STUDIES TOWARD THE SYNTHESIS OF PHOTOLABILE HNO DONORS – AN EXPLORATION OF SELECTIVITY FOR HNO GENERATION A thesis submitted to the Kent State University Honors College in partial fulfillment of the requirements for Departmental Honors by Zachary Alan Fejedelem August, 2015 Thesis written by Zachary Alan Fejedelem Approved by ________________________________________________________________, Advisor ________________________________________________________________, Advisor ________________________________________________________________, Chair, Department of Chemistry & Biochemistry Accepted by _____________________________________________________, Dean, Honors College ii TABLE OF CONTENTS LIST OF FIGURES……………………………………………………...…………….…vi LIST OF TABLES………………………………………………………………………..ix ACKNOWLEDGMENTS………………………………………………….......................x CHAPTER 1. INTRODUCTION……………………………………………………..….1 1.1 Introduction to HNO……………………………………………....1 1.1.1 The unique qualities of HNO……………………………………...1 1.1.2 Drawbacks and issues of HNO…………………………………....5 1.1.3 Importance of HNO donors……………………………….………6 1.2 Examples of HNO donors………………………………………...7 1.2.1 Angeli’s Salt (AS)………………………………………………...7 1.2.2 Piloty’s Acid (PA)………………………………………………...8 1.2.3 HNO-generating diazeniumdiolates…………………………..…12 1.2.4 Cyanamide…………………………………………………….…12 1.2.5 Nitrosocarbonyls…………………………………………………14 1.2.6 Hydroxylamine…………………………………………………..16 1.2.7 α-Acyloxy-C-nitroso compounds………………………………..16 1.2.8 Photolabile HNO and NO donors………………………………..17 1.3 Our research group’s family of current HNO donors…………....20 iii 1.3.1 Previous work on first family of photoactivatable HNO donors..20 1.3.2 Previous synthesis of target photolabile HNO donors…………..22 1.4 Photolysis results from HNO donors 22………………………....25 1.4.1 Photolysis results of first HNO donor 22a……………………....25 1.4.2 Proposed photolysis mechanism………………………………...27 1.5 Thesis project goal……………………………………………....29 1.5.1 Thesis project……………………………………………………29 1.5.2 Proposed photolysis mechanism………………………………...31 2. RESULTS AND EXPERIMENTAL DISCUSSION…………………....33 2.1 Attempted synthesis of ɑ-methyl-substituted photolabile caged CF3SO2NHOHNM HNO donor 29……………………………...33 2.1.1 Synthetic strategy A towards α-methyl-substituted CF3SO2NHOHNM HNO donor 29……………………………...33 2.2 Reevaluation of synthetic route for producing photolabile caged CF3SO2NHOHNM HNO donor 29……………………………...42 2.2.1 Second synthetic strategy (B) toward the preparation of photolabile HNO donor 29…………………………………………………...42 2.2.2 Reduction step modification to the synthesis of photolabile HNO donor 29………………………………………………………….44 2.2.3 Mitsunobu reaction step modification to the synthesis of photolabile HNO donor 29…………………………………........49 2.3 Potential future goals…………………………………………….55 3. EXPERIMENTAL DETAILS……………………………………….......57 3.1 General considerations…………………………………………..57 iv 3.2 Experimental details and schemes………………………….…..58 REFERENCES…………………………………………………………………………79 v LIST OF FIGURES Figure 1.1: Lewis structure of HNO………………………………………………………1 Figure 1.2: Possible biosynthetic pathway to HNO from the nitric oxide synthase (NOS) intermediate N-hydroxy-L-arginine (reproduced from Irvine)……………………………2 Figure 1.3: Sequence of reactions for HNO and thiols……………………………………5 Figure 1.4: Equation showing the formation of the HNO dimer and subsequent products…………………………………………………………………………………...5 Figure 1.5: The Lewis structure of Angeli’s salt………………………………………….7 Figure 1.6: Decomposition of Angeli’s salt to form HNO………………………………..8 Figure 1.7: Reaction showing generation of HNO from Piloty’s acid……………………9 Figure 1.8: Piloty acid derivatives for rapid HNO release (reproduced from Miyata)….10 Figure 1.9: Barbiturate analogs for the rapid release of HNO (reproduced from Toscano)............................................................................................................................10 Figure 1.10: Toscano patent for Piloty’s acid derivatives (reproduced from Toscano)…11 Figure 1.11: Toscano’s clinical trial Piloty’s acid analogs………………………………12 Figure 1.12: General reaction scheme for NONOate generation of HNO……………….12 Figure 1.13: Equation demonstrating the bioactivation of cyanamide…………………..13 Figure 1.14: Equation showing the instability of nitrosocarbonyl compounds………….14 Figure 1.15: Mechanism of base/esterase catalysis of N,O-bisacylated 4-chloro derivatives (reproduced from Nagasawa)…………………………………………….….15 Figure 1.16: Reaction showing the generation of HNO by α-acyloxy-C-nitroso hydrolysis………………………………………………………………………………..16 Figure 1.17: Photodecomposition of ethyl nitrodiazoacetate in 75:25 acetonitrile/water (reproduced from Toscano)…………………………………………………………..….18 vi Figure 1.18: Example of pathway for the generation of HNO from the retro-Diels Alder reaction (reproduced from Nakagawa)……………………………………………...