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Asymmetric induction in the photochemistry of α-oxoamides and bicycle aryl ketones Wang, Keyan 2004

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ASYMMETRIC INDUCTION IN THE PHOTOCHEMISTRY OF a-OXOAMIDES AND BICYCLIC ARYL KETONES by KEYAN WANG B.Sc , Hangzhou University, P.R.China, 1989 M.Sc., Tsinghua University, P.R.China, 1995 A THESIS SUBMITTED IN PARTIAL F U L F I L M E N T OF THE REQUIREMENTS FOR THE D E G R E E OF DOCTOR OF PHILOSOPHY in THE F A C U L T Y OF G R A D U A T E STUDIES (DEPARTMENT OF CHEMISTRY) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH C O L U M B I A May 2004 ©Keyan Wang, 2004 Abstract Enantioselective photochemical synthesis of a P-lactam (methyl 4-[3-hydroxy-2,2-dimethyl-l-(l-methylethyl)-4-oxo-3-azetidinyl]benzoate) was investigated via the ionic chiral auxiliary method. Solid state photolysis of the chiral salts formed from optically pure amines and the achiral a-oxoamide reactant containing a carboxylic acid functional group gave variable results, but through the use of a number of auxiliaries it was possible to achieve a high degree of enantioselectivity in the P-lactam (up to 99 % ee at 99 % conversion of the starting a-oxoamide). Suspension of the prolinamide salt in hexane allowed the photoreaction to be carried out on a 500 mg scale, thus demonstrating the synthetic utility of the solid state ionic chiral auxiliary approach to asymmetric synthesis. The covalent chiral auxiliary method was also investigated for asymmetric synthesis of the P-lactam. Solid state photolysis of a chiral ester formed from an optically pure alcohol and the achiral a-oxoamide gave up to 95% de at 100 % conversion. Suspension of the chiral ester in water allowed the photoreaction to be carried out on a 200 mg scale. X-ray crystallographic data from a number of a-oxoamides provided insight on the origin of the observed enantioselectivity/diastereoselectivity. The prediction of the absolute configuration of the P-lactam based on the topochemical control principle was validated by crystal structure-reactivity correlations. Asymmetric induction in the Norrish/Yang photochemistry of a series of three bicyclic aryl ketones, bicyclo[2.2.2]octyl ketones, bicyclo[2.2.1]heptyl ketones and dimethylated bicyclo[2.2.1]heptyl ketones, was also studied by using the ionic chiral auxiliary method. Photolysis of the chiral salts in the crystalline state gave high ee's for bicyclo[2.2.2]octyl ketones, high de's for bicyclo[2.2.1]heptyl ketones, and both high ee's and de's for dimethylated bicyclo[2.2.1]heptyl ketones. ii Through the use of X-ray crystallography, the solid state reactivities were rationalized based on topochemical expectations with the aid of strain energy calculations on the photoproducts. Non-topochemical reactions were also found in this study. Molecular mechanics calculations were conducted to predict the solid state conformations of the substrates prior to the laboratory work. The calculations were successful in the prediction of enantioselectivity for the three bicyclic aryl ketones investigated. In this way, molecular mechanics serves as a basis for crystal engineering in asymmetric synthesis. i i i Table of Contents Abstract i i Table of Contents iv List of Figures vii i List of Tables xiii List of Symbols and Abbreviations xv Acknowledgements xviii Dedications x r x INTRODUCTION 1 Chapter 1 Introduction 2 1.1 Preamble 2 1.2 Crystal Engineering 4 1.3 Solid State Chemistry and the Topochemical Postulate 6 1.4 Type II Photochemistry of Ketones 11 1.4.1 General Aspects of Type II Photochemistry 11 1.4.2 Hydrogen Abstraction Geometric Parameters 14 1.4.3 Geometric Requirements for Cleavage and Cyclization 16 1.5 Asymmetric Induction 18 1.5.1 Asymmetric Induction in Solid State Chemistry and Photochemistry 18 1.5.2 The Ionic Chiral Auxiliary Method 20 1.6 Photochemistry of cc-Oxoamides 23 1.7 Research Objectives 27 RESULTS A N D DISCUSSION 30 Chapter 2 Asymmetric Synthesis of P-Lactam Derivatives 31 2.1 Preparation of Substrates 31 2.1.1 Preparation of cc-Oxoamides 38, 66 and 68 31 2.1.2 Preparation of Chiral Salts 67a-l 32 2.2 Photochemical Studies of Ester 38 > 33 2.3 Asymmetric Induction by the Ionic Chiral Auxiliary Method 35 2.3.1 Determination of the Enantioselectivity 35 2.3.2 Asymmetric Induction Results 36 2.4 Asymmetric Induction by the Covalent Chiral Auxiliary Method 42 2.5 Structure-Reactivity Correlations 46 2.5.1 Crystallographic Studies and Molecular Modeling 46 2.5.2 Enantioselectivity/Diastereoselectivity in the Photolysis of a-Oxoamides 50 2.5.3 Conformational Enantiomerism and Absolute Configuration 52 2.6 Summary 56 Chapter 3 Asymmetric Synthesis in the Photocyclization of Bicyclic Aryl Ketones 58 3.1 General Considerations 58 3.2 Substrate Preparation 61 3.2.1 Synthesis of Bicyclo[2.2.2]octyl Ketones 85, 54-56 61 3.2.2 Synthesis of Bicyclo[2.2.1]heptyl Ketones 57-59 63 3.2.3 Synthesis of Dimethylated Bicyclo[2.2.1]heptyl Ketones 60-62 65 3.3 Photochemical Studies and Identification of Photoproducts 69 3.3.1 Photochemical Studies of Ketones 85, 54-55 69 3.3.2 Identification of Photoproducts 111, 112,115 and 116 71 3.3.3 Photochemical Studies of Ketones 57 and 58 76 3.3.4 Identification of Photoproducts 119 and 120 77 3.3.5 Photochemical Studies of Ketones 60 and 61 .....82 3.3.6 Identification of Photoproducts 124 and 125 84 3.4 Asymmetric Induction Studies 93 3.4.1 Asymmetric Induction in the Solid State Photolysis of Bicyclo[2.2.2]octyl Ketones 93 3.4.1.1 Determination of the Enantioselectivity 93 3.4.1.2 Asymmetric Induction Results 95 3.4.2 Asymmetric Induction in the Solid State Photolysis of Bicyclo[2.2.1]heptyl Ketones 97 3.4.2.1 Determination of the Enantioselectivity 97 3.4.2.2 Asymmetric Induction Results 99 3.4.3 Asymmetric Induction in the Solid State Photolysis of Dimethylated Bicyclo[2.2.1]heptyl Ketones 101 3.4.3.1 Determination of the Enantioselectivity 101 3.4.3.2 Asymmetric Induction Results 103 3.5 Molecular Mechanics Calculations and X-ray Crystallographic Studies 105 3.5.1 Bicyclo[2.2.2]octyl Substrates .....105 3.5.2 Bicyclo[2.2.1]heptyl Substrates 109 3.5.3 Dimethylated Bicyclo[2.2.1]heptyl Substrates 112 3.5.4 Molecular Mechanics Calculations on Yang photocyclization Products 116 3.6 Structure-reactivity Studies 119 3.6.1 Topochemical Control Reactions 119 3.6.1.1 Structure-reactivity Analysis of Bicyclo[2.2.2]octyl Substrates 119 3.6.1.2 Structure-reactivity Analysis of Bicyclo[2.2.1]heptyl Substrate 59d 124 3.6.1.3 Structure-reactivity Analysis of Dimethylated Bicyclo[2.2.1]heptyl Substrate 62a 127 3.6.2 Non-topochemical Control Reactions 130 3.7 Summary 135 E X P E R I M E N T A L 140 Chapter 4 Synthesis of Starting Materials 141 4.1 General Considerations 141 4.2 Synthesis of a-Oxoamides 38, 66, 67 and 68 146 4.2.1 Preparation of a-Oxoamides 38 and 66 146 4.2.2 Preparation of a-Oxoamide Salts 67 151 4.2.3 Preparation of a-Oxoamide 68 166 4.3 Synthesis of Bicyclo[2.2.2]octane Derivatives 85, 54, 55 and 56 169 vi 4.3.1 Preparation of Ketones 85, 54 and 55 169 4.3.2 Preparation of Bicyclo[2.2.2]octyl Salts 56 177 4.4 Synthesis of Bicyclo[2.2.1]heptane Derivatives 57, 58 and 59 194 4.4.1 Preparation of Ketones 57 and 58 194 4.4.2 Preparation of Bicyclo[2.2.1 jheptyl Salts 59 202 4.5 Synthesis of Dimethylated Bicyclo[2.2.1]heptane Derivatives 60, 61 and 62 218 4.5.1 Preparation of Ketones 60 and 61 218 4.5.2 Preparation of Dimethylated Bicyclo[2.2.1]heptyl Salts 62 234 Chapter 5 Photochemical Studies 245 5.1 General Considerations 245 5.2 Photochemical Studies of a-Oxoamides 246 5.2.1 Preparative Photolysis of a-Oxoamide 38 246 5.2.2 Preparative Photolysis of Salt 67a 249 5.2.3 Preparative Photolysis of a-Oxoamide 68 250 5.3 Photolysis of Bicyclo[2.2.2]octane Derivatives 85 and 55 253 5.3.1 Preparative Photolysis of Bicyclo[2.2.2]octyl Ketone 85 253 5.3.2 Preparative Photolysis of Bicyclo[2.2.2]octyl Ketone 55 255 5.4 Photolysis of Bicyclo[2.2.1]heptane Derivatives 58 and 61 258 5.4.1 Preparative Photolysis of Bicyclo[2.2.1]heptyl Ketone 58 258 5.4.2 Preparative Photolysis of Dimethylated Bicyclo[2.2.1]heptyl Ketone 61 260 References 264 vii List of Figures Figure 1.1 Pictorial representation of asymmetric synthesis in solid state photochemistry: (a) photochemistry (blue), a builder of highly strained molecules; (b) solid state chemistry (green), a highly selective chemical transformation; (c) asymmetric synthesis (red), a major source of enantiomerically pure molecules 3 Figure 1.2 A solid state bimolecular reaction of a mixed crystal 5 Figure 1.3 /ra«s-Cinnamic acid photochemistry in solution and three polymorphic crystal forms 7 Figure 1.4 Pictorial representation of Cohen's "reaction cavity" concept: (a) starting material (dashed line) fits within the reaction cavity (solid line); (b) allowed solid state reaction where the product (dashed line) fits within the cavity; (c) disallowed reaction where the product (dashed line) does not fit within the cavity 9 Figure 1.5 Representation of a single crystal to single crystal photoreaction of a norbornane derivative 10 Figure 1.6 The Norrish type I reaction 11 Figure 1.7 Type II photochemistry of ketones 12 Figure 1.8 Yang photocyclization as a key step in the synthesis of Punctatin A 13 Figure 1.9 A [2 + 2] cycloaddition followed by a type II photocyclization 13 Figure 1.10 The synthesis of Coumestrol 14 Figure 1.11 Geometric parameters for hydrogen abstraction 15 Figure 1.12 Previous studies of y-hydrogen abstraction parameters in Yang photocyclization 16 Figure 1.13 Cleavage parameters cpi and 9 4 17 Figure 1.14 Cyclization parameters D and (3 17 Figure 1.15 Examples of asymmetric synthesis via Yang photocyclization in solution: (a) Griesbeck's intramolecular hydrogen bonding strategy; (b) Bach's intermolecular hydrogen bonding strategy 19 viii F i g u r e 1.16 A n example of the solid state ionic chiral auxiliary method for photochemical asymmetric synthesis; 21 F i g u r e 1.17 Schematic representation of the ionic chiral auxiliary approach to asymmetric induction in the solid state 22 F i g u r e 1.18 Comparison of the ionic chiral auxiliary approach to asymmetric induction and the Pasteur resolution method 23 F i g u r e 1.19 Proposed mechanism for the formation of azetidinone and oxazolidinone. (a) Whitten's single electron transfer (SET) mechanism. (b) Aoyama's biradical mechanism.(c) 24 F i g u r e 1.20 a-Oxoamides studied by Toda and others 25 F i g u r e 1.21 Absolute asymmetric synthesis of P-lactams 26 F i g u r e 1.22 Toda's host-guest approach to make enantiomerically enriched P-lactams 27 F i g u r e 1.23 Bicyclic aryl ketones selected for photochemical studies 28 F i g u r e 2.1 Synthesis of a-oxoamides 38, 66, 68 31 F i g u r e 2.2 The photoreaction of a-oxoamide 38 33 F i g u r e 2.3 HPLC trace for the resolution of racemic 39 on Chiralcel® OD® column (eluting solvents, hexanes/isopropanol 99/1; flow rate, 1.0 mL/min) 35 F i g u r e 2.4 HPLC trace for the resolution of racemic 40 on Chiralpak® AD® column (eluting solvents, hexanes/ethanol 93/7; flow rate, 1.0 mL/min) 35 F i g u r e 2.5 Photochemistry of a-oxoamide 68 42 F i g u r e 2.6 HPLC trace for the resolution of photoproduct 69 on Chiralcel OD (eluting solvents, hexanes/isopropanol 99/1; flow rate, 1.0 mL/min) 44 F i g u r e 2.7 HPLC trace for the unsuccessful resolution of photoproduct 70 on Chiralcel OD (eluting solvents, hexanes/ethanol 99/1; flow rate, 0.5 mL/min) 44 F i g u r e 2.8 Photochemistry of a-oxoamide 38 47 F i g u r e 2.9 Photocleavage from zwitterionic intermediate 47 F i g u r e 2.10 Molecular conformation in crystals of salt 67a 51 ix Figure 2.11 The reaction course of salt 67a in the crystalline state. In the ORTEP representation of salt 67a, carbonyl oxygen is colored red, y hydrogens H a and H a ' green 51 Figure 2.12 Conformational enantiomerism in crystals of salt 67f. 53 Figure 2.13 Inverting the pro-R conformer and overlapping it with the pro-S conformer in the crystal of salt 67f 53 Figure 2.14 The reaction course of ester 68 in crystalline state. In the ORTEP representation of ester 68, carbonyl oxygen is colored red, y hydrogens H a and H a ' green 55 Figure 2.15 The reaction course of salt 67c in crystalline state. In the ORTEP representation of salt 67c, carbonyl oxygen is colored red, y hydrogens H a and H a ' green 55 Figure 3.1 Previous studies in a-adamantyl acetophenones 58 Figure 3.2 a-Bicycloalkylacetophenone compounds selected for study 59 Figure 3.3 Synthesis of bicyclo[2.2.2]octyl ketones 85, 54-55 61 Figure 3.4 Synthesis of bicyclo[2.2.1]heptyl ketones 57-58 63 Figure 3.5 A three-component reaction in an unsuccessful synthesis of compound 91 64 Figure 3.6 Proposed synthesis of ketone 61 65 Figure 3.7 A n unsuccessful attempt for the methylation of ketone 58 66 Figure 3.8 Synthesis of monomethylated bicyclo[2.2.1]heptyl ketone 97 66 Figure 3.9 Synthesis of ketones 60 and 61 67 Figure 3.10 Photolysis of ketones 85, 54-55 in solution and the solid state 69 Figure 3.11 NOE spectrum for cyclobutanol 112 with irradiation at 2.41ppm (H4) 73 Figure 3.12 NOE spectrum for cyclobutanol 111 with irradiation at 2.58ppm (H4) 75 Figure 3.13 ORTEP representation of photoproduct 111. In the hydroxyl group, the oxygen atom is colored red, the hydrogen atom green 75 Figure 3.14 Photolysis of ketones 57 and 58 in solution and the solid state 76 Figure 3.15 Partial N O E S Y spectrum for cyclobutanol 119 79 Figure 3.16 Partial N O E S Y spectrum for cyclobutanol 120 82 Figure 3.17 Photolysis of ketones 60 and 61 in solution and solid state 82 X Figure 3.18 Partial N O E S Y spectrum for cyclobutanol 124 86 Figure 3.19 ORTEP representation of photoproduct 125. In the hydroxyl group, the oxygen atom is colored red, the hydrogen atom green 89 Figure 3.20 Partial N O E S Y spectrum for cyclobutanol 125 90 Figure 3.21 NOE spectrum for cyclobutanol 126 with irradiation at 3.09 ppm (He) 92 Figure 3.22 H P L C traces for the resolution of racemic cyclobutanols 115 and 116 on a Chiralcel OD column (eluting solvents, hexanes/isopropanol 99/1; flow rate, 1.0 mL/min) 94 Figure 3.23 HPLC traces for the resolution of racemic cyclobutanols 119 and 120 on a Chiralpak A D column (eluting solvents, hexanes/IPA 98/2; flow rate, 0.60 mL/min) 98 Figure 3.24 HPLC traces for the resolution of racemic cyclobutanols 124 and 125 on a Chiralpak A D column (eluting solvents, hexanes/ethanol 98/2; flow rate, 1.0 mL/min) 102 Figure 3.25 Conformers obtained by M M + calculations and X-ray crystallographic studies for bicyclo[2.2.2]octyl ketones. (A) Conformer 55-1, the lowest energy (36.00 Kcal/mol) conformer of ester 55 (MM + ) ; (a) the conformer from the crystal structure of acid 54 107 Figure 3.25 (Continued) (B) conformer 55-2, the second lowest energy (36.26 Kcal/mol) conformer of ester 55 (MM + ) ; (b) the two conformers (b-1 and b-2) in the crystal structure of salt 56b; the conformation of crystal 56a (not shown in the Figure) is virtually same as b-1 in crystal 56b and the conformer 55-2 (MM + ) 108 Figure 3.26 Conformers obtained by M M + calculations and X-ray crystallographic studies for bicyclo[2.2.1]heptyl substrates, (ai) The conformer in the crystal of ester 58; (a2) the conformer (anion part) in the crystal of salt 59d; (A), (B), (C), (D) are calculated conformers of ester 58 with total energy 39.43, 39.49, 39.62, and 39.82 Kcal/mol, respectively. In the ORTEP representations ai and a2, the carbonyl oxygen is colored red, y-hydrogen H a green and H a - blue xi Figure 3.27 Conformers obtained by M M + calculations and X-ray crystallographic studies for dimethylated bicyclo[2.2.1]heptyl substrates, (a), (b), (ci), (c2) are the conformers in the crystals of compounds 62a (anion part), 61, 62c (anion part), 62e (anion part); (A), (B), (C), (D) are calculated conformers of ester 61 with energy 42.41, 43.20, 43.64, and 44.69 Kcal/mol respectively. In the ORTEP representations, the carbonyl oxygen is colored red, the y hydrogen H a green and H a ' blue 114 Figure 3.28 Conformational correlations between bicyclo[2.2.1]heptyl ketone 58 and dimethylated bicyclo[2.2.1]heptyl ketone 61 by M M + calculations 115 Figure 3.29 Possible Norrish type II photocyclization products 116 Figure 3.30 Proposed mechanism for the formation of ketone 126 118 Figure 3.31 The solid state reactivity of conformer 55-1 122 Figure 3.32 The rotations (a) and (b) (same as the rotations in pathways 2, 3, and 4 shown in Figure 3.31) 122 Figure 3.33 Free energy profile for rationalizing the diastereoselectivity in the photolysis of bicyclo[2.2.2]octyl ketones 123 Figure 3.34 The solid state reactivity of salt 59d 126 Figure 3.35 The solid state reactivity of salt 62a 129 Figure 3.36 The solid state reactivity of salt 62e 132 Figure 3.37 Proposed mechanism for salt 62e 133 Figure 3.38 The solid state reactivity of ester 61 134 Figure 3.39 The possible pathway for the solid state photolysis of ester 61 134 Figure 3.40 Large motions involved in a thermal crystalline state reaction 135 Figure 3.41 The lowest energy conformations (55-1, 58-1, 61-1) of esters 55, 58 and 61 identified by M M + calculation. The carbonyl oxygen is colored red, y-hydrogen H a (close to oxygen) green, y-hydrogen H a ' (enantiotopic with Ha) blue 137 Figure 3.42 Norrish type II reactions studied previously in the Scheffer group 138 Xll List of Tables Table 2.1 Preparation of chiral salts of acid 66 33 Table 2.2 Photolyses of cc-oxoamide 38 in solution and solid state 34 Table 2.3 Chromatographic data for enantiomeric excess determination of photoproducts 39 and 40 36 Table 2.4 Asymmetric induction in the photolysis of chiral salts 67a-e 38 Table 2.5 Asymmetric induction in the photolysis of chiral salts 67f-l 39 Table 2.6 Photochemistry of chiral salts 67a suspended in hexanes 40 Table 2.7 Solution phase photolyses of chiral salt 67a 41 Table 2.8 Determination of the enantiomeric excess (ee) of photoproduct 40 41 Table 2.9 Chromatographic data for enantiomeric excess determination of photoproducts 69 and 70 43 Table 2.10 Asymmetric induction in the photolyses of chiral ester 68 45 Table 2.11 Crystallographic studies and molecular modeling3 49 Table 2.12 Comparison of the predicted configuration and sign of rotation 56 Table 3.1 Preparation of chiral salts of acid 54 62 Table 3.2 Preparation of chiral salts of acid 57 65 Table 3.3 Preparation of chiral salts of acid 60 69 Table 3.4 Photolysis of ketones 85, 54, 55 in solution (CH 3 CN) 70 Table 3.5 Photolysis of ketones 85, 54, and 55 in the solid state 71 Table 3.6 Comprehensive N M R assignments for cyclobutanol 112 72 Table 3.7 Comprehensive N M R assignments for cyclobutanol 111 74 Table 3.8 Photolysis of ketones 57-58 in solution (CH 3 CN) 77 Table 3.9 Photolysis of ketones 57-58 in the solid state 77 Table 3.10 Comprehensive N M R assignments for cyclobutanol 119 78 Table 3.11 Comprehensive N M R assignments for cyclobutanol 120 81 Table 3.12 Photolysis of ketones 60-61 in solution (CH 3 CN) 83 Table 3.13 Photolysis of ketones 60-61 in the solid state 84 Table 3.14 Comprehensive N M R assignments for cyclobutanol 124 85 Table 3.15 Comprehensive N M R assignments for cyclobutanol 125 88 xiii Table 3.16 Comprehensive N M R assignments for ketone 126 91 Table 3.17 Chromatographic data for enantiomeric excess determination of cyclobutanols 115 and 116 95 Table 3.18 Asymmetric induction in the photolysis of chiral salts 56a-m 96 Table 3.19 Chromatographic data for enantiomeric excess determination of cyclobutanols 119 and 120 99 Table 3.20 Asymmetric induction in the photolysis of chiral salts 59a-m 100 Table 3.21 Chromatographic data for enantiomeric excess determination of cyclobutanols 125 and 124 103 Table 3.22 Asymmetric induction in the photolysis of chiral salts 62a-h 104 Table 3.23 Hydrogen abstraction and cyclization parameters for bicyclo[2.2.2]octyl substrates 106 Table 3.24 Hydrogen abstraction and cyclization parameters for bicyclo[2.2.1]heptyl substrates 110 Table 3.25 Hydrogen abstraction and cyclization parameters for dimethylated bicyclo[2.2.1]heptyl substrates 113 Table 3.26 Molecular mechanics studies on possible cyclobutanol photoproducts 118 Table 3.27 Comparison of the predicted configuration and sign of rotation 131 xiv List of Symbols and Abbreviations v m a x absorption maxima (IR spectroscopy) Xmax absorption maxima (UV spectroscopy) A angstrom A heat 8 chemical shift (ppm) °C degrees Celsius s molar extinction coefficients anal. analysis APT attached proton test Ar aryl aq. aqueous bp boiling point br broad calcd calculated cone. concentrated conv conversion COSY ' H - 1 ! ! correlation spectroscopy d doublet dd doublet of doublets de diastereomeric excess DCI desorption chemical ionization D M F dimethylformamide D M P U /VjA^'-dimethylpropyleneurea ee enantiomeric excess EI electron impact ESI Electrospray ionization GC gas chromatography h hour(s) hept heptet XV hv light 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 Hz hertz ID inner diameter IPA isopropanol IR infrared J coupling constant (Hz) L D A lithium diisopropylamine L R M S low resolution mass spectrometry LSIMS liquid secondary ionization mass spectra M molarity Me methyl M H z megahertz M O M methoxymethyl m multiplet mg milligram min minute mL milliter mp melting point mmol millimole mol mole N M R nuclear magnetic resonance NOE nuclear Overhauser enhancement NOESY two-dimensional nuclear Overhauser spectroscopy nm nanometer ORTEP Oak Ridge Thermal Ellipsoid Program Ph phenyl 'Pr isopropyl ppm parts per million psi pounds per square inch q quartet quint quintet RT room temperature s singlet S E M 2-(trimethylsilyl)ethoxymethyl t triplet temp temperature THF tetrahydrofuran TMS trimethylsilyl Tol tolyl U V / VIS ultraviolet / visible XVll Acknowledgements I would like to express my deepest gratitude to Professor John Scheffer for his valuable guidance, encouragement, and support on my research and study over the last five years. I appreciate his patience and understanding in helping me write this thesis. I am grateful to Dr Brian Patrick (UBC X-ray crystallography laboratory), Professor Menahem Kaftory and Dr. Mark Botoshansky (Department of Chemistry, Technion, Israel), Professor Dario Braga and Dr. Lucia Maini (Department of Chemistry, University of Bologna, Italy), and Shuang Chen for their help on X-ray crystal structure determinations. I would like to express my appreciation to the staff in the N M R laboratory, mass spectrometry facilities, and the Chemistry Department at the University of British Columbia. Finally, I would like to thank the current and past members of the Scheffer group for their help and encouragement. xviii Dedications To M y Parents, Molly and Aaron with Love xix INTRODUCTION 1 C h a p t e r 1 I n t r o d u c t i o n Chapter 1 Introduction 1.1 Preamble The history of solid state chemistry can be traced back to the beginning of the nineteenth century. Wohler's synthesis of urea in 1828,1 the milestone event in organic chemistry, was the first solid state reaction. Trommsdorff s 1834 discovery that sunlight caused santonin crystals to become yellow and shatter, was the first solid state organic photochemical reaction. However, in-depth research in both solid state chemistry and solid state organic photochemistry was hampered by a poor understanding of the crystal structures that are the essential governing factor in solid state reactions. Computers made crystallography accessible to everyone. The combination of X-ray crystallography and photochemistry has contributed greatly to our understanding of photoreaction mechanisms and enabled photochemistry to be used as a synthetic tool. The solid state chemistry of drugs4 and crystal engineering5 in material sciences played an important role in the development of solid state chemistry/photochemistry. Photochemical techniques have greatly simplified the synthesis of numerous highly strained organic molecules, which are inaccessible by ground state chemistry.6 One of the fundamental features of the living world is its chirality. Chirality centres are common in the building blocks of the living world: amino-acids, carbohydrates and nucleic acids. For the most part, physiological processes are homochiral, i.e., they show 100% stereoselectivity and involve only one stereoisomer. Differential interactions with chiral targets, such as receptors, enzymes and ion channels, lead to chiral discrimination in physiological processes. The debate about the relative merits of racemic drugs and single-enantiomer drugs was short lived. Since 1992, the U.S. Food and Drug Administration (FDA) and the European Committee for Proprietary Medicinal Products have required manufacturers to research and characterize each enantiomer of a potential drug.7 Single-enantiomer drugs are rapidly growing from ~20 % of new drugs ten years ago to almost 75 % in 2002. 8 ( a ) Drug molecules approved by the U.S. FDA in 1998-2001 show the following approximate distribution: 52 % achiral; 30 % single enantiomer with several chirality centres; 7 % single enantiomer with one chirality centre; 7 % racemates; and 4 % multiple diastereomers.8(a) Drugs are now marketed or being developed as single 2 Chapter 1 Introduction enantiomers in place of previous racemic mixtures, a popular process in the pharmaceutical industry known as "chiral switching".8 Asymmetric synthesis is the main source of chiral drugs. Ground state chemistry is dominant in the field of asymmetric synthesis. Asymmetric synthesis in organic photochemistry, a subject that has been seen considerable recent activity,9 is still undeveloped compared to asymmetric synthesis in the ground state. The combination of solid state chemistry and photochemistry has two advantages: higher selectivity in solid state reactions and construction of highly strained molecules through photochemistry. Utilization of these two advantages in asymmetric synthesis (Figure 1.1) is the major subject of the present thesis. Figure 1.1 Pictorial representation of asymmetric synthesis in solid state photochemistry: (a) photochemistry (blue), a builder of highly strained molecules; (b) solid state chemistry (green), a highly selective chemical transformation; (c) asymmetric synthesis (red), a major source of enantiomerically pure molecules. 3 Chapter 1 Introduction 1.2 Crystal Engineering The term "crystal engineering" was coined by Schmidt1 0 in the 1970s with his pioneering work on the topochemical reactions of crystalline cinnamic acids. This term was widened in the 1990s by Desiraju5 with the following definition: "Crystal engineering is defined as the understanding of intermolecular interactions in the context of crystal packing and in the utilization of such understanding in the design of new solids with desired physical and chemical properties". Polymorphism is defined as the existence of the same chemical substance in more than one crystalline form and pseudopolymorphism refers to solvent inclusion in crystals.11 Polymorphs have different physical and chemical properties, such as different melting points, different chemical reactivities, different dissolution rates and different bioavailabilities. They can be interconverted by phase transformations induced by heat or mechanical stress, or by solvent-mediated processes. The existence of polymorphism means the free energy difference between the different forms is quite small, which obviously hinders the prediction of crystal structures. In this case polymorphism is a distinct roadblock to crystal engineering. Polymorphism is very common in many drugs. The polymorphism of cinnamic acid will be described in greater detail in the next section of this chapter. Amorphous solids have no regular crystal packing or shape. When a crystal is reduced to the size of 10" cm, the region of atomic dimensions, it is no longer an ordered array of atoms or molecules, i.e., it is no longer a crystal! An amorphous solid gives no X-ray diffraction pattern. Amorphous solids have a rapid dissolution rate, which is pharmaceutically desirable, but they are also relatively unstable, a pharmaceutically undesirable property.4(a) Several techniques have been used in crystal engineering: X-ray crystallography, statistical analysis of the Cambridge Structural Database (the advantage of this method is that any distortion in individual X-ray structures is averaged), spectroscopy (NMR, IR), thermal analysis, and computation. The ultimate step in crystal engineering must be the prediction of the crystal structure. To date, precise prediction of crystal structures is still a daunting task, even with the most powerful computational methods, because crystal packing is governed by many weak, 4 Chapter 1 Introduction noncovalent intermolecular forces. Hydrogen bonding and metal-ligand coordination, the strong intermolecular interactions in crystals, were successfully utilized to engineer the assembly of supramolecular networks. The most recent review of hydrogen bonding in the solid state was reported by Steiner. To date, understanding of the intra- and intermolecular interactions leading to an observed crystal packing is incomplete, and attempts at engineering crystals have largely been a process of trial and error, as solid state chemistry itself is still in the stage of "Chem Is Try". With the current limitations of crystal engineering in the design of multiple-component systems, solid state studies have focussed primarily on the reactions of single component crystals, e.g., rearrangements and dimerizations. An effective strategy for performing heterobimolecular solid state reactions comes from the growth of mixed crystals formed by co-crystallization of two structurally similar molecules such as the amides shown in Figure 1.2, or by host-guest complexes formed through hydrogen bonding. Compounds 1 and 2 crystallize together. Upon photolysis the co-crystal was transformed into the mixed dimer 3 as well as the anti head-to-tail homodimer 4 with excellent regio- and stereocontrol.14 Host-guest chemistry will be described in more detail in a later part of this chapter. .CONH 2 "r f 3 4 Figure 1.2 A solid state bimolecular reaction of a mixed crystal. Today crystal engineering is expanding to the self-assembly of both organic and inorganic systems and more: molecular crystals,15 nanostructures,16 metal-organic frameworks,17 solid state pharmaceutical chemistry,4 coordination polymers,18 theoretical 5 Chapter 1 Introduction chemistry, crystallography, and crystal growth. A quote from Braga et al}9 is used to conclude this section: "In the materials chemistry area, crystal engineering is perceived as a working strategy, a utilitarian method with relevant interdisciplinary interactions with biology, informatics and physics; in the supramolecular chemistry area, crystal engineering is perceived as a way to exploit non-covalent interactions to assemble molecules in solid supermolecules; in the area of solid state reactivity, crystal engineering is seen as the tool that allows topochemical control of reactivity and stereochemistry, as well as the understanding and exploitation of solvent-free, environmentally more friendly reactions, and/or heterogeneous reactions with potentials for sensing and trapping of molecules or for the preparation of otherwise elusive molecules; in the theoretical chemistry area, the challenge of crystal engineering is to predict the outcome of a crystallization process, hoping that this knowledge will then suggest methods of control; in the area of biology and biotechnology, crystal engineering is the investigation of the interaction between biological matrices and crystalline phases; For crystallography, crystal engineering provides the push and additional motivation to improve methods of data collection, data storage, data mining and most importantly, to develop friendly and portable methods for direct structure determination from powder diffraction data; in the field of polymorphism, crystal engineering is perceived as a conceptual (and practical) way to tackle the relationship between kinetics and thermodynamics, to generate polymorphs and pseudo-polymorphs on purpose by a judicious choice of the crystallization conditions, and to practise ways to trick nature into doing what the researcher needs". 1.3 S o l i d State C h e m i s t r y a n d the T o p o c h e m i c a l Postulate The field of crystal engineering began with the study of organic solids. Far from being a "chemical cemetery", a crystal provides a more selective chemical reaction medium than conventional isotropic fluid media. Generally, solid state reactions tend to occur with minimum atomic/molecular motion, the so-called topochemical principle. This concept was first formulated by Kohlshutter in 1918.21 It was not until the advent of modern X-ray crystallographic techniques in the 1960's that the fundamental topochemical rules finally emerged thanks to the pioneering work of Schmidt and 6 Chapter 1 Introduction co-workers on the intermolecular [2 + 2] photocycloaddition reactions of rra«.s-cinnamic acid derivatives 22 Ph. COOH hu Solution P h x ^ O O H 6 Ph N HOOC P h x Ph. Ph N HOOC. COOH > h COOH ^COOH COOH Ph hu a form ho P form ho y form Ph HOOC. COOH Ph 7 (a-truxillic acid) Ph Ph COOH COOH 8 (p-truxinic acid) No reaction Figure 1.3 rrcms-Cinnamic acid photochemistry in solution and three polymorphic crystal forms As shown in Figure 1.3, photolysis of trans-cirmamic acid (5) in solution affords cis-cinnamic acid (6). In the solid state, rrans-cinnamic acid crystallizes in three polymorphic forms: a, P, and y. Irradiation of the a form, in which the molecules are packed with a head-to-tail pattern and a center-to-center distance between the two nearest parallel double bonds of 3.8 A, gives a head-to-tail dimer, a-truxillic acid (7). The molecules in the metastable P form are packed head-to-head with a nearest neighbor contact between two parallel double bonds of 3.9 A. The mirror symmetric P-truxinic acid (8) is formed upon photolysis of the p form of rra«s-cinnamic acid in the solid state. The y form, in which the adjacent and parallel double bonds are offset with a center-to-center distance of 4.7 A, is photochemically stable. This photostability was interpreted as being due to lattice constraints which do not permit the potentially reactive centres to move 7 Chapter 1 Introduction sufficiently close together to form a photodimer. Interestingly, the metastable P form of /rans-cinnamic acid undergoes a thermal phase transition to give the more stable a form in the solid state at about 50 °C. Irradiation of P form crystals at high temperature (>50 °C) gave both a truxillic acid and P truxinic acid 2 2 ( b ) This example shows both the topochemical control of solid state reactions and the reactivity differences among polymorphs. It should also be noted that solid-state photochemical reactions may offer distinct advantages over the corresponding solution reactions, because they allow control of the regio- and stereochemistry of the products (such as truxillic and truxinic acids) and control of the course of the reaction. After studying the [2 + 2] photocycloaddition of trans-cinnamic acid and its derivatives, Schmidt proposed that the centre-to-centre distance between two adjacent double bonds should be less than a critical distance of approximately 4.2 A for the occurrence of [2 + 2] photocycloaddition in the solid state. The distance between the reacting double bonds is not the only determining factor for solid state [2 + 2] photocycloaddition. Parallel alignment of the reacting double bonds is also required. There are examples in which the distance between the centres of adjacent double bonds is within the proposed reaction limit, but the double bonds are not parallel to each other. In these cases, no photodimerization reaction was observed in the solid state.23 Nonetheless, a few cases have been reported where the reacting double bonds were not exactly parallel but the photodimerization reaction was observed. For example, in crystals of 7-methoxycoumarin, the reactive double bonds are rotated by about 65 ° with respect to each other, and the centre-to-centre distance between them is 3.83 A. In spite of this unfavorable arrangement, solid state photodimerization did occur.2 4 Another exception was found in the [2 + 2] photocyclization of 4-formylcinnamic acid, where photocyclization did occur upon irradiation even though the parallel double bonds are more than 4.8 A apart in the crystal.2 5 Most exceptions to the topochemical rules were explained by crystal disorder or defects.4'5 Such exceptions should not be considered as serious violations of Schmidt's original concepts in the topochemical postulate, but should be integrated into the original basic idea by widening its scope. More recently, it was suggested that orbital overlap rather than double bond centre-to-centre distance might be considered.26 Hydrogen abstraction geometric parameters defined by Scheffer Chapter 1 Introduction and co-workers in solid state Norrish type II reactions are directly concerned with orbital overlap, which will be described in the following section of this thesis. Following Schmidt's topochemical postulate based on the solid state [2 + 2] photocyclization of cinnamic acid derivatives, another general concept called the "reaction cavity" 2 7 was introduced by Cohen as an aid in interpreting the course of solid state reactions. According to Cohen, each individual molecule within a crystal is located in a cavity composed of the neighboring molecules. As the reaction proceeds, the physical geometry of the reactant changes as the product is formed. As shown in Figure 1.4, only the reaction involving minimal changes in geometry is allowed; the reactions with transition state geometries incompatible with the cavity wil l be disfavored. Recently, Ramamurthy et a/.28expanded the reaction cavity concept to include other organized media, leading to the development of solution-like photochemical behavior in organized media (such as polymer films, liquid crystals, zeolites, glasses, micelles, cyclodextrins, clays) (c) Figure 1.4 Pictorial representation of Cohen's "reaction cavity" concept: (a) starting material (dashed line) fits within the reaction cavity (solid line); (b) allowed solid state reaction where the product (dashed line) fits within the cavity; (c) disallowed reaction where the product (dashed line) does not fit within the cavity. The concept of the reaction cavity is based on the assumption that topochemically controlled reactions occur in the bulk of the crystal rather than at defect sites. Lattice 9 Chapter 1 Introduction defects, disorder, amorphous solids, and phase transitions have frequently been used to explain deviations from topochemical behavior. A topotactic29 reaction involves a single-crystal-to-single-crystal transformation in which a single crystal of the reactant is converted into a single crystal of the product without any phase separation during the reaction. A recent example within the Scheffer group is shown in Figure 1.5. X-ray diffraction studies showed that during photolysis a single crystal of the starting material underwent Yang photocyclization to form the cyclobutanol photoproduct in up 93 % conversion without breaking the crystal lattice. Starting material in single crystal Mixture of starting material and Photoproduct in single crystal photoproduct in single crystal Figure 1.5 Representation of a single crystal to single crystal photoreaction of a norbornane derivative 31 32 Several other concepts such as molecular volume and free space, local stress, stenc compression,33 and "latent" reactivity34 have been utilized to interpret solid state reactivity. 10 Chapter 1 Introduction 1.4 Type II Photochemistry of KetonesJ3 1.4.1 General Aspects of Type II Photochemistry Ketones have attracted more photochemical research than any other compound. Both aliphatic and aromatic ketones absorb ultraviolet light in the 290-330 nm region. Following n-»7t* excitation, three major types of reaction can occur: Norrish Type I, Norrish Type II and photoreduction.38 The Norrish type I reaction is also known as a-fission (or a-cleavage), in which the cleavage of the bond between the carbonyl carbon and the a-carbon results in an acyl radical and an alkyl radical (Figure 1.6). The radicals can undergo a variety of subsequent reactions (decarbonylation and/or radical coupling, or hydrogen abstraction) to achieve stability. Photoreduction, which involves an intermolecular hydrogen atom abstraction, is rare in solid state photochemistry and will not be discussed in this thesis. Figure 1.6 The Norrish type I reaction. The Norrish type II reaction is among the most thoroughly investigated of all photoreactions and has been reviewed a number of times.3 9 A Norrish type II reaction involves abstraction of a y hydrogen atom by the (n, n*) excited ketone to give either a Norrish type II cleavage product, or a Yang cyclization 4 0 product as shown in Figure 1.7. The excited state of ketone 10 may undergo y hydrogen atom abstraction to form 1,4-hydroxybiradical intermediate 11, which has been detected by laser flash photolysis and trapped by S-deuterated thiols or oxygen.41 1,4-Hydroxybiradical 11 has three fates: (1) reverse hydrogen transfer (disproportionation) to regenerate ketone 10, (2) cleavage of the central carbon-carbon bond to form alkene 12 and enol 13 (ketone 14 formed by tautomerization), or (3) Yang cyclization to form cyclobutanol 15. Type II reactions may occur from either the singlet or triplet excited state of the molecule; however, phenyl ketones have been found to react exclusively from the triplet excited state.42 11 Chapter 1 Introduction 1 , 5 hydrogen l_l J^3 abstraction O ho Q ' H . ^ - " R 2 Norrish R R type II J cleavage r-. " p ' 3 X / R 2 O ' M T + R A Ri R. 10 reverse hydrogen transfer 12 13 O i 14 11 Yang cyclization OH R 3 * ^—R, 15 Figure 1.7 Type II photochemistry of ketones Abstraction of a y-hydrogen atom to form a 1,4-biradical is favored because it proceeds via a six-membered transition state; however, (3-, 5-, e- or even further long-range hydrogen abstraction may be observed, especially when no y-hydrogen atoms are available. 