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Asymmetric induction in the photochemistry of 2-benzoyladamantane-2-carboxylic acid derivatives Zenova, Alla Yurevna 2000

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ASYMMETRIC INDUCTION IN THE PHOTOCHEMISTRY OF 2 -BENZOYLADAMANTANE-2 -CARBOXYLIC ACID DERIVATIVES by ALLA YUREVNA ZENOVA Diploma in Chemistry, Moscow State University, Russia, 1986 A THESIS SUBMITTED IN PARTIAL F U L F I L L M E N T OF THE REQUIREMENTS FOR THE DEGREE OF M A S T E R OF SCIENCE 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 F E B R U A R Y 2000 © Alia Yurevna Zenova, 2000 In presenting t h i s thesis i n p a r t i a l f u l f i l m e n t of the requirements for an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, I agree that the Library s h a l l make i t f r e e l y a v a i l a b l e for reference and study. I further agree that permission for extensive copying of t h i s thesis for s c h o l a r l y purposes may be granted by the head of my department or by his or her representatives. I t i s understood that copying or p u b l i c a t i o n of t h i s thesis f o r f i n a n c i a l gain s h a l l not be allowed without my written permission. Department of The U n i v e r s i t y of B r i t i s h Columbia Vancouver, Canada ABSTRACT The photochemistry of P-keto ester 28 has been studied in solution as well as the crystalline state. In both media this compound undergoes Yang photocyclization, followed by a spontaneous retro-aldol ring opening to afford 5-keto ester 42 as the major photoproduct, with both benzoyl and methoxycarbonyl groups in axial positions. 28 The observed photoreactivity of P-keto ester 28 was correlated to its X-ray crystal structure. Crystallographic analysis revealed that only one y-hydrogen in the molecule lies within a reasonable distance (2.42 A) from the ketone oxygen for abstraction to occur. The angular parameters associated with y-hydrogen abstraction as well as the geometric .parameters associated with the reactivity of intermediate 1,4-hydroxybiradical were derived from the crystallographic data. The (-)-menthyl, (-)-bornyl and (+)-fenchyl esters of P-keto acid 36 were prepared to explore asymmetric induction by covalent chiral auxiliaries. In the solution phase photolyses of all chiral esters studied, two possible diastereomeric 5-keto esters n analogous to 8-keto ester 42 were formed in unequal amounts. Low diastereoselectivity (14-28% de) in the solution phase photolyses reflected the extent of asymmetric induction due to the direct influence of the 36 chiral auxiliary. Asymmetric induction in the solid state photolysis was studied for the (-)-bornyl and (+)-fenchyl P-keto esters. The solid state photoreaction, in which chiral information is provided by the rigid crystal environment, proceeded with high diastereoselectivity (>95% de) at quantitative conversion for the (-)-bornyl ester and with low (18% de) diastereoselectivity for (+)-fenchyl ester. The diastereoselectivity observed in the solid state was correlated with the X-ray crystal structure data for the corresponding compound. The ionic chiral auxiliary approach was also tested in the photoreaction of P-keto acid 36. Owing to its thermal instability, P-keto acid 36 was prepared in situ at low temperature and its chiral salt with optically active R-(+)-a-methylbenzylamine was obtained. The solid state photolysis of this chiral salt, followed by diazomethane work up, led to the methyl P-keto ester 42 with an excellent enantiomeric excess (>99%) at quantitative conversion of the starting material. iii TABLE OF CONTENTS Abstract 1 1 Table of Contents iv List of Figures viii List of Tables xiv Acknowledgements xvi Chapter 1. INTRODUCTION i 1.1. General Considerations 1 1.2. Photochemistry of Ketones 3 1.3. Retro-Aldol Ring Opening in Cyclobutanols 8 1.4. S olid State Reactions. Crystal Structure-Solid State Reactivity Correlation Method 11 1.5. Geometric Requirements for Intramolecular Hydrogen Atom Abstraction 12 1.6. Structure and Reactivity of 1,4-Hydroxybiradical Intermediates in the Norrish Type II Photoreaction. 15 1.7. Asymmetric Induction in Solution State Photochemistry: Covalent Chiral Auxiliary Approach 17 1.8. Asymmetric Induction in Solid State Photochemistry 21 1.9. Research Obj ectives 27 RESULTS AND DISCUSSION Chapter 2. Preparation of Substrates 30 2.1. Methyl 2-Benzoyltricyclo[3.3.1. l3'7]decane-2-carboxylate (28) 30 2.2. Chiral (3-Keto Esters 33, 34 and 35 31 2.2.1. Attempted Preparation of Chiral Esters via Transesterification ofp-Keto Ester 28 32 2.2.2. Preparation of Chiral Esters via Low Temperature Acylation of Corresponding Ester Enolates with Benzoyl Chloride 33 2.3. Preparation of Chiral Salt ofp-Keto Acid 36 36 2.3.1. Cleavage of P-Keto Ester 28 36 2.3.2. Carboxylation of Phenyl Tricyclo[3.3.1.13,7]dec-2-yl Methanone 37 2.3.3. Acylation of Acid 26 Dianion with Benzoyl Chloride 38 2.3.4. Preparation of Salt 40 by Cleavage of tert-Buty\ Ester 39 with CF 3 CO O H 39 Chapter 3. Photochemical Studies 41 3.1. Photochemical Studies of P-Keto Ester 28 41 3.1.1. Preparation of Photoproducts 41 3.1.2. Determination of Photoproduct 42 Stereochemistry 47 3.1.3. Determination of Photoproduct 43 Stereochemistry 54 3.1.4. Determination of Photoproduct 44 Stereochemistry 60 3.1.5. Mechanism of Photoreaction of P-Keto Ester 28.. 66 3.1.6. Geometric Parameters of P-Keto Ester 28 from X-ray Crystallography 71 3.2. Photochemical Studies of P-Keto Ester 34 75 3.2.1. Solution State Photolysis of p-Keto Ester 34 75 3.2.2. Determination of Photoproduct 47 A Stereochemistry 76 3.2.3. Determination of Photoproduct 47B Stereochemistry 83 3.2.4. Solid State Photolysis of P-Keto Ester 34 90 3.2.5. Asymmetric Induction in the Solution and Solid State Photolysis of P-Keto Ester 34 92 3.3: Photochemical Studies of p-Keto Ester 35 97 3.3.1. Preparation and Identification of Photoproducts 97 3.3.2. Determination of Photoproduct 49A Stereochemistry 107 3.3.3. Determination of Photoproduct 49B Stereochemistry 107 3.3.4. Asymmetric Induction in Solution and the Solid State Photolysis of p-Keto Ester 35 108 3.4. Photochemistry of P-Keto Ester 33 110 3.5. Photochemistry of Salt 40 I l l 3.6. Asymmetric Induction in Solution Versus Solid State. Conclusions and Further Applications '.. 113 EXPERIMENTAL Chapter 4. Preparation of Starting Material 115 4.1. General Procedures 115 4.2. Synthesis of Methyl 2-Benzoyltricyclo[3.3.1.l3,7]d e c a n e_ 2-carboxylate (28) 120 v i 4.3. Syntheses of p-Keto Esters 33, 34 and 35 125 4.4. Synthesis of Salt 40 135 Chapter 5. Photochemical Studies 141 5.1. General 141 5.2. . Preparation and Characterization of Photoproducts 142 5.2.1. Photolysis of p-Keto Ester 28 142 5.2.2. Detection of an Intermediate, 41, by 1 3 C N M R 158 5.2.3. Base-Catalyzed Isomerization of Photoproduct 42 159 5.2.4. Base-Catalyzed Protium - Deuterium Exchange in Photoproduct 42 161 5.2.5. Base-Catalyzed Hydrolysis of Photoproduct 42 163 5.2.6. Photolysis of Compound 34 165 5.2.7. Photolysis of Compound 35 176 5.2.8. Photolysis of Compound 33 187 5.2.9. Photolysis of Salt 40 188 5.2.10. Transesterification of Photoproducts Obtained by Photolyses of Keto Ester 34 189 References 190 Appendix 1 195 Appendix II 196 List of Figures Figure 1.1. Electronic configurations of a ketone, showing the occupancy of carbbnyl bond orbitals in: (a) the ground state, (b) the n - » 7 T * singlet excited state, and (c) the n —»7t* triplet excited state 3 Figure 1.2. The Norrish type I photochemical reaction 4 Figure 1.3. The Norrish type I reaction of (S)-(+)-2-phenylpropiophenon 5 Figure 1.4. The photoreduction of ketones 6 Figure 1.5. The Norrish type II photoreaction 7 Figure 1.6. Conformations of the 1,4-biradicals 8 Figure 1.7. The de Mayo reaction 9 Figure 1.8. The photoreaction of ethyl 2-benzoyl-4-methylvalerate 9 Figure 1.9. The retro-aldol ring opening in photoproduct 3 10 Figure 1.10. The photoreaction of 2-benzoyl-2-methyl-l-tetralone 10 Figure 1.11. Parameters defining the spatial relationship for the abstraction of a hydrogen atom by the carbonyl oxygen atom. d=distan'ce between . hydrogen and oxygen, O H ; 9= O H-C angle; A= C=0""H angle and co= dihedral angle formed between the O-H vector and its projection on the nodal plane of the 0 = 0 group 13 Figure 1.12. Yang photocyclization of adamantyl aryl ketones 16 Figure 1.13. 1,4-hydroxybiradical intermediate formed in the Norrish type II photoreaction of adamantyl aryl ketones 17 Figure 1.14. Asymmetric induction in a [2+2] photocycloaddition 18 Figure 1.15. Asymmetric induction in the Paterno-Buchi reaction 18 Figure 1.16. The photoreaction of (-)-menthyl 2-acetylbenzoate 19 viii Figure 1.17. Asymmetric induction in the photocyclization of 8 and 11 20 Figure 1.18. Solid state asymmetric bromination of 14 21 Figure 1.19. Unimolecular absolute asymmetric photoreactions in chiral crystals 22 Figure 1.20. Asymmetric induction in the solid state [2+2] photocyclization of (S)-(+)-20 23 Figure 1.21. Solid state [2+2] photocyclization of compound 21 24 Figure 1.22. Use of an ionic chiral auxiliary in the solid state Norrish type II photoreaction 26 Figure 2.1. Synthesis of methyl 2-benzoyltricyclo[3.3.1.13'7]decane-2-carboxylate (28) 31 Figure 2.2. Attempted transesterification of methyl ester 28 32 Figure 2.3. Decarboxylation or cleavage at the ketone group of P-keto ester 28 32 Figure 2.4. Preparation of chiral esters via low temperature acylation of their corresponding ester enolates with benzoyl chloride 33 Figure 2.5. The *H N M R spectra (500 MHz, CDC13) of a) P-keto ester 33; b) P-keto ester 34; c) P-keto ester 35 35 Figure 2.6. Attempted cleavage of P-keto ester 28 36 Figure 2.7. Attempted carboxylation of ketone 37 37 Figure 2.8. Acylation of dianions of carboxylic acids ". 38 Figure 2.9. Preparation of salt 40 by cleavage of fert-butyl ester 39 with C F 3 C O O H 39 Figure 3.1. Photoreaction of P-keto ester 28 41 Figure 3.2.a. The lH N M R spectrum (500 MHz, CDC13) of p-keto ester 42 44 Figure 3.2.b. The ' H N M R spectrum (500 MHz, CDC13) of P-keto ester 43 45 Figure 3.2.c. The *H N M R spectrum (500 MHz, CDC13) of p-keto ester 44 46 ix Figure 3.3. Partial H M B C spectrum (500 MHz, CDC13) of photoproduct 42 50 Figure 3.4. Partial COSY spectrum (500 MHz, CDC13) of photoproduct 42 51 Figure 3.5. N O E difference experiment on photoproduct 42 a) irradiation at 5=3.45 ppm (H-4), b) irradiation at 5=2.50 ppm (H-2), c) irradiation at 5=2.54 ppm (H-9'), d) off-resonance spectrum .52 Figure 3.6. N O E difference experiment on photoproduct 42 a) irradiation at 5=1.81 ppm (H-8), b) off-resonance spectrum 53 Figure 3.7. Selected N O E correlations used for ester 42 stereochemistry determination 54 Figure 3.8. Partial H M B C spectrum (500 MHz, CDC13) of photoproduct 43 57 Figure 3.9. Partial COSY spectrum (500 MHz, CDC13) of photoproduct 43 58 Figure 3.10. NOE difference experiment on photoproduct 43 a) irradiation at 5=3.64 ppm (H-4), b) irradiation at 5=2.76 ppm (H-3), c) irradiation at 5=2.72 ppm (H-2), d) off-resonance spectrum 59 Figure 3.11. Selected NOE correlations used for ester 43 stereochemistry determination 60 Figure 3.12. Partial H M B C spectrum (500 MHz, CDC13) of photoproduct 44 62 Figure 3.13. Partial COSY spectrum (500 MHz, CDC13) of photoproduct 44 63 Figure 3.14. NOE difference experiment on photoproduct 44 a) irradiation at 5=3.55 ppm (H-4), b) irradiation at 5=3.19 ppm (H-2), c) off-resonance spectrum 64 Figure 3.15. N O E difference experiment on photoproduct 44 a) irradiation at 5=1.66 ppm (H-9), b) irradiation at 5=1.97 ppm (H-9'), c) off-resonance spectrum 65 Figure 3.16. Selected N O E correlations used for ester 44 stereochemistry determination 66 Figure 3.17. 1 3 C N M R spectra a) of P-keto ester 28 before irradiation; b) of the resulting reaction mixture immediately after irradiation at 0°C for 130 min.; c) of the same reaction mixture after staying 3 days at room temperature 67 Figure 3.18. Two faces of enol (enolate) protonation leading to two possible epimeric products 69 Figure 3.19. Base-catalyzed epimerization of photoproduct 42 70 Figure 3.20. X-ray crystal structure of P-keto ester 28 73 Figure 3.21. 