The development of new multidentate, non-innocent, and/or chiral ligands for application in transition metal-based asymmetric catalysis, small molecule activation, and alternative energy processes — Cain
My research interests include development of new multidentate, non-innocent, and/or chiral ligands for application in transition metal-based asymmetric catalysis, small molecule activation, and alternative energy processes. Without giving up too much information, we plan to target a largely unexplored class of C1-Symmetric, P-Stereogenic ligands, rationally designed multidentate ligands for dinitrogen reduction, and phosphaalkene-based ligands as redox active / non-innocent platforms for interesting chemical transformations. If these projects interest you, please do not hesitate to contact me or stop by my office.
For more information, please visit our group website, Synthesis in Paradise.
Theoretical Investigation of Silicon Nanoparticles — Head
Theoretical Investigation of Silicon Nanoparticles
Silicon is an inexpensive and environmentally friendly semiconductor making it the central element used in most modern electronic devices. Currently there is tremendous interest in developing a silicon based optical device which could be directly integrated with silicon based microelectronic circuits. Unfortunately, bulk crystalline Si has inefficient light emitting capabilities due to it being an indirect gap semiconductor. In the early 1990’s porous Si, fabricated by electrochemically etching Si wafers in HF, was found to exhibit a surprisingly bright luminescence. Chemical characterization showed porous Si to essentially correspond to an array of Si nanocrystallites with dimensions of order of a few nanometers. Further studies have now synthesized ligand passivated Si nanoparticles which also exhibit bright luminescence. The nanometer dimensions of these particles suggest the bright luminescence and emitted wavelengths are a consequence of quantum confinement effects although the detailed origin of the emission is still being debated by researchers. The main emphasis of the research in my group is to theoretically investigate the geometric structures of the atoms composing passivated Si nanoparticles using quantum chemistry calculations. Calculations are needed because experimentally it is very difficult to elucidate the exact stoichiometry, let alone the structure, for a single nanoparticle. Using our theoretically determined atomic arrangements, we perform electronic structure calculations to better understand the origin of the optical properties in passivated Si nanoparticles. The overall goal is to perform quantum chemistry calculations which can then be used as a guide to tailoring the passivated Si nanoparticle’s optical properties for use in a real practical optical device.
Nanoparticle Structure Determination using Global Optimization Methods
These days most quantum chemistry computer programs, such as Gaussian or GAMESS, include local energy optimization routines for finding the equilibrium structures of molecules. At an equilibrium structure the energy E of a molecule has the derivative dE/dq=0 for each of the 3N nuclear coordinates q. The different possible stable isomers for a particular stoichiometry correspond to different local minima on the molecular potential energy hypersurface E(q). Chemical reactions where a reactant structure R changes to a product structure P can be interpreted in terms of moving from the R local minimum to the P local minimum via some transition state structure on the potential energy hypersurface. The most stable isomer for a particular stoichiometry is the local minima with lowest molecular energy E and is called the global minimum structure. Optimization routines in quantum chemistry codes usually find the local minimum (and equilibrium structure) associated with the catchment region of the starting guess structure and do not find the structure’s global minimum. This is a good thing because it enables quantum chemistry calculations to determine the structure and properties for different species present in a chemical reaction.
However, in passivated Si nanoclusters, such as SixHy, the number of local minima grow exponentially with increasing nanocluster sizes and we need to know what are the possible low energy structures for SixHy. Thus in our lab we have been developing cluster global optimization techniques to find the lowest energy structure for passivated Si nanoclusters. Our global optimization strategy is based on a genetic algorithm (GA) which is inspired by the Darwinian evolution process. The GA works by randomly selecting and mating the more fit individuals in a generation to produce the next generation of offspring, where the fitness is some measure of the energetic stability for an individual cluster structure. The global minimum is eventually located because some of the new cluster conformations created by the GA have lower energies than the structures in previous generations. A good mating operator causes good structural features in a cluster to be passed to the next generation while maintaining structural diversity in the overall population. Genetic algorithms are increasingly being used in a number of global optimization problems in chemistry ranging from crystal structure prediction and protein folding in biomolecules to parameter development for empirical and semi-empirical quantum mechanical calculations. Most of the cluster global optimization work so far has been on clusters with unpassivated surfaces since this avoids needing to develop special theoretical techniques to treat the surface atoms. Our major accomplishment has been to develop a GA which can be applied to the covalent networks found in SixHy clusters, where so far we have performed calculations with L = H and F.