3 5 ( b ) It was first suggested by Wagner that chair-like six-membered transition states for y-hydrogen abstraction are favorable.43 However, crystallographic studies by Scheffer et al. disclosed that a boat-like transition state is often favored in the solid state.30'44 It is well known that some photochemical reactions6 like [2 + 2] photocyclization and the di-7i-methane reaction are synthetically useful. Type II photochemistry was also used in the synthesis of a variety of natural and/or non-natural products. Examples include: Taxane precursors (type I and II cleavage),45 the Aflatoxin family (1,6-hydrogen abstraction and Yang cyclization),4 6 Enediynes,47 Lignan paulownin (1,6-hydrogen abstraction and Yang cyclization),4 8 and Dodecahedrane.49 The synthetic utility of 1,9-, 1,12-, and other remote hydrogen atom abstractions was explored by Breslow 5 0 and Kraus et al.51 The synthetic uses and other applications of the type II reaction were briefly reviewed by Wagner 3 5 ( b ) and Kraus et al.52 A few examples are given below. Paquette's synthesis of Punctatin A (19) was accomplished using the Yang cyclization as a key step to make cyclobutanol 18 from ketone 16 (Figure 1.8). 12 Chapter 1 Introduction Figure 1.8 Yang photocyclization as a key step in the synthesis of Punctatin A Compound 22 (Figure 1.9) was synthesized by a [2 + 2] cycloaddition followed by a type II photocyclization in 50 % yield. 5 4 Six years later this methodology was used in the synthesis of Filiformin by another research group, although the previous study was not cited.5 5 As in this case, it is little wonder that people think the type II reaction has only a few uses in natural product synthesis.30 Some reactions in the area of hydrogen abstraction are reported without the key words of Norrish type II, Yang cyclization or even photochemistry/photochemical. ,OH O 20 21 50 % Figure 1.9 A [2 + 2] cycloaddition followed by a type II photocyclization Coumestrol 25, a phytoestrogen, was synthesized in five steps via a key step involving photochemical cyclization of glyoxylate ester 23 as shown in Figure 1.10.5 6 13 Chapter 1 Introduction O MeO' OMe hu MeO' H Q vC02Me OMe 2 BBr3 1 HCI HO' Coumestrol OH 23 24 25 28.5 % from 23 Figure 1.10 The synthesis of Coumestrol In solution, triplet 1,4-hydroxybiradicals are long enough lived to experience conformational interchange. Thus, the products derived from these intermediates will be strongly influenced by the geometry at which triplet-to-singlet intersystem crossing occurs, and may not necessarily correlate with the geometry of the initially formed biradical, or its lowest energy conformer. In the solid state, correlation of (n, 7t*) excited state reactivity with the geometry of the ground state ketone is valid for aromatic ketones because the excitation is known to be highly localized in the carbonyl group such that geometric changes in the rest of the molecule are negligible, with only a slight lengthening (ca. 0.1 A) of the carbonyl double bond. 5 7 It is not the case for aliphatic ketones because the carbonyl carbon of the (n, rc*) excited state becomes pyramidalized.58 It is important to emphasize that such structure-reactivity relationships are only approximate using ground state structures correlated with excited state reactivity. From the triplet excited state, the Norrish type II reaction is a two step process, hydrogen abstraction followed by cyclization and/or cleavage of the resulting biradical. The geometric parameters for each process are also broken down into different sections for the purpose of discussion. 1.4.2 Hydrogen Abstraction Geometric Parameters30'59 As with Schmidt's work on the topochemical postulate, which started with the definition of a set of geometric parameters describing the relative geometry necessary for solid state [2 + 2] photocycloaddition, hydrogen abstraction geometric parameters were also defined by Scheffer for the solid state Norrish type II reaction.60 14 Chapter 1 Introduction Figure 1.11 Geometric parameters for hydrogen abstraction Four geometric parameters associated with the abstraction process are shown in Figure 1.11. The first, d, is the distance between the carbonyl oxygen and the y-hydrogen. The second parameter A is defined as the C=0.. .H angle. The third parameter is 9, defined as the C-H. . . 0 angle. The fourth parameter is oo, the angle by which the y-hydrogen atom lies outside the mean plane of the carbonyl group. From a theoretical standpoint, ideal values for the four parameters have been proposed. The ideal value of d is 2.72 A , the sum of the van der Waals radii for a hydrogen and an oxygen atom.61 Because hydrogen abstraction involves the n-orbital on oxygen, the ideal value of co, the deviation of the y-hydrogen atom from the mean plane of the carbonyl group, is 0°. On the basis of mathematical and experimental kinetic studies, Wagner has proposed that the abstraction rate is proportional to cos co. Ab initio calculations by Houk have likewise shown that the enthalpy of activation increases significantly as 0 deviates from 180°, suggesting that a linear O. . .H-C arrangement (9 = 180°) is preferred.63 The ideal value for the A parameter is complicated by the fact that two models of the (n, 71*) excited state ketone exist. In the so-called "rabbit ear" conception, the atomic orbitals on oxygen are hybridized, and the two non-bonding sp2 hybrids are degenerate, each forming a 120° angle with the carbonyl C=0 bond axis. In the model proposed by Kasha, 6 4 the oxygen atom is not hybridized, resulting in non-degenerate non-bonding orbitals, one largely of 2s character, and the other 2p-like. The latter, which forms an angle of 90° with respect to the C=0 bond axis, contains the 15 Chapter 1 Introduction unpaired electron in the excited state. In general, therefore, the ideal A angle is thought to lie in the 90-120° range. Inspection of the above data reveals that it is geometrically impossible for all of the atoms to be ideally aligned in a six-membered transition state; some of the parameters must deviate significantly from their optimum values. The solid state study of 3 series of compounds by Scheffer et al. has provided average values for y-hydrogen atom abstraction (Figure 1.12 and Table l . l ) . 5 9 ' 6 0 O O ^ A r O 26 27 28 Figure 1.12 Previous studies of y-hydrogen abstraction parameters in Yang photocyclization Table 1.1 Ideal and crystallographically determined y-hydrogen abstraction parameters d(A) C D ( ° ) 9(°) A(°) Ideal <2.72 0 180 90-120 26 2.73 ± 0.03 52 ± 5 115 ± 2 83 ± 4 27/28 2.63 ± 0.06 58 ± 3 114 ± 1 81 ± 4 1.4.3 Geometric Requirements for Cleavage and Cyclization30'59 For a better understanding of the structure-reactivity relationships involved in 1,4-hydroxybiradical cleavage and/or cyclization, other geometrical parameters were defined by Scheffer et al. Cleavage parameters (pi and 94 are shown in Figure 1.13. The dihedral angle cpi represents the overlap angle between the /?-orbital on the carbonyl carbon C i , with the C2-C3 a bond that would be fragmented in a cleavage reaction. Another dihedral angle 94 represents the overlap angle between the /(-orbital on C4 with the C2-C3 a bond. The overlap between these orbitals is proportional to coscpi and coscp4.65 The ideal 16 Chapter 1 Introduction geometry for cleavage is with both q>i and 9 4 equal to 0°, the angle at which maximum overlap would be achieved. Those angles are only available from X-ray crystallography when the following assumptions are met: (1) the Ci and C 4 carbons are sp2 hybridized and (2) no conformational changes occur in the molecule following hydrogen abstraction. It seems likely that these assumptions are valid for solid state reactions, where conformational motions are severely restricted. Figure 1.13 Cleavage parameters 9 1 and 9 4 There are two parameters (Figure 1.14) related to the cyclization reaction. One is D, the distance between the radical centers (equal to the distance between the two reacting centers in the ground state). The ideal value of D should be less than 3.4 A , the sum of the van der Waals radii for two carbon atoms. Another parameter p is the dihedral angle between the /7-orbital on Ci and the C 2 - C 4 vector. The ideal situation for cyclization is when P = 0°, i.e., the p-orbital on Ci is pointed directly toward the /^-orbital on the on C 4 carbon, allowing for closure of the cyclobutane ring. Figure 1.14 Cyclization parameters D and P 17 Chapter 1 Introduction 1.5 Asymmetric Induction 1.5.1 Asymmetric Induction in Solid State Chemistry and Photochemistry There are a number of ways to obtain optically pure compounds. Pasteur resolution, which was developed 150 years ago, is used to separate racemates using acid-base reactions followed by crystallization of diastereomeric salts.66 The obvious limitations of the Pasteur approach are that it is labor-intensive and gives only a 50 % maximum yield. Isolation of natural products and manufacture by enzymatic processes also provide single enantiomers. Asymmetric synthesis, however, is the most powerful and general tool to 67 produce optically pure compounds. Asymmetric synthesis in a photochemical reaction can be achieved by conducting a reaction in a chiral environment. The chiral environment could be a chiral solvent, reactant, sensitizer, auxiliary or circularly polarized light. 6 8 Yang photocyclization of a-amido alkylaryl ketones in solution was reported by Griesbeck et al.69 with >95% de using an intramolecular hydrogen bonding strategy (Figure 15a). A n intermolecular hydrogen bonding strategy was used by Bach et al. in a Norrish/Yang photoreaction in solution and 26 % ee was achieved (Figure 15b).70 Attempts at photochemical asymmetric synthesis in solution usually give photoproducts with low enantiomeric excess. 18 Chapter 1 Introduction F i g u r e 1.15 Examples of asymmetric synthesis via Yang photocyclization in solution: (a) Griesbeck's intramolecular hydrogen bonding strategy; (b) Bach's intermolecular hydrogen bonding strategy. Asymmetric syntheses in "organized" media include:71 (1) zeolites with chiral inductors or chiral auxiliaries; (2) cyclodextrins; (3) chiral crystals. The chiral crystalline state is the most organized chiral medium and often leads to high ee's. Several approaches have been studied in the chiral crystalline state: (1) absolute asymmetric synthesis; (2) host-guest method; (3) covalent chiral auxiliary method; (4) ionic chiral auxiliary method. The host-guest method, in which an achiral guest molecule forms a chiral inclusion complex with an optically pure host compound, wil l be described in a later section of this chapter. The covalent chiral auxiliary method is used commonly in ground state chemistry. Achiral molecules may spontaneously crystallize in one of the 65 chiral space groups, thereby providing a chiral environment for asymmetric induction in solid state photoreactions, a process known as "absolute asymmetric synthesis", i.e. without the imposition of an external asymmetric source.72 The first absolute asymmetric synthesis was reported by Schmidt and co-workers over three decades ago on the gas-solid bromination of /?,p-dimethylchalcone.73 The first photochemical studies in absolute 19 Chapter 1 Introduction asymmetric synthesis were done by Schmidt7 4 (bimolecular [2 + 2] addition) and Scheffer75 (unimolecular di-7t-methane reaction). However, crystallization of achiral compounds in chiral space groups is rare and unpredictable.76'77 At present, absolute asymmetric synthesis is generally an unreliable method of making enantiomerically enriched substances. A method of guaranteeing the presence of a chiral space group is needed and will be synthetically useful in organic chemistry, especially for the preparation of compounds unavailable by common ground state chemistry. The ionic chiral auxiliary method was developed with this in mind. 1.5.2 The Ionic Chiral Auxiliary Method A n achiral reactant molecule containing a carboxylic acid (or an amine) is reacted with an optically pure amine (or an optically pure acid), which becomes the so-called ionic chiral auxiliary,7 8 to form an optically pure salt. Such salts must crystallize in chiral space groups, which provide the asymmetric environment necessary for chiral induction. After photolysis, the chiral ammonium ion can be easily removed by diazomethane (CH2N2) workup, giving the desired photoproduct as its methyl ester, which is easily purified by chromatography. The following (Figure 1.16) is one example.79 Salt 36, formed between an achiral acid and an optically pure amine, was photolyzed in the solid state and afforded ester 37 with an enantiomeric excess of 97 % after diazomethane workup for removing the chiral amine. 20 Chapter 1 Introduction Figure 1.16 A n example of the solid state ionic chiral auxiliary method for photochemical asymmetric synthesis The energy level diagram shown in Figure 1.17 demonstrates the general concept. Since the crystalline environment is chiral, reaction of the photolabile salt can proceed via either of two diastereomeric transition states of different energy. The pathway with the lowest kinetic barrier proceeds at a greater rate, and the product of this photoreaction will predominate. 21 Chapter 1 Introduction \ ^ p ~ C 0 0 C H 3 (+)-Chiral product tcH2N2 V ^ p - C O O C H 3 (-)-Chiral product t CH 2 N 2 0 © COO H3N" 0 © COO H3N-Photolysis in the crystalline state COO H3N™-( + Chiral Crystal Acid-base reaction COOH + H2N' Optically pure amine Auxiliary Achiral acid Photoreactive substrate Figure 1.17 Schematic representation of the ionic chiral auxiliary approach to asymmetric induction in the solid state. The ionic chiral auxiliary method utilizes "remote" chiral induction, unlike the traditional ground state method of asymmetric synthesis in which the chiral auxiliary is tightly bound to the reactive substrate near the site of reaction. It is the chiral crystalline environment that controls molecular conformation and packing in the crystals and determines the asymmetric induction. This will be discussed in greater detail in the next part of this thesis. Three conditions must be met in studies of asymmetric induction in the Yang photocyclization reaction using ionic chiral auxiliaries: (1) Straight-chain aryl alkyl ketones, which crystallize in extended conformations with inaccessible y-hydrogen atoms, are ruled out. Only ketones that crystallize in conformations favorable for hydrogen abstraction can be investigated. (2) The chiral auxiliary must be easily attached prior to reaction and easily removed after reaction. (3) The substrates must crystallize in chiral space groups. Compared to the traditional covalent auxiliary approach, the ionic chiral auxiliary method has a variety of advantages, including ease of introduction and removal of the 22 Chapter 1 Introduction chiral auxiliary and the fact that salts form robust ionic crystals with high melting points (resisting crystal breakdown during the reaction). The ionic chiral auxiliary method joins the two concepts of absolute asymmetric synthesis and Pasteur resolution in one procedure; moreover, it overcomes the drawbacks that absolute asymmetric synthesis is not general and that the maximum yield for Pasteur resolution is only 50 % (Figure 1.18). The ionic chiral auxiliary method has been applied by the Scheffer group to a wide variety of photochemical reactions to achieve near-quantitative de's and ee's.7 8 It is worth noting that both methods employ crystalline ammonium carboxylate salts. 1 rxn COOH 1 H 2 N — ( + ) 2 recrystallization Pasteur Resolution Technique I—COOH 2 H 2 N — ( + ) 3 recrystallization + maximium yield 50% 0 © ST\ l ^ C O O H 3 N™-( '+J < ^ ™ C O ( ^ H 3 N ™ ( + ) maximium yield 100% "COOH 3 rxn Ionic Chiral Auxiliary Concept Figure 1.18 Comparison of the ionic chiral auxiliary approach to asymmetric induction and the Pasteur resolution method. 1.6 Photochemistry of a-Oxoamides The photochemistry of a-oxoamides (A^/V-dialkylarylglyoxylamides) in the solid state was originally investigated by Aoyama et a/. 8 0 and studied extensively by Toda et a/. 8 1 23 Chapter 1 Introduction o Y ( a ) A^Vy hu o 38 Ar Ar- Pc oxazolidin-4-one 40 o Y (b) Ar^yNY O 38 et COOCH 3 Ar o 1 h u OHY 0-"Y z, JkH* OHY B 1' HO Ar azetidin-2-one (P-lactam) 39 Figure 1.19 Proposed mechanism for the formation of azetidinone and oxazolidinone. (a) Whitten's single electron transfer (SET) mechanism.82 (b) Aoyama's biradical mechanism.80*-0-' Two mechanisms have been proposed for P-lactam (azetidinone) formation. One suggested by Whitten et a/. 8 2 is depicted in Figure 1.19(a), in which P-lactam formation is thought to involve photoinduced single electron transfer from nitrogen to the benzoyl group (forming zwitterion Z i ) followed by transfer of a tertiary y-proton (k H + ) from one of the isopropyl groups to the carbonyl oxygen. This generates 1,4-hydroxybiradical B, which closes to form P-lactam (azetidinone) 39. In this mechanism, oxazolidinone 40 is formed via a second intramolecular electron transfer to produce zwitterion Z2 followed by ring-closure. The second mechanism was proposed by Aoyama 8 0 ( c ) (Figure 1.19(b)), in which the 1,4-hydroxybiradical (B, triplet or singlet) is formed directly upon photolysis of 38. The subsequent steps are same as Whitten's mechanism. The most recent studies on the mechanism of P-lactam formation were carried out by Mariano et al.S3 in which he 24 Chapter 1 Introduction concluded that Aoyama's mechanism (the hydrogen atom abstraction route) is more probable than Whitten's mechanism (SET-proton-transfer route) based on studies of the photoreactions of A^trimethylsilylmethyl- and A^-tributylstannylmethyl-substituted ct-oxoamides. Photolysis of a-oxoamides in solution usually yields oxazolidinones as the chief products, while photolysis in the solid state affords azetidinones as the major photoproducts. Biradical B and zwitterionic intermediate Z 2 exist as two different conformers in which the intramolecular electronic distribution is controlled by the molecular geometry. Zwitterionic intermediate Z 2 adopts a different conformation from biradical B, which reduces the steric hindrance in the latter (By M M X molecular mechanics calculations it was found that the plane containing the hydroxyl group, the anionic carbon and the carbonyl group is twisted from the plane defined by N-alkyl group and the N=C bond).82 In solution the extended conformer Z 2 is energetically favorable and the formation of oxazolidinone 40 via nucleophilic ring closure, in which large motions are necessary, is preferred. In the solid state, on the other hand, biradical B can not twist to form zwitterion Z 2 , and therefore azetidinone 39 is produced via this biradical intermediate. A variety of a-oxoamides has been explored photochemically by Toda and others to make P-lactams and penicillin derivatives (Figure 1.20). Figure 1.20 a-Oxoamides studied by Toda and others. 25 Chapter 1 Introduction Photochemical asymmetric synthesis from a-oxoamides was first studied by Aoyama et a/. 8 0 ( e ) and subsequently by Toda et a/.8 1 Toda and coworkers were the first to report that compounds 41a and 41b serendipitously crystallize in the chiral space group P2i2[2i . 8 ! ( g ) The absolute asymmetric synthesis method was used successfully for a-oxoamides 41a and 41b, but it did not work for ortho- (41c) and para- (41d) substituted a-oxoamides owing to their crystal packing in centrosymmetric space groups (Figure 1.21). Ar CH, -CH, hv Ar-O _QI_I solid state r -CH, CH, 41 50 -CH, CH, a Ar=—•<^y> space group: P2 1 2,2 1 75% yield, 93% ee b Ax =—<^> space group: P2 1 2,2 1 750/0 1 0 0 o / o e e Cl c Ar = — ^ ~ ^ - C I space group: Pbca 50% yield, 0% ee d A r = — s p a c e group: P2,/n 42% yield, 0% ee Cl Figure 1.21 Absolute asymmetric synthesis of P-lactams Enantioselective photocyclization of a-oxoamides to p-lactams was also achieved in nearly quantitative ee by the "inclusion complex method" (Figure 1.22), in which a 1:2 inclusion complex of a-oxoamide 51 with the optically pure host 52 can be crystallized in a chiral space group. 8 1 ( a ) 26 Chapter 1 Introduction Guest hv P h C O C O N M e 2 si solid state + H O - C P h 2 (R, R)-(-) Host H -Q H O H O - C P h 2 52 OH Ph ' O Me 53 40% yield, 100% ee Guest/Host = 1:2 Figure 1.22 Toda's host-guest approach to make enantiomerically enriched P-lactams Some drawbacks of the host-guest approach are the following: (1) only certain combinations of host and guest can form crystalline complexes suitable for photolysis; (2) the optically active host molecules are time-consuming and expensive to prepare; (3) separation of the host molecules from reaction mixture following photolysis is much more difficult than the diazomethane workup in the ionic chiral auxiliary approach. 1.7 Research Objectives The first project to be described in this thesis deals with the solid state asymmetric photochemical transformation of a-oxoamides to P-lactams. A number of a-oxoamides have been studied by Toda and others as shown in Figure 1.20. Compound 38, a derivative of oxoamide 41 which has been studied intensively by Toda, was selected as a target molecule in this project for the following reasons: to use the ionic chiral auxiliary method, and to compare the results with Toda's methods. Photocyclization of a-oxoamides in the solid state is a Norrish/Yang reaction, which has been the focus of much recent work in Dr. Scheffer's laboratory using the ionic chiral auxiliary approach. The goals of this project are: (1) to further explore the generality and synthetic utility of the ionic chiral auxiliary method; (2) to show that the ionic chiral auxiliary method can be carried out on a 100-500 mg scale, making the procedure synthetically useful. Although the two methods (absolute asymmetric synthesis and host-guest inclusion 27 Chapter 1 Introduction complex) described in last section lead to [3-lactams in respectable ee, both lack generality. The solid state covalent chiral auxiliary method was also applied to the photochemistry of a-oxoamide derivatives in this thesis. Unlike traditional ground state asymmetric synthesis using covalent chiral auxiliaries, the solid state covalent auxiliary method is a long-range asymmetric induction in which the chiral crystalline environment rather than the covalent auxiliary itself is responsible for asymmetric induction. The second project to be described in this thesis deals with the study of the solid state asymmetric photocyclization of derivatives of bicyclic aryl ketones 55, 58 and 61 (Figure 1.23). These bicyclic aryl ketone systems were selected as targets for continued studies on the Yang photocyclization similar to those on admantyl ketone 36, in which high ee was achieved. Like ketone 36, ketones 56, 59, 62 can not undergo type II cleavage, since anti-Bredt olefins would be generated. The photochemistry of these bicyclic aryl ketones has not been studied previously. A l l three target molecules are achiral and their cyclization products are chiral molecules, allowing for asymmetric induction to be studied. In bicyclo[2.2.1]heptyl ketones, regioselectivity could also be studied because the y-hydrogens on the one- and two-carbon bridges are potentially abstractable. A l l three target molecules were equipped with a carboxylic acid group in the phenyl ring, making it possible to apply the ionic chiral auxiliary method in the asymmetric induction. Two diastereomeric cyclobutanols are possible from photolysis of the ketones, and therefore diastereoselectivity could also be studied in this project. x x x 54,55,56 57,58,59 60,61,62 For compounds 54, 57, 60, X = C O O H For compounds 55, 58, 61, X = C O O C H , For compounds 56, 59, 62, X = COO © © N H 3 R Figure 1.23 Bicyclic aryl ketones selected for photochemical studies 28 Chapter 1 Introduction Solid state X-ray structure-reactivity correlation studies were carried out to rationalize the results in both projects. Molecular mechanics has been shown to provide information useful for the crystal engineering of type II photochemistry.30 Therefore, HyperChem M M + calculations85 were conducted throughout these projects. 29 Chapter 2 Results and Discussion RESULTS AND DISCUSSION 30 Chapter 2 Results and Discussion C h a p t e r 2 A s y m m e t r i c Syn thes is o f p - L a c t a m D e r i v a t i v e s 2.1 Preparation of Substrates 2.1.1 Preparation of cc-Oxoamides 38, 66 and 68 The target molecules 66 and 68 were synthesized in an expeditious and straightforward fashion as shown in Figure 2.1. CH 3 CO-Pd complex, CO // Vv. Br — — 7-* C H 3 C O — ( 7 X ) — C O O C H 3 63 CH3OH 70°C (93 %) 64 (88 %) Se02 Pyridine 100°C O O C O O C H 3 38 (99 %) 1 (COCI)2,DMF 2 (/-C 3H 7) 2NH (90 %) HOOC-C » // w C O O C H 3 65 LiOH C H 3 O H / H 2 O RT R*NH2 e 0 COO R*NH 66 (74 %) O 1 (COCI)2,DMF Ph 2 H O - C H 2 - C ^ „ H Me Salts (83-100%) 67 68 Ph 'H Me Figure 2.1 Synthesis of a-oxoamides 38, 66, 68 Commercially available bromide 63 was converted into ester 64 in a yield of 93 % by palladium (O)-catalyzed methoxycarbonylation.86 a-Oxoacid 65 was prepared by one-step oxidation with selenium dioxide 8 7 in pyridine in 88 % yield. It was interesting to find 31 Chapter 2 Results and Discussion that a-ketocarboxylic acid 65 was a previously unknown compound and was recently claimed as an inhibitor of phosphoryl tyrosine phosphases in a U.S. patent. Using a standard synthetic method, the target molecule 38 was synthesized from acid 65. Quantitative hydrolysis of ester 38 with lithium hydroxide afforded the target acid 66. The crude product thus obtained was an analytically pure pale yellow solid without further purification. Acid 66 was linked with chiral amines by ionic bonding and a chiral alcohol by covalent bonding. Recrystallization of chiral ester 68 or chiral salts 67a-l gave chiral crystals for asymmetric induction and X-ray crystallographic studies. Esters 38 and 68 gave spectra fully in agreement with assigned structures, which were confirmed by X-ray crystallography. 2.1.2 Preparation of Chiral Salts 67a-l Chiral salts 67a-l were prepared with acid 66 and various optically pure, commercially available amines as outlined in Table 2.1. The detailed procedure to make crystalline salts is given in the Experimental Section. A l l salts were characterized by N M R , DR., MS and R O elemental analysis. The 1:1 stoichiometric ratio of acid to chiral amine was confirmed by 1 H-NMR, elemental analysis and MS. The formation of an ammonium carboxylate bond was evidenced by changes in the IR spectra for the salts. Asymmetric and symmetric stretches consistent with carboxylates90 were observed in the salts with two intense bands from 1300 to 1650 cm"1. The structures of salts 67a, 67c, 67e, 67f, and 67g were confirmed by X-ray crystallography. 32 Chapter 2 Results and Discussion Table 2.1 Preparation of chiral salts of acid 66 salt amine recryst solvent cryst morphol mp(°C) 67a L-prolinamide MeOH plates3 202-206 67b R-(+)-bornylamine MeOH needles 183-185 67c R-(-)-1 -cyclohexylethylamine MeOH needles3 178-182 67d S-(+)-1 -aminoindane MeOH plates 192-195 67e (1R, 2S)-(+)-m-l-amino-2- MeOH plates3 180-182 indanol 67f R-(+)-1 -phenylethylamine MeOH needles3 178-181 67g S-(-)-1 -phenylethylamine MeOH needles3 179-181 67h (IS, 2R)-(+)-norephedrine MeOH needles 145-148 67i (1R, 2R)-(-)-pseudoephedrine MeOH needles 168-172 67j (-)-c/5-myrtanylamine MeOH plates 127-130 67k S-(+)-2-pyrrolidinemethanol C H 3 C N prisms 116-119 671 S-(+)-AT-methyl-l- ethyl acetate needles 126-128 phenylethylamine 3 X-ray crystal structure obtained. 2.2 Photochemical Studies of Ester 38 Although a-oxoamide 38 is a previously unknown compound, its photochemistry is 81 similar to that of a-oxoamide 41 (Figure 1.21), which was extensively studied by Toda. The photochemical results are outlined in Figure 2.2 and Table 2.2. Figure 2.2 The photoreaction of a-oxoamide 38 33 Chapter 2 Results and Discussion A l l solution photolyses were performed in benzene at room temperature following Toda's procedure.81 Both solid state and solution photolyses are very efficient, with 100 % conversion in 2 hours. The crystals of a-oxoamide 38 were photolyzed to 100 % conversion at room temperature without melting. cc-Oxoamide 38 shows different photochemical behavior in solution and in the solid state. Azetidinone 39 is the major photoproduct in the solid state photolysis of a-oxoamide 38. In solution, however, oxazolidinone 40 is the major photoproduct. The photoproduct ratio 39/40 is consistent between GC analysis and isolated yield (Table 2.2). The different photochemical behavior in solution and the solid state has been discussed in the Introduction of this thesis. Both photoproducts 39 and 40 were isolated and fully characterized by the spectroscopic techniques outlined in the Experimental Section. For photoproduct 39, particularly diagnostic were a broad OH stretch in the infrared spectrum at 3441 cm"1 and two methyl singlets at 1.59 and 0.91 ppm in the ' H - N M R spectrum. Photoproduct 40 also has two methyl singlets at 1.58 and 1.53 ppm in the ' H - N M R spectrum, and has an additional one methine singlet hydrogen at 5.21 ppm rather than an O H peak in the IR spectrum. The structure of photoproduct 39 was also confirmed by X-ray crystallography. The preparative scale photolysis of 38 in solution provided isolated racemic 39 and 40, not only for characterization of the photoproducts, but also for the chiral H P L C analysis in the resolution of the enantiomers. Table 2.2 Photolyses of a-oxoamide 38 in solution and solid state medium time (h) conv (%)a 39/40 crystal 2 100 73/27b benzene 2 100 25/75b crystal 2 100 66/34c benzene 2 100 29/7 l c a Percentage of total G C integral due to the disappearance of the corresponding starting material. b Products ratio from GC analysis. c Products ratio from isolated yields. 34 Chapter 2 Results and Discussion 2.3 Asymmetric Induction by the Ionic Chiral Auxiliary Method 2.3.1 Determination of the Enantioselectivity Following the preparative scale photolysis of a-oxoamide 38 in solution, photoproducts 39 and 40, which are presumably racemic, were used to test the resolution conditions with chiral HPLC. The enantiomeric excess of each sample was determined using a H P L C column containing a chiral stationary phase, a Chiralcel® OD® column for P-lactam 39 and a Chiralpak® AD® column for oxazolidinone 40. The chromatographic conditions for 39 and 40 are outlined in Table 2.3, and typical HPLC traces are shown in Figures 2.3 and 2.4. Figure 2.3 HPLC trace for the resolution of racemic 39 on Chiralcel® OD® column (eluting solvents, hexanes/isopropanol 99/1; flow rate, 1.0 mL/min) Figure 2.4 HPLC trace for the resolution of racemic 40 on Chiralpak A D column (eluting solvents, hexanes/ethanol 93/7; flow rate, 1.0 mL/min) 35 Chapter 2 Results and Discussion Table 2.3 Chromatographic data for enantiomeric excess determination of photoproducts 39 and 40. compound column HPLC conditions Retention Time (min)a U V detector (nm) Solvents Flow rate (mL/min) 39 O D b 254 99/1 hexanes/fPA 1.0 A : 31.8 B: 47.7 40 A D C 254 93/7 hexanes/EtOH 1.0 A : 14.7 B: 30.0 A refers to the first eluted peak, B to the second. b Chiralcel® OD® (25 cm x 0.46 cm ID), Chiral Technologies Inc. c Chiralpak® AD® (25 cm x 0.46 cm ID), Chiral Technologies Inc. 2.3.2 Asymmetric Induction Results The a-oxoamide salts 67a-I were photolyzed in the solid state on an analytical scale (2-5 mg). The salt 67a was also photolyzed in solution (CH3OH and CH3CN) and as a crystalline powder suspended in hexane (5 mg scale, 100 mg scale and 500 mg scale). The time of photolysis for each solid state reaction was controlled to different lengths so that the enantiomeric excess could be determined at a variety of conversions. Some salts, especially those that melted during photolysis at room temperature, were photolyzed at low temperature (-20 °C). Following photolysis, the salt sample was treated with ethereal diazomethane, converting the carboxylate anions to the corresponding methyl esters, and filtered through a short plug of silica gel to remove the chiral auxiliary. The photolysis and workup are described in detail in the Experimental Section. The conversion percentage as well as the product composition was determined by GC analysis. Isolated yields are reported for the photolyses in 100 and 500 mg scale. Isolation of each photoproduct by silica gel column chromatography was required before the ee determination by chiral HPLC owing to the overlapping of the two photoproduct peaks on chiral HPLC. Because compound 39 is the major photoproduct in the solid state photochemistry of a-oxoamides, the asymmetric induction study was focused mainly on this substance. For convenience, the 12 salts can be divided into 2 groups: 5 salts with high ee (> 90 % ee for 36 Chapter 2 Results and Discussion 39) and 7 salts with low ee (< 65 % ee for 39). Four of the five salts in the high ee group shown in Table 2.4 (67a, 67b, 67c, 67d) stayed at a high ee level without significant decrease when the conversion was increased. This photochemical behavior suggests a possible single-crystal-to-single-crystal reaction. Unfortunately, attempts at crystallographic study for a single-crystal-to-single-crystal transformation were not successful. After photolysis the neat single crystal became cloudy and was not suitable for X-ray crystallographic analysis. A dramatic decrease of ee with increasing conversion was found for the (IR, 2S)-(+)-c/s,-l-amino-2-indanol salt (67e); this is probably due to crystal breakdown during the course of photolysis, leading to loss of asymmetric induction in the crystalline state. 37 Chapter 2 Results and Discussion Table 2.4 Asymmetric induction in the photolysis of chiral salts 67a-e salt amine temp conva 39/40" eec (%) (°C) (%) for 39 67a L-prolinamide RT 58 53/1 +99 67a L-prolinamide RT 88 82/1 >+99 67a L-prolinamide RT 92 89/0 +99 67a L-prolinamide RT 100 97/3 +99 67b R-(+)-bornylamine -20 78 74/3 -98 67b R-(+)-bornylamine RT 37 36/1 -98 67b R-(+)-bornylamine RT 73 70/3 -98 67b R-(+)-bornylamine RT 89 84/4 -98 67b R-(+)-bornylamine RT 100 92/7 -96 67c R-(-)-1 -cyclohexylethylamine -20 22 15/7 -91 67c R-(-)-1 -cyclohexylethylamine RT 32 24/4 -85 67c R-(-)-1 -cyclohexylethylamine RT 60 38/15 -83 67d S-(+)-1 -aminoindane -20 84 78/3 +95 67d S-(+)-1 -aminoindane RT 80 74/3 +88 67d S-(+)-1 -aminoindane RT 100 94/5 +89 67e (IR, 2S)-(+)-cw-l-amino-2- -20 92 68/9 +81 indanol 67e (IR, 2S)-(+)-cw-l-amino-2- RT 23 15/1 +91 indanol 67e (IR, 2S)-(+)-cis-l-amino-2- RT 58 44/7 +71 indanol 67e (IR, 2S)-(+)-cw-l-amino-2- RT 75 59/9 +58 indanol 67e (IR, 2S)-(+)-cw-l-amino-2- RT 88 70/8 +53 indanol 67e (IR, 2S)-(+)-cw-l-amino-2- RT 98 75/10 +45 indanol a Percentage of total GC integral due to the disappearance of the corresponding starting material. b Percentage yield of products from G C analysis; the total percentage yield of 39 and 40 is less than the percentage of conversion due to other side products. c Enantiomeric excess (ee) values measured on a chiral OD column. Sign of rotation was obtained at the sodium D-line (589 nm). 38 Chapter 2 Results and Discussion The seven salts in the low ee group are shown in Table 2.5. The reasons for the low ee's, which could be crystal breakdown, crystal melting (67k, 671), and conformational enantiomerism, will be discussed in the next section. Table 2.5 Asymmetric induction in the photolysis of chiral salts 67f-l s a l t a m i n e t e m p ( ° C ) c o n v a ( % ) 39/40b e e c ( % ) f o r 39 67f R - ( + ) - 1 - p h e n y l e t h y l a m i n e R T 9 8 8 1 / 1 0 + 3 67g S - ( - ) - 1 - p h e n y l e t h y l a m i n e R T 9 9 7 9 / 1 0 - 3 67h ( I S , 2 R ) - ( + ) - n o r e p h e d r i n e R T 5 9 3 0 / 1 5 - 6 0 67h ( I S , 2 R ) - ( + ) - n o r e p h e d r i n e R T 7 8 4 1 / 2 2 - 4 9 67h ( I S , 2 R ) - ( + ) - n o r e p h e d r i n e R T 1 0 0 5 4 / 3 1 - 4 3 67i ( 1 R , 2 R ) - ( - ) - p s e u d o e p h e d r i n e R T 2 8 1 5 / 6 - 6 0 67i ( 1 R , 2 R ) - ( - ) - p s e u d o e p h e d r i n e R T 4 4 2 1 / 7 - 5 5 67i ( 1 R , 2 R ) - ( - ) - p s e u d o e p h e d r i n e R T 7 9 3 7 / 1 4 - 4 1 67i ( 1 R , 2 R ) - ( - ) - p s e u d o e p h e d r i n e R T 1 0 0 4 7 / 1 7 - 3 6 67j ( - ) - c / 5 - m y r t a n y l a m i n e R T 5 2 2 5 / 8 + 4 7 67j ( - ) - c / s - m y r t a n y l a m i n e R T 8 9 5 0 / 1 7 + 3 9 67j ( - ) - c w - m y r t a n y l a m i n e R T 1 0 0 6 3 / 2 1 + 3 7 67k S - ( + ) - 2 - p y r r o l i d i n e m e t h a n o l - 2 0 2 3 1 8 / 5 - 6 2 67k S - ( + ) - 2 - p y r r o l i d i n e m e t h a n o l R T 5 6 d 2 9 / 2 7 - 4 9 67k S - ( + ) - 2 - p y r r o l i d i n e m e t h a n o l R T 1 0 0 d 6 2 / 3 8 - 4 7 671 S - ( + ) - i V - m e t h y l - l - - 2 0 8 4 8 0 / 3 - 1 0 p h e n y l e t h y l a m i n e 671 S - ( + ) - J V - m e t h y l - l - R T 3 9 d 3 3 / 3 - 2 9 p h e n y l e t h y l a m i n e 671 S - ( + ) - i V - m e t h y l - l - R T 6 9 d 6 4 / 5 - 1 4 p h e n y l e t h y l a m i n e 671 S - ( + ) - A f - m e f h y l - l - R T 1 0 0 d 8 6 / 1 1 - 8 p h e n y l e t h y l a m i n e Percentage of total GC integral due to the disappearance of the corresponding starting material. b Percentage yield of products from GC analysis; the total percentage yield of 39 and 40 is less than the percentage of conversion due to other side products. c Enantiomeric excess (ee) values measured on a chiral OD column. Sign of rotation was obtained at the sodium D-line (589 nm). d Crystal melting observed. 3 9 Chapter 2 Results and Discussion In a dramatic demonstration of the synthetic potential of the ionic chiral auxiliary approach, a large scale solid state photoreaction was carried. Suspending the crystalline powder in a solvent in which it is insoluble, like HPLC grade hexanes, solves the problem of large scale solid state photochemistry. First, small scale hexane suspensions were investigated to see i f there was any different photochemical behavior between the pure crystal and suspension in hexanes. Table 2.6 shows the photochemical similarity between the pure crystal and crystalline powder suspension in hexanes. A hexane suspension of 500 mg of the prolinamide salt was irradiated to 99 % conversion to afford a 91 % isolated yield of photoproduct 39 with an ee of > 99 %. T a b l e 2.6 Photochemistry of chiral salts 67a suspended in hexanes scale (mg) isolated 39(%) temp(°C) conv (%)a 39/40b eec (%) for 39 5 - RT 48 48/0 >+99 5 - RT 99 92/2 +99 100 86 RT 98 93/3 +98 100 84 RT 99 88/3 +98 500 91 RT 99 94/2 >+99 " Percentage of total G C integral due to the disappearance of the corresponding starting material. b Percentage yield of products from G C analysis; the total percentage yield of 39 and 40 is less than the percentage of conversion due to other side products.0 Enantiomeric excess (ee) values measured on a chiral OD column. Sign of rotation was obtained at the sodium D-line (589 nm). Emphasizing the importance of the crystalline state to asymmetric induction, photolysis of the salts in solution gave negligible enantiomeric excess, e.g., 5-6 % shown in Table 2.7. 40 Chapter 2 Results and Discussion Table 2.7 Solution phase photolyses of chiral salt 67a solvent conva (%) 39/40" ee c(%)for 39 C H 3 C N 100 64/16d +6.2 MeOH 100 29/68 +5.1 a Percentage of total G C integral due to the disappearance of the corresponding starting material. b Percentage yield of products from GC analysis. The total percentage yield of 39 and 40 is less than the percentage of conversion due to other side products.c Enantiomeric excess (ee) values measured on a chiral OD column. Sign of rotation was obtained at the sodium D-line (589 nm). d Becomes cloudy after photolysis. The enantiomeric excess of the minor photoproduct 40 was only measured in a few cases owing to its low yield. Essentially, racemic photoduct 40 was obtained in all measured cases (Table 2.8), and a possible explanation will be given in the next section. Table 2.8 Determination of the enantiomeric excess (ee) of photoproduct 40 salt amine/medium temp conv . 39/40b ee (%)c ee (%)d ( ° Q (%)a for 39 for 40 67a L-prolinamide/ MeOH RT 100 29/68 +5 6 67a L-prolinamide/1 OOmg RT 100 76/18 +99 4 suspended in hexanes 67a L-prolinamide/1 OOmg RT 100 78/15 +95 0 suspended in hexanes 67c R-(-)-1 -cyclohexylethylamine RT 100 92/5 -80 0 67k S-(+)-2-pyrrolidinemethanole RT 60 38/20 -44 0 67k S-(+)-2-pyrrolidinemethanole RT 56 29/27 -49 0 67k S-(+)-2-pyrrolidinemethanole RT 100 62/38 -47 0 67m S-(+)-2- RT 100 49/40 +13 3 (methoxymethyl)pyrrolidinee a Percentage of total G C integral due to the disappearance of the corresponding starting material. b Percentage yield of products from G C analysis; the total percentage yield of 39 and 40 is less than the percentage of conversion due to other side products. c Enantiomeric excess (ee) values measured on a chiral OD column. Sign of rotation was obtained at the sodium D-line (589 nm). d Enantiomeric excess (ee) values measured on a chiral A D column. Sign of rotation was undetermined due to unavailability of enantiomeric-enriched 40.e Crystal melting observed. 