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Asymmetric induction and reaction selectivity in solid state organic photochemistry Netherton, Matthew Russell 2000

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ASYMMETRIC INDUCTION A N D REACTION SELECTIVITY IN SOLID STATE O R G A N I C P H O T O C H E M I S T R Y by M A T T H E W RUSSELL NETHERTON  B.Sc.(Hons.), The University of Western Ontario, 1995  A THESIS SUBMITTED IN PARTIAL F U L F I L M E N T OF T H E REQUIREMENTS FOR T H E D E G R E E OF D O C T O R OF PHILOSOPHY in T H E F A C U L T Y OF G R A D U A T E STUDIES (DEPARTMENT OF CHEMISTRY) We accept this thesis as conforming to the required standard  T H E UNIVERSITY OF BRITISH C O L U M B I A N O V E M B E R 2000 ©Matthew R. Netherton, 2000  In  presenting  this  thesis in  degree at the University of  partial  fulfilment  of  the  requirements  for  an advanced  British Columbia, I agree that the Library shall make it  freely available for reference and study. I further agree that permission for extensive copying of this thesis for department  or  by  his  or  scholarly purposes may be granted her  representatives.  It  is  by the head of  understood  that  copying  my or  publication of this thesis for financial gain shall not be allowed without my written permission.  The University of British Columbia Vancouver, Canada Date  DE-6 (2/88)  Abstract  A number of aromatic ketones were synthesized, and their type II photochemistry studied in solution and in the solid state. The purpose of these investigations was to elucidate the geometric parameters responsible for partitioning of the intermediate 1,4hydroxybiradicals among the possible cleavage, cyclization, and reverse hydrogen transfer pathways. The four ketones studied proved to be very sensitive to changes in the disposition of the carbonyl chromophore, the position of which dictates the anticipated geometry of the biradical intermediate. In particular, it was found that cleavage was only efficient when reasonable overlap between the radical centres and the a-bond undergoing scission was present. Parameters governing the efficiency of the Yang photocyclization were also established. In addition, y-hydrogen/deuterium exchange was observed on photolysis of an unreactive aromatic ketone using tert-butanol as solvent. This reaction is unprecedented in ketones that undergo y-hydrogen abstraction, and is indicative of the high efficiency of reverse hydrogen transfer relative to other reaction pathways in this system.  The ionic chiral auxiliary method of asymmetric induction was investigated in the solid state photochemistry of a series of macrocyclic aminoketones. Salts were formed between the achiral aminoketones (ring sizes of twelve, fourteen, and sixteen) and optically pure acids. The resulting chiral crystals were irradiated in the solid state, and the photoproducts analyzed for enantiomeric purity. Enantioselectivities ranging from poor to excellent were obtained, and X-ray crystallographic data from a number of these compounds provide insight on the origin of the observed stereoselectivities.  11  The  same  technique  for  asymmetric  induction was  also  studied  in a  benzocyclohexadienone system which undergoes photochemical rearrangement to form a chiral benzobicyclo[3.1.0]hexanone derivative. The planarity of this system was expected to limit conformational bias in product enantiodetermination, and thus allow the anisotropic directing effects of the chiral cavity to be studied. The enantioselectivities observed for these salts was generally low, although one derivative displayed possible synthetic utility (ee ca. 80%). Two reactant crystal structures were obtained, one of which contained a unique arrangement in which two photoreactive benzocyclohexadienone moieties were present in the optically active crystal as conformational enantiomers. The net result of the analysis is that the enantioselectivity observed on photolysis of this substrate is independent of conformational bias. Further computational studies are required to garner a complete understanding of this reaction.  iii  Table of Contents Abstract Table of Contents List of Figures List of Tables List of Symbols and Abbreviations Acknowledgements Dedication  ii iv viii xii xiii xvi xvii  Introduction  l  Chapter 1 - Introduction  1  1.1 Preamble  :  1  1.2 Crystal Engineering  2  1.3 Factors Influencing Solid State Reactivity  5  1.4 Type II Photochemistry of Ketones  9  1.5 Geometric Requirements for Hydrogen Abstraction  12  1.6 Photochemistry of Linearly Conjugated Cyclohexadienones  15  1.7 Asymmetric Induction and the Ionic Chiral Auxiliary Concept  18  1.8 Research Objectives  22  Results and Discussion  25  Chapter 2 - Competition between Cyclization, Cleavage and Reverse Hydrogen Transfer in the Solid State Norrish/Yang Type II Photochemistry of a Homologous Series of Spiroadamantyl Ketones  25  2.1 Synthesis of the Spiroadamantyl Ketones  25  2.1.1 Retro synthetic Analysis  25  2.1.2 Preparation of Spiroketones 5and 6 by Intramolecular Acylation  27  2.1.3 Synthesis of Spiroketones 7 and 8 by Ring-Closing Metathesis  29  2.1.4 Synthesis of the Unsaturated Spiroketone 70  31  2.2 Solution and Solid State Photolysis of Spiroketones 5-8  33  2.2.1 Photochemistry of Spiroketone 5  33  2.2.2 Photochemistry of Spiroketone 6  37  IV  2.2.3 Photochemistry of Spiroketone 7  43  2.2.4 Photochemistry of Spiroketone 8  45  2.3 Solid State Structure-Reactivity Correlations  48  2.3.1 Hydrogen Abstraction Parameters and Biradical Geometries  49  2.3.2 Geometric Requirements for Cleavage  52  2.3.3 Geometric Requirements for Cyclization  55  2.3.4 Summary of Biradical Reactivity  57  2.4 Photochemistry of the Unsaturated Adamantyl Spiroketones 68 and 70  58  2.4.1 Photochemistry of Unsaturated Ketone 68  58  2.4.2 Photochemistry of Unsaturated Ketone 70  59  2.5 Summary  63  Chapter 3 - Asymmetric Induction in the Solid State Photochemistry of Macrocyclic Aminoketone Salts  64  3.1 Synthesis of the Aminoketones 3.1.1 Synthesis of the Twelve-membered Aminoketone 12  64 64  3.1.2 Synthesis of the Fourteen- and Sixteen-membered Aminoketones 14 and 16  65  3.2 Solution State Photochemistry of the Macrocyclic Aminoketones  68  3.2.1 Solution State Photochemistry of Cycloalkanones  68  3.2.2 Aminoketone Photochemistry  70  3.2.3 Quantum Yield Studies of Compound 14  74  3.3 Identification of the Photoproducts  77  3.3.1 Independent Synthesis of Reduced Product 119  77  3.3.2 Synthesis of the Type II Cleavage Products 123 and 126  79  3.3.3 Preparation of the Secondary Photoproduct 129  80  3.3.4 Stereochemical Assignment of the Cyclobutanol Photoproducts  81  3.4 Preparation of Optically Active Salts of the Macrocyclic Aminoketones  83  3.5 Photochemistry of the Optically Active Salts  88  3.5.1 Solution State Photolyses of the Optically Active Salts  89  3.5.2 Solid State Photolyses of the Optically Active Salts 3.6 Solid State Structure-Reactivity Correlations  90 94  3.6.1 Solid State Structure of Salt 147  95  3.6.2 Solid State Structure of Salt 128  97  3.6.3 Structure-Reactivity Relationships for Salts of the Fourteen-Membered Aminoketone  98  3.7 Summary  102  Chapter 4 - Asymrnetric Induction in the Solid State Photochemistry of Linearly Conjugated Benzocyclohexadienone Salts  103  4.1 Synthesis of the Photochemical Substrate 52  103  4.2 Photochemistry of Compounds 52 and 166  104  4.3 Resolution of Ketoacid Photoproduct 53  107  4.4 Preparation of Optically Active Salts of Acid 52  109  4.5 Solution State Photochemistry of the Optically Active Salts  112  4.6 Solid State Photochemistry of the Optically Active Salts  112  4.7 Solid State Structure-Reactivity Analysis  115  4.8 Summary  117  Experimental  119  Chapter 5 - Preparation of Substrates  119  5.1 General Considerations  119  5.2 Synthesis of Adamantyl Spiroketones 5, 6, 7, 8, and 70  123  5.2.1 Preparation of the Five-Membered Adamantyl Spiroketone 5  123  5.2.2 Preparation of the Six-Membered Adamanyl Spiroketones 6 and 70  129  5.2.3 Preparation of the Seven-Membered Adamantyl Spiroketone 7  134  5.2.4 Preparation of the Eight-Membered Adamantyl Spiroketone 8  144  vi  5.3 Synthesis of the Macrocyclic Aminoketones 12,14, and 16 and Their Salts  '.  151  5.3.1 Preparation of the Twelve-Membered Aminoketone 12  151  5.3.2 Preparation of the Twelve-Membered Aminoketone Salts  154  5.3.3 Preparation of the Fourteen-Membered Aminoketone 14  160  5.3.4 Preparation of the Fourteen-Membered Aminoketone Salts  165  5.3.5 Preparation of the Sixteen-Membered Aminoketone 16  178  5.3.6 Preparation of the Sixteen-Membered Aminoketone Salts  184  5.4 Synthesis of the Linearly Conjugated Benzocyclohexadienone 52 and its Salts  189  5.4.1 Preparation of the Benzocyclohexadienone Carboxylic Acid 52  189  5.4.2 Preparation of the Benzocyclohexadienone Salts  195  Chapter 6 - Photochemical Studies  209  6.1 General Considerations  209  6.2 Photolysis of Adamantyl Spiroketones 5, 6, 7 and 8  211  6.3 Photolysis of Macrocyclic Aminoketones and Their Salts  222  6.3.1 Preparative Photolysis of Compound 12 in Solution  222  6.3.2 Independent Preparation of Alcohol Photoproduct 119  224  6.3.3 Solution Photolysis of Hydrochloride Salt 127  225  6.3.4 Independent Synthesis of Fourteen-Membered Cleavage Photoproduct  227  6.3.5 Preparative Photolysis of Aminoketone 16  233  6.3.6 Independent Synthesis of Sixteen-Membered Cleavage Photoproduct 126  235  6.4 Photolysis of Benzocyclohexadienone Derivatives 6.5 Resolution of Acid 53 with Brucine  240 ,  6.6 Quantum Yield Determinations  243 245  References  246  vii  L i s t of Figures Figure  Caption  1.1  Crystal engineering in directed solid state synthesis  1.2  (a) Ideal geometry for triacetylene 1,6-polymerization;  Page 3  (b) Monomer alignment in an engineered crystal  4  1.3  Template directed solid state dimerization  5  1.4  A thermal crystalline state reaction  6  1.5  Solid state bimolecular reaction of a mixed crystal  7  1.6  Illustration of the 'reaction cavity' concept  8  1.7  Solid state synthesis of a-cuparenone (21)  8  1.8  Type II photochemistry of ketones  10  1.9  Dependence of reaction pathway on biradical conformation  11  1.10  Geometric parameters for y-hydrogen atom abstraction  12  1.11  Two models of the ketone excited state  13  1.12  Although the C=0"'H distance is favourable, a A value of 90° betrays a lackof orbital overlap  15  1.13  Photochemical pathways of linearly conjugated cyclohexadienones  16  1.14  Synthesis of crocetin dimethyl ester (40) using dienone-ketene photochemistry  17  1.15  Crystalline state absolute asymmetric syntheses  19  1.16  The photoreaction of (3-ketoester 4 5 is highly diastereoselective in the crystalline state, but gives poor results in solution  20  A n example of the ionic chiral auxiliary concept in the solid state Yang photocyclization of salt 4 8  21  Schematic representation of the ionic chiral auxiliary approach to asymmetric solid state synthesis: reaction via diastereomeric transition states  21  General scheme for the solid state photochemistry of macrocyclic aminoketone salts  23  1.20  Photorearrangement of benzocyclohexadienone 52  24  2.1  Retrosynthetic analysis for spiroketones 5-8  25  2.2  Preparation of ester 62  26  1.17 1.18  1.19  Vlll  Figure  Caption  Page  2.3  Synthesis of spiroketones 5 and 6  27  2.4  ORTEP representations of (a) 5; (b) 6  28  2.5  Synthesis of ketones 7 and 8  29  2.6  ORTEP representations of (a) 68; (b) 7; (c) 8  30  2.7  Synthesis of compound 70  31  2.8  ORTEP representation of ketone 70  32  2.9  Photochemistry of ketone 5  33  2.10  Competing secondary photolysis reaction of 72  34  2.11  ' H N M R vinylic region (5 5-6 ppm) after photolysis of 5 showing signals due to enol tautomer 71 (E) and keto epimers 72 (K)  35  2.12  Formation of silyl enol ether 76  36  2.13  Solvent-biradical hydrogen-bonding decreases the rate of reverse hydrogen transfer relative to product formation  37  2.14  Deuteration of 6 through H-D exchange in the biradical  38  2.15  (a) H N M R of 6; (b) H{'H} N M R of deuterated 6  2.16  Photochemistry of spiroketone 6 as an aqueous suspension  41  2.17  ORTEP representation of photoproduct 78  42  2.18  Photolysis of spiroketone 7  43  2.19  Partial C N M R of crude solid state reaction mixture of 7  44  2.20  ORTEP representation of photoproduct 81  45  2.21  Solution and solid state photochemistry of spiroketone 8  46  2.22  ORTEP representation of cyclobutanol 82  46  2.23  Partial C N M R spectrum of the crude 8 solid state photosylate  47  2.24  Kinetic scheme for type II ketone photochemistry  49  2.25  Comparison of carbonyl group orientations in spiroketones 5-8  50  2.26 2.27  Hydrogen abstraction parameters for type II photochemistry Solid state biradical geometry  51 53  2.28  Geometric parameters for cyclization  55  !  2  1 3  1 3  ix  39  Figure  Caption  Page  2.29  Photochemistry of unsaturated ketone 87  59  2.30  Photochemistry of unsaturated spiroketone 70  62  2.31  Mechanism for photorearrangement of 93 to 94  62  3.1  Synthesis of aminoketone 12  65  3.2  Synthetic scheme for macrocycles 14 and 16  66  3.3  Synthesis of bromoester 106  67  3.4  General scheme for type II photochemistry of cycloalkanones  68  3.5  Solution state photochemistry of aminoketone 12  70  3.6  Solution state photochemistry of aminoketones 14 and 16  71  3.7  Secondary photolysis of cleavage product 123  72  3.8  A portion of the C N M R spectrum (C6D ) of the crude reaction mixture after exhaustive photolysis of 120 in MeCN  73  3.9  1 3  6  Excited state reactivity of aliphatic ketones (a) in the absence and (b) in the presence of a triplet quencher  75  3.10  Preparation of aminoalcohol 119  77  3.11  400 M H z ' H N M R spectra (C D ) of (a) fraras-cyclobutanol 125, and 6  6  (b) c/s-cyclobutanol 124  78  3.12  Independent preparation of cleavage products 123 and 126  79  3.13  Synthetic scheme for amine 129  80  3.14  Chiral G C trace showing the separation of starting material (14) and products Ideal and crystallographically derived average H -abstraction  89  geometries  94  3.16  ORTEP representation of the macrocyclic cation in salt 147  96  3.17  ORTEP representation of the macrocyclic cation in salt 128  97  3.18  ORTEP representation of the macrocycle in salt 149  99  3.19  ORTEP representations of the macrocycle in salt 148  101  4.1  Synthetic scheme for the preparation of ketoacid 52  103  4.2  Solution state photolysis of compounds 52 and 166  104  4.3  ORTEP representation of photoproduct 53  105  3.15  Y  x  Figure  Caption  Page  Absorption spectra for benzocyclohxadienones 70 and 166 in acetonitrile .-  105  4.5  Relative ordering of excited states in compounds 70 and 166  106  4.6  Solvent-induced reordering of excited states leads to different photochemical reactions for compound 169  107  4.7  ORTEP representation of salt 171  108  4.8  Chiral G C chromatogram showing the configuration of each enantiomer of ester 167  109  ORTEP representation of the benzocyclohexadienone moieties in salt 183  115  ORTEP representation of the asymmetric unit for salt 183 showing the pseudo-inversion center  118  Root-mean-square overlays of the anions: (a) native conformations in 183. (b) Chirality-matched conformations in 183  118  4.4  4.9 4.10 4.11  xi  List of Tables Table  Caption  Page  1.1  Ideal and crystallographically derived H -abstraction geometries  14  2.1  Photochemistry of ketone 5 in various media  34  2.2  Comprehensive N M R assignment data for ketone 6 in 1:1 CD3OD / CeD^  40  2.3  Values of a for ketones 5-8  50  2.4  Hydrogen abstraction parameters for the solid state spiroketones  51  2.5  Geometric parameters for biradicals derived from 5-8  54  2.6  Cyclization parameters for the 1,4-hydroxybiadicals  56  2.7  Photoproduct yields from 70 under various photolysis conditions  60  3.1  Product distributions in solution state cycloalkanone photochemistry  69  3.2  Product distributions for solution state photolyses of the macrocyclic aminoketones and their hydrochloride salts  72  3.3  Isolated yields from preparative scale photolyses of the macrocycles  74  3.4  Quantum yield determinations for aminoketone 14  75  C N M R chemical shifts (C6D ) for the methine carbon in cyclobutanols 144  82  3.5 3.6  r  1 3  6  C N M R chemical shifts (C6D ) for the methine carbons in aminocyclobutanols produced on photolysis of the aminoketones  1 3  6  of ring size N  82  3.7  Optically active salts prepared from aminoketone 12  84  3.8  Optically active salts prepared from aminoketone 14  84  3.9  Optically active salts prepared from aminoketone 16  86  3.10  Additional salts prepared from the macocyclic aminoketones  87  3.11  Solution state photolyses of some optically active aminoketone salts  90  3.12  Solid state photolysis of optically active salts of aminoketone 14  92  3.13  Solid state photolysis of optically active salts of aminoketone 12  93  3.14  Solid state photolysis of optically active salts of aminoketone 16  93  4.1  Optically active salts prepared from acid 52  110  4.2  Diastereotopic splitting of the gem-dimethyl groups in salts of acid 52  112  4.3  Solid state photolysis of optically active salts of benzocyclohexadienone 52  113  xii  List of Symbols and Abbreviations  A  angstrom  A  heat to reflux  §  chemical shift (ppm)  <D  quantum yield  anal.  analysis  APT  attached proton test  aq.  aqueous  bp  boiling point  br  broad  Bu  butyl  BuOH  tertiary-butyl alcohol  CeD  benzene-^  l  6  calcd  calculated  CAS  Chemical Abstracts Service  cat.  catalytic  Cbz  carbobenzyloxy  CDCI3  chloroform-d  CD3OD  methanol-^  CI  chemical ionization  COSY  ' H - ! ! correlation spectroscopy  Cy  cyclohexyl  d  doublet  DBU  1,8-diazabicyclo[5.4.0]undec-7-ene  DBP  dibenzoyl peroxide  DCM  dichloromethane  de  diastereomeric excess  DEPT  distortionless enhancement by polarization transfer  1  DHQD PYR  hydroquinidine 2,5-diphenyl-4,6-pyrimidinediyl diether  DIPA  diisopropylamine  2  DEPEA DMF DMPU  AfA'-diiospropylethylamine dimethylformamide ^,7Y'-dimethylpropyleneurea  ee  enantiomeric excess  EI  electron impact  Et20  diethyl ether  EtOAc  ethyl acetate  EtOH  ethanol  GC  gas chromatography  Grubbs catalyst  bis(tricyclohexylphosphine)benzylideneruthenium (IV) dichloride  h  hour(s)  HO Ac  acetic acid  hv  light  HMBC  heteronuclear multiple bond connectivity  HMQC  heteronuclear multiple quantum coherence  HPLC  high performance liquid chromatography  HRMS  high resolution mass spectrometry  IR  infrared  IUPAC  International Union of Pure and Applied Chemistry  J  coupling constant (Hz)  LAH  lithium aluminum hydride  LDA  lithium diisopropylamide  LRMS  low resolution mass spectrometry  M  molarity  Me  methyl  MeOH  methanol  MeCN  acetonitrile  Mosher's acid  a-methoxy-a-(trifluoromethyl)phenylacetic acid  mp  melting point  NBS NMR  /V-bromosuccinimide nuclear magnetic resonance  xiv  NOE  nuclear Overhauser effect  OAc  acetate  ORTEP  Oak Ridge Thermal Ellipsoid Program  PCC  pyridinium chlorochromate  ppm  parts per million  Ph  phenyl  'Pr  isopropyl  q  quartet  quint  quintet  RCM  ring-closing metathesis  s  singlet  SDS  sodim dodecylsulfonate  t  triplet  Tf  triflate (trifluoromethanesulfonate)  TFA  trifluoroacetic acid  THF  tetrahydrofuran  TIPS  triisopropylsilyl  TMS  trimethylsilyl  Ts  tosyl (4-toluenesulfonyl)  TsOH  4-toluenesulphonic acid  U V / VIS  ultraviolet / visible  XV  Acknowlegdements  I would like to express my gratitude to to Dr. John Scheffer for his guidance, encouragement, and support over the last five years. I can only hope that some of his patience, wisdom, and analytical ability has rubbed onto me. None of the work presented in this thesis could have been carried out without the enormous effort of Dr. Eugene Cheung in the U B C structural chemistry laboratory. Eugene's ever-friendly manner and crystallographic genius have made our collaboration a very enjoyable one. Special thanks goes to Carl Scott for proofreading this manuscript. Lastly, I would like to thank the current and past members of the third floor research groups for providing a stimulating and genial working atmosphere.  XVI  For my parents, with love  xvii  Introduction  Chapter 1  C h a p t e r 1 - Introduction  1.1 Preamble The study of organic chemistry relies on the development and interpretation of conceptual models in order to characterize patterns of observed reactivity, and perhaps more importantly, to predict and design reactivity with new synthetic targets in mind. In 1  constructing these models, information from theoretical, mechanistic, methodological, and synthetic studies are brought together to provide a set of rules, which attempt to reconcile  both the  underlying theory and experimental  observations.  As more  experimental data are collected, and methods to quantify the fundamental physical forces involved in these chemical transformations become more sophisticated, the model evolves to become a more complete and useful predictive tool. Because compounds in solution are relatively unencumbered by the surrounding solvent  molecules,  dynamic  processes  such  as  conformational  exchange  and  intermolecular collision occur freely. With the geometry of the reactant in a constant state of flux, it is often difficult to amap the most probable trajectory for the reaction under study. In addition, several reaction pathways, each possibly giving rise to different products (e.g.  stereoisomers,  adducts) may be in competition, thus complicating  interpretation with respect to a given model of reactivity. Such conformational flexibility requires additional measures to enforce a uniform mode of reactivity and improve reaction selectivity. In solution these constraints are often achieved through the use of tailored reagents and catalysts that interact with the reactive substrate in a specific manner. Examples of this strategy include the use of a sterically congested base to remove selectively the least hindered proton from a ketone during the formation of a kinetic enolate, and the asymmetric hydrogenation of an olefin mediated by an optically active catalyst. An  alternative  to the  approaches  outlined above  involves  replacing the  conventional isotropic solution medium with a more organized and constrained environment. By confining reactants in an anisotropic reaction cavity, conformational flexibility and diffusion are reduced such that molecular geometry and intermolecular  1  Introduction  Chapter 1  interactions are limited and thus more uniform than in solution. As a result, chemical reactions performed in such media tend to be more selective than their solution state counterparts as reaction trajectories that were attainable in solution become inaccessible. Access to 'latent' modes of chemical reactivity, those processes that do not proceed in solution but are favoured in the solid state, provides new synthetic avenues that are unavailable via conventional methodology.  2  Examples of organized and constrained  media include polymer films, liquid crystals, zeolites, glasses, clays, and crystals. Reactions in the crystalline phase, in particular, have been extensively studied. In general, since the crystal lattice is constructed from a single structural element (i.e. the unit cell) which is repeated ad infinitum in three dimensions, all reactant molecules exist in the same conformation and are subject to the same anisotropic forces from neighbouring molecules. In addition to the increased selectivity imparted by geometric uniformity, studies of reactivity in the crystalline state provide valuable mechanistic insight. The exact structure of the crystal may be determined through single crystal X-ray diffraction, providing structural information which is not available for the corresponding solution state reactions. When this information is compared to the observed outcome of a solid state reaction, powerful insight into the reaction's geometric and steric requirements is gained. Indeed, this solid state structure-reactivity  correlation  method, because it is  based on reactions involving identically oriented reactants for which quantitative information is available (e.g. interatomic distances and angles), has proven to be a valuable tool in defining and refining models of chemical reactivity.  1.2 Crystal Engineering Although the crystal structure-reactivity approach is able to predict and explain the manner in which solid state reactions proceed, it gives no control over how molecules are arranged within a crystal. The term crystal engineering  4  refers to the study of the  chemical and physical properties of crystalline solids with the goal of understanding and directing the crystallization process. ' When employed in tandem, structure-reactivity 5 6  analysis and crystal engineering allow retro synthetic analysis from a desired product to a crystalline starting material, and from these reactant crystals to their individual chemical  2  Introduction  Chapter 1  solid state reaction  TARGET PRODUCT  structure-  crystallization  REACTANT CRYSTAL  STARTING COMPONENTS  crystal engineering  reactivity  Figure 1.1 Crystal engineering in directed solid state synthesis  components. In this way, the design of highly selective solid state syntheses is, in theory, made possible from first principles (Figure 1.1).  7  Even though the  current understanding of the intra- and intermolecular  interactions leading to an observed crystal packing is incomplete, and attempts to engineer crystals have largely been a process of trial and error, significant inroads have been made. A n elegant solid state study by Lauher et al*  describes the  1,6-  polymerization of a triacetylene, a long-standing synthetic problem of considerable interest and a transformation unknown in solution (Figure 1.2). From previous theoretical studies, and experimental data from structure-reactivity correlations, the geometrical 9  10  relationships required for successful reaction have been defined (Figure 1.2.a). The ideal crystal would see the monomers tilted 28°, with a distance of 3.5 A between neighbouring chains and a repeat distance of 7.4 A. After analyzing two model systems, a two-component crystal composed of vinylogous amide 1 and triacetylene 2 was prepared (Figure 1.2.b). X-ray crystallography confirmed that a suitable arrangement had been engineered (tilt 29.2°; intermolecular distance 3.49 A; repeat distance 7.14 A), and yirradiation of the crystalline solid indeed led to the desired polymer. In another system investigated by MacGillivray et al.,  u  resorcinol (3) was  employed as a template to organize two molecules of diene 4 such that their double bonds were in a geometry suitable for efficient [2 + 2] photocycloaddition to occur in the solid state. The yield of a single photoproduct, cyclobutane 9, was quantitative, in stark contrast to the solution state reaction which produces a number of cyclobutane stereoisomers (Figure 1.3).  3  Chapter 1  Introduction  Figure 1.2 (a) Ideal geometry for triacetylene 1,6-polymerization; (b) Monomer alignment in an engineered crystal.  Introduction  Chapter 1  1.3 Factors Influencing Solid State Reactivity Photochemical reactions are often chosen for study in the solid state for a number of reasons. Light, which may be viewed as a 'reagent' in these transformations, is easily introduced into the crystal without disrupting the lattice. The wavelength of radiation may be tailored to the absorption characteristics of the photochemical substrate, and reactions may be carried out at ambient or reduced temperature. Thermal reactions, although not precluded from crystalline state chemistry, suffer the disadvantage that the thermal energy required to promote reactivity also increases the likelihood of crystal melting and concomitant loss of crystal lattice rigidity and regularity. A n interesting example of a 12  thermal solid state reaction comes from the research of Toda et al.  and is illustrated in  Figure 1.4. When crystals of the thermally labile diallene 10 are heated to 150 °C, a  5  Introduction  Chapter 1  11  Figure 1.4 A thermal crystalline state reaction.  spontaneous electrocyclic rearrangement takes place in which dimethylenecyclobutene 11 is formed. With the current limitations of crystal engineering in the design of multiplecomponent systems, solid state studies have focussed primarily on unimolecular reactions (e.g.,  rearrangements)  and dimerizations.  An effective  strategy  for performing  /zeterobimolecular solid state reactions comes from the growth of mixed crystals formed by co-crystallization of two structurally similar molecules. Compounds with similar structural features, such as acrylamide (13) and cinnamamide (15) will often crystallize together in a regular array (Figure 1.5).  13  Subsequent reaction (irradiation in this case)  selectively produces the mixed dimer 17 as well as the anti head-to-tail homodimer 18 with excellent regio- and stereocontrol. With the advent of modern X-ray crystallographic techniques in the 1960's, seminal work by Schmidt and co-workers provided a set of guidelines, the topochemical rules, to which solid state reactions should adhere. ' Chief among these is the principle 14 4  of least motion, which supposes that, since crystalline state reactions proceed in a constrained environment, they do so with a minimum of atomic and molecular motion. Thus, when two or more reaction pathways are chemically available to a reacting species, the reaction course involving the least atomic displacement should be favoured. Schmidt was also able to define a set of geometric parameters describing the relative geometry  6  Introduction  Chapter 1  .CONH;  H NOC 2  "^-CONHo  s  17  13 hv  H NOC 2  15 ,CONH  two-component crystal H NO(f  TT  2  2  ^  18  Figure 1.5 Solid state bimolecular reaction of a mixed crystal.  (e.g. distances, and angles) necessary for the [2 + 2] photocycloaddition of substituted cinnamic acids to proceed successfully. Solid state reaction theory was furthered by Cohen and co-workers with the development of the reaction cavity concept. '  15 16  In this paradigm, the reacting molecule is  considered to exist in a cavity bounded by its nearest neighbours. As the shape of the molecule changes along a reaction pathway through transition state to product, steric interactions between the cavity and any intermediate structure will favour transition state geometries that least interfere with the cavity walls (Figure 1.6). A n elegant illustration of reaction cavity and topochemical control comes from the work of Garcia-Garibay et al. on the total synthesis of a-cuparenone (21, Figure 1.7).  17  On photolysis of ketone  precursor 19, expunction of carbon monoxide leads to formation of 1,5-biradical 20. Constrained by the reaction cavity, the biradical cyclizes to 21 with retention of stereochemistry at the benzylic position. It should be noted, however, that not all solid state reactions can be understood from simple inspection of the crystal structure. The  7  Chapter 1  Introduction  Allowed  Disallowed  Figure 1.6 Illustration of the 'reaction cavity' concept. Processes are allowed only if the transition state (dashed line) fits within the cavity (solid line).  reaction depicted in Figure 1.4 is decidedly non-topochemical, with a large motion of compound 10 required, from the s-trans to the reactive s-cis conformation, before the reaction can proceed. The role of crystal surface reactions, lattice defects and phase transitions have been invoked to help explain such results. 12  More quantitative approaches to the analysis of solid state reactivity have also been put forward. In general, these involve constructing a computer model of a section 18  Figure 1.7 Solid state synthesis of ct-cuparenone (21). Confinement in the reaction cavity promotes stereoselective cyclization.  8  Introduction  Chapter 1  of the reactant crystal based on X-ray crystallographic data. A chemical reaction is simulated by replacing a molecule in the centre of the mini crystal lattice with a species representing the transition state of a proposed reaction pathway. Computer modelling then allows the cumulative effect of this replacement on the surrounding molecules to be calculated. In this manner the energetic requirements for a number of reaction pathways may be compared, and a prediction made on the outcome of a solid state reaction for which qualitative assessment of the crystal structure provides no obvious answers.  1.4 Type II Photochemistry of Ketones  19  Both aliphatic and aromatic ketones absorb ultraviolet (UV) light in the 290-330 nm region.  Photons of this energy promote an electron from one of the non-bonding  orbitals on oxygen, to the anti-bonding n* orbital of the carbonyl chromophore in what is referred to as an n—>n* transition. After this electron promotion, the resulting excited state species possesses an unpaired electron localized on each of the oxygen and carbon atoms, and the reactivity of this moiety may in some ways be likened to that of a 1,2biradical (22).  21  In the type II reaction, an intramolecular hydrogen atom abstraction  occurs by the oxygen  atom of the excited  state ketone,  and the result is a  hydroxybiradical (Figure 1.8). Abstraction of a y-hydrogen atom to form a 1,4-biradical (23) is favoured as it proceeds via a six-membered transition state; however, P- and 5hydrogen abstraction may also be observed, especially when no y-hydrogen atoms are available for reaction.  o. 22  Three reaction pathways are available to the intermediate 1,4-hydroxybiradical: (1) disproportionation via reverse-hydrogen transfer, thus reforming the starting ketone in a degenerate reaction; (2) scission of the ot-p C-C a-bond (the Norrish Type U reaction),  9  Introduction  Chapter 1  the result of this cleavage being an enol (24) and an alkene (25), which subsequently tautomerizes to the corresponding ketone; (3) cyclization of the biradical (Yang photocyclization) to form a cyclobutanol (26). Partitioning among these three pathways is believed to be controlled by the conformation and spin multiplicity of the intermediate biradical.  193  In particular, overlap between the two half-filled p-orbitals and the breaking  a-bond is a stereoelectronic requirement for cleavage. The transoid, gauche, and cisoid conformations shown in Figure 1.9 all potentially allow such requirements to be met. 22  Cyclization, on the other hand, requires that the two radical centres overlap efficiently. For this to occur, the directionality of the p-orbitals and their separation must be taken into account, and the transoid geometry is clearly not acceptable.  R \ HO* "  Yang photocyclization  1  R' R  26  hv CX  O H  H  reverse hydrogen transfer  R'  H  H  23  Norrish type cleavage  OH  24  \ R"  25 Figure 1.8 Type II photochemistry of ketones.  In addition to these geometric requirements, there is an additional electronic aspect to consider. For any of the three pathways to proceed, the biradical must exist in the singlet state, i.e. with unpaired electrons of opposite spin. In general, aromatic ketones undergo type U hydrogen abstraction from the triplet excited state, while, for aliphatic ketones, both the singlet and triplet species may have lifetimes sufficiently long for type II abstraction to occur. In solution, any triplet 1,4-hydroxybiradicals, since they 23  cannot  undergo  intramolecular reaction,  are  long  enough  lived  to  experience  conformational interchange. Thus, the products derived from these intermediates will be  10  Introduction  Chapter 1  HO/ 0_J.^ /  transoid  A cleavage  cyclization cisoid J  Figure 1.9 Dependence of reaction pathway on biradical conformation.  strongly influenced by the geometry at which triplet—>singlet intersystem crossing occurrs, and may not necessarily correlate with the geometry of the initially formed biradical, or its lowest energy conformer(s).  24  Conducting these reactions in the solid  state circumvents this thorny issue, as the biradical is trapped in the crystal lattice and has limited conformational flexibility. In addition, since biradical formation involves only the motion of a hydrogen atom over a relatively short distance, the geometry of the biradical should resemble that of the starting ketone. Correlation of crystalline ground state ketone structures with observed reactivity, therefore, should provide quantitative data not available from solution state studies.  11  Chapter 1  Introduction  Figure 1.10 Geometric parameters for y-hydrogen atom abstraction.  1.5 Geometric Requirements for Hydrogen Abstraction Extensive crystalline state studies by Scheffer and co-workers on type II hydrogen abstraction has provided a detailed model that quantifies the geometric requirements for this process.  25  Four parameters uniquely define the disposition of a hydrogen atom with  respect to the reactive n-orbital on the oxygen atom of the electronically excited carbonyl group. These are illustrated in Figure 1.10: d, the O H interatomic distance; A, the C=0 H angle; 9, the O H-C angle; and co, the dihedral angle that the O-H vector makes with respect to the nodal plane of the 7t-system. Correlation of (n,7i*) excited state reactivity with the geometry of the ground state ketone is valid because the excitation is known to be highly localized in the carbonyl group such that geometric changes in the rest of the molecule are negligible. From a theoretical standpoint, ideal values for the four parameters have been deduced. The sum of the van der Waals radii for a hydrogen and an oxygen atom is 2.72 A,  27  and this value has been put forward as the optimum value of d, as it ensures that  orbitals from the oxygen and hydrogen atoms are in close contact. The angle co measures the deviation of the hydrogen atom under consideration with the plane that contains the half-filled oxygen n-orbital. Overlap is maximized when co is 0°, and approaches zero as an orthogonal geometry is approached (co = 90°). On the basis of mathematical and experimental kinetic studies,  Wagner has proposed that the abstraction rate is  proportional to COS co. Ab initio calculations by Houk have likewise shown that the 2  28  enthalpy of activation increases significantly as 9 deviates from 180°, suggesting that a  12  Introduction  Chapter 1  Figure 1.11 Two models of the ketone excited state: (a) Kasha's proposal -oxygen unhybndized; (b) Sp -hybridized 'rabbit ear' model.  