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Dynamic Combinatorial Chemistry Using Amino-Acids as Building Blocks, and Use of Carbonyl Ylides as Dipoles in Dipolar C...

Permanent Link: http://ufdc.ufl.edu/UFE0021322/00001

Material Information

Title: Dynamic Combinatorial Chemistry Using Amino-Acids as Building Blocks, and Use of Carbonyl Ylides as Dipoles in Dipolar Cycloadditions
Physical Description: 1 online resource (88 p.)
Language: english
Creator: Klein, Sophie
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2007

Subjects

Subjects / Keywords: acids, amino, carbonyl, chemistry, combinatorial, cycloadditions, dipolar, dynamic, ylides
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Over the past decade, combinatorial chemistry has been widely used to create large libraries of compounds and to screen them to find new materials and biologically active molecules. A more specific approach is dynamic combinatorial chemistry. Constituents of the library are formed through reversible bonds between small components, and each of the constituents is in thermodynamic equilibrium in the reaction mixture. When a specific target is added to the library, the constituent that has the best binding feature with the target is selectively expressed, and the equilibrium is shifted to this specific compound. We were interested in studying the comportment of simple amino acid derivatives toward dynamic combinatorial chemistry. An alkyl chain containing a terminal double bond was added to amino acids to form the building blocks. We first synthesized homodimers from each building block through cross-metathesis using Grubbs? second generation catalyst to study them. Then the amino acid derivatives were mixed with the catalyst to form a library of dimers. The addition of a cation in the mixture under specific conditions shifted the equilibrium. All the results were analyzed by HPLC. The second project was focused on the formation of heterocycles using 1,3-dipolar cycloadditions. Dipolar cycloadditions have been an efficient method to quickly form heterocycles, and have been especially used for the synthesis of natural products. Among the different dipoles available for the 1,3-dipolar cycloadditions, we studied the use of a cyclic carbonyl ylide as dipole. The use of this particular dipole with appropriate dipolarophiles can lead to highly substituted oxygen heterocycles. The compounds obtained from the reaction with the carbonyl ylide and various dipolarophile were analyzed. After having formed the precursor of the carbonyl ylide from levulinic acid, it was mixed with a rhodium catalyst and a dipolarophile. Various dipolarophiles, containing either electron-withdrawing groups or electron-donating groups, were tested. The stereochemistry of the compound obtained was analyzed and explained in terms of frontier molecular orbital theory.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Sophie Klein.
Thesis: Thesis (Ph.D.)--University of Florida, 2007.
Local: Adviser: Enholm, Eric J.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2009-08-31

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Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2007
System ID: UFE0021322:00001

Permanent Link: http://ufdc.ufl.edu/UFE0021322/00001

Material Information

Title: Dynamic Combinatorial Chemistry Using Amino-Acids as Building Blocks, and Use of Carbonyl Ylides as Dipoles in Dipolar Cycloadditions
Physical Description: 1 online resource (88 p.)
Language: english
Creator: Klein, Sophie
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2007

Subjects

Subjects / Keywords: acids, amino, carbonyl, chemistry, combinatorial, cycloadditions, dipolar, dynamic, ylides
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Over the past decade, combinatorial chemistry has been widely used to create large libraries of compounds and to screen them to find new materials and biologically active molecules. A more specific approach is dynamic combinatorial chemistry. Constituents of the library are formed through reversible bonds between small components, and each of the constituents is in thermodynamic equilibrium in the reaction mixture. When a specific target is added to the library, the constituent that has the best binding feature with the target is selectively expressed, and the equilibrium is shifted to this specific compound. We were interested in studying the comportment of simple amino acid derivatives toward dynamic combinatorial chemistry. An alkyl chain containing a terminal double bond was added to amino acids to form the building blocks. We first synthesized homodimers from each building block through cross-metathesis using Grubbs? second generation catalyst to study them. Then the amino acid derivatives were mixed with the catalyst to form a library of dimers. The addition of a cation in the mixture under specific conditions shifted the equilibrium. All the results were analyzed by HPLC. The second project was focused on the formation of heterocycles using 1,3-dipolar cycloadditions. Dipolar cycloadditions have been an efficient method to quickly form heterocycles, and have been especially used for the synthesis of natural products. Among the different dipoles available for the 1,3-dipolar cycloadditions, we studied the use of a cyclic carbonyl ylide as dipole. The use of this particular dipole with appropriate dipolarophiles can lead to highly substituted oxygen heterocycles. The compounds obtained from the reaction with the carbonyl ylide and various dipolarophile were analyzed. After having formed the precursor of the carbonyl ylide from levulinic acid, it was mixed with a rhodium catalyst and a dipolarophile. Various dipolarophiles, containing either electron-withdrawing groups or electron-donating groups, were tested. The stereochemistry of the compound obtained was analyzed and explained in terms of frontier molecular orbital theory.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Sophie Klein.
Thesis: Thesis (Ph.D.)--University of Florida, 2007.
Local: Adviser: Enholm, Eric J.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2009-08-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2007
System ID: UFE0021322:00001


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1 DYNAMIC COMBINATORIAL CHEMISTRY USING AMINO ACIDS AS BUILDING BLOCKS, AND USE OF CARBONYL YL IDES AS DIPOLES IN DIPOLAR CYCLOADDITIONS By SOPHIE KLEIN A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2007

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2 2007 Sophie Klein

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3 To my parents Albert and Mich elle and my brother Jrme

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4 ACKNOWLEDGMENTS First of all, I would like to thank my parents Albert and Michelle for their patience and their love, for their support over th ese four years, even if I was far from home, and for having the right words to encourage me when I wanted to qu it or when I had very difficult times. I would like to thank my brother Jrme, fo r being the only one in my fam ily to understand my struggles and successes in the lab, spending hours on the phone talking about chemistry, life, and family. I would also like to acknowledge my sister Valerie. I also wish my grandmother could see me finally achieve my PhD. I would like to sincerely acknowledge my advi sor Dr. Eric Enholm fo r all his help and support throughout my graduate career at the Univ ersity of Florida. I thank him for taking me under his wing when I first arrived, for being a ment or and helping me when I had troubles in the lab. I thank him for his patience, his a dvices, and being an excellent teacher. I would also like to thank my committee me mbers, Dr. Castellano, Dr. McElwee-White, Dr. Sloan and Dr. Duran for their help over the y ears and their precious advices during my oral examination. I would like to especially thank esp ecially Dr Castellano, fo r letting me using his labs HPLC. I would also like to thank Dr Ion Guiv irigua for being here when I needed enlighten for NMR solving problems and for assisting to my defense. I would like to thank all my labmates thro ughout the years, Dr Aarti Joshi, Kalyan Mondal, Ryan Martin, Josh Caccamis, our REUs students Vincent Rietsch, Celia Brancour and Janeirys Cruiz, and a special th ank to Dr Jed Hastings and Dr Tammy Low for their friendship, for our discussions about everything from chemistry to who will be the next one to host our melting pot dinners, and making the atmosphere in the lab truly enjoyable. I would also like to

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5 thank Dr Dennis Wright for letting me join hi s group during my REU internship, and Dr Chris Whitehead, with whom I first discover the Gainesville life and for his help in the lab. I would also like to sincerely acknowledge Dr Florent Allais, not only for being my labmate but also my roommate, for helping me during my first year, fo r his friendship, his humo r and his music, even if we had and still have some disagreements about various subjects, and th at life with him wasnt all easy, but thats what all real friendship is about! I also would like to thank all my friends at the Chemistry department, Dr Delmy Diaz, Dr Frances Chang, David Snead, Fedra Leonik, Neil St owe, Dr Genay Jones, and especially the French mafia, Dimitri Dascier, Sophie Bernar d, Roxanne Fabre for our golf weekends, Emilie Galand, my roommates for three mo nths Rachid Matmour and Aziz Ndoye, with whom I really had a good and relaxed time, Frederic Lagreze and Alex Alabbas. Finally, I would like to dear ly acknowledge John Peak, whos been supporting me these last years through all my highs and lows, and w hos always been here when I needed him.

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6 TABLE OF CONTENTS ACKNOWLEDGMENTS...............................................................................................................4 LIST OF TABLES................................................................................................................. ..........8 LIST OF FIGURES................................................................................................................ .........9 LIST OF SCHEMES................................................................................................................ ......11 ABSTRACT....................................................................................................................... ............13 CHAPTER 1 HISTORICAL BACKGROUND..............................................................................................15 Dynamic Combinatorial Chemistry...................................................................................15 Combinatorial Chemistry............................................................................................15 Dynamic Combinatorial Chemistry............................................................................17 Dipolar Cycloadditions......................................................................................................21 General Considerations...............................................................................................21 Carbonyl Ylides as 1,3-dipoles...................................................................................24 2 DYNAMIC COMBINATORIAL LIBRARY...........................................................................29 Introduction................................................................................................................... .....29 Results and Discussion.......................................................................................................33 Formation of the Amino Acid Derivatives.................................................................33 Generation of the Library............................................................................................37 Effects of concentration.......................................................................................39 Effects of equivalent of template.........................................................................39 Effects of temperature..........................................................................................42 Shifting of the equilibrium...................................................................................43 Conclusion..................................................................................................................... ....45 3 USE OF CARBONYL YLIDES AS DI POLES FOR DIPOLAR CYCLOADDITIONS.........46 Introduction................................................................................................................... .....46 Results and Discussion.......................................................................................................49 Formation of the Precursor for Carbonyl Ylide..........................................................49 Dipolarophiles.............................................................................................................51 Mechanism..................................................................................................................57 Conclusion..................................................................................................................... ....59 4 EXPERIMENTAL SECTION...................................................................................................61 General methods................................................................................................................61

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7 Experimental Procedures and Data....................................................................................61 APPENDIX: SPECTRAL DATA.................................................................................................76 LIST OF REFERENCES............................................................................................................. ..83 BIOGRAPHICAL SKETCH.........................................................................................................88

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8 LIST OF TABLES Table Page 1-1 Differences between CC and DCC..........................................................................................19 1-2 Reactivity of metal-based catalysts........................................................................................ .30 2-2 Results of BOC-Phe and BOC-Le u toward esterification and CM.........................................35 2-3 Results of the chosen amino aci ds toward esterification and CM...........................................36 3-1 List of dipolarophiles..................................................................................................... ..........52

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9 LIST OF FIGURES Figure Page 1-1 Different approaches to CC. A) split-m ix synthesis. B) Parallel synthesis.............................17 1-2 Principle of DCC........................................................................................................... ..........18 1-3 Example of the amplification of the best binder......................................................................18 1-4 Molding and casting process in DCC......................................................................................20 1-5 Common 1,3-dipoles......................................................................................................... ......23 1-6 Type I and type III interactions........................................................................................... ....28 2-1 Amino acids used for DCC................................................................................................... ...33 2-2 Potential nonproductive chel ate of ruthenium carbene...........................................................35 2-3 Conditions used: no Li+, 25C, 0.001M..................................................................................40 2-4 Conditions used: Li+ 1 equiv., 25C, 0.001M.........................................................................41 2-5 Conditions used: no Li+, 50oC, 0.005M...................................................................................42 2-6 Conditions used: Li+ 5 equiv., 50oC, 0.005M..........................................................................43 2-7 Conditions used: no Li+, 25oC, 0.005M...................................................................................44 2-8 Conditions used: Li+ 5 equiv., 25oC, 0.005M..........................................................................44 3-1 HOMO-LUMO of carbonyl ylide and dipolarophiles.............................................................58 A-1 NMR of 2-6................................................................................................................. ............76 A-2 NMR of 2-7................................................................................................................. ............76 A-3 NMR of 2-8................................................................................................................. ............77 A-4 NMR of 2-9................................................................................................................. ............77 A-5 NMR of 2-10................................................................................................................ ...........78

