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Reaction selectivity and asymmetric synthesis in solid state organic photochemistry Chen, Shuang 2004

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REACTION SELECTIVITY A N D A S Y M M E T R I C SYNTHESIS IN SOLID STATE ORGANIC PHOTOCHEMISTRY by SHU ANG CHEN B . S c , Suzhou University, P. R. China, 1996 M.Sc . , Suzhou University, P. R. China, 1999 A THESIS S U B M I T T E D I N P A R T I A L F U L F I L M E N T O F T H E R E Q U I R E M E N T S F O R T H E D E G R E E O F D O C T O R O F P H I L O S O P H Y in T H E F A C U L T Y O F G R A D U A T E S T U D I E S ( D E P A R T M E N T O F C H E M I S T R Y ) We accept this thesis as conforming to the required standard T H E U N I V E R S I T Y O F B R I T I S H C O L U M B I A M A Y 2004 ©Shuang Chen, 2004 Abstract The Norrish/Yang type II photochemistry of four bicyclo[3.3.1]nonyl phenyl ketones was studied in solution and in the crystalline state. In both media, the bicyclic ketones without a-methyl substituents were found to be photochemically inert, while the cc-methyl substituted ones underwent Yang photocyclization to give endo-aryl cyclobutanols as predominant products. An unusual 1,4-hydroxybiradical disproportionation reaction was also observed during the photolysis of the a-methylated bicyclo[3.3.1]nonyl phenyl ketones, although it was a minor process (< 5%). By utilizing the ionic chiral auxiliary method, chiral ammonium carboxylate salts (7 in total) were formed between optically pure amines and the achiral bicyclo[3.3.1]nonyl phenyl ketone derivative containing a carboxylic acid substituent. Photolysis of these salts in the solid state afforded the cyclobutanol product with fair to excellent enantiomeric excesses (45% - 96%). A homologous series of spirobicyclo[3.3.1]nonyl ketones (4 in total) was synthesized and their Norrish/Yang type II photochemistry was investigated both in solution and in the solid state. These compounds were chosen for investigation because the conformation of the 1,4-biradicals formed by y-hydrogen atom abstraction could be varied in a regular and incremental fashion by changing the size of the ketone-containing spiro ring. X-ray crystallographic analysis of these compounds provided detailed information about the geometric factors responsible for the partitioning of the intermediate 1,4-hydroxybiradicals among cleavage, cyclization, and reverse hydrogen transfer. Parameters governing the efficiency of the type II cleavage and Yang cyclization i i were established, respectively. The results indicate that while geometry does have a strong influence on the 1,4-hydroxybiradical partitioning among cyclization, cleavage and reverse hydrogen transfer, a full understanding of the results requires that the strain involved in forming the cyclization products be taken into account. The ionic chiral auxiliary approach for asymmetric induction was also investigated in a c/s-bicyclo[4.3.0]non-8-ylacetophenone system, which undergoes the Norrish type II photocleavage reaction to yield a simple chiral alkene — cis-3a, 4, 5, 6, 7, 7a-hexahydro-lH-indene. Irradiation of chiral salts (5 in total) in the crystalline state gave enantioselectivities ranging from poor to moderate (ee = 11% - 67%). Single crystal X-ray diffraction studies were performed on a number of these compounds, and on this basis, the structure-reactivity relationships involved were discussed. in Table of Contents Abstract i i Table of Contents iv List of Figures : viii List of Tables xii List of Symbols and Abbreviations xiii Acknowledgements xvii I N T R O D U C T I O N 1 C h a p t e r 1 I n t r o d u c t i o n 1 1.1 Solid State Organic Photochemistry 1 1.2 Type II Photochemistry of Ketones 9 1.2.1 The Norrish/Yang Type II Reaction 9 1.2.2 Electronic Aspects of Type II Reactions 12 1.2.3 Geometric Requirements for the Norrish/Yang Type II Reaction 13 1.2.4 Cyclization versus Cleavage 15 1.3 Asymmetric Photochemistry 19 1.3.1 Asymmetric Induction in Crystalline-State Photochemistry 19 1.3.2 The Ionic Chiral Auxiliary Concept 22 1.4 Research Objectives 27 References 31 R E S U L T S A N D D I S C U S S I O N 3 8 C h a p t e r 2 P h o t o c h e m i s t r y a n d A s y m m e t r i c I n d u c t i o n o f 9 - B e n z o y l -b i c y c l o [ 3 . 3 . 1 ] n o n a n e D e r i v a t i v e s 3 8 2.1 Preparation of Substrates 38 2.1.1 Synthesis of 9-Benzoylbicyclo[3.3.1]nonanes 60 and 61 39 2.1.2 Synthesis of 9-Benzoyl-9-methylbicyclo[3.3.1]nonanes 71-73 40 2.2 Photochemical Studies and Identification of Photoproducts 43 2.3 Asymmetric Induction Studies 51 2.3.1 Preparation of Optically Active Salts of Keto Acid 73 51 2.3.2 Solution State Photolysis of the Optically Active Salts 53 iv 2.3.3 Solid State Photolysis of the Optically Active Salts 54 2.4 Solid State Structure-Reactivity Correlations 59 2.5 Summary 67 References 68 C h a p t e r 3 N o r r i s h / Y a n g T y p e I I P h o t o c h e m i s t r y o f a H o m o l o g o u s S e r i e s o f S p i r o b i c y c l o [ 3 . 3 . 1 ] n o n y l K e t o n e s 7 0 3.1 Synthesis of the Spirobicyclo[3.3.1]nonyl Ketones 70 3.1.1 Synthesis of Spiroketones 49 and 50 by Intramolecular Friedel-Crafts Acylation 71 3.1.2 Synthesis of Spiroketones 51 and 52 by Ring-Closing Metathesis 73 3.2 Photochemical Studies of Spiroketones 49-52 76 3.2.1 Photochemistry of Spiroketone 49 77 3.2.2 Photochemistry of Spiroketone 50 81 3.2.3 Photochemistry of Spiroketone 51 83 3.2.4 Photochemistry of Spiroketone 52 88 3.3 Crystal Structure-Solid State Reactivity Correlations 91 3.3.1 Hydrogen Abstraction Parameters and Biradical Geometries 93 3.3.2 Geometric Requirements for Cleavage 97 3.3.3 Geometric Requirements for Cyclization 100 3.3.4 The Strain Factor 103 3.4 Summary 105 References 106 C h a p t e r 4 E n a n t i o s e l e c t i v e P h o t o c h e r n i c a l S y n t h e s i s o f a S i m p l e A l k e n e v i a t h e S o l i d S t a t e I o n i c C h i r a l A u x i l i a r y A p p r o a c h 1 0 7 4.1 Introduction 107 4.2 Choice and Synthesis of Starting Materials I l l 4.2.1 Choice of Starting Ketones I l l 4.2.2 Synthesis of m-Bicyclo[4.3.0]non-8-ylacetophenone derivatives 113 4.3 Photochemistry of cz's-Bicyclo[4.3.0]non-8-ylacetophenone derivatives 141 and 142 116 4.4 Asymmetric Induction Studies 118 4.5 Solid State Structure-Reactivity Correlation 124 4.6 Summary and Outlook 130 References 131 E X P E R I M E N T A L 1 3 3 C h a p t e r 5 P r e p a r a t i o n o f S u b s t r a t e s 1 3 3 5.1 General Considerations 133 5.2 Synthesis of 9-Benzoylbicyclo[3.3.1]nonanes 60, 61, 71, 72, and 73 and Chiral Salts 84-90 139 5.2.1 Synthesis of 9-Benzoylbicyclo[3.3.1]nonane 60 139 5.2.2 Synthesis of 9-Benzoylbicyclo[3.3.1]nonane 61 145 5.2.3 Synthesis of 9-Benzoyl-9-methylbicyclo[3.3.1]nonane 71 148 5.2.4 Synthesis of 9-Benzoyl-9-methylbicyclo[3.3.1]nonane 72 156 5.2.5 Synthesis of 9-Benzoyl-9-methylbicyclo[3.3.1]nonane 73 160 5.2.6 Synthesis of Chiral Salts 84-90 162 5.3 Synthesis of Spirobicyclo[3.3.1]nonyl Ketones 49-52 170 5.3.1 Synthesis of the Five-Ring Spirobicyclo[3.3.1]nonyl Ketone 49 170 5.3.2 Synthesis of the Six-Ring Spirobicyclo[3.3.1]nonyl Ketone 50 173 5.3.3 Synthesis of the Seven-Ring Spirobicyclo[3.3.1]nonyl Ketone 51 176 5.3.4 Synthesis of the Eight-Ring Spirobicyclo[3.3.1]nonyl Ketone 52 185 5.4 Synthesis of cw-Bicyclo[4.3.0]non-8-ylacetophenones 141 and 142 and Chiral Salts 143-147 192 5.4.1 Synthesis of cz's-Bicyclo[4.3.0]non-8-ylacetophenone 141 192 5.4.2 Synthesis of cw-Bicyclo[4.3.0]non-8-ylacetophenone 142 198 5.4.3 Synthesis of Chiral Salts 143-147 200 References 208 C h a p t e r 6 P h o t o c h e m i c a l S t u d i e s 2 0 9 vi 6.1 General Considerations 209 6.2 Photolysis of 9-Benzoyl-9-methylbicyclo[3.3.1]nonanes 71 and 72 211 6.3 Photolysis of Spirobicyclo[3.3.1]nonyl Ketones 49-52 217 6.4 Photolysis of c/s-Bicyclo[4.3.0]non-8-ylacetophenone 141 225 References 229 vii List of Figures Figure 1.1 Examples of solid state photochemical reactions showing: (a) higher reaction selectivity, and (b) latent reactivity 3 Figure 1.2 Photochemistry of fraws-cinnamic acids 10 5 Figure 1.3 Pictorial representation of the reaction cavity concept for solid state reactions 7 Figure 1.4 Crystalline state photolysis of (2R, 4«S)-2-carbomethoxy-4-cyano-2,4-diphenyl-3-butanone 13 7 Figure 1.5 The Norrish/Yang type II photoreaction 9 Figure 1.6 Photoreaction of 1 -phenyl- 1-pentanone 16 9 Figure 1.7 (5-Hydrogen abstraction reaction of benzoquinone-diene Diels-Alder adduct 20.... 10 Figure 1.8 8-Hydrogen abstraction of THP protected 4-hydroxy-4-methyl-2-pentanone 23.... 10 Figure 1.9 e-Hydrogen abstraction of naphthoquinone methide 26 11 Figure 1.10 c^-Hydrogen abstraction of p-(o-alkylphenoxy)propiophenone 29 11 Figure 1.11 Yang photocyclization as the key step in the synthesis of punctatin A (32) 12 Figure 1.12 Norrish type II elimination as the key step in the synthesis of (±)-a-acoradiene B (35) 12 Figure 1.13 Electronic configuration of a ketone, showing the occupancy of the carbon-oxygen bond orbitals (a) in the ground state, (b) in the !(n, 7r*) excited state and (c) in the 3(n, n*) excited state 13 Figure 1.14 Geometric parameters for y-hydrogen abstraction 14 Figure 1.15 Two models of the carbonyl excited state: (a) Kasha model, and (b) 'rabbit ear' model 15 Figure 1.16 1,4-Biradical conformations and their partitioning among cleavage and cyclization in Norrish/Yang type II reaction 17 Figure 1.17 Solid state absolute asyrnmetric synthesis of dibromide 39 from chalcone 38 20 Figure 1.18 Crystalline state absolute asymmetric synthesis: (a) chiral R-thiolactam 41 from achiral a,P-unsaturated thioamide 40. (b) di-rc-methane rearrangement product 43 from achiral dibenzobarrelene 42 21 viii Figure 1.19 Schematic presentation of the 'ionic chiral auxiliary' approach to solid state asymmetric synthesis. In the example shown, formation of the (+)-product is favored kinetically 23 Figure 1.20 An example of the ionic chiral auxiliary concept in the solid state di-7i-methane rearrangement of salt 44 , 24 Figure 1.21 Comparison of the ionic chiral auxiliary approach and the Pasteur resolution procedure 25 Figure 1.22 Synthesis of alkene 53 via photoelimination of c/s-bicyclo[4.3.0]non-8-ylacetophenone 54 : 30 Figure 2.1 9-Benzoylbicyclo[3.3.1]nonane derivatives 46 chosen for photo-chemical and asymmetric induction studies 38 Figure 2.2 Retrosynthetic analysis for 9-benzoylbicyclo[3.3.1]nonane derivatives 46. ..39 Figure 2.3 Synthesis of phenyl ketones 60 and 61 .....40 Figure 2.4 Synthesis of phenyl ketones 71-73 41 Figure 2.5 ORTEP representations of (a) 60, (b) 61, (c) 71, and (d) 72 42 Figure 2.6 Photoreactivity of the phenyl ketones 60, 61, 71, and 72 in solution and the solid state 44 Figure 2.7 Possible mechanism for deuteration of ketones 60 and 61 45 Figure 2.8 Photoreactivity of ketones 71 and 72 in solution 46 Figure 2.9 ORTEP representations of photoproducts (a) 75, (b) 76, and (c) 77 48 Figure 2.10 Relevant NOE correlations used in establishing the stereochemistry of compound 74 50 Figure 2.11 Chiral HPLC trace showing the separation of racemic 76 55 Figure 2.12 Hydrogen abstraction parameters for type II photochemistry 59 Figure 2.13 (a) 1,4-Hydroxybiradical intermediate derived from ketones 60, 61, 71, and 72; (b) The angle (3 61 Figure 2.14 Reaction pathway of ketones 71/72 63 Figure 2.15 Formation of compounds 75/77 from photolysis of ketones 71/72 66 Figure 3.1 Strategies for building the N ring of spiroketones 49-52 70 Figure 3.2 Synthesis of spiroketones 49 and 50 71 Figure 3.3 ORTEP representations of (a) 49 and (b) 50 72 ix Figure 3.4 Synthesis of spiroketones 51 and 52 74 Figure 3.5 ORTEP representations of (a) 103, (b) 51, and (c) 52 75 Figure 3.6 Photochemistry of spiroketone 49 77 Figure 3.7 ! H N M R vinyl region (8 5.4-5.7 ppm) after photolysis of ketone 49 showing signals due to the intermediate enol 105 (E) and the two diastereomers of ketone 106 (K): (a) after photolysis; (b) immediately following addition of catalytic trifluoroacetic acid; (c) six minutes after addition; (d) pure sample of ketone 106 78 Figure 3.8 Competing secondary photoreaction of ketone 106 80 Figure 3.9 Photochemistry of spiroketone 50 81 Figure 3.10 Possible mechanism for deuteration of spiroketone 50 82 Figure 3.11 Photochemistry of spiroketone 51 83 Figure 3.12 Possible mechanism for formation of photoproducts 112 and 113 from spiroketone 51 84 Figure 3.13 NOE interactions used in establishing the stereochemistry of compound 112.. 87 Figure 3.14 Photochemistry of spiroketone 52 88 Figure 3.15 Transformation of alcohol 115 to ketone 158 89 Figure 3.16 ORTEP representation of 114 90 Figure 3.17 The gauche 1,4-hydroxyradical model 92 Figure 3.18 Carbonyl group position in spiroketones 49-52 93 Figure 3.19 Hydrogen abstraction parameters for Norrish type II photoreaction 95 Figure 3.20 Representation of (pi in the solid state biradical derived from: (a) ketone 49, (b) ketones 50-52, and representation of 94 in the solid state biradical derived from (c) ketones 49-52 98 Figure 3.21 Representation of cyclization parameter [3: (a) in biradical derived form ketone 49 (H x); (b) in biradical derived from ketones 50-52 101 Figure 3.22 Photocyclization products of spiroketones 49-52 103 Figure 4.1 The Norrish type II photoelimination reaction 108 Figure 4.2 Photoelimination reaction of fraw.s-a-4-methylcyclohexylacetophenone (124) . .109 Figure 4.3 Strategy for achieving asymmetric induction in synthesis of enantiomerically enriched olefin 126 110 x Figure 4.4 Photochemistry of a-cycloalkylacetophenones 131 and 134 I l l Figure 4.5 General structure of compounds 54 112 Figure 4.6 Sequence taken for synthesis of compounds 141-147 114 Figure 4.7 Photochemistry of c/s-Bicyclo[4.3.0]non-8-ylacetophenone derivatives 141 and 142 117 Figure 4.8 Photolysis of chiral salts 143-147 119 Figure 4.9 Epoxidation of alkene 53 119 Figure 4.10 NOE interactions used in establishing the stereochemistry of compound 151.. 121 Figure 4.11 Chiral GC chromatogram showing the separation of the two enantiomers of compound 151 121 Figure 4.12 ORTEP representation of 141 125 Figure 4.13 Mechanism of photoelimination of keto ester 141 127 Figure 4.14 Crystal structures of anion part of salts (a) 144 and (b) 147 128 xi List of Tables Table 2.1 Photolysis of ketones 60, 61, 71, and 72 in solution and the crystalline state 43 Table 2.2 Comprehensive N M R assignment data of endo-aryl cyclobutanol 74 in CeD6 49 Table 2.3 Chiral salts prepared from keto acid 73 52 Table 2.4 Solution state photolysis of some optically active salts of keto acid 73 54 Table 2.5 Chromatographic data for the resolution of racemic 76 55 Table 2.6 Solid state photolysis of optically active salts of keto acid 73 57 Table 2.7 Hydrogen abstraction parameters for compounds 60, 61, 71, and 72 60 Table 2.8 Geometric data for ketones 60, 61, 71, and 72 62 Table 3.1 Photochemistry of spiroketone 49 in various media 80 Table 3.2 Photolysis of spiroketone 51 84 Table 3.3 Comprehensive N M R assignment data of endo-aryl cyclobutanol 112 in CeD6 85 Table 3.4 Photochemistry of spiroketone 52 88 Table 3.5 Values of a for ketones 49-52 and 71 94 Table 3.6 Hydrogen abstraction parameters for ketones 49-52 and 71 95 Table 3.7 Geometric data for biradicals derived from ketones 49-52 and 71 99 Table 3.8 Cyclization parameters for the 1,4-hydroxybiradicals derived from ketones 49-52 and 71 100 Table 3.9 Strain energy for ketones 49-52 and their corresponding photo-cyclization products 103 Table 4.1 Chiral salts prepared from keto acid 142 115 Table 4.2 Results of Photolyzing Ketones 141 and 142 116 Table 4.3 Comprehensive N M R assignment data for 151 in C 6 D 6 120 Table 4.4 Asymmetric Induction in the Photolyses of Chiral Salts 143-147 122 Table 4.5 Geometric Data for Compounds 141,144 and 147 125 xii List of Symbols and Abbreviations Vmax absorption maxima (IR spectroscopy) -^max absorption maxima (UV 1 VIS spectroscopy) A angstrom 5 chemical shift (ppm) °C degrees Celsius s molar extinction coefficient X wavelength anal. analysis APT attached proton test aq. aqueous Ar aryl BB broadband ( 1 3 C NMR) 9-BBN 9-borabicyclononane bp boiling point br broad Bu butyl l BuOH tert-butyl alcohol C 6 D 6 benzene-ek calcd calculated cat. catalytic CDCI3 chloroform-^ CD2CI2 methylene chloride-c/2 C D 3 O D methanol-^ CI chemical ionization cone. concentrated COSY correlation spectroscopy Cy cyclohexyl d doublet DCI desorption chemical ionization D C M dichloromethane DEPT distortionless enhancement by polarization transfer DIPA diisopropylamine D M P U A^A^dimethylpropyleneurea DMSO dimethylsulphoxide ee enantiomeric excess EI electron impact E t 2 0 diethyl ether EtOAc ethyl acetate EtOH ethanol eV electron volt(s) fs femto-second g grams GC gas chromatography Grubbs catalyst benzylidene-bis(tricyclohexylphosphine)dichlororuthenium h hour(s) hv light HO Ac acetic acid H M B C heteronuclear multiple bond connectivity H M Q C heteronuclear multiple quantum coherence HPLC high performance liquid chromatography HRMS high resolution mass spectrometry EPA isopropyl alcohol IR infrared J coupling constant (Hz) kPa kilopascal(s) L A H lithium aluminum hydride L D A lithium diisopropylamide lit. literature L R M S low resolution mass spectrometry LSDVIS liquid secondary ionization mass spectrometry xiv m multiplet M molarity Me methyl M e C N acetonitrile MeOH methanol mg milligram M H z megahertz min minute(s) mL milliliter(s) mrnHg millimeter(s) of mercury mmol millimole(s) M O M methoxymethyl mp melting point MS mass spectrometry nm nanometer(s) N M O 4-methylmorpholine N-oxide N M R nuclear magnetic resonance NOE nuclear overhauser enhancement NOESY two-dimensional nuclear overhauser effect spectroscopy OAc acetate ORTEP oak ridge thermal ellipsoid program PCC pyridinium chlorochromate pet. petroleum Ph phenyl ppm parts per million 'Pr isopropyl psi pounds per square inch q quartet quint quintet R C M ring-closing metathesis s singlet xv S E M 2-(trimethylsilyl)ethoxymethyl t triplet TFA trifluoroacetic acid THF tetrahydrofuran THP tetrahydropyranyl TPAP tetrapropylammonium perruthenate U V / VIS ultraviolet / visible W watt xvi A c k n o w l e d g e m e n t s I would like to express my deepest gratitude to my supervisor, Dr. John Scheffer, for his guidance, encouragement, and support over the last five years. I am also indebted to Dr. Brian Patrick in the U B C structural chemistry laboratory and Dr. Lucia Maini in the University of Bologna for determining the X-ray crystal structures presented in this thesis. I am grateful to the staff of the N M R and Mass Spectrometry labs in the University of British Columbia. None of the work presented in this thesis could have been carried out without their assistance and advice. Finally, I would like to thank the current and past members of the Scheffer research group for providing a stimulating and friendly working atmosphere. xvii To my parents, sister, and my loving wife xviii Chapter 1 Introduction INTRODUCTION Chapter 1 Introduction 1.1 Solid State Organic Photochemistry The study of organic photochemistry can be traced back to Trommsdorff s 1834 discovery that sunlight causes santonin crystals to become yellow and shatter.1 In spite of this important discovery in the crystalline state, studies of organic photochemical reactions were mainly focused on the liquid state over the next 150 years. The historical reason behind this is that, for many years, chemists viewed molecular crystals as lattices made up of frozen chemical entities that can at most undergo very small translational and librational motions. Relying on the principle that reactions require mobility, many chemists considered crystalline state organic chemistry hardly worth investigating, and the Nobel laureate Leopold Ruzicka even referred to the crystalline state as "a chemical cemetery".2 In recent years, however, chemists have come to realize that the atomic and molecular motions in the crystalline state are not as restricted as originally thought,3 and that there is much can be learned from studying chemical reactions in the crystalline state. During the past few decades, there has been a growing interest in studying organic photochemical reactions in organized and constrained solid media. Examples of such media include polymer films, liquid crystals, zeolites, glasses, micelles, and organic crystals.4'5 In this thesis, we shall be concerned only with the last type, crystalline state organic photochemistry, although the term solid state organic photochemistry is often used. Photochemical reactions are chosen for study in the crystalline state for a number of 1 Chapter 1 Introduction reasons: (1) light can easily penetrate the crystal without disrupting the lattice, (2) the wavelength of irradiation may be adjusted to excite a specific chromophore of the photochemical substrate, and (3) solid state photochemical reactions may be carried out at ambient or reduced temperatures. Thermal reactions, on the other hand, are not commonly studied in the crystalline state. This is mainly due to the fact that the thermal energy required to promote solid state reactivity can also increase the possibility of crystal melting and lead to the destruction of crystal lattice rigidity and regularity. Unlike in conventional isotropic solution media, where conformational exchange and intermolecular collision occur freely, reactants in crystals are confined in an anisotropic reaction cavity, where conformational flexibility and diffusion of molecules are restricted. As a result, photochemical reactions performed in the crystalline state tend to show higher reaction selectivities than their solution state counterparts. In some cases, latent reactivity of the confined molecules is observed. Examples of reactions showing these advantages are depicted in Figure 1.1. Photolysis of acetonitrile solutions of ketone 1 produced cyclobutanol 2 (47%) and 3 (47%) along with 6% of cyclopentanone 4 (Figure 1.1a). In contrast, when crystals of 1 were irradiated, the primary product 2 was obtained in 81% yield along with a new product (5, 19%), and products 3 and 4 were not observed.6 This solid state reaction is more selective than its solution counterpart in terms of the formation of product 2. Moreover, the latent solid state photochemical behavior of ketone 1 is manifested by the formation of cyclopropanol 5, a product not observed in solution. Figure 1.1b shows another example of latent reactivity, where phenyl ketone 6 undergoes a typical Norrish type I cleavage reaction in acetonitrile to give primarily radical coupling product 7. Irradiation of crystals of 6, however, afforded the oxetanes 8 2 Chapter 1 Introduction b) exo-Ph endo-Ph 8 9 63% . 12% Figure 1.1 Examples of solid state photochemical reactions showing: (a) higher reaction selectivity, and (b) latent reactivity. As early as 1918, Kohlschutter proposed the topochemical postulate, which states 3 Chapter 1 Introduction that reactions in the crystalline state occur with a minimum of atomic and molecular motion.8 This shed the first light on how reactions occur in the crystalline state. With the advent of modern X-ray crystallographic techniques in the 1960's, Schmidt and co-workers were able to further develop this idea to topochemical rules based on their studies of the solid state intermolecular [2+2] photocycloaddition of aromatically-substituted trans-cirmamic acids (Figure 1.2).9 Cinnamic acids 10 were previously found to undergo only trans-cis photoisomerization in solution,10 while Schmidt's research showed that, depending on which polymorphic form they adopt, crystalline state trans-cinnamic acids can have totally different modes of reactivity. When crystals of the a-form of cinnamic acid 10a were irradiated, a-truxillic acid 11, the head-to-tail [2+2] cycloaddition product, was obtained. Irradiation of crystals of the [3-form of cinnamic acid 10P gave the head-to-head cycloaddition product, P-truxillic acid 12, while the y-form 10y showed no observable reaction in the crystalline state. Examination of the X-ray structures of these three crystal polymorphs revealed that it was the molecular packing in the crystal lattice that determined the orientation and distance between the two reacting double bonds, which, in turn, determined their reactivity. For the a-form crystals, cinnamic acid molecules 10a were found to lie in a head-to-tail arrangement with the adjacent double bond-to-double bond distance being 3.6-4.1 A. In the P-form crystals, cinnamic acid molecules 10P were packed in a head-to-head manner with the double bond-to-double bond distance being 3.9-4.1 A. The photostable y-form crystals of cinnamic acid lOy, while head-to-tail aligned, were found to have a much longer double bond-to-double bond distance of 4.7-5.1 A. Based on these results, Schmidt et al. were able to formulate the following topochemical rules:9 1) the nature of the molecular 4 Chapter 1 Introduction packing in the crystal is more important than the intrinsic reactivity of the molecule itself, 2) the separation distances and the relative orientation of the reacting functionalities are governing factors of the reaction, and 3) different polymorphic crystals of a molecule may exhibit different reactivities. These rules provide the basic guidelines to which solid state reactions should adhere. p \ hv COOH solution 10 Ph^ ^COOH /so-10 Ph HOOC. COOH hv 3.6-4.1A c r y s t a | Ph 10a Ph HOOC. /—7\ V — I COOH Ph 11 Ph Ph. / COOH 3.9-4.1A COOH 10(3 hv crystal Ph Ph \ COOH COOH 12 Ph HOOC. / COOH h v /4.7-5.1A crystal Ph no reaction 10y Figure 1.2 Photochemistry o f fraws-cinnamic acids 10. 11 12 The solid state reaction theory was further advanced by Cohen and Weiss with their development of the reaction cavity concept. In this model, each individual 5 Chapter 1 Introduction reacting molecule in a crystal is considered to be restricted in a cavity bounded by the van der Waals surface of the nearest neighboring molecules. As reaction occurs, the reacting molecule changes its shape in a way that any large motions of the molecule are resisted by steric interactions imposed by the cavity wall. For a reaction that can go though two or more possible reaction pathways, the product whose formation involves minimal geometric changes will be preferred (Figure 1.3). In other words, solid-state reactions tend to be restricted to least motion pathways that limit the number of possible products. Qualitatively, this model explains the fact that chemical reactions conducted in the crystalline phase are often more regio-, diastereo-, and enantioselective than their solution-phase counterparts. One example that illustrates the topochemical control within the reaction cavity is shown in Figure 1.4.13 While solution photolysis of (2R, 4S)-2-carbomethoxy-4-cyano-2,4-diphenyl-3-butanone (13) gave a mixture of products, irradiation of crystalline (2R, *45)-13 led to highly efficient decarbonylation. The intermediate radical pairs 14, constrained by the reaction cavity, underwent a highly stereospecific radical-radical combination that led to the formation of (2R, 3i?)-15 with quantitative enantiomeric excess. 6 Chapter 1 Introduction allowed disallowed Figure 1.3 Pictorial representation of the reaction cavity concept for solid state reactions, (a) starting material (dashed line) in original reaction cavity (solid line), (b) allowed product (dashed line) which fits within the cavity (solid line), (c) disallowed product (dashed line) which does not fit within the cavity (solid line). hv (+)-(2R, 4S)-13 CO / M e . . . / C N : Ph^' 'p h \ M e 0 2 C , N P h 14 CO / M e . / C N \ M e 0 2 C , \ P h / (+)-(2R, 3R)-15 100% ee Figure 1.4 Crystalline state photolysis of (2R, 4S)-2-carbomethoxy-4-cyano-2,4-diphenyl-3-butanone 13. Recently, more quantitative models have been proposed for understanding and predicting crystalline state photochemistry. 1 4 In general, the calculation o f these models consists of the following steps: (1) computationally building a mini-crystal lattice based on the X-ray crystal structure of the reactant and its nearest neighbors, (2) removing and replacing the central molecule in the mini-lattice with a species representing the transition 7 Chapter 1 Introduction state of a hypothetical reaction path (the species can be a reaction product, a reaction intermediate or a reaction transition state generated by quantum or molecular mechanics), (3) evaluating the energy of the resulting mini-lattice using molecular mechanics, and (4) in a similar manner, calculating and comparing the energetic requirements of alternative reaction pathways, and predict the outcome of the solid state reaction. 8 Chapter 1 Introduction 1.2 Type II Photochemistry of Ketones 1.2.1 The Norrish/Yang Type II Reaction The Norrish/Yang type II reaction is one of the most thoroughly studied and well-understood processes in organic photochemistry.15 In its simplest form, a y-hydrogen-containing ketone undergoes an initial 1,5-hydrogen atom abstraction to form a 1,4-hydroxybiradical. This biradical intermediate has three fates: a) reverse hydrogen transfer to regenerate the starting ketone in its ground state, b) cleavage of the central carbon-carbon bond to form an alkene and an enol, which subsequently tautomerizes to the corresponding ketone (known as the Norrish type II elimination), and c) Yang cyclization to form a cyclobutanol derivative (Figure 1.5). One example of a Norrish/Yang type II reaction is shown in Figure 1.6. Hk - O H hv OH Reverse H-transfer Yang cyclization Norrish type II elimination OH Figure 1.5 The Norrish/Yang type II photoreaction. O hv Ph OH Ph-16 17 18 Figure 1.6 Photoreaction of 1-phenyl-1-pentanone 16. 19 The biradical's existence in the Norrish/Yang type II reaction has been well 9 Chapter 1 Introduction established by trapping studies with thiols 1 6 and by racemization of ketones with chiral y-carbons.17 The 1,4-biradical intermediate generated by intramolecular hydrogen 7 0 abstraction is very short-lived, with a lifetime of probably no more than 10" -10" s, while the time scales for hydrogen atom transfer and biradical closure or cleavage are 70-90 fs and 400-700 fs, respectively.18 In the Norrish type II reaction, it is generally the y-hydrogen atom that is abstracted, which can be understood on the basis of an energetic preference for a six-membered transition state. However, (3-, S-, e- and even ^-hydrogen abstractions are possible when no y-hydrogens are available or y-hydrogens are geometrically unfavorably oriented. Examples of these reactions are illustrated in Figure 1.7-10. 20 21 22 Figure 1.7 p-Hydrogen abstraction reaction of benzoquinone-diene Diels-Alder adduct 20. 1 9 23 24 25 Figure 1.8 8-Hydrogen abstraction of THP protected 4-hydroxy-4-methyl-2-pentanone 23. 2 0 10 Chapter 1 Introduction 29 30 <*i Figure 1.10 (^-Hydrogen abstraction of R-(o-alkylphenoxy)propiophenone 29. 2 2 Although the Norrish/Yang photoreaction has not been applied synthetically as often as other photochemical reactions, there are some unique uses of this chemistry in natural product synthesis. One example is Paquette's synthesis of punctain A (32), where a stereoselective transformation of ketone 33 to Jrans-cyclobutanol 34 is achieved through Yang cyclization (Figure 1.11). Another example comes from Diez-Masa's 1981 synthesis of (i)-a-acoradiene B (35),24 where a 5, s-unsaturated ketone intermediate 36 is prepared via a Norrish type II elimination of properly alkylated bicyclo[4.2.0]octan-2-one 37 (Figure 1.12). 11 Chapter 1 Introduction Figure 1 .12 Norrish type II elimination as the key step in the synthesis of ( ± ) - c c -acoradiene B (35) . 