Some of the globally optimized SixHy clusters we have obtained so far are shown below:
Figure 1. Ab Initio global minima determined for (a) Si10H16, (b) Si10H14, © Si14H20, (d) Si14H18, (e) Si18H24 and (f) Si18H22.
These results show that when the Si cluster core is passivated with enough H atoms, as in Si10H16, Si14H20 and Si18H24, the core adopts a bulk Si like structure. However, in the clusters Si10H14, Si14H18 and Si18H22, with 2 less H atoms the global minima have very different Si core structures.
In the SixHy global optimization studies the H atom serves as a prototypical passivating ligand which simplifies performing the calculations. Recently we have performed global optimization calculations with F as the passivating ligand. As illustrated below we find that specific SixLy stoichiometries have quite different lowest energy Si core structures when passivated by F atoms.
Figure 2. Ab Initio global minima for Si7L14, Si8L14, Si10L16 and Si10L14 where L is H or F in the right and left columns.
In the SixHy clusters, we find the H atoms tend to spread out evenly over the Si atoms, whereas for SixFy the F atoms favor forming SiF3 groups. We are currently developing strategies to globally optimize Si nanoclusters with OH, CH3 and OCH3 as the passivating ligand L.
Other Research Interests
I am also interested in performing quantum chemistry calculations related to adsorption of molecules on surfaces. The usual approach is to model the extended surface by a cluster of atoms with the same geometric arrangement of atoms at the active site of interest on the extended surface. We then perform quantum chemistry calculations using the GAMESS or Gaussian computer packages to investigate various properties such as the geometric structure at the preferred adsorption site for an adsorbate, the strength of the chemisorption interaction and identify any characteristic vibrational information.
The emphasis of my research program is in the area of natural products chemistry, specifically biosynthesis and the isolation of natural products from plants and fungi. — Hemscheidt
From the very beginning when structures of natural products were first established, chemists have been interested in the question how the producing organisms elaborate these fascinating structures. Consequently, over the past 40 years considerable progress has been made in establishing a reasonably accurate picture of these processes. The current interest is mostly focussed firstly on mechanistic questions and secondly on approaches to manipulate these pathways to arrive at new natural products by means of genetic engineering techniques.
Alkaloids. We have been working over the past several years on a study of the mechanism of formation of a group of alkaloids that at first glance may not appear to be related structurally, namely the tropane alkaloids, e.g. 1, and the lycopodium alkaloids such as lycopodine 2. Studies to elucidate the mechanism by which the tropane nucleus is formed are ongoing. The simplicity of the structure belies the difficulty of the problem which has seen much work over the past 40 years without a definitive, mechanistically satisfying picture emerging. I have summarized the extant evidence in a recent review ( Topics in Current Chemistry Vol. 209 pp. 177-206, Springer Verlag, 2000.
Vitamin B6 and Ginkgotoxin. There is considerable evidence that the biosynthesis of pyridoxine 3 is different in prokaryotes(bacteria) and eukaryotes, but only in the former group of organisms, specifically in E. coli, has it been possible to elucidate this process in detail. Ginkgotoxin 4, the 4’-O-methylether of pyridoxine, is a neurotoxin that occurs in the leaves of the maidenhair tree, Ginkgo biloba. Cell cultures and seedlings of the tree produce enough of this toxin to allow the study of the biosynthesis of this vitamin in plants. While first results suggested that the biosynthetic pathway in E. coli and Ginkgo is related (Fiehe et al. J. Nat. Prod., 2000, 63, 185-189), as yet unpublished results have shown unequivocally that this is not the case. We are investigating the biosynthesis of ginkgotoxin and of pyridoxine in yeast as models for the eukaryotic pathway using both chemical and biochemical approaches.
Tolytoxin. Tolytoxin is a cytotoxic compound formed by the blue-green alga ( cyano bacterium) Scytonema ocellatum. It was discovered several years ago by the group of Prof. Moore in collaboration with Dr Greg Patterson, formerly also of this department. We have begun to search for the genecluster that encodes the formation of this natural product. The goal of this work is to understand how the stereochemistry of the methyl groups is controlled and to use this information to prepare analogs of this compound for biological evaluation. The mechanism of formation of the unusual enamide moiety is also of interest.
ISOLATION AND STRUCTURE ELUCIDATION
In collaboration with Dr. Susan Mooberry at the Southwest Foundation for Biomedical Research in San Antonio, TX, we have been screening for and isolating natural products with activity against the cytoskeleton, specifically microtubules and microfilaments. These structures are vital for a variety of cell functions and are formed by the reversible polymerization of proteins. Our biological assay detects compounds that interfere with the polymerization as well as with breakdown of assembled cytoskeletal structures.