1,4-hydroxybiradical 74 Figure 3.22. Solution state photolysis of P-keto ester 34 75 Figure 3.23. a) Partial H M B C spectrum (500 MHz, CDC13) of photoproduct 47A b) Partial COSY spectrum (500 MHz, CDC13) of photoproduct 47A 78 Figure 3.24. Partial COSY spectrum (500 MHz, CDC13) of photoproduct 47A 79 Figure 3.25. N O E difference experiment on photoproduct 47A a) irradiation at 5=3.43 ppm (H-4), b) irradiation at 6=2.51 ppm (H-2), c) irradiation at 6=2.57 ppm (H-9'), d) irradiation at 5=2.93 ppm (H-3), e) irradiation at 5=2.41 ppm (H-l), f) off-resonance spectrum 80 Figure 3.26. Selected N O E correlations used for ester 47A stereochemistry determination. 82 Figure 3.27. a) Partial H M B C spectrum (500 MHz, CDC13) of photoproduct 47B b) Partial COSY spectrum (500 MHz, CDC13) of photoproduct 47B 84 Figure 3.28. Partial COSY spectrum (500 MHz, CDC13) of photoproduct 47B 85 Figure 3.29. Partial ! H N M R spectra (400 MHz, CDC13) of a) photoproduct 47B; b) photoproduct 47A 87 Figure 3.30. NOE difference experiment on photoproduct 47B a) irradiation at 5=2.92 ppm (H-3), b) irradiation at 6=2.41 ppm (H-l) , c) irradiation at 5=3.44 ppm (H-4), d) irradiation at 5=2.51 ppm (H-2), e) off-resonance spectrum 89 Figure 3.31. Selected NOE correlations used for ester 47B stereochemistry determination 90 xi Figure 3.32. Solid state photolysis of P-keto ester 34 90 Figure 3.33. X-ray crystal structure of P-keto ester 34 93 Figure 3.34. The suggested absolute configurations of 47A and 47B 94 Figure 3.35. A simplified kinetic scheme for the formation of diastereomers 47A and 47B 96 Figure 3.36. Photochemistry of P-keto ester 35 97 Figure 3.37. The *H N M R spectrum (400 MHz, CDC13) of a) photoproduct 49A; b) photoproduct 49B 99 Figure 3.38. Partial H M B C spectrum (500 MHz, CDC13) of photoproduct 49A 101 Figure 3.39. Partial COSY spectrum (500 MHz, CDC13) of photoproduct 49A 102 Figure 3.40. N O E difference experiment on photoproduct 49A a) irradiation at 5=3.44 ppm (H-4), b) irradiation at 5=2.53 ppm (H-2), c) off-resonance spectrum 103 Figure 3.41. Partial H M B C spectrum (500 MHz, CDC13) of photoproduct 49B 104 Figure 3.42. Partial COSY spectrum (500 MHz, CDC13) of photoproduct 49B 105 Figure 3.43. NOE difference experiment on photoproduct 49B a) irradiation at 6=3.43 ppm (H-4), b) irradiation at 5=2.52 ppm (H-2), c) irradiation at 5=1.75 ppm (H-8), d) off-resonance spectrum 106 Figure 3.44. Selected NOE correlations used for ester 49A stereochemistry determination 107 Figure 3.45. Selected NOE correlations used for ester 49B stereochemistry determination 108 Figure 3.46. Photochemistry of p-keto ester 33 110 Figure 3.47. Photochemistry of salt 40 111 xii Figure 3.48. The ratios of enantiomers 42A and 42B formed in: a) photoreaction of P-keto ester 28, b) solid state photoreaction of chiral salt 40, followed by diazomethane work up 112 Figure 5.1. Photoreaction of P-keto ester 28 142 List of Tables Table 1.1. Theoretical ideal values of the geometrical parameters for hydrogen atom abstraction by an excited carbonyl oxygen 14 Table 1.2. Asymmetric induction in the solid-state photochemistry of salts 22(a-c) 26 Table 3.1. Conditions and product distribution for the photolysis of P-keto ester 28 42 Table 3.2. 1 3 C N M R data of intermediate 41 and cyclobutanol 45 68 Table 3.3. Geometrical parameters for y-hydrogen abstraction in p-keto ester 28 72 Table 3.4. Crystallographically derived biradical parameters for P-keto ester 28 74 Table 3.5. ! H N M R (500 MHz, CDC13) chemical shifts of the adamantane protons in 6-keto esters 42, 47A, and 47B 88 Table 3.6. Selected proton chemical shits of the adamantane fragments in compounds 44 and 48 91 Table 3.7. Transesterification of photoproducts obtained by photolysis of keto ester 34 97 Table 3.8. *H N M R (500 MHz, CDCI3) chemical shifts of the adamantane protons in S-keto esters 42, 49A, and 49B 100 Table 3.9. Results of the solid state photolysis of P-keto ester 35 109 Table 3.10. y-H abstraction distances in P-keto ester 35 crystals 109 Table 3.11. Methine proton chemical shifts for 6-keto esters 42, 47A/47B, 49A/49B, and a mixture of 50A/50B I l l Table 5.1. ^ H N M R data (400 and 500 MHz, CDCI3) for major photoproduct 42 145 Table 5.2. 125.8/500 M H z 1 3 C , ! H - shift correlations via H M Q C (one bond couplings) and H M B C (long-range couplings) for major photoproduct 42 147 Table 5.3. lH N M R data (400 and 500 MHz, CDCI3) for photoproduct 43 150 xiv Table 5.4. 125.8/500 M H z 1 3 C , ! H - shift correlations via H M Q C (one bond couplings) and H M B C (long-range couplings) for photoproduct 43 152 Table 5.5. lU N M R data (400 and 500 MHz, CDCI3) for photoproduct 44 155 Table 5.6. 125.8/500 M H z 1 3 C , ! H - shift correlations via H M Q C (one bond couplings) and H M B C (long-range couplings) for photoproduct 44 157 Table 5.7. *H N M R data (400 and 500 MHz, CDCI3) for photoproduct 47A 167 Table 5.8 125.8/500 M H z 1 3 C , ! H - shift correlations via H M Q C (one bond couplings) and H M B C (long-range couplings) for photoproduct 47A 169 Table 5.9. lH N M R data (400 and 500 MHz, CDCI3) for photoproduct 47B 172 Table 5.10. 125.8/500 M H z 1 3 C , ! H - shift correlations via H M Q C (one bond couplings) and H M B C (long-range couplings) for photoproduct 47B 174 Table 5.11. lH N M R data (400 and 500 MHz, CDCI3) for photoproduct 49A 178 Table 5.12. 125.8/500 M H z 1 3 C , ! H - shift correlations via H M Q C (one bond couplings) and H M B C (long-range couplings) for photoproduct 49A 180 Table 5.13. lH N M R data (400 and 500 MHz, CDCI3) for photoproduct 49B 183 Table 5.14. 125.8/500 M H z ^ C ^ H - shift correlations via H M Q C (one bond couplings) and H M B C (long-range couplings) for photoproduct 49B 185 xv A C K N O W L E D G E M E N T S I would like to express my deepest gratitude to my research supervisor, Professor John R. Scheffer, for his valuable guidance, encouragement and support during the course of my research and in the preparation of this thesis. I would like to thank Marietta Austria and Liane Darge of the N M R laboratory, the staff of the Mass Spectrometry facilities, Mr Peter Bonda of the Elemental Analysis Laboratory and the Chemistry departmental staff. I am grateful to Eugene Cheung for the X-ray crystallographic analysis. I especially would like to thank Carl Scott for all his help and support, for proof-reading my entire thesis, and for being a great friend during my study at U B C . I am grateful to all past and present members of the Scheffer group for their friendship and support. Special thanks go out to Eugene Cheung, Ken Chong, Mathew Netherton and Kang Ting for their help during my work and preparation of this thesis. Finally, I would like to thank my family for their support and understanding. xv i Chapter 1. INTRODUCTION 1.1. General Considerations The design of reactions that yield optically active compounds is emerging as one of the most fascinating topics in modern organic chemistry. Asymmetric synthesis is increasingly becoming the normal mode of synthesis rather than the exception, and it is now usually possible to prepare compounds with excellent degrees of enantio- or diastereoselectivity using modern ground state synthetic methods.1'2 Asymmetric photochemistry unites the potentials and problems of enantioselective ground state chemistry and photochemistry. The following points summarize the advantages of photochemical processes. Light drives the reaction, which leads to the involvement of electronically excited states. Selective excitation of specific components in the system is made possible through the choice of wavelength. The substrate in its excited state usually exhibits reactivity that is completely different from that observed in the ground state. Because of the high energy introduced by the absorption of photons, only low activation energies are needed, making low-temperature experiments possible. Photoreactions often provide a direct and efficient route to one-step syntheses of thermally inaccessible or difficult-to-obtain compounds.3 A chiral influence in photochemical reactions in solution can be introduced by a variety of means: using circularly polarized light, chiral solvents, catalysts or complexing agents, chiral sensitizers, resolved chiral reagents or chiral auxiliaries.4 The use of a chiral 1 auxiliary - an optically active substituent appended to an achiral substrate - requires at least one equivalent of chiral source per substrate molecule. The additional steps, such as a substrate preparation and/or auxiliary removal are also unavoidable. Nevertheless, the high level of stereocontrol and the versatility of the process make the use of chiral auxiliaries one of the most attractive methods of asymmetric induction in photochemical synthesis. In recent years topochemically controlled photochemical processes in organized media have become of interest for asymmetric synthesis.5 Examples of organized media include crystals, polymer matrices, zeolites, micelles, and monolayers. These can dramatically alter the selectivity of photoproduct formation, as compared to the solution state. Of various types of organized media, the most extensive work has been done with the crystalline phase, where molecules are organized so that they are arranged in a repeating pattern in three dimensions. Absolute asymmetric synthesis in solid state photochemistry is based on the possibility that achiral molecules may crystallize in one of the sixty-five chiral space groups, thereby providing a chiral environment for the solid state reaction.6 However, crystallization of achiral compounds in chiral space groups is rather rare and unpredictable.5b A more practical approach to asymmetric synthesis in solid state reactions involves the use of the chiral auxiliary method. Compounds containing chiral auxiliaries are required to crystallize in chiral space groups, thereby introducing a rigid chiral environment which very often becomes the sole source of asymmetry in the photoreaction. . In recent years, the ionic chiral auxiliary method - with emphasis on its application in solid state asymmetric photosynthesis - has become one of the main research topics in 2 Dr. Scheffer's group.7 This thesis will focus primarily on the further development of covalent and ionic chiral auxiliary applications in the Norrish type II photoreaction of adamantyl aryl ketones. 1.2. Photochemistry of Ketones Ketones have perhaps undergone more photochemical investigations than any other class of compound.8 Since the ground state HOMO of a ketone is the n-orbital, the lowest energy transition that a ketone can undergo upon excitation is the n—»7t* type (Fig. 1.1). (a) a* 71* h v (b) a* 71* ISC (c) Figure 1.1. Electronic configurations of a ketone, showing the occupancy of carbonyl bond orbitals in: (a) the ground state, (b) the n ->7t* singlet excited state, and (c) the n -»7t* triplet excited state. 3 The n,7t* lowest energy singlets of aliphatic ketones undergo intersystem crossing to their n,7t* lowest energy triplets with rates <108 s"1, slow enough that some singlet reactions can occur. In contrast, the rapid (MO^s" 1) intersystem crossing in most aryl ketones usually produces exclusive triplet state reactivity. After excitation, three main types of reactions can occur: Norrish type I (a-cleavage), Norrish type II and photoreduction. The a-cleavage reaction of carbonyl compounds was studied in great detail by Bamford and Norrish and has become known as the Norrish type I reaction.9 The primary step in this reaction is the dissociation of a photoexcited carbonyl compound by cleavage of the bond between the carbonyl carbon and the a-carbon (Fig. 1.2). The occurrence of this process can be understood in terms of the weakening of the co-bond by overlap with the vacant n-orbital on oxygen.8 Cleavage is faster for ketones in which more stable radicals are formed. For example, acetone and benzophenone are relatively stable toward formation of products from a-cleavage, whereas methyl fert-butyl ketone and phenyl fert-butyl ketone yield a-cleavage products efficiently.10 An additional increase in reactivity is observed when strain is released, as in the case of cyclic ketones.11 Once cleavage has occurred, the radical pair produced has a variety of fates such as radical recombination, + •R Figure 1.2. The Norrish type I photochemical reaction. 