4 1 Chapter 2 Results and Discussion 2.4 Asymmetric Induction by the Covalent Chiral Auxiliary Method The traditional covalent chiral auxiliary method, which has been extensively used for asymmetric synthesis in ground state chemistry, was also applied here to solid state photochemistry. In compound 68, the covalent chiral auxiliary R-(+)-2-phenyl-l-propanol was introduced via ester formation with AM3is(l-methylethyl)-a-oxo-benzeneacetamide-4-carboxylic acid (66). The photoreactive portion of the a-carbonyl in the a-oxoamide moiety was at the para position of the aromatic ring, that is, far away from the chiral auxiliary. Thus this covalent chiral auxiliary is a remote chiral auxiliary. Me Figure 2.5 Photochemistry of a-oxoamide 68 The solution phase photochemistry of a-oxoamide 68 proceeded to give 70 oxazolidinone as a major photoproduct and azetidinone 69 as a minor photoproduct as shown in Figure 2.5 and Table 2.10. These photoproducts, having a diastereomeric excess (de) of 0 % owing to the remote chiral auxiliary, were used to test the separation conditions on chiral HPLC. The solution phase photolysis also served as a method of producing sufficient amounts of the photoproducts for characterization. The identification of photoproducts 69 and 70 was virtually identical to that of photoproducts 39 and 40 described previously. The percentage conversion as well as the product composition was determined by GC. Isolated yields are reported for the 200 mg scale photolysis. Isolation of each photoproduct through silica gel chromatography was necessary owing to the overlapping of the two photoproduct peaks on chiral HPLC. Following purification, the diastereomeric excess of azetidinone 69 was determined using a. HPLC column containing a chiral stationary phase, Chiralcel® OD® (Figure 2.6). Unfortunately, the diastereomers of photoproduct 70 could not be separated by all in-house chiral HPLC 42 Chapter 2 Results and Discussion columns, and best results were obtained using the OD column with hexanes/EtOH as the eluting solvents (Figure 2.7). It was found that the chiral HPLC trace of oxazolidinone 70 from the photolysis of oxoamide 68 in the solid state showed two peaks indicating a de of approximately 0 %. This result is in agreement with the previous study, which showed an enantiomeric excess for oxazolidinone 40 of 0 % in the solid state using the ionic chiral auxiliary approach. Therefore other methods to separate the diastereomers of compound 70 were not attempted. The detailed conditions of chromatographic separation for photoproducts 69 and 70 are outlined in Table 2.9. Table 2.9 Chromatographic data for enantiomeric excess determination of photoproducts 69 and 70. Compound Column HPLC conditions Retention Time (min)a U V detector (nm) Solvents Flow rate (mL/min) 69 O D b 254 99/1 hexanes/IPA 1.0 A : 37.0 B: 50.3 70 O D b 254 99/1 hexanes/EtOH 0.5 A : 45.5 B: 49.0 a A refers to the first eluted peak, B to the second. b Chiralcel® OD® (25 cm x 0.46 cm ID), Chiral Technologies Inc 43 C h a p t e r 2 R e s u l t s a n d D i s c u s s i o n M l O * n t n u t u Figure 2.6 HPLC trace for the resolution of photoproduct 69 on Chiralcel OD (eluting solvents, hexanes/isopropanol 99/1; flow rate, 1.0 mL/min) Figure 2.7 HPLC trace for the unsuccessful resolution of photoproduct 70 on Chiralcel OD (eluting solvents, hexanes/ethanol 99/1; flow rate, 0.5 mL/min) Table 2.10 shows that excellent diastereomeric excess (> 84 % de for photoproduct 69) was obtained even at quantitative conversion by the solid state covalent chiral auxiliary approach. The de was enhanced to 92% at low temperature. Once again, to demonstrate the synthetic utility of solid state photochemistry in asymmetric synthesis, a large scale solid state photoreaction was achieved by the suspension of powdered crystalline oxoamide 68 in a solvent in which it is insoluble, such as water. Surprisingly, suspension in water gave higher de's than pure crystal photoreaction on both the 5 mg and 200 mg scales. A n obvious explanation of this result is lacking at the present time. With increasing of conversion, the de remains in the 95 % level without significant 44 Chapter 2 Results and Discussion decrease. Once again, a single-crystal-to-single-crystal experiment was not successful in the photolysis of oxoamide 68. The single crystal of oxoamide 68 also became cloudy after photolysis. Table 2.10 Asymmetric induction in the photolyses of chiral ester 68 medium temp conv a 69/70b de c(%) Peakd (°C) (%) for 69 pure -25 26 18/4 92 B crystals pure RT 26 16/6 85 B crystals pure RT 81 53/16 85 B crystals pure RT 98 66/17 84 B crystals Suspension RT 46 38/4 94 B in H 2 0 Suspension RT 94 75/10 95 B i n H 2 0 200 mg RT 100 67/8e 95 B suspension i n H 2 0 MeOH RT 100 12/65 6 B MeOH RT 100 14/63 13 B Benzene RT 100 8/77 0 B a Percentage of total GC integral due to the disappearance of the corresponding starting material. b Percentage yield of products from G C analysis. The total percentage yield of 69 and 70 is less than the percentage of conversion due to other side products.0 Diastereomeric excess (de) values measured oh a chiral OD column. d Peaks A and B represent two diastereomers of 69; Peak A refers to the first peak eluted as the predominant diastereomer in the H P L C analysis, B to the second. e Isolated yields. 45 Chapter 2 Results and Discussion The photolysis of oxoamide 68 in solution (MeOH and benzene) also gave negligible diastereomeric excess as shown in Table 2.10. Once again, this demonstrates the importance of the crystalline state to asymmetric induction using remote chiral auxiliaries. The covalent chiral auxiliary method is not applied to the second project in this thesis because ionic chiral auxiliary method has obvious advantages: (a) it is easier to add and easier to remove ionic chiral auxiliaries than covalent chiral auxiliaries; (b) ionic bonding makes salts potentially high melting point. 2.5 Structure-Reactivity Correlations 2.5.1 Crystallographic Studies and Molecular Modeling As expected according to the previous studies of Aoyama and Toda 8 0 ' 8 1 , photolysis of a-oxoamides in the solid state produced P-lactam 39 as a major product and oxazolidinone 40 as a minor product and unisolated trace amounts of type II cleavage products (<5%, detected by GCMS) as shown in Figure 2.8. In solution photolyses, the major product is oxazolidinone 40 rather than P-lactam 39. The photochemical results for a-oxoamide 38 are shown in Table 2.2. As described in the introduction section of this thesis, the different photochemical behavior of a-oxoamide 38 in the solid state and in solution can be attributed to the presence of intermediates Z2 and B. The extended zwitterion Z2 is unfavorable in the solid state and rapid ring closure from biradical B affords P-lactam 39. However, in solution the extended zwitterion Z2 is energetically favorable and ring closure produces oxazolidinone 40. Type II photocleavage also occurs via zwitterionic intermediate Z 2 (Figure 2.9). 8 0 ( c ) 46 Chapter 2 Results and Discussion o 40 Figure 2.8 Photochemistry of a-oxoamide 38 Figure 2.9 Photocleavage from zwitterionic intermediate. The photoreactions of a-oxoamides provide the first example of type II reactions that involve zwitterionic intermediates. The intermediacy of 1,4-hydroxybiradicals in normal type II reactions is well established.91 The geometric requirements for hydrogen atom abstractability60 and 1,4-hydroxybiradical reactivity92 in the Norrish type II reaction were intensively explored in the Scheffer group using X-ray crystallography and molecular modeling. However, the geometric requirements for hydrogen atom abstractability, 1,4-hydroxybiradical reactivity (for the formation of azetidinones) and zwitterion reactivity (for the formation of oxazolidinones and photocleavage products) in the type II reactions of a-oxoamides have not been previously studied. The formation of oxazolidinones and 47 Chapter 2 Results and Discussion photocleavage products via zwitterionic intermediate Z2 is not a topochemically controlled process since large motions are involved. Table 2.11 shows that the hydrogen abstraction parameters d, co, A, and 0 for six crystalline a-oxoamides (average shown in entry 7) are very close to the M M + calculation values (entry 9) and also close to the data obtained from previous studies of normal Norrish/Yang photoreactions studied in the Scheffer group (entry 8). This explains the efficiency of hydrogen abstraction in the type II reactions of a-oxoamides. The average p (entry 7) is 6°, which is favorable for photocyclization from biradicals to form azetidinones (ideal value, P = 0°). Experimentally, all compounds in entries 1-6 were photolyzed in solid state to form azetidinones as the major products. The biggest difference between entries 7 (current studies in a-oxoamides) and 8 (previous studies in regular ketones) are cpi and 9 4 . The values of cpi = 8° and 9 4 = 5° in entry 7 suggest the photocleavage should be favorable (ideal values, cpi and 9 4 = 0° ) for compounds in entries 1-6. However, there were no significant amounts of cleavage products obtained from the photolysis of the oxoamides in the current studies and in the previous studies by Aoyama and Toda. 8 0 ' 8 1 The angles of 9 1 and 9 4 might not be applicable to the judgement of the efficiency of the photocleavage and the reason could be due to the fact that the photocleavage of oxoamides is not via biradical intermediate but via a zwitterion intermediate. For the same reason, the efficiency of the formation of oxazolidinones might be unpredictable by parameters measured from X-ray crystal structures of ground state a-oxoamides. 48 Chapter 2 Results and Discussion T a b l e 2.11 Crystallographic studies and molecular modeling3 , H a 0 N H || Ar /fm/7 Ar, 1 ^ 4 2A1A n u V ' Ar (/%)OH entry compound H d PH q>i(°) <P4(°) d(A) <D(°) A(°) en D(A) 1 ~/N _ I L i— < \~~^)~~ c o o c h 3 | o \ = / a 18 2 0 7 2.58 53 66 119 2.91 a' 5.00 b 10 1 1 7 2.67 54 62 1 2 0 2.88 b' 5.06 2 X . 0 / / V. H.N H a 2 1 9 2.77 52 54 113 2.84 a' 5.09 b 2 0 2 2.74 52 54 119 2.81 /f+-1J—f[ T V—COO© 13 —j o \ = / b' 5.08 3 a 0 1 1 2.73 54 56 124 2.85 —"—n—\ / — C o o e ^ g ^ - O O N H , a' 5.12 4 0 Z' *\ S H , a • 3 9 3 2.71 53 56 117 2.82 N—"—n—(f y—COO© © 3 \  0 w a' 4.93 5 -^ N ^ n r _/~Y_c00el H = 1 0 W a 10 1 1 6 2.65 54 62 1 2 0 2.87 a' 5 . 0 2 6 _ _ l 0 ^ — \ 0 Ph / N J L i r A V C 0 C H H - H a 6 7 2 2.65 56 60 123 2.85 - f 0 W V C H 3 a' 5.07 7 b average 1-6 a 6 8 5 2.69 54 59 119 2.85 a' 5.05 8 C a 22 56 56 2.68 62 82 106 2.88 9 I 0 r,—^ N-"—[|—V y—C00CH3 \ 0 W MM+ calculation a 2 8 12 2.68 60 62 104 2.84 a' • 4.31 I I L _ I I 1 1 1 L-g 1 1 1 a See the Introduction of this thesis for the definition of all parameters in this table. Entry 7 is the average data from entries 1-6. c Data from the previous studies in the Scheffer group. See reference. d In entries 1 and 2, there are two independent conformers in the asymmetric unit. Hydrogens a and a' are enantiotopic in one conformer; hydrogens b and b' are also enantiotopic but in the other conformer. 49 Chapter 2 Results and Discussion 2.5.2 Enantioselectivity/Diastereoselectivity in the Photolysis of a-Oxoamides Asymmetric synthesis via the solid state ionic chiral auxiliary method and the covalent chiral auxiliary method was described in sections 2.3 and 2.4. Near-quantitative ee's and de's were achieved in a number of salts and in ester 68. One chiral ester (68) and four chiral salts were studied by X-ray crystallography as shown in Table 2.11 (entries 2-6). The data in entries 3-6 show that one chiral conformation of the a-oxoamide is preorganized for reaction in the crystalline state. The photoexcited carbonyl oxygen is much closer to one abstractable y hydrogen (0-H a , within 2.72 A) than the other (0-Ha>, -5.03 A), so only the hydrogen abstraction from H a is favorable to form biradical B. Assuming that biradical B has a conformation similar to that of its a-oxoamide precursor and reacts with least motion (topochemical control), ring closure from biradical B with retention of configuration at the carbonyl carbon is favored to produce the major enantiomer of the p-lactam. A specific example is salt 67a shown in Figures 2.10 and 2.11. This salt crystallizes in a unique pro-S conformation. It is apparent that y hydrogen H a (in green), which lies at a distance of 2.73 A from the carbonyl oxygen (in red), is much more favorably disposed for hydrogen transfer than is y hydrogen Ha> (in green, O-Ha- distance 5.12 A), and there can be little doubt that H a is preferentially abstracted in the solid state. The stereochemistry of biradical closure can also be reasonably interpreted in terms of the molecular conformation shown in Figure 2.11. Again, assuming that the biradical has a conformation similar to that of its a-oxoamide precursor, least motion closure of the biradical should lead to the (S) absolute configuration at the newly generated chirality center (retention). Formation of the (R) enantiomer requires rotation around the C1-C2 bond (Figure 2.10). Such a process is associated with its concomitant large amplitude motions of the pendant aryl and hydroxyl groups, and is expected to be topochemically forbidden in the rigid, close-packed environment of the crystal. 50 Chapter 2 Results and Discussion (a) Unique Pro-S conformation in the crystals of salt 67a (b) ORTEP representation of salt 67a. Carbonyl oxygen is colored red, 7 hydrogens H a and H a ' green. Figure 2.10 Molecular conformation in crystals of salt 67a. Figure 2.11 The reaction course of salt 67a in the crystalline state. In the ORTEP representation of salt 67a, carbonyl oxygen is colored red, y hydrogens H a and H a ' green. 5 1 Chapter 2 Results and Discussion In solution, rotation around the C1-C2 bond is allowed and enantiomeric/ diastereomeric excess was not obtained. A number of salts in Table 2.5 showed low ee in the solid state asymmetric induction studies. An obvious reason in the case of salts 67k and 671 is crystal breakdown, because the crystals melted during photolysis. The reason for the low ee in salts 67f and 67g is "conformational enantiomerism", which will be described in next section. Due to the unavailability of crystal structures there is no firm evidence to explain the low ee in the case of salts 67h, 67i, 67j. From previous studies in the Scheffer group, 4 4 ' 7 8 it is a typical result that a number of salts lead to low ee's while others lead to near-quantitative ee's in the solid state asymmetric induction studies, and a number of reasons can account for the low ee: (1) crystal melting and crystal breakdown; (2) conformational enantiomerism; (3) disorder in the crystal where two or more conformations of the reactive ion are distributed randomly in the crystal (static disorder) or are thermally interconverting (dynamic disorder). In the solid state photolysis of salts, the minor oxazolidinone product 40 is virtually racemic. The mechanism in Figure 2.8 shows the chirality center on oxazolidinone 40 is formed upon proton transfer from zwitterion 73. Because racemic oxazolidinone was obtained in the solid state photoreaction, the proton transfer apparently occurs with equal ease from the re- and si- faces in the chiral crystalline environment. This is the same reason that a de of 0 % for oxazolidinone 70 was obtained in the solid state photoreaction. v 2.5.3 Conformational Enantiomerism and Absolute Configuration Low ee (3 %) was observed in the solid state photolysis of salts 67f and 67g (Table 2.5). The X-ray crystal structure of salt 67f (Figure 2.12) shows that it contains equal amounts of two independent and mirror image related anion moieties (carboxylate ions) in the asymmetric unit, while the cation moieties (phenylethylammonium ions) retain their absolute configuration. The near-perfect enantiomeric relationship between the carboxylate ions was disclosed by computationally inverting one and overlapping it with the other, which leads to a root-mean-square error (RMSE) of 0.06 A (Figure 2.13). Half of the molecules in the crystal have conformations that lead to the (R)-(3-lactam, while the other half are conformationally poised to form (S). Two facts account for the low but 52 Chapter 2 Results and Discussion measurable 3% ee: (1) the two sets of conformers are not perfect mirror images of one another; (2) they are diastereomerically related when the presence of the (R)-ammonium ion is considered, so they react at slightly different rates (the molecular packing in the crystal is in a chiral space group: C2). Similar conformational effects have been reported by Scheffer at al. and termed "conformational enantiomerism".94 R-(+)-phenylethyllamine salt Figure 2.12 Conformational enantiomerism in crystals of salt 67f. Figure 2.13 Inverting the pro-R conformer and overlapping it with the pro-S conformer in the crystal of salt 67f 53 Chapter 2 Results and Discussion The X-ray crystallographic studies on the photolysis of a-oxoamide 68 allow the determination of the absolute configuration. Using the same method as described in section 2.5.2 and Figure 2.11, photoproduct 69 should have the (R) configuration at the newly formed chirality center (Figure 2.14). The (R) configuration was confirmed by X-ray structure determination of photoproduct 69. Thus we see that the concepts of conformational control (preorganization with a unique conformation during the crystallization) and topochemical control (least motion during the ring closure) are successful in rationalizing the asymmetric induction and predicting the absolute configuration of the product(s) in the solid state photolysis of a-oxoamides. 54 Chapter 2 Results and Discussion Figure 2.14 The reaction course of ester 68 in crystalline state. In the ORTEP representation of ester 68, carbonyl oxygen is colored red, y hydrogens H a and H a ' green. hv Ar HOxk* O N R photoproduct Figure 2.15 The reaction course of salt 67c in crystalline state. In the ORTEP representation of salt 67c, carbonyl oxygen is colored red, y hydrogens H a and H a - green. 55 Chapter 2 Results and Discussion By the same method, the absolute configuration of the photoproduct of salt 67c was also predicted to be (R) (Figure 2.15). The absolute configurations of photoproducts from 67a, 67c and 67e were predicted as (S), (R), (S), and their signs of rotation were measured as (+), (-) and (+) respectively. The predicted configurations were completely consistent with the signs of rotation of the photoproduct p-lactams as shown in Table 2.12. Table 2.12 Comparison of the predicted configuration and sign of rotation a-oxoamide measured [a] a predicted absolute configuration of Ci 67a + S 67c - R 67e + S a Signs of rotation were determined at the sodium D-line. 2.6 Summary 1. By using the solid state ionic chiral auxiliary approach and the solid state covalent chiral auxiliary approach, nearly quantitative enantiomeric/diastereomeric excesses were obtained in the photolysis of a-oxoamides. 2. By suspension in hexanes (or water), asymmetric synthesis in solid state photochemistry can be carried out on a preparative scale without loss of ee (or de). Therefore, the ionic chiral auxiliary method and the covalent chiral auxiliary method were demonstrated to be synthetically useful in the asymmetric synthesis of P-lactams via solid state photoreaction of a-oxoamides. 3. X-ray crystallography and molecular modeling were used for the first time in the study of hydrogen atom abstraction and 1,4-hydroxybiradical reactivity in the type II reactions of a-oxoamides. Using X-ray crystallography, the conformational and topochemical control in the enantiomeric/diastereomeric induction was also studied and the absolute configuration of the P-lactams determined. 56 Chapter 2 Results and Discussion 4. Using the ionic chiral auxiliary method, some salts led to low ee's in the solid state asymmetric induction studies. It is a typical result that a number of salts lead to low ee's while others lead to near-quantitative ee's in the solid state asymmetric induction studies. Crystal breakdown and conformational enantiomerism were used to rationalize the results. 57 Chapter 3 Results and Discussion C h a p t e r 3 A s y m m e t r i c Syn thes is i n the P h o t o c y c l i z a t i o n o f B i c y c l i c A r y l K e t o n e s 3.1 General Considerations Asymmetric induction studies in type II reactions have been the focus of much recent work in the Scheffer laboratory.44 One example is shown in Figure 3.1. 78 COOMe COOMe COOMe 75 14% 1 ketonization 2 oxidation in air MeOOC 76a 36 1 hv solid state 0 © *~ COO H 3 N R * 2 C H 2 N 2 workup 1 hv chloroform 2 C H 2 N 2 workup COOMe up to 37 % ee COOMe 37/75 -5.5/1 COOMe 75 0%ee 37/75-1.6/1 o %< Figure 3.1 Previous studies in a-adamantyl acetophenones 79 58 Chapter 3 Results and Discussion a-Adamantyl acetophenone 74 was photolyzed in acetone, producing photocyclization products 37 (major product), 75 (minor product) and 76 (trace), which is formed from the biradical following ketonization and oxidation in air (Figure 3.1). No cleavage photoproduct 77, a bridgehead alkene (anti-Bredt olefin), was found in this reaction. Using the ionic chiral auxiliary method, cyclobutanol 37 was formed with up to 97 % ee.79 The X-ray crystal structure of salt 36 showed the distances from the carbonyl oxygen to the six y-hydrogens are: 0 -H a , 2.70 A; 0-H a - , 3.14, 3.47, 4.5, 4.74, 4.91 A (For clarity only one of the five y-hydrogens Ha> is shown in Figure 3.1). Enantiomeric excess was achieved owing to the fact that only one y-hydrogen (H a in Figure 3.1) is within 3.0 A of the carbonyl oxygen, and hydrogen abstraction of H a (followed by the radical coupling under the rule of topochemical control described in section 2.5.2 in the oxoamide project) is favored. The second project of this thesis is an extension of the project of Yang photocyclization of a-adamantyl acetophenone derivatives. 54,55,56 57,58,59 60,61,62 For compounds 54, 57, 60, X = C O O H For compounds 55, 58, 61, X = COOCH3 For compounds 56, 59, 62, X = C O O 0 © N H 3 R Figure 3.2 a-Bicycloalkylacetophenone compounds selected for study. In total, three bicyclic aryl ketone systems (Figure 3.2) were chosen for asymmetric induction studies using the ionic chiral auxiliary method. First bicyclo[2.2.2]octyl ketones 54-56 were studied and the long alkyl chain substrates were selected owing to the simplicity of synthesizing the substrates from commercially available 4-pentylbicyclo[2.2.2]octyl carboxylic acid. Like adamantyl ketone 74, there are six y-hydrogens in the bicyclo[2.2.2]octyl ketones. This project also rules out the possibility of 59 Chapter 3 Results and Discussion type II cleavage, in which an anti-Bredt olefin would be generated. Secondly, the bicyclo[2.2.1]heptyl ketones 57-59 were selected as research targets, in which regioselectivity could also be studied because the y-hydrogens on both the one- and two-carbon bridges are potentially abstractable. The dimethylated bicyclo[2.2.1]heptyl ketones 60-62 have similar abstractable y-hydrogens as ketones 57-59. However, the solid state conformations of ketones 60-62 should be different from those of ketones 60-62; therefore, their photochemical diastereoselectivity and/or enantioselectivity might be different. The photochemistry of these bicyclic aryl ketones has not been studied previously. A l l three target molecules are achiral and their cyclization products are chiral molecules, allowing for asymmetric induction to be studied. A l l three target molecules incorporate a carboxylic acid group in the phenyl ring, making it possible to apply the ionic chiral auxiliary method in the asymmetric induction. Two diastereomeric cyclobutanols were possible from photolysis of each substrate and therefore diastereoselectivity was also studied in this project. 60 Chapter 3 Results and Discussion 3.2 Substrate Preparation 3.2.1 Synthesis of Bicyclo[2.2.2]octyI Ketones 85,54-56 Figure 3.3 Synthesis of bicyclo[2.2.2]octyl ketones 85, 54-55 As shown in Figure 3.3, bicyclo[2.2.2]octyl ketones 54 and 55 were synthesized according to a method based on a modification of literature procedures.95 Starting from commercially available 4-pentylbicyclo[2.2.2]octyl carboxylic acid (79), 4-pentylbicyclo[2.2.2]octylmethanol (80) was prepared in a yield of 92 % by reduction with lithium aluminum hydride. The methanesulfonyl group (a good leaving group) was introduced into alcohol 80 to form 4-pentylbicyclo[2.2.2]octane-l-methanol methanesulfonate (81) quantitatively. 4-Pentylbicyclo[2.2.2]octane-l-acetonitrile (82) was prepared from compound 81 in 87 % yield using S N A T reaction through treatment with sodium cyanide in refluxing anhydrous DMF. Hydrolysis of the cyano group in compound 82 was accomplished using the harsh condition of sulfuric acid (50 %). Following acid chloride formation from acid 83 with thionyl chloride, an attempt to make 6 1 Chapter 3 Results and Discussion ketone 55 in a one-pot procedure was unsuccessful by using nucleophilic addition to the acid chloride with a Grignard reagent, generated in situ from diisopropylmagnesium chloride and methyl p-iodobenzoate.96 Following the traditional strategy used within our group, 9 5 ( b ) the synthesis of ketones 54 and 55 was completed from acid 83 in a total yield of 59 % in four steps. A l l new compounds gave spectra in agreement with the assigned structures. Using commercially available optically pure amines, thirteen chiral crystalline salts 56a-m were prepared from acid 54 as listed in Table 3.1. The detailed procedure to make the salts is given in the Experimental Section. A l l 13 salts were characterized by N M R , IR, MS and elemental analysis. The structures of salts 56a,b were confirmed by X-ray crystallography. Table 3.1 Preparation of chiral salts of acid 54 salt amine recryst solvent cryst morphol mp(°C) 56a R-(-)-1 -cyclohexylethylamine MeOH plates3 173-176 56b L-prolinamide MeOH plates" 170-172 56c (IS, 2R)-(+)-norephedrine MeOH needles 170-173 56d (IR, 2R)-(-)-pseudoephedrine MeOH needles 118-119 56e R-(-)-1 -aminoindane MeOH needles 182-185 56f S-(+)-1-aminoindane MeOH needles 184-186 56g (IS, 2R)-(-)-cis-l-amino-2- MeOH needles 162-165 indanol 56h S-(-)-p-tolylethylamine MeOH needles 187-189 56i (IR, 2R)-(-)-amino-l-phenyl- MeOH prisms 140-142 1, 3-propanediol 56j S-(+)-2- MeOH powder 76-80 (methoxymethyl)pyrrolidine 56k R-(+)-1 -phenylethylamine MeOH needles 185-187 561 S-(-)-1 -phenylethylamine MeOH needles 185-187 56m (-)-cz's-myrtanylamine MeOH prisms 155-157 X-ray crystal structure obtained. 62 Chapter 3 Results and Discussion 3.2.2 Synthesis of BicycIo[2.2.1]heptyl Ketones 57-59 93 (94%) 92 (90%) 91 (50%) KOH, ethanol Reflux, 20 h COOH COOCH3 57(91%) 58(100%) Figure 3.4 Synthesis of bicyclo[2.2.1]heptyl ketones 57-58 Due to the commercial unavailability of bicyclo[2.2.1]heptyl carboxylic acid, the synthetic methodology used in the synthesis of the bicyclo[2.2.2] analogues could not be used to prepare bicyclo[2.2.1]heptyl ketones 57 and 58, and an alternative methodology was sought (Figure 3.4). Following the chlorination of commercially available norcamphor (86) with phosphorus pentachloride to form 2,2-dichloronorcamphor (87), selective rearrangement of compound 87 with aluminum trichloride led to l-chlorobicyclo[2.2.1]heptane (88) which served as the source of the bicyclo[2.2.1]heptane skeleton.97 A lithium-halogen exchange98 between chloride 88 and lithium wire was carried out in refluxing cyclohexane followed by the addition of cuprous cyanide to generate bicyclo[2.2.1]hept-l-yl lithium cuprate. This lithium cuprate was added with epoxide 90 (easily obtained from epoxidation of alkene 89 with m-CPBA 89 90 (76%) 63 Chapter 3 Results and Discussion 3-chloroperoxybenzoic acid) to produce alcohol 91 (the key step for preparing bicyclo[2.2.1]heptyl ketone 58). The yield for this reaction was disappointingly low (50 % isolated) and is likely due in part to the steric hindrance of the tertiary carbanion involved in the substitution reaction. However, this reaction was a successful synthetic shortcut with two carbons and one aryl group added in one step. It is interesting to mention that when epoxide 90 was contaminated with ethyl acetate, the only isolated product was compound 94. This three-component reaction was performed by mistake (Figure 3.5). £1 1) Li, cyclohexane, reflux 2) -78 °C, CuCN 88 + OAc F Ethyl acetate 94 ( - 1 0 % ) -78 °C to RT Figure 3.5 A three-component reaction in an unsuccessful synthesis of compound 91 Following Jones oxidation of alcohol 91, ketones 57 and 58 were again prepared by the traditional methods used within our group. Spectral data for all new compounds were in agreement with the assigned structures. Using commercially available optically pure amines, thirteen chiral salts of acid 57 were prepared as outlined in Table 3.2. As described in section 2.1.2, all salts were characterized by N M R , IR, MS and elemental analysis. The structure of salt 59d was confirmed by X-ray crystallography. 64 Chapter 3 Results and Discussion Table 3.2 Preparation of chiral salts of acid 57 salt amine recryst solvent cryst morphol mp(°C) 59a L-prolinamide MeOH plates 162-163 59b (IS, 2R)-(-)-cz's-l-amino-2- MeOH needles 166-168 indanol 59c S-(-)-p-tolylethylamine MeOH needles 177-179 59d R-(-)-1 -cyclohexylethylamine MeOH needles3 175-176 59e (IS, 2R)-(+)-norephedrine MeOH needles 144-147 59f R-(+)-1 -phenylethylamine MeOH needles 166-167 59g S-(-)-1 -phenylethylamine MeOH needles 165-166 59h (IR, 2R)-(-)-amino-l-phenyl- MeOH powder 132-133 1, 3-propanediol 59i (-)-cz'5-myrtanylamine MeOH needles 152-154 59j S-(+)-2- MeOH powder 108-113 (methoxymethyl)pyrrolidine 59k R-(+)-Bornylamine MeOH needles 156-159 591 S-(+)-1-aminoindane MeOH needles 172-174 59m {IR, 2R)-(-)-pseudoephedrine MeOH powder 127-129 X-ray crystal structure obtained. 3.2.3 Synthesis of Dimethylated Bicyclo[2.2.1]heptyl Ketones 60-62 The straightforward method to make substrate 62 would be a double methylation starting from ketone 58 as shown in the Figure 3.6. Figure 3.6 Proposed synthesis of ketone 61 65 Chapter 3 Results and Discussion A variety of methylation methods were tried. The first attempt to make ketone 61 was to use lithium diisopropylamide and methyl iodide (LDA/CH3I) for methylation. Ketone 58 was treated with L D A and D M P U followed by addition of methyl iodide. Unfortunately, reduced alcohol 95 was formed as a single product (Figure 3.7), which is in agreement with similar reports in literature." Monitoring the reaction by GCMS showed that reduction of ketone 58 occurred before methyl iodide was added to the reaction mixture. Figure 3.7 A n unsuccessful attempt for the methylation of ketone 58 Mono-methylation was easily achieved in 85 % yield by using sodium hydride and methyl iodide in THF, although the methyl ester was also converted to carboxylic acid 96 as shown in Figure 3.8. Monomethylated carboxylic acid 96 was easily transformed into methyl ester 97 through treatment with diazomethane. C O O C H 3 COOH C O O C H 3 58 96 97 Figure 3.8 Synthesis of monomethylated bicyclo[2.2.1]heptyl ketone 97 The second methylation was unsuccessful after numerous attempts were made. First, the LDA/CH3I method was used for the second methylation which led 100 % recovery of the starting material. The starting material was also recovered when lithium 66 Chapter 3 Results and Discussion bis(trimethylsilyl)amide or sodium hydride was used in this reaction. Potassium t-butoxide and methyl iodide were used in the second methylation and gave 5-10 % of the desired dimethylated product 61. In this reaction, improvement of the yield and separation of the mono-methylated and dimethylated products was unsuccessful. Based on this difficulty in making ketone 61, it was decided to revert to the traditional synthetic strategy previously used in making bicyclo[2.2.2]octane derivatives. .Cl 1) Li, cyclohexane, reflux N^COOH - CO -2) 0 °C, C 0 2 3) H 2 0/H + LAH CH 2OH 99(100%) 9 8 ( 5 3 % ) 88 —v , CH 3 S0 2 CI . Py ^ C H 2 C O Q H | H 2 SQ 4 K<CH 2 CN _ NaCN J ^ H 2 0 M s /J~y HAc ^O DMF 102(78%) 101(83%) C H 2 N 2 C H 3 \ ^ X H 2 C O O C H 3 1)LDA/DMPU /JZ7 2)CH3I 103(100%) 100(92%) X H C O O C H 3 7 104(89%) 1) LDA/DM PU K 3 ^ 1 j ^ 0 O C H 3 2) CH3I OCI 105(85%) LAH 106(85%) 1) soci2 1 2)PhF CH 2OH 107(89%) 1) PCC 2) p-F-PhMgCI C O O C H 3 60(91%) ^ COOH Figure 3.9 Synthesis of ketones 60 and 61 67 Chapter 3 Results and Discussion As shown in Figure 3.9, starting from 1-chloronorbornane (88) the carboxylic acid 98 was produced with a yield of 53 % through a lithium-halogen exchange reaction followed by addition of gaseous carbon dioxide. Following the same procedures as used in the synthesis of bicyclo[2.2.2]octane derivatives, acid 102 was obtained in 4 steps from acid 98 with an overall yield of 60 %. Starting from ester 103, the L D A / C H 3 I method was applied twice to produce dimethylated ester 105 in an overall yield of 76 %. SN2 displacement reaction of sterically hindered ester 105 was conducted using sodium thiomethoxide in D M F to obtain the desired acid 106 in 85 % yield. The method chosen for the synthesis of ketone 109 was Friedel-Crafts reaction using fluorobenzene and the acid chloride generated from acid 106. This method had been used previously in the synthesis of bicyclo[2.2.2]octyl ketones. Unfortunately, it was found that the increased steric hindrance provided by the presence of the dimethyl substituents at the a carbon hindered the reaction. Therefore, the synthesis of ketones 60 and 61 proceeded through an even longer synthetic route as shown in Figure 3.9. Alcohol 107 was synthesized by reduction of ester 105 with lithium aluminum hydride. Addition of the /?-fluorophenyl ketone functionality was accomplished to form alcohol 108 by adding /»-fluorophenylmagnesium bromide to the aldehyde generated from oxidation of alcohol 107 with PCC. Once again utilizing PCC oxidation of alcohol 108, ketone 109 was prepared in 99 % yield. Following the same procedure used previously, the synthesis of ketone 61 was completed in 3 steps from ketone 109 with an overall yield of 69 %. Again, using the acid-base reaction described in section 2.1.2, eight chiral salts of acid 60 were prepared as outlined in Table 3.3. A l l salts were characterized by N M R , IR, MS and elemental analysis. The structures of salts 62a, 62c, 62e were confirmed by X-ray crystallography. 68 Chapter 3 Results and Discussion Table 3.3 Preparation of chiral salts of acid 60 salt amine recryst solvent cryst morphol mp(°C) 62a R-(-)-l-cyclohexylethylamine MeOH plates" 187-189 62b (IR, 2R)-(-)-pseudoephedrine MeOH prisms 134-135 62c (IR, 2S)-(+)- (-)-cls-1-amino- MeOH needles" 202-204 2-indanol 62d S-(-)-p-tolylethylamine MeOH prisms 181-184 62f R-(-)-1 -aminoindane MeOH needles 198-200 62e L-prolinamide MeOH plates" 164-166 62g R-(+)-1 -phenylethylamine MeOH needles 175-177 62h (IR, 2S)-(-)-norephedrine MeOH needles 157-159 X-ray crystal structure obtained. 3.3 Photochemical Studies and Identification of Photoproducts 3.3.1 Photochemical Studies of Ketones 85, 54-55 85X=CN 111X = CN 112X = CN 54X = COOH 113X = COOH 114X = COOH 1 CH N 55X=COOMe 115X = COOMe 116 X = COOMe-- 1 2 2 Figure 3.10 Photolysis of ketones 85, 54-55 in solution and the solid state The photochemical studies of ketones 85, 54-55 were performed in both solution and the solid state. Figure 3.10, Table 3.4 and Table 3.5 summarize the photochemical results in both media. A l l photolyses in solution were conducted at room temperature with acetonitrile as a solvent. Low temperature (-10 or -25 °C) was applied to the solid state photolyses of ketones 54 and 55 to minimize crystal melting during the formation of 69 Chapter 3 Results and Discussion photoproducts. Product ratios were analyzed by chiral HPLC because the peaks of the two photoproducts were overlapped on GC. Tables 3.4 and 3.5 show that all three ketones have similar photochemical behavior1 0 0 in both solution and the solid state, producing two Yang photocyclization products (cyclobutanols 111, 113, 115 and 112, 114, 116). The cis photoproducts (112, 114, 116) are formed more favorably in the solid state than in solution. A l l photoproducts (acids 113 and 114 were converted into esters 115 and 116 through treatment with diazomethane) were isolated by column chromatography and fully characterized by spectroscopic analysis. The structure of photoproduct 111 was also confirmed by X-ray crystallography. It was found that the crystalline state photolysis of ketone 85 produced racemic cyclobutanols 111 and 112 (resolution of the enantiomers was accomplished using a chiral A D column; eluting solvents, hexanes/isopropanol 95/5; flow rate, 1.0 mL/min). Table 3.4 Photolysis of ketones 85, 54, 55 in solution (CH 3 CN) ketone X temp (°C) time (h) conv (%)a photoproduct ratio 85 C N RT 2 78 112/111 57/43" 85 C N RT 2 100 112/111 64/36° 54 COOH RT 2 71 116/115" 73/27" 55 COOMe RT 0.7 98 116/115 68/32" 55 COOMe RT 3 100 116/115 69/3 l c a Percentage of total GC integral due to the disappearance of the corresponding starting material. b Product ratio from chiral H P L C analysis. c Product ratio from isolated yields. d After diazomethane workup. 70 Chapter 3 Results and Discussion Table 3.5 Photolysis of ketones 85, 54, and 55 in the solid state ketone X temp ( ° Q time (h) conv (%)a photoproduct ratio 85 C N RT 14 42 112/111 78/22 b ' c 54 COOH RT 13 87 116/115d 88/12b 54 COOH -10 9 45 116/115d 93/7b 55 COOMe RT 2 30 116/115 93/7b 55 COOMe -25 10 35 116/115 97/3b a Percentage of total GC integral due to the disappearance of the corresponding starting material. b Product ratio from chiral H P L C analysis. c Crystal melting observed. d After diazomethane workup. 3.3.2 Identification of Photoproducts 111, 112,115 and 116 The identification of photoproduct 116 is virtually same as that of photoproduct 112. For simplification, therefore, only the identification of cyclobutanol 112 is described in detail. The structure of cyclobutanol 112 was elucidated by N M R spectroscopy with the aid of IR, MS, and elemental analysis. The IR spectrum shows a broad O-H stretch around 3400 cm"1. Mass spectroscopy and elemental analysis confirmed that the compound is a structural isomer of the starting material. On the basis of the N M R data, the structural assignments of cyclobutanol 112 are shown in Table 3.6. 71 Chapter 3 Results and Discussion T a b l e 3.6 Comprehensive N M R assignments for cyclobutanol 112 1 0 / f e o H »<"5"6C313 2 2 2 1 1 =iA 112 ? 7 n Carbon # , 3 C 5 (ppm) ' H 5 (ppm) fromHMQC ' H - ' H COSY H M B C H - H N O E 1 33.04 - - H 4 , H 2 2 44.96 H a , 2.03, IH, d, J=12.0Hz H b , 2.23, IH, d, J=12.0Hz H 2 H 4 3 79.22 - - H i 2 / H i 6 i H 2 , H 5 4 47.17 2.41, IH, m H 5 H 2 , H 5 H i 2 / H i 6 , H2b 5 29.50 1.64 and 1.41, 2H ,m H 4 6 31.40 - - H 5 11 110.98 - - H , 2 / H 1 6 12/16 126.32 7.46, 2H, d, J=8.2Hz H 1 3 / H 1 5 H 1 3 / H 1 5 13/15 132.66 7.63, 2H, d, J=8.2Hz H 1 2 / H ] 6 H i 2 / H 1 6 14 153.62 - - H 1 3 / H 1 5 17 119.23 - - H 1 3 / H 1 5 18 41.70 1.12, 2 H , m 21 23.08 1.35, 2 H , m H22 H 2 2 22 14.24 0.88 3H, t, J=7.2Hz H 2 I H 2 1 O H - 2.10, IH, s, br - - -The presence of a para disubstituted aromatic ring was determined from the 'H-NMR (7.46 ppm, 2H, d,J= 8.2 Hz and 7.63 ppm, 2H, d, J = 8.2 Hz) and COSY spectra. The COSY, H M Q C and H M B C spectra are complicated by overlapping proton signals at carbons 7, 8, 9, 10, 19, 20. However the structure is still well-established from other parts of the spectra. From H M Q C , the primary, secondary, tertiary and quaternary carbons and correlated hydrogens were elucidated. The chemical shift of quaternary carbon 3 is 79.22 ppm owing to the direct connection with oxygen. The carbon-carbon connections were established from H M B C and COSY. The relative stereochemistry was determined by 72 Chapter 3 Results and Discussion one-dimensional (ID) selective NOE (Figure 3.11). The NOE experiment shows the close proximity between H4 and H12/H16 as well as H4 and Ff.2b-H2b H12/H16 T P 7 1 I ' ' 1 ' ' 6 H, 1 2' T 1 X I'T'"1 1 • • 1 1 1 1 Figure 3.11 NOE spectrum for cyclobutanol 112 with irradiation at 2.41ppm (H4) The identification of photoproduct 115 is same as that of photoproduct 111. Again for simplification, only the identification of cyclobutanol 111 is described in detail. The structure of cyclobutanol 111 was also elucidated mainly by N M R spectroscopy, with the aid of IR, MS, and elemental analysis and confirmed by X-ray crystallography (Figure 3.13). The IR spectrum shows abroad O-H stretch around 3400 cm"1. Mass spectroscopy and elemental analysis confirmed that the compound is a structural isomer of the starting material. On the basis of the N M R data, the structural assignments for cyclobutanol 111 are shown in Table 3.7. 73 C h a p t e r 3 R e s u l t s a n d D i s c u s s i o n Table 3.7 Comprehensive N M R assignments for cyclobutanol 111 13 , 1 2 ^ v J 4 ^ C N *AH\ s H b \ jj 1 7 ^ j f / ^ 4 = 3 16 2 0 ^ 2 1 22 111 C a r b o n # , 3 C 5 ( p p m ) ' H 5 ( p p m ) f r o m H M Q C ' H - ' H C O S Y H M B C ' H - H N O E 1 3 2 . 6 8 - - H 4 , H 2 2 4 3 . 3 5 H a , 2 . 7 2 , I H , d , J = 1 2 . 2 H z H b , 2 . 0 5 , I H , d , J = 1 2 . 2 H z H 2 H 4 3 7 8 . 9 5 - - H i 2 / H | 6 , H 2 , H 5 4 5 2 . 1 3 2 . 5 8 , l H , m H 5 H 2 , H 5 O H , H 2 b 5 3 3 . 2 0 1 . 6 2 a n d 1 . 1 0 , 2 H , m H 4 6 2 6 . 9 0 - - H 5 1 1 1 1 1 . 5 1 - - H i 2 / H 1 6 1 2 / 1 6 1 2 9 . 0 6 7 . 5 0 , 2 H , d , J = 8 . 3 H z H 1 3 / H 1 5 H 1 3 / H 1 5 1 3 / 1 5 1 3 2 . 5 2 7 . 6 9 , 2 H , d , J = 8 . 3 H z H | 2 / H i 6 H 1 2 / H 1 6 1 4 1 4 8 . 5 3 - - H13 /H15 1 7 1 1 9 . 2 3 - - H 1 3 / H i 5 1 8 4 1 . 3 7 1 . 0 5 , 2 H , m 2 1 2 3 . 0 2 1 . 2 5 , 2 H , m H 2 2 H 2 2 2 2 1 4 . 2 1 0 . 8 6 3 H , t , J = 7 . 3 H z H 2 , H 2 i O H - 2 . 1 0 , I H , s , b r - - -The presence of a para disubstituted aromatic ring was determined from the ' H - N M R (7.50 ppm, 2H, d, 8.3 Hz and 7.69 ppm, 2H, d, J = 8.3 Hz) and C O S Y spectra. The COSY, H M Q C and H M B C spectra are also complicated by overlapping proton peaks at carbons 7, 8, 9, 10, 19, 20, but the structure is well-established from the other part of the spectra and was confirmed by X-ray crystallography. From H M Q C , the structure of the primary, secondary, tertiary and quaternary carbons, and correlated hydrogens was elucidated. The chemical shift of quaternary carbon 3 is 78.95 ppm owing to the direct connection with oxygen. The carbon-carbon connections were established from H M B C 7 4 Chapter 3 Results and Discussion and COSY. The relative stereochemistry was determined by ID selective NOE (Figure 3.12). The NOE experiment shows the close proximity between H 4 and H 2 b as well as H 4 and OH. From the X-ray structure (Figure 3.13), the aromatic ring is oriented close to one of hydrogens H 5 (l.lOppm, strong shielding effect from aromatic ring), and hydrogen H 2 a (2.72 ppm) is strongly deshielded by the aromatic ring. H 2 b Figure 3.13 ORTEP representation of photoproduct 111. In the hydroxyl group, the oxygen atom is colored red, the hydrogen atom green. 7 5 Chapter 3 Results and Discussion 3.3.3 Photochemical Studies of Ketones 57 and 58 x x X 57 X = COOH 58 X = COOMe 117 X = COOH 119 X = COOMe 118 X = COOH 120 X = COOMe "]~| CH 2 N 2 Figure 3.14 Photolysis of ketones 57 and 58 in solution and the solid state Photochemical studies of ketones 57-58 were conducted in both solution and the solid state. Figure 3.14 and Tables 3.8 and 3.9 summarize the photochemical results in both media. A l l photolyses in solution were conducted at room temperature in acetonitrile. Product ratios were analyzed by chiral HPLC because the peaks of the two products were overlapped on GC. Tables 3.8 and 3.9 show that ketones 57 and 58 have similar photochemical behavior in both solution and the solid state, producing two Yang photocyclization products (cyclobutanols 117,119 and 118,120). The trans photoproduct 119 is formed in a greater yield in the solid state than in solution. Acid 57 is photochemically inert in the solid state. A l l photoproducts (products 117 and 118 were converted into products 119 and 120 through treatment with diazomethane) were isolated by flash chromatography and fully characterized by spectroscopic analysis. 76 Chapter 3 Results and Discussion Table 3.8 Photolysis of ketones 57-58 in solution (CH 3 CN) ketone X temp time conv photoproduct (°C) (h) (%)a ratio 57 COOH RT 4 99 119/120" 51/49c 58 COOMe RT 2 100 119/120 53/47c 58 COOMe RT 4 100 119/120 56/44d a Percentage of total G C integral due to the disappearance of the corresponding starting material. b After diazomethane workup. 