Higuchi Biosciences Center - University of Kansas

Fall 2008 Science Talks
December 5, 2008

E1. A Metathesis Cascade Strategy to Skeletally Diverse Sultams
Kyu Ok Jeon, Alan Rolfe, Dinesh Rayabarappu, Kelly Volp, Iman Omar and Paul R. Hanson
*Department of Chemistry, 1251 Wescoe Hall Dr., University of Kansas, Lawrence, KS 66045-7582
The Center for Chemical Methodology and Library Development at the University of Kansas, 1501 Wakarusa Drive, Lawrence, KS 66047

A Tandem metathesis approach is developed for the synthesis of a variety of tricyclic sultams. N-Allyl bicyclic oxanorbornene scaffolds prepared via intramolecular Diels-Alder chemistry were subjected to Grubbs II metathesis catalyst with acrylates, to provide a tricyclic sultam in good yields via tandem ROM-RCM-CM process. Studies have revealed that in the absence of CM partner, a dimer adduct was formed via ROM-RCM and dimerization. The reaction was further extended to a enyene metathesis process.

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E2. A strategy for identifying small molecules that interact with specific signaling pathways in Caenorhabditis elegans
Martin L. Hudson (1, 2) and Brian D. Ackley (2)
1. Higuchi Biosciences Center, University of Kansas, Lawrence, KS, 66045
2. Department of Molecular Biosciences, University of Kansas, Lawrence, KS, 66045

Identifying the site and mechanism of action of a small molecule drug is crucial to understanding how a drug functions in vivo. Traditional high-throughput screening usually begins with a receptor or enzyme target and generally relies on competition assays against a labeled substrate or native agonist. But how does one discover additional components in a signaling pathway that could provide alternative small molecule targets e.g., for back-up compounds or to understand off-target effects?

One possibility is to use the power of genetics in model organisms such as worms, flies or mice as a background for a screen in a specific pathway. During C. elegans development, multiple genes function redundantly to coordinate the development of the embryo. Loss of function in a single gene generally leads to a weak phenotype. However, loss of function in two or more genes required in embryonic development usually leads to an enhanced or synthetic lethal phenotype. This kind of genetic interaction can be used as the basis for small molecules screens in specific pathways. In this case, a single mutant worm with a weak phenotype in a parallel pathway becomes the screening background i.e. the sensitized strain. Worms are then treated with compounds from small molecule libraries and their embryos screened for synthetic lethal phenotypes.

To provide further specificity, screening is carried out in parallel with wild-type worms and a mutant background that you specifically want to target. If a small molecule shows a synthetic lethal phenotype with the enhancer mutant but no phenotype with wild-type or the target mutants, we conclude that the small molecule most likely acts in the same pathway as the target mutant.

This strategy was validated by mutations in the C. elegans LAR-like protein tyrosine phosphatase and Eph receptor genes. These mutants show weak phenotypes alone but are synthetic lethal in combination with each other. Sodium orthovandate is a specific inhibitor of protein tyrosine phosphatase activity. This compound shows no effects in worms but in an Eph receptor mutant background, shows a strong lethal phenotype. We will present a detailed description of this strategy and preliminary data from RNAi genetic screens that function in a similar manner.

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E3. b-Keto Sultams: Exploitation in Diversity Oriented Synthesis & Library Production
Thiwanka Samarakoon, Audrey Y. Le, Daniel Barrera, Paul R. Hanson¹
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Dr, Lawrence, KS 66045-7582.
NIH Center of Excellence in Chemical Methodologies and Library Development (KU-CMLD), Lawrence, KS 66045-7582

Anthranilic acid derived sulfonamides have been found to have an attractive biological profile including inhibition of MMP-15, Factor Xa, monoamine reuptake, aldesterone synthase and protein tyrosine kinase. The synthetic utility of these scaffolds are yet to be utilized in diversity oriented synthesis. Our efforts towards the exploitation of of anthranilic acid derived b-keto sultams in library production and diversity oriented synthesis (DOS) are presented. This strategy employs anthanilic acids derived alkyl sulfonamides undergoing a Dieckman-type cylization to synthezise followed by triflation to yield a number of core β-tryifyl sultams. Suzuki reaction with a number of boronic acids have been performed to yield a 4 X 4 protypical library. A CuI mediated nucleophile additon on the triflate has also been performed with thiols, phenols, anilines and alcoxides to produce a 4 X 4 protypical library. We have also carried out Robinson annulations, Intramolecular Heck cylizations and ring closing metathesis to synthesize diverse sultams via the core β-ketosultam.

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E4. Development of ROMP-derived Reagents for Library Production: OACC, ODCT and OMAm
Alan Rolfe, Ryan Kurtz, Kelly A. Volp, Iman Omar and Paul R. Hanson*, Department of Chemistry, 1251 Wescoe Hall Dr., University of Kansas, Lawrence, KS 66045. The Center for Chemical Methodologies and Library Development at the University of Kansas (KU-CMLD), 2121 Simons Drive, Structural Biology Center, West Campus, Lawrence, KS 66047.