A recent example of active compounds isolated include the microtubule poison taccalonolide A (6) from a plant. We are currently studying the chemistry of taccalonolide to understand which structural features of the molecule are essential for biological activity.
Reaction dynamics in extreme environments — Kaiser
Applications and methodology development of high-resolution solid-state nuclear magnetic resonance (NMR) for the study of novel systems — Kumashiro
Her research program is centered about the applications and methodology development of high-resolution solid-state nuclear magnetic resonance (NMR) for the study of novel systems, such as connective tissue proteins. Extramural support for Dr. Kumashiro’s research program includes a CAREER award from the National Science Foundation.
Current research projects focus on elastin,a vertebrate protein with remarkable biomechanical properties. The elastic properties of a number of physiological structures, such as blood vessels and skin, are believed to originate from elastin, an amorphous, crosslinked protein comprised largely of small hydrophobic amino acids. The three-dimensional structures of insoluble elastin remains elusive, as crystallographic tools and even the most sophisticated solution NMR spectroscopy cannot be used to study this insoluble protein. Therefore, for many years, the true nature of elasticity in biological systems has remained controversial, as none of the existing models could be confirmed or rebutted with high-resolution structural data.
Now, with the advent of high magnetic fields and a growing number of high-resolution solid-stateNMR experiments, the structural characterization of elastin is in progress in our laboratories. Solid-state NMR has proven to be a powerful tool in the characterization of molecular and bulk properties of many compounds. For instance, isotropic chemical shift and chemical shift anisotropy are relative measures of the shielding of a specific nucleus and are sensitive probes of chemical or electronic environments. More elaborate experiments are used to ascertain other structural parameters, such as internuclear distances or torsion angles, as demonstrated by others for a range of peptides and proteins. In addition, a number of experiments are used to determine dynamical features. These experiments include, e.g., relaxation measurements that are analogous to those done in the solution state. Finally, in addition to the application of now-routine solid-state NMR experiments for structural studies of proteins and polymers, we have also endeavored to develop, adapt, and apply new methods for these samples.
We have adopted an approach that includes use of a wide range of elastin and elastin peptide samples. In this manner, we anticipate that a global model for biological elasticity will emerge, rather than a set of observations that may or may not be specific for a given elastin-based motif.
One set of work focuses on characterization of the natural-abundance 13C populations in elastin isolated from tissue, in addition to elastin peptides from numerous collaborators. With regards to the latter, these ongoing collaborations include elastin peptides from synthesis as well as recombinant methods.
In addition to the natural-abundance 13C work, we have developed a unique approach to isotopic labeling of this vertebrate protein. As bacterial expression methods lack the natural mechanism for crosslinking, we have adapted a protocol using a mammalian cell line to produce insoluble elastin with 13C, 15N, and 2H-labels at key amino acids. Not only does this approach provide unambiguous structural assignments for the enriched sites, but it increases the number of NMR experiments that are now feasible for this complex system.
Our early work, which includes both the natural-abundance and isotopically-enriched preparations, highlight the unusual mobility of large segments of elastin. Furthermore, our data show strong support for models of elastin structure that involve significant structural heterogeneity (rather than regular or repeating structures). The curious reader is encouraged to consult recent publications from this lab for additional information.
The S-Adenosylmethionine-Dependent Radical Enzymes — Jarrett
The S-Adenosylmethionine-Dependent Radical Enzymes
Organic radicals are used by a number of enzymes to catalyze biochemical transformations with high-energy barriers that would be difficult to accomplish through non-radical heterolytic chemistry. Well known examples include the reduction of an alcohol to an alkane catalyzed by ribonucleotide reductase or carbon chain rearrangements catalyzed by methylmalonyl CoA mutase or glutamate mutase. Organic radicals can be generated in enzymes through only three general schemes: metal-activated oxygen chemistry, adenosylcobalamin chemistry, or reduction of the sulfonium of S-adenosylmethionine (AdoMet).
Enzymes that catalyze the reduction of AdoMet all contain a [4Fe-4S] cluster that interacts covalently with the methionyl portion of AdoMet. This interaction likely plays an important role in promoting electron transfer into the relatively low-potential sulfonium. We are interested in understanding how the electronic structure of the FeS cluster and the sulfonium are perturbed by this interaction, and whether electron transfer and sulfonium reduction requires a structurally specific interaction or simply close proximity.
