Abstracts

[Spring Semester 2006]

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Spring Semester 2007 [Top]

Feb 23

Abstract: Progress toward the synthesis of the potential chemotherapeutic, macrolide natural product dictyostatin and its 16-normethyl analogue will be presented.  In particular, a rapid, three-step synthesis of a C11-C23 segment precursor has been accomplished.  This two-directional sequence utilizes C₂-symmetric intermediates and consists of a double asymmetric hetero Diels-Alder reaction followed by a highly diastereoselective, kinetically-controlled Meerwein-Ponndorf-Verley reduction.  Efforts to desymmetrize and elaborate this intermediate will also be discussed.

New Strategies in Molecular Self-Assembly: Lyotropic Liquid Crystals from Designed Helical b-Peptides presented by Will Pomerantz

 Abstract: Liquid crystalline phases in water (aqueous lyotropic liquid crystals) have been utilized for a variety of applications including protein structure determination, alignment of inorganic materials, and sensing devices.  However, due to a lack of self-assembling systems which can be systemically studied, the underlying principles for controlling this hierarchical assembly process has been limited.  In this talk, the rational design of b-peptides which self-assemble to form liquid crystalline (LC) phases will be detailed . Due to the modularity of solid-phase synthesis, we further illustrate how facile sequence and side-chain manipulations can be readily assessed for fine-tuning of the physical properties of these new materials. These findings hope to demonstrate that highly folded b-peptides can produce LC phases at shorter lengths than do a-helical a-peptides and can provide a basis for tailoring properties of LC phases. 

 Expanding Peptoid Architecture Using Tunable Noncovalent Interactions presented by Ben Gorske

Abstract: Peptoids, or oligomers of N-substituted glycine, are an important class of non-native polymers whose close structural similarity to natural a-peptides and ease of synthesis offer significant advantages for the study of biomolecular interactions and the development of biomimetics. Elucidation of the interactions that impact peptoid folding is essential for the development of general rules for the design of new and discrete peptoid structures. To this end, we have examined the effects of pentafluoroaromatic functionality on the conformational profiles of peptoids. The microwave-assisted incorporation of a new fluorinated monomer unit has allowed us to both examine p-stacking and electronic effects in peptoids and control peptoid structure. Subsequent work focused on the regulation of peptoid amide isomerism will also be discussed.

Teaching old dyes new tricks: Fluorogenic labels based on rhodamine and fluorescein presented by Luke Lavis

 Traditional small-molecule fluorescent labels are always fluorescent. That attribute can obscure valuable information in biological experiments. We have developed versatile “latent” fluorophores that overcome this limitation. At the core of these latent fluorophores are the familiar rhodamine and fluorescein dye structures. Chemical decoration of these dyes yield stable latent fluorophores that can be attached to cationic proteins. Enzyme activity in specific locations within a cell educes fluorescence, enabling the tracking of the proteins in live human cells. The modular design of these “fluorogenic labels” permits the facile synthesis of an ensemble of small-molecule probes for the illumination of numerous biochemical and cell biological processes.

Title: Communication Breakdown: Design, Synthesis, and Evaluation of Synthetic Modulators of Bacterial Cell-Cell Communication presented by Grant D. Geske

This talk will report the investigation of synthetic ligands with the ability to modulate gram-negative bacterial cell-cell communication.  The ability of bacteria to communicate with themselves and function as a group is central in the growth and spread of infectious disease. Gram-negative bacteria use a chemical ‘language’ of small molecules and their cognate protein receptors to monitor their local population density in a phenomenon known as ‘quorum sensing’. The development of methods to control bacterial quorum sensing would serve as an invaluable way to investigate new antivirulents as therapeutics. We have designed and synthesized synthetic ligands using the full arsenal of computational, synthetic organic, and combinatorial chemistry techniques. We recently validated this integrated approach, through the first solid phase synthesis of a library of non-natural N-acyl homoserine lactones. Evaluation of this library revealed a set of synthetic quorum sensing antagonists and agonists. Furthermore, we are currently investigating the effects of these synthetic ligands in virulence assays and in other relevant gram-negative strains

Application of Intramolecular Aza-[3 + 3] Annulation to Syntheses of Coccinellidae Defensive Alkaloids presented by Aleksey Gerasyuto

Intramolecular aza-[3 + 3] annulation was shown to be a powerful tool in syntheses of various alkaloids such as gephyrotoxin, tangutorine, deplancheine and cylindricine C. Herein we report application of this tandem process to total syntheses of azaphenalene natural products. Cycloadduct precursor 2 was prepared in 5 steps from cis-disubstituted lactam 1 which is readily accessible from commercially available compounds. Intramolecular [3 + 3] annulation of aldehyde 2 leads to formation of tricycle 3 as a single diastereomer. Conversion of dihydroazaphenalene 3 to precoccinelline, hippodamine and myrrhine will be presented.

