Molecular Multifunctionalization via Electronically Coupled Lactones

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Molecular Multifunctionalization via Electronically Coupled Lactones
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Baker, Matthew B
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Doctorate ( Ph.D.)
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University of Florida
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Chemistry
Committee Chair:
Castellano, Ronald K
Committee Members:
Merz, Kenneth Malcolm
Wagener, Kenneth B
Schanze, Kirk S
Law, Brian K

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Subjects / Keywords:
awesome -- aza-adamantanetrione -- chemistry -- lactone -- multifunctionalization -- organic -- scaffold -- supramolecular
Chemistry -- Dissertations, Academic -- UF
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Chemistry thesis, Ph.D.
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Abstract:
Though few in number, methods for the construction of designed multivalent molecular architectures from a small molecule core have allowed access to rationally designed functional molecules.  Common strategies for the construction of multivalent, multifunctional molecules are presented and reviewed for their respective strengths and weaknesses; the desymmetrization of a small molecule core is noted as an ideal strategy for the rapid synthesis of complex and multifunctionalized molecular architectures. Two C3-symmetricbenzotrilactones are found to provide a stepwise approach to multifunctionalization via kinetic deactivation.  The high reactivity and selectivity of a benzotrifuranone (BTF) derivative to sequential aminolysis has been shown to work with a broad range of amines; the high synthetic fidelity of the BTF core has been demonstrated through its high-yielding, one-pot multifunctionalization.  In addition, a benzotripyranone (BTP) derivative is shown to provide lower, but still synthetically useful, selectivities for sequential aminolysis.  The ability of these electronically coupled(via the aromatic core) lactones to provide synthetically useful selectivities exhibits the generality of the approach. The significant difference in reactivity between the starting and intermediates along the pathway are examined utilizing both experimental and theoretical results. Traditional linear free-energy relationships, spectroscopic data, and advanced quantum chemical calculations implicate an unusually large inductive deactivation (of the remaining lactones) upon a ring opening event.  The rate constants of BTF, and its partially ring opened intermediates, are quantified via stopped-flow infrared measurements; rate constants orders of magnitude indifference allow enable the synthetic selectivity.  The utility of BTF as a precursor for the synthesis of C3- and Cs-symmetric 1-aza-adamantanetrione (AAT) organogelators is also explored.  The ring opening of BTF has allowed the synthesis of previously inaccessible derivatives, the investigation of binary gelation mixtures, and the synthesis of the first desymmetrized AAT organogelators to date.
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by Matthew B Baker.
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Thesis (Ph.D.)--University of Florida, 2012.
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Adviser: Castellano, Ronald K.
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1 MOLE C ULAR MULTIFUNCTIONALIZATION VIA ELECTRONICALLY COUPLED LACTONES By MATTHEW BRANDON BAKER A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2012

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2 2012 Matthew Brandon Baker

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3 To the moon and back

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4 ACKNOWLEDGMENTS First and foremost, I would like to acknowledge the difficulty in writing this section. I would not be able to p roduce this document without the guidance and support of more people than can possibly be named. I want to begin by thanking those who have significantly impacted my development as an individual; whether you realize it or not, you will not be forgotten. I would like to thank my family for their relentless support and involvement over the years. Michael and Cheryl Baker, thank you for all of your past and continued sacrifices providing me with numerous opportunities for success, many of which you never ha d. I particularly thank my mo ther for her unwavering dedication to learning and her unwavering conviction between right and wrong. I thank my father for his strength, wisdom, and ability to find humor in nearly any situation. Even when he saw green slug s on hospital walls, his inability to understand failure has made him the best role model a young man can ask for. Andrew Baker, thank you for being a brother in every sense of the wor d. Even without knowing it, you continually humble and inspire me; I l ook forward to taking over the world with you. I cannot express my thanks enough to my advisor, Ronald Castellano. I thank him for his enthusiasm for science, his patience for folly, and his relentless pursuit of excellence. It is rare that a young, acco mplished scientist puts his students ahead of himself; in this aspect he is wise far beyond his years. Without his guidance, support, and money, I would have never truly discovered a love for science I could have never made this journey without him; I h ave to thank him f or making it harder than i t has to be and easier than it should be at the same time.

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5 Since I cannot put my dog ahead of family and advisor, at this time I would like to thank Dixie. She has grounded me throughout some of the most difficu lt years of my life, never asked for anything but food, and still acts like I am the most interesting person in the world. Given every chance possible to leave, she has remained a steadfast companion for the last ten years. I would like to thank my lab ma tes in the Castellano lab, and peers at the University of Florida. Noted thanks go to Ashton Bartley, Spencer Moreland, Jonathan Tasseroul, Alexandre Sigrist, Christopher Marth, Ben Schulze, Raghida Bou Zerdan, Pam Cohn, Mike Meese and Yan Li, all of whom I had the opportunity to work beside and learn from during this journey. I would like to thank my committee members individually: Dr. Ken Wagener for continually opening doors for me and acknowledging my strengths and weaknesses, alike; Dr. Kirk Schanz e for teaching me physical organic chemistry and the acceptable use of comic sans; Dr. Ken Merz for providing instruction and guidance for my interests in computational chemistry; Dr. Law for providing uncharacteristic time and enthusiasm for my research a long with the opportunity to test ideas.

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6 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 9 LIST OF FIGURES ................................ ................................ ................................ ........ 11 ABSTRACT ................................ ................................ ................................ ................... 17 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .... 19 Precise Multifunctionalization of Organic Scaffolds ................................ ................ 19 Orthogonal Functional Group Manipulation ................................ ...................... 21 Selective Protection/Deprotec tion ................................ ................................ .... 25 Cyclization of Linear Precursors ................................ ................................ ....... 27 Stepwise Functionalization ................................ ................................ ............... 29 Discussion ................................ ................................ ................................ ........ 33 Overview of Dissertation ................................ ................................ ......................... 34 2 SEQUENTIAL AMINOLYSIS OF BENZOTRIFURANONE ................................ ..... 36 Overview ................................ ................................ ................................ ................. 36 Benzofuran 2 ones ................................ ................................ ........................... 37 Benzopyran 2 ones ................................ ................................ .......................... 37 Transformations of Benzolact 2 ones ................................ ............................... 38 Benzotrifuranone (BTF) ................................ ................................ .......................... 39 Improved Synthesis of Benzotrifuranone ................................ .......................... 39 Aminolysis of BTF ................................ ................................ ............................ 43 Ring openings ................................ ................................ ............................ 44 One pot synthesis ................................ ................................ ...................... 47 Installation of chiral amino acids ................................ ................................ 49 Benzotripyranone (BTP) ................................ ................................ ......................... 51 S ynthesis of Benzotripyranone ................................ ................................ ......... 51 Aminolysis of Benzotripyranone ................................ ................................ ....... 52 Characterization ................................ ................................ ................................ ...... 54 NMR Spectrosocpy ................................ ................................ .......................... 54 Furanones ................................ ................................ ................................ .. 54 Pyranones ................................ ................................ ................................ .. 57 Infrared Spectroscopy ................................ ................................ ...................... 59 Crystal Structure Analysis ................................ ................................ ................ 61 Discussion ................................ ................................ ................................ .............. 66 Experimental ................................ ................................ ................................ ........... 68 Methods ................................ ................................ ................................ ............ 68

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7 General procedures ................................ ................................ ................... 68 Crysta l structure (2 3) ................................ ................................ ................ 69 Crystal structure (2 14c) ................................ ................................ ............. 69 Crystal structure 2 21 ................................ ................................ ................. 70 Crystal structure 2 22b ................................ ................................ ............... 71 Synthesis ................................ ................................ ................................ .......... 72 3 STRUCTURE/REACTIVITY RELATIONSHIPS ................................ ...................... 95 Overview ................................ ................................ ................................ ................. 95 Quantum Chemical Calculations ................................ ................................ ............. 98 Furanone Series ................................ ................................ ............................... 98 Pyranone Series ................................ ................................ ............................. 101 Analysis ................................ ................................ ................................ .......... 103 Aminolysis Kinetics of BTF ................................ ................................ ................... 104 Discussion ................................ ................................ ................................ ............ 108 Methods ................................ ................................ ................................ ................ 109 Quantum Chemical Calculations ................................ ................................ .... 109 Pseudo First Order Kinetics ................................ ................................ ............ 110 4 RAPID SYNTHESIS OF 1 AZA ADAMANTANETRIONE ORGANOGELATORS WITH CONTROL OF SYMMETRY ................................ ................................ ....... 111 Overview ................................ ................................ ................................ ............... 111 Synthesis of AATs ................................ ................................ ................................ 114 Characterization of Supramolecular Assemblies ................................ .................. 118 C 3 symmetric Derivatives ................................ ................................ ............... 118 Addressing Synthetic Limitations of AAT Chemistry ................................ ............. 125 Limitat ions to AAT cyclization ................................ ................................ ......... 125 Post cyclization AAT Transformation ................................ ............................. 126 Discussion ................................ ................................ ................................ ............ 129 Experimental ................................ ................................ ................................ ......... 131 Methods ................................ ................................ ................................ .......... 131 Representative gel formation ................................ ................................ ... 132 T gel determination ................................ ................................ ..................... 132 Representative gel freeze drying procedure ................................ ............ 132 Critical point drying (CPD) of 4 5f gel ................................ ....................... 132 Synthesis ................................ ................................ ................................ ........ 133 5 CONCLUSIONS ................................ ................................ ................................ ... 158 Sequential Aminolysis of Benz otrifuranone ................................ ........................... 158 Structure/Property Relationships ................................ ................................ .......... 160 Rapid Synthesis of 1 Aza adamantanetrione Organogelators with Control of S ymmetry ................................ ................................ ................................ .......... 161

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8 APPENDIX A SUPPLEMENTARY INFORMATION FOR CHAPTER 2 ................................ ....... 164 B SUPPLEMENTARY INFORMATION FOR CHAPTER 3 ................................ ....... 198 C SUPPORTING INFORMATION FROM CHAPTER 4 ................................ ............ 213 LIST OF REFERENCES ................................ ................................ ............................. 215 BIOGRAPHICA L SKETCH ................................ ................................ .......................... 226

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9 LIST OF TABLES Table page 2 1 Results of dehydration reaction (2 3) condition screening. .................... 42 2 2 Aminolysis of BTF. a ................................ ................................ ............................ 46 2 3 Aminolysis of BTP. a ................................ ................................ ............................ 53 3 1 Structural measurements and reactivity desc riptors from DFT calculations (furanone derivatives). a ................................ ................................ ..................... 100 3 2 Structural measurements and reactivity descriptors from DFT calculations (pyranone derivatives) a ................................ ................................ ..................... 102 3 3 Measured experimental rate constants. a ................................ .......................... 106 4 1 A representative library of C 3 symmetric AAT derivatives synthesized in two steps from BTF. ................................ ................................ ................................ 116 4 2 Solubility and gelation profiles of selected AAT derivatives. a ............................ 119 4 3 Nucleophiles used for formation of phloroglucinols unsuitable for cyclization. 125 A 1 Calculated product distributions (averages and variances from simulations) as a function of stoichiometry. ................................ ................................ .......... 196 B 1 Atomic coordinates for the optimized structure of 2 3 ................................ ....... 199 B 2 Atomic coordinates for the optimized structure of 2 14 ................................ ..... 201 B 3 Atomic coordinates for the optimized structure of 2 15 ................................ ..... 203 B 4 Summary of calculated molecular reactivity descriptors for optimized structures ................................ ................................ ................................ .......... 204 B 5 Summary of calculated reactivity descriptors (localized to each carbonyl) for optimized structures ................................ ................................ ......................... 204 B 6 Summary of calculated charges for phenolic oxygens fo r optimized structures. ................................ ................................ ................................ ......... 204 B 7 Summary of measured bond lengths for optimized structures. ......................... 204 B 8 Atomic coordinates for the op timized structure of 2 21 (no imaginary frequencies; HF = 1030.49306250) ................................ ................................ 206

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10 B 9 Atomic coordinates for the optimized structure of 2 22 (no imaginary frequencies; HF = 1126.41773020) ................................ ................................ 208 B 10 Atomic coordinates for the optimized structure of 2 22 (no imaginary frequencies; HF = 1222.33991454) ................................ ................................ 210 B 11 Summary of cal culated molecular reactivity descriptors for optimized pyranone structures ................................ ................................ .......................... 211 B 12 Summary of calculated reactivity descriptors (localized to each carbonyl) for optimized structures ................................ ................................ ......................... 211 B 13 Summary of calculated charges for phenolic oxygens for optimized structures 211 B 14 Summary of measured bond lengths for optimi zed structures .......................... 212

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11 LIST OF FIGURES Figure page 1 1 Schematic for multivalent dendrimers/particles, polymers, and small molecules ................................ ................................ ................................ ........... 19 1 2 Major strategies for the mult ifunctionalization of molecules ............................... 21 1 3 ............ 22 1 4 Weck and coworkers employ Schiff base formation and Huisgen cycloaddition in the formation of a multifunctional dendrimer ............................. 23 1 5 An orthogonally reactive peptide scaffold as prepared by Boturyn and co workers ................................ ................................ ................................ ............... 24 1 6 Model synthesis of a multifunctional cyclic peptoid from an orthogonally protected precursor ................................ ................................ ............................ 25 1 7 Synthesis of a multifunctional oligobenzoate scaffold from an orthogonally protected precursor ................................ ................................ ............................ 26 1 8 A simple and direct route to a ABCD meso patterned porphyrin involves the formation of a ABCD bilane and then subsequent scaffold cyclization ............... 27 1 9 Solid phase peptoid synthesis followed by cyclization yields a tri f unctionalized aminomethyl benzoate scaffold ................................ ................... 28 1 10 Synthetic approaches to a hypothetical trifunctional molecule directly from a symmetric molecular core ................................ ................................ ................... 30 1 11 Desymmetrization of a tetra alkyne core leads to statistical product mixtures .... 31 1 12 Cyanuric chloride allows the sequential multifunctionalization of its m olecular core via selective nucleophilic displacements ................................ ..................... 32 1 13 Sequential functionalization of cyanuric chloride with various biologically relevant substituents in a parallel, automated synthe sis provided over 40,000 unique compounds for enzyme inhibition assays ................................ ............... 33 2 1 Examples of benzolactones found in natural products, drug, and dye chemistry ................................ ................................ ................................ ............ 36 2 2 Benzofuran 2 ones are well suited to a variety of chemical transformations ...... 37 2 3 Shown are the unsaturated and saturated versions of benzopyran 2 ones ....... 38

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12 2 4 Synthesized from phloroglucinol ( 2 2 ), BTF ( 2 3 ) was developed to allow quick and reliable access to symmetric and amido phloroglucinols ( 2 4 ) .... 39 2 5 Classical approaches toward the synthesis of benzofuran 2 one (2 1 ) .............. 40 2 6 Previous synthesis of cyclization precursor tri isopropyl phloroglucinol ( 2 9 ) ..... 41 2 7 Improved synthetic route to the formation of 2 3 from common intermediate 2 7 ................................ ................................ ................................ ...................... 42 2 8 Statistical outcome of the reaction between B TF and one equivalent of an amine nucleophile assuming equal reactivity among all the lactone species. .... 43 2 9 The one pot synthesis of C S symmetric phloroglucinols from BTF in high yield and u nder 24 hours. ................................ ................................ ................... 48 2 10 Attempts at synthesis of diastereomers led to complex product mixtures prohibiting characterization at both the monolactone ( 2 15 ) and phloroglucinol ( 2 16 ) stages. ................................ ................................ .............. 49 2 11 Installation of enantiopure amino acids occurs with no racemiz ation ................. 50 2 12 Synthesis of benzotripyranone ( BTP, 2 21 ). ................................ ....................... 51 2 13 Sample HPLC analy sis of crude reaction mixture ................................ ............... 54 2 14 Sample 1 H NMR sepectra for benzotrifuranone ( 2 3 ), a benzodifuranone ( 2 14a ), a benzomonofuranone ( 2 15aa ), and a phloroglucinol ( 2 16aaa ). ........... 55 2 15 Structure 2 14a with 1 H NMR chemical shifts (in ppm), 13 C NMR chemical shifts (in ppm), and diagnostic heteronuc lear couplings are labeled. ................. 56 2 16 Structure 2 with 1 H NMR chemical shifts (in ppm), 13 C NMR chemical shifts (in ppm), and diagnostic heteronuclear couplings are labeled. ................. 57 2 17 1 H NMR resonances (in CDCl 3 ) for BTP are complicated and show overlapped aliphatic peaks (2.6 3.2 ppm) for ring opened products ................ 58 2 18 Structure 2 22b with 1 H NMR chemical shifts (in ppm), 13 C NMR chemical shifts (in ppm), and diagnostic heteronuclear couplings labeled ....................... 59 2 19 Solid state IR spectra ................................ ................................ ......................... 60 2 20 Solution phase IR spectra of the BTF series in acetonitrile solution shows stepwise decreases in C=O (lactone) stretching freq uency ................................ 60 2 21 O RTEP representations for crystal structures of benzolactone derivatives 2 3, 2 14c, 2 21, and 2 22b ................................ ................................ ................... 62

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13 2 22 X ray crystal structure of 2 3 ................................ ................................ ............... 63 2 23 Crystal packing of 2 14c ................................ ................................ ..................... 64 2 24 Crystal packing of 2 21 ................................ ................................ ....................... 65 2 25 Crystal packing of 2 22b ................................ ................................ ..................... 65 3 1 Traditional amide bond synthesis ................................ ................................ ....... 95 3 2 Experimental characterization of lactone derivatives speaks to stepwise decreases in aminolysis rate s ................................ ................................ ............. 97 3 3 DFT calculations of benzofuranone derivatives show LUMOs localized to the reactive lactones and stepwise increases in LUMO levels upon ring opening .... 98 3 4 DFT calculations of benzopyranone derivatives show LUMOs localized to the reactive lactones and stepwise increases in LUMO levels upon ring opening .. 101 3 5 Representative n heptylaminolysis plots of compounds 2 3 (top), 2 14 (middle), and 2 15 (bottom) ................................ ................................ .............. 105 4 1 Synthesis of AAT (4 2) from phloroglucinol (4 1) precursors ............................ 111 4 2 Calculated conformation and assembly of arylamido AAT architectures ...... 112 4 3 A schematic of past and present procedures for construction of amido AATs ................................ ................................ ................................ ................. 113 4 4 The co ntrol of stiochiometry, solubility, and temperature allows for control of BTF ring openings. ................................ ................................ ........................... 117 4 5 The utilization of 4 7a and 4 6a a llows for the synthesis of C s symmetric AAT molecules ................................ ................................ ................................ ......... 118 4 6 Inverted gels formed from AATs in sealed glass vials upon heating and cooling at ambient temperature ................................ ................................ ........ 120 4 7 Micrographs of dried gels ................................ ................................ ................. 122 4 7 Polarized optical microscopy (POM) images of the native gel phases ............. 123 4 8 Previous attempts at synthetic tr ansformation of the AAT core ........................ 127 4 9 Initial synthetic attempts to f orm AATs with synthetic handles ......................... 128 4 10 The first successfu l post cyclization functionalization of an AAT molecule was accomplished throug h a thiol ene coupling strategy ................................ ......... 129

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14 A 1 1 H NMR ( d 6 DMSO) of crude reaction mixture to form 2 14a from BTF at 0 C ................................ ................................ ................................ .................... 164 A 2 1 H NMR ( d 6 DMSO) of crude reaction mixture to form 2 14a from BTF at 40 C. ................................ ................................ ................................ .................... 165 A 3 Time arrayed 1 H NMR ( d 7 DMF) of re action mixture at 50 C .......................... 166 A 4 1 H NMR ( d 7 DMF) of compound 2 16aaa at 50 C ................................ ........... 166 A 5 1 H NMR ( d 7 DMF) of benzylamine ( b ) at 50 C ................................ ................ 167 A 6 1 H NMR of 2 14a in d 6 DMSO (crude) ................................ .............................. 167 A 7 1 H NMR of 2 14a in d 6 DMS O (purified) ................................ ........................... 168 A 8 13 C NMR of 2 14a in d 6 DMSO (purified) ................................ .......................... 168 A 9 1 H NMR of 2 14b in d 6 DMSO (crude) ................................ .............................. 169 A 10 1 H NMR of 2 14b in d 6 DMSO (purified) ................................ ........................... 169 A 11 13 C NMR of 2 14b in d 6 DMSO (purified) ................................ .......................... 170 A 12 1 H NMR of 2 15aa in d 6 DMSO (crude) ................................ ............................ 170 A 13 1 H NMR of 2 15aa in d 6 DMSO (purified) ................................ ......................... 171 A 14 13 C NMR of 2 15aa in d 6 DMSO (purified) ................................ ........................ 171 A 15 1 H NMR of 2 and 2 in d 6 DMSO (crude) ................................ ....... 172 A 16 1 H NMR of 2 in d 6 DMSO (purified) ................................ ........................ 172 A 17 13 C NMR of 2 in d 6 DMSO (purified) ................................ ....................... 173 A 18 1 H NMR of 2 16aaa in d 6 DMSO (crude) ................................ .......................... 173 A 19 1 H NMR of 2 16aaa in d 6 DMSO (purified) ................................ ....................... 174 A 20 13 C NMR of 2 16aaa in d 6 DMSO (purified) ................................ ...................... 175 A 21 1 H NMR of 2 16cjk in d 6 DMSO (purified) ................................ ......................... 175 A 22 13 C NMR of 2 16cjk in d 6 DMSO (purified) ................................ ....................... 176 A 23 1 H NMR of 2 16cjk in d 6 DMSO (one pot procedure, column purified) ............. 176 A 24 13 C NMR of 2 16cjk in d 6 DMSO (one pot procedure, column purified) ............ 177

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15 A 25 ESI MS of 2 16cjk (one pot procedure, column p urified) ................................ .. 178 A 26 1 H NMR of 2 22e in CDCl 3 ................................ ................................ ................ 179 A 27 13 C NMR of 2 22e in CDCl 3 ................................ ................................ .............. 180 A 28 1 H NMR of 2 23ee in CDCl 3 ................................ ................................ .............. 181 A 29 13 C NMR of 2 23ee in CDCl 3 ................................ ................................ ............ 182 A 30 1 H NMR spectrum of compound 2 14a in DMSO d 6 ................................ ......... 183 A 31 Expansion of the gHMBC spectrum of compound 2 14a in DMSO d 6 .............. 184 A 32 Expansion of the gHMBC spectrum of com pound 2 14a in DMSO d 6 .............. 185 A 33 Expansion of the gHMBC spectrum of compound 2 14a in DMSO d 6 .............. 186 A 34 1 H NMR spectrum of compoun d 2 in DMSO d 6 ................................ ...... 187 A 35 Expansion (downfield region) of 1 H NMR spectrum of compound 2 in DMSO d 6 ................................ ................................ ................................ ......... 187 A 36 Expansion (upfield region) of 1 H NMR spectrum of compound 2 in DMSO d 6 ................................ ................................ ................................ .......... 188 A 37 gHMBC spectrum of compound 2 in DMSO d 6 ................................ ....... 188 A 38 Expansion of the gHMBC spectrum of compound 2 in DMSO d 6 ........... 189 A 39 Expansion of the gHMBC spectrum of compound 2 in DMSO d 6 ........... 190 A 40 Expansion of the gHMBC spectrum of compound 2 in DMSO d 6 ........... 191 A 41 1 H NMR of 2 22b in d 6 DMSO ................................ ................................ .......... 191 A 42 Aliphatic region of 1 H NMR of 2 22b in d 6 DMSO ................................ ............. 192 A 43 Aromatic region of 1 H NMR of 2 22b in d 6 DMSO ................................ ............ 192 A 44 gHMBC spectrum of compound 2 22b in DMSO d 6 ................................ ......... 193 A 45 Aliphatic region of gHMBC spectrum of compound 2 22b in DMSO d 6 ........... 194 A 46 Plot of simulated average product distributions as a fun ction of reactant stoichiometry ................................ ................................ ................................ .... 197 B 1 Atomic numbering for optimized structure of 2 3 (BTF ) ................................ .... 198

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16 B 2 Atomic numbering for optimized structure of 2 14 (BDF) ................................ .. 200 B 3 Atomic numbering for the optimized structure of 2 15 (BMF) ........................... 202 B 4 Atomic numbering for the optimized structure of 2 21 (BTP) ............................ 205 B 5 Atomic numbering for the optimized structure of 2 22 (BDP) ........................... 207 B 6 Atomic numbering for the optimized structure of 2 23 (BMP) ........................... 209 C 1 Representative 1 H NMR of compound 4 4c in d 6 DMSO ................................ .. 213 C 2 Representative 1 H NMR of compound 4 5c in d 6 DMSO ................................ .. 213 C 3 Representative 1 H NMR of compound 4 4d in d 6 DMSO ................................ 214 C 4 Representative 1 H NMR of compound 4 5d in d 6 DMSO ................................ 214

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17 Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree o f Doctor of Philosophy MOLECULAR MULTIFUNCTIONALIZATION VIA ELECTRONICALLY COUPLED LACTONES By Matthew Brandon Baker August 2012 Chair: Ronald K. Castellano Major: Chemistry Though few in number, methods for the construction of designed multivalent molecular a rchitectures from a small molecule core have allowed access to rationally designed functional molecules. Common strategies for the construction of multivalent, multifunctional molecules are presented and reviewed for their respective strengths and weaknes ses; the desymmetrization of a small molecule core is noted as an ideal strategy for the rapid synthesis of complex and multifunctionalized molecular architectures. T wo C 3 symmetric benzotrilactones are found to provide a stepwise approach to multifunction alization via kinetic deactivation. The high reactivity and selectivity of a benzotrifuranone (BTF) derivative to sequential aminolysis has been shown to work with a broad range of amines; the high synthetic fidelity of the BTF core has been demonstrated through its high yielding, one pot multifunctionalization. In addition, a benzotripyranone (BTP) derivative is shown to provide lower, but still synthetically useful selectivities for sequential aminolysis. The ability of these electronically coupled (v ia the aromatic core) lactones to provide synthetically useful selectivities exhibits the generality of the approach.

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18 T he significant difference in reactivity between the starting and intermediates along the pathway are examined utilizing both experimental and theoretical results Traditional linear free energy relationships, spectroscopic data, and advanced qu antum chemical calculations implicate an unusually large inductive deactivation (of the remaining lactones) upon a ring opening event The rate con stants of BTF and its partially ring opened intermediates are quantified via stopped flow infrared measurements ; rate constants orders of magnitude in difference allow enable the synthetic selectivity The utility of BTF as a precursor for the synthesi s of C 3 and C s symmetric 1 aza adamantanetrione (AAT) organogelators is also explored The ring opening of BTF has allowed the synthesis of previously inaccessible derivatives, the investigation of binary gelation mixtures, and the synthesis of the first desymmetrized AAT organogelators to date.

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19 CHAPTER 1 INTRODUCTION Precise Multifunctionalization of Organic Scaffolds By c reating macromolecular assemblies from a bottom up approach, the chemist is able to rationally design, observe, and test the cumulat ive effect of multi valent i nteractions on molecular and supramolecular properties The interest in multivalent structures has spurred the study of dendrimers, polymers, biological membranes and assemblies, host guest interactions, and self assembling sm al l molecules. During these studies, t he ability to create multivalent small and macromolecules has allowed the synthesis of densely functionalized designer molecules with rationally designed properties Furthermore, t he creation of multifunctionalized mul ti valent architectures allows the incorporation of different functional domains, and their imparted properties within a singular architecture ; multifunctionalization has ushered in a new generation of hybrid materials used as diagnostic tools and designer materials. Figure 1 1. Schematic for multi valent dendrimers/particles, polymers, and small molecules (from left to right) a) homofunctionalization yields multiple copies of a functional unit, while b) multifunctionali zation yields multiple copies of different functional units to create hybrid structures Multivalent structures ( Figure 1 1a ), where in multiple copies of a desired functional unit are distributed throughout a singular molecular structure have been well st udied due to their generally straightforward synthesis S ome synthetic strategies allow for the

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20 construction of the molecular target from building blocks with the functional moieties but more commonly (poly)functionalization is performed af ter construction of the parent molecular (or polymeric) framework. The latter approach allows for the installation of a much wider variety of appendages that may not tolerate conditions used during the construction of the core During the studies of mul tivalent functional architectures, many methods for the introduction of multiple copies of different functionalities have emerged Th e multifunctionalization (heterofunctionalization) s hown in Figure 1 1b enables the marriage of dissimilar units within a single molecule ultimately a chieving the ability to create molecular scaffold s with hybrid properties The incorporation of two functional domains into a single molecule can now be accomplished by several methods The statistical multifunctionalizatio n of a molecular architecture has proven useful in the macromolecular community ; 1 4 however, new and old methods for the precise placement of molecular entities are emerging as extremely powerful tools for the creation of discrete structures for both fundamental studies and practical applications. This Chapter will ai m to review strategies towards the precise functionalization of molecular scaffolds Considerations of recent strategies in the small molecule community will be examined as well as strategies towards dendritic structures 5 due to their near discrete nature. Within these communities, four major strategies for molecular multifunctionalization have emerged ( Figure 1 2 ) : 1. Orthogonal functional group manipulation ; 2. s elective protectio n/deprotection; 3. c yclization of linear precursors; and 4. Stepwise functionalization

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21 Figure 1 2 Major strategies for the multifunctionalization of molecules a) orthogonal functional group manipulation b) protection /deprotection c) cyclization of a linear precurso r d) stepwise functionalization Orthogonal Functional Group Manipulation Shown schematically in Figure 1 2 a o rthogonal functional group manipulation involves install ation and then selective transform ation o f different functional groups within the same molecule. Although a common strategy for the synthesis of small and large molecules alike, execution of this approach with extremely high yield, high specificity, and under mild reaction conditions proves pers istently challenging.

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22 Additionally, orthogonal functional group manipulations require the installation of extraneous bonds and specific functional groups; consequently, this strategy is generally limited to medium and large molecules. Figure 1 3 able functional groups attached to scaffolds (center figure) for the multifunctionalization of molecular architectures (resultant linkers after transformation are in boxes) Since the enjoin to investiga 6 the number and utility of specific, mild, and high yielding functional group transformations has blossomed and the strategies outlined find utility in the synthetic, materials, 7 9 medical, 10 and chemical biology 11 communities With selected examples s hown in Figure 1 3 p opular

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23 transformations employed in the literature include the modification of activated functional groups, 12,13 Michael type addition, 14 thiol exchange, 15 thiol ene addition, 16 ATRP, 17 modification of aldehydes or ketones, 18,19 Huisgen cycloadditons, 7 Diels Alder additions, 20,21 and palladium cross coupling 22 among few others. reactions for the multifunctionalization of small molecules, dendrimers, 23,24 and polymers 3,25,26 has been the subject of numerous reviews. Figure 1 4 Weck and coworkers employ Schi ff base formation and Huisgen cycloaddition in the formation of a multifunctional dendrimer 23 In recent literature, Weck and co workers utilized monofunc tionalized building blocks to synthesize Newkome type dendrimers with selectively reactive functional groups on the periphery ( Figure 1 4 ) 23 In a conver gent strategy, the coupling of two differentially functionalized half dendrimers (one with an aldehyde, one with an azide) produced a dendrimer suitable for orthogonal transformations through oxime ligation 19

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24 and Huisgen cycloaddition. Strategies outlined from the above study also led to the formation of polyamide dendrons multifunctionalized with aminocyanine dyes for imaging in the near infrared region 27 Figure 1 5 An or thogonally reactive peptide scaffold as prepared by Boturyn and co workers ; amino acids are abbreviated 28 Orthogonally reactive peptide scaffolds have been prepare d by Boturyn and co workers 28 allowing the coupling of two different peptide ligands to a cyclic core. Interestingly in this work, the authors were able to show se quential Huigsen cycloaddition and oxime formation allowing the synthesis of a library of multifunctionalized architectures with a single purification step ( Figure 1 5 ) The ligation or transformation of orthogonally reactive functional groups is normally used in the synthesis of medium to large size multifunctionalized architectures. These strategies require the formation of several bonds between the two reactants and are therefore used mainly to couple functional units to the scaffolds. While this strat egy requires the installation of specific functional groups into the molecule, the high yields of the multifunctionalized targets and the generality of the approach fuel its continued use across the chemical sciences.