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10 A-6 NMR of 2-11................................................................................................................ ...........78 A-7 NMR of 2-12................................................................................................................ ...........79 A-8 NMR of 2-13................................................................................................................ ...........79 A-9 NMR of 2-14................................................................................................................ ...........80 A-10 NMR of 2-15............................................................................................................... ..........80 A-11 NMR of 3-5................................................................................................................ ...........81 A-12 NMR of 3-6................................................................................................................ ...........81 A-13 NMR of 3-11............................................................................................................... ..........82 A-14 NMR of the mixture of 3-12 and 3-13..................................................................................82

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11 LIST OF SCHEMES Scheme Page 1-1 General mechanism of 1,3-dipolar cycloadditions..................................................................21 1-2 Examples of 1,3-dipolar cycloadditions. A) Azide alkyne Huisgen reaction. B) Diazoalkane 1,3-dipolar cycloaddition. C) Ozonolysis......................................................................................22 1-3 Proposed mechanism of copper (I) -catalyzed synthesis of azoles..........................................24 1-4 Generation of carbonyl ylides.............................................................................................. ....25 1-5 Generation of cyclic carbonyl ylides.......................................................................................26 1-6 Possible isomers with asymmetrical dipolarophiles................................................................27 2-1 General mechanism for olefin metathesis...............................................................................29 2-2 Cross-metathesis using Grubbs second gene ration catalyst and amino acid derivatives.......30 2-3 Olefin CM done by Miller................................................................................................... ....31 2-4 Possible combinations of amino acid deri vatives formed through cross-metathesis..............32 2-5 General synthesis of amino acid derivatives...........................................................................34 3-1 General mechanism......................................................................................................... .......46 3-2 Synthesis of nemorensic acid by Hodgson..............................................................................47 3-3 Koyamas approach of the synthesi s of the core of zaragozic acid.........................................47 3-4 General mechanism us ing samarium diiodide.........................................................................48 3-5 Synthesis of the core of phorbol........................................................................................... ...48 3-6 General tandem cyc lization-cycloaddition..............................................................................49 3-7 Synthesis of diazo-dione 3-1............................................................................................... ....50 3-8 Formation of the by-product................................................................................................ ....50

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12 3-9 General synthesis of polycyclic molecules..............................................................................51 3-10 Reaction with DMAD as dipolarophile.................................................................................52 3-11 Diethyl fumarate and dimet hyl maleate as dipolarophiles....................................................53 3-12 Possible isomers.......................................................................................................... ..........54 3-13 Reaction using methyl acrylate a nd methyl propiolate as dipolarophiles.............................55 3-14 Reaction using EVE as dipolarophile....................................................................................55 3-15 Possible products from r eaction using crotonaldehyde.........................................................56 3-16 Reaction with crotonaldehyde.............................................................................................. .57 3-17 Aldehydes derivative from D-ma nnitol and di-acetone glucose...........................................57

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13 Abstract of Dissertation Pres ented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy DYNAMIC COMBINATORIAL CHEMISTRY USING AMINO ACIDS AS BUILDING BLOCKS, AND USE OF CARBONYL YLID ES AS DIPOLES IN DIPOLAR CYCLOADDITIONS By Sophie Klein August 2007 Chair: J. Eric Enholm Major: Chemistry Over the past decade, combinatorial chemis try has been widely used to create large libraries of compounds and to screen them to find new materials and biologically active molecules. A more specific approach is dynamic combinatorial chemistry. Constituents of the library are formed through reve rsible bonds between small co mponents, and each of the constituents is in thermodynamic equilibrium in the reaction mixture. When a specific target is added to the library, the constituent that has the be st binding feature with the target is selectively expressed, and the equilibrium is shifted to th is specific compound. We were interested in studying the comportment of simple amino ac id derivatives toward dynamic combinatorial chemistry. An alkyl chain containing a terminal double bond was added to amino acids to form the building blocks. We first synthesized hom odimers from each building block through crossmetathesis using Grubbs sec ond generation catalyst to st udy them. Then the amino acid derivatives were mixed with the catalyst to form a library of dimers. Th e addition of a cation in the mixture under specific conditions shifted the equilibrium. All the resu lts were analyzed by HPLC.

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14 The second project was focused on the fo rmation of heterocycles using 1,3-dipolar cycloadditions. Dipolar cycloadditions have b een an efficient method to quickly form heterocycles, and have been es pecially used for the synthesi s of natural products. Among the different dipoles available for the 1,3-dipolar cycloadditions, we studied the use of a cyclic carbonyl ylide as dipole. The use of this partic ular dipole with approp riate dipolarophiles can lead to highly substituted oxygen heterocycles. The compounds obtained from the reaction with the carbonyl ylide and various dipolarophile were an alyzed. After having formed the precursor of the carbonyl ylide from levulinic acid, it was mi xed with a rhodium catal yst and a dipolarophile. Various dipolarophiles, contai ning either electron-withdraw ing groups or electron-donating groups, were tested. The stereochemistry of th e compound obtained was an alyzed and explained in terms of frontier molecular orbital theory.

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15 CHAPTER 1 HISTORICAL BACKGROUND This dissertation will present two distinct pr ojects. The first one wi ll discuss the use of amino acids as building blocks for dynamic combinatorial chemis try (DCC). For the last decade, this method has been used as a way to quickly discover molecules that can react or bind to specific targets. This methodol ogy has been used es pecially in drug di scovery and in the biological field. Among a library of compounds th ermodynamically in equilibrium with each other, the addition of a target or guest can push the equilibrium to the compound that have the most affinity with this target. The findings of amino acids used as building blocks for DCC and their comportment with a specifi c target, in this case a simple cation will be presented. The second project will talk about 1,3-dipol ar addition using carbonyl ylides as dipoles. Dipolar cycloadditions proved to be a good way to make highly subs tituted heterocycles over the years. The stereochemistry in these reactions can also be predicted by FMO theory. The reaction of carbonyl ylides with va rious dipolarophiles will be discus sed, along with the stereochemistry of the heterocycles obtained. Dynamic Combinatorial Chemistry Combinatorial Chemistry The need to find biologically active substances and molecules that interact selectively with specific targets has led to combinatorial chemistry (CC). This approach has been actively pursued over the last twenty years, primarily because one gains quick access to novel pharmaceuticals through the screening of a vast collection of molecules. In traditional combinatorial chemistry, one can obtain a large library of related molecules, using the same chemical reactions that are specific, irreversible and stereoselective, and then can test them for

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16 the desired properties. This approach was fi rst focused on creating libraries of peptides1 and oligonucleotides. The beginnings of this method can be traced back to 1963, when Merrifield first introduced a seminal solid-pha se synthesis of peptides. Howe ver, CC only started to develop in the 1980s, with the research from Furka,2 Geysen,3 and Houghten.4 Furka et al first developed a solution-phase synthesis in 1982, also known as the split-mix synthesis. In 1984, Geysen et al. invented the parallel synthesis to pro duce peptides on a pin-shaped solid support, and the next year, Houghten et al. devised a solid-phase parallel synthesi s of peptides, using mesh packets, or tea-bags as reaction chambers and filtration devices. Since then, CC has become a useful tool for the biological field in drug development.5 It also has been used in the material sciences, as the properties of many materials, like high-t emperature superconductors, ferroelectrics or magnetic materials, depend on the interaction with the environment.6 With this methodology, a large number of molecules can be synthesized at once, without having to make each of them separately. Large libraries are obtained by combining building blocks using automated methods. The library obtained can contain hun dreds of compounds (Figure 1-1).7 Because not all of the compounds are useful, they are then screened at once with a specific target, and the most active combination is detected. Having a larger, more diverse compound library on hand can thus increase the probability of finding compounds that have a therapeutic or commercial interest. The entities obtained are all discrete molecules, so they can be archived for later use. One drawback is that CC is static, meaning the products obtained are distinct static entities and cannot change ex cept under chemical methods.

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17 Figure 1-1. Different approaches to CC. A) split-mix synthesi s. B) Parallel synthesis. Dynamic Combinatorial Chemistry Another approach to this new area is the dynamic combinator ial chemistry (DCC).8 In traditional CC, the synthesis of the library and th e screening are distinct steps. In DCC, the library and the screening can be performed at on ce. Instead of having a di stinct physical library of compounds, a virtual librar y of compounds is generated, each of them being in thermodynamic equilibrium in the reaction mixture. The building blocks can undergo all the combinations possible, and because they are comb ined in a reversible way, all the recombinants are virtually available at any ti me in the reaction (Figure 1-2).9 In contrast to traditional combinatorial chemistry, this approach is ther modynamic, target-driven, adaptive, and based on Le Chateliers principle.

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18 Figure 1-2. Principle of DCC If a specific template is added to the equilibrium, the molecule presenting the best recognition features to the target will be selectively expressed, and so, the equilibrium will be driven to only one compound. This approach was first describe d in the molecu lar recognition field, using ligands as building blocks and a metal cation as th e target. A ligand can then be determined as the best binder to a specific cation (Figure 1-3),10 analyzing the reaction by different methods like HPLC, fluorescence spectrosc opy, if the ligand is attached to a fluorescent bead, or NMR. This is under ideal conditions. In the case described in chapter 2, great difficulties were encountered with this amplification, even though th e library clearly shifted. Figure 1-3. Example of the amplif ication of the best binder.

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19 Table 1-1. Differences between CC and DCC COMBINATORIAL LIBRARY DYNAM IC COMBINATORIAL LIBRARY Real set Non-reversible Systematic Preformed by synthesis In absence of target Virtual set Reversible Recognition-directed Self-assembled In presence of target Different reversible reactions forming c ovalent bonds can be used. Hioki and Still11 for example used disulfide bond formation. They screen ed a library of tripeptides to find the best binder to a disulfide-linked small molecule r eceptor. The molecule was also linked to a fluorescent bead, which allowed them to eas ily check by fluorescent microscopy which tripeptide bonded best. Huc and Lehn12 used imine reactions to obtain a virtual library using four amines and 3 aldehydes as building blocks. In this case, an enzyme was used as the amplifier for one of the combinations. Non-covale nt interactions can also be used to combine building blocks. Rebek et al.13 studied the formation of molecular capsules by hydrogenbonding. These capsules were obta ined by binding the subunits via hydrogen bonds. They were formed only if a guest with the suitable shape wa s present in the mixture, empty capsules werent formed. In this work, the guest molecule s were ethyltrimethyl ammonium cation and methylquinuclidinium cation. Metal coordination14 and Van der Waals interactions are also been used as reversible interactions.

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20 Figure 1-4. Molding and casting process in DCC Building blocks can recognize a target either through casting or molding (Figure 1-4), as explained by Lehn and Eliseev.15 In the casting process, one comb ination of substrates has the best shape and feature to bind to the target. Before the addition of a receptor, the building blocks interact with each other in a re versible way, creating a virtual co mbinatorial library. By adding the receptor, the combination th at fits the target is selectively amplified by shifting the equilibrium. Nicolaou et al.16 used the casting process to identify the best ligands for vancomycin receptors. In the molding proce ss, the building blocks are assembled around the target. The combinations of building blocks are no t formed prior to the addition of a target; once the substrate is added to the mixture of building blocks, it interacts with the ones that have the best binding affinity. Rebek used this method to make the library of capsules, and Reinhoudt17 selectively amplified zinc-porphy rin units that have the best affinity with a heteroatomic substrate containing zinc-b inding pyridine groups. DCC has been used extensively to make libraries of biomolecules, including enzymes18 and lectins,19 and the wide variety of building bl ocks can include non natural elements,

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21 carbohydrates20 or nucleotides.21 This technique has also been used for material sciences, as supramolecular entities can be used to form novel adaptive material. Most of the libraries are based on aminoaci d derivatives, but no work has been done on simple amino acids as building blocks. In this re search, simple amino acid derivatives were used as elements for DCC, and the reversible cross-metathesis reaction with the Grubbs second generation catalyst was utilized. Cross-metathesis has been effici ent as a reversible method for DCC, and the second generation catalyst was used to avoid possible racemization of chiral amino acids. Dipolar Cycloadditions General Considerations Over the years, 1,3-dipolar cycloadditions have been widely used as an excellent way to prepare heterocycles, es pecially for total synthesis of natural compounds. The reaction, between a 1,3-dipole and a dipolarophile, us ually substituted alkenes, forms a wide range of heterocycles like pyrazolines, isoxazolines and tetrahydrofurans. In recent years, research has been focused on controlling the stereochemistry of these reactions, either by choosing an appropriate substrate, or by using chiral catalysts. A B C DE A DE C B R=H,allyl,ester,OR,NR,... R R R R A B C 1,3-dipole dipolarophile Scheme 1-1. General mechanis m of 1,3-dipolar cycloadditions.