Progress Toward the Total Synthesis of the Bryostatin Macrocycle: Emphasis on the Southern Fragment presented by Vicki Wilde

The bryostatins are a family of 20-membered ring macrolides, which exhibit anti-tumor and anti-Alzheimer’s activity.  Each of the bryostatins is made up of three highly substituted tetrahydropyran rings.  The C17-C27 segment, the southern fragment, of the bryostatin macrocycle is quickly and efficiently synthesized via DIBAl-H/Horner-Wadsworth-Emmons coupling and acetonide migration/glycal formation cascade. 

The fully elaborated southern fragment of the bryostatin macrocycle can be completed in only 21 linear steps, with a total of 26 linear steps for the completion of bryostatin 7.                                                                                

Synthesis of an Aminothiazole Library as Inhibitors of NDP-sugar Utilizing Enzymes” presented by Emily Dykhuizen

The biosynthesis of glycoproteins and glycolipids are mediated by hundreds of glycosyltransferases.  Selective inhibition of glycosyltransferases in vivo would be invaluable in dissecting the regulation and function of important cell surface carbohydrate groups.  To accomplish this goal, we have used computer modeling to design a 2-aminothiazole scaffold to bind in the active site of a1,3-galactosyltransferase.  Using this scaffold, we have synthesized a 2000 membered library of neutral, drug-like compounds using a one bead one compound approach in order to identify selective, cell permeable inhibitors of glycosyltransferases. 

We have developed a general high-throughput screen based on fluorescence anisotropy to detect competitive binding in the UDP (uridine 5’ diphoshate) binding site of the enzyme.  We first screened our library against UDP-galactopyranose mutase (UGM), isomerizes UDP-galactopyranose (Galp) to UDP-galactofuranose (Galf), an essential component of the bacterial cell wall. Although this enzyme is not a glycosyltransferase, it utilizes the same substrate, UDP-galactose.  Hits with mid micromolar affinity were identified and directed libraries are being synthesized.  In addition, screens against a1,3-galactosyltransferase are underway. 

"Bioisosteres in Medicinal Chemistry" presented by Robert Zambias

The object of Lead optimization is to maintain or improve the activity of a lead compound for a specific target while improving its pharmacological properties. The use of bioisosteric replacements can be of significant value in this process. A review of bioisosteric replacements for Hydrogen, Carboxylates, Esters, Amides and Phenols with examples of their use in drug research will be presented. The synthesis of these compounds will also be discussed.

"Organocatalytic Michael Reactions, Mannich Reactions and Application of Mannich Reactions in the Concise Synthesis of β2-Amino Acids" presented by Robin Chi

Asymmetric organocatalysis offers alternative (sometimes better) strategies for achieving direct organic transformations. Our research has led to explicit mechanistic studies of Michael addition of aldehydes to enones, and a highly enantioselective catalyst system for Michael reactions. Very recently, we have developed a new organocatalytic Mannich reaction for aminomethylation of aldehydes. Mechanistic studies revealed that non-hydrogen-bonded ionic interactions at the Mannich reaction transition state can influence the stereochemical outcome. The new organocatalytic process constitutes the key step in an efficient synthesis of β2-amino acids with >50% overall yield and minimal chromatographic purifications.

"Acetalization/Ring-Closing Metathesis for Synthesis of Tetrahydropyran-Containing Natural Products" presented by Chris Marvin

Acetalization of C2 symmetric 3,4-dihydroxy-1,5-hexandienes with unsaturated aldehydes (or transacetalization with acetals) followed by ring-closing metathesis allows rapid access to the 6,8-dioxabicyclo[3.2.1]oct-2-ene ring system. This bridged system has been utilized in the synthesis of a variety of natural products. Specifically, progress utilizing this strategy towards thromboxane B­2 and preliminary studies towards spicamycin will be described.