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25 Selective Protection/Deprotection Sel ective protection/deprotection strategies boast the benefit of excellent synthetic fidelity for the synthesis of architectures with identical functional linkages ( Figure 1 2b ). After the construction of a n orthogonally protected scaffold a single protect ing group is removed allowing transformation at specific site s within the molecule; s equential deprotection/coupling events are performed to yield the multifunctionalized target. This approach suffers from poor atom economy and multiple labor intensive sy nthetic steps being required to produce a single target. Figure 1 6. Model synthesis of a multifunctional cyclic peptoid from an orthogonally protected precursor 29 S elective ligation or selective protection/deprotec tion protocols are quite popular in the chemical biology and biochemistry communities Towards the synthesis of artificial peptoid receptors, Liskamp and coworkers prepared an orthogonally protected triazacyclophane scaffold ( Figure 1 6 ). 29 After cou pling this scaffold to a solid support, iterative deprotections and peptide couplings could produce a targe t molecule in high

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26 yield. While the solid phase synthesis simplifies the procedural and purification efforts, this strategy requires 6 steps to form the scaffold, then an additional 9 steps to yield a target compound ; in total, a labor intensive effort. Similar strategies have been used in the synthesis of other biologically relevant scaffolds including steroids, 30 glycoclusters, 31,32 bile acids, 33,34 enzyme mimics, 35 multifunctional dendrimers, 36 and ha ve found widespread utility in combinatorial chemistry. 32,37,38 Figure 1 7 Synthesis of a multifunctional oligobenzoate scaffold from an orthogonally protected precursor 39 Materials and supramolecular chemistry also exploit orthogonal protection/deprotection strategies in order to form multifunctional materials. Lehmann and coworkers synthesized an orthogonally protected p hloroglucinol 39 ( Figure 1 7 ) en route to the synthesis of a library of oligobenzoate mesogens with predictable morphologies. 40,41 The synth esis of the orthogonally protected scaffold took only three steps, while the synthesis of a multifunctional target molecule took five transformations.

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27 Nevertheless, the lack of product mixtures and easy removal of byproducts allowed the synthesis of a lab or intensive and small library of these oligobenzoates. The protection/deprotection strategy has also proven its use through the preparation of oxazole scaffolds, 42 diamine tweezers, 43 and mul tifunctional adamantane dendrimers. 44 While the use of protection/deprote ction strategies involves extra labor and poor atom economy, the step wise uncovering of traditionally reactive functional groups allows for the precise synthesis of structures based on their parent materials. Additionally, when structural fidelity is a m ust and over or under functionalization is an issue synthetically, the use of protecting groups is often the only way to multifunctional architectures. Cyclization of Linear Precursor s Another strategy seen in the small molecule community (similar to conv ergent dendrimer synthesis) is the linear synthesis of a multifunctional molecule before cyclization into a small molecule scaffold. Popular in the porphyrin community 45,46 and for peptidometic materials, 47,48 this is a niche strategy only useful for scaffolds that can be formed by cyclization of individually synthesized linear precursors Figure 1 8 A simple and dir ect route to a ABCD meso patterned porphyrin involves the formation of a ABCD bilane and then subsequent scaffold cyclization 45 A current strategy for the synthesis of ABCD porphyrin s includes the synthesis of a linear ABCD bilane before tandem template mediated cyclization and oxidation

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28 ( Figure 1 8 ). 45 Lindsey and coworkers were able to optimize reaction conditions, allowing facile synthesis of meso patterned porphyrins While this strategy requires the formatio n of one bilane for every one porphyrin target, the placeme nt of functional attachments is precise and the product is easily separated from starting material. Additionally, their one pot strategy prevents linear oligomerization through metal templating t he cyclization occurs in high yields and at high concentration, and the strategy allows the synthesis of a variety of bilanes and porphyrin s on a gram scale. Figure 1 9. Solid phase peptoid synthesis followed by cyclizat ion yields a tri functionalized aminomethyl benzoate scaffold 49 Hamilton and coworkers 49 were able to utilize solid phase peptide synthesis in the construction of oligomeric aminomethyl benzoates prior to cyclization to form scaffolds multifunctionalized with various amino acid residues ( Figure 1 9 ) Provided optimized

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29 solid phase reaction conditions, t his strategy afforded high yields throughout the synthesis, and a 15% overall yield of the multifunct ionalized scaffold over 15 steps. Resulting in a rigid core with three appendages on the same face of the central cycle this general methodology allows for the synthesis of libraries of homo or multifunctionalized architectures towards the investigation of binding to protein surfaces. While the synthesis of a linear oligomer followed by cyclization is a niche strategy, it has proven useful for the synthesis of specific desymmetrized macrocyclic structures; however, t his strategy is generally plagued by a lengthy oligomer synthesis prior to a final cyclization in a carefully optimized final step S olid phase synthesis of the oligomeric precursor greatly simplifies th e approach and makes it viable for a number of pepti d om im etic scaffolds yet the number of accessible scaffolds remains extremely limited Stepwise Functionalization T he aforementioned strategies to multifunctionalized architectures require the differentiation of a molecule or scaffold prior to final functionalization ( i.e orthogonal transfo rmations, protection/deprotection) or the formation of the core ( i.e cyc lization of a linear precursor) A conceptually appealing synthetic approach to discrete multifunctional architectures begins with a highly symmetric, shape persistent scaffold beari ng three or more identical reactive sites serving as a starting point for divergent synthesis ( Figure 1 2d ) 41,50 55 Illustr ated in the context of a hypothetical trifunctional target ( Figure 1 10 ), classic stochastic functionalization ( Figure 1 10a ) an approach wherein there is little to no kinetic differentiation between the reactive sites of the starting material and partia lly reacted intermediates is generally plagued by complex reaction mixtures, poor atom economy, difficult separations, and low overall

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30 yields. 41,56,57 Occasionally, a situation presents itself where each functionalization decreases the reactivity of the remaining functional groups, allowing for higher than statistical yields ( Figure 1 10b ) and straightforward multifunctionalization. 56,58 60 Figure 1 10 Synthetic approaches to a hypothetical trifunctional molecule directly from a symmetric molecular core. a) stepwise, stochastic functionalization where there is little differen ce between the reactivity of starting materials and products b) stepwise, sequential transformations where each transformation diminishes the reactivity of remaining the functional groups While stochastic functionalization of a symmetric small molecule is not the most elegant method, when the mixture of products is easily separable and the starting materials are synthetically accessible it is often the simplest and most direct method. T he reaction outcomes are rarely purely stochastic; however, without s ignificant differentiation of reactivity the functionalization yields complex product mixtures. 57,61 Dur ing the synthesis of desymmetrized polyphenylene dendrimers ( Figure 1 11 ) M llen and coworkers 61 encountered product mixtures, but facile separation of the desire d monofunctionalized derivative made this a feasible strategy. Here the first two functiona lizations proceeded statistically, while subsequent functionalizations were

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31 minimized, presumab ly due to steric interference. Such stepwise desymmetrization of a core has allowed for the synthesis of a variety of polyphenylene dendrimers with interesting amphiphilic properties and tailorable functions. 57 Figure 1 11. Desymmetrization of a te tra alkyne core leads to statistical product mixtures 61 A more desirable situation exists ( Figure 1 10b ) when there is useful kinetic differentiation between competing reactive sites and a gradual decrease in reactivity upon each transformation; this sce nario lends itself to the stepwise, rapid, and efficient build up of complex molecular structure. Symmetrical molecular scaffolds amenable to synthetically useful non stochastic functionalization via three or more symmetry equivalent reactive sites are ex ceedingly rare; discovered in the 1800s, cyanuric chloride (2,4,6 trichloro 1,3,5 triazine) remains one of the only examples. 52,58,62,63

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32 Delineated by Moffatt and coworkers 58 cyanuric chloride can be sequentially functionalized with control of temperature (first substitution occurs at 0 C, the second at room temperature, and the third above 60 C with primary amine nucleophile s ). Furthermore, i ts chlorine atoms can be substituted by up to three dif ferent nucleophiles in a one pot 64,65 procedure, and this unique reactivity profile has facilitated access to multif unctional systems spanning the biological, supramolecular, synthetic, and materials sciences. 52 54,62,66,67 Figure 1 12. Cyanuric chloride allows the sequen tial multifunctionalization of its molecular core via selective nucleophilic displacements 58 Harnessing the power of cyanuric chlorides sequential transformations, Gustafson and coworkers 68 coupled peptides, aminimides, carbohydrates, and ketoamides in a one pot, automated parallel solution phase synthesis ( Figure 1 13 ) This approach allowed the synthesis of over 40,000 derivatives on a 50 mol scale, with an average crude purity of 85% E xecuting the synthetic procedure in 96 well format allowed for direct analysis via high throughput scree ning and provided 390 positive hits for protease inhibition. This study clearly shows the synthetic power of a specific, high yielding, and sequent ial functionalization of a small molecule core.

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33 Figure 1 13. Sequential functionalization of cyanuric chloride with various biologically relevant substituents in a parallel, automated synthesis provided over 40,000 uniqu e compounds for enzyme inhibition assays Discussion Allowing the synthesis of discrete molecules with multiple functional motifs, multifunctionalization strategies have enabled the synthesis of a multitude of hybrid and multifunctional structures. While molecular multifunctionalization presents unique synthetic challenges, common strategies including orthogonal functional group transformation, protection/deprotection strategies, cyclization of linear precursors, and stepwise functionalization have all dem onstrated the ability to attach different functional units within a single molecule. While all strategies exhibit proven utility, each has its limitations: orthogonal transformations require the installation of extraneous bonds and specific functional gro ups; protection/deprotection strategies are plagued by labor intensive syntheses and poor atom economy; cyclization of a linear precursor requires linear synthetic procedures and careful optimization of cyclization conditions; stepwise

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34 functionalization of ten combats stochastic functionalization, poor yields, and tedious separations. As a rare, but particularly powerful solution, the high yielding, stepwise multifunctionalizatio n strategy. cyanuric chloride exhibits stepwise and selective substitutions, with a variety of nucleophiles, under synthetically useful conditions. The versatility shown by cyanuric chloride has led to its us e as the de facto choice in construction of dissymmetric, multifunctionalized molecules. The multifunctionalization of cyanuric chloride is not perfect; cyanuric chloride is a potent lachrymator, is unstable to moisture, generates a molar equivalent of HC l with each transformation, generally requires the co addition of a base, and requires temperatures (greater than 60 C for the third substitution) unsuitable for sensitive functional groups. Consequently, the search for new general multifunctionalization p rotocols particularly stepwise desymmetrization procedures is needed. Multifunctionalization methodologies have broadly impacted the chemical sciences, allowing the creation of hybrid molecular structures. Development of novel scaffolds, methods, and a pplications promise to provide access to designer molecules in the future. Overview of Dissertation This document reflects both published 59,69 72 and unpublished observations during the investigation of symmetric yet electronically coupled (via an aromatic core), tri lactone scaffolds to provide synthetically useful differences in aminolysis rate. The ability to show large differences in reaction rates within a symmetric structure can lead to the high control of reactivity patterns towards multivalent and multifunctionalized molecular architectures.

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35 Chapter 2 will present the s ynthesis (previous ly reported) 71 of symmetric five and six membered ring benzolactones and their reactivity towards alkyl amine nuc leophiles. General synthetic observations will be presented, along with structural assignments and crystal structure analysis. Chapter 3 will attempt to analyze and rationalize the differences in aminolysis rates between the structures studied. Insight i nto the ability and limitations of current methods to predict this reactivity will be discussed as well as the generality of the electronically coupled lactone strategy. Chapter 4 will demonstrate the ability of electronically coupled lactone scaffolds to provide not only the efficient synthesis of a library of functional compounds, but also the control over substitution pattern towards hybrid structures. Chapter 5 will provide an overview of the project in its entirety. Future directions for the project will be briefly discussed

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36 CHAPTER 2 SEQUENTIAL AMINOLYSIS OF BENZOTRIFURANONE Overview Impossible to review in their entirety, benzolactones have known a rich chemical heritage including polymeric additives, natural products, antioxidants, and useful sy nthetic handles The construction of l arge macrocyclic benzolactones have attracted much synthetic attention recently due to the potent cytotoxicicity (ng/mL) in fibroblast tumor models and mitochondrial ATPase inhibition by benzolactone natural products 73 76 and related derivatives. 77 While these benzo 1 lactones are currently of much chemical significance, this study will focus on the construction and subsequent transformations of benzo 2 lactones. Figure 2 1 Examples of benzolactones found in natural products drug, and dye chemistry. Shown are benzo 1 lactones Oximidine II and Zearalenone, benzo 2 furanones Isoauraone and Fumimycin, and benzo 2 pyranones Warfarin and Calomelanol A 1 Portions of this Chapter are reprinted with permission from Baker, M. B.; Ghiviriga, I.; Castellano, R. K. Ch emical Science 2012 3 1095 1099.

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37 Benz o furan 2 ones A particularly interesting class of benzolactones are the benzofuran 2 ones ( 2 1 ) five membered ring lactones normally synthesized from phenolic precursors. The benzofuran 2 ones are common to natural products 78,79 ( Figure 2 1 ), pigment chemistry, 80 polymer stabilizers, 81 and synthetic building blocks. 82 The furanones around the aromatic ring allow for a rich chemical profile including ring opening, enolization, substitution, and radical stabilization among others ( Figure 2 2 ) T his multitude of potential transformations has led to wide use of benzofuranones in materials chemistry, synthetic chemistry, and supramolecular chemistry. Figure 2 2 Benzofuran 2 ones are well suited to a variety of chemical transformations including a) keto enol tautomerization b) nucleophilic ring opening c) radical trapping d) O alkylation or acylation e) delocalized anion formation and f) C alkylation or acylation Benzopyran 2 ones With a 6 membered ring, the ben zopyran 2 ones ( 2 2a ) are simple ring expanded analogs of 2 1 While the unsaturated coumarin ( Figure 2 3 ) is the a popular unit in medicinal chemistry (warfarin anticoagulant class Figure 2 1 folk medicine Dicoumarol

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38 from moldy clover Figure 2 3 ), the u nsaturated 3,4 dihydrocoumarin ( Figure 2 3 ) has garnered interest du e to various biological activities 83 85 including aldose reductase inhibition 86 HIV 1 reverse transcriptase inhibition, 87 and is found in various natural product architectures ( Figure 2 1 ) 88 Additionally, this dihydro umarin mo tif has found application as a food additive, 89 and been copolymerized with epoxides. 90 Figure 2 3 Shown are the unsaturated and saturated versions of benzopy ra n 2 ones. Naturally occurring Dicoumarol has a long history in folk medicine Transformations of Benzolact 2 ones As seen in Figure 2 2 b be n zofuran 2 ones are particularly suited for ring opening with a suitable nucleophile providing the corresponding substituted phenol 2 1b Though multifunctional benzofuran 2 ones have not bee n discussed before in the literature, the synthesis of a C 3h symmetric benzotrilactone could provide access to a wide range of multifunctional chemical structures. During the exploration of phloroglucinol as a substrate for the synthesis of novel low mo lecular weight organogelators (LMWOGs see Chapter 4 ), 91 benzofuranones were isolated en route to deprotection of phloroglucinol precursors (Andy Lampkins, dissertation). Quickly envisioned was the possibility to form a symm etrical benzotrifuranone ( BTF, 2 3 ) with great synthetic potential. Derived from phloroglucinol, BTF is a C 3 h symmetric version of a simple 5 membered ring benzolactone Acting as a

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39 masked phloroglucinol, BTF was originally envisioned ( Figure 2 4 2 3 ) and shown, to allow facile access to a variety of symmetric amido phloroglucinols ( 2 4 ). Figure 2 4 Synthesized from phloroglucinol ( 2 2 ), BTF ( 2 3 ) was developed to allow quick and reliable access to symmetric and amido phloroglucinols ( 2 4 ) During the exploration of BTF, it was postulated that the synthesis of a ring expanded analog benzotripyaranone ( BTP 2 21 ) should provide similar ring opening reactivity, yet allow access to more flexible amido phlorogluc inols. While both BTF and BTP are readily suited to form symmetric phloroglucinols with peripheral amides, their ability to form derivatives of lower symmetry was also questioned. With electronically coupled units and varying degrees of ring strain, it wa s postulated that these symmetric trilactones could give rise to non stochastic sequential functionalization providing access to a wide range of chemical structures. This Chapter will discuss the synthetic chemistry and procedures for the sequential rin g opening of both BTF and BTP. Benzotrifuranone (BTF) Improved Synthesis of Benzotrifuranone Shown in Figure 2 5 t he installation of lactone subunits has become routine chemistry usually requiring acidic and/or dehydrative conditions. With the demand for mu l ti gram quantities, several high yielding strategies are presented toward the synthesis of 2 1 benzofuran 2 one; 92 therefore, it was envisioned that similar acid

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40 catalyzed or dehydrative intramolecular acylation strategies could be employed towards construction of the BTF tetracyclic structure. Of note here is the potential for multiple products when synthesizing BTF via an intramolecular cyclization strategy ( Figure 2 5 b ) ; even with quantitative conversions, the regioselectivity of the cycl ization will compete to form symmetric products, 2 3 and 2 5 among others The initial synthetic plan involved introduction of esters on the periphery of the phloroglucinol core, forming BTF via an intramolecular acid catalyzed trans esterification. As previously reported, 91,93 tri methoxy tri isopropyl ester 2 8 could be accessed from 1,3,5 trimethoxybenzene in four moder ate to high yielding steps ( Figure 2 6 ). Subsequent studies to optimize the cyclization towards the formation of 2 3 yielded complex product mixtures ( Figure 2 5 b ) leading to intensive separations for isolation of BTF and preventing this reaction pathwa y from utility on a larger scale. Figure 2 5 a) Classical approaches toward the synthesis of benzofuran 2 one ( 2 1 ) b) extended to the synthesis of BTF. Cyclization en route to BTF provides the potential for multiple product mixtures

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41 Figure 2 6 a) Previous synthesis of cyclization precursor tri isopropyl phloroglucinol ( 2 9 ) b) S ubsequent trans esterification is plagued by moderate yields and extensive purification to yield 2 3 (y ields determined by NMR of crude reaction mixture) Noticing that the current methodology involved the transesterification of the compound under reversible conditions, an alternative route to BTF was envisioned involving the irreversible dehydration of a t riacid ( 2 13 ) available via hydrolysis of 2 9 ( Figure 2 7 ). First realized as a potential route through dehydration effected by P 2 O 5 in refluxing toluene, optimization studies identified mild heating in polyphosphoric acid (PPA) as the cleanest and highes t yielding method for the synthesis of 2 3 from 2 13 ( Table 2 1 ). Results with the stronger dehydrating agents (P 2 O 5 POCl 3 ) indicated degradation of the starting material/products while molecular sieves (4 ) or heating was not sufficient to effect conver sion. Interestingly, when cyclization was effected under reversible conditions (toluene/acid) the C 2 symmetric 2 11acid was isolated as the major product; from this result and others ( vide infra ) it is hypothesized that the symmetric dilactone ( 2 11 ) is m ore thermodynamically stable than the trilactone ( 2 3 ). One of the major successes for this dehydration p athway was the simple purificati on of the desired compound. Mentioned above, unavoidable is the formation of a

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42 symmetrical dilactone derivative; howe ver, due to the large difference in DCM solubility between the two, selective extractions of 2 4 from an aqueous layer with DCM yields reagent grade material without further purification. Figure 2 7 Improved synthetic ro ute to the formation of 2 3 from common intermediate 2 7 Table 2 1. Results of dehydration reaction ( 2 13 2 3 ) condition screening Dehydrating agent Conditions Yield of 2 3 POCl 3 Reflux, 1 hour < 10% POCl 3 Reflux 4 hours < 10% PPA 110 C, 4 hours 20% PPA 130 C, overnight 40% PPA 110 C, overnight 50% TFA Toluene, reflux, overnight No product ( 2 11 ac id obtained) 4 molecular sieves 120 C trace P 2 O 5 Toluene, reflux, 5 h 11% Oven 160 C Neat, 24 h trace A shortened synthesis of BTF was recently realized ( Figure 2 7 ) as 2 13 can be directly prepared from intermediate 2 7 via simultaneous demethyla tion and hydrolysis in concentrated hydrobromic acid at reflux 94 following a basic work up. These two improve ments in the preparation of BTF have led to increased overall yields (from 1,3,5 trimethoxybenzene) from 4 % to 11 %, while greatly simplifying the purification and time of synthesis. Despite some of the moderate yields and difficulty in manipulation of

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43 hig hly polar intermediates, BTF can now be reliably prepared on a multi gram scale for further study. This improved synthetic procedure has been published, along with the conversion of BTF to benzofurans via O acylation ( Figure 2 2d ) 69,72 Aminolysis of BTF Three products are conceivable upon the aminolys is of BTF ( Figure 2 8 ), in addition to unreacted starting material ( 2 3 ): dilactone 2 14 monolactone 2 15 and phloroglucinol 2 16 In the absence of kinetic modelling, statistical simulations can accurately determine the expected product ratios given th e stoichiometry of the reactants. Using mathematical software ( see Appendix A for details ), the expected product distribution when adding 1.0 equiv alent of an amine to BTF ( 2 3 ) is 35.8% of 2 3 36.8% of 2 14 19.0% of 2 15 and 8.4% of 2 16 ; under purely statistical control, addition of 1.0 equiv of amine to BTF would provide the highest yield of 2 14 36.8%. Looking a bit further, adding 2.0 equiv of amine to BTF would provide 9.4% of 2 3 22.7% of 2 14 26.5% of 2 15 and 41.5% of 2 16 Under purely s tatistical control, addition of 1.7 equiv of amine to BTF would provide the highest maximum theoretical yield of 2 15 a mere 27.4%. Figure 2 8 Statistical outcome of the reaction between BTF and one equivalent of an amine nucleophile assuming equal reactivity among all the lactone species

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44 To clarify numbering conventions, compounds in this section will be numbered based on their core structure ( Figure 2 8 ) followed by a letter denoting the specific nuclophile(s) use d in amide bond formation. In the example above, 2 14a is compound 2 14 appended with one amine labelled a ( a corresponds to he p t ylamine based on numbering in Table 2 2 ). Multiple letters following a structure number correspond to the number and order of nucleophilic addition ( e.g. compound 2 16cgh and 2 16chg are the same compound, yet the nucleophiles g and h were added in a different order). Monitoring the reactions by TLC and 1 H NMR is straightforward (see below for detailed discussion) By 1 H NMR, the chemically unique phenolic OH resonances arising from 2 14 2 15 and 2 16 are far downfield (9 11.5 ppm) in DMSO d 6 resolved, and easily integrated. In addition the chemically unique alpha methylene protons appear in the 4.1 3.5 ppm region, are resolved, and easily integrated in the absence of interference with H 2 O at 3.33 ppm. By TLC (silica gel), the products are easily resolved in acetone/DCM mixtures and ninhydrin staining show s distinctive colo rs depending on the number of remaining lacton es. Desired compounds were isolated via column chromatography; in all cases this led to a decrease in isolated yield due to the instability of the furanone rings to silica gel. This instability is thought to be due to the methy lenes (easily enolizable). 69 Ring openings Entry 1 reveals the highly non statistical product distribution that results upon addition of 1.0 equiv of heptylamine ( a ) to BTF ( 2 3 in DMF at 41 C); dilactone 2 3 a is formed as > 96% of the crude product mixture in a reaction that is complete (TLC analysis) in ~ 15 minutes ( Table 2 2 ) The excellent yield of 2 3 a is diminished only modestly as the reaction temperature is raised to 0 C ( 92% ) and then 40 C ( 88% see

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45 Appendix A for details ). The monoaminolysis selectivity and rate remain high for (arylmethyl)amines b and c (entries 4 and 5 ), cyclic secondary amine s e f and g (entr ies 7 9 ), and even moderately hindered branched amine h (entry 10 reaction takes 3 hours with sterically hindered amines ). The fidelity is not reduced in the presence of weaker alcoholic nucleophiles ( d ; entry 6 ), presumably including some amount of water (in DMF). C hiral amino acids (ev en when introduced as their HCl salts with co added base) proceed selectively and with retention of configuration (entry11 see below for detailed information ) Addition of 2.0 equiv of heptylamine to BTF (entry 2 ) shows excellent conversion (> 92%) to mo nolactone 2 15 aa within three hours at 41 C; addition instead of a slight excess (3.4 equiv) of heptylamine to BTF provides phloroglucinol 2 16 aaa as the exclusive product upon warming to room temperature overnight (entry 3 ). Verified experimentally by 1 H NMR, the aminolysis reactions (under the reaction conditions shown) are irreversible ( see Appendix A for further detail ). The conclusion from these entries is that the aminolysis reactions of 2 3 2 14 and 2 15 (using relatively unhindered aliphatic a mines) occur at sufficiently different rates to afford useful selectivities on useful timescales (minutes to half a day) under mild conditions. Finally, while the excellent selectivity of the BTF system puts a premium on stoichiometric precision and react ant purity, reactions have used commercially received amines without additional purification, been performed on ~ 50 mg scale, and are tolerable to air and moisture.

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46 Table 2 2 Aminolysis of BTF a Entry SM (2 ) RNH 2 Eq uiv RNH 2 % 2 3 b Yield 2 14 b (%) Yield 2 15 b (%) Yield 2 16 b (%) 1 3 a 1.0 < 1 14 a 96 (75) c < 3 ND d 2 3 a 2.0 ND trace 15 aa 92 (72) c < 8 3 3 a 3.4 ND ND ND 16 aaa 99 (92) 4 3 b 1.0 < 8 14 b 92 (74) c ND ND 5 3 c 1.0 ND 14 c 95 (60) c < 5 ND 6 3 d 1.0 < 3 14 d 91 d (23) c < 6 ND 7 3 e 1.0 < 2 14 e 98 (78) c ND ND 8 3 f 1.0 ND 14 f 96 (77) c < 4 ND 9 3 g 1.0 <2 14 g 98 (78) c ND ND 10 3 h 1.0 < 3 14 h 91 (79) c < 6 ND 11 3 i 1.0 < 1 14 i 9 6 ( 76) c < 3 ND 1 2 14 a d 1.0 ND 15 ad 96 e < 4 13 14 c j 1.0 < 2 15 c j 95 f (76) c,f < 2 14 15 c j f k 1.3 trace 16 c jk 98 (96) a General reaction conditions are shown in the scheme For synthetic procedures see the Synthesis sec t ion b Yields have been determined by 1 H NMR analysis and are reported as percent ages of the crude mixture (mass recovery for the crude mixture was > 97% unless noted otherwise; ND = not detected). Isolated yields (after column chromatography) are shown in parentheses. c Sensitivity of the lactones to silica gel reduced the isolated y ield in most cases by 15 20%. d Only 78% of the crude theoretical mass was recovered; some material was lost during workup e 45:55 mixture of two regioisomers ( 2 15 ad' and 2 15 ad'' respectively) that could be partially separated. f 62:38 mixture of two regioisomers ( 2 15 cg' / 2 15 cg'' ) that could not be separated or assigned.

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47 Desymmetrization of BTF gives compound 2 14 featuring two chemically distinct lactones that should undergo aminolysis (in the presence of a common amine) at different rates. Trea tment of 2 14 a with 1.0 equiv alent of a differentiating amine (e.g., ethanolamine d entry 1 2 ) helps to clarify the situation Partially resolved via silca gel chromatography, regioisomers 2 15 ad' and 2 15 ad'' are p roduced in a combined 96% yield as a 45: 55 mixture, respectively (structural assignment of 2 performed with 1 H 13 C HMQC, see below for details) A similar regioisomeric ratio (~ 1.5 :1, inseparable and unassignable) is found upon treatment of 2 14 c with j (entry 13 ); these results reflect the expectedly similar reactivity of the two lactones of 2 14 and are predicted from structure reactivity analysis ( vide infra ). Important to note, sets of regioisomers would produce the same product upon addition of a final amine nucleophile ( e.g. 2 16cj k entry 14) One pot synthesis The data discussed above establishes the feasibility of a one pot, sequential aminolysis protocol involving BTF ( 2 3 ) and three different amines to produce a differentially substituted phloroglucinol ( Figure 2 9 ). Amines w 9,95,96 functi onality c (a furan), j (an alkene), and k (an alkyne) were selected to illustrate the concept. Access to the target, 2 16 c jk could first be completed in a stepwise fashion through the reaction of 2 15 c j (as a mixture of both regioisomers) with propar gylamine (entry 1 4 ). Taken together with entries 5 and 1 3 the essentially quantitative final aminolysis step predicts an overall yield of 88% for 2 16 c jk if prepared in a one pot procedure from 2 3

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48 Figure 2 9 The on e pot synthesis of C S symmetric phloroglucinols from BTF in high yield and under 24 hours Execution of the one pot approach ( Figure 2 9 ), involving the sequential addition of each different amine (with reaction times of 45 min, 6 h, and 16 h), gratifyingl y produces C s symmetric 2 16 c jk as the major product in ~ 85% isolated yield with suitable purity as determined by elemental analysis and 1 H NMR spectroscopy ( see Appendix A for further information) Two additional examples show that neither changing the order of amine addition (e.g., 2 14 c 2 15 c k 2 16 c kj ) nor the nature of the amines (e.g., through the synthesis of 2 16 abd ) compromises the one pot reaction outcome. It is reasonable to assume that a conventional stochastic synthesis ( vide supra ) of targets like 2 16cjk would be met with a d ismal overall yield and require significantly more steps, purification, resources, and time.