linear O H-C arrangement is preferred. Pinpointing an ideal value for the A parameter 29  is complicated by the fact that two models of the (n,7t*) excited state ketone exist (Figure 1.11). In the so-called 'rabbit ear' conception, the atomic orbitals on oxygen are hybridized, and the two non-bonding sp hybrids are degenerate, each forming a 120° 2  angle with the carbonyl C=0 bond. In the model proposed by Kasha, the oxygen atom 30  is not hybridized, resulting in non-degenerate non-bonding orbitals, one largely of 2s character, and the other 2p-like. The latter, which forms an angle of 90° with respect to the O O bond, contains the unpaired electron in the excited state. In general, therefore, the ideal A angle is thought to lie in the 90-120° range. Inspection of the above data reveals that it is geometrically impossible for all of the atoms to be ideally aligned in a six-membered transition state; some of the parameters must deviate significantly from their optimum value. The solid state study of two series of compounds by Scheffer et al.  has provided average values for y-hydrogen abstraction  parameters in the homologous macrocyclic aliphatic ketones 27, ketones  32  31  and for the aromatic  28 and 29 (Table 1.1). A number of important points are revealed in these  numbers. The fact that both the aliphatic and aromatic ketones possess such similar geometries in the solid state provides strong support for this idea that such orientation is a general predictor of successful y-hydrogen atom abstraction. Considerable deviation of the © (up to 62°) and 9 (as low as 113°) angles from ideal values clearly does not prevent the abstraction process. The fact that A lies closer to 90° than 120° fits more closely with the Kasha model, but by no means excludes the possibility of the 'rabbit ear' orbital  13  Introduction  Chapter 1  configuration. The interatomic distance d is arguably the most useful predictor of type U reactivity. In cases where more than one hydrogen atom is properly aligned for abstraction, only abstraction of the closer atom is observed. To date, the largest reported value  33  of d for successful  y-hydrogen atom abstraction is 3.10 A (vide infra),  demonstrating that the upper limit for C=0 "H contact extends beyond the van der Waals limit. It must be emphasized, however, that a favourable value of d alone does not ensure that abstraction will take place. Figure 1.12 illustrates a transformation proposed by Prinzbach et al.  34  in which two consecutive photocyclizations were envisaged. Although  the calculated abstraction distance of 2.34 A was indeed favourable, failure of the photochemical transformation of diketone 30 to product 31 may reasonably be attributed to its co angle of - 9 0 ° , rigidly constrained by the cage structure.  35  Table 1.1 Ideal and crystallographically derived FL-abstraction geometries.  d(A)  »(°)  oo  A(°)  Ideal  <2.72  0  180  90-120  27  2.73 ± 0.03  52 ± 5  115 ± 2  83 ± 4  28/29  2.63 ± 0.06  58 ± 3  114+1  81 ± 4  14  Introduction  Chapter 1  Figure 1.12 Although the C=?0""H distance is favourable, a A value of 90° betrays a lack of orbital overlap.  1.6 Photochemistry of Linearly Conjugated Cyclohexadienones Conjugation  of  the  carbonyl chromophore with  36  aliphatic double  bonds  dramatically changes its excited state chemistry compared to that of aliphatic and aromatic  ketones.  In  particular,  the  photochemistry  of  linearly  conjugated  cyclohexadienones (and benzocylohexadienones) 32 has been a subject of much research, as their reactions tend to proceed cleanly and efficiently while providing products of greater structural complexity. In addition to their synthetic potential, mechanistic studies on the photochemistry of these compounds have provided an interesting and detailed picture of the reaction pathways. Most notable among these discoveries is the dependence of the mode of reactivity on the nature of the excited state (i.e. (n,7c*) or (71,71*)).  36b  The general mechanistic scheme is outlined in Figure 1.13. Reaction via the '(n,7c*) surface results in a-cleavage, a type I photochemical process which gives rise to the twisted singlet biradical 33. Simple bond rotations bring the isolated radical centres into conjugation with the rc-system of the diene, thus forming ketene 34. The formation of the ketene intermediates has been unambiguously confirmed by low temperature IR studies in frozen matrices. In the presence of a suitable nucleophile, the ketene may also be trapped to form compounds of general structure 35. In the absence of such trapping agents, the unsaturated ketene may either undergo an electrocyclization to re-form the starting cyclohexadienone 32, or proceed to bicyclo[3.1.0]hexane  36 by way of an  internal crossed [4 + 2] cycloaddition. The same bicylic product is formed when the reaction proceeds by way of the  manifold, a fact which greatly complicates the  15  Introduction  Chapter 1  Figure 1.13 Photochemical pathways of linearly conjugated cyclohexadienones.  study of this reaction. In this process, however, no ketene intermediate is involved. While Quinkert et al. have suggested that a concerted [TT^+OY] rearrangement may be in operation,  3611  others have proposed that the [1,2] shift involves a zwitterionic (37) or 36b  biradical intermediate. Regardless of the excited state involved, triplet quenching studies have •I  established that both pathways proceed exclusively from singlet excited states. Through manipulation  of  experimental conditions  (e.g.  solvent,  additives)  and substrate  functionalization, it has been possible to alter the relative energies of the \n,n*) and excited states and thus exercise a measure of control over reactivity. Ultraviolet spectroscopy has also proven useful in determining which of the two excited states is of lower energy, and hence responsible for the observed reactivity.  16  Introduction  Chapter 1  A synthetic application of this reaction is shown in Figure 1.14. Dienone 38 is J/  readily synthesized from 2,6-dimethylphenol and (£)-l,4-dibromobut-2-ene in two steps. Photolysis of this compound in methanol gives rise to diester 39 via an intermediate diketene. Further oxidation leads to crocetin dimethyl ester (40), providing an efficient route to this natural polyene.  Figure 1.14 Synthesis of crocetin dimethyl ester (40) using dienone-ketene photochemistry.  17  Introduction  Chapter 1  1.7 Asymmetric Induction and the Ionic Chiral Auxiliary Concept The demand for optically pure, rather than racemic synthetic molecules, has increased dramatically over the last decade. This pressure stems largely from the pharmaceutical and biotechnology industries, and has fuelled research interest such that asymmetric synthesis has become the rule rather than the exception. At the heart of the matter is the desire to selectively alter an achiral molecule in such a way that more of one product enantiomer is formed than the other. In solution, excellent results have been achieved using optically active reagents, catalysts, and auxiliaries. Crystalline state chemistry has also proven effective at asymmetric induction, through the action of crystal to molecular chirality transfer. Of the 230 space groups in which a molecule may crystallize, 65 are chiral. This means that, since no inversion or reflection symmetry elements are present in these crystals, all molecules in the lattice are influenced by the same chiral anisotropic forces. Achiral molecules that crystallize in this manner are hence expected to react such that one product enantiomer is favoured over TO  another. This process is termed absolute asymmetric synthesis, since no external source of optical activity (e.g. a chiral auxiliary) is influencing the reaction. In this manner, the chirality of the crystal lattice is manifested in the absolute configuration of the optically active product. Figure 1.15 illustrates two such photochemical transformations. In the first example, single crystals of dibenzobarrelene 41, which crystallizes in the chiral space group P2i2i2i, are transformed into dibenzosemibullvalene 42 in greater than 95% enantiomeric excess.  The second reaction, taken from the work of Toda et al, concerns  the Yang photocyclization of a-oxoamide 43, which also crystallizes in  P2\2\2\.  Crystalline state photolysis of single crystals of compound 43 affords the chiral (3-lactam 44 in 93% enantiomeric excess.  40  While the crystallization of achiral molecules in chiral space groups is by no means an uncommon occurrence, it is neither a general nor a predictable phenomenon. This severely limits the utility of absolute asymmetric reactions in synthesis. A more general approach to solid state asymmetric induction is to use the conventional concept of a chiral auxiliary. By covalently attaching an optically active moiety to the reactive substrate, one is assured of obtaining optically active crystals, as enantiomerically pure compounds are required to crystallize in chiral space groups. A n example of this  18  Chapter 1  Introduction  >95% ee  93% ee  Figure 1.15 Crystalline state absolute asymmetric syntheses: (a) A di-Tt-methane rearrangement; (b) A Yang photocyclization.  approach is illustrated in Figure 1.16. While solution state photolysis of P-ketoester 45 gives rise to diastereomers  46 and 47 with low stereoselectivity (14% de), the  corresponding crystalline state reaction is far more selective, with a measured de of 96%. Not only does this example illustrate the selectivity afforded by conducting the 41  reaction in the solid state, but also emphasizes a critical difference between the mechanism of action of chiral auxiliaries in the solution and solid states. In solution, the chiral auxiliary is generally required to alter the steric environment at the reaction site, by either blocking or facilitating access in a stereoselective manner. Attachment of the auxiliary in close proximity to the reaction locale is not, however, a requirement in the solid state. The mere presence of a stereogenic element conveys chirality throughout the entire crystal lattice, and this influence is manifested in the conformation of the reactant and the shape of the reaction cavity, the ultimate determinants of the reaction's steric course.  19  Introduction  Chapter 1  45  46  47  Figure 1.16 The photoreaction of P-ketoester 45 is highly diastereoselective in the crystalline state, but gives poor results in solution.  The fact that the optically active moiety does not need to be tightly bound to the reactive substrate provides a great degree of flexibility in the design of asymmetric solid state reactions, and this has been exploited by Scheffer and co-workers. Through the use of ionic chiral auxiliaries, salts are formed between an achiral, photoreactive carboxylic 42  acid (or amine) and an optically pure amine (acid). Figure 1.18 demonstrates the general concept. Since the crystalline environment is chiral, reaction of the photolabile ion can proceed via either of two diastereomeric transition states of differing energy. The pathway with the lowest kinetic barrier proceeds at a greater rate, and the product of this reaction will predominate  4 3  Subsequent removal of the ionic auxiliary with simple acid-  base extraction provides the optically active photoproduct. A n example of this concept put into practice is shown in Figure 1.17. Optically active salt 48 provides cyclobutanol 49 after crystalline state photolysis and subsequent diazomethane workup.  44  Since salts are generally higher melting than molecular solids, they tend to better retain their crystallinity and resist melting during photolysis. The ease with which the ionic chiral auxiliary can be 'attached' or changed rivals typical solution state chemistry, and in all reports on this method to date an effective (>80% ee) ionic auxiliary has been found. Although crystals suitable for X-ray crystallographic analysis are not required for successful asymmetric induction, solid state structure-reactivity correlations resulting from these studies have helped lend further detail to existing reaction models.  20  Introduction  Chapter 1  Figure 1.17 A n example of the ionic chiral auxiliary concept in the solid state Yang photocyclization of salt 48.  coo  0  (+)-Chiral product it  (-)-Chiral product  ©  ©  Photolysis in the crystalline state ©  0  ^coo  ©  Chiral Crystal  k Acid-base reaction COOH Optically pure amine Auxiliary  Achiral acid Photoreactive substrate  Figure 1.18 Schematic representation of the ionic chiral auxiliary approach to asymmetric solid state synthesis: reaction via diastereomeric transition states.  21  Introduction  Chapter 1  1.8 Research Objectives This thesis reports on three separate studies, each designed to explore a different aspect of crystalline state chemistry through solid state structure-reactivity correlation. The first project stems from earlier studies in our laboratory on the solid state 32  Norrish/Yang Type II photochemistry of phenyladamantylketones 29 (Table 1.1).  X-ray  crystallography has revealed that, regardless of the substituent on the phenyl ring, all of these ketones adopt solid state conformations in which the mean plane of the carbonyl group is roughly orthogonal to the plane bisecting the adamantyl skeleton. Since all the compounds possessed similar solid state geometries, it was not surprising that they reacted in the same manner, producing only the endo-aryl cyclobutanols (see Figure 1.17). In order to probe the effect of carbonyl geometry on the reaction outcome, and to model the reaction for a number of different ketone geometries, our interest lay in studying a series of benzoyladamantyl ketones in which the disposition of the photoreactive carbonyl group could be altered systematically. Our strategy was to synthesize spiroadamantyl ketones 5-8, compounds in which a methylene chain of varying length constrains the orientation of the carbonyl group through the introduction of five- to eight-membered  rings. Previous experience  with adamantane-derived  compounds in our laboratory suggested that the substrates chosen would have a reasonable chance of forming crystals suitable for X-ray crystallographic analysis.  6  7  8  Since a great deal of our studies on the ionic chiral auxiliary approach to asymmetric synthesis have employed optically active cations as the chiral influence, we sought to extend this methodology by studying salts in which the anion introduces chirality to the crystal lattice. The macrocyclic amino ketones 12, 14, and 16 seemed  22  Introduction  Chapter 1  12  H  H  14  16  to be logical choices for the photolabile achiral component of the salts for a number of reasons. The synthesis of compound 12 has been reported in the literature  45  and is  straightforward, thus allowing a number of different salts to be synthesized and in quantity. Cyclic ketones, in contrast to their acyclic analogues, are known to give rise to a greater proportion of cyclization versus cleavage products in their type II photochemistry. This is advantageous because it is the chiral cyclobutanol products 50 and 51 that are of interest; cleavage products are achiral and thus give no information on solid state asymmetric induction (Figure 1.19). The possibility of selectivity in the formation of either the cis- or trans-f\xsco\ cylobutanols adds another element that may be analyzed in terms of the solid state geometry. Being a type II photoreaction, these systems will contribute further to the reactivity model we have formulated for these processes.  23  Introduction  Chapter 1  In the third study, exploration of solid state asymmetric induction was again the main objective. The object of this undertaking was to provide information on how solid state reactivity is influenced by the anisotropic cavity in which the reactive substrate lies. In the previous Type n photoreactivity studies, conformational bias alone was able to explain the observed reactivity, as typically only one of two enantiotopic hydrogen atoms is capable of reacting. The substrate in this instance was chosen based on its limited conformational lability. The anion in optically active salts of carboxylic acid 52 is hypothesized to be nearly planar, with only small conformational variations expected among its different solid state structures. Removing the conformational bias would thus allow the influence of the cavity to be evaluated on its own, as the rearrangement to ketone 53 proceeds (Figure 1.20).  O  O hv  H0 C  C0 H  2  2  52  53  Figure 1.20 Photorearrangement of benzocyclohexadienone 52.  24  Results and Discussion  Chapter 2  Results and Discussion  Chapter 2 - Competition between Cyclization, Cleavage and Reverse Hydrogen Transfer in the Solid State Norrish/Yang Type II Photochemistry of a Homologous Series of Spiroadamantyl Ketones 2.1 Synthesis of the Spiroadamantyl Ketones 2.1.1 Retrosynthetic Analysis Two different strategies were employed in the synthesis of ketones 5-8 (Figure 2.1). Retrosynthetic analysis of the key spirocyclization step led to the disconnection of bond a as a logical first choice. Formation of the five- and six-membered compounds 5 and 6 via an intramolecular Friedel-Crafts acylation from the corresponding acyclic precursors 54 and 55 was indeed successful. Attempts to form the seven-membered substrate 7 by this method from its corresponding acyl derivative (n = 3, X = CI) resulted solely in acyclic products lacking a carbonyl moiety, presumably due to the slow rate of cyclization of the intermediate acylium ion relative to decarbonylation. Ring-closing metathesis (RCM),  46  which has emerged as a powerful tool in the synthesis of medium-  sized rings, proved an efficient route to the seven- and eight-membered spiroketones 7 47  and 8. Bond disconnection b illustrates this strategy, with dienes 56 and 57 as the cyclization precursors.  N 5 6  54 55  5 6 7 8  56 57  N 5 6 7 8  Figure 2.1 Retrosynthetic analysis for spiroketones 5-8. 25  N 7 8  n X f 1 OH Friedel-Crafts 2 OMe IJDisconnection  UL 0 1  1  Ring-Closing Metathesis Disconnection  Results and Discussion  Chapter 2  The source of the adamantane-2-carbonyr skeleton for all of the spiroketones reported here was adamantane-2-carboxylic acid (58), which was prepared by the method of Alberts et al. Wittig  from the commercially available 2-adamantanone (59) (Figure 2.2).  olefination  of  this  ketone  with  the  ylide  formed  from  methoxymethyltriphenylphosphonium bromide provided enol ether 60. This compound was subsequently hydrolyzed to aldehyde 61, which was oxidized to the desired acid 58. The overall yield for this one-pot process was 64%. Preparation of the known methyl ester 62 was achieved by reaction of 58 with oxalyl chloride followed by in situ quenching of the resultant acid chloride with methanol. It is interesting to note that the traditional Fisher esterification protocol (acid 58, methanol, cat. H2SO4, A) led to the decomposition of 58.  H sS—OMe  O Ph P=CHOCH 3  H 0 3  3  60  59  ©  el  CHO  61  Jones reagent C0 Me 2  CQ H 2  58 (64%)  62 (99%) Figure 2.2 Preparation of ester 62.  2 7  * The IUPAC name for the parent hydrocarbon adamantane is tricyclo[3.3.1.1 ' jdecane. 26  Results and Discussion  Chapter 2  2.1.2 Preparation of Spiroketones 5and 6 by Intramolecular Acylation The synthesis of compounds 5 and 6, starting from ester 62, is outlined in Figure 2.3. Alkylation of the lithium enolate of ester 62 with either benzyl bromide or 2-phenethyl bromide afforded the esters 185 and 55 respectively. During the reaction, an equivalent of butyllithium was added to the enolate to re-form L D A from DIP A. The sterically congested ester products were inert to conventional hydrolysis conditions (e.g. Li OH, methanol-water, A; NaCN, DMSO, A), but 185 yielded, albeit sluggishly, to the "in situ iodotrimethylsilane" reagent of Olah et al.  49  yield. In a one-pot procedure this acid was  giving carboxylic acid 54 in good  subsequently  transformed into the  corresponding acid chloride, which was treated with aluminum chloride to effect the intramolecular acylation. The overall yield of spiroketone 5 from ester 62 was 58%. Hydrolysis of ester intermediate 55 proved to be more difficult than that of its shorter chain homologue. Failure of the Olah procedure in cleaving this ester group prompted the search for alternative reaction conditions, especially those known to be effective in the hydrolysis of sterically hindered systems. One such literature procedure,  50  which employed boron trichloride as the cleaving reagent, was attempted. Instead of ester hydrolysis, however, it was found that treatment of 55 with boron trichloride effected the Friedel-Crafts reaction directly, without the need to proceed by way of the acid chloride as in the case of ketone 5. Spiroketone 6 was synthesized in 86% overall yield from 62.  6 (97%)  Figure 2.3 Synthesis of spiroketones 5 and 6. 27  5 (77%)  Chapter 2  Results and Discussion  Spectral data for compounds 5 and 6 were in full accord with the assigned structures, hi addition, X-ray crystal structures for these compounds were obtained and are presented in Figure 2.4.  (b) Figure 2.4 ORTEP representations of (a) 5; (b) 6.  28  Results and Discussion  Chapter 2  2.1.3 Synthesis of Spiroketones 7 and 8 by Ring-Closing Metathesis  C0 Me  C0 Me  LAH, THF, A  2  2  1) LDA; BuLi, THF Br" DMPU, -78°C to RT  6  3  (  g  2  %  PCC D C M H  6  4  LJ^Ivl|—^ 65  I) ) s  n  R  =  C  H  2 °  H  R = CHO  (  8 3 %  (89%)  Grubbs catalyst DCM  68 69  56 n = 0 (86%) 57 n = 1 (93%)  n = 0 (92%) n = 1 (90%)  66 n = 0 (72%) 67 n = 1 (90%)  H , Pd/C EtOAc 2  7 8  n = 0 (96%) n = 1 (97%)  Figure 2.5 Synthesis of ketones 7 and 8.  Both the seven- and eight-membered spiroketones (7 and 8) were synthesized from a common aldehyde precursor, 65 (Figure 2.5). This compound was prepared by alkylation of ester 62 with allyl bromide to first form ester 63, followed by reduction to alcohol 64, and subsequent PCC oxidation. The syntheses diverged at this point, where a Grignard 51  reagent, possessing either a vinyl or an allyl substituent in the ortho position, was reacted with 14. The products of these reactions, the homologous alcohols 66 and 67, are the ultimate  precursors  to  7  and  29  8,  respectively.  )  Although  Chapter 2  Results and Discussion  Chapter 2  Results and Discussion  ring-closing metathesis was attempted on these alcohol substrates, no detectable reaction took place. After oxidation to the corresponding ketones 56 and 57, however, treatment with the Grubbs catalyst  52  in dichloromethane led smoothly to the desired unsaturated  spiroketones 68 and 69 in excellent yields. The structure of compound 68 was confirmed by X-ray crystallography (Figure 2.6.a). Catalytic hydrogenation of the unsaturated carbocycles led cleanly to the desired ketones 7 and 8. The overall yields, starting from ester 62, were 37% (7) and 50% (8). The spectroscopic and X-ray crystallographic data (Figure 2.6) for these compounds are in accord with the assigned structures.  2.1.4 Synthesis of the Unsaturated Spiroketone 70 Preparation of the unsaturated six-membered spiroketone 70 was achieved in a one-pot procedure starting from the corresponding saturated compound. Benzylic bromination of compound 6 with NBS was followed immediately by dehydrobromination of the intermediate bromide with D B U in THF. This sequence afforded ketone 70 in 48% yield (Figure 2.7). The X-ray crystal structure is presented in Figure 2.8.  6  70  Figure 2.7 Synthesis of compound 70.  31  Chapter 2  32  Results and Discussion  Chapter 2  Results and Discussion  2.2 Solution and Solid State Photolysis of Spiroketones 5-8 Before structure-reactivity correlations were undertaken, the photochemistry of the spiroketones was explored in both solution and the crystalline state. Preparative solution photolyses readily provided the reaction products for structural determination, while analytical scale solid state reactions were undertaken to determine the mode of reactivity in that medium.  2.2.1 Photochemistry of Spiroketone 5  Figure 2.9 Photochemistry of ketone 5.  Pyrex-filtered irradiation of ketone 5 in both the solid state and in solution proceeded exclusively via Norrish Type II cleavage (Figure 2.9). In solution, photolyses were conducted in the presence of solid barium oxide in order to scavenge any acidic impurities that might promote the tautomerization of intermediate enol 71 to ketone epimers 72. Upon prolonged irradiation, or in the presence of catalytic acid or base, secondary photolysis (Norrish Type II cleavage) of 72 competed with the primary photoreaction such that only trace amounts of, the initial product were observed. 1-Indanone (73) was the only product isolated under these conditions, while peaks with the correct mass for dienes 74 (formed from reaction at carbon X) and 75 (formed from reaction at carbon Y) were observed by GC-MS of the reaction mixture (Figure 2.10). Compound 72 was the only product observed when 5 was photolysed to low conversion  33  Results and Discussion  Chapter 2  Figure 2.10 Competing secondary photolysis reaction of 72.  in the solid state. Above 2% conversion, compounds 73, 74, and 75 are also observed, presumably through the competitive enol-keto tautomerization and secondary photolysis seen in solution. Table 2.1 summarizes the photochemistry of 5.  Table 2.1 Photochemistry of ketone 5 in various media. Photolysis Conditions'  1  2:1 tert-butanol / C H , BaO 6  6  MeCN, BaO, -20 °C 2:1 tert-butanol / C H , 1% HO Ac 2:1 tert-butanol / C H , 1% N H 6  6  6  6  3  RT Solid state 0°C  Duration  % Conversion  1.5 h 2.3 h 3.0 h 2.0 h 1.5 h 0.2 h 0.7 h 6.0 h 6.0 h ll.Oh  40 72 42 86 81 2 4 10 7 16  72 (% yield) 38 54 29 16 8 2 2.5 7 5 7  13  b  73 (% yield)  b  trace 12 6 64 62 0 1.5 3 2 8  "Pyrex filtered light, 4 5 0 W Hanovia medium pressure mercury lamp. G C analysis.  The  intermediacy of enol 71 was established by  J  H N M R spectroscopy.  Photolysis of 5 at 0 °C in 2:1 tert-butanol-^io / benzene-^ to 40% conversion revealed two new resonances in the vinylic region (5 5.42 ppm and 5 5.79 ppm) corresponding to the newly formed 1,2-disubstituted double-bond (Figure 2.11). A second spectrum, taken immediately after the addition of a trace amount of trifluoroacetic acid (TFA), contains  34  Chapter 2  Results and Discussion  vinylic signals for the enol as well as four new resonances (8 5.34 ppm, § 5.38 ppm, § 5.60 ppm, 5 5.72 ppm) arising from the two newly formed ketone epimers 72. Another spectrum acquired five minutes later contained no enol signals, indicating that complete conversion to the keto tautomers had occurred. Since the solvent system employed for this experiment contained exchangeable deuterium atoms, the enolic O-H resonance was not observed. A signal for these relatively acidic alcohol protons was observed as a singlet at 5 6.32 ppm, however, when the solvent was acetonitrile-da; the O H signal for propen-2-ol has previously been observed a 5 8.40 ppm in tetramethylsilane.  53  In  acetonitrile-c/3, the vinylic resonances appeared at 5 5.50 ppm and 5 5.87 ppm. The Norrish Type II reaction has provided ready access to numerous enols,  54  and extensive  kinetic and thermodynamic characterization of the closely related 1-indanone enol-keto system has been reported by Kresge et al.  55  Figure 2.11 H N M R vinylic region (8 5-6 ppm) after photolysis of 5 showing signals due to enol tautomer 71 (E) and keto epimers 72 (K): (a) after photolysis; (b) immediately following addition of catalytic TFA; (c) five minutes post addition; (d) purified sample of !  72. 35  Chapter 2  Results and Discussion  The diastereomeric ketone products 72 were isolated as a single chromatographic band. Integration of the H N M R signals revealed that the two epimers were present in ]  equal amounts, indicating that protonation of the intermediate enol proceeded without any stereoselectivity under the reaction conditions. Treatment of ketone mixture 72 with triisopropyl triflate and triethylamine produced one product, silyl enol ether 76, in 87% yield (Figure 2.12). This result provides conclusive evidence that the two diastereomers are epimeric a to the carbonyl group, and that both arise from enol ether 71.  Figure 2.12 Formation of silyl enol ether 76.  36  Results and Discussion  Chapter 2  2.2.2 Photochemistry of Spiroketone 6 In sharp contrast to its smaller-ring homologue, the six-membered spiroketone 6 proved to be remarkably photostable. Although the starting material was eventually consumed (recovery was 50% after irradiation for 29 h in 2:1 tert-butanol / benzene), no major photoproducts were isolated. This suggests that both the cyclization and cleavage pathways are kinetically much slower than the degenerate reverse hydrogen transfer from 1,4-hydroxybiradical 77 back to starting material. The use of Lewis base solvents that are capable of hydrogen-bonding with the 1,4-hydroxybiradical, such as tert-butanol, is welldocumented  56  in attenuating the rate of reverse-hydrogen  transfer relative to the  cyclization and cleavage pathways (Figure 2.13). The photostability of 6 under these conditions is rather unusual, and therefore warranted further investigation.  products  6  77  Figure 2.13 Solvent-biradical hydrogen-bonding decreases the rate of reverse hydrogen transfer relative to product formation. In the case of 77, however, this failed to promote product formation. To  confirm that biradical 77 was indeed being produced, photolysis was  conducted in tert-butanol-OD. Irradiation for 29 h afforded recovered starting material 6 (50%  after  chromatography)  into  which  deuterium  had  been  incorporated  stereospecifically at the axial positions of either or both of the y-carbons (Figure 2.14). The  intermediate biradical 77 is able to exchange its alcohol protium atom for a  deuterium donated by the solvent. The biradical then undergoes reverse-transfer back to the starting material 6-d\. In this process,  37  up to two deuterium atoms may be  Results and Discussion  Chapter 2  incorporated. Mass spectrograph^ analysis of starting material recovered from the above experiment determined the overall deuteration at the y-carbon to be 31%, corresponding to abundances for 6-Jo, 6-d\, and 6-d of 48%, 42%, and 10% respectively. Deuteration 2  could also be achieved using 7% D2O in M e C N as the solvent. In this case 12% deuteration was achieved in 24 h, with abundances for 6-Jo, 6-d\, and 6-d of 78%, 20%, 2  and 2% respectively.  77  77  Figure 2.14 Deuteration of 6 through H-D exchange in the biradical.  2  1  Evidence for the stereospecificity of deuterium incorporation comes from H{'H} Z  N M R studies. Figure 2.15 shows the proton N M R spectrum for the aliphatic region of 6 (solvent 1:1 C D O D / C6D ), and the corresponding deuterium spectrum of the deuterated 3  6  product. The presence of a deuterium resonance at the axial hydrogen's frequency ( H  aX)  5  2.24 ppm), and the absence of any signal corresponding to its geminal partner (H , 5 1.51 eq  ppm) strongly supports the mode of reactivity presented. Intermolecular abstraction of deuterium by 77 is precluded, as this would give rise to product deuterated at both the  38  Results and Discussion  Chapter 2  1  13  axial and equatorial positions. Complete assignment of the H and presented in Table 2.2. Because H  a x  C N M R data are  lies squarely in the deshielding region of the  carbonyl group, its chemical shift is influenced by the magnetic anisotropic effect and is downfield from that of H .  5 7  e q  Deuteration via the mechanism described here is not a general phenomenon. Similar experiments conducted by Wagner et a/.  58  on Y,y-J -nonaphenone failed to 2  produce products where deuterium was replaced by protium from the solvent. Indeed, trapping of 1,4-hydroxybiradicals is often achieved intermolecularly, through the addition of efficient radical scavengers such as thiols, stannanes, molecular oxygen, hydrogen 59  59  60  selenide, hydrogen bromide, and selenoketones . A recent report by Neckers et al 61  62  63  64  proposed that H/D exchange in a 1,5-hydroxybiradical proceeded as outlined here, but the researchers have not quantified the extent of deuteration nor provided experimental details for this work.  I ppm  1 2 . 5  Figure 2.15 (a) H N M R of 6; (b) ]  1  :  2 . 0  K{ B) N M R of deuterated 6.  2  X  39  !—  1.5  Results and Discussion  Chapter 2  4  ' H 8 (ppm) (correlations from HMQC)  ' H - ' H COSY correlations  H M B C (long-range) C - H correlations  Carbon #  C6 (ppm)  1  143.05  2  128.96  3  133.05  4  127.23  5  128.14  6  135.08  —  —  H2, H4, H9,H10  7  207.42  —  —  H2, H5,H9,H10  8  50.42  —  —  H9,H10,H12 ,H16"  9  31.83  10  24.78  11  32.45  , 3  —  1.92 t, .7=6.3 Hz, 2H 2.64 t, .7=6.3 Hz, 2H 1.86 br s, 2H H 2.24 d,J= 12.9 Hz, 2H  34.91  13  28.93  14  39.27  15  28.63  16  33.64  H3  H4, H10  H2, H4  H5,H10  H3,H5  H2,H10,  H4  H3  eq  H10  H10  H9  H2, H9  H12 , H12 , H16*,H16" ax  a x  12  1  H3,H5,H9,H10  —  7.00 d, .7=7.5 Hz, IH 7.28 m, IH 7.13 t , J = 7 . 5 H z , IH 7.83 d, .7=7.7 Hz, IH  1 3  H9  eq  H12eq,H13,Hll H14,H16"  Heql.51 d, 7= 12.9 Hz, 2H 1.77 m, IH 1.60 br s, 2H 1.73 m, IH H' 1.90 obscured m, 2H H" 1.49 d, J= 14.1 Hz, 2H  H12 ,H13,Hll ax  H12 , H12 , H14, H13,H15  H14,H16"  H16',H16",H14  H12 ,H14,H16'  ax  eq  Hll  eq  H11,H15,H16" H12 ,H14 eq  H11,H15,H16'  Table 2.2 Comprehensive N M R assignment data for ketone 6 in 1:1 C D 3 O D / C^Dc.  40  Chapter 2  Although ketone  Results and Discussion  6 proved to be photostable under conventional reaction  conditions, reactivity was observed when the ketone was irradiated as a suspension in water to which a small amount of surfactant (sodium dodecylsulfonate, SDS) had been added. Ordinarily, irradiation of suspensions provides a convenient method for the scaleup of solid state reactions, and gives rise to the same products as observed in the 'dry' analytical runs. In this case, however, alcohol 78, which is not produced under any other conditions, was isolated in 21% yield (51% based on recovered starting material). A mechanism,  proceeding  through the  expected  cyclobutanol 79  with  subsequent  rearrangement to the stabilized cyclopropylcarbinyl cation 80, can be envisaged for this transformation (Figure 2.16). During the reaction, the product was observed to slough off the reactant crystals, forming a second, fluffy, solid phase. This observation, and the fact that the reaction proceeds only in the presence of water, suggests that this process likely involves interactions between water and the ketone molecules on the solid surface, and is not a uniform process occurring in the bulk solid. The structure of alcohol 78 was determined by X-ray crystallography (Figure 2.17).  78  80  Figure 2.16 Photochemistry of spiroketone 6 as an aqueous suspension.  41  Chapter 2  Results and Discussion  Chapter 2  Results and Discussion  2.2.3 Photochemistry of Spiroketone 7 While the five-membered ketone followed the Norrish Type II cleavage pathway and the six-membered spiroketone underwent only reverse hydrogen transfer from its 1,4hydroxybiradical, the next homologue in the series, compound 7, reacted via the Yang photocyclization to afford cyclobutanol 81 in both the crystalline state and in solution (Figure 2.18). Preparative photolysis in 2:1 tert-butanol / benzene provided photoproduct 81 in 57% yield (76% based on recovered starting material).  Figure 2.18 Photolysis of spiroketone 7.  The same reaction also proceeded cleanly in the solid state. Figure 2.19 shows a portion of a  1 3  C N M R spectrum of the crude reaction mixture after solid state irradiation  (20 h, Pyrex filter). Only signals from the starting material (o) and product (x) are seen, attesting to the selectivity of the reaction. Product analysis by G C was not possible due to the thermal instability of the cyclobutanol photoproduct. The structure of photoproduct 81 was confirmed by X-ray crystallography (Figure 2.20).  43  Chapter 2  44  Results and Discussion  Chapter 2  Results and Discussion  Figure 2.20 ORTEP representation of photoproduct 81.  2.2.4 Photochemistry of Spiroketone 8 The photochemistry of the eight-membered spiroketone 8 mirrored that of the seven-membered ring, with cyclization as the sole reaction pathway. Qualitatively, this reaction proceeded faster than that of 7, with complete conversion to product after 10 h of irradiation (Pyrex filter, ter/-butanol / benzene 2:1, 72% isolated yield) (Figure 2.21). The structure of the cyclobutanol photoproduct 82 was confirmed by X-ray crystallography (Figure 2.22), and possessed the same relative stereochemistry as compound 81 at the carbinol centre, with the aryl group endo to the adamantyl skeleton. Solid state photolysis proceeded cleanly, affording only 82. G C analyses were again hampered by the thermal lability of the photoproduct. However,  1 3  C N M R analysis (Figure 2.23) of the crude solid  45  Chapter 2  Results and Discussion  state photosylate showed only signals due to starting material 8 (labeled o) and photoproduct 82 (labeled x).  Figure 2.21 Solution and solid state photochemistry of spiroketone 8.  Figure 2.22 ORTEP representation of cyclobutanol 82.  46  Chapter 2  47  Results and Discussion  Results and Discussion  Chapter 2  2.3 Solid State Structure-Reactivity Correlations The five- through eight-membered spiroketones display the full range of type II photochemistry. In addition to cyclobutanols, which were the only products observed in the previous study of acyclic adamantyl aryl ketones, a cleavage product was observed 65  in the current study. The remarkable solution and solid state photostability of the sixmembered ketone 6, as well as the unique reactivity it displays under irradiation as a suspension in water, provides an additional and unexpected mode of reactivity in type II photochemistry. Fortuitously, each of the four ketones followed only one of the three pathways  (cleavage,  cyclization, reverse-hydrogen  transfer),  thus  simplifying the  following analysis. From a kinetic standpoint, three unimolecular rate constants control the partitioning of the 1,4-hydroxybiradical intermediate (83) among the possible reaction pathways (Figure 2.24). These are k , the rate of reverse hydrogen transfer, k H  cy  the rate of  cyclization, and k i, the rate of a-bond cleavage. The hydrogen abstraction efficiency and c  the rate of reverse H transfer (k ), although determining factors in the overall rate of H  product formation, do not contribute to the observed product ratios. Cleavage will predominate if k i > k , and will account for greater than 99% of observed products when c  kci/kcy >  cy  100. Exclusive formation of the cyclization product likewise indicates that k  cy  is  likely at least two orders of magnitude larger than k i. Where no reaction is observed it c  can be concluded that both kci and k  cy  are much smaller than k , and are essentially H  unable to compete with the pathway back to the starting ketone. Analysis of the solid state geometries of the intermediate 1,4-biradicals in light of their differing reactivities will serve to reconcile the predicted mechanism with experimental observations.  48  Chapter 2  Results and Discussion  Figure 2.24 Kinetic scheme for type II ketone photochemistry.  