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22 The mechanism of the cycloadditions is concerted, and involves the 4 electron of the dipolar compound and the 2 electrons of the dipolaroph ile. This reaction is also stereoconservative, which can allow predicting the stereochemistry of the final compound. The first report of 1,3-dipolar cycloaddition is found back in 1888 by Buchner,22 who studied the reaction of diazoacetic ester (found five year s earlier by Curtius)23 with --unsaturated esters. In 1928, the Diels-Alder reaction was found24 and its synthetic applications became obvious. However, general applications of 1,3-dipolar cycloadditions were not studied until the 1960s by Huisgen.25 O NN+ N N N N O + A) B) C-N+ N CO2Et EtO2C N N CO2Et EtO2C N N CO2Et EtO2C H Isomerization +-O O+ O R2 R1 R3 R4 O O O R3 R4 R1 R2 1,3 cycloaddition retro-1,3 cycloaddition + R3 R4 O R1 R2 O+ -O R1 R2 O+ -O R3 R4 O 1,3 cycloaddition O O O R4 R3 R1 R2 R3 R4 O R1 R2 O work-up C) Scheme 1-2. Examples of 1,3-dipolar cycloa dditions. A) Azide alkyne Huisgen reaction. B) Diazoalkane 1,3-dipolar cycloaddition. C) Ozonolysis.

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23 Huisgen investigated a large range of di polarophiles and 1,3-dipoles, among them azides and alkynes that react in the azide alkyne Huisgen cycloaddition, considered the cream of the crop of click chemistry26 (Scheme 1-2) He also studied diazo compounds as 1,3-dipoles, and the ozonolysis, ozone being th e 1,3-dipole. At the same time, studies by Woodward and Hoffman27 and later by Houk et al.28 contributed to the understanding of the mechanism of such reactions. Since the initial discovery, a lot of work has been done to extend the use of dipolarophiles and 1,3 dipol es, as this method proved very usef ul for the synthesis of natural compounds containing substituted heterocycles.29 Figure 1-5 shows comm on 1,3-dipoles used for cycloadditions, such as nitrile oxides or azide s, and the dipolarophiles can be simple or substituted alkenes and alkynes, but also can be enol ethers,30 vinylic selenides31 and aldehydes.32 N+ N+ NN+ OO+ N+ N+ OAzomethineYlidesAzomethineIminesNitronesCarbonylYlides NitrileYlidesNitrileOxides NN+ NAzides Figure 1-5. Common 1,3-dipoles A number of catalysts has also been studied to improve the yields and stereochemistry of the final compounds. Borane-based33 or ruthenium-based catalysts34 are some examples of catalysts improving the reaction. Sharpless et al .35 also studied a copper-catalyzed reaction, which is no longer a classic Huis gen reaction, due to the nonconcer ted mechanism (Scheme 1-3).

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24 LnCu R1 CuLn-1 R1 H NN+ NR2 R1 CuLn-1 NR2 N+ N N N N CuLn-2 R1 R2 N N N R1 R2 CuLn-1 N N N R1 R2 Scheme 1-3. Proposed mechanism of coppe r (I)-catalyzed synthesis of azoles. Carbonyl Ylides as 1,3-dipoles One type of 1,3-dipole that can be used for a 1,3 -dipolar cycloaddition is the carbonyl ylide. The use of these dipoles with appropriate dipola rophiles can lead to hi ghly substituted oxygen heterocycles. The compounds obtained via these r eactions have been increasingly studied, as these units can be found in natu ral compounds such as ionophores,36 macrocyclic antibiotics37 or other marine products. Scheme 1-438 represents the different met hods that have been used to obtain carbonyl ylides. Thermolysis or photolysis of epoxides,39 thermal extrusion of nitrogen from oxadiazolines40 or extrusion of carbon diox ide from dioxalan-4-ones41 proved to be good methods to generate carbonyl ylides. However, th e reaction of a metallo-carbenoid, from a diazo compound, with a carbonyl gr oup is the easiest way to form these ylides. The discovery of rhodium-based catalysts was a big step in the fi eld, as it permitted one to obtain easily the carbonyl ylides and trap them subsequently with dipolarophiles as a tandem process.

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25 O+ N2 O O N2 O AB O N N O OO O -N2AB Transition metal -CO2h h + + CarbonylYlide Scheme 1-4. Generati on of carbonyl ylides. The generation of carbonyl ylides requires a carbonyl group and a metallo-carbenoid group, obtained from the reaction of a diazo group with the metal catalyst. If the carbonyl and the diazo groups are on the same alkyl chain, the reac tion is intramolecular. It can lead to a five, six or seven-membered ring carbonyl ylide depending on the number of carbons separating the carbonyl and the diazo group (Schem e 1-5). If a carbonyl is on the -position to the diazo, the ylide is a five-membered ring. The six-membered ring is formed when a carbonyl is at the position, and one position further gives the seven-membered ring, although very li ttle research has been done on these compounds, five and six membered rings being preferred. However, these seven-membered rings are also us ed in natural product synthesis.

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26 O R1 O N2 n O R1 O Rh2L4 O+ n O R1 n Rh2L4 R1=aryl,allyl,O-allyl,N-allyl L=bidendateligand n=1,2,3 Scheme 1-5. Generation of cyclic carbonyl ylides. The carbonyl group reacting with the metallo-carbenoid can eith er be a ketone, an ester, and even an amide group, however ketones and amid es are more used to form carbonyl ylides, as they are more reactive than esters in this case. The formation of carbonyl ylides by intermolecular reaction has been less studied and examples are limited.43 However, they can be trapped with the same methodology as the other types of ylides. Trapping the carbonyl ylides with different dipolarophiles has been studied over the years by many groups. The addition of these compounds can lead to highly substituted cyclic compounds, done in a tandem manner instead of a st epwise path. In genera l, dipolarophiles are substituted alkenes or alkynes, aldehydes, or even ketones. If the dipolarophile added is asymmetrical, the addition can be done in two different ways, as show n in Scheme 1-6. The dipolarophiles can add in an endo or exo manner, and the substi tuents can be found at the 6position, bearing the methyl group, or the 7-positi on, having the negative charge. The groups on the dipolarophiles can thus play a great role concerning the regiochemistry of the final compound.

PAGE 27

27 O+ O A B O O O O O O O O A B A A B B B A + 6 7 Scheme 1-6. Possible isomers w ith asymmetrical dipolarophiles. The regiochemistry is based on the FMO theo ry. Two types of interactions can occur, either a type I or a type III interaction, as defined by Sustmann44 (Figure 1-6). If the dipolarophile contains an elect ron-withdrawing group, the mo lecular orbitals of this dipolarophile have a lower en ergy, and the principal inte raction is between the HOMOdipole and the LUMOdipolarophile. If the dipolarophile has an elec tron-donating group, the interaction is between the HOMOdipolarophile and the LUMOdipole. The major interaction takes place when the difference in energy between the HOMO and LUMO are the smallest. However, in some cases, the difference of energies between the HOMO and th e LUMO for the type I might be close to the difference in energies between the molecular orbi tals for the type III. A mix of isomers could thus be obtained, and the ratios between these isomers could vary depending on the dipolarophiles used.

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28 HOMO LUMO HOMO LUMO HOMO LUMOElectron-poor dipolarophile 1-3Dipole Electron-rich dipolarophile TypeI TypeIII E Figure 1-6. Type I and type III interactions In summary, DCC proved to be a good method to make large libraries, and express one compound over the other possibilities in the pres ence of a target. Chapter 2 will present the findings about DCC using amino acids as build ing blocks. After amino acid derivatives are synthesized by a simple method, they will be mi xed with a specific target and the reaction mixture will be analyzed by HP LC to see if any changes in product ratios can be observed. The third chapter will discuss the chemistry a nd stereochemistry of carbonyl ylides mixed with various dipolarophiles. These dipolarophi les are aldehydes and substituted alkenes. The stereochemistry and regiochemistry of the co mpounds obtained will also be discussed and rationalized with the FMO theory.

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29 CHAPTER 2 DYNAMIC COMBINATORIAL LIBRARY Introduction As mentioned in Chapter 1, DCC has been used more and more over the past decade, especially in drug discovery, as a way to quick ly discover biologically active substances among vast libraries. Because a large variety of amino aci ds are available in nature or synthetically, DCC could be a good method to make impressive virt ual libraries of these amino acids. A lot of work has been done previously on using peptides, car bohydrates or other el ements as building blocks. A wide range of reversible reactions has al so been studied over the years. In our lab, it was decided to study the comportment of simple am ino acids as building blocks for DCC, and to study the possible shifting of the library when a target is adde d to the virtual library. As a reversible reaction, cross-metathesis (CM) us ing Grubbs second generation catalyst seemed suitable for this purpose (Scheme 2-1).45 Ru L PCy3 Ph Cl Cl -PCy3Ru L R Cl Cl +olefin Ru L R Cl Cl Ru L Cl Cl R Ru L Cl Cl R R R R -olefin Scheme 2-1. General mechanism for olefin metathesis

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30 The second generation Grubbs catalyst 2-1 was used because a ruthenium-based catalyst is most reactive and has a higher turnover with olef in than other metal-based catalyst (Table 2-1), it is easier to handle than the catalyst 1st generation, and its also more stable than the 1st generation Grubbs and Schrock catalysts.46 Table 1-2. Reactivity of metal-based catalysts. Titanium Tungsten Molybdenum Ruthenium Acids Acids Acids Olefins Alcohols, Water Alcohols, Water Alcohols, Water Acids Aldehydes Aldehydes Aldehydes Alcohols, Water Ketones Ketones Olefins Aldehydes Esters, Amides Olefins Ketones Ketones Olefins Esters, Amides Esters, Amides Esters, Amides aa1 aa2 aa3 aa4 Grubb'scatalystII Ru PCy3 N N Mes Mes Cl Cl Ph aa1 aa2 aa3 aa4 X X X X 32possibilities (16cis,16trans) n n n n n n n n2-1 Scheme 2-2. Cross-metathesis using Grubbs second generation catalyst and amino acid derivatives It was also decided to use this Grubbs ca talyst for this study, because no reports have been made previously on amino acids coupled by CM with Grubbs se cond generation. CM has Increasing Reactivity