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49 Installation of chiral amino acids The ability to synthesize chiral amido phloroglucinols from BTF has already been demonstrated; 97 however, the ability to install chiral amino acids or peptides, without racemization, has not been directly investigated. Shown in Table 2 1 ( entry i), L phenylalanine methyl ester can reliably form a dilactone derivative ( 2 14i ) in high yield when added as an HCl salt with a slight excess of a mild base (di isopropylethyl amine, DIPEA). Figure 2 10 Attempts at synthesis of diastereomers led to complex product mixtures prohibiting characterization at both the monolactone ( 2 15 ) and phloroglucinol ( 2 16 ) stages In order to determine the enantiopurity of the ring opened products, the synthesis of diastereomeric sets of compounds could be accomplished through the installation of a second amino acid in its enantiopure and racemic forms. Shown in Figure 2 10 the installation of a second L phenylalanine methylester was accomplished in good yield,

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50 yet the correspon ding synthesis of the diastereomeric mixture (L; DL) was complicated by the regioisomeric mixture seen in 2 and 2 and not fully characterizable. Unfortunately, attempts to open the final lactone ring with achiral benzyl amine led to complex reacti on mixtures, including the postulated aminolysis of methyl esters within the structures. Figure 2 11 Installation of enantiopure amino acids occurs with no racemization. The presence of a small peak in the HPLC trace of 2 14i can be attributed to the enantiopurity of the starting material Fortunately, the synthesis of both a chiral dilactone ( 2 14i L enantiomer) and a racemic dilactone ( 2 14l D,L mixture) from phenylalanine methyl esters allowed for the enantiomeric excess to be determined via chira l HPLC. Shown in Figure 2 11 there appears to be no epimerization under the reaction conditions employed ( 41 C, DMF, DIPEA, HCl salt of phenylalanine methyl ester, 6 hours). This result provides

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51 encouragement for this methodology to allow the installat ion of amino acids and peptides around the core without racemization. Benzotripyranone (BTP) Synthesis of Benzotripyranone Previously published, 71 the synthesis of benzotripyranone (BTP 2 21 3,4,7,8,11,12 h exahydro 2 H dipyrano[2,3 f:2',3' h]chromene 2,6,10 trione Figure 2 1 2 ) occurs through similar strategies to BTF, but the final step is an acid cataly z ed trans esterification. Sta rting from a protected tri bromomethyl phloroglucinol ( 2 17 ), alkylation with diethyl malonate affords 2 18 in good yield. Saponification followed by decarboxylation and esterification yields tri isopropyl ester 2 19 ; careful demet h ylation Figure 2 1 2 Synthesis of benzotripyranone ( BTP 2 21 )

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52 with BBr 3 then affords tri isopropyl ester phloroglucinol 2 20 Cyclization is effected by acid catalyzed trans esterification affording BTP ( 2 21 ) in quantitative yield. Noted in the previous section ( Figure 2 5 ), cyclization can form a mixture of products due to incomplete cyclization or a lack of regioselectivity. Interestingly, the formation of 2 21 is performed under reversible conditions, yet all material is converted to the desired product; while the synthesis of BTF ( vide supra ) struggled with the formation of other stable species, BTP is a stable thermodynamic sink for the reaction and poor atom economy, but proceeds through soluble derivatives that are easily isolated during the synthesis. Aminolysis of Benzotripyranone As a trifunctional molecule, BTP faces the same predicted statistical outcome as BTF ( Figure 2 8 ). Monitoring the am inolysis of BTP is considerably more difficult than BTF; while products can be separated and visualized via TLC (KMnO 4 stain), the 1 H NMR is complicated and unsuitable for quantifying reaction outcomes. Consequently, HPLC analysis was employed to quantify the crude reaction mixtures upon ring opening Benzotripyranone ( 2 21 ) was also shown to form dilactone ( 2 22 ) as the major product when treated with one equivalent of an appropriate amine, at low temperature ( 41 C) in DMF. Shown in Table 2 3 the dilac tone ( 2 22 ) was formed in suitable yields (65 80%) when treated with alkyl ( a ), methylbenzyl ( b ), secondary (cyclic e acyclic m ) amines as well as a protected amino acid ( i ). The aminolysis of BTP occurs more slowly than BTF; aminolysis with good nucle ophiles ( e.g. pyrrolidine) was completed

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53 within 15 minutes (by TLC analysis), while hindered nucleophiles ( e. g. diethyl amine) took overnight to complete. Treating BTP ( 2 21 ) with 2.0 equivalents of an amine yields the corresponding monolactone 2 23 Usi ng similar conditions ( 41 C, DMF) and longer reaction times, 2 23bb and 2 23ee could be produced in 61% and 90% isolated yields, respectively. The ring openings could be monitored via TLC and took overnight (slowly warming to RT) to show full conve rsion. The selectivities found mirror those for the first ring opening; as is the case for BTF, ring opening fidelity remains consistent. Table 2 3. Aminolysis of BTP a Entry RNH 2 2 21 b (%) Yield 2 22 b (%) Yield 2 23 b (%) 1 a 22a (70) 2 b 15 22b 70 (65) 15 3 e 5 22e 90, (86) 5 4 i 22i (76) 5 m 22m (80) a General reaction conditions are shown in the scheme. For synthetic procedures, see the Synthesis section. b Yields have been determined by HPLC analysis and are reported as percentages of crude mixture (mass recovery for the crude mixture was > 97%. Isolated yields are shown in parentheses. Entries 1, 4, and 5 yielded a mixture of products, but were not quantified via HPLC. As an example, the analysis of th e addition of one equiv. of benzyl amine to BTP ( entry 2, Figure 2 1 3 ) via HPLC showed lower selectivity than BTF; forming 2 22b as 70% of the crude mixture and 2 22e as 90% of the crude mixture Even so, selectivities are still well above a stochasticall y controlled process. Gratifyingly, the isolated yields (65% for 2 22b and 86% for 2 22e ) show no significant losses during the purification

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54 procedure. The increased stability of these products, as compared to BTF, is thought to be due to the lower acidi ty (higher stability) of protons on the six membered pyranone ring. Figure 2 1 3 Sample HPLC analysis of crude reaction mixture. Example is from entry 2 in Table 2 3 a) trace of pure 2 21 ; b) trace of pure 2 22b ; c) trace of pure 2 23bb ; d) trace of c rude reaction mixture Characterization NMR Spectrosocpy Furanones With its highly symmetric structure, the 1 H NMR of BTF ( 2 3 ) consists of a single peak at 4.03 ppm (in d 6 DMSO, Figure 2 1 4 ). Upon ring opening with amine nucleophiles, the compound is des ymmetrized: Dilactone ( 2 14a ) shows the appearance of a OH singlet (10.64 ppm) and a NH triplet (8.21 ppm, J = 5.3 Hz) downfield, while the methylenes are now split into three singlets with the two most downfield belonging to the remaining lactone ring s (3.92, 3.78, 3.46 ppm); m onolactone ( 2 14aa ) shows t wo separate OH singlets (11.13, 10.03 ppm) and NH triplets (8.38 ppm, J = 5.3 Hz ; 8.15 ppm, J = 5.4

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55 Hz) with upfield shi f ts in the methylene protons (3.70, 3.48, 3.43 ppm) Upon formation of the p hloroglucinol, a symmetric structure satisfingly shows one OH singlet (10.72 ppm), one NH triplet (8.46 ppm, J = 5.4 Hz) and a single methylene signal (3.48 ppm). During formation of multifunctionalized, nonsymmetric structures the general trends rema in the same, but the lack of symmetry is seen in the spectra. Figure 2 14 shows signature regions of the proton spectra, but more examples of symmetric and nonsymmetric 1 H NMR spectra can be seen in Appendix A. Figure 2 1 4 Sample 1 H NMR sepectra for b enzotrifuranone ( 2 3 ), a benzodifuranone ( 2 14a ), a benzomonofuranone ( 2 15aa ), and a phloroglucinol ( 2 16aaa ). Symmetry is broken and then restored among the OH, NH, and methylene protons These spectroscopic trends are also reproduced in the 13 C NMR spectra ( d 6 DMSO) of 2 3 2 14 2 15 and 2 16 A single carbonyl 13 C peak (C=O lactone) at 173.4 ppm in 2 3 is converted into two downfield signals at 174.2 and 173.9 ppm (C=O

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56 lactone) and an upfield signal at 170.1 ppm (C=O amide) in the structure of 2 14a The spectr um of compound 2 15aa shows one upfield signal at 174.6 ppm (C=O ester) and two downfield signals at 172.3 and 171.5 ppm (C=O amide). In order to conclusiv ely assign the chemical shifts seen in the 1 H and 13 C NMR sepctra with the structure of 2 14a gHMBC 2D NMR experiments were carried out in d 6 DMSO (see Appendix for spectra). The chemical shift assignments for compound 2 14a are based on the 1 H 13 C one b ond and long range couplings observed in the gHMBC spectrum (crucial couplings are outlined in Figure 2 1 5 ) Figure 2 1 5 Structure 2 14 a with 1 H NMR chemical shifts (in ppm), 13 C NMR chemical shifts (in ppm), and diagno stic heteronuclear couplings are labeled The regioisomers of 2 15ad were partially separable by column chromatography and structure elucidation w as made based on the 1 H 13 C one bond and long range couplings observed in the gHMBC spectrum ( in d 6 DMSO, Figu re 2 1 6 see Appendix A for further detail ) The regiochemistry of compound 2 15 is revealed by the OH protons at 10.02 and 11.09 ppm, which each couple with the carbon two bonds away. Compound 2 was identified as the minor regioisomer in the mi xture, establishing a 45:55 ratio between 2 and 2 15ad respectively.

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57 Figure 2 1 6 Structure 2 15 with 1 H NMR chemical shifts (in ppm), 13 C NMR chemical shifts (in ppm), and diagnostic heteronuclear couplings are labeled Pyranones The highly symmetric structure of BTP ( 2 21 ) yields a n NMR spectrum (in CDCl 3 ) consisting of two signals split as triplets in the aliphatic region (3.09 ppm, J = 7.5 Hz ; 2.79 ppm, J = 7.2 Hz). Unlike the BTF series, while ring opening (structures 2 22 and 2 23 ) does desymmetrize the aliphatic region, it does not provide the resolution necessary to assign the peaks ( Figure 2 1 7 ) Taken in CDCl 3 2 22b shows one OH singlet (9.84 ppm) and one NH triplet (5.88 ppm, J = 3.2 Hz); the 1 H N MR spectrum of compound 2 2 3bb shows two OH singlets (9.84 and 9.35 ppm) and two NH triplets (6.09 ppm, J = 5.6 Hz ; 6.01 ppm, J = 5.5 Hz). The 13 C NMR (CDCl 3 ) spectrum of BTP shows a single resonance far downfield (167.8 ppm, C=O lactone) corresponding t o the equivalent ester carbonyls within the structure. The 13 C NMR of ring opened product 2 22b (in CDCl 3 ) shows the peaks shifted downfield relative to 2 21 ; a peak at 174.5 ppm corresponds to the newly formed amide C=O while two partially resolved peaks at 168.4 ppm correspond to the remaining lactone C=O carbons. The 13 C NMR (in CDCl 3 ) of monolactone 2 22bb

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58 Figure 2 1 7 1 H NMR resonances (in CDCl 3 ) for BTP are complicated and show overlap ped aliphatic peaks (2.6 3.2 ppm) for ring opened products also shows three peaks in the far downfield region; signals at 175.2 and 174.9 ppm correspond to the amide C=O s while the signal at 169.5 ppm corresponds to the remaining lacto n e C=O. Assigned below, and seen in all pyranone based structures, the 13 C NMR chemical shifts of the methylene carbons to the aromatic ring are found in the range 17.0 18.4 ppm range. Sample 1 H NMR and 13 C NMR spectra for the compounds 2 22 and 2 23 can be found in Appendix A In order to conclusively assign the chemical shifts seen in the 1 H and 13 C NMR sepctra with the structure of 2 22b gHMBC 2D NMR experiments were carried out in d 6 DMSO (better resolution then CDCl 3 in aliphatic region, see Appendix for spectra). The chemical shift assignments for compound 2 22b are based on the 1 H 13 C one bond and long range couplings observed in the gHMBC spectrum (crucial couplings are outlined in Figure 2 1 8 )

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59 Figure 2 1 8 Structure 2 22b with 1 H NMR chemical shifts (in ppm), 13 C NMR chemical shifts (in ppm), and diagnostic heteronuclear couplings labeled The regioisomeric lactone carbonyl 13 C chemical shifts were unresolved Infrared Spectroscopy Infrared (IR) spectroscopy also reflects stepwise changes in the lactone carbonyl stretching frequencie s ( C=O lactone) upon ring opening of BTF ( 2 3 to 2 14 to 2 15 ). In the solid state (film deposited from CDCl 3 ), t he stepwise decreases are quite consistent ( Figure 2 1 9 ) ; 2 3 shows a maximum at 1816 cm 1 2 14a shows a maximum at 1808 cm 1 while 2 15aa shows a maximum at 1801 cm 1 The stepwise trends in carbonyl stretching frequencies are also reproduced in acetonitrile solution ( Figure 2 20 ) decreasing from 1820 to 1812 to 1809 cm 1 ( 2 3 2 14a 2 15aa respectively). The C=O values for the BTF ser ies compare well with that of unsubstituted 2 (3H) benzofuranone (1804 cm 1 nujol mull), 98 2,4,6 (NO 2 ) 3 substituted phenyl acetates (1803 cm 1 CCl 4 solution), 99 and 2,4,6 (NO 2 ) 3 3 CF 3 substituted phenyl acetates (1808 cm 1 CCl 4 solution). 99

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60 Figure 2 1 9 Solid state IR spectra a) clearly show stepwise decreases in C=O (lactone) stretc hing frequency for BTF derivatives, while b) the trends in the BTP series is less conclusive. IR were recorded as thin films deposited from CHCl 3 ; spectra have been normalized and off set for comparison Figure 2 20 Solution phase IR spectra of the BTF series in acetonitrile solution shows stepwise decreases in C=O (lactone) stretching frequency. Notice the broader resonance of 2 14a due to the two different (unresolved) lactone s in the molecule The trend found for the BTF series is not reproduced in the solid state infrared spectra of the BTP seri es. Shown in Figure 2 17 there is a decrease in C=O value from 2 21 (BTP, 1771 cm 1 ) to 2 22e (BDP, 1765 cm 1 lactone peaks unresolved); however, the monopyranone shows an increase in stretching frequency ( 2 23ee BMP, 1768 cm

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61 1 ). These values are con sistent with those of unsubstituted chroman 2 one (1774 cm 1 liquid film) 98 and compare to 2 CF 3 substituted phenyl acetates (1774 cm 1 CCl 4 solution) 99 and 2,4 dibromo substituted phenyl acetates (1774 cm 1 CCl 4 solution). Crystal S tructure A nalysis Fortunately, single crystals for crystal structure determination were obtained for compounds 2 3 2 14c 2 21 and 2 22b Shown in Figure 2 21 the crystal structures of the molecules are labelled with diagnostic bond lengths f or direct comparison. When comparing the benzofuranones ( 2 3 and 2 14c ) to the benzopyranones ( 2 21 and 2 22b ), the five member ed ring lactone structures are characterized by both shorter C=O (lactone) bond lengths ( 2 3 average 1.194 2 14c average 1.19 6 ) and longer O C =O bond lengths ( 2 3 average 1.388 2 14c average 1.388 ) as compared to the six member ed ring lactones ( average C=O: 2 21 1.201 ; 2 22b 1.205 ; average O C =O: 2 21 1.378 ; 2 22b 1.367 ). Longer C=O bond lengths are also seen upon ring opening ( e.g. from 2 3 to 2 14e ). Interestingly, there is a larger distortion of the aromatic ring within the five membered ring series ( 2 3 and 2 14e ); the structure of BTF ( 2 3 ) exhibits a bond length alteration (BLA) of 0.021 while the s tructure of BTP ( 2 21 ) shows a BLA of only 0.003 In BTF, the aromatic bonds contained in the lactone ring are significantly longer than the aromatic bonds between the two rings; in BTP the opposite is true, though much smaller in magnitude.

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62 Figure 2 21 ORTEP representations for crystal structures of benzolactone derivatives 2 3 2 14c 2 21 and 2 22b Bond lengths indicated are given in a ngstrom s The crystal structure of BTF ( 2 3 ) has been previously reported and is reproduced in Figure 2 22 69 Notably, this crystal is noncentrosymmetric and occupies the orthorhombic space group aba2 a rare example of polar crystal formation from an achiral, C 3h symmetric molecule. The unit cell contains two similar, but different, structures of BTF; these structures are denoted as A and B in Figure 2 22 Shown in

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63 Figure 2 22 X ray crystal structure of 2 3 : a) CPK model shows the unique chiral helical arrangement of 2 3 ; b) O C=O interactions define the molecular packing (distances in molecules labeled ) Figure 2 22b t he packing structure of 2 3 (dipolar) interactions 100 and C 101 Noticeably different between the two structures, deviations from planarity are less in A than in B. In A the plane defined by the aromatic core deviates between 0.98 degrees and 2.00 de grees from planes formed by the lactone rings ; in B the plane defined by the aromatic core deviates between 2.91 degrees and 3.65 degrees from plan es formed by the lactone rings As some standard of measure, the torsional angles formed across the C Ar O b ond (defined by C Ar1 C Ar2 O C carbonyl where C Ar1 and C Ar2 are common to the lactone ring, e.g. C3B C4B O1B C1B) are used to describe the structural changes effecting the orbital overlap between the lactone and the Counterintuitive when compared to deviations from planarity ( vide supra ) the average absolute torsion ange for structure A is 2.35 degrees while the less planar structure B has an average torsion of 1.34 degrees.

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64 Figure 2 23 Crystal packing o f 2 14c a) T he view along the b axis shows the anti parallel dimer stacking of the symmetric structure. b) A n alternate view shows the major hydrogen bond ing contacts between adjacent stacks; distances are reported in angstrom s The crystal of 2 14c was grown via slow diffusion of benzene into a concentrated solution of 2 14c in THF; the X ray crystal structure is shown in Figure 2 23 The crystal occupies the monoclinic space group P21/n As opposed to the chiral crystal structure of 2 3 the single cr ystal of 2 14c shows an anti parallel arrangement (stacking along the b axis) of a single species. O=C hydrogen bonds defining the interface between the two anti parallel stacks as shown in Figure 2 23 b. Addition ally, short anti parallel contacts (2.928, O O) between the two e the stacks via electrostatic interactions. The deviations from planarity are more significant in the structure of 2 14c ; here the plane defined by the aromatic core deviates 1.86 degrees and 5.32 degrees from the planes formed from the lactone rings. The torsion dihedral defined by C7 dihedral smaller at 0.50 degrees. The phenoli c C Ar

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65 anti parallel to the aromatic C=C bond at a dihedral of 169.30 degrees (defined by Figure 2 2 4 Crystal packing of 2 2 1 a) A herringbone pattern is seen along the b axis and b) major contact s include interactions Figure 2 2 5 Crystal packing of 2 22b a) S tacks of dimers dominate the crystal structure with b) interactions within and between adjacent stacks stabilizing this form

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66 A single crystal of BTP ( 2 21 ) was grown via slow diffusion of heptane into chloroform. This crystal occupies the P21/n space group The packing shows a herringbone arrangement of molecules dominated by weak interactions 102,103 and Figure 2 24 ). 100 With more conformational freedom, the average torsion dihedral across the C AR O bond is 19.86 degrees. Shown in Figure 2 2 5 a single crystal of 2 22b was grown via slow evaporation from a chloroform solution. This cr ystal is occupies the P 1 s pace group. The packing shows dimers of 2 21b arranged in columns, with H bonding between the columns defining the structure. The arrangement of molecules is dominated by slipped stack, interactions, 102,103 and 100 and both inter and seven membered ring intra molecular 97 H bonds ( Figure 2 2 5 b ). Similar to the structure of 2 21 there is more torsional freedom across the C AR O bond at 19.23 and 16.80 degrees. Discussion Using two C 3 symmetric benzotrilactones (BTF, 2 3 and BTP, 2 21 ), the ability for electronically coupled lactones to allow f or selective and stepwise aminolysis transformations has been investigated. Intermediates and products within the reaction pathways have been characterized by NMR spectroscopy (all derivatives) and X ray structure analysis ( 2 3 2 14c 2 21 and 2 22b ). The sequential ring opening of the three lactones in structure of BTF ( 2 3 ) with alkyl amines occurs quickly (15 min 16 h), with high fidelity (> 95% average selectivity quantitative material recover ), and under mild reaction conditions ( 41 C rt in DMF) The synthetic utility of this methodology is showcased through the high yielding, one pot synthesis of three multifunctionalized phloroglucinol architectures and the installation of

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67 enantiopure protected amino acids. The stepwise desymmetrization o f the C 3 symmetric core is cleanly seen through both 1 H and 13 C NMR spectroscopy. Crystal structures of two furanone derivatives ( 2 3 and 2 14c ) exhibited mostly planar lactone rings with noticeable bond length alteration within the aromatic ring. The si x membered ring analogue, BTP ( 2 21 ) exhibited lower aminolysis selectivity than BTF ( 2 3 ) 70 90% of desired product as quantified via HPLC. The aminolysis reactions were slower (2 h for the first ring opening) under identical conditions ( 41 C ). Th e stepwise desymmetrization of BTP is seen via NMR spectroscopy, but overlapping signals prevents quantitative measurements. Two crystal structures of pyranone derivatives were obtained ( 2 21 and 2 22b ) and characterized by twisted lactone rings, aromatic membered ring hydrogen bonding ( 2 22b ). Currently, the scope and applicability of the stepwise reactivity for BTF is being investigated through the construction of multifunctional materials and biologically relevant architectur es. The implementation of BTF as a synthetically useful scaffold will allow for easy iterative synthesis of a wide range of molecules for structure/property relationships and screening. Additionally, future studies will include the synthesis and aminolys is of acyclic and methyl substituted furanones to examine the scope of electronically coupled lactones as a general methodology for the multifunctionalization of a molecular core.

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68 Experimental Methods General procedures Reagents and solvents were purchased from Acros or A ldrich and used without further purification unless otherwise specified. DMF was degassed in 20 L drums and passed through two sequential purification columns (molecular sieves) under a positive argon atmosphere using a custom Glass Contour solvent system (Glass Contour, Inc.); DMF was also allowed to equilibrate to the atmosphere in order to show tolerance to atmospheric conditions. Thin layer chromatography (TLC) was performed on Dynamic Adsorbents, Inc. aluminum backed TLC plates with visualization via UV light and ninhydrin staining; interestingly, products stained different colors based on the number of lactone rings present. Flash column chromatography was performed using Purasil SiO 2 60 230 400 mesh silica gel from Whatman using mobile phases as in dicated within procedures. Infrared spectra were obtained on a Perkin Elmer Spectrum One FT IR spectrometer using a NaCl salt plate; samples were prepared by dropcasting compounds as a solution in chloroform. 1 H NMR, 13 C NMR and 1 H 13 C gHMQC spectra were recorded on a Varian Inova spectrometer operating at 500 MHz for 1 H and at 125 MHz for 13 C, and on a Varian VNMRS system operating at 600 MHz for 1 H and 150 MHz for 13 proton H C 39.50 ppm; gHMQC spectra are reported uncorrected) Abbreviations used are s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). MS spectra (HRMS) were acquired on a Bruker APEX II 4.7 T Fourier Transf orm Ion Cyclone Resonance mass spectrometer (Bruker Daltonics, Billerica, MA).

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69 Crystal structure (2 3) Data were collected at 173 K on a Siemens SMART PLATFORM equipped with A CCD area detector and a graphite monochromator utilizing MoK radiation ( = 0.71073 ). Cell parameters were refined using up to 8192 reflections. A full sphere of data (1850 frames) was collected using the scan method (0.3 frame width). The first 50 frames were re measured at the end of data collection to monitor instrument and crystal stability (maximum correction on I was < 1 % ). Absorption corrections by integration were applied based on measured indexed crystal faces. The structure was solved by the Direct Methods in SHELXTL6, and refined using full matrix least squares. The non H atoms were treated anisotropically, whereas the hydrogen atoms were calculated in ideal positions and were riding on their respective carbon atoms. The asymmetric unit consists of two chemically equivalent but crystallographically independent molecules. A total of 325 parameters were refined in the final cycle of refinement using 4097 reflections with I > 2 (I) to yield R 1 and wR 2 of 4.39% and 10.07%, respectively. Refinement was done using F 2 Crystal structure (2 14c) X Ray Intensity data w ere collected at 100 K on a Bruker DUO diffractometer using MoK radiation ( = 0.71073 ) and an APEXII CCD area detector. Raw data frames were read by program SAINT and integrated using 3D profiling algorithms. The resulting data were reduced to produce hkl reflections and their intensities and estimated standard deviations. The data were corrected for Lorentz and polarization effects and numerical absorption corrections were applied based on indexed and measured faces.

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70 The structure was solved and re fined in SHELXTL6.1, using full matrix least squares refinement. The non H atoms were refined with anisotropic thermal parameters and all of the H atoms were calculated in idealized positions and refined riding on their parent atoms. In addition to the m olecule, there is a half benzene solvent molecule in the asymmetric unit (located on an inversion center). The protons on N1 and O5 were obtained from a Difference Fourier map and refined freely. In the final cycle of refinement, 3866 reflections (of wh ich 3028 are observed with I > 2 (I)) were used to refine 261 parameters and the resulting R 1 wR 2 and S (goodness of fit) were 4.33 %, 12.85 % and 1.078 respectively. The refinement was carried out by minimizing the wR 2 function using F 2 rather than F values. R 1 is calculated to provide a reference to the conventional R value but its function is not minimized. Crystal structure 2 21 X Ray Intensity data were collected at 100 K on a Bruker SMART diffractometer using MoK radiation ( = 0.71073 ) and an APEXII CCD area detector. Raw da ta frames were read by program SAINT 1 and integrated using 3D profiling algorithms. The resulting data were reduced to produce hkl reflections and their intensities and estimated standard deviations. The data were corrected for Lorentz and polarization e ffects and numerical absorption corrections were applied based on indexed and measured faces. The structure was solved and refined in SHELXTL6.1, using full matrix least squares refinement. The non H atoms were refined with anisotropic thermal parameter s and all of the H atoms were calculated in idealized positions and refined riding on their parent atoms. In the final cycle of refinement, 2869 reflections (of which 2295 are observed with I > 2 (I)) were used to refine 190 parameters and the resulting

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71 R 1 wR 2 and S (goodness of fit) were 3.81 %, 9.20 % and 1.020 respectively. The refinement was carried out by minimizing the wR 2 function using F 2 rather than F values. R 1 is calculated to provide a reference to the conventional R value but its function is not minimized. Crystal structure 2 22b X Ray Intensity data were collected at 100 K on a Bruker SMART diffractometer using MoK radiation ( = 0.71073 ) and an APEXII CCD area detector. Raw data frames were read by program SAINT 1 and integrated using 3D profiling algorithms. The resulting data were reduced to produce hkl reflections and their intensities and estimated standard deviations. The data were corrected for Lorentz and polarization effects and numerical absorption corrections were applied based on indexed and measured faces. The structure was solved and refined in SHELXTL6.1, using full matrix least squares refinemen t. The non H atoms were refined with anisotropic thermal parameters and all of the H atoms were calculated in idealized positions and refined riding on their parent atoms. The N1 and O5 protons were obtained from a Difference Fourier map and refined free ly. In the final cycle of refinement, 4274 reflections (of which 3762 are observed with I > 2 (I)) were used to refine 270 parameters and the resulting R 1 wR 2 and S (goodness of fit) were 3.42 %, 8.78 % and 1.032 respectively. The refinement was carried out by minimizing the wR 2 function using F 2 rather than F values. R 1 is calculated to provide a reference to the conventional R value but its function is not minimized.

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72 Synthesis 2,2',2'' (2,4,6 trihydroxybenzene 1,3,5 triyl)triacetic acid ( 2 13). A solution of 2 7 (5.8 g, 20 mmol) in HBr (48%, 65 mL) was heated to reflux overnight. The reaction was then cooled to room temperature, allowing a precipitate to form. The precipitate was filtered, yielding a light brown powd er (3.17 g) identified as 2 11 acid Subsequently, the eluant was diluted with water (200 mL) and extracted with ethyl acetate (10 100 mL) yielding a viscous oil containing mostly 2 11 acid Both fractions of 2 11 acid were combined and hydrolyzed with NaOH (15.0 g NaOH in 60 mL H 2 O) at 70 C for 3 h. The resultant solution was cooled in an ice bath, acidified with concentrated HCl, and extracted with ethyl acetate (13 100 mL). The organics were combined, dried with MgSO 4 clarified with activated ca rbon, and evaporated yielding 2 13 (3.8 g, 57%) as a light brown solid. 1 H NMR ( d 6 DMSO) 3.46 (s, 6H), 8.24 (br s, 3H), 11.94 (br s, 3H). 13 C NMR ( d 6 DMSO) 29.7, 103.0, 153.0, 173.5. HRMS (ESI) calculated for C 12 H 13 O 9 [ M +Na] + 323.0363, found 323.0374 B enzo[1,2 b :3,4 b' :5,6 b'' ]trifuran 2,5,8(3 H ,6 H ,9 H ) trione ( Benzotrifuranone BTF, 2 3 ) Polyphosphoric acid (PPA, 30.0 g) and triacid 2 13 (2.71 g, 9.03 mmol) were

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73 mixed and heated to 110 C with stirring for 16 h. Th e reaction mixture was cooled to 0 C in ice bath and ice cold water (300 mL) was added with stirring. The resultant aqueous solution was then extracted with DCM (4 100 mL, emulsion). The organics were combined, washed with water (50 mL) and brine (50 m L), then dried with Na 2 SO 4 and evaporated in vacuo to yield 2 3 (1.03 g, 46%) as a tan powder. This product could be further purified by flash column chromatography (1:3 EtOAc/hexanes) and obtained as an off white powder. 1 H NMR ( d 6 13 C NMR ( d 6 30.1, 101.9, 148.8, 173.4. HRMS (CI) calculated for C 12 H 6 O 6 [ M +H] + 247.0243, found 247.0229. Elemental a nal. calcd for C 12 H 6 O 6 : C, 58.55; H, 2.46. Found: C, 58.26; H, 2.34. Representative ring openin g procedure. N heptyl 2 (4 hydroxy 2,7 dioxo 2,3,7,8 tetrahydrobenzo[1,2 b :3,4 b ']difuran 5 yl)acetamide ( 2 14 a). To a reaction vessel equipped with stir bar was added BTF ( 2 3 ) (51.4 mg, 209 mol) and DMF (3 mL). The solution was stirred at room temper ature until complete dissolution of the BTF then cooled in a dry ice/acetonitirile cold bath ( 41 C). After temperature equilibration, one equivalent of a 0.500 M solution of heptylamine in DMF was slowly added dropwise (418 L, 209 mol). The reaction was then allowed to stir under a blanket of argon, in the cold bath, for 30 min; after this time, the reaction was allowed to warm to room temperature before being poured into EtOAc (about 100 mL). The

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74 organic layer was washed thrice with water (some brin e may be needed to simplify extraction) and then once with brine. The organics were dried over Na 2 SO 4 and volatiles removed in vacuo yielding compound 2 14 a (75 mg, 99%) as an off white solid. The product could be purified via column chromatography (5% a cetone in DCM, R f 0.3) to yield analytically pure material (57 mg, 75%). IR (film from CHCl 3 ) 1808 cm 1 (C=O stretch) ; 1 H NMR ( d 6 DMSO) 10.64 (s, 1H), 8.21 (t, J = 5.3 Hz, 1H), 3.92 (s, 2H), 3.78 (s, 2H), 3.46 (s, 2H), 3.04 (q, J = 6.6 Hz, 2H), 1. 34 (m, 10H), 0.85 (t, J = 6.0 Hz, 3H). 13 C NMR ( d 6 DMSO) 174.2, 173.9, 170.1, 153.2, 151.8, 147.8, 105.2, 102.7, 97.1, 38.9, 31.2, 30.9, 30.8, 30.6, 28.9, 28.4, 26.3, 22.1, 14.0. HRMS calcd for C 19 H 23 NO 6 [M+Na] + 384.1418; found, 384.1419. N Benzyl 2 (4 hydroxy 2,7 dioxo 2,3,7,8 tetrahydrobenzo[1,2 b :3,4 b ']difuran 5 yl)acetamide (2 14 b). To a stirred solution of BTF (62 mg, 250 mol) in DMF (3 mL) at 41 C was dropwise added a benzylamine solution in DMF (500 L of a 0.500 M solution, 250 mol). Aft er 2 h (reaction complete in 30 min via TLC), the reaction solution was worked up in the same manner as compound 2 14 a yielding 88 mg of crude material (quant). Compound 2 14 b was further purified via column chromatography (5% acetone in DCM, R f o yield 65 mg (74%) of a white powder. 1 H NMR ( d 6 DMSO) 10.38 (s, 1H), 8.61 (t, J = 5.8 Hz, 1H), 7.28 (m, 5H), 4.29 (d, J = 5.9 Hz, 2H), 3.94 (s, 2H), 3.81 (s, 2H), 3.54 (s, 2H). 13 C NMR ( d 6 DMSO) 174.2,

PAGE 75

75 173.9, 169.9, 153.5, 151.5, 147.8, 139.2, 128. 3, 127.2, 126.8, 105.0, 102.7, 97.1, 42.3, 31.0, 30.6, 30.6. HRMS calcd for C 19 H 15 NO 6 [M+CH 3 OH+H] + 386.1234; found, 386.1245. N (Furan 2 ylmethyl) 2 (4 hydroxy 2,7 dioxo 2,3,7,8 tetrahydrobenzo[1,2 b :3,4 b ']difuran 5 yl)acetamide (2 14 c). A solution of BTF (100 mg, 406 mol) in DMF (6 mL) was cooled in an acetonitrile/dry ice bath under a blanket of argon. After temperature equilibration, a solution of furfurylamine in DMF (812 L of a 0.500 M solution, 406 mol) was added dropwise over 5 minutes. The reaction was allowed to stir at low temperature for 3 h, before a work up similar to compound 2 14 a yielding a dark yellow crude solid (138 mg, 99%). Product could be purified via column chromatography (5% acetone in DCM, R f 2 14 c as a yellow solid (83 mg, 60%). 1 H NMR ( d 6 DMSO) 10.32 (s, 1H), 8.57 (t, J = 5.5 Hz, 1H), 7.57 (s, 1H), 6.39 (dd, J = 3.0, 1.9 Hz, 1H), 6.25 (d, J = 2.7 Hz, 1H), 4.27 (d, J = 5.6 Hz, 2H), 3.92 (s, 2H), 3.79 (s, 2H), 3.49 (s, 2H). 13 C NMR ( d 6 DMSO) 174.2, 173.9, 169.8, 153.5, 152.0, 151.5, 147.8, 142.1, 110.4, 106.9, 105.0, 102.6, 97.1, 35.8, 31.0, 30.6, 30.4. HRMS not obtainable by various methods. Elemental analysis calcd for C 17 H 13 NO 7 : C, 59.48; H, 3.82; N, 4.08. Found: C, 59.09; H, 3.74; N, 3.77.