4 disproportionation and decarbonylation. The latter occurs only when a very stable radical (e.g., tert-a\ky\ or benzyl) is formed or considerable strain is relieved in a cyclic system. Figure 1.3 represents an example of Norrish type I reaction of (S)-(+)-2-phenylpropiophenone.12 Ph H Pfi C H 3 racemization hv 3 retention Ph Pff^ X Ph H , , C H 3 disproportionation Ph H Ph N H Figure 1.3. The Norrish type I reaction of (S)-(+)-2-phenylpropiophenon Another reaction that can occur upon the photoexcitation of ketones is photoreduction, involving an intermolecular hydrogen atom abstraction. The primary products from intermolecular hydrogen abstraction by a ketone are a ketyl radical and radical of the hydrogen donor. Ketyl radicals may dimerize to give pinacols, undergo further hydrogen abstraction from a donor molecule to yield a secondary alcohol, or combine with the donor radical to yield an adduct (Fig. 1.4). The preferred final product depends upon the relative rate coefficients of the secondary processes and varies appreciably from system to system. 5 Figure 1.4. The photoreduction of ketones. The Norrish type II reaction involves an intramolecular y-hydrogen abstraction,14 resulting in the formation of a 1,4-hydroxy biradical that has been detected by laser flash photolysis and trapped by thiols or oxygen.15 Abstractions of P- and 5-hydrogens are usually observed only when no y-hydrogens are available for abstraction, reflecting the preference for regioselective abstraction via a six-membered rather than five- or seven-membered transition states.14b Once the 1,4-biradical is formed, it can react by three possible routes: (1) cleavage to form an alkene and enol which tautomerizes to a ketone, (2) Yang cyclization to a cyclobutanol, and (3) reverse hydrogen abstraction to re-form the original ketone (Fig. 1.5). 6 Factors that affect the partitioning of 1,4-biradicals between cleavage, reverse hydrogen transfer and cyclization have been reviewed by Scaiano et al16 Cleavage appears to be driven by the stereoelectronic necessity for overlap of the breaking bond with both singly occupied p orbitals of the biradical.17 Anything that prevents such molecular alignment retards or suppresses cleavage. Figure 1.6 shows various 1,4-biradical conformations, ranging from transoid through gauche to cisoid. The cisoid suffers eclipsing interactions about the middle carbon-carbon bond. In the transoid and cisoid conformations, all four carbon atoms are coplanar, and in the gauche, the y-carbon is rotated out of the plane of the other three carbons by 60° so as to relieve eclipsing about the central C-C bond. Owing to overlap considerations, the gauche and cisoid 1,4-biradical intermediates can undergo both cyclization and cleavage, while the transoid arrangement undergoes cleavage exclusively.14b 7 transoid gauche cisoid Figure 1.6. Conformations of the 1,4-biradicals. It has been shown that a-alkyl substituents in acyclic ketones greatly alter the cyclization/cleavage ratios. For example, a-methyl and a,oc-dimethyl substitution of valerophenone increases the percentage of cyclization from 10 to 29 and 89%, respectively.17b The increase in cyclization product formation has been attributed to nonbonded interactions present in the 1,4-biradical, affecting the ease with which the biradical can reach the conformation necessary for cleavage. 1.3. Retro-Aldol Ring Opening in Cyclobutanols The sequence of [2+2] photocycloaddition between an alkene and an enolized 1,3-dicarbonyl compound followed by a retro-aldol fragmentation of the initially formed cyclobutanol was discovered by deMayo and bears his name.18 Thus, irradiation of acetylacetone in the presence of cyclohexene yields an acylcyclobutanol which undergoes spontaneous retro-aldol ring-opening to give a 1,5-diketone (Fig. 1.7).19 8 XX —xx- O o Figure 1.7. The de Mayo reaction. Ring opening analogous to that in the de Mayo reaction has also been observed for Norrish/Yang type II cyclization products when the initially formed cyclobutanols contained acyl or alkoxycarbonyl groups.2 0'2 1 Hasegawa et al. studied the photochemical reactions of ot-alkyl P-keto esters.20 It has been found that irradiation of ethyl 2-benzoyl-4-methylvalerate (1) gives the products of Norrish type II cleavage (2) and cyclization (3) in 87% and 9% yield, respectively (Fig. 1.8). A small amount of another product, 5-keto ester 4, is also formed. Formation of the latter product was explained in terms of a retro-aldol ring opening of the cyclization product (3). Indeed, when heated in benzene, cyclobutanol 3 rearranged easily and quantitatively to 5-keto ester (4) (Fig. 1.9). 'OEt / COOEt + 1 2 3 4 Figure 1.8. The photoreaction of ethyl 2-benzoyl-4-methylvalerate. 9 Figure 1.9. The retro-aldol ring opening in photoproduct 3. Formation of cyclobutanol 3 with its hydroxyl group cis to the ethoxycarbonyl group was explained by a neighboring group effect in the 1,4-biradical cyclization. The hydroxyl group in the 1,4-biradical intermediate is expected to be located so that an intramolecular hydrogen bond is formed to the carbonyl oxygen of the ester substituent. Owing to this hydrogen bonding, the reverse hydrogen transfer is suppressed in the 1,4-biradical, so the quantum yield for disappearance of ethyl 2-benzoyl-4-methylvalerate was found to be unity. A retro-aldol ring opening of Norrish/Yang type II cyclization products has also been observed in the photoreaction of 2-benzoyl-2-methyl-l-tetralone (5) (Fig.1.10).21 The cyclobutanol 6 could not be detected or isolated due to its thermal instability. 70% yield Figure 1.10. The photoreaction of 2-benzoyl-2-methyl-1-tetralone. 10 1.4. Solid State Reactions. Crystal Structure-Solid State Reactivity Correlation Method. Chemical reactions that take place in the crystalline state occur with a minimum of atomic and molecular motion. This concept, originally formulated by Kohlschutter 2 2 and elaborated by Schmidt,23 Cohen,2 4 and most recently by Weiss et al.25 is known as the topochemical postulate. The topochemical postulate derives from the fact that molecules in crystals are densely packed, so that the motions of any given molecule in the lattice are resisted by the presence of its neighbors. Solid state reactions often differ from reactions in fluid phases, where atomic and molecular motions do not have such restraints. The selectivity of organic reactions in solution is controlled by electronic and steric effects, while reaction selectivity in the solid state is governed mainly by two important factors: the conformation and the packing arrangement of reacting molecules. In contrast to isotropic media, in which an organic molecule may adopt many conformations, molecules in crystals rarely adopt more than one conformation, which is usually the minimum energy conformation. The limited molecular motion and packing of the reactant in crystals will consequently affect conformationally sensitive reactions and can greatly alter the product distribution that would normally be observed in liquid phase photoreactions. It is difficult to obtain accurate pictures of the prereaction shapes and orientations of conformationally mobile organic molecules in solution or the gas phase. However, in the solid state, such elucidations have been facilitated by X-ray crystallography. This technique gives an intimate picture of the reactant molecules and their surroundings prior to reaction. Since solid state reactions occur with a minimum of atomic and molecular motion, these structural 11 data can give insights into the corresponding transition states and intermediate structures. The Crystal Structure-Solid State Reactivity Correlation method involves the correlation of such structural data with observed solid state reactivity for a series of closely related compounds. As a result, the geometric parameters for reaction can be deduced. It is well established that intermolecular packing arrangements play an important role in controlling solid state bimolecular reactions. In the pioneering work of G.M.J. Schmidt and co-workers on the geometric requirements for the [2+2] photocycloaddition reaction of cinnamic acids, the distance and angular requirements for the reaction were established and the structure and stereochemistry of the products were shown to be directly related to the molecular structure as it exists in the bulk crystal.23 The Solid State Structure-Reactivity Correlation method was also applied to an intramolecular reaction in order to elucidate the geometric requirements for the Norrish type II reaction.26'7b 1.5. Geometric Requirements for Intramolecular Hydrogen Atom Abstraction The geometry of hydrogen abstraction by the triplet (n,7T*) excited state is crucial in determining if such a reaction will take place. As depicted in Figure 1.11, the hydrogen abstraction geometry can be described by four parameters.263 12 Figure 1.11. Parameters defining the spatial relationship for the abstraction of a hydrogen atom by the carbonyl oxygen atom. d=distance between hydrogen and oxygen, O H ; 0= O H-C angle; A= C=0 H angle and co= dihedral angle formed between the O-H vector and its projection on the nodal plane of the C=0 group. The first of these parameters is d, the distance between the carbonyl oxygen and the Y-hydrogen (C=0"'Hy). It has been suggested that the optimum value of d should be close to 2.12k, the sum of the van der Waals radii for oxygen and hydrogen. The second parameter is given by the symbol A and is defined as the C=0 H y angle. The optimum value of A should lie between 90-120°, depending on the hybridization of the orbitals containing the non-bonding electrons on oxygen.2 6 a The third parameter, 0, is defined as the C - H r O angle. According to theoretical studies, a linear C-H y ' "0 arrangement (0=180°) is the preferred orientation.27 The fourth parameter is co, the angle by which the y-hydrogen atom lies outside the mean plane of the carbonyl group. Since the non-bonding orbital involved in the abstraction lies in the nodal plane of the % bond, the ideal value of co is expected to be 0° . 2 8 The ideal values of the geometrical parameters for effective hydrogen atom abstraction by the carbonyl oxygen are summarized in Table 1.1. 13 Table 1.1. Theoretical ideal values of the geometrical parameters for hydrogen atom abstraction by an excited carbonyl oxygen. d(A) «(°) A(°) e o <2.72 0 90-120 180 In extensive work by Scheffer and co-workers on the elucidation of the geometric requirements for y-hydrogen atom abstraction, three separate systems were studied by the 26a Crystal Structure-Solid State Reactivity Correlation method: a-cycloalkylacetophenones, macrocyclic diketones,26b and cyclohexyl/adamantyl aryl ketone derivatives.26c'd'7b In all systems studied, similar structure-reactivity relationships were seen. Thus, for seventeen various substituted compounds having the basic a-cycloalkylacetophenone structure, the crystallographically determined abstraction distance d was found to be 2.74+0.16A, with co=43+9° and A=84+8° (6 was not calculated).263 For eleven photochemically reactive medium and large ring aliphatic diketones, whose crystal structures were determined, the 'average value of d was 2.7310.03A with co=52±5°, A=83+4°, and 9=115+2°. 2 6 b For the cyclohexyl/adamantyl aryl ketones the corresponding values were d=2.63+0.06A, co=58+3°, A=81±4°, and 6=114+1 °. 7 b The results listed above indicate that abstractions are indeed preferred when the C = 0 - H y distance is close to the sum of the van der Waals radii of hydrogen and oxygen. This does not mean that hydrogen abstraction is limited to such distances. A value of d as great as 3.09 A was found for a compound that undergoes efficient Norrish/Yang type II 14 photochemistry. In contrast, the prediction that the y-hydrogen should lie in the same plane as the oxygen n-orbital (o=0°) is not consistent with the experimental data (co~50-60°). Wagner has suggested that the rate of type II hydrogen atom abstraction should show a cos^o dependence.29 Therefore, co can be quite large, but still lead to respectable rates of abstraction, e.g. when co=60°, cos2 60=0.25 and abstraction is predicted to occur at 25% of its maximum rate.266 The average experimental values of A (84°, 83° and 81°) are in reasonably good agreement with the hypothetical ideal value of 90-120°. Finally, the average experimental value for 6 (-115°) indicates that large deviations may be expected in this parameter. 