0 Product ratio from chiral H P L C analysis. d Product ratio from isolated yields. Table 3.9 Photolysis of ketones 57-58 in the solid state ketone X temp (°C) time (h) conv (%)a photoproduct ratio 57 COOH RT 70 0 119/120" 58 COOMe RT 1.5 17 119/120 65/35c a Percentage of total G C integral due to the disappearance of the corresponding starting material. b After diazomethane workup. 0 Product ratio from chiral H P L C analysis. 3.3.4 Identification of Photoproducts 119 and 120 The structure of cyclobutanol 119 was elucidated by N M R spectroscopy with the aid of IR, MS, and elemental analysis. The IR spectrum shows a broad O-H stretching vibration around 3400 cm"1. Mass spectroscopy and elemental analysis confirmed that the compound is a structural isomer of the starting material. On the basis of the N M R data, the structural assignments for cyclobutanol 119 are shown in Table 3.10. 77 Chapter 3 Results and Discussion Table 3.10 Comprehensive N M R assignments for cyclobutanol 119 COOCH 3 12 W 16 17 11 / / \ \14 o H b H f s H b 1 n \ / 9 V / V ~ P < 3 g / " "^ ~~7<4 '"OH Hb 119 Carbon # 1 3 C5 (ppm) 'H 5 (ppm) from HMQC 'H-'H COSY HMBC 'H-'H NOE 1 41.84 - - H 2 a , H 2 b i H 4 2 35.99 Ha3.10, IH, d,J=12.6Hz Hb2.31, IH, d, J= 12.6 Hz H 2 a / H 2 b - H 2 a - H n / H i 5 3 79.03 - - H 2 a , H 2 b i H 4 4 56.93 2.23, lH,m H 5 H 2 a , H 5 i H 8 H 2 b , H 5 b 5 37.25 1.59 (H5b) and 1.29 (H5a), 2H, m H 5 , H 4 , H 6 - Hn/H 1 5 6 38.79 1.93, lH,m H 5 , H 7 -7 28.49 1.54 and 1.20, 2H, m H 7 , H 6 , H 8 H8, H 9 8 34.52 1.51 and 1.40, 2H, m Hg, H 7 H 2 b , H 4 , H 9 9 41.05 1.01 (H9a) and 0.81(H9b), 2H, m H 9 - H11/H15 10 129.47 - - H n / H i 5 11/15 128.52 7.43, 2H, d, J = 8.4 Hz H ) 2 /Hi4 Hi 2/Hi4 H9b(0.81ppm) H5a(1.29ppm) H2a(3.10ppm) 12/14 129.69 8.01, 2H, d, J = 8.4 Hz H u / H i 5 H11/H15 13 148.27 - - Hi 2 /H 1 4 16 167.11 - - Hi 2 /H 1 4 , Hp 17 52.32 3.88, 3H, s - -OH - 2.43, IH, s, br - -The presence of a para disubstituted aromatic ring was determined from the ^ - N M R (7.43 ppm, 2H, d, J = 8.4 Hz and 8.01 ppm, 2H, d, J = 8.4 Hz) and C O S Y spectra. From H M Q C , the primary, secondary, tertiary and quaternary carbons, and correlated hydrogens were identified. The chemical shift of quaternary carbon 3 is 79.03 ppm owing to the direct connection with oxygen. The carbon-carbon connections were established from H M B C and COSY. The relative stereochemistry was determined by NOESY (Figure 3.15). The NOESY experiment shows the close proximity between H 4 and H 2 b , 78 Chapter 3 Results and Discussion H 4 and H 5 b , H 9 b and H H / H i 5 , H 2 a and H n / H i 5 , H 5 a and H n / H i 5 . In compound 119, hydrogens H 5 a (1.29 ppm) and 11% (0.81 ppm) are shielded by the aromatic ring and H 2 a (3.10 ppm) is deshielded. H2 a H11/H15 H. 5a 9b • 1 0 a 1 1 Figure 3.15 Partial N O E S Y spectrum for cyclobutanol 119 79 Chapter 3 Results and Discussion 15b H 4 A i L l •0 s ©, i > So @ 8 <! Q {! fl ' II $*%^t / rj © y <? 7 3 ^ CD i s 3 •0 « i l * <3 a 1 i' £8 e 3.0 2;5 S.0 1.5 i . O Figure 3.15 Partial N O E S Y spectrum for cyclobutanol 119 (Continued) The structure of cyclobutanol 120 was also elucidated mainly by the N M R spectroscopy, with the aid of IR, MS, and elemental analysis. The IR spectrum shows a broad O-H stretching vibration around 3400 cm"1. Mass spectroscopy and elemental analysis confirmed that the compound is a structural isomer of the starting material. On the basis of the N M R data, the structural assignments for cyclobutanol 120 are shown in Table 3.11. 80 Chapter 3 Results and Discussion Table 3.11 Comprehensive N M R assignments for cyclobutanol 120 9 H a ^ b 0 H 1 4 1 3 C O O C H 3 120 1 6 1 7 Carbon # 1 3 C8 (ppm) 'H § (ppm) from HMQC 'H-'H COSY HMBC ' H - H NOE 1 45.14 - - H 2 a , H2b H 8 , H 9 2 38.28 H a 2.36, IH, d, J = 12.4 Hz Hb2.51, IH, d, J= 12.4 Hz H2a/H2b 3 77.25 - - H n / H 1 5 j H 2 a , H 2 b 4 50.80 2.11, IH, m H 5 H 2 a , H 5 > H 8 , H 9 H2b, H5, H 7 , H 8 5 33.61 1.95 and 1.53, 2H, m H5, H 4 H 2 a , H2b, H 7 6 37.45 2.22 IH, m H 7 7 28.75 1.67 and 1.22, 2H,m H7, H 6 H 8 H 9 8 33.63 1.50 and 1.27, 2H, m Hs, H 7 H 7 , H 9 9 42.09 2.00 and 1.36, 2H, m H 9 H2a, H2b, H 8 10 128.70 - - H n / H 1 5 11/15 125.13 7.40, 2H, d, J = 8.3 Hz H12/H14 H12/H14 H 4 , H 2 b 12/14 129.77 7.97, 2H, d, J = 8.3 Hz H u / H 1 5 H l t /Hi5 13 153.12 - - H i 2 / H 1 4 16 166.91 - - H i 2 / H i 4 , H 1 7 17 52.04 3.88, 3 H , s - -OH - 1.87, br, IH, s - -The presence of a para disubstituted aromatic ring was determined from the ' H - N M R (7.40 ppm, 2H, d, J= 8.3 Hz and 7.97 ppm, 2H, d,J= 8.3 Hz) and COSY spectra. From H MQ C , the primary, secondary, tertiary and quaternary carbons, and correlated hydrogens were identified. The chemical shift of quaternary carbon 3 is 77.25 ppm owing to the direct connection with oxygen. The carbon-carbon connections were established from H M B C and COSY. The relative stereochemistry was determined by NOESY (Figure 3.16). The NOESY experiment shows the close proximity between H 4 and H 2 b , H 4 a n d H u / H 1 5 , H 2 b and H n / H 1 5 . 81 Chapter 3 Results and Discussion H11/H15 H 2b 2.5 1.5 Figure 3.16 Partial NOESY spectrum for cyclobutanol 120 3.3.5 Photochemical Studies of Ketones 60 and 61 0 GO » •• 0 7.a •7.4 -7.5 •7.B •8.0 60 X = COOH 61 X = COOMe <, 'OH H (trace) x 121 X = COOH 122 X= COOH 123 X = COOH I r u N 124 X = COOMe 125 X = COOMe 126 X = COOMe-^-l 2 2 Figure 3.17 Photolysis of ketones 60 and 61 in solution and solid state 82 Chapter 3 Results and Discussion The photochemical studies of ketones 60-61 were conducted in both solution and the solid state. Figure 3.17 and Tables 3.12 and 3.13 summarize the photochemical results in both media. A l l photolyses in solution were performed at room temperature with acetonitrile as the solvent. The conversions and product ratios were analyzed from chiral HPLC because photoproducts 124 and 125 decomposed on the GC column. The percentage of minor ketone 126 was not recorded in the analytical scale photolysis owing to peak overlapping of ketones 61 and 126 on chiral HPLC. As shown in Tables 3.12 and 3.13, photolysis of ketones 60-61 produced two Yang photocyclization products, 124 and 125 (by treatment with diazomethane in the case of ketone 60). The trans photoproduct 124 is formed in a greater yield in the solid state than in solution. Photoproducts 124 and 125 were isolated by flash chromatography and fully characterized by spectroscopic analysis. The structure of cyclobutanol 125 was confirmed by X-ray crystallography. Table 3.12 Photolysis of ketones 60-61 in solution (CH 3 CN) ketone X temp (°C) time (h) conv (%)a photoproduct ratio 60 COOH RT 2 85 124/125b 68/32c 61 COOMe RT 2 83 124/125 64/36c 61 COOMe RT 11 100 124/125/126 64/32/4d a Percentage of total chiral H P L C integral (response factors were applied) due to the disappearance of the corresponding starting material. b After diazomethane workup. c Product ratio from chiral H P L C analysis. d Product ratio from isolated yields. 83 Chapter 3 Results and Discussion Table 3.13 Photolysis of ketones 60-61 in the solid state ketone X temp (°C) time (h) conv (%)a photoproduct ratio 60 COOH RT 6 96 124/125b 94/6c 60 COOH -20 9 95 124/125" 98/2c 61 COOMe RT 14 98 124/125 57/43 c , d 61 COOMe RT 4 50 124/125 84/16C 61 COOMe -10 13 20 124/125 90/10C a Percentage of total chiral H P L C integral (calibrated with response factors) due to the disappearance of the corresponding starting material.b After diazomethane workup. 0 Product ratio from chiral H P L C analysis. d Crystal melting observed. 3.3.6 Identification of Photoproducts 124 and 125 The structure of photoproduct 124 was elucidated by N M R spectroscopy with the aid of IR, MS, and elemental analysis. The IR spectrum showed a broad O-H stretching vibration around 3400 cm"1. Mass spectroscopy and elemental analysis confirmed that the compound was a structural isomer of the starting material. Based on the N M R data, the structural assignments for cyclobutanol 124 are outlined in Table 3.14. 84 Chapter 3 Results and Discussion Table 3.14 Comprehensive N M R assignments for cyclobutanol 124 u .COOCH 3 H 10 1 2 4 Carbon # 1 3 C 5 (ppm) ' H 5 (ppm) from H M Q C ' H - ' H COSY H M B C ' H - H N O E 1 44 .96 - - H10, H u 2 52.19 - - H 4 , Hjo, H U j Hg, H 9 3 82.20 - - H13/H17, Hn, H10, H 4 4 54.65 2.26, IH, m H 5 H 5 , H 8 , H 9 H n , H 8 5 37.01 2.07 and 1.68, 2H, m H 5 , H 4 , H 6 H 7 , H 9 6 38.25 2.10, l H , m Hj. H 7 H 7 , H 9 7 28.39 1.58 and 1.21, 2 H , m H 7 , H 6 > H 8 H6, H 5 > H 8 , H 9 8 29.03 1.40, 2 H , m H 8 , H 7 H 4 , H 9 9 39 .82 1.10, 2 H , m H 9 H 4 , Hs. Hg, H 7 10 25.46 1.19, 3 H , s - H n 11 23.48 1.33, 3 H , s - H10 12 128.76 - - H 1 3 / H 1 7 13/17 129.16 7.58 2H, d , J = 8 . 5 H z H14/H16 H 1 4 / H 1 6 H10, H 5 > H 9 14/16 129.27 7.95 2H, d, 7 = 8 . 5 Hz H13/H17 H i 3 / H 1 7 15 150.10 - - H 1 4 / H 1 6 18 166.92 - - Hi4/Hi6,Hi 9 19 52.27 3.88, 3 H , s - -O H - 2.31, IH, s, br - - H n The presence of a para disubstituted aromatic ring was elucidated from the ! H - N M R (7.58 ppm, 2H, d,J = 8.5 Hz and 7.95 ppm, 2H, d,J= 8.5Hz) and COSY spectra. From H M Q C , it was easy to identify the primary, secondary, tertiary and quaternary carbons and their correlated hydrogens. Quaternary carbon 3 is distinguished an absorption at 82.20 ppm owing to the direct connection with oxygen. The carbon-carbon connections were deduced from H M B C and COSY. The relative stereochemistry was established by N O E S Y (Figure 3.18). Notable NOE interactions were found between H 4 and H n , OH and H n , H 1 3 / H 1 7 and H10. 85 Chapter 3 Results and Discussion H 1 3 / H 1 7 H 5 H 10 H, fl (10 1 W\ u • o 3 OH H 11 1 5 & 3 -Figure 3.18 Partial N O E S Y spectrum for cyclobutanol 124 Similarly, the structure of compound 125 was established by N M R spectroscopy with the aid of IR, MS, and elemental analysis. The IR spectrum of cyclobutanol 125 also 86 Chapter 3 Results and Discussion showed a broad O-H stretching vibration around 3400 cm"1. Mass spectroscopy and elemental analysis were used to determine that the compound was a structural isomer of the starting material. From the N M R data, the structural assignments of compound 125 are given in Table 3.15. 87 Chapter 3 Results and Discussion Table 3.15 Comprehensive N M R assignments for cyclobutanol 125 11 io V / .OH 9k/S^ 13 *0r 1 6 COOCH, 1 2 5 18 19 J Carbon # 1 3 C 5 (ppm) ' H 5 (ppm) from H M Q C ' H - ' H COSY H M B C ' H - H N O E 1 4 3 . 3 7 - - H10, H u 2 5 4 . 3 4 - - H 4 , H 8 , H , 0 , H n 3 81.37 - - H i 3 / H i 7 > H10, Hu , O H 4 43 .08 2.45, IH, m H 5 O H , H 8 . H i 3 / H 1 7 i H n , H 5 j H 8 5 32.64 1.77 and 1.56, 2H, m H 5 . H 4 , H 6 H 9 6 37.99 2.22, IH, m H 5 , H 7 , H 9 -7 28.54 1.63 and 1.31, 2H ,m H 7 , H 6 , H 8 H 8 8 29.76 1.34 and 1.21, 2 H , m Hs, H 7 H 4 9 39.31 2.03 and 1.30, 2H, m H 6 , H 9 H 4 , H 5 j H 8 , H 7 10 24.29 1.22, 3 H , s - H „ 11 20.02 0.74, 3 H , s - H10 12 129.17 - - H13/H17 13/17 126.87 7.35, 2H, d, J = 8.5 Hz H i 4 / H i 6 H i 4 / H i 6 H 4 , H n 14/16 129.68 7.97, 2H, d, J = 8.5 Hz H i 3 / H 1 7 H | 3 / H i 7 15 150.67 - - H 1 4 / H ) 6 18 -166.98 - - H i ^ ^ . H ^ 19 52.26 3.89, 3 H , s - -O H - 1.68, IH, s, br - -(7.35 ppm, 2H, d, J= 8.5 Hz and 7.97 ppm, 2H, d, J= 8.5Hz) and COSY spectra. From H M Q C , it was easy to identify the primary, secondary, tertiary and quaternary carbons and their correlated hydrogens. The chemical shift of quaternary carbon 3 is 81.37 ppm. The carbon-carbon connections were established by H M B C and COSY. The relative stereochemistry was determined by NOESY (Figure 3.20). The N O E S Y experiment shows the close proximity between H 4 and H n , H 4 and H 1 3 / H 1 7 , H 1 3 / H 1 7 and H n . The chemical shift of Hn is 0.74 ppm owing to the shielding effect of the aromatic ring. This 88 Chapter 3 Results and Discussion shielding effect is supported by the X-ray structure in which the aromatic ring is oriented to Hu - Compared to photoproduct 124, H 4 in compound 125 is slightly deshielded by the aromatic ring (H 4 in compound 125: 2.45 ppm; H 4 in compound 124: 2.26 ppm). The structure of cyclobutanol 125 was confirmed by X-ray crystallography (Figure 3.19). Figure 3.19 ORTEP representation of photoproduct 125. In the hydroxyl group, the oxygen atom is colored red, the hydrogen atom green. 89 Chapter 3 Results and Discussion H 11 » H 1 3 / H 1 7 "1 SIP* ' -2.5 ; ZM H 4 £ H 11 c lyf C 0 { 1 IS 0 1 OP* ' 1.6 1.4 i;s 1:0.. , o.e Figure 3.20 Partial N O E S Y spectrum for cyclobutanol 125 The structure of photoproduct 126 was elucidated by N M R spectroscopy with the help of IR, MS, and elemental analysis. The IR spectrum shows an absorption at 1730 (ester) and 1681 (ketone) cm"1. The presence of ester and ketone carbonyl carbons was 90 Chapter 3 Results and Discussion confirmed by 1 3 C - N M R , with peaks at 166.54 and 203.38 ppm respectively. Mass spectroscopy showed that the compound 126 has a mass of 298, two atomic units less than that of starting ketone 61 (the mass of ketone 61: 300). Based on the N M R data, the structural assignments for compound 126 are given in Table 3.16. Table 3.16 Comprehensive N M R assignments for ketone 126 12 0 f t j H 17 \ C O O C H 3 . „ 18 19 126 Carbon # 1 3 C 5 (ppm) ' H 5 (ppm) from H M Q C ' H - ' H COSY H M B C ' H - H N O E 1 45.58 - - H B , H 1 2 2 54.11 - - H 1 3 , H 1 2 3 203.38 - - H 1 3 , H i 2 > H 1 4 4 132.90 - - H 1 5 , H n 5 134.44 - - H]4 6 42.60 3.09, IH, m H 7 H n , H n , H 7 H u , Hio, H 7 7 41.70 2.26 and 1.64, 2H, m H 7 , H 6 - H 8 H 9 8 37.70 2.30, IH, m H 9 , Hn, H 7 H 7 , H ) 0 9 29.75 1.77 and 1.70, 2H, m H 9 , Hio, Hg Hio, H n 10 29.85 1.45, 2H ,m Hio, H 9 H 9 , H n 11 37.38 1.28 and 1.04, 2H, m Hn, H 8 Hio, Hg, H 7 12 18.69 1.26, 3H,s - H , 3 13 23.33 1.10, 3H,s - H i 2 H 6 14 126.64 7.92, IH, d, J = 8.1Hz H , 5 -15 127.21 7.85, l H , m Hu, H n H , 7 16 148.34 - - H ] 4 17 130.11 7.84, IH, m H 1 5 H , 5 18 166.53 - - His/Hn.His 19 52.36 3.90, 3H, s -91 Chapter 3 Results and Discussion 1 H - N M R shows that ketone 126 no longer has a para disubstituted aromatic structure (the two doublet feature is lacking). From FFMQC, the primary, secondary, tertiary and quaternary carbons and their correlated hydrogens were identified. The carbon-carbon connections were obtained from H M B C and COSY. The relative stereochemistry was established from ID selective NOE (Figure 3.21). The NOE provided information on the close proximity between H6 and Hi3. H 6 Figure 3.21 NOE spectrum for cyclobutanol 126 with irradiation at 3.09 ppm (H 6) 92 Chapter 3 Results and Discussion 3.4 Asymmetric Induction Studies • . . 3.4.1 Asymmetric Induction in the Solid State Photolysis of Bicyclo[2.2.2]octyl Ketones 3.4.1.1 Determination of the Enantioselectivity The large scale solution phase photolysis of ketone 55 provided racemic photoproducts 115 and 116 used for testing the chiral HPLC resolution conditions. Manually premixed compounds 55, 115 and 116 were injected onto a Chiralcel® OD® column to find 5 peaks as shown in Figure 3.22. The detailed chiral H P L C conditions are outlined in Table 3.17. The less polar ketone 55 was eluted from the chiral column at 8 minutes. The two enantiomers of cyclobutanol 116 were eluted at 25.1 minutes (peak A) and 33.2 minutes (peak B). The retention times of the two enantiomers of cyclobutanol 115 were 46.0 minutes (peak C) and 60.1 minutes (peak D). 93 Chapter 3 Results and Discussion K Id1 ItlKUlH Figure 3.22 HPLC traces for the resolution of racemic cyclobutanols 115 and 116 on a Chiralcel OD column (eluting solvents, hexanes/isopropanol 99/1; flow rate, 1.0 mL/min) 94 Chapter 3 Results and Discussion Table 3.17 Chromatographic data for enantiomeric excess determination of cyclobutanols 115 and 116. Column H P L C conditions Retention Time (min)a U V detector (nm) Solvents Flow rate (mL/min) O D b 254 99/1 1.0 116: hexanes/IPA A: 25.1 B: 33.2 115: C: 46.0 D: 60.1 a A refers to the first eluted peak, B to the second, C to the third and D to the fourth. b Chiralcel® OD® (25 cm x 0.46 cm ID), Chiral Technologies Inc. 3.4.1.2 Asymmetric Induction Results Crystalline salts 56a-m were photolyzed on an analytical scale (2-5 mg). The time of photolysis for each solid state reaction was controlled to different lengths so that the enantiomeric excess could be determined at a variety of conversions. Some salts were photolyzed at low temperature (-25°C). Following photolysis the salts were treated with ethereal diazomethane, which converted the carboxylate anions into methyl esters. The percentage conversion was determined by GC analysis. The de and ee were measured by chiral HPLC using a Chiralcel® OD® column as described above. Asymmetric induction results for all 13 salts are shown in Table 3.18. Salts 56a-b were found to be photochemically stable. Again, a number of salts lead to low ee's while others lead to near-quantitative ee's; this is a typical result in the solid state asymmetric induction studies. For salt 56c, near quantitative ee's for both photoproducts were obtained at near quantitative conversions. These results will be discussed in section 3.5. 95 Chapter 3 Results and Discussion Table 3.18 Asymmetric induction in the photolysis of chiral salts 56a-m salt amine conv temp de b ee" for ee" for (%)a (%) 116 (%) 115 (%) 56a R-(-)-1 -cyclohexylethylamine 0 RT - - • -56b Prolinamide 0 RT - - -56c (IS, 2R)-(+)-norephedrine 77 -25 +58 +95 -99 56c (IS, 2R)-(+)-norephedrine 55 RT +80 +96 -99 56c (IS, 2R)-(+)-norephedrine 80 RT +76 +93 -95 56c (IS, 2R)-(+)-norephedrine 95 RT +79 +88 -95 56d (IR, 2R)-(-)-pseudoephedrine 70 -25 +16 -78 +98 56d (IR, 2R)-(-)-pseudoephedrine 15 RT +57 -84 +91 56d (IR, 2R)-(-)-pseudoephedrine 98 RT +48 -49 +56 56e R-(-)-1 -aminoindane 42 -25 +31 +90 -96 56e R-(-)-1 -aminoindane 35 RT +28 +76 -94 56e R-(-)-1 -aminoindane 80 RT +33 +54 -75 56f S-(+)-1 -aminoindane 70 -25 +21 -77 +93 56f S-(+)-1 -aminoindane 83 -25 +24 -78 +89 56f S-(+)-1 -aminoindane 30 RT +23 -88 +93 56f S-(+)-1 -aminoindane 56 RT +33 -64 +90 56f S-(+)-1 -aminoindane 85 RT +32 -52 +74 56f S-(+)-1 -aminoindane 96 RT +30 -45 +65 56g (IS, 2R)-(-)-cis-1 -amino-2-indanol 40 RT +34 +82 -95 56g (IS, 2R)-(-)-cis-1 -amino-2-indanol 87 RT +38 +65 -77 56h S-(-)-tolylethylamine 50 -25 +76 +58 -26 56h S-(-)-tolylethylamine 5 RT +88 +72 -62 56h S-(-)-tolylethylamine 95 RT +81 +28 -13 56i (1R, 2R)-(-)-2-amino-1 -phenyl-1,3- 50 -25 +80 +49 -50 propanediol -49 56i (IR, 2R)-(-)-2-amino-1 -phenyl-1,3- 30 RT +69 +44 propanediol +38 -38 56i (1R, 2R)-(-)-2-amino-1 -phenyl-1,3- 66 RT +63 propanediol 56j S-(+)-2-(methoxymethyl)pyrrolidine 8 -25 +64 -56 +94 56j S-(+)-2-(methoxymethyl)pyrrolidine 5 RT +81 -77 +72 56j S-(+)-2-(methoxymethyl)pyrrolidine 16 RT +75 -71 +36 56j S-(+)-2-(methoxymethyl)pyrrolidine 30 c RT +75 -55 +30 56j S-(+)-2-(methoxymethyl)pyrrolidine 60 c RT +76 -42 +28 56k R-(+)-1 -phenylethylamine 60 RT +69 +4 -29 56k R-(+)-1 -phenylethylamine 87 RT +55 +8 -24 561 S-(-)-1 -phenylethylamine 36 RT +66 -4 +27 561 S-(-)-1-phenylethylamine 62 RT +57 -9 +18 56m (-)-cis-myrtanylamine 46 RT +15 +19 -11 56m (-)-cis-myrtanylamine 93 RT +12 +7 -3 a Percentage of total G C integral due to the disappearance of the corresponding starting material. b Diastereomeric excess (de) and enantiomeric excess (ee) values were measured on a Chiralcel OD column. The de values were calculated with the equation: de (%) = 116 (%) -115 (%). Sign of rotation was obtained at the sodium D-line (589 nm). c Crystal melting observed. 96 Chapter 3 Results and Discussion 3.4.2 Asymmetric Induction in the Solid State Photolysis of Bicyclo[2.2.1 ]heptyl Ketones 3.4.2.1 Determination of the Enantioselectivity The large scale solution phase photolysis of ketone 58 provided racemic cyclobutanols 119 and 120 used for testing the chiral HPLC resolution conditions. The mixture of compounds 58, 119 and 120 was separated into 5 peaks by a Chiralpak® AD® HPLC column as shown in Table 3.19 and Figure 3.23. Ketone 58 was eluted from the chiral HPLC at ca. 16 minutes. Cyclobutanol 120 was eluted at 52.6 minutes (peak A) and 72.2 minutes (peak C). The retention times of the two enantiomers of cyclobutanol 119 were 66.0 minutes (peak B) and 79.6 minutes (peak D). 97 Chapter 3 Results and Discussion Z 3 . S O s 0,00 a.00 A I c 1 . IV- • , , i m a . o n 4 . 0 0 \ 6 . O O \ a.00 .OH COOMe 120 I O ' HtnuUi 58 1 B D A B C D 4 . 0 a x i O 1 nlautai COOMe 119 120: A , C 119: B , D Figure 3.23 HPLC traces for the resolution of racemic cyclobutanols 119 and 120 on a Chiralpak A D column (eluting solvents, hexanes/IPA 98/2; flow rate, 0.60 mL/min) 98 Chapter 3 Results and Discussion Table 3.19 Chromatographic data for enantiomeric excess determination of cyclobutanols 119 and 120. Column HPLC conditions Retention Time (min)a U V detector (nm) Solvents Flow rate (mL/min) A D b 254 98/2 0.60 120: hexanes/IPA A : 52.6 C: 72.2 119: B: 66.0 D: 79.6 a A refers to the first eluted peak, B to the second, C to the third and D to the fourth. b Chiralpak® AD® (25 cm x 0.46 cm ID), Chiral Technologies Inc. 3.4.2.2 Asymmetric Induction Results Salts 59a-m were photolyzed in the solid state on an analytical scale (2-5 mg). The time of photolysis for each solid state reaction was controlled to different lengths so that the enantiomeric excess could be determined at a variety of conversions. Some salts were photolyzed at low temperature (-25°C). Following photolysis the salts were treated with diazomethane, converting the carboxylate anions into methyl esters. The percent conversion was determined by GC analysis. The de and ee were measured by chiral HPLC using a Chiralpak® AD® column as described above. Asymmetric induction results for all 13 salts are outlined in Table 3.20. Salt 59a proved to be photochemically inert after 33 hours of solid state photolysis at room temperature. However, the photolysis of salt 59a in acetonitrile afforded racemic photoproducts 119 and 120 (119/120 = 53/47) with a conversion of 71% in 4 hours. Two of the 13 salts (59b,c) showed near-quantitative de's. A l l 13 salts gave modest to low ee's (< 80 %). These results will be discussed in the section 3.5. 99 Chapter 3 Results and Discussion Table 3.20 Asymmetric induction in the photolysis of chiral salts 59a-m salt amine conv temp deb ee" for ee" for (%)a 120 (%) 119 (%) 59a L-prolinamide 0 RT - - -59b (IS, 2R)-(-)-cis-1 -amino-2-indanol 43 RT -95 -35 +39 59b (IS, 2R)-(-)-cis-1 -amino-2-indanol 84 RT -95 -27 +39 59b (IS, 2R)-(-)-cis-1 -amino-2-indanol 94 RT -94 -23 +33 59c S-(-)-p-tolylethylamine 18 -25 -98 +51 -42 59c S-(-)-p-tolylethylamine 94 -25 -92 -15 -13 59c S-(-)-/j-tolylethylamine 40 RT -88 -64 -2 59c S-(-)-/j-tolylethylamine 93 RT -82 -68 +17 59c S-(-)-p-tolylethylamine 97 RT -82 -73 +21 59d R-(-)-1 -cyclohexylethylamine 80 -25 -39 -37 +38 59d R-(-)-1 -cyclohexylethylamine 94 RT -39 -30 +36 59e (IS, 2R)-(+)-norephedrine 30 -25 0 -76 +62 59e (IS, 2R)-(+)-norephedrine 54 RT -23 -65 +63 59e (IS, 2R)-(+)-norephedrine 78 RT -39 -55 +45 59e (IS, 2R)-(+)-norephedrine 82 RT -42 -40 +39 59e (IS, 2R)-(+)-norephedrine 96 RT -59 -31 +36 59f R-(+)-1 -phenylethylamine 14 RT -45 +11 -42 59f R-(+)-1 -phenylethylamine 18 RT -50 +21 -45 59f R-(+)-1 -phenylethylamine 80 RT -76 +24 -51 59f R-(+)-1 -phenylethylamine 94 RT -76 +19 -50 59g S-(+)-1 -phenylethylamine 43 RT -66 -5 +44 59g S-(+)-1 -phenylethylamine 78 RT -76 -11 +42 59g S-(+)-1 -phenylethylamine 83 RT -79 -10 +41 59g S-(+)-1 -phenylethylamine 92 RT -76 -8 . +43 59h (IR, 2R)-(-)-2-amino-1 -phenyl-1,3- 48 -25 -56 -53 +22 propanediol 59h (1R, 2R)-(-)-2-amino-1 -phenyl-1,3- 63 RT -60 -33 +22' propanediol 59h (IR, 2R)-(-)-2-amino-1 -phenyl-1,3- 64 RT -63 -30 +23 propanediol 59h (1R, 2R)-(-)-2-amino-1 -phenyl-1,3- 81 RT -62 -31 +28 propanediol 59i (-)-cis-myrtanylamine 8 -25 +50 +24 +19 59i (-)-cis-myrtanylamine 28 RT +37 +27 +23 59i (-)-cis-myrtanylamine 91 RT -12 +22 +1 59j S-(+)-2-(methoxymethyl)pyrrolidine 7 -25 -22 +33 -19 59j S-(+)-2-(methoxymethyl)pyrrolidine 23 RT -43 +19 -15 59j S-(+)-2-(methoxymethyl)pyrrolidine 61 RT -46 +10 -6 59k R-(+)-bornylamine 67 -25 -60 -3 +4 59k R-(+)-bornylamine 45 RT -60 -14 +5 59k R-(+)-bornylamine 73 RT -61 -3 +3 59k R-(+)-bornylamine 91 RT -64 -1 -1 59k R-(+)-bornylamine 94 RT -65 0 +2 591 S-(+)-1 -aminoindane 8 -25 -26 -5 +12 59m (IR, 2R)-(-)-pseudoephedrine 68 RT -11 +23 +6 a Percentage of total GC integral due to the disappearance of the corresponding starting material. b Diastereomeric excess (de) and enantiomeric excess (ee) values were measured on a Chiralpak A D column. The de values were calculated with the equation: de (%) = 120 (%) -119 (%). Sign of rotation was obtained at the sodium D-line (589 nm). 100 Chapter 3 Results and Discussion 3.4.3 Asymmetric Induction in the Solid State Photolysis of Dimethylated Bicyclo[2.2.1]heptyl Ketones 3.4.3.1 Determination of the Enantioselectivity The large scale solution phase photolysis of ketone 61 produced cyclobutanols 124 and 125 used for testing the chiral HPLC resolution conditions. Fortunately, cyclobutanols 124 and 125 could be resolved with good baseline separation on a Chiralpak® AD® column giving a total 5 peaks including the achiral starting material, ketone 61. The detailed chiral HPLC separation is outlined in Table 3.21 and Figure 3.24. 101 Chapter 3 Results and Discussion O .DO X .1 a.oo 3.DO K I D 1 n( n u l » B a.oo 1.00 a.oo a.oo i .00 s.oo COOMe 125 . 3 *.oo i .oo a.DO D COOMe 124 61 125 / j c A B 124 \ D J..00 a.oo a.oo A.OO S . O O 125:A, B 124: C , D Figure 3.24 HPLC traces for the resolution of racemic cyclobutanols 124 and 125 on a Chiralpak A D column (eluting solvents, hexanes/ethanol 98/2; flow rate, 1.0 mL/min) 102 Chapter 3 Results and Discussion Table 3.21 Chromatographic data for enantiomeric excess determination of cyclobutanols 125 and 124. Column HPLC conditions Retention Time (min)a U V detector (nm) Solvents Flow rate (mL/min) A D b 254 98/2 1.0 125: hexanes/EtOH A: 19.7 B:25.6 124: C: 30.9 D: 43.0 a A refers to the first eluted peak, B to the second, C to the third and D to the fourth. b Chiralpak® AD® (25 cm x 0.46 cm ID), Chiral Technologies Inc. 3.4.3.2 Asymmetric Induction Results Salts 62a-h were photolyzed in the solid state on an analytical scale (2-5 mg). The time of photolysis for each solid state reaction was controlled to different lengths so that the enantiomeric excess could be determined at a variety of conversions. Each salt was also photolyzed at low temperature (-20 °C). After photolysis the salts were treated with ethereal diazomethane, converting the carboxylate anions into methyl esters, and filtered through a short plug of silica gel to remove the chiral auxiliary. The percent conversion as well as the product composition was determined by chiral H P L C due to the decomposition of the photoproducts on the GC column. Preweighed equal amounts of cyclobutanol 124 and starting material ketone 61 were injected onto the chiral HPLC column to find that their response factors are equal with the U V detector at 254 nm. The de and ee were obtained by HPLC using a Chiralpak® AD® column as described above. Asymmetric induction results for all 8 salts are outlined in Table 3.22. Four of the eight salts (62a-d) showed near-quantitative ee for cyclobutanol 124. Most salts gave good to excellent de's ( > 80 %) in the solid state. Once again, a number of salts led to low ee's while others led to near-quantitative ee's, which is a typical result in the solid state asymmetric induction studies. These results will be discussed in section 3.5. The 103 Chapter 3 Results and Discussion photolysis of salt 62a in methanol gave racemic cyclobutanols 124 and 125 (124/125 = 65/35) at 99 % conversion. This highlights the importance of the crystalline state in the asymmetric induction. Table 3.22 Asymmetric induction in the photolysis of chiral salts 62a-h salt amine conva temp de b eeD'c for ee" for (%) (%) 125 (%) 124 (%) 62a R-(-)-1 -cyclohexylethylamine 99 -20 -99 U M -99 62a R-(-)-1 -cyclohexylethylamine 55 RT -96 U M -98 62a R-(-)-1 -cyclohexylethylamine 88 RT -95 U M -98 62a R-(-)-1 -cyclohexylethylamine 99 RT -94 U M -98 62a R-(-)-1 -cyclohexylethylamine 100 RT -92 U M -99 62b (IR. 2R)-(-)-pseudoephedrine 18 -20 -97 -73 +93 62b (IR. 2R)-(-)-pseudoephedrine 48 -20 -93 -65 +90 62b (IR. 2R)-(-)-pseudoephedrine 55 RT -85 -61 +61 62b (IR. 2R)-(-)-pseudoephedrine 100 RT -75 -42 +51 62c (IR, 2S)-(+)-cis-1 -amino-2-indanol 94 -20 -88 0 +86 62c (IR, 2S)-(+)-cis-1 -amino-2-indanol 65 RT -84 -7 +84 62c (1R, 2S)-(+)-cis-1 -amino-2-indanol 97 RT -80 -5 +80 62d S-(-)-/7-tolylethylamine 65 -20 -46 -56 +65 62d S-(-)-p-tolylethylamine 76 -20 -58 -41 +42 62d S-(-)-p-tolylethylamine 33 RT -36 -19 +91 62e L-prolinamide 25 -20 -82 +10 -60 62e L-prolinamide 50 RT -75 +5 -46 62e L-prolinamide 70 RT -61 +6 -46 62f R-(-)-1 -aminoindane 10 -20 -85 -3 -67 62f R-(-)-1 -aminoindane 16 RT -87 +3 -48 62g R-(+)-1 -phenylethylamine 70 -20 -83 -4 -10 62g R-(+)-1 -phenylethylamine 50 RT -87 0 -6 62 h (IR, 2S)-(-)-norephedrine 28 -20 -84 -18 -24 62h (IR, 2S)-(-)-norephedrine 45 RT -80 -8 -9 a Percentage of total H P L C integral (chiral A D column) due to the disappearance of the corresponding starting material (after calibration using the response factor), b Diastereomeric excess (de) and enantiomeric excess (ee) values were measured on a Chiralpak A D column. The de values were calculated with the equation: de (%) = 125 (%) -124 (%). Sign of rotation for cyclobutanol 124 was obtained at the sodium D-line (589 nm). c For the high de cases, ee for the minor diastereomer 125 is immeasurable (UM). The sign of ee for minor product 125 is not the sign of rotation, but calculated from the equation: ee (%) = peak A (%) - peak B (%). Peak A and peak B are shown in Figure 3.24. 104 Chapter 3 Results and Discussion 3.5 Molecular Mechanics Calculations and X-ray Crystallographic Studies 3.5.1 Bicyclo[2.2.2]octyl Substrates Ester 55 was studied by molecular mechanics calculations, and acid 54 and salts 56a-b were studied by X-ray crystallography (Table 3.23 and Figure 3.25). Because there are no Norrish type II cleavage products formed in all bicyclic substrates, cleavage parameters (cpi and 94) wil l not be discussed in this section. The lowest energy conformation (55-1, Figure 3.25(A)) of ester 55 is similar to the X-ray structure of acid 54 (Figure 3.25(a)), because there is a similarity in the carbonyl oxygen position (the carbonyl oxygen is situated much closer to y hydrogen H a than Ha>) and in the aryl group orientation (the phenyl ring faces H a ) . From the hydrogen abstraction and cyclization parameters described in the Introduction section, it was found that the crystal structure of acid 54 and conformer 55-1 (the lowest energy conformer) presented in Table 3.23 have parameters (co, A, 0) within favorable limits of the "ideal" values. Because there is no significant difference in the values of the angles co, A and 6 among different crystal structures studied in this project, in the following part of this thesis, only the d, P and D values among hydrogen abstraction and cyclization parameters are discussed to rationalize the enantioselectivity, diastereoselectivity and photostability. Although hydrogen abstractions have been observed at distances (d) up to 3.15 A , 1 0 1 studies of Norrish type II abstraction have shown that, in a competitive situation, a difference in the distance (d) of only 0.27 A wil l lead to exclusive abstraction of one hydrogen over the other.102 There are no crystal structures of salts 56d-g obtained; however, it is reasonable to assume that salts 56d-g might crystallize in a conformation similar to conformer 55-1 and the differentiation between the two enantiotopic y hydrogens and topochemical control account for the high enantiomeric excess observed for these compounds, which will be described in the following section. The second lowest energy conformation (55-2) of ester 55 is similar to the X-ray structures of salts 56a and 56b, because there is a similarity among them in the carbonyl oxygen position (the carbonyl oxygen is located nearly equidistant from y hydrogens H a and Ha> as shown in Figure 3.25 and Table 3.23) and in the aryl group orientation (the phenyl ring bisects H a -H a ' ) . Salts 56a and 56b are photochemically inert. The reason 105 Chapter 3 Results and Discussion could be that the large (3 and D values retard the rate of ring closure of the biradical. Previous studies in the Scheffer group showed that reverse hydrogen transfer is dominant when the D value is as large as -3.2 A 1 0 3 or the (3 value is as large as 68°. 3 0 For salts 56a and 56b, both P and D values are very close to these critical upper limit values as shown in Table 3.23. Table 3.23 Hydrogen abstraction and cyclization parameters for bicyclo[2.2.2]octyl substrates conformer notes y-H d(A) O A(°) 0(°) D(A) 55-1 the lowest energy conformer a 34 2.71 63 84 100 3.08 a' 3.56 55-2 the second lowest energy conformer a 61 2.43 28 105 112 3.19 a' 60 2.47 38 97 116 3.24 54 X-ray structure a 29 2.65 62 78 114 3.02 similar to 55-1 a' 3.71 56a X-ray structure a 57 2.46 35 94 123 3.14 similar to 55-2 a' 65 2.55 25 98 118 3.20 56b a X-ray structure a 68 2.46 24 97 123 3.20 similar to 55-2 a' 52 2.58 36 94 118 3.17 b 69 2.46 24 98 122 3.19 b' 52 2.59 36 94 117 3.16 1UV1V U1V L * T V/ UIWV^ VUUVUV •VUM.A.A.VA.Xl.W.U M.M.M. ** w J — } j O U one conformer; y hydrogens b and b' are also enantiotopic but in the other conformer. : enantiotopic in 106 Chapter 3 Results and Discussion (a): 54 Figure 3.25 Conformers obtained by M M + calculations and X-ray crystallographic studies for bicyclo[2.2.2]octyl ketones. (A) Conformer 55-1, the lowest energy (36.00 Kcal/mol) conformer of ester 55 (MM + ) ; (a) the conformer from the crystal structure of acid 54. 107 Chapter 3 Results and Discussion (b-1) (b-2) (b): 56b Figure 3.25 (Continued) (B) conformer 55-2, the second lowest energy (36.26 Kcal/mol) conformer of ester 55 (MM + ) ; (b) the two conformers (b-1 and b-2) in the crystal structure of salt 56b; the conformation of crystal 56a (not shown in the Figure) is virtually same as b-1 in crystal 56b and the conformer 55-2 (MM"1). 108 Chapter 3 Results and Discussion 3.5.2 Bicyclo[2.2.1]heptyl Substrates Ester 58 was studied by molecular mechanics calculations, and ester 58 and salt 59d were studied by X-ray crystallography (Table 3.24 and Figure 3.26). It was found that the lowest energy conformation (58-1) of ester 58 predicted by M M + is similar to its X-ray structure and that of salt 59d, because there is a similarity among them in the carbonyl oxygen position (the carbonyl oxygen is located nearly equidistant from y hydrogens H a and H a ' as shown in Figure 3.26 and Table 3.24) and in the aryl group orientation (the phenyl ring bisects H a-H a-). It is thus not surprising that salt 59d gave modest ee (~ 38%) as shown in Table 3.20. The rationale for this result will be described in the following section. The higher energy conformations (58-2, 58-3, 58-4) as shown in Figure 3.26 have not been found by X-ray crystallography. Although only one salt (59d) has had its X-ray crystal structure determined, all 13 salts of acid 57 gave moderate to low ee's, which suggests most salts might crystallize in the lowest energy conformation (58-1). Due to the unavailability of an X-ray structure for acid 57 and salt 59a, no evidence can be provided to explain their photostability. However, we may speculate that its photostability could also be due to high D and P values, the same reason as for salts 56a-b. The lowest energy conformer 58-1 (MM + ) shows a D value of 3.23 A (larger than 3.20 A) and a p value of 61° (close to 68°). This result is also consistent with the low photocyclization rate of other salts of acid 57 (Their quantum yield were not determined, but the solid state photocyclizations were completed after 24 hours for most bicyclo[2.2.1]heptyl ketones; most of the other Yang photocyclizations in this thesis can be finished in less than 5 hours). 109 Chapter 3 Results and Discussion Table 3.24 Hydrogen abstraction and cyclization parameters for bicyclo[2.2.1]heptyl substrates ft Ha Ar / a / Y 4 2A1A O H > f ^ A r - # O H 3 1Jk-nL W \ V conformer notes y-H- PO d(A) co(°) A(°) 9(°) D(A) 58-1 the lowest energy conformer 2a 61 2.59 28 108 103 3.23 2a' 61 2.59 28 108 103 3.23 58-2 the second lowest energy conformer 2a 27 2.99 39 90 91 3.10 2a' 4.48 58-3 the third lowest energy conformer 2a 23 2.64 65 82 118 3.14 2a' 5.00 58-4 the fourth lowest energy conformer l a 29 2.85 64 84 102 3.17 la ' 3.43 2a 26 3.54 41 41 104 3.14 2a' 4.63 58 X-ray structure 2a 55 2.63 20 103 107 3.20 similar to 58-1 2a' 67 2.74 32 97 108 3.21 59d X-ray structure 2a 60 2.58 12 102 108 3.16 similar to 58-1 2a' 64 2.71 11 100 108 3.14 * H , a and H l a ^ are two enantiotopic y hydrogens in one-carbon bridge. H 2 a , H 2 a ' are enantiotopic y hydrogens in two-carbon bridge. 110 Chapter 3 Results and Discussion (a,): 58 (a2): 59d (A): 58-1 (B): 58-2 (C): 58-3 (£)): 58-4 Figure 3.26 Conformers obtained by M M + calculations and X-ray crystallographic studies for bicyclo[2.2.1]heptyl substrates, (ai) The conformer in the crystal of ester 58; (a2) the conformer (anion part) in the crystal of salt 59d; (A), (B), (C), (D) are calculated conformers of ester 58 with total energy 39.43, 39.49, 39.62, and 39.82 Kcal/mol, respectively. In the ORTEP representations ai and a2, the carbonyl oxygen is colored red, Y-hydrogen H a green and H a blue. i l l Chapter 3 Results and Discussion 3.5.3 Dimethylated Bicyclo[2.2.1]heptyI Substrates Ester 61 was studied by molecular mechanics calculations, and ester 61 (X=COOMe) and its derivatives 110 (X=CN), 109 (X=F), 60 (X=COOH), 62a (R(-)-l-cyclohexylethylamine salt), 62c ((IR, 2S)-(+)-cw-l-amino-2-indanol salt), 62e (L-prolinamide salt) were studied by X-ray crystallography (Table 3.25 and Figure 3.27). It was interesting to find that the lowest energy conformation (61-1) of ester 61 is similar to the X-ray structures of compounds 110, 109, 60 and 62a, because there is a similarity among them in the carbonyl oxygen position (the carbonyl oxygen is situated between the one-carbon bridge and the two-carbon bridge with a distance much closer to y hydrogen H a than Ha-) and in the aryl group orientation (the phenyl ring faces the hydrogens at the one-carbon bridge); the second lowest energy conformation (61-2) is similar to the X-ray structure of ester 61, because there is a similarity between them in the carbonyl oxygen position (the carbonyl oxygen is close to a y hydrogen at the one-carbon bridge) and in the aryl group orientation (the aryl group points to the two-carbon bridge side); and the third lowest energy conformation (61-3) is similar to the X-ray structures of salts 62c and 62e, because there is a similarity among them in the carbonyl oxygen position (the carbonyl oxygen is situated between the two two-carbon bridges and is much closer to y hydrogen Ffa than H a ) and in the aryl group orientation (the phenyl ring faces hydrogen Ha<). No X-ray crystal structure was found with the fourth lowest energy conformation (61-4), in which the carbonyl oxygen is situated equidistant from y hydrogens H a and H a -between the two-carbon bridges. As shown in Table 3.25, the hydrogen abstraction and cyclization parameters for all substrates are within favorable limits of the "ideal" values. Upon photolysis, all substrates underwent rapid Norrish/Yang photocyclization to form cyclobutanols. The structure-reactivity correlation will be discussed in the following section. It is interesting to note that, as shown in Figure 3.28, conformations 58-1, 58-2, 58-3 and 58-4 of the bicyclo[2.2.1]heptyl ketones are similar (in carbonyl oxygen position and aryl group orientation) to conformers 61-4, 61-3, 61-1, and 61-2 in the dimethylated bicyclo[2.2.1]heptyl ketones respectively. 112 Chapter 3 Results and Discussion Table 3.25 Hydrogen abstraction and cyclization parameters for dimethylated bicyclo[2.2.1]heptyl substrates conformer notes y-H* PO d(A) o A(°) 0(°) D(A) 61-1 the lowest energy conformer 2a 19 2.59 67 78 118 3.06 2a' 5.07 61-2 the second lowest energy conformer l a 35 2.74 61 90 107 3.22 la ' 3.56 2a 18 3.26 48 48 108 3.03 2a' 4.79 61-3 the third lowest energy conformer 2a 9 2.76 57 83 105 2.90 2a' 4.46 61-4 the fourth lowest energy conformer 2a 59 2.38 30 114 103 3.14 2a' 65 2.47 30 112 104 3.23 110 X-ray structure 2a 4 2.88 62 65 120 3.01 similar to 61-1 2a' 5.05 109 X-ray structure 2a 3 2.96 59 60 119 2.99 similar to 61-1 2a' 5.03 60 X-ray structure 2a 6 2.83 63 66 119 3.00 similar to 61-1 2a' 5.03 61 X-ray structure l a 46 2.61 42 96 112 3.20 similar to 61-2 l a ' 3.40 2a 4 3.06 55 56 112 2.99 2a' 4.70 62a X-ray structure 2a 1 2.96 61 60 119 3.01 similar to 61-1 2a' 5.08 62c X-ray structure 2a 6 3.28 62 63 94 3.05 similar to 61-3 2a' 4.02 62e X-ray structure 2a 7 3.11 67 66 95 2.98 . similar to 2a' 3.84 61-3 H l a and H l a hydrogens in are two enantiotopic y hydrogens in the one-carbon bridge. H 2 a , H 2 a ' are enantiotopic y the two-carbon bridge. 113 Chapter 3 Results and Discussion (c2): 62e (C): 61-3 (D): 61-4 Figure 3.27 Conformers obtained by M M + calculations and X-ray crystallographic studies for dimethylated bicyclo[2.2.1]heptyl substrates, (a), (b), (ci), (c2) are the conformers in the crystals of compounds 62a (anion part), 61, 62c (anion part), 62e (anion part); (A), (B), (C), (D) are calculated conformers of ester 61 with energy 42.41, 43.20, 43.64, and 44.69 Kcal/mol respectively. In the ORTEP representations, the carbonyl oxygen is colored red, the y hydrogen H a green and Ha> blue. 114 Chapter 3 Results and Discussion Ketone 58 Dimethylated ketone 61 the fourth lowest energy conformer 58-4 fj-l the third lowest energy conformer the second lowest energy conformer the lowest energy conformer 53.1 61-1 Figure 3.28 Conformational correlations between bicyclo[2.2.1]heptyl ketone 58 and dimethylated bicyclo[2.2.1]heptyl ketone 61 by M M + calculations. 