PAGE 76

76 2 (4 Hydroxy 2,7 dioxo 2,3,7,8 tetrahydrobenzo[1,2 b :3,4 b ']difuran 5 yl) N (2 hydroxyethyl)acetamide (2 14 d). To a stirred solution of BTF (25.2 mg, 102 mmol) in DMF (1.5 mL) at 41 C was dropwise added an ethanolamine solution in DMF (204 L of a 0.500 M solution, 102 mol). After 2 h (reaction complete in 30 min), the reaction solution was worked up in the same manner as compound 2 14 a yielding 26 mg (78%) of crude material. The compound could be further purified via flash column chromatography (10% MeOH in DCM, R f = 0.4) to yield 2 14 d (7 mg, 23 % ) as an amorphous solid. 1 H NMR ( d 6 DMSO) 10.60 (s, 1H), 8.22 (t, J = 5.4 Hz, 1H), 4.68 (t, J = 5.4 Hz, 1H), 3.92 (s, 2H), 3.79 (s, 2H), 3.49 (s, 2H), 3.41 (q, J = 5.8 Hz, 2H), 3. 13 (q, J = 5.5 Hz, 2H). 13 C NMR ( d 6 DMSO) 174.2, 173.9, 170.4, 153.3, 151.7, 147.8, 105.2, 102.7, 97.1, 59.6, 41.8, 30.9, 30.7, 30.6. HRMS calcd for C 14 H 13 NO 7 [M+H] + 308.0765; found, 308.0759. 4 Hydroxy 5 (2 oxo 2 (pyrrolidin 1 yl)ethyl)benzo[1,2 b :3 ,4 b ']difuran 2,7(3 H ,8 H ) dione (2 14 e). To a stirred solution of BTF (88 mg, 350 mol) in DMF (5 mL) at 41 C was added pyrrolidine solution in DMF (690 L of 0.503 M solution, 350

PAGE 77

77 mol). After 3 h (reaction complete by TLC in 15 min), the reaction solut ion was worked up in the same manner as compound 2 14 a yielding 109 mg (quant) of crude white material. The compound could be further purified via column chromatography (5% acetone in DCM, R f 2 14 e (85 mg, 78%) as a fine white powder. 1 H NMR ( d 6 DMSO) 10.21 (s, 1H), 3.94 (s, 2H), 3.79 (s, 2H), 3.58 (m, 4H), 3.29 (m, 2H), 1.93 (q, J = 6.8, 2H), 1.80 (q, J = 6.8, 2H). 13 C NMR ( d 6 DMSO) 174.2, 173.9, 167.8, 153.4, 151.5, 147.7, 105.0, 102.8, 97.0, 46.4, 45.7, 31.0, 30.6, 29.6, 25.6, 24 .0. HRMS calcd for C 16 H 15 NO 6 [M+H] + 318.0972; found, 318.0966. 4 Hydroxy 5 (2 oxo 2 (piperidin 1 yl)ethyl)benzo[1,2 b :3,4 b' ]difuran 2,7(3 H ,8 H ) dione (2 14f) To a stirred solution of BTF ( 50 mg, 203 mol) in DMF (5 mL) at 41 C was added cyclohexyl amine solution in DMF ( 410 L of 0.50 0 M solution, 203 mol). After 6 h (reaction complete by TLC in 3 hours ), the reaction solution was worked up in the same manner as compound 2 14 a yielding 66 mg (quant) of crude white m aterial. The compound could be further purified via column chromatography (5% acetone in DCM, R f 2 14f ( 48 mg, 7 2 %) as a fine white powder. 1 H NMR ( d 6 DMSO) 10.21 (s, 1H), 3.94 (s, 2H), 3.83 (m, 2H), 3.79 (s, 2H), 3.5 4 (m, 2 H), 1.68 1.58 (m, 4H), 1.57 1.50 (m, 2H) 13 C NMR ( d 6 DMSO) 174.2, 173.9, 167.8, 153.4, 151.5, 147.7, 105.0, 102.8, 97.0, 48.3 43.4, 31.0, 30.6, 29.6 26.5, 25.0, 22.8 HRMS calcd for C 17 H 1 7 NO 6 [M+H] + 3 31 10 72; found, 3 31 110 6.

PAGE 78

78 4 hydroxy 5 (2 morpholino 2 oxoethyl)benzo[1,2 b:3,4 b']difuran 2,7(3 H ,8 H ) dione (2 14 g ) To a stirred solution of BTF ( 14.9 mg, 60.5 mol) in DMF ( 2 mL) at 41 C was added morpholine solution in DMF ( 121 L of 0.50 M solution, 60.5 mol). After 3 h the reaction solution was worked up in the same manner as compound 2 14 a yielding crude white ma terial. The compound could be further purified via column chr omatography (5% acetone in DCM ) yielding 2 14 g ( 15.2 mg, 60 %) as a fine white powder 1 H NMR ( d 6 DMSO) 9.93 (s, 1H), 3.94 (s, 2H), 3.79 (s, 2H), 3.62 (m, 6H), 3.56 (t, J = 4.0 Hz, 2H), 3.44 ( t, J = 4.5 Hz). 13 C NMR ( d 6 DMSO) 174.2, 173.9, 168.0, 153.5, 151.2, 147.6,104.8, 103.1, 97.0, 66.1, 45.6, 42.8, 31.1, 30.5, 27.8 HRMS calcd for C 16 H 15 NO 7 [M+H] + 3 34.0921 ; found, 3 34 .09 17 2 (4 Hydroxy 2,7 dioxo 2,3,7,8 tetrahydrobenzo[1,2 b :3,4 b '] difuran 5 yl) N isopropylacetamide (2 14h ). To a cooled solution ( 41 C) of BTF (51 mg, 210 mol) in DMF (3 mL) was dropwise added a solution of isopropylamine in DMF (410 L of a 0.500 M solution, 210 mol). The reaction was completed in 3 h and worked up in the same manner as 2 14 a, yielding 62 mg (98%) of tan solids. Further purification via flash

PAGE 79

79 chromatography (5% acetone in DCM, R f 2 14 f as a semi crystalline solid (50 mg, 79%). 1 H NMR ( d 6 DMSO) 10.78 (s, 1H), 8.24 (d, J = 7.5 Hz, 1H), 3.92 (s, 2H), 3.82 (m, 3H), 3.47 (s, 2H), 1.06 (d, J = 6.6 Hz, 6H). 13 C NMR ( d 6 DMSO) 174.2, 173.9, 169.5, 153.2, 151.9, 147.8, 105.3, 102.7, 97.1, 40.8, 30.9, 30.9, 30.6, 22.2. HRMS not obtainable by various methods. Elemental analysis calcd for C 15 H 15 NO 6 : C, 59.01; H, 4.95; N, 4.59. Found: C, 58.01; H, 4.87; N, 4.26. 5 Phenoxy 6 ( amido L ph enylalanyl methylester) 1,3 benzodifuranone ( 2 16i ). To a solution of BTF (66.4 mg, 270 mol) and L phenylalanine methylester hydrochloride (58.2 mg, 270 mol) in DMF (4.0 mL), cooled to 41 C, was dropwise added di isopropylethylamine (47.0 L, 270 mol ) with stirring. TLC indicated complete conversion after 6 hours, but the reaction was allowed to stir for 16 hours, warming to room temperature. The reaction mixture was then poured into EtOAc, washed with water, 0.1 N HCl, water, brine and then dried ov er Na 2 SO 4 Volatiles were removed in vacuo yielding 115 mg (quant.) of crude material. The compound was further purified via co lumn chromatography (5% acetone in DCM, R f 2 16i (85 mg, 74%) as a white solid. 1 H NMR ( d 6 DMSO) 10.14 (s, 1H), 8.52 (d, J = 7.7 Hz, 1H), 7.27 (m, 2H), 7.21 (m, 3H), 4.45 (m, 1H), 3.93 (s, 2H), 3.78 (s, 2H), 3.59 (s, 3H), 3.47 (s, 1H), 3.46 (s, 1H), 2.98 (m, 2H); 13 C NMR ( d 6 DMSO ) 174.1, 173.8, 171.8, 169.7, 153.5,

PAGE 80

80 151.4, 147.8, 137.0, 129.1, 128.2, 126.5, 104.9, 102.4, 97.0, 53.8, 51.8, 36.7, 31.1, 30.6, 30.1. HRMS not obtainable by various methods. Elemental analysis calculated C 22 H 19 NO 8 (425.4) calcd. C 62.12, H 4.50, N 3.2 9; found C 61.95 H 5.04 N 2.97 Methyl 2 (2 (4 hydroxy 2,7 dioxo 2,3,7,8 tetrahydrobenzo[1,2 b:3,4 b']difuran 5 yl)acetamido) 3 phenylpropanoate ( 2 16l ). To a solution of BTF (65 mg, 260 mol), L phenylalanine methylest er hydrochloride (28.4 mg, 130 mol) and R phenylalanine methylester hydrochloride (28.4 mg, 130 mol) in DMF (5 mL), cooled to 41 C, was dropwise added di isopropylethylamine (48.3 L, 280 mol) with stirring. The reaction was allowed to slowly warm to rt overnight. The reaction was poured into EtOAc, washed with water, 0.1 N HCl, water, brine and then dried over Na 2 SO 4 Volatiles were removed in vacuo and compound was isolated by flash chromatography (5% acetone in DCM, R f 61 mg ( 70 %) of brown solids. 1 H NMR ( d 6 DMSO) 10.14 (s, 1H), 8.54 (d, J = 7.6 Hz, 1H), 7.24 (m, 5H), 4.46 (t, J = 7.5 Hz, 1H), 1.82 (s, 1H), 2.07 (s, 1H), 3.06 (s, 3H), 3.46 (s, 2H), 3.02 (dd, J = 13.7, 6.0 Hz, 1H), 2.93 (dd, J = 18.7, 8.5 Hz). 13 C NMR ( d 6 DMSO) 174.1, 173.9, 171.8, 169.7, 153.5, 151.4, 147.8, 137.0, 129.1, 128.2, 126.5, 104.9, 102.4, 97.0, 53.8, 51.8, 36.7, 31.1, 30.6, 30.1. HRMS unobtainable via various methods.

PAGE 81

81 2,2' (4,6 Dihydroxy 2 oxo 2,3 dihydrobenzofuran 5, 7 diyl)bis( N heptylacetamide) (2 15 aa). To a cooled solution ( 41 C) of BTF (51.2 mg, 208 mol) in DMF (3 mL) was dropwise added a solution of heptylamine in DMF (832 L of a 0.500 M solution, 416 mol). The reaction was complete within 3 h by TLC anal ysis, but was allowed to stir in the cold bath for 6 h before warming to room temperature. A work up similar to compound 2 14 a was performed, yielding 95 mg (96%) of crude off white material. Compound could be further purified via flash column chromatogr aphy (10% acetone in DCM, R f 2 15 aa (71 mg, 72%). IR (film CHCl 3 ) 1801 cm 1 (C=O stretch); 1 H NMR ( d 6 DMSO) 11.13 (s, 1H), 10.03 (s, 1H), 8.38 (br s, 1H), 8.15 (br s, 1H), 3.70 (s, 2H), 3.48 (s, 2H), 3.43 (s, 2H), 3.03 (m, 4H), 1.39 (m, 4H), 1.23 (br s, 16H) 0.85 (t, J = 6.3 Hz, 6H). 13 C NMR ( d 6 DMSO) 174.6, 172.3, 171.5, 155.5, 151.8, 150.7, 106.6, 100.7, 98.4, 38.9, 38.9, 31.6, 31.2, 31.2, 30.8, 28.8, 28.7, 28.4, 28.3, 26.3, 22.0, 13.9 (three carbon signals were not observed/resolved). HRMS calcd for C 26 H 40 N 2 O 6 [M+Na] + 499.2779; found, 499.2791. 2 (4,6 Dihydroxy 7 (2 ((2 hydroxyethyl)amino) 2 oxoethyl) 2 oxo 2,3 dihydrobenzofuran 5 yl) N heptylacetamide and 2 (4,6 dihydroxy 5 (2 ((2

PAGE 82

82 hydroxyethyl)amino) 2 oxoethyl) 2 oxo 2,3 dihydrobenzofuran 7 yl) N h eptylacetamide ( 2 15 To a stirred solution of 2 14 a (50.0 mg, 138 mol) in DMF (3 mL) at 41 C was dropwise added ethanolamine solution in DMF (277 L of 0.500 M solution, 138 mol). After 6 h (the reaction was complete in about 3 h), th e reaction solution was worked up in the same manner as compound 2 14 a yielding 57 mg (98%) of crude material that was a 45:55 ratio of 2 15 to 2 15 1 H NMR in DMSO is shown below. 2 (4,6 Dihydroxy 7 (2 ((2 hydroxyethyl)amino) 2 oxoethyl) 2 oxo 2 ,3 dihydrobenzofuran 5 yl) N heptylacetamide ( 2 15 Compound 2 15 could be partially separated by flash column chromatography (R f from the above reaction mixture. 1 H NMR ( d 6 DMSO) 11.10 (s, 1H), 10.03 (s, 1H), 8.43 (t, J = 5.0 Hz, 1H), 8.17 (t, J = 5.0, 1H), 4.69 (t, J = 5.3 Hz, 1H), 3.70 (s, 2H), 3.48, (s, 2H), 3.46 (s, 2H), 3.41 (q, J = 5.5 Hz, 2H), 3.13 (q, J = 5.6 Hz, 2H), 3.03 (q, J = 6.4 Hz, 2H), 1.39 (m, 2H), 1.23 (s, 8H), 0.85 (t, J = 6.5 Hz, 3H). 13 C NMR ( d 6 DMSO) 174.6, 172.3, 171.8, 155.5, 151.8, 150.7, 106.6, 100.7, 98.4, 59.5, 41.9, 38.9, 31.6, 31.2, 31.2, 30.8, 28.8, 28.4, 26.3, 22.0, 13.9. HRMS calcd for C 21 H 30 N 2 O 7 [M+H] + 423.2126; found, 423.2136.

PAGE 83

83 N Allyl 2 (5 (2 ((furan 2 ylmethyl)amino) 2 o xoethyl) 4,6 dihydroxy 2 oxo 2,3 dihydrobenzofuran 7 yl)acetamide and N allyl 2 (7 (2 ((furan 2 ylmethyl)amino) 2 oxoethyl) 4,6 dihydroxy 2 oxo 2,3 dihydrobenzofuran 5 yl)acetamide ( 2 15 2 15 A solution of 2 14 c (90 mg, 260 mol) in DMF (6 mL) was cooled to 41 C in a dry ice/acetonitrile bath before dropwise addition of allylamine (520 L of a 0.500 M solution, 260 mol). The reaction was allowed to stir at low temperature for 6 h, before warming to room temperature and working up similar to c ompound 2 14 a yielding a yellowish crude solid (105 mg, quant). The compounds could be further purified via column chromatography (no separation of regioisomers was possible on silica) yielding a mixture of 2 15 c j and 2 15 c j as an amorphous solid (80 m g, 76% yield, 62:38 ratio of regioisomers). 1 H NMR in d 6 DMSO and 13 C NMR in d 6 DMSO provided below. HRMS calcd for C 20 H 20 N 2 O 7 [M+Na] + 423.1163; found, 423.1183. 2 (4,6 Dihydroxy 2 oxo 5 (2 oxo 2 (prop 2 yn 1 ylamino)ethyl) 2,3 dihydrobenzofuran 7 yl) N (furan 2 ylmethyl)acetamide and 2 (4,6 dihydroxy 2 oxo 7 (2 oxo 2 (prop 2 yn 1 ylamino)ethyl) 2,3 dihydrobenzofuran 5 yl) N (furan 2 ylmethyl)acetamide ( 2 15 c k 2 15 c k A solution of 2 14 c (67 mg, 200 mol) in DMF (3 mL) was cooled to 41 C in a d ry ice/acetonitrile bath before dropwise

PAGE 84

84 addition of propargylamine (390 L of a 0.5 M solution, 200 mol). The reaction was allowed to stir at low temperature for 8 h, before warming to rt and pouring into EtOAc. The organic layer was washed with deioniz ed H 2 O (thrice) and brine, and then dried over Na 2 SO 4 The volatiles were removed in vacuo to yield an amorphous solid (79 mg, quant). The compounds could be further purified via column chromatography (10% acetone in DCM, R f isomers was possible on silica) yielding a mixture of 2 15 c k and 2 15 c k as an amorphous solid (54 mg, 70% yield). 1 H NMR in d 6 DMSO and 13 C NMR in d 6 DMSO provided below for comparison. 3,5 phenoxy 4,6 ( amido L phenyl alanyl methylester ) benzomonofuranone (2 15ii). To a solution of BTF (75 mg, 300 mol) and L phenylalanine methylester hydrochloride (125 mg, 580 mol) in DMF (5 mL), cooled to 41 C, was dropwise added di isopropylethylamine (104 L, 594 mol) with stirr ing. The reaction was allowed to slowly warm to rt overnight, and then mild heating to 40 C for 2 hours was necessary to push the reaction to completion. The reaction was poured into EtOAc, washed with water, 0.1 N HCl, water, brine and then dried over N a 2 SO 4 Volatiles were removed in vacuo and compound was isolated by flash chromatography (1:1 hexanes:EtOAc, R f 0.4) to yield 162 mg (88%) of brown solids. 1 H NMR ( d 6 DMSO ) 10.24 (s, 1H), 9.64 (s, 1H), 8.79 (d, J = 7.4 Hz, 1H), 8.47 (d, J = 7.6 Hz, 1H), 7.35 7.07 (m, 10H), 4.45 (m, 2H), 3.70 (s, 2H), 3.57 (s, 6H), 3.52 3.39 (m, 4H), 3.07 2.91 (m, 4H). 13 C NMR ( d 6 DMSO) 174.6, 172.0, 171.7, 171.6, 171.4, 155.1, 151.9, 150.4, 136.9, 129.1, 128.2,

PAGE 85

85 126.6, 106.3, 100.5, 98.1, 53.9, 53.8, 51.9, 51.8, 36.7, 36.6, 31.7, 30.6, 30.3. HRMS calculated for C 32 H 32 N 2 O 10 [M+Na] + 627.1949, found 627.1946. 3,5 phenoxy 4 ( amido D/L phenylalanyl methylester) 6 ( amido L phenylalanyl methylester) benzomonofuranone (2 15il ). To a solution of 2 16l (58 mg, 136 mol) and L phenylalanine methylester hydrochloride (65 mg, 300 mol) in DMF (5 mL) cooled to 41 C, was dropwise added di isopropylethylamine (52 L, 300 mol) with stirring. The reaction was allowed to slowly warm to rt overnight, and then mild heating to 40 C for 2 hours was necessary to push the reaction to completion. The reactio n was poured into EtOAc, washed with water, 0.1 N HCl, water, brine and then dried over Na 2 SO 4 Volatiles were removed in vacuo and compound was isolated by flash chromatography (10% acetone in DCM, R f solids. 1 H NMR ( d 6 DMSO ) 10.24 (s, 1H), 9.63 (s, 1H), 8.76 (d, J = 7.4 Hz, 1H), 8.44 (d, J = 7.6 Hz, 1H), 7.35 7.07 (m, 10H), 4.45 (m, 2H), 3.70 (s, 2H), 3.57 (s, 6H), 3.52 3.39 (m, 4H), 3.07 2.91 (m, 4H). 2,2',2' (2,4,6 Trihydroxybenzene 1,3,5 triyl)tris( N heptylacetamide) ( 2 16 aaa). To a cooled solution ( 41 C) of BTF (50 mg, 200 mol) in DMF (3 mL) was dropwise

PAGE 86

86 added heptylamine (77 mg, 670 mol) with stirring. The reaction was allowed to warm slowly to room temperature overnight. The next day, the reaction was worked up similar to compound 2 14 a yielding 120 mg (quant) of crude material. The material could be further purified via column chromatography (R f 2 16 aaa (110 mg, 92%) as a waxy solid. 1 H NMR ( d 6 DMSO) 10.72 (s, 3H), 8.46 (t, J = 5.4 Hz, 3H), 3.48 (s, 6H), 3.03 (q, J = 6.6 Hz, 6H), 1.40 (m, 6H), 1.23 (s, 24H), 0.84 (t, J = 6.7 Hz, 9H). 13 C NMR ( d 6 DMSO) 173.7, 153.8, 102.8, 39.0, 31.3, 31.2, 28.7, 28.3, 26.3, 22.0, 13.9. HRMS calcd for C 33 H 57 N 3 O 6 [M+Na] + 614.4140; found, 614.4167. N Allyl 2 (3 (2 ((furan 2 ylmethyl)amino) 2 oxoethyl) 2,4,6 trihydroxy 5 (2 oxo 2 (prop 2 yn 1 ylamino)ethyl)phenyl)acetamide ( 2 16 cgh). Stepwise procedure. A solution of 2 15 c j and 2 15 c j (47 mg, 120 mol) in DMF (3 mL) was cooled to 41 C in a dry ice/acetonitrile bath before dropwise addition of allylamine (300 L of a 0.500 M solution, 150 mol). The reaction was allowed to stir at low temperature for 6 h before warming to room temperature. The reaction was worked up as described for compound 2 14 a yielding a brown amorphous solid (52 mg, 96%). The compound could be further purified via column chromatography (R f % MeOH/DCM) yielding 2 16 c jk as an amorphous solid (52 mg, 96% yield). 1 H NMR ( d 6 DMSO) 10.22 (s, 1H), 10.16 (s, 1H), 10.08 (s, 1H), 8.81 (t, J = 4.9 Hz, 1H), 8.73 (t, J = 4.8 Hz,

PAGE 87

87 1H), 8.53 (t, J = 5.0 Hz, 1H), 7.57 (s, 1H), 6.38 (dd, J =2.9, 1.9 Hz, 1H ), 6.26 (d, J = 2.9 Hz, 1H), 5.78 (dddd, J = 17.5, 10.2, 5.5, 5.1 Hz, 1H), 5.14 (dd, J = 17.2, 1.5 Hz, 1H), 5.06 (dd, J = 10.3, 1.4 Hz, 1H), 4.27 (d, J = 5.1 Hz, 2H), 3.86 (dd, J = 5.2, 2.3 Hz, 2H), 3.70 (t, J = 5.2 Hz, 2H), 3.52 (s, 4H), 3.49 (s, 2H), 3.1 2 (t, J = 2.4 Hz, 1H). 13 C NMR ( d 6 DMSO) 173.4, 173.4, 173.1, 153.8, 153.8, 151.5, 142.2, 134.6, 115.6, 110.5, 107.2, 102.9, 102.9, 102.8, 80.6, 73.3, 41.3, 35.8, 31.2, 31.1, 30.9, 28.3 (one peak not observed/resolved). HRMS calcd for C 23 H 25 N 3 O 7 [M+Na] + 478.1585; found, 478.1603. O ne pot procedure A solution of BTF (116 mg, 471 mol) in DMF (6 mL) was cooled to 41 C in a dry ice/acetonitrile bath before dropwise addition of distilled furfurylamine (942 L of a 0.500 M solution, 471 mol). After allo wing the reaction to proceed for 45 min, distilled allylamine (942 L of a 0.500 M solution, 471 mol) was added dropwise to the reaction mixture. After allowing the reaction to proceed for 6 h, distilled propargylamine (1.88 mL of a 0.500 M solution, 942 L) was added dropwise; the reaction mixture was then allowed to stir overnight, slowly warming to room temperature. The next day, the reaction mixture was poured into EtOAc, and the organic layer was separated and washed with H 2 O (thrice) and brine. Af ter drying over Na 2 SO 4 the volatiles were removed in vacuo yielding a yellow powder (220 mg, quant). The reaction mixture could be further purified via column chromatography (R f 5% MeOH/DCM) yielding sufficiently pure 2 16 c jk as a yellow solid ( 182 mg, 85% yield). Mass spectrum, 1 H NMR, and 13 C NMR shown below. Elemental analysis calcd for C 23 H 25 N 3 O 7 : C, 60.65; H, 5.53; N, 9.23. Found: C, 60.50; H, 5.55; N, 9.17.

PAGE 88

88 N Benzyl 2 (3 (2 (heptylamino) 2 oxoethyl) 2,4,6 trihydroxy 5 (2 ((2 hydroxyeth yl)amino) 2 oxoethyl)phenyl)acetamide ( 2 16 abd). One pot procedure. A solution of BTF (35 mg, 142 mol) in DMF (3 mL) was cooled to 41 C in a dry ice/acetonitrile bath before dropwise addition of heptylamine (284 L of a 0.500 M solution, 142 mol). Af ter allowing the reaction to proceed for 45 min, benzylamine (284 L of a 0.500 M solution, 142 mol) was added dropwise to the reaction mixture. After allowing the reaction to proceed for 6 h, aminoethanol (284 mol of a 0.500 M solution, 142 mol) was a dded dropwise; the reaction mixture was then allowed to stir overnight, slowly warming to room temperature. The next day, the reaction mixture was poured into EtOAc, and the organic layer was separated and washed with H 2 O (thrice) and brine. After drying over Na 2 SO 4 the volatiles were removed in vacuo yielding a tan powder (75 mg, quant). The reaction mixture could be further purified via column chromatography (R f 2 16 abd as a white solid (60 mg, 80% yie ld). 1 H NMR and 13 C NMR shown below. HRMS calcd for C 28 H 39 N 3 O 7 [M+Na] + 552.2680; found, 552.2694.

PAGE 89

89 5 hydroxy 6 (3 oxo 3 (pyrrolidin 1 yl)propyl) 3,4,9,10 tetrahydropyrano[2,3 f]chromene 2,8 dione ( 2 22e ) To a solu tion of BTP ( 2 21 50 mg, 174 mol) in DMF (5 mL), cooled to reaction (5% acetone in DCM). The reaction was allowed to warm to roo m temperature, diluted with EtOAc, and washed sequentially with 0.1N HCl, DI H 2 O (x3), then brine. The organics were dried over Na 2 SO 4 and volatiles were removed en vacuo yielding amorphous yellow solids. Compound 2 22e was isolated via column chromatog raphy (acetone into DCM gradient, R f 95% yield) 1 H NMR (CDCl 3 ) 10.78 (s, 1H), 3.47 (t, J = 6.8 Hz, 2H), 3.00 (m, 6H), 2.73 (m, 6H), 1.97 (q, J = 6.7 Hz, 2H), 1.86 (q, J = 6.6 Hz, 2H). 13 C NMR (CDCl 3 ) 172.6, 168.5, 168.4, 152.7, 14 9.7, 147.8, 112.7, 107.8, 102.3, 46.7, 46.2, 35.0, 28.8, 28.7, 25.9, 24.3, 18.0, 17.7, 17.3. IR (dropcast from CHCl 3 C=O 1771 cm 1

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90 3,3' (5,7 dihydroxy 2 oxochroman 6,8 diyl)bis(1 (pyrrolidin 1 yl)propan 1 one) ( 2 23ee ) To a solution of BTP ( 2 21 overnight and was wo rked up similar to compound 2 22e yielding an amorphous solid. Compond 2 23ee was isolated via column chromatography (5% acetone in DCM, R f 0.3) as a white solid (72 mg, 90% yield). 1 H NMR (CDCl 3 ) 10.37 (s, 1H), 10.32 (s, 1H), 3.44 (t, J = 6.8 Hz, 4 H), 3.35 (m, 4H), 2.94 (m, 6H), 2.68 (m, 6H), 1.88 (m, 8H). 13 C NMR (CDCl 3 ) 173.2, 172.8, 169.7, 153.8, 151.9, 149.6, 113.5, 108.0, 103.0, 46.6, 46.6, 46.1, 46.1, 35.3, 34.9, 29.3, 25.9, 24.3, 18.3, 17.8, 17.6. IR (dropcast from CHCl 3 ) C=O 1765 cm 1 N benzyl 3 (5 hydroxy 2,8 dioxo 2,3,4,8,9,10 hexahydropyrano[2,3 f]chromen 6 yl)propanamide ( 2 22b ) To a solution of BTP ( 2 21

PAGE 91

91 DMF (5 mL), cooled to 41C, was dropwise added a benzylamine solution (34 but the reaction was allowed to warm to RT slowly overnight. The reaction mixture was worked up similar to 2 22e Compound 2 22b was isolated via column chromat ography (acetone in DCM gradient, R f mg, 76% yield). 1 H NMR (CDCl 3 ) 9.84 (s, 1H), 7.28 (m, 3H), 7.17 (m, 2H), 5.88 (t, J = 3.2, 1H), 4.40 (d, J = 5.7 Hz, 2H), 2.97 (m, 6H), 2.70 (m, 6H). 13 C NMR (CDCl 3 ) 174.5, 168.4, 152.1, 149.6, 147.8, 128.8, 127.9, 127.8, 112.3, 107.1, 104.5, 44.1, 35.3, 28.8, 28.6, 18.0, 17.8, 17.3. 1 H NMR ( d 6 DMSO) 173.0, 168.0, 167.9, 151.1, 149.1, 147.1, 139.0, 128.3, 127.2, 126.8, 112.2, 107.1, 102.6, 42.3, 34.5, 28. 1, 27.9, 18.3, 17.6, 16.8. HRMS calcd. for C 22 H 21 NO 6 [M+Na] + 418.1261, found 418.1272. 3,3' (5,7 dihydroxy 2 oxochroman 6,8 diyl)bis( N benzylpropanamide) ( 2 23b ) To a solution of 2 21 41C, was dropwise reaction mixture was allowed to stir for 12 hours before warming to RT; the reaction was worked up similar to 2 22e Compound 2 23b was isolated via column chromatography (acetone into DCM gradient, R f solid (53 mg, 61% yield). 1 H NMR (CDCl 3 ) 9.84 (s, 1H), 9.35 (s, 1H), 7.28 (m, 6H),

PAGE 92

92 7.14 (m, 4H), 6.09 (t, J = 5.6, 1H), 6.01 (t, J = 5.5, 1H), 4.39 (d, J = 5.7 Hz, 2H), 4.37 (d, J = 5.8, 2H), 2.92 (m, 6H), 2.67 (m, 6H). 13 C NMR (CDCl 3 ) 175.2, 174.9, 169.5, 153.4, 151.6, 149.7, 137.4, 137.3, 128.8, 128.7, 127.7, 127.7, 113.3, 107.9, 103.5, 44.0, 35.8, 35.3, 29 .2, 18.5, 17.8, 17.8. HRMS cacld. for C 29 H 30 N 2 O 6 [M+Na] 525.1996, found 525.2011. N heptyl 3 (5 hydroxy 2,8 dioxo 2,3,4,8,9,10 hexahydropyrano[2,3 f]chromen 6 yl)propanamide ( 2 22a ) To a solution of 2 21 (49.3 mg, 171 DMF (3 mL), cooled to hours before warming to RT overnight; the reaction was worked up similar to 2 22e (10% taken out for HPLC). Compound 2 22a was isolated via column chromatography (hexanes/EtOAc, R f 71% yield). 1 H NMR (CDCl 3 ) 10.03 (s, 1H), 5.55 (t, J = 3.8 Hz, 1H), 3.24 (q, J = 5.6 Hz 2H), 2.98 (m, 6H), 2.70 (m, 6H), 1.46 (m, 1H), 1.27 (m, 1H), 0.88 (t, J = 6.6 Hz, 3H). HRMS calcd. for C 22 H 29 NO 6 [M+Na] + 426.1887, found 426.1895.

PAGE 93

93 ( S ) methyl 2 (3 (5 hydroxy 2,8 dioxo 2,3,4,8,9,10 hexahydropyrano[2,3 f] chromen 6 yl)propanamido) 3 phenylpropanoate (2 22i ). To a solution of 2 XB phenylalanine methyl ester hydrochloride (18.3 mg, 84.6 41C, was dropwise added di isopropylethyl amine tir for 3 hours before warming to 0C for 3, then to room temperature overnight; the reaction was worked up similar to 2 XA. Compound 2 XH was isolated via column chromatography (hexanes/EtOAc) yielding an amorphous solid (30 mg, 76% yield). 1 H NMR (CDCl 3 ) 9.52 (s, 1H), 7.21 (m, 3H), 6.92 (dd, J = 7.0, 2.1 Hz, 2H), 6.03 (d, J = 7.5 Hz, 1H), 4.84 (q, J = 5.9 Hz, 1H), 3.13 (dd, J = 13.7, 5.9 Hz, 1H), 3.08 (dd, J = 14, 5.8 Hz, 1H), 2.98 (m, 6H), 2.67 (m, 6H). 13 C NMR (CDCl 3 ). 174.5, 171.4, 168.3, 168.2, 152.0, 149.7, 147.9, 135.2, 129.1, 128.6, 127.3, 112.2, 107.9, 102.7, 53.6, 52.5, 37.5, 35.2, 28.7, 28.6, 18.0, 17.6, 17.4. 13 C NMR ( d 6 DMSO) 172.9, 171.9, 168.0, 167.9, 149.0, 147.0, 137.0, 129.0, 128.2, 126.5, 112.1, 107.1, 102.7, 53.8, 51.8, 36.7, 34. 1, 28.0, 28.0, 18.2, 17.7, 16.8. HRMS calcd. for C 22 H 25 NO 8 [M+Na] + 490.1472, found 490.1471.