PAGE 31

31 been studied by a few groups47 as a reversible reaction for DCC, but not with simple amino acid derivatives. These molecules have obvious impor tance in the biological and pharmaceutical field, as the core of more complex molecules for these fields. Derivatives of amino acids containing olefin moiety have been prepared and coupled with CM,48, 49 but the preparation of the derivatives required at least four steps, and the CM was done using Grubbs first generation catalyst. Only one group, Miller et al. ,50 made a series of allyl and homoallylamide derivatives of BOC-protected amino acids, but his synthesis required the preparati on of the allyl chain added to the amino acids (Scheme 2-3). His results for the preparation of these deri vatives were positive, but the CM reaction using Grubbs first generati on catalyst gave more than one product, with some showing a migration of the double bond, a nd some of the derivatives did not yield any product for the reaction. H N N H O BOC R n Grubbs'I CH2Cl2roomtemp.N H H N BOC R O N H O H N BOC R H N N H O BOC R n=1 n=2 HN NH O BOC R NH HN O BOC R +R=Benzyl, Indol-3-ylmethyl, 1-naphtylmethyl Scheme 2-3. Olefin CM done by Miller. In the research presented here, the alke ne moiety can be added easily by simple esterification of protected amino acids. As shown in Scheme 2-2, if four amino acids derivatives are able to undergo cross-metathes is, a library of at least 32 possi bilities of combinations can be made. The different combinations can lead to 4 homodimers and 12 heterodimers, each of them

PAGE 32

32 being cis or trans (Scheme 2-3). Although using the Grubbs second generation catalyst allows for thermodynamic control, trans compounds should predominant. However, we need to keep in mind that the Grubbs catalyst s econd generation can lead to so me isomerization of the double bond; it might thus be possible to see mo re than 32 possibilities of products.51 1 2 3 4 1 2 3 4 1 2 3 4 Homodimers1 3 4 2 2 2 2 3 4 1 1 1 1 2 4 3 3 3 1 2 3 4 4 4 Grubbs'II Scheme 2-4. Possible combinati ons of amino acid derivatives formed through cross-metathesis. The next step is to choose a good template th at can shift the equilibr ium to one particular compound, and if so, find out which compound is fa vored over the other pos sibilities. Different groups proved that a cation, such as Li+,52 Ag+ 53 or Cu+, 54 could be a good choice for a template, as it can shift a library of compounds toward one particular compound. It wa s thus decided to use Li+ and ephedronium chloride as a target.

PAGE 33

33 Results and Discussion Formation of the Amino Acid Derivatives Before generating the library, preliminary st udies were made on the reactivity of amino acid derivatives toward cross-metathesis. First, homodimers of these derivatives were made by combining each compound with itse lf by self cross-metathesis to test the cross-metathesis reaction. Five amino acids were chosen. Phenylalanin e, alanine, methionine, leucine and proline have very different groups, so we could have a variety of templa tes used for the dynamic library that would interact differently with the groups (Figure 2-1). BOC H N OH O BOC H N OH O BOC H N OH O BOC H N OH O OH O S N BOC L-Alanine (Ala) L-Leucine (Leu) L-Phenylalanine (Phe) L-Methionine (Met) L-Proline (Pro) Figure 2-1. Amino acids used for DCC. Alanine is one of the simple st amino acids, having only an -methyl group. Leucine has an isopropyl group attached, so it seemed to be a good choice as an allyl chain. Phenylalanine has a benzyl group which could have aromatic interactions with templates. Methionine possesses an alkyl chain with a sulfur atom and Proline is a rigid amino acid, which is also an interesting group to work with. All the amino acids were pr otected with a BOC group on the N-terminus to prevent side reactions, like the addition of an al kyl moiety at the N-terminus. Besides, all the N-

PAGE 34

34 BOC-protected amino acids are commercially available. The general scheme of the esterification of the amino acids is shown on Scheme 2-4. N H R1 OH O BOC N H R1 O O BOC DIC,HOBt DMAP CH2Cl2HO n n + n=1,3 BOC= O O Scheme 2-5. General synthesis of amino acid derivatives. The behavior of BOC-Phenylalanine and BOC-Leucine toward the esterification and cross-metathesis was first studied. A terminal vinyl group was added to the amino acids. The vinyl group was installed using allylic alcohol with DIC as the coupling agent. HOBt was used to prevent racemization of the chir al amino acids and DMAP was used as catalyst (Scheme 2-4). The reaction only took two hours, followed by TLC and the urea byproduct was filtered before purifying the crude by chromatography. Good yields on the order of 90% were obtained for the compounds 2-2 and 2.3 Each of the derivatives was then reacted with itself by self-CM to form their homodimers 2-4 and 2-5 The reactions were done unde r argon at reflux, using 10% catalyst, at 1M concentration in chloroform. Poor yields for th e cross-metathesis were obtained (Table 2-2). These yields for the cross-metathesis coul d be explained by steric effects, the groups being too close to each other, so a longer chain was attached by using 4-pentenol instead of allylic alcohol. Miller and others55 also reasoned that coordination between the ruthenium and oxygen containing functionality could trap the catalyst in an unproductive coordination state (Figure 2-2).

PAGE 35

35 Ru H Cl Cl O O N N Mes Mes N H R BOC Figure 2-2. Potential nonproductive chelate of ruthenium carbene. Table 2-2. Results of BOC-Phe and BO C-Leu toward esterification and CM. Amino acid R group Esterification Cross-metathesis BOCPhe HN O O BOC 2-2 88% HN O O BOC NH O O BOC 2-4 30% BOC-Leu i-propyl HN O O BOC 2-3 90% HN O O BOC NH O O BOC 2-5 24% Good yields were achieved for both Fisher es terification and cross-metathesis (Table 23). Three more amino acid derivatives, from BOC-proline, BOC-Methionine and BOC-Alanine, were made and reacted with Gr ubbs II. All three amino acids also gave good yields for both

PAGE 36

36 reactions. Ratios between cis produc ts and trans products could be determined, as it was difficult to see the coupling constant by NMR. In contrast to Millers work, these reactions gave good yields for all the derivatives, and no migr ation of the double bond could be detected. Table 2-3. Results of the chosen ami no acids toward esterification and CM. Amino acids R groups Esterification % Cross-metathesis % BOC-Phe HN O O BOC 2-6 70% HN O O BOC NH O O BOC 2-11 78% BOC-Leu i-Propyl HN O O BOC 2-7 90% HN O O BOC NH O O BOC 2-12 80% BOC-Ala Methyl HN O O BOC 2-8 88% HN O O BOC NH O O BOC 2-13 70%

PAGE 37

37 Table 2-3. Continued Amino acids R groups Esterification % Cross-metathesis % BOC-Pro N BOC O O N BOC 2-9 85% O O O O N N BOC BOC 2-14 85% BOC-Met S HN O O BOC S 2-10 72% HN O O BOC NH O O BOC S S 2-15 75% A longer alkyl chain proved to enhance the yi elds, so we made an attempt to form an even longer chain using hexenol and the BOC-Leuc ine. However, it did not increase the yields dramatically for the cross-metathes is (90% for the esteri fication, 85% for the cross-metathesis). Generation of the Library Knowing that the building blocks can underg o cross-metathesis with good yields, the DCC using this type of building blocks was st udied. The reactions were conducted with the amino acid monomers along with the Grubbs catalyst and a temp late. The system was kept closed so ethylene generated from the reaction w ould be present to keep equilibrium conditions. Lithium ion was chosen as the target because it is a simple metal, known to coordinate to the amino acids. Sanders and coworkers51 showed that Li+ can select one cyclic pseudopeptide

PAGE 38

38 among 10 different possibilities. Besi des, it has been demonstrated that this cation has been used in the pharmacological field.56 Edrophonium chloride was also chosen as template, because of its positive charge and its relevant importance in medicine. N+ OH Cl-EdrophoniumChloride Because the reaction is reversible, it needs to be stopped before it is analyzed by HPLC. Ethyl vinyl ether was chosen to quench the reaction in order to prevent the equilibrium from changing when aliquots were take n from the reaction to be studi ed. This shuts down the Grubbs catalyst, because the ethyl vinyl ether react s with the Grubbs catalyst irreversibly,57 forming a Fisher carbene. All the results were analyzed by HPLC Synergi Hydro RP, reverse phase. The solvent used was H2O/ACN 35/65. The wavelength used wa s 227 nm, chosen after some UV-Vis experiments on the monomers and the dimers were conducted. Unfortunately, the conditions us ed to form the library were not optimal. After some first attempts, where the HPLC traces obtained with the conditions used to make each dimer were too complicated to analyze, it was decided to work on only three amino acids derivatives. To make the library, only three monomers 2-6 2-9 and 2-10 from BOC-Pro, BOC-Phe and BOC-Met, were used at equimolar concentrations. Their side groups are very different from each other, and having only three amino acids for the study can simplify the analysis of HPLC traces. The catalyst was kept at 10% equivalent for all th e reactions. Reactions were performed at 0.5M, 0.1M, 0.05M, 0.01M, 0.005M and 0.001M, at room temper ature or at 50C, to see the effects of dilution and temperature. Different amount of te mplates were also scre ened (10 equiv., 5 equiv.

PAGE 39

39 and 1 equiv. of Li+, 1 and 3 equiv. of edrophonium chloride ). The template was either added before the catalyst, so pre-coordination could ta ke place between the target and the amino acids, or added after 90 minutes or 4 hours of reaction between the monomers and the catalyst. Two reactions were run in parallel for each conditions ; one being a mixture of monomers and catalyst, the other a mixture of monome rs, catalyst and template. Effects of concentration. After analyzing the different concentrations, it was concluded that at a lower concentration, the cross-metathesis could take place more easily than at a more concentrated solution. From 1M to 0.01M, no changes were observed between th e HPLC traces representing reaction mixtures with or without template. At 0.005M, a change was observed (different peaks were observed from HPLC without template and HPLC with templa te) so all the later reactions were conducted at 0.005M in chloroform. Effects of equivalent of template As mentioned earlier, Sanders et al. proved that macrocycles formed by peptides could undergo dynamic equilibrium, and the addition of 5 equivalents of LiCl could express one macrocycle over the others. Tests with the additi on of 1 equivalent of lithium perchlorate were done first. By comparing the HPLC tr aces of reactions conducted with no Li+ (Figure 2-2) and with one equivalent of Li+ (Figure 2-3), a change could be se en in the equilibrium, but not the expected change. Instead of having one co mpound predominantly formed over the other possibilities, a reducti on of the peak at 6 minutes was seen.

PAGE 40

40 Figure 2-3. Conditions used: no Li+, 25C, 0.001M When the reactions were conducted with 5 equivalents of lithium, with the same conditions, a better shift in the equilibrium was obtained. With 10 equivalents, similar HPLC traces were obtained. With the ephodronium chlo ride as a template, no change between the HPLC trace without the target and the HPLC trace with th e target was observed, so it was decided not to use this template in the future.

PAGE 41

41 Figure 2-4. Conditions used: Li+ 1 equiv., 25C, 0.001M The time of the addition of template was also studied. The template could be added before the catalyst (t = 0), so pre-coordina tion would take place between the monomers and the template prior to the reaction. It can also be a dded after the reaction has been running for a time; in this case, the dimers would already be formed, and the coordi nation would take place between the dimers and the template. The template was added either 90 minutes or 4 hours after the catalyst and the monomers were mixed. No difference between the HPLC traces representing the reaction mixture with the template added before the catalyst or added 90 minutes after the catalyst could be observed. It is thought that, becau se the concentration of the solution is low, it takes more time for the dimers to form in thes e conditions, so the additi on of the template after only 90 minutes would not be drama tically different than if it was added before the catalyst. The

PAGE 42

42 addition of template 4 hours after the catalyst wa s also tested, and no major changes between the two HPLC traces representing the mixture without template and the mixture with template could be seen either, so it was decided that the te mplate would be added before the catalyst for subsequent reactions. Effects of temperature In the preliminary studies, reactions to fo rm the dimers were performed at 50C. However, for the DCC studies, having the reacti ons running at 50C proved to be inefficient. Under reflux, the HPLC traces of reactions run w ith the template were more complicated than the HPLC traces representing the mixture without template. It showed a multitude of peaks, and no compound was apparently favored over ot her possibilities (Figures 2-4 and 2-5). Figure 2-5. Conditions used: no Li+, 50oC, 0.005M

PAGE 43

43 It is thought that the possibl e coordination between the temp late and the building blocks is broken when the temperature is elevated, so no shift could be seen on HPLC. The reactions were then conducted at room temperature to ma ke sure that coordination could occur between the building blocks and the template. Figure 2-6. Conditions used: Li+ 5 equiv., 50oC, 0.005M Shifting of the equilibrium Some deviation in the equilibrium could be reported. Figure 2-6 represents the HPLC trace when no lithium was used at 25oC and 0.005M in chloroform.

