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The Synthesis of Oxazole-Containing Natural Products by Thomas H. Graham BS, Virginia Tech, 1995 Submitted to the Graduate Facul

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The Synthesis of Oxazole-Containing Natural Products by Thomas H. Graham BS, Virginia Tech, 1995 Submitted to the Graduate Facul The Synthesis of Oxazole-containing Natural Products by Thomas H. Graham BS, Virginia Tech, 1995 Submitted to the Graduate Faculty of Arts and Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2006 UNIVERSITY OF PITTSBURGH FACULTY OF ARTS AND SCIENCES This dissertation was presented by Thomas H. Graham It was defended on January 5, 2006 and approved by Professor Paul E. Floreancig, Department of Chemistry Professor Kazunori Koide, Department of Chemistry Professor John S. Lazo, Department of Pharmacology Professor Peter Wipf, Department of Chemistry Dissertation Director ii ABSTRACT The Synthesis of Oxazole-containing Natural Products Thomas H. Graham, PhD University of Pittsburgh, 2006 The first section describes the synthesis of the C1’ to C11’ side chain of leucascandrolide A. The key step of the synthesis is a modified Robinson-Gabriel synthesis of the oxazole. The C1’ to C11’ side chain was constructed in 9 steps and 7% overall yield. The second section describes the synthesis of 2-alkynyl oxazoles and subsequent transformations into a variety of useful motifs. The conjugate addition of nucleophiles to 2-alkynyl oxazoles under basic conditions affords vinyl ethers, vinyl thioethers and enamines. The addition of ethanedithiol affords dithiolanes that can be transformed into ethyl thioesters and ketones. Nucleophilic additions of thiols to 2- alkynyl oxazolines affords oxazoline thioethers. Additions of halides under acidic conditions stereoselectively affords vinyl halides that can be further transformed by Sonogashira cross-coupling reactions. The third section describes the synthesis of (-)-disorazole C1 and analogs. The macrocycle was constructed with minimal protecting group manipulations, using mild esterification and Sonogashira cross-coupling reactions. The convergent synthesis of disorazole C1 allowed for the synthesis of additional analogs. These analogs include the C14-t-butyl and C17-18-cyclopropane derivatives. Results from preliminary biological evaluations of synthetic intermediates, analogs and derivatives are also discussed. iii ACKNOWLEDGEMENTS I extend my sincere appreciation to Professor Peter Wipf for the opportunity to study in his laboratories. I also thank the members of my dissertation committee, Professor Paul E. Floreancig, Professor Kazunori Koide and Professor John S. Lazo. Dr. Alexander P. Ducruet and Dr. Rachel P. Sikorski in the laboratories of Professor John S. Lazo and Professor Andreas Vogt, respectively, are acknowledged for conducting the biological evaluations of disorazole C1 and analogs. Additional collaborators include Professor Billy W. Day, Professor Susan P. Gilbert, Professor William S. Saunders and Professor Claire E. Walczak (Indiana University, Bloomington). I thank the past and present members of the Wipf group and Michelle Woodring for her help throughout the years. I also thank Dr. Fu-Tyan Lin and Dr. Damodaran Krishnanachary for NMR spectroscopy, Dr. Kasi Somayajula and Dr. John Williams for mass spectroscopy and Dr. Steven J. Geib for x-ray crystallography. I thank the University of Pittsburgh for financial support. Additional funding was provided by the National Institutes of Health and Merck Research Laboratories. Roche is acknowledged for providing a graduate research award. On a personal note, I thank Dr. Tamara D. Hopkins for her friendship and competitive spirit. I thank Dr. Philip F. Hughes for inspiring me to pursue a career in organic synthesis. I thank Professor Neal Castagnoli, Jr. for introducing me to organic synthesis. Finally, I thank my mother and father, my brother and my sisters for their continued support and encouragement. iv LIST OF ABBREVIATIONS Ac acetyl AcOH acetic acid aq. aqueous 9-BBN 9-borabicyclo[3.3.1]nonane BHT 2,6-di-tert-butyl-4-methylphenol BINOL 1,1’-bi(2-naphthol) BrCCl3 bromotrichloromethane Bu butyl i-Bu isobutyl t-Bu tert-butyl 18-C-6 18-crown-6 ether CBS Corey-Bakshi-Shibata (oxazaborolidine) Chloramine T N-chloro-para-toluenesulfonamide sodium salt CI chemical ionization d day(s) DAST (diethylamino)sulfur trifluoride dba dibenzylidene acetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene Deoxofluor™ bis(2-methoxyethyl)aminosulfur trifluoride DiBAl-H diisobutyl aluminum hydride DIEA diisopropylethylamine DIP-Cl DIP-chloride™; B-chlorodiisopinocampheylborane DIPT diisopropyl tartrate DMAP 4-dimethylaminopyridine DMS dimethylsulfide DPTC dipyridylthionocarbonate 3,4-DMB 3,4-dimethoxybenzyl DMF N,N-dimethylformamide DMSO dimethylsulfoxide EDC 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide EDCI 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide EI