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Development of Synthetic Methodologies Towards Cyclic DEVELOPMENT OF SYNTHETIC METHODOLOGIES TOWARDS CYCLIC HYDROXAMIC ACID-BASED NATURAL PRODUCTS BY RANJAN BANERJEE A Dissertation Submitted to the Graduate Faculty of WAKE FOREST UNIVERSITY GRADUATE SCHOOL OF ARTS AND SCIENCES in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Chemistry December 2010 Winston-Salem, North Carolina Approved By: S. Bruce King, Ph.D., Advisor Pradeep K. Garg, Ph.D., Chairman Rebecca W. Alexander, Ph.D. Christa L. Colyer, Ph.D. Paul B. Jones, Ph.D. ACKNOWLEDGEMENTS I want to express my thanks and sincere gratitude to Dr. S. Bruce King, for all his academic support and chemistry help, support, and advising throughout my Ph.D career. I owe him a lot for helping me develop into an organic chemisty, guiding my projects and his patience in helping me improve my scientific writing. I am really fortunate to have shared his immense scientific knowledge and learn from his amazing mentoring ability. I am also thankful to Dr. Paul Jones and Dr. Rebecca Alexander for being my committee members. I really want to thank Dr. Cynthia S. Day for crystallographic help and Dr. Marcus W. Wright for NMR assistance. They have always been extremely helpful with any data interpretation and experiment setup needed. I thank my previous lab mates Dr. Sarah Knaggs, Dr. Weibin Chen, Dr. Mike Gorczyski, Brad Poole and the present lab mates Mai Shoman, Raje Mukherjee, Dr. Richard Macri, Dr. Mallinath Hadimani, Dr. Susan Mitroka, Craig Clodfelter, Julie Reisz and Jenna DuMond for their assistance and friendship. I appreciate the friendship and support I received from my Wake Forest friends Tanya Pinder, Dr. Uli Bierbach, Lu Rao, Rajsekhar Guddneppanavar, Jayati Roychoudhuri, Zhidong Ma, Samrat Dutta, Lindsey Davis, John Solano, R.P. Oates, Zhouli Zho and Sandhya Bharti. I am really indebted to Subhasis De for his enormous help to start my American life and really appreciate his friendship. I am also very thankful to my roommates Saurav Sarma, Sebastial Berisha, Edison Munoz-Recuay, Angelo Malvestio, Matt Koval, Joe Maye, Dhruv Gandhi, Anand Gondalerkar and Ben Rosenberg. My very special thanks and love to my beautiful girlfriend Erika Bechtold for bringing so much joy and happiness in life. Erika has always been an amazing support, my very best friend and the sweetest thing I have ever known. She has changed my life and I enjoy it every moment. I am also thankful to Erika’s roommates Charlie and Jeremy for their friendship and support. My sincere love and gratitude goes to my father and mother for being the best parent in the world. Word cannot express my thankfulness for their endless love, countless sacrifices and tremendous encouragement throughout my life. I will be indebted to them forever and I thank God for blessing my life with their kind souls. I wish to dedicate this work to my parents and Erika. TABLE OF CONTENTS LIST OF FIGURES…………………………………………………………………… LIST OF TABLES…………………………………………………………………….. ABSTRACT…………………………………………………………………………… CHAPTER 1: INTRODUCTION………………………………………………………...1 1.1 Hydroxamic Acids………………………………………………………..1 1.2 Basic Structure…………………………………………………………....2 