1.2.2 Electronic Aspects of Type II Reactions Figure 1.13 depicts the orbitals of the carbon-oxygen bonds of a carbonyl group, the chromophore present in the ketone compounds that were investigated for the present work. It shows, in its ground state (Figure 1.13a), 2 electrons with opposite spin occupying the same non-bonding orbital of the carbonyl oxygen. When a photon of wavelength around 300 nm is absorbed by the ketone, the electronic structure of the molecule changes. Absorption of the photon occurs in such a short period of time (~ 10"15 s) that it is often assumed that the positions of the nuclei in the molecule do not change during this period. Excitation by light promotes one electron from the non-bonding n-orbital into the n* anti-bonding orbital (Figure 1.13b) with retention of spin. This excited state is called the singlet n, pi-star '(n, n*) excited state. From this singlet excited state, 12 Chapter 1 Introduction spin inversion or intersysterm crossing (ISC) may occur and a triplet n, pi-star 3(n, 7T*) excited state may be produced. In the triplet excited state, the electrons in the singly occupied n and n* orbitals have the same spin (Figure 1.13c). For aliphatic ketones, Norrish type II reactions may take place from either the singlet or triplet n, 71* excited state. On the other hand, for aromatic ketones, it is found that only the triplet excited state is responsible for both elimination and cyclization in Norrish type II reaction. This is due to the much more rapid intersystem crossing for aromatic ketones. In this thesis, all the photochemical substrates we investigated are aromatic ketones and it is from their corresponding 3(n, 7t*) excited states that the Norrish/Yang type II reactions occur. CT* 71* Energy hv a* 71* ISC CT* 71* (a) (b) (c) Figure 1.13 Electronic configuration of a ketone, showing the occupancy of the carbon-oxygen bond orbitals (a) in the ground state, (b) in the ](n, 71*) excited state and (c) in the 3(n, Tr*) excited state. 1.2.3 Geometric Requirements for the Norrish/Yang Type II Reaction Norrish type II reactions have been extensively studied in the crystalline state by Scheffer and co-workers.27 Four parameters, one distance and three angles, have been defined to quantify the geometric requirements for the hydrogen abstraction process. These parameters are illustrated in Figure 1.14: d, the distance between the carbonyl 13 Chapter 1 Introduction oxygen and the y-hydrogen to be abstracted; 0, the O—H y-C y angle; A, the C=0—HY angle; and co, the 'out-of-plane' angle between the y-hydrogen and the carbonyl group. The values of these parameters can be easily obtained by analyzing X-ray crystallographic data of ground state starting ketones. Here, correlating the structure of ground state ketones with their excited state reactivity is considered valid because the excitation of the carbonyl group is known to be highly localized, and there is no significant geometric change in the rest of the molecule.28 Figure 1.14 Geometric parameters for y-hydrogen abstraction. From a theoretical point of view, ideal values for the four parameters have been deduced. The optimum value of d is expected to be 2.72 A , the sum of the van der Waals radii for a hydrogen and an oxygen atom,29 as this ensures both atoms are in close contact. The ideal value of 0 angle should be 180°, as this allows for maximum overlap 30 between the oxygen atom and the C-H Y a bond. Assuming abstraction by the nonbonding orbital on oxygen,3 1 the most desirable value of A is expected to be in the range of 90° to 120°, depending on the model used for the (n, n*) excited state carbonyl (Figure 1.15). In the Kasha model, the atomic orbitals on oxygen are not hybridized and 32 the angle between the 2p orbital on oxygen and the C=0 bond is 90°. If the 'rabbit ear' model is used, the ideal value of A should be 120°, as the non-bonding atomic orbitals on 14 Chapter 1 Introduction the carbonyl oxygen are considered to be sp2 hybridized. The angle co measures the deviation of H Y from the mean plane of the carbonyl group. Orbital overlap is maximized 33 when co is 0°, and approaches zero as co draws close to 90°. (a) (b) Figure 1.15 Two models of the carbonyl excited state: (a) Kasha model, and (b) 'rabbit ear' model. In reality, it is geometrically impossible for all of the atoms to be ideally aligned for the y-hydrogen abstraction process and large variations are ordinarily observed. Among the four parameters, the C=0—H y distance d is probably most useful for predicting Norrish type II reactivity, and it should be < 2.72 A for a successful y-hydrogen abstraction to occur. However, values of d as large as 3.10 A have been reported.34 Values of co are most often observed in the range of 17° to 62°, and values of parameter 8 are rarely above 125° or lower than 95°. This clearly shows that hydrogen abstraction can occur with quite large deviations in the four parameters as long as the orbital overlap is sufficient. 1.2.4 Cyclization versus Cleavage As mentioned in a previous section, the 1,4-hydroxybiradical generated in the Norrish/Yang type II reaction can partition itself among cleavage, cyclization, and 15 Chapter 1 Introduction reverse hydrogen transfer. It is believed that the conformation and spin multiplicity of the intermediate biradical control the biradical partitioning among these pathways. In particular, cleavage is favored when there is good overlap of both half-occupied p orbitals at Ci and C4 with the cleaving C2-C3 rj-bond. On the other hand, cyclization is preferred when the two p-orbitals at radical centers Ci and C4 overlap each other efficiently. Figure 1.16 shows how different conformations of the 1,4-hydroxybiradical can affect the reaction pathways. For the transoid conformation, where the C1-C2 and C3-C4 a bonds are anti-periplanar, cyclization is out of the question, since overlap of the two p-orbitals is geometrically impossible. Cleavage, on the other hand, is feasible when the p-orbitals on both Ci and C4 are parallel to the C2-C3 a bond. In the gauche conformation, the two radical centers at Ci and C4 are close to one another, and overlap of the two p-orbitals leads to cyclization products. At the same time, overlap between the two p-orbitals and the C2-C3 o bond is possible and this leads to the formation of cleavage products. In the cisoid conformation, where the C1-C2 and C3-C4 bonds are eclipsed, the biradical is in its maximum energy conformation. Since it is unlikely for biradicals to adopt this conformation, the biradical reactivity from the cisoid conformation is not discussed. 16 Chapter 1 Introduction cleavage only transoid cyclization and cleavage maximum energy conformation, biradical reactivity is not treated. cisoid Figure 1.16 1,4-Biradical conformations and their partitioning among cleavage and cyclization in Norrish/Yang type II reaction. In addition to these geometric requirements, the spin multiplicity of the biradical intermediate must also be taken into account. For any of these three reaction pathways to occur, the biradical must be in its singlet state. For the aromatic ketones studied in this thesis, the biradical intermediate is a triplet since the hydrogen abstraction occurs from a triplet excited carbonyl group. In solution, one problem associated with this is that the long-lived triplet biradical intermediate may experience conformational interchange before and during its intersystem crossing to the singlet. As a consequence, the product distribution may not necessarily reflect the geometry of the initially formed biradical. 17 Chapter 1 Introduction However, by working in the crystalline state, the problems of multiple reactive biradical conformers and conformation-dependent intersystem crossing can be avoided. This is due to the fact that most organic compounds crystallize in and are restricted to their lowest energy conformations, and y-hydrogen abstraction in the crystalline state involves very little motion of the associated heavy atoms.36'37 Therefore, the geometry of the conformationally-locked biradical intermediate should resemble the X-ray crystal structure of the starting ketone, and this allows direct structure-reactivity relationships to be established for these reactive intermediates. 18 Chapter 1 Introduction 1.3 Asymmetric Photochemistry In contrast to the ever-growing subject of asymmetric induction in the ground state, asymmetric photochemistry, which transforms achiral starting materials into chiral products via excited-state reactions, has not been extensively explored until recently. Among the approaches that have been taken are (1) photolysis with circularly polarized light, 3 9 (2) the use of chiral photosensitizers,40 (3) the use of chiral solvents,38 (4) the use of chiral additives,3 8'4 1 (5) attachment of covalent chiral auxiliaries,38 (6) photolysis in the cavities of chiral host molecules, ' and (7) photolysis of chiral crystals. ' By far, the most promising results have come from solid-state asymmetric photochemistry, in which chiral information is provided by the rigid environment in chiral host-guest complexes or chiral crystals. In this thesis, we shall focus on the study of asymmetric photochemistry in chiral crystals. 1.3.1 Asymmetric Induction in Crystalline-State Photochemistry In 1969, Penzien and Schmidt discovered that the achiral compound 4,4'-dimethylchalcone (38) spontaneously crystallizes in the chiral space group P2i2]2i, and when enantiomorphously pure single crystals of this compound are treated with bromine vapor, the chiral dibromide (39) is obtained in 6% enantiomeric excess (Figure 1.17).44In this reaction, the optically active product is formed from an achiral starting material without the intervention of external optical activity. The achiral molecules that crystallize in a chiral space group are under the influence of the chiral crystal lattice obtained by spontaneous crystallization, and this provides the asymmetric environment that favors the formation of one product enantiomer over the other. A process like this has been termed 19 Chapter 1 Introduction as 'absolute asymmetric synthesis'. The above experiment represents the first example of such a process. Space group: P212121 Enantiomeric excess: 6% Figure 1.17 Solid state absolute asymmetric synthesis of dibromide 39 from chalcone 38. Although absolute asymmetric synthesis was first found in a ground state reaction, most of its success was achieved in photochemical reactions, in particular, unimolecular photorearrangement reactions. Two examples of which are shown in Figure 1.18. In the first example (Figure 1.18a), single crystals of ct,P-unsaturated thioamide 40, which spontaneously crystallize in the chiral space group Fl\, were irradiated to give P-thiolactam 41 in greater than 97% enantiomeric excess.45 The second example (Figure 1.18b), taken from the work of Scheffer et al.,46 concerns the di-7t-methane rearrangement of achiral dibenzobarrelene (42), which crystallizes in two polymorphic forms, one chiral (P2\2\2\) and the other achiral (Pbca). Irradiation of single crystals of the chiral polymorph produced the rearrangement product 43 in greater than 95% enantiomeric excess. When single crystals of the achiral polymorph was photolyzed, photoproduct 43 was obtained in racemic form. 20 Chapter 1 Introduction 42 43 Space Group Enantiomeric Excess P2 12 12 1 (chiral) > 95% Pbca (achiral) 0% Figure 1.18 Crystalline state absolute asymmetric synthesis: (a) chiral P-thiolactam 41 from achiral a, P-unsaturated thioamide 40; (b) di-7t-methane rearrangement product 43 from achiral dibenzobarrelene 42. While irradiation of chiral crystals often achieves high enantioselectivity, absolute asymmetric synthesis as a general method of asymmetric induction suffers two severe drawbacks. First, for absolute asymmetric synthesis to be successful, the achiral molecules must crystallize in a chiral space group. However, the great majority of achiral compounds do not crystallize in one of the 65 chiral space groups. The total number of crystallographic space groups (chiral plus achiral) is 230. 4 7 Second, as shown in the second example above (Figure 1.18b), spontaneous crystallization of an achiral molecule does not yield its chiral crystals in a predictable way. Due to the lack of understanding of 21 Chapter 1 Introduction the relationship between molecule structure and crystal structure, it is basically impossible to predict when an achiral molecule w i l l crystallize in a chiral space group. Therefore, a method that guarantees the presence of chiral space groups is required to furnish asymmetric induction in solid state photochemistry. 1.3.2 The Ionic Chiral Auxiliary Concept The ionic chiral auxiliary approach developed by Scheffer and co-workers is one of the most effective asymmetric induction methods in the field o f photochemistry. 4 8 Figure 1.19 illustrates this concept with a hypothetical solid state photochemical reaction. A n achiral carboxylic acid-containing photoreactive substrate is transformed into a chiral salt by a simple acid-base reaction with an optically pure amine. Since the amine auxiliary is chiral, the salt is required to crystallize in one o f the 65 chiral space groups, and this provides the asymmetric medium in which the photoreaction is carried out. Upon photolysis, the reaction proceeds through the lower of two diastereomeric transition states with differing energy, which leads to the observed enantiodiscrimination. After reaction, removal o f the ionic auxiliary is easily achieved by treatment o f the reaction mixture with ethereal diazomethane solution and the corresponding methyl ester derivative of the photoproduct is obtained. A n example of this concept put into practice is given in Figure 1.20. Chiral salt 44, formed between the achiral dibenzobarrelene derivative and an optically pure amine, after solid state irradiation and subsequent diazomethane workup, provides di-7t-methane rearrangement product 45 with an enantiomeric excess o f 80% 4 9 22 Chapter 1 Introduction photolys is in the crystal l ine state < ^ ) ^ C O O H 3 N — ( + ) chiral crystal ac id-base react ion achiral ac id opt ical ly pure amine photoreact ive substrate auxi l iary Figure 1.19 Schematic presentation of the 'ionic chiral auxiliary' approach to solid state asymmetric synthesis. In the example shown, formation of the (+)-product is favored kinetically. 23 Chapter 1 Introduction C0 2 Me I C0 2 Et I i *• Et0 2 C V \ 2) CH 2N 2workup 1) hv, solid state 44 45 96% yield 80% ee Figure 1.20 An example of the ionic chiral auxiliary concept in the solid state di-Tt-methane rearrangement of salt 44. The solid state ionic chiral auxiliary approach to asymmetric synthesis has close parallels to the Pasteur resolution procedure, a widely used method that resolves racemic carboxylic acids by fractional crystallization of their corresponding diastereomeric salts (Figure 1.21). Both methods require the formation of crystalline salts between acids and optically pure amines. The ionic chiral auxiliary method, however, has an advantage over the conventional Pasteur resolution procedure in terms of yield. In the Pasteur resolution method, chemical reaction is executed before the resolution and from the resulting racemic product, the maximum possible yield of a given enantiomer is 50%. On the other hand, Scheffer's ionic chiral auxiliary approach starts with an achiral reactant, and formation of the product is carried in an in situ manner. Provided that the activation energy difference is sufficiently large for the enantio-differentiating step, near-quantitative yields of a single product enantiomer can in principle be obtained. 24 Chapter 1 Introduction Ionic Ch i ra l Aux i l i a ry A p p r o a c h H 2 N — ( + 0 © C02 H 3 N -react ion m a x i m u m yield 1 0 0 % C0 2H co2H A C02H A C Q 2 H m a x i m u m yield 5 0 % + react ion H 2 N P a s t e u r Reso lut i on P r o c e d u r e F i g u r e 1.21 Comparison of the ionic chiral auxiliary approach and the Pasteur resolution procedure. The ionic chiral auxiliary method has been tested in a variety of photochemical transformations and shown to be a general method of asymmetric induction in solid state reactions. Among the types of reaction that have been studied are: the Yang photocyclization reaction,50 the Paterno-Buchi reaction,7 the di-7t-methane rearrangement reaction,51 the Norrish type II photoelimination reaction,52 the 8-hydrogen abstraction reaction,53 photoreaction of benzocyclohexadienone derivatives,54 photoreaction of tropolone derivatives,55 and cis-trans isomerization of diphenylcyclopropane derivatives.56 There are a number of practical reasons that make the ionic chiral auxiliary approach such a popular method: 1) the auxiliary is taken from a large pool of inexpensive, commercially available chiral amines, 2) attachment and removal of the auxiliary use simple acid-base chemistry, 3) either enantiomer of the photoproducts may be produced by simply switching the chirality of the auxiliary, 4) ionic salt crystals 25 Chapter 1 Introduction generally have strong lattice forces and high melting points, which are important for crystalline state reactions to achieve high conversions without loss of topochemical control, and 5) preparative scale reactions may be conducted by suspending the salt crystals in hexanes.5 7 26 Chapter 1 Introduction 1.4 Research Objectives The work described in this thesis was conducted with two objectives in mind: to improve our knowledge of Norrish/Yang type II photochemistry through solid state structure-reactivity correlations and to further explore the ionic chiral auxiliary approach as a general method of asymmetric induction in photochemical reactions. These two objectives are fulfilled through the following three projects. The first project, the study of the photochemistry of 9-benzoyl-bicyclo[3.3.1]nonane derivatives (46), complements our earlier studies on the solid-state Norrish/Yang type II photochemistry of phenyladamantyl, and phenylnorbornyl ketones (47 and 48), 3 7 ' 5 8. In these two previous systems hydrogen abstraction occurred from either a rigid six-membered ring or a rigid five-membered ring, while in the bicyclo[3.3.1]nonane system hydrogen abstraction occurs from a relatively flexible six-membered ring, allowing for the effects of small changes in ring geometry on the hydrogen abstraction process and the reaction outcome to be examined. 9-Benzoylbicyclo[3.3.1]nonane derivatives 46 are achiral molecules and give chiral Yang photocyclization products upon photolysis. As hydrogen abstraction could occur on either of the two enantiotopic y-hydrogen atoms, this allows the enantioselectivity of the reaction to be studied using the ionic chiral auxiliary method. 27 Chapter 1 Introduction R' 46 47 48 R = H, CH 3 R' = H, COOMe The second project in this thesis is a natural extension o f the first project. In order to model the reaction o f benzoylbicyclo[3.3.1]nonyl ketones with different carbonyl geometries and to investigate the effect o f carbonyl geometry on the corresponding 1,4-hydroxybiradical behavior, the crystalline state photochemistry o f a series of spirocyclic ketones 49-52 was studied. These compounds were chosen for investigation because the conformation o f the 1,4-hydroxybiradicals formed by y-hydrogen atom abstraction could be varied in a regular and incremental fashion by changing the size of the ketone-containing spiro ring. Also, previous experience with bicyclo and tricyclophenylketones in our laboratory indicated that the compounds chosen would have a high chance of forming crystals suitable for X-ray structure determination, allowing for solid state structure-reactivity relationships to be established. 49 50 51 52 28 Chapter 1 Introduction In the third study, our goal was to enantioselectively synthesize a simple chiral alkene, cz's-3a,4,5,6,7,7a-hexahydro-l//-indene 53, via an asymmetric Norrish type II photoelimination reaction of cw-bicyclo[4.3.0]non-8-ylacetophenone derivatives 54 (Figure 1.22). This system was selected for study for a number of reasons. First, the preparation of enantiomerically pure simple (unfunctionalized) olefins is difficult because their resolution through direct Pasteur techniques is essentially impossible.59 Several approaches have been taken to the asymmetric synthesis of simple chiral olefins: (1) asymmetric Wittig-type reactions using chiral cyclic phosphonamides,60 (2) asymmetric elimination reactions of N-chiral amine oxides,61 (3) asymmetric Hoffman elimination of N-chiral quaternary ammonium salts, and (4) asymmetric radical fragmentation reactions of S-chiral sulfoxides.63 For the most part, the thermal solution phase 1, 2-elimination reactions mentioned above give low ee's. This is due mainly to the fact that the elevated temperatures used in ground state elimination reactions facilitate equilibrium between conformational diastereomers and reduce the reaction rate differences between diastereomeric transition states. We believe that these factors can be overcome in asymmetric Norrish type II photoelimination reactions using the solid-state ionic chiral auxiliary approach. Second, the synthesis of starting compound 54 is straightforward and the alkene product 53 has been reported in the literature.64 Third, the 5-ring system is known to give a great proportion of cleavage versus cyclization products in its type II photochemistry.65 In this study, solid state X-ray structure-reactivity correlation studies were also performed to rationalize the enantioselectivity. 29 Chapter 1 Introduction H H 54 hv Solution and Solid State O. /=\ + y — ( \ />—x 55 e © . X = C0 2Me, C0 2H, C0 2 H 3N-R Figure 1.22 Synthesis of alkene 53 via photoelimination from czs-bicyclo[4.3.0]non-8-ylacetophenone 54. 30 Chapter 1 Introduction R e f e r e n c e s 1 Trommsdorff, H . Ann. Chem. Pharm. 1834, 11, 190. 2 Dunitz, J. D. Trans. Am. Cryst. Assoc. 1984, 20, 1. 3 Gavezzotti, A. ; Simonetta, M . Chem. 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Chem. Soc. 1965, 87, 4009; (e) Dougherty, T. J. J. Am. Chem. Soc. 1965, 87, 4011. 2 6 (a) Wagner, P. J.; Kochevar, I. J. Am. Chem. Soc. 1968, 90, 2232; (b) Wagner, P. J.; Hammond, G.S.J. Am. Chem. Soc. 1966, 88, 1245. 2 7 Uunels, H . ; Scheffer, J. R. Tetrahedron 1999, 55, 885 and references therein. Wagner, P. J. In CRC Handbook of Photochemistry and Photobiology; CRC Press: Boca Raton. 1995; Chapter 38. 2 9 Bondi, A . J. Phys. Chem. 1964, 68, 441. See also: Edward, J. T. J. Chem. Educ. 1970, 47,261. 3 0 Dorigo, A. E.; Houk, K . N . J. Am. Chem. Soc. 1987,109, 2195 and references therein. 3 1 (a) Wagner, P. J. In Rearrangements in Ground and Excited States; de Mayo, P., Ed.; Academic Press: New York, 1980; Vol . 3; pp 405; (b) Turro, N . J. Modern Molecular Photochemistry; Benjamin-Cummings: Menlo Park, C A , 1978; Chapter 10 and references therein. (a) Kasha, M . Radiat. Res. 1960, Suppl. 2, 243; (b) Zimmerman, H . E. Tetrahedron 1963, 19, 393. Scheffer, J. R. In Organic Solid State Chemistry; Desiraju, G. R., Ed.; Elsevier: Amsterdam, 1987; pp 1-45. 3 4 Cheung, E.; Netherton, M . R.; Scheffer, J. R.; Trotter, J. Org. Lett. 2000,2, 77. 3 5 Scaiano, J. C ; Lissi, E. A. ; Encina, M . V . Rev. Chem. Intermediates 1978, 2, 139. 3 6 Gudmundsdottir, A . D.; Lewis, T. J.; Randall, L. H . ; Scheffer, J. R.; Rettig, S. J.; Trotter, J.; Wu, C.-H. J. Am. Chem. Soc. 1996,118, 6167. 33 Chapter 1 Introduction 3 7 Leibovitch, M . ; Olovsson, G.; Scheffer, J. R.; Trotter, J. J. Am. Chem. Soc. 1998, 120, 12755. 3 8 (a) Everitt, S. R. L.; Inoue, Y . In Molecular and Supramolecular Photochemistry: Organic Molecular Photochemistry; Ramamurthy, V . , Schanze, K . S., Eds.; Marcel Dekker: New York, 1999; Vol . 3, pp 71; (b) Inoue, Y . Chem. Rev. 1992, 92, 741; (c) Rau, H . Chem. Rev. 1983, 83, 535; (d) Bach, T. Synthesis 1998, 683; (e) Fleming, S. A. ; Bradford, C. L. ; Gao, J. J. In Molecular and Supramolecular Photochemistry: Organic Photochemistry; Ramamurthy, V . , Schanze, K . S., Eds.; Marcel Dekker: New York, 1997; Vol . l ,pp 187. 3 9 (a) Kagan, H . B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249; (b) Suarez, M . ; Schuster, G. B. J. Am. Chem. Soc. 1995,117, 6732. 4 0 (a) Inoue, Y . ; Ikeda, H. ; Kaneda, M . ; Sumimura, T.; Everitt, S. R. L. ; Wada, T. J. Am. Chem. Soc. 2000, 122, 406; (b) Ioue, Y . ; Tsuneishi, H . ; Hakushi, T.; Tai, A . J. Am. Chem. Soc. 1997, 119, All; (c) Tsuneishi, H. ; Hakushi, T.; Tai, A . ; Inoue, Y . J. Chem. Soc, Perkin Trans. 2 1995, 2057. 4 1 Pete, J. P. Adv. Photochem. 1996, 21, 135. 4 2 (a) Tanaka, K. ; Toda, F. Chem. Rev. 2000, 100, 1025; (b) Toda, F. Acc Chem. Res. 1995, 28, 480. 4 3 (a) Vaida, M . ; Popovitz-Biro, R.; Leiserowitz, L.; Lahav, M . In Photochemistry in Organized and Constrained Media; Ramamurthy, V. , Ed.; V C H Publisher, Inc.: New York, 1991; Chapter 6; (b) Scheffer, J. R.; Garcia-Garibay, M . In Photochemistry on Solid Surfaces; Anpo, M . , Matsuura, T., Eds.; Elsevier: Amsterdam, 1989; Chapter 9.3; (c) Leibovitch, M . ; Olovsson, G.; Scheffer, J. R.; Trotter, J. Pure Appl. Chem. 1997, 69, 34 Chapter 1 Introduction 815; (d) Caswell, L.; Garcia-Garibay, M . A. ; Scheffer, J. R.; Trotter, J. J. Chem. Educ. 1993, 70, 785. 4 4 Penzien, K. ; Schmidt, G. M . Angew. Chem., Int. Ed. Engl. 1969, 8, 608. 4 5 Sakamoto, M . ; Takahashi, M . ; Kamiya, K. ; Yamaguchi, K. ; Fujita, T.; Watanabe, S. J. Am. Chem. Soc. 1996, 118, 10664. 4 6 (a) Evans, S. V. ; Garcia-Garibay, M . ; Omkaram, N . ; Scheffer, J. R.; Trotter, J.; Wireko, F. J. Am. Chem. Soc. 1986, 108, 5648; (b) Caswell, L . ; Garcia-Garibay, M . ; Scheffer, J. R.; Trotter, J. J. Chem. Ed. 1993, 70, 785. 4 7 (a) Jacques, J.; Collet, A. ; Wilen, S. H . Enantiomers, racemates and resolutions. Wiley, New York, 1981; (b) Brock, C. S.; Dunitz, J. D. Chem. Mater. 1994, 6, 1118. 4 8 (a) Gamlin, J. N . ; Jones, R.; Leibovitch, M . ; Patrick, B.; Scheffer, J. R.; Trotter, J. Acc. Chem. Res. 1996, 29, 203; (b) Scheffer, J. R. Can. J. Chem. 2001, 79, 349. 4 9 Gudmundsdottir, A . D.; Scheffer, J. R. Tetrahedron Lett. 1990, 31, 6807. 5 0 (a) Cheung, E.; Netherton, M . R.; Scheffer, J. R.; Trotter, J.; Zenova, A . Tetrahedron Lett. 2000, 41, 9673; (b) Schultz, A . G.; Taveras, A . G.; Taylor, R. E.; Tham, F. S.; Kulling, R. K . J. Am. Chem. Soc. 1992, 114, 8725; (c) Cheung, E.; Netherton, M . R.; Scheffer, J. R.; Trotter, J. J. Am. Chem. Soc. 1999, 121, 2919; (d) Cheung, E.; Kang, T.; Raymond, J. R.; Scheffer, J. R.; Trotter, J. Tetrahedron Lett. 1999, 40, 8729; (d) Jones, R.; Scheffer, J. R.; Trotter, J. Tetrahedron Lett. 1992, 33, 5481. Also see Ref. 37. 5 1 Janz, K . M . ; Scheffer, J. R. Tetrahedron Lett. 1999, 40, 8725. Also see Ref. 48a. 5 2 Chong, K . C. W.; Scheffer, J. R. J. Am. Chem. Soc. 2003,125, 4040. 35 Chapter 1 Introduction 1 (a) Cheung, E.; Rademacher, K . ; Scheffer, J. R.; Trotter, J. Tetrahedron 2000, 56, 6739; (b) Cheung, E.; Rademacher, K. ; Scheffer, J. R.; Trotter, J. Tetrahedron Lett. 1999, 40, 8733. * Cheung, E.; Netherton, M . R.; Scheffer, J. R.; Trotter, J. Tetrahedron Lett. 1999, 40, 8737. 5 Scheffer, J. R.; Wang, L. J. Phys. Org. Chem. 2000,13, 531. 5 Cheung, E.; Chong, K . C. W.; Jayaraman, S.; Ramamurthy, V . ; Scheffer, J. R.; Trotter, J. Org. Lett. 2000, 2, 2801. ' Scheffer, J. R.; Wang, K. Synthesis 2001, 1253. 1 Patrick, B. O.; Scheffer, J. R.; Scott, C. Angew. Chem., Lnt. Ed. Engl. 2003, 42, 3775. ? Partial kinetic resolution of unfunctionalized simple olefins has been reported. For references on kinetic resolution of axially dissymmetric cyclic alkenes by asymmetric dihydroxylation, see: Hoveyda, A . H. ; Didiuk, M . T. Current Org. Chem. 1998, 2, 489 and references therein. For references on kinetic resolution of terminal alkenes by alkene polymerization with chiral zirconocene catalysts, see: Bercaw, J. E.; Min, E. Y . -J.; Levy, C. J.; Baar, C. R. Polym. Mater. Sci. Eng. 2002, 87, 62 and references therein. } Hanessian, S.; Delorme, D.; Beaudoin, S.; Leblanc, Y . J. Am. Chem. Soc. 1984, 106, 5754. 1 Goldberg, S. I.; Lam, F-L. J. Am. Chem. Soc. 1969, 91, 5113. 2 Cope, A .C . ; Funke, W. R.; Jones, F. N . J. Am. Chem. Soc. 1966, 88, 4693. 5 Imboden, C ; Villar, F.; Renaud, P. Org. Lett. 1999, 7, 873. 1 Stierman, T. J.; Johnson, R. P. J. Am. Chem. Soc. 1985,107, 3971. 36 Chapter 1 Introduction ' Ariel, S.; Evans, S. V . ; Garcia-Garibay, M . ; Harkness, B. R.; Omkaram, N . ; Scheffer, J. R.; Trotter, J. J. Am. Chem. Soc. 1988,110, 5591. 37 Chapter 2 Results and Discussion RESULTS AND DISCUSSION Chapter 2 Photochemistry and Asymmetric Induction of 9-Benzoylbi-cyclo[3.3.1]nonane Derivatives 2.1 Preparation of Substrates R! = H, C02Me, C02H Figure 2.1 9-Benzoylbicyclo[3.3.1]nonane derivatives 46 chosen for photochemical and asymmetric induction studies. The 9-benzoylbicyclo[3.3.1]nonane derivatives chosen for the present study have the general structure 46 (Figure 2.1). Retrosynthetic analysis of ketones 46 showed that the benzoyl functionality can be formed by a Grignard reaction of aldehyde 56 or 57 followed by oxidation of the corresponding alcohol. Compounds 56 and 57, as the source of the bicyclo[3.3.1]nonane-9-carbonyl skeleton, should be easily synthesized by the method of Alberts et al.1 from the known ketone 58, which in turn can be prepared from commercially available 9-BBN (59) (Figure 2.2). 38 Chapter 2 Results and Discussion R' H .0 H B R 46 56R = H 57 R = CH3 58 59 R = H, CH3 R' = H, C02Me, C02H Figure 2.2 Retro synthetic analysis for 9-benzoylbicyclo[3.3.1]nonane derivatives 46. 2.1.1 Synthesis of 9-Benzoylbicyclo[3.3.1]nonanes 60 and 61 Bicyclo[3.3.1]nonyl phenyl ketones 60 and 61 were synthesized as shown in Figure 2.3. Bicyclo[3.3.1]nonan-9-one (58), which served as the source of the bicyclo[3.3.1]nonyl skeleton for all the phenyl ketones studied here, was prepared by carbonylation of 9-BBN. 2 Wittig olefmation of this ketone provided enol ether 62, which was subsequently hydroylzed to form aldehyde 56. The overall yield for this one-pot process was 92%. Aldehyde 56 was found to be unstable and was used directly in a Grignard reaction with phenyl magnesium bromide to afford alcohol 63. PCC oxidation of this alcohol led to the target compound 60 in excellent yield (93%). In a similar manner, phenyl ketone 61 was synthesized. It is worth noting that the Grignard reagent (4-(carbomethoxy)phenyl magnesium iodide) used in the synthesis of ketone 61 was prepared by the method of Cohiez et al. and its reaction with aldehyde 56 was carried out in THF at -40 °C. 3 Under these conditions, the Grignard reagent selectively attacked the aldehyde carbonyl group and alcohol 64, the precursor of ketone 61, was obtained in 57% yield. 39 Chapter 2 Results and Discussion 60 (93%) 63(61%) Figure 2.3 Synthesis of phenyl ketones 60 and 61. 2.1.2 Synthesis of 9-Benzoyl-9-methylbicyclo[3.3.1]nonanes 71-73 Figure 2.4 outlines the synthetic route taken for the preparation of 9-methylbicyclo[3.3.1]nonyl phenyl ketones 71-73. Starting from aldehyde 56, an oxidation reaction gave the desired acid 65 in 78% yield. Treatment of this acid with ethereal diazomethane solution yielded the corresponding methyl ester 66. Alkylation using L D A / M e l equipped the bicyclo[3.3.1]nonyl skeleton with a methyl group at the 9-position. Reduction/oxidation manipulation transformed ester 67 to aldehyde 57 in a nearly quantitative yield. This aldehyde was also found to be unstable and was used 40 Chapter 2 Results and Discussion directly in Grignard reactions to give alcohols 69 and 70, which upon PCC oxidation, led to phenyl ketones 71 and 72 respectively. Mi ld hydrolysis of ester 72 with lithium hydroxide gave keto acid 73 in a nearly quantitative yield. CHO NaCIO, NaH2P04 ? ° 2 H CH,N 2 I N 2 56 65 (78%) LAH 68 (99%) PCC C02Me i-PrMgCI IC6H4COOMe T PhMgBr 70 (90%) 57 (99%) C02H 72(100%) 73(99%) Figure 2.4 Synthesis of phenyl ketones 71-73. C02Me 66 (88%) 1. LDA 2. Mel, DMPU O ^ O C H 3 / ^ A C H 3 67 (82%) 71 (95%) A l l these phenyl ketones were fully characterized by ! H and 1 3 C N M R , FT-IR, HRMS, U V and elemental analysis (see details in Chapter 5). Single crystal X-ray 41 Chapter 2 Results and Discussion crystallographic determinations were also performed for compounds 60, 61, 71, and 72 (Figure 2.5). (c) (d) Figure 2.5 ORTEP representations of (a) 60, (b) 61, (c) 71, and (d) 72. 