2.3.1 Hydrogen Abstraction Parameters and Biradical Geometries Superposition of the X-ray structures of the crystalline ketones provides an illustration of how the orientation of the carbonyl moiety varies with ring size (Figure 2.25). Because the adamantyl skeleton is rigid and possesses the same conformation in each of the four ketones studied, the primary factor in differentiating reactivity among the ketones is the relative position of the carbonyl group with respect to the adamantane system. The angle a, defined as the deviation of the carbonyl group from the plane bisecting the adamantane ring through carbons A , B, and C, allows a quantitative comparison to be made between the structures. In compound 5, a is 9°, and the carbonyl group projects out over the adamantyl framework (Table 2.3). The C=0 bond in the sixand eight-membered ketones share nearly identical geometries that eclipse one of the C-C bonds in the adamantane moiety. The seven-membered ketone 7 most closely resembles the acyclic systems studied previously, where the carbonyl group, and the aryl group anti to it, prefer an alignment nearly perpendicular to the adamantyl anchor. Compund 84, for example, has an a value of 86°.  49  Results and Discussion  Chapter 2  Figure 2.25 Comparison of carbonyl group orientations in spiroketones 5-8.  Compound  Oxygen  Ring (X(°)  Size  Atom Colour  Solid State Reactivity  5  5  9  green  6  6  59  red  7  7  80  blue  cyclization  8  8  61  yellow  cyclization  84  —  86  —  ' N o reaction observed i n the anhydrous solid state  Table 2.3 Values of a for ketones 5-8.  50  Ph  cleavage NR  a  cyclization  84  Results and Discussion  Chapter 2  In the previous chapter, the parameters used in predicting the feasibility of hydrogen atom abstraction in the type II photochemistry of ketones were presented. Figure 2.26 and Table 2.4 describe these values for the ketones under current study, as well as average values from the X-ray data of compounds 85.  65  For compounds 6-8, one  of the two y-hydrogen atoms (denoted H for the atom toward which the carbonyl is x  directed, and H for its conformationally diastereotopic partner) is in close proximity to y  the carbonyl oxygen (H , d < 2.72 A), while the other is too far removed to participate (d x  > 3.10 A). For ketone 5 whose carbonyl group lies almost directly between H and H , it 5  x  y  is impossible to predict which y-hydrogen is preferentially abstracted, if either. Two modes of reactivity are possible, and therefore both possible 1,4-hydroxybiradicals must be considered.  Figure 2.26 Hydrogen abstraction parameters for type II photochemistry. d(A)  co(°)  9(°)  A(°)  <2.72  0  180  90-120  2.35  66  120  98  Hy  2.37  50  123  91  H  2.39  33  119  96  Hy  3.10  58  111  60  H  2.48  55  119  85  Hy  3.33  46  112  45  H  2.34  41  121  94  3.13  55  114  56  2.63 ± 0.03  58 ± 3  114+1  81+4  Ideal 5  6  7  8  66  H  x  x  x  x  Hy Average (85)  85 X = F, C 0 M e , and others  Table 2.4 Hydrogen abstraction parameters for the solid state spiroketones.  51  2  Chapter 2  Results and Discussion  In constructing the biradical model, a number of assumptions are made. Since the abstraction process involves only the transfer of a single hydrogen atom over a distance of -2.5 A, the positions of the heavy atoms in the solid state 1,4-hydroxybiradical should correlate well to those in the ground state ketone. The resulting unpaired electrons are placed in p-type orbitals whose directionalities are orthogonal to the calculated mean plane of the sp -hybrized carbon radical centres. Combining the positional data from X 2  ray crystallography with the guidelines for hydrogen atom abstraction geometry and biradical formation listed above allows a picture such as Figure 2.27 to be constructed for each biradical intermediate. Subsequent analysis of these models allows the efficiency of the cyclization and cleavage reactions to be examined in terms of biradical structure.  2.3.2 Geometric Requirements for Cleavage The geometry of the biradicals may be characterized by three torsion angles as defined with reference to structure 86 (Figure 2.27, Table 2.5). Angle 91 is defined as the dihedral angle between the C2-C3 a bond and the p-orbital lobe on Ci with which it most nearly overlaps; 94 is likewise defined as the analogous angle involving the C2-C3 a bond and the most favourably oriented p-orbital lobe on C 4 . The third angle is given the symbol 9 and refers to the C1-C2-C3-C4 torsion angle. In the present instance, this angle is fixed at 63 ± 1° (gauche) owing to the rigid, adamantane carbon skeleton. The same conformational rigidity fixes the 94 angle at a value of 30 ± 1° for the compounds studied. This greatly simplifies the analysis, as only one parameter, 91, is responsible for the variance in geometry, and hence the reactivity among the four biradicals. For  the cleavage process to occur, overlap between the a-bond undergoing  scission (C2-C3) and both p-orbitals (Ci and C4) must be efficient.  67  Maximum overlap  (100%) will occur when the p/o orbitals are eclipsed, i.e. 91 and 94 are 0°. Similarly, when the orbitals are orthogonal (91 or 94 is 90°) no overlap occurs, and cleavage is prevented. Since the overlap of a p orbital and an adjacent a-type orbital is proportional z  to the cosine of their dihedral angle,  68  the functions C O S 91 and C O S 94 are direct  measures of the extent of p/a overlap, and as such, may be used to predict the efficiency of the cleavage reaction.  52  Results and Discussion  Chapter 2  86  Figure 2.27 Solid state biradical geometry: (a) Representation of cpi in 5. (b) Representation of (pi in 7. (c) Representation of cp for all spiroketones. 4  53  Results and Discussion  Chapter 2  9i (°)  C O S cpi  94 (°)  C O S cp4  9(°)  -21  0.93  29  0.87  -64  40  0.77  -30  0.87  62  6  -87  0.05  31  0.86  -63  7  70  0.34  30  0.87  -62  8  -85  0.09  31  0.86  -62  84  66  0.41  30  0.87  -63  Biradical H  5  x  Hy  Table 2.5 Geometric parameters for biradicals derived from 5-8. Figure 2.27.C clearly shows the 'fixed' 94 angle, and it is easy to see that significant overlap (86-87% of the maximum) exists between the C2-C3 a-bond (shown in green) and the C 4 p orbital. For the biradicals derived from compound 5 (Ff abstraction x  pictured in Figure 2.27.a), C O S cpi is at least 0.77, and this considerable overlap is readily apparent in the figure. Thus, the good overlap of both radical orbitals with the C2-C3 o~bond in the 5 system is consistent with its type II cleavage photochemistry. In sharp contrast to this, the C] p-orbitals in the biradicals derived from 6 and 8 lie nearly perpendicular to the C2-C3 bond. Low calculated overlaps of 5% and 9% respectively predict that cleavage in these cases should be very inefficient. Indeed, the remarkable stability of the biradical derived from 6 with respect to both cleavage and cyclization attests to the fact that cleavage from this geometry is extremely disfavoured. Compound 7 (Figure 2.27.b), for which cyclization is the only observable mode of reactivity, is also poorly aligned for cleavage at the Ci centre, with a predicted overlap of only 34%. This is similar to the acyclic compounds of which 84 is representative (41% calculated overlap), and for which no cleavage is observed. Overall, therefore, while perfect orbital overlap is not required for cleavage, it should at least be very good and should involve both porbitals. The data clearly indicate that excellent overlap on one side and poor overlap on the other does not lead to cleavage.  54  Chapter 2  Results and Discussion  2.3.3 Geometric Requirements for Cyclization Having dealt with the features that favour 1,4-hydroxybiradical cleavage, it is equally important to focus on the geometric factors that facilitate cyclization. Intuitively, it makes sense that Yang photocyclization will proceed efficiently when the radicalcontaining carbon atoms Ci and C 4 are close to one another, most likely < 3.40 A, which is the sum of the van der Waals radii  69  for two carbon atoms. The C1-C4 distances  calculated here are given the symbol D, and are well within the van der Waals limit for each of the ketones investigated (Table 2.6). A second important consideration is the directionality of the orbitals in question, i.e. how well the orbitals on these radical centres overlap. Interaction is maximized when the Ci orbital is parallel to the C 2 - C 4 vector, this angle being represented by the parameter (3 (Figure 2.28, Table 2.6). Likewise, interaction between the two radical centres diminishes as P approaches 90°.  Figure 2.28 Geometric parameters for cyclization: (a) biradical derived from 5 (H ); (b) biradical derived from 7. x  55  Chapter 2  P(°)  D(A)  52  3.03  69  3.08  6  59  3.07  7  39  3.02  8  61  3.05  84  32  3.02  Parent Ketone H  5  x  Hy  Results and Discussion  Table 2.6 Cyclization parameters for the 1,4-hydroxybiadicals.  The biradical derived from the seven-membered spiroketone, 7, (Figure 2.28.b) possesses the most favourable geometry for cyclization, again similar to that of the acyclic compound 84. In the six- and eight-membered compounds, also similar in geometry, P lies around 60°. The five-membered ketone, 5, which arguably adopts the least favourable cyclization geometry, might also be hindered along this pathway by the kinetic barrier required to produce a strained cyclobutanol. This situation is readily illustrated in the case of compounds 6 and 8. While the disposition of the carbonyl groups (a) in these two compounds differs only by 2°, the eight-membered ring cyclizes, while its six-membered homologue is remarkably unreactive. The formation of a 6,4-trans ring fusion in the cyclization to cyclobutanol 79 must be very inefficient, so much so that it can not compete with reverse-hydrogen transfer. Steric interactions between the biradical and the crystal lattice can be ruled out as causative factors, as 6 undergoes reverse hydrogen transfer in solution as well as in the solid state, hi the special case where 6 is photolysed as an aqueous suspension, water is thought to aid in the formation of 79, though how this is achieved is not understood. Subsequent cyclobutanol rearrangement to the observed product 78 proceeds under unusually mild conditions, most likely driven by the high strain energy associated with the cyclobutanol intermediate. The corresponding 8,4-trans fused cyclobutanol 82 readily forms upon irradiation of 8 and is stable in water.  56  Chapter 2  Results and Discussion  2.3.4 Summary of Biradical Reactivity The photochemical reactivity displayed by the benzoyladamantane system is exquisitely sensitive to the geometry of the intermediate 1,4-hydroxybiradicals. Recalling the kinetic scheme for biradical reactivity introduced in Figure 2.23, a physical basis can now be ascribed to the efficiencies of the cleavage and cyclization processes. Compound 5 exists in a conformation for which cleavage is favourable and cyclization improbable (k i » c  key), and this prediction is borne out by experiment. For ketones 7 and 8, biradical  geometry disfavours the cleavage reaction, but orbital alignment for cr-bond formation is acceptable (k  cy  »  k i), and cyclization is indeed the observed outcome. Compound 6, c  although similar in geometry to 8, is not able to cyclize in the anhydrous solid state, most likely owing to the kinetic barrier associated with the production of a strained cyclobutanol (79). In this instance, only reverse hydrogen transfer occurs, and no new compounds are formed (k » H  k i, k ). c  cy  57  Results and Discussion  Chapter 2  2.4 Photochemistry of the Unsaturated Adamantyl Spiroketones 68 and 70 In the course of preparing the saturated adamantyl spiroketones, two solid unsaturated analogues, 70 and 68, were synthesized and subsequently characterized by X ray crystallography (70: Figure 2.8; 68: Figure 2.24.a). Their photochemistry was investigated in both the solid state and in solution.  70  52  68  2.4.1 Photochemistry of Unsaturated Ketone 68 The  crystal structure of compound 68 revealed that this achiral molecule  crystallizes in space group P2\2\2\,  one of the 65 chiral space groups. Thus the  possibility that an 'absolute' asymmetric reaction, one in which the asymmetry is presented spontaneously (through crystallization) and is not provided by an external source of optical activity,  38  might be possible on irradiation of a single crystal of the  ketone. Unfortunately, however, 68 proved to be photochemically unreactive in the solid state. Although a y-hydrogen is suitably positioned for abstraction to occur in a type II fashion (d = 2.47 A), photochemical reactions in conjugated systems of this type, such as 87, are known to proceed only through reaction at the site of the double bond (Figure 2.29).  70  The  resulting  products  are  either  dimers  (88)  produced  via  [2+2]  photocycloaddition reactions, or other adducts (89, 90, and 91) resulting from the highly reactive is-cycloheptene intermediate (92). Solution photolysis of 68 produced a complex mixture of compounds that lacked vinylic H N M R signals, and were not volatile enough ]  to be observed by G C , characteristics consistent with product dimers. Study of this system was not pursued further.  58  Chapter 2  Results and Discussion  O  MeO  H  89 Figure 2.29 Photochemistry of unsaturated ketone 87.  2.4.2 Photochemistry of Unsaturated Ketone 70 Enone 70 contains the l-(2//)-naphthalenone chromophore, the photochemistry of which is investigated further in Chapter 4 through the study of compound 52 and its derivatives. A n overview of the photochemistry of the broader class of linearly conjugated cyclohexadienones is given in Chapter 1, and the photoreactivity of 70 will be presented in the context of this introduction. Irradiation (Pyrex or Uranium filter) of 70 in both the solid state and solution proceeded efficiently with cyclopropane 93 as the sole primary photoproduct (Figure 2.30). This compound is itself photochemically labile and rearranges to a-naphthol derivative 94. This secondary photolysis is competitive with the consumption of 70 when Pyrex-filtered light is used (k > 290 nm) such that the concentration of 93 is low throughout the reaction. When light of longer wavelength is employed (k > 330 nm), the efficiency of the secondary photolysis relative to that of the first is decreased, and 93 may  59  Results and Discussion  Chapter 2  be obtained in moderate yield (Table 2.7). This phenomenon is easily explained by the decreased absorbance of 93 (A, 1350; X  m a x  Filter  max  = 301 nm, s = 310) versus 70 (k x  ) = 318 nm, s =  ma  (n,7t*) = 356 nm, s = 740) at longer wavelengths.  Solvent  2  MeCN EtOH Pyrex Solid State  MeCN Uranium Solid State  Irradiation  Conversion  Time (min)  (%)  60  88  2  83  15  85  12  67  30  96  2  86  20  40  22  14  60  77  24  48  150  97  2  93  10  20  18  trace  40  55  44  1  90  85  69  13  30  30  21  9  105  59  29  30  15  93 (%)  b  94 (%)  b  450W Hanovia medium pressure mercury lamp. GC analysis.  a  Table 2.7 Photoproduct yields from 70 under various photolysis conditions.  The mechanism of this reaction was clearly established as proceeding by way of ketene intermediate 95, which is known in analogous systems to arise from the '(n,7t*) excited state. Irradiation of 70 in M e C N containing dimethylamine gave rise to amide 71  96 in 82% yield, with no trace of compounds 93 or 94 (Figure 2.30). Formation of 93, therefore, occurs only via the thermal crossed [2+4] internal cycloaddition of ketene 95, and does not proceed from 70 by the concerted [7t +0"2 ] a  2  a  71a  or step-wise mechanisms  72  proposed for cyclohexadienones that react from the '(71,71*) excited state. The position of the double bond in compound 96 was confirmed by the presence of an olefinic quaternary centre in the  1 3  C N M R spectrum. The benzylic methylene doublet (5 3.30 ppm) in the ' H  N M R spectrum also confirms that the double bond is not in conjugation with the phenyl  60  Results and Discussion  Chapter 2  ring. The structure of photoproduct 93 is completely in accord with the observed spectral data and reaction mechanism. The geminal methine protons on the cyclopropane ring give rise to a diagnostic pair of doublets (§ 2.28, 2.87 ppm, J= 4.6 Hz) which form an isolated spin system (verified by a COSY experiment). In addition, the carbonyl stretching frequency of 1695 cm" is consistent with the presence of a more highly 1  73  strained indanone rather than tetralone ring system,  and correlates well to the ketone  stretching frequency in 5 which is 1694 cm" . The carbonyl JR bands for the larger six1  through eight-membered rings 6-8 occur at 1686, 1683, and 1681 cm" , respectively. 1  72  The mechanism for the transformation of 93 to 94 also has literature precedent. Photoinduced cleavage of the  internal cyclopropane bond leads to  zwitterionic  intermediate 97. Subsequent [l,2]-alkyl migration produces ketone 98 which readily aromatizes to its stable enol tautomer, photoproduct 94. Spectral data for compound 94 were in accord with the assigned structure, most notably the reduction in number of C 1 3  and ' H N M R signals resulting from the introduction of a molecular plane of symmetry. In addition, N O E difference experiments confirm the substitution pattern of the naphthalene system as shown in Figure 2.31.  61  Chapter 2  Results and Discussion  Chapter 2  Results and Discussion  2.5 Summary Constraining the carbonyl group in the benzoyladamantane system by introducing spiro-fused rings of varying sizes has proven an effective strategy in obtaining biradical geometeries that are inaccessible in the acyclic series. The structural similarity of the four saturated homologues has simplified the correlation of structure and reactivity, as only a few key parameters differ among the biradical intermediates. Analysis of the data has provided a quantitative assessment of the extent of orbital overlap required for the cleavage and cyclization reactions to occur. The remarkable photostability of the biradical in the six-membered ring system, in which one p-orbital is orthogonal to the abond and hence can not participate in a cleavage reaction, not only supports the accepted model for this type of reactivity, but also highlights the predictive value of solid state structure analysis. The results are also significant as they present numerical structural data, in terms of angles and distances, that may be used to engineer molecules, crystals, and other assemblies with selective, 'designer' reactivities. Although the unsaturated spiroketone 70 did not show any difference in reactivity between the solid and solution states, it demonstrated that the linearly conjugated benzocyclohexadienone system reacts cleanly and efficiently in the solid state. This compound served as a model for a series of compounds based on the  l-(2H)-  naphthalenone chromophore. The photochemistry of these compounds is concerned with solid state asymmetric synthesis and is described in chapter 4 of this thesis.  63  Results and Discussion  Chapter 3  Chapter 3 - Asymmetric Induction in the Solid State Photochemistry of Macrocyclic Aminoketone Salts 3.1 Synthesis of the Aminoketones The  macrocyclic aminoketones  12,  14,  and 16  were synthesized  via a  straightforward Dieckmann condensation - decarboxylation approach under high dilution conditions. The twelve-membered compound (12) was first synthesized by Spanka et al.,  14  and the same general approach was employed in the preparation of the previously  unknown fourteen- and sixteen-membered aminoketones 14 and 16.  12  H  H  14  16  3.1.1 Synthesis of the Twelve-membered Aminoketone 12 Figure 3.1 shows the synthetic scheme for macrocycle 12. Cyclization precursor 99 was prepared from methylammonium chloride and the commercially available (Aldrich) ethyl 6-bromohexanoate (100) according to a procedure modified from that which Leonard et al.  15  used to prepare similar compounds. Addition of aminodiester 99 to  a refluxing suspension of potassium tert-butoxide in anhydrous xylenes over forty hours was achieved using a syringe pump in order to maintain low starting material concentration, and thus minimize dimerization. The material isolated following acidcatalyzed ester hydrolysis and decarboxylation consisted of a mixture of the desired twelve-membered aminoketone (12) and the twenty-four-membered dimer 101. The dimer was isolated by fractional crystallization from diethyl ether, and the remaining monomer purified by vacuum sublimation. Although not observed in the literature  64  Results and Discussion  Chapter 3  procedure, dimers similar to compound 101 condesations of shorter-chain aminodiesters.  76  have been reported for Diekmann  In the literature procedure, a specially 74  designed high-dilution apparatus was used for the macrocyclization, and a yield of 68% was obtained. Without such equipment, the effective diester concentration was higher than that previously reported, resulting in a lower yield of ketone 99 (31%) and concomitant dimer formation.  Et0 C  C0 Et  2  C0 Et  2  2  DIPEA, Kl MeCN  A 'N Me  O  JL 12  + Me-N  99  24  1) KO*Bu, xylenes, A 2) HCI, A  (62%)  N-Me J  N Me  12 (31%) O  101 (13%) Figure 3.1 Synthesis of aminoketone 12.  3.1.2 Synthesis of the Fourteen- and Sixteen-membered Aminoketones 14 and 16 Two modifications to the above procedure were employed in the synthesis of the fourteen- and sixteen-membred aminoketones. The macrocycles were prepared as their TVbenzyl derivatives, with the nitrogen protecting groups removed in the final step to liberate the desired secondary amines 14 and 16. The seco aminodiesters 102 and 103  65  Results and Discussion  Chapter 3  Br-sr  NH 104 + >C0 Et 2  ;  DIPEA, Kl 1  MeCN  Et0 C*  A  9  105 n = 7 106 n = 8  y N i >C0 Et 2  102 n = 7 (82%) 103 n = 8 (85%)  1) Na N(TMS) Et 0 2  A 2) HCI, A  Pd/C, MeQH HC0 R n = 7, R = N H 4 n = 8, R = H 2  14 n = 7 (99%) 16 n = 8 (94%)  107 n = 7 (85%) 108 n = 8 (60%)  Figure 3.2 Synthetic scheme for macrocycles 14 and 16.  were prepared in good yield via dialkylation of benzylamine (104) with ethyl 7bromoheptanoate (105) and ethyl 8-bromooctanoate (106) respectively (Figure 3.2). The Dieckmann condensations were effected using sodium hexamethyldisilazide in reluxing diethyl ether, a protocol employed by Hurd et al. in the synthesis of the natural macrocyclic ketone zearalanone.  77  As in the case of the twelve-membered ring, high-  dilution conditions were maintained, with addition of the diesters proceeding over a period of 40 hours. The TV-benzyl macrocycles 107 and 108 were isolated in good yield following acid catalyzed ester hydrolysis and decarboxylation. Palladium catalyzed hydrogenolysis of 107 proceeded smoothly with ammonium formate in refluxing methanol, while debenzylation of 108 was optimal at room temperature with formic 78  acid as the hydrogen donor. Aminoketones 14 and 16 were isolated as low-melting  66  2  Results and Discussion  Chapter 3  amorphous solids (33-34 °C and 50-51  °C respectively), which gave spectra and  elemental analyses consistent with their assigned structures. X-ray crystallographic analysis of salts of these two amines (vide infra) confirmed the identity of the macrocyclic aminoketones. While compound 105 was commercially available (Aldrich), bromoester 106 was synthesized in three steps from 1,8-octanediol (109) (Figure 3.3). Monobromination of diol 109 was achieved according to the procedure of Kang et al.  79  and was followed  directly by Jones oxidation to give 8-bromooctanoic acid (110). Fisher esterification completed the preparation of the eight carbon alkylating agent 106. Although the reaction conditions employed for the above macrocyclizations were not identical, the product yields follow the general trend reported by Leonard et al.  80  for  the preparation of cycloalkanones with rings sizes of eleven to fifteen. In this study, the yield of cyclic monomer was observed to increase with ring size, with a corresponding decrease in dimer formation (< 3% for cyclotetradecanone). Steric repulsion between the alkylene chains in the Dieckmann cyclization of straight-chain diesters is cited  80  as the  main kinetic barrier in the formation of medium-sized rings (nine- to twelve-membered); such strain is avoided in larger rings, where cyclization is more efficient.  OH  HO  109  1)48% HBr C H A 6  6  2) C r 0 , H S 0 acetone 3  2  Br  C0 R 2  4  EtOH cat. H S 0 2  A  Figure 3.3 Synthesis of bromoester 106.  67  110 R = H (61%) 4  106 R = Et (95%)  Results and Discussion  Chapter 3  3.2 Solution State Photochemistry of the Macrocyclic Aminoketones The three macrocyclic aminoketones under study were first photolyzed in solution in order to determine their photoreactivity and to isolate and characterize their photoproducts. In all three cases, the expected Norrish/Yang Type H photochemistry proceeded cleanly and efficiently.  3.2.1 Solution State Photochemistry of Cycloalkanones In looking at the photochemistry of the cyclic aminoketones, it is useful to review the photochemical behaviour of the medium-sized and macrocyclic alkanones 111, which have been studied previously in solution.  Figure 3.4 depicts the reactivity of these  compounds, which display typical Type II photochemistry in producing both cis- and rra«5-cyclobutanols (112 and 113 respectively) as well as cleavage product 114. In the smaller rings (eleven- to thirteen-membered), cycloalkanols 115 are produced in low yield via photoreduction of the. excited state ketone by solvent.  81d  Table 3.1 presents the  data from these studies, as well as the ratio of cis- and trans- cyclobutanols (112:113) and the ratio of products derived from cyclization to those from cleavage (112+113:114).  Figure 3.4 General scheme for type II photochemistry of cycloalkanones.  68  Results and Discussion  Chapter 3  Table 3.1 Product distributions in solution state cycloalkanone photochemistry. 813  N(lll)  % 112  % 113  % 114  % 115  % other  3  cis 1 trans  Cyclization/  Ratio  cleavage Ratio  11  40  14  8  12  26  2.9  6.8  12  64  11  8  7  10  5.8  9.4  13  45  23  18  5  9  2.0  3.8  14  39  12  30  <1  20  3.3  1.7  15  17  11  52  <1  14  1.5  0.5  16  13  9  58  <1  20  1.4  0.4  U n k n o w n products, polymers, etc.  A number of trends come to light when looking at these results. Intermolecular hydrogen abstraction leading to the photoreduced product 115 decreases as ring size increases, and becomes negligible at ring sizes of fourteen and above. This phenonenon is can  be attributed to conformational restrictions to closure and cleavage  of the  intermediate cyclic 1,4-biradical 116, such that intermolecular processes are able to compete.  82  In addition, both the ratio of cis- to £ra«.s-cyclobutanol and the ratio of  cyclization to cleavage products decrease as N increases. These trends are consistent with the greater conformational flexibility and reduced transannular interactions experienced by the intermediate 1,4-biradicals in the larger rings.  81d  Indeed, these ratios approach 83  those observed for acyclic ketones; photolysis of valerophenone  gives a cisltrans ratio  of 0.3 and a cyclization/cleavage ratio of 0.3. It should be noted, however, that except for conformationally rigid systems such as those described in Chapter 2 of this thesis, conformational analysis is of limited utility in predicting product ratios in solution state type II photochemistry. Since the 1,4-biradical intermediate may revert to the starting 84  116 69  Results and Discussion  Chapter 3  ketone as well as proceeding on to product, the reaction outcome does not necessarily correlate with reactant conformer populations, and can be determined largely by nonminimum energy geometries.  85  3.2.2 Aminoketone Photochemistry The photochemistry of the macrocyclic aminoketones proceeded in a fashion analogous to that of the cycloalkanones discussed in the previous section. Figure 3.5 outlines the reactivity of the twelve-membered species 12, and Figure 3.6 depicts the photochemistry of the fourteen- and sixteen-membered homologues 14 and 16. The product ratios for the solution reactivity of these compounds are summarized in Table 3.2.  12  117  118  119  Figure 3.5 Solution state photochemistry of aminoketone 12.  The two larger macrocycles (14 and 16) yielded both cis- and fraws-cyclobutanols from the Yang photocyclization, as well as the Norrish type II cleavage product. Since the latter is itself photolabile, the product ratios for 14 and 16 are reported at low conversion. For the twelve-membered compound, only cyclization (117 and 118) and photoreduction (119)  products were obtained. This differs  cyclododecanone photochemistry  from the studies of  (Table 3.1) where a small amount (8%) of cleavage  81  was reported. Additionally, it was discovered that the intermolecular photoreduction pathway could be suppressed if the hydrochloride salt 120 was photolyzed in place of the free base 12. Hydrogen atoms on carbons a- to an amine nitrogen are known to be susceptible to radical abstraction.  86  There is no lone electron pair on the protonated  ammonium nitrogen to stabilize an a-carbon radical, however, and intermolecular  70  Results and Discussion  Chapter 3  O  o  N )„(  h v (Pyrex) solution  )„(  N H  14 16  N n 14 1 16 2  121 n = 1 124 n = 2  122 n = 1 125 n = 2  123 n = 1 126 n = 2  Figure 3.6 Solution state photochemistry of aminoketones 14 and 16.  photoreduction via radical abstraction at this site is energetically less favourable. Preparative scale photolyses of the three macrocycles, conducted in order to isolate and characterize their photoproducts, were thus performed on their hydrochloride salts (120, 127, and 128) in acetonitrile.  O  O  14  16  N H H  120  127  0  0  CI  CI H  H  128  The isolated yields for the preparative photolyses are presented in Table 3.3. The low yields reported do not reflect poor reaction selectivity and are easily explained by practical considerations. The cis- andfr-a/w-cyclobutanolsare not readily separable by chromatographic methods, and thus the yield of pure samples of these compounds was low. The cleavage products 123 and 126 are themselves photolabile, and their isolated yields do not reflect the portion that was consumed during irradiation. Figure 3.7 illustrates the secondary photolysis of 123 to 129 that was observed qualitatively by C 1 3  71  Results and Discussion  Chapter 3  o hv (Pyrex) C D 6  (+acetone)  6  N' H  "NT H  129  123  Figure 3.7 Secondary photolysis of cleavage product 123.  N M R spectroscopy of the crude reaction mixture. Diene 129 was too volatile for practical isolation; its spectroscopic data were determined from an authentic sample (vide infra). To further illustrate the clean nature of these reactions, a sample of 120 was irradiated in acetonitrile until no starting material remained. The crude reaction mixture was analyzed by  1 3  C N M R following basic workup. The spectrum is remarkably clean, displaying only  peaks for cyclobutanols 117 and 118. A portion of this spectrum is reproduced as Figure 3.8.  Table 3.2 Product distributions for solution state photolyses aminoketones and their hydrochloride salts.  3  Substrate  Solvent  cis  trans  % Cleavage  % 119  cisltrans  Cyclization/  •Ratio  Cleavage Ratio  12  CeH6  65  18  0  17  3.6  —  120  MeCN  68  32  0  0  2.2  —  CeH6  50  23  27  —  2.2  2.7  BuOH  50  28  22  —  1.8  3.5  MeCN  49  29  22  —  1.7  3.4  40  16  44  —  2.5  1.3  MeCN  39  11  50  —  3.5'  1.0  BuOH  29  16  55  —  1.8  0.8  MeCN  30  30  40  —  1.0  1.5  14 127 16  l  l  128 a  % Cyclobutanol  of the macrocyclic  Pyrex-filtered light (k > 290 nm). Product ratios determined b y G C at l o w conversion (< 10%).  72  Chapter 3  73  Results and Discussion  Results and Discussion  Chapter 3  Table 3.3 Isolated yields from preparative scale photolyses of the macrocycles. Ring Size  Cyclobutanol  2  Cleavage  cis  trans  12  117 (16%)  118(11%)  14  121 (35%)  122 (24%)  123 (8%)  16  124 (17%)  125 (8%)  126 (32%)  c  Photoreduced 119(30%)  b  —  —  —  "Photolysis (Pyrex filter) o f aminoketone hydrochloride salts in acetonitrile solution unless otherwise noted. Photoreduction product isolated from photolysis o f the free amine. C o m p o u n d 119 is not formed on photolysis o f the hydrochloride salt. Data represent photolysis o f the free amine. b  c  3.2.3 Quantum Yield Studies of Compound 14 In order to provide a more quantitative  analysis  of the  solution state  photochemistry described above, quantum yields (<D) for product formation from the fourteen-membered aminoketone 14 were measured, at 313 nm. The quantum yield of a photochemical process reflects the probability that a particular event will take place once a photon has been absorbed by the molecule under study. In other words, the quantum yield measures the efficiency of a pathway available to the excited state species. For the photochemical process A->[A*]—»—>B, the mathematical expression for <D (quantum B  yield for the formation of B) is presented here:  Number of molecules B formed per unit time per unit volume OB =  Quanta of light absorbed by A per unit time per unit volume The quantum yields for ketone 14 were determined both in benzene and in 2:1 tertbutanol / benzene. As mentioned in Chapter 2 (Section 2.2.2, Figure 2.13), the addition of Lewis bases such as tert-butanol stabilize the 1,4-hydroxybiradical type II intermediate against disproportionation back to the starting ketone, thus increasing the proportion that go on to product (cyclization or cleavage). As can be seen in Table 3.4, the quantum yields for product formation roughly double on addition of the alcohol. The total quantum yield for product formation from cyclotetradecanone in cyclohexane solution is 0.29 as reported by Schulte-Elte et a/.,  81a  and agrees favourably with our result. Quantum yields  for cycloalkanones with ring sizes from eleven sixteen were in the range of 0.10 to 0.38. Information on the multiplicity of the photochemical reaction, that is whether it occurs from a singlet or triplet excited state, may be garnered through quenching experiments. Figure 3.9 illustrates this concept. In part (a), irradiation promoted the  74  Results and Discussion  Chapter 3  products  Figure 3.9 Excited state reactivity of aliphatic ketones (a) in the absence and (b) in the presence of a triplet quencher.  ground state molecule A to its singlet excited state. Ignoring decay process which return *A* back to the ground state, this species may react to give products, or undergo intersystem crossing (isc) to the lower energy triplet excited state ( A*). Reaction to 3  product can proceed via this species also. Certain chemical species, dubbed quenchers, are able to deactivate triplet excited species through energy transfer. For this to occur, the quencher's triplet energy must be lower than that of the species being quenched (i.e, the energy transfer must be exothermic). If the concentration of quencher is sufficient, reaction from the triplet excited state is completely suppressed, and quantum yields determined under these conditions will reflect reactivity along the singlet manifold only (Figure 3.9.b).  Table 3.4 Quantum yield determinations for aminoketone 14. 3  Cyclobutanols Solvent  ^cleavage  Ototal  ® trans  <$>cis  benzene  0.105 ± 0 . 0 0 9  0.048 ± 0.003  0.057 ± 0.004  0.210 ± 0 . 0 1 6  terr-butanol  0.218 ± 0 . 0 0 3  0.120 ± 0 . 0 0 3  0.097 ± 0.003  0.435 ± 0.009  ^singlet  0.0241 ± 0.014  0.0046 ± 0 . 0 1 0  0.0143 ± 0.007  0.043 ± 0 . 0 1 2  'Reported ± the estimated standard deviation.  75  Results and Discussion  Chapter 3  For aryl ketones, such as those described in Chapter 2 of this thesis, inter-system crossing is an efficient process and type II photochemistry proceeds exclusively through triplet excited states. For aliphatic ketones, however, isc is much less eficient, and both singlet and triplet pathways contribute to product formation. Quenching studies were undertaken with aminoketone 14 in benzene, using 2,5-dimethyl-2,4-hexadiene as the triplet energy acceptor (quencher). The results of these experiments are summarized under the heading 0 i giet in Table 3.4. Comparing this number to Obenzene, which S  n  represents both singlet and triplet contributions to the quantum yield, 20% of products arise from the singlet excited state. Direct participation of the singlet excited state in type II product formation is known to be a minor process; for cyclododecanone it accounts 87  for only 5% of product formation in cyclohexane.  76  81d  Results and Discussion  Chapter 3  3.3 Identification of the Photoproducts Because the photochemical reactions of the aminoketones involve rearrangements that produce mixtures of structural isomers and diastereomers (i.e., the cis- and transcyclobutanols), not only did isolation of the pure compounds prove challenging, but also assignment of their correct structure and stereochemistry. The prescence of many unfunctionalized methylene carbons and relative lack of heteroatoms and elements of unsaturation unfortunately meant that most of the ' H N M R signals appeared as overlapping muliplets in the aliphatic region (5 1.0 - 2.5 ppm), and hence were not of much use in structure elucidation. Figure 3.11 cyclobutanols 124  (cis) and 125  depicts the  (trans), photoproducts of the  N M R spectra of sixteen-membered  aminoketone 16. Secondary photolysis of the cleavage products 123 and 126 also hampered its isolation and characterization. Although all spectra and analyses of the isolated products were completely in accord with the assigned structures, they could not unambiguously confirm the atomic connectivity. To help resolve this issue the cleavage and reduction products were independently synthesized, while the cyclobutanol physical and spectral information was compared to data from analogous compounds.  3.3.1 Independent Synthesis of Reduced Product 119 The  structure of photoproduct 119  was readily confirmed by borohydride  reduction of aminoketone 12 in ethanol (Figure 3.10).  Me  Me  119 (96%)  12 Figure 3.10 Preparation of aminoalcohol 119.  77  Results and Discussion  Chapter 3  —1 2.6  •  I  2.1  '  1 2.2  1  1 2.0  1  1 1.8  1 PPM  1  .  1.6  1 1.a  1  , 1.2  ,  1 1.0  ,  , .8  ,  ,.6  (b) Figure 3.11 400 M H z *H N M R spectra (C D ) of (a) trans'-cyclobutanol 125, and (b) cw-cyclobutanol 124. 6  78  6  Chapter 3  Results and Discussion  3.3.2 Synthesis of the Type II Cleavage Products 123 and 126  1) (COCI) , PhH cat. DMF 2  O OH  NH,  2) NH3(g) 130 n = 1 131 n = 2 (72%)  132 n = 2  K C0 NaOH Bu NHS0 PhMe 2  NH /  cat. TsOH PhH -H 0 2  3  4  A  OH  OH  133  4  Br  -"-2  n  136 n=1 137 n=2  134 n = 1 135 n = 2  138 n = 1 (46%) 139 n = 2 (60%)  (64%) (60%)  n = 1  1) LAH, THF.A n =2  O  ©  1) LAH, THF,A^  0  2) H 0 ; OH 3  ©  0  2) H 0 ; OH 3  3) HCI(g), n-pentane n =2 K C0 hexanes 2  3  123 n = 1 (58%) 126 n = 2 (89%)  140 n = 2 (78%) Figure 3.12 Independent preparation of cleavage products 123 and 126.  