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94 N,N diethyl 3 (5 hydroxy 2,8 dioxo 2,3,4,8,9,10 hexahydropyrano[2,3 f]chromen 6 yl)propanamide ( 2 22m ). To a solution of 2 21 (3 DMF (5 mL), cooled to overnight at room temperature; the reaction was worked up similar to 2 22e (10% taken out for HPLC). Compound 2 22m was isolated via column chromatography (hexanes/EtOAc) yielding an amorphous solid (22 mg, 60% yield). 1 H NMR (CDCl 3 ) 10.77 (s, 1H), 3.38 (q, J = 7.2 Hz, 2H), 3.30 (q, J = 7.2 Hz, 2H), 3.01 (m, 6H), 2.75 (m, 6H), 1.15 (t, J = 7.3 Hz, 2H), 1.11 (t, J = 7.2 Hz, 2H). 13 C NMR (CDCl 3 ) 172.4, 168.6, 168.4, 153.0, 149.5, 147.6, 113.1, 104.8, 102.5, 44.3, 42.4, 35.0, 25.2, 24.7, 23.2, 22.3, 18.0, 17.7, 17.3. HRMS calcd. for C 19 H 23 NO 6 [M+Na] + 384.1418, found 384.14 37.

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95 CHAPTER 3 STRUCTURE/REACTIVITY RELATIONSHIPS Overview Due to its ubiquity in natural systems 104 and importance in synthesis 105,106 chemical biology, 107 and materials chemistry 108,109 the amide bond 110,111 is one of the most studied functional units in the c hemical s ciences. Accounting for 16% of all reacti ons in the medicinal/pharmaceutical industry 112 much work has been performed towards understanding the mechanism 113 117 and structure/reactivity relationships 115,118 120 between activated acids and amine nucleop hiles ( Figure 3 1 a ). 2 Figure 3 1. Traditional amide bond synthesis a) involves the coupling of a free amine with an activated carboxylic acid derivative. With this same strategy, b) phenyl acetates and c) benzolact 2 on es can be utilized for amide bond formation. In the absence of detailed mechanistic studies, the extensive experimental and theoretical work considering aminolysis of substituted phenyl acetates (R 3 PhOC(=O)R 1 Portions of this Chapter are reprinted with permission from Baker, M. B.; Ghiviriga, I.; Castellano, R. K. Chemical Science 2012 3 1095 1099.

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96 Figure 3 1b ) in polar aprotic solvents serves as the most comprehensive starting point to rationalize the differential aminolysis reactivity of BTF ( 2 3 2 14 2 15 ) and BTP ( 2 21 2 22 2 23 ) derivatives ( Figure 3 1c ) 113,114,116,119,121 123 Universally observed for R 3 PhOC(=O )R 1 is a decrease in the rate of aminolysis upon the introduction of electron donating substituents (R 3 ) to Ph, the leaving group portion. F rom 2 3 ( 2 21 ) to 2 14 ( 2 22 ) to 2 15 ( 2 23 ) ( Figure 3 2 ), each successive aminolysis event converts one OC(=O)C H 2 substituent to a less inductively withdrawing OH substituent (which may be partially deprotonated (i.e., O phenyl oxygen of a common lactone ring ( I (O ) = 0.26; I (OH) = 0.33; I (OC(=O)CH 3 ) = 0.42 124 ). Currently, the state of protontation (i.e., OH vs. O ) state of products and reactants are unknown under the reaction conditions; unsubstituted phenol and methylamine have identical pKa values in water (10.0 125 and 10.0, 126 respectively) and dissimilar values in acetonitrile (29.1 125 and 18.4, 126 respectively). Shown in Figure 3 2a t he increasingly deshielded lactone carbonyl 13 C NMR resonances and lower C=O wavenumbers (see Chapter 2 for detailed information) from 2 3 to 2 14 a (neutral) to 2 15 aa (neutral) speak to the stepwise increase of electron density to the benzene ring ba sed on trends known for meta and para substituted phenyl acetates. 120,127,128 It follows that the aminolysis rate should decrease from 2 3 to 2 14 to 2 15 and that the nearly identical 1 3 C NMR (assigned via 1 H 13 C HMQC coupling, see Chapter 2 for details) chemical shifts and IR resonances ( unresolved) for the two lactones of 2 14 qualitatively predict their similar aminolysis reactivities. 129

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97 F igure 3 2 Experimental characterization of lactone derivatives speaks to stepwise decreases in aminolysis rates in both the a) furanone and b) pyranone series. Within both series the r ing opening via aminolysis c) effectively converts an inductively wit hdrawing meta substituent ( OAc) to a more inductively donating meta substituent ( OH, or O ). a signals for multiple lactones were not resolved, b chemical shifts reported as ppm in d 6 DMSO, c differences in chemical shift from Figure 2 13 due to spectru m reference, d chemical shifts reported as ppm in CDCl 3 C arbonyl stretching frequencies ( C=O lactone, cm 1 ) are recorded as thin films on NaCl plates deposited from CHCl 3 Similar trends for the 13 C NMR signals are found in the BTP series (from 2 21 to 2 22e to 2 23ee ), again speaking to the stepwise increase in electron density, but the stepwise decrease in C=O wavenumbers is not reproduced ( Figure 2 8b ). While there is a decrease in the C=O ester frequency upon the first ring opening ( 2 21 1771 cm 1 to 2 22 1765 cm 1 ), the monolactone structure ( 2 23 1768 cm 1 ) shows a slightly higher

PAGE 98

98 C=O ester signal. Consequently, the lactone carbonyl resonance frequency trends do not support stepwise reactivity decreases and perhaps begin to reflect the loss of selectivity (as compared to BTF) towards ester aminolysis (see Chapter 2). It is noted that the IR absorption trend of the BTP series ( 2 22e and 2 23ee are tertiary amides) in the solid state may be due to a differing hydrogen bonding environment (as c ompared to secondary amides of BTF). Further studies aim to eliminate this discrepancy. Quantum C hemical C alculations Furanone Series Figure 3 3 DFT calculations of benzofuranone derivatives show LUMOs localized to the reactive lactones and stepwise increases in LUMO levels upon ring opening. R = Me; values are calculated at the B3LYP/6 311++G** level of theory.

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99 Advancements in quantum chemical calculations have established correlations between several ground state reactivity descriptors (in the gas phase) and the aminolysis rates of simple esters, without a priori knowledge of the rate determining transition state or mechanistic pathway. 121,123 Within the BTF series ( 2 3 2 14 2 15 ), o u r observed stepwise reactivity trend is accompanied by changes in bond lengths and reactivity descriptors calculated for optimized model structures ( Table 3 1 Figure 3 3 ) using the B3LYP/6 311++G ** method ology; notably, structural features found in the cr ystal structures (see above) are well represented in these minimized models An increase in the C=O (entry 1 ) and decrease in the O C (=O) (entry 2 ) bond lengths (from 2 3 to 2 14 to 2 15 ) reflect progressive weakening of the carbonyl double bond (confir med by IR, and mirrored in the crystal structures, vide supra ) and strengthening of the O C (=O) single bond (again mirrored in the crystal structures) Th e structural data, together with increasing l occupancy values 118 (NBO partitioning scheme, 130 entry 5) from 2 3 to 2 15 are consistent with greater delocalization of the phenolic oxygen electrons into the lactone carbonyl, decreased carbonyl reactivity, and slower O C ( =O) bond cleavage. Th e reactiv ity trend is also mirrored by decreasing global electrophilicity values 131,132 ( entry 6, a meas urement of increasing LUMO energies (entry 7); the accompanying LUMO plots on energy minimized structures ( Figure 3 3 ) further identify the lactone carbonyl groups as disparately electrophilic centres. T he tre nds seen in the NBO atomic charge s of the atoms involved in bond cleavage are more cryptic with respect to the observed reactivity trend. A tomic charges show an increase of negative charge at the O C=O oxygen (entry 4) moving from 2 3

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100 to 2 15 ; increased electron density on the leaving group can hinder bond cleavage For phenyl acetates, Galabov et al. have shown that a more positive carbonyl carbon has been shown to correlate well with faster ami nolysis rate, 121 yet in the series from 2 3 to 2 15 the atomic charge at the car bon increases upon ring opening (entry 3). Based on previous benchmarking studies, the average q C of 2 3 (BTF) would suggest aminolysis rates comparable to p halo phenyl acetates while the q C of 2 15 (BMF) would suggest an aminolysis rate exceeding that o f p nitro phenyl acetate. The discrepancy between this study and previous st udies is not currently apparent; however it is noted that Galabov et al. 121 found electrostatic potential at the nuclei (EPN) 133,134 values to be the best electrostatic descriptor of aminolysis rates in phenyl acetates. Seen also in this current study (entry 7), the EPN values of the carbony l carbon better predict the changes in reactivity than do the NBO carbon charges. Table 3 1 Structural measurements and reactivity descriptors from DFT calculations ( furanone derivatives) a Entry Descriptor 2 3 ( BTF ) 2 14 2 15 1 C=O ( ) 1.188 b 1.190, 1.1 91 c 1.193 2 O C =O ( ) 1.401 b 1.401, 1.394 c 1.394 3 q C ( C =O) d 0.815 b 0.817, 0.817 c 0.819 4 q O ( O C=O) d 0.521 b 0.524, 0.542 c 0.545 5 occ. (C=O) d 0.180 b 0.183, 0.187 c 0.190 6 (eV) e 1.73 1.38 1.10 7 LUMO (eV) 1.589 1.142 0.745 8 V C f b 14.620, 14. 626 c 14.636 a Data are derived from B3LYP/6 311++G** gas phase calculations on the following model compounds: 2 3 2 14 (where R 1 = CH 3 ), and 2 15 (where R 1 = R 2 = CH 3 ). b Average values reported for the spectroscopically symmetric structure. c Values are given for lactones containing C 1 (adjacent to OH) and C 5 (adjacent to CH 2 ), respectively d Atomic charges and occupancy of the lactone carbonyl orbital obtained from NBO population analysis. e Calculate d global electrophilicity index. f Electr ostatic Potential at Nuclei.

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101 Pyranone Series Figure 3 4. DFT calculations of benzopyranone derivatives show LUMOs localized to the reactive lactones and stepwise increases in LUMO levels upon ring opening. R = Me; values are calculated at the B3LYP/6 311++G** level of theory. Within the BTP series ( 2 21 2 22 2 23 ), also observed are stepwise changes in bond lengths and reactivity descriptors calculated for optimized model structures ( Figure 3 4 and Table 3 2 ) using the B3LYP/6 311++G ** method ology in the gas phase. I ncrease in the C=O (entry 1 ) and decrease in the O C (=O) (entry 2 ) bond lengths (from

PAGE 102

102 2 21 to 2 22 to 2 23 ) again reflect weakening of the carbonyl double bond (confirmed by IR, and mirrored in the crystal structures, vide supra ) and st rengthening of the O C (=O) single bond (mirrored in the crystal structures) I occupancy values (entry 5), decreasing global electrophilicity values ( entry 6 ), and inc reasing LUMO energies (entry 7) further support the step wise decrease in reactivity among the remaining lactone rings. Again the NBO atomic charge trends show an increase of negative charge at the O C=O oxygen (entry 4) moving from 2 21 to 2 23 ; likewise an increase of positive charge ( q C entry 3) at the ca rbonyl carbons is found in the BTP series. Within this series of compounds, it is determined that EPN values ( V C entry 8) also better reflect the decreas e of positive charge at the carbonyl carbon from 2 21 to 2 23 Table 3 2 Structural measurements an d reactivity descriptors from DFT calculations (pyranone derivatives ) a Entry Descriptor 2 21 ( BTP ) 2 22 2 23 1 C=O ( ) 1.196 b 1.19 8 1.19 9 c 1.200 2 O C =O ( ) 1.383 b 1.379, 1.377 c 1.373 3 q C ( C =O) d 0.817 b 0.819, 0.819 c 0.820 4 q O ( O C=O) d 0.552 b 0.547, 0.554 c 5 occ. (C=O) d 0.181 b 0.18 7 0.18 8 c 0.193 6 (eV) e 1.59 1.25 1.00 7 LUMO (eV) 1.412 0.986 0.653 8 V C f 632 c 14.646 a Data are derived from B3LYP/6 311++G** gas phase calculations on the following model compounds: 2 21 2 22 (where R 1 = CH 3 ), and 2 23 (where R 1 = R 2 = CH 3 ). b Average values reported for the spectroscopically symmetric structure. c Values are given for lactones containing C 9 (adjacent to OH) and C 5 (adjacent to CH 2 ), respectively d Atomic charges and occupancy of the lactone carbonyl orbital obtained from NBO population analysis. e Calculated global electrophilicity index. f Elect rostatic Potential at Nuclei.

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103 Analysis Although the reactivity descriptor trends are difficult to translate into a reaction mechanism at this stage they a) are mostly consistent with structure reactivity relationships derived from simpler esters and b) te ntatively e stablish an inductive argument to explain the stepwise changes in lacto ne aminolysis rate from 2 3 to 2 15 and 2 21 to 2 23 Previously noted, both the selectivity and the reactivity of BTF ( 2 3 ) are higher than that of its ring expanded analo gue, BTP ( 2 21 ). Calculated r eactivity descriptors clearly predict the enhanced reactivity of BTF over BTP with several descriptors ( LUMO and V C ) predicting the second ring opening of BTF (reactivity of 2 15 ) comparable in reactivity to the first ring op ening of BTP (reactivity of 2 21 ) a qualitative observation during synthesis The ability of the reactivity descriptors investigated to describe the differences in selectivity for the first ring opening between BTF ( 2 3 to 2 14 ) and BTP ( 2 21 to 2 22 ) is more difficult. Since the selectivity is attributed to differences in reaction rates, larger differences between reactivity descriptors from 2 3 to 2 14 as compared to 2 21 to 2 22 are required for qualitative correlations. Only the O C(=O) bond lengt hs (entry 2), carbonyl carbon atomic charge ( q O O C(=O), entry 4), electrophilic index ( entry 6), and the LUMO values (entry 7) show larger changes in the BTF series as compared to the BTP series. These trends by no means establish correlation, but the inability of the remaining reactivity descriptors to qualitatively predict this differe nce in selectivity is noted.

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104 Aminolysis Kinetics of BTF Quantification of absolute rate constants for the sequential aminolysis of BTF ( 2 3 ) can provide data to compare against the structure/reactivity relationships found in simpler systems ( vide infra ). Additionally, due to the lack of kinetic data for the su bstitution of cyanuric chloride (only monohydrolysis 135 is presented in the literature), this study represents the first kinetic quantification of a C 3 symmetric synthetic organic scaffold exhibiting high stepwise reactivity. Therefore, relative r ate constants for the aminolysis of each intermediate will also provide a benchmark for the high selectivity found in this system. The aminolysis of phenyl acetates in polar aprotic solvents has been extensively studied from both an experimental 113 116,121,127 and a theoretical point of view. 121,123,136 Normally, the kinetics of ester aminolysis follows second order rate laws, 113,114,121,127 while some studies have even presented evidence for a third order process. 116,122 In light of this data, pseudo first order conditions have been chosen for initials studies to simplify the analysis. Additionally, since deprotonation of intermediates 2 14 and 2 15 has been suggested ( Fig ure 3 2 ), a large excess of base (and nucleophile) will standardize this effect Due to the rapid aminolysis of BTF ( 2 3 vide infra ), t he aminolysis kinetics of derivatives 2 3 2 14 and 2 15 by n heptylamine in acetonitrile were followed by stopped flo w IR spectroscopy. Though the starting materials and the products have overlapping IR bands, the rate of disappearance of the C=O stretching frequency will correlate directly to the rate of starting material disappearance. Experiments were carried out un der pseudo first order conditions ( 20 equiv n heptylamine) for compounds 2 3 ( monitored at 1820 cm 1 ), 2 14 (monitored at 1812 cm 1 ), and 2 15

PAGE 105

105 (monitored at 1809 cm 1 ); data used for determination of k obs was limited to the linear portion of the pseudo f irst order rate plot. Figure 3 5. Representative n heptyl aminolysis plots of compounds 2 3 (top), 2 14 (middle), and 2 15 (bottom) in acetonitrile at 24 C as followed by FTIR spectroscopy. Plots on the left are time evolved differences (arrows show ev olution); plots on the right are pseudo first order kinetic plots (linear regressions are given for representative plots).

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106 A summary of the kinetic results obtained is given in Table 3 3 and examples of the pseudo first order kinetic analysis of compounds 2 3 2 14 and 2 15 are given in Figure 3 5 Immediately apparent is the quick first ring opening of 2 3 at room temperature. With a half life under one second (0.979 s), the first ring opening is difficult to track with precision; however, repeated meas urements have shown an average second order rate constant of 6.94 M 1 s 1 For reference, the aminolysis rate of 2 3 is more than an order of magnitude faster than the aminolysis of p nitrophenyl acetate under nearly identical conditions. 121 Table 3 3 Measured experimental rate constants a Compound k b [ M 1 s 1 ] ln k 2 3 6.94 1.94 2 14 0.125 2.08 2 15 0.012 6 4.37 p Nitrophenyl acetate c 0.2137 1.54 p Trifluoromethylphenyl c acetate 0.0199 3.92 Phenyl acetate c 1.95 x 10 4 8.54 a Pseudo first order rate constants at 24C for the n heptylaminolysis of lactones in acetonitrile b k = k obs /[C 7 H 15 NH 2 ] c n butylaminolysis in acetonitrile at 25 C. 121 The ring o penings of 2 14 and 2 15 are both much slower than the initial ring opening; with half lives of 54 seconds and 537 seconds respectively, the final ring openings are more than an order of magnitude slower than the first and nearly an order of magnitude apar t Shown in M 1 s 1 3 3 the last two ring openings are comparable to p nitrophenyl acetate and p trifluoromethylphenyl acetate respectively 121 Having limited quantitative data, correlations between reactivity indices and the aminolysis rates of 2 3 2 14 and 2 15 cannot be conclusively drawn, but comparisons between the data set w ithin this study and those in the literature are appropriate. Alluded to earlier, the most similar study in the literature is the computational and

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107 experimental study on the n butylamino lysis of para substituted phenyl acetates (in acetonitrile, at 25 C) as performed by Galabov et al. 121 In the previous study, the correlation betwee n DFT calculated reactivity indices (at the B3LYP/6 311++G** level of theory) were linearly correlated to the natural log of second order rate constants. Immediately apparent when comparing this study to previous studies is the inability for reactivity t rends within one series of compounds (substituted phenyl acetates) to quantitatively predict reactivity within a related, but different, structural environment. As an example, the strong correlation between V C (EPN) and ln( k ) found henyl acetates would predict a rate constant of 7.91 x 10 7 M 1 s 1 for aminolysis of BTF ( 2 3 ) far from the observed rate constant of 6.94 M 1 s 1 Despite the inability to directly predict reactivities between dissimilar structures, the linear correlation between a reactivity index and the reaction rate should more accurately describe the relationships within similar structures. Though Galabov et al. show a good positive correlation with q C (C=O) NBO atomic charges and aminolysis rates, this study finds a negative correlation between the NBO charge at the carbonyl carbon and the reaction rate. Fortunately, this study, and the one performed by Galabov, both find a positive correlation between the electrostatic potential at nuclei (EPN, V C ) and the natural l og of the second order reaction rate (ln( k )). While the aminolysis of para substituted phenyl acetates finds a linear correlation between V C and ln( k ) with a slope of 330, within the BTF series, the linear correlation slope is smaller at 230. The difficu ltly translating quantitative correlations between reactivity indices and rate constants are clearly shown in the present study.

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108 Discussion The selectivity seen through the stepwise aminolysis of BTF ( 2 3 ), and to a lesser extent BTP ( 2 21 ), has been attri buted to the electronic (inductive) changes of the aromatic core upon ring opening. Seen through the conversion of one OC(=O)CH 3 substituent to a OH substituent ( e.g. 2 3 to 2 14 ), the remaining lactones (phenyl acetates) are less reactive due to the in creased electron density in the aromatic ring (leaving group). In BTF derivatives, evidence for decreased reactivity of the lactone rings upon ring opening ( 2 3 to 2 16 ) is seen in both the 13 C NMR chemical shifts and C=O resonances of the lactone carbon yl carbon. The same trend is seen for the 13 C NMR chemical shifts of the BTP series ( 2 21 to 2 23 ) but the C=O resonances do not follow a distinct trend. In lieu of complex mechanistic studies, quantum chemical calculations on the ground state structure s support an increase in electron donation as being linked to decreased reactivity upon ring opening. While the majority of the calculated reactivity indices follow trends established in the literature, the NBO atomic charges show an opposite trend ( for b oth the BTF and BTP series of compounds ) The calculated reactivity descriptors were not able to conclusively predict the differences in aminolysis selectivity between BTF ( 2 3 ) and BTP ( 2 21 ). Future in silico experiments aim to determine the structure and energetics of the aminolysis transition states for 2 3 and 2 21 in addition to quantification of the ring strain (or strain relief in transition state) found within the five and six membered ring benzotrilactone families. Pseudo first order kinetic rates for the n heptylaminolysis of 2 3 2 14a and 2 15aa were recorded in acetonitrile at room temperature. As seen synthetically, the

PAGE 109

109 aminolysis of the 2 3 occurs extremely rapidly more than one order of magnitude faster than p nitrophenyl acetate. Subsequent ring openings are characterized by rates that are nearly an order of magnitude apart from one another. The kinetic rates observed were not well predicted by previous literature benchmarks, indicating the inability to accurately compare esters with significant structural differences. Additionally, t he linear correlation between the reactivity descriptor EPN ( V C Table 3 1 entry 8) and the natural log of the second order rate constant (ln( k obs /[C 7 H 15 NH 2 ])) was found to be smaller in magnitude t han that reported in the literature, suggesting more complexities in the reactivity of BTF ( 2 3 ) and its derivatives. Future kinetic experiments will quantify the aminolysis rate of the pyranone derivatives ( 2 21 2 22 and 2 23 ) in order to expand the da ta set used to make structure/reactivity relationships. In addition, the activation energy of transition states and the influence of the phenolic oxygen protonation state ( 2 22 and 2 23 ) on the amino lysis rate remain to be determined. Methods Quantum Chem ical Calculations Input files, molecular geometries and orbital density plots were generated using Gabedit. 137 Low energy structures were optimized in G03 138 employing the B3LYP functional 139 141 up to the 6 311++G(d,p) basis set; 142,143 in all cases no negative frequencies were found in the optimized geometries. Atomic charges were calculated via two different partitioning methods: Mulliken charges 144 and NBO charges. 130 NBO partitioning also allows for the calculation of orbital occupancies. Electrophilicity values ( ) were calculated according to the relationship 2 / where is the electronic chemical potential and is the global hardness. 132 Th e values

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110 of and 145 by and Pseudo First Order Kinetic s Pseudo first order kinetics of the aminolysis of BTF ( 2 3 ) at 24 C was followed on a Bruker Vertex 80V infrared spectrophotometer, coupled with a TgK Scientific SF 61/Stopped Flow injection system equipped with a 100 m path length stopped flow cell. All experiments were carried out in acetonitrile solution; the temperature varied by 0.2 C. At minimum, a 15 fold excess of n heptylamine was present at all times. Typical concentrations of the lactone were around 0. 005 M, while n heptylamine was present at 0.1 M. Each rate constant was determined as the average of three independent runs. Maximum deviations from the mean were 3% for BTF ( 2 3 ), 10% for BDF ( 2 14a ), and 18% for BMF ( 2 15aa ).

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111 CHAPTER 4 RAPID SYN THESIS OF 1 AZA ADAMANTANETRIONE ORGANOGELATORS WITH CONTROL OF SYMMETRY Overview In the late 1980s Risch and coworkers demonstrated the ability for peralkylated phloroglucinols ( 4 1 ) to be cyclized into substituted 1 aza adamantane triones 146 ( AATs 4 2 ) via a Mannich type reaction 147 ( Figure 4 1 ). This simple synthetic procedure was the basis for early exploration of AAT molecules ability to self assemble via electrostatic interactions ( vide infra ) and provided motivation for improved synthesis of persubstituted phloroglucinols as previously me ntioned. This Chapter will briefly summarize previous work performed with AATs and then showcase the use of benzotrifuranone ( BTF 2 3 ) as a synthon to rapidly build a small library of AAT derivatives to elucidate supramolecular structure/property relatio nships Figure 4 1. Synthesis of AAT ( 4 2 ) from phloroglucinol ( 4 1 ) precursors as demonstrated by Risch and coworkers 147 (HMTA = hexamethylenetetramine) 3 1 Aza adamantanetriones 93,147 ( AATs 4 2 ), with their tricyclic aminoketone 148 cores, are unique scaffolds enabling studies of through bond 149,150 (hyperconjugative 151 153 ) interactions (TBI) at both the molecular 93,154 156 and supramolecular 70,91,157 level. The rigidity of the core maintains orbital overlap and communication bet ween the donor (amine) and acceptor (carbonyls) through the intervening C bonds (D A Portions of this Chapter are reprinted with permission from Baker, M. B.; Yua n, L.; Marth, C. J.; Li, Y.; Castellano, R. K. Supramolecular Chemistry 2010 22 789 802.

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112 interactions). Previously shown with alkyl (R = alkyl) and ester (R = CH 2 CO 2 R') functionalized AATs, molecular level consequences of D A interactions include de creased basicity of the bridgehead nitrogen, 156 bond length alteration, as well as the coupled UV absorption. 93 Furthermore, as the AAT core bears a significant dipole alon g its C 3 axis and can be functionalized through organic synthesis, this class of compounds appears attractive for dipole directed self assembly 70,91,157 161 and supramolecular materials construction. Accordingly, several aryl (R = CH 2 Ar ) and aryl amide (R = CH 2 CONHAr) derivatives have been shown to gelate organic solvents 70,91,157 at low concentrations (< 1 wt%). Complementary theoretical studies have additionally explored the propensity for AATs to adopt a propeller conformation ( Figure 4 2 ) and self assemble in a 1 D head to tail manner ; 148,162,163 interestingly, this ass embly process is accompanied by a decrease of the HOMO LUMO gap through emergence of a unique supramolecular electronic structure ( Figure 4 2 ) Figure 4 2. Calculated conformation and assembly of aryl amido AAT architectures; a) 3 D CPK model of aryl amide AAT conformation ; b) c alculated 1 D stack of simple aryl amide substituted AAT molecules. Also s hown is a calculated gas phase dimerization energy (DFT(LDA)/cc pVDZ) 163

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113 While computation has implicated assemblies of AATs as unique low band gap supramolecular architectures, 163 rapid access to diversely substituted targets facilitating structure assembly studies has remained elusive. The previous synthetic approa ch to aryl amide functionalized AATs ( 4 5 ) for example, involved construction of a methyl protected C 3 symmetric phloroglucinol substrate 4 3 BBr 3 deprotection to afford the native aryl amide phloroglucinol 4 4 and subsequent cyclization with hexamethyl enetetramine (HMTA) ( Figure 4 3 ). 91 Figure 4 3. A schematic of past and present procedures for construction of amido AATs. Ring opening of BTF ( 2 3 bottom ) to form tri amide phloroglucinol derivatives ( 4 4 ) provides a much milder route to aryl amide AATs ( 4 5 ) than those (top) 91 involving BBr 3 deprotection, and opportunities to ra tionally prepare non C 3 symmetric derivatives. Ar = aryl. Two relatively simple aryl amide AATs have been prepared in this way ( 1a and 1b Table 4 1 ), 91 but the demanding and late stage deprotection step has limited access t o a structurally diverse family of compounds. A straightforward solution is presented here, made possible by the recent development of a phloroglucinol derived trilactone, benzotrifuranone (BTF 2 3, Figure 4 3 ). 69 As a note to the reader, the synthesis of the

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114 AAT library in this study was achieved before understanding the full potential of BTF as a synthon. Synthesis of AATs First s hown is the synthesis of (previously inacc essible ) C 3 s ymme tric phloroglucinol derivatives ( substrates for cycliza tion into the corresponding tri amide AAT s) available in one step through nucleophilic ring opening of three lactone rings ( Figure 4 3 ) This synthetic approach allows rapid prep aration of AAT targets with increased structural diversity (e.g., bearing electron rich, electron deficient, and expanded aromatic substituents) and, for the first time, demonstration of how complementary aromatic interactions 102,164 166 can affect AAT assemb ly via mixed gels. 167,168 Secondly presented is a BTF based approach to efficiently prepare the first functionalized AATs of lower ( C s ) symmetry (i.e., AATs bearing two different types of aryl amide substituents). D esymmetrization commences wit h stepwise ring opening of 2 3 to afford (depending on the reaction conditions) primarily monolactone 4 6 or dilactone 4 7 ; a procedure attributed to through the aromatic core and supported through further in vestigation ( Chapter 2 ). Subsequent ring opening with a second aniline (H 2 NAr 1 ) and cyclization affords non C 3 symmetric AATs capable of displaying hybrid structures and properties Synthesis of C 3 symmetric AATs The general reaction scheme for C 3 symme tric AAT formation from BTF is shown in Figure 4 3 Benzotrifuranone (BTF, 2 3 ) was synthesized on multi gram scale as mentioned in Chapter 2 and published in 2009 69 Shown in Table 4 1 a variety of electron rich and deficient anilines could be used to open the lactone rings of 2 3 providing rapid access to phloroglucinol substrates for cyclization into AATs During this

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115 study BTF was simply stirred with an excess of nucle ophile in an aprotic solve nt at temperatures ranging from 60 C to 110 C ( unreacted ) aniline could be recovered through selective extraction and subsequent purification) ; results shown in previous C hapters provide more optimized conditions Anilines in e ntries i v vii and viii were able to fully react with 2 3 in toluene at reflux with the exhaustively ring opened species ( 4 4a e g and h respectively) precipitat ing from solution as the major product in good yield (30 80%) Alt hough 3,5 dimethox yaniline is known to be a good nucleophile, 169 compound 4 4 d (entry iv) was only formed in appreciable yield after several nights of heating (now in TH F at reflux) due to the insolubility of a partially ring opened ( diamide monolactone ) intermediate (i.e., 4 6 d in Figure 4 3 ) Several other entries ( ii vi and x ) required the slightly more polar THF to realize complete conversion, including anilines featuring more electron deficient substituent s (entries xi and xii ). Phloroglucinols bearing electron deficient aromatics ( 4 4 g, h, k, l ) tended to form fairly insoluble materials, attributed to the increased hydrogen bonding of the amide unit along with the stacking interactions expected for the less electron rich aromatic rings. 102,170 Not surprisingly, highly electron deficient anilines (pe rfluoroanili n e and dimethyl 5 aminoisophthalate ) and those with electron withdrawing para substituents ( p nitroaniline, p cyanoaniline and 7 ac e tyl 2 aminonaphthalene ) were unable to form the corresponding phloroglucinol (mixtures of ring opened products were formed, not shown) ; th ese result s were attributed to poor nucleophilicity of the aniline derivatives. At this point, it is i mportant to recognize, species 4 4 c f and h were previously inaccessible from intermediate 4 3 ( Table 4 1 ).