42 Chapter 2 Results and Discussion 2.2 Photochemical Studies and Identification of Photoproducts The photochemistry of phenyl ketones 60, 61, 71, and 72 was explored in both the solution and crystalline state. The reaction products were readily obtained by preparative scale solution photolysis and the solid state reactions were performed on an analytical scale to determine the mode of reactivity in that medium. The details of the experiments as well as the apparatus used are given in the Experimental section (Chapter 6). Table 2.1 and Figure 2.6 summarize the photochemical results in both media. Table 2.1 Photolysis of ketones 60, 61, 71, and 72 in solution and the crystalline state. Ketone Medium Time (h) Conversion (%)a Products (%r 60 C H 3 C N 24 1:2 r-Butanol/Benzene 24 (no reaction) Crystal '24 61 C H 3 C N 24 1:2 r-Butanol/Benzene 24 (no reaction) Crystal 48 71 74 75 C H 3 C N C 1 65 62 2 2 89 85 3 8 100 92 3 Crystal0 24 100 92 5 72 76 77 C H B C N 0 1 98 91 4 Crystal0 24 100 90 5 a Percentage of total GC integral due to the disappearance of the corresponding starting material. Percentage of total GC integral due to the corresponding product. c The combined percentage of the reported compounds is less than unity because of some unidentified GC peaks. 43 Chapter 2 Results and Discussion R' hv (Pyrex) No Reaction Observed solution or solid state 60 R = H, R' = H 61 R = H, R' = C02Me R' R' hv (Pyrex) 6 + solution or solid state R 71 R = CH3, R' = H 72 R = CH3, R' = C02Me 74 R = CH3, R' = H 76 R = CH3, R' = C02Me 75 R = CH3, R' = H 77 R = CH3, R' = C02Me Figure 2.6 Photoreactivity of the phenyl ketones 60, 61, 71, and 72 in solution and the solid state. Compounds 60 and 61 were found to be photochemically inert in acetonitrile. In order to determine whether the lack of reactivity of ketones 60 and 61 is the result of regeneration of starting materials through rapid reverse hydrogen transfer of 1,4-hydroxybiradicals 78 and 79 (Figure 2.7), these two ketones were photolyzed in 1:2 t-butyl alcohol/benzene. Wagner has shown that Lewis base solvents, such as f-butyl alcohol, can retard the reverse hydrogen transfer process of 1,4-hydroxybiradicals through hydrogen bonding, and enhance the quantum yield of photoproduct formation.4 However, photolysis of ketones 60 and 61 in /-butyl alcohol/benzene showed no observable reactivity either. In order to see i f biradicals 78 and 79 were indeed being produced by irradiation of ketones 60 and 61, a radical trapping experiment was conducted. Photolyses of ketones 60 and 61 were conducted in 1:2 rert-BuOD/benzene. Figure 2.7 suggests a possible mechanism for deuteration of ketones 60 and 61 under 44 Chapter 2 Results and Discussion these conditions. If reversible hydrogen transfer is responsible for the observed lack of product formation, deuterium should be incorporated at either (both) of the y-carbons and compounds 80 and 81 would be expected (Figure 2.7). However, after 24-hour irradiation (Pyrex), no deuterium incorporation was found by GCMS analysis. Therefore, at this point, it is uncertain whether biradicals 78 and 79 are actually generated in solution photolyses. Further discussion of this topic is given in Section 2.4. !rt-BuOD T •] tert-BuOH 60 R' = H 61 R' = C02Me 78 R' = H 79 R' = C02Me 78D R' = H 79D R' = C02Me 80 R' = H 81 R' = C02Me Figure 2.7 Possible mechanism for deuteration of ketones 60 and 61. As shown in Figure 2.6 and Table 2.1, solution photolysis of 9-methyl substituted ketones 71 and 72 yielded primarily Yang photocyclization products 74 and 76 along with small amounts (< 5%) of the unusual 1,5-disproportionation products 75 and 77. These minor products are presumably formed by a novel disproportionation of the 45 Chapter 2 Results and Discussion intermediate 1,4-hydroxybiradicals (82 and 83) in which a hydrogen atom on C5 is transferred to the radical center on Ci (Figure 2.8). As far as we are aware, this type of disproportionation is unknown for 1,4-hydroxybiradicals, although 1,5-hydroxybiradical disproportionation has been observed before.5 The stereochemistry of the major photoproducts (74 and 76) was later determined to have the aryl group in the endo position although generation of exo-aryl products is theoretically possible. It is interesting to note that in the photochemistry of a-methyl substituted ketones 71 and 72, no photocleavage products were observed. 75 Y=H 77 Y=C0 2Me Figure 2.8 Photoreactivity of ketones 71 and 72 in solution. The results of solid state photolysis of ketones 60, 61, 71, and 72 were strikingly similar to their solution counterparts, with 60 and 61 showing no photoreactivity and 71 46 Chapter 2 Results and Discussion and 72 affording photoproducts 74-77. A l l the photoproducts (74-77) were fully characterized by ID ! H and 1 3 C (BB and APT) N M R , 2D ' H - H COSY, ' H - 1 3 C H M Q C , H M B C , and NOESY, FT-IR, FIRMS as well as elemental analysis. The structures of photoproducts 75, 76, and 77 were also confirmed by X-ray crystallography (Figure 2.9). The details of the separation conditions along with the analytical data of the products are given in the Experimental section (Chapter 6). Because of the lack of suitable single crystals for X-ray crystallographic analysis, the structure of compound 74 was established primarily through interpretation of its N M R spectroscopic data. Listed in Table 2.2 are the signals from the *H and l 3 C N M R spectra of this compound, along with the correlations determined from 2D COSY, FIMQC, H M B C and N O E S Y experiments. Analyzing these data, one can easily establish the atom connectivity sequence in this molecule, as shown in Table 2.2. APT and H M Q C experiments revealed that this compound contains eleven alkyl carbons: one methyl carbon (CIO), five methylene carbons (C2, C3, C6, C7, C8), three methine carbons ( C l , C4, C5), one tertiary carbon (Cl 1), and one quaternary carbon (C9), which is in agreement with the cyclobutanol structure formed from Yang cyclization of the starting ketone (71). Moreover, the fact that there was no vinyl proton signal in the *H N M R spectrum or ketone carbon peak in the 1 3 C N M R spectrum eliminates the possibility of it being a photocleavage product. The endo-ary\ configuration at C l 1 was determined based on the results of NOESY experiment, and the important correlations are depicted in Figure 2.10. 47 Chapter 2 Results and Discussion Chapter 2 Results and Discussion Table 2.2 Comprehensive N M R assignment data of endo-aryl cyclobutanol 74 in CeD 6. 1 3 / Ax15 2 / i 11 10 > r - ' C H 3 / Q 3 L-Pr ;i / - 6 Carbon # 1 3 C 5 (ppm) XW 5 (ppm) (correlations from HMQC) ' H - ' H COSY correlations H M B C (long-range) " C - ' H correlations ' H - ' H NOESY correlations 1 37.62 1.95 (m, IH) H2, H8 H2, H3, H7, H8,H10 H2, H7, H8, H13 2 18.29 1.60 (m, IH) H1,H3 H1,H3,H4, H8 H1,H3,H13 1.36 (m, IH) 3 20.23 1.61 (m, 2H) H2, H4 H2 H2, H6, H7, H8,H13 4 36.11 2.72 (br, IH) H3,H5 H2, H3, H5, H6, H3,H5 5 46.37 2.57 (dt, 7=4,9, 1.3 Hz, 1 H) H4, H6 H3, H4, H6, H7,H10 H4, H6 6 24.53 1.85 (m, IH) H5,H7 H7 H5,H7 1.74 (m, IH) 7 22.55 1.14 (m, IH) H6, H8 H5, H6, H8 H1,H6, H8 0.89 (m, IH) 8 27.56 1.58 (m, IH) H1,H7 H1,H2, H6, H7 H1,H7, H8, H10 1.25 (m, IH) 9 46.26 - - H1,H2, H4, H5, H6, H10 -10 17.77 1.27 (s, 3H) - H5 H8 11 82.64 - - H5,H10 -12 144.04 - - H13,H14 -13 128.65 7.17 (m, 2H) H14,H15 H14,H15 H2, H3, H14 14 125.29 7.11(m, 2H) H13,H15 H13,H15 H2, H3, H13,H15 15 127.17 7.14 (m, IH) H13,H14 H13,H14 H13 - - OH 1.39 (s, IH) - - H4, H5 49 Chapter 2 Results and Discussion 50 Chapter 2 Results and Discussion 2.3 Asymmetric Induction Studies 2.3.1 Preparation of Optically Active Salts of Keto Acid 73 In order to apply the solid state ionic chiral auxiliary method to asymmetric induction in the photochemistry of 9-methylbicyclo[3.3.1]nonyl phenyl ketones, a number of crystalline salts were prepared by reaction of keto acid 73 with commercially available optically active amines. Table 2.3 lists the crystal morphology, crystallization solvents and melting points of these chiral salts. The chiral auxiliaries of these salts were selected according to two criteria: (1) the pKa of the reacting acid should be lower than that of the protonated amine by about 3 units,6'7 because this ensures complete proton transfer from the acid to the amine instead of forming a neutral hydrogen bonded complex; (2) the amine selected does not possess chromophores that interfere with the phenyl ketone absorption at 320-330 nm. The formation of an ammonium carboxylate linkage between the acid and amine was confirmed by the melting point and FT-IR spectrum of each salt. The melting points of all the salts are different from both keto acid 73 and the corresponding amines. In the IR spectrum of keto acid 73, the C=0 stretches of the ketone and carboxylic acid exist as broadened bands at 1695 cm"1 and 1680 cm' 1 respectively. In the spectra of the salts, these absorptions are replaced by a single sharper band at ~ 1675 cm"1 corresponding to the C=0 stretch of the ketone. At the same time, two new intense bands (1300-1600 cm"1) Q due to the symmetric and asymmetric stretches of the carboxylate anion are observed. The 1:1 acid/base stoichiometry of all the salts was confirmed by ' H N M R spectroscopy, ESI (or LSEMS) mass spectroscopy and elemental analysis. 51 Chapter 2 Results and Discussion Table 2.3 Chiral salts prepared from keto acid 73. 0 ^.COO ^ffCH3 Salt Cation Recrystallization Solvent Crystal Morphology mp C C ) 84 H © H 3 C - V N H 3 6 (S)-(-)-1 -phenylethylamine MeOH / C H 3 C N needles 211-213 85 H © H 3 C - - C - N H 3 6 (R)-(+)-1 -phenylethylamine MeOH / C H 3 C N needles 211-213 86 NH 3 © (IS, 2R)-(-)-cis-l-amino-2-indanol MeOH / C H 3 C N powder 190(dec.) 87 © H 3 N N N,H /C-CHzOH C 2 H 5 (i?)-(-)-2-amino-1 -butanol MeOH powder 159-162 88 H 2 0 L-prolinamide MeOH / C H 3 C N powder 210-211.5 52 Chapter 2 Results and Discussion Table 2.3 continued Salt Cation Recrystallization Solvent Crystal Morphology mp (°C) 89 w © N ' CH 3 (R)-(-)-l-cyclohexylethylamine MeOH powder 192-195 90 © b!H3 4- r^—H H O ^ V C \ V CH2OH 6 (li?,2i?)-(-)-2-amino-l-phenyl-1,3-propanediol MeOH / C H 3 C N powder 142-143 2.3.2 Solution State Photolysis of the Optically Active Salts In order to determine whether the ionic chiral auxiliary has any effect on the product distribution or the steric course of the photoreaction in solution state, a number of the optically active salts were photolyzed in a mixture of acetonitrile and water. Following irradiation, the reaction mixture was treated with excess ethereal diazomethane solution to form the corresponding methyl esters 76 and 77. A l l the solution state reactions afforded essentially the same product ratio of cyclobutanol 76 and alkene 77 as that observed in the solution photolysis of keto ester 72. Photoproduct 76 was later determined to be racemic. The enantiomeric excess of photoproduct 77 was not measured owing to its small quantity in the reaction mixture. These results show that, in solution, the anisotropy of the chiral ion has no influence on the reaction selectivity. The results of these experiments are presented in Table 2.4. 53 Chapter 2 Results and Discussion Table 2.4 Solution state photolysis of some optically active salts of keto acid 73 Salt Amine Conversion (%) 76 (%) 77 (%) Optical Activity for 76 84 (5)-(-)-l-phenylethylamine >99 92 4 racemic 87 (i?)-(-)-2-amino-l-butanol >99 91 5 racemic 89 (£)-(-)-1-cyclo-hexylethylamine >99 91 4 racemic 2.3.3 Solid State Photolysis of the Optically Active Salts Each of the salts listed in Table 2.3 was irradiated in the crystalline state. The procedure consisted of crushing ca. 5 mg of the salt to be photolyzed between two Pyrex microscope slides, taping the plates together, sealing the resulting sandwiches in polyethylene bags under a positive nitrogen atmosphere, and irradiating the ensembles with the output from a water-cooled 450 W medium pressure mercury lamp. Photolyses were generally carried out at room temperature. For some runs that required low temperature during photolysis, a Cryocool CC-100 II Immersion Cooling System (Neslab Instrument Inc.) was used with ethanol as the coolant. The salts were irradiated for varying lengths of time in order to determine the dependence of the ee values on the extent of conversion. In order to achieve high conversions it was usually necessary to rotate the sample 180° midway through the irradiation, exposing the rear side of the slide to the light and allowing as much of the sample as possible to react. No color change or melting of the crystals was observed during the reaction, and following irradiation, the reaction mixture was dissolved in ethyl acetate or methanol and treated with excess ethereal diazomethane to form the corresponding methyl esters 76 and 77. Following 54 Chapter 2 Results and Discussion diazomethane treatment, the organic layer containing the esterified photoproducts and starting material was washed with water and filtered through a short-path silica gel column to remove the chiral auxiliary. The mixture was then analyzed by GC for yield and conversion. Due to the overlap of the product and starting ketone peaks in the chiral HPLC analysis, preparative HPLC was used to isolate photoproduct 76 (Waters Radialpak™ uPorasil™ silica column, 10% EtOAc in hexanes, 5 mL/min). Following purification, the enantiomeric excess of photoproduct 76 was measured using chiral HPLC (Chiralcel® OC column). Details of the chromatographic separations for racemic 76 are shown in Table 2.5. Figure 2.11 depicts a chiral HPLC trace of racemic 76. Table 2.5 Chromatographic data for the resolution of racemic 76. Column Chiralcel® OC Column Specifications 250mm L x 4.6 mm I.D. Solvents 98 : 2 (hexanes : 2-propanol) Flow Rate 0.5 mL/min U V Detector 254 nm Retention Time a A : 60.4 min; B : 70.2 min a A refers to the first eluted peak, B to the second. m CO <=> ( 0 l i i l i i i i i i 'i 1 1 f i i I I I I I I I I I 1 1 I I i i > 1 1 1 1 i 1 1 1 1 u r I I 1 1 I I I I i 1 1 1 1 1 1 i 1 1 1 1 1 1 i i • " " " ' 0,0 8 0 ' " Figure 2.11 Chiral H P L C trace showing the separation of racemic 76. 55 Chapter 2 Results and Discussion The results of the solid state photolysis of chiral salts 84-90 are summarized in Table 2.6. Irradiation of the salts in the crystalline state leads to asymmetric induction with product ee's ranging from 3% to 95%. The highest ee was observed for salt 89 formed between acid 73 and (R)-(-)- 1-cyclohexylethylamine, where an enantiomeric excess of 95% was achieved at 38% conversion of the reaction. Among all the salts studied, salt 90 showed a particularly low enantioselectivity (3% ee). The low enantioselectivity observed is likely due to the phenomenon of conformational enantiomerism,9 in which equal amounts of both enantiomeric conformers of the achiral photolabile carboxylate exist within the crystal lattice. Each conformer abstracts one of the two enantiotopic y-hydrogens and forms opposite enantiomers of the same photoproduct. In addition, crystal disorder could also be a cause for the low enantioselectivity observed in photolysis of salt 90. In a disordered crystal, two or more conformations of the reactive ion are distributed randomly throughout the crystal (static disorder) or are thermally interconverting (dynamic disorder). Since our attempts to grow crystals of salt 90 suitable for X-ray analysis were not successful, the exact reason for the low enantioselectivity of salt 90 is unclear. 56 Chapter 2 Results and Discussion Table 2.6 Solid state photolysis of optically active salts of keto acid 73. Salt Amine Temp. (°C) Time (min) Conv. ( % ) a ee ( % ) b [a f 84 0S)-(-)-i-phenylethylamine r.t.d 120 >99 . 7 0 + -20 15 31 91 + -20 30 60 86 + -20 240 >99 81 + -70 180 44 86 + 85 (*)-(+)-!-phenylethylamine r.t.d 120 >99 73 --20 15 36 90 --20 30 72 86 --20 60 89 86 --70 120 93 80 -86 (IS, 2i?)-(-)-cis-l- amino-2-indanol r.t.d 120 83 49 + -20 60 55 86 + -20 180 73 60 + -20 300 95 54 + 87 (i?)-(-)-2-amino-1-butanol r.t.d 120 98 25 --20 30 21 38 --20 240 81 29 -88 L-prolinamide r.t.d 120 94 60 + -20 30 26 94 + -20 180 87 77 + -70 180 56 93 + 89 (/?)-(-)- 1-cyclo-hexylethylamine r.t.d 120 >99 36 --20 10 38 95 --20 30 64 84 --20 120 97 70 -90 (li?,2i?)-(-)-2-amino-l-phenyl-l,3-propanediol r.t.d 120 >99 3 + -20 60 35 17 + -20 240 84 7 + -70 180 68 6 + a Percentage of total GC integral due to the disappearance of the corresponding starting material. The enantiomeric excess for photoproduct 76 was determined using a Chiralcel® OC HPLC column. c Sign of rotation of 76 at the sodium D-line. d r.t., room temperature. 57 Chapter 2 Results and Discussion Photolysis of the (5)-(-)- and (i?)-(+)-l-phenylethylamine salts (84 and 85) afforded nearly equal optical yields of the enantiomers of cyclobutanol 76 (after diazomethane work up). A system like this allows access to both enantiomers by simple exchange of the ionic chiral auxiliary. Table 2.6 also shows that the product ee declines with increasing reaction conversion. This is not unexpected, since the salts react to give products that presumably do not "fit" into the original crystal lattice, and defect sites are generated. As the reaction proceeds, the rigidity and regularity of the crystal lattice is gradually lost. As a result, the photoreaction loses its topochemical control and enantioselectivity declines. Low temperature photolysis can be used to compensate this effect. As shown in Table 2.6, for reactions conducted at reduced temperature (-20°C), enantioselectivities are better than those obtained at room temperature. Specifically, at -20°C, quantitative conversion to cyclobutanol 76 from salt 84 occurred in 81% ee in comparison to 70% ee at room temperature. Further reducing the reaction temperature to -70°C provided limited improvement on enantioselectivity, while longer irradiation time was required. 58 Chapter 2 Results and Discussion 2.4 Solid State Structure-Reactivity Correlations In the previous chapter, four parameters (d, co, A, and 9) used to quantify the geometric requirements for the type II hydrogen abstraction process were presented. Figure 2.12 and Table 2.7 list the values of these parameters for ketones 60, 61, 71, and 72. In each ketone, there are two y-hydrogen atoms, H x and H y , which could be abstracted upon irradiation. It is evident that there is a large difference (> 0.64 A) in the abstraction distance d for the two y-hydrogen atoms. For example, ketone 60 has H x (d = 2.48 A) lying well within the ideal value of 2.72 A, while H y lies far away (d = 3.12 A). Although hydrogen atom abstractions have been observed with d distances as long as 3.15 A, 1 0 it has been known for Norrish type II reactions that a difference in d of only 0.27 A will lead to the exclusive abstraction of one hydrogen over the other.11 Moreover, the values of other parameters (oo, A, and 0 from Table 2.7) for H x are also closer to the ideal values than those for H y . Therefore, it is H x in each ketone that should be abstracted. Figure 2.12 Hydrogen abstraction parameters for type II photochemistry. 59 Chapter 2 Results and Discussion Table 2.7 Hydrogen abstraction parameters for compounds 60, 61, 71, and 72. Ketone H d(A) a o b A(°)C 0(°)d 60 H x 2.48 30 97 118 Hy 3.12 77 58 111 61 H x 2.46 30 99 116 Hy 3.17 74 60 110 71 H x 2.50 57 86 118 Hy 3.49 91 41 105 72 H x 2.52 63 78 119 Hy 3.69 94 35 105 Ideal values <2.72 0 90-120 180 a C=0-Hy distance.b Deviation of Hy from the mean plane of the carbonyl group. c C=0"Hy angle. d C-Hy-O angle. Since hydrogen abstraction in the solid state is considered to occur with a minimum movement of the heavy atoms, geometric data derived from the ground state ketone can be used to analyze the behavior of the corresponding 1,4-hydroxybiradical intermediate. For this purpose, we define two torsional angles with reference to Figure 2.13a, which is a depiction of the 1,4-hydroxybiradicals derived from ketones 60, 61, 71, and 72. Angle (pi is defined as the dihedral angle between the C2-C3 bond and the p-orbital on d , and angle 94 is likewise defined as the analogous angle between the C2-C3 bond and the p-orbital on C4. The p-orbitals at Ci and C4 are assumed to be orthogonal to the O-C1-C2 and C3-C4-C5 planes, respectively. 60 Chapter 2 Results and Discussion (a) (b) Figure 2.13 (a) 1,4-Hydroxybiradical intermediate derived from ketones 60, 61, 71, and 72; (b) the angle p. It is generally believed that cleavage of 1,4-hydroxybiradicals is favored by good overlap between the p-orbitals on Ci and C 4 with the C2-C3 bond. 1 2 The overlap between these orbitals is proportional to coscpi and COS94,13 and the best geometry for cleavage can be expected when cpi and 9 4 = 0° and coscpi = coscp4 = 1. The values of coscpi and COS94 for the 4 ketones investigated in the present study are given in Table 2.8. Also shown in Table 2.8 are the values of angle p, defined as the dihedral angle between the p-orbital on Ci and the C2-C4 vector (Figure 2.13b). The most favorable geometry for cyclization exists when p = 0°, i.e., when the p-orbital on Ci is pointing directly at the p-orbital on C 4 . Table 2.8 also gives the values of the distance D, defined as the distance between Ci and C 4 . For Yang photocyclization to be successful, the radical-containing carbon atoms Ci and C 4 must be close to one another, i.e. D < 3.4 A , which is the sum of the van der Waals radii for two carbon atoms.14 61 Chapter 2 Results and Discussion Table 2.8 Geometric data for ketones 60, 61, 71, and 72. Ketone cpi(°) coscpi <P4(°) COS94 P D(A) 60 88 0.03 39 0.78 61 3.13 61 86 0.07 39 0.78 62 3.15 71 65 0.42 35 0.82 35 3.01 72 59 0.52 36 0.81 28 2.90 As described in a previous section, in the solid state, cc-methylated bicyclo[3.3.1]nonyl phenyl ketones 71 and 72 underwent Yang photocyclization and yielded endo-aryl cyclobutanols 74 and 76 as primary photoproducts. In this case, it is relevant to ask why neither exo-aryl cyclobutanols nor photocleavage products were obtained. To answer this question, consider the idealized reaction pathway shown in Figure 2.14. X-ray crystallography shows that ketones 71 and 72 adopt joint chair-chair conformations, in which the benzoyl group is in the axial position and the mean plane of carbonyl group is roughly orthogonal to the plane bisecting the bicyclo[3.3.1]nonane ring between y-hydrogen atoms H x and H y . H x , in this case, is in closer proximity to the carbonyl group than H y (for H x : d = 2.50 A in ketone 71, and 2.52 A in ketone 72; for H y : d = 3.49 A in ketone 71, and 3.69 A in ketone 72). The other parameters (co, A, and 9) in Table 2.7 also suggest that H x is in a more favorable position for hydrogen abstraction than Hy. Upon photoexcitation and hydrogen abstraction, 1,4-hydroxybiradical intermediate 91 will be generated (Figure 2.14). With coscp4«80% and coscpi « 50% (only 50% of maximum overlap between p-orbital on Ci and the C2-C3 bond, insufficient), the geometry of this biradical intermediate is poor for cleavage, as cleavage requires good overlap of both p-orbitals with the cleaving C2-C3 bond. But this 62 Chapter 2 Results and Discussion biradical is good for cyclization with (3 « 30° (indicating there is a good overlap of the two p-orbitals at C i and C4) and D = 2.90 A in ketone 72, and 3.01 A in ketone 71. As a result, cyclization of biradical 91 with retention of configuration at C\ and C4 leads to the predominant endo-aryl photoproducts 74/76. On the other hand, for cleavage to occur, an approximate 90° rotation of the aryl and hydroxyl groups about the C1-C2 bond of biradical 91 is required in order to align the p-orbital on Ci with the C2-C3 a bond (see Figure 2.14, structure 92). An additional 90° rotation of the aryl and hydroxyl groups about the C1-C2 bond will lead to biradical 93, ring closure of which will give exo-aryl cyclobutanol products. Both processes involve unfavorable rotations about the C1-C2 bond and are topochemically forbidden in the solid state. Therefore, endo-aiy\ cyclobutanols 74/76 are the major products formed in the photoreaction of ketones 71/72. endo-aryl cyclobutanol 74/76 cleavage product endo-aryl cyclobutanol Figure 2.14 Reaction pathway of ketones 71/72. 63 Chapter 2 Results and Discussion For ketones 60 and 61, the geometric parameters for H x are all within favorable limits of the "ideal" values. As mentioned above, the values for parameter d (2.48 A for ketone 60 and 2.46 A for ketone 61), representing the distance between the carbonyl oxygen and the y-hydrogen to be abstracted, are well within the optimum value (2.72 A). Values for parameter 6 (118° for ketone 60, and 116° for ketone 61), though being far from the ideal value of 180°, are within the practical range of 95-125°. Values for parameter A (97° for ketone 60, and 99° for ketone 61), representing the C=0—Hy angle, lie in the preferred range of 90-120° and suggest that the real picture of the excited state carbonyl is close to the Kasha model. Values for parameter co (30° for both ketones 60 and 61), measuring the 'out-of-plane' angle between the y-hydrogen and the carbonyl group, are within the common deviations from the ideal value. A l l these data strongly suggest that ketones 60 and 61 are well aligned to undergo hydrogen abstraction, even though in these cases attempted trapping of the biradical intermediates was unsuccessful.15 Then, why do ketones 60 and 61 fail to produce any photoproduct? As can been seen from Table 2.8, ketones 60 and 61 lead to biradicals in which only the p-orbital on C4 is reasonably oriented for cleavage, the other (on Ci) being very poorly aligned (coscpi = 3-7%, i.e. 3-7% of maximum overlap). Since cleavage requires good overlap of both p-orbitals with the cleaving C2-C3 bond, it is easy to understand why no cleavage product was found in the photolysis of ketones 60 and 61. Then, why do these ketones fail to photocyclize? Part of the reason may be the D distance between the Ci and C4 radical centers. The data in Table 2.8 show that the C1—C4 distances in compounds 60/61 are 3.13/3.15 A, whereas the distances for ketones 71/72 are 3.01/2.90 A. This difference 64 Chapter 2 Results and Discussion is caused by a buttressing effect between the a group and the aryl group. In ketones 60 and 61, steric interaction between the a-hydrogen and the aryl group is less than that between the a-methyl group and the aryl group in ketones 71/72. As a result, C) is 'pushed' closer toward C4 in ketones 71/72 than it is in ketones 60 and 61 as it can been seen from the difference of C1-C2-C3 angle in these ketones. For the a-methylated ketones 71/72, the Ci-C 2 -C 3 angles are 106 and 110°, whereas they are 114 and 116° for the nonmethylated derivatives 60/61. Moreover, the failure of the nonmethylated ketones 60 and 61 to form cyclobutanols may also be attributed to poor orbital overlap between the p-orbitals on Ci and C4, as indicated by the p angle (-60° for ketones 60/61). In the solid state, ketones 60 and 61 adopt conformations in which the C=0 group is virtually eclipsed with the C2-C3 CT bond (O1-C1-C2-C3 « 0°). Owing to the methyl/aryl steric interaction, the same angle in ketones 71/72 is -30°. In other words, the p-orbital on Ci in ketone 60 or 61 is rotated -30° further away from the p-orbital on C 4 than that it is in ketone 71 or 72, and this makes cyclization an unfavorable process for ketones 60 and 61. With both cyclization and cleavage slowed, reverse hydrogen transfer is the only geometrically favorable pathway for ketones 60 and 61. Finally, formation of photoproducts 75 and 77 observed in the photolysis of ketones 71 and 72 can be seen to be the result of a 1,5-disproportionation of biradical intermediate 155, which in turn is formed by a ring flip of initially formed biradical 91 (Figure 2.15). X-ray crystallographic analysis showed that the distance between Ci and the equatorial hydrogen atom on C5 in ketones 71 and 72 is 4.08 and 4.02 A respectively. It is unlikely that 1,5-disproportionation could happen directly from the chair-chair biradical 91 without a significant geometry change of the bicyclic ring. On the other 65 Chapter 2 Results and Discussion hand, a ring flip of biradical 91 at the C 5 end leads to the boat-chair biradical 155, in which the hydrogen atom on C 5 is brought close to the radical center on Ci, and a 1,5-disproportionation process should occur easily. Because this ring flipping process is energetically unfavorable, in an established equilibrium, the population of biradical 155 is less than that of biradical 91. Moreover, 1,5-disproportionation is likely to be a slower process than Yang cyclization. Therefore, only small amounts of disproportionation products 75 and 77 were observed in the photolysis of ketones 71 and 72. R' R' 71 R' = H 72 R' = C0 2 Me 91 ring flip R' R' 75 R" = H 77 R' = C0 2 Me 155 Figure 2.15 Formation of compounds 75/77 from photolysis of ketones 71/72. 66 Chapter 2 Results and Discussion 2.5 Summary The photochemistry of several bicyclo[3.3.1]nonyl phenyl ketones was studied in solution and the solid state. In both media, non a-methylated bicyclo[3.3.1]nonyl phenyl ketones (60 and 61) were found to be photochemically inert, while Yang photocyclization was found to be the major process for a-methylated bicyclo[3.3.1]nonyl phenyl ketones (71 and 72), with endo-aryl cyclobutanols (74 and 76) being the major products. A n unusual 1,4-hydroxybiradical disproportionation reaction was also observed during the photolysis of ketones 71 and 72, although it was a minor process (< 5%). B y utilizing the ionic chiral auxiliary method, high enantioselectivities (up to 95%) were achieved for a number of the optically active salts on photolysis in the solid state. In addition, structure-reactivity correlation studies were performed based on the crystal structure data of ketones 60, 61, 71, and 72 to rationalize their photochemical behavior. 67 Chapter 2 Results and Discussion R e f e r e n c e s 1 Alberts, A . H . ; Wynberg, H. ; Strating, J. Synth. Comm. 1972, 2, 79. 2 Carlson, B . A . ; Brown, H . C. Org. Synth. 1978, 58, 24. 3 (a) Boymond, L. ; Rottlander, M . ; Cahiez, G.; Knochel, P. Angew, Chem., Int. Ed. Engl. 1998, 37, 1701. (b)Lee, J.-s.; Velarde-Ortiz, R.; Guijarro, A . ; Wurst, J. R.; Rieke, R. D. J. Org. Chem. 2000, 65, 5428. 4 Wagner, P. J. Acc. Chem. Res. 1983,16, 461. 5 Wagner, P. J.; Laidig, G. Tetrahedron Lett. 1991, 32, 895. 6 (a) Etter, M.C. ; Adsmond, D.A. J. Chem. Soc, Chem. Commun. 1990, 589; (b) Johnson, S.L.; Rumon, K . A . J. Phys. Chem. 1965, 69, 74. 7 There are exceptions for this rule, see: Liao, R.-F.; Lauher, J.W.; Fowler, F.W. Tetrahedron 1996, 52, 3153. 8 Dolphin, D.; Wick, A . In Tabulation of Infrared Spectral Data; John Wiley and Sons: New York, 1977; pp. 295. 9 Cheung, E.; Kang, T.; Netherton, M . R.; Scheffer, J. R.; Trotter, J. Am. Chem. Soc. 2000,122, 11753. 1 0 Koshima, H. ; Matsushige, D.; Miyauchi, M . Cryst. Eng. Comm. 2001, 33, 1. 1 1 Lewis, T. J.; Rettig, S. J.; Scheffer, J. R.; Trotter, J. Mol. Cryst. Liq. Cryst. 1992, 219, 17. 1 2 Wagner, P. J.; Kelso, P. A . ; Kempainen, A . E. J. Am. Chem. Soc. 1968, 90, 5896. 1 3 Burdett, J. K . Molecular Shapes; Wiley-Interscience: New York, 1980; p. 6. 1 4 Bondi, A . J. Phys. Chem. 1964, 68, 441. 