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Synthesis of Biologically Active Heterocycles and Development of New Organometallic Methodologies

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Synthesis of Biologically Active Heterocycles and Development of New Organometallic Methodologies Synthesis of Biologically Active Heterocycles and Development of New Organometallic Methodologies by David M. Arnold B.S., Kings College, 2005 Submitted to the Graduate Faculty of Arts and Sciences in partial fulfillment of the requirements for the degree of Master of Science University of Pittsburgh 2010 UNIVERSITY OF PITTSBURGH Arts and Sciences This thesis was presented by David M. Arnold It was defended on 12/9/10 and approved by Dr. Dennis P. Curran, Distinguished Service Professor of Chemistry and Bayer Professor, Department of Chemistry Dr. Kazunori Koide, Associate Professor, Department of Chemistry Thesis Director: Dr. Peter Wipf, Distinguished University Professor, Department of Chemistry ii Copyright © by David M. Arnold 2010 iii Synthesis of Biologically Active Heterocycles and Development of New Organometallic Methodologies David M. Arnold, M.S. University of Pittsburgh, 2010 The study of the synthesis of highly functionalized heterocyclic compounds represents an important subset of synthetic organic transformations leading to target compounds with a wide set of applications in medicinal chemistry, biological chemistry, materials sciences and natural product synthesis. Through this work, synthetic strategies leading to a novel set of ester linked substituted quinoline – uracil scaffolds have been developed and the resulting products were found to be inhibitors of MPK1, an important target in cancer research. This work has also led to the development and implementation of novel synthetic strategies toward highly functionalized, traditionally pharmacologically important 6-amino-, 6-hydroxy- and 6-oxo-uracil and 4,6- dihydroxypiperidone scaffolds. A novel Plk1-PBD inhibitor from this series would be important to probe the mechanism of this enzyme during mitosis and to develop a clinical candidate for this validated cancer target. The Plk1-PBD research endeavor also documents a case for a tandem synthetic/analytical structure determination study. The structure of an initially elusive compound from a high throughput screening of 97,090 compounds was determined by this approach. Finally, the utility of novel heterocyclic sulfonyl and sulfinyl nitrogen protecting groups has been demonstrated through the addition of organometallic reagents to 2- methylthiadiazole-, 2-benzothiazolesulfonylbenzaldimines and 2-pyridylsulfinylbenzaldimines. It was found that these addition reactions proceeded with a variety of organometallic iv nucleophiles including Gringnard reagents, organozinc and organocuprates. The heterocyclic sulfonyl protecting groups were easily cleaved from the α-branched amines, affording a useful protecting group strategy for the synthesis of this important class of compounds. v TABLE OF CONTENTS TABLE OF CONTENTS ........................................................................................................... VI LIST OF TABLES ...................................................................................................................... XI LIST OF FIGURES .................................................................................................................. XII LIST OF SCHEMES ............................................................................................................... XIV ACKNOWLEGEMENTS ..................................................................................................... XVII ABBREVIATIONS ............................................................................................................... XVIII 1.0 SYNTHESIS AND BIOLOGICAL ACTIVITY OF A FOCUSED LIBRARY OF MITOGEN-ACTIVATED PROTEIN KINASE PHOSPHATASE INHIBITORS ................ 1 1.1 INTRODUCTION ............................................................................................... 1 1.1.1 Brief biological background ......................................................................... 1 1.1.2 Project background ...................................................................................... 2 1.1.3 Library design ............................................................................................... 4 1.2 LIBRARY SYNTHESIS ..................................................................................... 5 1.2.1 Synthesis of 2,8-substituted quinolinecarboxylic acid sodium salts ......... 5 1.2.2 Synthesis of 1-N-alkyl-3-N-alkyl-5-chloroacetyl-6-aminouracils ............. 8 1.2.3 Synthesis of the final library compounds.................................................. 11 1.3 BIOLOGICAL RESULTS FOR MKP-1 INHIBITORS................................ 15 1.4 CONCLUSIONS ................................................................................................ 