The AdoMet Radical Enzyme Biotin Synthase
Biotin (vitamin H) is synthesized in microbes and plants through a conserved biosynthetic pathway that generates dethiobiotin from L-alanine, pimeloyl CoA, CO2, and NH3 (from AdoMet). The final step in the pathway requires the substitution of sulfur for hydrogen at the C6 and C9 positions to create the thiophane ring. The enzyme that catalyzes this step in the reaction contains iron-sulfur clusters and is an AdoMet-dependent radical enzyme. The overall reaction catalyzed is:
In collaboration with Dr. Cathy Drennan (MIT), we have determined the structure of the enzyme from E. coli with substrates bound. On the basis of this structure, and related mechanistic studies, we have proposed that the biotin thiophane sulfur is derived from a [2Fe-2S] cluster bound within the core of the enzyme. Current studies are focused on obtaining spectroscopic evidence for a dethiobiotin-FeS cluster covalent intermediate and understanding the role of conserved protein residues in guiding this transformation.
In Vivo Iron-Sulfur Cluster Assembly
Although simple iron-sulfur clusters are spontaneously assembled in solution, virtually all known organisms contain specific proteins that function to guide the controlled assembly of [2Fe-2S] and [4Fe 4S] clusters. One of the most conserved systems for iron-sulfur cluster assembly, the ISCsystem, is contained within a single genetic operon in E. coli that codes for 7 proteins: a pyridoxal phosphate-dependent cysteine desulfurase that generates S0 as persulfide sulfur destined for cluster assembly (IscS), two possible scaffold proteins that can bind either [2Fe-2S], [4Fe 4S], or Fe2+/3+ under various experimental conditions (IscU and IscA), a ferredoxin for redox control (Fdx), and an ATP-dependent chaperone/co-chaperone pair that may assist in folding/unfolding or cluster transfer (HscA and HscB).
We have found that the chaperone HscA and the scaffold IscU will form a complex with several apoproteins that are targets for FeS cluster transfer. Our current studies are focused on cluster assembly in biotin synthase, which is stably folded in the apoprotein state, and where correct cluster assembly can be distinguished from indiscriminant assembly by the ability of the resulting protein to form biotin. Current studies focus on using spectroscopic methods to characterize the state of the FeS cluster prior to and during the cluster transfer process.
- Model studies of sulfonium reduction chemistry.
- Re-engineering biotin synthase to contain a spectroscopic probe to follow AdoMet cleavage and radical generation.
- Mutagenesis of conserved protein residues in biotin synthase to probe the role of the enzyme in guiding the radical chemistry.
- Use of deuterated dethiobiotin to determine isotope effects for the cleavage of C-H bonds by biotin synthase, to better understand the transition state structure.
- Spectroscopic and electrochemical studies of cluster assembly and transfer within protein members of the ISC system.
- Mutagenesis of conserved protein residues in ISC proteins to probe the role of the proteins in controlling cluster assembly and targeting to specific apoproteins.
Development of catalytically enhanced complex aluminum hydrides as vehicular hydrogen storage materials — Jensen
The atomic structures of membrane proteins and protein complexes using x-ray crystallography and other biophysical methods — Ng
Proteins are miraculous molecular machines with fascinating relationships between structure and function. My research focuses on the atomic structures of membrane proteins and protein complexes using x-ray crystallography and other biophysical methods. Through structure determination and computational analysis, I seek to dissect the atomic mechanisms of protein allostery, recognition, and information transfer. I apply these approaches to protein kinases and receptors, proteins that drive cancer and are active drug targets. Other topics that interest me are structure based drug design and developing methodology for crystallography and other scattering based biophysical approaches.
Organic synthesis — Tius
Organic synthesis has marked impressive advances during the past few decades. Sensitive new analytical techniques have had a large role in bringing this about, particularly the developments in NMR. Problems that arise during the execution of a total synthesis very often suggest areas in which existing methodology is deficient. This, in turn, creates a challenge and an opportunity to address the deficiency by developing new methodology.