68 Chapter 2 Results and Discussion 5 The trapping experiment consisted of irradiating ketones 60 and 61 in 1:2 tert-BuOD/benzene and looking for deuterium incorporation at the y-position. No exchange was detectable for ketones 60 and 61. Attempts to observe such exchange in y,y-d2-nonaphenone were similarly unsuccessful. See: Wagner, P.J.; Kelso, P.A.; Kemppainen, A .E . ; McGrath, J .M.; Schott, H.N.; Zepp, R.G. Am. Chem. Soc. 1971, 94, 7506. 69 Chapter 3 Results and Discussion Chapter 3 Norrish/Yang Type II Photochemistry of a Homologous 3.1 Synthesis of the Spirobicyclo[3.3.1]nonyl Ketones The most challenging part of the synthesis of ketones 49-52 is building the N ring with different ring sizes (N = 5, 6, 7, 8) (Figure 3.1), because the bicyclo[3.3.1]nonyl moiety can be obtained from the known compound 58. Two different synthetic strategies were adopted for the construction of the N ring. Formation of the five- and six-membered N ring of ketones 49 and 50 was accomplished via an intramolecular Friedel-Crafts acylation of compounds 94 and 95, while a ring closing metathesis (RCM) reaction was employed as the key step for the construction of the seven- and eight-membered N ring of spiroketones 51 and 52. Series of Spirobicyclo[3.3.1]nonyl Ketones o. ,OMe Friedel-Crafts Acylation a / 94 n = 1 95n = 2 49 N 50 N 51 N 52 N 5 6 7 8 b ^ Ring-Closing Metathesis 58 101 n = 0 102 n = 1 Figure 3.1 Strategies for building the N ring of spiroketones 49-52. 70 Chapter 3 Results and Discussion 3.1.1 Synthesis of Spiroketones 49 and 50 by Intramolecular Friedel-Crafts Acylation The synthetic sequence for ketones 49 and 50 is outlined in Figure 3.2. Alkylation of ester 66 using L D A and benzyl bromide or 2-phenylethyl bromide afforded esters 94 and 95 respectively. Intramolecular ring closure of 94 and 95 was achieved by stirring the esters in a boron trichloride/dichloromethane solution. In this one-pot reaction, boron trichloride plays two roles. First, it is the cleaving reagent for the starting esters to form the corresponding acid chlorides.1 Second, it acts as the Lewis acid catalyst in the subsequent Friedel-Crafts acylation reaction. Both spiroketones 49 and 50 were synthesized in satisfactory yields (88% for 49, 71% for 50). Figure 3.2 Synthesis of spiroketones 49 and 50. Spectral data obtained for ketones 49 and 50 were in full agreement with the assigned structures. In addition X-ray crystal structures for these ketones were obtained and are presented in Figure 3.3. 71 Chapter 3 Results and Discussion Chapter 3 Results and Discussion 3.1.2 Synthesis of Spiroketones 51 and 52 by Ring-Closing Metathesis The synthetic route taken to synthesize spiroketones 51 and 52 is depicted in Figure 3.4. Starting from ester 66, alkylation using L D A and allyl bromide equipped the bicyclo[3.3.1]nonyl skeleton with an allyl group at the 9-position. Reduction/oxidation manipulation transformed ester 96 to aldehyde 98, which was used directly to react with the Grignard reagents or/^o-vinylphenyl magnesium bromide or ort/zo-allylphenyl magnesium bromide to form alcohols 99 and 100 respectively. PCC oxidation transformed alcohols 99 and 100 to the corresponding ketones 101 and 102, to which the ring closure metathesis method was applied. Treatment with Grubbs catalyst (benzylidene-bis(tricyclohexylphosphine)dichlororuthenium)2 led to the unsaturated seven- and eight-ring spiroketones 103 and 104 in excellent yields (97% for 103, 95% for 104). The structure of compound 103 was confirmed by X-ray crystallographic analysis (Figure 3.5a). Finally, catalytic hydrogenation of the double bonds in compounds 103 and 104 afforded the target compounds 51 and 52. 73 Chapter 3 Results and Discussion 101 n = 0(61%) 103n = 0(97%) 51 n = 0 (96%) 102n = 1(83%) 104n = 1(95%) 52 n = 1 (96%) Figure 3.4 Synthesis of spiroketones 51 and 52. The spectroscopic data for these two spiroketones (51 and 52) are in full agreement with the assigned structures, which were confirmed by X-ray crystallography. Figure 3.5b and 3.5c present ORTEP drawings of ketones 51 and 52. 74 Chapter 3 Results and Discussion Chapter 3 Results and Discussion 3.2 Photochemical Studies of Spiroketones 49-52 Each of the four spiroketones was irradiated in the crystalline state. The procedure consisted of crushing ca. 5 mg of the ketone to be photolyzed between two Pyrex microscope slides, taping the plates together, sealing the resulting sandwiches under nitrogen in polyethylene bags, and irradiating the ensembles with the output from a water-cooled 450 W medium pressure mercury lamp. Conversions were generally kept below ca. 25% in order to minimize crystal melting during photolysis. Preparative scale photolyses for the purpose of product isolation and characterization were carried out in solution, which led to results essentially identical to those observed in the solid state. The photoproducts were isolated by column chromatography and their structures established by high resolution N M R and other spectroscopic methods. In one case (photoproduct 114), the structure was corroborated by X-ray crystallography. Details of the workup and photoproduct isolation and characterization procedures for the photolysis of ketones 49-52 are given in Chapter 6. 76 Chapter 3 Results and Discussion 3.2.1 Photochemistry of Spiroketone 49 tert-BuOH/C6H6(1:2) B a O ( s ) hv (Pyrex) cat. acid/base or Solid State 49 105 -1:1 epimeric mixture 106 Figure 3.6 Photochemistry of spiroketone 49. In both solution and the solid state, the five-membered ring spiroketone 49 underwent exclusive Norrish type II cleavage to afford the corresponding ring-opened photoproduct 106 (Figure 3.6) as an approximately 1:1 mixture of two diastereomers. This is formed by non-stereoselective ketonization of intermediate enol 105, which could be detected by J H N M R in the photolysis of ketone 49. Figure 3.7a shows the vinyl region of the ! H N M R spectrum of ketone 49 following photolysis in 2:1 benzene-de/tert-butyl alcohol-Jj. The resonances around 8 5.62 ppm are assigned to the vinyl hydrogens of enol 105 formed by cleavage of the 1,4-hydroxybiradical. Figure 3.7b shows a second spectrum taken immediately after the addition of a trace amount of trifluoroacetic acid. This spectrum contains vinyl proton signals for the enol as well as new resonances (around 8 5.53 ppm) corresponding to the two newly formed epimers of ketone 106. Another spectrum (Figure 3.7c) acquired six minutes later contained only ketone signals, indicating that complete conversion to the keto tautomers had occurred. 77 Chapter 3 Results and Discussion - I I--: i i. r .... I 5.8 5 .7 5.6 5 .5 5.A 5 .3 Figure 3.7 ' H N M R vinyl region (5 5.4-5.7 ppm) after photolysis of ketone 49 showing signals due to the intermediate enol 105 (E) and the two diastereomers of ketone 106 (K): (a) after photolysis; (b) immediately following addition of catalytic trifluoroacetic acid; (c) six minutes after addition; (d) pure sample of ketone 106. The structure of ketone 106 was determined by analyzing its spectroscopic data. The FT-IR spectrum of photoproduct 106 showed one strong absorption at 1709 cm"1, indicating the presence of a carbonyl group in this molecule. HRMS and elemental analysis confirmed that product 106 has the same chemical formula as the starting material and is a structural isomer of ketone 49. In addition to that, the observation of lH 78 Chapter 3 Results and Discussion signals in the vinyl region of the 'H NMR spectrum suggests that compound 106 is a Norrish type II photocleavage product of ketone 49. With two sets of separated carbon signals in the 1 3 C NMR spectrum, it is easy to conclude that compound 106 is actually a mixture of two epimers. Further examination of the ! H NMR spectrum revealed that the two epimers are in an approximately 1:1 ratio. The results of 1 3 C BB and APT experiments showed that there are 17 different carbons within each set of carbon signals: 8 alkyl (6 CH 2 and 2 CH), 2 vinyl, 6 aromatic and 1 carbonyl, indicating this is the result of a direct bond breaking between C a and Cp of the starting ketone Figure 3.6. Upon prolonged irradiation, photoproduct 106 underwent a secondary Norrish type II photocleavage reaction to produce 1-indanone (107), 1,4-cyclooctandiene (108) and 1,5-cyclooctandiene (109) (Figure 3.8). Due to their volatility, 1,4-cyclooctandiene and 1,5-cyclooctandiene were not isolated from the reaction mixture, and their presence was confirmed by matching their mass spectral fragmentation patterns and GC retention times with those of authentic samples. In order to keep this secondary photoreaction to minimum extent, anhydrous barium oxide was added to the solution photolysis to scavenge any acidic impurities that might promote the enol-keto tautomerization of enol 105. By doing so, the yield of compound 106 was improved. In the solid state, the photoreaction of spiroketone 49 was slow and compound 106 was also the major product observed at low conversion. Table 3.1 summarizes the photochemistry of ketone 49. 79 Chapter 3 Results and Discussion 106 107 108 109 Figure 3.8 Competing secondary photoreaction of ketone 106. Table 3.1 Photochemistry of spiroketone 49 in various media. Medium Time(h) Conversion (%)a 106 (%)b 107 (%)b 108 + 109 (%)b 1:2 /-Butyl alcohol/C6H6 + BaO ( s ) c 1 49 39 2 2 3 85 47 11 11 Solid State 3 1 trace - -18 6 4 1 1 a Percentage of total GC integral due to the disappearance of the corresponding starting material. Percentage of total GC integral due to the corresponding product. c The combined percentage of the reported compounds is less than unity because of some unidentified GC peaks. 80 Chapter 3 Results and Discussion 3.2.2 Photochemistry of Spiroketone 50 In striking contrast to its five-membered ring analogue, the six-membered ring spiroketone 50 appeared to be photochemically inert, giving only trace amounts (<1%) of unidentified short retention time peaks on GC. The lack of photoproduct formation in the case of ketone 50 suggests that both the photocyclization and photocleavage pathways are kinetically slow and can not compete with reverse hydrogen transfer of biradical intermediate 110 (Figure 3.9). Products 50 110 Figure 3.9 Photochemistry of spiroketone 50. In order to see whether biradical 110 was indeed being produced by irradiation of spiroketone 50, a radical trapping experiment was conducted. Photolysis of ketone 50 was conducted in 1:2 tert-buty\ alcohol-e?//benzene-d<5. Figure 3.10 suggests a possible mechanism for deuteration of ketone 50 under these conditions. If reversible hydrogen transfer is responsible for the observed lack of product formation, deuterium will be incorporated at either of the y-carbons and compound 112 wil l be generated (Figure 3.10). However, after 24-hour irradiation (Pyrex), no deuterium incorporation was found by GCMS analysis. Therefore, at this point, it is uncertain whether biradical 110 is actually generated in solution photolysis. Further discussion of this topic is given in Section 3.3.1. 81 Chapter 3 Results and Discussion Chapter 3 Results and Discussion 3.2.3 Photochemistry of Spiroketone 51 Unlike the five-ring spiroketone, the seven-ring spiroketone 51 reacted predominantly to form Yang cyclization product 112 (66% based on recovered starting material) in solution (Figure 3.11). Formation of a small amount (< 3%) of a second photoproduct (113) was also observed. This minor product (113) is presumably formed by a novel 1,5-disproportionation of the boat-chair 1,4-hydroxybiradical 157, in which a hydrogen atom on C5 is transferred to the radical center on C i (Figure 3.12). In this case, biradical 157 is in equilibrium with the initially formed chair-chair biradical 156 through a ring flip at the C5 end. Since this ring flipping process is an energetically unfavorable process, only a small amount of disproportionation product 113 was observed in the photolysis of ketone 51. We recall that this type of disproportionation reaction was also observed in the photochemistry of the nonspiro 9-benzoyl-9-methylbicyclo[3.3.1]nonane ketones 71 and 72 discussed in Chapter 2. 1:2 tert-butanol / benzene or solid state hv (Pyrex) 51 112 113 Figure 3.11 Photochemistry of spiroketone 51. 83 Chapter 3 Results and Discussion Figure 3.12 Possible mechanism for formation of photoproducts 112 and 113 from spiroketone 51. The same reaction also occurred in the solid state, although it was slower than its solution counterpart. Table 3.2 summarizes the photochemistry o f spiroketone 51 in both media. Table 3.2 Photolysis of spiroketone 51. Medium Time (h) Conversion (%)a 112 (%y 113 (%)b 1:2 t-Butyl alcohol/Benzene 0 24 38 35 1 40 54 47 2 64 75 60 2 Solid State 24 18 17 1 1 I 1 1 1 r ' a Percentage of total GC integral due to the disappearance of the corresponding starting material. Percentage of total GC integral due to the corresponding product.c The combined percentage of the reported compounds is less than unity because of some unidentified GC peaks. 84 Chapter 3 Results and Discussion Photoproduct 112 was characterized by ' H and 1 3 C (BB and APT) N M R , 2D ' H - H COSY, ' H - ' 3 C H M Q C and H M B C , NOESY, FT-IR, L R and H R M S as well as elemental analysis. The results of HRMS and elemental analysis confirmed that compound 112 has the same molecular mass as the starting ketone 51, while its FT-IR spectrum showed the presence of the alcohol functionality through the characteristic O-H stretching in the 3300-3500 cm"1 region. The atom connectivity sequence in this molecule was established through interpretation of the N M R spectroscopic data. Listed in Table 3.3 are the signals from the ' H and 1 3 C N M R spectra and the correlations observed in the H M Q C , H M B C and NOESY experiments. The stereochemistry at the hydroxyl-bearing carbon atom in compound 112 was established on the basis of the results of NOESY experiments, and the important correlations are depicted in Figure 3.13. Table 3.3 Comprehensive N M R assignment data of endo-aryl cyclobutanol 112 in C6D6. 1 5 ^ V J 1 9 / 8 Carbon # 1 3 C 6 (ppm) ' H 5 (ppm) (correlations from HMQC) ' H - ' H COSY correlations H M B C (long-range) 1 3 C - ' H correlations ' H - ' H NOESY correlations 1 25.72 2.04 (m, 2H) H2, H6 H2, H3, H5 H2, H6, H7 H8, H9, 2 22.37 0.93 (dd, J = 8.2 and 14.4 Hz, IH) 1.38 (m, IH) H1,H3 H3, H6, H9 H1,H9, H17 3 31.90 1.91 (m, IH) H2, H9 H1,H2, H5, H9,H10 H2, H9, 85 Chapter 3 Results and Discussion Table 3.3 continued. Carbon # 1 3 C 5 (ppm) 'H 5 (ppm) (correlations from HMQC) 'H-'H COSY correlations HMBC (long-range) ^C-'H correlations l H-'H NOESY correlations 4 48.21 H2, H3, H5, H6, H7, H9, H10,H11 5 37.91 2.79 (m, 1 H) H6, H7 H1,H7, H8 H6, H7, H10, OH 6 48.70 2.44 (m, IH) H1,H5 H1,H2, H5,H7 H1,H5, OH 7 20.98 1.58 (m, IH) 1.68 (m, IH) H5,H8 H5, H8, H9 H1,H5, H8,H9 8 18.93 1.33 (m, IH) 1.64 (m, IH) H7, H9 H3, H5, H7, H9 H1,H7, H9 9 27.69 1.45 (m, IH) H3,H8 H2, H3, H7, H8 H1,H2, H3, H7, H8 10 30.01 I. 75 (m, IH) 2.20 (dt, .7=5.1 and II. 6 Hz, IH) H l l H3,H5,H11, H12 H5,H11, H12 11 23.46 1.62 (m, IH) 1.73 (m, IH) H10,H12 H10,H12 H10,H12 12 36.77 2.59 (m, IH) 3.25 (m, IH) H11,H14 H10,H11,H14 H10,H11, H14 13 142.27 - - H11,H12,H14, H15,H17 -14 131.57 7.02 (m,lH) H12,H15 H12,H15,H16, H17 H12 15 125.88 7.02 (m, IH) H14,H16, H17 H14,H16,H17 H17 16 127.16 7.02 (m, IH) H15,H17 H14,H15,H17 H17 17 125.39 7.19 (m, IH) H15,H16 H14,H15,H16 H1,H2, H15,H16 18 143.21 - - H14,H16,H17 19 83.01 - - H1,H3,H5, H6,H17 -- - OH 1.02 (br, IH) - - H5,H6 86 Chapter 3 Results and Discussion 112 Figure 3.13 NOE interactions used in establishing the stereochemistry of compound 112. Because of its similar polarity to cyclobutanol 112 and the small quantity formed in the reaction, alkene 113 could only be obtained as a 112/113 mixture. Careful examination of the 'H NMR spectrum of this mixture revealed that compound 113 has characteristic vinyl proton signals similar to those of alkenes 75 and 77, which are 1,5-disproportionation products in the photoreactions of non spiroketones 71 and 72 (see Chapter 2). Later, in the study of the photochemistry of spiroketone 52, a similar 1,5-disproportionation product 115 was obtained, and that compound has a similar mass fragmentation pattern and GC retention time as compound 113. 87 Chapter 3 Results and Discussion 3.2.4 Photochemistry of Spiroketone 52 The photochemistry of the eight-ring spiroketone 52 was found to be similar to that of the seven-ring analogue, with Yang cyclization as the predominant reaction pathway. Formation of a small amount of 1,5-disproportionation product 115 (< 17%) was also observed (Figure 3.14). Table 3.4 summarizes the photochemical results for compound 52. The reaction proceeds quite slowly both in the solid state and in solution, e.g. 92% conversion was achieved after 6-day irradiation in 1:2 tert-butyl alcohol/benzene. 52 114 115 Figure 3.14 Photochemistry of spiroketone 52. Table 3.4 Photochemistry of spiroketone 52. Medium Time (h) Conversion (%)a 114 (%)b 115 (%)b 1:2 t-Butyl alcohol/Benzene0 48 15 10 3 144 92 58 17 Solid State 20 9 7 2 1 1 1 1 g a Percentage of total GC integral due to the disappearance of the corresponding starting material. Percentage of total G C integral due to the corresponding product. c The combined percentage of the reported compounds is less than unity because of some unidentified GC peaks. 88 Chapter 3 Results and Discussion During photoproduct isolation, it was found that secondary alcohol 115 has a polarity similar to cyclobutanol 114, and it could not be obtained as a pure compound. Compound 115 was thus transformed into its corresponding ketone 158 by using the oxidizing reagent TPAP (tetrapropylammonium perruthenate) / N M O (4-methylmorpholine N-oxide) 4 (Figure 3.15). Ketone 158 showed a significant difference in polarity to the tertiary alcohol 114, and it was obtained as a pure compound. The structure of photoproduct 115 was thus deduced on the basis of the spectral data of its derivative ketone 158. On the other hand, the structure of the primary photoproduct, cyclobutanol 114, was confirmed by X-ray crystallographic analysis (Figure 3.16), which showed that compound 114 has the same relative stereochemistry at the hydroxyl-bearing carbon atom as its seven ring analogue (112), with the aryl group endo to the bicyclo[3.3.1]nonane ring. T P A P / N M O 115 158 Figure 3.15 Transformation of alcohol 115 to ketone 158. 89 Chapter 3 Results and Discussion Figure 3.16 O R T E P representation of 114. 90 Chapter 3 Results and Discussion 3.3 Crystal Structure-Solid State Reactivity Correlations With each of the 4 spiroketones undergoing one of the three reaction pathways (cleavage, reverse hydrogen transfer, and cyclization), compounds 49-52 exhibit the full range of Norrish type II photochemistry. In addition to that, a novel 1,5-disproportionation reaction was observed in the photochemistry of ketones 51 and 52. Spiroketones 49-52 were chosen for investigation because the conformations of the 1,4-biradicals formed by y-hydrogen atom abstraction are varied in a regular and incremental fashion by changing the size of the ketone-containing spiro ring. Since hydrogen abstraction in the solid state is considered to occur with a minimum movement of the heavy atoms, geometric data derived from the ground state ketones (49-52) can be used to analyze the behavior of the corresponding 1,4-hydroxybiradical intermediates, and it allows direct structure-reactivity relationships to be established for these reactive intermediates. Based on the crystallographic results, the 1,4-hydroxybiradicals derived from the spiroketones may be modeled as shown in Figure 3.17. The crystallographic data reveal that the C 1 - C 2 - C 3 - C 4 torsion angle is essentially constant at 61.4 ± 2.6° (gauche) for all four compounds investigated in the present study, and that the C 1 — C 4 distance is likewise nearly constant at 3.04 ± 0.08 A. The major structural difference between homologues lies in the extent of rotation about the C 1 - C 2 bond, which varies with the spiro ring size. The effect of this difference is to change the overlap of the p-orbital on Ci with both the C 2 - C 3 bond and the p-orbital on C4, and this key structural feature affects biradical reactivity in this system. Our hypothesis is that cleavage is favored by good overlap between the p-orbitals on Ci and C4 with the C2 - C 3 bond, cyclization is favored by good 91 Chapter 3 Results and Discussion overlap of the p-orbitals on d and C 4 with each other, and reverse hydrogen transfer dominates when neither o f the above conditions is met and the O H group is close to C 4 . A s we shall see, the crystallographic data support this hypothesis, but a full interpretation of the results requires that the strain involved in forming the cyclization products be taken into account. Figure 3.17 The gauche 1,4-hydroxyradical model. 92 Chapter 3 Results and Discussion 3.3.1 Hydrogen Abstraction Parameters and Biradical Geometries Figure 3.18 illustrates the different carbonyl group orientations of the four spiroketones by superposing their X-ray crystal structures. For the purposes of discussion, we define a as the deviation angle of the carbonyl group from the plane bisecting the bicyclo[3.3.1]nonane ring between y-hydrogen atoms H x and H y . Measurement of the a angle of this series of spiroketones allows us to quantitatively compare the positions of the carbonyl group in these ketones (Table 3.5). In compound 49, a is 20°, and the carbonyl group (blue) lies between H x and H y . The carbonyl group in the six-ring ketone 50 (red) is essentially eclipsed with one of the C - C bonds in the bicyclo[3.3.1]nonane moiety. The seven-ring ketone 51, like its acyclic analogue (ketone 71), has its C = 0 group (cyan) aligned nearly orthogonal to the plane bisecting the bicyclo[3.3.1]nonane ring. Finally, the carbonyl group in eight-ring ketone 52 (yellow) is at a position somewhere between its six- and seven-ring homologues. Figure 3.18 Carbonyl group position in spiroketones 49-52. 93 Chapter 3 Results and Discussion Table 3.5 Values of a for ketones 49-52 and 71. Ketone Ring Size a ( ° ) Oxygen Atom Colour Reaction2 49 5 20 blue C L 50 6 59 red R H 51 7 83 cyan C Y 52 8 70 yellow C Y 71 - 85 - C Y 71 Me a C L = cleavage; R H T =' reverse hydrogen transfer; C Y = cyclization. As mentioned in the Introduction, four parameters (d, co, A, and 0) can be used to quantify the geometric requirements for the type II hydrogen abstraction process. Figure 3.19 and Table 3.6 list the values of these parameters for spiroketones 49-52 and their acyclic analogue (ketone 71). In each ketone, there are two y-hydrogen atoms, H x and H y , which could be abstracted upon irradiation. For ketones 50-52 and 71, it is evident that there is a large difference (> 0.65 A) in the abstraction distance d for the two y-hydrogen atoms. For example, ketone 50 has H x (d = 2.37 A) lying well within the ideal value of 2.72 A, while H y lies far away (d = 3.02 A). Although hydrogen atom abstractions have been observed with d distances as long as 3.15 A, 6 it has been known for Norrish type II reactions that a difference in d of only 0.27 A will lead to the exclusive abstraction of one hydrogen over the other.7 The other parameters (co, A, and 0) in Table 3.6 also suggest that H x is in a much more favorable position for hydrogen abstraction than H y . Therefore, it is H x in ketones 50-52 and 71 that should be abstracted. For ketone 49, because its carbonyl group lies between Ffx and H y (the difference in d distance is 0.09 A for these two hydrogen atoms), it is impossible to predict which y-hydrogen atom is abstracted 94 Chapter 3 Results and Discussion preferentially. Therefore, both possible 1,4-hydroxybiradicals derived from ketone 49 must be considered. Figure 3.19 Hydrogen abstraction parameters for Norrish type II photoreaction. Table 3.6 Hydrogen abstraction parameters for ketones 49-52 and 71. Ketone H d(A) co(°) A(°) 9(°) 49 H x 2.39 18 98 118 Hy 2.48 54 84 118 50 H x 2.37 29 100 119 Hy 3.02 79 59 112 51 H x 2.45 54 86 120 Hy 3.41 90 44 107 52 H x 2.43 43 93 119 Hy 3.32 82 51 108 71 H x 2.50 57 86 118 Hy 3.49 91 41 105 Ideal Values <2.72 0 90-120 180 For ketone 50 (the "unreactive" 6-membered ring spiroketone), the geometric parameters (d, co, A, and 9) for H x are all within favorable limits o f the "ideal" values. 95 Chapter 3 Results and Discussion The value for parameter d (2.37 A), representing the distance between the carbonyl oxygen and the y-hydrogen to be abstracted, is well within the optimum value (2.72 A). The value of the parameter 9 (119°), though being quite far from the ideal value of 180°, is within the practical range of 95-125°. The value of A (100°), representing the C=0—Hy angle, lies in the preferred range of 90-120° and suggests that the real picture of the excited state carbonyl is close to the Kasha model. The value of parameter co (29°), measuring the 'out-of-plane' angle between the y-hydrogen and the carbonyl group, is within the common deviations from the ideal value. A l l these data strongly suggest that ketone 5 0 is well aligned to undergo hydrogen abstraction, even though in this case g attempted trapping of the biradical intermediate was unsuccessful. 96 Chapter 3 Results and Discussion 3.3.2 Geometric Requirements for Cleavage The geometry of the biradicals (115, n = 1-4) derived from spiroketones 49-52 may be described by two torsion angles as depicted in Figure 3.20. Angle cpi is defined as the dihedral angle between the C2-C3 bond and the p-orbital on C | , and angle 94 is likewise defined as the analogous angle between the C2-C3 bond and the p-orbital on C4. The p-orbitals at C] and C4 are assumed to lie orthogonal to the O-C1-C2 and C3-C4-C5 planes, respectively (Figure 3.20). The overlap between these orbitals is proportional to coscpi and C O S 9 4 , 9 and as mentioned earlier, the best geometry for cleavage can be expected when cpi and 94 = 0° and coscpi = coscp4 = 1. The values of coscpi and COS94 for the 4 ketones investigated in the present study as well as for acyclic analogue 71 are listed in Table 3.7. Also shown in Table 3.7 is angle which refers to the C1-C2-C3-C4 torsion angle. The crystallographic data reveal that this torsion angle is essentially constant at 61.4 ± 2.6° (gauche) for all four spiroketones investigated in the present study. This is likely due to the rigid carbon skeleton of the bicyclo[3.3.1]nonane ring. The same conformational rigidity can be found for angle 94 , the value of which is basically fixed at 36.8 ± 4.2° for the spiroketones studied. 97 Chapter 3 Results and Discussion (c) Figure 3.20 Representation of cpi in the solid state biradical derived from: (a) ketone 49, (b) ketones 50-52, and representation of 94 in the solid state biradical derived from (c) ketones 49-52 98 Chapter 3 Results and Discussion Table 3.7 Geometric data for biradicals derived from ketones 49-52 and 71. Parent Ketone <Pl(°) coscpi <P4(°) COS(p4 49 H x 50 0.64 39 0.78 59 Hy 11 0.98 35 0.82 61 50 89 0.02 41 0.75 62 51 67 0.39 33 0.84 61 52 80 0.17 36 0.81 64 71 65 0.42 35 0.82 60 As can be seen from Table 3.7, in the biradical derived from spiroketone 49, there is reasonably good overlap between both radical-containing p-orbitals and the central C2-C 3 bond (coscpi > 64%; coscp4 > 78%). This is consistent with the Norrish type II cleavage chemistry observed for the 5-ring (n = 1) ketone 49. In contrast, the 6-ring (n = 2) ketone 50, leads to a biradical in which only the p-orbital on C4 is reasonably oriented for cleavage, the other (on Ci) being very poorly aligned (2% of maximum overlap). The subsequent failure of this biradical to cleave is clear evidence that cleavage requires overlap of both p-orbitals with the cleaving C2-C3 bond. Cyclization is the preferred mode of reaction for the biradical formed by photolyzing the 7-ring (n = 3) spiroketone 51, and this can be understood as being due to the relatively poor cleavage geometry (coscpi = 39%, only 39% of maximum overlap, not sufficient). The same reasoning applies to the non-spirocyclic ketone 71, which has biradical geometry (coscpi = 42%) similar to that of the 7-ring compound and likewise undergoes mainly Yang photocyclization in the crystalline state. Finally, the geometry of the biradical formed by photolysis of the 8-ring (n = 4) ketone 52 is also poor for cleavage, with coscpi = 17%. 99 Chapter 3 Results and Discussion 3.3.3 Geometric Requirements for Cyclization Having discussed the geometric requirements for biradical cleavage, it is equally important to discuss the geometric features that favor cyclization. One useful measurement for analyzing possible cyclization is parameter D, representing the distance between Ci and C 4 . Ideally, for any Yang cyclization to be successful, D should be < 3.4 A, which is the sum of the van der Waals radii for two carbon atoms. As can be seen in Table 3.8, values of D (< 3.10 A) are well below this criteria for the four spiroketones studied. Also shown in Table 3.8 are the values of angle P, defined as the dihedral angle between the p-orbital on Q and the C 2 - C 4 vector (Figure 3.21). The most favorable geometry for cyclization can be expected when p = 0°, i.e., when the p-orbital on C\ is pointing directly at the p-orbital on C 4 . Likewise, as P approaches 90° cyclization becomes least favorable. Table 3.8 Cyclization parameters for the 1,4-hydroxybiradicals derived from ketones 49-52 and 71. Parent Ketone P(° ) D(A) 49 H x 79 3.09 Hy 41 2.96 50 61 3.08 51 38 2.99 52 49 3.06 71 35 3.01 100 Chapter 3 Results and Discussion (a) (b) Figure 3.21 Representation of cyclization parameter (3: (a) in biradical derived form ketone 49 (H x ) ; (b) in biradical derived from ketones 50-52. Among the four spiroketones, the seven-ring compound 51 possesses the most favourable geometry for cyclization (f3 = 38°), which is similar to that of the non-spirocyclic ketone 71 ((3 = 35°). For the rest of the spiroketones (49, 50, and 52), the value of angle P increases as the ring size decreases, with cyclization geometry moderately good in the eight-ring ([3 = 49°) , poor in the six-ring ((3 = 61 °), and worst in the five-ring ((3 = 79° for H x ) . A s can be seen from Table 3.8, of the two possible biradical intermediates from 5-ring ketone 49, the one derived from hydrogen abstraction of H y has a reasonably good geometry for cyclization (p = 41°). However, Yang cyclization from the five-ring ketone was not observed. This is most likely due to the fact that biradical derived from ketone 49 has a moderately strained bicyclic carbon skeleton, and cyclization of which would lead to a prohibitively strained trans-fused 5/4 ring system. Therefore, it is not surprising that cleavage is the exclusive mode of reaction detectable for the 5-ring spirocycle. 101 Chapter 3 Results and Discussion As can be seen from Table 3.7 and Table 3.8, the geometry of the biradical derived from 8-ring spiroketone 52 is somewhat similar to that of its 6-ring counterpart 50 (for 52, coscpi = 17% and.P = 49°; for 50, coscpi = 2% and p = 61°), yet the former cyclizes while the latter reacts exclusively via reverse hydrogen transfer. The logical conclusion from these results is that cyclization is slowed in the 6-ring case, not only by the biradical geometry, but also by the difficulty in forming a /raws-fused 6/4 ring junction-containing photoproduct, a rate-retarding effect that is lessened in the 8-ring case. With both cyclization and cleavage slowed, reverse hydrogen transfer becomes the sole process undergone by 6-ring ketone 50. 