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116 The phloroglucinol derivatives 4 4 a j were then subjected to standard AAT fo rming cyclization conditions 91,93,147,157 As a general procedure, the phloroglucinol substrate was stirred in i PrOH at reflux in the presence of 1.5 3 equivalents of HMTA over one to five nights (c ompounds 4 4 b h i and j needed longer reaction times due to poor solubility of the phloroglucinol ); the corresponding insoluble AAT s were simply collected by filtration and then w ash ed. Table 4 1. A representative library of C 3 symmetric AAT derivatives synthesized in two steps from BTF Entry Nuc leophile (NH 2 Ar) Yield ( 4 4 ) Yield ( 4 5 ) Entry Nucleophile (NH 2 Ar) Yield ( 4 4 ) Yield ( 4 5 ) i 78% a ( 4 4a ) 75% b ( 4 5a ) vi 91 % c ( 4 4f ) 40% b ( 4 5f ) ii 56% c ( 4 4b ) 61% b ( 4 5b ) vii 76% a ( 4 4 g ) 35% b ( 4 5g ) iii 78% c ( 4 4c ) 53% b ( 4 5c ) viii 68% a ( 4 4h ) 21% b ( 4 5h ) iv 42% c ( 4 4d ) 11% b ( 4 5d ) ix 55% d ( 4 4i ) 66% b ( 4 5i ) v 33% a ( 4 4e ) 53% b ( 4 5e ) x 25% c ( 4 4j ) 65% b ( 4 5j ) a 9 equiv of nucleophile and 1 equiv of BTF in toluene at reflux 16 48 h, b phloroglucinol substrate and 1.5 3 equiv of HMTA in i PrOH at reflux 16 120 h, c 9 equiv of nucleophile a nd 1 equiv of BTF in THF at reflux 16 72 h, d 6 equiv of nucleophile and 1 equiv of BTF in DMF 120 C 24 h, e no reaction after five days. Synthesis of C s symmetric AATs Shown in previous chapters and alluded to earlier the b etween the three lactone rings of BTF ( 2 3 ) via its central aromatic core are the basis for a controllable stepwise ring opening strategy to form lower symmetry phloroglucinol derivatives ( Figure 4 4 ) The synthesis of dilactone 4 7 a can be realized in 56 % yield

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117 (86% based on recovered starting material) using an excess of aniline, mild heating (40 C), and a limited reaction time (8 h). Th is result speaks to a relatively rapid initial ring opening of BTF even in the presence of the weakly nucleophilic an ilines (as compared to alkyl amines) Monolactone 4 6 a could be prepared in good yield ( 4 5 % ) using slightly warmer temperatures, longer reaction times, and a small excess of aniline. In light of the results found in previous chapters, the synthesis of 4 6 a and 4 7 a represent initial, un optimized conditions and moderate ly selec tive ring openings. Figure 4 4 The c ontrol of st o i chiometry, solubility, and temperature allow s for control of BTF ring openings ; percentages ar e based on isolated or recovered material Both the monolactone 4 6 a and dilactone 4 7 a were then used to prepare C s symmetric AAT molecules as shown in Figure 4 5 Dilactone 4 7 a was synthesized with an excess of 4 dodecylaniline in hot THF to afford phl oroglucinol 4 4abb isolated by si mple filtration; cyclization then led to a 56% yield of AAT 4 5abb Correspondingly, the monolactone 4 6 a could be ring opened in hot DM F by naphthylamine providing phloroglucinol 4 4aai in good yield (70%). Subsequent cyclization with HMTA produced

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118 the C s symmetric AAT 4 5aai one of two possible hybrid structures of AATs 4 5a and 4 5i Figure 4 5 The u t ilization of 4 7 a and 4 6 a allows for the synthesis of C s symmetric AAT molecules. Characterization of Supramolecular Assemblies C 3 symmetric D erivatives Given that previous ly prepared 4 5 b showed self assembly behavior in solution and the ability to gelat e organic solvents, 91 the newly synthesized AAT derivatives were tested for analogous behavior in a representative selection of organic solvents ( Table 4 2 ) The majority of the derivatives synthesized are exceedingly insolu ble in most solvents, aside from DMF, DMSO and pyridine a trend found for other AATs O f the structures in Table 4 1 compounds 4 4e, g and j form gels (as d efined by the inverted vial technique 171 173 ) in a limited range of solvent s upon heating ( to form an isotropic phase ) and cooling at ambient temperature ( Figure 4 6 ) AAT 4 5 e form s a n opaque gel atinous phase in CHCl 3 ( Figure 4 6 a ) from 0.25 2 wt% AAT 4 5 g forms an opaque gel in 1,1,2,2 tetrachloroethane (TCE ; Figure 4 6 b ) from 0.25 1 wt% and AAT 4 5 j

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119 creates translucent gels in both toluene ( Figure 4 6 c ) and benzene (not shown) from 0.2 3 wt % Worth noting, these gel phase s remain stable over the course of several weeks. Table 4 2. Solubility and gelation profiles of selected AAT derivatives a 4 5c 4 5d 4 5e 4 5g 4 5h 4 5i 4 5j Hexanes I I I I I I I CHCl3 I I G [0.25] (0.3, 45) I I I Gb TCE I I S G [0.25] (0.3, 110) I I -4 5 e + 4 5 g [0.3]c (0.3, 55) THF I I I P I I I MeCN I I P I I P P Toluene I I I I I I G [0.2] (0.3, 72) Benzene I I I I I I G [0.2] Pyridine S S S S S S S DMF S S S S S S S DMSO S S S S S S S a All concentrations are given in w/w % Critical gelation concentrations (CGCs) are given in brackets. T gel concentrations and values (C) are given in parentheses. I = insoluble in solvent to 0.05 wt%; G = gel as determined by inverted vial te chnique; P = compound precipitates from isotropic mixture; S = compound is soluble in solvent up to 2 wt % b Gel forms at 45 C. c Equimolar mixture. 174 the T gel of a 0.3 wt% solution of 4 5 g in TCE was measured to be 110 C the most thermally stable gel for this class of compounds to date while the T gel of a 0.3 wt% solution of 4 5 e in CHCl 3 was determined to be 45 C. The sol gel transition p robed in the preceding experiments is not wholly reversible; once partially melted, the mixture does not return to the gel state upon cooling, but must be heated to an isotropic mixture and allowed to cool again (a process that may be

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120 Figure 4 6. Invert ed gels formed from AATs in sealed glass vials upon heating and cooling at ambient temperature. a ) 0.30 wt% compound 4 5e in CHCl 3 ; b ) 0.30 wt% compound 4 5g in TCE; c ) 0.2 wt% compound 4 5j in toluene; d ) 0.30 wt% of an equimolar 4 5e and 4 5g in TCE; e ) 0.25 wt % equimolar amounts of 4 5e and 4 5g in a 2:1 mixture of CHCl 3 : TCE; f ) 0.40 wt% compound 4 5m in CHCl 3 repeated multiple times ) Unexpected given the high thermal stability exhibited by these gels, moderate shock to the formed gel results in an immediate breakdown of the gel phase to a viscous suspension of the material. This behavior is believed to be due to a more crystalline (anisotropic) gel formed with these derivatives, in direct contrast with (translucent) gels of 4 5j in toluene ( T gel = 72 C). Cooling after melting of the 4 5 j gel results in a semi gel (unable to support its own weight, but gelatinous) while agitation also results in a semi gel. These previous results speak towards the inability of the gel network to repair itself. Rap id access from BTF ( 2 3 ) to aryl amide AAT derivatives 4 5 with diverse aromatic substituents has allowed the exploration of mixed AAT assemblies for the first time. This line of investigation is relatively new, but is already showing a role for

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121 complemen tary aromatic interactions in the self assembly and gel forming behavior of the molecules A n equimolar (binary) mixture of 4 5 e and 4 5 g for example, forms a gel in both neat TCE ( critical gelation concentration ( CGC )= 0.3 wt % and T gel = 55 C ) and a 1: 2 (w/w) TCE:CHCl 3 ( CGC = 0.2 wt% ) solution ( Figures 4 6 d and 4 6 e wt% is calculated using the mass of the binary mixture ). O f note here is that compound 4 5 g is unable to gel TCE below a concentration of 0.25 wt% and that compound 4 5 e is freely soluble in TCE up to 2 wt%, yet the combination of the two enables gelation of the solvent system. While little can be inferred with respect to molecular level ordering from this result, it does suggest that there is some complementarity between the molecules in the gel network The ability to form mixed gels within a system unlocks the possibility for further control of gel morphologies and properties; multi component gels ha ve already proven promising for mixed gels with H bonding motifs. 167,175 ,176 Samples of gels 4 5 e and 4 5 g were freeze dried (lyophilized) for imaging of the underlying morphology forming the basis for the gel networks Evident in the TEM micrographs ( Figures 4 7 a d ), all samples show the presence of high aspect ratio fibe rs common to many organogelators. 173,177 179 Fibers here can be on the order of millimeters in length, and consist of bundles (4 10) of sheets with the individual sheets averaging 200 nm in width. The fibers in the micrographs appear brittle, with fracturing and splintering of the structures at the extremes. The overall morphology contrasts with previous ly studied 4 5 b that showed mostly lamellar architectures on the nanoscale. 91

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122 Figure 4 7. M icrographs of dried gels. TEM images of a ) high aspect ratio fibers formed in the freeze dried gel of 4 5e ; nanoscale features within the fib ers formed in the freeze dried gel of 4 5e ( b ) and 4 5g ( c ); d ) fibrous aggregates formed within the mixed gel of 4 5e and 4 5g e ) and f ): SEM images of the entangled fiber networks formed in the CPD gel sample of 4 5j To gain better insight into the mo rphology of the toluene gel of 4 5 j SEM was used to image critical point dried (CPD) gel samples 180,181 In the CPD gel sample of 4 5 j a lamellar sheet architecture is observed with layers of uniform thickness of about 5 m ( Figures 4 7 e and f ). The surface of the sheets reveals ~3 m entangled fibers and s maller fibers are observed among the entangled fibers comprising the self assembled network. Both fibrous and lamellar architectures have been observed before in the A AT systems, but this is the first case where both morphologies are visible in one sample. While TEM and SEM techniques provide insightful nanoscale image s not necessarily observed are architectures best reflecting the assemblies constituting the

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123 native or ganogel phase (i.e., often observed are assemblies formed upon solvent evaporation that survive the freeze drying or CPD process ). As a gentler technique, s tructures within the native gel s can be imaged at lower resolution by polarized optical microscopy (POM). The gels of 4 5 e in CHCl 3 and 4 5 g in TCE have been studied in this way to reveal features not present in the TEM micrographs ( Figure 4 8 ). While the former shows a fairly uniform distribution of crystalline (birefringent) fibers, the latter shows a dual morphology. E vident in the micrograph of 4 5 g is spherulitic crystal growth, usually detrimental to 1 D fibrous gel formation 182 C loser inspection also shows the presence of extremely high aspe ct ratio and flexible fibers dispersed Figure 4 7. Polarized optical microscopy ( POM ) images of the native gel phases (top row is 4 5e in CHCl 3 ; bottom row is 4 5g in TCE; the images on the right side have been taken with the polarizers crossed). Noti ce the high concentration of anisotropic (crystalline) fibers within both micrographs as well as the distinctly different morphologies found in the two systems.

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124 throughout the sample ; the longer fibers are only weakly birefringen t at the ir edges. Quick c ooling of a solution of 4 5 g in TCE le a d s to formation of mostly well dispersed crystalline fibers ( not shown ), and no gel formation It is hypothesized that the dual morphology of the gel formed from 4 5g at room temperature imparts its impressive therma l stability to this system ( vida supra ). C s symmetric D erivatives C s symmetric 4 5aai shows no evidence of gelation of the solvents tested, a result consistent with its poor solubility and the lack of gelation of its AAT congeners 4 5 a and 4 5 i ; however, h ybrid 4 5abb does gel CHCl 3 quite efficiently ( Figure 4 5 f transparency and parameters (CGC ~ 0.4 wt% and T gel ~ 50 C) are similar to properties previously reported for C 3 symmetric 4 5 b (CGC ~ 0.5 wt% and T gel ~ 57 C), 91 but obviously quite unique from non gelator 4 5 a Also, akin to transparent gels 4 5 b and 4 5 j the 4 5abb gel is quite resistant to shock and maintains its integrity under mild agitation. It is anticipated that access to lower symmetry and hybrid AATs will provide a unique way to identify the structural elements most responsible for the gelation pro perties of this molecular class and even an approach to rationally tune macromolecular properties. Established thus far AAT compounds with lon g alkyl chains on the periphery form more optically clear and mechanically stable gels, while the simple aryl 157 or aryl amide 91 AAT derivatives form highly crystalline networks that are able to immob ilize solvent. Investigation into the rheology of AAT gels has been given attention, but has not yet drawn connections between the bulk properties, observed morphologies, and molecular structures of the systems.

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125 Addressing Synthetic Limitations of AAT Che mistry Limitations to AAT cyclization Rapid access to diversely functionalized phloroglucinol substrates from BTF has shed new light on the scope of the AAT forming cyclization step (the conversion of 4 4 to 4 5 ). While tolerant of multiple functional gro ups, at least two classes of phloroglucinols ( 4 4 ) do not react well. Those bearing quite electron deficient aromatics or exogenous heteroatoms (e.g., 4 4 k l and m ) show no evidence (by 1 H NMR analysis) of AAT formation under the standard conditions eve n over five nights. The result is best explained by the significant insolubility (due to the forces identified above) of the substrates. Not implicated, by absence of lactone or acid products, is re lactonization of the phloroglucinol substrates under th e HMTA cyclization conditions; preliminary evidence does show that this can occur under acidic conditions (e.g., trifluoroacetic acid/toluene). Also unsuitable for AAT formation are highly soluble Table 4 3 Nucleophiles used for formation of phlorogluci nols unsuitable for cyclization Entry Nuc leophile (NH 2 Ar) Yield ( 4 4 ) Yield ( 4 5 ) Entry Nucleophile (NH 2 Ar) Yield ( 4 4 ) Yield ( 4 5 ) xi 36% a ( 4 4k ) -b x v 55% c ( 4 4o ) -b xii 40% a ( 4 4l ) -b x vi 78% c ( 4 4p ) -b x iii 39 % a ( 4 4m ) -b x vii 67% c ( 4 4q ) -b x iv 88 % c ( 4 4n ) -b a 9 equiv of nucleophile and 1 equiv of BTF in THF at reflux 16 48 h, b corresponding phloroglucinol substrate and 1.5 3 equiv of HMTA in i PrOH at reflux 16 120 h, c 9 equiv of nucleophile and 1 equiv of BTF in THF 12 h.

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126 phlorogluci nol derivatives with long chain alkoxy aromatics ( 4 4n and 4 4o ) or phloroglucinols with secondary amides ( 4 4p and 4 4q ). These negative results speak to the delicate balance between the solubility of the phloroglucinol starting material and insolubility of the AAT product dictating cyclization success G iven that the formation of the AAT core occurs at the expense of phloroglucinol aromaticity, precipitation of the product represents a potential driving force for the reaction. Further investigation int o the scope of the HMTA cyclization has further suggested precipitation of the product as a pre requisite for successful conversion. Post cyclization AAT Transformation As noted in the previous section, the cyclization of phloroglucinol substrates into AA T molecules is sensitive to solubility Under specific conditions (soluble phloroglucinol, insoluble AAT product) the cyclization proceeds in good yields; however, many substrates do not yield the triple Mannich reaction ( Table 4 3 ). In order to expand the use of AAT as a supramolecular synthon, and investigate putative AAT 1 D assemblies is to introduce stabilizing peripheral interactions to the core Previous synthetic methodology has focused on the installation of peripheral groups prior to AAT forma tion, but given sensitive cyclization chemistry a reliable AAT with functional could allow facile installation of peripheral functionality Previous work 93,154,156 has demonstrated the stability of the AAT core to standard reagents (Figure 4 8). AATs are unreactive under common nitroge n and carbonyl functionaliz ation conditions suggesting the core may be usefully tolerant to a variety of distal transformations.

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127 Figure 4 8 Previous attempts at synthetic transformation of the AAT core. Ideal for successful implementation of a post cyclization transformation is a mild, high yielding (especially so in light of the three fold transformation s necessary), and functionally tolerant click reaction. 6 While several reactions have two of the most popular in materials scie nce and biology are the thiol ene coupling 16 and the Cu catalyzed 1 ,3 dipolar cy c loaddition of azides and alkynes. 8,183 Analyzing the speci fic substrates necessary for reaction s has led to the pursuit of AAT molecules with terminal double and triple bonds as substrates for post cyclization functionalization ( Figure 4 9 ) Shown in Figure 4 9 starting from BTF, simple alkyl amines s uch as allyl amine and propargyl amine could produce phloroglucinols 2 16jjj and 2 16kkk in good yield ; h owever, subsequent cyclization attempts did not yield the corresponding AAT derivatives in good yield In both cases, evidence for the cyclization of the substrate was confirmed by NMR and HRMS, yet isolation of the AAT was not accomplished. As a comparative structure compound 2 16kkk was coupled with benzyl azide, producing

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128 phloroglucinol 2 16mmm in good yield ; subsequent cyclization yielded AAT 4 5 t T he synthesis of this compound via the originally proposed route was never realized. Figure 4 9 Initial synthetic attempts to form AATs with synthetic handles Difficulty in the synthesis of an amide based AAT with functional synthetic handles led to investigation of known compound 93 4 2a as a functional precursor With three peripheral double bonds this compound is well suited to serve as a substrate for thiol ene coupling; additionally th e higher solubility of 4 2a as compared to amide based

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129 AATs, allow s for easier product isolation. When c ompound 4 2a was subjected to thiol ene coupling conditions with an excess of 2 mercapto ethanol, tri thioether 4 2b was indeed generated ( Figure 4 10 ). Though the product was isolated in low yield this presents the first successful post cyclization functionalization performed on an intact AAT core. This initial success holds promise for ac cessing richly functionalized AAT derivatives through similar post cyclization coupling reaction s Figure 4 10 The first successful post cyclization functiona lization of an AAT molecule was accomplished through a thiol ene coupling strategy Discussion New approaches to the synthesis of fully substituted phloroglucinols ( 4 4 ) from a common benzotrifuranone (BTF, 2 3 ) precursor have provided efficient access to previously unattainable C 3 and C s symmetric 1 aza adamantan etriones (AATs, 4 5 ). The synthetic chemistry has enabled preparation of a structurally diverse ten component library of C 3 symmetric aryl amide AATs, and exploration of the first binary AAT based organogel systems. Enhanced gelation has been observed fo r ensembles containing AAT monomers with electronically complementary aromatic substituents ( 4 5e and 4 5 g ). Introduction of an expanded aromatic substituent to the AAT scaffold has provided a molecule ( 4 5j ) that effectively immobilizes aromatic solvents at low concentrations (~ 0.3 wt%). Quite uniquely, BTF also enables a stepwise approach to prepare the first differentially functionalized phloroglucinol derivatives and ultimately C s

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130 symmetric AAT molecules; one derivative, 4 5 abb forms translucent gel s at ~ 0.4 wt% in chloroform. This discovery bodes well for the construction of chimeric AAT molecules for structure property elucidation and the creation of hybrid functional materials. The organogels derived from both the C 3 and C s symmetric AAT syst ems have been characterized both macroscopically and on the nanoscale. Electron microscopy of the gel morphologies shows high aspect ratio fibers underlying the gel network superstructures in most cases. Polarized optical microscopy has allowed imaging o f the native organogel phases, and reveals striking morphology differences between gels that also share different optical and/or phase stability properties. During this study, multiple phloroglucinol derivatives ( 4 4 Table 4 3 ) were formed from BTF, but further conversion to AATs under various cyclization conditions failed Phloroglucinols prone to aggregation were prohibitively insoluble and were never converted to AATs under the conditions tested; phloroglucinols with high solubility showed uncharacte rizable degradation products Given these negative results on both ends of the solubility spectrum, clearly a balance is needed with respect to the starting material and product solubilities To expand the scope of functionalized AAT construction the syn thesis of an AAT with versatile functional synthetic handles was explored. Two phloroglucinol derivatives with terminal double and triple bonds ( 2 16jjj and 2 16kkk respectively) were synthesized; however, neither saw successful conversion to an AAT. Ab andoning the amido AAT for a simpler al l yl substituted AAT, led to the first successful post cyclization transformation via thiol ene chemistry.

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131 O verall, access to a broader array of AATs is beginning to draw previously inaccessible relationships between structure, solubility, and gel appearance/stability within this class of self assembling molecules. Among the most alluring future lines of investigation with the AATs remains their exploration in the context of supramolecular electronics. 184 Efforts here could be leveraged by the BTF methodol ogy that can provide molecular and supramolecular AAT structures rapidly. Experimental Methods Reagents and solvents were purchased from Acros, Aldrich, or Fluka and used without further purification unless otherwise specified; 2 naphthylamine was purchase d from Toronto Research Chemicals Inc. THF and DMF were degassed in 20 L drums and passed through two sequential purification columns (molecular sieves) under a positive argon atmosphere using a custom Glass Contour solvent system (Glass Contour, Inc.). Thin layer chromatography (TLC) was performed on Dynamic Adsorbents, Inc. aluminum backed TLC plates with visualization via UV light or staining. 1 H NMR and 13 C NMR were recorded on a Varian Mercury 300, Gemini 300, or an Inova 500 spectrometer. Chemical to residual protonated solvent (CHCl 3 H C H 2.50 C H C 123.9, 135.9, 150.4 ppm). Abbreviations used are s (singlet) d (doublet), t (triplet), q (quartet), and m (multiplet). Representative 1 H and 13 C NMR of selected compounds are presented in Appendix C. MS spectra (HRMS) were acquired on a Bruker APEX II 4.7 T Fourier Transform Ion Cyclone Resonance mass spectromet er (Bruker Daltonics, Billerica, MA). DSC and TGA thermograms were taken on a Thermal Analysis DSC Q1000 and TGA Q5000,

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132 respectively. POM images were recorded by a Leica DFC295 camera using a Leica DMLP microscope coupled with a Linkam LTS350 heating sta ge. Representative gel formation 1 Aza adamantanetrione 4 5 g (5.1 mg, 0.3% by weight) and 1,1,2,2 tetrachloroethane (TCE, 1.71 g) were combined in a sealed vial. The vial was heated with a heat gun until a homogenous solution was formed. The vial was th en allowed to gradually cool to room temperature on the bench top, during which time the gel rapidly formed (ca. 10 min). T gel determination An organogel of 4 5 g in TCE with a volume of ca. 2.0 mL was prepared in a vial with a diameter of 10 mm. After the gel had aged for 12 hours at 25 C, a steel ball with a diameter of 2 mm was placed on top of the gel, the vial was resealed, and placed in an oil bath. The temperature was slowly increased (ca. 0.5 C/min), and monitored using a thermometer submerged in a vial containing an equal weight of neat TCE also in the oil bath, while observing the position of the steel ball. The temperature at which the ball touched the bottom of the vial was taken as the T gel This experiment was carried out three times, and the T gel values obtained were reproducible to within 2 C. Representative gel freeze drying procedure A vial containing the organogel of 4 5 g in TCE was frozen in liquid nitrogen and transferred to a freeze dry system (Labconco FreeZone 4.5 L) overnight. Critical point drying (CPD) of 4 5f gel Supercritical fluid drying of 4 5 f gels was performed in a 3000 psi rated vessel (Parr Instruments). Samples were placed into regenerated cellulose dialysis bags with a pore diameter of 12000 to 14000 MWCO (Fisher Scientific, USA). Samples were placed

PAGE 133

133 inside the drying chamber and liquid CO 2 was introduced. Toluene was exchanged with liquid CO 2 over 5 6 solvent exchange steps. After complete solvent removal, the vessel containing the liquid CO 2 was heated via a w ater jacket and water bath to 50 C and 1500 psi. At equilibrium, the supercritical CO 2 was released from the vessel at a rate no greater than 4 L/min. Synthesis (3s,5s,7s) 3,5,7 T ris(3 ((2 hydroxyethyl)thio)propyl) 1 az aadamantane 4,6,10 trione (4 2 b ). To a solution of 1,1,2,2 tetrachloroethane (3 mL) was added 4 2a (23 mg, 0.077 mmol), followed by 2 mercaptoethanol (33 mg, 0.43 mmol) and then AIBN (3.4 mg, 0.02 mmol). The reaction was heated to 100 C overnight under an argon atmosphere. After cooling to room temperature, the reaction mixture was run through a plug of silica, washed with 10% MeOH in DCM, and then organic solvent was removed in vacuo Purification of the residue by preparat ive TLC (10% MeOH in DCM) yi elded compound 4 2b (7.1 mg, 11%) as a white solid. 1 H NMR ( d 6 DMSO 2.57 (m, 6H), 2.65 (t, J =7.0 Hz, 6H), 3.43 (s, 6H), 3.52 (m, 6H), 4.76 (t, J =5.6 Hz, 3H). 13 C NMR ( d 6 DMSO HRMS (ESI) calcd for C 24 H 39 NO 6 S 3 [M+K] + 556.1832, found 556.1835.

PAGE 134

134 Representative s ynthesis of p hloroglucinols from BTF: s ynthesis of 2,2',2'' (2,4,6 trihydroxybenzene 1,3,5 triyl)tris( N (3,4 dimethoxyphenyl)acetamide) ( 4 4e). To a 25 mL round bottom flask equipped with stirbar and reflux condenser was added BTF 2 3 (250 mg, 1.02 mmol) and 4 aminoveratrole (1.40 g, 9.14 mmol) followed by degassed toluene (10 mL). The reaction vessel was placed in an oil bath and heated to reflux overnight under an argon atmosphere. The solution was then cooled to room temperature and the precipitates were removed by filtration and subsequently washed with toluene, ethyl acetate, and hexanes. Compound 4 4 e (240 mg, 33%) was obtained as a light brown solid and used without further purification. 1 H NMR ( d 6 (m, 24H), 6.88 (d, J = 8.8 Hz, 3H), 7.09 (dd, J = 8.7, 2.2 Hz, 3H), 7.32 (d, J = 2.2 Hz, 3H), 9.53 (s, 3H), 10.12 (s, 3H). 13 C NMR ( d 6 104.60, 111.39, 111.94, 132.33, 144.99, 148.46, 153.64, 171.35. HRMS (ESI) calculated for C 36 H 40 N 3 O 12 [M+H] + 706.2607, found 706.2608. 2,2',2'' (2,4,6 Trihydroxybenzene 1,3,5 triyl)tris( N phenylacetamide) (4 4a). The compound was synthesized starting from BTF (150 mg, 0.610 mmol), aniline (283

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135 mg, 3.00 mmol), and DMF (7 mL). The reaction vessel was heated to 120 C for 15 h. Upon cooling to room temperature, the reaction mixture was poured into brine (50 mL) and extracted with EtOAc. The combined organic layers were washed with 1 M HCl and water, and then dried over Na 2 SO 4 The solvent was removed and the residue was purified by flash column chromatography (1/3 to 1/1 EtOAc/hexanes) to yield 4 4 a (240 mg, 97%). The spectroscopic data matches the literature. 12 1 H NMR ( d 6 (s 6H), 7.05 (t, J = 7.5 Hz, 3H), 7.30 (t, J = 7.8 Hz, 6H), 7.61 (d, J = 7.8 Hz, 6H), 9.32 (s, 3H), 10.21 (s, 3H). 13 C NMR ( d 6 153.6, 171.6. 2,2',2'' (2,4,6 Trihydroxybenzen e 1,3,5 triyl)tris( N (4 dodecylphenyl)acetamide) (4 4 b). BTF (52 mg, 0.21 mmol) was added to a stirred solution of 4 dodecylaniline (405 mg, 1.55 mmol) in THF (5 mL). The reaction vessel was heated to reflux for 16 h. Precipitates were removed by filtrati on and washed with hexanes to yield 4 4 b (122 mg, 56%) as a white solid. The spectroscopic data matches the literature. 12 1 H NMR ( d 6 DMSO / CDCl 3 J = 6.5 Hz, 9H), 1.21 (m, 66H), 3.70 (s, 3H), 7.04 (d, J = 8.5 Hz, 6H), 7.46 (d, J = 8.5 Hz, 6H), 9.71 (s, 3H), 10.11 (s, 3H).

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136 2,2',2'' (2,4,6 Trihydroxybenzene 1,3,5 triyl)tris( N (4 methoxyphenyl)acetamide) (4 4 c). BTF (78 mg, 0.32 mmol) and p anisidine (40 mg, 3.2 mmol) were heated to reflux overnight in toluene (5 mL). Isolation of solids from the reaction mixture by filtration and subsequent washing yielded 4 4 c (152 mg, 78% yield) as a white powder. 1 H NMR ( d 6 87 (d, J = 8.9 Hz, 6H), 7.50 (d, J = 8.9 Hz, 6H), 9.64 (s, 3H), 10.14 (s, 3H). 13 C NMR ( d 6 DMSO) 32.20, 55.13, 103.41, 113.82, 121.09, 131.83, 153.69, 155.42, 171.42. HRMS (ESI) calculated for C 33 H 34 N 3 O 9 [M+H] + 616.2290, found 616.2283. 2,2',2'' (2,4,6 Trihydroxybenzene 1,3,5 triyl)tris( N (3,5 dimethoxyphenyl)acetamide) (4 4 d). BTF (150 mg, 0.62 mmol) and 3,5 dimethoxyaniline (1.16 g, 7.57 mmol) were heated to reflux overnight in THF (4 mL). After cooling to room temp erature, precipitates were removed by filtration and subsequently was he d with EtOAc and hexanes. Further isolation of product from the filtrate was possible by column chromatography with a 5% MeOH:DCM eluent. The

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137 products from both purification methods we re combined to yield 4 4 d (177 mg 42 % yield) as a light brown solid. 1 H NMR ( d 6 J = 1.9 Hz, 6H), 9.13 (s, 3H), 10.10 (s, 3H). 13 C NMR ( d 6 97.51, 103.31, 140.64, 153.55, 160.42, 1 71.47. HRMS (ESI) calculated for C 36 H 40 N 3 O 12 [M+H] + 669.2555, found 669.2594. 2,2',2'' (2,4,6 Trihydroxybenzene 1,3,5 triyl)tris( N (2,3 dihydrobenzo[b][1,4]dioxin 6 yl)acetamide) (4 4 f). BTF (100 mg, 0.41 mmol) and 2,3 dihydrobenzo[ b ][1,4]dioxin 6 amine (490 mg, 3.2 mmol) were combined in THF (10 mL) and the reaction vessel was heated to reflux overnight. After cooling to room temperature, the solvent was removed in vacuo and the residue was redissolved in EtOAc and wa shed with 0.1 N HCl, deionized (DI) H 2 O, and then dried over Na 2 SO 4 Remaining solvent was removed in vacuo to yield 4 4 f (260 mg, 91%) as a brown solid. 1 H NMR ( d 6 J = 8.6 Hz, 3H), 6.98 (dd, J = 8.8 Hz, 2.2 Hz 3H), 7.22 (d, J = 2.2 Hz, 3H), 9.49 (s, 3H), 10.07 (s, 3H). 13 C NMR ( d 6 153.62, 171.32. HRMS (ESI) calculated for C 36 H 33 N 3 O 12 Na [M+Na] + 722.1956, found 722.1947.

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138 2,2',2'' (2,4,6 Trihydroxybenzene 1,3,5 triyl)tris( N (4 fluorophenyl)acetamide) (4 4 g). BTF (100 mg, 0.41 mmol) and p fluoroaniline (400 mg, 3.66 mmol) were heated to reflux in toluene (10 mL) overnight. The solids were rem oved by filtration and washed with toluene, EtOAc, and hexanes to yield compound 4 4 g (180 mg, 76%) as an off white powder. 1 H NMR ( d 6 J = 8.8 Hz, 6H), 7.62 (dd, J = 8.9, 5.0 Hz, 6H), 9.25 (s, 3H), 10.24 (s, 3H). 13 C NMR ( d 6 103.40, 115.26 (d, J = 22.6 Hz), 121.11 (d, J = 7.5 Hz), 135.32 (d, J = 1.3 Hz), 153.63, 158.04 (d, J = 239 Hz), 171.4 1. HRMS (ESI) calculated for C 30 H 28 F 3 N 4 O 6 [M+NH 4 ] + 602.1509, found 602.1528. 2,2',2'' (2,4,6 Trihydroxybenzene 1,3,5 triyl)tris( N (4 methylesterphenyl)acetamide) (4 4 h). BTF (200 mg, 0.81 mmol) and methyl 4 aminobenzoa te (1.80 g, 12.2 mmol) were heated to reflux in THF (10 mL) over two days. The THF was then removed in vacuo and the solids were suspended and sonicated in ethyl acetate, and isolated by filtration to yield compound 4 4 h (380 mg, 68%) as a white powder 1 H NMR ( d 6 J =

PAGE 139

139 8.8 Hz, 6H), 7.91 (d, J = 8.8 Hz, 6H), 8.85 (s, 3H), 10.42 (s, 3H). 13 C NMR ( d 6 32.48, 51.86, 103.29, 118.47, 123.79, 130.26, 143.60, 153.57, 165.80, 171.58. HRMS (ESI) calculated for C 36 H 34 N 3 O 12 [M+H] + 700.2137, found 700.2147. 2,2',2'' (2,4,6 Trihydroxybenzene 1,3,5 triyl)tris( N (naphthalen 2 yl)acetamide) (4 4 i). BTF (86 mg, 0.35 mmol) was dissolved in DMF (5 mL) and heated to 60 C while sparging the solution with argon. 2 Naphthylamine (450 mg, 3.2 mmol) was added in one aliquot and the reaction was allowed to stir under argon at 120 C over two nights. The reaction mixture was cooled, poured into EtOAc, and washed with 0.1 N HCl, H 2 O, and brine. The organic layers were dried over Na 2 SO 4 and the solvent was removed in vacuo The residue was triturated with DCM and the insoluble material was removed by filtration and washed to yield 4 4 i (130 mg, 55%) as a light tan solid. 1 H NMR ( d 6 (s, 6H), 7.40 (m, 3H), 7.45 (m, 3H), 7.64 (d, J = 8.6 Hz, 3H), 7.79 (d, J = 8.1 Hz, 3H), 7.83 (d, J = 8.1Hz, 3H), 7.86 (d, J = 8.8 Hz, 3H), 8.30 (s, 3H), 9.31 (s, 3H), 10.37 (s, 3H). 13 C NMR ( d 6 120.05, 124.63, 126.38, 127. 30, 127.47, 128.33, 129.78, 133.36, 136.51, 153.68, 171.75. HRMS (ESI) calculated for C 42 H 33 N 3 O 6 Na [M+Na] + 698.2262, found 698.2253.