1.3 Biological Importance of Hydroxamic Acids…………………………….2 1.3.1 Enzyme Inhibitors…………………………………………………2 1.3.1.1 Matrix Metalloproteinase Inhibition……………………..2 1.3.1.2 Histone Deacetylase Inhibition…………………………..4 1.3.1.3 TNF-Alpha Converting Enzyme Inhibition……………...5 1.3.2 Therapeutic Uses of Hydroxamic Acids…………………………..6 1.3.2.1 Antimalarial Activity…………………………………….6 1.3.2.2 Antimelanogenic Agents………………………………....7 1.3.2.3 NO Donors……………………………………………….7 1.4 Biological Importance of Cyclic Hydroxamic Acids……………………..8 1.4.1. Iron Uptake by Siderophores……………………………………...8 1.4.2 Lipoxygenase Inhibitory Activity………………………………….9 1.4.3 Therapeutic Application of Cycllic Hydroxamic Acids………….10 1.4.3.1 Prostate Cancer Therapeutics……………………………10 1.4.3.2 Growth Inhibitors Tumor Cell Lines…………………....11 1.4.3.3 Analgesic Activity………………………………………12 i 1.5 Synthetic Approaches to Hydroxamic Acids…………………………….12 1.5.1 Simple Hydroxamic Acids………………………………………..12 1.5.2 Angeli-Rimini Reaction…………………………………………..13 1.5.3 Solid Phase Modification…………………………………………13 1.5.4 Oxidation of N-Boc protected Amides…………………………...14 1.5.5 N-Substituted Hydroxamic Acids………………………………...15 1.5.6 Solid Phase Synthetic Approach………………………………….16 1.5.7 Nitroso-ene Reactions…………………………………………….17 1.5.7.1 Intermolecular Nitroso-ene Reactions…………………..18 1.6 Synthesis of Cyclic Hydroxamic Acids…………………………………..20 1.6.1 Reductive Cyclization of Aliphatic Nitro Acids…………………..20 1.6.2 Synthesis of the Cobactin Core……………………………………20 1.6.3 Heterocycle Based Synthesis: Tungstate Catalyzed Oxidation of Tetrahydro Quinoline……………………………………………..21 1.6.4 Oxidation of Lactams to Cyclic Hydroxamic Acids……………...22 1.6.5 Phenyliodine(III) Bis Trifluoroacetate Mediated Ring-closure…...22 1.6.6 Photochemical Synthesis of Cyclic Hydroxamic Acids…………..23 1.6.7 Intramolecular Nitroso-ene Reaction……………………………...24 1.6.8 Ring Expansion of Cyclic Ketones ……………………………… 26 1.6.9 Piloty’s Acid-Based Rearrangements of Cyclic Ketones to Make Cobactin…………………………………………………………...27 1.7 Piloty’s Acid: A Nitroxyl Donor…………………………………………27 1.7.1 Nitroxyl (HNO) Chemistry……………………………………….28 1.8 Mycobactin – S…………………………………………………………..30 ii 1.8.1 Biosynthesis of Mycobactins……………………………………………31 CHAPTER 2: SYNTHESIS OF CYCLIC HYDROXAMIC ACID THROUGH –NOH INSERTION OF KETONES……………………………………………34 2.1 Introduction………………………………………………………………35 2.2 Synthesis of N-Hydroxy Benzenesulfohydroxamic Acid (Piloty’s acid)...36 2.3 -NOH Insertion Reaction of Cyclic Ketones…………………………….36 2.3.1 Synthesis of N-hydroxy Piperidone………………………………36 2.3.2 -NOH Insertion Reaction in Cyclobutanones…………………….38 2.3.3 Solid phase modification………………………………………….42 2.4 Mechanism of –NOH insertion reaction………………………………….43 2.5 Scope of –NOH Insertion Reaction………………………………………49 2.5.1 Synthesis of O-Protected Cyclic Hydroxamic Acids…………….49 2.5.2 –NOH Insertion Reaction in α-Substituted Cyclopentanone…….50 2.5.3 -NOH Insertion in Cyclohexenone……………………………….51 2.5.4 Investigation of a Cobactin Synthesis Using the –NOH Insertion Reaction………………………………………………………...52 2.6 Experimental……………………………………………………………...54 CHAPTER 3: PROGRESS TOWARDS THE SYNTHESIS OF THE COBACTIN CORE AND MYCOBACTIC ACID UTILIZING NITROSO-ENE REACTION………………………………………………………….71 