102 Chapter 3 Results and Discussion 3.3.4 The Strain Factor In order to reveal the relationship between the rate of biradical cyclization (kcr) and the spiro ring size (n), molecular mechanics calculations were carried out using the HyperChem/ChemPlus software package (version 5.11/2.0). Table 3.9 lists the calculation results of the strain energy (E s t r a i n ) for ketones 49-52 and their corresponding photocyclization products. Also shown in Table 3.9 are the values of the strain energy change (AE s t r ain) for each of these spiroketone/cyclization product pairs (Figure 3.22). 49n = 1 116n = 1 50 n = 2 117 n = 2 51 n = 3 112 n = 3 52 n = 4 114 n = 4 Figure 3.22 Photocyclization products of spiroketones 49-52. Table 3.9 Strain energy for ketones 49-52 and their corresponding photocyclization products. Ketone/ Cyclization Photoproduct Pair Ring Size Estrain o f Ketone (kcal/mol) Estrain o f Cyclization Photoproduct (kcal/mol) (kcal/mol) 49/116 5 17.3 89.9 72.6 50/117 6 15.3 61.7 46.4 51/112 7 27.8 57.6 29.8 52/114 8 34.5 63.2 28.7 103 Chapter 3 Results and Discussion According to the Eyring equation (Eq. 3.1), key is expected to decrease as AG* increases, while AG* is determined by AH* and AS* (Eq. 3.2). As illustrated in Figure 3.22, because a 4-membered ring is being formed in each case and cyclization occurs from a fixed conformation with relatively few degrees of freedom, it is reasonable to assume that the AS* of each cyclization process does not change appreciably with spiro ring size. As a result, AH* (~ strain energy change (AE s t rain)) is expected to be the determining factor in the rate of ring closure. t k = Ae-AG/RT (Eq.3.1) AG* = AH* - TAS? (Eq. 3.2) As can be seen from Table 3.9, AEstrain is greatest when n = 1 and least when n = 4. The increase in strain energy (AEstrain) in going from ketone 49 to cyclobutanol 116 was calculated to be 72.6 kcal/mole. In the case of the 50 to 117 conversion, AE s t r a in -46.4 kcal/mole, which decreased to 29.8 kcal/mole for the 51/112 pair and 28.7 kcal/mole for the 52/114 pair. As a result, the relative rate of biradical cyclization (key) would be expected to decrease with decreasing n. In agreement with this analysis, no cyclization was observed when n = 1 (49) or 2 (50). The effect of ring strain is most clearly seen in the different behavior of the n = 2 (50) and n = 4 (52) biradicals. The X-ray data show that the biradical from the 6-ring spiroketone has a geometry similar to that of the 8-ring analogue, yet formation of a cyclization photoproduct was not observed in 6-ring case. This is most likely due to the fact that cyclization of the 6-ring 1,4-hydroxybiradical involves a much higher AE s t r a in in comparison to the 8-ring analogue. 104 Chapter 3 Results and Discussion 3.4 Summary The five- through eight-ring spirobicyclo[3.3.1]nonyl ketones (49-52) display all three possible reaction pathways of Norrish type II photochemistry — cleavage, reverse hydrogen transfer, and cyclization. A n unusual 1,5-disproportionation was also observed as a minor reaction pathway in the photochemistry of ketones 51 and 52. X-ray crystallographic analysis reveals that the orientation of the p-orbital on Ci of the 1,4-hydroxybiradical with respect to the C 2 - C 3 sigma bond involved in cleavage, as well as the p-orbital on C4 involved in cyclization, alters systematically with different spiro ring size. A full interpretation of the effect of spirocyclic ring size on biradical partitioning requires consideration of two factors: the geometry of the intermediate 1,4-hydroxybiradicals as deduced from X-ray crystallography of the parent ketones, and the increase in strain energy accompanying cyclization (AEstrain)- For the five-ring spiroketone, geometric factors favor cleavage, and since cyclization is strongly disfavored by ring strain, cleavage predominates. For the six-ring, cleavage is strongly disfavored by geometry as the C 2 - C 3 bond is well aligned with only one of the two p-orbitals, and cyclization, while geometrically feasible, is disfavored by ring strain. The result is exclusive reverse hydrogen transfer. For the seven-, eight-ring or acyclic analogues, geometric factors favor cyclization over cleavage, and since cyclization is no longer prohibited by ring strain, this becomes the dominant observable pathway. 105 Chapter 3 Results and Discussion References 1 Manchand, P. S. J. Chem. Soc, Chem. Commun. 1 9 7 1 , 667. 2 (a) Schwab, P.; France, M . B.; Ziller, J. W.; Grubbs, R. H . Angew. Chem., Int. Ed. Engl. 1 9 9 5 , 34, 2039; (b) Schwab, P.; Grubbs, R. H. ; Ziller, J. W . Am. Chem. Soc. 1996 , 118, 100. 3 As far as we are aware, this type of disproportionation is unknown for 1,4-hydroxybiradicals, although it has been observed in the case of a 1,5-hydroxybiradical. See: Wagner, P.J.; Laidig, G. Tetrahedron Lett. 1 9 9 1 , 32, 895. 4 Ley, S. V . ; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1 9 9 4 , 7, 639. 5 For details of photochemistry of ketone 7 1 , see Chapter 2 of this thesis. 6 Koshima, FL; Matsushige, D.; Miyauchi, M . Cryst. Eng. Comm. 2 0 0 1 , 33, 1. 7 Lewis, T. J.; Rettig, S. J.; Scheffer, J. R.; Trotter, J. Mol. Cryst. Liq. Cryst. 1 9 9 2 , 219, 17. 8 The trapping experiment consisted of irradiating ketone 5 0 in 1:2 tert-BuOD/benzene and looking for deuterium incorporation at the y-position. No exchange was detectable for ketone 50 . Attempts to observe such exchange in y,y-d2-nonaphenone were similarly unsuccessful. See: Wagner, P.J.; Kelso, P.A.; Kemppainen, A.E . ; McGrath, J .M.; Schott, H.N.; Zepp, R.G. J. Am. Chem. Soc. 1 9 7 1 , 94, 7506. 9 Burdett, J.K. Molecular Shapes; Wiley-Interscience: New York, 1980; p. 6. 106 Chapter 4 Results and Discussion Chapter 4 Enantioselective Photochemical Synthesis of a Simple A l k e n e v i a t h e S o l i d State Ionic Chiral Auxiliary Approach 4.1 Introduction Owing to the wide applicability of alkenes as building blocks in organic synthesis, the development of new methods of asymmetric synthesis of chiral olefins is highly desirable. The preparation of enantiomerically pure simple (unfunctionalized) olefins is difficult because their resolution through direct Pasteur techniques is essentially impossible.1 Several approaches have been taken to the asymmetric synthesis of simple chiral olefins: (1) asymmetric Wittig-type reactions using chiral cyclic phosphonamides, (2) asymmetric elimination reactions of N-chiral amine oxides,3 (3) asymmetric Hoffman elimination of N-chiral quaternary ammonium salts,4 and (4) asymmetric radical fragmentation reactions of S-chiral sulfoxides.5 For the most part, the thermal solution phase 1, 2-elimination reactions mentioned above give low ee's. This is due mainly to the fact that the elevated temperatures used in ground state elimination reactions facilitate equilibrium between conformational diastereomers and reduce the reaction rate differences between diastereomeric transition states. We reasoned that these factors could be overcome in asymmetric Norrish type II photoelimination reactions using the solid-state ionic chiral auxiliary approach.6 The Norrish type II photoelimination reaction is one of the most thoroughly studied and well-understood processes in organic photochemistry. In its simplest form, a y-hydrogen-containing ketone (118) fragments to the corresponding alkene (119) and methyl ketone (120) (Figure 4.1). In the case of aromatic ketones, the mechanism involves initial y-hydrogen atom abstraction from the (n,7i*)3 excited state to afford a 107 Chapter 4 Results and Discussion triplet 1,4-hydroxybiradical intermediate (121). The 1,4-hydroxybiradical intersystem crosses and cleaves to afford alkene (119) and enol (122), which subsequently tautomerizes to the corresponding ketone (120). A competing process is cyclization of the 1,4-hydroxybiradical to form a cyclobutanol (123) (Yang photocyclization).8 This is normally a minor reaction pathway (<10%), but can predominate for certain ketones.7 A third option available to the 1,4-hydroxybiradical intermediate is reverse hydrogen transfer to regenerate the starting ketone (118), a process responsible for lowering the quantum yield. Figure 4.1 The Norrish type II photoelimination reaction. Consider the Norrish type II photoelimination reaction of trans-a-A-methylcyclohexylacetophenone (124) (Figure 4.2). The products in this case will be acetophenone (125) and racemic 4-methylcyclohexene (126) because the two conformers (124a and 124b) of £ra/7s-a-4-methylcyclohexylacetophenone are in rapid equilibrium and there is no element of asymmetry in the molecule that would favor abstraction of a y-hydrogen from one side of the plane of symmetry over the other. Our strategy for achieving asymmetric induction in this reaction is depicted in Figure 4.3 based on the formation of a crystalline salt (128) between a prochiral, carboxylic acid-containing 123 108 Chapter 4 Results and Discussion photoreactant (129) and an optically pure, photoinert amine. Since the ionic auxiliary (the ammonium ion in this case) is optically pure, such salts are required to crystallize in chiral space groups, and this provides the asymmetric medium in which to carry out the photoreaction. The dense packing of the crystal prevents large conformational motions and ensures that only one conformational diastereomer of the photoreactant (128) will be present. In other words, the molecule is pre-organized for abstraction of only one of the diastereotopic y-hydrogen atoms. Upon photolysis, the chiral auxiliary attached to the aromatic ring of the aryl ketone is lost as part of the Norrish type II cleavage process, leaving the enantiomerically enriched olefin (126) behind. 124b (R)-126 Figure 4.2 Photoelimination reaction of /ra«s-a-4-methylcyclohexylacetophenone (124) 109 Chapter 4 Results and Discussion C 0 2 H X) 129 126 H 2 N R * Norrish type II Photoelimination 0 © C 0 2 H 3 N R * hv 0 © C 0 2 H3NR* Solid State 128 130 Figure 4.3 Strategy for achieving asymmetric induction in synthesis of enantiomerically enriched olefin 126. In recent years, the solid state ionic chiral auxiliary approach has shown success in asymmetric induction in a variety of solid state-compatible photochemical reactions.6 To demonstrate the generality of this approach, as well as to develop a new method of asymmetric synthesis of simple chiral alkenes, we decide to use this approach on the Norrish type II photoelimination reaction to synthesize the enantiomerically enriched olefin cw-3a, 4, 5, 6, 7, 7a-hexahydro-l//-indene (53). H H 53 110 Chapter 4 Results and Discussion 4.2 Choice and Synthesis of Starting Materials 4.2.1 Choice of Starting Ketones In a paper published in 1988,9 Scheffer and co-workers showed that the solid state irradiation of a series of a-cycloalkylacetophenones formed various cycloalkenes via Norrish type II photoelimination. Among them, a-cyclopentylacetophenone (131) afforded excellent chemical yields (>90%) of cyclopentene (132), while a-cyclohexylacetophenone (134) gave relatively low yields (<40%) of cyclohexene (135), the major product being the corresponding cyclobutanol (Figure 4.4). In order to study asymmetric induction in these reactions, appropriate substitution on the cycloalkane ring is required, e.g., adding substituents at the 4-position of a-cyclohexylacetophenone and at the 3- and 4-positions of a-cyclopentylacetophenone. Although preparation of photoreactants containing a 4-substituted cyclohexane ring would be easier, it seemed to us that photoreactants containing a disubstituted cyclopentane ring would be a better choice in terms of chemical yields. Bearing this in mind, we decided to synthesize compounds with a common structure of 54 (Figure 4.5). 4 132 (> 90%) 133 131 Cl Cl h v 4 134 135 (< 40%) 133 157 Figure 4.4 Photochemistry of a-cycloalkylacetophenones 131 and 134. I l l Chapter 4 Results and Discussion 9- "K/r* H 54 0 © X = C0 2 Me, C 0 2 H , C 0 2 H 3 N - R * Figure 4.5 General structure of compounds 54. 112 Chapter 4 Results and Discussion 4.2.2 Synthesis of cis-Bicyclo[4.3.0]non-8-y!acetophenone derivatives cz's-Bicyclo[4.3.0]non-8-ylacetophenone derivatives 141 and 142 were synthesized as outlined in Figure 4.6. Ketone 140 was first prepared as a mixture of diastereomers, and recrystallization of the mixture from EtO Ac/petroleum ether gave cis bicyclo[4.3.0]non-8-yl acetophenone derivative 141. Hydrolysis of keto-ester 141 afforded the corresponding keto-acid 142, which was then reacted with a variety of optically pure amines to form chiral salts 143-147 through acid-base chemistry. The amines were chosen randomly from the chiral pool, major criteria being that they should not absorb light under the photolysis conditions and that they should be readily available. The salts were shown to have 1:1 acid base stoichiometry by elemental analysis. Table 4.1 lists the crystal morphology, crystallization solvents, and melting points of these chiral salts. In addition, the IR and *H and l 3 C N M R spectra were all in agreement with the proposed structures. 113 Chapter 4 Results and Discussion H H Figure 4.6 Sequence taken for synthesis of compounds 141-147. 1 1 4 Chapter 4 Results and Discussion Table 4.1 Chiral salts prepared from keto acid 142. >"OC0® H Salt Cation Recrystallization Solvent Crystal Morphology mp(°C) 143 H 2 o L-prolinamide MeOH / C H 3 C N needles 145-146.5 144 H © H 3 C - C - N H 3 6 (R)-(+)-1 -phenylethylamine MeOH / C H 3 C N needles3 172-173 145 H © H 3 C - C - ^ N H 3 6 (<S)-(-)-1 -phenylethylamine MeOH / C H 3 C N needles 172-173 146 H 3N © (IR, 2S)-(+)-cis-l-amino-2-indanol MeOH / C H 3 C N powder 146-148 147 ^ H © ( \ _ C ^ n h 3 ^ C H 3 (*)-(-)-1-cyclohexylethylamine MeOH/ C H 3 C N needles3 169-171 X-ray crystal structure obtained. 115 Chapter 4 Results and Discussion 4.3 Photochemistry of c/5,-Bicyclo[4.3.0]non-8-y!acetophenone derivatives 141 and 142 A l l solution and solid-state photolyses were conducted using a 450-W Hanovia medium-pressure mercury lamp fitted with a Pyrex filter (k > 290 nm). Samples in solution were photolyzed to complete conversion and the crystalline samples were irradiated to various degrees of conversion as determined by gas chromatography (GC). Low temperature photolyses were performed in order to minimize the extent of the breakdown of the crystal lattice. The results of photolyzing ketones 141 and 142 are summarized in Table 4.2. Table 4.2 Results of Photolyzing Ketones 141 and 142. Entry Ketone Reaction Medium Temp.(°C) Conv.(%)a 53(%)b 148(%)b 1 141 C H 3 C N r.t.c 100 56d 38d 2 Crystalline state r.t. 51 16 33 3 Crystalline state -20 34 12 21 4 142 C H 3 C N e r.t. 100 53d 44d 5 Crystalline state r.t. 85 29 52 6 Crystalline state (hexanes suspension) r.t. 100 55 d 40 d 7 Crystalline state (hexanes suspension) -20 100 55 d 38d a Percentage of total GC integral due to the disappearance of the corresponding starting material. Percentage of total GC integral due to the corresponding product.c r.t., room temperature. d Compounds 53 and 148 are not in 1:1 GC ratio. This is presumably due to different GC detector responses. Irradiation of ketones 141 and 142, either in solution or the solid-state, led efficiently and exclusively to the corresponding Norrish type II cleavage products 53 and 116 Chapter 4 Results and Discussion 148/149 (Figure 4.7). In principle, irradiation of 141/142 could have formed Yang cyclization product 150, but this was not observed. Moreover, no secondary products arising from photolysis of compounds 53 and 148/149 were observed within the irradiation period. For convenience by GC analysis, compound 149 was transformed quantitatively into the corresponding ester 148 by treatment with ethereal diazomethane. Not unexpectedly, the yields of alkene 53 obtained in the solid-state irradiations (entries 2, 3, and 5 in Table 4.2) were relatively low compared to those obtained in solution (entries 1 and 4 in Table 4.2). We attribute this to the fact that alkene 53 is a volatile liquid, which evaporates partially during the crystalline-state reaction and workup. To improve the yields, the crystalline-state irradiation of keto-acid 142 was carried out in hexanes suspensions (entries 6, and 7 in Table 4.2). Alkene 53 generated during the reaction dissolved in the hexanes and was retained; as a result the yields of alkene 53 were significantly improved. Compounds 53 and 148 are known compounds and their spectral data are in total agreement with literature values. 1 0 ' 1 1 M o. Solution k / k / / \ / / or H Solid state 148 X = C02Me 141X = C02Me r ^ ^ - X 149X = C0 2H 142 X = C0 2H HO H No formation of 150 was observed. H 150 Figure 4.7 Photochemistry of c«-Bicyclo[4.3.0]non-8-ylacetophenone derivatives 141 and 142. 117 Chapter 4 Results and Discussion 4.4 Asymmetric Induction Studies Salts 143-147 formed between carboxylic acid 142 and a number of commercially available, enantiomerically pure amines were prepared and crystallized (see Chapter 5). Each of the salts (143-147) was irradiated as a hexane suspension (Figure 4.8). Photolyses were generally carried out through Pyrex at room temperature, although some runs were conducted at -20°C. The salts were irradiated for varying lengths of time in order to determine the dependence of the ee values on the extent of conversion. Following irradiation, the mixtures were treated with excess ethereal diazomethane to form the corresponding methyl ester 148. After diazomethane treatment, the organic layer containing the alkene 53, esterified photoproduct 148, and starting material was washed with water and subjected to short-path silica gel chromatography in order to remove the chiral auxiliary. The mixtures were then analyzed by GC for conversion as well as composition. Direct measurement of the ee's of alkene 53 met with no success (insufficient separation). Alkene 53 was thus transformed into its corresponding epoxide derivatives, compounds 151 and 152 (94:6 by GC), by treatment with w-CPBA (Figure 4.9). The formation of epoxide 151 is favored because the convex face of alkene 53 is less sterically hindered in comparison with its concave face (Figure 4.9). Epoxide 151 was isolated and its structure was determined through interpretation of the N M R spectroscopic data (Table 4.3). The stereochemistry of compound 151 was established by the NOE interactions shown in Figure 4.10. The optical purity of alkene 53 was thus determined by measuring the ee of epoxide 151 using chiral GC (SUPELCO /?-Dex™ 350 Custom Capillary Column, 120°C at 1.37 mL/min). A typical chromatogram for a chiral GC analysis is shown is Figure 4.11. 118 Chapter 4 Results and Discussion 148 Figure 4.8 Photolysis of chiral salts 143-147. Concave Face Convex H * V r * , > ^ F a c e Figure 4.9 Epoxidation of alkene 53. 119 Chapter 4 Results and Discussion Table 4.3 Comprehensive N M R assignment data for 151 in CeD 6. Carbon # 1 3 C 5 (ppm) ! H 5 (ppm) (correlations from HMQC) ' H - ' H COSY correlations H M B C (long-range) 1 3 C - ' H correlations NOE interactions 1 59.96 2.97 (d, J= 2.8 Hz, IH) H9 H2, H 3 a , H8p H2, H 3 a , H4 a , H9 2 37.82 1.84 (m, IH) H 3 a , H3p, H7, H l , H 3 a , H4 a , H4 B , H7, H8 0 H I , H 3 a , H3p, H8p 3 25.09 H a , 0.52 (ddt, 7=3.6, 12.8, and 13.1 Hz, IH) H2, H3p, H4 a , H4 P H2, H4 a , H4p, H 5 a , H5 P H1,H2, H3p, H4 a , H4 B Hp 1.28 (m, IH) H2, H 3 a , H4 a , H4p -4 24.82 H a , 1.29 (m, IH) H 3 a , H3p, H4 P , H 5 a , H5 P H 3 a , H3p, H 5 a , H5p, H 6 a , H6 P -Hp, 0.88 (m, IH) H 3 a , H3p, H4 a , H 5 a , H5p H 3 a , H4 a , H 5 a , H5p 5 21.93 H a , 0.89 (m, IH) H4 a , H4p, H5p, H6 a , H6p H 3 a , H3p, H4 a , H 6 a , H6p, H7, H5p, H 6 a Hp, 1.40 (m, IH) H4 a , H4p, H 5 a , H6 a , H6 P H4p, H 5 a , H6 P 6 25.30 H a , 1.37 (m, IH) H 5 a , H5p, H6 B , H7 H4 a , H5p, H7, H 8 a , -Hp 1.27 (m, IH) H 5 a , H5p, H6 a , H7 7 29.87 1.95 (m, IH) H2, H6 a , H6p, H8 a , H8p H1,H2, H6p, H8„, H8 0 , H9 H 8 a 8 29.09 H a , 1.16 (ddd, 7= 1.1, 11.1, and 13.5 Hz, IH) H7, H8p, H9 H2, H 6 a , H7, H9 H7, H8p, H9 Hp, 1.62 (dd, 7=7.5 and 13.5 Hz, IH) H7, H 8 a H7, H8 a , H9 9 54.58 3.08 (dm, 7=2.8 Hz, IH) H l , H 8 a H2, H 8 a , H8p HI , H8 a , H8p, 120 Chapter 4 Results and Discussion 151 Figure 4.10 NOE interactions used in establishing the stereochemistry of compound 151. Figure 4.11 Chiral GC chromatogram showing the separation of the two enantiomers of compound 151. The results of the photochemical studies of salts 143-147 in the solid state are summarized in Table 4.4. In addition to the solid-state runs, each of the salts was photolyzed in solution (methanol); in every case, racemic photoproducts were obtained. 121 Chapter 4 Results and Discussion Table 4.4 Asymmetric Induction in the Photolyses of Chiral Salts 143-147. Salt Amine Temp. (°C) Conv. (%)a ee (%)b [a] c 143 L-prolinamide r.t.d 15 30 + r.t. 59 21 + r.t. 82 17 + r.t. >99 12 + 144 (/?)-(+)-1 -phenylethylamine r.t. 4 53 + r.t. 28 37 + r.t. 82 33 + r.t. >99 32 + -20 4 67 + -20 . >99 44 + 145 (£)-(-)-1 -phenylethylamine r.t. 10 39 -r.t. 59 37 -r.t. 90 35 -r.t. 98 31 --20 14 45 -146 (li?,25)-(+)-cz5-l-amino-2-indanol r.t. 7 23 + r.t. 45 21 + r.t. 94 17 + -20 10 25 + 147 (R)-(-)-1 -cyclohexylethylamine r.t. 20 15 + r.t. 77 12 + r.t. 92 11 + -20 21 19 + 3 Percentage of total G C integral due to the disappearance of the corresponding starting material. The enantiomeric excess of the photoproduct 53 was determined via measuring the ee's of its epoxide derivative 151.c Sign of rotation of 151 at the sodium D-line. d r.t., room temperature. 122 Chapter 4 Results and Discussion As can be seen from Table 4.4, in the presence of ionic chiral auxiliaries, enantiomeric excess was induced in the cis-3a, 4, 5, 6, 7, 7a-hexahydro-l//-indene (53), although only to a moderate extent. Using (i?)-(+)-l -phenylethylamine as the chiral auxiliary, the product alkene 53 from salt 144 was obtained in 32% ee at complete conversion, while in the presence of (>S)-(-)-l-phenylethylamine (salt 145), the opposite enantiomer was obtained in 31% ee. Access to both enantiomers is thus available by simple exchange of the ionic chiral auxiliary. Table 4.4 also shows that an increase in conversion leads to decreasing ee values. This is not unexpected, since the salts react to give products that presumably do not "fit" into the original crystal lattice, and defect sites are generated. As shown in Table 4.4, low temperature photolysis can be used to compensate this effect. For reactions conducted at reduced temperature (-20°C), enantioselectivities were better than those obtained at room temperature. Specifically, at -20°C, quantitative conversion to alkene 53 from salt 144 occurred in 44% ee in comparison to 32% ee obtained at room temperature. This is probably due mainly to heat removal from the photolyzed crystals, thus maintaining crystallinity. 123 Chapter 4 Results and Discussion 4.5 Solid State Structure-Reactivity Correlation As mentioned in the previous section, irradiation of compounds 141/142 could have formed Yang cyclization product 150, but this was not observed. In order to obtain a better understanding of why these ketones undergo Norrish type II photoelimination exclusively, the X-ray crystal structure of keto-ester 141 was determined (Figure 4.12). The geometric data derived from its X-ray structure are summarized in Table 4.5. Correlation of excited state reactivity with the geometry of the ground state ketone is considered to be valid in this case because the (n,7i*)3 excitation is known to be highly localized on the carbonyl group such that geometric changes in the rest of the molecule 12 are negligible. Moreover, since hydrogen abstraction in the solid state is likely to occur with minimum motion of the associated heavy atoms, geometric data derived from X-ray crystallography can also be used to analyze the behavior of the 1,4-hydroxybiradical intermediate.13 As shown in Table 4.5, among the four y-hydrogens, only Ha and Hb are close enough to the carbonyl oxygen for hydrogen abstraction to occur (d = 3.07 and 3.01 A respectively), while He and Hd (d > 4.6 A) are too far away. Moreover, it is evident that abstraction of either Ha or Hb would produce the same 1,4-hydroxybiradical. 124 Chapter 4 Results and Discussion Figure 4.12 ORTEP representation of 141. Table 4.5 Geometric Data for Compounds 141,144 and 147. Compound H 94(°) M>(°) d(A)a co(°)b A(°)C 9(°) d 141 a 84 34 68 3.07 29 99 85 b 84 34 68 3.01 48 75 88 c 84 61 172 4.65 13 65 63 d 84 61 172 4.71 4 52 60 144 a 82 58 68 2.82 35 97 102 b 82 58 68 3.35 45 70 71 c 82 35 173 4.67 2 50 65 d 82 35 173 4.73 10 68 61 147 a 83 31 68 2.85 37 83 95 b 83 31 68 3.09 13 102 81 c 83 59 174 4.78 18 60 59 d 83 59 174 4.70 3 50 64 A C = 0 . . . Hy distance.b Deviation of Hy from the mean plane of the carbonyl group. c C = 0 . . . Hy angle. d C -Hy.. .O angle. 125 Chapter 4 Results and Discussion For the purposes of discussion, we define 3 torsion angles with reference to Figure 4.13, which is a depiction of the 1,4-hydroxybiradical intermediate (153) derived from ketone 141: \\i refers to the C1-C2-C3-C4 torsion angle; 91 is defined as the dihedral angle between the C2-C3 a bond and the p-orbital lobe on C i ; 94 is defined as the dihedral angle between the C2-C3 o bond and the p-orbital lobe on C4. The p-orbitals at C i and C4 are assumed to lie perpendicular to the O-C1-C2 and C3-C4-C5 planes, respectively. For the cleavage process to occur, overlap between the a-bond undergoing scission (C2-C3) and both radical-containing p-orbitals (at C i and C4) must be efficient.14 Maximum overlap (100%) will occur when the p/a orbitals are eclipsed, i.e. when 91 and 94 are 0° (0,0 geometry). It seems likely that cyclization, which requires through-space overlap of these same p-orbitals, will also prefer a biradical geometry close to 0,0, provided that the radical centers are gauche (or better). By using the crystal structure data for ketone 141, the calculated <J-TI orbital alignments for biradical 153 are 91 = 84° and 94 = 34° (Table 4.5). The results indicate that biradical 153, while gauche = 68°), is far from the 0,0 geometry preferred for cleavage or cyclization. According to the well-known topochemical principle, which states that reactions in the crystalline-state occur with a minimum of atomic and molecular motion,1 5 it is reasonable to predict that biradical 153 undergoes preferential (-) rotation at both C i and C 4 to form biradical conformer 154 in which the 0,0 geometry requirement is fulfilled. The directions and magnitudes of the rotations required to align the p-orbitals in the 0,0 geometry are shown in Figure 4.13. Biradical 154 is a relatively unstrained species. It behaves normally in its preference for cleavage to lead to the observed products 53 and 148.16 The fact that Yang cyclization was not observed in this study can also be explained by the fact that the cj's-fused 5/4 ring 126 Chapter 4 Results and Discussion junction-containing photoproduct 150 is quite strained ( E s t r a m = 30.5 kcal/mol for a ef-fused 5/4 ring system),17 while cleavage of 141 relieves strain (-0.4 kcal/mol) via formation of a cyclopentene ring from a cyclopentane ring 18,19 hv H 0 Xh Ar (-) 141 153 C1 Rotation Required to Form 154: (-)84° C4 Rotation Required to Form 154: (-)34° K-). 4(-) 154 150 Figure 4.13 Mechanism of photoelimination of keto ester 141. 127 Chapter 4 Results and Discussion (b) Figure 4.14 Crystal structures of anion part of salts (a) 144 and (b) 147. Two salts (144 and 147) of keto-acid 142 provided crystals that were suitable for X-ray crystallographic analysis. The geometric data summarized in Table 4.5 reflect their high similarity to the crystal structure of keto-ester 141, which accounts for their photochemical reactivity and lack of cyclization reaction. Figure 4.14a shows the solid state conformation of the anion portion of salt 144. Since the absolute configuration of the counterion is known, the absolute configuration of the reacting ketone can be assigned unequivocally. The X-ray crystal structure of 144 clearly shows the carbonyl group poised to abstract only one y-hydrogen (Ha, d = 2.82 A), while the others are too far away (Hb, He, and Hd, d > 3.3 A). The biradical formed on abstraction of Ha would have a gauche geometry (C-OH and CY-Hb bonds in a syn relationship), and subsequent 128 Chapter 4 Results and Discussion cleavage of C2-C3 should lead to the (3ai?, 7a/?)-enantiomer of photoproduct 53. On the other hand, formation of the (3aS, 7a5)-enantiomer would require an approximate 180° rotation of the benzoylmethyl group about the C2-C3 axis prior to hydrogen abstraction, which is presumably topochemically unfavorable in the solid state. These findings clearly explain the enantioselectivity observed for salt 144. However, with all five salts studied in this work, only low to moderate ee's were obtained for photoproduct 53. How can this be explained? The answer to this question may lie in the Norrish type II photoelimination reaction itself. Photoelimination of m-bicyclo[4.3.0]non-8-ylacetophenone derivatives, a process involving breaking one molecule into two, unavoidably destroys the original crystal lattice. Also, photoproduct 53, a liquid, softens the solid-state medium. As a result, topochemical control decreases as the reaction proceeds. Nevertheless, the solid-state medium remains viscous to retard complete conversion of the original conformer to a diastereomeric mixture via rotation about the C2-C3 bond, and this accounts for the moderate ee's observed in this work. 129 Chapter 4 Results and Discussion 4.6 Summary and Outlook In summary, we have demonstrated that the solid-state ionic chiral auxiliary approach can be used to synthesize the enantiomerically enriched simple alkene cis-3a,4,5,6,7,7a-hexahydro-l#-indene (53) via a Norrish type II photoelimination reaction. The results of the present work have once again demonstrated that the solid-state ionic chiral auxiliary approach to asymmetric induction is a reliable method for achieving enantioselectivity in a variety of different photoreactions. Through the use of X-ray crystallography, crystal structure-solid state reactivity relationships were developed and used to explain the observed photochemical reactivity and enantioselectivity. The X-ray data obtained in the present work, in addition to those already collected from previous Norrish/Yang studies, can serve as a reference source for predicting the Norrish/Yang photoreactivity of future systems. Owing to crystal-lattice breakdown, the current system (czs-bicyclo[4.3.0]non-8-ylacetophenones) did not exhibit high enantioselectivity in its asymmetric photoelimination. Therefore, our future studies wil l be focused on systems that afford solid alkene products and are less subject to crystal-lattice breakdown during 20 the photolysis process. 130 Chapter 4 Results and Discussion References 1 Partial kinetic resolution of unfunctionalized simple olefins has been reported. For references on kinetic resolution of axially dissymmetric cyclic alkenes by asymmetric dihydroxylation, see: Hoveyda, A . FL; Didiuk, M . T. Current Org. Chem. 1998, 2, 489 and references therein. For references on kinetic resolution of terminal alkenes by alkene polymerization with chiral zirconocene catalysts, see: Bercaw, J. E.; Min, E. Y . -J.; Levy, C. J.; Baar, C. R. Polym. Mater. Sci. Eng. 2002, 87, 62 and references therein. 2 Ffanessian, S.; Delorme, D.; Beaudoin, S.; Leblanc, Y . J. Am. Chem. Soc. 1984, 106, 5754. 3 Goldberg, S. I.; Lam, F-L. J. Am. Chem. Soc. 1969, 91, 5113. 4 Cope, A .C . ; Funke, W. R.; Jones, F. N . J. Am. Chem. Soc. 1966, 88, 4693. 5 Imboden, C ; Villar, F.; Renaud, P. Org. Lett. 1999,1, 873. 6 (a) Gamlin, J. N . ; Jones, R.; Leibovitch, M . ; Patrick, B.; Scheffer, J. R.; Trotter, J. Acc. Chem. Res. 1996, 29, 203; (b) Scheffer, J. R. Can. J. Chem. 2001, 79, 349. 7 For general reviews of the Norrish/Yang type II reaction, see: (a) Wagner, P.; Park, B.