1.6. Structure and Reactivity of 1,4-Hydroxybiradical Intermediates in the Norrish Type II Photoreaction Thorough investigation of the solid and solution state photochemistry of adamantyl aryl ketones revealed that in both media adamantyl aryl ketones bearing methyl substituents a to the benzoyl group undergo stereoselective Yang photocyclization to afford ewrfo-arylcyclobutanols (Fig. 1.12).2 6 c'd'7 b 15 hv CH 3 solid or solution Figure 1.12. Yang photocyclization of adamantyl aryl ketones. Since hydrogen atom abstraction in the solid state is likely to occur with a minimum of motion in the carbon framework, geometric data derived from X-ray crystallographic analysis could be also used to analyze the behavior of the 1,4-hydroxybiradical intermediates.711 In order to describe the structure of the biradical intermediate, two torsion angles were defined (Fig. 1.13). Assuming that the hybridization of the biradical centers is sp2, angle cpi was defined as the dihedral angle between the C2-C3 a bond and the p-orbital lobe on Ci with which it most nearly overlaps; cp4 was defined as the analogous angle involving the C2-C3 a bond and the most favorably oriented /?-orbital lobe on C 4 . Owing to the rigid adamantane carbon skeleton, the Ci-C 2-C 3-C 4 torsion angle is fixed at 63±1° (gauche). As was mentioned earlier, cleavage of 1,4-biradicals requires good overlap between the radical-containing p-orbitals and the C 2 - G 3 bond, i.e. (pi=(p4~0°. Failing that, and provided that C i and C 4 are within a reasonable distance of one another (D<3.40A, which is the sum of the van der Waals radii for two carbon atoms), cyclization of the 1,4-biradical occurs with "retention of configuration" at the Ci and C 4 carbons and leads directly to the major endo-ary\ photoproduct. The formation of exo-arylcyclobutanols requires sterically constrained 180° rotation about the C1-C2 bond, which is topochemically forbidden in the solid state. Only 16 traces of exo-products were detected in solution state photolyses of some 2-methyl-2-adamantyl aryl ketones. 1.7. Asymmetric Induction in Solution State Photochemistry: Covalent Chiral Auxiliary Approach Asymmetric synthesis is defined as a process that converts a prochiral unit into a chiral unit so, that unequal amounts of stereoisomeric products (enantio- or diastereomeric) result.30 Asymmetric photochemistry introduces the idea of enantio- or diastereo-differentiation into the reactions of electronically excited states or reactive intermediates. A chiral influence in solution state photochemical reactions can be introduced by several different means: using circularly polarized light, chiral solvents, chiral sensitizers, resolved chiral reactants and chiral auxiliaries. The last approach, where a chiral substituent in a photosensitive molecule may induce the preferential formation of one diastereomer, if a new chiral element is created in the photoreaction, has been investigated intensively in recent years. The great interest in this area of photochemical asymmetric induction is probably a Figure 1.13. 1,4-hydroxybiradical intermediate formed in the Norrish type II photoreaction of adamantyl aryl ketones. 17 reflection of the ease with which asymmetric induction using chiral substituents can be carried out and the wide range of substrates to which it can be applied..The chiral sources are usually selected from the pool of optically active natural products. The asymmetric induction in these reactions can be governed by several factors, including the steric, electronic and hydrogen-bonding interactions in the excited and/or ground states. Several types of intra- and intermolecular photochemical reactions have been utilized in studies of photochemical asymmetric induction by a chiral handle. Typical examples of such inductions are [2+2] photocycloadditions (Fig.1.14)31 and the Paterno-Buchi reaction of ketones with olefins (Fig. 1.15)32 Ph CH302. 1) hv Ph V 2) H + , MeOH C02(-)-bornyl Ph. Ph v NC02Me Ph^ + VC0 2Me Ph >C02Me C02Me 20% ee 90-94% ee Figure 1.14. Asymmetric induction in a [2+2] photocycloaddition. O H3C CH3 hv H3C H3C-CH. Ph 7 C02R* -O CH3 R*= (-)-8-Phenylmenthyl yield 42% (>96% de) Figure 1.15. Asymmetric induction in the Paterno-Buchi reaction. 18 Asymmetric induction in solution phase photolyses was extended to reactions involving hydrogen abstraction and subsequent radical coupling, however, only relatively low diastereoselectivities were achieved for this type of photoreaction. Thus, photolysis of (-)-menthyl 2-acetylbenzoate in 2-propanol leads to hydrogen abstraction from the solvent, followed by dimerization of the resulting arylhydroxyethyl radicals, giving unstable diastereomeric dl- and meso- pinacols (Fig. 1.16).33 The spontaneous lactonization of the pinacols eliminates the chiral auxiliaries and produces a 1:1 mixture of dl- and ineso-dilactones in good chemical yield (80%). The de of the final product 7 is temperature-dependent, ranging from 19-22% between 55 and -6°C. dl meso meso 7 Figure 1.16. The photoreaction of (-)-menthyl 2-acetylbenzoate. A better diastereoselectivity has been observed in some photocyclization reactions 19 that proceed via intramolecular hydrogen abstraction. Thus, photocyclization of chiral N-(2-benzoylethyl)-N-tosylglycinamides 8 and 11 leads to the formation of 3-hydroxyprolines 9, 10 and 13, respectively (Fig. 1.17).34 The first reaction proceeds with 7.3:1 selectivity and the second leads to a single photoproduct, probably as a result of the steric influence of the auxiliary in the 1,5-biradical intermediate 12 formed by hydrogen abstraction. Figure 1.17. Asymmetric induction in the photocyclization of 8 and 1 1 . 20 1.8. Asymmetric Induction in Solid State Photochemistry In solid state asymmetric photochemistry the chiral influence is provided by the rigid crystal environment. While all resolved chiral molecules must crystallize in chiral space groups, achiral molecules do not necessarily have to crystallize in an achiral space group and may crystallize in one of the 65 chiral space groups.5b Therefore, enantiomorphously pure crystals can provide optically active environments for solid state asymmetric photoreactions. This process, which proceeds from a prochiral starting material to a chiral product without using any externally imposed chiral reagent, is termed as absolute asymmetric synthesis.6 The first absolute asymmetric synthesis was reported by Penzien and Schmidt in 1969.35 It was shown that achiral 4,4'-dimethylchalcone 14 crystallizes spontaneously in the chiral space group P 2 , 2 i 2 , . When single crystals of this compound are treated with bromine vapor, the chiral dibromide 15 is produced in 6% enantiomeric excess (Fig. 1.18). Thus, it is the reaction medium, the chiral crystal lattice, that provides the asymmetric influence that favors the formation of one enantiomer over the other. Br Ar=p-tolyl 14 15 Figure 1.18. Solid state asymmetric brornination of 14. 21 Scheffer et al. employed absolute asymmetric synthesis in the Norrish type II photoreaction.36 Solid state photolysis of achiral adamantyl ketone 16, which crystallizes in the chiral space group P21212,, led to the formation of cyclobutanol 17 in 80% enantiomeric excess (Fig. 1.19). Another example of an absolute asymmetric photorearrengement reaction in the solid state - the photochemical conversion of achiral a-oxoamide derivative 18 - was originally discovered by Aoyama et al.31 and extensively studied by Toda with co-workers.38 Compound 18 crystallizes in the chiral space group P2,2121 and when irradiated yields chiral (3-lactam alcohol 19 in 93% enantiomeric excess. Figure 1.19. Unimolecular absolute asymmetric photoreactions in crural crystals. Although the crystallization of achiral molecules in chiral space groups is well documented, it is rare and unpredictable. Even rarer is to find materials exhibiting this behavior that also react chemically in the solid state and produce chiral products. As a result, very few absolute asymmetric syntheses have been reported. 22 A more practical approach to enantiomerically enriched products in solid state reactions involves the use of a "chiral handle" - an optically active auxiliary which forces the compound to crystallize in a chiral space group. One example of a chiral handle application concerns the asymmetric photodimerization of benzene 1,4-diacrylates.39 The chiral see-butyl group was used to induce the compound to crystallize in a chiral space group. When a solid sample of ethyl ester (S)-(+)-20 was irradiated at 5°C, the chiral dimer, HP (S)-(+)-20 Figure 1.20. Asymmetric induction in the solid state [2+2] photocyclization of (S)-(+)-20. 23 trimer and higher polycyclobutane oligimers were obtained in high optical yields approaching 100% (Fig. 1.20). Irradiation of the enantiomeric R-(-)-20 isomer yielded products showing optical rotations of the same magnitude but of opposite sign. The ambiguity that the asymmetry of the products was induced by the chiral handle instead of being the result of the chiral crystal environment was resolved by an experiment in which the ethyl group in the optically pure ester 20 was replaced by a methyl group. This compound, 21, crystallized in a chiral space group P2j with two molecules in the asymmetric unit related by a pseudo centre of symmetry. Irradiation of a solid sample of compound 21 results in the formation of two diastereomers, that after removal of the sec-butyl group, yield a racemic mixture of two dimers (Fig. 1.21). This, suggests that the chiral crystal environment alone controls the chirality of the cyclobutane products, and the role of the chiral handle is only to drive the monomers to a chiral space group. COOsec-Bu Figure 1.21. Solid state [2+2] photocyclization of compound 21. 24 Another general approach to utilizing crystal chirality in asymmetric synthesis was developed by Scheffer et al. and involves the use of ionic chiral auxiliaries.7 This approach is based on the simple idea that an achiral compound containing a carboxylic acid group could be forced into a chiral space group by formation of a salt with an optically active amine. If the carboxylate-containing portion of such a salt can undergo a photochemical reaction that generates at least one new chiral centre, the photolysis of this salt in the solid state followed by esterification of the products would lead to mixture whose enantiomeric excess provides a measure of the extent of asymmetric induction by the crystalline medium. The opposite approach, in which the cationic component of the salt is the photoreactant and the anion is the chiral auxiliary, is equally valid. There are several advantages to working with salts, such as their high melting points and strong lattice forces compared to purely molecular crystals. This permits the reactions to be carried out to higher conversions without crystal breakdown. The ease of removing of the ionic chiral auxiliaries makes this method even more attractive compared to the covalent chiral auxiliary approach. A great deal of work involving the application of the ionic chiral auxiliary method to asymmetric induction in the solid state has been carried out.40 Some results of an asymmetric version of the Norrish type II photoreaction of 2-methyl-2-adamantyl aryl ketones are given in Figure 1.22 and Table 1.2. 7 b While not all of the optically active amines tested gave good results, most worked reasonably well and some gave excellent results. Enantioselectivity was found to increase with decreasing temperature, but significantly longer irradiation times were 25 required. The enantiomeric excesses were found to decline with increasing conversion, although for many salts ee's of 80% and higher could be obtained at nearly complete conversion. None of the salts gave any detectable asymmetric induction upon photolysis in methanol or acetonitrile. 