3.1 Intramolecular Nitroso-ene Reaction Approach to the Synthesis of Cobactin Core………………………………………………………….71 3.1.1 Retrosynthesis of Cobactin ……………………………………..71 3.1.2 Intramolecular Nitroso-ene Reactons: Results and Discussion…72 3.2 Structure Elucidation of Mycobactin …………………………………..76 iii 3.3 Investigation of Intermolecular Nitroso-ene Approach towards the Synthesis of Cobactin and Mycobactic Acid…………………………...76 3.3.1 Synthesis of the Precursor Alkene and Diels-Alder Cycloadduct (Acyl-nitroso Precursor) for a Nitroso-ene Reaction………………….78 3.3.2 Nitroso-ene Reaction…………………………………………...78 3.3.3 Progress Towards the Synthesis of Mycobactic Acid Utilizing a Nitroso-ene Reaction…………………………………………..83 3.4 Nitroso-ene Reactions of Acetyl-Nitroso Compounds…………………86 3.5 Nitroso-ene Reactions of Benzoyl Nitroso compounds………………...87 3.6 Experimental……………………………………………………………90 CHAPTER 4: SUMMARY …………………………………………………………...114 REFERENCES……………………………………………………………………….117 APPENDIX…………………………………………………………………………..136 SCHOLASTIC VITA………………………………………………………………...181 iv LIST OF FIGURES Figure 1. X-ray Diffraction structure of N-hydroxy piperidone (85) …………. 38 Figure 2. X-ray Diffraction Structure of 89 …………………………………… 39 Figure 3. Figure 3. X-ray Diffraction Structure of 94…………………………. 42 Figure 4. X-ray Diffraction Structure of Compound 127 …………………….. 75 v LIST OF TABLES Table 1. Results of –NOH insertion with cyclopentanone towards N-hydroxy piperidone synthesis…………………………………………………. 37 Table 2. Results of –NOH Insertion into cyclobutanone ………………………40 Table 3. Gas Chromatography Results: Hydrolysis of acyloxy nitroso ………. 47 vi LIST OF ABBREVIATION Boc tert-Butyloxy carbonyl Cbz Carboxybenzyl DCC N, N’-Dicyclohexylcabodiimide DIBOA 2,4-dihydroxy-2H-1,4-benzooxazin-3(4H)-one DMA Dimehtylanthracene DMAP 4-Dimethylaminopyridine DMD Dimethyldioxirane DMF Dimehtylformamide DMSO Dimehtylsulfoxide DNA Deoxyribonucleic Acid E Entgegen EDC 1-Ethyl-3-(3-dimethylaminopropoyl)carbodiimide FR900098 Fosmidomycin GC Gas chromatography HCl Hydrochloric acid HDAC Histone deacetylase HETE Hydroxyeicosatetraenoic acid HNO Nitroxyl HOAt 1-Hydroxy-7-azabenzotriazole IC50 Half maximal inhibitory activity MMP Matrix metalloproteinase MS Mass Spectrometry NMR Nuclear magnetic resonance NO Nitric Oxide vii PIFA Phenylidoine (III) bis(trifluoroacetate) Ppm Parts per million SAHA Suberoylanilide hydroxamic acid TACE Tumor necrosis factor alpha converting enzyme TBDMSCl tert-Butyl dimethylsilyl chloride TBDPSCl tert-Butyl chlorodiphenylsilane TFA Trifluoroacteic acid THF Tetrahydrofuran TIMP Tissue inhibitor of metalloproteinases TLC Thin layer chromatogrpahy TMD Trifluoromethyl dioxiranes TNF Tumor Necrosis Factor TSA Tricostatin A Z Zussamen viii Abstract Hydroxamic acids are an important class of bioactive compounds with wide uses as anti-bacterial, or anti-inflammatory agents and a key component of many natural products, mainly siderophores (low-molecular-weight iron sequestering agents) in lower organisms. Hydroxamic acid based analogs may find potential therapeutic uses in the inhibition of siderophore biosynthesis. Our research targets to develop new synthetic methodology towards making
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