115 Chapter 3 Results and Discussion 3.5.4 Molecular Mechanics Calculations on Yang photocyclization Products Figure 3.29 Possible Norrish type II photocyclization products. The geometry (obtained from X-ray crystallography or predicted from molecular modeling) of the parent ketones has been used successfully in explaining 1,4-hydroxybiradical reactivity in solid state Norrish type II reactions.60 However, previous studies in the Scheffer group showed that a full understanding of the results requires consideration of the strain energy of the cyclization products.92 Molecular mechanics 116 Chapter 3 Results and Discussion calculations were also conducted to estimate the relative strain energy and total energy of (potential) Yang photocyclization products in this thesis.104 Ester 55 has 6 y-hydrogens and in theory can (by the Norrish/Yang photocyclization mechanism shown in Figure 1.7) undergo y-hydrogen abstraction to form cyclobutanols 115 and 116 (Figure 3.29). By M M + calculation, it was found that cyclobutanol 116 has a slightly lower total energy and strain energy than cyclobutanol 115 as shown in Table 3.26. The photochemical studies of ester 55 (See section 3.3.1) showed cyclobutanol 116 is the major photoproduct both in solution (116/115- 68/32) and the solid state (116/115-93/7). Ester 58 has 6 y-hydrogens and its possible Yang photocyclization products are cyclobutanols 119-120, 127-130. However, only cyclobutanols 119-120 were isolated. This might be due to the fact that cyclobutanols 127-130 have significantly higher total energy and strain energy than cyclobutanols 119-120 as shown in Table 3.26. Cyclobutanol 119 has a slightly higher total energy and strain energy than cyclobutanol 120; however, photochemical studies of ester 58 (section 3.3.3) showed that cyclobutanol 119 was formed preferentially both in solution (119/120 - 53/47) and the solid state (119/120- 65/35). This will be discussed in the next section of structure-reactivity studies using topochemical expectations. Ester 61 also has 6 y-hydrogens and its possible Norrish type II photocyclization products are cyclobutanols 124-125 and 131-134 as shown in Figure 3.29. However, only cyclobutanols 124-125 were isolated. This might also be due to the fact that cyclobutanols 131-134 have significantly higher total energy and strain energy than cyclobutanols 124-125 as shown in Table 3.26. Cyclobutanol 124 has a slightly higher total energy and strain energy than cyclobutanol 125; however, photochemical studies of ester 61 (section 3.3.5) showed that cyclobutanol 124 was formed preferentially both in the solid state (124/125- 64/36) and solution (124/125- 84/16). This result will also be discussed in the next section. The formation of minor photoproduct ketone 126 probably proceeds via the mechanism shown in Figure 3.30; a similar photoproduct was also formed in the 70 photolysis of the adamantyl ketones studied by Jie Yang. Although the formation of minor photoproduct 126 is thermodynamically favorable (total energy, 38.79 Kcal/mol; 117 Chapter 3 Results and Discussion strain energy, 25.80 Kcal/mol; angle strain, 14.44 Kcal/mol), it is not a topochemically favorable photoproduct. The nearest distance (D126) from carbon 5 to carbon 6 (Figure 3.30) is greater than 3.20 A (in conformer 61-1, DU6 = 4.87 A ; in conformer 61-2, Dj 2 6 = 3.32 A ; in conformer 61-3, Dm = 4.55 A; in conformer 61-4, D ] 2 6 = 5.16 A). Table 3.26 Molecular mechanics studies on possible cyclobutanol photoproducts molecule total energy strain energy angle strain (kcal/mol) (kcal/mol) (kcal/mol) 116 74.93 57.78 44.46 115 76.86 59.38 45.44 120 75.53 65.87 55.48 119 77.57 67.57 56.53 128 100.54 88.15 76.69 127 99.22 86.73 75.75 129 93.38 82.40 70.01 130 92.03 80.39 68.64 125 78.40 67.88 57.06 124 84.21 71.97 59.08 132 107.08 92.23 78.88 131 102.15 88.62 76.67 133 101.47 87.64 73.64 134 96.68 83.38 70.41 126 Figure 3.30 Proposed mechanism for the formation of ketone 126 To conclude this section, highly strained cyclobutanols (127-130 and 131-134 with high angle strain1 0 5) were not detected either in solution or the solid state. 118 Chapter 3 Results and Discussion 3.6 Structure-reactivity Studies 3.6.1 Topochemical Control Reactions 3.6.1.1 Structure-reactivity Analysis of Bicyclo[2.2.2]octyl Substrates No X-ray crystal structures were obtained for salts 56c-g (high ee's achieved). However, organic molecules generally crystallize in or near their minimum energy conformations.5 Assuming one of salts 56c-g crystallized in the lowest energy conformation (55-1) in the asymmetric unit as shown in Figure 3.25(A), its solid state photochemical diastereoselectivity and enantioselectivity can be analyzed as follows. As shown in Table 3.24, only y-hydrogen H a is within the proposed hydrogen abstraction distance of 2.7 ± 0.2 A (0-H a , 2.71 A). In conformer 55-1 (Figure 3.31), there are two diastereotopic carbonyl faces (re and si) and the carbonyl si face is closer to the reacting y-hydrogen H a than the corresponding re face. Upon photolysis, only y-hydrogen H a is abstracted to form biradical 55-1-BR-l. In biradical 55-1-BR-l, there are another two diastereotopic faces (re and si) at the radical-bearing carbon 6. As shown in Figure 3.31, there are four possible pathways for forming a single bond between the two radical centers in intermediate 55-1-BR-l. Pathway 1 involves bond formation between the si face of the p orbital at C l and the si face of the p orbital at C6 (Cl si + C6 si), to give rrans-cyclobutanol 115(1S) with the (S) absolute configuration at C l . Pathway 2, C l si + C6 re, gives cw-cyclobutanol 116(1S) with the C1(S) absolute configuration; pathway 3, C l re + C6 si, gives cw-cyclobutanol 116(1R) with the C1(R) absolute configuration; pathway 4, C l re + C6 re, gives fr-ans-cyclobutanol 115(1R) with the C1(R) absolute configuration. Among these four possible pathways, pathway 1 involves the least motion (direct radical coupling without rotation (a) or (b)); therefore, Jrans-cyclobutanol 115(1S) is the topochemically favored photoproduct. In contrast, pathways 2, 3 and 4 require certain molecular motions (rotation (a) and/or rotation (b)) to bring the corresponding p orbital lobes into position for bond formation. However, cz's-cyclobutanol 116 is the major photoproduct for all salts 56, ester 55 and acid 54, both in the solid state and solution (sections 3.3.1 and 3.4.1.2). Previous studies on a-adamantyl acetophenones in the Scheffer group showed that the rotation of the adamantyl group (C3 symmetry) around the C2-C3 bond (called rotation a) is considered to involve the least hindrance 119 Chapter 3 Results and Discussion (Figure 3.32), because this movement does not require much void space. /y On the other hand, the rotation of the phenone-salt moiety around C1-C2 bond (called rotation b), which requires more void space, is topochemically disallowed. Bicyclo[2.2.2]octyl substrates have C3 symmetry and rotation (a) should also be topochemically allowed. Recalling the M M + calculations (Table 3.26), cw-cyclobutanol 116 has lower energy than rra/is-cyclobutanol 115. As we know that the more stable product is also the one that is formed faster in many cases,106 it is reasonable to speculate that the lower energy photoproduct cyclobutanol 116 (the major diastereomer) is formed faster than cyclobutanol 115 (the minor diastereomer) as shown in Figure 3.33 (a similar rationale was used in the studies of adamantyl ketones by Jie Yang 7 9). The formation of 116(1R) and 115(1R), which involve the topochemically disallowed rotation (b), should be unfavorable. This explains why high ee's for both cyclobutanol 115 and 116 were obtained for most salts 56. 120 Chapter 3 Results and Discussion /K\ >l I I I I M ,\ 3 1 Ar (\ O O s / O re R = n-pentyl 55-1 hu I solid state 55-1-BR-2 I rotation b -180° 55-1-BR-3 least motion radical coupling pathway 1 C1 si + C6 si radical coupling 1 .Ar pathway 2 C1 si + C6 re 2 radical 1 >pHa coupling pathway 3 Ar C1 re + C6 si H b 116(1R) Ar radical coupling a pathway 4 C1 re + C6 re 55-1-BR-4 121 Chapter 3 Results and Discussion Figure 3.31 The solid state reactivity of conformer 55-1 2 ( f r o n t C ) 1 ( r e a r C ) + cr ~0 R N H 3 rotation (a) phenone-salt moiety 2 ( f r o n t C ) 1 ( r e a r C ) RNhU i 1 • i • i i i rotation (b) phenone-salt moiety Figure 3.32 The rotations (a) and (b) (same as the rotations in pathways 2, 3, and 4 shown in Figure 3.31) 122 Chapter 3 Results and Discussion Figure 3.33 Free energy profile for rationalizing the diastereoselectivity in the photolysis of bicyclo[2.2.2]octyl ketones. 123 Chapter 3 Results and Discussion 3.6.1.2 Structure-reactivity Analysis of Bicyclo[2.2.1]heptyl Substrate 59d The X-ray crystal structure of salt 59d (Figure 3.26(a2)) shows that the carbonyl oxygen is situated nearly equidistant from y-hydrogens F£a and H a - (0-H a , 2.58 A; 0-F£a-, 2.71 A). Both y-hydrogens Ffa and H a - should therefore be abstractable. As shown in Figure 3.34, abstraction of y-hydrogen F£a forms biradical 59d-BR-l upon photolysis. Analysis similar to that used in the previous section is shown in Figure 3.34 and reveals that there are four possible pathways for forming a single bond between the two radical centers of intermediate 59d-BR-l. Pathway 1 involves bond formation between the re face of the p-orbital at C l and re face of the />-orbital at C6 (Cl re + C6 re) to give trans-cyclobutanol 119(1R) with the C1(R) absolute configuration. Pathway 2, C l si + C6 re, gives cw-cyclobutanol 120(1S) with the C1(S) absolute configuration; pathway 3, C l si + C6 si, gives rrarcs-cyclobutanol 128(1S) with the C1(S) absolute configuration; pathway 4, C l re + C6 si, gives c/s-cyclobutanol 127(1R) with the C1(R) absolute configuration. Among these four possible pathways, pathway 1 involves the least motion (direct radical coupling without rotation (a) or (b)); therefore, cz's-cyclobutanol 119(1R) is the topochemically favored photoproduct. In contrast, pathways 2, 3 and 4 require certain molecular motions (rotation (a) and/or rotation (b)) to bring the corresponding ^-orbital lobes into position for bond formation. Photochemical studies of salt 59d (section 3.4.2.2) showed that rrans-cyclobutanol 119 is the major photoproduct in the solid state (119/120 ~ 69/31). This result is in agreement with the topochemical analysis: the major photoproduct is the topochemically favored rra«^-cyclobutanol 119 via pathway 1. This result also suggests that rotation (a) in pathway 2 (for the formation of cyclobutanol 120), involving the rotation of the bicyclo[2.2.1]heptyl group (without C 3 symmetry), requires more void space than rotation of the bicyclo[2.2.2]octyl and adamantyl groups that have C3 symmetry. Cyclobutanols 127 and 128 (via pathways 3 and 4) were not isolated in the photolysis, which might be due to the following: (1) they are highly strained (angle strain) compounds; (2) pathways 3 and 4 are non-topochemical processes involving rotation (b). Considering another hydrogen abstraction (H a') in salt 59d, biradical coupling gives rrans-cyclobutanol 119(1S) following direct ring-closure and c/'s-cyclobutanol 120(1R) following rotation (a) and then ring-closure. Because the carbonyl oxygen has almost the 124 Chapter 3 Results and Discussion same distance to y-hydrogens H a and H a ' , low ee is expected for both rrans-cyclobutanol 119 and cz's-cyclobutanol 120. Two facts account for the low but measurable 30-40 % ee's for both rraws-cyclobutanol 119 and a's-cyclobutanol 120: (1) the 0 - H a and 0-H a-distances are not exactly equal (2.58 versus 2.71 A); (2) the biradical intermediates are diastereomerically related when the presence of the ammonium ion is considered, so they react at slightly different rates. 125 Chapter 3 Results and Discussion Hb' least motion radical ,»\Ar coupling pathway 1 3 C1 re + C6 re radical coupling pathway 2 C1 si + C6 re 59d-BR-2 | rotation b -90° radical coupling pathway 3 C1 si + C6 si 59d-BR-3 radical coupling pathway 4 C1 re + C6 si 59d-BR-4 Figure 3.34 The solid state reactivity of salt 59d O si CZ) re 5 6 i Ar 119(1R) 5 Hill II Hill 11^, 127(1R) 126 Chapter 3 Results and Discussion 3.6.1.3 Structure-reactivity Analysis of Dimethylated Bicyclo[2.2.1]heptyl Substrate 62a The X-ray crystal structure of salt 62a showed that the carbonyl oxygen is situated closer to y-hydrogen 6H a than 5H a ' (0-6H a , 2.96 A; 0-5H a ' , 5.08 A). As a result only y-hydrogen 6H a is abstractable. As shown in Figure 3.35, abstraction of y-hydrogen 6H a forms biradical 62a-BR-l upon photolysis. Similar analysis as in the previous sections is shown in Figure 3.35 and indicates that there are four possible pathways for forming a single bond between the two radicals in the intermediate 62a-BR-l. Pathway 1 involves bond formation between the re face of the p-orbital lobe at C l and the re face of the p-orbital lobe at C6 (Cl re + C6 re), to give rrans-cyclobutanol 124(1R) with the C1(R) absolute configuration. Pathway 2, C l re + C6 si, gives czs-cyclobutanol 131(1R) with the C1(R) absolute configuration; pathway 3, C l si + C6 re, gives ds-cyclobutanol 125(1S) with the C1(S) absolute configuration; pathway 4, C l si + C6 si, gives trans-cyclobutanol 132(1 S) with the C1(S) absolute configuration. Among these four possible pathways, pathway 1 involves the least motion (direct radical coupling without rotation (a) or (b)); therefore, fraws-cyclobutanol 124(1R) is the topochemically favored photoproduct. In contrast, pathways 2, 3 and 4 require certain molecular motions (rotation (a) and/or rotation (b)) to bring the corresponding />-orbital lobes into position for bond formation. Photochemical studies of salt 62a (section 3.4.3.2) showed that trans-cyclobutanol 124 is the dominant photoproduct in the solid state (124/125 ~ 98/2). This result agrees that the major photoproduct is the topochemically favored trans-cyclobutanol 124 via pathway 1, and also suggests that rotation (b) in pathway 3 is disfavored to form minor photoproduct 125. Cyclobutanols 131 and 132 (via pathways 2 and 4) were not isolated, and the reason might be: (1) they are highly strained (angle strain) compounds; (2) pathways 2 and 4 are non-topochemical processes involving rotations (a) and/or (b). Hydrogen abstraction of 5H a ' in salt 62a, followed by biradical coupling, gives trans-cyclobutanol 124(1S) (with direct ring-closure) and m-cyclobutanol 125(1R) (with rotation (b) and then ring-closure). However, hydrogen abstraction from 5H a ' is disallowed because of a high d value (5.08 A). This accounts for the near-quantitative ee for rrans-cyclobutanol 124 in the photolysis of salt 62a. The high ee in the solid state 127 Chapter 3 Results and Discussion photolysis of bicyclo[2.2.2]octyl ketones was ascribed to the differentiation in the biradical ring-closure (least motion versus rotation b) in section 3.6.1.1; however, the differentiation in hydrogen abstraction (H a versus H a ' ) , which is used in bicyclo[2.2.1]heptyl ketones, also could be used in rationalizing the high ee's in bicyclo[2.2.2]octyl ketones. 128 Chapter 3 Results and Discussion H aO rotation b 62a-BR-2 62a-BR-3 rotation a O si 3^ re least motion radical coupling pathway 1 C1 re + C6 re radical coupling pathway 2 C1 re + C6 si radical coupling pathway 4 C1 si + C6 s/ 124(1R) .Ar H H aO 131(1R) radical coupling pathway 3 C1 s;' + C6re 125(1S) 132(1S) 62a-BR-4 Figure 3.35 The solid state reactivity of salt 62a 129 Chapter 3 Results and Discussion 3.6.2 Non-topochemical Control Reactions The diastereoselectivity and/or enantioselectivity (the sign of rotation for the major photoproduct) in the solid state photolysis of salts 62c, 62e and ester 61 in the dimethylated bicyclo[2.2.1]heptyl ketones can not be rationalized using topochemical expectations. No firm evidence can be provided to explain the results. The topochemical analysis of substrates 62e and 61 followed by non-topochemical speculations will be described in this section. The analysis of salt 62c is virtually the same as salt 62e because they are near-mirror-image-related. The X-ray structure of salt 62e showed that the carbonyl oxygen is situated closer to y-hydrogen 6H a than 5H a- (0-6H a , 3.11 A; 0-5Ha>, 3.84 A). Although a d value of 3.11 A is significantly greater than the ideal d value of 2.7 ± 0.2 A, hydrogen abstractions over distances as great as 3.15 A have been recorded.101 Assuming that y-hydrogen 6H a is the only abstractable hydrogen, biradical 62e-BR-l will be formed upon photolysis as shown in Figure 3.36. Analysis similar to that used in the previous sections is shown in Figure 3.36, which indicates that there are four possible pathways for forming a single bond between the two radical centers in the intermediate 62e-BR-l. Pathway 1 involves bond formation between the re face of the p-orbital lobe at C l and the re face of the /?-orbital lobe at C6 (Cl re + C6 re), to give m-cyclobutanol 125(1R) with the C1(R) absolute configuration. Pathway 2, C l re + C6 si, gives rraws-cyclobutanol 132(1R) with the C1(R) absolute configuration; pathway 3, C l si + C6 re, gives rrans'-cyclobutanol 124(1S) with the C1(S) absolute configuration; pathway 4, C l si + C6 si, gives cis-cyclobutanol 131 (IS) with the C1(S) absolute configuration. Among these four possible pathways, pathway 1 involves the least motion (direct radical coupling without rotation (a) or (b)); therefore, /ra/is-cyclobutanol 125(1R) is the topochemically favored photoproduct. In contrast, pathways 2, 3 and 4 require certain molecular motions (rotation (a) and/or rotation (b)) to bring the corresponding />-orbital lobes into position for bond formation. Photochemical studies of salt 62e (section 3.4.3.2) showed that rrans-cyclobutanol 124 is the dominant photoproduct in the solid state (124/125 ~ 88/12). This result suggests that pathway 3 (formation of 124(1S) via rotations a and b) is favored over pathway 1 (formation of 125(1R) without rotations a and b), which is seriously against topochemical 130 Chapter 3 Results and Discussion expectations. It was also found that the predicted configurations of photoproduct 124 (using topochemical analysis) were not consistent with the sign of rotation of photoproduct 124 as shown in Table 3.27. Photoproduct 124 was found to be (-), (-), and (+) from the photolysis of salts 62a, 62e, 62c respectively (Table 3.22), but the predicted absolute configurations were (IR) (from Figure 3.35), (IS) (from Figure 3.36), (IR) (the conformation of 62c and 62e are near mirror-image-related, see Figure 3.27). No obvious explanation is available to rationalize these results. Due to the high d value (3.11 A) in the crystal of salt 62e, hydrogen abstraction might be very slow and reverse hydrogen transfer might be fast; therefore, the formation of cyclobutanol 125 via pathway A would be retarded in the solid state (Figure 3.37). Alternative pathway (B) might be dominant, in which reversible type I cleavage in the crystal might change the conformation (In Figure 3.37: 62e, the carbonyl oxygen points down —» 62e-Ia —> 62e-Ib —> 62e-b, the carbonyl oxygen points up) so seriously that the d value in 62e-b are feasible for Norrish type II reaction to form cyclobutanol 124. Only 1-10 % type I cleavage photoproduct 135 (Figure 3.37: (i) hydrogen transfer to form the aldehyde; (ii) oxidation in the air to form the acid; (iii) treating with diazomethane to form ester 135) was found by GCMS in the photolysis of all dimethylated bicyclo[2.2.1]heptyl ketones in both solid state and solution. Ester 135 has not been found in the photolysis of bicyclo[2.2.1]heptyl ketones. Table 3.27 Comparison of the predicted configuration and sign of rotation substrate measured sign of rotation [a] a for photoproduct 124 predicted absolute configuration at C l for photoproduct 124 62a - (IR) (from Figure 3.35) 62e - (IS) (from Figure 3.36) 62c + (IR) (the anion parts of salts 62c and 62 e are near mirror-image-related) Signs of rotation were determined at the sodium D-line. 131 Chapter 3 Results and Discussion 62e-BR-1 125(1 R) r o t a t i o n a -108° 62e-BR-3 rotation a -108° Figure 3.36 The solid state reactivity of salt 62e 132 Chapter 3 Results and Discussion 62e-1-BR O H a sA r radical coup l ing \ retention pathway A . O H a 125 Minor diastereomer solid state [o] HO' / ? C H 2 N 2 ^ \ in " M e O O C — ( \ />—< Ar 135(1-10%) trace photoproduct H a Ar conformation 6 change H b 62e C = C . H a distance: 3.11 A radical 6 3 coupling H b retention 5 •124 pathway B Major diastereomer 62e-b-BR Figure 3.37 Proposed mechanism for salt 62e Another compound that behaves in a non-topochemical manner is ester 61. The X-ray crystal structure of ester 61 shows that the carbonyl oxygen is situated closer to f hydrogen 4 H i a at the one-carbon bridge ( 0 - 4 H i a , 2.61 A; 0-4Hi a >, 3.40 A). Abstraction of hydrogen 4 H i a would form cyclobutanols 133 and 134. However, the M M + calculations (Table 3.26) show that both cyclobutanols 133 and 134 are highly strained molecules; therefore, formation of these cyclobutanols should be disfavored as shown in Figure 3.38. Photochemical studies of ester 61 (section 3.3.5) showed that /ram-cyclobutanol 124 is the dominant photoproduct in the solid state (124/125 ~ 84/16). Again, there is no clear explanation for the formation of major photoproduct 124 from the photolysis of ester 61 in the solid state. A possible pathway is shown in Figure 3.39. The distance from the carbonyl oxygen to a y-hydrogen 6H2 a at a two-carbon bridge is 3.06 A, and the abstraction of 6H2 a followed by radical coupling forms cyclobutanols 124 and 125 by the same pathway as salts 62c and 62e. Again, due to the high d value (3.06 A) in the crystal 133 Chapter 3 Results and Discussion of ester 61, hydrogen abstraction might be very slow, and reversible type I cleavage in the crystal (Figure 3.39) might change the conformation so seriously (non-topochemical process, unpredictable) that the d value becomes feasible for the Norrish type II reaction. 61 61-BR-1 1 3 3 1 3 4 C=O. . .H 1 a distance: 2.61 A Figure 3.38 The solid state reactivity of ester 61 C=O.. .H 2 a distance: 3.06 A ^ same as 62c Pathway A transfer 61-BR-1 Pathway B Figure 3.39 The possible pathway for the solid state photolysis of ester 61 The conformation change via a reversible type I reaction must involve large motion. However, large motions during solid state reactions are certainly known. A thermal solid 107 state reaction, illustrated in Figure 3.40, comes from the research of Toda et al. When crystals of the thermally labile diallene 136 are heated to 150 °C, a spontaneous electrocyclic rearrangement takes place with dimefhylenecyclobutene 137 being formed. 134 Chapter 3 Results and Discussion Figure 3.40 Large motions involved in a thermal crystalline state reaction. To conclude this section, we speculate that the non-topochemical process might become dominant when the hydrogen abstraction parameter d value is significantly greater than the ideal value of 2.7 ± 0.2 A (For salt 62e, 0 -6H 2 a = 3.11 A ; for salt 62c, O-6 H 2 a = 3.28 A; for ester 61, 0 -6H 2 a = 3.06 A). 3.7 Summary Solid state unimolecular reactions such as the Norrish/Yang photocyclization, are usually controlled by molecular conformation, since specific intermolecular packing arrangements are generally not required. Because organic molecules generally crystallize in or near their minimum energy conformations, it is a simple and useful matter to use molecular mechanics, which is frequently utilized in the Scheffer group, to search minimum energy conformations, and thereby make predictions concerning the probable success of hypothetical type II reactions in crystals. M y research project was also guided by conducting molecular mechanics calculations and comparing them with the data pool (molecular mechanics calculations and X-ray structural data) within the group. Using molecular mechanics calculations, it was found that the distances from the carbonyl oxygen to y-hydrogens Ffa and H a ' are 2.71 and 3.54 A respectively in the lowest energy conformation (55-1) of bicyclo[2.2.2]octyl ketone 55 (Figure 3.41). It is little wonder that the ee's are high for most salts 56 of the corresponding acid. In contrast, M M + calculations showed that bicyclo[2.2.1]heptyl ketone 58 has a Cs-symmetric minimum energy conformation (58-1 ih Figure 3.41) in which the carbonyl oxygen is equidistant (d = 2.59 A) from the enantiotopic y-hydrogens H a and H a ' on the 2-carbon 135 Chapter 3 Results and Discussion bridges and much further (d = 4.80 A) from the y-hydrogens on the 1-carbon bridge. Such a conformation is poorly suited for high levels of asymmetric induction, since this requires selective abstraction of H a over H a - . The asymmetric induction studies are in agreement with this expectation, since low ee's (average -35 %) were obtained in the solid state photolysis of bicyclo[2.2.1]heptyl ketones. In seeking ways to achieve discrimination between y-hydrogens H a and H a ' , ester 61 was investigated by molecular mechanics. This showed that placing two methyl groups next to the carbonyl group should have the desired effect, since the minimum energy conformation (61-1) of the methylated analogue (Figure 3.41) situates the ketone oxygen much closer to H a than H a ' (2.59 A versus 5.07 A). Again, the asymmetric induction studies are in agreement with this in that near-quantitative ee's were obtained in the photolysis of dimethylated bicyclo[2.2.1]heptyl ketones. Overall, therefore, molecular mechanics predicts that derivatives of ester 61 (salt 62) have a much better chance of giving high levels of asymmetric induction than those from ester 58. In this way, molecular mechanics serves as a basis for crystal engineering. Although the multistep synthesis of dimethylated bicyclo[2.2.1]heptyl ketones was challenging, M M + calculations indicated a good opportunity for achieving excellent ee for the dimethylated bicyclo[2.2.1]heptyl ketones before all laboratory work began. Moreover, high diastereoselectivity was achieved as an additional bonus. 136 Chapter 3 Results and Discussion 55-1 58-1 61-1 Figure 3.41 The lowest energy conformations (55-1, 58-1, 61-1) of esters 55, 58 and 61 identified by M M + calculation. The carbonyl oxygen is colored red, y-hydrogen H a (close to oxygen) green, y-hydrogen H a ' (enantiotopic with H a ) blue. M M + calculations did successfully predict molecular conformations in the solid state. However, exceptions do occur, because the second or the third lowest energy conformation is sometimes adopted in the crystalline state. This is probably one of the reasons why some salts lead to low ee's while others lead to near-quantitative ee's, a typical result in solid state asymmetric induction studies. However, a large commercially available chiral amine pool can be (and has been, for my substrates) tested to find some chiral amine salts with outstanding ee and/or de. Molecular mechanics, as a crystal engineering tool, is truly useful and successful in achieving high levels of enantioselectivity and diastereoselectivity for the Yang photocyclization of bicyclic aryl ketones. Previous studies3 0 , 7 9 in the Scheffer group showed that the photoreactions in Figure 3.42(1-3) gave a clean single product, and the photoreactions in Figure 3.42(4-6) gave a mixture of photoproducts. These results suggest that rotation around the C1-C2 bond is 137 Chapter 3 Results and Discussion seriously hindered when the a-carbon C2 is a quaternary carbon. The dimethyl group can not only change the conformation (change the C = 0 — H a and C = 0 — H a ' distances) to achieve high enantioselectivity, but also can hinder the rotation around C1-C2 bond to achieve high diastereoselectivity. Figure 3.42 Norrish type II reactions studied previously in the Scheffer group As with previous studies in the Scheffer group,68 in solution photolysis, the diastereoselectivity is low compared to that observed in the solid state, and enantioselectivity is completely lost, because rotations (a) and (b) become more feasible in solution and/or because unique chiral conformation that is present in the crystal does not necessarily exist in solution (or i f it does, would not be necessarily kept intact during 138 Chapter 3 Results and Discussion the photolysis). The solid state photostable substrates (with high D and p values) did react in solution phase photolyses, because the conformations with high D and p values in the solid state are not necessarily the same as those in solution, or i f the same, would not be immobilized in solution. Also in accord with previous studies,30'92 some solid state reactivity could not be explained by topochemical control and the conformation of the starting material only. Non-topochemical processes have been found in this research and their full understanding is currently a matter of speculation. Norrish type II solid state photochemical reactivity is the overall result of the competition between the following processes: (1) y-hydrogen abstraction (parameters: d, co, A, 0); (2) Yang cyclization (parameters D and P); (3) Norrish type II cleavage (parameters cpi and 94); (4) reverse hydrogen transfer; (5) the strain energy of the photoproducts; (6) single electron transfer (as in oxoamide substrates); (7) competing type I cleavage; (8) crystal disorder, crystal defects (before photolysis); (9) crystal breakdown (after photolysis); (10) molecular/atomic motion in the crystal (e.g. rotations (a) and (b) described above). Research in solid state chemistry and crystal engineering is still in its infancy. This is both an opportunity and a challenge for the chemistry community. 139 EXPERIMENTAL 140 C h a p t e r 4 E x p e r i m e n t a l C h a p t e r 4 Syn thes is o f S t a r t i n g M a t e r i a l s 4.1 G e n e r a l C o n s i d e r a t i o n s Infrared Spectra (IR) Infrared spectra were recorded on a Perkin-Elmer 1710 Fourier-transform spectrometer. Solid samples (~2 mg) were ground with IR grade K B r (100-200 mg) in an agate mortar and pelleted in an evacuated die (Perkin-Elmer 186-0002) with a laboratory press (Carver, model B) at 17,000 psi. Liquid samples were analyzed either neat as thin films between two sodium chloride plates or as chloroform solutions in a sodium chloride cell. The positions of selected absorption maxima (v m a x ) are reported in units of cm"1. Melting Points (mp) Melting points were determined on a Fisher-Johns hot stage apparatus and are uncorrected. When recrystallized samples were measured, the solvent of recrystallization is given in parenthesis. 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), and Bruker AV-400 (400 MHz). Chemical shifts (5) are reported in parts per million (ppm) and are referenced to the residual ! H solvent signals with tetramethylsilane (8 0.00 ppm) as an external standard: chloroform (7.24 ppm), benzene (7.16 ppm), dichloromethane (5.32 ppm), methanol (3.30 ppm), and acetonitrile (1.93 ppm). The signal multiplicity, coupling constants, number of hydrogen atoms, and assignments are given in parentheses. Multiplicities are abbreviated as follows: multiplet (m), singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint), heptet (hept), and broad (br). Nuclear Overhauser Enhancement (NOE) spectra were acquired on the Bruker AV-400 spectrometer. ' H ^ H correlation spectroscopy (COSY) was conducted on the Bruker AV-400 spectrometer. 1 4 1 Chapter 4 Experimental Two-dimensional Nuclear Overhauser Enhancement Spectroscopy (NOESY) was conducted on the Bruker AV-400 spectrometer. Carbon nuclear magnetic resonance ( 1 3C NMR) 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), Bruker AM-400 (100.5 MHz) spectrometers. A l l experiments were conducted using broadband *H decoupling. Chemical shifts (8) are reported in ppm and are referenced to the center of the solvent multiplet with tetramethylsilane (8 0.0 ppm) as an external standard: chloroform (77.0 ppm), benzene (128.0 ppm), dichloromethane (54.0 ppm), methanol (49.0 ppm), and acetonitrile (118.2 ppm). Some spectra are supported by data from the Attached Proton Test (APT). Where these are given, (-) denotes a negative APT peak corresponding to a methine (CH) or methyl (CH3) carbon centre, while (+) corresponds to a quaternary (C) or methylene (CH2) carbon centre. Two dimensional 1 3 C - ' H correlation spectra were obtained on the Bruker AV-400 instrument using the Heteronuclear Multiple Quantum Coherence (HMQC) experiment for one-bond correlations and the Heteronuclear Multiple Bond Connectivity (HMBC) experiment for long-range connectivities. Mass Spectra (MS) Low and high resolution mass spectra (LRMS and HRMS) were recorded on a Kratos MS 50 instrument using electron impact (EI) ionization at 70 eV or on a Kratos MS 80 spectrometer using desorption chemical ionization (DCI) with the ionization gas noted. The masses of organic salts were determined on a Kratos IIHQ hybrid mass spectrometer by recording liquid secondary ionization mass spectra (LSIMS), or a Bruker Esquire~LC (low resolution) or a 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 a Agilent 6890+ gas chromatograph, using electron impact (EI) ionization at 70 eV. Mass to charge ratios (m/e) are given, with relative intensities in parentheses, where applicable. Molecular ions are designated as M + . 142 Chapter 4 Experimental Ultraviolet-Visible Spectra (UV/VIS) UV/VIS spectra were recorded on a Perkin-Elmer Lambda-4B UV/VIS spectrometer in the spectral grade solvents indicated. Absorption maxima (A.max) are reported in nanometers (nm), with molar extinction coefficients (s) reported in parentheses in units o f M ' W 1 . Microanalysis ( A n a l . ) Elemental analyses were obtained for new compounds when possible. These were performed in-house by Mr. Peter Borda or Minaz Lakha, under the supervision of Dr. Yun Ling, on a Carlo Erba C H N Model 1106 analyzer. Crystallography Single crystal X-ray analysis was performed either in-house on 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), or externally (Dr. Lucia Maini under the supervision of Professor Dario Braga, Department of Chemistry, University of Bologna, Italy; and Dr. Mark Botoshansky under the supervision of Professor Menahem Kaftory, Dept of Chemistry, Technion, Haifa, Israel). Data collection and structural refinements were conducted by Dr. Brian Patrick. Some structures were refined by Keyan Wang, under the supervision of Dr. Brian Patrick. Structures are presented as ORTEP drawings at the 50% probability level. Geometric parameters for hydrogen abstraction, cleavage and cyclization were measured by WinGX vl.64.05. The average error for the parameters is within 0.01 A (for the distances) or within 1° (for the angles). Gas Chromatography (GC) Gas chromatographic analyses in a helium carrier gas were performed on a Hewlett-Packard 5890A gas chromatograph fitted with a flame ionization detector, or on an Agilent 6890 gas chromatograph, equipped with an Agilent 5970N mass selective 143 Chapter 4 Experimental detector. Data were collected on a Hewlett-Packard 3392A integrator (5890) or using Agilent's Chemstation software (6890). The following Hewlett-Packard fused-silica capillary columns were used: HP-5MS (30 m x 0.25 mm x 0.25 pm ID), HP-5 (30 m x 0.25 mm x 0.25 pm ID), and HP-35 (15 m x 0.25 mm x 0.25 pm ). Analyses were run with a split injection port (split ratios between 25:1 and 100:1) and column head pressures ranging from 100 kPa to 250 kPa. High Performance Liquid Chromatography (HPLC) High performance liquid chromatography (HPLC) was performed on a Waters 600E system coupled to either a Waters 486 tunable U V detector or a Waters 994 photodiode array detector under the conditions indicated. Enantiomeric excesses (ee) were determined using a Chiralcel OD™, Chiralpak AS™, or Chiralpak AD™ column (250mmx4.6mm) from Chiral Technologies, Inc., with a hexanesTPA eluent. Data were collected using the Waters Maxima software package. Optical Rotations Optical rotation data was recorded on a Jasco P-1010 polarimeter at room temperature at the sodium D-line (589.3 nm). Silica Gel Chromatography Analytical thin layer chromatography (TLC) was carried out on commercial pre-coated silica gel plates (E. Merck, type 5554). Preparative chromatography was performed using either the flash column method with Merck 9385 or Silicycle silica gel (particle size 230-400 mesh), or by radial chromatography on a Chromatotron (Harrison Research, model 7924T) using plates of 1 or 2 mm thickness prepared from E M Science silica gel 60 PF254 with gypsum (7749-3). Solvents and Reagents Tetrahydrofuran (THF) and diethyl ether were heated to reflux over the sodium ketyl of benzophenone under an argon atmosphere and distilled prior to use. Anhydrous 144 Chapter 4 Experimental dichoromethane and benzene were obtained by refluxing over calcium hydride under an argon atmosphere and distilling prior to use. Unless otherwise noted, all other solvents and reagents were used without further treatment, and all the reactions were conducted under a dry argon atmosphere in oven or flame-dried glassware. 145 Chapter 4 Experimental 4.2 Synthesis of a-Oxoamides 38, 66, 67 and 68 4.2.1 Preparation of a-Oxoamides 38 and 66 Methyl 4-acetylbenzoate (64) 64 Following a modification of the procedure of Gerlach and Wollmann, 8 6 a solution of 4-bromoacetophenone (63) (10.0 g, 50.3 mmol), [l,l'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (1.22 g, 1.50 mmol), in methanol (50mL), D M F (100 mL) and diisopropylethylamine (17.5 mL, 10.5 mmol) was purged for 10 min with gaseous CO. The solution was stirred under a positive pressure of CO for 5 h at 70 °C. The resulting dark red mixture was quenched with 0.5 M HCI (300 mL) and extracted with benzene (3 x 100 mL). The combined extracts were washed with sat. aq. NaCl (2 x 100 mL), dried (Na2S04) and evaporated to dryness. Purification by column chromatography on silica gel (petroleum ether-diethyl ether, 5:1) afforded 8.2 g (93 %) of methyl 4-acetylbenzoate (64) as a white solid. mp: 94-95 °C. (Li t . 1 0 8 mp 95.0-95.5 °C) J H NMR (400 MHz, CDCI3): 5 8.10 (d, J= 8.5 Hz, 2H), 7.98 (d, J = 8.5 Hz, 2H), 3.93 (s, 3H), 2.62 (s, 3H). 1 3 C NMR (75 MHz, CDCI3): 5 197.48, 166.19, 140.22, 133.88, 129.80, 128.17, 52.42, 26.83. IR (KBr pellet): v 3016, 2961, 1723, 1679, 1572, 1502, 1437, 1409, 1359, 1284, 1195, 1134, 1016, 957, 870, 851, 833, 771, 744, 698, 615, 593, 530 cm"1. 146 Chapter 4 Experimental L R M S (EI): m/z (relative intensity) 178 ( M + , 13.9), 163 (100), 147 (21.1), 135 (26.1), 120 (6.6), 103 (13.8), 91 (10.0), 76 (18.3). H R M S (EI): m/z calcd for C10H10O3 178.0630, found 178.0633. Anal. Calcd for C i 0 H i 0 O 3 : C 67.41, H 5.66. Found: C 67.71, H 5.74. 4-(Methoxycarbonyl)-a-oxo-benzeneacetic acid (65) A solution of methyl 4-acetylbenzoate (64) (2.0 g, 11.2 mmol) in pyridine (50 mL) containing selenium dioxide (2.0 g, 18.0 mmol) was heated to be refluxing under N2 at 100 °C for 3.5 h. The precipitate was removed by filtration and the filtrate was evaporated. The residue was neutralized with 1 M HCI (100 mL). The mixture was extracted with E t 2 0 (3 x 100 mL). The combined ethereal extracts were washed with water and extracted with I N sodium bicarbonate (3 x 50 mL). After washing with diethyl ether (50 mL), the aqueous layer was acidified with concentrated hydrochloric acid, causing the precipitation of a white solid. The suspension was extracted with diethyl ether (3 x 100 mL) and the ethereal layers were washed with water (50 mL), brine (50 mL) and dried (Na2SC>4). The solvent was removed in vacuo to yield crude product. Recrystallization from benzene gave 2.05 g (88 %) of 4-(methoxycarbonyl)-a-oxo-benzeneacetic acid (65) as a white solid. m p 99-101 °C. J H N M R (CD 3 CN, 300 MHz): 5 8.14 (m, 4H), 3.91 (s, 3H). 1 3 C N M R (CD 3 CN, 75 MHz): 8 187.12, 163.96, 163.33, 136.66, 136.41, 131.18, 130.62, 53.21. 65 147 Chapter 4 Experimental IR (KBr pellet): v 3506 (br), 1729, 1680 (d), 1441, 1409, 1284,1222, 1115, 753 cm"1. LRMS (DCf , isobutane): m/z (relative intensity) 209 (M + +l , 34.8), 181 (100), 163 (56.3), 149 (58.2), 121 (5.9), 103 (3.1), 76 (1.3). HRMS (DCf , isobutane): m/z calcd for C i 0 H 9 O 5 (M + +l) 209.0450, found 209.0446. Anal . Calcd for C i 0 H 8 O 5 : C 57.70, H 3.87. Found: C 57.70, H 3.89. Methyl N, A^'-bis(l-methvlethyl)-a-oxo-benzeneacetamide-4-carboxylate (38) Oxalyl chloride (12.2 g, 8.4 mL, 96 mmol) was added dropwise to a cold (-5 °C) solution of compound 65 (2.0 g, 9.6 mmol) and D M F (0.7 g, 0.70 mL, 9.6 mmol) in anhydrous THF (30 mL). The solution was stirred for 2 h under N 2 at room temperature. Unreacted oxalyl chloride along with D M F and THF were removed in vacuo and the resulting yellow solid residue dissolved in anhydrous CH2CI2 (30 mL). Diisopropylamine was added dropwise at -5 °C under N2 and the resulting mixture stirred at room temperature for 2 h. The reaction was quenched by addition of 1 M HCI (40 mL), the layers separated, and the aqueous layer further extracted with CH2CI2 (3 x 100 mL). The organic layers were combined, washed with brine (2 x 50 mL) and H 2 0 (2 x 50 mL), and dried (Na2SC>4). Removal of the solvent in vacuo followed by silica gel column chromatography of the residue (petroleum ether-ethyl acetate, 9:1) afforded 2.52 g (90 %) of amide 38 as a light yellow solid. m p 128-129 °C. (needles from diethyl ether) 148 Chapter 4 Experimental UV (CH3OH): X 204.9 (1.72xl0 4), 255.0 (1.56xl0 4), 360.1 (226) nm (M^cm"1). *H NMR (CDCI3, 400 MHz): 5 8.14 (d, J= 8.2 Hz, 2H), 7.97 (d, J = 8.2 Hz, 2H), 3.93 (s, 3H), 3.67-3.55 (m, 2H), 1.56 (d, J= 6.9 Hz, 6H), 1.15 (d, J= 6.6 Hz, 6H). 1 3 C NMR (CDCI3, 75 MHz): 8 190.05, 166.32, 165.97, 136.53, 134.92, 130.07, 129.39, 52.55, 50.20, 46.20, 20.57, 20.26. IR (KBr pellet): v 2968, 1722, 1682, 1634, 1444, 1372, 1282, 1232, 1107, 730 cm"1. LRMS (EI) m/z (relative intensity) 291 ( M + , 0.66), 260 (4.9), 163 (35.4), 135 (10.6), 128 (71.0), 104 (11.6), 86 (100), 76 (11.0). HRMS (EI) m/z calcd for C i 6 H 2 i N 0 4 291.1471, found 291.1469. Anal . Calcd for C 1 6 H 2 i N 0 4 : C 65.96, H 7.27, N 4.81. Found: C 66.07, H 7.38, N 4.75. This structure was confirmed by X-ray crystallographic analysis Habit colorless needles Space group P I a, A 6.1660(5) b,A 11.084(1) c, A 24.163(2) o ( ° ) 90.06(1) P(°) 93.14(1) Y(°) 100.60(1) Z 4 R 0.121 149 Chapter 4 Experimental A^,A^'-Bis(l-methvlethvl)-a-oxo-benzeneacetamide-4-carboxvlic acid (66) O \ II N - C - C C O O H o 66 A solution of compound 3 8 (316 mg, 1.09 mmol) in methanol (10 mL) was added to a solution of lithium hydroxide monohydrate (230 mg, 5.4 mmol) in water (30 mL). The resulting solution was stirred for 0.5 h at room temperature. The solution was acidified with concentrated HCI (3 mL) and extracted with E t 2 0 (3 x 50 mL). The combined extracts were washed with brine (2 x 30 mL), dried (Na2S04) and concentrated in vacuo to afford 300 mg (99 %) of acid 66 as a light yellow solid. mp 203-205 °C. J H N M R (CD3OD, 400 MHz): 8 8.20 (d, J= 8.6 Hz, 2H), 8.00 (d,J= 8.6 Hz, 2H), 3.70 (m, 2H), 1.56 (d, J= 6.8 Hz, 6H), 1.20 (d, J= 6.6 Hz, 6H). 