PAGE 140

140 2,2',2'' (2,4,6 Trihydroxybenzene 1,3,5 triyl)tris( N (7 dodecyl naphthalen 2 yl)acetami de) (4 4 j). BTF (26 mg, 0.11 mmol) and 7 dodecyl 2 aminonaphthalene (290 mg, 0.9 4 mmol ) were combined in THF (5 mL) and allowed to stir at reflux overnight. Upon cooling, precipitates formed in the reaction mixture that were removed by filtration and was hed to yield 4 4 j (30 mg, 25%) as a white powder. 1 H NMR ( d 5 J = 6.6 Hz, 9H), 1.32 (m, 54H), 1.68 (m, 6H), 2.73 (t, J = 7.2 Hz, 6H), 4.38 (s, 6H), 7.39 (d, J = 8.7 Hz, 3H), 7.89 (m, 15 H), 8.63 (s, 3H), 11.74 (s, 3H). 13 C NMR ( d 5 44, 36.52, 105.30, 118.31, 121.61, 123.12, 126.89, 128.33, 128.72, 128.77, 131.77, 133.15, 136.82, 140.25, 155.92, 174.34. HRMS (ESI) calculated for C 78 H 105 N 3 O 6 Na [M+Na] + 1202.7901, found 1202.7805. 2,2',2'' (2,4,6 Trihy droxybenzene 1,3,5 triyl)tris( N (3 cyanophenyl)acetamide) (4 4 k). BTF (200 mg, 0.81 mmol) and 3 aminobenzonitrile (2.10 g, 17.6 mmol) were heated to reflux in dry, degassed THF over three nights. The reaction precipitates were removed by filtration and w ashed with hot EtOAc and hot i PrOH to yield 4 4 k (175 mg,

PAGE 141

141 36%) as an off white powder. 1 H NMR ( d 6 (dt, J = 7.0, 2.1 Hz, 3H), 8.08 (s, 3H), 8.83 (s, 3H), 10.40 (s, 3H). 13 C NMR ( d 6 DMSO) 18.70, 121.72, 123.64, 126.66, 130.22, 139.97, 153.58, 171.57. HRMS (ESI) calculated for C 33 H 25 N 6 O 6 [M+H] + 601.1830, found 601.1825. 2,2',2'' (2,4,6 Trihydroxybenzene 1,3,5 triyl)tris( N (3 nitrophenyl)acetamide) (4 4 l). BTF (75 mg, 300 mol) and 3 nitroaniline (630 mg, 4.6 mmol) were heated to reflux in dry, degassed THF overnight. Precipitates from the reaction were removed by filtration and washed to yield compound 4 4 l (80 mg, 40%) as a white powder. 1 H NMR ( d 6 DMSO ) (s, 3H). 13 C NMR ( d 6 147.93, 153.60, 171.60. HRMS (ESI) calculated for C 30 H 24 N 6 O 12 Na [M+Na] + 683.1344, found 683 .1344. 2,2',2'' (2,4,6 T rihydroxybenzene 1,3,5 triyl)tris( N (4 (dimethylamino)phenyl)acetamide) (4 4m). BTF (24.8 mg, 0.101 mmol) was added to a stirred solution of N,N dimethylbenzene 1,4 diamine (68.8 mg, 0.505 mmol ) i n THF

PAGE 142

142 and the r eaction was heated to reflux for 16 hours. Solvent was removed in vacuo and the solids were sonicated in EtOAc and isolated by filtration and washing yielding 4 4m (66.0 mg, 39%) as a deep purple solid. 1 H NMR ( d 6 DMSO 2.84 (s, 18H), 3.68 (s, 6 H), 6.67 (d J = 9.1 Hz, 6 H), 7.40 (d J = 8.9Hz, 6H), 9.99 (s, 3H), 10.07 (s, 3 H). 13 C NMR ( d 6 DMSO 2,2',2'' (2,4,6 T rihydro xybenzene 1,3,5 triyl)tris( N (3,4,5 tris(octyloxy)phenyl)acetamide) (4 4n). BTF ( 44.3 mg, 0.1 8 mmol) was added to a stirred solution of 3,4,5 (dodecyloxy)aniline ( 1.0 g, 1 6 mmol ) in THF and the r eaction was heated to 55 C for 16 hours. Solvent was remov ed in vacuo yielding a purple amorphous solid. The residue was purified via column chromatography (DCM then 3% MeOH in DCM, R f 0.5 in latter solvent system) yielding 4 4n ( 134 mg, 55 %) as a purple solid. 1 H NMR ( CDCl 3 0.88 (t, J = 7.1 Hz, 27H), 1.20 1.60 (m, 174 H), 1.75 ( m, 22 H), 3.75 (s, 6H) 3.90 (m, 18H), 6.71 (s, 6H), 7.85 (s, 3H), 9.82 ( s, 3 H) 13 C NMR ( CDCl 3 14.3 2 2.9 26.4, 29.6, 29.7, 29.9, 30.0, 30.5, 32.2, 69.4, 73.7, 100.0, 100.3, 103.3, 132.5, 135.9, 153.4, 154.2, 173.0

PAGE 143

143 2,2',2'' (2,4,6 T rihydroxybenzene 1,3,5 triyl)tris( N (3,4,5 tris(dodecyloxy)phenyl)acetamide) (4 4o) BTF ( 74 mg, 0. 3 mmol) was added to a stirred solution of 3,4,5 (octyloxy)aniline ( 1.0 g, 2.7 mmol ) in THF and the r eaction was heated to 60 C for 16 hours. Solvent was removed in vacuo yielding a purple amorphous solid. The residue was purified via column c hromatography (DCM then 3% MeOH in DCM, R f 0.5 in latter solvent system) yielding 4 4n ( 448 mg, 88 %) as a purple solid. 1 H NMR ( CDCl 3 0.88 (t, J = 7.1 Hz, 27H), 1.20 1.60 (m, 98 H), 1.75 ( m, 28 H), 3.77 (s, 6H) 3.91 (m, 18H), 6.73 (s, 6H), 7.91 (s, 3H) 9.87 ( br s, 3H) 2,2',2'' (2,4,6 T rihydroxybenzene 1,3,5 triyl)tris( N,N diethylacetamide) (4 4p) BTF (80.0 mg, 0.33 mmol) and diethylamine (237 mg, 3.25 mmol) were stirred in THF (10 mL) overnight. Solvent was remove d and the residue was purified via flash column chromatography with 1/3 EtOAc/hexanes yielding 4 4p (118 mg, 78%) as a yellow oil. 1 H NMR (CDCl 3 ) J = 7.18 Hz, 9H), 1.28 (t, J = 7.04 Hz, 9H), 3.37 (q, J = 7.33 Hz, 6H), 3.67 (q, J = 7.33 Hz, 6H), 3.77 (s, 6H) 11.00 (s, 3H). 13 C NMR (CDCl 3

PAGE 144

144 14.6, 28.7, 41.1, 43.4, 102.0, 154.7, 174.3. HRMS (ESI) calculated for C 24 H 40 N 3 O 6 [ M + H] + 466 .2912, found 466.2925. 2,2',2'' (2,4,6 T rihydroxybenzene 1,3,5 triyl)tris(1 (piperidin 1 yl)ethanone) (4 4q) BTF (80 mg, 0.32 mmol) and piperidine (272 mg, 3.20 mmol) were stirred in THF (10 mL) overnight, then solvent was removed and residues were purified via flash column chromatography with 1/3 EtOAc/hexanes yielding compound 4 4q (206 mg, 67%) as a yellow oil. 1 H NMR (CDCl 3 ) 1.57 (m, 6H) 1.58 1.68 (m, 12H), 3.54 (t, J = 5.63 Hz, 6H), 3.79 (s, 6H), 3.83 (t, J = 5.50 Hz, 6H), 10.65 (s, 3H). 13 C NMR (CDCl 3 calculated for C 27 H 40 N 3 O 6 [ M + H] + 502.29 12, found 502.2916. 2,2',2'' (2,4,6 T rihydroxybenzene 1,3,5 triyl)tris( N allylacetamide) ( 2 16jjj ). BTF (100 mg, 0.41 mmol) and allylamine (348 mg, 6.1 mmol) were stirred overnight at RT in acetonitirile (5 mL). The nex t day, the solution was heated to 60 C for 1 h and then cooled to RT. Solvent was removed in vacuo and the resultant oil was purified via

PAGE 145

145 column chromatography (10% MeOH in DCM) yielding 2 16jjj (131 mg, 77%) as a brown powder. 1 H NMR ( d 6 J = 5.3 Hz, 6H), 5.09 (m, 6H), 5.78 (m, 3H), 8.56 (t, J = 5.5 Hz, 3H), 10.32 (s, 3H). 13 C NMR ( d 6 41.94, 103.59, 116.26, 135.23, 154.41, 174.10. HRMS was not obtainable by various methods. 2,2',2'' (2,4,6 T rihydroxybenzene 1,3,5 triyl)tris( N (prop 2 ynyl)acetamide) ( 2 16kkk ). To a 10 ml round bottom flask was added trilactone (200 mg, 0.8 mmol) and acetonitrile (5 mL). The solution was then sparged with argon, propargyl am ine (1.0 g, 18.1 mmol) was added dropwise, and the reaction was allowed to stir under an argon atmosphere overnight. The next day, the reaction was placed in a warm oil bath (60 C) for an hour, and then cooled to room temperature. The solvent was remove d in vacuo and the crude reaction material was recrystallized from MeOH/H 2 O yielding compound 2 16kkk (208 mg, 63%) as brownish needle crystals. 1 H NMR ( d 6 J = 2.3 Hz, 3H), 3.49 (s, 6H), 3.87 (dd, J = 5.3, 2.3 Hz), 8.76 (t, J = 5.3 Hz, 3H ), 9.98 (s, 3H). 13 C ( d 6 (ESI) calculated for C 21 H 21 N 3 O 6 [ M + H] + 412.1503, found 412.1518.

PAGE 146

146 2,2',2'' (2,4,6 T rihydroxybenzene 1,3,5 triyl)tris( N ((1 benzy l 1H 1,2,3 triazol 4 yl)methyl)acetamide) ( 2 16mmm ). To a round bottom flask purged with argon was added compound 2 16kkk (75 mg, 180 mol) and sodium ascorbate (11 mg, 55 mol) under an argon stream. The vessel was then sealed and degassed THF (3 mL), b enzyl azide (150 mg, 1.1 mmol), and copper sulfate pentahydrate (4.5 mg, 18 mol) in H 2 O (1 mL) were all added sequentially in a dropwise fashion. The reaction mixture immediately formed a precipitate and was allowed to stir at room temperature overnight. The next day, solvents were removed in vacuo and the crude reaction mixture was purified via column chromatography using 10% MeOH in DCM. Compound 2 16 mmm (140 mg, 93%) was recovered as a slightly off white solid. 1 H NMR ( d 6 (br s, 6H), 4. 29 (d, J = 5.0 Hz, 6H), 5.55 (s, 6H), 7.32 (m, 15H), 7.96 (s, 3H), 8.78 (br s, 3H), 10.01 (s, 3H). 13 C NMR ( d 6 6 52.7, 102. 9 123.1, 12 8 0 128. 1 128.7, 136.0, 144. 5 153.7, 173.3. HRMS (ESI) calculated for C 42 H 42 N 12 O 6 [ M + Na] + 833.32 42, found 833.3258.

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147 2,2' (2,4,6 Trihydroxy 5 (2 oxo 2 (phenylamino)ethyl) 1,3 phenylene)bis( N (4 dodecylphenyl)acetamide) (4 4abb ). To a solution of compound 4 7 (40 mg, 120 mol) in THF (5 mL) was added 4 dodecylaniline (120 mg, 470 mol). The reaction was heated to 70 C overnight after which the THF was removed in vacuo to yield tan solids. The crude material was dissolved in hot EtOAc/hexanes and allowed to slowly precipitate upon cooling. Filtration and washing wi th 0.1 N HCl yielded 4 4abb (61 mg, 59%) as a waxy, off white solid. 1 H NMR ( d 6 J = 6.4 Hz, 6H), 1.23 (br s, 36H), 1.52 (m, 4H), 3.70 (br s, 6H), 7.06 (m, 5H), 7.29 (t, J = 7.9 Hz, 2H), 7.48 (d, J = 8.5 Hz, 4H), 7.60 (d, J = 7.9 Hz, 2H), 9.43 (m, 3H), 10.12 (s, 2H), 10.17 (s, 1H). 13 C NMR ( d 6 32.31, 34.52, 103.41, 103.49, 119.37, 119.49, 123.38, 128.39, 128.68, 136.43, 137.48, 138.90, 153.65, 171.52. HRMS (ESI) calcu lated for C 54 H 76 N 3 O 6 [M+H] + 862.5729, found 862.5719. 2,2' (2,4,6 Trihydroxy 5 (2 (naphthalen 2 ylamino) 2 oxoethyl) 1,3 phenylene)bis( N phenylacetamide) (4 4aii ). A stirring solution of 4 6 (86 mg, 0.20

PAGE 148

148 mmol) in DMF (5 mL) was treated with 2 naphthylamine (34 mg, 0.24 mmol) and heated to 120 C for 12 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with 10% HCl and water. The combined organic layers wer e dried with Na 2 SO 4 The solvent was then removed in vacuo and the crude product was purified via column chromatography (hexane/EtOAc 1:1) to afford 4 4aii (80 mg, 70%) as a yellow solid. 1 H NMR ( d 6 DMSO) 3.73 (s, 4H), 3.78 (s, 2H), 7.05 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 7.5 Hz, 4H), 7.43 (m, 2H), 7.62 (m, 5H), 7.85 (m, 3H), 8.28 (s, 1H), 9.31 (s, 2H), 9.32 (s, 1H), 10.19 (s, 2H), 10.37 (s, 1H). 13 C NMR ( d 6 DMSO) 13.58, 20.26, 31.86, 59.25, 102.94, 105.26, 115.01, 117.88, 118.85, 119.55, 120.32, 122.91 124.5, 125.33, 125.8, 125.9, 126.82, 126.95, 127.84, 127.96, 128.23, 129.29, 132.87, 134.49, 136.02, 138.41, 146.14, 153.15, 171.09, 171.26. HRMS (ESI) calculated for C 34 H 29 N 3 O 6 Na [M+Na] + 598.1949, found 598.1944. Repre sentative Procedure for the Synthesis of AATs from Phloroglucinols: Synthesis of N (3,4 D imethoxyphenyl) 2 (4,6,10 trioxo 5,7 di 3,4 dimethoxyphenylcarbamoylmethyl 1 aza tricyclo[3.3.1.13,7]dec 3 yl) acetamide ( 4 5 e). To a 10 mL round bottom flask with st irbar and reflux condenser was added compound 4 4 e (125 mg, 0.180 mmol) followed by HMTA (75 mg, 0.53 mmol) and degassed i PrOH (4 mL). The reaction vessel was then put in an oil bath and allowed to

PAGE 149

149 reflux with stirring overnight under an argon atmosphere The next day the reaction vessel was allowed to cool to room temperature and the precipitates were removed by filtration and washed with i PrOH (1 mL). The solids were then resuspended in ethyl acetate (10 mL), sonicated, and filtered to yield compound 4 5 e (75 mg, 53%) as a slightly tan solid. 1 H NMR ( d 6 DMSO 6.84 (d, J = 8.8 Hz, 3H), 7.01 (dd, J = 8.6, 1.6 Hz, 3H), 7.27 (d, J = 1.6 Hz, 3H), 9.87 (s, 3H). 13 C NMR ( d 6 DMSO ) 33.66, 55.35, 55.73, 70 .21, 70.37, 104.08, 110.74, 112.06, 133.07, 144.54, 148.49, 167.15, 198.27. HRMS (ESI) calculated for C 39 H 43 N 4 O 12 [M+H] + 759.2872, found 759.2902. 2,2',2'' ((3s,5s,7s) 4,6,10 Trioxo 1 azaadamantane 3,5,7 triyl)tris( N (4 m ethoxyphenyl)acetamide) ( 4 5 c). To a solution of 4 4 c (99 mg, 0.16 mmol) in i PrOH (5 mL) was added HMTA (60 mg, 0.43 mmol) and the solution was brought to reflux over three nights under argon. Precipitates formed during the reaction that were removed by filtration and washed, yielding 4 5 c (37 mg, 34%) as a white solid. 1 H NMR ( d 6 DMSO J = 8.7 Hz, 6H), 7.39 (d, J = 8.7 Hz, 6H), 9.81 (s, 3H). 13 C NMR ( d 6 DMSO 120. 36, 132.54, 154.88, 167.04, 198.32. HRMS (ESI) calculated for C 36 H 37 N 4 O 9 [M+H] + 669.2555, found 669.2594.

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150 2,2',2'' ((3s,5s,7s) 4,6,10 Trioxo 1 azaadamantane 3,5,7 triyl)tris( N (3,5 dimethoxyphenyl)acetamide) ( 4 5 d). To i PrOH (5 mL) was added 4 4 d (99 mg, 0.14 mmol) followed by HMTA (56 mg, 0.40 mmol) and the reaction mixture was allowed to reflux for two days. After cooling to room temperature, isolation and washing of the precipitates from the reaction yielded 4 5 d (1 1 mg, 11%) as a light orange solid. 1 H NMR ( d 6 DMSO J = 1 Hz, 6H), 9.98 (s, 3H). 13 C NMR ( d 6 DMSO 140.96, 160.41, 167.63, 198.13. HRMS (ESI ) calculated for C 36 H 40 N 3 O 12 [M+H] + 759.2872, found 759.2877. 2,2',2'' ((3s,5s,7s) 4,6,10 Trioxo 1 azaadamantane 3,5,7 triyl)tris( N (2,3 dihydrobenzo[b][1,4]dioxin 6 yl)acetamide). ( 4 5 f) To a solution of 4 4 f (100 mg, 0 .15 mmol) in i PrOH (5 mL) was added HMTA (64 mg, 0.46 mmol) and the reaction vessel was heated to reflux overnight. Precipitates from the reaction mixture were

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151 removed by filtration, resuspended in EtOAc, and filtered again with washing to yield 4 5 f (44 mg, 40%) as a light brown solid. 1 H NMR ( d 6 DMSO 4.19 (d, J = 6.5 Hz, 12H), 6.73 (d, J = 8.6 Hz, 3H), 6.92 (dd, J = 8.1 Hz, 2.2 Hz, 3H), 7.15 (d, J = 2.2 Hz, 3H), 9.82 (s, 3H). 13 C NMR ( d 6 DMSO 70.15, 107.96, 112.10, 116.60, 133.05, 138.95, 142.84, 167.07, 198.25. HRMS (ESI) calculated for C 39 H 37 N 4 O 12 [M+H] + 753.2403, found 753.2398. N (4 Fluorophenyl) 2 (4,6,10 trioxo 5,7 di 4 fluorphenylcarbamoylmethyl 1 az a tricyclo[3.3.1.13,7]dec 3 yl) acetamide ( 4 5 g). To a solution of 4 4 g (95 mg, 160 mol) in i PrOH was added HMTA (69 mg, 490 mol) and the mixture was heated to reflux overnight. Removal of the solids by filtration and subsequent washing yielded 4 5 g ( 33 mg, 35%) as a white powder. 1 H NMR ( d 6 DMSO 7.10 (t, J = 8.8 Hz, 6H), 7.54 (dd, J = 8.7, 5.0 Hz, 6H), 10.07 (s, 3H). 13 C NMR ( d 6 DMSO J = 22.3 Hz), 120.52 (d, J = 7.7 Hz), 135.73, 157.7 1 (d, J = 238 Hz), 167.45, 198.25. HRMS (DART) calculated for C 33 H 28 F 3 N 4 O 6 [M+H] + 633.1961, found 633.1979.

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152 N (4 Methylesterphenyl) 2 (4,6,10 trioxo 5,7 di 4 methylesterphenylcarbamoylmethyl 1 aza tricyclo[3.3.1.13,7]dec 3 yl) acetamide ( 4 5 h). To a solution of 4 4 h (42 mg, 60 mol) in i PrOH was added HMTA (25 mg, 180 mol) and the reaction was heated to reflux over three nights. Solids from the reaction mixture were removed by filtration, washed, and dried to yield co mpound 4 5 h (10 mg, 21%) as a slightly tan powder. 1 H NMR ( d 6 DMSO 6H), 7.67 (d, J = 7.7 Hz, 6H), 7.88 (d, J = 7.4 Hz, 6H), 10.40 (s, 3H). 13 C NMR ( d 6 DMSO 57, 165.74, 168.05, 198.27. HRMS (ESI) calculated for C 39 H 37 N 4 O 12 [M+H] + 753.2402, found 753.2416. 2,2',2'' ((3s,5s,7s) 4,6,10 Trioxo 1 azaadamantane 3,5,7 triyl)tris( N (naphthalen 2 yl)acetamide) ( 4 5 i). To a solution of 4 4 i (49 mg, 0.072 mmol) in i PrOH was added HMTA (30 mg, 0.22 mmol) and the reaction mixture was heated to reflux for 120 hours. After cooling, the insoluble material was isolated, triturated with

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153 EtOAc, isolated by filtration, and washed to yield 4 5 i (35 mg, 66%) as a slightly tan solid. 1 H NMR ( d 6 DMSO J = 7.5 Hz, 3H), 7.52 (d, J = 8.6 Hz, 3H), 7.80 (m, 9H), 8.29 (s, 3H), 10.24 (s, 3H). 13 C NMR ( d 6 DMSO 24.35, 126.31, 127.19, 127.38, 128.22, 129.54, 133.44, 136.51, 167.61, 198.31. HRMS (ESI) calculated for C 45 H 36 N 4 O 6 Na [M+Na] + 751.2517, found 751.2517. 2,2',2'' ((3s,5s,7s) 4,6,10 Trioxo 1 azaadamantane 3,5,7 triyl)tris( N (7 dodecyl naphthalen 2 yl)acetamide) ( 4 5 j). To a solution of 4 4 j (25 mg, 0.021 mmol) in i PrOH was added HMTA (8.8 mg, 0.063 mmol) and the reaction mixture was allowed to reflux for 120 hours. After cooling, the insoluble material was isolated, trit urated with EtOAc, again isolated by filtration, and washed to yield 4 5 j (17 mg, 65%) as a white powder. 1 H NMR ( d 5 J = 6.9 Hz, 9H), 1.29 (m, 60H), 1.67 (m, 6H), 2.73 (t, J = 7.6 Hz, 6H), 4.37 (s, 6H), 7.38 (d, J = 8.2 Hz, 3H), 7.68 ( s, 3H), 7.8 (d, J = 8.5 Hz, 3H), 7.87 (m, 6H), 8.61 (s, 3H), 11.73 (s, 3H). 13 C NMR ( d 5 23.63, 26.75, 28.34, 30.30, 30.33, 30.53, 30.60, 30.65, 32.40, 32.81, 36.90, 72.11, 75.87, 117.39, 121.57, 127.24, 128.55, 129.02, 131.75, 133.74, 1 40.11, 169.59, 200.21. HRMS (ESI) calculated for C 81 H 108 N 4 O 6 Na [M+Na] + 1255.8167, found 1255.8136.

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154 2,2' ((1s,3r,5s,7r) 4,6,10 Trioxo 7 (2 oxo 2 (phenylamino)ethyl) 1 azaadamantane 3,5 diyl)bis( N (4 dodecylphenyl)acetamid e) ( 4 5abb ). To a solution of 4 abb (51 mg, 59 mol) in i PrOH was added HMTA (17 mg, 120 mol) and the reaction mixture was allowed to reflux over two nights. After cooling, the insoluble material was isolated by filtration and washed with 0.1 N HCl, i P rOH, and EtOAc before being dried in vacuo to yield 4 5abb (30 mg, 56%) as a white, flaky solid. 1 H NMR ( d 6 DMSO J = 6.7 Hz, 6H), 1.23 (br s, 36H), 1.52 (m, 4H), 2.77 (m, 6H), 3.91 (m, 6H), 7.00 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 8.2 Hz, 4H), 7 .25 (t, J = 7.8 Hz, 2H), 7.41 (d, J = 8.1 Hz, 4H), 7.53 (d, J = 8.0 Hz, 2H), 9.82 (s, 2H), 9.93 (s, 1H). 13 C NMR ( d 6 DMSO ) 70.23, 118.85, 118.92, 122.72, 128.10, 128.40, 136.67, 136.84, 139.18, 167.18, 167.41, 198.12, 198.16. HRMS (ESI) calculated for C 57 H 79 N 4 O 6 [M+H] + 915.5994, found 915.5981.

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155 2,2' ((1r,3r,5s,7s) 7 (2 (Naphthalen 2 ylamino) 2 oxoethyl) 4,6,10 trioxo 1 azaadamantane 3,5 diyl)bis( N phenylacetamide) ( 4 5aai ). A solution of 4 4aai (90 mg, 0.16 mmol), HMTA (66 mg, 0.48 mmol), and i PrOH (5 mL) was heated to reflux for 2 days. After cooling to room temperature, the mixture was filtered to afford an off white solid. The solid was washed with 5% HCl and water to afford 4 5aai (41 mg, 43%) as an off white solid. 1 H NMR ( d 6 J = 7.5 Hz, 2H), 7.26 (t, J = 7.8 Hz, 4H), 7.45 (m, 8H), 7.81 (m, 3H), 8.27 (s, 1H), 10.01 (s, 2H), 10.23 (s, 1H). 13 C NMR ( d 6 d 6 DMSO) 33.21, 69.71, 69.88, 114.19, 118.35, 119.28, 122.33, 123.85, 125.81, 126.69, 126.88, 127.72, 128.08, 129.03, 132.95, 136.36, 138.80, 167.03, 167.28, 197.79. HRMS (ESI) calculated for C 37 H 32 N 4 O 6 Na [M+Na] + 651.2214, fo und 651.2208. 2,2',2'' ((3s,5s,7s) 4,6,10 T rioxo 1 azaadamantane 3,5,7 triyl)tris( N ((1 benzyl 1H 1,2,3 triazol 4 yl)methyl)acetamide) (4 5t). To a solution of 4 4t in i PrOH (3 mL) was added HMTA (29 mg reflux overnight. After cooling to room temperature, the solids from the reaction were removed by filtration, washed with EtOAc and then dried in vacuo yielding compound 4 5t (23 mg, 40%) as a white solid. 1 H N MR ( d 6 DMSO) 2.53 (s, 6H), 3. 8 9 (br s, 6H),

PAGE 156

156 4. 32 (d J = 5.0 Hz, 6H), 5.54 (s, 6H), 7.32 (m 15H), 7.86 (s, 3H), 8.42 (br s 3H). 13 C NMR ( d 6 DMSO) 136.02, 144.46, 173.32, 198.23. 2,2' (4,6 Dihydroxy 2 oxo 2,3 dihydrobenzofuran 5,7 diyl)bis( N phenylacetamide) ( 4 6 ). To a solution of BTF (100 mg, 0.40 mmol) in DMF (2 mL) was dropwise added an aniline solution (3.2 mL of a 0.5 M solution, 1.6 mmol). The resulting solution was allowed to stir over two nights in a 70 C oil bath, after which the reaction was diluted with EtOAc (200 mL), washed with 0.3 N HCl, DI H 2 O, then brine, and dried over Na 2 SO 4 The solvent was removed in vacuo and the residue was purified by column chromatography (1/10 acetone/DCM) to yield 4 6 (79 mg, 45%) as an off white solid. 1 H NMR ( d 6 DMSO J = 7.6 Hz, 2 H), 7.34 7.23 (m, 4H), 7.59 (d, J = 7.9 Hz, 4 H), 9.55 (s, 1 H), 9. 70 (s, 1 H), 10.05 (s, 1 H), 10.24 (s, 1H). 13 C NMR ( d 6 DMSO 106.69, 119.02, 119.25, 123.00, 123.37, 128.65, 128.70, 138.92, 139.27, 150.45, 152.18, 155.02, 169.69, 170.31, 174.63. HRMS (ESI) calculated for C 24 H 22 N 2 O 6 [M+H] + 433.1394, found 433.1389. 2 (4 Hydroxy 2,7 dioxo 2,3,7,8 tetrahydrobenzo[1,2 b:3,4 b']difuran 5 yl) N phenylacetamide ( 4 7 )

PAGE 157

157 was dropwise added an aniline s olution (560 mg in 12 mL DMF, 6.0 mmol). The resulting solution was allowed to stir for 8 h in a 40 C oil bath. The reaction was next diluted with EtOAc (200 mL), washed with 0.3 N HCl, DI H 2 O, then brine, and dried over Na 2 SO 4 The solvent was removed i n vacuo and the residue was purified by column chromatography (1/20 acetone/DCM) to yield 4 7 (76 mg, 56%) as an off white solid. 1 H NMR ( d 6 DMSO J = 7.4 Hz, 1H), 7.29 (t, J = 7.9 Hz, 2H), 7.59 (d, J = 8.1 Hz, 7H), 10.07 (s, 1H), 10.13 (s, 1H). 13 C NMR ( d 6 DMSO 15 3.7, 168.3, 173.9, 174.1. HRMS (ESI) calculated for C 18 H 15 NO 6 [M+H] + 340.0816, found 340.0813.

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158 CHAPTER 5 CONCLUSIONS This work has tested the hypothesis that symmetrically equivalent, electronically coupled lactone rings can provide access to multifuncti onliazed molecules via synthetically useful difference in aminolysis kinetics upon sequential ring opening. The popular strategies towards discrete, multifunctional molecules have been reviewed; strengths and weaknesses for each strategy have been illustra ted through current examples in the literature. Additionally, due to the limited number of strategies for multifunctionalization, especially the sequential desymmetrization of scaffolds, the need for new approaches and methodologies has been identified. S equential Aminolysis of Benzotrifuranone Two C 3 symmetric benzotrilactones (benzotrifuranone, BTF, 2 3 and benzotripyranone BTP, 2 21 ) have been used to investigate ability for electronically coupled lactones to allow for selective and stepwise aminolysis transformations. Intermediates ( 2 14 a singly ring opened difuranone from BTF ; 2 15 a doubl y ring opened monofuranone from BTF ; 2 22 a singly ring opened dipyranone from BTP; and 2 23 a doubly ring opened monopyranone from BTP) within the reaction pat hways have been characterized by NMR spectroscopy (all derivatives), IR spectroscopy (selected examples), and X ray structure analysis ( 2 3 2 14c 2 21 and 2 22b ). The sequential ring opening of the three lactones in BTF ( 2 3 ) with alkyl amines occurs quickly (15 min 16 h), with high fidelity (> 95% average selectivity, quantitative material recovered), and under mild reaction conditions ( 41 C rt in DMF). The synthetic utility of this methodology is showcased through the high yielding, one pot syn thesis of three multifunctionalized phloroglucinol architectures ( 2 16 ) and the

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159 installation of enantiopure protected amino acids. The stepwise desymmetrization of the C 3 symmetric core is cleanly seen through both 1 H and 13 C NMR spectroscopy. Infrared s pectroscopy shows stepwise decreases in the stretching frequency of the lactone carbonyls and the c rystal structures of two furanone derivatives ( 2 3 and 2 14c ) exhibited mostly planar lactone rings with noticeable bond length alteration within the aromat ic ring. The six membered ring analogue, BTP ( 2 21 ) exhibited lower aminolysis selectivity than BTF ( 2 3 ) 70 90% yield of the desired dipyranone ( 2 22 ) as quantified via HPLC. The aminolysis reactions were slower (2 h for the first ring opening) under identical conditions ( 41 C ). The stepwise desymmetrization of BTP is seen via NMR spectroscopy, but overlapping signals prevents quantitative measurements ; the thin film infrared spectra do not show clear stepwise trends Two crystal structures of pyran one derivatives were obtained ( 2 21 and 2 22b ) and characterized by twisted lactone rings, membered ring hydrogen bond s ( 2 22b ). Currently, the scope and applicability of the stepwise reactivity for BTF is being investigated through the construction of multifuncti onal materials and biologically relevant architectures. The implementation of BTF as a synthetically useful scaffold will allow for easy iterative synthesis of a wide range of molecules for structure/property relationships and screening. Additionally, fu ture studies will include the synthesis and aminolysis of acyclic and methyl substituted furanones to examine the scope of electronically coupled esters as a general methodology for the multifunctionalization of a molecular core.