Figure 3.12 outlines the synthetic scheme employed for the preparation of the aminoketone cleavage products 123 (produced from the fourteen-membered ring) and 126  (from photolysis of the sixteen-membered ring). While oxoamide 130  was  commercially available (Aldrich), the nine carbon homologue 131 was synthesized from  79  Results and Discussion  Chapter 3  the corresponding acid 132 via its acid chloride. The carbonyl groups were protected by reaction with neopentyl glycol (133) to give the corresponding cyclic ketals (134 or 135). Alkylation of the amide nitrogen atoms was effected using a solid-liquid phase-transfer go  protocol developed by Gajda and Zwierzak  using either 5-bromo-l-pentene (136) or 6-  bromo-l-hexene (137) as the alkylating agent. The secondary amide products (138 or 139) were subsequently reduced to their corresponding secondary amines with lithium aluminum hydride. An acidic workup was employed in order to remove the ketal protecting group. In the case of compound 123, the amine was extracted from the reaction mixture after addition of alkali. The longer-chain homologue 126 was isolated and characterized first as its hydrochloride salt 140; the free amine was subsequently liberated by reaction with potassium carbonate and characterized.  3.3.3 Preparation of the Secondary Photoproduct 129 Since diene 129 was too volatile to be isolated from photolysis reaction mixtures of 14 or 123 (see Figure 3.7 above), it was synthesized independently (Figure 3.13) and its presence confirmed by identification of its  Br  C N M R signals in the crude photosylate  136 K C0 NaOH Bu NHS0 PhMe 2  141  1 3  4  3  4  1)NH ,Na MeOH 3(l)  2) HCI  CI  HN  N© H 143 (60%)  129 Figure 3.13 Synthetic scheme for amine 129.  80  Results and Discussion  Chapter 3  mixtures. Dialkylation of 4-toluenesulfonamide (141) with 5-bromo-l-pentene (136) gave the tertiary sulfonamide 142. Reductive cleavage of the sulfonyl group with sodium in liquid ammonia, followed by reaction with hydrogen chloride, afforded ammonium salt 143.  The free amine, 129, was liberated in situ by reaction with a suspension of  potassium carbonate in benzene-^- N M R analysis was then performed.  3.3.4 Stereochemical Assignment of the Cyclobutanol Photoproducts Assignment of the relative stereochemistry of the cis/trans cyclobutanol pairs was based on a number of observations. By analogy with the known reactivity of mediumsized and large-ring cycloalkanones (ring sizes 11 to 16, see Table 3.1) for which the cyclobutanols with a cis ring fusion were formed preferentially, the predominant cyclobutanol in the solution state aminoketone photolyses was designated as the cis diastereomer (see Table 3.2). Additional support for this assignment comes from the empirical observation, reported independently in three different studies, ' ' 81d  among cis/trans  89  90  that  cyclobutanol pairs, the trans isomer is eluted first during gas  chromatogaphy on a poly(siloxane) column (26 pairs in total). The behaviour of the cyclobutanols studied herein are consistent with this observation. More compelling evidence for the stereochemical assignments presented here comes from analysis of the cyclobutanol  1 3  C N M R spectra in benzene-^,. Specifically, in  the series of compounds 144 studied by Scheffer and Lewis, ' the chemical shifts of the 90  91  bridgehead methine carbons were consistently found to occur ca. 6-9 ppm further downfield in the ew-fused systems (Table 3.5). Additionally, the chemical shift ranges for the cis- (48.6 to 50.1 ppm) and trans- (40.4 to 43.7 ppm) diastereomers are relatively small and do not overlap. The spectroscopic data from the aminocyclobutanols studied here  fit well with this model (Table 3.6).  A tentative explanation based on  conformationally-dependent anisotropic shielding has been put forward to explain this phenomenon.  90  81  Results and Discussion  Chapter 3  HO  144  Table 3.5  1 3  C N M R chemical shifts (CeD ) for the methine carbon in cyclobutanols 144. 6  trans-144 8 (ppm)  n  cis-144 5 (ppm)  1  48.6  2  49.2  40.4  8.8  3  49.8  41.6  8.2  4  a  A8 (ppm)  —  —  —  a  42.2  —  5  50.1  43.1  7.0  6  49.5  43.4  6.1  7  50.1  43.5  6.6  8  50.1  43.7  6.4  'Structures confirmed b y X - r a y crystallography.  Table 3.6 C N M R chemical shifts (C D ) for the methine carbons aminocyclobutanols produced on photolysis of the aminoketones of ring size N . 1 3  3  6  6  N  cis 8 (ppm)  trans 5 (ppm)  12  51.2  43.3  7.9  14  50.1  43.1  7.0  16  50.0  43.7  6.3  Signal assignments confirmed with either the D E P T or A P T pulse programs.  82  AS (ppm)  in  Chapter 3  Results and Discussion  3.4 Preparation of Optically Active Salts of the Macrocyclic Aminoketones Optically active salts of the macrocyclic aminoketones were generally prepared by reacting equimolar amounts of the amine, as a solution in ether, and the commercially obtained optically active acid dissolved in an appropriate solvent. In cases where the salt precipitated on mixing, the solids were filtered, dried, and subsequently recrystallized. When no spontaneous crystallization occurred, the solvent was removed in vacuo, and the residual solid or oil recrystallized. The most effective recrystallization method for these salts was found to be vapour diffusion of petroleum ether or w-pentane into a chloroform solution of the salt. This was generally achieved by placing a vial with the chloroform solution in a sealed Erlenmeyer flask containing a reservoir of the hydrocarbon solvent. Crystallization was achieved over a period of days to weeks. The composition and stoichiometry of the organic salts were unambiguously determined by  !  H NMR  spectroscopy and elemental analysis. Solvent or water of crystallization, where present, could also be detected through these procedures. Although salt formation via reaction of the aminoketones with a large number of optically active acids (12: 18; 14: 22; 16: 25) was conducted, the fraction of attempts that produced crystalline salts was low. In many of the failed attempts, the salt would 'oil out' of solution during recrystallization (common), or crystallization of the free acid would occur, leaving the amine in solution (rare). The frequency of these failures suggests that the problem is intrinsic to the macrocycles; however, the origin of this phenomenon (e.g, hygoscopicity, effective solvent entrainment, effects due to conformational lability, etc.) is not understood. The fact that the fourteen-membered macrocycle exhibited the greatest success in salt formation is also puzzling, and rules out simple explanations for this behaviour based on melting point or substitution at nitrogen (i.e. secondary versus tertiary amines) for the free amines. The identity and melting points of the optically active salts are detailed in Tables 3.7 (12), 3.8 (14), and 3.9 (16). Some achiral salts prepared from the aminoketones are described in Table 3.10. Salt crystals suitable for X-ray crystallographic analysis were obtained for four compounds, including one derived from each of the twelve-, fourteen-, and sixteen-membered macrocycles.  83  Results and Discussion  Chapter 3  Table 3.7 Optically active salts prepared from aminoketone 12.  Me Salt  145  Anion  X  H Recrystallization Solvent  mp (°C)  CHC1 / pet. ether  78-80  CHCI3 / pet. ether  78-80  MeOH / water  154-157  3  so° 3  146  147  a  OCXoo  06""°  0  'X-ray crystal structure obtained.  Table 3.8 Optically active salts prepared from aminoketone 14.  0  r j 14  \ ® J N Anion  Salt  H H  Recrystallization Solvent  mp(°C)  CHCI3 / pet. ether  139-140  co© 148  a  H HO  OH H C0 H 2  84  Results and Discussion  Chapter 3  Table 3.8 continued Anion  Salt  (: O  2  mp (°C)  CHC1 / pet. ether  117-120  CHCI3 / pet. ether  117-120  MeOH  207-210  CHCI3 / pet. ether  132  CHCI3 / pet. ether  132  CHCI3 / pet. ether  166-167  CHCI3 / pet. ether  103-104  H  HO— — H  149  Recrystallization Solvent  a  H— — H  3  (: o © 2  C: 0 H 2  H— — OH  150  H— — H  C; o © 2  151  >°  <  e co 152  b  ^  /  2  V''OMe  QTcF r  v  3  0  C0 153  2  JJ O M e  1  154 s o  3  °  © 155  C0 H C 3  2  H  0 [|  J  85  Results and Discussion  Chapter 3  Table 3.8 continued Anion  Salt 0  co  2  Recrystallization Solvent  mp (°C)  CHC1 / pet. ether  142-143  CHCI3 / pet. ether  130-131  CHCI3 / pet. ether  189-191 (dec.)  o  156  3  0 C0  2  157  0  u  H ^ N ^ O ^ V ^ l - f  H  ©  158  a  X - r a y crystal structure obtained. Partial crystallographic analysis performed (vide infra). b  Table 3.9 Optically active salts prepared from aminoketone 16.  c)  \  16  )  M  H H Salt  Anion  159  L >° 0  o  0  86  Recrystallization Solvent  mp (°C)  CHCI3 / n-pentane  235-240 (dec.)  Results and Discussion  Chapter 3  Table 3.9 continued Anion  Salt  Recrystallization Solvent  mp (°C)  CHCI3 / w-pentane  154-155  CHCI3 / M-pentane  155-156  0  co  2  160  H ^  H  N  Me  T  S  0  co  2  161  Table 3.10 Additional salts prepared from the macocyclic aminoketones. Salt  120  Structure  6V Me  127  182-183  EtOH / E t 0  112-113  0  E t 0 / MeOH  179-180  o=s=o  H  VV  2  1  cp  2  N H  E t 0 / MeOH  H  1  Me  mp (°C)  2  V0 ]  162  X  Recrystallization Solvent  H  87  Results and Discussion  Chapter 3  Table 3.10 continued Structure  Salt  Recrystallization Solvent  mp (°C)  MeCN  200-202 (dec.)  0  128  a  N H a  H  X - r a y crystal structure obtained.  3.5 Photochemistry of the Optically Active Salts Because the products derived from Type II cleavage are achiral, they are of no value in assessing the extent of asymmetric induction in the photoreactions of the optically active salts. The cyclobutanol photoproducts, however, measurement  are chiral, and  of their enantiomeric excess was used to gauge the efficiency  of  asymmetric induction. Enantiomeric excesses were measured by chiral G C following photolysis of the salt and basic workup to remove the chiral auxiliary and liberate the photoproducts as free amines. Resolution of the cyclobutanol enantiomers could be achieved for all but compounds 118 and 125, the trans-cyclobutanol photoproducts of the twelve- and sixteen-membered aminoketones. A typical chromatogram for a chiral G C run is depicted in Figure 3.14. The starting material (14), cleavage product (123), and both enantiomers of the cis- and frYms-cyclobutanols (121 and 122 respectively) are cleanly resolved. In the case of compound 121, enough enantiomerically enriched compound was isolated to allow the sign of optical rotation to be determined; the peaks for 121 in Figure 3.14 are labelled to reflect these results. For all other ee determinations, the predominant enantiomer is designated as either the first or second enantiomer eluted from the GC.  88  Results and Discussion  Chapter 3  cleavage  starting material trans-cyclobutanols  [  cis-cyclobutanols  (+) (-)  Figure 3.14 Chiral G C trace showing the separation of starting material (14) and products.  3.5.1 Solution State Photolyses of the Optically Active Salts In previous studies using ionic chiral auxiliaries, asymmetric induction was observed only in the solid state photolyses. In the solution state, the optically active ions had no effect in directing the steric course of the photoreaction. The same holds true in the present instance. A number of the optically active salts were photolysed in acetonitrile solution and their photoproducts subsequently analyzed by chiral GC. A l l chiral products were produced as racemic mixtures. The product ratios are also essentially anionindependent, a further indication that, in solution, the anisotropy of the chiral ion has no effect on reaction selectivity. The results of these experiments are presented in Table 3.11. Refer to Table 3.2 for solution state photolysis data for the free amines and their hydrochloride salts.  89  Results and Discussion  Chapter 3  Table 3.11 Solution state photolyses of some optically active aminoketone salts. Cyclobutanol (%) f  Salt  Cleavage (%)  cis  trans  a  65  35  b  51  25  24  43  29  29  145 148  d  141  b  —  45  31  24  c  32  25  g  43  c  26  28  g  44  151 ' b  161 159  g  e  Twelve-membered macrocycle. Fourteen-membered macrocycle. Sixteen-membered macrocycle. Photolyses conducted i n M e C N with Pyrex-filtered light. Conversions kept below 10% to minimize secondary reactions. Water added to effect salt dissolution. Measured enantiomeric excesses were n i l within error limits. E e determination not available for this compound (see text). a  b  c  d  e  f  B  3.5.2 Solid State Photolyses of the Optically Active Salts Irradiation of the salts in the solid state leads to the expected asymmetric induction and enhanced photoproduct selectivity. The most striking results are those involving the fourteen-membered macrocycle (Table 3.12). On examination of the data a general trend is immediately apparent: while solution state irradiation leads to a cis:trans cyclobutanol ratio of approximately 2:1, little or none of the trans-isomev is produced when the salts are photolyzed in the crystalline state. Enantiomeric excesses for the ciscyclobutanol in the solid state range from excellent (148, 141, 150) to negligible (156). Particularly impressive is the formation of cz's-cyclobutanol 121 in 81.9% ee from salt 151 at 69% conversion. As expected, irradiation of enantiomeric salts (e.g., 141 and 150, 152 and 153) gives rise to enantiomeric cyclobutanols of similar ee. This result demonstrates that the reacting systems are well-behaved, and can provide access to either product enantiomer with a simple substitution of the ionic chiral auxiliary. The dramatic change in reactivity exhibited on switching from solution to solid state photolysis highlights the importance of conformational rigidity in controlling the course of the reaction. The crystalline state photochemistry of the enantiomeric salts 145 and 146, derived from the twelve-membered macrocycle, display a marked improvement in  90  Chapter 3  Results and Discussion  cis:trans selectivity in the solid state versus solution (Table 3.13). The enantioselectivity of  cz's-cyclobutanol formation is, however, mediocre, and decreases rapidly with  increasing conversion. This progressive decline in enantioselectivity is thought to result from the breakdown of the ordered crystal lattice as photoproducts replace starting material. The rate of this decline varies widely among the salts studied and is an important factor, along with ee, that must be considered when evaluating the synthetic utility of these reactions. The crystalline state photochemistry of salts 161, 160, and 159, all derived from the sixteen-membered aminoketone, show poor reaction selectivity in the solid state (Table 3.14). A l l three photoproducts are produced in significant quantities, while the observed ees for the czs-cyclobutanol are low. Although, as indicated in Chapter 1, the ability to predict crystals structures and hence design solid state asymmetric reactions a priori is not currently available, the ionic auxiliary method for asymmetric induction seems well-suited to a combinatorial approach to chiral auxiliary selection. Since only a small quantity of salt is required to test the efficacy of a particular ionic auxiliary, and synthesis of the salts is, in principle, a trivial matter, rapid screening should be possible. In addition, photolysis of the test samples in parallel, with subsequent chiral G C (or HPLC) analysis, would allow identification of promising candidate auxiliaries with minimal consumption of starting material. Although X-ray quality crystals are required in order to analyze the steric course of the reaction, they are not necessary for synthetic purposes. Salt 151 (Table 3.12) exmplifies this fact: although it crystallizes as fine needles which are too small to mount for X-ray crystallographic analysis, it produces product with high enantioselectivity in the solid state.  91  Results and Discussion  Chapter 3  Table 3.12 Solid state photolysis of optically active salts of aminoketone 14.  Salt  148  149  150  151  Acid  (2R, 3i?)-tartaric acid  (5)-malic acid  (i?)-malic acid (i?)-2-hydroxy-5,5-dimethyl4-phenyl-l,3,2dioxaphosphorinane-2-oxide  152  (i?)-Mosher's acid  153  (»S}-Mosher's acid  154  (1S)-10-camphorsulphonic acid  155  TV-Cbz-L-alanine  156  /V-Cbz-L-phenylalanine  157  7Y-Cbz-L-valine  158  2,3:4,6-di-0-isopropylidene2-keto-L-gulonic acid  % Yield  %  3  % ee  b  Conversion  121  122  123  3  3  0  0  41.4  5  5  0  0  42.9  7  7  0  0  44.6  13  13  0  0  44.3  24  24  0  0  43.8  10  5  0  4  >98  20  9  0  11  95.3  31  13  0  18  92.9  50  20  1  29  85.5  60  24  2  32  81.3  11  6  0  5  >98  6  6  0  trace  >98  21  17  0  4  >98  30  23  0  7  96.0  53  35  0  18  88.7  69  45  0  24  81.9  5  5  0  0  20.9  9  9  0  trace  18.7  11  9  trace  2  17.8  25  20  1  4  11.4  4  4  0  trace  52.8  12  10  0  2  44.7  24  18  1  5  35.1  6  6  0  trace  41.3  15  12  1  2  37.8  6  4  0  2  6.4  22  13  1  8  2.4  7  6  trace  1  32.6  15  10  2  3  30.2  5  4  1  0  26.3  28  16  5  7  5.5  a  -  -  +  -  +  -  + +  "Irradiations conducted at -20°C o n 5-10 m g samples o f crushed crystals sandwiched between two Pyrex plates. Y i e l d s were determined b y G C following basic workup. Enantiomeric excesses reported for compound 121. Indicates the sign o f rotation o f the predominant enantiomer o f 121 at the sodium D-line. b  92  Results and Discussion  Chapter 3  Table 3.13 Solid state photolysis of optically active salts of aminoketone 12.  Salt  Acid  145  (1S)-10-camphorsulphonic acid  146  (1R)-10-camphorsulphonic acid  % Yield  %  3  % ee  b  Conversion  117  118  15  11  3  24.7  21  17  3  19.2  4  4  trace  47.0  7  7  trace  36.8  12  10  2  29.4  25  21  4  15.0  27  20  4  15.2  a°  1  2  irradiations (Corning glass #9720 filter employed) conducted at -20°C o n 5-10 m g samples o f crushed crystals sandwiched between two quartz plates. Y i e l d s were determined b y G C following basic workup. Enantiomeric excesses reported for compound 117. i n d i c a t e s the order o f elution o f the predominant enantiomer o f 117 from the chiral G C column. b  Table 3.14 Solid state photolysis of optically active salts of aminoketone 16.  Salt  161  160  159  Acid  (i?)-Mosher's acid  iV-tosyl-L-alanine  (R)-2 -hydroxy- 5,5-dimethyl4-phenyl-1,3,2dioxaphosphorinane-2-oxide  % Yield  %  3  % ee  b  Conversion  124  125  126  8  4  2  2  40.6  27  18  9  5  41.3  47  24  10  13  39.0  10  3  3  4  16.3  23  6  5  12  15.5  41  9  4  28  6.4  8  5  2  1  27.9  22  9  7  6  24.9  29  7  6  16  25.2  2  2  1  "Irradiations conducted at -20°C o n 5-10 m g samples o f crushed crystals sandwiched between two Pyrex plates. Y i e l d s were determined b y G C following basic workup. Enantiomeric excesses reported for compound 124. Indicates the order o f elution o f the predominant enantiomer o f 124 f r o m the chiral G C column. b  93  Results and Discussion  Chapter 3  3.6 Solid State Structure-Reactivity Correlations  d(A)  co(°)  en  A(°)  Ideal  <2.72  0  180  90-120  Average  2.73 ± 0.03  52 ± 5  115 ± 2  83 ± 4  Figure 3.15 Ideal and crystallographically derived average (based on a series of aliphatic ketones) H -abstraction geometries. 91  y  The four crystal structures that were obtained for various salts (147, 148, 149, and 128) of the macrocyclic aminoketones were analyzed in light of their observed photoreactivity. The geometric parameters pertaining to y-hydrogen abstraction are reviewed in Figure 3.15. It is important to keep in mind that, while the ground state geometry is useful as a model in predicting excited state reactivity, the distance and angular geometric parameters obtained from crystallographic studies do not necessarily reflect the geometry of the excited state species. For aliphatic ketones in particular, significant pyramidalization of the carbonyl carbon (22-45°) upon electronic excitation has been predicted by ab initio studies.  92  While this effect is thought to play a minimal  role in type II reactions of aromatic ketones, such as those dealt with in Chapter 2 of 93  this thesis, the ketones with which we are concerned here are aliphatic, and thus the notion of 'ideal' parameter values may be more relaxed. Since the theoretical studies were based on the situation in the solution state, it is unknown what effect the crowded crystalline environment may have in limiting pyramidalization.  94  94  Results and Discussion  Chapter 3  3.6.1 Solid State Structure of Salt 147  S  1 2  N  Me  H  •  H 0 2  147  Binaphthylphosphoric  acid, a commercially available  and widely applied  resolving agent, was one of only three optically active acids that formed a crystalline 95  salt with aminoketone 12. The X-ray crystal structure of the cation from this compound is shown in Figure 3.16. The abstraction parameters for the two inside y-hydrogens (H : d = a  3.06 A, co = 56°, A = 62°, 0 = 121°; H : d = 2.93 A, co = 56°, A = 72°, 6 = 110°), reveal b  that, although the d values  are larger than usual, abstraction of Hb may be  stereoelectronically possible. This salt did not react on irradiation in the solid state. This lack of observed reactivity may also be due to quenching of the ketone excited state by the naphthalene rings via energy transfer. Naphthalene is known to quench the triplet excited state of benzophenone efficiently,  96  and would thus be able to quench the higher-  energy excited state of an aliphatic ketone. In order to coerce the salt into reacting in the solid state, it was exposed to yradiation from a C o source at total doses up to 30 Mrad. This attempt failed, however, 60  97  and the starting material was recovered unchanged. Although no conclusive structurereactivity correlations can be drawn from this example, it does provide unequivocal proof of the structure of the twelve-membered macrocycle.  95  Chapter 3  Results and Discussion  Results and Discussion  Chapter 3  3.6.2 Solid State Structure of Salt 128  Figure 3.17 ORTEP representation of the macrocyclic cation in salt 128.  The only salt of the sixteen-membered macrocycle that provided crystals suitable for X-ray analysis was the achiral hydrochloride salt 128. Although it too failed to react in the solid state, analysis of the abstraction geometries for the closest two y-hydrogen atoms shed light on its photostability. Figure 3.17 shows the macrocycle, as well as the chloride counterion. The two y-hydrogen atoms located on the same side of the ring as the carbonyl group lie on the same carbon and possesss the following abstraction parameters: H (d = 3.59 A, co = 41°, A = 67°, 6 - 87°); H (d = 3.26 A, co - 55°, A = 58°, 9 = 111°). c  d  The hydrogen atoms on the y-carbon labelled X are both >4 A away from the carbonyl oxygen, and lie on the opposite side of the macrocycle. Both H and Hd lie well beyond c  the average d (2.73 ± 0.03 A) reported in Figure 3.15, and this would seem the most  97  Chapter 3  Results and Discussion  likely explanation for the lack of observed solid state reactivity. The angular parameters for H abstraction also deviate significantly from previously determined values. c  3.6.3 Structure-Reactivity Relationships for Salts of the Fourteen-Membered Aminoketone Three salts of aminoketone 14 provided crystals that were suitable for X-ray crystallographic analysis. In the case of salt 152 (derived from 14 and (i?)-Mosher's acid), the space group and unit cell data could be determined (PI; a = 11.273(1) A, b = 12.758(2) A, c = 9.4415(8) A; a = 93.14(1)°, p = 102.28(1)°, y = 65.50(1)°; Z = 2), however the macrocycles were found to be extremely disordered and could not be refined satisfactorily. This disorder is reflected in low ee (ca. 20%, see Table 3.12) observed after solid state photolysis of this salt, even to low conversions. This example raises an interesting point concerning the application of structure-reactivity analysis in conjunction with the ionic chiral auxiliary method: in previous studies, X-ray quality crystals could be grown almost exclusively for salts which demonstrated high enantioselectivities. Those salts which showed poor asymmetric induction generally do not form crystals suitable for crystallographic structure determination. As a result, the reactivity of highly selective solid state processes has been well studied, while structural and mechanistic information relating to crystals that display poor enantioselectivity is scarce. With crystal structures of both the (^-malate salt 149, which gives rise to very high product ee, and the (2R, 2R)tartrate salt 148, for which only moderate (ca. 44% ee) enantioselectivity results, we are able to contrast and compare cases in which both high and low selectivities in the photochemistry of aminoketone 14 arise.  98  Results and Discussion  Chapter 3  Figure 3.18 ORTEP representation of the macrocycle in salt 149.  Figure 3.18 shows the solid state conformation of the macrocycle in salt 149. Since the absolute configuration of the counterion is known, the absolute configuration of the reacting macrocycle can be assigned unequivocally. The X-ray structure clearly shows the carbonyl group poised to abstract only one y-hydrogen (H ), the others being e  too far away (> 4 A) and/or unfavourably oriented. At 3.09 A, the 0 0  H distance is e  the longest measured to date for an aliphatic ketone. The angular parameters for H are: 94  e  co = 56°, A = 60°, 9 = 117°; co and 9 are within the range of average values reported in Figure 3.15, while A is 23° lower than the average value of 83°. The fact that d and A deviate significantly from typical values may suggest that some change in geometry is occurring on ketone excitation. The biradical formed on abstraction of H has a pxe-cis geometry (C-OH and C -H e  Y  bonds in a syn relationship), such that topochemically controlled, least motion cyclization leads to (-)-cw-cyclobutanol 121. The configuration of the intermediate biradical is such that the (-)-cw-cyclobutanol 121 should possess the (IS, 12S) stereochemistry. Thus, the  99  Results and Discussion  Chapter 3  high enantioselectivity of the reaction is governed by the abstraction of only one of two enantiotopic y-hydrogens, while the product cis/trans diastereoselectivity arises from the fixed conformation of the intermediate biradical. In the solid state photochemistry of salt 148, the moderate ee of cyclobutanol 121 (ca. 44% in favour of the (-)-enantiomer) must be rationalized. Analysis of the X-ray data revealed disorder in the macrocycle. Two conformations were found (occupancy ratio 72:28), which differ only in the placement of four methylene groups. Figure 3.19.a shows the superposition of the two conformers. The atoms coloured purple belong to the major conformer, while those in yellow are part of the minor conformer. The major conformer contains only one abstractable y-hydrogen (Figure 3.19.b; Hf-: d = 2.77 A, co = 49°, A = 82°, 6 = 114°), and the absolute configuration of the ring is similar to that of 149, such that formation of the (-)-enantiomer of cyclobutanol 121 is expected from reaction at this site.  For  the  minor  solid  state  conformer  (Figure  3.19.c),  however,  the  stereoelectronically favoured y-hydrogen is H (d = 2.60 A, co = 47°, A = 95°, 6 = 113°), g  which predicts formation of the (+)-enantiomer of cyclobutanol 121. It is tempting, therefore, to equate the 44% enantiomeric excess favouring (-)-121 with the 72% - 28% = 44% difference in conformer population, and this seems to be the most straightforward esplanation of the reduced stereochemistry in this case. Complete discrimination in the type II abstraction of the nearer of two y-hydrogen atoms whose d values differ by 0.27 A has previously been observed.  91  The explanation put forward above requires that the two conformers react with equal quantum efficiencies,  and that the minor conformer reacts exclusively by  abstraction of H . A n alternative scenario is one in which the 44% ee is the accidental g  result of the minor conformer reacting more efficiently (more favourable abstraction parameters) than the major one, but with less than 100% enantioselectivity. Regardless of the details, it is clear that competing reactions from independent conformers are resposible for the low ee.  '  100  Chapter 3  Results and Discussion  Figiure 3.19 ORTEP representations of the macrocycle in salt 148: (a) major (purple) and minor (yellow) conformers superimposed; (b) major conformer; (c) minor conformer.  101  Results and Discussion  Chapter 3  3.7 Summary Application of the ionic chiral auxiliary approach to asymmetric synthesis has been extended to include enantioselective photochemical reactions of amines, employing acids as the chiral auxiliaries. High enantioselectivities were achieved for a number of the optically active salts on photolysis in the solid state. In addition, solid state structurereactivity  correlations  have  revealed  the  origin  of  both  high  and  moderate  stereoselectivities, data for the latter of which have been hard to come by. These studies have also hinted that disorder of the molecules in the crystalline state may play a large role in instances where low selectivities are observed. In terms of the geometric requirements for hydrogen abstraction in the solid state, the long d value of 3.09 A observed in salt 149, along with the shortest abstraction distance possible in the unreactive sixteen-membered salt 128 (3.26 A), would seem to define an upper limit for d values in the Type II abstraction of aliphatic ketones.  102  Results and Discussion  Chapter 4  Chapter 4 - Asymmetric Induction in the Solid State Photochemistry of Linearly Conjugated Benzocyclohexadienone Salts 4.1 Synthesis of the Photochemical Substrate 52  186  163 (91%)  164 (69%) 1) LDA, -78°C 2) PhNTf  52 (98%)  166(85%)  2  165(87%)  Figure 4.1 Synthetic scheme for the preparation of ketoacid 52.  The previously unknown ketoacid 52 was prepared in five steps from 1-tetralone (186) in an overall yield of 45% (Figure 4.1). Dimethylation of ketone 186 with methyl iodide and potassium hydride furnished the substituted tetralone 163. Employing a general procedure reported for the oxidation of benzylic methylene groups to the corresponding  aromatic  ketones,  98  compound  163  was  oxidized  with tert-  butylhydoperoxide and catalytic chromium trioxide to dione 164. Enolate formation followed by O-alkylation with A^-phenyltrifluoromethanesulfonimide led smoothly to vinyl triflate 165.  Palladium(0)-catalyzled methoxycarbonylation  99  103  of this substrate  Results and Discussion  Chapter 4  provided the a, (3-unsaturated methyl ester 166 in good yield. Quantitative hydrolysis of this ester with lithium hydroxide afforded the target acid 52; the crude product thus obtained was an analytically pure white solid, and was used without further purification.  4.2 Photochemistry of Compounds 52 and 166 Photolysis (k = 350 nm) of compounds 52 and 166 in solution yields the benzobicyclo[3.1.0]hexane  photoproducts 53 and 167 respectively (Figure 4.2). The  reactions proceed cleanly and efficiently, and no secondary photoproducts arising from reaction of 53 or 167 were observed. The structure of acid 53 was confirmed by X-ray crystallography (Figure 4.3), and this compound could be transformed quantitatively into ester 167 upon treatment with diazomethane.  hv (350 nm)  E t 0 (R = H) or MeCN (R = Me) 2  COoR 52 R = H 166 R = Me  R0 C 2  53 R = H (87%) 167 R = Me(82%)  Figure 4.2 Solution state photolysis of compounds 52 and 166. While  this  reaction  is  formally  equivalent  to  the  conversion  of  benzocyclohexadienone 70 to benzobicyclo[3.1.0]hexane 93 (discussed in section 2.4.2, Figure 2.30), it does not proceed via the \n,n*) excited state and thus does not involve a ketene intermediate (see section 1.6 for a detailed description of this reaction). Irradiation of 166 in the presence of a large excess of dimethylamine failed to produce any amide from the trapping of a transient ketene; only product 167 was isolated. This is consistent with reaction from the (71,71*) manifold, which most likely proceeds by way of the 1  dipolar or diradical intermediate 168.  100  Further evidence in support of the (71,71*) 1  pathway comes from a comparison of the U V absorption spectra of compounds 70 and 166 (Figure 4.4). While the lowest energy absorption band for compound 70 corresponds to an (n,7r*) transition,  101  in compound 166 this band is shifted to higher energy (shorter  104  Results and Discussion  Chapter 4  3.0000-]  200  300  100  50Q  UflVELEHGTH Figure 4.4 Absorption spectra for benzocyclohxadienones 70 and 166 in acetonitrile (5.0 x 10" M). 4  105  Results and Discussion  Chapter 4  A, B = • or A=0 B=©  168 wavelength). Figure 4.5 illustrates the relative energies of the '(n^*) and  '(71,71*)  excited  states for the compounds in question, and indicates the difference in the nature of the reactive (lowest'energy) excited state for each. A n analogous reordering of excited states has been observed in the photochemistry of compound 169  (Figure 4.6).  100  In  methylcyclohexane, the absorption spectrum of ketone 169 resembles that of ketone 70 (Figure 4.4, red line), and products derived from ketene intermediates are observed. When the solvent is 2,2,2-trifluoroethanol, the absorption spectrum of dienone 169 is similar to that of compound 166 (Figure 4.4, blue line). Photolysis in this medium results in  compound  170,  spectroscopically.  100  and no  ketene  transient  could  be  trapped or  observed  As has been noted for previously investigated cyclohexadienones,  102  photolysis of 166 proceeded in the presence of the triplet quencher piperylene (2 M concentration), suggesting that reactions of this type occur from a singlet excited state.  1  E  1  (n,7i*)  (71,71*)  W*) 70  166  Figure 4.5 Relative ordering of excited states in compounds 70 and 166.  106  Results and Discussion  Chapter 4  o  170 Figure 4.6 Solvent-induced reordering of excited states leads to different photochemical reactions for compound 169. 100  4.3 Resolution of Ketoacid Photoproduct 53 In order to map the absolute steric course of solid state reactions, it is necessary to know the absolute stereochemistry of both the crystalline starting material (salts of acid 52 in this case) and the resulting product (ketoacid 53). Since the ionic chiral auxiliaries employed in these studies are of known absolute configuration, it remains only to assign the configuration of the stereogenic centres in the optically active photoproduct, i.e., to determine which enantiomer of 53 is produced in excess. To achieve this goal, a classical Pasteur resolution  103  of racemic carboxylic acid 53 was carried out, employing brucine as  the resolving agent. A crop of the optically pure salt 171 was recovered in 30% yield, and subsequently recrystallized. X-ray crystallographic analysis of salt 171 revealed that the anion possessed the (laS, 6a/?) absolute configuration (Figure 4.7). Treatment of this 11  optically pure salt with diazomethane provided the corresponding methyl ester, (laS, 6ai?)-167. Chiral G C analysis of this product then allowed the absolute configuration  The numbering scheme for compound 53 is based on its C A S name: 6,6a-dihydro-l,l-dimethyl-6-oxocycloprop[a]indene-la(l/f)-carboxylic acid.  11  107  Chapter 4  Results and Discussion  Figure 4.7 ORTEP representation of salt 171. Stereocentres of interest are shown in green.  108  Results and Discussion  Chapter 4  o  Figure 4.8 Chiral G C chromatogram showing the configuration of each enantiomer of ester 167.  of the enantiomers of ester 167 to be identified on the G C trace. Figure 4.8 depicts a chiral G C chromatogram of racemic 167 with the absolute configuration assignments labelled for each peak.  4.4 Preparation of Optically Active Salts of Acid 52 Salts of carboxylic acid 52 were formed with twelve optically pure amines of known  absolute  configuration.  The  identity,  melting  points,  and  solvent  of  recrystallization for these compounds are reported in Table 4.1. The spectral data and elemental analysis results provided the stoichiometry for each of the salts synthesized. The presence of water or solvent of crystallization could also be detected from these analyses.  109  Results and Discussion  Chapter 4  Table 4.1 Optically active salts prepared from acid 52. 0  Cation  Salt  172  a  H  Recrystallization Solvent  mp(°C)  EtOAc  182-184  M e C N / «-pentane  84-88  Et 0  134 (sharp)  Et20 / «-pentane  96-104  MeOH / E t 0  107-109  Et 0  129-138 (dec.)  (T\  H  HQ H 173  L  1  u  NH  H 174  175  3  ©  f \ A / /  N  3  H  2  f)\  N  176 H  H  H  3  II \  2  177  2  'X-ray crystal structure obtained.  110  Results and Discussion  Chapter 4  Table 4.1 continued Cation  Salt  178  p'H H  OH  © OH  148-149  M e C N / hexanes  144-145  Et 0  101-103  2  ©^H  H H  A K I T /f  H  H  ac  EtOAc  OMe  181  183  143-148  HH  180  b  MeOH / E t 0 2  © OH  182  mp (°C)  HH  0  179  Recrystallization Solvent  3  H  «V4  H0  MeOH / E t 0  187-189  MeOH / E t 0  187-190 (dec.)  2  2  ::x4?i-  2  H  l  X - r a y crystal structure obtained. F o r m s a 2:1 salt. Salt is complexed with one equivalent o f free acid. b  c  Ill  Results and Discussion  Chapter 4  4.5 Solution State Photochemistry of the Optically Active Salts For four of the chiral salts, the  1 3  C N M R signal for the gem-dimethyl carbons in  the carboxylate moiety was split into two peaks. Close contact between the chiral cation and achiral anion in the solvated ion pair places the two methyl groups in a diastereotopic relationship. This phenomenon has been exploited for the determination of enantiomeric purity of compounds by N M R spectroscopy, in which case the optically pure ion is known as a chiral solvating agent.  104  Table 4.2 lists the chemical shift difference for the  two methyl groups measured in chloroform-J at 75 MHz. Despite the chiral anisotropy displayed by these salts in solution, asymmetric induction in the photoproduct was not observed after irradiation of these compounds in chloroform. Diastereotopic splitting was not observed in the H N M R spectra of any of the salts of acid 52. :  Table 4.2 Diastereotopic splitting of the gem-dimethyl groups in salts of acid 52. Salt  177 181 180 173  1 3  C A5(ppm) 0.04 0.05 0.08 0.04  4.6 Solid State Photochemistry of the Optically Active Salts The previous chapter of this thesis described the application of the ionic chiral auxiliary method of asymmetric synthesis in the Norrish/Yang type II photochemistry of macrocyclic aminoketones. In those systems, a large degree of conformational flexibility was present in the reactant, thus allowing it to crystallize in a chiral conformation that favoured formation of one enantiomer of the product over the other. With planar molecules such as compound 52, however, such biases are expected to be small. The origin of asymmetric induction in this case may have less to do with the conformation of the reactant and may be more influenced by the availability of free space in the crystal lattice. Molecular modelling (HyperChem MM+) of the methyl ester 166 predicts a planar ring system, with the molecule possessing overall C symmetry. It was expected, s  therefore, that the benzocyclohexadienone moiety in the optically active salts formed from acid 52 should also be planar.  