22(a-c) Figure 1.22. Use of an ionic chiral auxiliary in the solid state Norrish type II photoreaction. Table 1.2. Asymmetric induction in the solid-state photochemistry of salts 22(a-c). amine conversion, %, temp. ee, % (S)-(-)-a-methylbenzylamine (22a) 13.5%, room temp. (+)-87.5 64%, room temp. 86.0 19.9%, -40°C 88.2 (R)-(+)-a-methylbenzylamine (22b) 3.5%, rom temp. (-)-88.0 82.3%, room temp. 82.4 22.6%, -40°C 87.3 (lR,2S)-(-)-norephedrine (22c) 2.9%, room temp. 87.8 26.8%, room temp. 74.8 7.8%, -40°C 87.9 26 1.9. Research Objectives The present study is an extension of previous work from our laboratory on the Norrish/Yang type II photoreaction of adamantyl aryl ketones. As shown in the introduction, solution and solid state photolysis of 2-methyl-2-adamantyl aryl ketones led to the stereoselective formation of erafo-arylcyclobutanols (Fig. 1.12). On the other hand, a-unsubstituted ketones were found to be completely unreactive. X-ray crystallography revealed that, regardless of the nature of the a-substituent, adamantyl aryl ketones adopt conformations in which the mean plane of the carbonyl group is roughly orthogonal to the plane bisecting the cyclohexane ring between the y-hydrogen atoms. As a result, one of these hydrogen atoms is closer to the carbonyl oxygen and therefore more favorably oriented for abstraction than the other. Asymmetric induction studies were carried out by providing the reactant with carboxylic acid substituents to which ionic chiral auxiliaries were appended via salt formations with optically active amines (Fig. 1.22). Irradiation of these salts in solution gave racemic cyclobutanols, while in the crystalline state moderate to near-quantitative enantiomeric excesses were obtained. Our interest to extend the studies of adamantyl aryl ketones to systems where the a-methyl substituent is replaced by the alkoxycarbonyl group was driven by two main reasons. First, we were interested in the possibility of obtaining different photoproducts, since in the case of a-alkoxycarbonyl substituted adamantyl aryl ketones, the initially formed cyclobutanols can undergo a retro-aldol ring opening to afford the corresponding 5-keto 27 esters, which are expected to be photochernically inert, owing to the lack of substituents a to the carbonyl group. Second, asymmetric induction in such systems can be studied by the introduction of a "chiral handle" in form of esters of optically pure alcohols (covalent chiral auxiliary) or by forming salts of the corresponding carboxylic acid with optically pure amines (ionic chiral auxiliary). For photochemical reactions in solution, the covalent chiral auxiliary exerts a direct asymmetric influence governed by the steric, electronic and hydrogen-bonding interactions in the excited and/or ground state. For chemical reactions carried out in the solid state, the chiral handle ensures the presence of a rigid chiral environment by forcing the substrate to crystallize in a chiral space group. By comparing the difference in asymmetric induction in the solid state and solution, the relative importance of the direct versus the environmental effect for a given reaction may be determined. Thus, the first objective of the present research is to investigate how the replacement of an a-methyl substituent by a methoxycarbonyl group would alter the solution and solid state photochemistry of adamantyl aryl ketones. The second objective of this study is to correlate the reactivity of methyl |3-keto ester with its crystallographically derived structure. From the X-ray data it is possible to determine the y-hydrogen atom abstraction geometry and preferential behavior of the 1,4-hydroxybiradical intermediate. This information can be combined with the previous results to further extend the structure-solid state reactivity correlations for adamantyl aryl ketones. 28 The third objective is to use covalent chiral auxiliaries in the form of esters of natural chiral alcohols ((-)-menthol, (-)-borneol and (+)-fenchyl alcohol), and study their asymmetric influence on the solution and solid state photoreactions in question. For the solid state reactions X-ray crystallographic analysis can be used to correlate the results on asymmetric induction to the crystal structures of the chiral 3-keto esters. As an extension of this research topic, the relative importance of the direct and the environmental effects introduced by the chiral auxiliaries on the solution and solid state photoreactions may be determined. As the last goal of this study, the ionic chiral auxiliary approach is also to be tested on the asymmetric solid state photoreaction of the chiral salt of the corresponding (3-keto acid with optically active R-(+)-a-methylbenzylamine. 29 RESULTS AND DISCUSSION Chapter 2 . Preparation of Substrates 2.1. Methyl 2-Benzoyltricyclo[3.3.1.13'7]decane-2-carboxylate (28). Methyl 2-benzoyltricyclo[3.3.1.13'7]decane-2-carboxylate (28) was first synthesized by M . Netherton.41 Following his procedure ester 28 was prepared from adamantanone (23) (Aldfich), in a five step synthesis (Fig.2.1). The conversion of adamantanone (23), to 2-adamantane carboxylic acid (26) was previously described as a one-pot procedure by A.H.Alberts et al.42 The final step in the synthesis was a modified procedure developed by M.Rathke and J.Deitch for the preparation of P-keto esters from lithium ester enolates and acid chlorides43, in which N,N-dimethylpropyleneurea (DMPU) was added as a dipolar aprotic co-solvent. The ability of D M P U to solvate the lithium cation, thereby increasing the charge density on the enolate moiety, can lead to an enhancement of the eholate nucleophilicity.44 The NMR, mass, and IR spectra of ester 28 were identical to those obtained by M . Netherton and the structure was confirmed by X-ray crystallographic analysis. The U V spectrum of ester 28 in «-pentane showed an absorption band at 332 nm corresponding to an n-Tt* electronic transition. 30 CHOCH, Ph 3P=CHOCI-l3 H , 0 23 24 CHO COOH Jones^ reagent C H 2 N , 25 26 COOCH 3 LDA, THF, DMPU-78° i BzCI , -78°C * COOCH, C P h & 27 28 Figure 2.1. Synthesis of methyl 2-benzoyltricyclo[3.3.1.13,7]decane-2-carboxylate (28). 2.2. Chiral P-Keto Esters 33, 34 and 35 (-)-Menthyl 2-benzoyltricyclo[3.3.1.13'7]decane -2-carboxylate (33) (-)-Bornyl 2-benzoyltricyclo[3.3.1.13'7]decane -2-carboxylate (34) (+)-Fenchyl 2-benzoyltricyclo[3.3.1.13'7]decane -2-carboxylate (35) One of the goals of this research was to investigate the asymmetric induction by covalent chiral auxiliaries. Readily available natural chiral alcohols (-)-menthol, (-)-borneol, (+)-fenchyl alcohol were chosen for preparation of P-keto esters 33, 34, 35. Two synthetic approaches to chiral esters 33, 34, 35 were investigated. 31 2.2.1. Attempted Preparation of Chiral Esters via Transesterification of p-Keto Ester 28 GHgOH Figure 2.2. Attempted transesterification of methyl ester 28. Originally, transesterification reaction of methyl P-keto ester 28 was considered as a possible route to the desired chiral P-keto esters 33, 34 and 35. However, attempts to transesterify methyl P-keto ester 28 using />toluene sulfonic acid or sodium ethoxide as catalysts were unsuccessful. Depending on the reaction conditions and amount of catalyst used, compound 28 either failed to react or gave a product of cleavage at the ketone group under basic catalysis. Acid catalyzed transesterification of P-keto ester 28 always led to the appearence of a decarboxylation product (Fig. 2.3). 28 Figure 2.3. Decarboxylation or cleavage at the ketone group of P-keto ester 28. 32 Employing tetraisopropyl and tetraethyl titanates, recommended as exceptionally mild and efficient catalysts for transesterification,45 was also unsuccessful. No products of transesterification were detected. 2.2.2. Preparation of Chiral Esters via Low Temperature Acylation of Corresponding Ester Enolates with Benzoyl Chloride 30 (R= (-)-menthyl); 33 (R= (-)-menthyl); 31 (R= (-)-bornyl); 34 (R= (-)-bornyl); 32 (R= (+)-fenchyl). 35 (R= (+)-fenchyl). Figure 2.4. Preparation of chiral esters via low temperature acylation of their corresponding ester enolates with benzoyl chloride. The second route to chiral p-keto esters involved the esterification of the corresponding alcohols with acid chloride 29 (Fig. 2.4). Generation of the ester enolates at 33 low temperature followed by their acylation with benzoyl chloride could lead to the desired (3-keto esters. By analogy with the synthesis of ester 28, L D A was selected as the base for the chiral ester enolate generation. However, this attempt to prepare ester 33 afforded the desired product in only 11% yield, with 50% of starting ester 30 recovered. This problem was overcome by using a mixture of potassium diisopropylamide with lithium fert-butoxide as a nonnucleophilic base (KDA) known for its ability to deprotonate weakly acidic compounds that are unaffected by L D A . 4 6 Indeed, deprotonation of ester 30 at -78°C in THF with freshly prepared K D A , followed by acylation of the resulting enolate with benzoyl chloride, afforded (3-keto ester 33 in 81% yield. Employing K D A for the enolate generation of esters 31 and 32 gave the corresponding products, 34 and 35, in 74% and 72% yields, respectively. Chiral P-keto esters 33, 34, and 35 are new compounds and were fully characterized by spectroscopic and analytical methods. For esters 34 and 35 X-ray diffraction analyses were carried out. The ^ N M R spectra of P-keto esters 33, 34, and 35 are shown in Figure 2.5. 34 Figure 2.5. The 'H NMR spectra (500 MHz, CDC13) of a) P-keto ester 33; b) P-keto ester 34; c) P-keto ester 35. 35 2.3. Preparation of Chiral Salt of p-Keto Acid 36 Application of the ionic chiral auxiliary concept of asymmetric induction in the photochemical reaction of (3-keto acid 36 required the preparation of its salt with an optically active amine. Several synthetic approaches were tested in the preparation of chiral salt of P-keto acid 36. 2.3.1. Cleavage of p-Keto Ester 28 Figure 2.6. Attempted cleavage of p-keto ester 28. Cleavage of esters to furnish carboxylic acids is usually carried out in a routine manner by acidic or basic hydrolysis, however, treatment of ester 28 with lithium hydroxide in methanol-water solution47 at room temperature gave no products of hydrolysis. The possibility of ester 28 cleavage under mild, non-hydrolytic conditions was also investigated. Perhaps the mildest method for ester dealkylation involves the use of lithium thiomethoxide or lithium thiopropoxide in H M P A . 4 8 However, P-keto ester 28 did not react 36 with lithium thiomethoxide and gave decarboxylation product when treated with lithium thiopropoxide. Lowering the reaction temperature to -40°C and using a mixture of H M P A and THF as the solvent resulted in the formation of acid 36 in trace amounts while 90% of the starting material was recovered. An attempt to cleave ester 28 using a mixture of chlorotrimethylsilane and sodium iodide in acetonitrile was also unsuccessful.49 2.3.2. Carboxylation of Phenyl TricycIo[3.3.1.137]dec-2-yl Methanone Figure 2.7. Attempted carboxylation of ketone 37. Although carboxylation of ketones in the presence of D B U (Fig. 2.7) is claimed to be the best method for the preparation of P-keto acids, both in yield and convenience of procedure,50 attempts to carboxylate ketone 37 in the presence of 2 eq. of D B U at room temperature or 0°C, under normal or elevated pressures (5 kg/cm2 of C0 2 ) were unsuccessful. Direct reaction of ketone 37 with carbon dioxide, promoted by a mixture of triethylamine and magnesium chloride in THF, 5 1 also failed to afford the desired product. Only starting material was recovered. 