PAGE 44

44 Figure 2-7. Conditions used: no Li+, 25oC, 0.005M Figure 2-8. Conditions used: Li+ 5 equiv., 25oC, 0.005M

PAGE 45

45 Figure 2-7 represents the reaction mixture when 5 equivalents of lithium were added to a standard reaction mixture under the same c onditions. As seen on HPLC traces, with Li+ as template, the two peaks at 14 were definitely favored over the others possible combinations. After multiple tries however, the structure of the favored compounds could not be found, as there were some difficulties to reproduce the results. Conclusion The project was to demonstrate the use of am ino acids as building bl ocks for DCC. After making each monomer and dimer separately, a library was made with three amino acids derivatives. To shift the equilibrium, Li+ as template was chosen. The reactions of esterification and CM to form the monomers and homodimers pr oved to be a very simple, fast and efficient method to make derivatives of am ino acids. This method could be used for other amino acids and thus, quickly obtain a larger library. Promising results were also obtained to shift the equilibrium of the library formed. After screening different concentrations, temperatures and amounts of template, the studies showed that a shift can defini tely be observed. A cha nge could definitely be seen in the equilibrium; however no structure could be defined, and more work would be needed to analyze the mixture.

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46 CHAPTER 3 USE OF CARBONYL YLIDES AS DIPO LES FOR DIPOLAR CYCLOADDITIONS Introduction The use of the dipolar cycloadditions in synthesis has seen increasing applications to form substituted heterocycles. One particular dipo le that can be used is a carbonyl ylide, which can lead to oxygen containing polycycles, especia lly saturated furans. Different methods can be used to form carbonyl ylides, but reactions be tween diazo compounds and a carbonyl group in the presence of transition metal catalysts is one of the easiest. In a one-pot reaction, a diazo compound and the metal catalyst react to form a metallo-carbenoid intermediate, which in presence of a carbonyl group, usually an aldehyde or ketone, can form the carbonyl ylide. Addition of an appropriate dipolaro phile in the reaction can thus lead to the cycloaddition of this dipolarophile to the carbonyl ylide and the fo rmation of a cyclic compound (Scheme 3-1). N2 O MLn O MLn O O MLn X Y O O Y X metallo-carbenoidcarbonylylide + 2+3 Scheme 3-1. General mechanism The carbonyl ylide can be either interor intramolecularly generated. Intramolecular reaction forms cyclic carbonyl ylides, and trappi ng of these species by dipolarophiles has been widely used to form complex heterocycles and in the total synthesis of natural products. This particular methodology has first been de monstrated by Ibata and co-workers,58 which then led to the development of an approach to construct substituted polycycles. Mostly five and sixmembered ring carbonyl ylides have been stud ied, but a few examples can be found of the generation of seven-membered rings and in termolecular generation of these compounds.

PAGE 47

47 Because the regioand stereochemistry of these reactions can be explained by the FMO theory, proper stereochemical control can be ach ieved. Up to four stereocenters can be obtained and controlled, which provides great synthetic valu e for this reaction, especially for the synthesis of natural products. This method has been used for example by Hodgson59 to synthesize nemorensic acid (Scheme 3-2). O O N2 Rh(II) propargyl bromide O O 1)H2,Pd/C 2)LDA,TMSCl 3)O3 O CO2H HO2CH2C cis-ne m o r ensicacidBr Scheme 3-2. Synthesis of nemorensic acid by Hodgson. Another example is the synthesis of zaragozic acid A. Three re lated synthesis have appeared from the laboratories of Koyama (Scheme 3-3),60 Hashimoto61 and Hodgson,62 all independently describing carbonyl ylide-cycloadditi on strategies for the construction of the heterocy clic core of this natural product. O O N2 E Ph 4 TMSO Rh2(OAc)4O O E Ph 4 TMSO Scheme 3-3. Koyamas approach of the s ynthesis of the core of zaragozic acid.

PAGE 48

48 These cycloadditions could be also used in conjunction with a second key reaction involving a reductive ethe r cleavage promoted by samarium diiodide (SmI2) that can be alkylated or acylated with various carbon electroph iles. The oxygen bridge obtained through the cycloaddition could be cleaved while leaving the carbon skeleton intact. Reactions with SmI2 are usually done in mild conditions and with decent yields. It involves the one-electron reduction of ketones and aldehydes to a samarium ketyl radical anion which can promote cyclizations, deoxygenations and reductions (Scheme 3-4). R OR' O R OR' OSmI2 SmI2HMPA THF SmI2R OSmI2 OR1SmI2 + R O R O E H2O E+R OSmI2 SmI2 OR' Scheme 3-4. General mechanism using samarium diiodide A few number of oxygen-bridge cleavage r eactions by samarium diioide are known, but none take advantage of the samarium enolate.63, 64 Cycloadditions coupled with samarium diiodide reactions could be a novel and importa nt approach to synthe sis cores of natural molecules like phorbol for example (Scheme 3-5). Th is molecule contains three cycles that could be obtained quickly by using the cycloaddition and tandem samarium diiodide ether cleavagealkylation reaction. O N2 O E Rh2Ln O O E SmI2 O HO HO HO OH HO Phorbol Scheme 3-5. Synthesis of the core of phorbol.

PAGE 49

49 This chapter presents the findings on cycl oaddition reactions usi ng a six-membered ring carbonyl ylide, formed in presence of a rhodium catalyst, with various dipolarophiles (Scheme 36). The rhodium (II) acetate was used as catalyst because it is cheaper than other possible rhodium catalysts. It is also known that rhodium (II) carboxylates used as catalysts are the most effective for bimolecular reacti ons employing diazo carbonyl compounds.63, 64 O O N2 O O RhL2 Rh2(OAc)4 O+ O O O X Y 3-2 3-1 XY RhLn O+ O RhLn X Y Scheme 3-6. General tandem cyclization-cycloaddition Results and Discussion Formation of the Precursor for Carbonyl Ylide Following the work of Padwa65, 66 on carbonyl ylides, the addition of different dipolarophiles on carbonyl ylides wa s studied, along with the ster eochemistry of the resulting molecules. The carbonyl ylide 3-2 made from the diazo-dione 3-1 is known to work in dipolar cycloadditions and is simple to prepare. Compound 3-1 can be easily made by reacting levulinic acid in ether for 30 minutes with triethylamine as a base and isobutyl chloroformate as the reagent. The intermediate obtained from this first reaction, a carbonic anhydride not stable

PAGE 50

50 enough to be purified by column, is filtered from the triethylamine hydrochloride, the solvent is evaporated and the resulting solution is added to a freshly prepared solution of diazomethane in ether at 0C. The crude obtained is chromatogr aphed on silica to afford the yellow oil diazodione 3-1 (Scheme 3-7). O O O O O O O OH O O Cl O O N2 + NEt30oCtort CH2N20oC3-33-1 Scheme 3-7. Synthesis of diazo-dione 3-1 Most of the attempts have led to modest yields, around 60%, probably because during the reaction, the enolate released from the reacti on between the anhydride and the diazomethane can then react with the anhydride to form an ester, and thus compete with the diazomethane (Scheme 3-8). The last yield can be obtai ned if the anhydride intermediate is added slowly to a solution containing 4.5 equivalents of diazomethane. O O O O O O O N2 CH2N20oC-O O O + -CO2 -O O O O O O O O O By-product 3-1 3-3 3-3 Scheme 3-8. Formation of the by-product. The next step is to use this dione with the rhodium (II) acetate as the catalyst to form the carbonyl ylide and trap it with various dipolarophiles. A solution of diazo-dione 3-1 and a chosen dipolarophile in benzene was degassed, and 1% to 2% equivalent of the rhodium catalyst was

PAGE 51

51 added (Scheme 3-9). After the rhodium displaced the nitrogen to form the metallo-carbenoid, the carbonyl ylide was obtained by cyclization and th e cycloaddition with the dipolarophile took place. When nitrogen was no long er released, the reaction was checked by TLC. The crude was chromatographed on silica gel and analyzed by NMR. O O N2 Rh2(OAc)4O+ O B O O A B O O B A and/or A 3-2 3-1 A,B=H,estergroups,alkylgroups,ethergroups. Scheme 3-9. General synthesis of polycyclic molecules. Dipolarophiles Various dipolarophiles were studied. We chose a variety of aldehydes, alkynes and alkenes. Simple symmetrical dipolarophiles were used to check the reaction and check the simple stereochemistry (endo or exo), as well as n on-symmetrical dipolaro philes to analyze the regiochemistry of the heterocycles obtained. The dipolarophiles used have groups that are either electron-withdrawing or elect ron-donating. Having electron-w ithdrawing groups or electrondonating groups can have an eff ect on the regiochemistry of the compounds obtained, as explained later in this chapter. Dipolarophiles also include alde hydes derived from sugars, as no reports have been done on these types of mol ecules. The list is found in the Table 3-1.

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52 Table 3-1. List of dipolarophiles. Aldehydes Alkynes Alkenes O Crotonaldehyde CO2Me MeO2C Dimethylacetylene dicarboxylate DMAD CO2Et EtO2C Diethyl Fumarate CO2Me MeO2C Dimethyl Maleate O OMe O O O 3-15 CO2Me Methyl Propiolate CO2Me Methyl Acrylate O Ethyl Vinyl Ether (EVE) O O O O O 3-17 Styrene CO2Et Methyl Cinnamate O O O Maleic Anhydride N Metacrylonitrile O O N2 Rh2(OAc)43-1 + O O 3-4 CO2Me MeO2C CO2Me MeO2C 70% Scheme 3-10. Reaction with DMAD as dipolarophile.

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53 Studies started with DMAD, which is a si mple symmetric alkyne. This alkyne was used first to test the reaction and give us an idea of future reactions. A yield of 70% was achieved, in accordance with the literat ure (Scheme 3-10). Next, the stereochemistry of the reaction w ith symmetrical alkenes was studied. For this purpose, dimethyl maleate and diethyl fumarate were used as dipolarophiles (Scheme 3-11). O O N2 Rh2(OAc)43-1 EtO2C CO2Et + O O Hb EtO2C CO2Et Hc Ha 3-5O O N2 Rh2(OAc)43-1 CO2Me + O O Hb EtO2C Hc MeO2C Ha 3-6MeO2C 50% 15% Scheme 3-11. Diethyl fumarate and dimethyl maleate as dipolarophiles Although a yield of 50% was achieved using th e diethyl fumarate, there was more trouble getting a yield higher than 15% for the dimethyl maleate. Howe ver, some product was obtained, which prompted to check the stereochemistr y. For each compound, the stereochemistry between Hb and Hc is locked by the nature of the starting material. 1H NMR showed a coupling constant of 7.3Hz for 3-5 and a coupling constant at 12.1 Hz for 3-6 For the stereochemistry between Ha and Hb, it was less obvious. For 3-5 the coupling constant of 7.8 Hz could be either a cis or a trans coupling constant. After some experiments on the 2D 1H NMR, it was concluded that Hb and Ha were in a cis configuration. For 3.6, it was then assumed that Ha and Hb were also cis, as

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54 the coupling constant was 8.1Hz. Besides, this c oupling constant was not close to the trans one found by Ibata,67 who has a coupling constant of 2.6Hz for his compound. The reaction with dimethyl maleate and diethyl fumarate thus gave us the endo isomer. Next, it was decided to use non-symmetric dipol arophiles, to see what kind of isomers we had, and in which ratios. Asymmetrical dipolarophile s can add to our dipoles in four ways, either endo or exo, and the different groups can be eith er on the 6 or the 7 positions (Scheme 3-12). By 1H NMR, it was possible to determine which one of the possible isomers was the major one obtained for each dipolarophile. O+ O A B O O O O O O O O A B A A B B B A + 6 7 Scheme 3-12. Possible isomers. When the reaction was conducted with methyl acrylate and methyl propiolate, both their ester groups added mainly to the 6-position of th e dipole, and in an exo manner for the methyl acrylate (Scheme 3-13). The reaction with the me thyl propiolate gave a better yield than the reaction with the methyl acrylate (75% vs 45% overall), and a better regioselectivity for the addition of the group on the 6-position (ratios 4: 1 vs 2:1). Also, the two isomers for methyl propiolate could be separated, whereas the isomers 3-9 and 3-10 were mixed in a same fraction.