19 vi 2.0 ADDITION OF ORGANOMETALLIC REAGENTS TO NOVEL HETEROCYCLIC SULFONYL AND SULFINYL BENZALDIMINES ............................. 20 2.1 INTRODUCTION ............................................................................................. 20 2.1.1 Overview of imines ...................................................................................... 20 2.1.2 Addition of organometallic reagents to imines ......................................... 23 2.1.2.1 Organolithium and Grignard reagents ............................................. 23 2.1.2.2 Dialkylzinc reagents ............................................................................ 27 2.1.2.3 Hydrozirconation and transmetallation............................................ 30 2.1.3 Introduction to Bts and Ths sulfonyl protecting groups ......................... 34 2.2 RESULTS AND DISCUSSION ........................................................................ 35 2.2.1 Synthesis of N-Bts- and N-Ths-benzaldimines ......................................... 35 2.2.2 Addition of organometallic reagents to the N-Bts- and N-Ths- benzaldimines ............................................................................................................. 37 2.2.2.1 Lithium reagents ................................................................................. 37 2.2.2.2 Grignard reagents ............................................................................... 38 2.2.2.3 Diethylzinc reactions ........................................................................... 40 2.2.2.4 Hydrozirconation – transmetallation reactions ............................... 41 2.2.3 Deprotection of N-Ths and N-Bts-sulfonamides ...................................... 45 2.2.4 Addition of organometallic reagents to heterocyclic benzothiazole- and pyridyl-2-sulfinylbenzaldimines................................................................................ 47 2.3 CONCLUSION .................................................................................................. 51 3.0 STRUCTURE ELUCIDATION AND SYNTHESIS OF A PUTATIVE POLO LIKE KINASE – POLO BOX DOMAIN (PLK1-PBD) INHIBITOR ................................... 52 vii 3.1 OVERVIEW ....................................................................................................... 52 3.2 INTRODUCTION ............................................................................................. 52 3.2.1 Project Background .................................................................................... 55 3.3 IDENTIFICATION OF THE STRUCTURE OF SID 861574 ...................... 57 3.3.1 Initial synthetic attempts toward the identification of SID 861574 ........ 57 3.3.1.1 Synthesis of the carboxylic acid analogue of 205 ............................. 58 3.3.1.2 Synthesis of the isomeric 6-aminouracils 206 and 207..................... 58 3.3.1.3 Synthesis of 6-aminouracil analogues 208 and 209 .......................... 59 3.3.1.4 Synthesis of the 6-hydroxyuracil analogue 210 ................................ 61 3.3.1.5 Conclusions of the initial synthetic attempt to identify the structure of SID 861574 ..................................................................................................... 62 3.3.2 Structure elucidation of SID 861574: Development of a controlled synthesis of N1,N3-differentially-substituted 5-methylene-6-hydroxy uracils ...... 63 3.3.3 Positive identification of the structure of SID 861574 and biological testing results against Plk1-PBD ............................................................................... 72 3.4 INVESTIGATIONS INTO THE SAMPLE COMPOSITION OF SID 861574 .......................................................................................................................... 75 3.5 INVESTIGATIONS INTO THE DECOMPOSITION OF 260 AND SID 861574 .......................................................................................................................... 78 3.5.1 High temperature decomposition of SID 861574 ..................................... 79 3.5.2 Room temperature decomposition of 260 vs. SID 861574 ....................... 82 3.6 INITIAL BIOLOGICAL TESTING RESULTS AGAINST PLK1-PBD .... 85 viii 3.7 IDENTIFICATION AND SYNTHESIS OF PUTATIVE IMPURITIES FOUND IN THE BIOLOGICALLY ACTIVE BATCH OF COMPOUND 265, DMA-NB245-3 .................................................................................................................... 87 3.8 FURTHER SYNTHESIS OF ANALOGUES FOR BIOLOGICAL TESTING AGAINST PLK1-PBD ..................................................................................... 99 3.9 SUMMARY ...................................................................................................... 100 4.0 EXPERIMENTAL PART ....................................................................................... 102 4.1
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