37 2.3.3. Acylation of Acid 26 Dianion with Benzoyl Chloride A P . Krapcho has reported a two step procedure in which dianions of carboxylic acids were treated with acid chlorides to produce ketones after the decarboxylation of P-keto acids formed in situ (Fig. 2.8).5 2 However, the authors found that attempts to isolate pure p-keto acids led to irreproducible and erratic results. Following this procedure we were also unable to obtain reproducible results and isolate p-keto acid 36 in pure form. GC analysis of the reaction mixture after diazomethane workup always showed the presence of the methyl ester of unreacted acid 26, along with the methyl ester of acid 36, in ratios varying from 1 : 4 to 11 : 1. The presence of the other acidic components, such as unreacted acid 26 and benzoic acid (product of hydrolysis of unreacted acyl chloride) made this procedure unsuitable for the in situ preparation of chiral salts of P-keto acid 36. R 1R 2CHCOOH LDA *• R 1R 2CC00 2"2Li + R,COCI HCI Figure 2.8. Acylation of dianions of carboxylic acids. 38 2.3.4. Preparation of Salt 40 by Cleavage of terf-Butyl Ester 39 with C F 3 C O O H A simple and efficient procedure by M . W. Logue 5 3 for the preparation of P-keto acids via cleavage of the corresponding tert-buty\ esters with trifluoroacetic acid was modified to prepare a chiral salt of P-keto acid 36. Generation of P-keto acid 36 in situ, followed by its reaction with a chiral amine, R(+)-a-methylbenzylamine, at low temperature led to the formation of the desired chiral salt 40 (Fig. 2.9). COOH (COCI);, DMF^ C H 2 C I 2 COCI f-BuOH, Et 3N a C H 2 C I 2 COOf-Bu 26 29 Vh KDA T H F , - 7 8 ° C BzCI, -78°C* "COOf-Bu C F 3 C O O H o°c 38 39 36 R-(+)-q-Methylbenzy laming Q°C, E t 2 0 COO 6 e H 40 Figure 2.9. Preparation of salt 40 by cleavage of ter/-butyl ester 39 with CF 3COOH. 39 Salt 40 appeared to be stable at room temperature, however attempts to recrystallize it from methanol, dimethyl sulfoxide and acetonitrile resulted in decomposition. Decomposition was somewhat slower in chloroform. The lH N M R spectrum in CDCI3 and elemental analysis confirmed that salt 40 was a 1:1 complex. LSEVIS mass spectrometry gave an (M+l) + peak. The IR spectrum of salt 40 showed a strong, broad absorption arising from the asymmetrical and symmetrical stretching of the N H 3 + group, centered at 2950 cm"1 and extended by multiple combination-overtone bands. In addition, the absorption bands corresponding to asymmetrical and symmetrical N H 3 + group bending appeared at 1629 cm"1 and 1520 cm"1. The carboxylate ion group gave two bands at 1552 cm"1 and 1383 cm"1 resulting from asymmetrical and symmetrical 0)2 stretching, respectively. 40 Chapter 3. Photochemical Studies 3.1. Photochemical Studies of P-Keto Ester 28 3.1.1. Preparation of Photoproducts Photochemically-induced Norrish/Yang type II reactions of adamantyl aryl ketones have been thoroughly investigated by Scheffer et allh It has been found that 2-methyl-2-adamantyl aryl ketones undergo Yang photocyclization to afford cyclobutanols as the sole photoproducts both in solution and in the solid state. On the basis of the structural similarity between the previously studied adamantyl aryl ketones and P-keto ester 28, it was expected that the latter would undergo a Yang photocyclization reaction to afford cyclobutanol 41, which could then undergo a retro-aldol reaction to form the corresponding 5-keto ester (Fig.3.1). "COOCH3 28 C O O C H 3 41 Figure 3.1. Photoreaction of P-keto ester 28. 41 In preliminary investigations, M . Netherton showed that photolysis of P-keto ester 28 in solution and in the solid state led to the formation of one major and two minor photoproducts that were not identified.41 In this study the three photoproducts, 42, 43 and 44, were isolated and identified. According to GC analysis, the product distribution was slightly different for solution and solid state photolyses. In solution, the product distribution was found to be affected by changes in the concentration of P-keto ester 28 (Table 3.1). Table 3.1. Conditions and product distribution for the photolysis of P-keto ester 28.. Experimental conditions for photolysis Conversion o f starting compound 28 ratio of 42:43:44 C H 3 C N (1.5xl(T 2M) 93% 86:11:3 5 hr CH 3 CN(3 .7x lO- 4 M) 100% 80:0:20 30 min crystalline state, 1 hr 68% 88:3:9 All three photoproducts were isolated by radial chromatography and their structures were determined on the basis of analytical and spectral data. Elemental and high resolution mass spectroscopic analyses revealed that photoproducts 42, 43, and 44 are structural isomers of P-keto ester 28. The IR spectrum of each photoproduct showed two absorption bands, —1730 cm"1 and «1680 cm"1, corresponding to the ester and ketone carbonyl groups. Absorption bands in the O-H stretching region were not detected, confirming the absence of cyclobutanol 41. Additionally, the absence of olefinic hydrogen peaks in the ^ N M R spectra 42 of the photoproducts excluded the possibility that any of them was a product of a Norrish type II cleavage reaction. All three photoproducts had similar 1 3 C N M R spectra showing two downfield signals corresponding to the ketone (202-204 ppm) and ester (174-175 ppm) carbonyl groups. A group of four signals between 128 ppm and 137 ppm corresponded to the six monosubstituted phenyl ring carbons, three signals in the region between 52 ppm and 44 ppm corresponded to the methyl group and two carbons a to the carbonyls. The rest of the 1 3 C N M R spectrum for each photoproduct showed four methine and four methylene carbons, in perfect agreement with the suggestion that photoproducts 42, 43, and 44 are all 5-keto esters. The lH N M R spectra of these compounds are shown in Figures 3.2.a-3.2.c. 43 44 45 46 3.1.2. Determination of Photoproduct 42 Stereochemistry The *H and 1 3 C N M R signal assignments and stereochemical determination for photoproduct 42 were based on HMQC, H M B C , COSY and N O E difference experiment data. Selected spectral features of photoproduct 42 are shown in Figures 3.3-3.6. Correlation of the APT and H M Q C data revealed that photoproduct 42 contained six methine and four methylene carbons, consistent with its expected structure. In the *H N M R spectrum, of the six methine signals, five were well resolved and one partially overlapped with the signal from one of the methylene protons. From the H M Q C data two methine protons could be correlated with two methine carbons bearing the electron-withdrawing benzoyl and methoxycarbonyl groups, and were easily assigned along with the corresponding carbons by inspecting the H M B C plot. The proton with a chemical shift of 3.45 ppm showed a long-range correlation with the ketone carbonyl carbon at 202.04 ppm and was assigned as H-4. The part of the multiplet at 2.54-2.50 ppm showed a long-range correlation with the ester carbonyl carbon at 173.70 ppm and was assigned as H-2. The assignment of protons H-4 and H-2 was crucial for the assignment of the remaining adamantane skeleton protons. The H M B C plot showed that H-2 had long-range correlations with methine carbons at 28.30 ppm and 32.97 ppm, and that H-4 had long-range correlations with carbons at 47 32.97 ppm and 28.84 ppm. The signal at 32.97 ppm was assigned to C-3 since only this carbon showed the long-range correlations with both the H-4 and H-2 protons. The signals at 28.30 and 28.84 ppm were assigned to C-1 and C-5, respectively. Correlations of the corresponding protons, H-3, H - l , and H-5, obtained from the COSY plot, confirmed that these assignments were correct. The last methine carbon (5=27.50 ppm) and corresponding proton (5=2.01-2.02 ppm) were assigned as C-7 and H-7. Having all the methine protons and carbons assigned, the rest of the signals could be determined from H M Q C and COSY data. From the H M Q C spectrum, the pairs of methylene protons and their corresponding carbons were determined. Fortunately, for each pair, one of the protons gave a well resolved multiplet and could be easily assigned from the COSY and H M B C data. For example, one methylene proton, from a pair, gave a multiplet at 1.58-1.54 ppm and the COSY spectrum showed correlations of this proton with both H - l and H-5, with the H M B C specrum showing long-range correlations with carbons C-2 and C-4. Based on these data the mutiplet at 1.58-1.54 was assigned as H-9, and the second methylene proton (part of a multiplet at 2.54-2.50 ppm) was assigned as H-9'*; the corresponding carbon signal at 29.02 ppm was assigned as C-9. Assignment of H-10', H-6, and H-8 was based on COSY correlations with the corresponding methine protons, H-3, H-5, and H - l . Having H-10', H-6, and H-8 assigned, the further assignment of H-10, H-6', H-8', and consequently C-10, C-6, C-8, was easily accomplished. Finally, the ' H chemical shifts in the phenyl group could be assigned from the relative intensities of their signals and the appearance of the multiplets. These assignments were checked by interpretation of COSY and H M B C plots. * H' indicates the more downfield proton of the pair 48 The N O E difference spectra provided information about the stereochemistry of photoproduct 42 (Fig.3.5 and 3.6). Irradiation of H-4 caused an enhancement of H-15 (the proton in the ortho position of the phenyl ring), H-3, H-5, H-10' and H-6. Although the enhancement of the H-3, H-5 and H-15 signals could be possible with H-4 in either the equatorial or axial position, the enhancement of H-10' and H-6 clearly indicated that H-4 must be in the equatorial position, providing its spatial proximity with H-6 and H-10'. Unfortunately the H-2 signal was partially overlapped with the H-9' methylene proton signal. Irradiation of H-2 resulted in significant enhancements of the H-3, H - l and H-9 signals along with small enhancements of the H-8, H-10* and H-5 signals, proving that the N O E response from the irradiation of both H-2 and H-9' was detected in this case. Indeed, irradiation at 2.53 ppm, corresponding to the resolved part of the H-9' signal, led to strong enhancement of its geminal partner H-9 and weak enhancement of H - l and H-5. The comparison of these two spectra allowed the conclusion that the enhancement of the H-8 signal was a response to the irradiation of H-2, and proved the equatorial orientation of H-2. Strong enhancement of H-2 upon the irradiation of H-8 confirmed this conclusion. Since the H-10 signal was not well resolved in the original 'H NMR spectrum, its enhancement in the NOE difference spectrum was not used as an argument for the assignment of the H-2 position. 49 Figure 3.3. Partial HMBC spectrum (500 MHz, CDC13) of photoproduct 42. 50 Figure 3.4. Partial COSY spectrum (500 MHz, CDC13) of photoproduct 42. 51 a) 3 5 10'6 JL^, • —^r-L^AX-v b) 3 1 ~T^f ~ ~ 10 8 Figure 3.5. NOE difference experiment on photoproduct 42 a) irradiation at 5=3.45 ppm (H-4), b) irradiation at 5=2.50 ppm (H-2), c) irradiation at 5=2.54 ppm (H-9'), d) off-resonance spectrum 52 b) 3.6 —i— 3.4 3.2 3.0 2.8 2.6 24 ppm 2.2 —i— 2.0 1.8 1.6 —r 1.4 Figure 3.6. NOE difference experiment on photoproduct 42 a) irradiation at 5=1.81 ppm (H-8), b) off-resonance spectrum. 53 3.1.3. Determination of Photoproduct 43 Stereochemistry 17 The *H and 1 3 C N M R signal assignments and stereochemical determination for photoproduct 43 were based on HMQC, H M B C , COSY and N O E difference experiment data. Selected spectral features of photoproduct 43 are shown in Figures 3.8-3.10. Correlation of the APT and H M Q C spectra revealed that photoproduct 43 has six methine protons. In the *H N M R spectrum, five of these are well resolved and one is partially overlapped with the signal of a methylene proton. The methine proton at 3.64 ppm showed a 54 long-range correlation with the ketone carbonyl carbon (8=203.82 ppm) and was assigned as H-4. The methine proton with 8=2.73 ppm showed a long-range correlation with the ester carbonyl carbon (8=175.00 ppm) and was assigned as H-2. The corresponding C-4 (48.02 ppm) and C-2 (50.50 ppm) assignments were determined from the H M Q C plot. As for photoproduct 42, the assignment of H-2, C-2, H-4, and C-4 was crucial for the assignment of the remaining methine protons. H-3 (8=2.76 ppm) was assigned as being the only methine proton which showed a long-range correlation with both C-2 and C-4. H - l (8=2.42 ppm) showed a COSY correlation with H-2, while H-5 (8=2.25 ppm) was correlated to H-4. The last methine proton (part of the multiplet at 1.85-1.82 ppm) was assigned as H-7. In contrast to photoproduct 42, only two methylene proton signals were well resolved, with five signals very close to each other, and one signal partially overlapped with H-7. Having all of the methine protons and carbons assigned, it was possible to determine all methylene protons and the corresponding carbons using COSY, HMQC, and H M B C data. The H-3 proton showed COSY correlations with a pair of methylene protons, assigned as H-10 (8=1.51-1.48 ppm) and H-10' (8=1.97-1.94 ppm). H - l showed COSY correlations with two pairs of methylene protons at 1.73-1.70 ppm / 1.85-1.82 ppm and at 1.81-1.77 ppm / 1.93-1.88 ppm. The latter pair of methylene protons also showed a correlation with H-5 and was therefore assigned as the H-9 / H-9' pair. Inspection of the H M B C spectrum confirmed that the assignment was correct as the corresponding C-9 carbon showed long-range correlations with both H-4 and H-2. The other pair of methylene protons was assigned as H-8 and H-8'. Consequently the last pair of methylene protons was assigned as H-6 (8=1.56-1.53 ppm) and H-6' (2.21-2.18 ppm). 