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55 The yields for these two products were calculate d based on the NMR. The exo conformations for 3-9 and 3-10 were supported by the literature,34 such that 2D NMR was not needed. O O N2 Rh2(OAc)43-1 + O O 3-7 CO2Me MeO2C O O CO2Me 3-8+ 75%O O N2 Rh2(OAc)43-1 CO2Me + O O CO2Me O O CO2Me +3-93-1045%Scheme 3-13. Reaction using methyl acrylat e and methyl propiola te as dipolarophiles O O N2 Rh2(OAc)43-1 O + O O O 3-11 Ha Hb Scheme 3-14. Reaction us ing EVE as dipolarophile The reaction involving ethyl vinyl ether as a dipolarophile also gave the exo product (Scheme 3-14). We were confident that the gr oup was added to the 7-position and in an exo manner, as the peak representing Ha was a singlet, probably because of a coupling constant too small to be seen on 1H NMR. However, some 2D 1H NMR studies were run to confirm the stereochemistry. Although the position is in accordance with the literature and the HOMOLUMO theory, the fact that the addition ended up exo is somewhat interesting. Padwa reported the same methodology with ethyl vinyl ether, but obtained the group added in an endo fashion.

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56 Another isomer could be seen, but only traces of it, and it wasnt possible to identify it. The 2D 1H NMR confirmed the isomer 3-11 Styrene and methyl cinnamate were very problematic, as we had a hard time purifying the compounds. Maleic anhydride and methacryloni trile didnt give any expected products, so these reactions werent pursued. O O N2 Rh2(OAc)43-1 O + O O O O O O O O O O O O Scheme 3-15. Possible products fr om reaction using crotonaldehyde Its known that aldehydes can also undergo di polar addition on dipoles It was interesting to see what kind of selectivity was obtained if a dipolarophile that contai ned both an alkene and an aldehyde was used, as no report has been done on these kinds of dipolarophile. The possible products could be either an addition of the double bond, addition of the aldehyde, or even a 1-4 addition (Scheme 3-15). Crotonaldehyde was used fo r this purpose. In th is specific reaction, the aldehyde was the strongest dipolarop hile rather than the alkene (Scheme 3-16). That would make sense as an aldehyde can have a closer HOMOLUMO interaction with the dipole than the alkene. Two isomers were obtained, with the addition being both endo and exo.

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57 O O N2 Rh2(OAc)43-1 O + O O O O O O +3-12 3-13 45% Scheme 3-16. Reaction with crotonaldehyde. Aldehydes from sugars were also tested. No reports have been done on using derivatives of sugars as templates for these types of reacti ons. Some aldehydes are commercially available, but simple procedures can afford the require d aldehydes. Here are examples for aldehydes derived from mannitol and di-acetone glucose (Scheme 3-17).68 Acetone,H2SO4O O O O HO OH OH OH OH OH O O O O O O O Periodicacid CH2Cl2D-Mannitol 3-1440% O OH O O O O EtI,NH4Br KOH,Acetone 90% O O O O O O Periodicacid CH2Cl2O O O O O Di-acetoneGlucose 3-15 3-16 3-1740%Scheme 3-17. Aldehydes derivative fr om D-mannitol and di-acetone glucose Studies of these particular dipol arophiles are in progr ess. Some encouraging results have been obtained, but more work is needed before reporting the results. Mechanism First of all, all non-symmetrical dipolar ophiles added in an exo manner. The endo conformation is usually more accessi ble due to secondary orbital inte ractions, but in this case, as explained by Padwa,65 some repulsive dipoles interactions ar e present in the system for the endo

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58 transition state, so to avoid these issues, produc ts are exo. The regiochemistry can be explained by the FMO theory. For most dipolar additions, the interaction is between the HOMO of the dipole and the LUMO of the dipolarophile (nor mal electronic demand). However, having an electron-withdrawing group or an electron-donating group on the di pole or the dipolarophile can perturb the system, and the in teraction HOMO-LUMO can be i nverse, having the HOMO of the dipolarophile interacting with the LUMO of the dipole. Usually, an el ectron-withdrawing group on the dipolarophile lowers the MO, therefore it favors the interaction LUMOdipolarophile HOMOdipole. This interaction is considered a Type I by Sustmann.44 An electrondonating group on the dipolarophile has the inve rse effect, (Type III) as an el ectron-donating group increases the MO of the dienophile. It is also known that the at oms with the largest coe fficients will interact. O O+ -7.95eV -0.93eVElectron-withdrawing groupondipolarophile Electron-donating groupondipolarophile TypeI TypeIIIZ Z X X Figure 3-1. HOMO-LUMO of carbonyl ylide and dipolarophiles.

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59 For our particular dipole, referring to cal culations by Padwa, the HOMO is at -7.95eV and the LUMO at -0.93eV. The coefficients for each orbital have also been calculated, with being -0.68eV and at +0.55eV for the HOMO, and at -0.37eV, at +0.45eV and at -0.62eV for the LUMO. The actual coefficients for the carbons of the dipolarophiles couldnt be found; however, following the trend explained by Houk,69 we know that for el ectron-poor dienophiles, the terminal carbon will have the greater coefficient for the HOMO and the LUMO. For an electron-rich dipolarophile, the terminal carbon has a greater co efficient in the HOMO; this trend is reverse for the LUMO. These rationaliz ations are summarized in Figure 3-1. The ester group on the asymmetrical alkenes and alkynes is electron-withdrawing, so the interaction between the dipolarophile and the dipole is a type I. The group is then found on the 6position, which is what we obtained for our majo r isomers for all our compounds. However, as the minor isomer, we obtained products with the groups on the 7-position. That can be explained by the fact that the E (HOMOdipole LUMOdipolarophile) and E (HOMOdipolarophile LUMOdipole) are close to each other, so th e type III can occur for our compounds. For methyl propionate and methyl acrylate especially, havi ng the same kind of groups, the difference resides in the double bond and triple bond. Methyl propiolate having a greater difference between the energies for type I and type III, the ratios obtained were better than the ones for methyl acrylate. For the ethyl vinyl ether, the ethoxy group bei ng an electron-donating group, the type III is the major factor, and thus, the group is added to the 7-positi on, which is in accordance to our finding. Conclusion Using carbonyl ylides and various dipol arophiles in 1,3-dipolar cycloadditions, polycycles were obtained, with a particular stereochemistry and regiochemistry, and the stereochemistry was rationalize d. This method may later be a pplied to dipolarophiles derived

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60 from sugars, as it is an ongoing wo rk in the lab. The next step of this synthe sis would be to break the oxygen bridge to create a seven-membered ring, useful in many natu ral products, by reacting these the heterocycles with samarium iodide. Th is reaction has already been tested with one compound, but more work will be needed to support these results.

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61 CHAPTER 4 EXPERIMENTAL SECTION General methods All NMR spectra were recorded using a Gemini, VXR or Mercury 300 MHz OXFORD spectrometer in CDCl3 with tetramethylsilane (TMS) as an in ternal standard. All chemical shifts are reported in ppm downfield relative to TMS. High-resolution mass spectrometry was performed by the services at the University of Florida. High performance liquid chromatography was performed on a Shimadzu LC-6AD. All reacti ons were run under an inert atmosphere of argon unless otherwise noted. Flas h column chromatography techniques were performed using Kiesel silica 60 (230-400 mesh). All yields refer to the isolated materials. Analytical TLC was performed using Kiesel gel 20 F-254 pre-coat ed 0.25mm silica gel plates, using UV light, p anisaldhyde in ethanol, permanganate stain, or phosphomolybdic acid in ethanol as indicators. All commercial compounds were purchased from Sigma-Aldrich or Acros Scientific. Experimental Procedures and Data General procedure for the esterification of amino acids: in a 25ml round bottom flask, BOCprotected amino acid (1 equiv. ) was dissolved in dichloromethane (ca. 1M) at 0C. Dimethylaminopyridine (0.3 equiv.), N,N-d iisopropyl carbodiimide (1.5 equiv.) and benzotriazole (1.2 equiv.) were added and the mixture was stirred for 30min before adding allyl alcohol or 4-pentenol (1.2 equiv.). The temperatur e was slowly raised to 25C. The reaction was monitored by TLC. After 2 hours, the white precip itate was filtered by gr avity, and the remaining solvent was evaporated under reduced pressure. Pu rification of the yellow solution by column chromatography (silica gel, hexane-ethyl acetate, 15:1 to 8:1) afforded the aminoacid derivative.

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62 Allyl-BOC-Phenylalanine 2-2 O HN O O O Yield: 88%; 1H NMR (CDCl3): 1.36 (s, 3H), 3.03 (t, J = 8.4Hz, 2H), 4.53 (d, J = 6.6Hz, 2H), 4.90 (bd, J = 9Hz, 1H), 5.16-5.26 (m, 2H), 5.73-5.84 (m, 1H), 7.10-7.25 (m, 5H); 13C NMR (CDCl3): 28.52, 38.57, 54.67, 66.17, 80.15, 119.17, 127.26, 128.77, 129.60, 131.73, 136.18, 147.46, 155.31, 171.83, 183.27; (m/z) (EI pos): 305.16, 249.09, 232.09, 220.14; HRMS calcd for [C17H23NO4]+: 305.1627, found 305.1631. Allyl-BOC-Leucine 2-3 O HN O O O Yield: 90%; 1H NMR (CDCl3): 0.87 (dd, J = 6.8 and 2.5Hz, 6H), 1.39 (s, 9H), 1.40-1.70 (m, 3H), 4.20-4.32 (m, 1H), 4.48-4.61 (m, 2H), 4.83 (bd, J = 6.9Hz), 5.16-5.30 (m, 2H), 5.78-5.91 (m, 1H); 13C NMR (CDCl3): 22.08, 23.09, 25.00, 28.53, 42.04, 52.32, 65.96, 80.06, 118.82, 131.94, 155.1, 172.0; (m/z) (CI pos): 357.27, 27 2.18, 216.12, 186.14, 130.09; HRMS calcd for [C14H25NO4 + H]: 272.1862, found 272,1860.