-S. In Organic Photochemistry; Padwa, A. , Ed.; Marcel Dekker: New York, 1991; Vol . 11, Chapter 4. (b) Wagner, P. J. In Molecular Rearrangements in Ground and Excited States; de Mayo, P., Ed.; Academic Press: New York, 1980; Chapter 20. (c) Wagner, P. J. Acc. Chem. Res. 1971, 4, 168. 8 Ariel, S.; Ramamurthy, V. ; Scheffer, J. R.; Trotter, J. J. Am. Chem. Soc. 1983, 105, 6959. 131 Chapter 4 Results and Discussion 9 Ariel, S.; Evans, S. V. ; Garcia-Garibay, M . ; Harkness, B. R.; Omkaram, N.; Scheffer, J. R.; Trotter, J. J. Am. Chem. Soc. 1988,110, 5591. 1 0 Stierman, T. J.; Johnson, R. P. J. Am. Chem. Soc. 1985,107, 3971. 1 1 Smissman, E. E.; L i , J. P.; Israili, Z . H . / . Org. Chem. 1968, 33, 4231. 12 Wagner, P. J. In CRC Handbook of Photochemistry and Photobiology; Horspool, W. M . ; Song, P.-S., Ed.; CRC Press: Boca Raton, 1995; Chapter 38. 1 3 Cheung, E.; Netherton, M . R.; Scheffer, J. R.; Trotter, J. Org. Lett. 2000, 2,11. 1 4 Wagner, P. J.; Kelso, P. A. ; Kempainen, A . E. J. Am. Chem. Soc. 1968, 90, 5896. 1 5 Schmidt, G. M . J. Pure Appl. Chem. 1971, 27, 647. 1 6 Scaiano, J. C ; Lissi, E. A. ; Encina, M . V . Rev. Chem. Intermed. 1978, 2, 139. Also see Ref. 7b, 7c and 9. 1 7 Engler, E. M . ; Andose, J. D.; Schleyer, P. R. J. Am. Chem. Soc. 1973, 95, 8005. 18 Cox, J. D.; Pilcher, G. In Thermochemistry of Organic and Organometallic Compounds; Academic Press: London, 1970; pp. 166, 571, 579, 580, and 590. 1 9 Fujisaki, N . ; Ruf, A. ; Gaumann, T. J. Am. Chem. Soc. 1985,107, 1605. Using the solid state ionic chiral auxiliary approach, high ee's have been obtained in the Norrish type II cleavage reaction with the alkene product being a solid: Chong, K. C. W.; Scheffer, J. R. J. Am. Chem. Soc. 2003,125, 4040. 132 Chapter 5 Experimental EXPERIMENTAL Chapter 5 Preparation of Substrates 5.1 General Considerations 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), Bruker AV-300 (300 MHz), Bruker WH-400 (400 MHz), Bruker AV-400 (400 MHz), and Bruker AMX-500 (500 MHz). Chemical shifts (5) 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), methylene chloride (5.32 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 Enhancement (NOE) spectra were acquired on the Bruker W H -400 and Bruker AV-400 spectrometers. Two-dimensional ' H - ' H Correlation 133 Chapter 5 Experimental Spectroscopy (COSY) and ' H - ' H Nuclear Overhauser Effect Spectroscopy (NOESY) were conducted on the Bruker WH-400, Bruker AV-400 or Bruker AMX-500 spectrometers. Carbon nuclear magnetic resonance ( 1 3 C N M R ) spectra were recorded on the following instruments: Bruker AC-200 (50.3 MHz), Bruker AV-300 (75.4 MHz), Bruker AV-400 (100.5 MHz), and Bruker AMX-500 (125.6 MHz). A l l experiments were conducted using broadband *H decoupling. Chemical shifts (8) 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), methylene chloride (53.8 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 3) carbon centre; while no assignment signifies a quaternary or methylene (CH2) carbon centre. Two-dimensional C- H correlation spectra were obtained on a Bruker AV-400 or Bruker AMX-500 spectrometer using the Heteronuclear Multiple Quantum Coherence ( H M Q C ) experiment for one-bond correlations and the Heteronuclear Multiple Bond Connectivity ( H M B C ) experiment for long-range (2, 3 bond) connectivities. 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 or as chloroform solutions coated on a sodium chloride plate. Solid 134 Chapter 5 Experimental samples (2-4 mg) were ground with IR grade K B r (100-200 mg) in an agate mortar and pressed into a disc (1 cm diameter) using 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 m a x ) are reported in units of cm"1. Ultraviolet-Visible Spectra (UV / VIS) UV/VIS 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 (A.m a x) are reported in nanometers (nm), with molar extinction coefficients (s) reported in parentheses in units of IVT'cm"1. 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, a Kratos MS 80 spectrometer using desorption chemical ionization (CI) with the ionizing gas noted, a Kratos Concept IIHQ hybrid spectrometer using liquid secondary ionization (LSEVIS), or a Bruker Esquire~LC (low resolution) or Micromass LCT (high resolution) spectrometer using electrospray ionization (ESI). Analyses were performed by in-house technicians under the supervision of Dr. G. Eigendorf or Dr. Yun Ling. Low resolution mass spectra and GC/MS data were also recorded on an Agilent 5973N mass selective detector, attached to an Agilent 6890 gas chromatograph, using electron impact (EI) ionization at 70 eV. 135 Chapter 5 Experimental Microanalysis (Anal.) Elemental analyses were obtained for most new compounds. These were performed by Mr. P. Borda or Mr. Minaz Lukha on a Carlo Erba C H N Model 1106 analyzer, or by Canadian Microanalytical Services Ltd. of Delta, B.C. . Crystallography Single crystal X-ray analysis was performed on either a Rigaku AFC6S four-circle diffractometer (Cu-Ka 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 determined by Dr. Brian Patrick in U B C or Dr. Lucia Maini in the University of Bologna. 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, or on an Agilent 6890 gas chromatograph, equipped with an Agilent 5970N mass selective detector. GC traces were recorded on a Hewlett-Packard 3392A integrator (5890) or using Agilent's Chemstation software (6890). The following 136 Chapter 5 Experimental Hewlett-Packard or Supelco fused silica capillary columns were used: HP-5 (30 m x 0.25 mm x 0.25 um ID), HP-5MS (30 m x 0.25 mm x 0.25 um ID), HP-35 (15 m x 0.25 mm x 0.25 um ID), Supelco beta-DEX 350 Custom Chiral Column (50% 6-TBDMS-2,3-dimethyl-(3-cyclodextrin dissolved in OV-1701, 20 m x 0.25 mm x 0.25 um ID). Analyses were run with a split injection port (split ratios between 25:1 and 100:1) with column head pressures of 100 kPa (achiral column) or 250 kPa (chiral column). High Performance Liquid Chromatography (HPLC) HPLC analyses were performed on a Waters 600E system coupled to a tunable U V absorbance detector (Waters 486). Preparative separations were conducted using a Waters Radialpak™ uPorasil™ preparative column (25 mm lOOmmm) with a hexanes : EtOAc eluent. Enantiomeric excesses (ee) were determined using a Chiralcel® OC (250 mm x 4.6 mm ID) from Chiral Technologies Incorporated, with a hexanes : IPA eluent. Data were collected using the Waters Maxima software package. Silica Gel Chromatography Analytical thin layer chromatography (TLC) was performed on commercial pre-coated (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) using plates of 1 or 2 mm thickness prepared from E M Science silica gel 60 PF254 with gypsum (7749-3). 137 Chapter 5 Experimental Solvents and Reagents THF and Et20 were refluxed over the sodium ketyl of benzophenone under an atmosphere of argon and distilled prior to use. Anhydrous dichloromethane, benzene, pyridine, and acetonitrile were purified 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- or flame-dried glassware. 138 Chapter 5 Experimental 5.2 Synthesis of 9-Benzoylbicyclo[3.3.1]nonanes 60, 61,71, 72, and 73 and Chiral Salts 84-90 5.2.1 Synthesis of 9-Benzoylbicyclo[3.3.1]nonane 60 Bicyclo[3.3.11nonan-9-one (58) Bicyclo[3.3.1]nonan-9-one was prepared by using the procedure of Carlson and Brown 1. To a solution of 9-borabicyclo[3.3.1]nonane (9-BBN, 44.5 g, 368 mmol) in THF (735 mL) was added a solution of 2,6-dimethylphenol (44.9 g, 368 mmol) in THF (85 mL) dropwise, and the mixture was stirred at room temperature for 3h . Once hydrogen evolution was complete, the reaction was cooled to 0°C, and dichloromethyl methyl ether (47.2 g, 37.2 mL, 403 mmol) was added. A solution of lithium triethylmethoxide (524 mmol, prepared from 524 mmol n-butyllithium and 524 mmol 3-ethyl-3-pentanol) in hexanes (328 mL) was then added slowly over approximately 30 min. The reaction mixture was warmed to room temperature and stirred for 1.5 h, during which time a heavy white precipitate of lithium chloride formed. A solution of 310 mL of 95% ethanol, 74 mL of water, and 44.5 g of sodium hydroxide was added, and the mixture was cooled to 0°C with efficient stirring. Oxidation was carried out over 40-45 min period by the slow, dropwise addition of 74 mL of 30% hydrogen peroxide, while the temperature was maintained below 50°C with a cooling both. After addition, the mixture was heated with stirring to 45-50°C for 2 h and then cooled to room temperature. Water (320mL) was added, and the aqueous phase was saturated with sodium chloride. The organic layer was ,0 58 139 Chapter 5 Experimental separated and washed with 105 mL of saturated aqueous sodium chloride. The solvents were removed on a rotary evaporator, and the residue was diluted with 530 mL of pentane, which was then extracted with 260 mL and 105 mL portions of aqueous 3 M sodium hydroxide to remove 2,6-dimethylphenol. After washing with 105 mL of saturated aqueous sodium chloride and drying over Na2SC>4, pentane was removed on a rotary evaporator. The 3-ethyl-3-pentanol was removed by distillation under a water aspirator vacuum, b.p. 54-56 °C (16 mmHg). The resultant semisolid residue was dissolved in pentane (210 mL) and filtered to remove the impurities. Ketone 58 was crystallized by cooling the filtrate to -78°C. Suction filtration and washing with -78°C pentane (50 mL) yielded analytically pure ketone 58 (40.2 g, 79%) as a white power (mp 152-154°C, lit. 1 154-156°C) mp: 152-154°C (Pentane) ] H N M R (CDC1 3, 400 MHz): 5 1.48-1.56 (m, 2H), 1.97-2.16 (m, 10H), 2.40 (br, 2H). 1 3 C N M R (CDCI3, 75 MHz): 8 20.60, 34.35, 46.59 (-ve), 222.01. IR(KBr) : 2922, 2853, 1721, 1450, 1314, 1242, 1076, 902, 731 cm"1. 140 Chapter 5 Experimental Bicyclo[3.3.11nonane-9-carboxaldehyde (56) and Bicvclor3.3.1]non-9-vl phenyl methanol (63) 56 63 A procedure modified from that of Alberts et al. was used.2 To a cooled (0°C), stirred suspension of methoxymethyltriphenylphosphonium chloride (43.5 g, 127.0 mmol) in Et20 (350 mL) was added w-butyllithium (90.9 mL of a 1.6 M solution in hexanes, 145.4 mmol) over 10 min. The mixture was warmed to room temperature and stirred for 2 h. A solution of bicyclo[3.3.1]nonan-9-one 58 (15.0 g, 108.5 mmol) in Et20 (150 mL) was then added slowly to the phosphorous ylide solution over 10 min, and the reaction mixture was stirred overnight at room temperature. In order to precipitate the suspended triphenylphosphine oxide byproduct, anhydrous ZnCh (20 g) was added, and the resulting solution was decanted. To this decanted solution was added perchloric acid (20 mL of a 35% aqueous solution) and the mixture was stirred vigorously for 3 h. The ethereal solution was washed with water (3 x 150 mL), dried (MgSO*4), and the solvent removed in vacuo to give bicyclo[3.3.1]nonane-9-carboxaldehyde 56 as a colourless oil (15.2 g, 92%>). This aldehyde was found to be unstable and was used directly without further purification. To a cold (-78 °C) solution of aldehyde 56 (251mg, 1.65 mmol) in THF (3 mL) was added phenyl magnesium bromide (1.8 mL of 1.0 M solution in THF, 1.8 mmol) dropwise. The reaction was allowed to warm to -20°C and quenched with 1 M HC1 (20 141 Chapter 5 Experimental mL) at that temperature. The resultant mixture was extracted with Et20 (3 x 20 mL), and the organic layer was washed with H 2 0 (20 mL), brine (20 mL), and dried over M g S 0 4 . Removal of solvent in vacuo and silica gel chromatography (14% EtOAc in petroleum ether) afforded alcohol 63 (231 mg, 61%) as a white powder. mp: 82-83°C (EtOAc / Pet. Ether) *H NMR (CDC1 3, 300 MHz): 8 1.15 (br, IH), 1.32-1.40 (m, IH), 1.42-2.09 (m, 14H), 2.28 (br, IH), 4.87 (d, J= 10.6 Hz, IH), 7.25-7.38 (m, 5H). I 3 C NMR (CDCI3, 75 MHz): 8 21.55, 22.49, 25.25, 25.75, 27.98 (-ve), 28.75 (-ve), 33.44, 33.82, 48.93 (-ve), 74.34 (-ve), 126.80 (-ve), 127.73(-ve), 128.48 (-ve), 143.98. IR(KBr): 3379, 3028, 2902, 2857, 1490, 1455, 1303, 1205, 1064, 1008, 899, 775, 756, 700 cm"1. HRMS (EI) Calcd for C i 6 H 2 2 0 230.1671 (M + ) , Found 230.1672. Anal. Calcd for C i 6 H 2 2 0 : C, 83.43; H , 9.63. Found: C, 83.17; H , 9.65. 9-Benzoylbicyclor3.3.1 ]nonane (60) A mixture of PCC (253 mg, 1.17 mmol) and Celite® 545 (500 mg) was added to a 142 Chapter 5 Experimental solution of alcohol 63 (135 mg, 0.59 mmol) in anhydrous dichloromethane (15 mL) and stirred for 10 h at room temperature. The reaction mixture was filtered through a column of Florisil® and the remaining solids were extracted well with anhydrous Et20. Removal of solvent in vacuo and silica gel chromatography (4% Et 20 in petroleum ether) gave ketone 60 (125 mg, 93%) as a white solid. mp: 52-53°C (Et20 / Pet. Ether) *H NMR (CDC13, 300 MHz): 5 1.43-2.10 (m, 12H), 2.28 (br, 2H), 3.18 (br, IH), 7.37-7.52 (m, 3H), 7.78-7.83 (m, 2H). 1 3 C NMR (CDCI3, 75 MHz): 5 21.49, 22.26, 26.44, 30.29 (-ve), 33.32, 50.21 (-ve), 127.92 (-ve), 128.39 (-ve), 132.08 (-ve), 137.32, 204.59. IR(KBr): 2948, 2920, 2860, 2844, 1679, 1595, 1447, 1286, 1216, 946, 752, 692 cm"1. UV/VIS (3.07 x 10"4 M, MeOH): 275(1603), 325(611) nm (M-W1). HRMS (EI) Calcd for C i 6 H 2 0 O 228.1514, Found 228.1513. Anal. Calcd for Ci 6 H 2 0 O: C, 84.16; H, 8.83. Found: C, 84.24; H, 8.93. 143 Chapter 5 Experimental This structure was confirmed by X-ray crystallographic analysis: Habit colorless prism Space group C2/c a, A 23.614(9) b,A 9.772(3) c A 13.140(10) cc(°) 90 P(°) 121.06(4) Y(°) 90 Z 8 R 0.0589 144 Chapter 5 Experimental 5.2.2 Synthesis of 9-Benzoylbicyclo[3.3.1]nonane 61 Bicyclo|"3.3.1~|non-9-yl (p-Carbomethoxv)phenvl Methanol (64) C0 2 CH 3 64 To a cold (-40 °C) solution of methyl 4-iodobenzoate (529 mg, 2.02 mmol) in THF (10 mL) was added isopropylmagnesium chloride (1.1 mL of a 2.0 M solution in THF, 2.2 mmol) over 10 min. After the reaction was stirred in the cold for 1 h, a solution of aldehyde 56 (292 mg, 1.92 mmol) in THF (4 mL) was added dropwise. The reaction was stirred for 3 h and quenched with 5% NH4CI (10 mL) aqueous solution. THF was removed and the resultant aqueous residue was extracted with Et20 (3 x 15 mL). The combined ethereal extracts were washed with brine (2 x 20 mL), and dried (MgSCu). Removal of the solvent in vacuo and silica gel chromatography (11% EtOAc in petroleum ether) afforded alcohol 64 (317 mg, 57%) as a white powder. mp: 148-149°C (EtOAc / Pet. Ether) 'H NMR (CDCI3, 300 MHz): 5 1.11 (br, IH), 1.32-2.02 (m, 14H), 2.27 (br, IH), 3.89 (s, 3H), 4.92 (d, J= 10.6 Hz, IH), 7.41 (d, J= 8.2 Hz, 2H), 7.99 (d, J= 8.2 Hz, 2H). 1 3 C NMR (CDCI3, 75 MHz): 5 21.47, 22.40, 25.21, 25.78, 27.92 (-ve), 28.67 (-ve), 33.35, 33.71, 49.18 (-ve), 52.03 (-ve), 73.83 (-ve), 126.87 (-ve), 129.33, 129.84 (-ve), 149.20, 166.92. 145 Chapter 5 Experimental IR(KBr): 3446, 2958, 2903,2850, 1724, 1610, 1436, 1283, 1178, 1112, 1064, 1016, 899, 864, 810, 779, 762, 733, 709, 566 cm-1. H R M S (CI) Calcd for Ci 8 H 2 8 N0 3 306.2069 (M + NH 4) +, Found 306.2071. A n a l . Calcd for C18H24O3: C, 74.97; H, 8.39. Found: C, 74.54; H, 8.33. 9-(p-Carbomethoxvbenzovl)bicyclo[3.3.1 "jnonane (61) C 0 2 C H 3 61 A mixture of PCC (371 mg, 1.7 mmol) and Celite® 545 (500 mg) was added to a solution of alcohol 64 (247 mg, 0.86 mmol) in anhydrous dichloromethane (35 mL) and stirred for 14 h at room temperature. The reaction mixture was filtered through a column of Florisil® and the remaining solids were extracted well with anhydrous Et20. Removal of solvent in vacuo and silica gel chromatography (20% EtOAc in petroleum ether) gave ketone 61 (245 mg, 100%) as a white solid. mp: 111-113°C (EtOAc / Hexanes) ' H N M R (C 6D 6, 400 MHz): 8 1.36-1.84 (m, 10H), 2.04-2.20 (m, 4H), 2.79 (s, IH), 3.46 (s, 3H), 7.65 (d, J= 8.2 Hz, 2H), 8.04 (d, J= 8.2 Hz, 2H). 1 3 C N M R (C 6D 6, 75 MHz): 8 21.88, 22.51, 26.69, 30.38 (-ve), 33.25, 50.51 (-ve), 51.52 (-ve), 130.00 (-ve), 130.33 (-ve), 133.42, 141.11, 165.98, 202.93. 146 Chapter 5 Experimental IR(KBr): 2958, 2919,2843, 1718, 1681, 1439, 1285, 1189, 1106, 1064, 765,724 cm"1. H R M S (EI) Calcd for C18H22O3 286.1569, Found 286.1561. Anal . Calcd for C i 8 H 2 2 0 3 : C, 75.50; H , 7.74. Found: C, 75.28; H , 7.99. This structure was confirmed by X-ray crystallographic analysis: Habit colorless prism Space group i>2i2i2i a, A 7.0235(4) b,A 10.8752(7) c, A 19.3291(13) a ( ° ) 90 P( ° ) 90 Y(°) 90 Z 4 R 0.038 147 Chapter 5 Experimental 5.2.3 Synthesis of 9-Benzoyl-9-methylbicyclo[3.3.1]nonane 71 Bicyclo[3.3.11nonane-9-carboxylic acid (65) 65 Aldehyde 56 (15.2 g, 99.9 mmol) and 2-methyl-2-butene (34.5 mL, 325.5 mmol) were dissolved in 150 mL of /-BuOH. A solution of 80% sodium chlorite (105g, 929 mmol) and sodium dihydrogen phosphate (90. lg , 653 mmol) in H2O (150 mL) was added to the stirred aldehyde-containing ?-BuOH solution via dropping funnel. The resultant mixture was stirred at room temperature for 12 h. Diethyl ether (200 mL) and H2O (200 mL) were added and two phases formed. The aqueous phase was extracted with diethyl ether (3 x 150 mL) and the combined organic extracts were extracted with 3 M NaOH (3 x 200 mL). The combined basic extracts were then washed with E t 2 0 (2 x 100 mL) and carefully acidified to a pH 3 with cone. HC1. The precipitated carboxylic acid was extracted into Et20 (3 x 200 mL), and the combined ethereal extracts were dried over MgS04. Removal of solvent in vacuo gave bicyclo[3.3.1]nonane-9-carboxylic acid 65 (13.1 g, 78%>) as a white solid. Recrystallization from EtOH / water yielded bicyclo[3.3.1]nonane-9-carboxylic acid 65 as colorless plates (mp 127.5-128.5 °C, lit. 3 128-129.5 °C). mp: 127.5-128.5°C ( E t O H / H 2 0 ) 148 Chapter 5 Experimental *H NMR (CDCI3, 300 MHz): 8 1.42-2.00 (m, 12H), 2.29 (br, 2H), 2.41 (br, IH), 10.01 (br, IH). 1 3 C NMR (CDCI3, 75 MHz): 8 21.34, 21.73, 26.82, 29.15 (-ve), 32.69, 47.29 (-ve), 181.06. IR(KBr): 3300-2500(br), 2918,2858, 1688, 1412, 1292, 1239, 1196, 953,744 cm"1. Methyl bicyclor3.3.11nonane-9-carboxylate (66) To a cold (0 °C) solution of bicyclo[3.3.1]nonane-9-carboxylic acid 65 (6.58 g, 39.1 mmol) in E t 2 0 (20 mL) was added excess CH2N2 ethereal solution. The resultant ethereal solution was filtrated through a short silica gel column and dried over MgSC>4. Removal of solvent and vacuum distillation afforded colorless liquid of methyl bicyclo[3.3.1]nonane-9-carboxylate 66 (6.28 g, 88%) as a colorless liquid. bp: 100-103 ° C / 6 m m H g ! H NMR (CDCI3, 300 MHz): 8 1.40-1.98 (m, 12H), 2.26 (br, 2H), 2.35 (br, IH), 3.67 (s, 3H). 1 3 C NMR (CDCI3, 75 MHz): 8 21.37, 21.80, 26.85, 29.31 (-ve), 32.69, 47.34 (-ve), 51.29 (-ve), 175.09. C02Me 66 149 Chapter 5 Experimental IR(neat): 2958, 2922, 2890, 2850, 1734, 1489, 1455, 1434, 1337, 1283, 1215, 1189, 1124, 1040, 1017, 929, 885 cm"1. H R M S (EI) Calcd for C , i H i 8 0 2 182.1307, Found 182.1307. Anal . Calcd for C n H 1 8 0 2 : C, 72.49; H, 9.95. Found: C, 72.02; H , 9.98. Methyl 9-methylbicvclo[3.3.11nonane-9-carboxylate (67) 67 To a cold (-78 °C) solution of L D A (prepared from 19.5 mmol DIPA and 18.1 mmol w-butyllithium) in THF (60 mL) was added methyl bicyclo[3.3.1]nonane-9-carboxylate 66 (2.54 g, 13.9 mmol) in THF (30 mL) over 15 min. After stirring in the cold (-78 °C) for 1.5 h, an additional portion of «-butyllithium (9.6 mL of a 1.6 M solution in rc-hexane, 15.3 mmol) was added dropwise. The reaction mixture was stirred for 30 min, followed by the addition of D M P U (5.0 mL, 42mmol). After 5 min, methyl iodide (9.89 g, 69.7 mmol) was added and the reaction was stirred in the cold (-78 °C) for 3 h before warming slowly to room temperature and stirring overnight. The reaction was quenched with water (80 mL) and extracted with E t 2 0 (3 x 70 mL). The combined ethereal extracts were washed with brine (2 x 100 mL), dried (MgSC^), and the solvent was removed in vacuo. Vacuum distillation afforded methyl 9-methylbicyclo[3.3.1]nonane-9-carboxylate 67 as a colorless liquid (2.24 g, 82%). 150 Chapter 5 Experimental bp: 96-99°C / 6 mmHg ! H N M R (CDCI3, 300 MHz): 8.1.23 (s, 3H), 1.34-2.05 (m, 14H), 3.67 (s, 3H). 1 3 C N M R (CDCI3, 75 MHz): 8 20.30, 20.87, 23.83 (-ve), 26.40, 29.39, 33.26(-ve), 46.17, 51.22 (-ve), 178.80. I R (neat): 2958, 2914, 2867, 1731, 1490, 1453, 1304, 1267, 1232, 1218, 1119, 1098, 991, 882, 771 cm"1. H R M S (EI) Calcd for Q 2 H 2 0 O 2 196.1463, Found 196.1460. A n a l . Calcd for C 2 H 2 0 O 2 : C, 73.43; H , 10.27. Found: C, 72.75; H , 10.28. 9-Methylbicvclof3.3.11nonvl Methanol (68) To a solution of ester 67 (2.18 g, 11.1 mmol) in THF (40 mL) was added lithium aluminum hydride (6.1 mL of a 1.0 M solution in THF, 6.1 mmol). The reaction was allowed to reflux for 16 h. The reaction was cooled and carefully quenched with saturated aqueous sodium sulfate solution until large particles of white precipitate were formed. The reaction mixture was filtered and removal of THF in vacuo gave an aqueous residue, which was extracted with Et20 (3 x 30 mL). The combined ethereal extracts were washed with brine (2 x 30 mL) and dried over MgSCu. Removal of solvent in vacuo gave alcohol 68 (1.85 g, 99%) as a white solid. 68 151 Chapter 5 Experimental mp: 117-119°C (EtOAc / Pet. Ether) * H N M R (CDCI3, 300 MHz): 5 1.07 (s, 3H), 1.18 (br, IH), 1.40-2.04 (m, 14H), 3.61 (s, 2H). 1 3 C N M R (CDCI3, 75 MHz): 5 20.66, 21.43, 21.48 (-ve), 27.22, 27.50, 32.91 (-ve), 36.76, 69.45. I R ( K B r ) : 3299(br), 2950, 2911, 2868, 1453, 1024, 733 cm - 1 . H R M S (EI) Calcd for C n H 2 o O 168.1514, Found 168.1507. Anal . Calcd for C n H 2 0 O : C, 78.51; H , 11.98. Found: C, 78.91; H , 12.10. 9-Methvlbicvclo|"3.3.11,nonyl Carboxaldehvde (57) and 9-Methvlbicvclo[3.3.1Tnonyl Phenyl Methanol (69) 57 69 A mixture of PCC (1.40 g, 6.48 mmol) and Celite® 545 (2.79 g) was ground with a mortar and pestle until homogeneous. This solid was added to a solution of alcohol 68 (545 mg, 3.24 mmol) in anhydrous dichloromethane (40 mL) and the mixture stirred for 2 h at room temperature. The reaction mixture was filtered through a column of Florisil® and the remaining solids triturated well with anhydrous E t 2 0 . Removal of solvent in vacuo gave aldehyde 57 (538 mg, 100%) as colorless oil, which was found to be unstable 152 Chapter 5 Experimental and was used without further purification. To a cold (0 °C) solution of phenyl magnesium bromide in THF (25 mL) was added aldehyde 57 (538 mg, 3.24 mmol in 5 mL of THF). The reaction was stirred in the cold (0 °C) for 2 h and quenched with 5% aqueous NH4CI solution (15 mL). THF was removed and the resultant aqueous phase was extracted with Et20 (3 x 20 mL). The combined ethereal extracts were washed with H 2 O (20 mL) and brine (20 mL), followed by drying (MgSCu) and removal of the solvent in vacuo. Silica gel chromatography (5% EtOAc in petroleum ether) afforded alcohol 69 (706 mg, 89%) as a white solid. m p : 118-118.5°C (EtOAc / Pet. Ether) * H N M R (CDCI3, 400 MHz): 5 0.85 (s, 3H), 1.27 (br, IH), 1.39 (m, IH), 1.50-1.62 (m, 4H), 1.66 (s, IH), 1.68-1.99 (m, 5H), 2.00-2.20 (m, 2H), 2.37 (m, IH), 5.40 (s, IH), 7.23 (m, IH), 7.29 (m, 2H), 7.37 (m, 2H). 1 3 C N M R (CDCI3, 100 MHz): 5 16.54 (-ve), 20.58, 20.87, 27.20, 27.60, 27.74, 27.85, 32.24 (-ve), 32.92 (-ve), 39.65, 74.13 (-ve), 126.93 (-ve), 127.47 (-ve), 127.55 (-ve), 142.45. I R ( K B r ) : 3395, 2943, 2912, 2868, 1491, 1461, 1020, 892, 761, 732, 703, 567 cm"1. H R M S (CI) Calcd for C 1 7 H 2 4 0 244.1827, Found 244.1834. Anal . Calcd for C i 7 H 2 4 0 : C, 83.55; H, 9.90. Found: C, 83.95; H , 10.02. 153 Chapter 5 Experimental 9-Benzovl-9-methvlbicyclo[3.3.11nonanes (71) A mixture of PCC (1.15 g, 5.33 mmol) and Celite® 545 (2.30 g) was ground with a mortar and pestle until homogeneous. This solid was added to a solution of alcohol 69 (651 mg, 2.66 mmol) in anhydrous dichloromethane (30 mL) and the reaction mixture was stirred for 10 h at room temperature. The reaction mixture was filtered through a column of Florisil® and the remaining solids triturated well with anhydrous Et20. Removal of solvent in vacuo and silica gel chromatography (3% Et20 in petroleum ether) gave ketone 71 (612 mg, 95%) as a white solid. mp: 67-68°C (EtOAc / Pet. Ether) *H NMR (CDC1 3, 300 MHz): 5 1.30-1.93 (m, 13H), 2.02-2.17 (m, 2H), 2.34 (br, 2H), 7.33-7.46 (m, 3H), 7.70-7.75 (m, 2H). 1 3 C NMR (CDCI3, 75 MHz): 5 20.20, 20.98, 23.63 (-ve), 26.82, 29.02, 33.90 (-ve), 50.79, 127.84 (-ve), 127.97 (-ve), 130.83 (-ve), 139.34, 209.84. IR(KBr): 2960, 2913, 2865, 1672, 1444, 1266, 1232, 1216, 1124, 963, 932, 721, 696, 663 cm"1. UV/VIS (2.39 x 10"4 M , MeOH): 285(1178), 330(720) nm ( M W 1 ) . 154 Chapter 5 Experimental HRMS (EI) Calcd for C i 7 H 2 2 0 242.1671, Found 242.1670. Anal . Calcd for C i 7 H 2 2 0 : C, 84.25; H, 9.15. Found: C, 84.45; H , 9.13. This structure was confirmed by X-ray crystallographic analysis: Habit colorless needle Space group PI a, A 6.9383(9) b, A 10.1035(5) c, A 10.1972(9) o n 101.473(9) P H 98.041(3) Y(°) 104.520(9) Z 2 R 0.0636 155 Chapter 5 Experimental 5.2.4 Synthesis of 9-Benzoyl-9-methylbicyclo[3.3.1]nonane 72 (9-MethvDbicvclor3.3.11non-9-vl (p-Carbomethoxv)phenvl Methanol (70) 70 A mixture of PCC (3.71 g, 17.2 mmol) and Celite® 545 (5.00 g) was ground with a mortar and pestle until homogeneous. This solid was added to a solution of alcohol 68 (1.81 g, 10.8 mmol) in anhydrous dichloromethane (120 mL) and the mixture was stirred for 2 h at room temperature. The reaction mixture was filtered through a column of Florisil® and the remaining solids triturated well with anhydrous Et20. Removal of solvent in vacuo gave aldehyde 57 (1.79 g, 99%) as colorless oil, which was used without further purification. To a cold (-40 °C) solution of methyl 4-iodobenzoate (2.85 g, 10.9 mmol) in THF (60 mL) was added isopropylmagnesium chloride (5.7 mL of a 2.0 M solution in THF, 11.4 mmol) over 10 min. The reaction was stirred in the cold (-40 °C) for 1 h. A solution of aldehyde 57 (1.73 g, 10.4 mmol) obtained above in THF (20 mL) was added. The reaction was stirred in the cold (-40 °C) for 3 h and quenched with 5% aqueous NH 4C1 (100 mL). THF was removed in vacuo and the resultant aqueous phase was extracted with E t 2 0 (3 x 70 mL). The combined ethereal extracts were washed with brine (2 x 100 mL), followed by drying (MgS0 4 ) and removal of the solvent in vacuo. Silica gel chromatography (14% EtOAc in petroleum ether) afforded alcohol 70 (2.82 g, 90%) as a 156 Chapter 5 Experimental white powder. mp: 135-137°C (EtOAc / Pet. Ether) *H N M R (CDCI3, 300 MHz): 5 0.79 (s, 3H), 1.90-2.40 (m, 15H), 3.88 (s, 3H), 5.43 (s, IH), 7.42 (d, J= 8.4 Hz, 2H), 7.93 (d,J= 8.4 Hz, 2H). 1 3 C N M R (CDCI3, 75 MHz): 5 16.56 (-ve), 20.48, 20.78, 27.15, 27.62 (br), 27.76, 32.19 (-ve), 32.90 (-ve), 39.91, 52.00 (-ve), 73.82 (-ve), 127.49 (-ve), 128.68 (-ve), 147.91 (br), 167.07. IR(KBr) : 3516(br), 2950, 2913,2868, 1724, 1610, 1490, 1460, 1436, 1283, 1192, 1111, 1034, 1018, 909, 869, 812, 770, 736, 715, 573 cm"1. H R M S (CI) Calcd for C 1 9 H 3 0 N O 3 320.2226 (M + N H 4 ) + , Found 320.2222. Anal . Calcd for C 1 9 H 2 6 O 3 : C, 75.46; H , 8.67. Found: C, 75.48; H , 8.73. 9-(p-Carbomethoxvbenzovl)-9-methylbicvclo[3.3.11nonane (72) A mixture of PCC (3.09 g, 14.3 mmol) and Celite® 545 (5.0 g) was ground with a mortar and pestle until homogeneous. This solid was added to a solution of alcohol 7 0 (2.71 g, 8.96 mmol) in anhydrous dichloromethane (100 mL) and the resulting mixture was stirred for 12 h at room temperature. The reaction mixture was filtered through a 72 157 Chapter 5 Experimental column of Florisil® and the remaining solids triturated well with anhydrous Et20. Removal of solvent in vacuo gave ketone 72 (2.69 g, 100%) as a white solid. mp: 137-138°C (EtOAc / Hexanes) *H N M R (CDC1 3, 300 MHz): 5 1.48 (s, 3H), 1.32-1.94 (m, 10H), 2.08 (m, 2H), 2.29 (br, 2H), 3.92 (s, 3H), 7.74 (d, J= 8.5 Hz, 2H), 8.03 (d, J= 8.5 Hz, 2H). 1 3 C N M R (CDCI3, 75 MHz): 8 20.10, 20.89, 23.64 (-ve), 26.71, 29.03, 33.74 (-ve), 51.04, 52.32 (-ve), 127.69 (-ve), 129.27 (-ve), 131.89, 143.20, 166.36, 209.71. IR (KBr) : 2950, 2906, 2857, 1722, 1666, 1497, 1435, 1401, 1279, 1235, 1190, 1108, 1017, 960, 934, 862, 738, 703 cm"1. UV/VIS (1.46 x 10"4 M , MeOH): 285(1459), 330(194) nm (M'cm" 1). H R M S (EI) Calcd for C,9H 2 403 300.1725, Found 300.1729. Anal . Calcd for C 1 9 H 2 4 O 3 : C, 75.97; H , 8.05. Found: C, 75.80; H , 8.00. 158 Chapter 5 Experimental This structure was confirmed by X-ray crystallographic analysis: Habit colorless needle Space group P2JC a, A 16.5562(5) b,k 11.0177(8) c,k 21.4829(12) <x(°) 90 P(°) 87.323(4) Y(°) 90 Z 4 R 0.0468 159 Chapter 5 Experimental 5.2.5 Synthesis of 9-Benzoyl-9-methylbicyclo[3.3.1]nonane 73 9-(p-Carboxvbenzovl)-9-methvlbicyclof3.3.1]nonane (73) C0 2H 73 To a solution of ester 72 (2.45 g, 8.16 mmol) in THF (50 mL) was added a solution of lithium hydroxide monohydrate (3.42 g, 81.6 mmol, in 25 mL of water). The reaction was stirred at room temperature for 20 h. The reaction solution was diluted with Et20 (200 mL) and extracted with water (3 x 100 mL). The combined aqueous extracts were acidified with cone. HC1 and extracted with E t 2 0 (3 x 100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), then dried over MgSC»4. Removal of solvent in vacuo yielded acid 73 (2.31 g, 99%) as a white powder. mp: 224-226°C (EtOH / H 2 0 ) ] H N M R (DMSO, 300 MHz): 81.20-2.16 (m, 15H), 2.22 (br, 2H), 7.82 (d, J= 8.2 Hz, 2H), 7.98 (d, J = 8.2 Hz, 2H). (no COOH signal was observed due to proton exchange with a trace amount of water in the solvent) 1 3 C N M R (DMSO, 75 MHz): 8 19.66, 20.41, 23.05 (-ve), 26.16, 28.47, 33.10 (-ve), 50.22, 127.71 (-ve), 129.12 (-ve), 132.78, 142.24, 166.66, 209.02. I R ( K B r ) : 3080-2720 (br), 2950, 2906, 2863, 1695, 1680, 1568,1505, 1431, 1401, 1316, 1295, 1214, 1126, 968, 933, 860, 807, 761, 731, 698, 543 cm"1. 160 Chapter 5 Experimental UV/VIS (1.68 x 10"4 M , MeOH): 285(2994), 335(333) nm (M-'cm"1). H R M S (EI) Calcd for C 1 8 H 2 2 O 3 286.1569, Found 286.1567. Anal . Calcd for C i 8 H 2 2 0 3 : C, 75.50; H , 7.74. Found: C, 75.23; H , 7.67. 161 Chapter 5 Experimental 5.2.6 Synthesis of Chiral Salts 84-90 (S)-(-)-\-Phenylethylamine Salt (84) 0 COO H 3 C - C H © 84 Keto acid 73 (86 mg, 0.30 mmol) and (5)-(-)-l-phenylethylamine (40 ul, 38 mg, 0.31 mmol) were dissolved in a hot mixture of acetonitrile and methanol. Upon cooling to room temperature, filtration gave salt 84 as colorless needles (98 mg, 80 %). mp: 211-213°C (MeOH / CH 3 CN) ' H N M R (CD3OD, 300 MHz): 5 1.30-2.25 (m, 18H), 2.33 (br, 2H), 4.42 (q, J= 6.8 Hz, IH), 7.41 (m, 5H), 7.73 (d, J= 8.4 Hz, 2H), 7.95 (d, J= 8.4 Hz, 2H). 1 3 C N M R (CD3OD, 75 MHz): 5 20.96 (-ve), 21.26, 22.01, 24.16 (-ve), 27.80, 30.11, 35.25 (-ve), 52.05, 52.26 (-ve), 127.60 (-ve), 128.44 (-ve), 129.89 (-ve), 130.05 (-ve), 130.26 (-ve), 140.11, 141.37, 141.99, 173.98, 212.09. IR(KBr) : 3447, 2915,2862, 2767, 1667, 1615, 1518, 1455, 1395, 1232, 1219, 1124, 1092, 965, 932, 844, 825, 764, 745, 695, 539 cm"1. H R M S (LSIMS) Calcd for C26H34NO3 (M + H + ) 408.2539, Found 408.2538. 162 Chapter 5 Experimental Ana l . Calcd for C26H33NO3: C, 76.62; H , 8.16; N , 3.44. Found: C, 76.34; H , 8.15; N , 3.43. (R)-(+)-l-Phenylethylamine Salt (85) Keto acid 73 (57 mg, 0.20 mmol) and (R)-(+)-l-phenylethylamine (27 u.1, 25 mg, 0.21 mmol) were dissolved in a hot mixture of acetonitrile and methanol. Upon cooling to room temperature, filtration gave salt 85 as colorless needles (64 mg, 79 %). mp: 211-213°C (MeOH / CH 3 CN) *H N M R ( C D 3 O D , 300 MHz): 8 1.30-2.25 (m, 18H), 2.33 (br, 2H), 4.42 (q, J = 6.8 Hz, IH), 7.41 (m, 5H), 7.73 (d, J= 8.4 Hz, 2H), 7.95 (d, J= 8.4 Hz, 2H). 1 3 C N M R (CD 3 OD, 75 MHz): 8 20.96 (-ve), 21.26, 22.01, 24.16 (-ve), 27.80, 30.11, 35.25 (-ve), 52.05, 52.26 (-ve), 127.60 (-ve), 128.44 (-ve), 129.89 (-ve), 130.05 (-ve), 130.26 (-ve), 140.20, 141.37,141.99, 173.98, 212.09. IR (KBr): 3446, 2915, 2864, 2766, 1668, 1615, 1519, 1456, 1396, 1232, 1219, 1124, 1092, 966, 933, 844, 825, 764, 744, 695, 539 cm"1. H R M S (ESI) Calcd for C26H34NO3 (M + H + ) 408.2539, Found 408.2544. 