55 The stereochemistry at C-2 and C-4 was determined using the NOE difference data (Fig.3.10). Irradiation of H-4 resulted in a significant enhancement of H-15 and moderate enhancements of H-3, H-5 and H-9'. While the NOE response of H-15, H-3, and H-5 is possible for H-4 being in either the axial or equatorial position, the enhancement of H-9' will occur only if both H-4 and H-9' are in axial positions, thus allowing close spatial proximity. Irradiation of H-3 induced strong enhancements of H-4 and H-15, while moderate enhancements of H-10' and H-10 were observed. Irradiation of H-2 resulted in significant enhancements of H - l , H-8, and H-10 and very weak enhancements of H-4 and H-15. Since H-2 and H-3 were overlapped in the 400 MHz spectrum, the enhancements of H-4 and H-15 were likely induced by partial irradiation of H-3. The strong enhancement of H-8 and H-10 clearly indicate the equatorial position of H-2. The stereochemical assignments of H-4 and H-2 were also confirmed by COSY correlations where H-4 showed W-coupling with H-10 and H-2 showed a W-coupling with H-9. 56 4 2 J £_JJrt_jA*JwdJL A f • J t 0 6 e t i i « l * I I" » I' •t t ^ TIT 1 1 1 ppn 3 2 1 re 3.8. Partial HMBC spectrum (500 MHz, CDC13) of photoproduct 4 3 . Figure 3.9. Partial COSY spectrum (500 MFlz, CDC13) of photoproduct 43. 58 a) 15 3 5 9' b) C) d) J ' UL 1' icV 10 8 10 PI i 1 • 1 ' i 1 1 ' • i 1 1 1 ' i 1 1 • 1 1 1 •' • i •' • 1 1 • ' 1 1 1 • ' 1 ' i • • 1 ' i • ' ' ' i 1 ' ' ' i ' • 1 ' i 1 ' 1 ' i 1 ' 1 ' i ' 1 1 • i 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm Figure 3.10. NOE difference experiment on photoproduct 43 a) irradiation at 5=3.64 ppm (H-4), b) irradiation at 6=2.76 ppm (H-3), c) irradiation at 6=2.72 ppm (H-2), d) off-resonance spectrum. 59 Figure 3 .11. Selected NOE correlations used for ester 43 stereochemistry determination. 3.1.4. Determination of Photoproduct 44 Stereochemistry 11 12 C O O C H 3 The *H and 1 3 C N M R signal assignments and stereochemical determination for photoproduct 44 were based on HMQC, H M B C , COSY and NOE difference experiment data. Selected spectral features of photoproduct 44 are shown in Figures 3.12-3.15. . As observed for photoproducts 42 and 43, the *H N M R spectrum of 5-keto ester 44 showed six methine proton signals. Three of these were well resolved, two were overlapped with each other and one was overlapped with signals from methylene protons. Protons H-4 (3.55 ppm) and H-2 (3.19 ppm), attached to downfield methine carbons C-4 (52.11 ppm) and C-2 (44.53 ppm), were readily differentiated by their long-range correlations to the ketone 60 carbonyl carbon (203.36 ppm) and the ester carbonyl carbon (174.9 ppm) respectively. Methine protons H-3 (5=2.73 ppm), H-5 (5=2.29 ppm), and H - l (5=2.32 ppm) were differentiated following the logic used for the proton assignments in photoproducts 42 arid 43. The overlapping signal from the methine proton in the multiplet at 1.92-1.85 ppm was assigned to H-7. Five out of eight methylene protons present in compound 44 gave well resolved signals in the ' H N M R spectrum and could be readily assigned as H-10 (1.75-1.75 ppm), H-10'(2.07-2.04 ppm), H-8 (1.60-1.57 ppm), H-8'(1.82-1.79 ppm) and H-9 (1.68-1.64) using the same arguments as for compounds 42 and 43. According to the H M Q C and COSY spectra, the partially resolved signal at 1.97-1.94 ppm belonged to H-9', the geminal partner of H-9. This assignment was confirmed by N O E difference experiment data where a strong enhancement of H-9' was observed upon the irradiation of H-9. The multiplet at 1.92-1.87 ppm was made up of the methine proton H-7 and a pair of methylene protons H-6 and H-6'. Further differentiation of proton signals was not possible. The stereochemistry of photoproduct 44 was derived from N O E difference experiments (Fig.3.14 and 3.15). The equatorial position of H-4 was deduced from the moderate enhancement of H-10 when H-4 was irradiated. Irradiation of H-2 resulted in a moderate enhancement of H-9',. confirming their 1,3-diaxial arrangement. The spatial proximity of H-2 and H-9' was also confirmed by enhancement of the H-2 signal upon irradiation of H-9'. 61 1 4 0 i i i • 1 1 ! i I 160 170 180 190 200 3P • ppa 4.0 3.5 3.0 Figure 3.12. Partial HMBC spectrum (500 MHz, CDC13) of photoproduct 44. 62 Figure 3.13. Partial COSY spectrum (500 MHz, CDC13) of photoproduct 44. b) I I 9' c) • i • 1 1 1 i 1 1 • 1 i • ' ' ' i i 1 1 1 ' i i • • 1 1 i • ' • • i 1 1 1 1 i 1 ' 1 1 i ' • 1 ' i—r 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm Figure 3.14. NOE difference experiment on photoproduct 44 a) irradiation at 5=3.55 ppm (H-4), b) irradiation at 5=3.19 ppm (H-2), c) off-resonance spectrum 64 I • — I — 1 — 1 I I I I • — I • I • I ' I ' I ' • • . 5 3 5 6 5 « 11 i I ?.) ?.b ?.« 1.2 !.» > 3 16 ! i '. » ppm Figure 3.15. NOE difference experiment on photoproduct 44 a) irradiation at 5=1.66 ppm (H-9), b) irradiation at 8=1.97 ppm (H-9'), c) off-resonance spectrum 65 4, 11 12 ' C O O C K , 5 6 7 Figure 3.16. Selected NOE correlations used for ester 44 stereochemistry determination. 3.1.5. Mechanism of Photoreaction of p-Keto Ester 28 Products isolated from the reaction mixture after photolysis of P-keto ester 28 supported the suggestion that the photoreaction proceeds via a Yang cyclization of the initially formed biradical rather than through a Norrish type II cleavage. Gyclobutanol 41, presumably formed upon cyclization of the biradical, undergoes ring opening leading to 5-keto esters, the driving force of the reaction being the release of cyclobutane ring strain. Although cyclobutanol 41 was not isolated, its formation as a reaction intermediate was confirmed by a 1 3 C N M R experiment. 1 3 C N M R spectra of a P-keto ester 28 sample were recorded before and immediately after the irradiation at 0°C (Fig.3.17). The latter spectrum showed the presence of eighteen new signals among the known signals of the starting ester 28 and major photoproduct 42. These signals were attributed to the intermediate 41. A complete disappearance of the signals attributed to cyclobutanol 41, with a concominant increase of the signals due to photoproduct 42, was observed after keeping the N M R tube at room temperature for three days. The 1 3 C N M R spectrum of cyclobutanol 41 was very similar to that of cyclobutanol 45 obtained by M . Leibovitch7 b (Table 3.2). 66 a) b) uLi c) - i — • — i — • — i — • — i — ' — i — i — ' — i — i — • — i — 1 — i — • — i — 1 — i — 1 — i — 1 — i — • — i — • — i — ' — i — • — i — • — i — • — i — i — r 210 200 190 180 170 160 150 140 130 120 110 100 90 80 7 0 60 5 0 4 0 3 0 2 0 t> ppm Figure 3.17. C NMR spectra a) of p-keto ester 28 before irradiation; b) of the resulting reaction mixture immediately after irradiation at 0°C for 130 min.; c) of the same reaction mixture after staying 3 days at room temperature. 67 Table 3.2. C N M R data of intermediate 41 and cyclobutanol 45. 4 , , O H 1 & - > ^ - 2 \ ^ 12 13 C-x | 1 3 C NMR, (100.6 MHz, CD3CN), ppm 1 3 C NMR, (125.8 MHz), APT ppm C-x C-12 175.60 146.51 147.36(+ve) C-Ph C-Ph C-Ph C-Ph 129.85 127.77 126.05 125.57 129.43(-ve) 129.21(-ve) 126.88(-ve) 125.11(-ve) 124.52(-ve) C-Ph C-Ph C-Ph C-Ph C-Ph C-2 85.45 83.20(+ve) C-2 C-l 58.51 49.99(+ve) C-l C-13 52.14 45.84 36.22 35.92 35.00 34.85 33.95 32.12 29.76 25.82 46.54(-ve) 37.54(-ve) 37.25(-ve) 35.95(+ve) 35.15(+ve) 34.22(+ve) 31.16(+ve) 29.40(-ve) 25.88(-ve) 18.96(-ve) C-12 68 Retroaldolization of cyclobutanol 41 results in two possible epimeric products, 5-keto esters 42 and 44, depending on the face of protonation of the enol (enolate) formed (Fig.3.18). In extensive studies on the stereochemistry of ketonization of enols under kinetic conditions, it has been shown that steric hindrance to approach of the proton donor is a major factor in controlling from which face a proton is delivered to the a-carbon.54 Significant steric congestion on the top face A makes face B protonation more favorable and leads preferentially to the formation of P-keto ester 42. Figure 3.18. Two faces of enol (enolate) protonation leading to two possible epimeric products. The mechanism proposed above for the phototransformation of ester 28 can not afford photoproduct 43. However, epimerization of photoproduct 42 at the a-carbon during the photolysis appears to be a reasonable explanation for the formation of ester 43. Two different types of such epimerization may occur under the photoreaction conditions: a-cleavage of product 42, followed by a recombination of the radical pair formed, and a base (acid) catalyzed epimerization. The latter may be induced by the enol(ate) moieties generated during the retroaldolyzation of cyclobutanol 41 or by traces of base or acid in the solvent. Pi C O O C H 3 69 Although it has been shown that 2-adamantyl aryl ketones are photochemically stable and do not undergo a- cleavage upon photolysis,76 the photostability of photoproduct 42 was tested. Irradiation of ester 42 in acetonitrile for 4 hours, the usual duration of P-keto ester 28 photolysis, led to the appearance of a small peak on GC trace, corresponding to ester 43, with the ratio of the two being 96:4 (conversion 15%). Three other unidentified compounds with retention times greater than that for ester 42 were also detected in trace quantities. Such a low yield of ester 43 suggests that the photoepimerization of ester 42 can be only partially responsible for the formation of photoproduct 43 in photolysis of P-keto ester 28. In order to confirm the possibility of base-catalyzed epimerization of photoproduct 42, a sample of this compound was stirred with sodium methoxide in methanol for 2 days. The composition of the equilibrium mixture was determined as follows: 42 - 10%, 43 - 82%, 44 -5%, and 46-3% (Fig.3.19). * stereochemistry of 46 was not proven Figure 3.19. Base-catalyzed epimerization of photoproduct 42. The low yield of product 44 in the base catalyzed isomerization of 42 rules out the likelihood of any noticeable contribution of such a process in the photochemical formation of P-keto ester 44 from 28. The base catalyzed isomerization of ester 42 in CD 3 OD resulted in a 70 very similar distribution of equilibrium products. N M R spectra of isolated 42D and 43D showed almost complete isotopic exchange at the position a to the ketone group, while only traces of deuterium incorporation occurred at the position a to the ester group. Since both a-cleavage and base induced isomerizations appear to be possible, we could not differentiate which one of them is responsible for the formation of P-keto ester 43. However, the concentration-dependant yield of ester 43 in solution photolyses of 28 (Table 3.1) might indicate that base-induced epimerization of 42 is a more credible scenario for the formation of ester 43. 3.1.6. Geometric Parameters of P-keto Ester 28 from X-ray Crystallography The solid state photochemical reactivity of P-keto ester 28 can be correlated to its molecular geometry. Indeed, the geometric requirements for the y-hydrogen abstraction and 1,4-biradical reactivity toward the cyclization must be met in compound 28 in order to undergo the photochemical transformation leading to 5-keto esters 42 and 44. Earlier we discussed four geometric parameters associated with the y-hydrogen abstraction process, as well as the parameters associated with the ring closure or cleavage of the 1,4-hydroxybiradical. X-ray analysis of P-keto ester 28 revealed that only one y-hydrogen (H-x) lies within a reasonable distance (2.42 A) to be abstracted, with the next o closest hydrogen (H-y) being too far removed (3.2 A) for abstraction to occur (Table 3.3). 