"New Strategies for Tandem Ring-Closing Metathesis and Applications Toward the Total Synthesis of Tartrolon B" presented by Yi Jin Kim

The rapid growth in the field of ring-closing metathesis (RCM) has allowed synthetic chemists to develop numerous methods to understand and control factors that affect the efficiency of ring closure as well as the reaction pathways leading to multiple products in enyne RCM.  We have developed a unique RCM platform based on the well-known stereodynamic behavior of N-substituted diacylhydrazines, which promotes an effective RCM of hydrazine-derived dienes and enynes to form 8- to 14-membered rings.  In an effort to further our understanding of enyne RCM, we also became interested in a tandem dienyne ring-closing metathesis of unsymmetrical alkynyl silaketals containing two tethered olefins.  Although dienyne RCM has traditionally been limited in utility due to its poor group selectivity, our studies have found that the well-known “Thorpe-Ingold Effect” can be utilized to effectively control the mode of bicyclization.  Furthermore, the resulting bicyclic siloxanes can undergo protodesilylation to generate diols containing 1,4-substituted 1,3-dienes with a stereochemically defined E,Z-diene moiety.  As a demonstration of its utility, we have implemented this methodology in the total synthesis of Tartrolon B.

Fall Semester 2005 [Top]

"Palladium(II) Complexes BearingN-Heterocyclic Carbene Ligands as Effective Catalysts for Intramolecular Aerobic Oxidative Amination" presented by Michelle Monnens Rogers

N-Heterocyclic carbene palladium(II) complexes catalyze the cyclization of nitrogen nucleophiles with pendent olefin for the formation of nitrogen heterocycles. These cyclization reactions proceed with good yields for a series of substrates.

"Heterocyclic Chemistry and Drug Discovery" presented by Dr. Roger Newton (Director of Science - Maybridge). Sponsored by Fisher Scientific.

Over 50% of the worlds top drugs are heterocycles. This seminar will explore the reasons for this and discuss pharmacophores, pharmacokinetics and the process of hit to lead optimization. Finally the talk will describe the discovery of a PARP inhibitor that has just entered clinical trials.

"Beta-Peptides as Inhibitors of Human Cytomegalovirus Virus-Cell Fusion" presented by Emily Payne English (Gellman Group)

Human cytomegalovirus (HCMV) is a human herpesvirus that poses a significant health risk to immune-compromised individuals.  HCMV fusion, the process by which the virus accesses the host cell, involves at least three glycoproteins on the virus and potentially several host-cell receptors.  However, little about the molecular details of the fusion process is understood.  We have designed and evaluated 12-helical b-peptides that block HCMV fusion.  These designs were based upon the hypothesis that a-helical coiled coil interactions in the HCMV glycoproteins are critical intermediates along the fusion pathway.  Current efforts are focused on understanding the nature of the fusion inhibition, exploring new foldamer scaffolds for inhibitor design, and using these foldamer inhibitors as tools for probing the mechanistic details of HCMV fusion.

"Progress Toward the Total Synthesis of Guanacastepene A" presented by Sarah V. Mailfeld (Lee Group)

Guanacastepene A is the parent member of a unique family of diterpene natural products isolated from an unclassified endophytic fungus living on the branch of a Daphnopsis americana tree in the Guanacaste Conservation Area in Costa Rica.  During screening for antibiotic activity, guanacastepene A exhibited excellent potency against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis.  The combination of guanacastepene A’s promising anti-bacterial action as well as its previously unreported 5-7-6 tricyclic skeleton renders it an attractive target for total synthesis.

"The Kinetics of Catalytic Hydrogenation of Aldehydes with a Triphenlyphosphine Substituted Analogue of the Shvo Catalyst" presented by Sharon Beetner (Casey Group)

Catalytic hydrogenation provides an attractive “greener” alternative to stoichiometric reducing agents such as LiAlH4 and NaBH4.  The Shvo catalyst system is the first example of a transition metal catalyst containing both an acidic and a hydridic hydrogen.  The substitution of one of the metal carbonyls with a triphenylphosphine ligand to form 1 significantly alters the properties of the catalytic system.  This new catalyst selectively reduces aldehydes in the presence of ketones and operates under milder conditions than the parent catalytic system.

The broad goal of our work is the design, synthesis, and evaluation of new small molecules that inhibit cell-cell communication mechanisms in bacteria. The ability of bacteria to communicate with themselves and function as a group is central in the growth and spread of infectious disease. Gram-negative bacteria use a chemical ‘language’ of small molecules (or autoinducers, typically N-acylated homoserine lactones) and their cognate protein receptors to monitor their local population density in a phenomenon known as ‘quorum sensing’. At high population densities, pathogenic bacteria use ‘quorum sensing’ to organize into structured communities called biofilms and activate virulence pathways that are the basis for myriad chronic infections. We have developed a MW accelerated solid phase approach that has allowed us to synthesize a library of non-native N-acyl homoserine lactones.  Evaluation of this library revealed a new set of ‘quorum sensing’ antagonists.  This seminar will present the on-going work in this area.