112  Results and Discussion  Chapter 4  As can be seen from the data in Table 4.3, only one chiral auxiliary, 1phenylethylamine (salt 175), gave a respectable enantiomeric excess (ca. 80%). The others gave ees ranging from 5-65%. Performing the photolyses at low temperatures had little effect on the product ee, except in the case of salt 182, where an increase of ca. 17% was realized when the reaction temperature was lowered from ambient to -78 °C. Although the majority of the salts do not provide product with synthetically useful optical purity, the result obtained for salt 175 (71% ee at 80% conversion) offers promise that further trials of ionic chiral auxiliaries can better this result.  Table 4.3 Solid state photolysis of optically active salts of benzocyclohexadienone 52. Salt  172  173  174  175  Amine  Temperature  (25)-diphenylmethylpyrrolidine  ambient  ambient  (IS, 25)-2-amino-l,3dihydroxypropylb enzene  -78 °C  (15, 2R, 5S)-czs-myrtanylamine  ambient  ambient  (S)-1 -phenylethylamine  -78 °C  176  177  (/?)-iV-benzyl-1 -phenylethylamine  ambient  ambient  (R)-1 -(4-methylphenyl)ethylamine  -78 °C  % Conversion  %ee  53  113  a  7  55.0  17  32.4  37  18.2  17  5.4  38  3.2  18  4.9  19  8.1  33  5.9  (la/?,  54  1.6  6aS)  64  1.2  25  81.0  39  75.6  (la/?,  80  70.6  6aS)  30  86.5  12  12.6  26  8.4  2  65.0  9  50.1  12  48.1  28  27.8  33  31.8  15  47.6  Absolute configuration o f the predominant enantiomer o f photoproduct 53 as measured b y chiral G C analysis o f the corresponding methyl ester 167.  a  Abs. Config.  (laS, 6a/?)  (laS,  6aR)  (laS, 6a/?)  (laS, 6a/?)  Results and Discussion  Chapter 4  Table 4.3 continued Amine  Salt  Temperature  ambient  hydroquinidine  178  ambient  (IR, 2S)-ephedrine  179  -78 °C  180  181  182  ambient  (IR, 2i?)-pseudoephedrine  (IS, 2 S)-2-amino-3-methoxy-lphenyl-1 -propanol  ambient  1  hydroquinidine 2,5-diphenyl-4,6pyrimidinediyl diether (DHQD PYR)  ambient  2  183  -78 °C ambient  brucine  % Conversion  %ee  a  18  12.9  39  12.6  (la/?,  50  10.7  6aS)  78  7.7  17  30.6  36  32.3  61  30.5  78  24.2  68  32.7  11  38.1  35  36.2  (laS,  57  31.8  6a/?)  67  29.1  7  23.7  12  21.9  40  15.8  36  35.6  56  35.1  (la/?,  69  36.7  6aS)  53  52.5  15  20.2  49  21.9  76  25.2  "Absolute configuration o f the predominant enantiomer o f photoproduct 53 as measured b y chiral G C analysis o f the corresponding methyl ester 167.  114  Abs. Config. 53  (laS,  6aR)  (laS, 6ai?)  (la/?,  6aS)  Chapter 4  Results and Discussion  4.7 Solid State Structure-Reactivity Analysis Two  of  the  optically  active  salts provided crystals  suitable  for X-ray  crystallographic analysis: 183, for which brucine was the ionic chiral auxiliary, and 172, the (25)-diphenylmethylpyrrolidine salt of acid 52. The brucine salt is actually a complex formed between a brucinium cation, the carboxylate anion of acid 52, and a molecule of the free acid. Thus, the photoreactive benzocyclohexadienone unit is present in two forms that are chemically and crystallographically independent, and reside in different chiral environments. Figure 4.9 shows the anion and free acid as found in the crystal; the carboxyl hydrogen atom is highlighted in green.  Figure 4.9 ORTEP representation of the benzocyclohexadienone moieties in salt 183.  115  Chapter 4  Results and Discussion  It seems likely that the presence of two independent photoreactive forms of the acid is responsible for the low enantioselectivity (ca. 20%) observed on solid state photolysis of this salt. In order to achieve high ees, each of the two components would need to produce the same photoproduct enantiomer, and do so with good selectivity. Although salt 172 consists of an optically active cation and the photoreactive anion in a 1:1 ratio, X-ray crystallographic analysis reveals that the solid state structure has a greater degree of complexity than anticipated. The crystal asymmetric unit, i.e. the minimum set of atoms required to describe the crystal structure before any elements of symmetry are introduced,  105  contains two sets of anion-cation pairs. For crystals of  organic compounds, the asymmetric unit typically contains one formula unit (e.g., molecule or anion-cation pair), but this need not be the case.  105  At first glance, the  situation encountered with this salt seems similar to that described above for salt 183, namely the presence of two independent photoreactive moieties reacting from different conformations and in differing chiral cavities. Closer examination of the asymmetric unit reveals, however, that a pseudo-centre of inversion is present, and the two independent anions are near-perfect conformational enantiomers. The ammonium counterions are not related by any elements of symmetry. Figure 4.10 shows the asymmetric unit for salt 183. The green atoms highlighted in the anion are related by inversion through the pseudocentre. The benzylic atoms of the cation (shown in yellow) both point out of the page and are therefore not related by inversion. The superposition of the two anion conformations is shown in Figure 4.11.a, and reveals that the ring systems are nearly coplanar. The pendant carboxyl groups, however, are related to the ring system with torsional angles of opposite sign (36.0° and -36.9°). The root-mean-square error (RMSE) calculated for the overlap of the two species is 0.47 A. Stereochemical inversion of one anion with subsequent superposition onto the other confirms that the anions are conformational enantiomers (Figure 4.11.b). The RMSE value for overlap in this case is negligible at 0.03 A. One would expect that, all other factors being equal, irradiation of crystals containing equal amounts of conformational enantiomers should result in a racemic photoproduct. The observed ee at 7% conversion is an astonishing 55%. This ee, then, is a direct measure of the anisotropic influence of the chiral crystalline environment, and is  116  Chapter 4  Results and Discussion  independent of the reactant's own conformational asymmetry. Since the overall enantioselectivity is the cumulative result of a large number of small interactions, prediction of the steric course of the reaction is not straightforward, and detailed computational analysis is required.  106  Such calculations are planned in collaboration with  experts in this field.  4.8 Summary The planar photosubstrate was expected to show little conformational bias in the solid state, thus relying on the chiral reaction cavity to exert the most influence on the stereoselectivity of the photoreaction. The generally low ees observed in the solid state photolyses are consistent with conformations where the ring system deviates little from an achiral geometry. The X-ray studies have provided some insight on the low ees by revealing two instances where more than one reactant geomertry is present in the crystal. In these cases, two independent asymmetric reactions are essentially taking place simultaneously, with the overall selectivity expressed in the measured ees. For salt 172, the serendipitous discovery that the two anion conformers were conformational enantiomers means that the enantioselectivity expressed on photolysis is not conformationally derived. Future studies will help to model the solid state chemical processes at work and discover what features of the crystal are responsible for steering this reaction.  117  Chapter 4  Results and Discussion  Figure 4.10 ORTEP representation of the asymmetric unit for salt 183 showing the pseudo-inversion center (•).  Figure 4.11 Root-mean-square overlays of the anions: (a) native conformations in 183. (b) Chirality-matched conformations in 183.  118  Chapter 5  Experimental  Experimental  Chapter 5 - Preparation of Substrates 5.1 General Considerations  Infrared Spectra (IR) Infrared spectra were recorded on a Perkin-Elmer model 1710 Fourier transform spectrometer. Liquid samples were analyzed neat as thin films between two sodium chloride plates. Solid samples (2-5 mg) were ground with IR grade KBr (100-200 mg) in an agate mortar and pelleted in an evacuated die (Perkin-Elmer 186-0002) with a laboratory press (Carver, model B) at 17,000 psi. The positions of selected absorption maxima (v  ) are reported in units of cm" . 1  max  Melting Points (mp) Melting points were determined on a Fisher-Johns hot stage apparatus and are uncorrected. When recrystallized samples were analyzed, the solvent of recrystallization is given in parentheses.  Nuclear Magnetic Resonance (NMR) Spectra Proton nuclear magnetic resonance ('H NMR) spectra were recorded in deuterated solvents as noted. Data were collected on the following instruments: Bruker AC-200 (200 MHz), Varian XL-300 (300 MHz), Bruker WH-400 (400 MHz), Bruker AM-400 (400 MHz), and Bruker AMX-500 (500 MHz). Chemical shifts (8) are reported in parts per million (ppm) of the spectrometer base frequency, and are referenced to the shift of the residual H solvent signals, with tetramethylsilane (8 0.00) as an external standard: ]  chloroform (7.24 ppm), benzene (7.15 ppm), acetonitrile (1.93 ppm), methanol (3.30 ppm), and dimethylsulfoxide (2.49 ppm). The signal multiplicity, coupling constants, number of hydrogen atoms, and assignments are given in parentheses following the signal position. Multiplicities are abbreviated as follows: multiplet (m), singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint), and broad (br). Nuclear Overhauser Effect  119  Experimental  Chapter 5  Difference (NOE) spectra were acquired on the Bruker WH-400 instrument. ^ - ' H correlation spectroscopy (COSY) was conducted on the Bruker WH-400 or Bruker AMX-500 spectrometers. Carbon nuclear magnetic resonance ( C NMR) spectra were recorded on the 13  following instruments: Bruker AC-200 (50.3 MHz), Varian XL-300 (75.4 MHz), Bruker AM-400 (100.5 MHz), and Bruker AMX-500 (125.6 MHz). A l l experiments were conducted using broadband H decoupling. Chemical shifts (5) are reported in ppm and !  are referenced to the centre of the solvent multiplet, with tetramethylsilane (5 0.0) as an external reference: chloroform (77.0 ppm), benzene (128.0 ppm), acetonitrile (29.8 ppm), methanol (49.0 ppm), and dimethylsulfoxide (39.5 ppm). Some spectra are supported by data from the Attached Proton Test (APT). Where these are given, (-ve) denotes a negative APT peak corresponding to a methine (CH) or methyl (CH ) moiety; while no 3  assignment signifies a quaternary or methylene (CH ) centre. 2  Two-dimensional C - ' H correlation spectra were obtained on the Bruker A M X 1 3  500 spectrometer using the Heteronuclear Multiple Quantum Coherence ( H M Q C ) experiment for one-bond correlations and the Heteronuclear Multiple Bond Connectivity (HMBC) experiment for long-range connectivities.  Mass Spectra Low and high resolution mass spectra ( L R M S and H R M S ) were recorded on a Kratos MS 50 instrument using electron impact (EI) ionization at 70 eV, or chemical ionization (CI) with the ionizing gas noted. Analyses were performed by in-hous technicians under the supervision of Dr. G. Eigendorf.  Ultraviolet-Visible Spectra (UV / VIS) Electronic absorption spectra were recorded on a Perkin-Elmer Lambda-4B U V / VIS  spectrometer in the solvents and concentrations indicated using spectral grade  solvents. Absorption maxima (X  max  ) are reported in nanometers (nm), with molar  extinction coefficients (s) reported in parentheses in units of M^cm" . 1  120  Chapter 5  Experimental  Microanalysis (Anal.) Elemental analyses were obtained for most new compounds. These were performed by Mr. P. Borda on a Carlo Erba C H N Model 1106 analyzer.  Crystallography Single crystal X-ray analysis was performed on either a Rigaku AFC6S fourcircle diffractometer (Cu-Koc or M o - K a radiation) or a Rigaku AFC7 four-circle diffractometer equipped with a DSC Quantum C C D detector (Mo-Ka radiation). Structures were determind by Eugene Cheung and Dr. Brian Patrick under the supervision of Dr. James Trotter. Structures are represented as ORTEP drawings at the 50% probability level.  Optical Rotations Optical rotation data were recorded on a Jasco-J710/ORD-M instrument at room temperature at the sodium D-line (589.3 nm).  Gas Chromatography (GC) Gas chromatographic analyses in a helium carrier gas were performed on a Hewlett-Packard 5890A or a 5890 Series II Plus gas chromatograph, each equipped with a flame ionization detector. The following fused silica capillary columns (Supelco) were used: DB-5 (30 m x 0.25 mm ID), Chiral Select 1000 (30 m x 0.25 mm ID), and a Custom Chiral Column (50% 6-TBDMS-2,3-dimethyl-(3-cyclodextrin dissolved in O V 1701, 20 m x 0.25 mm ID). Analyses were run with a split injection port (split ratios between 25:1 and 100:1) with column head pressures of 100 kPa (DB-5) or 250 kPa (chiral columns).  High Pressure Liquid Chromatography (HPLC) HPLC analyses were performed on a Waters 600E system coupled to a tunable U V absorbance detector (Waters 486) using an 88:12 isopropyl alcohol-hexane eluent. The Chiralcel AS column (250 mm x 4.6 mm ID) employed was obtained from Chiral Technologies Incorporated.  121  Experimental  Chapter 5  Silica Gel Chromatography Analytical thin layer chromatography (TLC) was performed on commercial precoated  (silica  gel  on  aluminum)  plates  (E.  Merck,  type  5554).  Preparative  chromatography was performed using either the flash column method with Merck 9385 silica gel (particle  size 230-400 mesh) or radial elution chromatography on a  Chromatotron (Harrison Research).  Solvents and Reagents THF and E t 0 were refluxed over the sodium ketyl of benzophenone under an 2  atmosphere of argon and distilled prior to use. Anhydrous dichloromethane, benzene, xylenes, and M e C N were obtained by refluxing the commercial solvent (Fisher Scientific) over calcium hydride and distilling prior to use. Unless otherwise noted, all reactions were conducted under an atmosphere of dry argon in oven-dried glassware.  122  Experimental  Chapter 5  5.2 Synthesis of Adamantyl Spiroketones 5, 6, 7, 8, and 70  5.2.1 Preparation of the Five-Membered Adamantyl Spiroketone 5  2-Tricvclo[3.3.1.1 ' ldecanecarboxylic Acid (58) and its Methyl Ester (62) 3 7  OH  O.  O.  OMe  58  A procedure modified from that of Alberts et al. was employed:  107  To a cooled (5°  C), stirred suspension of methoxytriphenylphosphonium chloride (20.0 g, 58.3 mmol) in E t 0 (200 mL) was added «-butyllifhium (41.6 mL of a 1.6 M solution in hexanes, 66.6 2  mmol) over five minutes. The mixture was warmed to room temperature and stirred for 1.5 h when it took on a rust colour. A solution of 2-adamantanone (7.5 g, 50.0 mmol) in E t 0 (100 mL) was added dropwise to the ylide solution, and the reaction mixture stirred 2  overnight at room temperature. Anhydrous ZnCl (10 g) was added to precipitate the 2  suspended triphenylphosphine oxide and the pale yellow solution was decanted. To this was added perchloric acid (10 mL of a 35% aqueous solution) and the mixture was stirred vigorously for 2 h. The E t 0 solution was washed with water (3 x 100 mL), dried 2  (MgS04), and the solvent  removed in vacuo to give the crude adamantane-2-  carboxaldehyde as a colourless oil (9.1 g). The crude aldehyde was oxidized directly in acetone (200 mL) with dropwise addition of Jones' Reagent (prepared from 6.3 g chromium trioxide, 18 mL water and 5.4 mL cone, sulfuric acid), maintaining the reaction temperature at 10-15 °C. After stirring for 2 h, the solvent was removed in vacuo, and the dark residue was taken up in water (500 mL) and extracted with E t 0 (3 x 250 mL). The organic extracts were combined and 2  extracted with 3 M K O H (5 x 100 mL). The combined basic extracts were washed with  123  Experimental  Chapter 5  Et20 (2 x 100 mL) and carefully acidified to a pH 3 with cone. HCI. The precipitated carboxylic acid was extracted into E t 0 (4 x 150 mL), and the combined ethereal extracts 2  were dried (MgSC^), followed by the removal of solvent in vacuo. Recrystallization from MeOH / water afforded adamantane-2-carboxylic acid (58) (6.2 g, 64% from 2adamantanone) as a white powder (mp 139-141 °C, lit.  107  141-143 °C).  To a room temperature solution of acid 58 (8.2 g, 45.6 mmol) in anhydrous dichloromethane (150 mL) was added oxalyl chloride (8 mL, 92 mmol) and D M F (20 p L). Evolution of CO and C 0 ceased after 1.5 h of stirring and the solvent was removed 2  in vacuo. The residue was placed under high vacuum (<1 Torr) to remove the last traces Of oxalyl chloride, then taken up in dichloromethane (100 mL). Anhydrous MeOH (10 mL) was added and the reaction stirred at room temperature for 45 minutes, followed by removal of the solvent in vacuo. The pale yellow residue was taken up in E t 0 (200 mL) 2  and washed successively with 5% aqueous sodium bicarbonate (30 mL), water (2 x 50 mL), and brine (50 mL). The organic layer was dried (MgS04) and the solvent removed in vacuo to yield methyl adamantane-2-carboxylate (62) (8.8 g, 99%) as a pale yellow oil which solidified upon standing. The product thus obtained gave spectra in agreement with those reported previously,  108  and was of sufficient purity to be used in subsequent  reactions.  mp: 131-133 °C  ' H N M R (400 MHz, CDCI3): 5 1.59 (br s, IH), 1.62 (br s, IH), 1.7-1.8 (br m, 4H), 1.81.9 (br m, 6H), 2.31 (br s, 2H), 2.59 (br s, IH, C H C 0 M e ) , 3.72 (s, 3H, CH ). 2  1 3  3  C N M R (100 MHz, CDCI3): 5 27.42, 27.47, 29.55, 33.57, 37.39, 38.12, 49.57, 51.30, 175.11.  '  IR(neat): 1734, 1453, 1344, 1266, 1201, 1174, 1100, 1051 cm" . 1  124  Experimental  Chapter 5  2-Benzyltricvclo[3.3.1.1 ' 1decane-2-carboxylic Acid (54) 3 7  54  To a cold (-78 °C) solution of L D A (prepared from 8.7 mmol DIPA and 8.04 mmol «-butyllithium) in THF (50 mL) was added ester 62 (1.20 g, 6.19 mmol) in THF (8 mL) over 15 minutes. After stirring in the cold for 1.5 h, an additional portion of nbutyllithium (4.3 mL of a 1.6 M solution in w-hexane, 6.81 mmol) was added dropwise. The reaction was stirred for 30 minutes, followed by the addition of D M P U (2.25 mL, 18.6 mmol). Benzyl bromide (5.3 g, 31 mmol) was added and the reaction stirred in the cold for 3 h before warming slowly to room temperature and stirring overnight. The reaction was quenched with water (65 mL) and extracted with E t 0 (3 x 50 mL). The 2  combined ethereal extracts were washed with brine (2 x 30 mL), dried (MgS04), and the solvent removed in vacuo. The residue was taken up in anhydrous M e C N (50 mL). To this solution was added sodium iodide (15 g, 100 mmol) and chlorotrimethylsilane (12.7 mL, 100 mmol). The reaction was refluxed under an atmosphere of dry argon for 26 h followed by careful quenching with water (50 mL). Extraction with E t 0 (3 x 75 mL) 2  was followed by successive washing with-25% aqueous sodium thiosulfate (50 mL) and water (2 x 30 mL). The acid was extracted into 10% aqueous K O H (4 x 70 mL) and the combined basic extracts washed with E t 0 (3 x 50 mL). The aqueous layer was carefully 2  acidified with cone. HC1 to a pH of 3 after which the precipitated carboxylic acid was extracted into E t 0 (3 x 75 mL), and the combined organic extracts dried (MgSCM). 2  Removal of the solvent in vacuo provided carboxylic acid 54 (1.26 g, 75%) as a white solid. The compound did not require further purification.  125  Experimental  Chapter 5  mp: 89-91 °C (rc-pentane)  J  H N M R (400 MHz, CDCI3): S 1.7-1.8 (br m, 6H), 1.8-2.0 (br m, 4H), 2.12 (br s, 2H), 2.24 (br s, IH), 2.27 (br s, IH), 3.06 (s, 2H, CH Ph), 7.10 (m, 2H), 7.22 (m, 3H), 2  C 0 H not observed. 2  1 3  C N M R (100 MHz, CDCI3): 5 27.22, 27.30, 31.95, 32.45, 35.53, 38.44, 41.51, 54.24, 126.55, 127.96, 129.48, 137.39, 182.04.  IR (KBr pellet): 3400-2500 (br), 1697, 1274, 1206, 738, 700 cm" . 1  H R M S (EI) calcd for C 1 8 H 2 2 O 2 270.1620, found 270.1622.  Anal. Calcd: C, 79.96; H , 8.20. Found: C, 80.01; H, 8.16.  Spiror2/7-indene-2.2'-tricvclor3.3.1.1 ' ldecan1-l('37f)-one (5) 3 7  5  To a solution of acid 54 (317 mg, 1.17 mmol) in anhydrous dichloromethane (15 mL) was added oxalyl chloride (2.35 mL of a 2.0 M solution in dichloromethane, 4.7 mmol) and D M F (3 uL). The reaction was stirred at room temperature for 2 h, when the evolution of CO and C 0 ceased. The solvent was removed in vacuo and the residue 2  placed under high vacuum (<1 Torr) to remove the last traces of oxalyl chloride. The crude acid chloride was taken up in dichloromethane (8 mL) and this solution was added  126  Experimental  Chapter 5  to a cooled (-23 °C) suspension of aluminum trichloride (700 mg, 5.2 mmol) in dichloromethane (10 mL) over ten minutes. The reaction was stirred in the cold for 3 h and allowed to warm to room temperature and stir overnight. After dilution with dichloromethane (50 mL) and quenching with water (20 mL), the organic layer was washed successively with saturated aqueous sodium carbonate (15 mL), water (15 mL), and brine (15 mL), followed by drying (MgSO^) and removal of the solvent in vacuo. Silica gel chromatography (Chromatotron, 2% E t 0 in petroleum ether) afforded the 2  ketone 5 (269 mg, 77%) as a white solid.  mp: 89-90 °C (EtOAc)  U N M R (400 MHz, CDC1 ): 5 1.53 (br s, IH), 1.56 (br s, IH), 1.66-1.83 (br m, 4H),  l  3  1.85-2.04 (br m, 6H), 2.80 (m, 2H), 3.18 (s, 2H, CH Ph), 7.30 (dt, J= 0.7, 7.3 Hz, 2  IH), 7.38 (d, J= 7.6 Hz, IH), 7.52 (dt, 7 = 1.1, 7.6 Hz, IH), 7.68 (d,J= 7.6 Hz, IH).  1 3  C N M R (100 MHz, CDCI3): 5 26.86 (-ve), 27.34 (-ve), 31.95, 33.97 (-ve), 35.67, 38.71, 40.60, 54.64, 124.02 (-ve), 125.94 (-ve), 127.11 (-ve), 134.23 (-ve), 136.86, 151.26, 209.63.  IR(KBr pellet): 1692, 1609, 1451, 952, 776, 728 cm" . 1  U V / VIS (6.90 x 10" M , MeCN): 294 (2480), 331 (70) nm (M^cm" ). 4  1  H R M S (EI) calcd for C i H O 252.1514, found 252.1516. 8  2 0  Anal. Calcd: C, 85.67; H , 7.99. Found: C, 85.39; H , 8.01.  127  Chapter 5  This structure was confirmed by X-ray crystallographic analysis:  Habit Space group  colourless plates  P2 lc x  a, A  6.7952(6)  b,A  6.7557(8)  c, A  28.909(3)  cc(°)  90  P(°)  92.94(1)  Y(°)  90  Z  4  R  0.053  128  Experimental  Experimental  Chapter 5  5.2.2 Preparation of the Six-Membered Adamanyl Spiroketones 6 and 70 Methyl 2-(2-Phenvlethvl)tricvclor3.3.1 • 1 ' ldecane-2-carboxvlate (55) 3 7  55  To a cold (-78 °C) solution of L D A (1.9 mmol; prepared from 2.1 mmol DIPA arid 1.9 mmolrc-butyllithium)in THF (30 mL) was added a solution of ester 62 (290 mg, 1.5 mmol) in THF (5 mL) over ten minutes. The reaction was stirred in the cold for 1.5 h, followed by the addition of D M P U (360 uL, 3.0 mmol) and further stirring for ten minutes. 2-(Bromoefhyl)benzene (450 uL, 3.0 mmol) was added over two minutes and the reaction mixture stirred for 5 h in the cold before warming to room temperature and stirring overnight. The reaction was quenched with 5% HC1 (25 mL) and taken up in E t 0 (150 mL). The mixture was extracted further with E t 0 (2 x 50 mL) and the 2  2  combined organic extracts washed successively with water (3 x 25 mL) and brine (25 mL), then dried (MgSCU), and concentration in vacuo. Silica gel chromatography (3% E t 0 in petroleum ether) gave 55 (415 mg, 89%) as a colourless oil. 2  !  H N M R (400 MHz, CDCI3): 8 1.60 (br s, IH), 1.63 (br s, IH), 1.69 (br s, 3H), 1.73 (br s, IH), 1.84 (br m, 4H), 1.99 (m, 4H), 2.18 (br s, 2H), 2.42 (m, 2H, CH Ph), 3.71 2  (s, 3H, CH ), 7.14 (m, 3H), 7.26 (m, 2H). 3  1 3  C N M R (75 MHz, CDC1 ): 8 26.98 (-ve), 27.44 (-ve), 30.15, 32.07 (-ve), 32.15, 35.59, 3  37.87, 38.35, 51.22 (-ve), 52.21, 125.75 (-ve), 128.27 (-ve), 128.34 (-ve), 142.39, 177.21.  129  Experimental  Chapter 5  IR(neat): 1729, 1603, 1455, 1250, 1197, 1152, 1099, 700 cm" . 1  H R M S (DCI, NH-3 + CH ) calcd for C oH 02 (M+H) 299.2011, found 299.2009. +  4  2  27  Anal. Calcd for C H O : C, 80.50; H , 8.78. Found: C, 80.72; H , 8.82. 2 0  2 6  2  3,4-Dihvdrospiro rnaphthalene-2( IH). 2'-tricvclo\3 3.1.1 ' 1 decani -1 -one (6) 3 7  6  To a cold (-78 °C) solution of ester 55 (565 mg, 1.9 mmol) in anhydrous dichloromethane (5 mL) was added boron trichloride (9.5 mL of a 1.0 M solution in dichloromethane, 9.5 mmol) over five minutes. The reaction was warmed slowly to 0 °C and stirred for 3 h after which it was poured onto crushed ice (10 g). Dichloromethane (125 mL) was added, and the organic layer washed successively with 5% aqueous sodium carbonate (25 mL), water (2 x 25 mL), and brine (50 mL), followed by drying of the organic layer (MgS04) and removal of the solvent in vacuo. Silica gel chromatography (5% E t 0 in petroleum ether) afforded the ketone 6 (491 mg, 97%) as a white solid. 2  mp: 99-100 °C (Et 0 / petroleum ether) 2  !  H N M R (400 MHz, CDC1 ): 5 1.58 (br s, IH), 1.62 (br m, 2H), 1.67 (br m, 3H), 1.86 (br 3  m, 2H), 1.97 (br s, 2H), 2.07 (br s, IH), 2.10 (br s, IH), 2.17 (br s, IH), 2.21 (m,  130  Experimental  Chapter 5  3H), 2.95 (t, J= 6.2 Hz, 2H, CH Ph), 7.14 (d, J= 7.6 Hz, IH), 7.24 (t, J= 1.6 Hz, 2  IH), 7.38 (t, J= 7.6 Hz, IH), 7.77 (d, J= 7.6 Hz). 1 3  C N M R (100 MHz, CDC1 ): 5 24.26, 27.75, 27.94, 31.14, 31.55, 33.10, 34.18, 38.62, 3  49.58, 126.41, 127.58, 127.93, 132.01, 134.32, 141.95,205.91.  IR (KBr pellet): 1686, 1603, 1217, 938, 902, 757, 740 cm" . 1  U V / V I S ( M e C N , 1.16 x 10" M): 285 (1230), 331 (80) nm (M^cm" ). 3  1  H R M S (EI) calcd for C i H 0 266.1671, found 266.1671. 9  2 2  Anal. Calcd: C, 85.67; H , 8.32. Found: C, 85.41; H , 8.39.  This structure was confirmed by X-ray crystallographic analysis:  Habit Space group  colourless cubes C2/c 17.788(2) 12.827(2) 12.960(2)  a(°)  90 104.178(7)  Y(°)  90  Z  8  R  0.050  131  Chapter 5  Experimental  Spirornaphthalene-2(l//). 2'-tricvclor3.3.1.1 ' ldecanl-l-one (70) 3 7  70  To a solution of ketone 6 (1.32g, 5.0 mmol) in carbon tetrachloride (25 mL) was added N-bromosuccinimide (900 mg, 5.5 mmol) and dibenzoyl peroxide (15 mg). The suspension was refluxed for 1.5 h followed by dilution with chloroform (100 mL). The organic layer was washed successively with water (3 x 15 mL) and brine (25 mL) followed by drying (MgSCv) and removal of the solvent in vacuo. The crude benzylic bromide was taken up in THF (40 mL). To this solution was added D B U (2.2 mL, 14.7 mmol) and the reaction was stirred for 40 h at room temperature. Water (30 mL) and Et20 (150 mL) were introduced and the organic layer washed successively with 5% HCI (2 x 15 mL), water (3 x 40 mL) and brine (50 mL). Following drying (MgS04) and removal of the solvent in vacuo,  the product was recrystallized from M e C N to yield  enone 70 (632 mg, 48%) as a white powder.  mp: 148-150 °C (MeCN)  J  H N M R (400 MHz, CDC1 ): 8 1.58-1.73 (br m, 6H), 1.88 (br m, 2H), 2.07 (br s, 2H), 3  2.19 (br m, 2H), 2.37 (br m, 2H), 6.47 (d,J= 10.0 Hz, IH), 6.69 (d,J= 10.0 Hz, IH), 7.06 (d, J= 7.3 Hz, IH), 7.23 (m, IH), 7.42 (td, / = 1.3, 7.6 Hz, IH), 7.62 (d, J = 7 . 0 H z , IH).  132  Experimental  Chapter 5  1 3  C N M R (100 MHz, CDC1 ): 5 27.06 (-ve), 27.65 (-ve), 34.02, 34.12, 34.28 (-ve), 38.61, 3  54.19, 124.56 (-ve), 125.50 (-ve), 126.29 (-ve), 127.74 (-ve), 132.59, 132.72 (-ve), 136.72, 138.48 (-ve), 208.83.  I R ( K B r pellet): 1687, 1621, 1598, 1451, 1202, 766 cm" . 1  U V / VIS (1.20 x 10" M , MeCN): 318 (1350), 356 (740) nm (M^cm" ). 3  1  H R M S (EI) calcd for C i H O 264.1514, found 264.1513. 9  2 0  Anal. Calcd: C, 86.32; H , 7.63. Found: C, 86.12; H , 7.57.  This structure was confirmed by X-ray crystallographic analysis:  Habit Space group a,  A  colourless prisms P2i/n  6.7536(8)  b,k  19.359(3)  c,k  10.638(1)  a(°)  90  P(°)  98.47(1)  Y(°)  90  Z  4  R  0.048  133  Chapter 5  Experimental  5.2.3 Preparation of the S even-Member ed Adamantyl Spiroketone 7 Methyl 2-(2-Propenvl)tricvclor3.3.1.1 ' ldecan-2-carboxvlate (63) 3 7  63  To a cold (-78 °C) solution of L D A (7.4 mmol; prepared from 7.9 mmol DIPA and 7.4 mmol «-butyllithium) in THF (80 mL) was added ester 62 (1.1 g, 5.7 mmol) in THF (15 mL) over ten minutes. After stirring in the cold for 1.5 h, an additional portion of «-butyllithium (3.9 mL of a 1.6 M solution in hexanes, 6.2 mmol) was added over ten minutes, and the reaction kept cold for 1 h. D M P U (1.37 mL, 11.3 mmol) was introduced, and the solution stirred for ten minutes followed by the dropwise addition of allyl bromide (2.74 g, 22.7 mmol). The reaction was stirred for 5 h at -78 °C, then warmed slowly and allowed to stir overnight at room temperature. The reaction was quenched with 5% HC1 (25 mL), taken up in Et20 (200 mL) and washed successively with water (2 x 25mL) and brine (50 mL). The organic layer was dried (MgSCu) and the solvent removed in vacuo. Silica gel chromatography (5% Et20 in petroleum ether) afforded methyl 2-(2-propenyl)adamantane-2-carboxylate (63) (1.22 g, 92%) as a colourless oil.  *H NMR (400 MHz, CDC1 ): 5 1.58 (br m, IH), 1.61 (br m, IH), 1.67 (br m, 4H), 1.80 3  (br m, 4H), 1.96 (br s, IH), 1.99 (br s, IH), 2.09 (br s, 2H), 2.43 (d, J= 7.4 Hz, 2H, CH2CH=CH ), 3.63 (s, 3H, C H ) , 4.98 (m, 2H, CH=CTJ2), 5.64 (m, IH, 2  3  CH=CH ). 2  134  Experimental  Chapter 5  1 3  C N M R (100 MHz, CDC1 ): 5 27.08 (-ve), 27.40 (-ve), 31.98 (-ve), 32.14, 35.56, 38.43, 3  40.23, 50.97 (-ve), 52.81, 116.95, 133.65 (-ve), 176.66.  IR(neat): 1731, 1640, 1462, 1435, 1211, 1131, 1100, 994 cm" . 1  H R M S (EI) calcd for O5H22O2 234.1620, found 234.1621.  Anal. Calcd: C, 76.88; H , 9.46. Found: C, 76.65; H , 9.46.  2-rHvdroxvmethvl)-2-(2-propenvl)tricvclo[3.3.1.1 ' ]decane (64) 3 7  64  To a solution of ester 63 (1.9 g, 8.0 mmol) in THF (100 mL) was added L A H (24 mL of a 1.0 M solution in THF, 24 mmol). The reaction was heated slowly, and allowed to reflux for 18 h. The reaction was cooled, quenched carefully with saturated aqueous sodium sulfate (5 mL) and saturated aqueous ammonium chloride (5 mL), dried (MgSC^), and the solvent removed in vacuo. Silica gel chromatography (20% E t 0 in 2  petroleum ether) provided the alcohol 64 (1.36 g , 83%) as a white powder.  mp: 49-50 °C  J  H N M R (400 MHz, CDCI3): 5 1.34 (s, IH), 1.54 (br s, 2H), 1.56 (br s, 2H), 1.61 (br s, 2H), 1.68 (br s, 2H), 1.85 (m, 2H), 1.98 (br s, IH), 2.01 (br s, IH), 2.04 (br s, IH),  135  Experimental  Chapter 5  2.08 (br s, IH), 2.40 (d, J= 7.5 Hz, 2H, CH2CH=CH ), 3.75 (s, 2H, CH^OH), 5.10 2  (m, 2H, CH=CH2), 5.88 (m, IH, CH=CH ). 2  , 3  C N M R (75 MHz, CDC1 ): 5 27.88 (-ve), 28.13 (-ve), 31.16 (-ve), 32.64, 32.85, 37.14, 3  39.59, 42.30, 65.13, 116.84, 135.59 (-ve).  IR (KBr): 3256 (br), 1820, 1637, 1476, 1461, 1446, 1032, 988, 908 cm' . 1  H R M S (DCI, N H + CH ) calcd for C i H 0 (M+H) 207.1749, found 207.1750. +  3  4  4  2 3  Anal. Calcd for C H 0 : C, 81.50; H, 10.75. Found: C, 81.34; H , 10.85. H  2 2  2-(2-Propenvl)tricvclor3.3.1.1 ' ldecane-2-carboxaldehyde (65) 3 7  O.  H  65  A mixture of Celite  545 (6g) and PCC (5.16 g, 23.9 mmol) was ground in a  mortar and pestle until homogeneous. This solid was suspended in a solution of alcohol 64 (3.18 g, 15.4 mmol) in anhydrous dichloromethane (100 mL) and stirred for 2.5 h at room temperature. Following the addition of anhydrous E t 0 (400 mL), the reaction 2  mixture was filtered through a column of Celite® 545 on Florisil® and the remaining solids triturated well with anhydrous Et 0. Solvent removal in vacuo was followed by 2  silica gel chromatography (3% E t 0 in petroleum ether) to give the aldehyde 65 (2.81 g, 2  89%) as a pale yellow oil.  136  Experimental  Chapter 5  !  H N M R (400 MHz, CDCI3): 5 1.57-1.78 (br m, 7H), 1.82 (br m, IH), 1.87 (br m, IH), 1.96-2.04 (br m, 3H), 2.36 (d, J= 7.7 Hz, IH), 5.02 (m, 2H, CH^CHj), 5.58 (m, IH, CH=CH ), 9.43 (s, IH, CHO). 2  1 3  C N M R (100 MHz, CDCI3): § 27.58 (-ve), 27.59 (-ve), 30.60, 31.79, 34.57, 36.71,  38.06, 54.03, 118.03 (-ve), 132.02, 207.43 (-ve),  IR (neat): 2669, 2698, 1728, 1640, 1460, 994, 915, 859 cm . -1  H R M S (EI) calcd for C i H O 204.1514, found 204.1512. 4  2 0  Dienol 66  66  To a suspension of Mg turnings (250 mg, 10.5 mmol) in THF (10 mL) was added iodine (30 mg) and 1,2-dibromoefhane (50 uL). The mixture was gently heated until evolution of ethylene ceased and the solution became colourless. 2-Bromostyrene (915 mg, 5.0 mmol) was added slowly so as to maintain a gentle reflux, and the reaction stirred for 1 h. Aldehyde 65 (500 mg, 2.45 mmol) in THF (10 mL) was introduced dropwise and the reaction stirred for 2 h at room temperature. The reaction was diluted with E t 0 (75 2  mL) and 5% HC1 (10 mL) and washed successively with water (3x15 mL) and brine (20 mL). The organic layer was dried (MgS0 ) and the solvent removed in vacuo. Silica gel 4  chromatography (7% E t 0 in petroleum ether) provided alcohol 66 (541 mg, 72% from 2  65) as a colourless oil.  137  Experimental  Chapter 5  ' i i N M R (400 MHz, CDCI3): 5 1.28 (br s, IH), 1.43 (m, IH), 1.57 (m, 2H), 1.70-1.85 (br m, 4H), 1.99 (br m, 2H), 2.10-2.27 (br m, 4H), 2.46 (d, J = 12 Hz, IH), 2.60 (d, J = 6.4 Hz, IH, CH2CH=CH ), 2.64 (d, J = 6.4 Hz, IH, CH2CH=CH ), 4.95 (m, 2  2  2H), 5.25 (dd, J= 1.3, 11.0 Hz, IH), 5.50 (dd, J= 1.1, 17.3 Hz, IH), 5.71 (s, IH, CHOH), 5.84 (m, IH), 7.19 (dd, J= 11, 17.3 Hz, IH), 7.25 (m, 2H), 7.38 (m, IH), 7.66 (m, IH).  1 3  C N M R (75 MHz, CDCI3): 5 27.24 (-ve), 27.88 (-ve), 30.63 (-ve), 31.60 (-ve), 32.83, 33.09, 33.14, 34.75, 35.16, 39.63, 45.95, 72.95 (-ve), 115.75, 115.81, 126.98 (ve), 127.31 (-ve), 127.45 (-ve), 129.05 (-ve), 136.86 (-ve), 137.07 (-ve), 137.85, 140.31.  IR(neat): 3457 (br), 1826, 1631, 1567, 1480, 1463, 1013, 909, 761, 732 cm" . 1  H R M S (DCI, N H + C H ) calcd for C22H32NO (M+NH ) 326.2484, found 326.2485. +  3  4  4  Anal. Calcd for C22H28O: C, 85.66; H , 9.15. Found: C, 85.75; H , 9.23.  Dienone 56  56  138  Experimental  Chapter 5  A mixture of Celite® 545 (1 g) and PCC (740 mg, 2.9 mmol) was ground in a mortar and pestle until homogeneous. This solid was suspended in a solution of alcohol 66 (450 mg, 1.46 mmol) in anhydrous dichloromethane (75 mL) and stirred for 3 h at room temperature. Following the addition of anhydrous E t 0 (150 mL), the reaction 2  mixture was filtered through a column of Celite® 545 on Florisil® and the remaining solids triturated well with anhydrous Et 0. Solvent removal in vacuo was followed by 2  silica gel chromatography (5% E t 0 in petroleum ether) to give the ketone 56 (386 mg, 2  86%) as a colourless oil.  *H N M R (400 MHz, CDC1 ): 6 1.5-1.7 (m, 8H), 1.76 (brm, IH), 1.83 (brm, IH), 2.11 3  (d, J= 12.5 Hz, 2H), 2.33 (br s, 2H), 2.78 (d, J= 7.3 Hz, 2H, C F L C H ^ H ^ , 5.05.1 (m, 2H), 5.28 (dd, J= 1.2, 9.0 Hz, IH), 5.64 (dd, J= 1.3, 17.4 Hz, IH), 5.73  (m, IH), 7.04 (dd,J= 11.0, 17.4 Hz, IH), 7.20 (dt,J= 1.1, 7.7, IH), 7.37 (dt,J= 0.8, 7.1Hz, IH), 7.55 (dd, .7=1.0, 7.7 Hz, IH), 7.62 (d, .7=7.6 Hz, IH).  1 3  C N M R (75 MHz, CDCI3): 8 26.69 (-ve), 27.30 (-ve), 32.41, 32.58 (-ve), 34.95, 38.36, 39.79, 57.37, 116.38, 117.15, 125.16 (-ve), 126.22 (-ve), 127.40 (-ve), 129.92 (ve), 133.58 (-ve), 135.12 (-ve), 137.65, 138.41, 209.96.  IR(neat): 1669, 1639, 1597, 1475, 1462, 1213, 1101, 995, 912, 771 cm" . 1  H R M S (EI) calcd for C H 0 306.1983, found 306.1990. 2 2  2 6  Anal. Calcd: C, 86.23; H , 8.55. Found: C, 86.16; H , 8.57.  139  Experimental  Chapter 5  Spiro[6//-benzocvcloheptene-6,2'4ricyclor33.1.1 ' 1decanl-5(7//)-one 3 7  (68)  68 To a solution of ketone 56 (250 mg, 0.82 mmol) under an atmosphere of argon in degassed, anhydrous dichloromethane (75 mL) was added a solution of Grubbs' catalyst (18 mg, 3 mol%) in degassed, anhydrous dichloromethane over ten minutes. A light orange colour replaced the initial purple colour, and the reaction was allowed to stir at room temperature for 12 h. Silica gel (1 g) and triethylamine (500 uL) were added and the mixture stirred for 1 h. The suspension was filtered through Celite® 545 and the solvent removed in vacuo. Purification by silica gel chromatography (10% E t 0 in 2  petroleum ether) afforded the enone 68 (210 mg, 92%) as a pale orange solid. Further purification by recrystallization from EtOAc provided a colourless product.  mp: 129-131 °C (EtOAc / petroleum ether)  *H N M R (400 MHz, CDCI3): 5 1.50-1.75 (br m, 10H), 1.82 (br m, 2H), 2.19 (br s, 2H), 2.63 (dd, J = 1.7, 5.2 Hz, 2H, CTJjCHKTl), 5.82 (dt, J = 5.2, 12.1 Hz, IH, CH CH=CH), 6.37 (d, J= 12.1 Hz, IH, CH CH=CH), 7.11 (d, J= 7.5 Hz, IH), 2  2  7.26 (m, IH), 7.38 (td, J = 1.4, 7.5 Hz, IH), 7.53 (dd,  1 3  1.0, 7.6 Hz, IH).  C N M R (100 MHz, CDCI3): 5 27.33, 27.74, 31.39, 32.71, 34.94, 35.47, 38.20, 52.17, 127.25, 127.46, 129.41, 130.07, 130.77 (2 acc. eq.), 133.08, 137.90, 209.62.  140  Experimental  Chapter 5  IR(KBr): 1671, 1596, 1460, 1421, 1269, 776, 765, 755 cm" . 1  H R M S (EI) calcd for C20H22O 278.1671, found 278.1671.  Anal. Calcd: C, 86.29; H , 7.97. Found: C, 86.00; H , 7.81.  This structure was confirmed by X-ray crystallographic analysis:  Habit Space group a,  A  colourless prisms P2i2i2i 12.320(4)  b,k  16.226(6)  c,k  7.352(3)  a(°)  90  P(°)  90  Y(°)  90  Z  4  R  0.044  141  Experimental  Chapter 5  8,9-Dihvdrospiro[6/j -benzocvcloheptene-6,2'-tricvclo[3.3.l.l ' ldecan1-5(7/f)-one (7) r  3 7  7  A suspension of 10% palladium on charcoal (15 mg) and ketone 68 (67 mg, 0.241 mmol) in EtOAc (5 mL) was placed under an atmosphere of FL.. The mixture was stirred for 1 h and filtered through Celite® 545. Removal of the solvent in vacuo provided analytically pure ketone 7 (65 mg, 96%) as a white solid.  mp: 143-144 °C (EtOAc)  J  H N M R (400 MHz, CDC1 ): 5 1.48-1.65 (br m, 6H), 1.76 (m, 4H), 1.89 (m, 2H), 1.943  2.08 (br m, 6H), 2.85 (d, J= 5.5 Hz, 2H, CH Ph), 7.08 (d, J= 7.2 Hz, IH), 7.24 2  (m, 2H), 7.31 (dd, J= 1.5, 7.2 Hz, IH).  1 3  C N M R (100 MHz, CDCI3): 5 23.63, 27.21 (-ve), 27.41 (-ve), 32.31, 32.80 (-ve), 34.92, 35.94, 36.43, 38.36, 56.04, 125.97 (-ve), 128.16 (-ve), 128.58 (-ve), 129.30 (-ve), 137.71, 141.46,213.33.  IR (KBr pellet): 1683, 1597, 1462, 1444, 1431, 1257, 952, 742, 635 cm" . 1  U V / V I S (1.06 x 10" M , MeCN): 274 (600), 316 (160) nm (M-'cm" ). 3  1  H R M S (EI) calcd for C20H24O 280.1827, found 280.1833.  142  Chapter 5  Anal. Calcd: C, 85.67; H , 8.63. Found: C, 85.51; H , 8.56.  This structure was confirmed by X-ray crystallographic analysis:  Habit Space group  colourless cubes  PI  a, A  10.898(4)  b,A  11.213(2)  c, A  7.218(6)  a(°)  99.52(3)  P(°)  109.01(4)  Y(°)  62.27(2)  Z  2  R  0.048  143  Experimental  Experimental  Chapter 5  5.2.4 Preparation of the Eight-Membered Adamantyl Spiroketone 8  2-Propenylbromobenzene (184)  Br  ^ V 184  The procedure of Boymond et al. was followed: 2-bromoiodobenzene  (4.57  g,  16.1  mmol)  in  109  To a cold (-25 °C) solution of  T H F (75  mL)  was  added  isopropylmagnesium chloride (8.9 mL of a 2.0 M solution in E t 0 , 17.8 mmol) over five 2  minutes. Stirring was continued in the cold for 1 h after which time allyl bromide (1.6 mL,  17.8 mmol) was added. After 30 minutes the reaction was warmed to room  temperature and stirred for 1 h. The reaction was quenched overnight with an aqueous solution (10 mL) containing 5% ammonium hydroxide and 5% ammonium chloride. Extraction with E t 0 (3 x 75 mL) was followed by successive washing of the combined 2  organic extracts with 5% HC1 (3 x 20 mL), 5% aqueous sodium bicarbonate (25 mL), water (2 x 25 mL), and brine (50 mL). After drying ( M g S C u ) , and removal of the solvent in vacuo, aryl bromide 184 (2.97 g, 93%) was isolated as a colourless liquid. The product was of sufficient purity to use in subsequent reactions.  !  H NMR (400 MHz, CDCI3): 8 3.50 (dt, J= 1.3, 8.5 Hz, 2H), 5.10 (m, 3H), 5.97 (m, IH), 7.06 (m, IH), 7.23 (m, 2H), 7.54 (m, IH).  1 3  C NMR (75 MHz, CDCI3): 5 40.17, 116.53, 124.54, 127.45, 127.79, 130.40, 132.72, 135.53, 139.39.  LRMS (EI) (m/z): 198 ( M { Br}, 35), 196 ( M { Br}, 37), 117 (100). +  79  +  144  81  Chapter 5  Experimental  Dienol 67  67  To a suspension of Mg turnings (1.5 g, 62.5 mmol) in THF (20 mL) was added iodine (50 mg) and 1,2-dibromoethane (100 uL). The mixture was gently heated until evolution of ethylene ceased and the solution became colourless. Aryl bromide 184 (2.0 g, 10.2 mmol) was added slowly so as to maintain a gentle reflux, and the reaction stirred for 1 h. Aldehyde 65 (1.16 g, 5.7 mmol) in THF (5 mL) was added dropwise and the reaction stirred for 2 h at room temperature. The reaction was diluted with Et20 (75 mL) and 5% HCI (10 mL) and washed successively with water (2 x 25 mL) and brine (20 mL). The organic layer was dried (MgSCXt) and the solvent removed in vacuo. Silica gel chromatography (7% E t 0 in petroleum ether) provided the alcohol 67 (1.64 g, 90% from 2  65) as a colourless oil.  *H N M R (400 MHz, CDCI3): 5 1.42 (br s, IH), 1.48 (dq, J = 2.5, 13.3 Hz, IH), 1.63 (m, 2H), 1.73 (m, 3H), 1.84 (br m, IH), 1.97 (br m, IH), 2.06 (m, IH), 2.15 (m, IH), 1.19-2.40 (m, 5H), 2.66 (dd, J= 65, 6.2 Hz, IH), 3.54 (dt, J= 1.4, 6.1 Hz, 2H), 4.90-5.08 (m, 4H), 5.64 (s, IH, CHOH), 5.85 (m, IH), 5.98 (m, IH), 7.19 (m, 3H), 7.62 (m, IH).  1 3  C N M R (75 M H z , CDCI3): 5 27.21, 27.85, 30.-80, 31.98, 32.94, 33.15 (2 acc. eq.), 34.39, 35.40, 37.91, 39.63, 45.69, 73.36, 115.72 (2 acc. eq.), 125.78, 127.22, 129.38, 130.52, 137.01, 138.17 (2 acc. eq.), 140.97.  145  Experimental  Chapter 5  IR (neat): 3470 (br), 1824, 1635, 1602, 1446, 1463, 996, 910, 739 cm" . 1  HRMS.(El) calcd for C23H30O 322.2297, found 322.2295.  Anal. Calcd: C, 85.66; H , 9.38. Found: C, 85.43; H , 9.41.  Dienone 57  A mixture of Celite  545 (8g) and PCC (1.0 g, 4.7 mmol) was ground in a mortar  and pestle until homogeneous. This solid was suspended in a solution of alcohol 67 (1.0 g, 3.1 mmol) in anhydrous dichloromethane (80 mL) and stirred for 1.5 h at room temperature. Following the addition of anhydrous E t 0 (150 mL), the reaction mixture 2  was filtered through a column of Celite® 545 on Florisil® and the remaining solids triturated well with anhydrous Et 0. Solvent removal in vacuo was followed by silica gel 2  chromatography (5% E t 0 in petroleum ether) to give the ketone 57 (924 mg, 93%) as a 2  colourless oil.  *H N M R (400 MHz, CDCI3): 8 1.51-1.70 (br m, 8H), 1.77 (br m, IH), 1.83 (br m, IH), 2.10 (s, IH), 2.13 (s, IH), 2.34 (s, 2H), 2.80 (d, J= 7.4 Hz, 2H), 3.47 (d, J= 6.8  146  Experimental  Chapter 5  Hz, 2H), 5.08 (m, 4H), 5.75 (m, IH), 6.04 (m, IH), 7.15 (m, IH), 7.33 (m, 2H), 7.57 (d, J = 7 . 8 H z , IH).  1 3  C N M R (75 MHz, CDC1 ): 5 26.63, 27.19, 32.34, 32.49, 34.90, 37.45, 38.31, 39.75, 3  57.25, 115.85, 117.00, 124.64, 125.16, 129.68, 131.19, 133.57, 137.62, 139.01, 139.60,210.02.  IR(neat): 1669, 1638, 1599, 1572, 1478, 1461, 1214, 1101, 995, 912, 745 cm" . 1  H R M S (CI, isobutane) calcd for C23H29O (M+H) 321.2218, found 321.2217. +  Anal. Calcd for C23H28O: C, 86.20; H, 8.81. Found: C, 86.34; H , 8.90.  Spiror67/-benzocvclooctene-6.2'-tricvclor3.3.1.1 ' 1decanl-5( 107/)-one 3 7  ,  (69)  69  To a solution of ketone 57 (410 mg, 1.28 mmol) under an atmosphere of argon in degassed, anhydrous dichloromethane (100 mL) was added a solution of Grubbs catalyst  110  (53 mg, 5 mol%) in degassed, anhydrous dichloromethane over ten minutes. A  light orange colour replaced the initial purple colour, and the reaction was allowed to stir at room temperature for 2 h. Silica gel (2 g) and triethylamine (1 mL) were added and the mixture stirred for 3 h. The suspension was filtered through Celite® 545 and the organic layer washed successively with 5% aqueous sodium bicarbonate (3x15 mL), 5% HCI (3  147  Experimental  Chapter 5  x 15 mL), water (3 x 20 mL), and brine (50 mL). The organic layer was dried (MgS04) and the solvent removed in vacuo to afford the enone 69 (336mg, 90%) as a pale yellow oil.  *H N M R (400 MHz, CDC1 ): 5 1.50-1.80 (br m, 6H), 1.80-2.00 (br m, 5H), 2.10 (br m, 3  IH), 2.28 (br m, 2H), 2.50 (m, 2H), 3.48 (m, 2H), 5.68 (m, IH), 5.79 (m, IH), 7.10-7.28 (m,4H).  1 3  C N M R (100 MHz, CDCI3): § 27.19, 27.63, 30.98 (br), 32.26, 32.18 (br), 32.26 (br), 33.52 (br), 34.67 (br), 35.00, 36.22 (br), 38.58, 59.76, 125.40, 126.33, 126.90, 128.39, 129.48, 129.64, 134.94, 141.39, 213.58. Slow conformational exchange at room temperature has broadened and split some of the carbon signals.  IR(neat): 1695, 1678, 1459, 1215, 1101,947, 754 cm" . 1  H R M S (EI) calcd for C i H 0 292.1827, found 292.1828. 2  2 4  Anal. Calcd: C, 86.26; H , 8.27. Found: C, 86.01; H , 8.28.  148  Experimental  Chapter 5  9J0-Dihvdrospiror6#^  (8)  8 A suspension of 10% palladium on charcoal (100 mg) and ketone 69 (1.53 g, 5.2 mmol) in EtOAc (20 mL) was placed under an atmosphere of H . The mixture was stirred 2  for 1 h and filtered through Celite® 545. Removal of the solvent  in vacuo provided  analytically pure ketone 8 (1.48 g, 97%) as a white solid.  mp: 118-119 °C (MeCN)  H N M R (400 MHz, CDC1 ): 5 1.30-1.48 (br m, 3H), 1.50-1.79 (br m, 6H), 1.80-2.10 (br  l  3  m, 8H), 2.28 (br s, 2H), 2.56 (br m, 2H), 2.86 (br m, IH), 7.07 (m, IH), 7.13 (m, 2H), 7.22 (m, IH).  1 3  C  N M R (75 MHz, DMSO-J ): 5 21.28, 26.47, 27.47, 29.09, 31.24 (br), 32.10, 6  32.43(br), 32.54 (br), 32.92, 33.38 (br), 36.06 (br), 38.13, 36.85, 123.27, 124.99, 128.37, 129.94, 138.75, 140.12,213.32.  I R ( K B r pellet): 1681, 1477, 1441, 1211,935,754 cm" . 1  U V / VIS (1.05  x 10" M , MeCN): 3  266 (380), 313 (105) nm  H R M S (EI) calcd for C i H 0 294.1984, found 294.1983. 2  2 6  149  (M'W ). 1  Chapter 5  Anal. Calcd: C, 85.67; H , 8.90. Found: C, 85.50; H , 9.00.  This structure was confirmed by X-ray crystallographic analysis:  Habit Space group  colourless prisms  Pna2\  a, A  19.318(4)  b,A  8.282(2)  c, A  10.045(1)  a(°)  90  P(°)  90  Y(°)  90  Z  4  R  0.041  150  Experimental  Experimental  Chapter 5  5.3 Synthesis of the Macrocyclic Aminoketones 12,14, and 16 and Their Salts  5.3.1 Preparation of the Twelve-Membered Aminoketone 12 Diethyl 6,6'-Methvliminodihexanoate (99)  CQ Et  EtQ C  2  2  i  This aminodiester was synthesized according to a procedure modified from that of Leonard et a/.  111  To a mixture of methylammonium chloride (9.2 g, 136 mmol), ethyl 6-  bromohexanoate (64.1 g, 298 mmol), and potassium iodide (45 g, 271 mmol) in anhydrous M e C N (500 mL) was added DIPEA (70 mL, 402 mmol) over 4 h. After stirring overnight at room temperature, the reaction was heated slowly to reflux. After 40 h the reaction was cooled and diluted with water (100 mL) and saturated aqueous potassium carbonate (200 mL). The reaction was extracted with Et20 (3 x 300 mL), and the combined organic extracts dried (MgSCU) and concentrated in vacuo to yield 99 (25.4 g, 62%) as a yellow oil. This compound was of sufficient purity to use in subsequent reactions.  ' H NMR (200 MHz, CDC1 ): 5 1.19 (t, J= 7.1 Hz, 6H, O C H C H ) , 1.15-1.68 (m, 8H), 3  2  3  2.13 (s, IH, N-CH ), 2.24 (t, J= 7.3 Hz, 8H), 4.06 (q, J= 7.1 Hz, 4H, OCH ). 3  , 3  2  C NMR (50 MHz, CDC1 ): 5 14.2, 24.9, 27.0, 27.1, 34.3, 42.2, 57.6, 60.1, 173.7. 3  151  Experimental  Chapter 5  7-Methvl-7-azacyclododecanone (12)  i  Me  12  A procedure modified from that of Spanka et al. was employed. To a refluxing 45  solution of potassium tert-butoxide (20.0 g, 178 mmol) in anhydrous xylenes (750 mL) was added aminodiester 99 (13.0 g, 45.3 mmol) in anhydrous xylenes (50 mL) over 40 h via syringe pump. Heating was continued for an additional 12 h at which time the reaction was cooled in an ice bath. Water (100 mL) and cone. HCI (200 mL) were added and the organic layer extracted successively with cone. HCI (6 x 75 mL) and 1:1 MeOH / water (200 mL). The combined aqueous extracts were reflux ed for 24 h, during which time carbon dioxide was evolved. The volume was reduced to ca. 200 mL by distillation, and the reaction cooled. Careful addition of 50% aqueous potassium hydroxide (final pH 11) was followed by extraction into Et20 (10 x 100 mL). The combined organic extracts were dried (MgS04) and concentrated in vacuo. Sublimation (60 °C, 3 Torr) provided ketone 12 (2.75 g, 31%) as a waxy white solid. Recrystallization of the sublimation residue from E t 0 provided aminoketone dimer 101 (1.12 g, 13%) as colourless plates. 2  Characterization of 12 mp: 33 °C (lit. value 33 °C) 45  ' H N M R (200 MHz, CDC1 ): 5 1.33 (m, 8H), 1.66 (m, 4H), 2.07 (s, 3H, N-CH ), 2.20 3  3  (m, 4H), 2.40 (m, 4H).  1 3  C N M R (50 MHz, CDC1 ): 5 22.71, 23.70, 25.61, 40.52, 43.38 (-ve), 54.53, 212.82. 3  152  Experimental  Chapter 5  IR(KBr pellet): 2929, 2789, 1705, 1472, 1309, 1142, 1047, 728 cm"  UV / VIS (2.6 x 10" M , n-pentane): 237 (320), 286 (30) nm ( M-i ' W-h ). 3  7.19-Dimethvl-7,19-diazacvclotetraeicosan-1,13-dione (101)  O  Me-N  r  24  A J  N \ -Me  O 101  mp: 80-81 °C (Et 0) 2  !  H NMR (200 MHz, CDCI3): 5 1.22-1.44 (m, 16H), 1.55 (quint, J= 7.2 Hz, 8H), 2.14 (s, 6H, CH ), 2.24 (t, J= 6.7 Hz, 8H), 2.36 (t, J= 7.2 Hz, 8H). 3  13  C NMR (50 MHz, CDCI3): 5 23.62, 26.67, 26.76, 45.53, 42.80, 56.75, 211.56.  IR(KBr pellet): 2935, 2777, 1701, 1459, 1420, 999, 726 cm" . 1  UV / VIS (2.7 x 10"' M , n-pentane): 237 (930), 285 (100) nm ( M ' W ) 1  HRMS (EI) calcd for C24H46N2O2 394.3559, found 394.3559.  Anal. Calcd: C, 73.04; H , 11.75; N , 7.10. Found: C, 73.30; H , 11.66; N , 6.94.  153  Chapter 5  Experimental  5.3.2 Preparation of the Twelve-Membered Aminoketone Salts  Hydrochloride Salt (120)  Into a solution of aminoketone 12 (450 mg, 2.28 mmol) in Et20 (25mL) was bubbled dry HCI gas for two minutes. The solvent was removed in vacuo to give salt 120 (490 mg, 93%) as a white powder.  mp: 182-183 °C  ]  H NMR (200 MHz, CDC1 ): 5 1.37-1.93 (m, 12H), 2.36-2.65 (m, 4H), 2.68 (d, J= 4.7 3  Hz, 3H), 2.80-3.09 (m, 4H), 12.15 (br s, IH, NH).  1 3  C NMR (50 MHz, CDCI3): 8 19.9, 21.1, 24.7, 41.2, 42.0, 51.5, 212.7.  IRfKBr pellet): 2931, 2634, 2596, 2460, 1702, 1475, 1446, 1118, 1022 cm" . 1  Anal. Calcd for C i H N O C l : C, 61.65; H, 10.35; N , 5.99. Found: C, 61.62; H , 10.21; N , 2  24  5.81.  154  Experimental  Chapter 5  (lSVlO-Camphorsulfonate Salt (145)  145  Aminoketone 12 (110 mg, 0.58 mmol) and (1 £)-(+)-10-camphorsulfonic acid (125 mg, 0.54 mmol) were combined in chloroform (5 mL). Petroleum ether was added until the solution became turbid, and the reaction placed in a freezer (-20 °C). After 24 h, crystals of salt 145 (70mg, 30%) were collected.  mp: 78-80 °C (chloroform / petroleum ether)  !  H N M R (400 MHz, CDCI3): 5 0.80 (s, 3H), 1.05 (s, 3H), 1.31-1.68 (m, 7H), 1.7-1.93 (m, 8H), 1.93-2.06 (m, 2H), 2.28 (dt, J= 18.2, 3.3 Hz, IH), 2.44 (ddd, J= 16.2, 8.4, 3.3 Hz, 2H), 2.55-2.66 (m, 3H), 2.81 (m, 4H), 2.95 (m, 2H), 3.15 (m, 2H), 3.25 (d, J= 14.5 Hz, IH), 10.7 (br s, IH, NH).  1 3  C N M R (75 MHz, CDCI3): 5 19.80, 19.85, 19.91, 19.99, 21.15, 21.19, 24.51, 24.62, 27.01, 41.12, 41.15, 42.51, 42.61, 42.97, 47.32, 47.98, 51.78, 51.85, 58.42, 212.81,217.10.  IR(KBr pellet): 3456 (br), 2953, 1741, 1697, 1471, 1191, 1055cm" . 1  Anal. Calcd for C 2 2 H N 0 S : C, 61.51; H , 9.15; N , 3.26. Found: C, 61.23; H , 9.39; N , 39  5  3.24.  155 1  Experimental  Chapter 5  q / ? H O-Camphorsulfonate Salt 146  0 so  3  o  Me  H 146  Aminoketone 12 (110 mg, 0.58 mmol) and (lic)-(+)-10-camphorsulfonic  acid  (125 mg, 0.54 mmol) were combined in chloroform (5 mL). Petroleum ether was added until the solution became turbid, and the reaction placed in a freezer (-20 °C). After 24 h, crystals of salt 146 (98mg, 42%) were collected.  The melting point and spectral data were identical to those reported for compound 145.  Anal. Calcd for C^HsgNOjS: C, 61.51; H , 9.15; N , 3.26. Found: C, 61.30; H , 9.16; N , 3.26.  156  Experimental  Chapter 5  (R)-l,r-Binaphthvl-2,2'-divl  Phosphate Salt Monohydrate 147  Aminoketone 12 (174 mg, 0.91 mmol) and (£)-(-)-l,l'-binaphthyl-2,2'-diyl hydrogen phosphate (300 mg, 0.86 mmol) were dissolved in separate portions of MeOH (3 mL each) and combined. Recrytallization from 2:1 MeOH / water yielded salt 147 monohydrate (280 mg, 59%) as a white solid.  mp: 154-157 °C (MeOH / water)  ' H N M R (400 MHz, CDC1 ): 5 1.12 (m, IH), 1.18-1.39 (m, 5H), 1.40-1.61 (m, 5H), 1.68 3  (br s, 2H), 2.03 (br s, 2H), 2.37 (m, 4H), 2.50 (s, 3H, N C H ) , 2.59 (m, 2H), 2.84 3  (m, IH), 7.22 (m, 2H), 7.37 (m, 4H), 7.55 (d, J= 8.8 Hz, 2H), 7.88 (d, 7= 8.1 Hz, 2H), 7.93 (d, J = 8.8 Hz, 2H), 12.13 (br s, IH, NH).  1 3  C N M R (75 MHz, CD S(0)CD ): 6 21.16, 21.48, 23.25, 39.58, 43.36, 52.63, 121.75, 3  3  122.69, 124.39, 126.04, 128.39, 129.68, 130.28, 131.96, 150.07, 150.20, 212.24.  IR (KBr pellet): 3348, 1698, 1265, 1107, 964, 833 cm" . 1  Anal. Calcd for C H N 0 P : C, 68.19; H , 6.80; N , 2.49. Found: C, 68.26; H , 6.78; N , 3 2  3 8  6  2.41.  157  Experimental  Chapter 5  This structure was confirmed by X-ray crystallographic analysis:  Habit  colourless hexagonal prisms  Space group  F l \ L \ l \  a, A  6.551(1)  b, A  12.531(1)  c, A  35.268(3)  a (°)  90  P (°)  90  (°)  90  Y  Z  4  R  0.042  4-Toluenesulfonate Salt 162  Me  H 162  To a solution of aminoketone 12 (80 mg, 0.42 mmol) in E t 0 (1 mL) was added 2  4-toluenesulfonic acid (78 mg, 0.45 mmol) in E t 0 (5 mL). Salt 162 (154 mg, 97%) 2  precipitated as a white solid.  mp: 112-113 °C (ethanol / Et 0) 2  158  Chapter 5  !  Experimental  H N M R (400 MHz, CDC1 ): 5 1.43 (m, 4H), 1.59 (m, 2H), 1.66-1.85 (m, 6H), 2.32 (s, 3  3H, ArCH ), 2.47 (m, 4H), 2.79 (d, J= 4.9 Hz, 3H), 2.95 (m, 2H), 3.08 (m, 2H), 3  7.16 (d, J= 8.0 Hz, 2H), 7.74 (d, J= 8.0 Hz, 2H), 10.51 (br s, IH, NH).  1 3  C N M R (75 MHz, CDCI3): 5 20.34, 21.21, 24.37, 40.94, 42.93, 52.25, 125.88, 128.75, 139.94, 142.17,212.55.  IR (KBr pellet): 3536,3047, 2958, 1704, 1479, 1192, 1124, 1036, 1011,683,569 cm" . 1  Anal. Calcd for C H i N 0 S : C, 61.76; H , 8.46; N , 3.79. Found: C, 61.54; H , 8.52; N , 19  3  4  3.64.  159  Experimental  Chapter 5  5.3.3 Preparation of the Fourteen-Membered Aminoketone 14 Diethyl 7.7'-Benzvliminodiheptanoate (102)  Et0 C  C0 Et  2  2  102  To a solution of ethyl 7-bromoheptanoate (32.6 g, 146 mmol), benzylamine (7.9 g, 74 mmol), and suspended potassium iodide (20 g, 120 mmol) in M e C N (200 mL) was added DIPEA (28.2 mL, 162 mmol) in three portions over 3 h. The reaction was brought to reflux and stirred for 18 h after which time it was cooled and concentrated in vacuo. The residue was taken up in a mixturre of Et20 (100 mL) and 10% aqueous sodium carbonate (200 mL) and extracted into Et20 (3 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSOx), and concentrated in vacuo. Silica gel chromatography (2% triethylamine in 2:1 hexanes / EtOAc) afforded the aminodiester 102 (23.7 g, 82%) as a pale yellow oil.  ' H N M R (200 MHz, CDC1 ): 8 1.22 (t, J= 7.1 Hz, 6H, CH ), 1.25 (m, 8H), 1.42 (m, 3  3  4H), 1.57 (m, 4H), 2.24 (t, J= 7.6 Hz, 4H), 2.35 (t, J= 6.8 Hz, 4H), 3.49 (s, 2H, PhCH ), 4.09 (q, J= 7.1 Hz, 4H, OCH ), 7.26 (m, 5H). 2  2  160  Experimental  Chapter 5  1 3  C N M R (50 MHz, CDCI3): 5 14.20, 24.91, 26.63, 26.99, 29.00, 34.27, 53.65, 58.59, 60.06, 126.53, 127.98, 128.71, 140.19, 173.75.  IR (neat): 2936, 1737, 1455, 1372, 1180, 1031, 737, 700 cm" . 1  H R M S (EI) calcd for C H 4 i N 0 419.3036, found 419.3025. 25  4  8 -B enzvl- 8 -azacvclotetradecanone ( 1 0 7 )  O  107 A 1L round bottomed flask was equipped with a Hickman still coupled to an efficient  condenser.  Into the flask was  introduced Et20 (750  mL) and sodium  hexamethyldisilazide (100 mL of a 1.0M solution in THF, 100 mmol), and the solution brought to reflux. A solution of aminodiester 1 0 2 (10.0 g, 20.4 mmol) in THF (50 mL) was introduced to the top of the condenser over 40 h via syringe pump. The reaction was allowed to reflux for an additional 2 h, then cooled in an ice bath. Glacial acetic acid (100 mL) and water (100 mL) were added, followed by removal of E t 0 in vacuo. Water (100 2  mL) and cone. HCI (200 mL) were introduced, and the solution refluxed for 4 h with continuous distillation (ca. 200 mL removed) at which time evolution of carbon dioxide was observed. The reaction was cooled in an ice bath and rendered strongly alkaline with  161  Chapter 5  Experimental  50% aqueous potassium hydroxide. Extraction with ET.2O (5 x 150 mL) was followed by washing of the combined ethereal extracts with water (2 x 100 mL) and brine (100 mL). Drying (MgSCXt) and concentration of the organic layer in vacuo was followed by Kugelrohr distillation (210 °C, 0.8 Torr) to yield the macrocycle 107 (5.20 g, 85%) as a colourless oil.  ' H N M R (400 MHz, CDCI3): 5 1.30 (m, 8H), 1.40 (m, 4H), 1.70 (m, 4H), 2.28 (t, J= 5.6 Hz, 4H), 2.47 (t, J= 6.2 Hz, 4H), 3.43 (s, 2H, PhCFL;), 7.25 (m, 5H).  1 3  C N M R (75 MHz, CDCI3): 5 23.29, 24.85, 26.59, 26.99, 40.51, 52.04, 58.07, 126.51, 127.95,128.86,140.14,212.26.  IR (neat): 3061, 1713, 1452, 1369, 976, 699 cm" . 1  H R M S (EI) calcd for C H i N O 301.2406, found 301.2407. 2 0  3  Anal. Calcd: C, 79.68; H , 10.36; N, 4.65. Found: C, 79.46; H , 10.46; N , 4.66.  162  Experimental  Chapter 5  8-Azacvclotetradecanone (14)  O  14  A suspension of 10% palladium on charcoal (50 mg) in MeOH (20 mL) containing aminoketone 107 (860 mg, 8.86 mmol) and ammonium formate (1.0 g, 15.9 mmol) was heated quickly and reluxed for eight minutes. The solution was allowed to cool for one minute, then filtered through a bed of Celite® 545 which was subsequently triturated with chloroform. The organic filtrate was concentrated in vacuo, and taken up in 30% aqueous potassium hydroxide (30 mL) and extracted with Et20 (3 x 40 mL). The combined organic extracts were washed successively with water (2 x lOmL) and brine (10 mL), followed by drying (MgS04), and concentration in vacuo. Macrocycle 14 (601 mg, 99%) was obtained as an analytically pure white solid.  mp: 33-34 °C (n-pentane)  !  H N M R (300 MHz, CDCI3): § 0.75 (br s, IH, NH), 1.28 (br m, 8H), 1.43 (quint, / = 5.7 Hz, 4H), 1.65 (quint, J= 6.3 Hz, 4H), 2.42 (t, J= 6.0 Hz, 4H), 2.52 (t, J= 5.4 Hz, 4H).  , 3  C N M R (75 MHz, CDCI3): 8 23.25, 24.40, 25.95, 27.61, 40.59, 46.38, 212.09.  IR(KBr pellet): 3346,3318,2937, 1711, 1365, 1107, 765,731,706 cm" . 1  163  Experimental  Chapter 5  U V / VIS O-hexane): 218 (370), 283 (30) nm  (M'W ). 1  H R M S (EI) calcd for C i H N O 211.1937, found 211.1932. 3  2 5  Anal. Calcd: C, 73.88; H , 11.92; N , 6.63. Found: C, 73.82; H , 12.11; N , 6.78.  164  Experimental  Chapter 5  5.3.4 Preparation of the Fourteen-Membered Aminoketone Salts  Hydrochloride Salt 127  O  H  H  A stream of dry HC1 gas was passed through a solution of aminoketone 14 (233 mg, 1.10 mmol) in E t 0 (10 mL). The white powder that precipitated (250 mg, 91%) was 2  filtered, washed with E t 0 (5 mL) and n-pentane (2x10 mL) and dried in vacuo. 2  mp: 179-180 °C (Et 0 / MeOH) 2  *H NMR (400 MHz, CDC1 ): 5 1.38 (m, 4H), 1.50 (m, 4H), 1.74 (m, 8H), 2.59 (t, J= 6.0 3  Hz, 4H), 2.93 (m, 4H), 9.31 (br s, 2H, NH ). 2  1 3  C NMR (75 MHz, CDCI3): § 22.04, 23.75, 24.08, 26.08, 40.16, 44.15, 212.01.  IR(KBr pellet): 3311, 2936, 1709, 1581, 1473 cm" . 1  Anal. Calcd for C H N 0 C 1 : C, 63.01; H, 10.58; N , 5.65. Found: C, 63.26; H , 10.53; N , 13  26  5.50.  165  Experimental  Chapter 5  (2R, 3i?)-Tartrate Salt 148  O  co 14  HHO-  0  -OH -H C0 H 2  © J  N  H H 148  To a solution of aminoketone 14 (182 mg, 0.86 mmol) in Et^O (2 mL) was added a solution of (2R, 3i?)-tartaric acid (130 mg, 0.86 mmol) in MeOH (2 mL). The solvent was removed in vacuo and the resulting amorphous solid recrystallized from chloroform / petroleum ether to give salt 148 as colourless crystals (85 mg, 27%).  mp: 139-140 °C (chloroform / petroleum ether)  !  H N M R (400 MHz, CD OD): 5 1.39 (m, 8H), 1.76 (m, 8H), 2.52 (t, J= 6.4 Hz, 4H), 3  3.01 (t, J= 6.5 Hz, 4H), 3.39 (s, 2H), 4.86 (br s, exchangeable H atoms).  1 3  C N M R (75 MHz, CD OD): 5 23.20, 24.53, 24.63, 27.29, 41.30, 45.13, 74.23, 177.08, 3  214.19.  I R f K B r pellet): 3322, 2941, 1737, 1703, 1625, 1578, 1408, 1260, 1113, 1068 cm" . 1  Anal. Calcd for C17H31NO7: C, 56.49; H , 8.65; N , 3.88. Found: C, 56.70; H , 8.78; N , 3.87.  166  Experimental  Chapter 5  This structure was confirmed by X-ray crystallographic analysis:  colourless plates  Habit Space group  P2i  A b, A c, A  8.6709(8)  a(°)  90  P(°)  104.675(9)  y(°)  90  z  .2  R  0.038  a,  10.209(1)  10.972(1)  (5)-Malate Salt 149  O C0 H 2  14  HO-  -H  H-  -H CO,©  N H H 149  Aminoketone 14 (33 mg, 0.16 mmol) and (5)-malic acid (21 mg, 0.16 mmol) were dissolved in refiuxing E t 0 (5 mL). The salt appeared as a white precipitate on cooling 2  and was filtered and dried (45 mg, 83%).  167  Experimental  Chapter 5  mp: 117-120 °C (chloroform / petroleum ether)  !  H N M R (400 MHz, CD OD): 5 1.38 (m, 8H), 1.72 (m, 8H), 2.51 (dd, J= 15.9, 7.6 Hz, 3  IH), 2.53 (t,J= 6.4 Hz, 4H), 2.78 (dd,J= 15.9, 5.1 Hz, IH), 3.00 (t,J= 6.4 Hz, 4H), 4.27 (dd, J= 5.2, 7.6 Hz, IH, CH(OH)), 4.88 (br s, exchangeable H atoms).  1 3  C N M R (100 MHz, CD OD): 6 23.19, 24.52, 24.65, 27.28, 41.29, 41.90, 45.11, 69.67, 3  176.45, 179.59,214.16.  IR(KBr pellet): 3389, 2941, 1708, 1561, 1093,676 cm" . 1  Anal. Calcd for C i H N 0 : C, 59.11; H , 9.05; N , 4.05. Found: C, 59.08; H , 9.12; N , 7  3 1  6  4.14.  This structure was confirmed by X-ray crystallographic analysis:  Habit Space group  colourless plates  Fl\  A b, A c, A  21.041(2)  a(°)  90  P(°)  99.015(8)  y(°)  90  z  2  R  0.031  a,  7.3378(8) 5.9150(4)  168  Experimental  Chapter 5  (ifl-Malate Salt 150  C0 H 2  H-  -OH  H-  •H CO  0  150  A solution of aminoketone 14 (121 mg, 0.57 mmol) in chloroform (2 mL) was added to a solution of (i?)-malic acid (76 mg, 0.57 mmol) in MeOH (1 mL). The solvent was removed in vacuo and the resulting solid recrystallized from chloroform / petroleum ether to afford salt 150 (160 mg, 81%).  The melting point and spectral data were identical to those reported for compound 149.  Anal. Calcd for C i H i N 0 : C, 59.11; H , 9.05; N , 4.05. Found: C, 59.14; H , 8.90; N , 7  3  6  3.95.  169  Experimental  Chapter 5  ( i?)-2-Hvdroxv-5,5-dimethvl-4-phenyl-l,3,2-dioxaphosphorinane-2-oxide Salt 151 ,  O  Aminoketone 14 (110 mg, 0.52 mmol) and (i?)-2-Hydroxy-5,5-dimethyl-4phenyl-l,3,2-dioxaphosphorinane-2-oxide (126 mg, 0.52 mmol) were dissolved in hot MeOH (5 mL). Cooling and subsequent slow evaporation of solvent led to fine white needles of salt 151 (142 mg, 60%).  mp: 207-210 °C (MeOH)  !  H N M R (400 MHz, CDCI3): 8 0.70 (s, 3H), 0.94 (s, 3H), 1.27 (quint, J = 7.1Hz, 4H), 1.40 (quint, J= 7.2 Hz, 4H), 1.67 (m, 8H), 2.44 (t, 7 = 7.1 Hz, 4H), 2.86 (m, 4H), 3.64 (dd, J 2  H H  = 10.2 Hz, V  CH OP, IH), 5.18 (d, V 2  H P  H P  = 23.7 Hz, IH, CH OP), 4.22 (d, J = 10.2 Hz, 2  = 2.2 Hz, IH, CHOP), 7.27 (br s, 5H), 9.72 (br s, 2H,  NH ). 2  1 3  C N M R (100 MHz, CDCI3): 5 17.45, 21.28, 22.15, 23.34, 23.42, 25.96, 29.68, 36.05, 40.31, 43.47, 85.16, 127.44, 127.55, 127.60, 138.04 (d, J p = 9.8 Hz), 212.21. 3  C  IR (KBr pellet): 3396, 2951, 1709, 1225, 1095, 1067, 791, 550 cm" . 1  Anal. Calcd for C H4oN0 P: C, 63.56; H , 8.89; N , 3.09. Found: C, 63.71; H , 9.02; N , 24  5  3.13.  170  Experimental  Chapter 5  (it)-a-Methoxv-a-(trifluoromethyl)phenvlacetate Salt 152  O  0  co  2  \''OMe CF  /  3  \  H H 152  To a solution of compound 14 (32 mg, 0.15 mmol) in E t 0 (1 mL) was added a 2  solution of (i?)-a-Methoxy-a-(trifluoromethyl)phenylacetic acid (/?-Mosher's acid, 35 mg, 0.15 mmol) in E t 0 (2 mL). The resulting solution was concentrated in vacuo and the 2  resulting white solid recrystallized from chloroform / petroleum ether to afford salt 152 (55 mg, 82%) as colourless prisms.  mp: 132 °C (sharp) (chloroform / petroleum ether)  !  H N M R (400 MHz, CDCI3): 5 1.25 (m, 8H), 1.54 (m, 8H), 2.39 (t, J= 6.1 Hz, 4H), 2.66 (m, 4H), 3.58 (s, 3H, OCH ), 7.33 (m, 3H), 7.68 (m, 2H), 9.60 (br s, 2H, NH ). 3  , 3  2  C N M R (75 MHz, CDC1 ): 6 21.98, 23.34, 23.71, 25.94, 40.08, 43.55, 54.92, 124.86 (q, 3  7  JCF = 289 Hz), 127.67, 127.75, 128.42, 136.24, 169.92,212.25.  IR(KBr pellet): 2936, 1709, 1641, 1372, 1171, 1147, 791,720 cm" . 1  Anal. Calcd for C H34F N0 : C, 62.01; H , 7.69; N , 3.14. Found: C, 62.15; H , 7.84; N , 23  3  4  3.16.  171  Experimental  Chapter 5  (S)- a-Methoxv-a-(trifluoromethvl)phenylacetate Salt 153  O  H  H 153  To a solution of compound 14 (48 mg, 0.23 mmol) in E t 0 (1 mL) was added a 2  solution of ( S)-a-Methoxy-a-(trifluoromethyl)phenylacetic acid (S-Mosher's acid, 54 1  mg, 0.23 mmol) in E t 0 (2 mL). The resulting solution was concentrated in vacuo and the 2  resulting white solid recrystallized from chloroform / petroleum ether to afford salt 153 (69 mg, 68%) as colourless prisms.  The melting point and spectral data were identical to those reported for compound 152.  Anal. Calcd for C23H34F3NO4: C, 62.01; H , 7.69; N , 3.14. Found: C, 61.78; H , 7.69; N , 3.14.  172  Experimental  Chapter 5  qsriO-Camphorsulfonate Salt 154  O  H H 154  Solid aminoketone 14 (128 mg, 0.61 mmol) and solid (l,S)-10-Camphorsulfonic acid (140 mg, 0.61 mmol) were combined and heated until a homogeneoud melt was achieved. The liquid was cooled and recrystallized from chloroform / petroleum ether to yield salt 154 as a white solid (212 mg, 79%).  mp: 166-167 °C (chloroform / petroleum ether)  H N M R (400 MHz, CDCI3): 8 0.83 (s, 3H, CH ), 1.10 (s, 3H, CH ), 1.38 (m, 10H), 1.72  l  3  3  (m, 8H), 1.87 (d, J= 18.2 Hz, IH), 2.00 (m, IH), 2.05 (t, J= 4.3 Hz, IH), 2.31 (dt, J= 18.2, 3.3 Hz, IH), 2.50 (t, J= 6.3 Hz, 4H), 2.64 (m, IH), 2.78 (d, J= 14.7 Hz, IH), 3.01 (m, 4H), 3.29 (d, J= 14.7 Hz, IH), 8.29 (br s, 2H, NH ). 2  1 3  C N M R (100 MHz, CDC1 ): 5 19.85, 20.01, 22.18, 23.37, 23.69, 24.70, 26.07, 27.00, 3  40.24, 42.65, 42.90, 44.12, 47.42, 47.88, 58.47, 212.10, 216.67.  IR(KBr pellet): 3449, 2942, 1735, 1703, 1621, 1468, 1149, 1030 cm" . 1  Anal. Calcd for C H , N 0 S : C, 62.13; H , 9.52; N , 3.15. Found: C, 62.28; H , 9.58; N , 2 3  4  5  3.19.  173  Chapter 5  Experimental  7V-Cbz-L-Alanine Salt 155  O  H H 155  A solution of aminoketone 14 (110 mg, 0.52 mmol) and ./V-Cbz-L-Alanine (116 nig, 0.52 mmol) in chloroform (5 mL) was concentrated in vacuo. The resulting glassy solid was recrystallized from chloroform / petroleum ether to give salt 155 (150 mg, 66%) as a white powder.  nip: 103-104 °C (chloroform / petroleum ether)  !  H N M R (400 MHz, CDC1 ): 8 1.35 (m, 13H), 1.68 (m, 8H), 2.47 (m, 4H), 2.74 (m, 4H), 3  4.08 (br s, IH), 5.10 (m, 2H), 5.76 (br s, IH), 7.35 (m, 5H), 8.5-9.1 (br s, 2H, NH ). 2  1 3  C N M R (75 MHz, CDCI3): 8 19.74, 22.18, 23.50, 23.94, 26.04, 40.39, 43.89, 51.56, 66.34, 128.02, 128.46, 136.78, 155.59, 178.08, 211.90.  IR (KBr pellet): 3333,2934, 1693, 1577, 1516, 1455, 1396, 1353, 1227, 1057, 702 cm" . 1  Anal. Calcd for C24H40N2O6: C, 63.69; H , 8.91; N , 6.19. Found: C, 63.30; H , 8.86; N , 6.15.  174  Experimental  Chapter 5  7V-Cbz-L-Phenvlalanine Salt 156  O  156  A solution of aminoketone 14 (149 mg, 0.71 mmol) and jty-Cbz-L-phenylalanine (211mg, 0.71 mmol) in chloroform (3 mL) was concentrated in vacuo and the remaining residue recrystallized from chloroform / petroleum ethert to give salt 156 (200 mg, 56%) as a white powder.  mp: 142-143 °C (chloroform / petroleum ether)  J  H N M R (400 MHz, CDCI3): 5 1.27 (m, 8H), 1.4-1.7 (m, 8H), 2.42 (t, J = 6.5 Hz, 4H), 2.67 (t, J = 4.6 Hz, 4H), 3.16 (m, 2H, PhCH ), 4.34 (br s, IH), 5.10 (m, 2H), 5.53 2  (m, IH), 7.18 (m, 5H), 7.29 (m, 5H), 8.4-9.2 (br s, 2H, NH ). 2  1 3  C N M R (75 MHz, CDC1 ): 5 22.17, 23.44, 23.82, 23.87, 38.23, 40.35, 43.62, 43.68, 3  56.62, 66.34, 126.23, 128.00, 128.42, 129.77, 136.80, 137.91, 155.53, 175.87, 175.90,211.87.  IR (KBr pellet): 3030, 2938,2863, 1712, 1529, 1396, 1232, 1045,700 cm" . 1  Anal. Calcd for C o H N 0 : C, 70.56; H , 8.29; N , 5.49. Found: C, 70.34; H , 8.31; N , 3  42  2  5  5.56.  175  Experimental  Chapter 5  A^-Cbz-L-Valine Salt 157  O  H H  A solution of aminoketone 14 (104 mg, 0.49 mmol) and A^-Cbz-L-valine (124 mg, 0.49 mmol) in chloroform (2 mL) was prepared and concentrated in vacuo. The residue recrystallized from chloroform / petroleum ether affording salt 157 (75 mg, 33%) as fine white needles.  mp: 130-131 °C (chloroform / petroleum ether)  ' H N M R (400 MHz, CDC1 ): § 0.89 (d, J= 6.8 Hz, 3H), 0.95 (d, J= 6.8 Hz, 3H), 1.32 3  (m, 8H), 1.66 (m, 8H), 2.18 (m, IH), 2.47 (t, J= 6.2 Hz, 4H), 2.78 (t, J= 6.0 Hz, 4H), 4.07 (br s, IH), 5.10 (s, 2H), 5.53 (m, IH), 7.36 (m, 5H); ammonium protons not observed. 1 3  C N M R (75 MHz, CDC1 ): 8 17.67, 19.54, 22.24, 23.55, 24.09, 26.03, 31.71, 40.42, 3  43.94, 60.97, 66.46, 128.02, 128.45, 136.80, 156.35, 176.90, 211.94.  IRfKBr pellet): 3282, 2938, 1713, 1543, 1403, 1236, 1091,759 cm' . 1  Anal. Calcd for C26H42N2O5: C, 67.50; H , 9.15; N , 6.06. Found: C, 67.64; H , 9.24; N , 6.04.  176  Chapter 5  Experimental  2,3:4,6-Di-0-isopropvlidene-2-keto-L-gulonate Salt 158  O  H H 158  Aminoketone 14 (35 mg, 0.17 mmol) and 2,3:4,6-di-0-isopropylidene-2-keto-Lgulonic acid monohydrate (48 mg, 0.17 mmol) were dissolved in chloroform (2 mL). Slow addition of petroleum ether afforded salt 158 (50 mg, 60%) as a white powder.  mp: 189-191 °C (dec.) (chloroform/petroleum ether)  ' H N M R (400 MHz, CDC1 ): 5 1.28 (s, 3H), 131 (m, 4H), 1.39 (s, 3H), 1.40 (m, 4H), 3  1.45 (s, 3H), 1.47 (s, 3H), 1.68 (m, 8H), 2.52 (t, J= 6.5 Hz, 4H), 2.93 (t, J = 6.5 Hz, 4H), 3.95-4.08 (m, 3H), 4.21 (d, 7 = 2.1 Hz, IH), 4.86 (s, IH), 7.7-8.8 (br s, 2H, NH ). 2  1 3  C N M R (75 MHz, CDCI3): 5 18.74, 22.25, 23.49, 23.63, 26.04, 26.08, 27.12, 28.85, 40.36, 43.49, 60.10, 72.70, 73.49, 87.02, 97.40, 112.22, 112.29, 171.15, 212.37.  IR (KBr pellet): 3444, 2935, 1710, 1611, 1374, 1188, 1133, 1110, 840 cm" . 1  Anal. Calcd for C25H43N0O8: C, 61.83; H , 8.92; N , 2.88. Found: C, 61.54; H , 9.12; N , 2.95.  177  Experimental  Chapter 5  5.3.5 Preparation of the Sixteen-Membered Aminoketone 16  8-Bromooctanoic A c i d  112  (110)  113  8-Bromooctanol was first prepared according to the procedure of Kang et al.:  A  solution of 1,8-octanediol (30.0 g, 205 mmol) and hydrobromic acid (25 mL of a 48% solution) in benzene (400 mL) was refluxed for 24 h with continuous removal of water from a Dean-Stark trap. The reaction mixture was cooled and extracted successively with 6 M potassium hydroxide (100 mL), 10% HCI (100 mL), water (2 x 100 mL), and brine (75 mL). The organic layer was dried (MgS04) and concentrated in vacuo to yield the crude bromoalcohol as a pale brown liquid (41.9 g). The bromoalcohol (10.0 g, 47.8 mmol) was oxidized at 0 °C in acetone (60 mL) by the slow addition of Jones' reagent (prepared from 13.4 g chromium trioxide, 40 mL water, and 11 mL of cone.  H2SO4).  After stirring for 1.5 h, water (500 mL) was added,  followed by extraction into Et20 (4 x 150 mL). After concentration in vacuo, the residue was taken up in 2 M potassium hydroxide (300 mL) and washed with E t 0 (2 x 50 mL). 2  "Acidification of the aqueous layer with cone. HCI produced a fine white precipitate which was extracted into E t 0 (4 x 100 mL). Drying (MgS04) was followed by 2  concentration in vacuo to give the bromoacid 110 as a pale green solid (6.5 g, 61 % from the crude bromoalcohol). Despite the trace chromium impurity, the acid thus obtained 112  was analytically pure and gave spectra in accord with those published previously,  mp: 35-36 °C (lit.  112  value 38 °C)  178  Experimental  Chapter 5  *H N M R (400 MHz, CDCI3): 8 1.35 (m, 4H), 1.43 (m, 2H), 1.62 (quint,/= 7.3 Hz, 2H), 1.84 (quint, J= 7.1 Hz, 2H), 2.33 (t, J= 7.3 Hz, 2H), 3.38 (t, J= 6.8 Hz, 2H).  1 3  C N M R (100 MHz, CDCI3): 8 24.49, 27.92, 28.36, 28.80, 32.66, 33.86, 33.94, 180.03.  IR (KBr pellet): 2933, 1708, 1470, 1429, 1408, 1242, 1187, 930, 644 cm" . 1  Ethyl 8-Bromooctanoate (106)  O 106  A solution of 8-bromooctanoic acid (110, 25.0 g, 111.6 mmol) and cone. H2SO4 (5.5 mL) in ethanol (325 mL) was refluxed for 8 h.. After cooling, water (100 mL) was added and the mixture extracted with Et^O (3 x 200 mL). The combined organic extracts were washed successively with saturated sodium carbonate (2 x 100 mL), water (2 x 100 mL) and brine (100 mL), then dried (MgSO"4). Concentration of the product in vacuo provided the bromoester 106 (26.6 g, 95%) as a pale yellow oil. Spectral data were in accord with those previously reported.  114  *H N M R (400 MHz, CDCI3): 8 1.22 (t, J= 7.1 Hz, 3H, C H ) , 1.31 (m, 4H), 1.39 (m, 3  2H), 1.60 (m, 2H), 1.83 (quint, / = 7.0 Hz, 2H), 2.27 (t, J= 7.5 Hz, 2H), 3.38 (t, J = 7.0 Hz, 2H), 4.10 (q, / = 7.1 Hz, 2H, OCH ). 2  1 3  C N M R (100 MHz, CDCI3): 8 14.21, 24.78, 27.91, 28.35, 28.86, 32.65, 33.84, 34.22, 60.14, 173.70.  IR(neat): 2934, 1736, 1183 cm" . 1  179  Experimental  Chapter 5  Diethyl S^'-Benzyliminodioctanoate (103)  Et0 C  C0 Et  2  2  \  /  103  A solution of ethyl 8-bromooctanoate (106, 12.0 g, 47.6 mmol), benzylamine (2.55 g, 23.8 mmol) and potassium iodide (9.0 g, 54.2 mmol) in M e C N (200 mL) was stirred at room temperature for 1.5 h. DIPEA (6.75 g, 52.4 mmol) was added and the reaction heated slowly and refluxed for 24 h. The reaction mixture was concentrated in vacuo and the residue taken up in Et20 (100 mL) and saturated sodium carbonate (150 mL). Extraction with Et20 (3 x 100 mL) was followed by successive washing of the combined organic layers with water (50 mL), 5% sodium bisulfite (50 mL), water (2x50 mL), and brine (50 mL). A viscous yellow oil was obtained after drying (MgSC^) and concentration in vacuo. Removal of a low-boiling fraction by distillation (bp 120-130 °C at 1.5 Torr) provided a residue that was chromatographed through a short column of silica (EtOAc eluent) to yield aminodiester 103 (9.1 g, 85%) as a pale yellow oil.  R N M R (400 MHz, CDC1 ): 5 1.20-1.31 (m, 18H), 1.43 (m, 4H), 1.59 (quint, J= 7.5  l  3  Hz, 4H), 2.25 (t, J= 7.5 Hz, 4H), 2.36 (t, J= 7.2 Hz, 4H), 3.50 (s, 2H, PhCH ), 2  4.10 (q, J = 7.1 Hz, 4H, OCH ), 7.20 (m, IH), 7.28 (m, 4H). 2  1 3  C N M R (100 MHz, CDC1 ): 6 14.16, 24.83, 26.84, 27.12, 29.02, 29.06, 34.23, 53.63, 3  58.52, 60.00, 126.47, 127.92, 128.68, 140.11, 173.71.  180  Experimental  Chapter 5  IR(neat): 2932, 1737, 1180 cm" . 1  H R M S (EI) calcd for C27H45NO4 447.3349, found 447.3346.  Anal. Calcd: C, 72.44; H , 10.13; N , 3.13. Found: C, 72.62; H , 10.14; N , 3.20.  9-Aza-9-benzylcyclohexadecanone (108)  O  108 A I L round bottomed flask was equipped with a Hickman still and coupled to an efficient  condenser. Into the flask was introduced Et20 (800  mL) and sodium  hexamethyldisilazide (80 mL of a 1.0M solution in THF, 80 mmol), and the solution brought to reflux. A solution of aminodiester 103 (8.0 g, 17.8 mmol) in THF (50 mL) was introduced to the top of the condenser over 40 h via syringe pump. The reaction was allowed to reflux for an additional 4 h, then cooled in an ice bath. Glacial acetic acid (80 mL) and water (50 mL) were added, followed by removal of E t 0 in vacuo. Water (160 2  mL) and cone. HCI (100 mL) were introduced, and the solution refluxed for 4 h with continuous distillation (ca. 150 mL removed) at which time evolution of carbon dioxide was observed. The reaction was cooled in an ice bath and rendered strongly alkaline with 50% aqueous potassium hydroxide. Extraction with Et20 (3 x 150 mL) was followed by washing of the combined ethereal extracts with water (2 x 50 mL) and brine (50 mL).  181  Chapter 5  Experimental  Drying (MgS0"4) and concentration of the organic layer in vacuo provided a brown oil which solidified on standing. Recrystallization from MeOH afforded aminoketone 108 (3.50 g, 60%) as a white solid.  mp: 41-42 °C (MeOH)  *H N M R (400 MHz, CDCI3): 5 1.21-1.43 (m, 16H), 1.65 (quint, J= 6.7 Hz, 4H), 2.33 (t, J= 6.2 Hz, 4H), 2.42 (t, J= 6.7 Hz, 4H), 3.49 (s, 2H, PhCFb), 7.20 (m, IH), 7.27 (m, 4H).  1 3  C N M R (100 MHz, CDCI3): 5 23.78, 26.20, 26.77, 28.08, 28.11, 41.83, 52.84, 59.55, 126.53, 127.96, 128.79, 140.38, 212.83.  IR (thin film): 2931, 2856, 1709, 1454, 737 cm" . 1  H R M S (EI) calcd for C H N O 329.2719, found 329.2717. 2 2  3 5  Anal. Calcd: C, 80.19; H , 10.71; N , 4.25. Found: C, 80.26; H , 10.83; N , 4.36.  182  Experimental  Chapter 5  8-Azacvclohexadecanone (16)  O  To a room temperature solution of aminoketone 1 0 8 (2.45 g, 7.45 mmol) in MeOH (70 mL) was added 96% formic acid (10 mL) and 10% palladium on charcoal (2.2 g). The mixture was stirred for 24 h then filtered through a bed of Celite® 545. The solids were triturated with chloroform. The organic filtrate was added to 25% K O H (35 mL), and the mixture extracted with E t 0 (3 x 75 mL). The combined organic extracts were 2  washed with water (2 x 20 mL) followed by brine (20 mL). Drying (MgS0 ), follwed by 4  concentration in vacuo provided analytically pure aminoketone 1 6 (1.67 g, 94%) as a white solid.  mp: 50-51 °C (n-pentane) *H NMR (400 MHz, CDCI3): 5 1.23-1.38 (m, 13H), 1.41 (quint, J= 6.3 Hz, 4H), 1.60 (quint, J= 6.9 Hz, 4H), 2.37 (t, J= 6.9 Hz, 4H), 2.58 (m, 4H).  1 3  C NMR (100 MHz, CDCI3): 8 23.34, 25.34, 27.22, 27.75, 27.99, 41.71, 47.20, 212.32.  IR(KBr pellet): 3441, 2930, 1708, 1460, 1127 cm" . 1  HRMS (EI) calcd for C i H N O 239.2249, found 239.2245. 5  2 9  Anal. Calcd: C, 75.26; H , 12.21; N , 5.85. Found: C, 75.18; H , 12.34; N , 5.87.  183  Experimental  Chapter 5  5.3.6 Preparation of the Sixteen-Membered Aminoketone Salts  Hydrochloride Salt 128  O  H H  Into a solution of aminoketone 16 (987 mg, 4.13 mmol) in Et O(50 mL) was 2  introduced dry HCI gas. The white precipitate that formed was filtered, washed with «-pentane (20 mL) and dried in vacuo, affording salt 128 (990 mg, 87%) as a white powder.  mp: 200-202 °C (dec.) (MeCN)  ' H N M R (400 MHz, CDCI3): 8 1.24 (m, 4H), 1.31 (quint, J= 7.0 Hz, 4H), 1.48 (quint, J = 6.3 Hz, 4H), 1.61 (m, 4H), 1.74 (quint, J= 8.0 Hz, 4H), 2.40 (t, J= 6.3 Hz, 4H, CH C=0), 2.97 (m, 4H, CH N), 9.42 (br s, 2H, NH ). 2  1 3  2  2  C N M R (100 MHz, CDC1 ): 8 22.72, 22.86, 24.55, 26.68, 27.38, 42.14, 44.10, 211.78. 3  IR (KBr pellet): 3436, 2937, 1703, 1590, 1467 cm" . 1  Anal. Calcd for C i H N O C l : C, 65.31; H , 10.96; N , 5.08. Found: C, 64.99; H, 11.02; N , 5  30  5.10.  184  Chapter 5  Experimental  This structure was confirmed by X-ray crystallographic analysis:  Habit  colourless prisms  P\  Space group  a,  A  b,A c,  9.980 12.345  A  a(°)  7.621 102.88 109.75 70.76  Y(°) Z  2  R  0.054  ( i?)-2-Hvdroxv-5,5-dimethvl-4-phenvl-l,3,2-dioxaphosphorinane-2-oxide Salt 159 ,  O  Aminoketone 16 (110 mg, 0.46 mmol) and (i?)