placed in the near-field of light scattering at the interface, converts some of the decaying components into a propagating field. The propagating field is then detected.  The probe can be scanned across the surface for imaging, and the size of the probe determines the spatial resolution of the image.  This will enable imaging chemical composition on the nanoscale, which remains a significant challenge in nanoscience.

Measuring Reaction Efficiency to Optimize Convergent Synthesis of a Combinatorial Library

We are developing convergent synthetic schemes to produce small molecule combinatorial libraries on solid support. Two different library compounds will be synthesized on beads separately, and one library compound will be transferred from one bead to another library compound on another bead. We are currently testing cross olefin metathesis as model studies for this purpose.   [2/04]

 [12/02]

To measure the transcriptional activity, it would be ideal to measure the concentration of transcribed RNA in vivo without disrupting cells. We are developing chemical sensors to measure RNA levels in vivo. To this end, we are currently using techniques in combinatorial chemistry, combinatorial biology, and fluorescent spectroscopy. This proposed method will enable us to study RNA levels in real-time. This method can be also used to screen libraries of small molecules to identify a regulator of transcription in a high-throughput mode. The REU student is expected to learn the state-of-the-art in vitro RNA selection procedures to find an RNA binder out of 1014 different RNA sequences.   [2/04]

New antennae for the development of luminescent lanthanide complexes - Project 1

     Coordination  of the lanthanide ion to an organic molecule that absorbs UV light and efficiently converts the resulting energy to the metal ion is an essential requirement to construct luminescent lanthanide complexes.  This combination of absorption and energy transfer from the ligand is called an “antenna effect.”  The antenna effect  was discovered in 1942, yet only a small set of organic molecules have been used as antennae for the sensitization of the various lanthanide cations emitting in the visible (Sm³⁺, Eu³⁺, Tb³⁺, Dy³⁺) and in the near-infrared (Nd³⁺, Yb³⁺) ranges.
     We propose here to systematically investigate and test several potential ligands of the family of flavanoids as antennae.  The molecules are natural products (present in beverage and food such as green tea or vegetables) that have oxygen donor ligands suitable for the forming a strong bond between the ligand and the lanthanide cation.   So far, these have not been explored for their ability to sensitize lanthanide cations.  Some examples of flavanoids to be tested in this project are depicted in the figure.  This project includes the comparison between the results obtained experimentally and the prediction obtained by computational methods (using the CAChe software). [3/04]

New antennae for the development of luminescent lanthanide complexes - Project 2

     Medical and biological assays targeted at protein detection require highly sensitive detection methods for low concentrations of analytes.  It is also necessary to be able to perform many analyses in a short period of time and without preliminary purification of the sample.  Lanthanide complexes are ideal candidates  since their emission can be easily discriminated from complex mixtures of molecules. The very long luminescence lifetimes of these lanthanide complexes allow for an easy discrimination between signal and fluorescent background noise through time-resolved measurements
     We also propose to use dendrimer ligands as antenna.   The end-branches of the dendrimers have been functionalized with a naphthalamide type groups in order act as an antenna for the lanthanide cations.  The amide groups in the dendrimer core have the ability to bind several luminescent lanthanide cations. [3/04]

Professor Joseph J. Grabowski

Electropspray ionization mass spectrometry principles are founded in guiding ions from atmospheric pressure into high vacuum for mass analysis and detection.  To achieve the best sensitivity within an instrument, all ion guides, aperture, and filters must be optimized.  The design, placement, and applied voltage of each part of the mass spectrometer can be adjusted in the optimization process.  To minimize the "trial and error" approach, computational methods can be employed as a first pass design strategy.  SIMION is a program that uses a 3D view to simulate the design and evaluation of ion-steering/analyzing electric and magnetic fields.  The undergraduate who chooses to work on this project will be responsible for working under the supervision of a graduate student, to learn the use and intricacies of the SIMION program, to teach the group how to use and master the software, while simultaneously designing and evaluatimg improved ion optics for the existing SWISS-484.  The student will then oversee the construction of the best set of optics by the machine shop, their installation in the instrument, and the evaluation of gains and improvements in ion handling.  [3/04]

Adventures in Photonic Materials

While major advances in transition metal catalyzed reactions have been made, it remains a continuing challenge to chemists to produce structures of high molecular complexity in a single synthetic operation from readily available starting materials. Clearly, one way this goal can be met is by combining two or more reactions in a single operation, i.e. a tandem sequence. We have discovered an expedient synthesis of cross-conjugated trienes using a transition metal catalyzed allenic Alder-ene reaction. We have also shown that these trienes are then amenable to subsequent Diels-Alder [4 + 2] cycloaddition reactions (eq. 1). Investigations pertaining to alternative cycloaddition reactions (i.e. [4 + 3] and [4 + 4] will be the topic of this project (eq. 2)
Ref:  A Rhodium(I)-Catalyzed Formal Allenic Alder-ene Reaction for the Rapid and Stereoselective Assembly of Cross-Conjugated Trienes, Kay M. Brummond, Hongfeng Chen, Peter Sill, Lingfeng You, J. Am. Chem. Soc. In Press.  [3/04]

A New Approach to Molecular Building Blocks

Measuring Dopamine and its Metabolites in the Brain

High-Resolution Imaging of Biological Membranes by Chemical Nanosensors.

Luminescence of Lanthanide Complexes to Detect Different Functional Groups

This project proposes to use the luminescence of lanthanide complexes to detect different functional groups (such as –OH, -COH, -COOH) present on surfaces (self-assembly monolayers – SAMS, the support being SiO₂, Gold or glass) with a high sensitivity.  Lanthanide complexes have very long luminescence lifetimes (up to several milliseconds).  This allows performing time-resolved measurements, where the long luminescence of the lanthanide complex reporters can be discriminated from the unwanted fluorescence arising from the surface (fluorescence background).  The removal of this noise will results in more sensitive detection by increasing very significantly the signal to noise ratio. The project includes surface chemistry (preparation of the different surfaces, formation of the self-assembly monolayer, attachment of the luminescent lanthanide complex on the surface of the monolayer).  The spectroscopy part will include the characterization of the luminescence of the lanthanide complex in solution and in the surface of the monolayer.  This project bridge several types of science, including inorganic chemistry, surface science and spectroscopy.  [4/04]