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63 Pentenyl-BOC-Phenylalanine monomer 2-6 O HN O O O Yield: 70%; 1H NMR (CDCl3): 1.42 (s, 9H), 1.68 (quintet, J = 7.1Hz, 2H), 2.05 (q, J = 7.2Hz, 2H), 3.12 (br, 2h), 4.102 (dt, J = 6.8Hz and 2.2Hz, 2H), 4.57 (br, 1H), 4.96-5.05 (m, 3H), 5.705.83 (m, 1H), 7.09-7.25 (m, 5H); 13C NMR (CDCl3): 27.6, 28.2, 29.8, 38.4, 54.4, 64.7, 79.7, 115.3, 126.9, 128.4, 129.2, 135.9, 137.2, 154.9, 171.8; (m/z) (CI pos): 334.20, 278.14, 188.11; HRMS calculated for [C19H27NO4 + H]+: 334.2013, found 334.2010. Pentenyl-BOC-Leucine monomer 2-7 O HN O O O Yield: 90%; 1H NMR (CDCl3): 0.95 (dd, J = 6.6Hz and 1.8Hz, 6H), 1.44 (s, 9H), 1.48-1.80 (m, 5H), 2.13 (q, J = 7.1Hz, 2H), 4.135 (t, J = 6.6Hz, 2H), 4.30 (br, 1H), 4.88 (br, 1H), 4.98-5.07 (m, 2H), 5.73-5.86 (m, 1H); 13C NMR (CDCl3): 22.4, 23.3, 25.2, 28.2, 28.8, 30.4, 42.4, 52.5, 65.0, 79.8, 115.8, 137.7, 155.2, 171.9; (m/z) (CI pos): 300.22, 244.15, 186.07, 129.99; HRMS calcd for [C16H29NO4 +H]: 300.2175, found 300.2172.

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64 Pentenyl-BOC-Alanine monomer 2-8. O HN O O O Yield: 88%; 1H NMR (CDCl3): 1.38 (d, J = 6.9 Hz, 3H), 1.45 (s, 9H), 1.75 (quintet, J = 7.0Hz, 2H), 2.13 (dq, J = 7.3 and 1.5Hz, 2H), 4.12 (dt, J = 6.7Hz and 2.1Hz, 2H), 4.28 (br, 1H), 4.965.04 (m, 3H), 5.73-5.86 (m, 1H); 13C NMR (CDCl3): 19.2; 28.1, 28.8, 30.4, 49.7, 65.1, 79.9, 115.9, 137.1, 155.2, 172.2; (m/z) (EI pos): 257.16, 144.10, 116.04, 88.04; HRMS calcd for C13H23NO4: 257.1627, found 257.1623. Pentenyl-BOC-Proline monomer 2-9 O N O O O Yield: 85%; 1H NMR (CDCl3): 1.44 (d, J = 14.1Hz, 9H), 1.72-1.79 (m, 2H), 1.83-2.00 (m, 3H), 2.13 (q, J = 7.2Hz, 2H), 2.192.29 (m, 1H), 3.363.60 (m, 2H), 4.06-4.34 (m, 3H), 4.96-5.06 (m, 2H), 5.73-5.86 (m, 1H); 13C NMR (CDCl3): 23.6, 24.3, 27.8, 28.4, 29.9, 30.9, 46.3, 59.1, 64.2, 79.8, 115.4, 137.2, 160.1, 173.2; (m/z) (EI pos): 283.18, 182.12, 170.12, 114.05; HRMS calcd for C15H25NO4: 283.1784, found 283.1783.

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65 Pentenyl-BOC-Methionine monomer 2-10 O HN O O O S Yield: 72%; 1H NMR (CDCl3): 1.45 (s, 9H), 1.76 (p, J = 6.9 Hz, 2H), 1.94 (sextet, J = 6.9Hz, 1H), 2.09-2.20 (m, 6H), 2.54 (t, J = 7.5 Hz, 2H), 4.17 (t, J = 7.5 Hz, 2H), 4.35-4.48 (m, 1H), 4.95-5.08 (m, 2H), 5.14 (br, 1H ), 5.17-5.86 (m, 1H); 13C NMR (CDCl3): 15.4, 27.7, 28.3, 29.9, 32.3, 52.8, 64.8, 79.9, 115.4, 137.1, 155.2, 172.2; (m/z) (EI pos): 317.17, 261.10, 192.99, 187.04; HRMS calcd for C15H27NO4: 317.1661, found 317.1661. General procedure for the synthesis of homodimers: in a round bottom flask, a mixture of amino acid derivative (1 equiv.) and Grubbs second generation cataly st (10 %) was stirred under argon in chloroform (ca. 1M), at 50C for 12h. After evaporating the solvent under reduced pressure, the resulting mixture was purified by flash ch romatography on silica gel (Hex/EtOAc, 15/1 to 3/1) to obtain the homodimer. BOC-Phenylalanine homodimer 2-4 HN O O O O O O HN O O

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66 Yield: 30%, 1H NMR (CDCl3): 1.34 (s, 18H), 3.00-3.10 (m, 4H), 4.54-4.60 (m, 6H), 4.90-4.98 (m, 2H), 5.64-5.72 (m, 2H), 7.00-7.35 (m, 10H); (m/z) (CI pos): 583.30, 483.23, 426.18, 348.15, 291.13; HRMS calcd for [C32H42N2O8 + H]+: 583.3014, found 583.3019. BOC-Leucine homodimer 2-5 HN O O O O O O H N O O Yield: 24%; 1H NMR (CDCl3): 0.95 (dd, J = 6.6 and 1.8Hz, 12H), 1.38 (s, 18H), 1.42-1.70 (m, 6H), 4.204.32 (m, 2H), 4.50-4.68 (m, 6H), 4.83 (d, J = 7.8Hz, 2H), 5.74-5.82 (m, 2H). BOC-Phenylalanine homodimer 2-11 HN O O O O O O HN O O Yield: 78%; 1H NMR (CDCl3): 1.34 (s, 18H), 1.57 (quintet, J = 7Hz, 4H), 1.89-1.95 (m, 4H), 3.00 (m, 4H), 4.01 (m, 4H), 4.49 (m, 2H), 4.92 (br d, J = 8.1Hz, 2H), 5.30 (m, 2H), 7.05-7.23 (m, 10H); 13C NMR (CDCl3): 28.3, 28.7, 38.4, 54.4, 64.7, 79.8, 126.9, 128.4, 129.3, 129.7, 136.0, 155.0, 171.9; (m/z) (ESI FTICR): 539.31, 483.25, 469.23; HRMS calcd for [C35H50N2O8 + H]+: 639.3640, found 639.3664.

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67 BOC-Leucine homodimer 2-12 HNO O O O O O H N O O Yield: 80%; 1H NMR (CDCl3): 0.95 (dd, J = 6.6Hz and 1.8Hz, 12H), 1.44 (s, 18H), 1.48-1.60 (m, 6H), 1.70 (quintet, J = 6.9Hz, 4H), 2.04-2.14 (m, 4H), 4.11 (t, J = 6.7Hz, 4H), 4.29 (br, 2H), 4.90 (br, 2H), 5.40-5.48 (m, 2H); 13C NMR (CDCl3): 21.9, 22.8, 24.7, 28.3, 41.9, 52.1, 64.5, 79.6, 126.1, 155.3, 173.4; (m/z) (ESI FTICR): 593.38, 471.34, 415.28, 401.26; HRMS calcd for [C30H54N2O8 +H]+: 571.3953, found 571.3973. BOC-Alanine homodimer 2-13 HNO O O O O O NH O O Yield: 70%; 1H NMR (CDCl3): 1.38 (dd, J = 6.9Hz and 3.6Hz, 6H), 1.44 (s, 18H), 1.65-1.76 (m, 4H), 2.05-2.11 (m, 4H), 4.13 (dt, J = 6.7Hz and 2.7Hz, 4H), 4.30 (b r, 2H), 5.0 (br, 2H), 5.375.49 (m, 2H); 13C NMR (CDCl3): 18.7, 28.3, 28.6, 31.8, 49.2, 64.6, 79.7, 126.1, 128.2, 129.8, 131.8, 155.0, 173.3.

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68 BOC-Proline homodimer 2-14 N O O O O O O N O O Yield: 85%; 1H NMR (CDCl3): 1.42 (d, J = 13.2Hz, 18H), 1.62-1.72 (m, 4H), 1.85-2.12 (m, 10H), 2.17-2.26 (m, 2H), 3.36-3.58 (m, 4H), 4.05-4.12 (m, 4H), 4.18-4.32 (m, 2H), 5.38-5.43 (m, 2H); 13C NMR (CDCl3): 23.6, 24.2, 27.8, 28.6, 30.0, 30.9, 46.5, 59.0, 64.2, 79.9, 126.4, 160.2, 172.9; (m/z) (CI pos): 539.33, 453.30, 439.28, 425.26, 383.21; HRMS calcd for [C28H46N2O8 + H]+: 539.3327, found 539.3332. BOC-Methionine homodimer 2-15 HNO O O O O O NH O O S S Yield: 75%; 1H NMR (CDCl3): 1.45 (s, 18H), 1.67-1.76 (m 4H), 1.93 (sextet, J = 6.8Hz, 2H), 2.03-2.14 (m, 12H), 2.54 (t, J = 7.3Hz, 4H), 4.11-4.18 (m, 4H), 4.364.42 (br, 2H), 5.16 (br, 2H), 5.40-5.55 (m, 2H); 13C NMR (CDCl3): 15.5, 28.3, 28.7, 29.9, 32.3, 52.8, 64.8, 79.9, 126.1, 129.8, 155.3, 172.3; (m/z) (ESI FTICR): 607.31, 507.25, 451.19; HRMS calcd for [C28H50N2O8S2 +H]+: 607.3081, found 607.3131. General procedure for DCL : in a round-bottom flask, 2-6 (1 equiv.), 2-9 (1 equiv.) and 2-10 (1 equiv.), were added in chloroform (ca. desired) with lithium perchlorat e (desired equiv.). The

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69 reaction was stirred for 10 min and Grubbs seco nd generation catalyst was added (10%). The reaction was put under reflux for 48 hr, with a liquots taken every 12 hr. The aliquot was quenched with ethyl vinyl ethe r (10 equiv.) and the solvent was reduced. The mixture was dissolved in ether, tris-(hydroxymethyl) phosphi ne was added and the solution was extracted with water, the ether layer dried over magnesium sulfate and filtered. The solvent was evaporated and the resulting mi xture was analyzed by HPLC. 1-Diazo-2,5-hexanedione 3-1 .55 O O N2 To a solution containing levulinic acid (637 mg, 5.50 mmo les, 1.5 equiv.) in anhydrous ether (0.5mL) at 0C was added triethylamine (1.0 mL, 7.32 mmoles 2 equiv.). After 5 min of stirring, isobutyl chloroform ate (500 mg, 3.66 mmoles, 1 equiv.) was added dropwise. The reaction was stirred for 30 min at room temperat ure, and the solution was filtered and the solvent evaporated. The filtrate was then added to a so lution of freshly prepared diazomethane (16.47 mmoles, 4.5 equiv.) and the reaction was stir red overnight. The solvent was removed under reduced pressure and the crude residue was pur ified by flash-chromatography (EtOAc/Hex 1:4) to obtain the product as pure pale yellow oil (308.7 mg, 60%). 1H NMR (CDCl3): 2.16 (s, 1H), 2.56 (bs, 2H), 2.76 (t, J = 6.3Hz, 2H), 5.31 (bs, 1H); 13C (CDCl3) 29.82, 33.92, 37.56, 54.58, 193.25, 206.94; IR (neat) 3092, 2915, 2098, 1714, 1636, 1359, 1317.