-2-hydroxy-5,5-dimethyl-4-phenyl  r  l,3,2-dioxaphosphorinane-2-oxide (111 mg, 0.46 mmol) were dissolved in hot MeOH (3 mL). The resulting solution was concentrated in vacuo and the residue recrystallized from chloroform / petroleum ether to give salt 159 (128 mg, 58%) as colourless needles.  185  Experimental  Chapter 5  mp: 235-240 °C (dec.) (chloroform / n-pentane)  *H N M R (400 MHz, CDC1 ): § 0.68 (s, 3H, CH ), 0.93 (s, 3H, C H ) , 1.23 (m, 8H), 1.32 3  3  3  (m, 4H), 1.55-1.69 (m, 8H), 2.36 (t, J = 6.3 Hz, 4H, CH C=0), 2.86 (m, 4H, 2  CH N), 3.64 (dd, J 2  = 10.9 Hz, J 3  2  H H  10.9 Hz, IH, CH OP), 5.12 (d, J 3  2  H P  = 23.7 Hz, IH, CH OP), 4.20 (d, J 2  H P  2  H H  =  = 2.3 Hz, IH, CHOP), 7.27 (m, 5H), 9.82 (br  s, 2H, NH ). 2  I 3  C N M R (100 MHz, CDC1 ): 5 17.43, 21.25, 22.43, 22.93, 24.57, 26.67, 27.42, 36.04 (d, 3  2  J p = 2.8 Hz, CH OP), 42.22, 43.56, 85.11 (d, J p = 2.7 Hz, CHOP), 127.38, 2  C  C  2  127.48, 127.62, 138.04, 138.15,211.76.  IR(KBr pellet): 3436, 2931, 1702, 1212, 1080, 1056 cm" . 1  Anal. Calcd for C H 4 N 0 P : C, 64.84; H , 9.21; N , 2.91. Found: C, 64.62; H , 9.25; N , 26  4  5  2.89.  AM-Toluenesulfonyl-L-Alanine Salt 160  O  H  H  To a solution of aminoketone 16 (90 mg, 0.38 mmol) in E t 0 (2 mL) was added a 2  solution of TY-4-toluenesulfonyl-L-alanine (92 mg, 0.38 mmol) in E t 0 (4 mL). The white 2  186  Experimental  Chapter 5  precipitate that formed was filtered and washed with n-pentane to give salt 160 (121 mg, 66%) as a white powder.  mp: 154-155 °C (chloroform/ w-pentane)  ' H N M R (400 MHz, CDC1 ): 5 1.20-1.45 (m, 17H), 1.61 (m, 8H), 2.38 (s, 3H,p-CH ), 3  3  2.42 (t, J= 6.0 Hz, 4H, C H C O ) , 2.83 (t, J= 8.0 Hz, 4H, CH N), 3.62 (q, J= 7.0 2  2  Hz, IH, CH), 6.00 (br s, IH, NHTs), 7.23 (AA'BB' d, J = 8.0 Hz, 2H), 7.74 (AA'BB' d, .7=8.0 Hz, 2H).  1 3  C N M R (75 MHz, CDC1 ): 5 20.35, 21.51, 22.61, 23.08, 24.40, 26.60, 27.32, 42.04, 3  44.13, 52.89, 71.66, 127.17, 129.48, 137.55, 142.90, 212.08.  IR (KBr pellet): 3436, 3284, 2932, 1702, 1641, 1577, 1343, 1168 cm" . 1  Anal. Calcd for C H 4 2 N 0 S : C, 62.21; H , 8.77; N , 5.80. Found: C, 62.31; H , 8.79; N , 25  2  5  5.73.  187  Experimental  Chapter 5  (R)- a-Methoxv-a-(trifluoromethvl)phenvlacetate Salt 161  To a solution of aminoketone 16 (91 mg, 0.38 mmol) in Et20 (1 mL) was added a solution of (i?)-a-methoxy-a-(trifluoromethyl)phenylacetic acid (i?-Mosher's acid, 89 mg, 0.38 mmol) in Et20 (2 mL). The white precipitate that formed was filtered and washed with «-pentane (5 mL) affording salt 161 (141 mg, 78%) as a white powder.  mp: 155-156 °C (chloroform / «-pentane)  ' H N M R (400 MHz, CDCI3): 8 1.13-1.39 (m, 12H), 1.46-1.67 (m, 8H), 2.37 (t, J= 6.3 Hz, 4H, C H 2 C O ) , 2.71 (t, J= 8.7 Hz, 4H, CH N), 3.53 (s, 3H, OCH ), 7.33 (m, 2  3  3H), 7.65 (m, 2H), 9.62 (br s, 2H, NH ). 2  1 3  C N M R (75 MHz, CDCI3): 5 22.64, 22.78, 24.55, 26.67, 27.37, 42.14, 43.82, 54.87, 125.51 (q, V  C F  = 288 Hz, CF ), 127.75, 127.87, 128.52, 135.67, 170.53, 212.08. 3  I R ( K B r pellet): 3435,2936, 2858, 1703, 1635, 1370, 1172, 1125,721cm- . 1  Anal. Calcd for C25H38F3NO4: C, 63.41; H , 8.09; N , 2.96. Found: C, 63.34; H , 7.98; N , 3.11.  188  Experimental  Chapter 5  5.4 Synthesis of the Linearly Conjugated Benzocyclohexadienone 52 and its Salts  5.4.1 Preparation of the Benzocyclohexadienone Carboxylic Acid 52  3,4-Dihvdro-2.2-dimethvl-1 (2#)-naphthalenone (163)  O  163  To a cold (0 °C) suspension of potassium hydride (3.0 g, 75 mmol) and methyl iodide (19.0 g, 134 mmol) in THF (200 mL) was added a-tetralone (5.0 g, 34 mmol) in THF (20 mL) over 0.5 h. After the evolution of hydrogen ceased, the mixture was warmed to room temperature and stirred for 16 h. The reaction was quenched by the careful addition of aqueous ammonium chloride (2.0 M , 75 mL) and was followed by extraction into Et20 (3 x 100 mL). The combined ethereal extracts were washed with water (75 mL) and brine (75 mL) followed by concentration in vacuo. Vacuum distillation afforded ketone 163 as a straw-coloured liquid (5.42 g, 91%).  bp 107-100 °C (3 Torr). Lit. bp: 126 °C (11 Torr),  115  137 °C (15 Torr),  116  150 °C (27  *H NMR (400 MHz, CDC1 ): 5 1.18 (s, 6H, CH ), 1.94 (t, J= 6.0 Hz, 2H), 2.95 (t, J = 3  3  6.0 Hz, 2H), 7.19 (d, J= 7.5 Hz, IH), 7.27 (t, J= 5.9 Hz, IH), 7.41 (t, J= 5.9 Hz, IH), 8.02 (d, .7=7.5 Hz, IH).  1 3  C NMR (50 MHz, CDC1 ): 8 24.21, 25.54, 36.45, 41.43, 126.43, 127.80, 128.55, 3  131.28, 132.85, 143.23,202.68.  189  Chapter 5  Experimental  IR(neat): 1689 cm" . 1  H R M S (EI) calcd for C i H 2  1 4  0 174.1045, found 174.1043.  2,3-Dihvdro-2,2-dimethvl-1,4-naphthalenedione  (164)  O  O 164  To a solution of ketone 163 (5.20 g, 29.9 mmol) in dichloromethane (50 mL) was added chromium trioxide (900 mg, 9.0 mmol) andtert-butylhydroperoxide(80 mL of a 70% solution in water) in four equal portions, with 20 h of stirring at room temperature between each addition. The biphasic reaction mixture was worked up with aqueous sodium thiosulfate (until no longer oxidizing to starch-iodide paper), and extracted into dichloromethane (3 x 50 mL). The combined organic extracts were washed with water (100 mL), brine (50 mL), and subsequently dried (MgSOx) and concentrated in vacuo. Silica gel chromatography (10% E t 0 in petroleum ether) afforded diketone 164 (3.87 g, 2  69%) as a pale yellow oil which solidified on standing.  mp: 44-45 ° C  ' H N M R (400 MHz, CDCI3): 5 1.29 (s, 6H), 2.91 (s, 2H), 7.71 (m, 2H), 7.99 (m, IH), 8.07 (m, IH).  1 3  C N M R (75 MHz, CDCI3): 5 25.73, 45.53, 51.96, 126.07, 127.51, 133.63, 133.91, 134.40, 134.86, 196.25,201.30.  190  Experimental  Chapter 5  IR (KBr pellet): 2970, 1696, 1594, 1291, 760 cm" . 1  H R M S (EI) calcd for C i H 0 2  1 2  2  188.0837, found 188.0837.  Anal. Calcd C, 76.57; H , 6.43. Found: C, 76.40; H, 6.38.  3,4-Dihydro-3.3-dimethvl-4-oxo-l-naphthalenyl Trifluoromethanesulfonate  (165)  O  To a cold (-78 °C) solution of L D A (10.8 mmol; formed by reaction of DIP A (1.7 mL, 11.8 mmol) and butyllithium (10.8 mmol)) in THF (120 mL) was added diketone 164 (1.85 g, 9.84 mmol) in THF (10 mL) over a period of 10 minutes. The solution was stirred in the cold for 1.5 h, followed by the addition of TY-phenyl triflimide (4.04 g, 11.3 mmol) as a solid in one portion. The suspension was allowed to warm to room temperature and stirred for an additional 2 h. Workup with aqueous sodium bicarbonate (5% solution, 20 mL) was followed by extraction into E t 0 (3 x 50 mL), washing of the 2  combined organic extracts with water (50 mL) followed by brine (50 mL), then drying (MgSCXO and concentration in vacuo. Purification by silica gel chromatography (15% E t 0 in petroleum ether) gave vinyl triflate 165 as an off-white solid (2.74 g, 87%). 2  mp: 39-40 °C  !  H N M R (400 MHz, C D ) : 5 0.98 (s, 6H), 5.80 (s, IH), 6.86 (t, J= 7.5 Hz, IH), 7.00 6  6  (dt, J= 0.9, 7.7 Hz, IH), 7.37 (d, J= 7.7 Hz, IH), 8.09 (dd, J= 1.1, 7.7 Hz, IH).  191  Experimental  Chapter 5  1 3  C N M R (50 MHz, C D ) : § 25.51, 45.57, 119.13 (q, V 6  6  C F  = 320 Hz), 122.01, 128.23,  129.47, 129.81, 129.89, 132.37, 134.48, 142.09, 198.78.  IR (KBr pellet): 2983, 1665, 1595, 1427, 1142, 1018, 837 cm" . 1  H R M S (EI) calcd for C 1 3 H 1 1 F 3 O 4 S 320.0330, found 320.0327.'  Anal. Calcd C, 48.75; H , 3.46. Found: C, 48.37; H , 3.76.  Methyl 3,4-Dihvdro-3,3-dimethyl-4-oxo-l-naphthalenecarboxvlate (166)  O  C0 Me 166 2  To a solution of Palladium (II) acetate (176 mg, 0.8 mmol), triphenylphosphine (444  m  g  ;  1.7 mmol), DIPEA (4.5 mL, 26 mmol), and anhydrous MeOH (20 mL) in D M F  (50 mL) was added vinyl triflate 165 (2.18 g, 6.80 mmol) under an atmosphere of carbon monoxide. The reaction was stirred at 50 °C for 9 h, during which time a steady stream of carbon monoxide gas was bubbled through the mixture. Addition of Et.20 (200 mL), followed by washing of the organic layer with brine (6 x 50 mL), drying (MgS04), and concentration  !  in vacuo provided ester 166 (1.33 g, 85%) as a pale yellow liquid.  H N M R (400 MHz, CDC1 ): 5 1.30 (s, 6H), 3.85 (s, 3H), 7.38 (dt, J= 1.0, 7.4 Hz, IH), 3  7.59 (dt, J= 1.5, 7.0 Hz, IH), 8.06 (dt, J= 1.4, 7.7 Hz, IH), 8.15 (d, J= 7.4 Hz, IH).  192  Experimental  Chapter 5  1 3  C N M R (75 M H z , CDC1 ): 5 25.14, 44.98, 52.08, 125.18, 126.47, 127.49, 128.38, 3  128.79, 134.03, 134.29, 148.96, 166.43,201.85.  IR (neat): 2970, 1729, 1682, 1595, 1032 cm" . 1  U V / VIS (MeCN, 5.0 x 10" M): 322 (2160) nm (M^cm" ). 4  1  H R M S (EI) calcd for C i H 0 230.0943, found 230.0949. 4  1 4  3  Anal. Calcd C, 73.03; H , 6.13. Found: C, 72.77; H , 6.15.  3,4-Dihydro-3.3-dimethvl-4-oxo-l-naphthalenecarboxylic Acid (52)  O  To a room temperature solution of ester 166 (545 mg, 2.37 mmol) in THF (10 mL) was added a solution of lithium hydroxide monohydrate (1.0 g, 24 mmol) in water (5 mL). The reaction mixture was stirred for 16 h, then diluted with E t 0 (50 mL) and 2  extracted into water (3 x 25 mL). The combined aqueous extracts were acidified to pH 4 with 2 M hydrochloric acid and extracted with E t 0 (3 x 40 mL). The combined organic 2  extracts were washed with water (2 x 25 mL) and brine (50 mL), then dried (MgS0 ) and 4  concentrated in vacuo to yield analytically pure acid 52 (502 mg, 98%) as a white powder.  193  Experimental  Chapter 5  mp: 161-162 °C  !  H N M R (400 MHz, CDC1 ): 5 1.37 (s, 6H), 7.30 (s, IH), 7.44 (dt, J= 0.8, 7.5 Hz, IH), 3  7.65 (dt, J= 1.4, 8.4 Hz, IH), 8.11 (dd, J = 1.4, 7.7 Hz, IH), 8.29 (d, J= 7.7 Hz, IH). Acidic proton not observed.  1 3  C N M R (100 MHz, CDC1 ): 8 25.08, 45.31, 124.31, 126.65, 127.72, 128.66, 128.92, 3  133.59, 134.41, 151.97, 171.46, 201.76.  IR(KBr pellet): 2976, 1695, 1673, 1251, 789 cm" . 1  U V / VIS (MeCN, 2.2  x 10" M): 320 (13,000) 3  H R M S (EI) calcd for C i H , 0 3  2  3  nm  (M'W ). 1  216.0786, found 216.0785.  Anal. Calcd C , 72.21; H , 5.59. Found: C , 71.95; H , 5.60.  194  Experimental  Chapter 5  5.4.2 Preparation of the Benzocyclohexadienone Salts  (25VDiphenvlmethvbvrrolidine Salt (172)  Carboxylic acid 52 (120 mg, 0.56 mmol) and (25)-Diphenylmethylpyrrolidine (133 mg, 0.56 mmol) were dissolved in hot EtOAc (4 mL). The solution was cooled and the solvent allowed to evaporate over a number of days. Crystals of salt 172 (159 mg, 63%) were collected, washed with n-pentane, and air-dried.  mp: 182-184 °C (EtOAc)  *H N M R (400 MHz, CDC1 ): 5 1.36 (s, 6H), 1.57 (m, IH), 1.85 (m, 3H), 2.90 (t, J= 6A 3  Hz, 2H), 4.15 (m, 5H), 7.1-7.3 (m, 9H), 7.42 (m, 2H), 7.60 (dt, J = 1.5, 7.9 Hz, IH), 8.09 (m, 2H).  1 3  C N M R (75 MHz, CDC1 ): 5 23.84, 25.51, 25.58, 30.76, 44.91, 44.99, 54.82, 61.98, 3  127.19, 127.23, 127.40, 127.44, 127.62, 127.66, 127.78, 128.11, 128.91, 128.95, 129.14, 133.85, 140.70, 141.39, 144.33, 171.80, 203.30.  IR (KBr pellet): 3434, 1669, 1639, 1553, 1476, 707 cm" . 1  Anal. Calcd for C H N O : C, 79.44; H , 6.89; N , 3.09. Found: C, 79.48; H , 6.86; N , 3 0  3 1  3  3.21.  195  Experimental  Chapter 5  This structure was confirmed by X-ray crystallographic analysis:  Habit  colourless blocks  Space group a,  A  b,k c,  A  14.299(1) 8.2457(6) 21.780(2)  a(°)  90  PC)  98.126(2)  Y(°)  90  Z  4  R  0.045  (IS, 25)-2-Amino-l,3-dihydroxvpropvlbenzene Salt (173)  To a cold (0 °C) solution of carboxylic acid 52 (100 mg, 0.46 mmol) and (IS, 2S)2-amino-l,3-dihydroxypropylbenzene (77 mg, 0.46 mmol) in E t 0 (3 mL) was added n2  pentane (6 mL) over 20 minutes. The precipitate that formed was filtered, washed with petroleum ether (5 mL) and air-dried, affording salt 173 (156 mg, 88%) as off-white microcrystals.  mp: 84-88 °C (MeCN / w-pentane)  196  Experimental  Chapter 5  !  H N M R (200 MHz, CDC1 ): 5 1.08 (s, 3H), 1.12 (s, 3H), 3.10 (m, IH), 3.36 (m, 2H), 3  4.60 (d, J= 8.3 Hz, IH), 6.44 (s, IH), 6.74 (br s, 5H), 7.0-7.4 (m, 7H), 7.85 (d, J = 7.6 Hz, IH), 7.95 (d, J= 6.4 Hz, IH).  1 3  C N M R (75 MHz, CDC1 ): 8 25.24, 25.28, 44.57, 58.69, 59.80, 72.10, 126.31, 126.81, 3  127.40, 127.78, 128.56, 128.73, 128.93, 131.66, 133.99, 135.75, 139.74, 142.57, 174.67, 203.10. The methyl groups are made disastereotopic due to close ionpairing in soluion.  IR (KBr pellet): 3362, 2916, 1670, 1556, 698 cm" . 1  Anal. Calcd for C22H25NO5: C, 68.91; H , 6.57; N , 3.65. Found: C , 68.96; H , 6.80; N , 3.86.  (IS. 2R. 55Vc&-Mvrtanvlainine Salt 174  To a solution of carboxylic acid 52 (100 mg, 0.46 mmol) in E t 0 (2 mL) was 2  added a solution of (IS, 2R, 5S)-a's-myrtanylamine (71 mg, 0.46 mmol) in Et20 (1 mL). Colourless crystals of salt 174 grew over a period of 1 h and were subsequently filtered and washed with cold E t 0 (1 mL). The yield was 124 mg (73%). 2  mp: 134 °C (sharp) (Et 0) 2  197  Experimental  Chapter 5  ' H N M R (400 MHz, CDCI3): § 0.67 (d, J= 9.3 Hz, IH), 0.78 (s, 3H), 1.05 (s, 3H), 1.29 (s, 6H), 1.36 (m, IH), 1.60-1.85 (m, 5H), 2.21 (m, 2H), 2.78 (m, 2H), 6.76 (s, IH), 7.34 (t, J= 6.7 Hz, IH), 7.51 (dt, J= 1.6, 7.9 Hz, IH), 8.06 (dd, J= 1.4, 6.9 Hz, IH), 8.16 (d, J = 7.3 Hz, IH). Ammonium protons appear as a broad peak 6.7-7.6 ppm (3H).  1 3  C N M R (100 MHz, CDC1 ): 6 19.59, 23.07, 25.60, 27.59, 32.92, 38.37, 40.23, 40.87, 3  40.91, 43.83, 44.77, 45.68, 126.87, 127.58, 127.83, 129.19, 131.26, 133.87, '  136.11,143.68,173.82,203.06.  IR (KBr pellet): 2916, 1682, 1640, 1551, 1392, 797 cm' . 1  Anal. Calcd for C 3 H N 0 : C, 74.76; H , 8.46; N , 3.79. Found: C, 74.96; H , 8.59; N , 2  3 1  3  3.79.  ffl-l-Phenylethvlamine Salt 175  To a solution of (5)-l-phenylethylamine (56 mg, 0.46 mmol) in E t 0 (1 mL) was 2  added a solution of carboxylic acid 52 (100 mg, 0.46 mmol) in E t 0 (2 mL). The solution 2  was cooled to -20 °C and slowly diluted with «-pentane (15 mL). The microcrystals that formed were filtered under argon, washed with anhydrous «-pentane (2 mL), and airdried to yield salt 175 (126 mg, 81%).  198  Experimental  Chapter 5  mp: 96-104 °C (precipitated by w-pentane in Et20 - other solvents gave rise only to oils)  J  H N M R (400 MHz, CDC1 ): 5 1.21 (s, 6H), 1.52 (d, J= 6.8 Hz, 3H), 4.20 (q, J= 6.6 Hz, 3  IH), 6.63 (s, IH), 7.19 (m, 2H), 7.28-7.65 (br m, 8H), 7.96 (d, J= 7.9 Hz, IH), 8.05 (dd, .7=1.4, 7.7 Hz, IH).  1 3  C N M R (75 MHz, CDC1 ): 5 21.68, 25.40, 44.59, 51.03, 126.04, 126.92, 127.37, 3  127.62, 128.41, 128.89, 129.01, 131.23, 133.85, 135.98, 139.10, 143.54, 173.69, 203.11.  I R f K B r pellet): 3444, 2965, 1677, 1637, 1543, 1397, 699 cm" . 1  Anal. Calcd for C i H N O : C, 74.75; H , 6.87; N, 4.15. Found: C, 74.35; H , 6.71; N , 3.94. 2  2 3  (iO-TY-Benzyl-l -phenylethylamine Salt 176  176  Solid  acid  52 (100  mg, 0.46  mmol) was mixed  with  (i?)-7V-benzyl-l-  phenylethylamine (98 mg, 0.46 mmol) and the resulting sticky oil taken up in MeOH (1 mL). To this was added petroleum ether (20 mL), and the resulting biphasic mixture allowed to stand open to the air. Crystallization of salt 176 as colourless prisms (152 mg, 77%) ensued.  199  Experimental  Chapter 5  mp: 107-109 °C (MeOH / Et 0) 2  J  H N M R (200 MHz, CDC1 ): 5 1.29 (s, 3H), 1.31 (s, 3H), 1.52 (d, J= 6.6 Hz, 3H), 3.72 3  (AB quartet, J= 13.0 Hz. 2H), 4.02 (q, J= 6.6 Hz, IH), 6.69 (s, IH), 7.2-7.4 (br m, 11H), 7.58 (m, IH), 8.11 (m, 2H), 9.60 (br s, 2H).  , 3  C N M R (100 MHz, CDC1 ): 5 21.47, 25.50, 25.53, 44.73, 49.41, 57.39, 127.22, 127.31, 3  127.44, 127.68, 128.33, 128.41, 128.57, 128.95, 129.10, 129.60, 131.01, 133.82, 133.91, 136.16, 139.16, 143.39, 172.42, 203.33.  I R ( K B r pellet): 2970, 1674, 1638, 1619, 1593, 1554, 1393, 705 cm" . 1  Anal. Calcd for C H29N0 : C, 78.66; H , 6.84; N , 3.28. Found: C, 78.73; H , 6.84; N , 28  3  3.30.  (i?)-l-(4-Methylphenyl)ethvlamine Salt 177  Carboxylic acid 52 (100 mg, 0.46 mmol) and (i?)-l-(4-methylphenyl)ethylamine (63 mg, 0.46 mmol) were dissolved in refluxing E t 0 (5 mL). The volume of solvent was 2  reduced to (1 mL) in vacuo and the resulting solution allowed to stand at room temperature for 2 h. Colourless crystals of salt 177 deposited on the bottom of the flask and were isolated by suction filtration (145 mg, 89%).  200  Experimental  Chapter 5  mp: 129-138 °C (dec.) (Et 0) 2  ' H N M R (200 MHz, CDC1 ): 5 1.15 (s, 6H), 1.46 (d, J = 6.8 Hz, 3H), 2.17 (s, 3H), 4.12 3  (q, J = 6.6 Hz, IH), 6.42 (s, IH), 7.04 ( A A ' B B ' quartet, J= 7.9 Hz, 4H), 7.32 (m, 2H), 7.83 (m, IH), 8.01 (m, IH), 8.88 (br s, 3H).  1 3  C N M R (75 MHz, CDC1 ): 5 21.03, 21.62, 25.33, 25.37, 44.53, 50.74, 125.98, 127.02, 3  127.31, 127.53, 129.00, 129.51, 129.53, 131.36, 133.73, 136.09, 137.98, 143.38, 173.70, 203.14. The methyl groups are made disastereotopic due to close ionpairing in soluion.  I R ( K B r pellet): 2973, 1688, 1635, 1562, 1522, 1392, 791 cm" . 1  Anal. Calcd for C 2 H N 0 : C, 75.19; H , 7.17; N , 3.99. Found: C, 75.06; H , 7.17; N , 2  25  3  3.97.  Hvdroquinine Salt 178  H  178  To a solution of carboxylic acid 52 (100 mg, 0.46 mmol) in E t 0 (3 mL) was 2  added hydroquinine (151 mg, 0.46 mmol) and MeOH (250 uL). The solution was heated to reflux and allowed to cool to room temperature. A white precipitate formed over 30  201  Experimental  Chapter 5  minutes and was subsequently isolated by suction filtration, washed with n-pentane (2 mL), and air-dried, affording salt 1 7 8 (208 mg, 89%) as a white powder.  mp: 143-148 °C (MeOH / Et 0) 2  ' H N M R (200 MHz, CDC1 ): 8 0.71 (t, J= 6.7 Hz, 3H), 1.12 (m, 3H), 1.33 (s, 3H), 1.36 3  (s, 3H), 1.4-2.0 (brm, 6H), 2.58 (dd,J = 3.3, 13.2 Hz, IH), 2.88 (dt, .7=4.7, 11.3 Hz, IH), 3.16 (t, J= 8.1 Hz, IH), 3.42 (m, IH), 3.63 (s, 3H), 4.14 (m, IH), 6.31 (s, IH), 6.56 (s, IH), 6.80 (d, J= 2.6 Hz, IH), 7.01 (dd, J= 2.4, 9.3 Hz, IH), 7.30 (t, J= 7.5 Hz, IH), 7.39 (d,J= 4.4 Hz, IH), 7.52 (dt, 7 = 1.5, 7.8 Hz, IH), 7.67 (d, J= 9.2 Hz, IH), 8.04 (m, 2H), 8.46 (d, J= 4.5 Hz, IH).  1 3  C N M R (100 MHz, CDC1 ): 8 11.42, 17.85, 24.59, 24.95, 25.68, 26.89, 35.66, 43.21, 3  44.64, 55.50, 56.56, 59.89, 65.97, 99.92, 118.30, 121.33, 125.11, 127.02, 127.26, 127.50, 128.99, 131.32, 132.39, 133.81, 136.46, 141.11, 143.49, 144.85, 146.97, 157.65,174.70,203.54.  IR (KBr pellet): 2963, 1673, 1638, 1620, 1592, 1240, 797 cm . -1  Anal. Calcd for C H N 0 3 3  3 8  2  5  C, 73.04; H , 7.06; N , 5.16. Found: C, 72.96; H , 7.11; N ,  5.19.  202  Experimental  Chapter 5  (IR, 2y>-Ephedrine Salt 179  To a solution of (IR, 2 S)-ephedrine (76 mg, 0.46 mmol) in E t 0 (3 mL) was 1  2  added a solution of carboxylic acid 52 (100 mg, 0.46 mmol) in E t 0 (1 mL). The white 2  precipitate of salt 179 formed immediately and was isolated by suction filtration (155 mg, 88%).  mp: 148-149 °C (EtOAc)  !  H N M R (400 MHz, CDCI3): 5 1.04 (d, J= 6.7 Hz, 3H), 1.28 (s, 6H), 2.61 (s, 3H), 3.20 (m, IH), 4.68 (d, J= 9.8 Hz, IH), 6.75 (s, IH), 7.32 (m, 6H), 7.51 (m, IH), 8.04 (d, J= 6.6 Hz, IH), 8.14 (d, J= 8.2 Hz, IH), 8.4-8.8 (br s, 3H).  1 3  C N M R (100 MHz, CDCI3): § 1.74, 25.49, 25.55, 30.16, 44.77, 60.73, 75.37, 127.06, 127.25, 127.33, 127.62, 128.47, 128.74, 129.10, 131.39, 133.96, 136.21, 140.42, 143.31,174.42,203.44.  I R f K B r pellet): 3311, 2965, 1681, 1638, 1576, 1390, 703 cm" .' 1  Anal. Calcd for C H27N0 : C, 72.42; H , 7.13; N , 3.67. Found: C, 72.78; H , 7.06; N , 23  4  3.65.  203  Experimental  Chapter 5  (IR, 2i?)-Pseudoephedrine Salt 180  A solution of (\R, 2i?)-pseudoephedrine (76 mg, 0.46 mmol) and carboxylic acid 52 (100 mg, 0.46 mmol) in EtOAc (6 mL) was concentrated in vacuo. The residue was taken up in M e C N (2 mL) and cooled to 0 °C. Petroleum ether (10 mL) was added dropwise with stirring. The white precipitate was isolated by suction filtration, washed with «-pentane (2 mL), and air-dried to give salt 180 (143 mg, 81%) as an off-white powder.  m  !  p  :  144-145 °C (MeCN / hexanes)  H N M R (400 MHz, CDCI3): 5 1.03 (d, J= 6.6 Hz, 3H), 1.30 (s, 6H), 2.61 (s, 3H), 3.19 (m, IH), 4.67 (d, J= 9.6 Hz, IH), 6.73 (s, IH), 7.32 (m, 6H), 7.5-7.8 (br s, 3H), 7.53 (m, IH), 8.04 (dd, J= 1.3, 7.8 Hz, IH), 8.13 (d, J= 7.5 Hz, IH).  1 3  C N M R (75 MHz, CDCI3): 5 12.69, 25.48, 25.56, 30.08, 44.70, 60.55, 75.33, 127.03, 127.24, 127.27, 127.57, 128.40, 128.68, 129.05, 131.84, 133.93, 136.28, 140.50, 142.72, 174.61, 203.50. The methyl groups are made disastereotopic due to close ion-pairing in soluion.  IR(KBr pellet): 3317, 1682, 1638, 1576, 1389, 703 cm" . 1  Anal. Calcd for C23H27NO4: C, 72.42; H , 7,13; N , 3.67. Found: C, 72.32; H , 7.17; N , 3.83.  204  Experimental  Chapter 5  (15, 2£)-2-Amino-3-mefhoxy-l-phenyl- 1-propanol Salt 181  C0  2  181  To a solution of carboxylic acid 52 (100 mg, 0.46 mmol) in Et 0 (2 mL) was, 2  added a solution of (IS, 2S)-2-amino-3-methoxy-l-phenyl-l-propanol (84 mg, 0.46 mmol) in Et 0 (3 mL). Colourless crystals of salt 181 (131 mg, 71%) grew over the 2  course of 24 h.  mp: 101-103 °C (Et 0) 2  *H N M R (200 MHz, CDCI3): 5 1.22 (s, 6H), 3.10 (s, 3H, OCH ), 3.16 (m, 2H), 3.39 (m, 3  IH), 4.80 (d, J= 9.3 Hz, IH), 6.72 (s, IH, C=CH), 7.32 (m, 6H), 7.46 (m, IH), 7.62 (br s, 4H, N H + OH), 8.02 (d, 7=7.8 Hz, IH), 8.11 (d, .7= 7.4 Hz, IH). 3  1 3  C N M R (75 MHz, CDCI3): 5 25.41, 25.47, 44.79, 57.44, 59.01, 69.93, 72.28, 126.63, • 127.19, 127.38, 127.76, 128.50, 128.77, 129.07, 130.82, 134.08, 135.96, 140.20, 143.99, 173.82, 203.25.  IR (KBr pellet): 2965, 1678, 1640, 1544, 1392, 703 c m . 4  Anal. Calcd for C H N 0 : C, 69.50; H , 6.85; N , 3.52. Found: C, 69.57; H , 6.90; N , 2 3  2 7  5  3.59.  205  Experimental  Chapter 5  DHOD7PYR Salt 1 8 2  182 Carboxylic acid 5 2 (100 mg, 0.46 mmol) and D H Q D P Y R (204 mg, 0.23 mmol) 2  were dissolved in hot MeOH (2 mL) and the resulting solution cooled to room temperature. Addition of E t 0 (3 mL) induced the crystallization of salt 1 8 2 (197 mg, 2  65%) as an off-white solid.  mp: 187-189 °C (MeOH / Et 0) 2  !  H N M R (400 MHz, CDCI3): 5 0.65(t, J= 6.0 Hz, 6H, C H C H ) , 0.81 (s, 6H, CH ), 0.87 2  3  3  (s, 6H, CH ), 1.36 (m, 2H), 1.50 (m, 2H), 1.66 (m, 4H), 1.83 (m, 2H), 2.21 (t, J = 3  11.6 Hz, 2H), 2.83 (t, J= 10.2 Hz, 2H), 2.98 (m, 2H), 3.21 (m, 2H), 3.42 (m, 4H), 3.81 (s, 6H, OCH ), 6.41 (s, 2H), 6.63 (m, 4H), 6.92 (m, 4H), 7.25 (m, 2H), 7.43 3  (dd, J= 2.4, 9.2 Hz, 2H), 7.48 (d, J= 4.5 Hz, 2H), 7.55 (t, J= 7.4 Hz, 2H), 7.79 (m, 12H), 7.93 (m, 2H), 8.06 (d, J= 9.2 Hz, 2H), 8.79 (d, J= 4.4 Hz, 2H).  , 3  C N M R (75 MHz, CDC1 ): 5 12.12, 19.44, 23.65, 24.21, 24.81, 25.17, 25.66, 35.42, 3  44.33, 48.34, 49.51, 56.53, 57.98, 72.62, 100.90, 104.37, 117.77, 123.17, 126.22, 126.77, 126.92, 127.00, 127.08, 127.67, 127.91, 128.36, 128.53, 129.18, 130.26,  206  Experimental  Chapter 5  130.46, 130.82, 131.04, 131.30, 131.89, 133.59, 135.43, 135.89, 142.23, 143.26, 144.67, 147.17, 159.18, 165.58, 173.54, 203.47.  IR(KBr pellet): 3414, 2962, 1667, 1620, 1591, 1543 cm" . 1  Anal. Calcd for C H N O i o . 5 : C, 74.47; H , 6.48; N , 6.35. Found: C, 74.45; H , 6.71; N , 82  85  6  6.10.  Brucine Complex 1 8 3  183 To a solution of brucine (191 mg, 0.46 mmol) in MeOH (5 mL) was added carboxylic acid 5 2 (100 mg, 0.46 mmol). The resulting solution was diluted with Et20 (5 mL) and sealed for 48 h. Colourless crystals (237 mg, 81%) of complex 1 8 3 were harvested from the mother liquor.  mp: 187-190 °C (MeOH / Et 0) 2  !  H N M R (200 MHz, CDCI3): 5 1.39-1.43 (m, IH), 1.32 (s, 12H, CH ), 1.71 (d,J= 15.1 3  Hz, IH), 2.02 (dd, 7 = 5.9, 13.4 Hz, IH), 2.25 (sextet, J=5.9 Hz, IH), 2.60 (dt, J = 4.0, 15.1 Hz, IH), 2.69 (dd, J = 3.0, 17.0 Hz, IH), 3.05-3.24 (m, 3H), 3.33 (br s, IH), 3.85 (s, 3H, OCH3), 3.87 (d,J= 3.9 Hz, IH), 3.90 (s, 3H, OCH ), 3.98 (d, J 3  207  Chapter 5  Experimental  = 10.4 Hz, IH), 4.05-4.27 (m, 3H), 4.36 (m, IH), 4.60 (br s, IH), 6.27 (m, IH), 6.91 (s, IH), 7.02 (s, 2H), 7.38 (m, 2H), 7.58 (m, 2H), 7.80 (s, IH), 8.08 (m, 2H), 8.23 (m, 2H).  1 3  C N M R (100 MHz, CDC1 ): 8 11.60, 15.24, 19.88, 24.67, 24.85, 25.10, 25.21, 27.19, 3  35.71, 42.87, 44.45, 56.33, 56.38, 57.95, 65.82, 73.04, 100.75, 104.43, 117.75, 122.93, 125.99, 126.90, 127.02, 127.22, 127.82, 127.93, 128.44, 128.64, 128.85, 130.38, 130.58, 130.90, 131.95, 133.77, 135.48, 135.95, 142.01, 144.63, 147.22, 159.13, 161.91, 165.49, 173.52, 203.49.  IR (KBr pellet): 3452, 2965, 2866, 2831, 2376, 1663, 1597, 1501, 1239, 1112, 793 cm" . 1  Anal. Calcd for C 8H oN Oio: C, 70.75; H , 6.18; N , 3.44. Found: C, 71.14; H , 6.03; N , 4  5  2  3.43.  This structure was confirmed by X-ray crystallographic analysis:  Habit  colourless prisms  Space group  P2,2]2i  a, A  9.569(1)  b,A  14.204(4)  c, A  29.98(1)  a(°)  90  PC)  90  Y(°)  90  Z  4  R  0.041  208  Chapter 6  Experimental  Chapter 6 - Photochemical Studies 6.1 General Considerations  Light Sources and Filters Irradiations were performed using either a 450 W Hanovia medium-pressure mercury lamp in a water-cooled immersion well, or a Rayonet Photochemical Chamber Reactor (model RPR-100) fitted with 16 RPR-3500 lamps (384 W total, line emission at 350 nm). Light from the Hanovia lamp was filtered through Pyrex (transmits X > 290 nm), Corning glass #9720 (transmits X > 232 nm, quartz reaction vessels used), or a uranium glass filter (transmits X > 330 nm).  Solution State Photolyses HPLC grade or spectral grade (Fisher Chemical) solvents were used for all solution state photochemical reactions. Reaction solutions were purged with nitrogen for at least 15 minutes prior to irradiation, and the reactions were performed either in sealed reaction vessels or under a positive pressure of nitrogen.  Analytical Solid State Photolyses The solid material (2-5 mg), either as ground single crystals or in polycrystalline form (powder), was sandwiched between two quartz plates and spread out to cover a surface area of approximately 10 cm . The plates were fixed to one another with tape, and 2  the assembly heat-sealed in a poly(ethylene) bag under nitrogen. Following irradiation, the sample was quantitatively washed from the plates with an appropriate solvent, and concentrated in vacuo. For neutral molecules, the sample was analyzed directly by gas chromatogrpahy and/or N M R spectroscopy. Photolysates of the salts derived from aminoketones 12, 14, and 16 were treated with dilute aqueous sodium hydroxide prior to analysis in order to liberate the free amines. Reaction mixtures containing ketoacid 52 or its salts were derivatized with diazomethane, and subsequent analysis based on the corresponding methyl ester 166.  209  Chapter 6  Experimental  Low-Temperature Studies A low temperature ethanol bath contained in an unsilvered Dewar vessel (Pyrex or quartz) was maintained by a Cryocool CC-100 II Immersion Cooling System (Neslab Instrument Inc.). Samples sealed in poly(ethylene) bags were suspended in the cold liquid and irradiated through the transparent walls of the Dewar vessel.  Reaction Conversion and Yield Determinations Yields and conversions for preparative scale photolyses were calculated based on the mass of the isolated, purified products. For analytical reactions, these values were based on the average integration of at least three G C analyses. The difference in G C detector response for a particular starting material and its reaction products was found to be negligible (all are structural isomers in most cases) and thus no corrections were applied to the integration data. The overall precision of the reported results is estimated to be ± 7%.  210  Experimental  Chapter 6  6.2 Photolysis of Adamantyl Spiroketones 5, 6, 7 and 8  Preparative Photolysis of Compound 5  H  hv (Pyrex) terf-BuOH/C H BaO (s) 6  6  (2:1)  5  72  A solution of ketone 5 (26 mg, 0.10 mmol) in 2:1 tert-butanol / benzene (10 mL) containing anhydrous barium oxide (10 mg) was irradiated (Pyrex filter, 450 W Hanovia lamp) for 4 h at room temperature. The solvent was removed in vacuo and the residue chromatographed (Chromatotron, 5% E t 0 in petroleum ether) to afford starting material 2  5 (9 mg, 35%) and ketone epimers (-1:1 by H NMR) 72 (12 mg, 46%; 71% based on l  recovered starting material).  2-(lR*. 3R*. 55 *)-Bicvclor3.3.11non-6-en-3-vl-2.3-dihvdro-l//-inden-l-one. Equal Mixture of 2R and IS Epimers (72) ,  mp: 88-96 °C (petroleum ether)  H  l  N M R (400 MHz, CDCI3): 5 0.96 (m, 2H), 1.28-1.40 (m, 4H), 1.50-1.84 (m, 8H), 1.88-1.97 (m, 2H), 2.06-2.26 (m, 4H), 2.36 (m, 2H), 2.72 (m, 2H), 2.91 (m, 2H), 3.08 (d, J= 8 Hz, IH), 3.11 (d, J= 8.0 Hz, IH), 5.48 (m, 2H), 5.74 (m, IH), 5.84 (m, IH), 7.30 (t, J= 7.0 Hz, 2H), 7.43 (m, 2H), 7.55 (t, J= 7.4 Hz, 2H), 7.70 (d, J = 7.6 Hz, 2H).  1 3  C N M R (100 MHz, CDCI3): S 24.34, 24.73, 25.61, 25.95, 27.01, 27.35, 27.61, 27.81, 29.13, 29.16, 30.71, 30.93, 31.74, 31.76, 34.69, 34.75, 51.20, 51.28, 123.51,  211  Experimental  Chapter 6  123.53, 123.93, 124.34, 126.42, 126.48, 127.15 (2 acc. eq.), 134.49 (2 acc. eq.), 135.35, 135.67, 137.59, 137.65, 154.07, 154.10, 208.99, 209.19.  IR(neat): 1709, 1609, 1464, 1435, 1325, 1280, 743 cm" . 1  H R M S (EI) calcd for C i H O 252.1514, found 252.1509. 8  2 0  Anal. Calcd: C, 85.67; H , 7.99. Found: C, 85.48; H , 8.08.  0-fm(2-Propvl)silyl-2-(17?*. 3R*. 55*)-bicvclor3.3.11non-6-en-3-vl-inden-l-ol (76)  76  To a solution of ketone epimers 72 (13 mg, 0.052 mmol) in anhydrous benzene (1 mL) was added triisopropyl trifluoromethanesulfonate  (15.2  uL, 0.057 mmol) and  triethylamine (10.8 uL, 0.078 mmol). The reaction was stirred at room temperature for 3 days, then diluted with n-pentane (20 mL), water (5 mL) and triethylamine (1 mL). The organic layer was dried (MgSC^) and the solvent removed in vacuo. Silica gel chromatography (Chromatotron, 2% E t 0 in petroleum ether) afforded silyl enol ether 76 2  (18.3 mg, 87%) as a colourless oil which solidified on standing.  mp: 82-84 °C  212  Experimental  Chapter 6  H N M R (400 MHz, C D ) : 5 1.17 (d, J= 2.2 Hz, 9H, CH ), 1.19 (d, J= 2.2 Hz, 9H,  l  6  6  3  CH ), 1.33 (m, 6H), 1.68 (m, IH), 1.91 (m, 3H), 2.15 (m, 2H), 2.31 (br s, IH), 3  2.95 (AB quartet, 2H, CH Ph), 3.27 (m, IH), 5.23 (dd, J= 4.4, 9.6 Hz, IH), 5.87 2  (t, J= 4.4 Hz, IH), 7.11 (t, J= 7.4 Hz, IH), 7.21 (d, J = 7.4 Hz, IH), 2.28 (t, J = 7.4 Hz, IH), 7.56 (d, J= 1A Hz, IH).  1 3  C N M R (75 MHz, CDC1 ): 8 13.71 (-ve), 18.12 (-ve), 24.70 (-ve), 25.39, 26.64 (-ve), 3  27.28 (-ve), 32.70, 32.77, 32.89, 34.83, 117.39 (-ve), 123.44 (-ve), 123.47 (-ve), 123.82 (-ve), 125.88 (-ve), 127.36, 136.05 (-ve), 141.08, 142.76, 147.13.  IR (thin film): 1620, 1464, 1370, 1137, 883 cm" . 1  H R M S (EI) calcd for C 7 H o O S i 408.2849, found 408.2845. 2  4  Anal. Calcd: C, 79.35; H , 9.86. Found: C, 79.08; H , 9.97.  Preparative Solid State Photolysis of Spiroketone 6 as an Aqueous Suspension  78  Ketone 6 (405 mg, 1.52 mmol) was finely ground in a mortar and pestle and suspended in distilled water (400 mL) containing sodium dodecylsulfonate (30 mg) as a surfactant. The rapidly stirred suspension was irradiated in an immersion well (450 W Hanovia lamp, Pyrex filter) for 72 h under an atmosphere of nitrogen during which time the solid became fluffy in appearance. Following photolysis, the suspension was saturated  213  Experimental  Chapter 6  with sodium chloride and extracted with Et20 (4 x 300 mL). The combined organic extracts were washed with brine (3 x 200 mL), dried (MgSC^), and concentrated in vacuo. Silica gel chromatography (10% Et20 and 1% triethylamine in petroleum ether) afforded recovered 6 (236 mg, 58%) and alcohol 78 (86 mg, 21%, 51% based on recovered starting material) as a white solid.  l,2,3,3a,4,5,6,7,l l c , l ld-Decahvdro-2.5-methano-5a//-benzo[clcyclopropare/lphenanthren-5a-ol (78) mp: 131-132 °C (MeCN)  R N M R (500 MHz, C D ) : 5 1.02 (s, IH, OH), 1.16 (ddd, J = 2.3, 3.8, 12.7 Hz, IH),  l  6  6  1.20-1.25 (m, 2H), 1.29-1.44 (m, 4H), 1.47 (ddd, J= 2.1, 5.0, 12.9 Hz, IH), 1.66 (br m, IH), 1.76 (br s, IH), 1.85-2.03 (m, 4H), 2.06 (dquint, J= 2.4, 13.4 Hz, IH), 2.53 (ddd, J= 2.1, 4.9, 16.2 Hz, IH), 3.26 (ddd, J = 5.0, 13.8, 16.2 Hz, IH), 6.46 (d, J= 7.9 Hz, IH), 7.01 (m, 2H), 7.06 (m, IH).  , 3  C N M R (100 MHz, C D ) : 5 22.78 (-ve), 26.47 (-ve), 26.60 (-ve), 26.62, 28.35, 28.66, 6  6  31.93, 32.43, 33.25, 34.93 (-ve), 36.45, 41.17 (-ve), 73.07, 122.62 (-ve), 124.39 (ve), 126.60 (-ve), 128.34 (-ve), 136.35, 142.77.  IR(KBr pellet): 3659 (br), 1494, 1449, 1055, 956, 739 cm" . 1  H R M S (EI) calcd for C H 0 266.1671, found 266.1663. 1 9  2 2  Anal. Calcd: C, 85.67; H , 8.32. Found: C, 85.80; H , 8.33.  214  Experimental  Chapter 6  This structure was confirmed by X-ray crystallographic analysis:  colourless prisms  Habit Space group  P\  A b, A c, A  24.676(4)  a(°)  99.87(1)  P(°)  101.20(1)  Y(°)  109.14(1)  a,  19.871(3)  12.999(2)  Z  16  R  0.050  Preparative Photolysis of Spiroketone 7  81  7  A solution of ketone 7 (100 mg, 0.36 mmol) in 2:1terr-butanol/ benzene (10 mL) was purged with nitrogen for 15 minutes and irradiated (Pyrex filter, 450 W Hanovia) for 60 h. Removal of the solvent in vacuo was followed by silica gel chromatography (10% E t 0 in petroleum ether). Starting material 7 (25 mg, 25%) and cyclobutanol 8 1 (57 mg, 2  57%; 76% based on recovered starting material) were isolated.  215  Experimental  Chapter 6  (7aS\ 7bS\ 9R\ US*. 11a/?*, llbS*. 13/?V6.7.7b.8,9,10.1Ula-Octahvdro-9,7a,ll[l,2,31propanetrivl-7a//-benzofc (81) mp: 130-132 °C (MeCN)  ' H N M R (500 MHz, CDC1 ): 5 0.79 (d, J = 11.6 Hz, IH), 0.97 (s, IH, OH), 1.45 (m, 3  IH), 1.55-1.63 (m, 6H), 1.69 (m, IH), 1.77 (m, 2H), 1.93 (br s, IH), 2.06 (m, IH), 2.14 (dt, J = 4.5, 12.8 Hz, IH), 2.20 (br s, IH), 2.48 (t, J= 6.0 Hz, IH), 2.55 (ddd,  J = 2.6, 5.8, 15.1 Hz, IH), 3.05 (m, IH), 3.21 (m, IH), 7.01 (m, 4H).  1 3  C N M R (125 MHz, CDC1 ): 5 23.92, 25.88, 30.18, 31.80, 32.29, 32.69, 34.01, 34.58, 3  35.84, 36.52, 38.77, 47.97, 51.05, 84.02, 125.84, 126.12, 126.87, 131.76, 141.78, 124.01.  IR (KBr pellet): 3462 (br), 1484, 1448, 1396, 1337, 763, 736 cm" . 1  H R M S (EI) calcd for C20H24O 280.1827, found 280.1823.  Anal. Calcd: C, 85.67; H , 8.63. Found: C, 85.82; H, 8.64.  This structure was confirmed by X-ray crystallographic analysis: Habit Space group  colourless prisms P2,/c  a, A  8.763(3)  b,A  14.060(5)  cA  11.890(2)  a(°)  90  P(°)  90.51(2)  Y(°)  90  Z  4  R  0.045  216  Experimental  Chapter 6  Preparative Photolysis of Spiroketone 8  8  82  A solution of ketone 8 (107 mg, 0.36 mmol) in 2:1 te/t-butanol / benzene (10 mL) was purged with nitrogen for 15 minutes and irradiated (Pyrex filter, 450 W Hanovia) for 10 h. The solvent was removed  in vacuo and the product purified by silica gel  chromatography (Chromatotron, 10% E t 0 in petroleum ether) to give cyclobutanol 8 2 2  (77 mg, 72%) as a colourless oil which solidified on standing.  Data for Cyclobutanol Photoproduct 8 2  mp: 79-80 °C (EtOAc)  J  H N M R (400 MHz, C D ) : 5 0.88 (d, J= 12.5 Hz, IH), 1.00 (s, IH, OH), 1.42-1.70 (m, 6  6  10H), 1.76 (br s, IH), 1.84 (m, IH), 2.00 (m, IH), 2.11 (br s, IH), 2.19 (br s, IH), 2.28 (m, IH), 2.50 (m, 2H), 2.85 (m, 2H), 6.95-7.10 (m, 4H).  1 3  C N M R (75 M H z , C D ) : § 24.76, 25.53, 26.52, 27.15, 29.80, 30.95, 32.08, 32.16, 6  6  33.80, 33.91, 35.30, 37.24, 47.16, 53.87, 82.63, 125.83, 126.14, 126.65, 130.81, 141.81, 145.33.  IR(KBr pellet): 3563, 1478, 1458, 971, 772, 751 cm" . 1  H R M S (EI) calcd for C i H 0 294.1984, found 294.1992. 2  2 6  217  Chapter 6  Experimental  Anal. Calcd: C, 85.67; H , 8.90. Found: C, 85.43; H , 9.08.  This structure was confirmed by X-ray crystallographic analysis:  Habit Space group  colourless prisms PlxIc  a, A  8.8308(1)  b, A  14.646(3)  c, A  12.0651(1)  a(°)  90  P(°)  90.954(1)  Y(°)  90  Z  4  R  0.054  Photolysis of Spiroenone 70  70  93  94  Ketone 70 (132 mg, 0.5 mmol) in M e C N (20 mL) was irradiated (uranium filter, 450 W Hanovia) for 80 minutes. Removal of solvent in vacuo followed by silica gel chromatography (Chromatotron, 3:2 cyclohexane / dichloromethane) afforded recovered starting material (52 mg, 39%), spirocyclopropyl ketone 93 (32 mg, 24%), and naphthol  94 (17 mg, 13%).  218  Experimental  Chapter 6  Photolysis of Cvclopropvlketone 93  Irradiation (Pyrex filter, 450 W Hanovia) of a solution of ketone 9 3 (45 mg, 0.2 mmol) in M e C N (5 mL) for 1 h. afforded naphthol 9 4 (39 mg, 87%) following removal of solvent  in vacuo  and silica gel chromatography (1:1 Et20 / petroleum ether).  Data for Cyclopropane 9 3  mp: 156-157 °C (solidified slowly from an oil)  ' H N M R (500 MHz, CDCI3): 5 1.06 (br s, IH), 1.23 (br s, IH), 1.42 (m, 2H), 1.60 (m, IH), 1.66 (m, IH), 1.72 (m, 3H), 1.80(m, IH), 1.90 (m, 4H), 2.28 (d, J= 4.6 Hz, IH), 2.87 (d, J = 4.6 Hz, IH), 7.25 (dt, J= 1.1, 7.5 Hz, IH), 7.40 (d, J = 7.5 Hz, IH), 7.45 (dt, J= 1.2, 7.5 Hz, IH), 7.53 (d, .7=7.5 Hz, IH).  1 3  C N M R (100 MHz, CDC1 ): 8 27.18 (-ve), 27.47 (-ve), 27.52 (-ve), 35.58, 35.81 (-ve), 3  35.87, 36.08, 36.86, 36.96, 40.01 (-ve), 41.08 (-ve), 60.74, 122.88 (-ve), 125.67 (ve), 126.73 (-ve), 133.56 (-ve), 137.87, 150.19, 201.42.  IR (KBr pellet): 1695, 1605, 1468, 1445, 1271, 1102, 761,712 cm" . 1  U V / VIS (MeCN): 301 (310) nm  (M'W ). 1  H R M S (EI) calcd for C H O 264.1514, found 264.1516. 1 9  2 0  Anal. Calcd: C, 86.32; H , 7.63. Found: C, 86.09; H , 7.66.  219  Experimental  Chapter 6  Data for g-Naphthol 94  mp: 144-145 °C (Et 0) 2  !  H N M R (400 MHz, CDC1 ): 5 1.54 (s, IH, OH), 1.77(s, IH), 1.80 (s, IH), 1.88 (br m, 3  3H), 1.91 (s, IH), 2.02 (m, 2H), 2.12 (m, 3H), 2.90 (t, J= 5.7 Hz, IH), 3.93 (t, J = 5.7 Hz, IH), 4.94 (s, IH), 6.63 (s, IH), 7.37 (t, / = 6.9 Hz, IH), 7.46 (t, J= 6.9 Hz, IH), 8.07 (d, J= 8.8 Hz, IH), 8.15 (d, J= 8.0 Hz, IH).  1 3  C N M R (125 MHz, CDCI3): 5 28.51 (-ve), 30.85 (-ve), 34.82, 35.08, 36.23, 42.37 (-ve), 111.40 (-ve), 121.88 (-ve), 122.95, 123.34 (-ve), 123.56 (-ve), 126.21 (-ve), 132.33, 135.81, 145.71, 148.86,  IR(KBr pellet): 3218 (br), 1626, 1601, 1576, 1441, 1396, 1067, 759 cm . -1  H R M S (EI) calcd for C H O 264.1514, found 264.1514. 1 9  2 0  Anal. Calcd: C, 86.32; H , 7.63. Found: C, 86.07; H , 7.61.  Photolysis of Spiroenone 70 in the Presence of Dimethylamine  220  Experimental  Chapter 6  Into a solution of ketone 7 0 (155 mg, 0.59 mmol) in M e C N (30 mL) was bubbled dimethylamine for five minutes. The solution was irradiated (450 W Hanovia lamp, uranium filter) for 1.5 h. Following removal of the solvent in vacuo and silica gel chromatography (1:1 Et20 / petroleum ether), amide 96 (148 mg, 82%) was isolated as a white solid.  Data for Amide 96  mp: 72-74 °C (Et 0) 2  J  H N M R (400 MHz, CDC1 ): S 1.69-1.80 (br m, 4H), 1.80-1.90 (br m, 6H), 1.94 (br s, 3  2H), 2.34 (br s, IH), 2.81 (s, 3H, CH ), 2.88 (br s, IH), 3.11 (s, 3H, CH ), 3.30, 3  3  (d, J= 7.4Hz, 2H, C^CHCFb), 5.14 (t, J= 7.4 Hz, IH, C=CH), 7.12 (m, IH), 7.17 (dt, J= 1.8, 6.7 Hz, IH), 7.26 (m, 2H).  1 3  C N M R (75 MHz, CDC1 ): 5 28.40, 29.65, 31.90, 34.44, 37.02, 38.63, 38.73, 39.63, 3  40.40, 113.64, 125.63, 125.70, 128.69, 128.11, 136.15, 138.22, 148.77, 171.36.  IR (thin film): 1646, 1505, 1448, 1393, 1268, 1220, 1067, 775, 755 cm" . 1  H R M S (EI) calcd for C i H N O 309.2093, found 309.2095. 2  2 7  Anal. Calcd: C, 81.51; H , 8.79; N , 4.53. Found: C, 81.36; H , 8.98; N , 4.53.  