electron-impact ionization equiv equivalent(s) ESI electrospray ionization Et ethyl EtOAc ethyl acetate h hour(s) HPLC high-pressure liquid chromatography HRMS high resolution mass spectroscopy HMPA hexamethylphosphoramide HOBT 1-hydroxybenzotriazole IBCF isobutylchloroformate v imid imidazole IR infrared spectroscopy KHMDS potassium bis(trimethylsilyl)amide LiHMDS lithium bis(trimethylsilyl)amide L-Selectride® lithium tri-sec-butylborohydride M molar MCPBA 3-chloroperbenzoic acid Me methyl min minute(s) mL milliliter(s) mol mole(s) Mp melting point MS molecular sieves, mass spectroscopy m/z mass/charge ratio NaHMDS sodium bis(trimethylsilyl)amide NBS N-bromosuccinimide NCS N-chlorosuccinimide NMM N-methylmorpholine NMO N-methylmorpholine-N-oxide NMR nuclear magnetic resonance NRPS non-ribosomal peptide synthetase PCWP peroxotungstophosphate Ph phenyl PIFA [bis(trifluoroacetoxy)iodo]benzene Piv pivaloyl PKS polyketide synthase PMB para-methoxybenzyl i-Pr isopropyl PPTS pyridinium para-toluenesulfonate Pr propyl PyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate) PyBrOP bromotripyrrolidinophosphonium hexafluorophosphate pyr pyridine quant. quantitative Red-Al® sodium bis(2-methoxyethoxy)aluminum dihydride rt room temperature SAR structure-activity relationship Select-Fluor™ N-chloromethyltriethylenediammonium fluoride Ser-OMe•HCl serine methyl ester hydrochloride SEM 2-(trimethylsilyl)ethoxymethyl SiO2 silica gel TBAF tetra-n-butylammonium fluoride TBDPS tert-butyldiphenylsilyl TBHP tert-butylhydroperoxide vi TBS tert-butyldimethylsilyl 2,4,6-TCBC 2,4,6-trichlorobenzoyl chloride TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy free radical TES triethylsilyl Tf triflate TFA trifluoroacetic acid TFAA trifluoroacetic anhydride TIPS triisopropylsilyl THF tetrahydrofuran TLC thin layer chromatography TMANO trimethylamine-N-oxide TMS trimethylsilyl TPAP tetra-n-propylammonium perruthenate Ts para-toluenesulfonyl TsDPEA N-(para-toluenesulfonyl)-1,2-diphenylethylenediamine vii TABLE OF CONTENTS List of Tables ...................................................................................................................x List of Figures................................................................................................................. xi List of Schemes............................................................................................................. xii 1. Synthesis of the C1’-C11’ Segment of Leucascandrolide A........................................1 1.1. Introduction.......................................................................................................1 1.1.1. The Biology of the Leucascandrolides.......................................................1 1.1.2. Approaches to the Synthesis of the C1’-C11’ Segment ...............................3 1.1.2.1. Leighton’s Synthesis...........................................................................4 1.1.2.2. Kozmin’s Synthesis.............................................................................5 1.1.2.3. Panek’s Synthesis and the Paterson Variant ......................................7 1.2. Synthesis of the C1’-C11’ Segment of Leucascandrolide A ..............................10 1.2.1. Retrosynthesis .........................................................................................10 1.2.2. Completion of the C1’–C11’ Segment.........................................................11 1.2.2.1. Cyclization–Oxidation Approach to the Synthesis of the Oxazole....12 1.2.2.2. Oxidation–Cyclization Approach to the Synthesis of the Oxazole....14 1.3. Summary and Conclusions .............................................................................15 1.4. Experimental Part............................................................................................16 1.4.1. General.....................................................................................................16 1.4.2. Experimental Procedures.........................................................................17 2. Conjugate Additions to 2-Alkynyl Oxazoles and Oxazolines..................................25 2.1. Conjugate Additions Under Basic Conditions.................................................25 2.1.1. Introduction..............................................................................................25 2.1.2. Synthesis and Conjugate Addition Reactions of a 2-Ethynyl Oxazole.....29 2.1.3. Conjugate Additions to Internal Alkynes ..................................................39 2.1.4. Preliminary Metal Chelation Studies ........................................................44 2.1.5. Conjugate Additions to Oxazolines..........................................................45 2.1.6. Synthesis of a 2-Allenyl Oxazole..............................................................47 2.2. Conjugate Additions Under Acidic Conditions................................................50
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