0 85 163 Chapter 5 Experimental Anal . Calcd for C26H33NO3: C, 76.62; H , 8.16; N , 3.44. Found: C, 76.35; H , 8.46; N , 3.47. (IS. 2fl)-(-)-c/J-l-Amino-2-indanol Salt (86) 86 Salt 86 was prepared by dissolving 57 mg (0.20 mmol) of keto acid 73 and 31 mg (0.21 mmol) of (IS, 27?)-(-)-cw-l-amino-2-indanol in a hot mixture of acetonitrile and methanol. Upon cooling to room temperature, filtration gave salt 86 as an off-white powder (71 mg, 81 %). mp: 190°C (Decom.) (MeOH / CH 3 CN) ' H NMR (CD 3 OD, 300 MHz): 5 1.28-2.00 (m, 13H), 2.18 (m, 2H), 2.33 (br, 2H), 3.01 (dd,J= 5.9 Hz and 16.3 Hz, IH), 3.22 (dd, J= 6.4 Hz and 16.3 Hz, IH), 4.54 (d, .7=5.9 Hz, IH), 4.70 (dd, .7=5.9 Hz and 11.3 Hz, IH), 7.31 (m, 3H), 7.46 (d,J = 7.3 Hz, 2H), 7.73 (d, J= 8.4 Hz, 2H), 7.96 (d, J= 8.4 Hz, 2H). 1 3 C NMR (CD3OD, 75 MHz): 8 21.24, 22.00, 24.15 (-ve), 27.80, 30.10, 35.24 (-ve), 40.09, 52.05, 58.71 (-ve), 72.08 (-ve), 126.14 (-ve), 126.64 (-ve), 128.40 (-ve), 164 Chapter 5 Experimental 129.44 (-ve), 129.89 (-ve), 130.77 (-ve), 138.47, 141.28, 141.99, 142.77, 174.11, 212.11. IR(KBr) : 3235, 2913, 2862, 2625, 1670, 1619, 1580, 1535, 1452, 1397, 1267, 1216, 1093, 966, 932, 844, 823, 803, 741, 567 cm"1. H R M S (ESI) Calcd for C Z T H J A N C X , (M + H + ) 436.2488, Found 436.2486. Anal . Calcd for C27H33NO4: C, 74.45; H , 7.64; N , 3.22. Found: C, 74.38; H , 7.68; N , 3.23. lR)-(-)-2-Amino-l-butanol Salt (87) Salt 87 was prepared by dissolving 57 mg (0.20 mmol) of keto acid 73 and 19 mg (0.21 mmol) of (ic)-(-)-2-amino-l-butanol in hot methanol. Upon cooling to room temperature, filtration gave salt 87 as an off-white powder (53 mg, 71 %). mp: 159-162°C (MeOH) ! H N M R (CD3OD, 300 MHz): 5 1.01 (t, J= 7.6 Hz, 3H), 1.25-2.00 (m, 15H), 2.18 (m, 2H), 2.33 (br, 2H), 3.08 (m, IH), 3.54 (dd, J= 6.7 Hz and 11.7 Hz, IH), 3.75 (dd, J= 3.7 Hz and 11.7 Hz, IH), 7.73 (d, J= 8.5 Hz, 2H), 7.96 (d,J= 8.5 Hz, 2H). 0 87 165 Chapter 5 Experimental 1 3 C N M R (CD3OD, 75 MHz): 5 10.16 (-ve), 21.25, 22.00, 23.67, 24.16 (-ve), 27.81, 30.11, 35.25 (-ve), 52.05, 55.98 (-ve), 61.99, 128.44 (-ve), 129.88 (-ve), 141.43, 141.96, 174.17,212.11. IR(KBr) : 3367, 2960, 2910, 2871, 1681, 1667, 1595, 1524, 1463, 1387, 1263, 1232, 1217, 1124, 1083, 964, 931, 869, 803, 747, 570 cm"1. H R M S (ESI) Calcd for C22H34NO4 (M + H + ) 376.2488, Found 376.2488. A n a l . Calcd for C22H33NO4: C, 70.37; H , 8.86; N , 3.73. Found: C, 70.28; H , 8.90; N , 3.76. L-Prolinamide Salt (88) Salt 88 was prepared by dissolving keto acid 73 (57 mg, 0.20 mmol) and L -prolinamide (24 mg, 0.21 mmol) in a hot mixture of acetonitrile and methanol. Upon cooling to room temperature, filtration gave salt 88 (72 mg, 90 %) as a white powder. mp: 210-211.5°C (MeOH / CH 3 CN) *H N M R (CD3OD, 300 MHz): 5 1.20-2.00 (m, 16H), 2.17 (m, 2H), 2.33 (br, 2H), 2.39, (m, IH), 3.31 (m, 2H), 4.19 (dd, J = 6.4 Hz and 8.4 Hz, IH), 7.73 (d, J= 8.4 Hz, 2H),7.97(d, .7=8.4 Hz, 2H). COO 0 88 166 Chapter 5 Experimental 1 3 C N M R (CD3OD, 75 MHz): 5 21.23, 21.99, 24.15 (-ve), 25.38, 27.79, 30.10, 31.25, 35.24 (-ve), 47.34, 52.07, 60.99 (-ve), 128.48 (-ve), 129.93 (-ve), 140.68, 142.21, 173.01, 173.71,212.07. IR (KBr): 3365, 3232, 2935, 2909, 2871, 1715, 1680, 1631, 1591, 1544, 1383, 1217, 1015, 963, 931, 827, 804, 744, 668, 641, 567 cm"1. H R M S (ESI) Calcd for C23H33N2O4 (M + H + ) 401.2440, Found 401.2451. Anal . Calcd for C23H32N2O4: C, 68.97; H , 8.05; N , 6.99. Found: C, 69.10; H , 8.09; N , 6.98. (#)-(-)-1-Cvclohexvlethylamine Salt (89) Salt 8 9 was prepared by dissolving keto acid 7 3 (57 mg, 0.20 mmol) and (/?)-(-)-1-cyclohexylethylamine (31 ul, 27 mg, 0.21 mmol) in hot methanol. Upon cooling to room temperature, filtration gave salt 8 9 as a white powder (71 mg, 86 %). mp: 192-195°C (MeOH) J H N M R (CD3OD, 300 MHz): 5 0.98-2.00 (m, 27H), 2.18 (m, 2H), 2.33 (br, 2H), 3.06 COO .0 89 (m, IH), 7.73 (d, J= 8.4 Hz, 2H), 7.96 (d, J= 8.4 Hz, 2H). 167 Chapter 5 Experimental 1 3 C N M R (CD3OD, 75 MHz): 5 16.07 (-ve), 21.24, 22.00, 24.15 (-ve), 26.92, 27.00, 27.08, 27.81, 28.82, 30.01, 30.11, 35.26 (-ve), 42.75 (-ve), 52.05, 53.39 (-ve), 128.42 (-ve), 129.85 (-ve), 141.61, 141.90, 174.20, 212.09. IR(KBr) : 3443, 2929, 2862, 2603, 2551, 2361, 2342, 2203, 1666, 1635, 1578, 1537, 1450, 1382, 1263, 1232, 1216, 1126, 964, 932, 868, 821, 804, 745, 568 cm"1. H R M S (ESI) Calcd for C26H40NO3 (M + H + ) 414.3008, Found 414.3009. Anal . Calcd for C26H39NO3: C, 75.50; H , 9.50; N , 3.39. Found: C, 75.31; H , 9.55; N , 3.46. (IR. 2i?V(-V2-Amino-1 -phenyl- 1.3-propanediol Salt (90) 90 Salt 90 was prepared by dissolving keto acid 73 (57 mg, 0.20 mmol) and (IR, 2i?)-(-)-2-amino-l-phenyl-1,3-propanediol (35 mg, 0.21 mmol) in a hot mixture of acetonitrile and methanol. Upon cooling to room temperature, filtration gave salt 90 as a white powder (76 mg, 84 %). mp: 142-143°C (MeOH / CH 3 CN) lH N M R (CD3OD, 300 MHz): 5 1.25-1.73 (m, 8H), 1.51 (s, 3H), 1.89 (m, 2H), 2.17 (m, 2H), 2.33 (br, 2H), 3.26 (m, IH), 3.47 (m, 2H), 4.73 (d, / = 8.6 Hz, IH) 7.37 (m, 5H), 7.72 (d, J= 8.6 Hz, 2H), 7.96 (d, J = 8.6 Hz, 2H). 168 Chapter 5 Experimental 1 3 C N M R (CD3OD, 75 MHz): 8 21.23, 21.98, 24.15 (-ve), 27.81, 30.10, 35.26 (-ve), 52.06, 60.23, 60.29 (-ve), 72.54 (-ve), 127.86 (-ve), 128.42 (-ve), 129.51 (-ve), 129.74 (-ve), 129.89 (-ve), 141.38, 141.97, 142.23, 174.13, 212.15. IR(KBr) : 3367, 2914,2864, 1668, 1582, 1542, 1493, 1453, 1386, 1229,1124, 1039, 968, 960, 932, 868, 840, 803, 746, 700, 572, 540 cm"1. H R M S (ESI) Calcd for C27H36NO5 (M + H + ) 454.2593, Found 454.2599. Anal . Calcd for C 2 7 H 3 5 N 0 5 : C, 71.50; H , 7.78; N , 3.09. Found: C, 71.34; H , 8.05; N , 3.41. 169 Chapter 5 Experimental 5.3 Synthesis of Spirobicyclo[3.3.1]nonyl Ketones 49-52 5.3.1 Synthesis of the Five-Ring Spirobicyclo[3.3.1]nonyl Ketone 49 Methyl 9-Benzylbicvclo[3.3.11nonane-9-carboxylate (94) 9 4 To a cold (-78 °C) solution of L D A (prepared from 3.85 mmol DIPA and 3.56 mmol M-butyllithium) in THF (45 mL) was added methyl bicyclo[3.3.1]nonane-9-carboxylate 66 (500 mg, 2.74 mmol) in THF (10 mL) over 15 min. The reaction was stirred in the cold (-78 °C) for 1.5 h, followed by the addition of D M P U (662 uL, 5.48 mmol). After 5 min, benzyl bromide (937 mg, 5.48 mmol) was added and the reaction was stirred in the cold (-78 °C) for 3 h before warming slowly to room temperature and stirring overnight. The reaction was quenched with 1 M HC1 aqueous solution (100 mL) and extracted with Et20 (3 x 60 mL). The combined ethereal extracts were successively washed with H 2 O (2 x 100 mL) and brine (100 mL), and dried over MgSC»4. Removal of solvent in vacuo and silica gel chromatography (3% E t . 2 0 in petroleum ether) afforded ester 94 (680 mg, 91%) as a white powder. mp: 65-66°C ( E t 2 0 / Hexanes) *H N M R (CDCI3, 300 MHz): 8 1.38-2.30 (m, 14H), 3.01 (s, 2H), 3.45 (s, 3H), 7.02-7.26 (m, 5H). 170 Chapter 5 Experimental 1 3 C N M R (CDCI3, 75 M H z ) : 8 20.26, 21.02, 26.79, 29.52, 32.22 (-ve), 41.78, 50.62 (-ve), 52.18 (-ve), 126.40 (-ve), 127.94 (-ve), 129.33 (-ve), 138.01, 175.84. IR(KBr) : 2960, 2913,2866, 1737, 1723, 1490, 1455, 1267, 1227, 1198, 1167, 1112, 1086, 1045, 740,700, 588 cm"1. H R M S (EI) Calcd for C 1 8 H 2 4 O 2 272.1776, Found 272.1782. Anal . Calcd for C i 8 H 2 4 0 2 : C, 79.37; H , 8.88. Found: C, 79.18; H , 8.79. Spiror2//-indene-2,9 ,-bicvclor3.3.nnonanl-l(3//)-one (49) To a cold (-78 °C) solution of ester 94 (416 mg, 1.53 mmol) in anhydrous dichloromethane (10 mL) was added boron trichloride (15.3 mL of a 1.0 M solution in dichloromethane, 15.3 mmol) over 10 min. The reaction was slowly warmed to 0 °C and stirred for 3 h before it was poured onto crushed ice (15 g). Dichloromethane (125 mL) was added and the mixture was stirred until all the ice melted. The organic phase was separated and successively washed with 5% aqueous sodium carbonate (50 mL), water (2 x 50 mL) and brine (75 mL), then dried (MgSO"4), and concentrated in vacuo. Silica gel chromatography (3% Et 2 0 in petroleum ether) afforded ketone 49 (323 mg, 88%) as a white solid. mp: 105.5-107.5°C (Hexanes) 49 171 Chapter 5 Experimental ! H N M R (CDCU, 300 MHz): 8 1.48-2.12 (m, 12H), 2.52 (m, 2H), 3.16 (s, 2H), 7.28-7.69 (m, 4H). 1 3 C N M R (CDCI3, 75 MHz): 8 20.48, 20.55, 26.78, 29.37, 33.51 (-ve), 38.94, 53.16, 123.94 (-ve), 125.99 (-ve), 127.10 (-ve), 134.13 (-ve), 136.87, 151.15, 209.99. IR(KBr) : 2947, 2917, 2876, 1693, 1605, 1463, 1456, 1433, 1281, 1124, 1089, 936, 764, 727, 679,592 cm"1. UV/VIS (1.75 x 10"4 M , MeOH): 294(2851), 340(65) nm ( M W 1 ) . H R M S (EI) Calcd for C 1 7 H 2 0 O 240.1514, Found 240.1514. Anal . Calcd for C i 7 H 2 0 O : C, 84.96; H , 8.39. Found: C, 84.59; H , 8.66. This structure was confirmed by X-ray crystallographic analysis: Habit colorless needle Space group P2x/n 6.8295(2) 19.8993(6) 9.9692(3) a ( ° ) 90 P(°) 107.0600(10) Y(°) 90 Z 4 R 0.0467 172 Chapter 5 Experimental 5.3.2 Synthesis of the Six-Ring Spirobicyclo[3.3.1]nonyl Ketone 50 Methyl 9-(2-Phenyleihvl)bicvclo|"3.3.1~|nonane-9-carboxylate (95) O OMe To a cold (-78 °C) solution of L D A (7.31 mmol; prepared from 7.87 mmol DIP A and 7.31 mmol «-butyllithium) in THF (50 mL) was added a solution of methyl bicyclo[3.3.1]nonane-9-carboxylate 66 (1.03 g, 5.62 mmol) in THF (10 mL) over ten min. The reaction was stirred in the cold (-78 °C) for 1.5 h, followed by the addition of D M P U (1.36 mL, 11.3 mmol). After 10 min, 2-(bromoethyl)benzene (1.14 mL, 11.3 mmol) was added over 2 min and the reaction mixture was stirred in the cold (-78 °C) for 5 h before warming slowly to room temperature and stirring overnight. The reaction was quenched with 1 M HC1 (100 mL) and taken up in E t 2 0 (150 mL). The mixture was extracted further with Et20 (2 x 100 mL) and the combined organic extracts were washed successively with water (2 x 100 mL) and brine (100 mL), then dried (MgSO^), and concentrated in vacuo. Silica gel chromatography (3% E12O in petroleum ether) gave ester 95 (1.31 g, 81%) as a colorless oil. J H NMR (CDCI3, 300 MHz): 5 1.41-2.05 (m, 14H), 2.15 (br, 2H), 2.42 (m, 2H), 3.73 (s, 3H), 7.12-7.31 (m, 5H). 1 3 C NMR (CDCI3, 75 MHz): 5 20.04, 21.29, 26.29, 29.46, 29.99, 31.97 (-ve), 37.82, 49.74, 51.19 (-ve), 125.79 (-ve), 128.28 (-ve), 128.36 (-ve), 142.42, 177.03. 173 Chapter 5 Experimental IR(neat): 3025,2950, 2914, 2867, 1728, 1603, 1489, 1455, 1311, 1261, 1239, 1197, 1163, 1117, 1087, 1050, 984, 890, 790, 759, 699 cm - 1 . H R M S (CI) Calcd for C19H30NO2 (M + N H 4 + ) 304.2277, Found 304.2276. Anal . Calcd for C19H26O2: C, 79.68; H , 9.15. Found: C, 79.61; H , 9.43. 3,4-Dihvdrospirornaphthalene-2(l/7).9,-bicyclo[3.3.11nonan1-l-one (50) To a cold (-78 °C) solution of ester 95 (1.09 g, 3.81 mmol) in anhydrous dichloromethane (20 mL) was added boron trichloride (20 mL of a 1.0 M solution in dichloromethane, 20 mmol) over 10 min. The reaction was slowly warmed to 0 °C and stirred for 3 h before it was poured onto crushed ice (20 g). Dichloromethane (200 mL) was added and the mixture was stirred until all the ice melted. The organic phase was separated and successively washed with 5% aqueous sodium carbonate (2 x 50 mL), water (2 x 50 mL) and brine (75 mL), then dried (MgSC»4), and concentrated in vacuo. Silica gel chromatography (3% Et 2 0 in petroleum ether) afforded ketone 50 (691 mg, 71%) as a white solid. mp: 92-93°C (Et 2 0 / Pet. Ether) 174 Chapter 5 Experimental *H N M R (CDCI3, 300 MHz): 5 1.45-1.65 (m, 6H), 1.75-2.24 (m, 10H), 2.97 (t,J= 6.3 Hz, 2H), 7.14 (d, J= 7.6 Hz, IH), 7.24 (dt, J = 7.7, 0.9 Hz, IH), 7.38 (dt, J= 7.6, 1.5 Hz, IH), 7.76 (dd, J= 7.7, 1.1 Hz, IH). 1 3 C N M R (CDCI3, 75 MHz): 5 20.66, 21.62, 24.24, 27.46, 28.71, 30.74, 31.55 (-ve), 47.35, 126.39 (-ve), 127.46 (-ve), 127.87 (-ve), 132.00 (-ve), 134.23, 141.92, 206.80. IR(KBr) : 2926, 2857, 1685, 1603, 1454, 1433, 1286, 1226, 1123, 932, 900, 757, 738, 659 cm"1. UV/VIS (1.89 x IO"4 M , MeOH): 285(2466), 330(150) nm ( M W 1 ) . H R M S (EI) Calcd for C i 8 H 2 2 0 254.1671, Found 254.1671. Anal . Calcd for C ] 8 H 2 2 0 : C, 84.99; H , 8.72. Found: C, 85.15; H , 8.66. This structure was confirmed by X-ray crystallographic analysis: Habit colorless prism Space group P2,/c 7.2743(2) 7.5960(2) 24.9959(6) c c ( ° ) 90 90.7360(10) Y(°) 90 z 4 R 0.0415 175 Chapter 5 Experimental 5.3.3 Synthesis of the Seven-Ring Spirobicyclo[3.3.1]nonyl Ketone 51 Methyl 9-(2-Propenvl)bicvclor3.3.n,nonane-9-carboxvlate (96) 96 To a cold (-78 °C) solution of L D A (21.9 mmol, prepared from 23.6 mmol DIPA and 21.9 mmol w-butyllifhium) in THF (120 mL) was added methyl bicyclo[3.3.1]nonane-9-carboxylate 66 (3.07 g, 16.8 mmol) in THF (30 mL) over 15 min. The reaction was stirred in the cold (-78 °C) for 1.5 h, followed by the addition of D M P U (4.1 mL, 33.7 mmol). After 5 min, allyl bromide (2.9 mL, 33.7 mmol) was added dropwise and the reaction was stirred in the cold (-78 °C) for 5 h before warming slowly to room temperature and stirring overnight. The reaction was quenched with 1 M HC1 aqueous solution (300 mL) and extracted with Et20 (3 x 200 mL). The combined ethereal extracts were successively washed with H2O (2 x 200 mL) and brine (200 mL), dried over MgSC>4, and concentrated in vacuo. Silica gel chromatography (3% Et20 in petroleum ether) and bulb-to-bulb distillation afforded ester 96 (3.49 g, 93%) as a colorless liquid. bp: 125-127°C7 6 mmHg 'H NMR (CDCI3, 300 MHz): 6 1.40-2.00 (m, 12H), 2.05 (br, 2H), 2.43 (d, J = 7.5 Hz, 2H), 3.68 (s, 3H), 4.98 (m, 2H), 5.65 (m, IH). 1 3 C NMR (CDCI3, 75 MHz): 8 20.07, 21.16, 26.26, 29.42, 31.80 (-ve), 40.13, 50.48, 51.00 (-ve), 117.03, 133.58 (-ve), 176.52. 176 Chapter 5 Experimental IR(neat): 2960, 2912, 2866, 1731, 1640, 1460, 1307, 1278, 1214, 1186, 1120, 1035,992, 580 cm"1. H R M S (EI) Calcd for C 1 4 H 2 2 O 2 222.1620, Found 222.1620. A n a l . Calcd for C14H22O2: C, 75.63; H, 9.97. Found: C, 75.97; H , 10.14. 9-Hvdroxvmethvl-9-(2-propenvl)bicyclo[3.3.11nonane (97) 97 To a solution of ester 96 (3.36 g, 15.1 mmol) in THF (60 mL) was added lithium aluminum hydride (8.3 mL of a 1.0 M solution in THF, 8.3 mmol). The reaction was allowed to reflux for 40 h. The reaction was cooled and carefully quenched with saturated sodium sulfate aqueous solution until large particles of white precipitate were formed. Filtration and removal of THF gave an aqueous residue, which was extracted with E12O (3 x 40 mL). The combined ethereal extracts were washed with brine (2 x 40 mL) and dried over MgS0 4 . Removal of solvent in vacuo and silica gel chromatography (25% Et20 in petroleum ether) gave alcohol 9 7 (2.67 g, 91%) as a white powder. mp: 51-52°C (Et 2 0 / Pentane) ' H N M R (CDCI3, 400 MHz): 5 1.38-2.10 (m, 14H), 2.37 (d, J = 7.5 Hz, 2H), 3.75 (s, 2H), 5.02-5.17 (m, 2H), 5.89 (m, IH). 177 Chapter 5 Experimental 1 3 C N M R (CDCI3, 100 MHz): 5 20.86, 21.07, 26.97, 27.24, 31.02 (-ve), 37.03, 39.66, 65.10, 116.89, 135.56 (-ve). IR(KBr) : 3371 (br), 3072, 2911, 2876, 1637, 1487, 1463, 1228, 1124, 1048, 1009, 910, 879,743,610 cm"1. H R M S (CI) Calcd for C i 3 H 2 6 N O (M + N H 4 + ) 212.2015, Found 212.2015. Anal . Calcd for C i 3 H 2 2 0 : C, 80.35; H , 11.41. Found: C, 80.06; H , 11.54. 9-(2-Propenyl)-bicyclo[3.3.11nonvl Carboxaldehvde (98) and 9-(2-Propenyl)-bicyclo-|"3.3.1]non-9-yl ort/?o-Vinvlphenvl Methanol (99) 98 99 A mixture of PCC (1.42 g, 6.59 mmol) and Celite® 545 (3.09 g) was ground with a mortar and pestle until homogeneous. This solid was added to a solution of alcohol 97 (927 mg, 4.77 mmol) in anhydrous dichloromethane (150 mL) and the mixture was stirred for 2 h at room temperature. The reaction mixture was filtered through a column of Florisil® and the remaining solids triturated well with anhydrous E t 2 0 . Removal of solvent in vacuo gave aldehyde 98 (915 mg, 99%) as colorless oil, which was used without further purification. To a suspension of M g turnings (570 mg, 23.8 mmol) in THF (30 mL) was added 1,2-dibromoethane (50 uL). The mixture was gently heated for 2 min. 2-Bromostyrene (1.83 g, 10.0 mmol) was then added slowly so as to maintain a gentle reflux, and the 178 Chapter 5 Experimental reaction stirred for 1 h. Aldehyde 98 (915 mg, 4.76 mmol) in THF (20 mL) was added dropwise and the reaction was stirred for 2 h at room temperature. The reaction was quenched with 1M HC1 (100 mL) and diluted with E t 2 0 (200 mL). The organic phase was separated and washed successively with water (2 x 100 mL) and brine (100 mL). The organic layer was dried (MgSCu) and the solvent removed in vacuo. Silica gel chromatography (5% E t 2 0 in petroleum ether) afforded alcohol 99 (1.12 g, 79% from 97) as a white solid. mp: 80-82°C (Et 2 0 / Pet. Ether) ! H N M R (CDCI3, 400 MHz): 5 1.20 (br, IH), 1.29-2.30 (m, 16H), 2.70 (d.d, J= 6.0 Hz andl6.4 Hz, IH), 4.96-5.10 (m, 2H), 5.28 (d.d, J= 10.9 Hz and 1.4 Hz, IH), 5.54 (d.d, J= 15.9 Hz and 1.4 Hz, IH), 5.63 (d, J= 4.7 Hz, IH), 6.07 (m, IH), 7.18-7.27 (m, 2H, overlapped with solvent signal), 7.39 (d.d, J = 6.9 Hz and 2.1 Hz, IH), 7.69 (d.d, J= 9.2 Hz and 2.1 Hz, IH). , 3 C N M R (CDCI3, 75 MHz): 8 19.94, 20.78, 26.95, 27.50, 27.89, 28.22, 30.33 (-ve), 31.83 (-ve), 35.52, 43.54, 73.14 (-ve), 115.52, 116.12, 127.05 (-ve), 127.38 (-ve), 127.66 (-ve), 129.10 (-ve), 136.86 (-ve), 137.30 (-ve), 138.27, 139.85. IR(KBr) : 3453 (br), 3067, 2915, 2872, 1630, 1480, 1467, 1443, 1411, 1259, 1123, 994, 908, 856, 761, 738, 711, 609, 566 cm"1. H R M S (CI) Calcd for C 2 , H 3 2 N O (M + N H 4 + ) 314.2484, Found 314.2485. Anal . Calcd for C 2 i H 2 8 0 : C, 85.08; H , 9.52. Found: C, 84.83; H , 9.62. 179 Chapter 5 Experimental 9-(2-Propenvl)-9-(o-vinvlbenzovl)bicyclo[3.3.1 lnonane (101) A mixture of PCC (1.20 g, 5.57 mmol) and Celite® 545 (2.50 g) was ground with a mortar and pestle until homogeneous. This solid was added to a solution of alcohol 99 (1.10 g, 3.71 mmol) in anhydrous dichloromethane (150 mL) and the mixture stirred for 12 h at room temperature. The reaction mixture was filtered through a column of Florisil® and the remaining solids triturated well with anhydrous E t 2 0 . Removal of solvent in vacuo and silica gel chromatography (5% E t 2 0 in petroleum ether) gave ketone 101 (673 mg, 61%) as colorless oil, which solidified upon standing. mp: 53-54°C (Et 2 0 / Pet. Ether) ' H N M R (CDC1 3, 300 MHz): 5 1.34-1.71 (m, 8H), 1.83 (m, 2H), 2.08 (m, 2H), 2.29 (br, 2H), 2.78 (d, J= 7.3 Hz, 2H), 5.04 (m, 2H), 5.27 (d.d, / = 11.2 Hz and 11.0 Hz, IH), 5.70 (m, 2H), 7.00 (d.d, J = 11.0 Hz and 17.4 Hz, IH), 7.21 (d.t, J= 7.6 Hz and 1.2 Hz, IH). 7.36 (d.t, 7= 7.8 Hz and 1.2 Hz, IH), 7.55 (d.d, J= 7.8 Hz and 1.2 Hz, IH), 7.61 (d, J = 7.9 Hz, IH). 1 3 C N M R (CDCI3, 75 MHz): 5 19.81, 20.99, 26.71, 28.94, 32.38 (-ve), 39.60, 55.20, 116.32, 117.18, 124.85 (-ve), 126.26 (-ve), 127.46 (-ve), 129.82 (-ve), 133.57 (-ve), 135.09 (-ve), 137.63, 139.16, 209.75. IR(KBr) : 3075,2916,2867, 1672, 1639, 1564, 1488, 1475, 1447, 1416, 1216, 1107, 994, 914, 769, 739, 667, 643, 575 cm"1. 180 Chapter 5 Experimental HRMS (EI) Calcd for C 2 i H 2 6 0 294.1984, Found 294.1984. Anal . Calcd for C 2 i H 2 6 0 : C, 85.67; H , 8.90. Found: C, 85.39; H , 8.94. Spiro[6#-benzocvcloheptene-6,9'-bicyclo\3.3.1 ]nonanl-5(7//)-one (103) 103 To a solution of ketone 101 (472 mg, 1.60 mmol) in deoxygenated anhydrous dichloromethane (110 mL) was added a solution of Grubbs' catalyst (benzylidene-bis(tricyclohexylphosphine)dichlororuthenium)4 (63 mg, 5 mol%) in deoxygenated anhydrous dichloromethane over 10 min. The initial purple colour was replaced by a light golden brown color. The reaction was stirred at room temperature for 12 h. The reaction solution was filtered through Florisil® and the solvent removed in vacuo. Silica gel chromatography (8% Et 2 0 in petroleum ether) afforded enone 103 (416 mg, 97%) as a pale brown solid. Further purification by recrystallization from EtOAc / Pet. ether provided colorless crystals. mp: 101-102°C (EtOAc / Pet. Ether) *H NMR (CDCI3, 300 MHz): 5 1.38-2.03 (m, 12H), 2.19 (br, 2H), 2.62 (d.d, J= 2.8, 5.2 Hz, 2H), 5.81 (d.t, J = 5.2 and 12.2 Hz, IH), 6.38 (d, J= 12.2 Hz, IH), 7.11 (d, J = 7.5 Hz, IH), 7.26 (d.t, J = 7.5 and 1.0 Hz, IH), 7.36 (d.t, 7 = 7.5 and 1.5 Hz, IH), 7.50 (d, J=7 .5Hz , IH). 181 Chapter 5 Experimental 1 3 C N M R (CDCI3, 75 MHz): 8 20.25, 21.48, 26.97, 28.96, 31.31 (-ve), 35.37, 49.69, 127.21 (-ve), 127.52 (-ve), 129.35 (-ve), 130.01 (-ve), 130.73 (-ve), 130.83 (-ve), 132.87, 138.21,209.72. IR(KBr) : 3019, 2911,2869, 1677, 1595, 1487, 1460, 1443, 1421, 1261, 1215, 1125, 925, 904, 863, 779, 764, 751, 652, 528 cm"1. UV/VIS (1.95 x 10"4 M , MeOH): 270(4049), 310(2466) nm (M-'cm"1). H R M S (EI) Calcd for C i 9 H 2 2 0 266.1671, Found 266.1671. Anal . Calcd for C i 9 H 2 2 0 : C, 85.67; H , 8.32. Found: C, 85.71; H , 8.44. This structure was confirmed by X-ray crystallographic analysis: Habit hexagonal prism Space group P2,/c a, A 7.6035(2) b,A 13.7072(2) c, A 14.1742(3) a ( ° ) 90 P ( ° ) 99.4540(10) Y(°) 90 Z 4 R 0.0435 182 Chapter 5 Experimental 8,9-Dihvdrospiro[6F-benzocvcloheptene-6.9,-bicvclo[3.3.1]nonanl-5(7/^)-one (51) 51 A suspension of 10% palladium on charcoal (18 mg) and ketone 103 (186 mg, 0.698 mmol) in EtOAc (25 mL) was placed under an atmosphere of FL. The mixture was stirred for 4 h and filtered through Celite® 545. Removal of the solvent in vacuo afforded ketone 51 (180 mg, 96%) as a white solid. Recrystallization from Et20 / Hexanes provided colorless crystals. mp: 75-76°C (Et 2 0 / Hexanes) *H N M R (CDC1 3, 300 MHz): 8 1.37-1.58 (m, 6H), 1.68-2.10 (m, 12H), 2.84 (m, 2H), 7.08 (m, IH), 7.18-7.33 (m, 3H). 1 3 C N M R (CDCI3, 75 MHz): 8 20.06, 21.07, 23.69, 26.53, 28.95, 32.59 (-ve), 35.77, 36.26, 53.48, 126.03 (-ve), 128.18 (-ve), 128.53 (-ve), 129.25 (-ve), 137.69, 141.96,213.51. IR(KBr) : 2914, 2864, 1679, 1599, 1487, 1446,1260, 1124, 951, 770, 740, 655 cm"1. UV/VIS (1.49 x IO"4 M , MeOH): 275(1294), 315(338) nm ( M W 1 ) . H R M S (EI) Calcd for C i 9 H 2 4 0 268.1827, Found 268.1827. Anal . Calcd for C 1 9 H 2 4 0 : C, 85.03; H , 9.01. Found: C, 85.29; H , 9.17. 183 Chapter 5 Experimental This structure was confirmed by X-ray crystallographic analysis: Habit colorless prism Space group Pbca a, A 10.0868(3) b,A 12.7692(4) c, A 22.9818(7) o(°) 90 P(°) 90 y(°) 90 z 8 R 0.0515 184 Chapter 5 Experimental 5.3.4 Synthesis of the Eight-Ring Spirobicyclo[3.3.1]nonyl Ketone 52 2-Propenylbromobenzene Br The procedure of Boymond et al. was followed.5 To a cold (-25 °C) solution of 2-bromoiodobenzene (9.14 g, 32.3 mmol) in THF (150 mL) was added isopropylmagnesium chloride (34.2 mmol, 17.1 mL of a 2.0 M solution in Et20) over 5 min. The reaction was stirred in the cold (-25 °C) for 1 h, followed by the addition of allyl bromide (3.1 mL, 34.2 mmol). The reaction was stirred in the cold (-25 °C) for another 30 min before warming slowly to room temperature and stirring for 1 h. The reaction was quenched with an aqueous solution (20 mL) containing 5% ammonium hydroxide and 5% ammonium chloride. Extraction with Et20 (3 x 120 mL) was followed by successive washing of the combined organic extracts with 5% HC1 (3 x 30 mL), 5% aqueous sodium bicarbonate (40 mL), water (2 x 40 mL), and brine (80 mL). After drying (MgSOx), and removal of the solvent in vacuo, 2-propenylbromobenzene (2.97 g, 93%) was obtained as a colourless liquid. * H N M R (300 MHz, CDC1 3): 5 3.52 (dt, J= 1.3, 8.5 Hz, 2H), 5.13 (m, 3H), 5.98 (m, IH), 7.07 (m, IH), 7.25 (m, 2H), 7.57 (m, IH). 1 3 C N M R (75 MHz, CDC1 3): 8 40.18, 116.54, 124.56, 127.46, 127.80, 130.41, 132.74, 135.54, 139.40. 185 Chapter 5 Experimental 9-(2-PropenvlVbicvclor3.3.11non-9-vl ortfto-(2-PropenvDphenvll Methanol (100) 100 A mixture of PCC (1.50 g, 6.96 mmol) and Celite® 545 (3.20 g) was ground with a mortar and pestle until homogeneous. This solid was added to a solution of alcohol 97 (1.08 g, 5.56 mmol) in anhydrous dichloromethane (150 mL) and the mixture was stirred for 2 h at room temperature. The reaction mixture was filtered through a column of Florisil® and the remaining solids triturated well with anhydrous Et^O. Removal of solvent in vacuo gave the aldehyde 98 (1.04 g, 97%) as colorless oil, which was used without further purification. To a suspension of M g turnings (649 mg, 27.0 mmol) in THF (40 mL) was added 1,2-dibromoethane (50 uL). The mixture was gently heated for 2 min; 2-propenylbromobenzene (2.26 g, 11.5 mmol) was then added slowly so as to maintain a gentle reflux, and the reaction stirred for 1 h. Aldehyde 98 (1.04 g, 5.41 mmol) in THF (25 mL) was added dropwise and the reaction was stirred for 2 h at room temperature. The reaction was quenched with 10% HC1 (75 mL) and diluted with Et20 (200 mL). The organic phase was separated and washed successively with water (2 x 75 mL) and brine (75 mL), and dried over MgSC>4. Removal of solvent in vacuo and silica gel chromatography (5% Et20 in petroleum ether) afforded alcohol 100 (1.29 g, 75% from 97) as colorless oil. 186 Chapter 5 Experimental ' H N M R (CDCI3, 300 MHz): 5 1.34 - 2.24 (m, 15H), 2.50 (d.d, J= 7.6 Hz andl6.3 Hz, IH), 2.82 (d.d, J= 5.8 Hz and 16.2 Hz, IH), 3.60 (m, 2H), 4.95 - 5.10 (m, 4H), 5.57 (d, J= 5.6 Hz, IH), 6.02 (m, 2H), 7.20 (m, 3H), 7.67 (m, IH). 1 3 C N M R (CDCI3, 75 MHz): 5 20.01, 20.64, 27.13, 27.46, 27.84, 27.95, 30.53 (-ve), 32.32 (-ve), 35.98, 38.12, 43.33, 73.15 (-ve), 115.41, 115.60, 125.87 (-ve), 127.35 (-ve), 128.89 (-ve), 130.89 (-ve), 137.60 (-ve), 138.33 (-ve), 139.19, 140.41. IR (KBr) : 3561 (br), 3071, 2915, 2872, 1633, 1487, 1467, 1442, 1411, 1260, 1123, 995, 909, 856, 760, 744, 630, 568 cm"1. H R M S (CI) Calcd for C 2 2 H 3 1 0 (M + H + ) 311.2376, Found 311.2380. Anal . Calcd for C 2 2 H 3 0 O : C, 85.11; H , 9.74. Found: C, 84.95; H , 9.86. 9-(2-Propenvl)-9-[o-(2-propenvl)benzoyl]bicvclo[3.3.11nonane (102) 102 A mixture of PCC (1.25 g, 5.80 mmol) and Celite" 545 (2.50 g) was ground with a mortar and pestle until homogeneous. This solid was added to a solution of alcohol 100 (1.20 g, 3.86 mmol) in anhydrous dichloromethane (150 mL) and the mixture was stirred for 12 h at room temperature. The reaction mixture was filtered through a column of Florisil® and the remaining solids triturated well with anhydrous E t 2 0 . Removal of solvent in vacuo and silica gel chromatography (6% Et 2 0 in petroleum ether) gave ketone 187 Chapter 5 Experimental 102 (988 mg, 83%) as colorless oil, which solidified upon standing, mp: 54-56°C (Et 2 0 / Pet. Ether) *H N M R (CDC1 3, 300 MHz): 8 1.35-1.71 (m, 8H), 1.84 (m, 2H), 2.09 (m, 2H), 2.30 (br, 2H), 2.80 (d, J = 7.3 Hz, 2H), 3.44 (d, J= 6.8 Hz, 2H), 5.07 (m, 4H), 5.74 (m, IH), 6.02 (m, IH), 7.14 (m, IH), 7.32 (d, / = 3.9 Hz, 2H). 7.55 (d, J= 7.8 Hz, IH). 1 3 C N M R (CDCI3, 75 MHz): 8 19.83, 20.97, 26.70, 28.95, 32.33 (-ve), 37.44, 39.64, 55.17, 115.95, 117.10, 124.77 (-ve), 124.97 (-ve), 129.67 (-ve), 131.27 (-ve), 133.63 (-ve), 137.64 (-ve), 139.61, 139.78, 209.89. IR(KBr) : 3074, 2915, 2868, 1672, 1637, 1460, 1435, 1217, 1123, 995, 914, 743, 643, 520 cm"1. H R M S (EI) Calcd for C 2 2 H 2 8 0 308.2140, Found 308.2139. Anal . Calcd for C 2 2 H 2 8 0 : C, 85.66; H , 9.15. Found: C, 86.09; H , 9.27. Spiror6//-benzocvclooctene-6.9 ,-bicvclor3.3.11nonanl-5(7//J0i^-one (104) 104 To a solution of ketone 102 (670 mg, 2.17 mmol) in deoxygenated anhydrous dichloromethane (70 mL) was added a solution of Grubbs' catalyst (benzylidene-188 Chapter 5 Experimental bis(tricyclohexylphosphine)dichlororuthenium)4 (54 mg, 3 mol%) in deoxygenated anhydrous dichloromethane over 10 min. The initial purple colour was replaced by a light golden brown color. The reaction was stirred at room temperature for 12 h. The reaction solution was filtered through Florisil® and the solvent was removed in vacuo. Silica gel chromatography (5% Et20 in petroleum ether) afforded enone 104 (578 mg, 95%) as an off-white solid. Further purification by recrystallization from hexanes provided colorless crystals. mp: 83-84°C (Hexanes) ! H N M R (CDCI3, 300 MHz): 5 1.50-1.75 (br, m, 6H), 1.80-2.05 (br, m, 6H), 2.21 (br, IH), 2.45 (br, m, 3H), 3.48 (br, m, 2H), 5.57-5.75 (m, 2H), 7.05-7.26 (m, 4H). 1 3 C N M R (CDCI3, 75 MHz): 8 20.01, 21.38, 26.81 (br), 28.10 (br), 28.32 (br), 30.10 (br, -ve), 31.05 (br), 31.73, 32.88 (br, -ve), 35.69, 57.33, 124.90 (-ve), 125.46 (-ve), 125.89 (-ve), 128.26 (-ve), 128.93 (-ve), 129.84 (-ve), 135.43, 141.14, 213.58. Slow conformational exchange at room temperature has broadened and split some of the carbon signals. IR(KBr) : 3019, 2912, 2867, 1694, 1458, 1284, 1243, 1218, 1120, 951, 936, 772, 727, 654, 594 cm"1. UV/VIS (1.78 x 10"4 M , MeOH): 265(286), 315(118) nm (M-'crn"1). H R M S (EI) Calcd for C20H24O 280.1827, Found 280.1828. Anal . Calcd for C20H24O: C, 85.67; H , 8.63. Found: C, 85.59; H , 8.80. 189 Chapter 5 Experimental 8,9-Dihvdrospiror6//-benzocyclooctene-6,9'-bicvcloD.3.1 lnonanl-5(7/f, 10#)-one (52) 52 A suspension of 10% palladium on charcoal (25 mg) and ketone 104 (249 mg, 0.89 mmol) in EtOAc (20 mL) was placed under an atmosphere of EL;. The mixture was stirred for 4 h and filtered through Celite® 545. Removal of the solvent in vacuo afforded ketone 52 (241 mg, 96%) as a white solid. Recrystallization from hexanes provided colorless crystals. mp: 102-103°C (Hexanes) N M R (CDC1 3, 300 MHz): 5 1.22-2.32 (br, m, 18H), 2.52-2.96 (br, m, 2H), 7.05-7.25 (m, 4H). 1 3 C N M R (CDCI3, 75 MHz): 5 19.74, 21.76, 22.06, 25.77 (br), 27.87 (br), 28.10 (br), 29.18, 29.42 (br, -ve), 31.80 (br), 32.61, 33.12 (br, -ve), 34.04, 55.44, 124.59 (-ve), 124.92 (-ve), 128.29 (-ve), 130.17 (-ve), 139.70 140.78, 215.29. Slow conformational exchange at room temperature has broadened and split some of the carbon signals. IR(KBr ) : 2911,2867, 1685, 1487, 1448, 1259, 1209, 1123,948, 935,911,753,663,565 cm"1. UV/VIS (1.56 x 10"4 M , MeOH): 265(247), 315(95) nm ( M W 1 ) . 190 Chapter 5 Experimental H R M S (EI) Calcd for C 2 o H 2 6 0 282.1984, Found 282.1983. Anal . Calcd for C 2 0 H 2 6 O : C, 85.06; H, 9.28. Found: C, 84.94; H , 9.59. This structure was confirmed by X-ray crystallographic analysis: Habit colorless prism Space group Pbca a, A 11.0402(3) b,A 10.0777(3) c A 28.1303(7) a ( ° ) 90 P(°) 90 y(°) 90 z 8 R 0.0487 191 Chapter 5 Experimental 5.4 Synthesis of m-Bicyclo[4.3.0]non-8-ylacetophenones 141 and 142 and Chiral Salts 143-147 5.4.1 Synthesis of c/s-Bicyclo[4.3.0]non-8-ylacetophenone 141 GaaJa«V2-(Brornornethvn-2.3,3a.4.7.7a-hexahvdro-l//-indene (137) To a cold (0 °C), stirred solution of triphenylphosphine (5.58 g, 21.3 mmol) and imidazole (2.90 g, 42.6 mmol) in CH3CN (50 mL) was added bromine (3.71 g, 23.2 mmol) dropwise. Stirring was continued in the cold for 30 min after which time hexahydro-l//-inden-2-ylmethanol6 136 (a -1:1 mixture of two isomers, 1.62 g, 10.6 mmol in 50 mL of diethyl ether) was added. After 5 h, the reaction was warmed to room temperature and stirred overnight. The reaction was quenched with 5% sodium bicarbonate (50 mL). Extraction with petroleum ether (3 x 75 mL) was followed by successive washing of the combined organic extracts with 5% aqueous sodium bicarbonate (50 mL) and brine (2 x 50 mL). The organic layer was dried (MgSCu) and the solvent was removed in vacuo. Silica gel chromatography (100% petroleum ether) and distillation (92-94 °C, 5 mmHg) provided bromide 137 (2.01 g, 88%) as a colorless liquid. bp: 92-94 °C / 5 mmHg H H 137 192 Chapter 5 Experimental ' H N M R (CDCI3, 400 MHz): 8 1.16-2.15 (m, 10H), 2.40-2.58 (m, IH), 3.40 (m, 2H), 5.60 (m, 2H). 