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70 General procedure for the rhodium -catalyzed cycloaddition reaction :55 a solution of 1-Diazo2,5-hexanedione 3-1 (100 mg, 0.71 mmoles, 1 equiv.) and the appropriate dipolarophile (1.5 equiv.) in benzene (0.05M) was degassed under argon. A catalytic amount of rhodium acetate (2% M) was added and the reaction was monito red by TLC. After the disappearance of the starting material (2 to 5 hr), the solvent was removed under reduced pressure and the residue was chromatographed with the appropriate solvent system. Dimethyl 1-methyl-4-oxo-8-oxabicy clo[3.2.1]oct-6-ene-6,7-dicarboxylate 3-4 .55 O CO2Me O MeO2C Yield: 75%; 1H NMR (CDCl3) 1.54 (s, 3H), 2.24 (dt, J = 6 and 3.6Hz, 2H), 2.44-2.54 (m, 1H), 2.76 (quintet, J = 9Hz, 1H), 3.79 (s, 3H), 3.89 (s, 3H), 4.84 (s, 1H); 13C NMR (CDCl3) 22.1, 32.7, 32.9, 52.6, 52.8, 85.9, 88.3, 135.7, 147.0, 161.1, 163.9, 199.3, 203.1; IR (neat) 2958, 2933, 1722, 1659, 1434, 1268; (m/ z ) (GC-CI): 255, 223, 195, 167; HRMS: calcd for [C12H14O6+H]+ 255.0863, found 255.0866.

PAGE 71

71 Diethyl 1-methyl-4-oxo-8-oxabi cyclo[3.2.1]octane -6,7-dicarboxylate 3-5 O O EtO2C CO2Et H H H Yield: 50%; 1H NMR (CDCl3): 1.23 (t, 3H, J = 7.2Hz), 1.32 (t, 3H, J = 7.2Hz), 1.36 (s, 3H), 2.11-2.19 (m, 2H), 2.44-2.52 (m, 2H), 3.55 (d, 1H, J = 7.5Hz), 4.06-4.30 (m, 5H), 4.52 (d, 1H, 7.8Hz); 13C NMR (CDCl3): 13.98, 14.20, 22.66, 33.21, 38.82, 51.67, 52.02, 61.53, 61.75, 83.07, 83.46, 169.45, 172.19, 203.63; IR (nea t): 2982, 1726, 1239, 1179; (m/ z ) (GC-CI): 285, 284, 239, 211. HRMS calcd for [C14H20O6 + H]+: 285.1333, found 285.1340. Dimethyl 1-methyl-4-oxo-8-oxabi cyclo[3.2.1]octane-6,7-dicarboxylate 3-6 O O MeO2C H H MeO2C H Yield: 15%; 1H NMR (CDCl3): 1.52 (s, 3H), 1.96-2.07 (m, 1H), 2.15-2.23 (m, 1H), 2.36 (ddd, J = 17.1, 8.7 and 1.5Hz, 1H), 2.72 (quintet, J = 2.7Hz), 3.25 (d, J = 12.6Hz), 3.63 (s, 3H), 3.69 (s, 3H), 3.64-3.76 (m, 1H), 4.33 (d, J = 8.1Hz, 1H); 13C NMR (CDCl3): 26.66, 29.65, 32.84, 33.09, 49.43, 52.26, 54.38, 60.36, 82.30, 169.68, 170.07, 205.36.

PAGE 72

72 Methyl 1-methyl-4-oxo8-oxabicy clo[3.2.1]oct-6-ene-6-carboxylate 3-7 .34, 55 O O MeO2C Yield: 60%; 1H NMR (CDCl3) 1.62 (s, 3H), 2.12-2.20 (m, 2H), 2.46 (ddq, 1H, J = 18.0, 3.6 and 1.5 Hz), 2.56-2.68 (m, 1H), 3.79 (s, 3H), 4.65 (s, 1H), 7.0 (d, 1H, J = 2.4Hz); 13C NMR (CDCl3) 22.83, 31.58, 33.12, 51.92, 85.69, 85.73, 139.78, 141.60, 163.08, 201.17; (m/z) (GCCI): 196, 164, 137, 109; HRMS calcd for C10H12O6: 196.0736, found 196.0730. Methyl 5-methyl-2-oxo-8-oxabicy clo[3.2.1]oct-6-ene-6-carboxylate 3-8.34,55 O O CO2Me Yield: 15%; 1H NMR (CDCl3) 1.53 (s, 3H), 1.95 (ddd, 1H, J = 13.8, 8.7 and 1.5 Hz), 2.212.31 (m, 1H), 2.47 (ddt, 1H, J = 18, 8.1 and 1.5 Hz), 2.64-2.75 (m, 1H), 3.77 (s, 3H), 4.81 (s, 1H), 7.0 (s, 1H); 13C NMR (CDCl3) 22.24, 32.57, 32.68, 52.21, 85.79, 86.46, 136.35, 147.34, 163.08, 200.45; HRMS calcd for [C10H12O6 + H]+: 197.0808, found 197.0812.

PAGE 73

73 Reaction of the diazo-dione with methyl acrylate: the reaction gave 2 ma jor stereoisomers, 3-9 and 3-10 both exo. The yield of each isomer was calcu lated by NMR, as the purification led to the mixture of the 2 major isomers. The stereoisom ers were compared with the literature for the resolution of the stereochemistry. Methyl 5-methyl-2-oxo-8-oxabi cyclo[3.2.1]octane -6-carboxylate 3-9 .34, 55 O O CO2Me Yield: 30%; 1H NMR (CDCl3): 1.38 (s, 3H), 2.00-2.25 (m, 3H ), 2.40-2.45 (m, 2H), 2.77 (ddd, 1H, J = 14.1, 8.0 and 6.3 Hz), 3.10 (dd, 1H, J = 9.3 and 6.3 Hz), 3.74 (s, 3H), 4.38 (d, 1H, J= 8.1 Hz); 13C NMR (CDCl3): 22.43, 32.10, 33.51, 38.33, 49.67, 52.09, 82.02, 82.60, 173.68, 206.56. Methyl 1-methyl-4-oxo8-oxabi cyclo[3.2.1]octane -6-carboxylate 3-10.34, 55 O O CO2Me Yield: 15%; 1H NMR (CDCl3): 1.50 (s, 3H), 1.85-1.94 (m, 1H), 2.00-2.22 (m, 2H), 2.30-2.40 (m, 1H), 2.42-2.50 (m, 2H), 3.04 (qt, 1H, J = 4.8 and 1.2Hz), 3.73 (s, 3H), 4.53 (s, 1H); 13C NMR (CDCl3): : 25.75, 32.72, 36.46, 37.91, 47.53, 52.60, 81.27, 84.94, 172.0, 205.8.

PAGE 74

74 7-ethoxy-5-methyl-8-oxabi cyclo[3.2.1]octan-2-one 3-11. O O O Yield: 20%; 1H NMR (CDCl3): 1.21 (t, 3H, J = 7.0 Hz), 1.53 (s, 3H), 1.81 (ddd, 1H, J = 13.5, 8.4 and 2.4 Hz), 1.88 (ddd, 1H, J = 13.9, 2.6 and 1.3Hz), 2.02-2.12 (m, 1H), 2.25 (ddd, 1H, J = 18.2, 9.9 and 8.4Hz), 2.39 (dd, 1H, J = 13.9 and 7.4 Hz), 2.49 (ddt, 1H, J = 17.5, 7.9 and 2.1Hz), 3.42 (dq, 1H, J = 9.0 and 7.0 Hz), 3.52 (dq, 1H, J = 9.0 and 7.0 Hz), 4.00 (dd, 1H, J = 7.5, 2.7), 4.29 (s, 1H); 13C NMR (CDCl3): 15.30, 26.22, 34.13, 36.37, 44.19, 65.29, 81.03, 82.86, 87.67, 206.73; (m/z) (GC-CI): 213, 185, 139, 113; HRMS calcd for [C10H16O3+H]+: 185.1172, found 185.1160. Reaction between diazodione and crotonaldehyde : the reaction gave two isomers, 3-12 and 313 The yields were calculated by NMR, as th e purification led to the mixture of the two products. Exo-(E)-5-methyl-7-(prop-1-enyl)-6 ,8-dioxabicyclo[3.2.1]octan-2-one 3-12. O O O

PAGE 75

75 Yield: 25%; 1H NMR (CDCl3): 1.62 (s, 3H), 1.69 (dd, J = 6.6 and 1.5Hz, 3H), 2.08-2.16 (m, 2H), 2.30-2.60 (m, 2H), 4.16 (s, 1H), 4.42 (d, J = 7.5Hz, 1H), 5.43-5.54 (m, 1H), 5.73 (ddd, J = 15.1, 6.6 and 0.9Hz, 1H); 13C NMR (CDCl3): 18.00, 24.75, 32.93, 35.45, 80.02, 85.45, 108.59, 129.66, 129.94, 205.98; Endo-(E)-5-methyl-7-(prop-1-enyl )-6,8-dioxabicyclo[3.2.1]octan-2-one 3-13. O O O Yield: 20%; 1H NMR (CDCl3): 1.58 (s, 3H), 1.69 (dd, J = 6.6 and 1.5Hz, 3H), 2.08-2.16 (m, 2H), 2.30-2.60 (m, 2H), 4.30 (d, J = 5.1Hz, 1H), 4.56 (dd, J = 6.2 and 1.6Hz, 1H), 5.27 (ddd, J = 15.3, 7.5 and 1.5Hz, 1H), 5.73 (m, 1H); 13C NMR (CDCl3): 18.33, 24.59, 34.00, 35.17, 79.69, 84.13, 108.32, 123.46, 132.93, 204.99; Tri-acetone mannitol 3-14.58 O O O O O O Yield: 60%; 1H NMR (CDCl3): 1.36 (s, 6H), 1.39 (s, 6H), 1 .43 (s, 3H), 3.93-4.01 (m, 4H), 4.08 (dd, J = 8.3 and 6.3 Hz, 2H), 4.16-4.24 (m, 2H); 13C NMR (CDCl3): 25.34, 26.53, 27.48, 66.28, 76.35, 79.40, 109.57, 110.16; HRMS calcd for [C15H26O6 + Na]+: 325.1622, found 325.1617.

PAGE 76

76 APPENDIX SPECTRAL DATA O HN O O O Figure A-1. NMR of 2-6 Figure A-2. NMR of 2-7 O HN O O O

PAGE 77

77 O HN O O O Figure A-3. NMR of 2-8 O N O O O Figure A-4. NMR of 2-9

PAGE 78

78 O HN O O O S Figure A-5. NMR of 2-10 HN O O O O O O HN O O Figure A-6. NMR of 2-11

PAGE 79

79 HNO O O O O O H N O O Figure A-7. NMR of 2-12 HNO O O O O O NH O O Figure A-8. NMR of 2-13

PAGE 80

80 N O O O O O O N O O Figure A-9. NMR of 2-14 HNO O O O O O NH O O S S Figure A-10. NMR of 2-15

PAGE 81

81 O O EtO2C CO2Et H H H Figure A-11. NMR of 3-5 O O MeO2C H H MeO2C H Figure A-12. NMR of 3-6

PAGE 82

82 O O H O Figure A-13. NMR of 3-11 O O O O O O Figure A-14. NMR of the mixture of 3-12 and 3-13

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88 BIOGRAPHICAL SKETCH Sophie Klein was born in Strasbourg, France, on August 23rd, 1979. After spending her childhood in Bischwiller, and get ting her baccalaureat with a minor in chemistry in 1997, she went to Strasbourg to pursue pha rmaceutical studies at the Univer sit Louis Pasteur. After two unsuccessful years, she entered the Chemistry De partment at the same university as a sophomore and completed her undergraduate st udies there. She had the opportuni ty to go to the University of Florida as part of the RE U program for four months in 2002 under the supervision of Dr Dennis Wright. She then went back to Strasbour g to complete her master in molecular and supramolecular chemistry in the laboratory of Dr Patrick Pale. She was accepted intothe Chemistry Department at the University of Flor ida in 2003, and joined the group of Dr Eric Enholm.