1 3 C N M R (CD3OD, 100 MHz): 8 191.46, 168.41, 168.25, 137.44, 131.44, 130.41, 52.16, 47.52, 20.49. I R (KBr pellet): v 2992, 1700, 1686, 1635, 1572, 1504, 1474, 1449, 1419, 1376, 1348, 1225, 1210, 1120, 992, 745, 730 cm - 1 . LRMS (Ef ) m/z (relative intensity) 277 ( M + , 3.4), 233 (2.4), 192 (3.6), 149 (48.6), 128 (100), 103 (3.0), 86 (75), 65 (7.4). H R M S (Ef) m/z calcd for C i 5 H 1 9 N 0 4 277.1314, found 277.1311. Anal . Calcd for C 1 5 H 1 9 N O 4 : C 64.97, H 6.91, N 5.05. Found: C 65.12, H 6.93, N 5.15. 150 Chapter 4 Experimental 4.2.2 Preparation of a-Oxoamide Salts 67 L-Prolinamide salt (67a) 67a A solution of acid 66 (459 mg, 1.66 mmol) in Et20 (50 mL) was added with stirring to a solution of L-prolinamide (198 mg, 1.74 mmol) in Et^O (100 mL). Stirring was continued for 1 h, after which time the precipitate that had formed (596 mg, 92 %) was filtered and washed with Et20. Recrystallization from MeOH afforded salt 67a as pale yellow plates. mp 202-206 °C U V (CH3OH): X 205.0 (2.02xl0 4), 259.9 (1.55xl0 4), 349.9 (302) nm ( M ' W ) . *H N M R (CD3OD, 300 MHz): 8 8.09 (d, J - 8.2 Hz, 2H), 7.91 (d, J= 8.2 Hz, 2H), 4.26 (m, IH), 3.70 (m, 2H), 3.33 (m, 2H), 2.41 (m, IH), 2.01 (m, 3H), 1.56 (d, J= 6.8 Hz, 6H), 1.18 (d, 7=6.6 Hz, 6H). 1 3 C N M R (CD3OD, 75 MHz): 8 192.06, 173.21, 172.47, 168.85, 144.70, 135.46, 130.84, 130.09, 60.87, 52.23, 47.27, 31.18, 25.25, 20.44. IR (KBr pellet): v 3346, 2973, 1715, 1681, 1641, 1597, 1557, 1449, 1376, 1231, 1135, 993,826, 754, 744 cm"1. L R M S (FAB: +LSIMS, matrix, thioglycerol): m/z 392 (M + +l , 9.8), 278 (100), 236 (31.3), 149 (48.4), 115 (42.9), 91 (10.1). 1 5 1 C h a p t e r 4 E x p e r i m e n t a l HRMS (FAB: +LSIMS, matrix, thioglycerol): m/z calcd for C 2oH3oN 30 5 ( M + + 1) 392.2185, found 392.2190. Anal . Calcd for C 2oH29N 30 5: C 61.36, H 7.47, N 10.73. Found: C 61.07, H 7.43, N 10.88. This structure was confirmed by X-ray crystallographic analysis Habit colorless plates Space group P2, a, A 6.9118(3) b , A 7.4585(3) c, A 20.6344(9) cc(°) 90 P( °) 97.894(2) y(°) 90 z 2 R 0.051 R-(+)-Bornylamine salt (67b) A solution of acid 66 (83 mg, 0.30 mmol) in Et20 (15 mL) was added to a solution of R-(+)-bornylamine (46 mg, 0.30 mmol) in E t 2 0 (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with Et20 and dried in vacuo to afford salt 67b (120 mg, 93 %) as an off-white powder. Recrystallization from MeOH afforded off-white needles. mp 183-185 °C 152 Chapter 4 Experimental U V (CH3OH): X 205.0 (2.31 x 104), 260.0 (1.75 x 104), 350.0 (276) nm ( J V r W 1 ) . ] H NMR (CD3OD, 400 MHz): 5 8.08 (d, J= 8.3 Hz, 2H), 7.91 (d, J = 8.3 Hz, 2H), 3.70 (m, 2H), 3.38 (d x d, Jj = 4.1 Hz, J2 = 10.8 Hz, IH), 2.32 (m, IH), 1.85 (m, IH), 1.74 (d, J = 4.5 Hz, IH), 1.56 (d, J= 6.8 Hz, 6H), 1.52 (m, 2H), 1.31 (m, IH), 1.18 (d, J= 6.6 Hz, 6H), 1.10 (d x d, J, =4.1 Hz, J2 = 13.6 Hz, IH), 0.96 (s, 3H), 0.94 (s, 3H), 0.93 (s, 3H). 1 3 C NMR (CD3OD, 75 MHz): 5 192.03 (+), 173.36 (+), 168.84 (+), 145.23 (+), 135.31 (+), 130.24 (-), 129.86 (-), 57.93 (-), 52.31 (-), 50.04 (+), 49.18 (+), 47.60 (-), 45.80 (-), 35.40 (+), 28.52 (+), 27.97 (+), 20.58 (-), 20.49 (-), 19.81 (-), 18.70 (-), 13.32 (-). IR (KBr pellet): v 3851 (br), 2961, 2199, 1675, 1640, 1585, 1542, 1460, 1374, 1236, 995,824, 742 cm"1. LRMS (FAB: +LSHMS, matrix: thioglyerol): m/z (relative intensity) 431 ( M + + 1, 15.5), 278 (12.4), 236 (5.3), 154 (100), 149 (11.2), 137 (21.4), 81 (11.0). HRMS (FAB: +LSIMS, matrix, thioglyerol): m/z calcd for C25H39N2O4 ( M + + 1): 431.2912, found 431.2905. Anal . Calcd for C25H 3 8 N 2 0 4 : C, 69.74; H , 8.90; N 6.51. Found: C, 69.73; H , 8.93; N , 6.40. R-(-)-l -Cyclohexylethylamine salt (67c) 153 Chapter 4 Experimental A solution of acid 66 (83 mg, 0.30 mmol) in Et^O (15 mL) was added to a solution of R-(-)-l-cyclohexylethylamine (38 mg, 0.30 mmol) in E t 2 0 (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with Et20 and dried in vacuo to afford salt 67c (118 mg, 97 %) as a white powder. Recrystallization from MeOH afforded colorless needles. m p 178-182 °C UV (CH 3 OH): X 204.9 (2.08 x 104), 260.0 (1.44 x 104), 350.1 (256) nm (M-'cm 4 ) . ] H NMR (CD3OD, 300 MHz): 5 8.08 (d, J= 8.4 Hz, 2H), 7.90 (d, J= 8.4 Hz, 2H), 3.69 (m, 2H), 3.07 (m, IH), 1.83-1.72 (m, 6H), 1.56 (d, J= 6.8 Hz, 6H), 1.51-1.43 (m, IH), 1.39-1.27 (m, 2H), 1.24 (d, 7=6.8 Hz, 3H), 1.18 (d, J=6 .6Hz , 6H), 1.11-0.99 (m, 2H). 1 3 C NMR (CD3OD, 75 MHz): 5 192.08, 172.80, 168.87, 145.28, 135.31, 130.81, 130.04, 53.37, 52.15, 47.43, 42.65, 30.01, 28.78, 27.06, 26.98, 26.90, 20.52, 20.45, 15.98. IR (KBr pellet): v 3468, 2974, 2941, 2859, 1672, 1652, 1584, 1554, 1454, 1379, 1235, 995, 744 cm"1. LRMS (FAB: +LSIMS, matrix, thioglyerol): m/z (relative intensity) 405 ( M + + 1, 27.8), 278 (21.1), 236 (8.0), 149 (10.2), 128 (100), 111 (8.8). HRMS (FAB: +LSIMS, matrix, thioglyerol): m/z calcd for C23H36N2O4 ( M + + 1): 405.2755, found 405.2752. Anal . Calcd for C 24H32N 20 4: C, 68.29; H, 8.97; N 6.92. Found: C, 68.27; H , 9.04; N , 7.32. 154 Chapter 4 Experimental This structure was confirmed by X-ray crystallographic analysis Habit colorless needles Space group P2J2J2J a, A 6.3807(3) b ,A 13.9934(7) c,A 25.779(1) cc(°) 90 P( °) 90 y(°) 90 z 4 R 0.056 S-(+)-l-Aminoindane salt (67d) A solution of acid 66 (83 mg, 0.30 mmol) in Et20 (15 mL) was added to a solution of S-(+)-l-aminoindane (40 mg, 0.30 mmol) in E t 2 0 (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with Et20 and dried in vacuo to afford salt 67d (123 mg, 100 %) as a white powder. Recrystallization from MeOH afforded colorless plates. m p 192-195 °C U V (CH 3 OH): X 204.9 (2.43 x 104), 260.0 (1.52 x 104), 350.1 (130) nm ( M ' W 1 ) . ! H NMR (CD3OD, 300 MHz): 6 8.07 (d, J = 8.3 Hz, 2H), 7.90 (d, 7 = 8.3 Hz, 2H), 7.47-7.33 (m, 4H), 4.76 (d x d , / ; = 5.2 Hz, J2 = 7.5 Hz, IH), 3.69 (m, 2H), 3.18-3.10 (m, 155 Chapter 4 Experimental IH), 3.02-2.92 (m, 1H), 2.62-2.54 (m, IH), 2.11-2.03 (m, 1H), 1.56 (d,J = 6.9 Hz, 6H), 1.18 (d, .7=6.6 Hz, 6H) . , 3 C N M R (CD 3 OD, 75 MHz): 8 192.12, 185.87, 168.91, 145.40, 140.02, 135.33, 130.83, 130.63, 130.05, 128.25, 126.35, 125.47, 56.94, 52.16, 47.45, 31.80, 31.01, 20.51, 20.44 . I R (KBr pellet): v 3565, 2975, 2663, 1678, 1638, 1580, 1542, 1459, 1386, 1235, 996, 754,743,519 cm"1. L R M S (FAB: +LSEV1S, matrix, thioglyerol): m/z (relative intensity) 411 ( M + + 1, 43.8), 348 (11.6), 278 (79.3), 236 (20.4), 217 (13.6), 215 (14.3), 214 (14.5), 149 (28.6), 134 (90.6), 117 (100), 91 (25.6). H R M S (FAB: +LSIMS, matrix, thioglyerol): m/z calcd for C24H31N2O4 ( M + + 1): 411.2285, found 411.2286. Anal . Calcd for C 24H3oN 20 4: C, 70.22; H , 7.37; N 6.82. Found: C, 70.21; H , 7.33; N , 7.20. (IR. 2S)-(+Vci's-l-Amino-2-indanol salt (67e) A solution of acid 66 (55 mg, 0.20 mmol) in E t 2 0 (15 mL) was added to a solution of (IR, 2S)-(+)-l-amino-2-indanol (30mg, 0.20 mmol) in E t 2 0 (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with E t 2 0 and dried in vacuo to afford salt 67e (77 mg, 91 %) as a white powder. Recrystallization from MeOH afforded colorless plates. 156 Chapter 4 Experimental m p 180-182 °C U V (CH3OH): X 210.1 (2.68 x 104), 260.0 (2.18 x 104), 350.0 (173) nm (TVl 'W 1 ) . ! H N M R (CD3OD, 300 MHz): 5 8.08 (d, J= 8.1 Hz, 2H), 7.90 (d, J= 8.1 Hz, 2H), 7.44-7.30 (m, 4H), 4.69 (m, IH), 4.55 (d, J = 5.9 Hz, IH), 3.69 (m, 2H), 3.26-2.97 (m, 2H), 1.56 (d, J= 6.6 Hz, 6H), 1.18 (d, J= 6.5, 6H). 1 3 C N M R (CD3OD, 75 MHz): 8 192.11, 174.02, 168.90, 145.08, 142.83, 138.13, 135.36, 130.90, 130.07, 128.44, 126.68, 126.19, 71.92, 58.58, 52.23, 47.51, 40.11, 20.51, 20.44. IR (KBr pellet): v 3324 (br), 2974, 2932, 2876, 1737, 1676, 1636, 1580, 1537, 1387, 1232, 1099, 993, 874, 741, 613 c m 4 . L R M S (FAB: +LSEMS, matrix: 3-NBA): m/z (relative intensity) 427 ( M + + 1, 22.6), 278 (24.9), 154 (18.5), 150 (100), 133 (47.6). H R M S (FAB: +LSIMS, matrix: 3-NBA): m/z calcd for C24H31N2O5 ( M + + 1): 427.2235, found 427.2235. Anal . Calcd for C24H30N2O5: C, 67.59; H , 7.09; N 6.57. Found: C, 67.41; H , 7.26; N , 6.69. 157 Chapter 4 Experimental This structure was confirmed by X-ray crystallographic analysis Habit colorless plates Space group P2j a, A 7.542(2) b , A 6.364(2) c, A 24.163(9) a ( ° ) 90 P( °) 93.96(4) Y(°) 90 Z 2 R 0.066 R-(+)-l-Phenylethylamine salt (67f) c o o e H 3 g H 67f A solution of acid 66 (83 mg, 0.30 mmol) in Et^O (15 mL) was added to a solution of R-(+)-l-phenylethylamine (36mg, 0.30 mmol) in Et^O (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with Et.20 and dried in vacuo to afford salt 67f (110 mg, 92 %) as a white powder. Recrystallization from MeOH afforded colorless needles. mp 178-181 °C UV (CH 3 OH): X 206.6 (2.74 x 104), 210.0 (2.55 x 104), 259.9 (1.81 x 104), 350.0 (280) nm (JVr'cnf1). 158 Chapter 4 Experimental ! H N M R (CD3OD, 300 MHz): 5 8.08 (d, J= 8.4 Hz, 2H), 7.90 (d, J= 8.4 Hz, 2H), 7.42 (m, 5H), 4.42 (q, J =6.9 Hz, IH), 3.69 (m, 2H), 1.61 (d, J= 6.9 Hz, 3H), 1.56 (d, J= 6.8 Hz, 6H), 1.18 (d, J =6.6, 6H). 1 3 C N M R (CD3OD, 100 MHz): 5 192.09, 173.38, 168.89, 145.19, 139.94, 135.33, 130.83, 130.26, 130.06, 127.63, 52.29, 52.17, 47.45, 20.87, 20.51, 20.44. IR (KBr pellet): v 3503, 2972, 2935, 1752, 1675, 1640, 1581, 1537, 1396, 1237, 1137, 997,826,745 cm"1. L R M S (FAB: +LSIMS, matrix: thioglycerol): m/z (relative intensity) 399 ( M + + 1, 41.0), 300 (10.6), 278 (49.3), 236 (22.1), 149 (39.8), 122 (100), 105 (67.3). H R M S (FAB: +LSIMS, matrix: thioglycerol): m/z calcd for C23H31N2O4 ( M + + 1): 399.2286, found 399.2279. Anal . Calcd for C23H30N2O4: C, 69.32; H , 7.59; N 7.03. Found: C, 69.23; H , 7.60; N , 7.02. This structure was confirmed by X-ray crystallographic analysis Habit colorless needles Space group C2 a, A 49.208(4) b , A 6.3851(4) c , A 13.812(1) <x(°) 90 P(°) 90.823(4) Y(°) 90 Z 8 R 0.083 159 Chapter 4 Experimental S-(-)-l -Phenylethylamine salt (67g) H 3 C O N - C - C — / ^ J r — C O O Q H $ ° 67g A solution of acid 66 (55 mg, 0.20 mmol) in E t 2 0 (15 mL) was added to a solution of S-(-)-l-phenylethylamine (26 mg, 0.20 mmol) in E t 2 0 (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with E t 2 0 and dried in vacuo to afford salt 67g (75 mg, 94 %) as a white powder. Recrystallization from MeOH afforded colorless needles. mp 179-181 °C UV (CH 3 OH): X 204.9 (2.57 x 104), 260.0 (1.50 x 104), 350.0 (218) nm ( M ' W 1 ) . J H N M R (CD3OD, 300 MHz): 5 8.09 (d, J= 8.5 Hz, 2H), 7.90 (d, J= 8.5 Hz, 2H), 7.41 (m, 5H), 4.42 (q, J = 6.9 Hz, IH), 3.69 (m, 2H), 1.61 (d, J= 6.9 Hz, 3H), 1.56 (d, J= 6.8 Hz, 6H), 1.18 (d, 7= 6.6, 6H). 1 3 C N M R (CD3OD, 100 MHz): 8 192.09, 173.38, 168.89, 145.19, 139.94, 135.32, 130.82, 130.25, 130.06 127.63, 52.29, 52.16, 47.44, 20.88, 20.51, 20.44. I R (KBr pellet): v 3564 (br), 2972, 2935, 1751, 1674, 1640, 1581, 1537, 1382, 1237, 1137, 996, 826, 745 cm"1. L R M S (FAB: +LSIMS, matrix: thioglycerol): m/z (relative intensity) 399 ( M + + 1, 53.2), 278 (100), 236 (28.8), 149 (48.4), 122 (83.3), 105 (56.2). H R M S (FAB: +LSIMS, matrix: thioglycerol): m/z calcd for C 2 3 H 3 i N 2 0 4 ( M + + 1): 399.2286, found 399.2283. 160 Chapter 4 Experimental Anal. Calcd for C23H30N2O4: C, 69.32; H , 7.59; N 7.03. Found: C, 69.57; H , 7.43; N , 6.82. This structure was also confirmed by X-ray crystallographic analysis and the X-ray data is identical to that of compound 67f. (IS. 2RV(,+VNorephedrine salt (67h) A solution of acid 66 (55 mg, 0.20 mmol) in Et20 (15 mL) was added to a solution of (IS, 2R)-(+)-norephedrine (31mg, 0.20 mmol) in Et^O (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with Et20 and dried in vacuo to afford salt 67h (75 mg, 88 %) as a white powder. Recrystallization from MeOH afforded colorless needles. mp 145-148 °C *H NMR (CD3OD, 300 MHz): 8 7.99 (d, J= 8.0 Hz, 2H), 7.81 (d, J= 8.0 Hz, 2H), 7.29 (m, 5H), 4.85 (m, IH), 3.60 (m, 2H), 3.21 (m, IH), 1.47 (d, J= 6.8 Hz, 6H), 1.09 (d, J = 6.5 Hz, 6H), 0.98 (d, J= 6.6, 3H). 1 3 C NMR (CD3OD, 75 MHz): 8 192.09, 174.01, 168.89, 145.10, 141.54, 135.34, 130.84, 130.09, 129.53, 128.99, 127.16, 73.52, 53.74, 52.23, 47.50, 20.51, 20.44, 12.36. IR (KBr pellet): v 3320 (br), 2977, 2076, 1734, 1675, .1636, 1540, 1382, 1232, 993, 798, 743,703 cm"1. 161 Chapter 4 Experimental LRMS (FAB: +LSIMS, matrix: glycerol): m/z (relative intensity) 429 ( M + + 1, 20.1), 278 (12.7), 152 (100), 149 (14.9), 134 (47.6). HRMS (FAB: +LSIMS, matrix: glycerol): m/z calcd for C24H33N2O5 ( M + + 1): 429.2391, found 429.2389. Anal . Calcd for C24H32N2O5: C, 67.27; H , 7.53; N 6.54. Found: C, 66.85; H , 7.64; N , 6.55. • (IR. 2RV(-VPseudoephedrine salt (67i1 A solution of acid 66 (55 mg, 0.20 mmol) in ET.2O (15 mL) was added to a solution of (IR, 2R)-(-)-pseudoephedrine (34mg, 0.20 mmol) in Et^O (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with Et20 and dried in vacuo to afford salt 67i (83 mg, 94 %) as a white powder. Recrystallization from MeOH afforded colorless needles. m p 168-172 °C U V (CH3OH): X 205.0 (2.37 x 104), 260.0 (1.65 x 104), 350.0 (279) nm ( M ' W 1 ) . J H NMR (CD3OD, 300 MHz): 8 8.12 (d, J= 8.3 Hz, 2H), 7.90 (d, J= 8.3 Hz, 2H), 7.31-7.41 (m, 5H), 4.60 (d, J = 9.2 Hz, IH), 3.60-3.68 (m, 2H), 3.20 (m, IH), 2.63 (s, 3H), 1.52 (d, J= 6.8 Hz, 6H), 1.13 (d, / = 6.6 Hz, 6H), 1.05 (d, J = 6.6, 3H). 1 3 C NMR (CD3OD, 75 MHz): 8 192.06, 173.97, 168.82, 145.18, 141.97, 135.32, 130.84, 130.06, 129.77, 129.66, 128.19, 75.55, 61.67, 52.14, 47.41, 30.45, 20.52, 20.44, 12.64. HQ 162 Chapter 4 Experimental IR (KBr pellet): v 3412 (br), 3241, 3037, 2974, 2477, 1744, 1672, 1651, 1600, 1558, 1455, 1373, 1235, 994, 743, 614 cm"1. L R M S (FAB: +LSIMS, matrix: 3-NBA): m/z (relative intensity) 443 ( M + + 1, 8.8), 278 (12.9), 166 (100), 154 (17.7), 148 (29.0), 136 (12.1). H R M S (FAB: +LSIMS, matrix: 3-NBA): m/z calcd for C25H35N2O5 ( M + + 1): 433.2548, found 433.2545. Anal . Calcd for C25H34N2O5: C, 67.85; H , 7.74; N 6.33. Found: C, 67.65; H , 7.71; N , 6.49. (-)-c*'s-Mvrtanvlamine salt (67i) A solution of acid 66 (83 mg, 0.30 mmol) in Et^O (15 mL) was added to a solution of (-)-cw-myrtanylamine (46mg, 0.30 mmol) in Et20 (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with E t 2 0 and dried in vacuo to afford salt 67j (119 mg, 92 %) as an off-white powder. Recrystallization from MeOH afforded pale yellow plates. m p 127-130 °C ! H N M R (CD3OD, 300 MHz): 5 8.08 (d, J = 8.2 Hz, 2H), 7.91 (d, J= 8.2 Hz, 2H), 3.70 (m, 2H), 2.93 (d, J = 7.6 Hz, 2H), 2.40 (m, IH), 2.31 (m, IH), 2.04-1.92 (m, 6H), 1.56 (d, J= 6.8 Hz, 6H), 1.22 (s, 3H), 1.18 (d, J= 6.6 Hz, 6H), 1.02 (s, 3H), 0.97 (d, J= 9.8 Hz, IH). 163 Chapter 4 Experimental 1 3 C N M R (CD3OD, 75 MHz): 8 191.95 (+), 173.28 (+), 168.73 (+), 145.26 (+), 135.27 (+), 130.22 (-), 129.53 (-), 52.25 (-), 47.53 (-), 46.14 (+), 44.56 (-), 42.32 (-), 40.73 (-), 39.48 (+), 33.68 (+), 28.10 (-), 26.66 (+), 23.40 (-), 20.59 (-), 20.50 (-), 20.34 (+). IR (KBr pellet): v 3440, 2980, 2941, 1679, 1639, 1541, 1450, 1376, 1233, 993, 740 cm"1. L R M S (FAB: +LSIMS, matrix, thioglyerol): m/z (relative intensity) 431 ( M + + 1, 10.7), 413 (10.4), 284 (5.3), 278 (6.4), 236 (5.0), 154 (100), 149 (14.1), 81 (16.1). H R M S (FAB: +LSIMS, matrix, thioglyerol): m/z calcd for C25H39N2O4 ( M + + 1): 431.2912, found 431.2913. Anal . Calcd for C25H38N2O4: C, 69.74; H , 8.90; N , 6.51; O, 14.86. Calcd for C25H38N204.1/4H20: C, 69.01; H , 8.92; N 6.44. Found: C, 68.92; H , 8.96; N , 6.67. S-(+V2-Pyrrolidinemethanol salt (67k) N - C - C — V 7 COO0©N 1 67k A solution of acid 66 (83 mg, 0.30 mmol) in Et^O (15 mL) was added to a solution of S-(+)-2-pyrrolidinemethanol (33 mg, 0.33 mmol) in E t 2 0 (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with E t 2 0 and dried in vacuo to afford salt 67k (106 mg, 93 %) as an off-white powder. Recrystallization from C H 3 C N afforded pale yellow prisms. m p 116-119 °C U V (CH3OH): X 210.0 (2.67 x 104), 260.0 (2.47 x 104), 350.1 (272) nm ( M - W 1 ) . 164 Chapter 4 Experimental *H N M R ( C D 3 O D , 300 MHz): 6 8.08 (d, J= 8.4 Hz, 2H), 7.91 (d, J= 8.4 Hz, 2H), 3.83-3.78 (m, IH), 3.76-3.57 (m, 4H), 3.27 (t, J = 7.4 Hz, 2H), 2.12-1.98 (m, 3H), 1.78-1.72 (m, IH), 1.56 (d, J=6 .8Hz , 6H), 1.18 (d, J= 6.6 Hz, 6H). 1 3 C N M R ( C D 3 O D , 75 MHz): 5 192.00, 173.51, 168.73, 145.00, 135.34, 130.78, 130.03, 61.69, 61.61, 52.07, 47.35, 46.43, 27.13, 24.88, 20.51, 20.44. IR (KBr pellet): v 3414, 2974, 1677, 1641, 1587, 1549, 1449, 1382, 1231, 1064, 994 L R M S (FAB: +LSIMS, matrix, thioglyerol): m/z (relative intensity) 379 ( M + + 1, 23.0), 278 (33.5), 217 (12.5), 214 (10.5), 149 (12.6), 102 (100), 91 (21.9). H R M S (FAB: +LSIMS, matrix, thioglyerol): m/z calcd for C20H31N2O5 ( M + + 1): 379.2234, found 379.2233. Anal . Calcd for C20H30N2O5: C, 63.47; H , 7.99; N 7.40. Found: C, 63.26; H , 8.00; N , 7.14. S-(+)-A/-methyl-l-phenylethylamine salt (671) A solution of acid 66 (83 mg, 0.30 mmol) in Et20 (15 mL) was added to a solution of S-(+)-/V-methyl-l-phenylethylamine (41 mg, 0.30 mmol) in Et20 (5 mL). The solution was stirred for 1 h. Removal of solvent in vacuo afforded salt 671 as a white powder. Recrystallization from ethyl acetate afforded colorless needles (103 mg, 83 %). m p 126-128 °C. cm -1 165 Chapter 4 Experimental UV (CH3OH): X 210.0 (2.43 x 104), 259.9 (1.72 x 104), 350.0 (290) nm (M^cm - 1). ' H N M R (CD3OD, 300 MHz): 5 8.09 (d,J= 8.5 Hz, 2H), 7.91 (d, J = 8.5 Hz, 2H), 7.45 (m, 5H), 4.28 (q, J = 6.9 Hz, IH), 3.69 (m, 2H), 2.54 (s, 3H), 1.65 (d,J= 6.9 Hz, 3H), 1.56 (d, J= 6.8 Hz, 6H), 1.18 (d, J= 6.6 Hz, 6H). 1 3 C N M R (CD3OD, 75 MHz): 5 192.01, 173.33, 168.76, 144.99, 137.84, 135.36, 130.82, 130.47, 130.36, 130.05, 128.63, 60.38, 52.09, 47.37, 31.44, 20.53, 20.45, 19.41. IR (KBr pellet): v 3443, 3002, 2972, 2938, 1670, 1646, 1540, 1455, 1383, 1373, 1234, 992,738 cm"1. L R M S (FAB: +LSEVIS, matrix, thioglyerol): m/z (relative intensity) 413 ( M + + 1, 7.9), 278 (16.3), 236 (9.5), 149 (25.8), 136 (100), 105 (30.3). H R M S (FAB: +LSIMS, matrix, thioglyerol): m/z calcd for C24H33N2O4 ( M + + 1): 413.2442, found 413.2441. Anal . Calcd for C 24H32N 20 4: C, 69.88; H , 7.82; N , 6.79; O, 15.51. Calcd for C 2 4 H 3 2 N 2 O 4 . I / 2 H 2 O : C, 68.38; H , 7.89; N 6.65. Found: C, 68.34; H , 7.76; N , 6.36. 4.2.3 Preparation of ct-Oxoamide 68 R-2-Phenylpropyl 4-[[bis(l-methylethvl)aminoloxoacetvllbenzoate (68) Oxalyl chloride (458 mg, 320 pL, 3.61 mmol) was added dropwise to a cold (-5 °C) solution of acid 66 (100 mg, 0.36 mmol) and D M F (1 pL) in anhydrous THF (3 mL). The solution was stirred for 3 h under N2 at room temperature. Unreacted oxalyl chloride 68 166 Chapter 4 Experimental along with D M F and THF was removed in vacuo and the yellow solid residue dissolved in anhydrous CH2CI2 (3 mL). R-(+)-2-phenyl-l-propanol (49 mg, 49 pL, 0.36 mmol) was added dropwise at -5 °C under N2 and the resulting mixture stirred at room temperature for 4 h. The reaction was quenched by addition of 1 M HCI (10 mL), the layers separated, and the aqueous layer further extracted with CH2CI2 (3 x 10 mL). The organic layers were combined, washed with brine (2 x 10 mL) and H2O (2 x 10 mL), and dried (Na2S04). Removal of the solvent in vacuo followed by silica gel column chromatography of the residue (petroleum ether-ethyl acetate, 8:2) afforded 106 mg (74%) of ester 68 as a light yellow solid. Recrystallization from Et20 afforded colorless platelets. m p 115-117 °C U V (CH3OH): X 204.9 (2.17 x 104), 255.0 (2.04 x 104), 360.0 (201) nm (M^cm"1). ' H N M R (CDCI3, 400 MHz): 5 8.02 (d, J= 8.5 Hz, 2H), 7.90 (d, J = 8.5 Hz, 2H), 7.23 (m, 5H), 4.37 (m, 2H), 3.57 (m, 2H), 3.19 (m, IH), 1.51 (d, J= 6.9 Hz, 6H), 1.33 (d, J = 7.0 Hz, 3H), 1.11 (d, .7=6.6, 6H). , 3 C N M R ( C D C 1 3 , 100 MHz): 5 190.04, 166.32, 165.35, 142.86, 136.48, 135.07, 130.01, 129.38, 128.57, 127.27, 126.82, 70.37, 50.19, 46.19, 39.00, 20.57, 20.26, 17.98. IR (KBr pellet): v 2974, 2934, 1714, 1678, 1646, 1452, 1281, 1230, 1108, 994, 965, 874, 732, 702 cm"1. L R M S (+CI, gas: C H 4 + NH 3 ) : m/z (relative intensity) 396 ( M + + 1, 100), 258 (14.0), 154 (16.6), 130 (50.5), 128 (60.7), 118 (27.4), 105 (17.4), 102 (25.1), 100 (20.8), 86 (13.2). H R M S (+CI, gas: C H 4 + NH 3 ) : m/z calcd for C 2 4 H 3 0 N O 4 ( M + + 1): 396.2175, found 396.2174. 167 Chapter 4 Experimental Anal. Calcd for C24H29NO4: C, 72.89; H , 7.39; N 3.54. Found: C, 72.57; H , 7.35; N , 3.70. This structure was confirmed by X-ray crystallographic analysis Habit colorless plates Space group P2j a, A 12.580(4) b,A 6.456(2) c, A 13.657(4) a ( ° ) 90 P(°) 99.283(8) Y(°) 90 Z 2 R 0.080 168 Chapter 4 Experimental 4.3 Synthesis of Bicyclo[2.2.2]octane Derivatives 85, 54, 55 and 56 4.3.1 Preparation of Ketones 85, 54 and 55 4-Pentvlbicvlor2.2.21octane-1 -methanol (80) 80 To a suspension of lithium aluminum hydride (2.18 g, 57.4 mmol) in diethyl ether (50 mL) was added dropwise a solution of acid 79 (4.3 g, 19.2 mmol) in diethyl ether (50 mL) at room temperature under an argon atmosphere. The mixture was stirred for 2.5 h. The reaction was quenched carefully with water (100 mL) at -78 °C. The resulting mixture was poured into 4 N HCI (40 mL), followed by extraction with ether (4 x 100 mL). The combined ethereal extracts were washed with brine (2 x 50 mL), dried (Na2S04). Removal of the solvent in vacuo provided alcohol 80 (3.71 g, 92%) as a yellowish solid. The compound did not require further purification. mp: 35.5-36.5 °C (Lit. 9 5 ( a ) bp: 150 °C/0.05mmHg). ! H NMR (400 MHz, CDC1 3): 5 3.16 (s, 2H), 2.16 (s, IH, OH), 1.31 (m, 12H), 1.26 (m, 2H), 1.16 (m, 4H), 1.04 (m, 2H), 0.85 (t, J= 7.2 Hz, 3H). 1 3 C NMR (100 MHz, CDC1 3): 8 71.46, 41.58, 33.12, 32.80, 30.85, 30.74, 28.21, 23.27, 22.60, 13.98. IR (KBr pellet): v 3306 (br), 2925, 2856, 1457, 1376, 1044 cm"1. LRMS (EI) m/z 210 (M + ) , 192, 179 (100), 163, 149, 135, 121, 109, 95, 93, 79, 67, 55. 169 Chapter 4 Experimental 4-Pentvlbicvclor2.2.2]octane-l-methanol methanesulfonate (81) To a solution of alcohol 80 (3.66 g, 17.4 mL) in dry pyridine (30 mL) was added methanesulfonyl chloride (2.99 g, 26.1 mmol, 2.03 mL) at room temperature. The reaction was stirred for 4 h at room temperature under an argon atmosphere. The resulting mixture was poured into ice water (200 mL) and extracted with diethyl ether (4 x 120 mL). The combined ethereal extracts were washed with 4 N HCI (2 x 30 mL), water (2 x 30) mL and brine (2 x 30 mL), and dried (Na2SC>4). Removal of the solvent in vacuo afforded compound 81 (5.01 g, 100 %) as a white solid. The compound did not require further purification. mp: 73-75 °C. *H N M R (300 MHz, CDC1 3): 5 3.80 (s, 2H), 2.94 (s, 3H), 1.38 (m, 6H), 1.35 (m, 6H), 1.24 (m, 2H), 1.15 (m, 4H), 1.03 (m, 2H), 0.83 (t, J= 7.0 Hz, 3H). 1 3 C N M R (75 MHz, CDCI3): 5 41.37, 36.95, 32.73, 32.09, 30.71, 30.29, 28.09, 23.23, 22.60, 14.01. I R ( K B r pellet): v 2953, 2922, 2867, 1321, 1174, 958, 538 cm"1. L R M S (+CI: gas, C H 4 + NH 3 ) m/z 306 ( M + + 18, 100), 223, 210, 192. H R M S (+CI: gas, C H , + NH 3 ) calcd for C15H32NO3S ( M + + 18) 306.2102, found 306.2103. . Anal . Calcd for C15H28O3S: C, 62.46; H , 9.78. Found: C, 62.45; H , 9.84. 170 Chapter 4 Experimental 4-Pentylbicyclo [2.2.2] octane-1 - acetonitrile (82) 82 C N To a solution of compound 81 (4.40 g, 15.3 mmol) in dry D M F (40 mL) was added sodium cyanide (1.12 g, 22.9 mmol). The resulting mixture was heated to be refluxing at 150 °C under an argon atmosphere for 17 h. The cooled reaction mixture was poured into ice-water (150 mL) and extracted with diethyl ether (4 x 120 mL). The combined ethereal extracts were washed with N a 2 C 0 3 (10%, 50 mL), H 2 0 (50 mL), and saturated NaCl (50 mL), then dried (Na2S04). Removal of solvent in vacuo afforded compound 82 (2.92 g, 87 %) as a yellowish solid. The compound did not require further purification. mp: 31.5-32.5 °C ( L i t . 9 5 ( a ) bp: 130 °C/2mmHg). *H N M R (300 MHz, CDC1 3): 5 2.06 (s, 2H), 1.46 (m, 6H), 1.37 (m, 6H), 1.22 (m, 2H), 1.15 (m, 4H), 1.05 (m, 2H), 0.83 (t, J= 7.1 Hz, 3H). 1 3 C N M R (75 MHz, CDC1 3): 8 118.09, 41.21, 32.69, 31.06, 30.73, 30.69, 30.14, 29.60, 23.20, 22.57, 13.98. IR (KF3r pellet): v 2932, 2860, 2248, 1457 cm"1. L R M S (EI) m/z 219, 190 (100), 176, 163, 148, 122, 107, 93, 79, 68, 55. 4-Pentvlbicyclor2.2.2~|octane-l-acetic acid (83) COOH 171 C h a p t e r 4 E x p e r i m e n t a l A solution of compound 82 (2.92 g) in sulfuric acid (1:1, 15 mL) and glacial acetic acid (40 mL) was heated to be refluxing at 130 °C for 24 h. Acetic acid in the cooled mixture was removed in vacuo and the dark residue was taken up in water (50 mL) and extracted with methylene chloride (5 x 50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), and dried (Na2S04). Removal of the solvent in vacuo afforded acid 83 (2.80 g, 88 %) as a white solid. The compound did not require further purification. mp: 72-73 °C (Lit. 9 5 ( a ) 70 °C). *H NMR (300 MHz, CDC1 3): 5 2.08 (s, 2H), 1.46 (m, 6H), 1.33 (m, 6H), 1.25 (m, 2H), 1.15 (m, 4H), 1.02 (m, 2H), 0.85 (t, J= 7.0 Hz, 3H). 1 3 C NMR (75 MHz, CDCI3): 5 178.73, 45.91, 41.61, 32.85, 31.33, 31.09, 30.97, 30.19,. 23.30, 22.69, 14.08. IR (KBr pellet): v 3565 (br), 2931, 2857, 1703, 1456, 1289, 1150, 962, 677 cm - 1 . 1 -(4-Fluorophenvl)-2-(4' -pentvlbicvclo 12.2,21oct-1 -vD ethanone (84) To a solid sample of acid 83 (2.23 g, 9.37 mmol) was added thionyl chloride (30 mL) at room temperature under an argon atmosphere. After stirring 20 min the solution was heated to be refluxing for 2 h. The excess thionyl chloride was removed in vacuo and the residue was redissolved in fluorobenzene (8 mL). The resulting solution was added dropwise to a suspension of anhydrous aluminum trichloride (5 g) in fluorobenzene (40 mL) at 0 °C (ice bath) over 30 min. The reaction was heated to be refluxing overnight (10 172 Chapter 4 Experimental h) and quenched by careful addition of water (100 mL). The mixture was extracted with diethyl ether (3 x 120 mL). The combined ethereal extracts were washed with water (5 x 50 mL), brine (2 x 50 mL), and dried (Na2S04). Removal of the solvent in vacuo afforded compound 84 (2.59 g, 88 %) as a yellowish liquid. The compound did not require further purification. *H N M R (400 MHz, CDC1 3): 5 7.90 (m, 2H), 7.06 (m, 2H), 2.67 (s, 2H), 1.49 (m, 6H), 1.31 (m, 6H), 1.23 (t, J = 7.3 Hz, 2H), 1.12 (m, 4H), 0.99 (m, 2H), 0.83 (t, J= 7.2 Hz, 3H). 1 3 C N M R (100 MHz, CDC1 3, APT: C, C H 2 : +; C H , C H 3 : -): 5 198.71 (+), 166.77 (+) and 164.24 (+), ('JC-F = 253 Hz), 135.10 (+), 130.91 (-) and 130.82 (-) , ( 3 J C . F = 9 Hz), 115.51 (-) and 115.29 (-), ( 2J C- F = 22 Hz), 48.39 (+), 41.60 (+), 32.80 (+), 32.00 (+), 31.84 (+), 31.14 (+), 30.16 (+), 23.23 (+), 22.63 (+), 14.03 (-). IR (neat): v 2926, 2858, 1675, 1599, 1506, 1456, 1235, 1157, 832,580 cm"1. L R M S (EI) m/z 316 (M + ) , 298, 177, 163, 138, 123 (100), 95, 79, 55. H R M S (EI) calcd for C 2 1 H 2 9 F O 316.2202, found 316.2202. Anal . Calcd for C 2 i H 2 9 F O : C, 79.70; H , 9.24. Found: C, 79.26; H , 9.11. l-(4-CvanophenvlV2-('4,-pentvlbicvclor2.2.21oct-l-vl) ethanone (85) 173 Chapter 4 Experimental To a solution of compound 84 (1.17 g, 3.70 mmol) in dry D M F (15 mL) was added sodium cyanide (0.27 g, 5.56 mmol). The mixture was heated to be refluxing at 150 °C under an argon atmosphere for 17 h. The cooled reaction mixture was poured into ice-water (100 mL) and extracted with diethyl ether (4 x 100 mL). The combined ethereal extracts were washed with Na2C03 (10%, 50 mL), H2O (50 mL), and saturated NaCl (50 mL), then dried (JN^SCu). Removal of the solvent in vacuo afforded compound 85 (0.983 g, 82 %) as a yellowish solid. The compound did not require further purification. mp: 89-91 °C. U V (CH3OH): X 205.0 (1.33 x 104), 250.0 (1.50 x 104), 290.0 (1.15 x 103) nm (NT'cm"1). *H N M R (300 MHz, CDCI3): 5 7.96 (d, J= 8.4 Hz, 2H), 7.72 (d, J= 8.4 Hz, 2H), 2.67 (s, 2H), 1.49 (m, 6H), 1.31 (m, 6H), 1.24 (m, 2H), 1.13 (m, 4H), 0.99 (m, 2H), 0.83 (t, J= 7.1Hz, 3H). 1 3 C N M R (75 MHz, CDC1 3 , APT: C, C H 2 : +; C H , C H 3 : -): 5 199.10 (+), 141.55 (+), 132.37 (-), 128.61 (-), 117.98 (+), 115.97 (+), 48.77 (+), 41.54 (+), 32.78 (+), 32.20 (+), 31.81 (+), 31.07 (+), 30.16 (+), 23.23 (+), 22.64 (+), 14.05 (-). I R ( K B r pellet): v 2954, 2923, 2853, 2228, 1688, 1456, 1402, 1207, 986, 826, 572 cm"1. L R M S (EI) m/z 323 (M + ) , 305, 252, 234, 178, 150, 130 (100), 102, 79, 55. H R M S (EI) calcd for C22H29NO 323.2249, found 323.2249. Anal . Calcd for C22H29NO: C, 81.69; H , 9.04; N , 4.33. Found: C, 81.86; H , 9.19; N , 4.41. 174 Chapter 4 Experimental l-(4-CarboxvlphenvlV2-( ,4 ,-Dentvlbicvclor2.2.21oct-l-vn ethanone (54) C O O H To a solution of potassium hydroxide (1.6 g) in water (8 mL) was added a solution of compound 85 (0.50g, 1.55 mmol) in ethanol (2 mL). The mixture was heated to be refluxing at 95 °C for 20 h. The reaction was quenched by adding water (50 mL). The solution was washed with methylene chloride (2 x 30 mL). The aqueous solution was carefully acidified to pH 2 with concentrated HCI. The precipitated carboxylic acid was extracted with diethyl ether (4 x 80 mL) and the combined ethereal extracts were washed with water (50 mL), brine (2 x 50 mL), and dried (Na2S04). Removal of the solvent in vacuo provided a yellowish solid. Recrystallization from ethanol afforded acid 54 (0.434 g, 82 %) as white plates. mp: 230-233 (decomposed) °C. *H NMR (300 MHz, CDC1 3): 5 8.16 (d, J= 8.3 Hz, 2H), 7.96 (d,J= 8.3 Hz, 2H), 2.76 (s, 2H), 1.50 (m, 6H), 1.32 (m, 6H), 1.24 (m, 2H), 1.14 (m, 4H), 1.01 (m, 2H), 0.84 (t, / = 7.0 Hz, 3H). 1 3 C NMR (75 MHz, CDCI3): 5 200.13, 170.24, 142.65, 132.45, 130.37, 128.25, 48.97, 41.61, 32.83, 32.20, 31.86, 31.15, 30.20, 23.26, 22.67, 14.07. I R ( K B r pellet): v 3540, 2924, 2856, 1684, 1667, 1506, 1426, 1289, 951, 875, 728 cm"1. LRMS (EI) m/z 342 (M + ) , 297 (100), 204, 178, 164, 149, 79, 55. 175 Chapter 4 Experimental H R M S (EI) calcd for C22H30O3 342.2195, found 342.2195. Anal . Calcd for C22H30O3: C, 77.16; H , 8.83. Found: C, 77.11; H , 8.72. l-(4-Methoxvcarbonvlphenvl)-2-(4'-pentvlbicvclor2.2.21oct-l-vl) ethanone (55) COOCH3 To a solution of acid 54 (0.100 g) in diethyl ether (5 mL) was added a solution of diazomethane in diethyl ether (10 mL, excess in the reaction) at room temperature. The reaction was stirred for 10 min. Removal of the solvent in vacuo provided a yellowish solid. Recrystallization from diethyl ether afforded ester 55 (0.104 g, 100 %) as white needles. mp: 98-100 °C (Et 20, needles). U V (CH3OH): X 205.1 (1.46 x 104), 249.9 (1.69 x 104), 290.0 (1.38 x 103) nm ( M ' W 1 ) . *H N M R (400 MHz, CDCI3): 8 8.07 (d, J= 8.3 Hz, 2H), 7.93 (d, J = 8.3 Hz, 2H), 3.92 (s, 3H), 2.73 (s, 2H), 1.49 (m, 6H), 1.31 (m, 6H), 1.24 (m, 2H), 1.13 (m, 4H), 0.99 (m, 2H), 0.83 (t, 7=7.1 Hz, 3H). 1 3 C N M R (75 MHz, CDCI3): 8 200.12, 166.29, 141.94, 133.49, 129.71, 128.14, 52.40, 48.90, 41.61, 32.82, 32.14, 31.84, 31.14, 30.18, 23.25, 22.66, 14.06. IR (KBr pellet): v 2925, 2856, 1718, 1666, 1457, 1280, 1113, 1016, 874, 734 cm"1. L R M S (EI) m/z 356 (M + ) , 341, 325, 297 (100), 178, 163, 135. 176 Chapter 4 Experimental HRMS (EI) calcd for C 2 3 H 3 2 0 3 356.2352, found 356.2349. Anal. Calcd for C 2 3 H 3 2 0 3 : C, 77.49; H , 9.05. Found: C, 77.46; H , 9.17. 4.3.2 Preparation of Bicyclo[2.2.2]octyl Salts 56 R-(-)-l-Cvclohexvlethylamine salt (56a) 56a A solution of acid 54 (85.5 mg, 0.25 mmol) in E t 2 0 (15 mL) was added to a solution of R-(-)-l-cyclohexylethylamine (31.8 mg, 0.25 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 56a (93.5 mg, 80 %) as a white powder. Recrystallization from MeOH afforded colorless plates. mp: 173-176 °C. *H NMR (300 MHz, CD 3 OD): 5 7.99 (d, J= 8.5 Hz, 2H), 7.90 (d, J= 8.5 Hz, 2H), 3.07 (m, IH), 2.77 (s, 2H), 1.84-1.70 (m, 5H), 1.56-1.50 (m, 6H), 1.37-1.32 (m, 8H), 1.28 (m, IH), 1.24 (d, J= 6.1 Hz, 3H), 1.20-1.10 (m, 7H), 1.10-0.95 (m, 4H), 0.87 (t, J= 7.0 Hz, 3H). 1 3 C NMR (75 MHz, CD 3 OD): 6 200.53, 172.47, 140.98, 140.16, 129.38, 127.85, 52.04, 48.79, 41.61, 41.30, 32.80, 32.07, 31.86, 31.13, 30.17, 29.31, 27.42, 25.90, 25.80, 25.69, 23.23,22.64,15.70,14.05. 177 Chapter 4 Experimental IR (KBr pellet): v 3 5 4 4 , 2921, 2856, 2185, 1685, 1635, 1585, 1539, 1456, 1383, 1207, 984, 780 cm"1. LRMS (ESI: 0.1% formic acid in MeOH) m/z 470 ( M + + 1, 100), 400 (20.4), 365 (18.6), 3 5 3 ( 5 5 . 3 ) , 3 4 3 (15.2), 291 (14.5), 255 (30.4), 160 (19.1). HRMS (ESI: 0.1% formic acid in MeOH) calcd for C30H48NO3 470.3634, found 470.3643. Anal . Calcd for C 3 0 H 4 7 N O 3 : C, 76.71; H , 10.09; N , 2.98; O, 10.22. Calcd for C 3 0 H 4 7 N O 3 . I / 4 H 2 O : C, 75.98; H , 10.10; N , 2 .95. Found: C, 75.66; H , 9 . 9 5 ; N , 3.17. This structure was confirmed by X-ray crystallographic analysis: Habit colorless plates Space group P2j a, A 10.0302(6) b , A 6.0826(3) c, A 23.4323(14) a ( ° ) 90 P(°) 91.654(2) Y(°) 90 Z 2 R 0.092 178 Chapter 4 Experimental L-Prolinamide salt (56b) 56b A solution of acid 54 (85.5 mg, 0.25 mmol) in diethyl ether (15 mL) was added to a solution of L-prolinamide (28.5 mg, 0.25 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 56b (95 mg, 83 %) as a white powder. Recrystallization from MeOH afforded colorless plates. mp: 170-172 °C. *H N M R (400 MHz, CD 3 OD): 5 8.00 (d, J= 8.3 Hz, 2H), 7.91 (d, J= 8.3 Hz, 2H), 4.26 (m, IH), 3.34 (m, 2H), 2.77 (s, 2H), 2.40 (m, IH), 2.00 (m, 3H), 1.52 (m, 6H), 1.34 (m, 6H), 1.27 (m, 2H), 1.16 (m, 4H), 1.02 (m, 4H), 0.86 (t, J= 7.0 Hz, 3H). 1 3 C N M R (75 MHz, CD 3 OD): 5 202.59, 173.79, 172.71, 142.75, 141.34, 130.32, 129.02, 60.87, 49.64, 47.25, 42.89, 34.05, 33.03, 32.81, 32.30, 31.23, 25.31, 24.36, 23.69, 14.43. IR (KBr pellet): v 3544, 3081, 2925, 2856, 1688, 1673, 1584, 1542, 1456, 1380, 1204, 775 cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z 457 ( M + + 1, 30.9), 229 (100). H R M S (ESI: 0.1% formic acid in MeOH) calcd for C27H41N2O4 457.3066, found 457.3060. 179 Chapter 4 Experimental Anal. Calcd for C27H40N2O4: C, 71.02; H , 8.83; N , 6.13. Found: C, 71.66; H , 8.81; N , 5.56. This structure was confirmed by X-ray crystallographic analysis: Habit colorless plates Space group P2, a, A 14.1956(14) b, A 9.6309(8) c , A 19.1279(18) a ( ° ) 90 P(°) 103.793 Y(°) 90 Z 4 R 0.059 (IS. 2RV(+VNorephedrine salt (56c) COQ HO NH © © 56c A solution of acid 54 (85.5 mg, 0.25 mmol) in diethyl ether (15 mL) was added to a solution of (IS, 2R)-(+)-norephedrine (37.8 mg, 0.25 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 56c (115 mg, 93 %) as a white powder. Recrystallization from MeOH afforded colorless needles. 180 Chapter 4 Experimental mp: 170-173 °C. *H N M R (300 MHz, CD 3 OD): 6 7.99 (d, 7= 8.5 Hz, 2H), 7.90 (d, 7= 8.5 Hz, 2H), 7.40-7.25 (m, 5H), 4.92 (d, J= 3.5 Hz, IH), 3.48 (d x q, J, = 3.5 Hz, J2 = 6.8 Hz, IH), 2.77 (s, 2H), 1.52 (m, 6H), 1.34 (m, 8H), 1.17 (m, 4H), 1.07 (d, 7 = 6.8 Hz, 3H), 1.02 (m, 2H), 0.87 (t, 7=7.1 Hz, 3H). 1 3 C N M R (75 MHz, CD 3 OD): 5 202.82, 173.95, 143.13, 141.56, 141.24, 130.29, 129.54, 128.98, 127.19, 73.79, 54.68, 49.69, 42.90, 34.05, 33.07, 32.86, 32.32, 31.26, 24.35, 23.67, 14.38, 12.61. IR (KBr pellet): v 3272, 2928, 2856, 2145, 1716, 1666, 1630, 1537, 1512, 1453, 1393, 1365, 1276, 763, 743, 704 cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z 494 ( M + + 1), 365 (100), 152. H R M S (ESI: 0.1% formic acid in MeOH) calcd for C31H44NO4 494.3270, found 494.3275. Anal . Calcd for C 3 i H 4 3 N 0 4 : C, 74.74; H , 8.80; N , 2.81. Found: C, 74.78; H , 8.76; N , 2.68. (IR. 2R)-(-)-Pseudoephedrine salt (56d) COO Ph NH2CH3 56d 181 Chapter 4 Experimental A solution of acid 54 (85.5 mg, 0.25 mmol) in diethyl ether (15 mL) was added to a solution of (IR, 2R)-(-)-pseudoephedrine (41.3 mg, 0.25 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 56d (110 mg, 87 %) as a white powder. Recrystallization from MeOH afforded colorless needles. mp: 118-119 °C. J H N M R (300 MHz, CD 3 OD): 5 7.99 (d, J= 8.6 Hz, 2H), 7.90 (d, J= 8.6 Hz, 2H), 7.40-7.35 (m, 5H), 4.52 (d, J= 9.2 Hz, IH), 3.34 (m, IH), 2.77 (s, 2H), 2.71 (s, 3H), 1.55-1.50 (m, 6H), 1.37-1.25 (m, 8H), 1.15-1.10 (m, 4H), 1.06 (d, / = 6.7 Hz, 3H), 1.05-0.95 (m, 2H), 0.87 (t, .7=7.1 Hz, 3H). 1 3 C N M R (75 MHz, CD 3 OD): 5 202.77, 174.02, 143.19, 141.99, 141.21, 130.29, 129.81, 129.72, 128.99, 128.18, 75.71, 61.76, 49.67, 42.91, 34.06, 33.06, 32.85, 32.32, 31.26, 30.55, 24.36, 23.69, 14.39, 12.72. IR (KBr pellet): v 3300, 2928, 2856, 2376, 1663, 1591, 1553, 1365, 1044, 1012, 762, 703 cm"'. L R M S (ESI: 0.1% formic acid in MeOH) m/z 508 ( M + + 1), 482, 460, 438 (100). H R M S (ESI: 0.1% formic acid in MeOH) calcd for C 3 2 H 4 6 N 0 4 508.3427, found 508.3420. Anal . Calcd for C 3 2 H 4 5 N 0 4 : C, 75.70; H, 8.93; N , 2.76. Found: C, 75.75; H , 8.98; N , 2.77. R-(-)-l-Aminoindane salt (56e) 182 Chapter 4 Experimental 5 6 e A solution of acid 54 (85.5 mg, 0.25 mmol) in diethyl ether (15 mL) was added to a solution of R-(-)-l-aminoindane (33.3 mg, 0.25 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 56e (99.5 mg, 84 %) as a white powder. Recrystallization from MeOH afforded colorless needles. mp: 182-185 °C. *H N M R (300 MHz, CDCI3): 5 7.71 (d, / = 8.0 Hz, 2H), 7.64 (d, J= 8.0 Hz, 2H), 7.50-7.49 (m, IH), 7.18-7.01 (m, 3H), 4.59 (m, IH), 2.83 (m, IH), 2.75 (m, IH), 2.71 (s, 2H), 2.37 (m, IH), 1.96 (m, IH), 1.53-1.48 (m, 6H), 1.35-1.30 (m, 6H), 1.27-1.22 (m, 2H), 1.18-1.12 (m, 4H), 1.05-0.95 (m, 2H), 0.84 (t,J= 7.1 Hz, 3H). 1 3 C N M R (75 MHz, CD 3 OD): 5 200.52, 172.29, 143.49, 140.28, 139.76, 139.13, 129.35, 128.76, 127.75, 126.96, 124.92, 124.52, 55.58, 48.82, 41.65, 32.83, 32.09, 31.90, 31.65, 31.19, 30.22, 30.16, 23.28, 22.68, 14.08. I R ( K B r pellet): v 3563, 2930, 2856, 2181, 1665, 1620, 1524, 1456, 1397, 808, 748 cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z 476 ( M + + 1, 100), 471 (13.2), 400 (27.0), 365 (39.8), 343 (22.1), 267 (96.7), 166 (58.3), 134 (38.2). H R M S (ESI: 0.1% formic acid in MeOH) calcd for C31H42NO3 476.3165, found 476.3157. 183 Chapter 4 Experimental Anal. Calcd for C31H41NO3: C, 78.28; H , 8.69; N , 2.94; O, 10.09. Calcd for C 3 i H 4 i N 0 3 . l / 3 H 2 0 : C, 77.30; H , 8.72; N , 2.91. Found: C, 77.19; H , 8.86; N , 2.75. S-(+)-l-Aminoindane salt (56f) A solution of acid 54 (85.5 mg, 0.25 mmol) in diethyl ether (15 mL) was added to a solution of S-(+)-l-aminoindane (33.3 mg, 0.25 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 56f (90 mg, 76 %) as a white powder. Recrystallization from MeOH afforded colorless needles. mp: 184-186 °C. *H NMR (300 MHz, CD 3 OD): 5 7.98 (d, J= 8.1 Hz, 2H), 7.90 (d, J=8.l Hz, 2H), 7.45-7.20 (m, 4H), 4.75 (m, IH), 3.12 (m, IH), 2.97 (m, IH), 2.77 (s, 2H), 2.59 (m, IH), 2.07 (m, IH), 1.52 (m, 6H), 1.34 (m, 8H), 1.18 (m, 4H), 1.03 (m, 2H), 0.87 (t, J= 7.0 Hz, 3H). 1 3 C NMR (75 MHz, CD 3 OD): 6 202.80, 173.89, 145.37, 143.08, 141.25, 140.21, 130.59, 130.29, 128.98, 128.24, 126.34, 125.42, 57.00, 49.69, 42.91, 34.06, 33.07, 32.87, 32.33, 31.95, 31.26, 31.01, 24.35, 23.68, 14.38. IR (KBr pellet): v 3564, 2928, 2856, 2663, 2142, 1664, 1620, 1526, 1456, 1397, 1274, 748, 740 cm"1. 184 Chapter 4 Experimental L R M S (ESI: 0.1% formic acid in MeOH) m/z 476 ( M + + 1), 347 (100), 267, 134, 117. H R M S (ESI: 0.1% formic acid in MeOH) calcd for C31H42NO3 476.3165, found 476.3160. Anal . Calcd for C 3 i H 4 i N 0 3 : C, 78.28; H , 8.69; N , 2.94; O, 10.09. Calcd for C 3 i H 4 i N 0 3 . l / 2 H 2 0 : C, 76.82; H , 8.73; N , 2.89. Found: C, 76.57; H , 8.72; N , 2.74. (IS. 2RV(-)-ds-l-Amino-2-indanol salt (56g) A solution of acid 54 (85.5 mg, 0.25 mmol) in diethyl ether (15 mL) was added to a solution of (IS, 2R)-(-)-cw-l-amino-2-indanol (37.3 mg, 0.25 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 56g (87.6 mg, 71 %) as a white powder. Recrystallization from MeOH afforded colorless needles. mp: 162-165 °C. *H N M R (300 MHz, CD 3 OD): 5 7.99 (d, J= 8.6 Hz, 2H), 7.91 (d, J= 8.6 Hz, 2H), 7.47-7.27 (m, 4H), 4.70 (m, IH), 4.54 (d, J = 5.9 Hz, IH), 3.22 (d xd,Jj = 16.2 Hz, J2 = 6.5 Hz, IH), 3.01 (d x d, J, = 16.2 Hz, J2 = 5.1 Hz, IH), 2.78 (s, 2H), 1.55-1.45 (m, 6H), 1.40-1.25 (m, 8H), 1.20-1.10 (m, 4H), 1.05-0.95 (m, 2H), 0.87 (t, J=7.3 Hz, 3H). C0% $ 56g 185 Chapter 4 Experimental 1 3 C N M R (75 MHz, CD 3 OD): 5 202.78, 173.66, 145.12, 142.81, 141.33, 140.78, 130.86, 130.34, 129.00, 128.44, 126.69, 126.14, 72.03, 58.72, 49.68, 42.92, 40.12, 34.08, 33.07, 32.86, 32.33, 31.27, 24.37, 23.70, 14.39. I R ( K B r pellet): v 3443, 2928, 2856, 1664, 1620, 1544, 1458, 1393, 809, 747 cm-1. L R M S (ESI: 0.1% formic acid in MeOH) m/z 492 ( M + + 1, 0.5), 487 (4.7), 150 (100). H R M S (ESI: 0.1% formic acid in MeOH) calcd for C31H42NO4 492.3114, found 492.3108. Anal . Calcd for C 3 i H 4 i N 0 4 : C, 75.73; H , 8.41; N , 2.85; O, 13.02. Calcd for C 3 1 H 4 1 N O 4 . I / 2 H 2 O : C, 74.37; H , 8.46; N , 2.80. Found: C, 74.04; H , 8.07; N , 2.65. S-(-)-p-Tolvlethylamine salt (56h) A solution of acid 54 (85.5 mg, 0.25 mmol) in diethyl ether (15 mL) was added to a solution of S-(-)-p-tolylethylamine (33.8 mg, 0.25 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 56h (110 mg, 92 %) as a white powder. Recrystallization from MeOH afforded colorless needles. mp: 187-189 °C. 56h 186 Chapter 4 Experimental *H N M R (300 MHz, CD 3 OD): 5 7.98 (d,J= 8.4 Hz, 2H), 7.90 (d, J= 8.4 Hz, 2H), 7.31 (d,J= 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 4.38 (q, J= 6.9 Hz, IH), 2.77 (s, 2H), 2.33 (s, 3H), 1.59 (d,J= 6.9 Hz, 3H), 1.55-1.45 (m, 6H), 1.40-1.25 (m, 8H), 1.20-1.10 (m, 4H), 1.05-0.95 (m, 2H), 0.87 (t,J= 7.1 Hz, 3H). 1 3 C N M R (75 MHz, CD 3 OD): 5 202.80, 175.49, 143.16, 141.23, 140.18, 137.07, 130.80, 130.29, 128.98, 127.52, 52.09, 49.69, 42.91, 34.06, 33.07, 32.87, 32.33, 31.26, 24.35, 23.68,21.12, 20.89, 14.38. I R ( K B r pellet): v 3544, 2927, 2858, 2164, 1664, 1612, 1586, 1522, 1396, 813, 763 cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z 478 ( M + + 1), 349 (100), 271, 136. H R M S (ESI: 0.1% formic acid in MeOH) calcd for C31H44NO3 478.3321, found 478.3329. Anal . Calcd for C31H43NO3: C, 77.95; H , 9.07; N , 2.93. Calcd for C 3 1 H 4 3N03 .1 /3H 2 0: C, 76.98; H , 9.10; N , 2.90. Found: C, 76.94; H , 9.12; N , 3.01. (IR, 2R)-(-)-Amino-1 -phenyl-1. 3-propanediol salt (56i) A solution of acid 54 (85.5 mg, 0.25 mmol) in diethyl ether (15 mL) was added to a solution of (IR, 2R)-(-)-amino-l-phenyl-1, 3-propanediol (41.8 mg, 0.25 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to 187 Chapter 4 Experimental afford salt 56i (80.1 mg, 63 %) as a white powder. Recrystallization from MeOH afforded colorless prisms. mp: 140-142 °C. f H N M R (300 MHz, CD 3 OD): 5 7.99 (d, J= 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.43-7.32 (m, 5H), 4.72 (d, J= 8.7 Hz, IH), 3.52 (d x d, J, = 3.8 Hz, J2 = 11.6 Hz, IH), 3.40 ( d x d , J ; = 6.1 Hz, J2= 11.6Hz, IH), 3.28-3.22 (m, IH), 2.77 (s, 2H), 1.55-150 (m, 6H), 1.37-1.32 (m, 6H), 1.30-1.25 (m, 2H), 1.18-1.16 (m, 4H), 1.05-0.95 (m, 2H), 0.87 (t, J = 7.1 Hz, 3H). 