…..19 Figure 1.19: General strategy for photodeprotection of the HNM group……………….20 Figure 1.20: Mechanistic depiction of the photocleavage of the HNM group……….....21 Figure 1.21: Deprotection of HNM photoprotecting group……………………………..22 Figure 1.22: Previous reaction scheme for producing the first generation of HNO donors……………………………………………………………………………………23 Figure 1.23: Depiction of reaction time effect on deprotection of silyl ether…………...24 Figure 1.24: Photolysis of HNM-ONHSO2CF3 monitoring by 19F NMR spectroscopy......................................................................................................................26 Figure 1.25: Photolysis mechanism showing the wanted and unwanted photolytic reactions and the products formed……………………………………………………....27 Figure 1.26: Comparison of original and new classes of HNO donors………………...29 Figure 1.27: Retrosynthetic sequence for two proposed synthetic strategies for developing HNO donor 29…………………………………………………………………………..30 Figure 1.28: Projected photolytic mechanism for the new target HNO donor 29………31 Figure 2.1: The directed ortho-metalation reaction scheme for producing the α-methyl modified HNO donor molecule…………………………………………………………34 Figure 2.2: Schematic showing the role of DMGs……………………………………...35 Figure 2.3: Chowdhury’s experiment with ortho-lithiation (reproduced from Chowdhury)……………………………………………………………………………..35 Figure 2.4: Ortho-regioisomers 35 and 35a…………………………………………….37 Figure 2.5: Two possible ortho-lithiation sites for compound 33………………………37 vii Figure 2.6: Expanded view of the 1H NMR chemical shift (ppm) α-methyl substituent on the regioisomers 35 and 35a…………………………………………………………….38 Figure 2.7: Reimer-Tiemann mechanism for ortho-formylation of phenols……………40 Figure 2.8: Original synthesis of first installment of photolabile caged CF3SO2NHOHNM HNO donor 22…………………………………………………………………………...42 Figure 2.9: Mechanism showing the intramolecular hydride transfer………………..…43 Figure 2.10: Synthetic strategy B for development of desired HNO donor 29………….44 Figure 2.11: HfCl4/NaBH4 reduction of an ester…………………….…………………..46 Figure 2.12: Intramolecular delivery of hydride to a α-carbonyl ester…………………..48 Figure 2.13: Mitsunobu reaction mechanism for the formation of compound 44……….50 Figure 2.14: Lossen Rearrangement mechanism encountered by Durand (reproduced from Durand)…………………………………………………………………………… 52 Figure 2.15: Schematic showing future potential ɑ-substituted HNM-ONHSO2CF3 HNO donors……………………………………………………………………………………56 Figure 3.1: Synthetic scheme for CF3SO2NH-OHNM HNO donor 29 (Strategy A)..…..58 Figure 3.2: Synthesis of (3-(methoxymethoxy)naphthalen-2-yl)methanol 50………..…62 Figure 3.3: Synthetic scheme for CF3SO2NH-OHNM HNO donor 29 (Strategy B)……66 viii LIST OF TABLES Table 2.1: HfCl4/NaBH4 reaction parameters and yields……………………………...47 ix ACKNOWLEDGEMENTS I would like to start by thanking my family. My mother, Mary Donnelly, strongly encouraged me at a young age to obtain and value an education. She has always been there to support me through the highs and lows of my scholastic pursuits as well as helping me maintain my focus when I would procrastinate a little too much. I would like to thank my brother, Nicholas Fejedelem, for being an emotional supporter and my friend through the years. Without him, my life would not have had that much excitement and fun. I would like to thank my father, Glenn Fejedelem, for always believing in me and for helping me develop a strong work ethic. I would also like to thank the faculty at the Department of Chemistry & Biochemistry for furthering my education and knowledge. I would like to thank Drs. Paul Sampson, Alexander Seed, and Nicola Brasch for their guidance, patience and support during my time as an undergraduate researcher and student. My time spent in their research labs has enriched my curiosity and appreciation for chemistry and science. I’d also like to thank my committee as a whole for taking time to participate in this process. I truly appreciate your willingness to participate. I’d also like to thank Erin Michael for her assistance with printing and overall support. She has been incredibly helpful by keeping everything in the department running smoothly. I’d also like to thank my fellow current and past members of the Brasch/Seed/Sampson research group. To Yang Zhou (Joe), Sonya Adas, Mohammad x Rahman, and Sean Carney—thank you for your mentoring, patience, and support. I’d also like to thank Nicholas Onuska for being an awesome lab mate and friend. xi 1 CHAPTER 1. INTRODUCTION 1.1 Introduction to HNO 1.1.1 The unique qualities of HNO HNO (nitrosyl hydride, nitroxyl, azanone, Figure 1.1) is a small inorganic molecule with unique chemical characteristics and has attracted