221  Experimental  Chapter 6  6.3 Photolysis of Macrocyclic Aminoketones and Their Salts 6.3.1 Preparative Photolysis of Compound 12 in Solution  12  117  118  119  A solution of aminoketone 12 (380 mg, 1.92 mmol) intert-butanol/ benzene 97:3 (100 mL) was purged with nitrogen and irradiated (450 W Hanovia lamp, Pyrex filter) for 26 h. The solution was concentrated in vacuo and chromatographed on silica gel (10% MeOH, 1% triethylamine in petroleum ether) to give cyclobutanol 117 (oil, 62 mg, 16%), cyclobutanol 118 (oil, 40 mg, 11%), and reduced product 119 (white solid, 114 mg, 30 %).  Data for (IR*. 10i?*)-4-Methvl-4-azabicvclor8.2.01dodecan-10-ol  !  (117)  H NMR (400 MHz, C D ) : 5 1.14 (m, IH), 1.25 (m, IH), 1.3-1.5 (m, 4H), 1.50-1.66 (m, 6  6  3H), 1.66-1.85 (m, 4H), 1.93 (s, 3H), 1.9-2.1 (m, 4H), 2.10-2.19 (m, 2H), 2.51 (m, IH).  1 3  C NMR (75 MHz, C D ) : 5 19.30, 22.57, 24.82, 25.30, 28.32, 33.64, 37.48, 44.36, 6  6  51.24 (CH), 54.72, 57.39, 76.87.  IR(neat): 3381, 2932, 1456, 1105 cm" . 1  HRMS (DCI, isobutane) calcd for C H N O (M+H) 198.1858, found 198.1856. +  1 2  2 4  222  Experimental  Chapter 6  Data for (\S\ 10i?*V4-Methvl-4-azabicvclor8.2.01dodecan-10-ol (118)  *H NMR (400 MHz, C D ) : 5 1.12-1.31 (m, 3H), 1.33-1.80 (m, 6H), 1.88 (m, 5H), 1.98 6  6  (s, 3H), 2.00 (m, IH), 2.15 (m, 5H).  1 3  C NMR (75 MHz, C D ) : 5 20.92, 22.43, 22.96, 26.46, 31.12, 34.12, 42.03, 43.16, 6  6  43.32 (CH), 55.74, 57.09, 76.62.  IR(neat): 3290, 2932, 1456, 1122, 1083 cm" . 1  HRMS (EI) calcd for C i H N O 197.1780, found 197.1783. 2  2 3  Data for 7-Methyl-7-azacyclododecanol (119)  mp: 34 °C («-pentane)  *H NMR (400 MHz, C D ) : 5 0.73 (br s, IH, OH), 1.13-1.28 (m, 6H), 1.31-1.49 (m, 6H), 6  6  1.54 (m, 2H), 1.71 (m, 2H), 1.91 (m, 2H), 2.00 (s, 3H, CH ), 2.31 (m, 2H), 3.80 3  (quint, J= 5.6 Hz, IH, CH(OH)).  1 3  C NMR (75 MHz, C D ) : 5 22.81, 23.18, 25.50, 34.74, 42.72, 54.86, 67.73. 6  6  IR (KBr pellet): 3349, 2927, 2856, 2781, 1467, 1006, 952, 724 cm" . 1  HRMS (EI) calcd for C H N O 199.1936, found 199.1936. 1 2  2 5  Anal. Calcd: C, 72.31; H , 12.64; N , 7.03. Found: C, 72.53; H , 12.65; N , 6.87.  223  Chapter 6  Experimental  6.3.2 Independent Preparation of Alcohol Photoproduct 119  119  To a solution of aminoketone 12 (98 mg, 0.48 mmol) in 95% ethanol (10 mL) was added sodium borohydride (20 mg, 0.53 mmol) in one portion. The reaction was stirred overnight and quenched cautiously with 2 M HC1 (3 mL). The solution was concentrated in vacuo, and the residue taken up in 2 M potassium hydroxide (10 mL) and extracted with Et20 (3 x 10 mL). The combined organic extracts were dried (MgS0 ) and 4  concentrated in vacuo to yield aminoalcohol 119 (94 mg, 96%). A n analytically pure sample could be obtained by sublimation (60 °C, 3 Torr).  See section 6.3.1 for characterization data for compound 119.  224  Experimental  Chapter 6  6.3.3 Solution Photolysis of Hydrochloride Salt 127  127  121  122  123  A solution of salt 127 (198 mg, 0.80 mmol) in M e C N (60 mL) was purged with nitrogen and irradiated (450 W Hanovia lamp, Pyrex filter) for 29 h. The photosylate was concentrated in vacuo and chromatographed on silica gel (Chloroform / MeOH / triethylamine 20:5:1) affording cyclobutanol 121 (oil, 59 mg, 35 %), cyclobutanol 122 (white solid, 41 mg, 24%), and cleavage product 123 (oil, 14 mg, 8%).  Data for (IB*. 12i?*V5-Azabicyclori0.2.01tetradecan-12-ol (121)  ]  H NMR (400 MHz, C D ) : 5 0.80-1.40 (m, 9H), 1.40-1.59 (m, 4H), 1.71 (m, 4H), 1.806  6  2.07 (m, 4H), 2.32-2.55 (m, 4H).  1 3  C NMR (75 M H z , C D ) : § 19.52, 22.99, 24.81, 28.45, 28.57, 28.99, 29.54, 33.90, 6  6  36.10, 48.24, 48.40, 50.11 (CH), 77.34.  IR(neat): 3364, 2922, 1456, 1350, 1261, 1116 cm . -1  HRMS (EI) calcd for C13H25NO 211.1936, found 211.1933.  Anal. Calcd: C, 73.88; H , 11.92; N , 6.63. Found: C, 73.88; H , 12.12; N , 6.69.  225  Chapter 6  Experimental  Data for (IS*. 12i?*V5-Azabicyclori0.2.01tetradecan-12-ol (122)  mp: 40-41 °C (Et 0) 2  *H NMR (400 MHz, C D ) : 5 1.14-1.72 (m, 15H), 1.88 (m, 2H), 2.08 (m, 2H), 2.23-2.48 6  6  (m, 6H).  1 3  C NMR (100 MHz, C D ) : 5 22.70, 23.23, 25.82, 27.06, 27.27, 27.77, 29.37, 34.08, 6  6  39.80, 43.13 (CH), 48.49, 48.91, 76.73.  IR(neat): 3282, 2927, 1456, 1260, 1127 cm" . 1  HRMS (EI) calcd for C H N O 211.1936, found 211.1936. 1 3  2 5  Anal. Calcd: C, 73.88; H , 11.92; N , 6.63. Found: C, 73.96; H , 11.98; N , 6.69.  Data for 8-(4-Pentenvlamino)-2-octanone (123)  *H NMR (400 MHz, C D ) : 5 0.70 (br s, IH), 1.10-1.28 (m, 4H), 1.35 (quint, J= 7.3 Hz, 6  6  2H), 1.46 (m, 4H), 1.67 (s, 3H), 1.94 (t,J= 7.5 Hz, 2H), 2.04 (q, J= 7.7 Hz), 2.48 (m, 2H), 5.00 (m, 2H), 5.79 (m, IH).  1 3  C NMR (75 MHz, C D ) : 5 24.00, 27.52, 29.31, 29.43, 29.90, 30.55, 31.95, 43.29, 6  6  49.72, 50.23, 114.57, 139.04, 206.31.  IR(neat): 2931, 1718, 1458, 1638, 1129,911 cm" . 1  HRMS (EI) calcd for C i H N O 211.1936, found 211.1939. 3  2 5  Anal. Calcd: C, 73.88; H , 11.92; N , 6.63. Found: C, 74.04; H , 12.02; N , 6.59.  226  Experimental  Chapter 6  6.3.4 Independent Synthesis of Fourteen-Membered Cleavage Photoproduct  6-(2.5.5-Trimethvl-n.31dioxan-2-vnhexanoic Acid Amide (134V  134  To a room temperature solution of 7-oxooctanamide (500 mg, 3.16 mmol) and 2,2-dimethyl-l,3-propanediol (480 mg, 4.62 mmol) in benzene (50 mL) was added 4toluenesulfonic acid (20 mg, catalyst). The solution was refluxed for 2 h with continuous removal of water via a Dean-Stark apparatus. The reaction was cooled and washed successively with saturated potassium carbonate (2 x 10 mL) and water (10 mL). The organic layer was dried ( K C 0 ) and concentrated in vacuo. Silica gel chromatography 2  3  (5:45:1 MeOH / EtOAc / triethylamine) afforded product 134 (462 mg, 64%) as a white solid.  mp: 101-102 °C (EtOAc)  *H N M R (400 MHz, C D ) : 8 0.62 (s, 3H), 0.94 (s, 3H), 1.22 (m, 2H), 1.32 (s, 3H), 1.54 6  6  (m, 4H), 1.75 (m, 4H), 3.36 (AB quartet, 4H), 4.18 (br s, IH), 5.28 (br s, IH).  1 3  C N M R (75 MHz, C D ) : S 20.09, 22.40, 22.89, 23.47, 25.70, 29.82, 29.84, 35.63, 6  6  39.03,70.31,99.01, 174.68.  I R ( K B r pellet): 3364, 3192, 2951, 1663, 1631, 1099 cm" . 1  H R M S (DCI, isobutane) calcd for C i H 6 N 0 (M+H) 244.1913, found 244.1913. +  3  2  3  227  Experimental  Chapter 6  Anal. Calcd for C i 3 H N 0 : C, 64.16; H , 10.35; N , 5.76. Found: C, 63.96; H , 10.37; N , 25  3  5.64.  6-(2,5,5-Trimethvl-ri,31dioxan-2-vl)hexanoic Acid Pent-4-envlamide (138)  H 138  To a warm (50°C) suspension of potassium carbonate (280 mg, 2.1 mmol), sodium hydroxide (140 mg, 3.5 mmol), tetrabutylammonium hydrogensulfate (50 mg, 0.15 mmol) and amide 134 (200 mg, 0.82 mmol) in toluene (8 mL) was added 5-bromo1-pentene (300 mg, 2.1 mmol) in three portions over a period of lh. The suspension was heated to reflux for 4h, then cooled and filtered. The solids were triturated with toluene (3 x 10 mL) and the combined organic filtrates dried (MgSC^) and concentrated in vacuo. Silica gel chromatography (EtOAc / hexanes 1:1; 1% triethylamine) provided two fractions, the more polar of which contained the desired product 138 (117 mg, 46%) as a colourless oil.  J  H N M R (400 MHz, C D ) : 5 0.62 (s, 3H), 0.95 (s, 3H), 1.31 (m, 7H), 1.55-1.70 (m, 4H), 6  6  1.82 (m, 6H), 3.05 (q, J = 6.8 Hz, 2H), 3.36 (AB quartet, 4H), 4.51 (br s, IH), 4.98 (m, 2H), 5.69 (m, IH).  1 3  C N M R (75 MHz, C D ) : 5 20.05, 22.38, 22.91, 23.49, 26.00, 29.32, 29.87, 29.94, 6  6  31.33, 36.51, 38.89, 39.19, 70.32, 98.99, 114.96, 138.28, 171.62.  IR (neat): 3295, 2949, 1646, 1556, 1095, 909 cm" . 1  228  Chapter 6  Experimental  H R M S (EI) calcd for C H N 0 3 311.2460, found 311.2467. 1 8  3 3  Anal. Calcd: C, 69.41; H , 10.68; N , 4.50. Found: C, 69.50; H , 10.71; N , 4.43.  8-(4-Pentenvlamino)-2-octanone  (123)  O H 123  To a solution of amide 138 (180 mg, 0.58 mmol) in THF (50 mL) was added lithium aluminum hydride (200 mg, 5.2 mmol). The suspension was refluxed for 8h, then cooled in an ice-water bath and quenched carefully with 50% aqueous potassium hydroxide (1 mL). Hydrochloric acid (7 M , 5 mL) was added carefully, and the resulting mixture stirred at room temperature for lh. The mixture was concentrated to ca. 20 mL in vacuo and rendered alkaline (to pH test paper) by the addition of 50% aqueous potassium hydroxide. The mixture was extracted with n-pentane (3 x 30 mL) and the combined organic extracts washed with water (2 x 10 mL), dried (MgS04), and concentrated in vacuo to give aminoketone 123 (71 mg, 58%) as a colourless oil.  See section 6.3.3 for characterization data for compound 123.  229  Experimental  Chapter 6  Af-fe(4-Pentenvl)-44oluenesulfonamide  (142)  142  To a solution of 4-toluenesulfonamide (480 mg, 2.8 mmol) in benzene (7 mL) was added sodium hydroxide (finely powdered, 600 mg, 15 mmol), potassium carbonate (600 mg, 6.1 mmol), and tetrabutylammoium hydrogensulfate (100 mg, 0.30 mmol). The resulting suspension was heated to 50 °C and 5-bromo-l-pentene (1.0 g, 6.7 mmol) was added over a period of 45 minutes. The reaction mixture was then refluxed for 4 h. After cooling to room temperature, the solids were filtered off and triturated with benzene (3 x 10 mL), and the combined organic filtrates washed with water (3x15 mL) and brine (10 mL). Drying (MgSO^) followed by concentration in vacuo afforded analytically pure 142 (764 mg, 89%) as a colourless liquid.  *H N M R (400 MHz, CDC1 ): 5 1.60 (quint, / = 7.5 Hz, 4H), 2.01 (q, J= 7.1 Hz, 4H), 3  2.40 (s, 3H), 3.09 (t,J= 7.5 Hz, 4H), 4.99 (m, 4H), 5.75 (m, 2H), 7.27 (d, J= 8.0 Hz, 2H), 7.67 (d, J= 8.0 Hz, 2H). 1 3  C N M R (100 MHz, CDCI3): § 21.46, 27.92, 30.80, 47.94, 115.25, 127.12, 129.58, 136.96, 137.47, 142.99.  IR(neat): 3077, 2933, 1641, 1599, 1342, 1160, 1092, 655 cm" . 1  H R M S (DCI, isobutane) calcd for C17H26NO2S (M+H) 308.1684, found 308.1685. +  230  Experimental  Chapter 6  Anal. Calcd for C17H25NO2S: C, 66.41; H , 8.20; N , 4.56. Found: C, 66.72; H , 8.37; N , 4.58.  to(4-PentenvDamine Hydrochloride ( 1 4 3 )  0 143 Into a 50 mL round bottomed flask containing sulfonamide 1 4 2 (820 mg, 2.67 mmol) and MeOH (500 uL, 19.8 mmol) was condensed anhydrous ammonia (20 mL). Solid sodium was dissolved in ca. 20 mg portions until a blue colour persisted, after which MeOH was introduced until the colour disappeared. The solution was allowed to warm under a constant stream of nitrogen during which time all of the ammonia evaporated. Aqueous potassium hydroxide (20 mL of a 2 M solution) was added to the residue, and the resulting mixture extracted into n-pentane (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgS04, and filtered. A stream of dry hydrogen chloride gas was passed through the pentane solution causing salt 1 4 3 to precipitate. The white solid (227 mg, 60%) was collected by suction filtration, washed with n-pentane (5 mL) and dried in vacuo.  ,  mp: >275 °C (dec.)  ' H N M R (400 MHz, CDCI3): 5 2.00 (quint, J= 7.3 Hz, 4H), 2.13 (m, 4H), 2.89 (m, 4H), 5.01 (m, 4H), 5.72 (m, 2H), 9.52 (br s, 2H).  1 3  C N M R (75 MHz, CDC1 ): 5 24.82, 30.74, 47.26, 116.41, 136.16. 3  231  Chapter 6  Experimental  IR (KBr pellet): 2938, 1644, 1594, 1445, 993, 913, 641 cm" . 1  Anal. Calcd for C i H N C l : C, 63.31; H , 10.63; N , 7.38. Found: C, 63.24; H , 10.77; N , 0  20  7.18.  In Situ Preparation offe(4-Pentenyl)amine(129)  129  Anhydrous potassium carbonate (50 mg) and salt 143 (25 mg) were suspended in benzene-^ (2 mL) and stirred together for 2 h. The solids were filtered off and the solution analyzed by H and !  J  1 3  C N M R spectroscopy:  H N M R (200 MHz, C D ): 8 0.46 (br s, IH), 1.44 (quint, J= 7.1 Hz, 4H), 2.03 (q, J = 6  6  7.1 Hz, 4H), 2.42 (t, J= 7.1 Hz, 4H), 5.01 (m, 4H), 5.79 (m, 2H).  1 3  C N M R (100 MHz, C D ) : § 29.87, 31.91, 49.60, 114.58, 139.03. 6  6  232  Experimental  Chapter 6  6.3.5 Preparative Photolysis of Aminoketone 16  16  124  125  126  A solution of aminoketone 16 (988 mg, 4.13 mmol) in M e C N (800 mL) was placed in an immersion well photoreactor and kept under an atmosphere of nitrogen. The solution was irradiated (450 W Hanovia lamp, Pyrex filter) for 21 h and subsequently concentrated in vacuo. Silica gel chromatography (chloroform / MeOH / triethylamine 20:5:1) afforded cyclobutanol 124 (white solid, 172 mg, 17%), cyclobutanol 125 (white solid, 81 mg, 8%) and cleavage product 126 (oil, 312 mg, 32%).  Data for (IR*. 14i?*)-6-Azabicvclori2.2.01hexadecan-14-ol  (124)  mp: 95-96 °C (Et 0) 2  ' H N M R (400 MHz, C D ) : 5 0.78 (br s, 2H), 1.00-2.09 (m, 23H), 2.48 (m, 4H). 6  1 3  6  C N M R (100 MHz, C D ): 5 19.25, 19.80, 22.60, 24.62, 24.73, 26.90, 28.25, 28.94, 6  3  29.47, 31.64, 34.31, 47.30, 47.52, 50.00 (CH), 76.42.  IR(KBr pellet): 3398, 2933, 1457, 1435, 1065 cm" . 1  H R M S (EI) calcd for C H N O 239.2249, found 239.2253. 1 5  2 9  Anal. Calcd: C, 75.26; H , 12.21; N , 5.85. Found: C, 75.38; H , 12.34; N , 5.81.  233  Experimental  Chapter 6  Data for (IS*. 14.R*)-6-Azabicvclo|T2.2.01hexadecan-14-ol (125)  mp: 94-95 ° C (Et 0) 2  !  H NMR (400 MHz, C D ) : 5 1.16-1.79 (m, 20H), 1.80-2.00 (m, 4H), 2.10 (m, IH), 2.28 6  6  (m, 2H), 2.48 (m, IH), 2.63 (m, IH).  1 3  C NMR (100 M H z , C D ) : 5 20.49, 22.41, 23.34, 23.44, 25.68, 27.25, 27.44, 27.88, 6  6  28.64, 32.86, 40.52, 43.62 (CH), 47.01, 47.50, 77.63.  IR(KBr pellet): 3259, 2932, 1462, 1274, 1125, 845 cm" . 1  HRMS (EI) calcd for C H N O 239.2249, found 239.2252. 1 5  2 9  Anal. Calcd: C , 75.26; H , 12.21; N , 5.85. Found: C , 75.45; H , 12.22; N , 5.77.  Data for 9-(5-Hexenvlamino)-2-nonanone (126)  *H NMR (400 MHz, C D ) : 5 0.47 (s, IH), 1.1-1.5 (m, 14H), 1.65 (s, 3H), 1.92 (t,J= 7.3 6  6  Hz, 2H), 1.99 (m, 2H), 2.50 (m, 4H), 5.00 (m, 2H), 5.78 (m, IH).  , 3  C NMR (100 MHz, C D ) : 5 23.99, 27.04, 27.60, 29.26, 29.48, 29.76, 30.13, 30.66, 6  6  34.07, 43.33, 50.18, 50.33, 114.57, 139.09, 206.99.  IR(neat): 2930, 1717, 1464, 1411, 1361,910 cm" . 1  HRMS (EI) calcd for C i H N O 239.2249, found 239.2249. 5  2 9  Anal. Calcd: C , 75.26; H , 12.21; N , 5.85. Found: C , 74.98; H , 12.16; N , 5.83.  234  Experimental  Chapter 6  6.3.6 Independent Synthesis of Sixteen-Membered Cleavage Photoproduct 126  8-Oxononanoic Acid Amide (131)  To a cold (0 °C) solution of 8-oxononanoic acid (6.0 g, 34.9 mmol) and D M F (250 uL) in dichloromethane (100 mL) was added oxalyl chloride (19 mL of a 2.0 M solution in dichloromethane, 38.0 mmol) over 20 minutes. The reaction was stirred in the cold for 2 h, after which time a steady stream of anhydrous ammonia was bubbled through the solution. The reaction was quenched with aqueous sodium carbonate (50 mL of a 10% solution), and extracted into dichloromethane (3 x 100 mL). The combined organic extracts were washed with brine (3x  60 mL), dried over MgS04, and  concentrated in vacuo. Recrystallization of the residue from water gave amide 131 (4.3 g, 72%) as white flakes.  mp: 91-92 °C (water)  *H N M R (400 MHz, CDCI3): 5 1.31 (m, 4H), 1.55 (quintet, J=  7.2 Hz, 2H), 1.62  (quintet, J= 7.2 Hz, 2H), 2.10 (s, 3H), 2.19 (t, J= 7.4 Hz, 2H), 2.40 (t, J = 7.3 Hz, 2H), 5.48 (br, s, 2H).  1 3  C N M R (75 MHz, CDCI3): 5 23.50, 25.21, 28.72, 28.85, 29.89, 35.67, 43.56, 175.53, 209.27.  IR (KBr pellet): 3392,3198, 2929, 1703, 1665, 1615, 1415 cm" . 1  H R M S (DCI, isobutane + NH ) calcd for C H i N 0 (M+H) 172.1338, found 172.1337. +  3  9  235  8  2  Experimental  Chapter 6  Anal. Calcd for C H N 0 : C, 63.13; H , 10.01; N , 8.18. Found: C, 63.49; H , 9.96; N , 9  1 7  2  8.05.  7-(2,5,5-Trimethyl-ri,31dioxan-2-vl)heptanoic Acid Amide ( 1 3 5 )  O  135 A round bottomed flask equipped with a Hickman still and an efficient condenser was charged with a solution of amide 1 3 1 (2.03 g, 11.8 mmol), 2,2-dimefhyl-l,3propanediol  (neopentyl  glycol,  1.80  g,  17.8  mmol) and 4-toluenesulfonic  acid  monohydrate (110 mg, 0.58 mmol) in benzene (200 mL). The solution was refluxed for 6 h, with periodic removal of water from the still. The solution was cooled and extracted sequentially with aqueous sodium carbonate (50 mL of a 10% solution) and brine (3 x 50 mL), dried  (MgSO"4)  and concentrated in vacuo. Recrystallization of the residue from  E t 0 afforded ketal 1 3 5 (1.8 g, 60%) as a white solid. 2  mp: 62-64 °C (Et 0) 2  J  H N M R (400 MHz, C D ) : 8 0.64 (s, 3H), 0.95 (s, 3H), 1.23 (m, 4H), 1.34 (s, 3H), 1.54 6  6  (m, 4H), 1.77 (m, 4H), 3.36 (AB quartet, J= 11.3 Hz, 4H, OCH ), 4.41 (br s, IH), 2  5.92(br s, IH).  1 3  C N M R (75 MHz, C D ) : 5 20.11, 22.40, 22.89, 23.65, 25.72, 29.58, 29.89, 30.06, 6  6  35.83, 39.14, 70.31, 99.07, 175.40.  236  Experimental  Chapter 6  IR(KBr pellet): 3382, 3197, 2937, 1665, 1094 c m . 4  H R M S (DCI, isobutane) calcd for C14H28NO3 (M+H) 258.2069, found 258.2070. +  Anal. Calcd for C i H 7 N 0 : C, 65.33; H , 10.57; N , 5.44. Found: C, 65.44; H , 10.50; N , 4  2  3  5.38.  7-(2,5,5-Trimethvl-ri,31dioxan-2-vl)heptanoic Acid Hex-5-envlamide (139)  To a warm (50 °C) suspension of potassium carbonate (280 mg, 2.1 mmol), sodium hydroxide (140 mg, 3.5 mmol), tetrabutylammonium hydrogensulfate (50 mg, 0.15 mmol) and amide 135 (212 mg, 0.82 mmol) in toluene (8 mL) was added 6-bromo1-hexene (318 mg, 2.1 mmol) in three portions over a period of lh. The suspension was heated to reflux for 4h, then cooled and filtered. The solids were triturated with toluene (3 x 10 mL) and the combined organic filtrates dried (MgSO-4) and concentrated in vacuo. Silica gel chromatography (1:1 EtOAc / hexanes; 1% triethylamine) provided two fractions, the more polar of which contained the desired product 139 (168 mg, 60%) as a colourless oil.  !  H N M R (400 MHz, CDCI3): 8 0.87 (s, 3H), 0.99 (s, 3H), 1.32 (s, 3H), 1.28-1.55 (m, 10H), 1.63 (m, 4H), 2.06 (q, J = 7.0 Hz, 2H), 2.12 (t, J = 7.4 Hz, 2H), 3.23 (q, / = 6.8 Hz, 2H), 3.47 (AB quartet, J= 11.3 Hz, 4H), 4.97 (m, 2H), 5.38 (br s, IH), 5.78 (m, IH).  237  Experimental  Chapter 6  1 3  C N M R (75 MHz, CDCI3): 8 20.22, 21.30, 22.50, 22.78, 23.25, 23.54, 25.54, 25.79, 26.11, 28.74, 28.93, 29.05, 29.28, 29.64, 29.89, 29.96, 33.30, 36.58, 36.80, 38.14, 39.37, 43.59, 70.35, 71.77, 98.98, 114.79, 138.37, 173.18. Two amide rotamers present.  IR (KBr pellet): 3296, 2936, 2861, 1551, 1457 cm" . 1  H R M S (EI) calcd for C20H37NO3 339.2773, found 339.2770.  Anal. Calcd C, 70.75; H , 10.98; N , 4.13. Found: C, 71.02; H , 10.91; N , 4.03.  9-(5-Hexenvlamino)-2-nonanone Hydrochloride (140)  O  1©J X H  0  CI  H 140  To a solution of amide 139 (197 mg, 0.58 mmol) in THF (50 mL) was added lithium aluminum hydride (200 mg, 5.2 mmol). The suspension was refluxed for 8h, then cooled in an ice-water bath and quenched carefully with 50% aqueous potassium hydroxide (1 mL). Hydrochloric acid (7 M , 5 mL) was added carefully, and the resulting mixture stirred at room temperature for lh. The mixture was concentrated to ca. 20 mL in vacuo and rendered alkaline (to pH test paper) by the addition of 50% aqueous potassium hydroxide. The mixture was extracted with n-pentane (3 x 30 mL) and the combined organic extracts washed with water (2 x 10 mL), and dried (MgSCV). A stream of dry hydrogen chloride was passed through the solution and the precipitate isolated by suction filtration, affording salt 140 (127 mg, 78%) as a white powder.  238  Experimental  Chapter 6  mp: 178-181 °C (dec.)  J  H N M R (400 MHz, CDC1 ): 5 1.2-1.6 (m, 10H), 1.87 (m, 4H), 2.06 (m, 2H), 2.11 (s, 3  3H), 2.40 (t, J= 7.3 Hz, 2H), 2.89 (m, 4H), 4.99 (m, 2H), 5.75 (M, IH), 9.51 (br s, 2H).  1 3  C N M R (100 MHz, CDC1 ): 5 23.54, 25.21, 25.72, 26.09, 26.65, 28.81, 28.89, 29.89, 3  33.01, 43.55, 47.40, 47.49, 115.34, 137.62, 208.98.  IR (KBr pellet): 3410, 2928, 1712, 1641, 1461, 1377, 1169,911 cm" . 1  Anal. Calcd for C i H N O C l : C, 65.31; H, 10.96; N , 5.08. Found: C, 65.19; H , 10.98; N , 5  30  4.92.  9-(5-Hexenylamino)-2-nonanone ( 1 2 6 )  O  A suspension of finely ground salt 1 4 0 (56 mg, 0.20 mmol) and anhydrous potassium carbonate (200 mg)ra-hexane(10 mL) was stirred for 6 h. The solids were filtered off and the filtrate concentrated in vacuo to yield aminoketone 1 2 6 (43 mg, 89%) as a colourless oil.  See section 6.3.4 for characterization data for compound 126.  239  Experimental  Chapter 6  6.4 Photolysis of Benzocyclohexadienone Derivatives Preparative Photolysis of Ketoester 166  C0 Me  Me0 C 167  2  2  166  A solution of ketoester 166 (206 mg, 0.90 mmol) in M e C N (10 mL) was purged with nitrogen and irradiated (Rayonet, 350 nm) for 3 h. The photosylate was concentrated in vacuo and the residue chromatographed (Chromatotron, 15% Et20 in petroleum ether) to give ketoester 167 (168 mg, 82%) as a colourless oil which solidified on standing.  Data  for  Methyl  6,6a-dihvdro-l.l-dimethyl-6-oxo-cvcloprop[a]indene-la(l//)-  carboxvlate (167) mp: 52-53 °C  ' H N M R (200 MHz, CDC1 ): 5 0.84 (s, 3H), 1.40 (s, 3H), 2.80 (s, IH), 3.83 (s, 3H), 7.36 3  (m, IH), 7.58 (m, 2H), 7.92 (d, J= 7.7 Hz, IH).  1 3  C N M R (100 MHz, CDC1 ): 5 16.73, 23.20, 44.76, 45.28, 50.12, 52.03, 123.10, 126.74, 3  127.73, 134.03, 136.82, 148.20, 168.78, 198.58.  IR (KBr pellet): 1732, 1714, 1605, 1232, 1210, 766 cm" . 1  H R M S (EI) calcd for C i H 0 230.0943, found 230.0943. 4  1 4  3  Anal. Calcd C, 73.03; H , 6.13. Found: C, 72.99; H , 6.10.  240  Chapter 6  Experimental  Preparative Photolysis of Ketoacid 52  A solution of ketoacid 52 (282 mg, 1.31 mmol) in E t 0 (7 mL) was purged with 2  nitrogen and irradiated (Rayonet, 35o nm) for 2.5 h. The photosylate was concentrated in vacuo and the residue recrystallized from EtOAc / hexanes to afford acid 53 (246 mg, 87%) as colourless prisms.  Data for 6,6a-Dihvdro-lJ-dimethvl-6-oxo-cvcloprop[a]ihdene-la(l/f)-carboxylic acid £53}  mp: 136-137 °C (EtOAc / hexanes)  ' H N M R (200 MHz, CDC1 ): 5 0.95 (s, 3H), 1.51 (s, 3H), 2.85 (s, IH), 7.38 (m, IH), 3  7.60 (m, 2H), 7.97 (d, J= 7.6 Hz, IH). Acidic proton not observed.  1 3  C N M R (100 M H z , CDCI3): 5 17.13, 23.29, 44.84, 45.61, 51.62, 123.45, 127.17, 128.07, 134.41, 136.87, 147.86, 174.54, 198.64.  I R ( K B r pellet): 2883, 1681, 1605, 1467, 1425, 1289, 1253, 1213 cm"'.  H R M S (EI) calcd for C i H 0 216.0786, found 216.0787. 3  1 2  3  Anal. Calcd C, 72.21; H, 5.59. Found: C, 72.29; H, 5.69.  241  Chapter 6  This structure was confirmed by X-ray crystallographic analysis:  Habit Space group  A A A  a, b,  c  irregular colourless crystals Pl\lc  10.874(2) 9.182(1) 11.247(2)  o(°)  90  P(°)  95.72(1)  Y(°)  90  Z  4  R  0.044  242  Experimental  Chapter 6  Experimental  6.5 Resolution of Acid 53 with Brucine  Brucine (194 mg, 0.50 mmol) and ketoacid 53 (108 mg, 0.50 mmol) were dissolved in hot MeOH (10 mL). The solution was slowly cooled to room temperature and left for 2 h. Crystals of optically pure (as determined by chiral G C and HPLC of the methyl ester 166 produced after diazomethane workup) salt 171 (91 mg, 30%) were recovered.  Data for Brucinium (la»S, 6ai?)-6,6a-Dihvdro-l,l-dimethvl-6-oxo-cvcloprop["q]indenela(17¥)-carboxylate»Methanol (171)  • MeOH  mp: 172-174 °C (MeOH)  ' H N M R (400 MHz, CD OD): 8 0.85 (s, 3H), 1.43 (s, 3H), 1.69 (d, J= 15.2 Hz, IH), 3  1.98-2.10 (m, 2H), 2.52 (dt, J= 4.2, 15.2 Hz, IH), 2.70 (dd, J= 3.0, 17.5 Hz, IH), 3.05 (dd, J= 8.4, 17.5 Hz, IH), 3.17-3.40 (m, 5H), 3.64 (m, IH), 3.81 (s, 6H, OCH ), 4.09 (m, 2H), 4.18 (m, 2H), 4.31 (br s, IH), 4.38 (m, IH), 6.28 (m, IH), 3  6.98 (s, IH), 7.35 (m, IH), 7.57 (m, 2H), 7.76 (s, IH), 8.00 (d, J= 7.7 Hz, IH).  1 3  C N M R (100 MHz, CD OD): 8 16.77, 24.70, 26.27, 31.90, 42.00, 42.75, 46.00, 51.15, 3  51.77, 53.21, 53.36, 56.69, 57.23, 60.89, 62.63, 65.12, 78.32, 78.37, 102.44, 107.64, 122.49, 123.80, 127.58, 128.59, 135.35, 135.41, 135.79, 137.21, 138.25, 148.36, 151.55, 152.75, 171.23, 174.71, 203.27.  243  Chapter 6  Experimental  Anal. Calcd for C 7 H o N 0 : C, 69.36; H , 6.29; N , 4.37. Found: C, 69.70; H , 6.59; N , 3  4  2  8  4.34.  This structure was confirmed by X-ray crystallographic analysis:  Habit Space group  a,  A  b,k c,  A  colourless prisms P2{l{l  x  9.4684(3) 12.4100(5) 26.978(2)  a (°)  90  P(°)  90  Y(°)  90  Z  4  R  0.039  244  Experimental  Chapter 6  6.6 Quantum Yield Determinations  Quantum yields for compound 14 were determined at 313 nm. This wavelength was isolated from light produced by a 450 W Hanovia medium-pressure mercury lamp using a combination of Corning 7-54 glass plates and a 0.002 M potassium chromate solution containing 5% potassium carbonate. Irradiations were carried out in a merry-goround  118  apparatus. The temperature was maintained at 21 ± 2 °C using a thermostat.  Photochemical production of acetophenone from valerophenone was used as the actinometer. The quantum yield for this reaction is known to be 0.33 at 313 nm for an opaque solution of valerophenone (ca. 0.1 M) in benzene.  119  A l l substrate and  actinometer solutions were degassed by subjecting them to three freeze-pump-thaw cycles, and subsequently flame-sealing them under vacuum. Valerophenone, benzene, 120  and tert-butanol were dried and distilled before use according to literature procedures. Stern-Volmer quenching experiments were conducted using 2,5-dimefhyl-2,4-hexadiene that was distilled from lithium aluminum hydride prior to use. All quantitative photoproduct measurements were made using standard gas chromatographic techniques. G C response factors were calculated relative to linear alkane internal standards (Cio to Cig). G C data were based on the average of three chromatographic runs, and quantum yield data were calculated based on the average of two parallel irradiations each of the actinometer and substrate solutions. Quantum yields reported are based on a plot of quantum yield versus photoproduct concentration and were extrapolated back to 0% conversion. Singlet quantum yields are based on the portion of the Stern-Volmer plot where the value oftyjfyremains constant and the slope is 0, indicating complete quenching of the triplet excited state. Quantum yields are reported ± the estimated standard deviation and are presented in Table 3.4.  245  Chapter 6  Experimental  References  1 Corey, E. J.; Cheng, X . - M . The Logic of Chemical Synthesis; John Wiley & Sons: New York. 1995. 2 For an example see: Cheung, E . ; Kang, T.; Scheffer, J. R.; Trotter, J. J. Chem. Soc, Chem. Commun., in press. 3.(a) Organic Solid State Chemistry; Desiraju, G. R. Ed., Elsevier: Amsterdam, 1987. (b) Photochemistry in Organized and Constrained Media; Ramamurthy, V . Ed.; V C H : New York, 1991. (c) Ito, Y. Synthesis 1998, 1. 4 Schmidt, G. M . J. Pure Appl. Chem. 1971, 27, 647. 5 Desiraju, G . R. Crystal Engineering: The Design of Organic Solids; Elsevier: Amsterdam. 1989. 6 Etter, M . C. Acc. Chem. Res. 1989, 23, 120. See also: Coe, S.; Kane, J. J.; Nguyen, T. L.; Toledo, L. M . ; Wininger, E.; Fowler, F. W.; Lauher, J. W. J. Am. Chem. Soc. 1997, 119, 86. 7 Vankatesan, K.; Ramamurthy, V . In Photochemistry in Constrained and Organized Media; Ramamurthy, V . , Ed.; V C H Publishers: New York. 1991; Chapter 4. 8 Xiao, J.; Yang, M . ; Lauher, J. W.; Fowler, F. W. Angew. Chem., Int. Ed. Engl. 2000, 39,2132. 9 Enkelmann, V . Chem. Mater. 1994, 6, 1337. 10 Kiji, J.; Wegner, K. G.; Schulz, R. C. Polymer 1973,14, 433. 11 MacGillivray, L . R.; Reid, J. L.; Ripmeester, J. A. J. Am. Chem. Soc. 2000,122, 7817. 12 Toda, F.; Tanaka, K.; Tamashima, T.; Kato, M. Angew. Chem., Int. Ed. Engl. 1998, 37, 2724. 13 (a) Hung, J. D.; Lahav, M . ; Luwich, M . ; Schmidt, G. M . J. Isr. J. Chem. 1972, 10, 585. (b) Cohen, M . D.; Cohen, R.; Lahav, M . ; Nie, P. L. J. Chem. Soc, Perkin Trans. 1973, 2, 1095. (c) Green, B. S.; Heller, L. J. Org. Chem. 1974, 39, 1960. 14 (a) Cohen, M . D.; Schmidt, G. M . J. J. Chem. Soc. 1964, 1996. (b) Cohen, M . D.; Schmidt, G. M . J.; Sonntag, F. I. J. Chem. Soc. 1964, 2000. (c) Schmidt, G. M . J. J. Chem. Soc. 1964, 2014.  246  Chapter 6  Experimental  15 Cohen, M . D. Angew. Chem., Int. Ed. Engl. 1975,14, 386. 16 Weiss, R. G.; Ramamurthy, V.; Hammond, G. S. Acc. Chem. Res. 1993, 26, 530. MCE.  News, 2000, 78, 40. See also: Yang, Z.; Garcia-Garibay, M . A. Org. Lett. 2000, 2, 1963.  18 Zimmerman, H . E . ; Sebek, P.; Zhu, Z. J. Am. Chem. Soc. 1998,  120, 8549 and  references therein. See also Garcia-Garibay, M . A.; Houk, K. N.; Keating, A. E . ; Cheer, C. J.; Leibovitch, M . ; Scheffer, J. R.; Wu, L . - C . Org. Lett. 1999, 1, 1279 and references therein. 19 For reviews of Type II photochemistry see: (a) Wagner, P. J. Acc. Chem. Res. 1971, 4, 168. (b) Wagner, P.; Park, B.-S. In Organic Photochemistry; Padwa, A., Ed.; Marcel Dekker: New York, 1991; Volume 11; Chapter 4. 20 Turro, N. J. Modern Molecular Photochemistry; Benjamin/Cummings: Menlo Park, California. 1978; Chapter 5. 21 Turro, N . J. Modern Molecular Photochemistry; Benjamin/Cummings: Menlo Park. 1978; p 364. 22 Weiss, R. G. In CRC Handbook of Phoochemistry and Photobiology; C R C Press: Boca Raton. 1995; Chapter 39. 23 Yang, N . C ; Elliot, S. P.; Kim, B. J. A. Chem. Soc. 1969, 91, 7551. 24 (a) Scaiano, J. C. Tetrahedron, 1982, 38, 879. (b) Griesbeck, A . G.; Mauder, H . ; Stadtmuller, S. Acc. Chem. Res. 1994, 27, 70. (c) Turro, N . J.; Buchachenko, A. L.; Tarasov, V . F. Acc. Chem. Res. 1995, 28, 69. (d) Caldwell, R. Pure Appl. Chem. 1984, 56, 1167. 25 JJimels, H.; Scheffer, J. R. Tetrahedron 1999, 55, 885 and references therein. 26 Wagner, P. J. In CRC Handbook of Phoochemistry and Photobiology; C R C Press: Boca Raton. 1995; Chapter 38. 27 Bondi, A . J. Phys. Chem. 1964, 68, 441. See also: Edward, J. T. J. Chem. Educ. 1970, 47,261. 28 Wagner, P. J. Top. Curr. Chem. 1976,  66,1.  29 Dorigo, A . E.; McCarrick, M . A.; Loncharich, R. J.; Houk, K. N. J. Am. Chem. Soc. 1990,112, 7508 and references therein.  247  Chapter 6  Experimental  30 Kasha, M . Radiat. Res. 1960, Suppl. 2, 243. See also: Zimmerman, H . E . Tetrahedron 1963, 19, 393. 31 Gudmundsdottir, A . D.; Lewis, T. J.; Randall, L. H . ; Scheffer, J. R.; Rettig, S. J.; Trotter, J.; Wu, C.-H. J. Am. Chem. Soc. 1996, 116, 6167. 32 Leibovitch, M . ; Olovsson, G.; Scheffer, J. R.; Trotter, J. J. Am. Chem. Soc. 1998,120, 12755. 33 Cheung, E.; Netherton, M . R.; Scheffer, J. R.; Trotter, J. Org. Lett. 2000, 2,11. 34 Lutz, G.; Pinkos, R.; Murty, B. A. R. C ; Spurr, P. R.; Fessner, W.-D.; Worth, H. F.; Knothe, L.; Prinzbach, H. Chem. Ber. 1992,125, 1741. 35 Sauers, R. R.; Edberg, L. A. J. Org. Chem. 1994, 59, 7061. 36 (a) Quinkert, G . Pure Appl. Chem. 1973, 33, 285. (b) Turro, N . J. Modern Molecular Photochemistry; Benjamin/Cummings:  Menlo Park. 1978; pp 512-514. (c)  Griffiths, J.; Hart, H . J. Am. Chem. Soc. 1968, 90, 3297. (d) Griffiths, J.; Hart, H. J. Am. Chem. Soc. 1968, 90, 5296. (e) Hart, H ; Murray, R. K. Jr. . Org. Chem. 1970, 35, 1535. 37 Quinkert, G. Chimia 1977, 31, 225. 38 (a) Caswell, L.; Garcia-Garibay, M . A.; Scheffer, J. R.; Trotter, J. J. Chem. Ed. 1993, 70, 785; (b) Feringa, B. L.; van Delden, R. A. Angew. Chem., Int. Ed. Engl. 1999, 55,3418. 39 Evans, S. V.; Garcia-Garibay, M . ; Omkaram, N.; Scheffer, J. R.; Trotter, J.; Wireko, F. J. Am. Chem. Soc. 1986,108, 5648. 40 Sekine, A.; Hori, K.; Ohashi, Y.; Yagi, M . ; Toda, F. J. Am. Chem. Soc. 1989, 111, 697. See also: Aoyama, H.; Hasegawa, T.; Omote, Y. J. Am. Chem. Soc. 1979, 101, 5343. 41 Cheung, E.; Netherton, M . R.; Scheffer, J. R.; Trotter, J.; Zenova, A. Tetrahedron Lett. 2000, in press. 42 Gamlin, J. N.; Jones, R.; Leibovitch, M . ; Patrick, B.; Scheffer, J. R.; Trotter, J. Acc. Chem. Res. 1996, 29, 203. 43 Cheung, E.; Netherton, M . R.; Scheffer, J. R.; Trotter, J. J. Am. Chem. Soc. 1999,121, 2919.  248  Chapter 6  Experimental  44 Leibovitch, M . ; Olovsson, G.; Scheffer, J. R.; Trotter, J. J. Am. Chem. Soc. 1998,120, 12755. 45 Spanka, G.; Rademacher, P.; Duddeck, H. J. Chem. Soc, Perkin Trans. 2 1988, 2119. 46 (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413; (b) Schuster, M . ; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036; (c) Armstrong, S. K. J. Chem. Soc, Perkin Trans. 1 1998, 371. 47 Maier, M . E. Angew. Chem., Int. Ed. Engl. 2000, 39, 2073. 48 Alberts, A . H.; Wynberg, H.; Strating, J. Synth. Comm. 1972, 2, 79. 49 Olah, G. A.; Narang, S. C ; Gupta, B. G. B.; Malhotra, R. J. Org. Chem. 1979, 44, 1247. 50 Manchand, P. S. J. Chem. Soc, Chem. Commun. 1971, 667. 51 Corey, E. J.; Suggs, W. Tetrahedron Lett. 1975, 31, 2650. 52 (a) Schwab, P.; France, M . B.; Ziller, J. W.; Grubbs, R. H . Angew. Chem., Int. Ed. Engl. 1995, 34, 2039; (b) Schwab, P.; Grubbs, R. H . ; Ziller, J. W. J. Am. Chem. Soc. 1996,118, 100. 53 Henne, A.; Fischer, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 435. 54 Turro, N . J. Modern Molecular Photochemistry; Benjamin/Cummings: Menlo Park, California. 1978; pp 386-392. 55 Jefferson, E. A.; Keefe, J. R.; Kresge, A . J. J. Chem. Soc, Perkin Trans. 2 1995, 2041. 56 (a) Wagner, P. J. J. Am. Chem. Soc. 1967, 89, 5898; Wagner, P. J.; (b) Kochevar, I. E.; Kemppainen, A . E. J. Am. Chem. Soc. 1972, 94, 7489. 57 Gunther, H . NMR Spectroscopy, Second Edition; John Wiley & Sons: New York. 1995; pp 82-84. 58 Wagner, P. J.; Kelso, P. A.; Kemppainen, A . E.; McGrath, J. M . ; Schott, H. N.; Zepp, R. G. J. Am. Chem. Soc. 1971, 94, 7506. 59 Wagner, P. J.; Kelso, P. A.; Zepp, R. G. J. Am. Chem. Soc. 1972, 94, 7480. 60 Adam, W.; Grabowski, S.; Wilson, R. M . Chem. Ber. 1989, 122, 561. 61 Andrew, D.; Weedon, A. C. J. Am. Chem. Soc 1995,117, 5647. 62 O'Neal, H. E.; Miller, R. G.; Gunderson, E. J. Am. Chem. Soc. 1974, 96, 3351. 63 Scaiano, J. C. J. Am. Chem. Soc. 1977, 99, 1494.  249  Experimental  Chapter 6  64 Hu, S.; Neckers, D. C. / . Chem. Soc., Perkin Trans. 2 1999, 1771. 65 Leibovitch, M . ; Olovsson, G.; Scheffer, J. R.; Trotter, J.  Am. Chem. Soc. 1998,120,  12755. 66 Ihmels, H.; Scheffer, J. R. Tetrahedron 1999, 55, 885. 67 Wagner, P. J.; Kelso, P. A.; Kempainen, A. E. J. Am. Chem. Soc. 1968, 90, 5896. 68 Burdett, J. K. Molecular Shapes; Wiley-Interscience: New York. 1980; p 6. 69 Bondi, A. J. Phys. Chem. 1964, 68, 441. 70 (a) Dunkelblum, E . ; Hart, H . ; Suzuki, M . J. Am. Chem. Soc. 1977, 99, 5074; (b) Suzuki, M . ; Hart, H ; Dunkelblum, E.; Li, W. J. Am. Chem. Soc. 1977, 99, 5083. 71 (a) Quinkert, G. Pure Appl. Chem. 1973, 33, 285; (b) Quinkert, G. Angew. Chem., Int. Ed. Engl. 1972,11, 1072. 72 Hart, H ; Murrary, R. K. J. / . Org. Chem. 1970, 35, 1535. 73 Dolphin, D.; Wick, A. In Tabulation of Infrared Spectral Data; John Wiley and Sons: New York. 1977; pp 175-240. 74 Spanka, G.; Rademacher, P.; Duddeck, H. J. Chem. Soc, Perkin Trans. 2 1988, 2119. 75 Leonard, M . J.; Fox, R. C.; Oki, M . J. Am. Chem. Soc. 1954, 76, 5708. 76 Leonard, N. J.; Oki, M . ; Chiavarelli, S. J. Am. Chem. Soc. 1955, 77, 6234. 77 Hurd, R. N.; Shah, D. H. J. Org. Chem. 1973, 38, 390. 78 Ram, S.; Spicer, L. D. Synth. Comm. 1987,17, 415. 79 Kang, S.-K.; Kim, W.-S.; Moon, B.-H. Synthesis 1985, 1161. 80 Leonard, N. J.; Schimelpfenig, C. W. Jr. J. Org. Chem. 1958, 1708. 81 (a) Schulte-Elte, K. H ; Willhalm, B.; Thomas, A. F.; Stoll, M . ; Ohloff, G. Helv. Chim. Acta 1911, 54, 1759. (b) Mori, T.; Matsui, K.; Nozaki, H . Tetrahedron Lett. 1970, 14, 1175. (c) Matsui, K.; Mori, T.; Nozaki, H . Bull. Chem. Soc. Jpn. 1971, 44, 3440. (d) Burchill, P. J.; Kelso, A . G.; Power, A. J. Aust. J. Chem. 1976, 29, 2477. 82 Simonaitis, R.; Cowell, G. W.; Pitts, J. N . Jr. Tetrahedron Lett.1961, 11, 3751 and references cited therein. 83 Lewis, F. D.; Hilliard, T. A. J. Am. Chem. Soc. 1970, 92, 6672. 84 Wagner, P. J. In CRC Handbook of Photochemistry and Photobiology; Horspool, W. M . and Song, P.-S. Eds.; C R C Press: Boca Raton, Florida. 1995, Chapter 38.  250  Experimental  Chapter 6  85 Ariel, S.; Evans, S.; Omkaram, N.; Scheffer, J. R.; Trotter, J. J. Chem. Soc., Chem. Commun. 1986, 375. 86 Turro, N . J. Modern Molecular Photochemistry; Benjamin/Cummings: Menlo Park. 1978, pp 377-380. 87 (a) Scaiano, J. R.; Lissi, E . A.; Encina, M . V. In Reviews of Chemical Intermediates, Volume 2; Elsevier: New York. 1978, pp 139-196. (b) Wagner, P.; Park, B.-S. In Organic Photochemistry, Volume 11; Padwa, A., Ed.; 1990, Chapter 4. 88 Gajda, T.; Zwierzak, A. Synthesis 1981, 1005. 89 Wagner, P. J.; Kelso, P. A.; kemppainen, A. E.; McGrath, J. M . ; Schott, H . N.; Zepp, R. G. J. Am. Chem. Soc. 1972, 94, 7506. 90 Lewis, T. J. Ph. D. Thesis, University of British Columbia, 1993. 91 Gudmundsdottir, A. D.; Lewis, T. J.; Randall, L . H . ; Scheffer, J. R.; Rettig, S. J.; Trotter, J.; Wu, C.-H.  Am. Chem. Soc. 1996,116, 6167.  92 Sauers, R. R.; Edberg, L. A . J. Org. Chem. 1994, 59, 7061. 93 (a) Hoffmann, R.; Swenson, J. R. J. Phys. Chem. 1970, 74, 415. (b) Wagner, P. J.; May, M . ; Haug, A . Chem. Phys. Lett. 1972, 13, 545. (c) Birge, R. R.; Pringle, W. C ; Leermakers, P. A . J. Am. Chem. Soc. 1971,  93, 6715. (d) Birge, R. R.;  Leermakers, P. A. J. Am. Chem. Soc. 1971, 93, 6726. 94 Ihmels, H.; Scheffer, J. R. Tetrahedron 1999, 55, 885. 95 Jacques, J.; Fouquey, C Tetrahedron Lett. 1971, 48, 4620. 96 Moore, W. M . ; Ketchum, M . J. Am. Chem. Soc. 1962, 84, 1369. 97 Gamma radiolysis experiments were graciously performed by Professor Masahiro Irie at Kyushu University, Japan. In his expert opinion, failure of the salt to react after exposure to 30 Mrad of radiation indicates that the substance is inert to gammaradiolysis. 98 Muzart, J. Tetrahedron Lett. 1987,  28, 2132.  99 Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1985, 26, 1109. 100 Quinkert, G. Pure Appl. Chem. 1973, 33, 285. 101 Turro, N . J. Modern Molecular Photochemistry; Benjamin Cummings: Menlo Park. 1978, p 107.  251  Experimental  Chapter 6  102 Griffiths, J.; Hart, H. J. Am. Chem. Soc. 1968, 90, 5296. 103 Jacques, J.; Collet, A.; Wilen, S. H . Enantiomers, Racemates, and Resolutions; Wiley-Interscience: New York. 1981, Chapter 5. 104 (a) Parker, D. Chem. Rev. 1991, 91, 1441. (b) Fulwood, R.; Parker, D. J. Chem. Soc, Perkin Trans. 2 1994, 57. 105 Ladd, M . F. C ; Palmer, R. A . Structure Determination by X-ray  Crystallography;  Plenum Press: New York. 1993; p 81. 106 (a) Zimmerman, H . E . ; Sebek, P.; Zhu, Z. J. Am. Chem. Soc. 1998, 120, 8549 and references cited therein, (b) Garcia-Garibay, M . A.; Houk, K. N.; Keating, A. E . ; Cheer, C. J.; Leibovitch, M . ; Scheffer, J. R.; Wu, L . - C . Org Lett. 1999,1, 1279. 107 Alberts, A. H.; Wynberg, H.; Strating, J. Synth. Comm. 1972, 2, 79. 108 Shultz, D. A.; Boal, A . K.; Farmer, G. T. J. Am. Chem. Soc. 1997, 119, 3846. 109 Boymond, L.; Rottlander, M . ; Cahiez, G.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1998,37, 1701. 110 Grubbs, R. H . ; Chang, S. Tetrahedron 1998, 54, 4413. 111 Leonard, N. J.; Fox, R.; Oki, M . ; Chiavarelli, S.  Am. Chem. Soc. 1954, 76, 5708.  112 Rama Rao, A. V.; Reddy, S. P.; Reddy, E. R. J. Org. Chem. 1986, 51, 4158. 113 Kang, S . - K ; Kim, W.-S.; Moon, B.-H. Synthesis 1985, 1161. 114 Yu, Q.; Yao, Z.-J.; Chen, X.-G.; Wu, Y . - L . J. Org. Chem. 1999, 64, 2440. 115 Marvell, E . N.; Geiszler, A. O.  Am. Chem. Soc. 1952, 74, 1259.  116 Clemo, G.; Dickenson, H . G. J. Chem. Soc. 1937, 255. 117 Sengupta, S. C. J. Prakt. Chem. 1938, 131, 82. 118 Murov, S. L. Handbook of Photochemistry; Marcel Dekker: New York, 1973. 119 Wagner, P. J.; Kochevar, I. E.; Kemppainen, A. E. J. Am. Chem. Soc. 1972, 94, 7489. 120 Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. Purification Chemicals; Second Edition, Pergamon Press: Oxford, 1980.  252  of Laboratory  

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