Efforts towards the integration of an assortment of ROMP-derived scavengers and reagents in parallel synthesis for generation of libraries have been developed within our program with the specific aim to reduce purification protocols to simple quench-filter methods. These high-load, algometric reagents are generated by the ROM polymerization of norbornene- or 7- oxonorbornene-based monomers employing the Grubbs metathesis catalyst to produce oligomers of controllable lengths with differential solubility profiles. An array of oligomeric ROMP-reagents, scavengers and supports have been developed and employed in diversity-generating reactions, such as acid coupling, alkylation/benzylation, sulfonylation, acylation, Mitsunobu reaction and several other reactions. Recent highlights in this area include the synthesis and application of a high load amine scavenger, algometric dichlorotriazine (DCT), vanishing support strategies and in-situ ROMP strategies.

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E5. Modular Approach to Compound Libraries Inspired by Martinellic Acid and the Steroid Nuclear Hormones
Li, K.* and Schoenen, F.J.
University of Kansas Center for Chemical Methodologies and Library Development (KU CMLD), University of Kansas, Lawrence, KS 66047, schoenen@ku.edu

The titanium-mediated cyclization¹ provides a reaction manifold to prepare compound libraries inspired by steroid nuclear receptor agonists and antagonists² and the natural product martinellic acid.³

As shown in the scheme, reaction of the alknyl aldehyde with an amine followed by titanium-mediated [2+2+1] cyclization under CO atmosphere generates pyrrolodihydroquinolines with structures reminiscent of bazedoxifene, a selective estrogen receptor modulator.

Alternatively, appropriately substituted alkynyl aldehydes, amines, and electrophiles may be reacted to afford key mono-cyclized intermediates that may be further functionalized to generate compounds containing the tricyclic core of martinellic acid.

The scope and limitations for these transformations have been explored and our progress to date, including the number and types of compounds that we have been prepared, will be described.

References:
1.Gao, Y.; Shirai, M.; Sato, F. Tetrahedron Lett. 1996, 37, 7787-7790.
2. Miller, C. P.; Collini, M. D.; Tran, Bach D.; Harris, H. A.; Kharode, Y. P.; Marzolf, J. T.; Moran, R. A.; Henderson, R. A.; Bender, R. H. W.; Unwalla, R. J.; Greenberger, L. M.; Yardley, J. P.; Abou-Gharbia, M. A.; Lyttle, C. R.; Komm, B. S. J. Med. Chem. 2001, 44, 1654-1657.
3. Ma, D.; Xia, C.; Jiang, J.; Zhang, J. Org. Lett. 2001, 3, 2189-2191.

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E6. Multidimensional Screening of Bicyclic Iminum Ethers Utilizing Microfluidics
Jennifer L. Treece¹, John R. Goodell², David Vander Velde¹, John A. Porco, Jr.², Jeffrey Aubé¹
¹Department of Medicinal Chemistry and Center for Chemical Methodology and Library Development (KU-CMLD), University of Kansas, 1251 Wescoe Hall Drive, 4070 Malott Hall, Lawrence, Kansas 66045
²Department of Chemistry and Center for Chemical Methodology and Library Development (CMLD-BU), Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215

Bicyclic iminium ethers, synthesized through the Lewis acid promoted reaction of ketones with hydroxyalkyl azides, have demonstrated utility as intermediates towards the formation of a diverse array of heterocycles. In an effort to expand the scope of reactivity, and assist in the generation of new chemotypes from these reactive intermediates, both simple and complex bicyclic iminium ethers were multidimensionally screened. Through the employment of a microfluidics-assisted reaction format a series of screens has been completed. The findings of these screens incorporating various nucleophiles and bases are reported.

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E7. Temporary Phosphate Tethers: Rapid Access to Advanced Polyol synthons in Natural Product Synthesis
Susanthi Jayasinghe, Alan Whitehead, Joshua D. Waetzig, James P. McParland, Christopher D. Thomas, Paul R. Hanson*, Department of Chemistry, University of Kansas, Lawrence, KS 66045

Classically silicon has been shown to be an effective temporary tether in constructing advanced polyol synthons due to its ability to rapidly couple two complex fragments, exhibit stability under reaction conditions and undergo facile removal. In this regard we report the effective utilization of phosphate in this fashion as well as a desymmetrization tool through our chiral, nonracemic bicyclic phosphates (R,R)- and (S,S)-1. These templates can be effectively used in stereo- and regioselective transformations, in which utilization of these advanced intermediates are applied toward the syntheses of Dolabelide C Fostriecin and Leustroducsin B.

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Higuchi Biosciences Center
University of Kansas
2099 Constant Avenue
Lawrence, KS 66047-2535
785-864-5183
hbc@ku.edu