1 3 C N M R (CDCI3, 75 MHz): 8 26.53, 27.67, 35.52 (-ve), 35.97 (-ve), 37.13, 37.80, 38.47 (-ve), 40.28, 40.80 (-ve), 40.91, 125.15 (-ve), 125.73 (-ve). IR(neat): 3020, 2912, 2834, 1656, 1450, 1433, 1355, 1336, 1291, 1220, 1172, 1036, 981, 935, 892, 831, 800, 752, 637, 589, 541 cm"1. H R M S (EI) Calcd for C i 0 H , 5 8 1 B r , 216.0337, Found 216.0340; Calcd for CioH, 5 7 9 Br, 214.0357, Found 214.0354. Methyl 4-(2-r(3aQr.7a«)-2.3.3a.4,7Ja-Hexahvdro-li/-inden-2-vn-l-hvdroxvethyl| Benzoate (138) To a suspension of Mg turnings (110 mg, 4.53 mmol) in THF (5 mL) was added 1,2-dibromoethane (25 u,L). The mixture was gently warmed and bromide 137 (650 mg, 3.02 mmol in 5 mL THF) was added slowly so as to maintain a gentle reflux. After stirring for 1 h, the reaction mixture was cooled to -78 °C and methyl 4-formylbenzoate (445 mg, 2.71 mmol in 5 mL) was introduced. After stirring for 1 h at -78 °C, the reaction was quenched with 5% HC1 (25 mL) and extracted with Et20 (3 x 25 mL). The H Q H 138 193 Chapter 5 Experimental combined organic layer was washed successively with water (3 x 25 mL) and brine (25 mL). After drying (MgSCu) and removal of the solvent in vacuo, the residue was subjected to silica gel chromatography (10% EtOAc in petroleum ether). Solvent removal in vacuo provided the alcohol 138 (~1:1 diastereomeric mixture by *H N M R , 467 mg, 51% from 137) as a white solid. mp: 65-68°C (EtOAc / Pet. Ether) ! H N M R (CDC1 3, 300 MHz): 5 0.97-2.30 (m, 14H), 3.87 (s, 3H), 4.67 (m, IH), 5.62 (m, 2H), 7.36 (d, J= 8.3 Hz, 2H), 7.95 (d, J= 8.3 Hz, 2H). 1 3 C N M R (CDCI3, 75 MHz): 5 26.65, 27.87, 27.92, 31.81 (-ve), 34.20 (-ve), 35.32 (-ve), 35.42 (-ve), 35.88 (-ve), 35.97 (-ve), 38.06, 38.40, 38.73, 39.00, 47.38, 47.53, 52.01 (-ve), 73.31 (-ve), 73.53 (-ve), 125.39 (-ve), 125.76 (-ve), 126.14 (-ve), 129.01, 129.70 (-ve), 150.18, 150.26, 166.93. IR(KBr) : 3421,3019, 2929, 2836, 2360, 2342, 1723, 1611, 1576, 1435, 1356, 1311, 1279, 1176, 1106, 1018, 966, 858, 772, 709, 668 cm - 1 . H R M S (EI) Calcd for C19H24O3 300.1725, Found 300.1723. Methyl 4-(l-Hvdroxy-2-r('3a«.7aQ:Voctahvdro-li7-inden-2-vllethvllBenzoate (139) HQ H 139 194 Chapter 5 Experimental A suspension of 10% palladium on charcoal (35 mg) and alcohol 138 (437 mg, 1.45 mmol) in EtOAc (15 mL) was placed under an atmosphere of FL. The mixture was stirred for 2 h and filtered through Celite® 545. Removal of the solvent in vacuo provided alcohol 139 (417 mg, 95%) as a white solid. mp: 88.5-90 °C (EtOAc / Pet. Ether) ' H N M R (CDC1 3, 300 MHz): 5 1.10-2.35 (m, 18H), 3.89 (s, 3H), 4.71 (m, IH), 7.38 (d, J = 8.2 Hz, 2H), 7.98 (d, J= 8.2 Hz, 2H). 1 3 C N M R (CDCI3, 75 MHz): 5 23.01, 23.59, 27.29, 28.73, 28.78, 32.36 (-ve), 34.35 (-ve), 36.56, 36.79, 36.91, 37.02, 38.66 (-ve), 38.70 (-ve), 38.78 (-ve), 38.85 (-ve), 47.69, 47.88, 52.01 (-ve), 73.36 (-ve), 73.57 (-ve), 125.75 (-ve), 125.78 (-ve), 129.06, 129.68 (-ve), 150.26, 150.35, 166.96. IR(KBr) : 3258, 2922, 2854, 1723, 1611, 1577, 1437, 1419, 1359, 1311, 1279, 1193, 1178, 1113, 1018, 965, 857, 829, 781, 709, 552 cm"1. H R M S (EI) Calcd for C19H26O3 302.1882, Found 302.1881. Methyl 4-r(2.3aq7ag)-Octahvdro-17/-inden-2-vlacetvll Benzoate (140) and Methyl 4-[(2<?,3a<x7aa)-Octahvdro-l.#-inden-2-ylacetyl1 Benzoate (141) A mixture of Celite® 545 (9.5 g) and PCC (6.17 g, 28.6 mmol) was ground with a 195 Chapter 5 Experimental mortar and pestle until homogeneous. This well mixed solid was suspended in a solution of alcohol 139 (4.33 g, 14.3 mmol) in dry dichloromethane (500 mL) and stirred overnight at room temperature. The reaction mixture was filtered through a short column of Celite® 545 on Florisil® and the remaining solids were triturated well with anhydrous Et20 (200 mL). Solvent removal in vacuo was followed by silica gel chromatography (2% EtOAc in petroleum ether) to give a cis, trans mixture of ketone 140 (3.83 g, 89%, ~1:1 diastereomeric mixture by ' H NMR) as a white solid. Repeated recrystallization in the solvent pair EtOAc/petroleum ether yielded diastereomerically pure ketone 141 (1.19 g, 31%) as thin colorless needles. mp: 103.5-105°C (EtOAc / petroleum ether) ] H N M R (CDC1 3, 400 MHz): 5 1.23-1.46 (m, 10H), 1.75-1.96 (m, 4H), 2.60 (m, IH), 2.99 (d, / = 7.2 Hz, 2H), 3.92 (s, 3H), 7.96 (d, J = 8.2 Hz, 2H), 8.08 (d, J= 8.2 Hz, 2H). 1 3 C N M R (CDCI3, 75 MHz): 8 23.03, 27.28, 31.91 (-ve), 36.84, 38.79 (-ve), 47.19, 52.41 (-ve), 127.93 (-ve), 129.77 (-ve), 133.60, 140.46, 166.27, 199.88. IR(KBr) : 2943, 2886, 2850, 1722, 1683, 1448, 1436, 1400, 1279, 1207, 1111, 999, 988, 965, 843, 832, 779, 765, 697 cm - 1 . UV/VIS (2.40 x 10"4 M , MeOH): 290(1423), 340(216) nm ( M W ) . H R M S (EI) Calcd for C19H24O3 300.1725, Found 300.1725. Anal . Calcd for C 9 H 2 4 O 3 : C, 75.97; H , 8.05. Found: C, 76.15; H , 8.04. This structure was confirmed by X-ray crystallographic analysis: 196 Chapter 5 Experimental Habit colorless needle Space group Pl a, A 5.5024(2) b, A 12.1266(6) c, A 12.4407(6) a ( ° ) 86.776(9) P(°) 79.404(8) Y(°) 78.122(8) Z 2 R 0.040 197 Chapter 5 Experimental 5.4.2 Synthesis of c/s-Bicyclo [4.3.0] non-8-ylacetophenone 142 4-f(2o:3a«Jaa)-Octahvdro-l//-inden-2-vlacetvl1benzoic Acid (142) }-^hco>H H 142 To a solution of ester 141 (600 mg, 2.00 mmol) in THF (40 mL) was added a solution of NaOH (10 g, 250 mmol) in water (90 mL). The reaction mixture was refluxed for 20 h, then cooled to room temperature. Diethyl ether (100 mL) was used to extract the mixture and the aqueous layer was treated with concentrated hydrochloric acid until it was strongly acidic. A large amount of sodium chloride was formed as a white precipitate. Another 100 mL of water was added to dissolve the sodium chloride and the mixture was extracted with Et20 (3 x 75 mL). The combined organic extracts were washed with water (2 x 75 mL) and brine (75 mL), then dried (MgS04) and concentrated in vacuo to afford acid 142 as a white solid. Recrystallization of acid 142 from the solvent pair EtOH/T^O gave analytically pure acid 142 (490 mg, 87%) as colorless flakes. mp: 221-222.5°C (EtOH / H 2 0 ) 'H NMR (DMSO, 400 MHz): 5 1.19-1.48 (m, 10H), 1.68-1.96 (m, 4H), 2.58 (m, IH), 3.08 (d, J= 7.2 Hz, 2H), 8.02 (m, 4H). Acidic proton not observed. 1 3 C NMR (DMSO, 75 MHz): 8 22.60, 26.88, 31.36 (-ve), 36.17, 38.66 (-ve), 46.52, 128.01 (-ve), 129.54 (-ve), 134.31, 139.94, 166.63, 199.73. 198 Chapter 5 Experimental IR (KBr ) : 3300-2000 (br), 2920, 2850, 1690, 1609, 1571, 1505, 1429, 1406, 1321, 1298, 1205, 1128, 1115, 999, 984, 948, 850, 826, 780, 769, 694, 566 c m 1 . UV/VIS (2.03 x 10"4 M , MeOH): 290(1911), 340(254) nm (M-'cm - 1). HRMS (EI) Calcd for C18H22O3 286.1569, Found 286.1568. Anal . Calcd for C18H22O3: C, 75.50; H , 7.74. Found: C, 75.65; H , 7.96. 199 Chapter 5 Experimental 5.4.3 Synthesis of Chiral Salts 143-147 L-Prolinamide Salt (143) 0 co2 H 2 O N H 2 H 143 Salt 143 was prepared by dissolving keto acid 142 (43 mg, 0.15 mmol) and L-prolinamide (18 mg, 0.16 mmol) in a hot mixture of acetonitrile and methanol. Upon cooling to room temperature, salt 143 was obtained as thin colorless needles (57 mg, 95 mp: 145-146.5 °C (MeOH / MeCN) J H N M R (CD 3 OD, 300 MHz): 5 1.11-1.95 (m, 17H), 2.28 (m, IH), 2.57 (m, IH), 2.94 (d, J= 7.3 Hz, 2H), 3.21 (m, IH, partly hidden under the solvent peak), 4.12 (dd, J = 6.8 Hz and 6.7 Hz, IH), 7.91-7.82 (m, 4H). No N H 2 or N H 2 + signal was observed due to proton exchange with the solvent. 1 3 C N M R (CD3OD, 75 MHz): 5 24.15, 25.31, 28.44, 31.24, 33.41 (-ve), 37.70, 40.28 (-ve), 47.27, 47.96, 60.91 (-ve), 128.76 (-ve), 130.40 (-ve), 139.84, 143.25, 172.73, 173.79, 202.51. IR (KBr): 3387, 3168, 2918, 2886, 2852, 1708, 1680, 1596, 1552, 1500, 1448, 1391, 1330, 1308, 1268, 1236, 1208, 1174, 1134, 1087, 1041, 1001, 988, 948, 929, 866, 840, 778, 704, 623,584 cm"1; %). 200 Chapter 5 Experimental L R M S (FAB, +LSIMS, matrix: glycerol): m/z 401 (M ++l), 385, 357, 325, 269, 247, 229, 207, 165, 149, 115(100), 81,70; H R M S (FAB, +LSIMS, matrix: glycerol): Calcd for C23H33N2O4, 401.2440, Found 401.2433 (M + H ) + . A n a l . Calcd for C 2 3 H32N 2 0 4 : C, 68.97; H , 8.05; N , 6.99. Found: C, 68.69; H , 8.06; N , 6.75. (R)-(+)-\-Phenylethylamine Salt (144) Keto acid 142 (43 mg, 0.15 mmol) and (i?)-(+)-l-phenylethylamine (20 ul, 19 mg, 0.16 mmol) were dissolved in a hot mixture of acetonitrile and methanol. Upon cooling to room temperature, salt 144 was obtained as colorless needles (55 mg, 90 %). mp: 172-173 °C (MeOH / MeCN). *H N M R (CD3OD, 300 MHz): 5 1.15-1.45 (m, 10H), 1.52 (d, J = 6.8 Hz, 3H), 1.67-1.95 (m, 4H), 2.58 (m, IH), 2.96 (d, J= 7.2 Hz, 2H), 4.33 (q, J= 6.8 Hz, IH), 7.32 (m, 5H), 7.87 (m, 4H). No NH3 + signal was observed due to proton exchange with the H 0\ / = \ 0 144 solvent. 201 Chapter 5 Experimental 1 3 C N M R (CD3OD, 75 MHz): 8 20.96 (-ve), 24.17, 28.46, 33.45 (-ve), 37.72, 40.15 (-ve), 47.97, 52.30 (-ve), 127.59 (-ve), 128.73 (-ve), 130.05 (-ve), 130.26 (-ve), 130.37 (-ve), 139.70, 140.11, 143.24,173.98, 202.59. IR(KBr): 2923, 2854, 1681, 1586, 1530, 1498, 1456, 1388, 1310, 1291, 1207, 1091, 986, 842, 778, 700, 537 cm-1. L R M S (FAB, +LSIMS, matrix: glycerol): m/z 408 (M + +l), 393, 379, 361, 333, 306, 287, 269, 243, 214, 185, 165, 149, 122(100), 105, 93, 75. H R M S (FAB, +LSIMS, matrix: glycerol): Calcd for C26H34NO3 408.2539, Found 408.2526 (M + H ) + . Anal . Calcd for C26H33NO3: C, 76.62; H , 8.16; N , 3.44. Found: C, 76.83; H , 8.23; N , 3.49. This structure was confirmed by X-ray crystallographic analysis: Habit colorless needle Space group 13.800(2) 6.3523(7) 13.447(2) an 90 P(°) 95.137(7) Y(°) 90 Z 2 R 0.043 202 Chapter 5 Experimental (S)-(-)-l-Phenylethylamine Salt (145) Keto acid 142 (43 mg, 0.15 mmol) and (S)-(-)-l -phenylethylamine (20 pl, 19 mg, 0.16 mmol) were dissolved in a hot mixture of acetonitrile and methanol. Upon cooling to room temperature, salt 145 was obtained as colorless needles (53 mg, 87 %). mp: 172-173 °C (MeOH / MeCN). ! H NMR (CD 3 OD, 300 MHz): 5 1.15-1.45 (m, 10H), 1.52 (d, J= 6.8 Hz, 3H), 1.67-1.95 (m, 4H), 2.58 (m, IH), 2.96 (d, J= 7.2 Hz, 2H), 4.33 (q, J = 6.8 Hz, IH), 7.32 (m, 5H), 7.87 (m, 4H). No NH3 + signal was observed due to proton exchange with the solvent. , 3 C NMR (CD3OD, 75 MHz): 5 20.96 (-ve), 24.17, 28.46, 33.45 (-ve), 37.72, 40.15 (-ve), 47.97, 52.30 (-ve), 127.59 (-ve), 128.73 (-ve), 130.05 (-ve), 130.26 (-ve), 130.37 (-ve), 139.70, 140.11, 143.24, 173.98, 202.59. IR(KBr): 2923, 2854, 1681, 1586, 1530, 1498, 1456, 1388, 1310, 1291, 1207, 1091, 986, 842, 778, 700, 537 cm"1. LRMS (FAB, +LSJMS, matrix: glycerol): m/z 408 (M + +l), 393, 379, 361, 333, 306, 287, 269, 243, 214, 185, 165, 149, 122(100), 105, 93, 75. 203 Chapter 5 Experimental HRMS (FAB, +LSIMS, matrix: glycerol): Calcd for C26H34NO3 408.2539, Found 408.2535 (M + H) + . Anal . Calcd for C26H33NO3: C, 76.62; H, 8.16; N, 3.44. Found: C, 76.75; H, 8.27; N, 3.14. (IR. 25V(+Vc*s-l-Amino-2-indanol Salt (146) 146 Salt 146 was prepared by dissolving 43 mg (0.15 mmol) of keto acid 142 and 23 mg (0.15 mmol) of (li?, 25)-(+)-cw-l-amino-2-indanol in a hot mixture of acetonitrile and methanol. Upon cooling to room temperature, salt 146 was obtained as a white powder (60 mg, 90 %). mp: 146-148 °C (MeOH / MeCN). 'H NMR (CD3OD, 300 MHz): 5 1.15-1.45 (m, 10H), 1.64-1.93 (m, 4H), 2.57 (m, IH), 2.85-3.14 (m, 2H), 2.92 (d, J = 7.2 Hz, 2H), 4.43 (d, J= 6.0 Hz, IH), 4.58 (dt, J = 6.0 Hz and 5.4 Hz, IH), 7.20 (m, 5H), 7.85 (m, 4H). No OH or N H 3 + signal was observed due to proton exchange with the solvent. 204 Chapter 5 Experimental I 3 C N M R (CD3OD, 75 MHz): 5 24.15, 28.45, 33.43 (-ve), 37.71, 40.11, 40.12 (-ve), 47.95, 58.61 (-ve), 71.95 (-ve), 126.19 (-ve), 126.63 (-ve), 128.40 (-ve), 128.72 (-ve), 130.38 (-ve), 130.82 (-ve), 138.19, 139.73, 142.79, 143.30, 173.98, 202.56. IR(KBr): 3216, 2922, 2853, 1683, 1591, 1542, 1391, 1309, 1208, 1098, 987, 841, 780, 740, 702 cm"1. L R M S (FAB, +LSIMS, matrix: glycerol): m/z 436 (M++l), 418, 399, 363, 334, 287, 269, 242, 222, 203, 165, 150(100), 133, 121, 93; H R M S (FAB, +LSIMS, matrix: glycerol): Calcd for C27H34NO4 436.2488, Found 436.2484 (M + H ) + . Anal. Calcd for C27H33NO4: C, 74.45; H, 7.64; N, 3.22. Found: C, 74.83; H, 7.82; N, 3.23. (i?)-(-)-l-Cvclohexylethvlamine Salt (147) 147 Salt 147 was prepared by dissolving keto acid 142 (43 mg, 0.15 mmol) and (R)-(-)-l-cyclohexylethylamine (23 ul, 20 mg, 0.16 mmol) in a hot mixture of acetonitrile and methanol. Upon cooling to room temperature, salt 147 was obtained as long colorless needles (59 mg, 94 %). 205 Chapter 5 Experimental mp: 169-171 °C (MeOH / MeCN). * H N M R (CD3OD, 300 MHz): 8 0.90-1.95 (m, 28H), 2.59 (m, IH), 2.96 (d, J= 1.2 Hz, 2H), 2.97 (m, IH, partly overlapped with the peak at 2.96ppm), 7.88 (m, 4H). No N H 3 + signal was observed due to proton exchange with the solvent. 1 3 C N M R (CD3OD, 75 MHz): 8 16.06 (-ve), 24.17, 27.00, 28.46, 28.82, 30.00, 33.46 (-ve), 37.72, 40.15 (-ve), 42.74 (-ve), 47.97, 53.39 (-ve), 128.72 (-ve), 130.35 (-ve), 139.64, 143.25, 174.03,202.61. IR(KBr): 2922, 2853, 1684, 1626, 1584, 1536, 1498, 1448, 1381, 1308, 1279, 1206, 1134, 1101, 1000, 986, 891, 839, 780, 702 cm"1. L R M S (FAB, +LSIMS, matrix: glycerol): m/z 414 (M + +l), 379, 310, 287, 269, 252, 220, 185, 149, 128(100), 93,70; H R M S (FAB, +LSIMS, matrix: glycerol): Calcd for C26H4oN03 414.3008, Found 414.3008 (M + H ) + . Anal. Calcd for C26H39NO3: C, 75.50; H , 9.50; N , 3.39. Found: C, 75.69; H , 9.61; N , 3.56. 206 Chapter 5 Experimental This structure was confirmed by X-ray crystallographic analysis: Habit colorless needle Space group P2i a, A 13.123(2) b,k 6.1476(5) c, A 14.954(2) a ( ° ) 90 P C ) 100.931(6) Y(°) 90 Z 2 R 0.054 207 Chapter 5 Experimental References 1 Carlson, B. A. ; Brown, H . C. Org. Synth. 1978, 58, 24 2 Alberts, A . H. ; Wynberg, FL; Strating, J. Synth. Comm. 1972, 2, 79. 3 House, H . O.; Cronin, T. H . J. Org. Chem. 1965, 30, 1061. 4 (a) Schwab, P.; Grubbs, R. H ; Ziller, J. W. Am. Chem. Soc. 1996, 118, 100; (b) Ftirstner, A. ; Langemann, K. ; J. Am. Chem. Soc. 1997, 119, 9130; (c) Miller, S. J.; Blackwell, Helen. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996,118, 9606. 5 Boymond, L. ; Rottlander, M . ; Cahiez, G.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1998,37, 1701. 6 Turecek, F.; Vystrcil, A . Collect. Czech. Chem. Commun. 1976, 41, 1571. 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 arc lamp in a water-cooled immersion well, or a 1000 W advanced Radiation Corporation (ARC) high-pressure Hg-Xe arc lamp in a Sciencetech model 201 air cooled arc lamp housing controlled with a 500-1000 W power supply operating at 800 W. Light emitted from the Hanovia lamp was filtered through Pyrex (transmits X > 290 nm). Light emitted from the A R C lamp was filtered through two dichroic filters (transmits X: 200-320 nm) and Pyrex (transmits X > 290 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 min prior to irradiation, and the reactions were performed either in sealed reaction vessels or under a positive pressure of nitrogen. Reactions were monitored by GC and/or T L C until a high conversion was reached or until the relative amounts of the major photoproducts decreased due to the emergence of minor or secondary photoproducts. In the case of ketone 49, anhydrous barium oxide was added to scavenge any acidic impurities that might promote the tautomerization of the intermediate enol to the corresponding ketone. By doing so, secondary photocleavage of the ketone was kept to a minimum. 209 Chapter 6 Experimental 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 3 cm2. The plates were fixed to one another with tape, and 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 chromatography and/or NMR spectroscopy. For salts or free acids, the sample was converted to the corresponding methyl ester with an ethereal solution of diazomethane, and in the case of salts, filtered through silica gel to remove the amine, before being analyzed by gas chromatography and/or high performance liquid chromatography. 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 results of GC analysis. The overall precision of the reported GC results is estimated to be ± 1%. 210 Chapter 6 Experimental 6.2 Photolysis of 9-Benzoyl-9-methylbicyclo[3.3.1]nonanes 71 and 72 Preparative Photolysis of Ketone 71 hv (Pyrex) CH3CN 71 74 75 A solution of ketone 71 (485 mg, 2.00 mmol) in acetonitrile (40 mL) was purged with nitrogen for 30 min and irradiated (Pyrex filter, 450 W Hanovia) for 7 h. Removal of the solvent in vacuo followed by silica gel chromatography (6% EtOAc in petroleum ether) afforded starting material 71 (17 mg, 4%), cyclobutanol 74 (442 mg, 93%; 98% based on recovered starting material), and alkene 75 (19 mg, 4%). Data for Cyclobutanol 74 ! H NMR (C 6 D 6 , 400 MHz): 5 0.89 (m, IH), 1.14 (m, IH), 1.23-1.27 (m, IH), 1.28 (s, 3H), 1.33-1.39 (m, 2H), 1.52-1.77 (m, 5H), 1.82-1.97 (m, 2H), 2.60 (m, IH), 2.71 (m, IH), 7.07-7.18 (m, 5H). 74 colorless oil. 211 Chapter 6 Experimental , 3 C N M R (CDCI3, 75 MHz): 8 17.77 (-ve), 18.29, 20.23, 22.55, 24.53, 27.56, 36.11 (-ve), 37.62 (-ve), 46.26, 46.37 (-ve), 82.64, 125.29 (-ve), 127.17 (-ve), 128.65 (-ve), 144.04. I R (KBr): 3441, 3027, 2923, 2874, 1479, 1452, 996, 882, 775, 702 cm-1. H R M S (EI) Calcd for C i 7 H 2 2 0 242.1671, Found 242.1672. A n a l . Calcd for C i 7 H 2 2 0 : C, 84.25; H, 9.15. Found: C, 84.00; H, 9.13. Data for Alkene 75 75 mp: 55-56.5 °C (EtOAc / Pet. Ether) * H N M R (CD 2C1 2, 300 MHz): 5 0.90 (s, 3H), 1.18-1.43 (m, 4H), 1.52-2.04 (m, 5H), 2.48 (m, IH), 2.70 (m, IH), 4.97 (br, IH), 5.73 (m, IH), 6.00 (m, IH), 7.20-7.40 (m, 5H). 1 3 C N M R (CD 2C1 2, 75 MHz): 8 15.77 (-ve), 16.57, 24.75, 29.52, 32.32, 33.22 (-ve), 35.48 (-ve), 40.04, 75.92 (-ve), 127.23 (-ve), 127.77 (-ve), 128.12 (-ve), 128.97 (-ve), 129.16 (-ve), 143.07. I R (KBr): 3431, 3057, 3015, 2940, 2918, 2864, 1492, 1472, 1453, 1015, 899, 763, 712, 608 cm - 1. H R M S (EI) Calcd for C i 7 H 2 2 0 (M +) 242.1671, Found 242.1672. 212 Chapter 6 Experimental Ana l . Calcd for C i 7 H 2 2 0 : C, 84.25; H , 9.15. Found: C, 84.05; H , 9.15. This structure was confirmed by X-ray crystallographic analysis: Habit colorless prism Space group P21/c a, A 10.4760(10) b, A 19.2596(18) c, A 13.6411(13) a ( ° ) 90 P(°) 93.4868(31) Y(°) 90 Z 8 R 0.0676 Preparative Photolysis of Ketone 72 72 76 " A solution of ketone 72 (501 mg, 1.67 mmol) in acetonitrile (50 mL) was purged with nitrogen for 30 min and irradiated (Pyrex filter, 450 W Hanovia) for 6 h. Removal of the solvent in vacuo followed by silica gel chromatography (11% EtOAc in petroleum ether) afforded cyclobutanol 76 (446 mg, 89%) and alkene 77 (27 mg, 5%). 213 Chapter 6 Experimental Data for Cyclobutanol 76 76 mp: 149-150 °C (EtOAc / Pet. Ether) 'H NMR (C 6 D 6 , 400 MHz): 5 0.85 (m, IH), 0.98 (m, 1H), 1.20 (s, 3H), 1.21-1.35 (m, 3H), 1.45-1.65 (m, 5H), 1.83(m, 2H), 2.52 (m, IH), 2.66 (m, IH), 3.53 (s, 3H), 7.09 (d, J= 8.2 Hz, 2H), 8.11 (d, 7= 8.2 Hz, 2H). 1 3 C NMR(C 6 D 6 , 100 MHz): 5 17.70 (-ve), 18.61, 20.46, 22.87, 24.61, 27.73, 36.19 (-ve), 37.62 (-ve), 46.42, 46.79 (-ve), 51.61 (-ve), 81.87, 125.73 (-ve), 129.45, 130.32 (-ve), 149.34, 166.64. IR (KBr): 3482, 2958, 2927, 2879, 1723, 1609, 1439, 1279, 1106, 1007, 861, 781, 712 cm"1. HRMS (EI) Calcd for Q9H24O3 300.1725, Found 300.1726. A n a l . Calcd for Q 9 H 2 4 O 3 : C, 75.97; H , 8.05. Found: C, 75.96; H , 8.28. 214 Chapter 6 Experimental This structure was confirmed by X-ray crystallographic analysis: Habit colorless prism Space group PI a, A 6.2815(4) b,k 7.2477(6) c k 18.7210(17) a(°) 79.329(9) P(°) 82.478(10) y(°) 69.225(8) z 2 R 0.0362 Data for Alkene 77 77 mp: 148-150 °C (CHC1 3 / Hexanes) ' H N M R (C 6 D 6 , 400 MHz): 8 0.85 (s, 3H), 1.03-1.12 (m, 2H), 1.20-1.30 (m, 3H), 1.48-1.80 (m, 4H), 2.35 (br, IH), 2.53(br, IH), 3.53 (s, 3H), 4.30 (s, IH), 5.62 (m, IH), 5.83 (m, IH), 7.29 (d, J = 8.3 Hz, 2H), 8.13 (d, J= 8.3 Hz, 2H). 215 Chapter 6 Experimental 1 3 C NMR (C 6 D 6 , 75 M H z ) : 5 15.71 (-ve), 16.52, 24.57, 29.36, 32.11, 32.90 (-ve), 36.16 (-ve), 40.09, 51.57 (-ve), 75.22 (-ve), 128.05 (-ve), 128.55 (-ve), 129.04 (-ve), 129.19 (-ve), 129.35, 148.50, 166.82. IR(KBr): 3524, 3017, 2950, 2921,2862, 1723, 1706, 1610, 1436, 1281, 1111, 1016, 860, 772, 724, 705,612 c m - 1 . HRMS (CI) Calcd for C 1 9 H 2 8 N O 3 (M + NH4+)318.2069, Found 318.2069. Anal . Calcd for C 1 9 H 2 4 O 3 : C, 75.97; H , 8.05. Found: C, 75.89; H , 8.36. This structure was confirmed by X-ray crystallographic analysis: Habit colorless prism Space group P21/n a, A 15.1864(11) b, A 6.8150(5) c, A 14.9981(10) cc(°) 90 P(°) 90.383(4) Y(°) 90 Z 4 R 0.0377 216 Chapter 6 Experimental 6.3 Photolysis of Spirobicyclo[3.3.1]nonyl Ketones 49-52 Photolysis of Spiroketone 49 106 107 108 109 A solution of ketone 49 (51 mg, 0.21 mmol) in 2:1 f-BuOH/C 6 H 6 (20 mL) containing anhydrous barium oxide (14 mg) was irradiated (Pyrex filter, 450 W Hanovia lamp) for 2 h at room temperature. Analysis of the reaction mixture by GG-MS indicated that the reaction had proceeded to 59% conversion, producing primary photoproduct 106 along with small amounts of secondary photoproducts: 1-indanone (107), and 1,4- and 1,5-cyclooctadiene (108 and 109). Removal of solvent followed by silica gel chromatography (5% E t 2 0 in petroleum ether) afforded starting material 49 (19 mg, 37%) and ketone epimers (-1:1 by ! H NMR) 106 (18 mg, 35%; 56% based on recovered starting material) as a colorless oil. Also isolated was 1-indanone 107 (3 mg, 11%, 17% based on recovered starting material) resulting from secondary photocleavage of ketone 106. Due to their volatility under the reaction conditions, 1,4- and 1,5-cyclooctadiene (108 and 109) were not isolated and their presence was confirmed by matching their mass 217 Chapter 6 Experimental spectral fragmentation patterns and GC retention times with those of authentic samples. Data for Ketone 106 (equal mixture of 2 epimers) *H NMR (CDCI3, 300 MHz): 5 0.98-1.67 (m, 6H), 1.97-2.43 (m, 5H), 2.63 (dm, IH), 2.87 (m, IH), 3.16 (m, IH), 5.64 (m, 2H), 7.33 (m, IH), 7.43 (m, IH), 7.55 (m, IH), 7.72 (m, IH). 1 3 C NMR (CDCI3, 75 MHz): 5 24.75, 24.86, 25.68, 25.71, 27.93, 28.16, 28.88, 28.94, 29.67, 30.38, 31.30, 34.62, 37.57 (-ve), 38.63 (-ve), 54.30 (-ve), 54.51 (-ve), 123.56 (-ve), 123.69 (-ve), 126.42 (-ve), 126.47 (-ve), 127.18 (-ve, 2 accidentally equivalent), 129.66 (-ve), 130.01 (-ve), 130.12 (-ve), 130.57 (-ve), 134.48 (-ve, 2 accidentally equivalent), 137.89, 138.04, 154.27, 154.67, 208.70, 208.88. IR(neat): 3013, 2923, 2853, 1709, 1610, 1464, 1327, 1282, 1204, 1183, 1098, 992, 882, 793, 750, 732, 640, 612 cm"1. HRMS (EI) Calcd for C i 7 H 2 0 O 240.1514, Found 240.1516. Anal . Calcd for C i 7 H 2 0 O : C, 84.96; H , 8.39. Found: C, 85.06; H , 8.61. 106 colorless oil. 218 Chapter 6 Experimental Data for 1- Indanone 107 O 107 m p : 37.5-38.5 °C (lit.1 40 °C) *H NMR (400 MHz, CDCI3): 6 2.68 (m, 2H), 3.12 (m, 2H), 7.35 (m, IH), 7.49 (m, IH), 7.57 (m, IH), 7.75 (m, IH). 1 3 C NMR (75 MHz, CDCI3): 5 25.82, 36.21, 123.74, 126,74, 127.30, 134.69, 137.13, 155.14, 207.06. LRMS (EI): 104 (94), 132 (100, M+). Ketone 106 was also found to be the major product (67%, at 6% conversion) resulting from irradiation of crystals of spiroketone 49; 1-indanone, 1,4-cyclooctadiene, and 1,5-cyclooctadiene were also observed by GC-MS, presumably through the competitive enol-keto tautomerization and secondary photolysis seen in solution. Photolysis of Spiroketone 50 Irradiation (24 h) of a 2:1 tert-butyl alcohol/benzene or acetonitrile solution of spiroketone 50 resulted only trace amounts (< 1%) of unidentified short retention time peaks on GC. Photolysis of spiroketone 50 in the solid state (48 h) also led to no detectable photoproducts. 219 Chapter 6 Experimental Photolysis of Spiroketone 51 2:1 tert-butyl alcohol / benzene hv (Pyrex) 51 1 1 2 1 1 3 A solution of ketone 51 (70 mg, 0.26 mmol) in 2:1 tert-butyl alcohol/benzene (50 mL) was purged with nitrogen for 30 min and irradiated (Pyrex filter, 450 W Hanovia) for 56 h. Removal of the solvent in vacuo followed by silica gel chromatography (6% Et20 in petroleum ether) afforded starting material 51 (14 mg, 20%) and cyclobutanol 112 (37 mg, 53%; 66% based on recovered starting material) as a colorless oil. Also isolated was a mixture of 2 components (2 mg, 3%). Careful examination of the ' H N M R spectrum of this mixture revealed that one component was cyclobutanol 112 and another component was an alkene (113) bearing characteristic vinyl proton signals similar to those of alkenes 75 and 77. Further attempts to purify alkene 113 were not successful owing to its small quantity and similar polarity to cyclobutanol 112. Data for Cyclobutanol 112 1 1 2 220 Chapter 6 Experimental colorless oil. ' H N M R (C 6 D 6 , 400 MHz): 8 0.93 (m, IH), 1.02 (br, IH), 1.15 (m, IH), 1.30-1.79 (m, 9H), 1.91 (m, IH), 2.04 (m, 2H), 2.20 (m, IH), 2.44 (m, IH), 2.59 (m, IH), 2.79 (m, IH), 3.25 (m, IH), 7.01 (m, 3H), 7.19 (m, IH). 1 3 C N M R (C 6 D 6 , 100 MHz): 5 18.93, 20.98, 22.37, 23.46, 25.72, 27.69, 30.01, 31.90 (-ve), 36.77, 37.91 (-ve), 48.21, 48.70 (-ve), 83.01, 125.39 (-ve), 125.88 (-ve), 127.16 (-ve), 131.57 (-ve), 142.27, 143.21. IR (neat): 3459, 2927, 2874, 1480, 1454, 1006, 968, 900, 757, 740, 644 cm-1. H R M S (EI) Calcd for C9H24O 268.1827, Found 268.1829. Anal . Calcd for C i 9 H 2 4 0 : C, 85.03; H, 9.01. Found: C, 85.08; H , 9.38. endo-Arylcyclobutanol 112 and alkene 113 were also found to be the only two products (96% and 4% respectively, at 18% conversion) resulting from irradiation of crystals of spiroketone 51 (GC analysis). Photolysis of Spiroketone 52 52 114 115 A solution of ketone 52 (179 mg, 0.63 mmol) in 2:1 tert-butyl alcohol/benzene 221 Chapter 6 Experimental (50 mL) was irradiated (Pyrex filter, 450 W Hanovia) for 156 h. Removal of the solvent in vacuo followed by silica gel chromatography (8% Et20 in petroleum ether) afforded starting material 52 (47 mg, 26%) and an oily mixture of compounds 114 and 115 (92 mg, 51%; 69% based on recovered starting material). Attempts to separate 114 and 115 failed due to the similar polarity of these two compounds. N M R analysis revealed that this mixture consisted of one secondary alcohol and one tertiary alcohol. The oxidizing reagent TPAP (tetrapropylammonium perruthenate) / N M O (4-methylmorpholine N -oxide) was used to oxidize the secondary alcohol component to the corresponding ketone 158, which showed a significant difference in polarity to the tertiary alcohol component. Silica gel chromatography (8% Et20 in petroleum ether) provided cyclobutanol 114 (73 mg, 41%; 55% based on recovered starting material) and ketone 158 (17mg, 9%; 13% based on recovered starting material). Oily compound 114 solidified upon standing while compound 158 remained as an oil. The structure of photoproduct 115 was deduced based on the spectral data of its derivative ketone 158. Data for Cyclobutanol 114 114 mp: 62-64 °C (Hexanes) 222 Chapter 6 Experimental * H N M R (C 6 D 6 , 400 MHz): 5 0.99 (m, IH), 1.04 (br, 1 H), 1.21 (m, IH), 1.30-1.50 (m, 4H), 1.51-1.70 (m, 5H), 1.75-1.90 (m, 3H), 2.00 (m, IH), 2.36 (m, 2H), 2.51 (IH, m), 2.61 (m, IH), 2.70 (m, IH), 2.90 (m, IH), 6.98 (m, IH), 7.04 (m, 2H), 7.13 (m, IH). 1 3 C N M R (C 6 D 6 , 100 MHz): 8 18.79, 20.75, 22.87, 25.37, 25.69, 27.15, 27.24, 27.80, 32.76 (-ve), 34.63, 36.57 (-ve), 48.25 (-ve), 49.82, 82.17, 126.17 (-ve), 127.25 (-ve), 127.26 (-ve), 131.82 (-ve), 141.92, 143.48. I R (KBr): 3471, 2928, 2870, 1479, 1455, 1320, 1083, 1013, 983, 964, 771, 740, 642 cm"1. H R M S (EI) Calcd for C 2 o H 2 6 0 282.1984, Found 282.1985. Anal . Calcd for C 2 0 H 2 6 O : C, 85.06; H , 9.28. Found: C, 85.03; H , 9.63. This structure was confirmed by X-ray crystallographic analysis: Habit colorless prism Space group P2i/c 8.915(3) 15.248(8) 23.181(5) cx(°) 90 P C ) 97.51(2) Y(°) 90 Z 8 R 0.0503 223 Chapter 6 Experimental Data for Ketone 158 158 colorless oil. J H N M R (C 6 D 6 , 400 MHz): 8 1.02-1.80 (m, 13H), 2.32 (br, 2H), 2.46 (br, IH), 2.81 (m, IH), 3.14 (m, 1H), 5.60 (m, IH), 5.86 (m, IH), 6.90-6.99 (m, 2H), 7.05 (m, IH), 7.35 (m, IH). 1 3 C N M R (C 6 D 6 , 100 MHz): 8 16.97, 19.27, 23.32, 29.37, 30.55, 30.82, 31.32 (-ve), 32.56, 34.56 (-ve), 54.42, 125.00 (-ve), 125.80 (-ve), 128.42 (-ve), 129.88 (-ve), 130.41 (-ve), 132.08 (-ve), 137.82, 142.89, 212.72. IR (KBr): 3015, 2914, 2865, 1683, 1446, 1236, 1208, 972, 920, 756, 710, 668, 632 c m 4 . H R M S (EI) Calcd for C20H24O 280.1827, Found 280.1831. Anal . Calcd for C20H24O: C, 85.67; H , 8.63. Found: C, 85.67; H , 8.65. endo-Arylcyclobutanol 114 and alkene 115 were also found to be the only two products (81% and 19% respectively, at 9% conversion) resulting from irradiation of crystals of spiroketone 52. 224 Chapter 6 Experimental 6.4 Photolysis of c/s-Bicyclo[4.3.0]non-8-yIacetophenone 141 Preparative Photolysis of c/^-Bicvclo[4.3.Qlnon-8-vlacetophenone 141 141 53 148 A solution of 1.01 g (3.36 mmol) of keto-ester 141 in 50 mL of acetonitrile was photolyzed through Pyrex for 3h. GC analysis indicated the complete consumption of starting material and the presence of two products (53 and 148) in a 58:36 ratio. The reaction mixture was extracted with pentane. The pentane layer was concentrated under reduced pressure at 0°C followed by bulb-to-bulb distillation to give alkene 53 (283 mg, 69%) as a clear oil. The acetonitrile layer was concentrated in vacuo and subjected to flash column chromatography (2% EtOAc in petroleum ether) to afford ketone 148 (424 mg, 71%) as a white solid. Compounds 53 and 148 are known compounds and their spectral data are in total agreement with literature values. 3 ' 4 Data for cis-(3aajaa)- 3a,4.5.6.7Ja-Hexahydro-li/-indene (53) H 53 colorless oil. ! H N M R (CDC1 3, 300 MHz): 5 1.22-1.65 (m, 8H), 1.98 (m, IH), 2.10-2.28 (m, 2H), 2.50 (m, IH), 5.67 (m, 2H) ppm. 225 Chapter 6 Experimental. , 3 C NMR (CDCI3, 75 MHz): 5 23.12, 23.21, 27.89, 28.50, 37.57, 43.69 (br), 130.02, . 136.66 ppm. IR (neat): 3055, 2928, 2853, 1656, 1446, 1355, 982, 852 cm"1. HRMS (EI) Calcd for C 9 H 1 4 122.1096, Found 122.1093. Data for Methyl 4-Acetylbenzoate (148) White solid. mp: 95-96 °C (lit.4 mp: 95.0-95.5 °C); *H NMR (CDCI3, 300 MHz) 8 8.11-8.08 (d, J= 8.7 Hz, 2H), 7.99-7.96 (d, / = 8.7 Hz, 2H), 3.92 (s, 3H), 2.61 (s, 3H) ppm. 1 3 C NMR(CDC1 3 , 75 MHz) 5 197.48, 166.17, 140.20, 133.86, 129.78, 128.17, 52.40, 26.82 ppm. IR (KBr): 2960, 1722, 1679, 1284, 1113, 770 cm"1. HRMS (EI) Calcd for Ci 0Hi 0O 3 ,178.0629, Found 178.0628. 148 226 Chapter 6 Experimental Preparation of (laaJb«,5aa,6a6yVOctahvdro-la/^-indeno[l,2-61oxirene (151). To a solution of alkene 53 (589 mg, 4.82 mmol) in CH 2 C1 2 (5 mL) was added a solution of 7 0 % m-chloroperoxybenzoic acid (1.78 g, 7.23 mmol) in CH 2 C1 2 (10 mL). The resulting mixture was heated under reflux with stirring for 1 h. Upon cooling, n-pentane was added to form a suspension. The supernatant liquid from the resulting suspension was passed through a short silica gel column. The eluent was concentrated and subjected to a second silica gel chromatography ( 2 % E t 2 0 in n-pentane). Removal of solvent (50 °C oil bath) followed by bulb-to-bulb distillation afforded epoxide 151 (473 mg, 71%) as a colorless oil. Data for (laaJba,5aQr,6aQr)-Octahydro-la//-indeno[L2-Z?loxirene (151) H *H NMR (CDC1 3, 400 MHz): 6 0.52 (m, IH), 0.83-0.96 (m, 2H), 1.16 (m, IH), 1.22-1.45 (m, 5H), 1.62 (dd, J= 7.5 Hz and 13.5 Hz, IH), 1.84 (m, IH), 1.95 (m, IH), 2.97 (m, IH), 3.08 (m, IH) ppm. 227 Chapter 6 Experimental 1 3 C N M R (CDCI3, 75 MHz): 5 21.93, 24.82, 25.09, 25.30, 29.09, 29.87, 37.82, 54.58, 59.96 ppm. IR (neat): 2929, 2853, 1452, 1397, 1265, 1219 cm"1. H R M S (EI) Calcd for C 9 H 1 4 0 138.1045, Found 138.1047. 228 Chapter 6 Experimental References 1 Parham, W. E . ; Jones, L. D.; Sayed, Y . J. Org. Chem. 1975, 40, 2394. 2 Ley, S. V . ; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 7, 639. 3 Stierman, T. J.; Johnson, R. P. J. Am. Chem. Soc. 1985,107, 3971. 4 Smissman, E . E . ; L i , J. P.; Israili, Z. H . J. Org. Chem. 1968, 33, 4231. 229 

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