1 3 C N M R (75 MHz, CD 3 OD): 5 199.97, 168.50, 142.53, 139.38, 129.15, 128.11, 127.62, 127.44, 126.72, 71.37, 60.00, 58.57, 47.92, 41.23, 32.25, 31.39, 31.07, 30.71, 29.78, 22.69, 22.06, 13.88. IR (KBr pellet): v 3272, 2923, 2856, 2170, 1692, 1583, 1525, 1456, 1396, 1205, 1042, 781,761,700 cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z 510 ( M + + 1, 0.1), 168 (100), 150 (22.7). H R M S (ESI: 0.1% formic acid in MeOH) calcd for C31H44NO5 510.3219, found 510.3226. Anal . Calcd for C31H43NO5: C, 73.05; H , 8.50; N , 2.75; O, 15.70. Calcd for C31H43NO5.H2O: C, 70.56; H , 8.60; N , 2.65. Found: C, 70.20; H , 8.42; N , 2.80. S-(+)-2-(Methoxvmethyl)pvrrolidine salt (56j) 188 Chapter 4 Experimental 56j A solution of acid 54 (85.5 mg, 0.25 mmol) in diethyl ether (15 mL) was added to a solution of S-(+)-2-(methoxymethyl)pyrrolidine (28.8 mg, 0.25 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 56j (101.7 mg, 89 %) as a yellowish powder. Recrystallization from MeOH afforded a pale yellow powder. mp: 76-80 °C. *H N M R (400 MHz, CD3OD): 8 8.00 (d, J= 8.5 Hz, 2H), 7.91 (d, 8.5 Hz, 2H), 3.77 (m, IH), 3.64 (d x d, J, = 3.5 Hz, J2 = 10.5 Hz, IH), 3.47 (d x d, J, = 7.9 Hz, J2 = 10.5 Hz, IH), 3.40 (s, 3H), 3.26 (m, 2H), 2.78 (s, 2H), 2.07 (m, 3H), 1.75 (m, IH), 1.55-1.50 (m, 6H), 1.37-1.32 (m, 6H), 1.30-1.25 (m, 2H), 1.18-1.16 (m, 4H), 1.04-1.01 (m, 2H), 0.87 (t, .7=7.1 Hz, 3H). 1 3 C N M R (75 MHz, CD 3 OD): 5 202.69, 173.16, 141.99, 141.56, 130.38, 129.04, 72.08, 60.74, 59.37, 49.69, 46.65, 42.91, 34.04, 33.07, 32.85, 32.32, 31.26, 27.29, 24.86, 24.36, 23.69, 14.39. IR (KBr pellet): v 3436, 2936, 2855, 1664, 1628, 1584, 1541, 1457, 1387, 1278, 1096, 954, 780 cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z 458 ( M + + 1, 0.11), 378 (5.0), 313 (27.7) 285 (100), 267 (14.4). 189 Chapter 4 Experimental H R M S (ESI: 0.1% formic acid in MeOH) calcd for C28H44NO4 458.3270, found 458.3271. Anal . Calcd for C28H43NO4: C, 73.48; H, 9.47; N , 3.06; O, 13.98. Calcd for C 2 8H 4 3N0 4 .1/2H 2 0: C, 72.07; H , 9.50; N , 3.00. Found: C, 71.99; H , 9.44; N , 2.60. R-(+)-l-Phenylethylamine salt (56k) 56k A solution of acid 54 (85.5 mg, 0.25 mmol) in diethyl ether (15 mL) was added to a solution of R-(+)-l-phenylethylamine (30.3 mg, 0.25 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 56k (95.2 mg, 82 %) as a white powder. Recrystallization from MeOH afforded colorless needles. mp: 185-187 °C. *H N M R (300 MHz, CD 3 OD): 5 7.98 (d, 7= 8.5 Hz, 2H), 7.90 (d, / = 8.5 Hz, 2H), 7.45-7.35 (m, 5H), 4.42 (q, J= 6.9 Hz, IH), 2.77 (s, 2H), 1.60 (d,J= 6.9 Hz, 3H), 1.55-1.50 (m, 6H), 1.40-1.25 ,(m, 8H), 1.20-1.10 (m, 4H), 1.05-0.95 (m, 2H), 0.87 (t, J= 7.1 Hz, 3H). 1 3 C N M R (75 MHz, CD 3 OD): 5 200.45, 172.05, 145.71, 140.48, 139.40, 129.52, 128.84, 128.23, 127.79, 126.30, 51.15, 48.82, 41.65, 32.84, 32.08, 31.88, 31.18, 30.21, 23.28, 22.68,21.77, 14.08. 190 Chapter 4 Experimental IR (KBr pellet): v 3544, 2927, 2856, 2559, 2198, 1716, 1661, 1627, 1581, 1532, 1456, 1394, 760, 739, 692 cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z 464 ( M + + 1, 94.4%), 459 (39.4%), 400 (69.7), 343 (78.7), 243 (100). H R M S (ESI: 0.1% formic acid in MeOH) calcd for C30H42NO3 464.3165, found 464.3163. Anal . Calcd for C30H41NO3: C, 77.71; H , 8.91; N , 3.02; O, 10.35. Calcd for C30H41NO3.I/3H2O: C, 76.72; H , 8.94; N , 2.98. Found: C, 76.43; H , 8.86; N , 2.98. S-(-)-l-Phenylethylamine salt (561) A solution of acid 54 (85.5 mg, 0.25 mmol) in diethyl ether (15 mL) was added to a solution of S-(-)-l-phenylethylamine (30.3 mg, 0.25 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 561 (105 mg, 91 %) as a white powder. Recrystallization from MeOH afforded colorless needles. mp: 185-187 °C. 561 191 Chapter 4 Experimental *H N M R (300 MHz, CD 3 OD): 5 7.98 (d, J= 8.3 Hz, 2H), 7.90 (d, J = 8.3 Hz, 2H), 7.43 (m, 5H), 4.42 (q, J= 6.8 Hz, IH), 2.77 (s, 2H), 1.61 (d, J= 6.8 Hz, 3H), 1.60-1.40 (m, 6H), 1.40-1.25 (m, 8H), 1.25-1.05 (m, 4H), 1.05-0.95 (m, 2H), 0.87 (t,J= 7.0 Hz, 3H). 1 3 C N M R (75 MHz, CD 3 OD): 8 202.80, 185.93, 143.10, 141.26, 140.19, 130.29, 130.26, 130.05, 128.98, 127.58, 52.33, 49.57, 42.91, 34.06, 33.07, 32.87, 32.33, 31.26, 24.35, 23.68, 20.99, 14.38. IR (KBr pellet): v 3568, 2927, 2857, 2557, 2204, 1720, 1661, 1631, 1581, 1531, 1392, 760, 739, 692 cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z 464 ( M + + 1), 335 (100), 122, 105. H R M S (ESI: 0.1% formic acid in MeOH) calcd for C30H42NO3 464.3165, found 464.3167. Anal . Calcd for C30H41NO3: C, 77.71; H, 8.91; N , 3.02; O, 10.35. Calcd for C 3 0 H 4 1 N O 3 . I / 2 H 2 O : C, 76.23; H, 8.96; N , 2.96. Found: C, 76.04; H , 8.85; N , 3.04. (-)-czs-Mvrtanylamine salt (56m) 56m A solution of acid 54 (85.5 mg, 0.25 mmol) in diethyl ether (15 mL) was added to a solution of (-)-c^-myrtanylamine (38.3 mg, 0.25 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was 192 Chapter 4 Experimental filtered, washed with diethyl ether and dried in vacuo to afford salt 56m (112 mg, 90 %) as a white powder. Recrystallization from MeOH afforded colorless prisms. mp: 155-157 °C. ! H N M R (300 MHz, CD 3 OD): 5 7.98 (d, J= 8.3 Hz, 2H), 7.90 (d, J= 8.3 Hz, 2H), 2.93 (d, J= 7.5 Hz, 2H), 2.77 (s, 2H), 2.44 (m, IH), 2.33 (m, IH), 1.98 (m, 5H), 1.60-1.45 (m, 7H), 1.40-1.25 (m, 8H), 1.23 (s, 3H), 1.22-1.10 (m, 4H), 1.02 (s, 3H), 1.00-0.90 (m, 3H), 0.87 (t, J=7.0 Hz, 3H). 1 3 C N M R (75 MHz, CD 3 OD): 5 202.81, 178.40, 143.33, 141.19, 130.27, 128.97, 49.69, 46.35, 44.71, 42.91, 42.46, 41.04, 39.59, 34.06, 33.72, 33.07, 32.87, 32.33, 31.26, 28.14, 26.69, 24.35, 23.68, 23.42, 20.44, 14.37. IR (KBr pellet): v 3544, 2925, 2856, 2145, 1671, 1620, 1585, 1537, 1367, 1272, 760, cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z 496 ( M + + 1), 367 (100), 307, 154. H R M S (ESI: 0.1% formic acid in MeOH) calcd for C 3 2H 5 oN0 3 496.3791, found 496.3785. Anal. Calcd for C 3 2 H 4 9 N 0 3 : C, 77.53; H , 9.96; N , 2.83; O, 9.68. Calcd for C 3 2 H 4 9 N 0 3 . 1 / 4 H 2 0 : C, 76.83; H , 9.97; N , 2.80. Found: C, 76.49; H , 10.02; N , 2.70. 193 Chapter 4 Experimental 4.4 Synthesis of Bicyclo[2.2.1]heptane Derivatives 57, 58 and 59 4.4.1 Preparation of Ketones 57 and 58 2.2-Dichlorobicvclor2.2.1 lheptane (87) Cl Cl 87 To a solution of norcamphor (25.0 g, 227 mmol) in PCI3 (15.0 mL), which was cooled in an ice bath, was added, in portions, PCI5 (53.Og, 255 mmol) over 15 min. The mixture was allowed to warm slowly to room temperature, and stirred overnight. The mixture was poured into 500 g of ice and extracted with n-pentane (3 x 300 mL). The combined organic extracts were washed with water (4 x 100 mL), brine (2 x 100 mL), and dried (MgS0 4 ). Purification by vacuum distillation afforded compound 87 as a white solid (31.8 g, 85%). bp: 80-82 °C/22mmHg (Li t . 9 7 ( b ) 65.0-68.1 °C/12.0-12.4mmHg). *H NMR (400 MHz, CDC1 3): 5 2.71 (s, IH), 2.60 (m, IH), 2.30 (m, IH), 2.08 (m, IH), 1.96 (m, 2H), 1.54 (m, 2H), 1.41 (m, IH), 1.17 (m, IH). 13C NMR (100 MHz, CDCI3): 5 95.06, 55.79, 55.20, 37.65, 37.49, 27.38, 25.20. LRMS (EI) m/z 165 (M+), 129, 93, 68 (100). l-Chlorobicvclor2.2.nheptane (88)97(b) 88 194 Chapter 4 Experimental To a cooled (0 °C) solution of compound 87 (31.7 g, 192 mmol) in wo-pentane (40 mL) and n-pentane (140 mL) (both z'sopentane and «-pentane were purified by distillation over anhydrous aluminum trichloride) was added anhydrous aluminum trichloride (12.4 g, 92.9 mmol) in small portions as rapidly as the hydrogen chloride evolution would permit. The mixture was stirred at room temperature for 8 h. The pentane layer was decanted and the remaining dark sludge was washed with «-pentane (4 x 80 mL). The combined pentane extracts were washed with 5% NaHC03 (2 x 80 mL), water (2 x 80 mL), and dried (Na 2S0 4). Distillation provided compound 88 (12.2 g, 49%) as a colorless liquid. bp: 146-152 °C (Li t . 9 7 ( b ) 70-71 °C/54 mmHg). *H N M R (300 MHz, CDC1 3): 5 2.17 (m, IH), 1.80 (m, 4H), 1.67 (m, 2H), 1.45-1.10 (m, 4H). 1 3 C N M R (75 MHz, CDC1 3): 5 69.77, 46.79, 38.40, 34.83, 30.93. L R M S (EI) m/z 130 (M + ) , 101(100), 95, 79, 67. 2-(4-Fluorophenyl)oxirane (90) 90 A solution of 3-chloroperoxybenzoic acid (w-CPBA -70%, 27.3 g, 110.7 mmol) in CH2CI2 (100 mL) was added to a solution of 4-fluorostyrene (8.5 g, 73.8 mmol) in CH2CI2 (300 mL) at room temperature. Stirring was continued for 12 h, after which time the reaction was quenched by saturated N a 2 S 0 3 (300 mL). The aqueous phase was extracted with CH2CI2 (3 x 200 mL). The combined organic extracts were washed with water (5 x 100 mL), brine (2 x 100 mL), and dried (Na2SC>4). Removal of the solvent in 195 Chapter 4 Experimental vacuo provided a yellowish liquid. Purification by column chromatography on silica gel (petroleum ether-ether, 95:5) afforded compound 90 (7.3 g, 76%) as a colorless liquid. ! H NMR (300 MHz, CDC1 3): 8 7.22 (m, 2H), 7.01 (m, 2H), 3.82 (dxd, J} = 2.7 Hz, J2 = 4.0 Hz, IH), 3.11 (dxd, J, = 4.0 Hz, J2 = 5.4 Hz, IH), 2.74 (dxd, Jj = 2.7 Hz, J2 = 5.4 Hz, IH). 1 3 C NMR (75 MHz, CDC1 3): 8 164.08, 160.82, 133.26, 133.23, 127.00, 126.89, 115.30, 115.01,51.46, 50.75. LRMS (EI) m/z 138 (M + ) , 109(100), 83, 57. l-(4 ,-Fluorophenvn-2-bicylo[2.2.11hept-l-vl ethanol (91) A suspension of lithium wire (0.53 g, 76.4 mmol, washed with petroleum ether and wiped with a paper towel) in dry cyclohexane (5 mL) was heated to reflux under an oxygen-free argon atmosphere. To the mixture was added a solution of 1-chloro bicyclo[2.2.1]heptane (88, 1.0 g, 7.6 mmol) in dry cyclohexane (5mL) over 30 min. The resulting mixture was heated to be refluxing for 10 h, after which time dry cyclohexane (20 mL) was added to dissolve the reaction mixture (the lithium carbanion solution). To a cold (-78°C) suspension of CuCN (0.34 g, 3.8 mmol, dried in vacuo) in THF (15 mL) was added the lithium solution over 15 min. The reaction was stirred at -78°C for 10 min before a solution of 2-(4-fluorophenyl)oxirane (90, 0.74 g, 5.4 mmol, 0.63mL) in THF (5 mL) was added dropwise over 15 min. The resulting solution was stirred at -78°C for 2 h followed by wanning slowly to room temperature. The reaction was quenched with saturated NH4CI (100 mL), and extracted with diethyl ether (3 x 100 mL). The combined F 91 196 Chapter 4 Experimental ethereal extracts were washed with water (2 x 40 mL), brine (2 x 40 mL), and dried (Na2SC>4). Removal of the solvent in vacuo provided a yellowish solid. Purification by column chromatography on silica gel (petroleum ether-ether, 9:1) afforded compound 91 ( 0.62 g, 50%) as a white solid. m p : 73.5-75.0 °C. *H NMR (300 MHz, CDCI3): 8 7.29 (m, 2H), 6.99 (m, 2H), 7.42 (m, 5H), 4.76 (m, IH), 2.12 (m, IH), 1.97 (m, 2H), 1.89 (s, IH), 1.60-1.64 (m, 3H), 1.40-1.15 (m, 7H). 1 3 C NMR (75 MHz, CDCI3): 8 163.70 and 160.46 ( l J c . F = 243 Hz), 141.59, 127.63 and 127.52 ( 3 J C - F = 8 Hz), 115.30 and 115.02 ( 2 J C - F = 21 Hz), 72.81, 46.19, 45.42, 44.44, 36.60, 34.88, 34.74, 30.87, 30.58. IR (KBr pellet): v 3255 (br), 2949, 2914, 2867, 1605, 1511, 1227, 1027, 838, 567 cm'1. LRMS ((ESI: 0.1% formic acid in MeOH) m/z 233 ( M + - l , 100), 185, 137. HRMS ((ESI: 0.1% formic acid in MeOH) calcd for C i 5 H i 8 F O ( M + - l ) 233.1342, found 233.1348. A n a l . Calcd for C i 5 H 1 9 F O : C, 76.89; H , 8.17. Found: C, 76.96; H , 8.29. l-(4,-Fluorophenyl)-2-bicvclor2.2.11hept-l-vl ethanone (92) F 92 197 C h a p t e r 4 E x p e r i m e n t a l To a solution of alcohol 91 (3.0 g, 12.8 mmol) in acetone (65 mL) was added dropwise Jones' Reagent (prepared from 2.0 g chromium trioxide, 5.5 mL water and 1.8 mL of cone, sulfuric acid), maintaining the reaction temperature at 10-15 °C. After stirring for 2h, the solvent was removed in vacuo, and the dark residue was taken up in water (80 mL) and extracted with diethyl ether (3x100 mL). The organic extracts were combined and washed with water (30 mL), brine (2x50 mL) and dried (Na2S04). Removal of the solvent in vacuo provided compound 92 (2.72 g, 92%) as a yellowish liquid. The compound did not require further purification. *H NMR (300 MHz, CDCI3): 8 7.96 (m, 2H), 7.09 (m, 2H), 3.13 (s, 2H), 2.15 (m, IH), 1.7-1.5 (m, 2H), 1.5-1.3 (m, 4H), 1.3-1.2 (m, 4H). 1 3 C NMR (75 MHz, CDCI3): 8 198.71, 167.28 and 163.91 ('JC-F = 253 Hz), 134.53 and 134.50 ( 4J C-F = 2 Hz), 130.93 and 130.81 ( 3 J C . F = 9 Hz), 115.64 and 115.35 ( 2J C-F = 22 Hz), 45.73, 43.90, 43.35, 36.39, 34.83, 30.57. IR (neat): v 3069, 2950, 2917, 2869, 1677, 1598, 1507, 1234, 1156, 833, 588 cm"1. LRMS (EI) m/z 232 (M + ) , 138, 123 (100), 95. HRMS (EI) calcd for C 1 5 H ] 7 F O (M + ) 232.1263, found 232.1265. Anal . Calcd for C 1 5 H 1 7 F O : C, 77.56; H , 7.38. Found: C, 77.90; H , 7.59. l-(4'-CvanophenvlV2-bicvclor2.2.11hept-l-vl ethanone (93) CN 93 198 Chapter 4 Experimental A mixture of compound 92 (2.72g, 11.7 mmol) and sodium cyanide (0.86g, 17.6 mmol) in anhydrous D M F (30 mL) was heated to be refluxing at 150 °C under an argon atmosphere for 17 h. The resulting dark mixture was quenched with water (150 mL) extracted with diethyl ether (3 x 100 mL). The combined extracts were washed with water (2 x 50 mL), brine (2 x 50 mL) and dried (Na2SC>4). Removal of the solvent in vacuo provided compound 93 (2.54 g, 94%) as a yellowish solid. The compound did not require further purification. m p : 53-54 °C. *H NMR (400 MHz, CDC1 3): 5 7.98 (d, J= 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 3.14 (s, 2H), 2.11 (m, IH), 1.54 (m, 2H), 1.40 (m, 4H), 1.21 (m, 4H). 1 3 C NMR (100 MHz, CDC13): 5 198.72, 140.80, 132.26, 128.48, 117.85, 115.87, 45.45, 43.70, 43.55, 36.50, 34.57, 30.38. IR (KBr pellet): v 2948, 2870, 2224, 1691, 1402, 1206, 999, 828, 578 cm"1. LRMS (EI) m/z 239 (M + ) , 210, 171, 130 (100), 102, 94, 79. HRMS (EI) calcd for Ci 6 H 1 7 NO (M + ) 239.1310, found 239.1313. Anal. Calcd for Ci 6 H , 7 NO: C, 80.30; H , 7.16; N, 5.85. Found: C, 80.00; H , 7.33; N, 5.92. l-(4 ,-carboxvlphenyl)-2-bicvclo[2.2.1]hept-l-vl ethanone (57) 57 COOH 199 Chapter 4 Experimental To a solution of potassium hydroxide (8.0 g, 143 mmol) in water (40 mL) was added a solution of compound 93 (2.54g, 10.6 mmol) in ethanol (10 mL). The mixture was heated to be refluxing at 95 °C for 20 h. The reaction was quenched with water (100 mL). The solution was washed with methylene chloride (2 x 30 mL). The aqueous solution was carefully acidified to pH 2 with concentrated HCI. The precipitated carboxylic acid was extracted with ether (4 x 150 mL) and the combined ethereal extracts were washed with water (2 x 30 mL), brine (2 x 30 mL), and dried (Na2SC»4). Removal of the solvent in vacuo provided a yellowish solid. Recrystallization from ethanol afforded compound 57 (2.50 g, 91%) as colorless plates. m p : 210-212 °C. ! H N M R (300 MHz, CDC1 3): 5 8.17 (d, J = 8.5 Hz, 2H), 8.01 (d, J = 8.5 Hz, 2H), 3.20 (s, 2H), 2.17 (m, IH), 1.58 (m, 2H), 1.41 (m, 4H), 1.27 (m, 4H). 1 3 C N M R (75 MHz, CDCI3): 5 199.89, 170.83, 142.04, 132.67, 130.38, 128.22, 45.69, 43.90, 43.88, 36.68, 34.80, 30.56. IR (KBr pellet): v 3543, 2948, 2867, 1686, 1290, 768 cm - 1 . LRMS (+CI: gas, NH 3 ) m/z 276 ( M + + 18, 27.0%), 259 ( M + + 1, 66.3%), 243 (15.8%), 232 (23.3%), 215 (100%), 149 (17.9%), 124 (18.0%). H R M S (+CI: gas, NH 3 ) calcd for C i 6 H 1 9 0 3 ( M + + 1) 259.1334, found 259.1335. Anal . Calcd for Ci6Hi 8 0 3 : C, 74.39; H , 7.02. Found: C, 74.65; H , 6.98. 2 0 0 Chapter 4 Experimental 1 -(4'-Methoxvcarbonvlphenyl)-2-bicvclor2.2.1 ]hept-1 -vl ethanone (58) To a solution of acid 57 (0.150 g) in diethyl ether (5 mL) was added a solution of diazomethane in diethyl ether (10 mL, excess in the reaction) at room temperature. The reaction was stirred for 10 min. Removal of the solvent in vacuo provided a white solid. Recrystallization from ethanol afforded ester 58 (0.158 g, 100 %) as colorless plates. m p : 76-77 °C. U V (CH 3 OH): X 205.0 (1.63xl0 4), 250.0 (2.15 x 104), 290.0 (1.73 x 103) nm (M^cm"1). *H N M R (300 MHz, CDCI3): 8 8.08 (d, J= 8.4 Hz, 2H), 7.96 (d, J= 8.4 Hz, 2H), 3.91 (s, 3H), 3.17 (s, 2H), 2.14 (m, IH), 1.59 (m, 2H), 1.39 (m, 4H), 1.25 (m, 4H). 1 3 C N M R (75 MHz, CDC1 3, APT: C, C H 2 : +; C H , C H 3 : -): 8 199.80 (+), 166.24 (+), 141.30 (+), 133.54 (+), 129.70 (-), 128.09 (-), 52.36 (-), 45.64 (+), 43.85 (+), 43.77 (+), 36.65 (-), 34.75 (+), 30.53 (+). IR (KBr pellet): v 2956, 2867, 1720, 1685, 1571, 1278, 1199, 1109, 764 cm"1. L R M S (EI) m/z 272 (M + ) , 213, 163 (100), 135, 104, 79. H R M S (EI) calcd for C i 7 H 2 o 0 3 (M + ) 272.1412, found 272.1412. Anal . Calcd for C 1 7 H 2 0 O 3 : C, 74.97; H , 7.40. Found: C, 75.17; H , 7.55. 201 Chapter 4 Experimental This structure was confirmed by X-ray crystallographic analysis: Habit colorless plates Space group P2,212, a, A 5.8460(10) b , A 11.314(2) c A 11.914(2) a ( ° ) 109.17(3) P(°) 98.08(2) Y(°) 96.16(2) Z 2 R 0.051 4.4.2 Preparation of Bicyclo[2.2.1]heptyl Salts 59 L-Prolinamide salt (59a) A solution of acid 57 (77 mg, 0.30 mmol) in diethyl ether (15 mL) was added to a solution of L-prolinamide (34 mg, 0.30 mmol) in E t 2 0 (15 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 59a (92 mg, 82 %) as a white powder. Recrystallization from MeOH afforded colorless plates. mp: 162-163 °C. 202 C h a p t e r 4 E x p e r i m e n t a l *H NMR (300 MHz, CD 3 OD): 6 7.94 (d,J= 8.2 Hz, 2H), 7.89 (d, J= 8.2 Hz, 2H), 4.16 (m, IH), 3.24 (m, 2H), 3.15 (s, 2H), 2.34 (m, IH), 2.07 (m, IH), 1.94 (m, 3H), 1.53 (m, 2H), 1.42 (m, 2H), 1.33 (m, 2H), 1.21 (m, 4H). 13C NMR (75 MHz, CD 3 OD): 5 202.57, 173.78, 172.91, 142.66, 140.74, 130.34, 128.98, 60.95, 47.31, 46.93, 44.74, 44.51, 37.93, 35.73, 31.56, 31.25, 25.35. IR (KBr pellet): v 3321, 2946, 2862, 1707, 1684, 1672, 1592, 1553, 1373, 1205, 996, 776 cm-1. LRMS (ESI: 0.1% formic acid in MeOH) m/z 373 ( M + + 1), 328 (100), 229, 115. HRMS (ESI: 0.1% formic acid in MeOH) calcd for C21H29N2O4 ( M + + 1) 373.2127, found 373.2131. A n a l . Calcd for C 2 , H 2 8 N 2 0 4 : C, 67.72; H , 7.58; N , 7.52. Found: C, 67.46; H , 7.76; N , 7.58. (IS, 2RVM-c/s-l-Amino-2-indanol salt (59b) A solution of acid 57 (77 mg, 0.30 mmol) in diethyl ether (15 mL) was added to a solution of (IS, 2R)-(-)-cw-l-amino-2-indanol (45 mg, 0.30 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 59b (100 mg, 82 %) as a white powder. Recrystallization from MeOH afforded colorless needles. 59b 203 Chapter 4 Experimental m p : 166-168 °C. *H N M R (300 MHz, CD 3 OD): 5 8.00 (d, J = 8.5 Hz, 2H), 7.94 (d, J= 8.5 Hz, 2H), 7.47 (m, IH), 7.30 (m, 3H), 4.71 (m, IH), 4.56 (d, J= 5.9 Hz, IH), 3.22 (d xdiJJ = 16.1 Hz, J2 = 6.5 Hz, IH), 3.21 (s, 2H), 3.02 (d x d , J , = 16.1 Hz, J2 = 5.0 Hz, IH), 2.14 (m, IH), 1.65-1.55 (m, 2H), 1.55-1.35 (m, 4H), 1.35-1.20 (m, 4H). 1 3 C N M R (75 MHz, CD 3 OD): 5 202.60, 173.97, 145.03, 142.79, 140.62, 138.24, 130.81, 130.33, 128.95, 128.40, 126.63, 126.19, 71.98, 58.65, 46.93, 44.75, 44.50, 40.10, 37.93, 35.73,31.56. IR (KBr pellet): v 3540, 3039, 2951, 2867, 2632, 2100, 1715, 1672, 1582, 1539, 1399, 744 cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z (relative intensity) 408 ( M + + 1, 3.7), 150 H R M S (ESI: 0.1% formic acid in MeOH) calcd for C 2 5H 3 oN0 4 ( M + + 1) 408.2176, found 408.2184. Anal . Calcd for C 2 5H 2 9N0 4 : C, 73.68; H , 7.17; N , 3.44. Found: C, 73.44; H , 7.17; N , 3.35. S-(-)-p-Tolvlethylamine salt (59c) (100). ,0 204 Chapter 4 Experimental A solution of acid 57 (77 mg, 0.30 mmol) in diethyl ether (15 mL) was added to a solution of S-(-)-/?-toIylethylamine (41 mg, 0.30 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 59c (105 mg, 89 %) as a white powder. Recrystallization from MeOH afforded colorless needles. m p : 177-179 °C. *H N M R (300 MHz, CD 3 OD): 8 7.99 (d, J= 8.5 Hz, 2H), 7.94 (d, J= 8.5 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), ), 7.23 (d, / = 8.1 Hz, 2H), 4.38 (q, / = 6.9 Hz, IH), 3.22 (s, 2H), 2.33 (s, 3H), 2.14 (m, IH), 1.59 (d, J = 6.9 Hz, 3H), 1.65-1.55 (m, 2H), 1.55-1.35 (m, 4H), 1.35-1.20 (m, 4H). 1 3 C N M R (75 MHz, CD 3 OD): 8 202.64, 173.97, 143.25, 140.56, 140.17, 137.02, 130.80, 130.31, 128.94, 127.53, 52.08, 46.95, 44.75, 44.51, 37.94, 35.74, 31.57, 21.12, 20.87. IR (KBr pellet): v 3544, 3020, 2952, 2868, 2145, 1716, 1671, 1620, 1525, 1395, 762 cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z 394 ( M + + 1, 100), 281 (5.8), 271 (28.9), 259 (4.9), 242 (89). H R M S (ESI: 0.1% formic acid in MeOH) calcd for C 2 5 H 3 2 N 0 3 ( M + + 1) 394.2382, found 394.2373. Anal. Calcd for C 2 5 H 3 I N 0 3 : C, 7630; H , 7.94; N , 3.56; O, 12.20. Calcd for C 2 5 H 3 i N 0 3 . l / 4 H 2 0 : C, 75.44; H , 7.98; N , 3.52. Found: C, 75.28; H , 8.10; N , 3.44. 205 Chapter 4 Experimental R-(-)-l-Cyclohexylethylamine salt (59d) 59d A solution of acid 57 (77 mg, 0.30 mmol) in diethyl ether (15 mL) was added to a solution of R-(-)-l-cyclohexylethylamine (38 mg, 0.30 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 59d (105 mg, 91 %) as a white powder. Recrystallization from MeOH afforded colorless needles. m p : 175-176 °C. *H NMR (300 MHz, CD 3 OD): 8 8.00 (d, J= 8.5 Hz, 2H), 7.94 (d, J= 8.5 Hz, 2H), 3.22 (s, 2H), 3.07 (m, IH), 2.14 (m, IH), 1.85-1.70 (m, 5H), 1.70-1.55 (m, 2H), 1.55-1.35 (m, 5H), 1.27 (m, 7H), 1.23 (d, J= 6.7 Hz, 3H), 1.06 (m, 2H). 1 3 C NMR (75 MHz, CD 3 OD): 8 202.62, 174.08, 143.46, 140.52, 130.29, 128.95, 53.40, 46.95, 44.76, 44.51, 42.74, 37.94, 35.75, 31.58, 30.02, 28.83, 27.08, 27.00, 26.92, 16.05. IR (KBr pellet): v 3564, 2943, 2865, 2164, 1716, 1681, 1624, 1584, 1532, 1382, 1208, 998, 780 cm"1. LRMS (ESI: 0.1% formic acid in MeOH) m/z (relative intensity) 542 (100), 386 ( M + + 1, 9.5), 281 (14.1), 259 (20.0), 242 (38.4). HRMS (ESI: 0.1% formic acid in MeOH) calcd for C 2 4 H 3 6 N 0 3 ( M + + 1) 386.2695, found 386.2692. 206 Chapter 4 Experimental Anal. Calcd for C 2 4H3 5 N0 3 : C, 74.77; H , 9.15; N , 3.63. Found: C, 74.53; H , 9.39; N , 3.60. This structure was confirmed by X-ray crystallographic analysis: Habit colorless needles Space group P2,2,2, a, A 6.197(1) b,A 17.606(3) c A 20.766(4) cc(°) 90 90 Y(°) 90 Z 4 R 0.065 (IS. 2RV(+VNorephedrine salt (59e) A solution of acid 57 (77 mg, 0.30 mmol) in diethyl ether (15 mL) was added to a solution of (IS, 2R)-(+)-norephedrine (45 mg, 0.30 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 59e (105 mg, 86 %) as a white powder. Recrystallization from MeOH afforded colorless needles. m p : 144-147 °C. 207 Chapter 4 Experimental ! H N M R (300 MHz, CD3OD): 8 8.01 (d, J= 8.6 Hz, 2H), 7.94 (d, J= 8.6 Hz, 2H), 7.40-7.25 (m, 5H), 4.93 (d, J= 3.4 Hz, IH), 3.49 (d x q , J ; = 3.4 Hz, J2 =6.6 Hz, IH), 3.22 (s, 2H), 2.14 (m, IH), 1.70-1.55 (m, 2H), 1.55-1.35 (4H, m), 1.35-1.20 (m, 4H), 1.07 (d,J = 6.6 Hz, 3H). I 3 C N M R (75 MHz, CD 3 OD): 8 202.65, 174.02, 143.23, 141.58, 140.58, 130.32, 129.53, 129.00, 128.96, 127.19, 73.74, 53.68, 46.95, 44.75, 44.51, 37.94, 35.74, 31.57, 12.56. I R ( K B r pellet): v 3352, 2950, 2869, 2088, 1716, 1684, 1635, 1588, 1554, 1518, 1393, 1206, 1051,780 cm"1. LRMS (ESI: 0.1% formic acid in MeOH) m/z (relative intensity) 410 ( M + + 1, 0.5), 259 (2.1), 152 (100). H R M S (ESI: 0.1% formic acid in MeOH) calcd for C25H32NO4 ( M + + 1) 410.2331, found 410.2320. Anal . Calcd for C25H31NO4: C, 73.32; H , 7.63; N , 3.42; O, 15.63. Calcd for C25H31NO4.I/4H2O: C, 72.95; H , 7.89; N , 3.27. Found: C, 72.68; H , 7.75; N , 3.30. R-(+)-l-Phenylethylamine salt (59f) 59f A solution of acid 57 (77 mg, 0.30 mmol) in diethyl ether (15 mL) was added to a solution of R-(+)-l-phenylethylamine (36 mg, 0.30 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 59f (90 mg, 79 %) as a white powder. Recrystallization from MeOH afforded colorless needles. 208 Chapter 4 Experimental m p : 166-167 °C. *H N M R (300 MHz, CD 3 OD): 5 7.92 (d,J= 8.0 Hz, 2H), 7.86 (d, J= 8.0 Hz, 2H), 7.33 (m, 5H), 4.35 (q, J = 6.7 Hz, IH), 3.14 (s, 2H), 2.06 (m, IH), 1.53 (d, J = 6.7 Hz, 3H), 1.51 (m, 2H), 1.41 (m, 2H), 1.32 (m, 2H), 1.20 (m, 4H). 1 3 C N M R (75 MHz, CD 3 OD): 5 202.62, 173.97, 143.20, 140.59, 140.13, 130.31, 130.25, 130.03, 128.95, 127.60, 52.31, 46.95, 44.76, 44.51, 37.94, 35.75, 31.57, 20.97. IR (KBr pellet): v 3521, 2947, 2866, 2211, 1716, 1684, 1672, 1622, 1584, 1524, 1386, 1208, 996, 779, 700 cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z 380 ( M + + 1), 335 (100), 122. H R M S (ESI: 0.1% formic acid in MeOH) calcd for C 2 4 H 3 0 N O 3 ( M + + 1) 380.2226, found 380.2234. Anal . Calcd for C 2 4 H 2 9 N 0 3 : C, 75.96; H , 7.70; N , 3.69. Found: C, 75.64; H , 7.79; N , 3.68. S-(-)-l -Phenylethylamine salt (59g) A solution of acid 57 (77 mg, 0.30 mmol) in diethyl ether (15 mL) was added to a solution of S-(-)-l-phenylethylamine (36 mg, 0.30 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was 209 Chapter 4 Experimental filtered, washed with diethyl ether and dried in vacuo to afford salt 59g (95 mg, 84 %) as a white powder. Recrystallization from MeOH afforded colorless needles. mp: 165-166 °C. *H N M R (300 MHz, CD 3 OD): 8 7.92 (d,J= 8.0 Hz, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.35 (m, 5H), 4.36 (q, J= 6.6 Hz, IH), 3.15 (s, 2H), 2.07 (m, IH), 1.54 (d, J= 6.6 Hz, 3H), 1.52 (m, 2H), 1.42 (m, 2H), 1..33 (m, 2H), 1.21 (m, 4H). 1 3 C N M R (75 MHz, CD 3 OD): 8 202.61, 173.98, 143.21, 140.59, 140.12, 130.31, 130.25, 130.03, 128.95, 127.60, 52.31, 46.95, 44.76, 44.51, 37.94, 35.74, 31.57, 20.97. IR (KBr pellet): v 3522, 2948, 2867, 2186, 1716, 1684, 1672, 1622, 1584, 1524, 1386, 1208,996,779,700 cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z 380 ( M + + 1), 335 (100), 122. H R M S (ESI: 0.1% formic acid in MeOH) calcd for C 2 4 H 3 0 N O 3 ( M + + 1) 380.2226, found 380.2235. Anal . Calcd for C24H 2 9 N0 3 : C, 75.96; H , 7.70; N , 3.69. Found: C, 75.74; H , 7.29; N , 3.87. (IR. 2RV(-)-2-Amino-1 -phenyl-1. 3-propanediol salt (59h) 59h 2 1 0 Chapter 4 Experimental A solution of acid 57 (77 mg, 0.30 mmol) in diethyl ether (15 mL) was added to a solution of (IR, 2R)-(-)-2-amino-l-phenyl-1, 3-propanediol (50 mg, 0.30 mmol) in diethyl ether (15 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 59h (85 mg, 67 %) as a white powder. Recrystallization from MeOH afforded a white powder. mp: 132-133 °C. ' H N M R (300 MHz, CD 3 OD): 8 8.01 (d, J= 8.5 Hz, 2H), 7.95 (d,J= 8.5 Hz, 2H), 7.43-7.32 (m, 5H), 4.73 (d, J= 8.7 Hz, IH), 3.53 (d x d, J, = 11.6 Hz, J2 = 3.7 Hz, IH), 3.40 (d x d, Jj = 11.6 Hz, J2 = 6.0 Hz, IH), 3.28-3.25 (m, IH), 3.22 (2H, s), 2.14 (m, IH), 1.61-1.57 (m, 2H), 1.51-1.47 (m, 2H), 1.44-1.39 (m, 2H), 1.35-1.31 (m, IH), 1.28 (m, 3H). 1 3 C N M R (75 MHz, CD 3 OD): 8 202.61, 173.74, 142.92, 142.12, 140.64, 130.35, 129.77, 129.57, 128.97, 127.88, 72.34, 60.31, 59.97, 46.94, 44.75, 44.50, 37.94, 35.73, 31.57. I R ( K B r pellet): v 3272, 2949, 2868, 1688, 1668, 1584, 1540, 1396, 1040, 760, 700 cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z (relative intensity) 426 ( M + + 1), 335, 259, 168 (100). H R M S (ESI: 0.1% formic acid in MeOH) calcd for C 2 5 H 3 2 N 0 5 ( M + + 1) 426.2280, found 408.2184. Anal . Calcd for C 2 5 H 3 1 N 0 5 : C, 70.57; H, 7.34; N , 3.29; O, 18.80. Calcd for C 2 5H 3 1 N0 5 .1 /4H 2 0: C, 69.83; H , 7.38; N , 3.26, Found: C, 69.72; H , 7,40; N , 3.03. 211 Chapter 4 Experimental (-)-ds-Mvrtanylamine salt (590 O cocg H '"CH2NH 5 © ' 59i A solution of acid 57 (77 mg, 0.30 mmol) in diethyl ether (15 mL) was added to a solution of (-)-cw-myrtanylamine (46 mg, 0.30 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 59i (110 mg, 89 %) as a white powder. Recrystallization from MeOH afforded colorless needles. mp: 152-154 °C. ' H N M R (300 MHz, CD 3 OD): 5 8.00 (d,J= 8.6 Hz, 2H), 7.94 (d, J= 8.6 Hz, 2H), 3.22 (s, 2H), 2.92 (m, 2H), 2.46-2.26 (m, 2H), 2.14 (m, IH), 2.10-1.85 (m, 5H), 1.70-1.30 (m, 8H), 1.28 (m, 3H), 1.22 (s, 3H), 1.01 (s, 3H), 0.96 (d, J= 9.8 Hz, IH). , 3 C N M R (75 MHz, CD 3 OD): 5 202.60, 174.11, 143.38, 140.52, 130.29, 128.95, 46.94, 46.29, 44.76, 44.70, 44.51, 42.44, 40.94, 39.56, 37.94, 35.75, 33.72, 31.57, 28.14, 26.69, 23.42, 20.43. IR (KBr pellet): v 3544, 2948, 2868, 2188, 1716, 1688, 1636, 1582, 1536, 1379, 1204, 996,780 cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z (relative intensity) 412 ( M + + 1, 18.5), 307 (15.2), 259 (0.3), 154(100). H R M S (ESI: 0.1% formic acid in MeOH) calcd for C 2 6 H 3 8 N 0 3 ( M + + 1) 412.2852, found 412.2852. 212 Chapter 4 Experimental Anal. Calcd for C26H37NO3: C, 75.87; H , 9.06; N , 3.40. Found: C, 75.71; H , 9.28; N , 3.36. S-(+V2-fMelhoxvmetfavl')pvrrolidine salt (59i) A solution of acid 57 (77 mg, 0.30 mmol) in diethyl ether (15 mL) was added to a solution of S-(+)-2-(methoxymethyl)pyrrolidine (35 mg, 0.30 mmol) in diethyl ether (5 mL). The solution was stirred for 1 h, after which time no precipitate was formed and removal of solvent in vacuo afforded salt 59j (112 mg, 100 %) as a pale yellow powder. Recrystallization from MeOH afforded a yellowish powder. mp: 108-113 °C. J H NMR (300 MHz, CD 3 OD): 5 8.02 (d, J= 8.5 Hz, 2H), 7.96 (d, J= 8.5 Hz, 2H), 3.78 (m, IH), 3.64 (d x d, J, = 10.5 Hz, J2 =3.6 Hz, IH), 3.47 (d x d, J / = 10.5 Hz, J2 = 7.7 Hz, IH), 3.39 (s, 3H), 3.27 (m, 2H), 3.23 (s, 2H), 2.14 (m, IH), 2.10-1.98 (m, 3H), 1.81-1.75 (m, IH), 1.61-1.57 (m, 2H), 1.51-1.47 (m, 2H), 1.42-1.38 (m, 2H), 1.34-1.28 (m, 4H). 1 3 C N M R (75 MHz, CD3OD): 6 202.52, 173.34, 142.27, 140.84, 130.39, 129.00, 72.08, 60.66, 59.36, 46.93, 46.62, 44.75, 44.52, 37.94, 35.73, 31.57, 37.32, 24.87. I R (KBr pellet): v 3352, 2947, 2866, 1685, 1636, 1586, 1542, 1376, 1201, 1101, 991, 783,699 cm"1. 59j .213 Chapter 4 Experimental L R M S (ESI: 0.1% formic acid in MeOH) m/z 374 ( M + + 1), 353, 285 (100), 198. H R M S (ESI: 0.1% formic acid in MeOH) calcd for C22H32NO4 ( M + + 1) 374.2331, found 374.2331. Anal . Calcd for C 2 2 H 3 1 N O 4 : C, 70.75; H , 8.37; N , 3.75. Found: C, 70.55; H , 8.28; N , 3.58. R-(+)-Bornvlamine salt (59k) A solution of acid 57 (77 mg, 0.30 mmol) in diethyl ether (15 mL) was added to a solution of R-(+)-bornylamine (46 mg, 0.30 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 59k (93 mg, 75 %) as a white powder. Recrystallization from MeOH afforded colorless needles. mp: 156-159 °C. J H N M R (300 MHz, C D 3 O D ) : 8 8.00 (d, J= 8.3 Hz, 2H), 7.94 (d, J= 8.3 Hz, 2H), 3.38 (d x d, J, = 3.5 Hz, J2 = 10.7 Hz, IH), 3.22 (s, 2H), 2.33 (m, IH), 2.14 (m, IH), 1.82 (m, IH), 1.72 (m, IH), 1.70-1.30 (m, 9H), 1.29-1.24 (m, 4H), 1.10 (m, IH), 0.95 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H). 1 3 C N M R (75 MHz, CD 3 OD): 8 202.58, 174.05, 143.37, 140.54, 130.29, 128.95, 57.95, 50.05, 46.94, 45.85, 44.76, 44.50, 37.94, 35.74, 35.54, 31.57, 28.54, 27.96, 19.85, 18.73, 13.33. 59k 214 Chapter 4 Experimental IR (KBr pellet): v 3544, 2953, 2869, 2136, 1716, 1686, 1669, 1624, 1588, 1514, 1379, 760 cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z (relative intensity) 412 ( M + + 1, 11.3), 307 (7.4), 259 (0.3), 154 (100). H R M S (ESI: 0.1% formic acid in MeOH) calcd for CaeHagNOs ( M + + 1) 412.2852, found 412.2843. Anal . Calcd for C26H37NO3: C, 75.87; H , 9.06; N , 3.40. Found: C, 75.48; H , 9.27; N , 3.29. S-f+Vl-Aminoindane salt (591) A solution of acid 57 (77 mg, 0.30 mmol) in diethyl ether (15 mL) was added to a solution of S-(+)-l-aminoindane (40 mg, 0.30 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 591 (87 mg, 74 %) as an off-white powder. Recrystallization from MeOH afforded pale yellow needles. mp: 172-174 °C. *H N M R (300 MHz, CD 3 OD): 8 7.98 (d, 7= 8.5 Hz, 2H), 7.93 (d, J= 8.5 Hz, 2H), 7.49 (m, IH), 7.30 (m, 3H), 4.75 (d xd,Jj = 5.2 Hz, J2 = 7.7 Hz, IH), 3.21 (s, 2H), 3.11 (m, IH), 2.96 (m, IH), 2.57 (m, IH), 2.14 (m, IH), 2.05 (m, IH), 1.65-1.55 (m, 2H), 1.55-1.35 (m,4H), 1.35-1.25 (m,4H). • 591 215 Chapter 4 Experimental 1 3 C N M R (75 MHz, CD3OD): 8 202.62, 173.97, 145.36, 143.19, 140.58, 140.14, 130.57, 130.30, 128.95, 128.22, 126.31, 125.47, 56.95, 46.94, 44.75, 44.50, 37.94, 35.74, 31.88, 31.57,31.00. IR (KBr pellet): v 3521, 2947, 2866, 2211, 1716, 1684, 1672, 1622, 1584, 1524, 1386, 1208, 996, 779, 700 cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z (relative intensity) 392 ( M + + 1, 100), 281 (14.8), 267 (14.5), 259 (14.0), 242 (44.6). H R M S (ESI: 0.1% formic acid in MeOH) calcd for C25H30NO3 ( M + + 1) 392.2226, found 392.2224. Anal . Calcd for C25H29NO3: C, 76.70; H , 7.47; N , 3.58. Found: C, 76.64; H , 7.70; N , 3.63. (IR. 2R)-(-)-Pseudoephedrine salt (59m) A solution of acid 57 (77 mg, 0.30 mmol) in diethyl ether (15 mL) was added to a solution of (IR, 2R)-(-)-pseudoephedrine (50 mg, 0.30 mmol) in diethyl ether (5 mL). The solution was stirred for 1 h, after which time no precipitate was formed and removal of solvent in vacuo afforded salt 59m (127 mg, 100 %) as a white powder. mp: 127-129 °C. 59m 216 Chapter 4 Experimental ' H N M R (300 MHz, CD 3 OD): 5 8.00 (d, 7 = 8.3 Hz, 2H), 7.95 (d, 7= 8.3 Hz, 2H), 7.40-7.30 (m, 5H), 4.52 (d, 7 = 9.2 Hz, IH), 3.36-3.31 (m, IH), 3.22 (s, 2H), 2.71 (s, 3H), 2.14 (m, IH), 1.65-1.55 (m, 2H), 1.55-1.45 (2H, m), 1.45-1.38 (m, 2H), 1.38-1.25 (m, 4H), 1.07 (0 ,7=6.7 Hz, 3H). 1 3 C N M R (75 MHz, CD 3 OD): 5 202.62, 174.02, 143.27, 141.98, 140.56, 130.32, 129.81, 129.73, 128.96, 128.18, 75.70, 61.76, 46.95, 44.75, 44.50, 37.94, 35.74, 31.57, 30.54, 12.72. IR (KBr pellet): v 3230, 3100, 2946, 2864, 2323, 1677, 1637, 1593, 1555, 1456, 1356, 1209, 1045,780, 700 cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z (relative intensity) 423 ( M + + 1), 378 (100), 331, 166. H R M S (ESI: 0.1% formic acid in MeOH) calcd for C26H34NO4 ( M + + 1) 424.2488, found 424.2483. Anal . Calcd for C26H33NO4: C, 73.73; H , 7.85; N , 3.31. Found: C, 73.79; H , 7.95; N , 3.33. 217 C h a p t e r 4 E x p e r i m e n t a l 4.5 Synthesis of Dimethylated Bicyclo[2.2.1]heptane Derivatives 60, 61 and 62 4.5.1 Preparation of Ketones 60 and 61 Bicvclor2.2.11heptane-l-carboxylic acid (98)9 7 ( b ) A suspension of lithium wire (6.0 g, 870 mmol) in anhydrous cyclohexane (30 mL) was heated to be refluxing under an oxygen-free argon atmosphere. A solution of 1-chloronorbonrane (88) (14.8 g, 113 mmol) in anhydrous cyclohexane (30 mL) was added over 30 min with stirring. The mixture was heated to be refluxing for 10 h before being cooled in an ice bath followed by addition of anhydrous cyclohexane (30 mL) and anhydrous H-pentane (40 mL). The argon stream was replaced by a stream of C O 2 , which was dried over anhydrous CaS04. The reaction was stirred at 0 °C under an atmosphere of C O 2 for 3 h followed by removing unreacted lithium wire and careful quenching with ice water (100 mL). The solution was acidified with 4N HCI (100 mL) and extracted with diethyl ether (3 x 200 mL). The combined ethereal extracts were washed with water (2 x 50 mL) and then extracted with 10% aqueous K O H (4 x 100 mL). The combined basic extracts were washed with diethyl ether (2 x 50 mL) followed by acidifying with concentrated HCI to a pH of 3 after which the precipitated carboxylic acid was extracted with diethyl ether (3 x 200 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL) and dried (MgSC>4). Removal of the solvent in vacuo provided acid 98 (8.41 g, 53 %) as a white solid. The compound did not require further purification. mp: 109-111 °C (Li t . 9 7 ( b ) 113.8-115.5 °C). *H NMR (300 MHz, CDC1 3): 5 11.26 (s, br, IH), 2.31 (m, IH), 1.94-1.85 (m, 2H), 1.72-1.63 (m, 2H), 1.58-1.50 (m, 4H), 1.36-1.28 (m, 2H). C O O H 98 218 Chapter 4 Experimental 1 3 C NMR (75 MHz, CDC1 3 ) APT: C, C H 2 : +; C H , C H 3 : -): 6 183.49 (+), 52.04 (+), 42.33 (+), 37.79 (-), 32.92 (+), 29.95 (+). IR (KBr pellet): v 2958, 2873, 1699, 1420, 1311, 960, 733 cm"1. LRMS (EI) m/z 140 (M + ) , 125, 111 (100), 95, 79, 67, 55. Bicvclo\2.2.1 lheptane-1 -methanol (99) To a suspension of lithium aluminum hydride (4.28 g, 107.1 mmol) in diethyl ether (100 mL) was added dropwise a solution of acid 98 (5.0 g, 35.7 mmol) in diethyl ether (100 mL) at room temperature under an argon atmosphere. The mixture was stirred for 1 h. The reaction was quenched carefully with water (100 mL) at -78 °C. To the resulting mixture was added Rochelle's salt (10% sodium tartrate in water, 60 mL), followed by extraction with diethyl ether (4x150 mL). The combined ethereal extracts were washed with water (2 x 50 mL), brine (2 x 50 mL), dried (Na 2S04). Removal of the solvent in vacuo provided compound 99 (4.50 g, 100 %) as a yellowish liquid. The compound did not require further purification. *H NMR (300 MHz, CDC1 3): 5 3.69 (s, 2H), 2.19 (m, IH), 1.65-1.55 (m, 2H), 1.52 (s, IH, OH), 1.48-1.39 (m, 2H), 1.34-1.26 (m, 2H), 1.24-1.17 (m, 2H), 1.15 (m, 2H). 1 3 C NMR (75 MHz, CDC1 3, APT: C, C H 2 : +; CH, C H 3 : -): 8 67.09 (+), 50.05 (+), 40.47 (+), 37.17 (-), 31.69 (+), 30.36 (+). IR (neat): v 3337 (br), 2950, 2868, 1455, 1144, 1032 cm"1. 99 219 Chapter 4 Experimental LRMS (EI) m/z 126 (M + ) , 108, 93, 79, 67 (100), 54. Bicvclo[2.2.1]heptane-l-methanol methanesulfonate (100) CH2OMs 100 To a solution of alcohol 99 (5.0 g, 39.7 mmol) in dry pyridine (50, mL) was added dropwise methanesulfonyl chloride (6.82 g, 4.6 mL, 59.5 mmol) in dry pyridine. The reaction was stirred for 4 h under argon atmosphere at room temperature. The resulting mixture was poured into ice water (200 mL) and extracted with diethyl ether (4x150 mL). The combined ethereal extracts were washed successively with 4 N HCI (2 x 50 mL), water (2 x 50) mL and brine (2 x 50 mL), and dried (TS^SCu). Removal of the solvent in vacuo afforded compound 100 (7.45 g, 92%) as a white solid. The compound did not require further purification. mp: 64-65 °C. *H NMR (300 MHz, CDC1 3): 5 4.30 (s, 2H), 2.98 (s, 3H), 2.23 (m, IH), 1.70-1.55 (m, 2H), 1.55-1.40 (m, 2H), 1.40-1.25 (m, 4H), 1.24 (m, 2H). 1 3 C NMR (75 MHz, CDCI3): 5 74.13 (+), 47.56 (+), 40.92 (+), 37.14 (-), 37.06 (-), 31.87 (+), 30.13 (+). IR (KBr pellet): v 2955, 2869, 1356, 1332, 1173,943,851,752 cm"1. LRMS (EI) m/z 204 (M + ) , 108, 93, 79 (100), 66, 54. HRMS (EI) calcd for C 9 H i 6 0 3 S 204.0820, found 204.0821. Anal . Calcd for C 9 H i 6 0 3 S : C, 52.91; H , 7.59. Found: C, 53.31; H , 7.89. 220 Chapter 4 Experimental Bicyclo\2.2.1 "|heptane-1 -acetonitrile (101) 101 To a solution of compound 100 (9.2 g, 45.1 mmol) in dry D M F (60 mL) was added sodium cyanide (3.30 g, 67.6 mmol). The mixture was heated to be refluxing at 150 °C under an argon atmosphere for 17 h. The reaction was quenched by adding ice-water (200 mL) followed by extraction with diethyl ether (4x150 mL). The combined ethereal extracts were successively washed with Na2C03 (10%, 80 mL), H2O (80 mL), and saturated NaCl (80 mL), and dried (Na2S04). Removal of solvent in vacuo gave a yellowish liquid. Silica gel chromatography (0.5 % diethyl ether in w-pentane) afforded compound 101 (5.05 g, 83 %) as a colorless liquid. ! H N M R (300 MHz, CD 2C1 2): 5 2.54 (s, 2H), 2.25 (m, IH), 1.71-1.68 (m, 2H), 1.54-1.48 (m, 2H), 1.42-1.26 (m, 6H). 1 3 C N M R (75 MHz, CD 2C1 2): 5 118.96 (+), 45.17 (+), 43.32 (+), 37.77 (-), 34.70 (+), 34.53 (+), 23.75 (+). IR (neat): v 2953, 2920, 2871, 2247, 1454, 1423, 1332, 739 cm"1. L R M S (EI) m/z 135 (M + ) , 120, 106, 95 (100), 80, 67, 53. H R M S (EI) calcd for C 9 H 1 3 N 135.1048, found 135.1048. Anal . Calcd for C 9 H , 3 N: C, 79.95; H , 9.69; N, 10.36. Calcd for C9H13N •1/12H20: C, 79.07; H , 9.71; N, 10.25. Found: C, 78.94; H , 9.84; N, 10.68. 2 2 1 Chapter 4 Experimental Bicyclor2.2.11heptane-l-acetic acid (102) | V C H 2 C O O H 102 To a solution of sulfuric acid (50 %, 15 mL) and glacial acetic acid (40 mL) was added compound 101 (5.50 g). The mixture was heated to be refluxing at 130 °C for 30 h. The reaction was quenched with water (100 mL) followed by extraction with w-pentane (5 x 100 mL). The combined organic extracts were washed with water (5 x 30 mL), and dried (Na2SC>4). Removal of solvent in vacuo gave a yellowish liquid. Silica gel chromatography (10% diethyl ether in petroleum ether) afforded acid 102 (4.89 g, 78 %) as a colorless liquid. *H N M R (300 MHz, CD 2C1 2): 5 11.53 (s, br, IH), 2.56 (s, 2H), 2.19 (m, IH), 1.68-1.59 (m, 2H), 1.54-1.48 (m, 2H), 1.46-1.39 (m, 2H), 1.36-1.27 (m, 4H). 1 3 C N M R (75 MHz, CD 2C1 2): 5 179.79, 45.41, 43.92, 40.57, 37.39, 34.86, 30.99. IR(neat): v 2952, 2870, 1707, 1450, 1411, 1296, 1264, 936, 657 cm"1. L R M S (EI) m/z 154 (M + ) , 125, 94 (100), 79, 67, 53. H R M S (EI) calcd for C 9 H i 4 0 2 154.0994, found 154.0994. Anal . Calcd for C 9 H i 4 0 2 : C, 70.10; H , 9.15. Found: C, 69.80; H , 9.41. Methyl bicyclor2.2.11hept-l-ylacetate (103) | V / C H 2 C O O C H 3 103 222 Chapter 4 Experimental To a solution of acid 102 (4.89 g) in diethyl ether (5 mL) was added a solution of diazomethane in diethyl ether (50 mL, excess in the reaction) at room temperature. The reaction was stirred for 10 min. Removal of the solvent in vacuo afforded ester 103 (5.33 g, 100 %) as a yellowish liquid. ! H N M R (400 MHz, CD 2C1 2): 5 3.61 (s, 3H), 2.49 (s, 2H), 2.17 (m, IH), 1.65-1.55 (m, 2H), 1.47-1.40 (m, 2H), 1.36-1.25 (m, 6H). 1 3 C N M R (100-MHz, CD 2C1 2): 5 173.17 (+), 51.30 (-), 45.65 (+), 43.91 (+), 40.50 (+), 37.40 (-), 34.91 (+), 30.01 (+). IR (neat): v 2952, 2870, 1738, 1437, 1331, 1251, 1175,1010 cm"1. L R M S (EI) m/z 168 (M + ) , 139, 107, 94, 79 (100), 67, 53. H R M S (EI) calcd for C i 0 H , 6 O 2 168.1150, found 168.1145. Anal . Calcd for C , 0 H , 6 O 2 : C, 71.39; H , 9.59. Found: C, 71.54; H , 9.94. Methyl q-(bicvclor2.2.1~|hept-l-yl)propanoate (104) C H 3 | V C H C O O C H 3 To a cold (-78 °C) solution of DIPA (diisopropylamine 6.5 mL, 46.5 mmol) in THE (100 mL) was added dropwise n-butyllithium (25.7 mL, 41.1 mmol). The mixture was warmed to 0 °C for 30 min before being cooled back to -78 °C as a cold L D A solution. To the cold (-78 °C) solution of L D A was added ester 103 (4.6 g, 27.4 mmol) in THF (40 mL) over 15 min. After stirring in the cold for 2 h, an additional portion of n-butyllithium (17.1 mL of a 1.6 M solution in n-hexane, 27.4 mmol) was added dropwise. The reaction was stirred for 30 min, followed by the addition of D M P U (6.6 mL, 54.8 mmol). After 10 104 223 Chapter 4 Experimental min methyl iodide (5.1 mL, 82.1 mmol) was added and the reaction stirred in the cold for 3 h before warming slowly to room temperature and stirring overnight. The reaction was quenched with water (100 mL) and extracted with diethyl ether (3 x 100 mL). The combined ethereal extracts were washed with brine (2 x 30 mL), and dried (MgSGx). Removal of the solvent in vacuo provided ester 104 (4.43 g, 89 %) as a yellowish liquid. The compound did not require further purification. ! H N M R (400 MHz, CD 2C1 2): 6 3.61 (s, 3H), 2.63 (q, J= 7.1 Hz, IH), 2.16 (m, IH), 1.65-1.35 (m,4H), 1.30-1.20 (m, 6H), 1.12 (d, 7= 7.1 Hz, 3H). 