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160 Structure/Property Relationships The selectivity seen through the stepwise aminolysis of BTF ( 2 3 ), and to a lesser extent BTP ( 2 21 ), has been attributed to the electronic (inductive) changes of the aromatic core upon ring opening. Seen through the conversion of one OC(=O)CH 3 substituent to a OH substituent ( e.g. 2 3 to 2 14 ), the remaining lac tones ( related to phenyl acetates) are less reactive due to the increased electron density in the aromatic ring (leaving group). In BTF derivatives, evidence for increased stability of the lactone rings upon ring opening ( 2 3 to 2 16 ) is seen in both the 13 C NMR chemical shifts and C=O resonances of the lactone carbonyl carbon. The same trend is seen for the 13 C NMR chemical shifts of the BTP series ( 2 21 to 2 23 ), but the C=O resonances do not follow a distinct trend. In light of complex mechanistic st udies, quantum chemical calculations on the ground state structures support the increase in electron donation as a mechanism of decreased reactivity upon ring opening. While the majority of the calculated reactivity indices follow trends established in th e literature, the NBO atomic charges show an opposite trend for both the BTF and BTP series of compounds. The calculated reactivity descriptors were not able to conclusively predict the differences in aminolysis selectivity between BTF ( 2 3 ) and BTP ( 2 21 ). Future in silico experiments aim to determine the structure and energetics of the aminolysis transition states for 2 3 and 2 21 in addition to quantification of the ring strain found within the five and six membered ring benzotrilactone families to p rovide insight for the selectivity differences. Pseudo first order kinetic rates for the n heptylaminolysis of 2 3 2 14a and 2 15aa were recorded in acetonitrile at room temperature. As seen synthetically, the

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161 aminolysis of 2 3 occurs extremely rapidly (more than one order of magnitude faster than analogous p nitrophenyl acetate). Subsequent ring openings are characterized by rates that are nearly an order of magnitude apart from one another. The kinetic rates observed were not well predicted by previ ous literature benchmarks, indicating the difficulty in compar ing series with significant structural differences. Additionally, the linear correlation between the reactivity descriptor EPN ( V C Table 3 1 entry 8) and the natural log of the second order r ate constant (ln( k obs /[C 7 H 15 NH 2 ])) was found to be smaller in magnitude than that reported in the literature, suggesting more complexities in the reactivity of BTF ( 2 3 ) and its derivatives. Future kinetic s experiments will quantify the aminolysis rate of the pyranone derivatives ( 2 21 2 22 and 2 23 ) in order to expand the data set used to make structure/reactivity relationships. In addition, the activation energy of transition states and the influence of the phenolic oxygen protonation state ( 2 22 and 2 23 ) on the aminolysis rate remain to be determined. Rapid Synthesis of 1 Aza adamantanetrione Organogelators with Control of Symmetry New approaches to the synthesis of fully arylamido substituted phloroglucinols ( 4 4 ) from a common benzotrifuranone (BTF 2 3 ) precursor have provided efficient access to previously unattainable C 3 and C s symmetric 1 aza adamantanetriones (AATs, 4 5 ). The synthetic chemistry has enabled preparation of a structurally diverse ten component library of C 3 symmetric aryl amide AATs, and exploration of the first binary AAT based organogel systems. Enhanced gelation has been observed for ensembles containing AAT monomers with electronically complementary aromatic substituents ( p fluoro derivative 4 5e and 3,4 dimethoxy derivativ e 4 5 g ). Introduction of an expanded aromatic substituent to the AAT scaffold has provided a naphthyl substituted molecule

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162 ( 4 5j ) that effectively immobilizes aromatic solvents at low concentrations (~ 0.3 wt%). Quite uniquely, BTF also enables a stepwis e approach to prepare the first differentially functionalized phloroglucinol derivatives and ultimately C s symmetric AAT molecules; one derivative, 4 4abb forms translucent gels at ~ 0.4 wt% in chloroform. The organogels derived from both the C 3 and C s s ymmetric AAT systems have been characterized both macroscopically and on the nanoscale. Electron microscopy of the gel morphologies shows high aspect ratio fibers underlying the gel network superstructures Polarized optical microscopy has allowed imagin g of the native organogel phases, and reveals striking morphology differences between gels that also share different optical and/or phase stability properties. During this study, multiple phloroglucinol derivatives ( 4 4 Table 4 3 ) were formed from BTF, but further conversion to AATs under various cyclization conditions failed. Phloroglucinols prone to aggregation were prohibitively insoluble and were never converted to AATs under the conditions tested; phloroglucinols with high solubility showed unchara cterizable degradation products. Given these negative results on both ends of the solubility spectrum, clearly a balance is needed with respect to the starting material and product solubilities. To expand the scope of functionalized AAT construction, the synthesis of an AAT with versatile functional synthetic handles was explored. Two phloroglucinol derivatives with terminal double and triple bonds ( 2 16j and 2 16k respectively) were synthesized; however, neither saw successful conversion to an AAT. Aba ndoning the amido AAT for a simpler allyl substituted AAT led to the first successful post cyclization transformation via thiol ene chemistry.

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163 Overall, access to a broader array of AATs is beginning to draw previously inaccessible relationships between structure, so lubility, and gel appearance/stability within this class of self assembling molecules. Among the most alluring future lines of investigation with the AATs remains their exploration in the context of supramolecular electronics. 184 Efforts here could be leveraged by the BTF methodology that can p rovide molecular and supramolecular AAT structures rapidly.

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164 APPENDIX A SUPPLEMENTARY INFORMATION FOR CHAPTER 2 Temperature D ependence of First Ring Opening of BTF Runs were performed identically to the formation of compound 2 14a shown below with respect to scale, stoichiometry, reaction time, and workup; only the temperature of the reaction was varied. The 1 H NMR spectrum of the crude reaction mixture for the 41 C run can be found as Figure A 6 Figure A 1. 1 H NMR ( d 6 DMSO) of crude reaction mixt ure to form 2 14 a from BTF at 0 C

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165 Figure A 2. 1 H NMR ( d 6 DMSO) of crude reaction mixture to form 2 14 a from BTF at 40 C Reversibility of reaction under elevated temperature conditions To an NMR tube was added 1 4 mg (23 mol) of compound 2 16aaa 0.7 mL of d 7 DMF, and 2.3 mg (21 mol) of benzylamine ( b ). The tube was then put into a VT controlled Mercury 300 spectrometer and held at a constant temperature of 50.0 0.1 C while 1 H NMR spectra were recorded at t = 0, 1 h, 2 h, and 3 h.

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166 Figure A 3. Time arrayed 1 H NMR ( d 7 DMF) of reaction mixture at 50 C; t = 0 is the bottommost spectrum, while t = 3 h is the topmost spectrum. Figure A 4. 1 H NMR ( d 7 DMF) of compound 2 16aaa at 50 C.

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167 Figure A 5. 1 H NMR ( d 7 DMF) of b enzylamine ( b ) at 50 C. Representative 1H NMR of Novel Compounds Figure A 6 1 H NMR of 2 14 a in d 6 DMSO (crude).

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168 Figure A 7 1 H NMR of 2 14 a in d 6 DMSO (purified). Figure A 8 13 C NMR of 2 14 a in d 6 DMSO (purified).

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169 Figure A 9 1 H NMR of 2 14 b in d 6 DMSO (crude). Figure A 10 1 H NMR of 2 14 b in d 6 DMSO (purified).

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170 Figure A 11 13 C NMR of 2 14 b in d 6 DMSO (purified). Figure A 12 1 H NMR of 2 15 aa in d 6 DMSO (crude).

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171 Figure A 13 1 H NMR of 2 15 aa in d 6 DMSO (purified). Figure A 14 13 C NMR of 2 15 aa in d 6 DMSO (purified).

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172 Figure A 15 1 H NMR of 2 15 and 2 15 in d 6 DMSO (crude). Figure A 16 1 H NMR of 2 15 in d 6 DMSO (purified).

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173 Figure A 17 13 C NMR of 2 15 in d 6 DMSO (purified). Figure A 18 1 H NMR of 2 16 aaa in d 6 DMSO ( crude).

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174 Figure A 19 1 H NMR of 2 16 aaa in d 6 DMSO (purified).

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175 Figure A 20 13 C NMR of 2 16 aaa in d 6 DMSO (purified). Figure A 21 1 H NMR of 2 16 c jk in d 6 DMSO (purified).

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176 Figure A 22 13 C NMR of 2 16 c jk in d 6 DMSO (purified). Figure A 23 1 H N MR of 2 16 c jk in d 6 DMSO (one pot procedure, column purified).

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177 Figure A 24 13 C NMR of 2 16 c jk in d 6 DMSO (one pot procedure, column purified)

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178 Figure A 25 ESI MS of 2 16 c jk (one pot procedure, column purified).

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179 Figure A 26 1 H NMR of 2 22e in CD Cl 3.

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180 Figure A 27 13 C NMR of 2 22e in CDCl 3.

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181 Figure A 28 1 H NMR of 2 23ee in CDCl 3

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182 Figure A 29 13 C NMR of 2 23ee in CDCl 3

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183 Figure A 30 1 H NMR spectrum of compound 2 14 a in DMSO d 6

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184 Figure A 31 Expansion of the gHMBC spectrum of compound 2 14 a in DMSO d 6

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185 Figure A 32 Expansion of the gHMBC spectrum of compound 2 14 a in DMSO d 6

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186 Figure A 33 Expansion of the gHMBC spectrum of compound 2 14 a in DMSO d 6

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187 Figure A 3 4 1 H NMR spectrum of compound 2 15 in DMSO d 6 Figure A 3 5 Expansion (downfield region) of 1 H NMR spectrum of compound 2 15 in DMSO d 6

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188 Figure A 3 6 Expansion (upfield region) of 1 H NMR spectrum of compound 2 15 in DMSO d 6 Figure A 3 7 gHMBC spectrum of compound 2 15 in DMSO d 6

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189 Figure A 3 8 Expansion of the gHMBC spectrum of compound 2 15 in DMSO d 6

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190 Figure A 3 9 Expansion of the gHMBC spectrum of compound 2 15 in DMSO d 6

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191 Figure A 40 Expansion of the gHMBC spectrum of compound 2 15 in DMSO d 6 Figure A 41 1 H NMR of 2 22b in d 6 DMSO

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192 Figure A 42 Aliphatic region of 1 H NMR of 2 22b in d 6 DMSO. Figure A 43 Aromatic region of 1 H NMR of 2 22b in d 6 DMSO.

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193 Figure A 4 4 gHMBC spectrum of compound 2 22b in DMSO d 6

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194 Figu re A 4 5 Aliphatic region of gHMBC spectrum of compound 2 22b in DMSO d 6 Expected S tatistical D istribution of P roducts In the absence of rigorous kinetic modeling, statistical simulations can accurately determine expected product ratios depending on the stoichiometry of the reactants. The reaction outcome can be modeled as balls being placed into barrels. Consequently, the simulation was initially set up to randomly place 100 balls into 100 barrels; given the maximum number of nucleophiles able to reac t with BTF ( 2 3 ) is three, the number of balls that can go into a barrel was limited to three as well. This simulation was repeated 1000 times, and the average number of barrels with 0 (unreacted BTF ( 2 3 )), 1 (BDF ( 2 14 )), 2 (BMF ( 2 15 )), or 3 (phloroglu cinol ( 2 16 )) balls the number of balls ranging from 10 (0.1 equiv) to 300 (3.0 equiv) to obtain product distributions as a function of stoichiometry. The simulations w ere performed using R

PAGE 195

195 ( http://cran.r project.org/ ). Averaged data for the simulations is provided below ( Table A 1 and Figure A 4 6 ). From these simulations, the expected product distribution when adding 1.0 equiv of an amine to BTF ( 2 3 ) is 35.8% of 2 3 36.8% of 2 14 19.0% of 2 15 and 8.4% of 2 16 ; under purely statistical control, addition of 1.0 equiv of amine to BTF would provide the highest yield of 2 3 36.8%. Looking a bit further, adding 2.0 equiv of am ine to BTF would provide 9.4% of 2 3 22.7% of 2 14 26.5% of 2 15 and 41.5% of 2 16 Under purely statistical control, addition of 1.7 equiv of amine to BTF would provide the highest maximum theoretical yield of 2 15 a mere 27.4%.

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196 Table A 1 Calculat ed product distributions (averages and variances from simulations) as a function of stoichiometry. Equiv of amine to BTF BTF (1) BDF (2) BMF (3) Phloro (4) Var of BTF Var of BDF Var of BMF Var of Phloro 0 1 0 0 0 0 0 0 0 0.1 0.90445 0.09123 0.00419 0.000 13 0.0000379 0.00144 0.0000338 0.00000128 0.2 0.81749 0.16603 0.01547 0.00101 0.00014 0.000501 0.000112 0.0000103 0.3 0.74068 0.22227 0.03342 0.00363 0.000267 0.000926 0.000225 0.0000328 0.4 0.6675 0.27214 0.05322 0.00714 0.000366 0.001222 0.000311 0.00 00613 0.5 0.6054 0.30404 0.07572 0.01484 0.000455 0.00146 0.000431 0.000112 0.6 0.54465 0.33355 0.09895 0.02285 0.00059 0.0018 0.000557 0.000175 0.7 0.49253 0.3492 0.12401 0.03426 0.000745 0.00221 0.00065 0.000225 0.8 0.44381 0.36041 0.14775 0.04803 0. 000795 0.00236 0.000927 0.000318 0.9 0.39868 0.36695 0.17006 0.06431 0.000882 0.00252 0.000993 0.000373 1 0.35818 0.36796 0.18954 0.08432 0.000802 0.0022 0.00113 0.000447 1.1 0.31565 0.36575 0.21155 0.10705 0.000805 0.00219 0.00132 0.000516 1.2 0.28549 0.36019 0.22315 0.13117 0.000833 0.00215 0.00144 0.000599 1.3 0.25325 0.34972 0.24081 0.15622 0.000815 0.00199 0.00157 0.000677 1.4 0.2261 0.33566 0.25038 0.18786 0.000812 0.00204 0.0017 0.000697 1.5 0.19998 0.31953 0.261 0.21949 0.000752 0.00185 0.001 85 0.000752 1.6 0.17422 0.30322 0.2709 0.25166 0.000797 0.00191 0.00189 0.000792 1.7 0.14948 0.28894 0.27368 0.2879 0.000725 0.00175 0.0022 0.000874 1.8 0.13071 0.26862 0.27063 0.33004 0.000647 0.00152 0.00197 0.000798 1.9 0.11166 0.24794 0.26914 0.371 26 0.000605 0.00141 0.00202 0.000806 2 0.09397 0.22668 0.26473 0.41462 0.00051 0.0012 0.00202 0.000784 2.1 0.0793 0.20156 0.25898 0.46016 0.000406 0.00103 0.00194 0.00071 2.2 0.06286 0.17832 0.24478 0.51404 0.000368 0.000996 0.00194 0.000683 2.3 0.0519 4 0.15671 0.23076 0.56059 0.000329 0.000854 0.00174 0.000624 2.4 0.04 0.13215 0.2157 0.61215 0.000257 0.00069 0.00155 0.000543 2.5 0.03052 0.10791 0.19262 0.66895 0.000218 0.000614 0.00148 0.000506 2.6 0.0212 0.08473 0.16694 0.72713 0.000149 0.000457 0. 0012 0.000398 2.7 0.01384 0.06167 0.13514 0.78935 0.0000985 0.0031 0.000961 0.000316 2.8 0.0074 0.03924 0.09932 0.85404 0.0000585 0.000201 0.000665 0.000213 2.9 0.00268 0.01763 0.0567 0.92299 0.0000232 0.0000954 0.000365 0.000113 3 0 0 0 1 0 0 0 0

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197 Figure A 4 6 P lot of simulated average product distributions as a function of reactant stoichiometry.

PAGE 198

198 APPENDIX B SUPPLEMENTARY INFORMATION FOR CHAPTER 3 Figure B 1 Atomic numbering for optimized structure of 2 3 ( BTF ).

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199 Table B 1 Atomic coordinat es for the optimized structure of 2 3 (no imaginary frequencies; HF = 912.5115279). C 0.95850 0.97856 0.00042 C 1.36189 0.36473 0.00027 C 3.21523 1.09339 0.00021 O 4.27976 1.62081 0.00126 C 0.66052 3.33087 0.00021 O 0.73629 4.51651 0.00132 C 2.55506 2.23723 0.00054 O 3.54457 2.89470 0.00090 C 2.85789 0.39329 0.00056 O 2.03086 1.84158 0.00043 H 3.30090 0.86619 0.88139 H 3.30130 0.86686 0.87979 O 2.60959 0.83728 0.00022 C 1.32588 0.34103 0.00020 C 0.36497 1.36231 0.00016 C 1.08891 2.67198 0.00049 H 0.90042 3.29267 0.87984 H 0.90060 3.29182 0.88147 O 0.57968 2.67919 0.00016 C 0.36811 1.31919 0.00040 C 0.99651 0.99696 0.00028 C 1.76945 2.27808 0.00055 H 2.40062 2.42473 0.88134 H 2.40127 2.42433 0.88000

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200 Figure B 2 Atomic numbering for optimized structure of 2 14 (BDF).

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201 Table B 2 Atomic coordinates for the optimized structure of 2 14 (no imaginary frequencies; HF = 1008.4404542) C 0.060447 1.075995 0.310104 C 1.281147 1.240914 0.036668 C 0.16 7238 3.3135 0.019145 O 0.179737 4.452066 0.021226 C 3.759295 1.332234 0.377183 O 4.878573 1.652305 0.623439 C 3.046954 0.930399 0.157171 O 2.876896 2.135785 0.053587 N 4.057096 0.233783 0.401738 C 5.005268 0.827054 1.337452 H 4.09889 0.75 9576 0.235262 H 5.090309 1.890018 1.119275 H 5.979102 0.351582 1.216019 H 4.673223 0.708722 2.372979 C 1.53913 2.698186 0.254105 O 0.725048 2.29509 0.350118 H 1.852832 2.95975 1.269039 H 2.271012 3.13679 0.43055 O 0.356152 2.531799 0.7436 27 C 0.124448 1.29326 0.505666 C 0.683015 0.128712 0.603924 C 2.117114 0.167834 1.0929 H 2.158919 0.690634 2.055533 H 2.467604 0.850789 1.259775 H 1.324732 2.560612 0.544307 O 3.365697 0.011465 0.408044 C 2.028338 0.084712 0.082405 C 1.472704 1.164677 0.180377 C 2.552526 2.186907 0.00452 H 2.35734 2.914648 0.788737 H 2.787591 2.757441 0.90775

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202 Figure B 3 Atomic numbering for the optimized structure of 2 15 (BMF).

PAGE 203

203 Table B 3 Atomic coordinates for the optimized st ructure of 2 15 (no imaginary frequencies; HF = 1104.3665103) C 0.173054 0.841579 0.008325 C 1.015561 0.214472 0.445965 C 2.840686 1.953826 0.241628 O 2.235538 2.929813 0.215507 C 1.851475 3.275796 0.359639 O 2.642385 4.139899 0.582871 C 3.70 8973 0.586933 0.288808 O 4.240654 0.529126 0.29159 N 4.203471 1.625623 0.417778 C 5.360069 1.509264 1.295725 N 4.143699 1.723528 0.021353 C 4.932935 2.566721 0.910737 H 3.663189 2.476859 0.436483 H 5.928913 2.440055 1.276693 H 5.06 2206 1.291455 2.326027 H 5.986562 0.694733 0.936554 H 4.55308 0.870368 0.326211 H 4.889896 2.210239 1.9442 H 5.971109 2.573311 0.576693 H 4.534253 3.579149 0.876337 C 2.132706 0.956506 1.149182 O 0.323307 2.191246 0.115424 H 1.721953 1.538862 1.981994 H 2.834011 0.234617 1.568945 H 0.558004 2.631443 0.040309 O 2.169047 2.060507 1.098873 C 1.159189 1.295291 0.625279 C 1.244831 0.111536 0.534454 C 2.446481 0.84565 1.096964 H 2.652547 0.486354 2.111234 H 2.218462 1.9086 1.154633 H 3.035235 1.616591 0.93099 O 2.147798 1.94026 0.62717 C 1.059307 1.15724 0.259813 C 0.024301 1.922205 0.25322 C 0.44368 3.358601 0.223968 H 0.176327 3.996368 0.41365 H 0.489502 3.841385 1.204776

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204 Table B 4 S ummary of calcul ated molecular reactivity descriptors for optimized structures Molecule HOMO (eV) LUMO (eV) (eV) 2 3 (BTF) 7.35149 1.58943 1 73 2 14 (BDF) 6.62602 1.14207 1 38 2 15 (BMF) 6.11717 0.74451 1 09 Table B 5 S ummary of calculated reactivity descr iptors (localized to each carbonyl) for optimized structures Molecule Lactone (C=O) q C Mulliken q C NBO C=O occ 2 3 (BTF) C 3 =O 4 0.331329 0.81445 0.18042 C 5 =O 6 0.330912 0.81571 0.18036 C 7 =O 8 0.330068 0.81586 0.18036 2 14 (BDF) C 3 =O 4 0.236066 0.81697 0.18718 C 5 =O 6 0.461656 0.81703 0.18328 2 15 (BMF) C 3 =O 4 0.203391 0.81885 0.18951 Table B 6 Summary of calculated charges for phenolic oxygens for optimized structures Molecule Oxygen atom q O Mulliken q O NBO V C EPN 2 3 (BTF) O 10 (C 3 =O 4 ) 0.121061 0.52149 14.610392 O 19 (C 5 =O 6 ) 0.120898 0.52135 14.610331 O 13 (C 7 =O 8 ) 0.120635 0.52086 14.610306 2 14 (BDF) O 16 (C 3 =O 4 ) 0.117032 0.54245 14.620161 O 26 (C 5 =O 6 ) 0.097476 0.52412 14.626342 2 15 (BMF) O 33 (C 3 =O 4 ) 0.120278 0.54458 14.6355 32 Table B 7 Summary of measured bond lengths for optimized structures Molecule Bond Length () 2 3 (BTF) C 3 =O 4 1.18802 C 5 =O 6 1.18806 C 7 =O 8 1.18802 Average C=O 1.18803 C 3 O 10 1.40091 C 5 O 19 1.40099 C 7 O 13 1.40101 Average O C (=O) 1.40091 2 14 (BDF) C 3 =O 4 1.19095 C 5 =O 6 1.18990 Average C=O 1.19043 C 3 O 16 1.39387 C 5 O 26 1.40050 Average O C (=O) 1.39719 2 15 (BMF) C 3 =O 4 1.19250 C 5 O 33 1.39393

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205 Figure B 4 Atomic numbering for the optimized structure of 2 21 (B TP ).

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2 06 Table B 8 Atomic coordinates for the optimized structure of 2 21 (no imaginary frequencies; HF = 1030.49306250 ) C 1.191066 0.686607 0.042048 C 1.226622 0.706425 0.053763 C 0.004266 1.372855 0.049129 C 1.215747 0.70781 0.154881 C 1.037079 3.555661 0.12025 7 O 0.907627 4.739213 0.007955 C 3.605638 0.891593 0.017984 O 4.557976 1.586713 0.181976 C 2.576429 2.662466 0.020025 O 3.65057 3.147464 0.222275 O 2.350349 1.43478 0.183909 C 3.633981 0.537748 0.504822 C 2.557325 1.401922 0.162365 H 4 .640272 0.92064 0.339032 H 3.464482 0.509515 1.588201 H 2.514128 2.385813 0.304793 H 2.811258 1.567361 1.216674 O 0.072515 2.757624 0.086658 C 2.3067 2.832705 0.502538 C 2.481651 1.514988 0.261807 H 2.245638 2.629795 1.578854 H 3.136058 3. 521143 0.344481 H 2.709684 1.719839 1.314999 H 3.328745 0.954 0.13319 C 0.060187 2.919681 0.07285 C 1.37832 3.370255 0.567454 O 2.4007 1.323857 0.320563 C 1.178652 0.68762 0.160418 C 0.00549 1.415809 0.064221 H 0.001833 3.292714 1 .102567 H 0.789003 3.343849 0.462939 H 1.365411 3.138814 1.639638 H 1.548723 4.441401 0.465335

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207 Figure B 5 Atomic numbering for the optimized structure of 2 22 (B DP ).

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208 Table B 9 Atomic coordinates for the optimized structure of 2 22 (no ima ginary frequencies; HF = 1126.41773020 ) C 0.11144 1.135438 0.810935 C 0.666663 0.157652 0.827304 C 0.104466 1.185926 0.274877 C 1.387053 1.01034 0.235373 C 0.202413 3.601803 0.039297 O 0.407475 4.6304 0.042034 C 3.618862 0.742441 0.100985 O 3.273368 1.838594 0.348781 C 3.930077 1.575127 0.482495 O 4.993995 1.669068 1.024792 N 4.441244 0.657197 1.170104 C 4.985278 1.837901 1.830606 H 4.706551 0.255867 1.503083 H 4.180792 2.523444 2.100951 H 5.508008 1.523328 2.733366 H 5.682616 2.369159 1.178123 O 0.780194 2.21226 1.293385 C 3.196843 0.579594 0.523373 C 1.998489 0.462306 1.479281 H 4.062117 0.956024 1.083164 H 2.987832 1.317025 0.256622 H 1.912953 1.414816 2.005834 H 2.213877 0.297555 2.233225 H 1.743553 2.11472 1.115138 O 0.509169 2.438955 0.231333 C 1.704163 3.456269 0.02792 C 2.129684 2.195915 0.790478 H 2.065975 3.40002 1.006165 H 2.102793 4.369986 0.46773 H 1.913952 2.315994 1.859647 H 3.206469 2.046362 0.708733 C 1.826914 2.7 25283 0.321058 C 3.342241 2.568425 0.491576 O 3.166391 0.455987 0.73753 C 1.901161 0.285847 0.183728 C 1.184974 1.363752 0.322966 H 1.607459 3.24845 0.61838 H 1.413646 3.340095 1.120459 H 3.560592 2.1929 1.499061 H 3.881256 3.507179 0 .366665

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209 Figure B 6 Atomic numbering for the optimized structure of 2 23 (B MP ).

PAGE 210

210 Table B 10 Atomic coordinates for the optimized structure of 2 22 (no imaginary frequencies; HF = 1222.33991454 ) C 1.011501 0.619188 0.628572 C 0.066784 0.927296 0.220765 C 0.984493 0.047345 0.649019 C 0.800958 1.336883 0.141823 C 0.252146 1.70436 0.684796 C 1.176099 0.711654 1.044609 C 0.375087 3.137492 1.126682 C 0.19573 4.05517 0.039122 C 1.573919 3.624315 0.403162 O 1.775919 2.270831 0.512515 O 0.170506 2.225592 0.628679 C 2.075249 0.238262 1.658789 C 3.477448 0.47154 1.072392 C 3.609089 1.767603 0.285868 N 4.672242 1.835401 0.55121 C 5.008527 3.014837 1.33608 O 2.483065 4.358123 0.679136 O 2.201423 1.096062 1.852267 C 1.895 036 1.735775 1.140179 C 3.005555 2.188275 0.178492 C 4.106476 1.155893 0.017002 N 4.879832 1.328689 1.117101 C 6.026135 0.490268 1.437232 O 2.828265 2.712476 0.424779 O 4.313672 0.24357 0.786342 H 5.269145 1.025655 0.618781 H 4.191 54 3.727182 1.23998 H 5.929619 3.48109 0.974603 H 5.131723 2.749549 2.388586 H 4.655416 2.094751 1.732715 H 6.018663 0.362607 0.761307 H 5.960065 0.133143 2.467465 H 6.96589 1.035253 1.307706 H 3.772308 0.380256 0.45341 H 4.203848 0 .528231 1.893221 H 1.79292 1.101601 2.264998 H 2.150365 0.613357 2.338383 H 1.1181 2.472922 0.710316 H 0.262606 5.096573 0.353511 H 0.449409 4.016306 0.847542

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211 H 1.420368 3.378509 1.32264 H 0.162347 3.299511 2.070106 H 1.262585 2.605124 1 .330989 H 2.343106 1.446609 2.093257 H 3.488283 3.087346 0.583066 H 2.573102 2.471337 0.785283 H 3.000762 0.564584 1.645194 Table B 11 S ummary of calculated molecular reactivity descriptors for optimized pyranone structures Molecule HOMO (e V) LUMO (eV) 2 21 (BTP) 7.0480 1.4123 1.59 2 22 (BDP) 6.2929 0.9856 1.25 2 2 3 (BMP) 5.7394 0.6528 1.00 Table B 12 Summary of calculated reactivity descriptors (localized to each carbonyl) for optimized structures Molecule Lactone (C=O) q C Mulliken q C NBO V C (EPN) C=O occ 2 21 (BTP) C 9 =O 10 0.230963 0.81839 14.621112 0.18102 C 5 =O 6 0.225851 0.81676 14.621164 0.18166 C 7 =O 8 0.222982 0.81839 14.621331 0.18157 2 2 2 (BDP) C 9 =O 10 0.226589 0.81931 14.635640 0.18662 C 5 =O 6 0.223706 0.81910 14.6319 83 0.18815 2 2 3 (BMP) C 9 =O 17 0.232811 0.82002 14.645828 0.19325 Table B 13 Summary of calculated charges for phenolic oxygens for optimized structures Molecule Oxygen atom q O Mulliken q O NBO 2 2 1 (BTP) O 27 (C 9 =O 10 ) 0.118186 0.54577 O 18 (C 5 =O 6 ) 0.124223 0.56516 O 11 (C 7 =O 8 ) 0.123809 0.54472 2 2 2 (BDP) O 34 (C 9 =O 10 ) 0.124268 0.54747 O 25 (C 5 =O 6 ) 0.092394 0.55359 2 2 3 (BMP) O 10 (C 9 =O 17 ) 0.082503 0.55429

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212 Table B 14 Summary of measured bond lengths for optimized structures Molecule Bond Length () 2 2 1 (BTP) C 9 =O 10 1.19579 C 5 =O 6 1.19590 C 7 =O 8 1.19588 Average C=O 1.19586 C 9 O 27 1.38314 C 5 O 18 1.38234 C 7 O 11 1.38259 Average O C (=O) 1.38269 2 22 (BDP) C 9 =O 10 1.19784 C 5 =O 6 1.19858 Average C=O 1.19821 C 9 O 34 1.37867 C 5 O 25 1.37675 Average O C (=O) 1.37771 2 2 3 (BMF) C 9 =O 17 1.20049 C 9 O 10 1.37284

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213 APPENDIX C SUPPORTING INFORMATION FROM CHAPTER 4 Figure C 1 Representative 1 H NMR of compound 4 4c in d 6 DMSO. Figure C 2 Representative 1 H NMR of compound 4 5c in d 6 DMSO.

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214 Figure C 3 Representative 1 H NMR of compound 4 4d in d 6 DMSO. Figure C 4 Representative 1 H NMR of compound 4 5d in d 6 DMSO.

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226 BIOGRAPHICAL SKETCH Matthew B. Baker was born in Columbia, South Carolina. Growing up in the suburban jungle of Irmo, South Carolina he de veloped an uncharacteristic love of all things orange. He attended, and graduated from Clemson University, in Clemson, South Carolina in 2006 with a B.S. in c hemistry. After working briefly at Tetramer Technologies LLC, he began his graduate career at th e University of Florida in the summer of 2007. Under the guidance of Prof. Ronald Castellano, his Ph.D. studies included synthetic organic and supramolecular chemistry, with a penchant for destroying aesthetically pleasing, symmetric molecules. Beginning in October 2012, he will defect to the Netherlands, joining the research group of Prof. Bert Meijer at the Eindhoven University of Technology.