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Synthesis and Optimization of Novel Amides Using the Ugi Reaction For Synthesis and optimization of novel amides using the Ugi reaction for anti-malarial screening A Thesis Submitted to the Faculty Of Drexel University by Khalid Baig S Mirza in partial fulfillment of the requirements for the degree of Doctor of Philosophy May 2010 © Copyright 2010 Khalid Baig S Mirza. All Rights Reserved ii Dedications This thesis is dedicated to my parents Naser Baig Salmani and Mrs. Sirajunnisa, my sister Ayesha Fatima and my brother Hafeez Baig. Their love, support and encouragement have made this possible. iii Acknowledgements First, I would like to thank Almighty God for helping me complete a task I had initiated. I would like to thank my research advisor, Dr. Jean-Claude Bradley, for his guidance and supervision. I would also like to thank my committee members, Prof. Frank Ji, Prof (Chair), Prof. Sally Solomon, Prof. Peter Wade, Prof. Louis Scerbo, Prof. Jun Xi and Prof. Susan Jansen-Varnum (Temple University) for providing their valuable input, reviewing my thesis and participating in the final defense. I would like to thank late Prof. Robert Hutchins who served as the Chair for my candidacy proposal committee. He had being an incredible mentor and teacher to me. I would like to thank Prof. Anthony Wambsgans for his support as a teacher and a friend. I would also like to thank Prof. Daniel King for serving on my proposal committee. I want to thank Prof. Lynn Penn for helping me every time I needed. I really appreciated your pragmatism and advice. I also want to thank Ed Doherty, Virginia Nesmith, Tina Lewinsky and Ed Thorn for providing the administrative support. I would like to thank every member for the Bradley group with whom I had an opportunity to interact and work with. I would like to thank Alicia Holsey, James Giammarco, Sean Gardner, Tim Bohinsky, Shannon Oseback and Emily Messner who worked with me and helped further the project. I would like to acknowledge all the graduate students I had a chance to interact with not only from Chemistry but also from other departments. You all made my stay at Drexel better. I would like to thank Neil Mukherjee, Sudipto Das, Renata Szyszka, Chris Castillo, Nick Paparoidamis, Jon Sofer, Kerry Drake, Hung Le, Dave-Berke Schlessel, Addy Kojtari, Gordon Tyson, Molly O’connor, April Holcombe all other I have missed to mention here. iv Abstract Synthesis and optimization of novel diamides using the Ugi reaction for anti-malarial screening Khalid Baig S Mirza, Jean-Claude Bradley, Ph.D. The primary goal of this work was to easily synthesize a library of diamides predicted to be potential anti-malarial agents. This thesis focuses on synthesis of those diamides by the Ugi reaction and further optimization studies. Solubility of the reactants and the Ugi product has been used to optimize the reaction. During the preliminary phase we focused on the synthesis of a library of active compounds obtained from Find-A-Drug, a non-profit computing project which serves to address a number of diseases. Although we were unable to synthesize any of the compounds from the Find-A-Drug library, the diamide nucleus served as ‘pharmacophore’ for the later libraries that were develop in collaboration with computational chemists. Some of the diamides synthesized showed promising results when tested for bio-activity against the plasmodium enzyme, falcipain-2. However, during the synthetic process of these diamides via the Ugi reaction it became clear that not every compound from the library could be synthesized by one general method. One major issues encountered was related to solubility of starting materials in methanol, the usual choice of solvent used for the Ugi reaction. Therefore, optimization studies were carried out to estimate the best solvent and conditions required in order to obtain a better yield with crystalline product, which would not require further chromatographic purification. In one of the optimization studies involving benzaldehyde, furfurylamine, boc-glycine and tert- butylisocyanide best results in terms of yield were obtained when the reaction was performed at v 0.4M concentration per component in methanol with 1.2eq imine. This was a significant improvement compared to the reaction performed under equimolar conditions with a 49% yield. Apart from solubility, reaction kinetics and solvent effects which played major role in the final yield of the reaction were also studied. In essence we postulate that knowing the kinetics and ‘by being able to predict the solubility of starting materials and products, one can predict the optimal solvent and concentration to carry out the reaction and isolate the Ugi product by simple filtration.’ vi TABLE OF CONTENTS ABSTRACT.....................................................................................................................................v LIST OF FIGURES.........................................................................................................................x LIST OF SCHEME .....................................................................................................................xiii LIST OF TABLES........................................................................................................................xiv CHAPTER 1: INTRODUCTION & OVERVIEW 1.1. The UsefulChem Project.....................................................................................................2 1.2. Overview and Organization of the thesis............................................................................4 1.3. References...........................................................................................................................7 CHAPTER 2: SODIUM HYDRIDE OXIDATION AND SOCIAL NETWORKING 2.1. Introduction.........................................................................................................................9 2.2. Experimental.....................................................................................................................12 2.3. Results and discussion......................................................................................................13 2.4. References.........................................................................................................................17 CHAPTER 3: DOPAL SYNTHESIS 3.1. Introduction.......................................................................................................................18 3.2. Enoyl Reductase inhibition...............................................................................................18 3.3. Riboneucleotide reductase (RNR) inhibition....................................................................19 3.4. Synthesis of 3, 4-dihydrophenylacetaldehyde [DOPAL].................................................23 3.5. References.........................................................................................................................26 vii CHAPTER 4: INITIAL ATTEMPS AT UGI REACTION AND IMINE KINETICS 4.1. Introduction.......................................................................................................................27 4.2. Imine Kinetics...................................................................................................................29 4.3. Initial Ugi Reactions.........................................................................................................31 4.4. Experimental.....................................................................................................................33 4.5. References.........................................................................................................................37 CHAPTER 5: THE FURFURYL CLEAVAGE 5.1. Introduction.......................................................................................................................39 5.2. Acid catalyzed ring opening reactions of furfuryl alcohols..............................................40 5.3. Furfuryl cleavage: A case for 1, 6 - Elimination..............................................................41 5.4. Results and Discussions....................................................................................................43 5.5. References.........................................................................................................................58 CHAPTER 6: AUTOMATED OPTIMIZATION OF A UGI REACTION 6.1. Introduction......................................................................................................................60 6.2. Experimental.....................................................................................................................61 6.3. Characterization of the Ugi product..................................................................................62 6.4. Data Analysis....................................................................................................................62 6.5. Results and Discussion.....................................................................................................67 6.51. Effect of solvent composition.........................................................................................67 6.52. Effect of reagent concentration.......................................................................................68 6.53. Effect of reagent concentration and reagent excess........................................................70 viii 6.6. References.........................................................................................................................71
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