In the broader discussion of organic synthesis, a feature that often gets scant attention is the practicality of the work. While it may be true that extraordinarily complex structures are amenable to assembly through synthesis, success may require truly heroic effort, and vast material and human resources for the production of modest quantities of material. Whereas this approach to the science may have been adequate in the past, in the future the issue of practicality will have to be addressed. This is especially true for materials with useful pharmacological properties that are not available through fermentation, and are therefore scarce. While organic synthesis is capable of producing complex natural products, these may be produced in quantities sufficient only for spectroscopic characterization. If the problem is to produce gram quantities of a material of molecular weight ca. 1000, there are two approaches that can be followed. The first is to treat this as a logistical problem, and to organize the efforts of a large team; the second approach is to redefine the way one thinks about problem solving in organic synthesis and to devise an approach which can be implemented by a small team. In our research we have attempted to follow this second approach.
We have ongoing work in three areas: total synthesis, the development of new synhetic methods and the preparation of specific ligands for the CB1 and CB2 receptors. This last area is part of a long-term collaborative effort with the medicinal chemistry group of Professor Alexandros Makriyannis (Center for Drug Discovery, Northeastern University).
Our methods development has focused on catalytic asymmetric versions of the Nazarov cyclization. In the past we had developed a series of very effective pyranose-derived chiral auxiliaries for use in the allene ether version of the Nazarov cyclization. More recently we have directed our attention to the development of organocatalysts as well as transition metal based catalysts for the Nazarov cyclization. Our initial attempts to use alpha-ketoenones (see compound 1) led to the development of a highly enantioselective cyclization that used diamine salt 2 as a stoichiometric reagent to produce alpha-hydroxyenones 3. The key to developing a successful catalytic process was to design a more reactive class of acyclic substrates that could be activated by weaker, non-covalent catalysts. We hypothesized that diketoesters such as 4 would be excellent substrates for Nazarov cyclizations because of their complementary polarization: carbon atom 2 bears a partial negative charge whereas carbon atom 5 bears a partial positive charge. We predicted that dual activation of 4 by an organocatalyst such as 5 would lead to Nazarov products. This proved to be the case, as indicated by the conversion of diketoester 6 to Nazarov product 7. The cyclizations of a series of diketoesters all led to products in good yields and enantioselectivities, however, the reaction was slow, presumably due to product inhibition. Efforts are underway to explore new catalysts and to modify the substrates so as to minimize product inhibition.
As a part of our collaboration with Professor Makriyannis (Northeastern University) we have prepared a series of tricyclic hybrid adamantyl cannabinoids (see structures 8 – 11). Both stereochemistries at C9 were examined. The affinities for human CB2 and rat CB1 receptors is indicated. The goal of this work is to determine whether there are specific interactions between the ligand (the cannabinoid) and the receptor (CB1 or CB2) that might give us the ability to design specificity into our structures. The chemistry in this project is more challenging than the structures might suggest.
Natural Product Drug Discovery — Williams
Natural Product Drug Discovery
Despite the long history of drug discovery from natural sources, the marine environment is still relatively untapped. Covering 70% of the Earth’s surface, the oceans contain all major phyla. The resulting intense competition for space and resources drives the evolution of specific and potent chemical defenses distinct from their terrestrial counterparts.
My research interests center on the discovery and evaluation of these small molecule chemical defenses from marine sources as potential drug leads for the treatment of cancers and Alzheimer’s Disease.
In collaboration with the other members of the Natural Products Cancer Biology program, marine extracts are screened against a variety of relevant cancer targets. The active constituents are then isolated using a combination of bioassay data and repeated separations. The structures of these metabolites are then determined primarily through the use of high-field NMR spectroscopy and chemical degradation.
New Natural Product Methodologies
Modern structure determination of small molecules still remains a challenging problem. The number of structural reassignments reported each year is testimony to the myriad of potential pitfalls. While classical approaches to structure determination rely heavily on chemical degradation, most modern approaches use non-destructive techniques to provide the same connectivity information. Any structure determination encompasses three discrete assignments: planar, relative and absolute. Advances in NMR instrumentation and NMR pulse sequences have greatly simplified the assignment of the planar structure, i.e., the constitutional connectivities between the various nuclei. Conversely, relative and absolute stereochemical assignments are becoming more challenging as the isolation of submicromolar quantities of metabolites becomes increasingly more common. Consequently, my group focuses on developing new methodologies for stereochemical determinations on small scale.
Organoelement chemistry and synthesis of hypervalent organobismuth complexes — Hyvl
My research interests include organoelement chemistry with emphasis on exploration of new synthetic transformations, reactivity and applications. The research in my group will focus on synthesis of hypervalent organobismuth complexes supported with specially-designed ligand scaffolds for their utilization in transition-metal catalyzed cross-couplings, small molecule activation and generation of metallodrugs.
The group website is coming soon…