1 3 C N M R (100 MHz, CD 2C1 2): 5 173.36 (+), 51.20 (-), 49.79 (+), 44.24 (-), 42.27 (+), 37.09 (-), 32.82 (+), 32.43 (+), 30.85 (+), 30.70 (+), 13.92 (-). IR (neat): v 2952, 2919,2869, 1738, 1458, 1435, 1350, 1193, 1176, 1157 cm"1. L R M S (EI) m/z 182 (M + ) , 167, 153, 123, 95 (100), 79, 67, 55. H R M S (EI) calcd for C n H i 8 0 2 182.1307, found 182.1305. Anal . Calcd for C n H 1 8 0 2 : C, 72.49; H , 9.95. Found: C, 72.36; H , 10.11. Methyl a-methvl-a-(bicvclo[2.2.1]hept-l-vl)propanoate (105) To a cold (-78 °C) solution of DIP A (diisopropylamine, 6.5 mL, 46.5 mmol) in THF (100 mL) was added dropwise H-butyllithium (25.7 mL, 41.1 mmol). The mixture was warmed to 0 °C for 30 min before being cooled back to -78 °C as a cold L D A solution. To the cold (-78 °C) solution of L D A was added ester 104 (4.43 g, 24.3 mmol) in THF (40 mL) over 15 min. After stirring in the cold for 2 h, an additional portion of n-105 224 Chapter 4 Experimental butyllithium (15.1 mL of a 1.6 M solution in w-hexane, 24.3 mmol) was added dropwise. The reaction was stirred for 30 min, followed by the addition of D M P U (6.6 mL, 54.8 mmol). After 10 min methyl iodide (5.1 mL, 82.1 mmol) was added and the reaction stirred in the cold for 3 h before warming slowly to room temperature and stirring overnight. The reaction was quenched with water (100 mL) and extracted with diethyl ether (3 x 100 mL). The combined ethereal extracts were washed with brine (2 x 30 mL), and dried (MgS0 4). Removal of the solvent in vacuo provided ester 105 (4.05 g, 85 %) as a yellowish liquid. The compound did not require further purification. 'H NMR (400 MHz, CD 2C1 2): 5 3:60 (s, 3H), 2.13 (m, IH), 1.57-1.50 (m, 4H), 1.31-1.26 (m, 4H), 1.17 (s, 6H), 1.20-1.14 (m, 2H). 1 3 C NMR (100 MHz, CD 2C1 2): 5 178.03 (+), 53.38 (+), 51.36 (-), 45.13 (+), 39.82 (+), 36.94 (-), 31.17 (+), 30.86 (+), 22.75 (-). IR (neat): v 2952, 2871, 1729, 1471, 1433, 1387, 1275, 1142, 988, 831 cm"1. L R M S (EI) m/z 196 (M + ) , 181, 167, 137, 107, 95 (100), 81, 67, 55. HRMS (EI) calcd for C i 2 H 2 0 O 2 196.1463, found 196.1466. Anal . Calcd for C , 2 H 2 0 O 2 : C, 73.43; H , 10.27. Found: C, 73.54; H , 10.52. 2-Methvl-2-bicvclo[2.2.1 Ihept-1 -yl-1 -propanol (107) CH2OH 107 To a suspension of lithium aluminum hydride (1.7 g, 45.9 mmol) in diethyl ether (30 mL) was added dropwise a solution of ester 105 (3.0 g, 15.3 mmol) in diethyl ether (30 mL) under argon atmosphere at room temperature. The mixture was stirred for 2.5 h. The 225 Chapter 4 Experimental reaction was quenched carefully with water (100 mL) at -78 °C. To the resulting mixture was added Rochelle's salt (10% sodium tartrate in water, 60 mL), followed by extraction with diethyl ether (4x100 mL). The combined ethereal extracts were washed with water (2 x 50 mL), brine (2 x 50 mL), dried (Na2S04). Removal of the solvent in vacuo provided a yellowish solid. Silica gel chromatography (2 % diethyl ether in petroleum ether) afforded alcohol 107 (2.3 g, 89 %) as a white solid. mp: 66-67 °C. ! H N M R (300 MHz, CDCI3): 6 3.45 (s, 2H), 2.12 (m, IH), 1.70-1.45 (m, 4H), 1.35-1.20 (m, 3H), 1.16 (s, IH), 1.15-1.05 (m, 3H), 0.91 (s, 6H). 1 3 C N M R (75 MHz, CDCI3): 5 70.53, 53.01, 38.73, 36.88, 36.27, 30.50, 30.22, 21.52. IR (KBr pellet): v 3243, 2949, 2867, 1456, 1364, 1204, 1059, 1033, 1008, 754 cm-1. L R M S (EI) m/z 168 (M + ) , 153, 137 (100), 95, 81, 67, 55. H R M S (EI) calcd for C11H20O 168.1514, found 168.1519. A n a l . Calcd for C n H 2 o O : C, 78.51; H , 11.98. Found: C, 78.45; H , 11.64. 1 -(4'-FluorophenvlV2-methvl-2-bicvclor2.2.1 lhept-1 -vl-1 -propanol (108) 108 F 226 Chapter 4 Experimental A mixture of Celite® 545 (2.4 g) and PCC (pyridinium chlorochromate, 2.4 g, 11.1 mmol) was ground with a mortar and pestle until homogeneous. This solid was suspended in a solution of alcohol 107 (1.16 g, 6.89 mmol) in anhydrous dichloromethane (40 mL) and stirred for 2.5 h at room temperature. Following the addition of anhydrous diethyl ether (200 mL), the reaction mixture was filtered through a column of Celite® 545 on Florisil® and the remaining solids triturated well with anhydrous diethyl ether. Solvent removal in vacuo gave a yellowish liquid (aldehyde). The residue was taken up in anhydrous THF (50 mL). To this solution was added dropwise 4-fluorophenylmagnesium bromide (8.3 mL, 8.3 mmol) at room temperature. The reaction was stirred under an atmosphere of dry argon for 2 h followed by careful quenching with ice water (50 mL) and 4N HCI (10 mL). Extraction with diethyl ether (3 x 100 mL) was followed by successive washing with water (40 mL) and saturated NaCl (2 x 30 mL), and drying (MgSC^). Removal of the solvent in vacuo provided alcohol 108 (1.72 g, 95 %) as a white solid. The compound did not require further purification. mp: 91-93 °C. J H N M R (300 MHz, CDC1 3): 5 7.29-7.24 (m, 2H), 7.02-6.94 (m, 2H), 4.70 (s, IH, CH), 2.13 (m, IH), 1.85-1.60 (m, 4H), 1.55 (s, IH, OH), 1.40-1.20 (m, 6H), 0.93 (s, 3H, CH 3 ) , 0.65 (s, 3H, CH 3 ) . 1 3 C N M R (75 MHz, CDC1 3): 8 163.50 and 160.40 ( ]JC-F = 233 Hz), 138.91 and 138.88 ( 4 J C - F = 2 Hz) 129.64 and 129.53 ( 3 J C . F = 8 Hz), 114.45 and 114.17 ( 2 J C - F = 21 Hz), 79.23, 54.67, 40.28, 39.99, 36.06, 31.34, 31.13, 30.82, 30.54, 23.57,17.67. IR (KBr pellet): v 3500, 2948, 2867, 1605, 1509, 1231, 1047, 840 cm"1. L R M S (EI) m/z 262 (M + ) , 244, 229, 215, 137 (100), 125, 95, 81, 67, 55. H R M S (EI) calcd for C i 7 H 2 3 F O 262.1733, found 262.1733. 227 Chapter 4 Experimental Anal. Calcd for C i 7 H 2 3 F O : C, 77.82; H, 8.84; F, 7.24; O, 6.10. Calcd for C i 7 H 2 3 F O l / 8 H 2 0 : C, 77.16; H, 8.86. Found: C, 77.29; H , 8.75. l-(4,-FluorophenvlV2.2-dimethvl-2-bicvclor2.2.11hept-l-vl ethanone (109) 109 A mixture of Celite® 545 (2.5 g) and PCC (pyridinium chlorochromate, 5.16 g, 11.6 mmol) was ground with a mortar and pestle until homogeneous. This solid was suspended in a solution of alcohol 108 (1.90 g, 7.25 mmol) in anhydrous dichloromethane (50 mL) and stirred for 5 h at room temperature. Following the addition of anhydrous diethyl ether (200 mL), the reaction mixture was filtered through a column of Celite® 545 on Florisil® and the remaining solids triturated well with anhydrous diethyl ether. Solvent removal in vacuo was followed by silica gel chromatography (2% diethyl ether in petroleum ether) to give ketone 109 (1.88 g, 99 %) as a white solid. Recrystallization from diethyl ether provided colorless plates. mp: 65-66 °C. U V (CH 3 OH): X 205.0 (1.27 x 104), 240.0 (6.97 x 103), 315.0 (2.27 x 102) nm ( M ' W 1 ) . ' H N M R (400 MHz, CDCI3): 8 7.56 (m, 2H), 7.02 (m, 2H), 2.13 (m, IH, CH), 1.60-1.50 (m, 4H), 1.32 (s, 6H, 2CH 3 ) , 1.30-1.20 (m, 6H). 1 3 C N M R (100 MHz, CDCI3): 5 209.59 (+), 164.98 (+) and 162.48 (+) ('JC-F = 250 Hz), 137.79 (+) and 137.76 (+)(4JC-F = 3 Hz), 130.09 (-) and 130.00 (-) ( 3 J C - F = 9 Hz), 114.95 (-) and 114.74 (-) ( 2 J C - F = 21 Hz), 53.55 (+), 50.17 (+), 39.84 (+), 36.11 (-), 31.15 (+), 30.43 (+), 24.41 (-). 228 Chapter 4 Experimental IR (KBr pellet): v 2978, 2956, 2919, 2869, 1660, 1598, 1507, 1231, 1160, 972, 845, 603 cm"1. L R M S (EI) m/z 260 (M + ) , 137, 123, 95 (100), 81, 67, 55. H R M S (EI) calcd for C i 7 H 2 i F O 260.1576, found 260.1578. Anal. Calcd for C i 7 H 2 l F O : C, 78.43; H , 8.13. Found: C, 78.21; H , 8.19. This structure was confirmed by X-ray crystallographic analysis: Habit colorless plates Space group P-l a, A 6.240(1) b , A 10.511(2) c , A 11.817(2) « ( ° ) 69.07(2) P(°) 80.75(2) Y(°) 76.46(2) Z 2 R 0.046 l-C4'.Cvanophenvl)-2.2-dimethvl-2-bicvclor2.2.11hept-l-vl ethanone (110) CN 110 To a solution of ketone 109 (1.10 g, 4.23 mmol) in dry D M F (12 mL) was added sodium cyanide (0.35 g, 7.14 mmol). The resulting mixture was heated to be refluxing at 150 °C under an argon atmosphere for 20 h. The cooled reaction mixture was poured into 229 Chapter 4 Experimental ice-water (100 mL) and extracted with diethyl ether (4x100 mL). The combined ethereal extracts were washed successively with Na2C03 (10%, 50 mL), H2O (50 mL), and saturated NaCl (50 mL), then dried (Na2SC»4). Removal of solvent in vacuo afforded ketone 110 (0.86 g, 76 %) as a yellowish solid. The compound did not require further purification for the next reaction. Purification by silica gel chromatography (diethyl ether/petroleum ether 95/5) gave a white solid. Recrystallization from diethyl ether afforded colorless plates. mp: 77-78 °C. *H N M R (300 MHz, CDC1 3): 5 7.65 (d, J= 8.6 Hz, 2H), 7.53 (d, J= 8.6 Hz, 2H), 2.14 (m, IH, CH), 1.60-1.50 (m, 4H), 1.29 (s, 6H, 2CH 3 ), 1.28-1.20 (m, 6H). 1 3 C N M R (75 MHz, CDC1 3): 5 210.32 (+), 145.86 (+), 131.80 (-), 127.53 (-), 118.09 (+), 113.55 (+), 53.53 (+), 50.28 (+), 39.72 (+), 36.05 (-), 31.19 (+), 30.40 (+), 24.10 (-). IR (KBr pellet): v 2955, 2864, 2228, 1669, 1456, 1399, 1248, 1161, 967, 840 cm"1. L R M S (EI) m/z 267 "(M+), 239, 207, 137, 130, 102, 95, 81 (100), 67, 55. H R M S (EI) calcd for C i 8 H 2 i N O 267.1623, found 267.1623. Anal . Calcd for C i 8 H 2 , N O : C, 80.86; H , 7.92; N , 5.24. Found: C, 80.46; H , 7.94; N , 5.18. 230 Chapter 4 Experimental This structure was confirmed by X-ray crystallographic analysis: Habit colorless plates Space group P2,/c a, A 10.708(2) b , A 11.226(2) c, A 12.599(2) a ( ° ) 90 P(°) 99.17(2) y(°) 90 z 4 R 0.065 l-(4,-Carboxvlphenvl)-2,2-dimethyl-2-bicvclor2.2.11hept-l-vlethanone (60) 60 To a solution of potassium hydroxide (5.0 g, 89 mmol) in water (20 mL) was added a solution of ketone 110 (0.76 g, 2.85 mmol) in ethanol (6 mL). The mixture was heated to be refluxing at 95 °C for 24 h. The reaction was quenched by water (100 mL). The solution was washed with methylene chloride (2 x 50 mL). The aqueous solution was carefully acidified to a pH 2 with concentrated HCI. The precipitated carboxylic acid was extracted with Et20 (4 x 100 mL) and the combined ethereal extracts were washed with water (50 mL), brine (50 mL) and dried (Na2SG*4). Removal of solvent in vacuo provided a white solid. Recrystallization from ethanol afforded acid 60 (0.74 g, 91 %) as colorless plates. mp: 174-176 °C. 231 Chapter 4 Experimental *H N M R (400 MHz, CDC1 3): 5 10.34 (s, br, IH), 8.10 (d, J= 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 2.12 (m, IH, OH), 1.58 (m, 4H), 1.31 (s, 6H, 2CH 3 ), 1.30-1.20 (m, 6H). 1 3 C N M R (100 MHz, CDCI3): 8 211.57, 171.47, 146.99, 130.13, 129.85, 126.92, 53.53, 50.26, 39.71, 36.07, 31.19, 30.43, 24.11. IR (KBr pellet): v 2951, 2868, 2660, 2534, 1689, 1660, 1416, 1280, 1123, 963, 740 cm"'. L R M S (EI) m/z 286 ( M + , 2.81), 241 (1.93), 150 (19.55), 149 (21.09), 137 (100), 95 (35.58), 81 (77.27), 67 (14.46), 55 (8.54). H R M S (EI) calcd for C 1 8 H220 3 286.1569, found 286.1568. Anal . Calcd for C i 8 H 2 2 0 3 : C, 75.50; H , 7.74; O, 16.76. Calcd for Ci 8 H 2 203«l /6H 2 0: C, 74.71; H , 7.78. Found: C, 74.80; H , 7.72. This structure was confirmed by X-ray crystallographic analysis: Habit colorless plates Space group P-l a, A 6.2920(10) b,A 10.809(2) c, A 11.733(2) a ( ° ) 80.32(2) P( °) 74.07(2) Y(°) 82.07(2) Z 2 R 0.064 232 Chapter 4 Experimental l-(4 ,-MethoxvcarbonvlphenvlV2,2-dimethyl-2-bicvclor2.2.llhept-l-vl ethanone (61) C O O C H 3 61 To a solution of acid 60 (0.200 g) in diethyl ether (5 mL) was added a solution of diazomethane in diethyl ether (15 mL, excess in the reaction) at room temperature. The reaction was stirred for 10 min. Removal of the solvent in vacuo provided a yellowish solid. Recrystallization from diethyl ether afforded ester 61 (0.210 g, 100 %) as colorless plates. mp: 90-93 °C. U V (CH3OH): A, 205.0 (1.52 x 104), 245.0 (1.57 x 104), 280.0 (1.28 x 103) nm ( M ' W ) . *H N M R (400 MHz, CDC1 3): 5 8.00 (d, J= 8.3 Hz, 2H), 7.48 (d, J= 8.3 Hz, 2H), 2.12 (m, IH, CH), 1.65-1.50 (m, 4H), 1.29 (s, 6H, 2CH 3 ) , 1.28-1.20 (m, 6H). 1 3 C N M R (100 MHz, CDC1 3): 5 211.46, 166.38, 146.10, 131.04, 129.16, 126.85, 53.50, 52.27, 50.22, 39.69, 36.05, 31.16, 30.41, 24.09. IR (KBr pellet): v 3003, 2954, 2932, 2870, 1730, 1667, 1437, 1279, 1108, 959, 862, 725 cm"1. L R M S (EI) m/z 300 (M + ) , 269, 241, 163, 137, 120, 95, 81 (100), 67, 55. H R M S (EI) calcd for C19H24O3 300.1725, found 300.1728. Anal . Calcd for C 1 9 H 2 4 O 3 : C, 75.97; H , 8.05. Found: C, 75.89; H , 8.21. 233 Chapter 4 Experimental This structure was confirmed by X-ray crystallographic analysis: Habit colorless plates Space group P2,/c a, A 6.060(1) b,A 21.958(4) c , A 12.833(2) a ( ° ) 90.00 P ( ° ) 107.10(3) Y(°) 90.00 Z 4 R 0.063 4.5.2 Preparation of Dimethylated Bicyclo[2.2.1]heptyl Salts 62 R-(-)-l-Cyclohexylethylamine salt (62a) 6 2 a A solution of acid 60 (71.5 mg, 0.25 mmol) in diethyl ether (15 mL) was added to a solution of R-(-)-l-cyclohexylethylamine (31.8 mg, 0.25 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 62a (102.6 mg, 99 %) as a white powder. Recrystallization from MeOH afforded colorless plates. mp: 187-189 °C. 234 Chapter 4 Experimental J H N M R (400 MHz, CD 3 OD): 5 7.94 (d, J= 8.3 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 3.06 (m, IH), 2.12 (m, IH), 1.82-1.45 (m, 11H), 1.33 (s, 6H), 1.30-1.26 (m, 8H), 1.23 (d,J = 6.8 Hz, 3H), 1.20-1.03 (m, 2H). 1 3 C N M R (100 MHz, CD 3 OD): 8 213.92, 174.24, 144.91, 140.53, 129.77, 127.67, 54.81, 53.38, 51.29, 42.72, 40.65, 37.39, 32.21, 31.47, 30.01, 28.81, 27.08, 27.01, 26.93, 24.59, 16.04. IR (KBr pellet): v 3500, 2930, 2867, 2605, 2211, 1664, 1639, 1580, 1535, 1450, 1374, 1266, 964, 755 cm-1. L R M S (ESI: 0.1% formic acid in MeOH) m/z 414 ( M + + 1, 100), 291 (2.02), 287 (1.88). Anal . Calcd for C26H 3 9 N0 3 : C, 75.50; H , 9.50; N , 3.39. Found: C, 75.10; H , 9.48; N , 3.56. This structure was confirmed by X-ray crystallographic analysis: Habit colorless plates Space group P2j a, A 13.017(1) b,A 6.2546(6) c,A 14.544(2) a ( ° ) 90.00 P(°) 95.511(5) Y(°) 90.00 Z 2 R 0.038 235 Chapter 4 Experimental (IR. 2R)-(-)-Pseudoephedrine salt (62b) 6 2 b A solution of acid 60 (71.5 mg, 0.25 mmol) in diethyl ether (15 mL) was added to a solution of (IR, 2R)-(-)-pseudoephedrine (41.3 mg, 0.25 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 62b (86.0 mg, 76 %) as a white powder. Recrystallization from CH3CN afforded colorless prisms. mp: 134-135 °C. ' H N M R (400 M H z , CD 3 OD): 8 7.94 (d, J= 8.5 Hz, 2H), 7.47 (d, J= 8.5 Hz, 2H), 7.42-7.33 (m, 5H), 4.51 (d, J = 9.2 Hz, IH), 3.33 (m, IH), 2.70 (s, 3H), 2.12 (m, IH), 1.67-1.56 (m, 4H), 1.33 (s, 6H), 1.30 (m, 6H), 1.06 (d, J = 6.7 Hz, 3H). , 3 C N M R (100 MHz, CD 3 OD): 5 213.95, 174.14, 144.96, 142.00, 140.37, 129.82, 129.81, 129.74, 128.18, 127.67, 75.73, 61.75, 54.81, 51.30, 40.65, 37.39, 32.22, 31.48, 30.55,24.59, 12.73. IR (KBr pellet): v 3392, 3032, 2956, 2868, 2775, 2496, 1719, 1674, 1658, 1592, 1550, 1468,1387,1043,755,700 cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z 452 ( M + + 1, 0.31), 331 (2.03), 287 (0.84), 167 (4.50), 166(100). Anal . Calcd for C 2 8 H 3 7 N 0 4 : C, 74.47; H , 8.26; N , 3.10. Found: C, 73.93; H , 8.43; N , 3.48. 236 Chapter 4 Experimental (TR. 2S)-(+)-czs-l-Amino-2-indanol salt (62c) A solution of acid 60 (71.5 mg, 0.25 mmol) in diethyl ether (15 mL) was added to a solution of (IR, 2S)-(-)-cw-l-amino-2-indanol (37.3 mg, 0.25 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 62c (67.0 mg, 62 %) as a white powder. Recrystallization from MeOH afforded colorless needles. mp: 202-204 °C. lH N M R (400 MHz, CD 3 OD): 8 7.94 (d, J= 8.1 Hz, 2H), 7.47 (d,J= 8.1 Hz, 2H), 7.40-7.26 (m, 4H), 4.70 (m, IH), 4.54 (d, J= 5.7 Hz, IH), 3.22 (d x d, J, = 16.3 Hz, J2 = 6.4 Hz, IH), 3.01 (d x d, J, = 16.3 Hz, J2 = 4.9 Hz, IH), 2.12 (m, IH), 1.67-1.53 (m, 4H), 1.33 (s, 6H), 1.30-1.24 (m, 6H). 1 3 C N M R (100 MHz, CD 3 OD): 8 213.93, 174.04, 145.05, 142.81, 140.13, 138.33, 130.85, 129.82, 128.43, 127.68, 126.68, 126.16, 72.00, 58.67, 54.81, 51.30, 40.65, 40.11, 37.39, 32.22,31.48, 24.58. IR (KBr pellet): v 3221, 2960, 2869, 2628, 2243, 1719small, 1667, 1580, 1535, 1399, 751 cm - 1 . L R M S (ESI: 0.1% formic acid in MeOH) m/z 436 ( M + + 1, 100), 299 (14.28), 287 (9.17), 150(23.84). 237 Chapter 4 Experimental Anal. Calcd for C27H33NO4: C, 74.45; H , 7.64; N , 3.22. Found: C, 74.21; H , 7.69; N , 3.62. This structure was confirmed by X-ray crystallographic analysis: Habit colorless needles Space group P2, a, A 8.041(2) b,A 6.0730(10) c A 23.606(5) o ( ° ) 90.00 P(°) 97.10(2) Y(°) 90.00 z 2 R 0.051 S-(-Vp-Tolvlamine salt (62d) A solution of acid 60 (71.5 mg, 0.25 mmol) in diethyl ether (15 mL) was added to a solution of S-(-)-p-tolylamine (33.8 mg, 0.25 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 62d (91.7 mg, 87 %) as a white powder. Recrystallization from MeOH afforded colorless prisms. mp:a81-184 °C. 238 Chapter 4 Experimental *H N M R (400 MHz, CD 3 OD): 8 7.94 (d, J= 8.5 Hz, 2H), 7.47 (d, J= 8.5 Hz, 2H), 7.31 (d, J= 8.1 Hz, 2H), 7.24 (d, 7= 8.1 Hz, 2H), 4.38 (q, J = 6.8 Hz, IH), 2.34 (s, 3H), 2.12 (m, IH), 1.68-1.52 (m, 4H), 1.59 (d,J = 6.8 Hz, 3H), 1.33 (s, 6H), 1.32-1.25 (m, 6H). 1 3 C N M R (100 MHz, CD3OD): 8 213.93, 174.12, 144.96, 140.34, 140.18, 137.03, 130.80, 129.79, 127.66, 127.53, 54.81, 52.06, 51.29, 40.65, 37.39, 32.21, 31.47, 24.58, 21.13,20.87. IR (KBr pellet): v 3552?, 2949, 2870, 2760, 2225, 1700, 1656, 1579, 1524, 1376, 972, 727 cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z 422 ( M + + 1, 100), 309 (3.41), 287 (10.68), 271 (8.27). Anal. Calcd for C27H35NO3: C, 76.92; H , 8.37; N , 3.32. Found: C, 76.52; H , 8.47; N , 3.49. L-Prolinamide salt (62e) 6 2 e A solution of acid 60 (71.5 mg, 0.25 mmol) in diethyl ether (15 mL) was added to a solution of L-prolinamide (28.5 mg, 0.25 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 62e (87.3 mg, 87 %) as a white powder. Recrystallization from MeOH afforded colorless plates. mp: 164-166 °C. 239 Chapter 4 Experimental ' H N M R (400 MHz, CD 3 OD): 5 7.95 (d, J= 8.3 Hz, 2H), 7.48 (d, J= 8.3 Hz, 2H), 4.17 (d x d, J, = 8.2 Hz, J2 = 6.4 Hz, IH), 3.32 (m, IH), 3.27 (m, IH), 2.38 (m, IH), 2.12 (m, IH), 2.00 (m, 3H), 1.67-1.56 (m, 4H), 1.33 (s, 6H), 1.30-1.26 (m, 6H). 1 3 C N M R (100 MHz, CD 3 OD): 8 213.83, 172.76, 172.41, 145.68, 138.29, 129.97, 127.76, 65.23, 61.02, 54.81, 51.30, 47.30, 40.64, 37.39, 32.22, 31.47, 31.15, 26.82, 26.40, 25.25,24.55. IR (KBr pellet): v 3345, 2967, 2869, 2443, 2232, 1672, 1596, 1549, 1375, 959, 759 cm-1. L R M S (ESI: 0.1% formic acid in MeOH) m/z 401 ( M + + 1, 100), 325 (4.74), 287 (5.30), 229 (19.07). Anal . Calcd for C23H32N2O4: C, 68.97; H , 8.05; N , 6.99. Found: C, 68.72; H , 8.01; N , 6.59. This structure was confirmed by X-ray crystallographic analysis: Habit colorless plates Space group P2,2,2i a, A 6.596(3) b , A 7.941(3) c A 40.33(2) ot(°) 90.00 P(°) 90.00 Y(°) 90.00 Z 4 R 0.084 240 Chapter 4 Experimental R-(-)-l-Aminoindane salt (62f) A solution of acid 60 (71.5 mg, 0.25 mmol) in diethyl ether (15 mL) was added to a solution of R-(-)-l-aminoindane (33.3 mg, 0.25 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 62f (85.3 mg, 81 %) as a white powder. Recrystallization from MeOH afforded colorless needles. mp: 198-200 °C. *H N M R (400 MHz, CD 3 OD): 5 7.94 (d, J= 8.4 Hz, 2H), 7.47 (d, J= 8.4 Hz, 2H), 7.46 (m, IH), 7.34-7.27 (m, 3H), 4.74 (d x d, / / = 7.6 Hz, J2 = 5.2 Hz, IH), 3.19-3.10 (m, IH), 3.01-2.93 (m, IH), 2.63-2.55 (m, IH), 2.12 (m, IH), 2.10-2.00 (m, IH), 1.67-1.56 (m, 4H), 1.33 (s, 6H), 1.30 (m, 6H). 1 3 C N M R (75 MHz, CD 3 OD): 8 213.96, 173.95, 145.36, 145.03, 140.33, 140.21, 130.56, 129.81, 128.23, 127.64, 126.34, 125.40, 57.03, 54.83, 51.32, 40.66, 37.39, 32.23, 32.04, 31.48,31.00, 24.58. IR (KBr pellet): v 3500, 2950, 2864, 2625, 2190, 1667, 1622, 1578, 1521, 1390, 1268, 749 cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z 420 ( M + + 1, 100), 341 (4.10), 323 (10.83), 287 (12.47), 267 (7.01). Anal . Calcd for C 2 7 H 3 3 N 0 3 : C, 77.29; H , 7.93; N , 3.34. Found: C, 77.04; H , 7.95; N , 3.38. 241 Chapter 4 Experimental R-(+)-l-Phenylethylamine salt (62g) X 0 H C O £ H 3 N 6 2 g A solution of acid 60 (71.5 mg, 0.25 mmol) in diethyl ether (15 mL) was added to a solution of R-(+)-l-phenylethylamine (30.3 mg, 0.25 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 62g (95.4 mg, 94 %) as a white powder. Recrystallization from MeOH afforded colorless needles. mp: 175-177 °C. *H N M R (400 MHz, CD 3 OD): 5 7.94 (d, J= 8.0 Hz, 2H), 7.47 (d, J= 8.0 Hz, 2H), 7.43 (m, 5H), 4.42 (q, J= 6.8 Hz, IH), 2.12 (m, IH), 1.61 (d, J= 6.8 Hz, 3H), 1.67-1.57 (m, 4H), 1.33 (s, 6H), 1.30-1.27 (m, 6H). 1 3 C N M R (75 MHz, CD 3 OD): 8 213.94, 173.92, 145.06, 140.20, 140.07, 130.26, 130.04, 129.82, 127.64, 127.57, 54.83, 52.34, 51.31, 40.65, 37.39, 32.22, 31.47, 24.58, 21.00. IR (KBr pellet): v 3500, 2952, 2869, 2558, 2178, 1657, 1627, 1579, 1528, 1456, 1394, 962,692 cm"1. L R M S (ESI: 0.1% formic acid in MeOH) m/z 408 ( M + + 1, 100), 309 (6.59), 287 (5.26), 243 (6.49). Anal . Calcd for C 2 6 H 3 3 N 0 3 : C, 76.62; H , 8.16; N , 3.44; O, 11.78. Calcd for C 2 6 H 3 3 N 0 3 • 1/3 H 2 0 : C, 75.51; H , 8.21; N , 3.39. Found: C, 75.25; H, 8.05; N , 3.75. 242 Chapter 4 Experimental (IR. 2S)-(-)-Norephedrine salt (62h) 62h A solution of acid 60 (71.5 mg, 0.25 mmol) in diethyl ether (15 mL) was added to a solution of (IR, 2S)-(-)-norephedrine (37.8 mg, 0.25 mmol) in diethyl ether (5 mL). The cloudy solution was stirred for 1 h, after which time the precipitate that had formed was filtered, washed with diethyl ether and dried in vacuo to afford salt 62h (106.0 mg, 97 %) as a white powder. Recrystallization from MeOH afforded colorless needles. mp: 157-159 °C. J H N M R (400 MHz, CD 3 OD): 5 7.94 (d, J= 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.38-7.35 (m, 4H), 7.32-7.28 (m, IH), 4.92 (d, J = 3.5 Hz, IH), 3.48 (m, IH), 2.12 (m, IH), 1.67-1.56 (m, 4H), 1.33 (s, 6H), 1.30-1.26 (m, 6H), 1.07 (d, 7 = 6.8 Hz, 3H). 1 3 C N M R (100 MHz, CD 3 OD): 5 213.95, 174.18, 144.97, 141.60, 140.35, 129.80, 129.54, 129.00, 127.67, 127.18, 73.72, 54.81, 53.65, 51.30, 40.65, 37.39, 32.22, 31.47, 24.59, 12.54. IR (KBr pellet): v 3392, 2963, 2870, 2839, 2499, 2092, 1716, 1671, 1583, 1545, 1392, 983,741 cm-1. L R M S (ESI: 0.1% formic acid in MeOH) m/z 438 ( M + + 1, 100), 303 (14.46), 152 (39.30). 243 Chapter 4 Experimental Anal. Calcd for C27H 3 5 N0 4 : C, 74.11; H , 8.06; N , 3.20; O, 14.63. Calcd for C27H35NO4 • 1/4 H 2 0 : C, 72.62; H, 8.13; N , 3.14. Found: C, 72.38; H , 8.18; N , 3.34. 244 Chapter 5 Experimental C h a p t e r 5 P h o t o c h e m i c a l S tud ies 5.1 General Considerations Light sources and filters Irradiations were performed using either a 450 W Hanovia medium-pressure mercury lamp in a water-cooled immersion well, or a 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-lk power supply operating at 800W. Light emitted from the Hanovia lamp was filtered through Pyrex (transmits X > 290 nm), and 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 Samples were dissolved in HPLC grade or spectral grade (Fisher Chemical) solvents and were purged by bubbling nitrogen through the solution for at least 15 min prior to irradiation. The reactions were performed either in sealed reaction vessels or under a positive pressure of nitrogen. Analytical solid state photolyses Solid samples (2-5 mg) were sandwiched between two microscope slides (Pyrex equivalent). The sample plates were then fastened together with tape and placed in a polyethylene bag before being heat-sealed under a positive pressure of 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 GC and/or N M R spectroscopy. For salts and free acids, the sample was converted to the corresponding methyl ester with an ethereal solution of diazomethane, and subsequent analysis was based on the corresponding methyl esters. In the case of salts, the sample was filtered through silica gel to remove the amines before being analyzed by GC and/or HPLC. 245 Chapter 5 Experimental Preparative scale solid state photolyses The solid material was suspended in HPLC grade hexanes (for salts) or distilled water (for esters), purging with nitrogen for 15 min prior to irradiation, and kept under a positive pressure of nitrogen during the photolysis. Following irradiation, the reaction mixture was extracted by methanol (for salts) or dichloromethane (for esters). The extracts were combined for analysis as previously described. Low-temperature studies A low temperature ethanol bath contained in an unsilvered Dewar vessel (Pyrex) was maintained by a Cryocool CC-100 II Immersion Cooling System (Neslab Instruments, 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 for preparative scale photolyses were calculated based on the mass of the isolated products. Conversions for preparative scale photolyses were based on the average integration of at least two GC analyses. Yields and conversions for analytical photolyses were also based on the average integration of at least two GC (or HPLC, response factors calibrated) analyses. The difference in GC detector response for a particular starting material and products was found to be negligible and thus no corrections were applied to the integration data since most materials are isomers. 5.2 Photochemical Studies of a-Oxoamides 5.2.1 Preparative Photolysis of a-Oxoamide 38 Solution state photolysis OH COOCH 3 Pyrex hu / O C O O C H 3 38 39 4 0 246 Chapter 5 Experimental A solution of a-oxoamide 38 (50 mg) was dissolved in benzene (15 mL) in a Pyrex photolysis tube. After purging the system with N 2 for 15 min, the solution was irradiated (450 W Hanovia lamp) for 2 h. Following removal of the solvent in vacuo and purification by radial chromatography (ethyl acetate/petroleum ether, 3/7), racemic photoproducts 39 (8 mg) and 40 (20 mg) were obtained as white solids. Solid state photolysis a-Oxoamide 38 (50 mg) was sandwiched between two microscopic slides (Pyrex equivalent). The sample plates were then fastened together with tape and placed in a polyethylene bag before being heat-sealed under a positive pressure of nitrogen. Following 2 h irradiation (450 W Hanovia lamp), the sample was quantitatively washed from the plates with dichloromethane, and concentrated in vacuo. Purification by radial chromatography (ethyl acetate/petroleum ether, 3/7) afforded racemic photoproducts 39 (21 mg) and 40 (11 mg) as white solids. Methyl 4-[3-hvdroxv-2,2-dimethvl-l-(l-methvlethyl)-4-oxo-3-azetidinyllbenzoate (39) 39 mp: 224-225 °C (plates, Et 2 0). *H N M R (CD 2C1 2 , 300 MHz): 5 8.47 (d, J = 8.7 Hz, 2H), 8.20 (d, J= 8.7 Hz, 2H), 4.03 (s, 3H), 3.68 (hept, / = 6.8 Hz, IH), 1.83 (s, IH), 1.59 (s, 3H), 1.45 (d, J = 6.8 Hz, 3H), 1.42 (d, J = 6.8 Hz, 3H). 0.91 (s, 3H). 1 3 C N M R (CDCI3, 100 MHz): 5 168.38, 166.77, 143.62, 129.69, 129.39, 126.66, 87.87, 67.30, 52.09, 44.20, 23.78, 22.27, 21.88, 21.74. 247 Chapter 5 Experimental IR (KBr pellet): v 3441(br), 2978, 1732, 1610, 1422, 1284, 1185, 1104, 772 cm-1. LRMS (EI) m/z 291 ( M + , 0.80), 260 (2.2), 206 (100), 191 (18.5), 163 (28.7), 147 (27.5), 100(23.5). HRMS (EI) m/z calcd for C , 6 H2iN0 4 291.1471, found 291.1477. Anal. Calcd for C i 6 H 2 i N 0 4 : C 65.96, H 7.27, N 4.81. Found: C 65.86, H 7.36, N 4.76. 2,2-Dimethvl-3-isopropvl-5-(4,-methoxvcarbonylphenvl)oxazolidin-4-one (40) 1 40 mp 112-114 °C (prisms from Et 2 0) J H NMR (CDCI3, 300 MHz): 5 8.02 (d, J= 8.38 Hz, 2H), 7.53 (d, J= 8.16 Hz, 2H), 5.21 (s, IH), 3.88 (s, 3H), 3.40 (hept, J= 6.90 Hz, IH), 1.58 (s, 3H), 1.53 (s, 3H), 1.47 (d, J = 6.83 Hz, 3H), 1.37 (d, J= 6.84 Hz, 3H). 1 3 C NMR (CDCI3, 75 MHz): 8 168.17, 166.88, 142.14, 129.83, 129.65, 125.98, 94.95, 77.17, 52.07, 46.12, 27.74, 26.64, 20.39, 19.98. IR (KBr pellet): v 2976, 1714, 1614, 1423, 1343, 1282, 1114, 753 cm"1. LRMS (EI): m/z (relative intensity) 291 ( M + , 2.7), 276 (73.5), 260 (16.6), 234 (49.4), 206 (100), 191 (43.4), 165 (16.9), 147 (98.6), 133 (37.9), 105 (14.3), 84 (15.4), 77 (14.2). HRMS (EI): m/z calcd for C i 6 H 2 i N 0 4 291.1471, found 291.1468. 248 Chapter 5 Experimental Anal. Calcd for C i 6 H 2 i N 0 4 : C 65.96, H 7.27, N 4.81. Found: C 66.17, H 7.31, N 4.84. 5.2.2 Preparative Photolysis of Salt 67a 3 9 ( 9 1 %, 9 9 % e . e . ) Crystals of salt 67a (500 mg, 1.28 mmol) were crushed in a mortar and pestle and suspended in 450 mL of HPLC grade hexanes (450mL) in a standard photochemical immersed well apparatus. The suspension was thoroughly degassed under N 2 and irradiated (Pyrex, 450 W Hanovia) with stirring for 6.5 h (99 % conversion). After photolysis the suspension was placed in a separatory funnel and extracted with methanol (3 x 100 mL). The methanol extracts were concentrated in vacuo and treated with an excess of ethereal C H 2 N 2 to form the corresponding methyl esters. Purification by silica gel chromatography (petroleum ethyl-ethyl acetate, 7:3) afforded compound 39 (338 mg, 91 %) as a white solid. Chiral HPLC analysis (OD column) indicated an optical purity of > 99 % ([a] 2 2 +113.1 (c = 1.07 % in MeOH)). Recrystallization from benzene provided colorless plates. Only a trace amount of photoproduct 40 (1 % from GC analysis) was formed in this reaction as a racemate. 249 Chapter 5 Experimental The structure of compound 39 was confirmed by X-ray crystallographic analysis: Habit colorless plates Space group P2i2i2, a, A 6.7631(3) b,A 10.6176(5) c A 22.061(1) <x(°) 90 P ( ° ) 90 Y(°) 90 Z 4 R 0.051 5.2.3 Preparative Photolysis of a-Oxoamide 68 Crystals of ester 68 (200 mg) were crushed in a mortar and pestle and suspended in deionized water (40 mL) in a Pyrex photolysis tube (100 mL). The suspension was thoroughly degassed under N 2 and irradiated (Pyrex, 450 W Hanovia) with stirring for 4.5 h (100 % conversion). After photolysis the suspension was placed in a separatory funnel and extracted with dichloromethane (3 x 40 mL). The organic extracts were concentrated in vacuo and purified by silica gel chromatography (petroleum ethyl-ethyl acetate, 8:2) to afford compound 69 (134 mg, 67 %) as a white solid and compound 70 (15 mg) as a yellowish liquid. Chiral HPLC analysis of compound 69 indicated an optical purity of 91 %. Recrystallization in ether provided optically pure compound 69 as colorless plates. The absolute configuration of compound 69 at the newly formed chirality center was determined to be (R) by X-ray crystallography. Photoproduct 70 was determined to be a racemate by chiral HPLC analysis (OD column). 250 Chapter 5 Experimental (2R. 3R*)-2-Phenylpropyl 443-hvdroxv-2,2-dimethvl-l-(l-methvlethvl)-4-oxo-3-azetidinyllbenzoate (69) mp 191-192 °C (plates, diethyl ether) ] H N M R (CDC1 3, 400 MHz): 5 7.76 (d, J= 8.0 Hz, 2H), 7.29 (m, 5H), 7.24 (d, J = 8.0 Hz, 2H), 5.44 (s, IH), 4.37 (m, 2H), 3.60 (m, IH), 3.24 (m, IH), 1.47 (s, 3H), 1.39 (d, J = 6.9 Hz, 3H), 1.32 (d, J= 6.8 Hz, 6H), 0.74 (s, 3H). 1 3 C N M R (CDCI3, 100 MHz): 8 168.47, 166.04, 143.43, 143.19, 129.70, 129.24, 128.47, 127.32, 126.65, 126.47, 87.82, 69.83, 67.33, 44.15, 38.99, 23.74, 22.27, 21.88, 21.73, 18.03. IR (KBr pellet): v 3246, 2975, 1727, 1703, 1671, 1407, 1273, 1099, 760 cm"1. L R M S (EI): m/z (relative intensity) 395 (M + ) , 310, 192 (100), 175, 105, 91, 77. H R M S (EI): m/z calcd for C24H29NO4 (M + ): 395.2097, found 395.2095. Anal . Calcd for C24H29NO4: C, 72.89; H , 7.39; N 3.54. Found: C, 72.64; H , 7.36; N , 3.68. 251 Chapter 5 Experimental This structure was confirmed by X-ray crystallographic analysis: Habit colorless plates Space group P2i a, A 10.7830(3) b, A 6.8387(5) c, A 14.6447(1) a ( ° ) 90 P(°) 91.9500(10) 90 Z 2 R 0.063 (2R. 3S*)-2-Phenvtpropvl 4T2. 2.-dimethvl-3-(l-methvlethvD-4-oxo-5-oxazolidinyll-benzoate (70) *H N M R (CDC1 3, 300 MHz): 5 7.97 (d, J= 8.2 Hz, 2H), 7.52 (d, J= 8.2 Hz, 2H), 7.28 (m, 5H), 5.20 (s, IH), 4.38 (m, 2H), 3.41 (hept, J= 6.8 Hz, IH), 3.24 (m, IH), 1.58 (s, 3H), 1.54 (s, 3H), 1.48 (d, J= 6.8 Hz, 3H), 1.38 (d,J = 6.8 Hz, 3H), 1.37 (d, J = 6.8 Hz, 3H). 1 3 C N M R (CDC1 3, 100 MHz): 5 168.20, 166.27, 143.18, 142.14, 130.01, 129.64, 128.51, 127.32, 126.70, 125.97, 94.96, 77.19, 69.84, 46.14, 39.07, 27.77, 26.67, 20.41, 19.84, 17.99. IR (KBr pellet): v 2976, 2937, 1713, 1708, 1613, 1430, 1351, 1272, 1109, 701 cm"1. 70 252 Chapter 5 Experimental L R M S (EI): m/z (relative intensity) 395 (M + ) , 380, 310, 278, 260, 147, 118 (100), 105, 91, 77. H R M S (EI): m/z calcd for C24H29NO4 (M + ): 395.2097, found 395.2095. Anal. Calcd for C24H29NO4: C, 72.89; H , 7.39; N 3.54. Calcd for C 2 4H29N0 4 .1/2H 2 0: C, 72.26; H , 7.48; N 3.46. Found: C, 72.21; H , 7.20; N , 3.49. 5.3 Photolysis of Bicyclo[2.2.2]octane Derivatives 85 and 55 5.3.1 Preparative Photolysis of Bicyclo[2.2.2]octyl Ketone 85 A solution of ketone 85 (82 mg) in acetonitrile (10 mL) was purged with N2 and irradiated (450 W Hanovia lamp) for 2 h. Removal of the solvent in vacuo and purification by chromatography (ether/petroleum ether, 3/7) afforded cyclobutanols 112 (50 mg, 61%, white solid), and 111 (28 mg, 34%, white solid). (3R*.4S*)-3-(4,-Cvanophenyl)-6-pentvltetracvclor4.2.2.0''41decan-3-ol (112) 9 1 1 2 CN mp: 105.0-106.0 °C (plates, diethyl ether). 253 Chapter 5 Experimental *H NMR (400 MHz, CDC1 3): 5 7.58 (d,J= 8.2 Hz, 2H), 7.41 (d, J = 8.2 Hz, 2H), 2.54 (m, IH), 2.36 (t, / = 9.9 Hz, IH), 2.20 (d, J= 12.0 Hz, IH), 2.03 (d, J= 12.0 Hz, IH), 2.01 (s, IH, OH), 1.65-1.48 (m, 6H), 1.40-1.05 (m, 11H), 0.85 (t,J= 7.1 Hz, 3H). 1 3 C NMR (75 MHz, CDCI3): 8 153.02, 132.29, 125.89, 118.84, 110.61, 78.91, 46.82, 44.56, 41.26, 33.64, 32.76, 32.71, 32.43, 32.02, 31.02, 29.12, 28.74, 23.47, 22.65, 14.04. IR (KBr pellet): v 3458, 3037, 2921, 2852, 2235, 1607, 1456, 1377, 1171, 1020, 848, 516 cm"1. LRMS (EI) m/z 323 (M + ) , 305, 252, 234, 178, 130 (100), 102, 79. HRMS (EI) calcd for C22H29NO 323.2249, found 323.2253. Anal . Calcd for C22H29NO: C, 81.69; H , 9.04; N , 4.33. Found: C, 81.83; H , 9.17; N , 4.21. (3S*.4S*V3-(4,-Cvanophenvl)-6-pentvltetracvclo|'4.2.2.01-4ldecan-3-ol (111) mp: 157.0-159.0 °C (plates, Et 2 0). *H NMR (300 MHz, CDC1 3): 8 7.66 (d, J= 8.3 Hz, 2H), 7.48 (d, J= 8.3 Hz, 2H), 2.70 (d, J= 12.2 Hz, IH), 2.57 (t, J= 9.9 Hz, IH), 2.10 (s, IH, OH), 2.07 (d, J= 12.2 Hz, IH), 1.63-1.48 (m, 4H), 1.23-0.99 (m, 14H), 0.83 (t,J= 7.1 Hz, 3H). 1 3 C NMR (75 MHz, CDCI3): 8 147.92, 132.21, 128.60, 118.74, 111.30, 78.70, 51.62, 43.02, 40.94, 33.55, 32.74, 32.47, 32.38, 31.80, 31.50, 27.70, 26.56, 23.36, 22.61, 14.06. 111 254 Chapter 5 Experimental I R ( K B r pellet): v 3515, 2924, 2856, 2228, 1607, 1449,1393, 1168,1060, 840, 559 cm-1. L R M S (EI) m/z 323 (M + ) , 305, 281, 252, 234, 178, 130 (100), 102, 79. H R M S (EI) calcd for C 2 2H 2 9 NO 323.2249, found 323.2250. Anal. Calcd for C 2 2 H 2 9 N O : C, 81.69; H , 9.04; N , 4.33. Calcd for C 2 2 H 2 9 N 0 . 1 / 4 H 2 0 : C, 80.57; H , 9.07; N , 4.27. Found: C, 80.78; H , 9.23; N , 4.17. This structure was confirmed by X-ray crystallographic analysis: Habit colorless plates Space group P-l a, A 6.5607(5) b,A 8.6511(7) c, A 17.3882(12) a ( ° ) 73.114(8) P(°) 77.067(9) Y(°) 85.352(11) Z 2 R 0.055 5.3.2 Preparative Photolysis of Bicyclo[2.2.2]octyl Ketone 55 A solution of ketone 55 (190 mg) in acetonitrile (120 mL) was purged with N 2 and irradiated (450 W Hanovia lamp) for 3 h. Removal of the solvent in vacuo and purification by chromatography (ethyl acetate/petroleum ether, 1/9) afforded 255 Chapter 5 Experimental cyclobutanols 116 (117 mg, 62%, yellowish liquid or white solid when solidified upon standing for months) and 115 (52 mg, 27%, white solid). (3R*. 4S*)-3-(4,-Carbomethoxyphenvn-6-r)entvltetracvclor4.2.2.01'4ldecan-3-ol (116) .OH mp: 75.0-75.5 °C (needles, diethyl ether). *H N M R (400 MHz, CDC1 3): 5 7.98 (d, J= 8.5 Hz, 2H), 7.36 (d, / = 8.5 Hz, 2H), 3.89 (s, 3H), 2.57 (m, IH), 2.40 (m, IH), 2.23 (d, J= 12.0 Hz, IH), 2.04 (d, J= 12.0 Hz, IH), 1.82 (s, IH, OH), 1.65 (m, IH), 1.60-1.48 (m, 6H), 1.38-1.06 (m, 10H), 0.86 (t, J= 7.1 Hz, 3H). 1 3 C N M R (75 MHz, CDC1 3): 5 166.89, 153.04, 129.87, 128.78, 125.07, 79.22, 52.07, 46.65, 44.47, 41.37, 33.70, 32.83, 32.75, 32.57, 32.11, 31.02, 29.28, 28.75, 23.52, 22.70, 14.07. IR (KBr pellet): v 3499, 2929, 2858, 1700, 1611, 1283,776 cm"1. L R M S (EI) m/z 356 (M + ) , 341, 325, 297 (100), 281, 253, 178, 163, 135. H R M S (EI) calcd for C 2 3 H 3 2 0 3 356.2352, found 356.2354. Anal . Calcd for C 2 3 H 3 2 0 3 : C, 77.49; H , 9.05. Found: C, 77.49; H , 9.36. (3S*. 4S*)-3-(4,-Carbomethoxvphenvl)-6-pentvltetracvclor4.2.2.01'41decan-3-ol (115) 116 COOCH 3 256 Chapter 5 Experimental C O O C H 3 mp: 72-73 °C. ' H N M R (400 MHz, CDCI3): 5 8.02 (d, J= 8.3 Hz, 2H), 7.44 (d, J= 8.3 Hz, 2H), 3.90 (s, 3H), 2.72 (d, J= 12.1 Hz, IH), 2.58 (m, IH), 2.06 (d, J= 12.1 Hz, IH), 1.90 (s, IH, OH), 1.62-1.48 (m, 4H), 1.25-0.96 (m, 14H), 0.83 (t, J= 7.1 Hz, 3H). 1 3 C N M R (75 MHz, CDC1 3): 5 166.89, 147.81, 129.64, 129.14, 127.81, 78.76, 52.11, 51.38, 42.96, 41.01, 33.60, 32.76, 32.53, 32.34, 31.83, 31.60, 27.59, 26.50, 23.36, 22.61, 14.06. IR (KBr pellet): v 3312, 2930,2856, 1726, 1611, 1436, 1279, 1112 cm"1. L R M S (EI) m/z 356 (M + ) , 341, 297 (100), 178, 163. H R M S (EI) calcd for C23H3203 356.2352, found 356.2347. Anal . Calcd for C 2 3 H 3 2 O 3 : C, 77.49; H, 9.05. Found: C, 77.06; H , 9.14. 257 Chapter 5 Experimental 5.4 Photolysis of Bicyclo[2.2.1]heptane Derivatives 58 and 61 5.4.1 Preparative Photolysis of Bicyclo[2.2.1]heptyl Ketone 58 A solution of ketone 58 (67 mg) in acetonitrile (20 mL) was purged with N 2 and irradiated (450 W Hanovia lamp) for 4 h. Removal of the solvent in vacuo and purification by chromatography (diethyl ether/petroleum ether, 2/8) afforded cyclobutanols 119 (29 mg, 43%, white solid) and 120 (23 mg, 34%, white solid). (IS*. 3R*. 4S*. 6S*)-3-(4,-Carbomethoxyphenvl)tetracvclor4.2.1.01'4lnonan-3-ol (120) mp: 96-98 °C. *H NMR (300 MHz, CDCI3): 8 7.98 (d, J= 8.3 Hz, 2H), 7.40 (d, J= 8.3 Hz, 2H), 3.88 (s, 3H, CH3O), 2.51 (d, J = 12.4 Hz, IH), 2.36 (d, J= 12.4 Hz, IH), 2.22 (m, IH), 2.11 (m, IH), 2.02 (m, IH), 1.95-1.88 (m, IH), 1.87 (s, IH, OH), 1.7-1.6 (m, IH), 1.6-1.4 (m, 2H), 1.4-1.3 (m, IH), 1.3-1.2 (m, 2H). 1 3 C NMR (100 MHz, CDCI3): 5 166.91, 153.11, 129.76, 128.66, 125.13, 77.24, 52.06, 50.76, 45.12, 42.08, 38.26, 37.44, 33.63, 33.61, 28.74. IR (KBr pellet): v 3499, 2951, 2866, 1698, 1607, 1437, 1282, 1156, 770, 704 cm' 1. P H 120 COOCH3 258 Chapter 5 Experimental LRMS (+CI: gas, NH 3 ) m/z (relative intensity) 290 ( M + + 18, 17.0), 273 ( M + + 1, 75.0), 271 (100), 255 (78.7), 288 (12.8). HRMS (+CI: gas, NH 3 ) calcd for C i 7 H 2 i 0 3 ( M + + 1) 273.1490, found 273.1492. A n a l . Calcd for C i 7 H 2 0 O 3 : C, 74.97; H , 7.40. Found: C, 74.67; H , 7.37. (IS*. 3S*. 4S*. 6S*)-3-(4,-Carbomethoxvphenvntetracvclor4.2.1.01'41nonan-3-ol (119) m p : 132-133 °C. *H NMR (300 MHz, CDC1 3): 5 8.01 (d, J = 8.4 Hz, 2H), 7.44 (d, J= 8.4 Hz, 2H), 3.89 (s, 3H, CH 3 0) , 3.10 (d, J = 12.6 Hz, IH), 2.40 (s, IH, OH), 2.31 (d, J = 12.4 Hz, IH), 2.23 (m, IH), 1.94 (m, IH), 1.60-1.50 (m, 3H), 1.40-1.25 (m, 2H), 1.25-1.15 (m, IH), 1.05 (m, IH), 0.82 (m, IH). 1 3 C NMR (75 MHz, CDC1 3): 5 168.76, 148.27, 129.69, 129.47, 128.52, 79.03, 56.93, 52.32, 41.84, 41.05, 38.79, 37.25, 35.99, 34.52, 28.49. IR (KBr pellet): v 3428, 2950, 2860, 1730, 1695, 1612, 1447, 1279, 1195, 1020, 856, 775,711 cm - 1 . LRMS (+CI: gas, NH 3 ) m/z (relative intensity) 290 ( M + + 18, 6.5), 273 ( M + + 1, 30.4), 271 (100), 255 (32.9). HRMS (+CI: gas, NH 3 ) calcd for C , 7 H 2 i 0 3 ( M + + 1) 273.1490, found 273.1492. C O O C H 3 119 259 C h a p t e r 5 E x p e r i m e n t a l Anal. Calcd for C 1 7 H 2 0 O 3 : C, 74.97; H , 7.40. Found: C, 74.67; H , 7.62. 5.4.2 Preparative Photolysis of Dimethylated Bicyclo[2.2.1]heptyl Ketone 61 A solution of ketone 61 (200 mg) in acetonitrile (50 mL) was purged with N 2 and irradiated (450 W Hanovia lamp) for 11 h. Removal of the solvent in vacuo and purification by chromatography (ether/petroleum ether, 2/8) afforded cyclobutanols 124 (101 mg, 51%, yellowish liquid or white solid when solidified upon standing for months), 125 (50 mg, 25%o, white solid), and ketone 126 (7 mg, 3.5%, white solid). 2.2-Dimethvl-(4'-carbomethoxv)benzo[4. 5"ltetracvclo[6.2.1.01,6"|undeca-3-one (126) O 126 mp: 105-107 °C. ! H NMR (400 MHz, CDCI3): 8 7.93-7.91 (m, IH), 7.86-7.83 (m, 2H), 3.91 (s, 3H), 3.06 (d xd,Jj = 9.5 Hz, J2 = 4.7 Hz, IH), 2.30 (m, IH), 2.29-2.22 (m, IH), 1.74-1.70 (m, IH), 1.69-1.63 (m, 2H), 1.45-1.42 (m, 2H), 1.26 (s, 3H), 1.24 (m, IH), 1.10 (s, 3H), 1.06-1.03 (m, IH). 260 Chapter 5 Experimental 1 3 C NMR (100 MHz, CDC1 3): 6 203.42 (+), 166.53 (+), 148.34 (+), 134.43 (+), 132.89 (+), 130.12 (-), 127.21 (-), 126.64 (-), 54.10 (+), 52.37 (-), 45.58 (+), 42.59 (-), 41.69 (+), 37.70 (-), 37.38 (+), 29.85 (+), 29.74 (+), 23.33 (-), 18.69 (-). IR (KBr pellet): v 2975, 2951, 2869, 1730, 1681, 1576, 1436, 1284, 1198, 1103, 975, 751 cm"1. LRMS (EI) m/z 298 ( M + , 100), 283, 189, 115. HRMS (EI) calcd for C19H22O3 298.1569, found 298.1570. A n a l . Calcd for Q9H22O3: C, 76.48; H , 7.43; O, 16.09. Calcd for Ci 9 H2203«l/6H 2 0: C, 75.72; H , 7.47. Found: C, 75.74; H , 7.48. (TR*. 3S*. 4S*. 6S*>2.2-Dimethvl-3-(4,-carbomethoxvphenvl)tetracyclor4.2.1.01,4lnonan-3-ol (125) m p : 110-115 °C (plates, CH 2C1 2). lH NMR (400 MHz, CDCI3): 5 7.97 (d, J= 8.5 Hz, 2H), 7.35 (d, J= 8.5 Hz, 2H), 3.89 (s, 3H), 2.47-2.43 (m, IH), 2.22 (m, IH), 2.04-2.02 (m, IH), 1.80-1.68 (m, IH), 1.65 (s, IH, OH), 1.63-1.56 (m, 2H), 1.34-1.30 (m, IH), 1.29-1.22 (m, 3H), 1.21 (s, 3H), 0.72 (s, 3H). 1 3 C NMR (100 MHz, CDC1 3): 5 166.98, 155.15, 129.53, 128.79, 126.43, 81.13, 53.84, 52.07, 43.12, 42.70, 39.07, 37.53, 32.33, 29.49, 28.20, 24.20, 19.93. 125 C O O C H 3 261 Chapter 5 Experimental IR (KBr pellet): v 3489, 2956, 2934, 2860, 1699, 1611, 1440, 1285, 1196, 1100, 768 cm"1. LRMS (EI) m/z 300 (M + ) , 282, 267, 253, 239, 207, 191, 163, 147, 135, 120 (100), 107, 91, 79, 67, 55. HRMS (EI) calcd for C19H24O3 300.1725, found 300.1727. Anal. Calcd for C i 9 H 2 4 0 3 : C, 75.97; H , 8.05. Calcd for C i 9 H 2 4 0 3 « 1 / 3 H 2 0 : C, 74.48; H , 8.11. Found: C, 74.05; H , 7.92. This structure was confirmed by X-ray crystallographic analysis: Habit colorless plates Space group P2,/C a, A 13.2582(6) b , A 6.2949(3) c , A 20.0604(9) a ( ° ) 90 P(°) 103.283(2) y(°) 90 z 4 R 0.057 262 Chapter 5 Experimental (IR*. 3R*. 4S*. 6S*)-2. 2-Dimethvl-3-(4'-carbomethoxyphenyl)tetracyclo|"4.2.1.O^Inonan-S-ol (124) m p : 77-78 °C. *H NMR (400 MHz, CDC1 3): 5 7.95 (d, J = 8.5 Hz, 2H), 7.58 (d, J= 8.5 Hz, 2H), 3.88 (s, 3H), 2.28-2.25 (m, IH), 2.21-2.04 (m, IH), 2.02 (s, IH, OH), 1.71-1.65 (m, IH), 1.60-1.55 (m, IH), 1.42-1.34 (m, 2H), 1.33 (s, 3H, CH 3 ) , 1.20 (m, IH), 1.19 (s, 3H, CH 3 ) , 1.12-1.05 (m, 2H). 1 3 C NMR (100 MHz, CDC1 3): 8 166.92 (+), 149.43 (+), 129.05 (-), 128.81 (-), 128.44 (+), 82.02 (+), 54.31 (-), 52.06 (-), 51.79 (+), 44.71 (+), 39.54 (+), 37.78 (-), 36.75 (+), 28.72 (+), 28.03 (+), 25.38 (-), 23.32 (-). IR (neat): v 3456 (br), 2952,2864,1725, 1611,1436, 1281,1187,1109,1004,716 cm-1. 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