71 Table 3.3. Geometrical parameters for y-hydrogen abstraction in P-keto ester 28. Y - H d,(A) A, 0 e, 0 ideal 2.72 0 90-120 180 H -x 2.42 50.24 89.49 119.50 H-y 3.20 50.26 50.85 114.37 The angular parameters are also better for H-x abstraction than those for H-y. Therefore, the crystallographic data provide evidence for more favorable abstraction of H-x in the P-keto ester 28 molecule (Fig.3.20). Since hydrogen abstraction in the solid state is likely to occur with a minimal motion in the carbon frame, geometric relationships derived from X-ray crystallography can also be used to analyze the fate of the l,4-hydroxybiradical.7b The Yang photocyclization should be favorable when radical-containing carbon atoms Ci and C 4 are close to each other, probably within 3.40 A (sum of van der Waals radii for two carbon atoms). Therefore, the interatomic distance D is one of the parameters to be considered. Biradical cleavage is expected to be favorable when there is good overlap between the orbitals of the cleaving C2-C3 sigma bond and two p-orbitals at C 4 and Ci. Dihedral angles 91 and 94 can be used to estimate the overlap. Angle (pi is the dihedral angle between the C2-C3 sigma bond and the p-orbital on Ci. Angle 94 is the dihedral angle between the C2-C3 bond and p-orbital on C 4 (Fig.3.21). 72 Figure 3.20. X-ray crystal structure of P-keto ester 2 8 . Figure 3.21. 1,4-hydroxybiradical. Based on the cpi and cp4 values listed in Table 3.4, we can conclude that 1,4-hydroxybiradical is poorly aligned for cleavage which is favorable only when both 91 and q>4 approach 0°.On the other hand, D (3.05 A) is in the required range for cyclization, which is in agreement with the photoreactivity observed for p-keto ester 28. Table 3.4. Crystallographically derived biradical parameters for P-keto ester 28. a-p bond <P4,(°) 91, O D,(A) C 2 - C 3 30.1 75.1 3.05 74 3.2. Photochemical Studies of |5-Keto Ester 34 3.2.1. Solution State Photolysis of p-Keto Ester 34 c c 47B COO-(-)-bomyl COO-(-)-bomyl + Figure 3.22. Solution state photolysis of P-ketp ester 34. Irradiation of an acetonitrile solution of P-keto ester 34 led to the formation of two photoproducts, 47A and 47B (Fig. 3.22), which were isolated by radial chromatography from the reaction mixture. The structures of photoproducts 47A and 47B were determined based on their analytical and spectral data. Elemental and high resolution mass spectroscopic analyses revealed that photoproducts 47A and 47B have the same formula and mass as P-keto ester 34. The IR spectrum of each photoproduct showed the absorption bands corresponding to the ketone and ester carbonyl groups. Since the photoreaction of ester 34 is likely to proceed by the same mechanism as the photoreaction of ester 28, it was suggested that photoproducts 47A and 47B were diastereomeric 8-keto esters, with both the benzoyl and ester substituents being in axial positions analogous to photoproduct 42. Spectral data confirmed the stereochemistry proposed for photoproducts 47A and 47B. 75 3.2.2. Determination of Photoproduct 47A Stereochemistry 7 47A The ! H and 1 3 C N M R signal assignments and stereochemical determination for photoproduct 47A were based on APT, HMQC, H M B C , COSY and N O E difference experiment data. Selected spectral features of photoproduct 47A are shown in Figures 3.23-3.25. The assignment of the protons of the norbornane moiety was not important for the stereochemical determination of compound 47A, however, the norbornane proton signals were overlapped with the signals due to the adamantane hydrogens in multiplets at 1.93-1.87 ppm and 1.75-1.67 ppm. Therefore, the assignment of the norbornane protons was necessary to determine the signal composition of these multiplets. Differentiation of the norbornane protons was possible starting from the methine proton, H-12 (5=4.65-4.61 ppm), which showed an H M Q C correlation with downfield carbon C-12 at 80.32 ppm. Carbons C-17 (5=36.35 ppm) and C-14 (8=27.33 ppm) were assigned from their long-range 76 correlations with H- l2 . The corresponding methylene proton pairs H-17/H-17' and H-14/H-14' were attributed to signals at 1.19-1.16/2.38-2.32 ppm and 1.23-1.20/1.93-1.87 ppm (part of multiplet), respectively. The signal at 1.34-1.28 ppm showed a COSY correlation with H-14 and was assigned to H-15, leading to the assignment of C-15 and H-15' (part of a multiplet at 1.75-1.67 ppm). Hydrogen H- l6 (part of multiplet at 1.75-1.67 ppm) was assigned based on its COSY correlation with H-17. It was also possible to differentiate all three methyl groups. Carbon atom C-21 showed a long-range correlation with H-12. A moderate enhancement of the 0.84 ppm signal (H-20) was observed upon irradiation of H-14 in an NOE difference experiment. The signal at 0.86 ppm was assigned to the remaining H- l9 methyl protons. The key protons, H-4 and H-2, in the adamantane fragment were assigned from their long-range correlations with the ketone (202.31 ppm) and ester carbonyl (173.55 ppm) carbons, respectively. Carbon atom C-3 was assigned from H M B C correlations with both H-2 and H-4, leading to the assignment of H-3 (2.93 ppm). Hydrogens H - l (2.41 ppm) and H-5 (2.22 ppm) were differentiated via their COSY correlations with H-2 and H-4, respectively. The signal at 2.14-2.11 ppm showed COSY correlations with H-3 and H-4 and was attributed to H-10'. Its geminal partner H-10 was assigned as part of a multiplet at 1.93-1.87 ppm. Hydrogen H-9 (5=1.62-1.59 ppm) was assigned from its COSY correlations with H - l , H-4 and H-5; H-9' was subsequently attributed to the signal at 2.57-2.53 ppm. 77 4.4 L 4.6 4.8 • 5.0 3 ppm Figure 3.23. a) Partial HMBC spectrum (500 MHz, CDC13) of photoproduct 47A. b) Partial COSY spectrum (500 MHz, CDCh) of photoproduct 47A. 7 8 Figure 3.24. Partial COSY spectrum (500 MHz, CDC13) of photoproduct 47A. 7 9 a) b) c) d) e) 0 10'6 10 8 9 10'10 8*89 JL i ' •' • i ' ' " i ' ' ' ' i ' •" i ' ' " i •''' i ' ' • • i ••" i " " i ' •'' i ' ' •' i " •• i • •" i •• • • i ••" i 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3 0 2.5 2.0 1.5 1.0 0.5 ppm Figure 3.25: NOE difference experiment on photoproduct 47A a) irradiation at 5=3.43 ppm (H-4), b) irradiation at 6=2.51 ppm (H-2), c) irradiation at 5=2.57 ppm (H-9'), d) irradiation at 6=2.93 ppm (H-3), e) irradiation at 6=2.41 ppm (H-l), f) off-resonance spectrum. 80 Assignment H-6 (5=1.85-1.83 ppm) was derived from its COSY correlation with H-5 and led to the assignment of H-6' as part of the multiplet at 1.93-1.87 ppm. Hydrogen H-7 (2.02-2.01 ppm) was determined from its COSY correlations with H-6 and H-10'. These two protons also showed H M B C correlations with the carbon assigned as C-8, leading to the determination of H-8 (part of a multiplet at 1.75-1.67 ppm) and H-8' (part of a multiplet at 1.93-1.87 ppm). The stereochemistry at C-2 and C-4 was determined from the N O E difference data (Fig.3.25). Irradiation of H-4 resulted in a strong enhancement of H-24, moderate enhancements of H-3 and H-5, and weak enhancements of H-10' and H-6. The spatial proximity of H-4 to H-10' and H-6 is possible only when H-4 is in an equatorial position. The equatorial orientation of H-4 could also be confirmed by its W-coupling with H-9, observed in the COSY spectrum. Irradiation of H-2 resulted in a significant enhancement of H-3, weak enhancements of one signal in the multiplet at 1.93-1.87 ppm, one signal in the multiplet at 1.76-1.67 ppm, and H-9. Since the enhancement of H-9 is not possible for either equatorial or axial H-2, and the H-2 signal is partially overlapped with the H-9' signal in the *H N M R spectrum, the probable cause of the H-9 signal appearance was a partial irradiation of H-9'. Indeed, irradiation at 2.55 ppm, the resolved part of H-9' signal, resulted in strong enhancement of H-9, moderate enhancement of H-5, and weak enhancement of H - l . Irradiation of H-3 resulted in a strong enhancements of H-2, H-4 and H-24, and weak enhancements of H-10' and H-10 (part of the multiplet at 1.93-1.87 ppm). Comparison of the NOE difference spectra obtained upon irradiation of H-2 and H-3 showed that the enhancement of H-10 was observed in both experiments. Irradiation of H - l resulted in weak 81 enhancement of H-9 and weak enhancements of H-8 and H-8', both signals in multiplets at 1.76-1.67 ppm and 1.93-1.87 ppm, respectively. Comparison of the N O E difference spectra obtained upon the irradiation of H-2 and H - l showed that the enhancement of H-8 was observed in both experiments. The spatial proximity of H-2 to H-10 and H-8 is possible only for equatorially oriented H-2. Figure 3.26. Selected NOE correlations used for ester 47A stereochemistry determination. 82 3.2.3. Determination of Photoproduct 47B Stereochemistry 7 47B The *H and 1 3 C N M R signal assignments and stereochemical determination for photoproduct 47B were based on APT, HMQC, H M B C , COSY, and N O E difference experiment data. Selected spectral features of photoproduct 47B are shown in Figures 3.27 and 3.28. Differentiation of the norbornane protons was possible starting from the methine proton, H-12 (5=4.86-4.82 ppm), which showed a correlation with downfield carbon C-12 (5=79.32 ppm). Carbon atoms C-17 (6=36.17 ppm) and C-14 (5=27.22 ppm) were assigned from their long-range correlations with H-12. The corresponding methylene proton pairs H-17/H-17' and H-14/H-14' were attributed to signals at 0.81-0.78/2.18-2.11 ppm and 1.25-1.19/1.94-1.76 ppm (part of a multiplet), respectively. Assignment of H-15 was based on its COSY correlation with H-14 and led to the assignment of its geminal partner H-15', using H M Q C and COSY spectra. Methyl protons at 0.84 ppm and 0.86 ppm showed H M B C correlations with the methine carbon at 44.84 ppm, which was assigned to C-16. The corresponding H- l6 signal was partially overlapped with H-15' and one of the adamantane methylene protons. 83 2 L.. i c I i . 0 t UJjJ • f i 1 1 1 j Figure 3.27. a) Partial HMBC spectrum (500 MHz, CDC13) of photoproduct 47B. b) Partial COSY spectrum (500 MHz, CDC13) of photoproduct 47B. 84 Figure 3.28. Partial COSY spectrum (500 MHz, CDC13) of photoproduct 4 7 B . 85 Protons H-4 and H-2 in the adamantane fragment were assigned via their long-range correlations with the ketone and ester carbonyl carbons. Carbon C-3 was assigned from H M B C correlations with both H-2 and H-4, leading to the assignment of H-3 (5=2.92 ppm). Protons H - l (5=2.41 ppm) and H-5 (5=2.21 ppm) were differentiated via their COSY correlations with H-2 and H-4, respectively. The NOE difference spectrum obtained by irradiation of H-3 contained a signal at 2.18-2.11 ppm, assigned to H-10, and a signal arising from the multiplet at 1.94-1.76 ppm, assigned to H-10'. Hydrogen H-9 (1.66-1.55 ppm) was assigned from its COSY correlations with H - l and H-5. Its geminal partner, H-9', was subsequently attributed to the signal at 2.58-2.55 ppm. Irradiation of H - l resulted in a moderate N O E response of H-2 and weak enhancements of H-9 as well as two methylene protons which were assigned as H-8 (1.75-1.74 ppm) and H-8' (part of a multiplet at 1.94-1.76 ppm). The last methylene carbon of the adamantane skeleton showed a long-range correlation with H-10' and was assigned to C-6. The corresponding pair of methylene protons gave two signals in the multiplet at 1.94-1.76 ppm. A comparison of the lH N M R spectra for diastereomers 47A and 47B revealed that the proton chemical shifts of the their adamantane fragments were almost identical, and very close to those of 5-keto ester 42 (Fig.3.29, Table 3.5). The chemical shifts of some protons of the norbornane moiety were different for 47A and 47B, probably reflecting their different spatial arrangements with respect to the ester carbonyl group. 86 to d d CO o at d T -*-» o 3 -o 8 a. o +-» o -G CL oo O ~ a. m oi to ei ei oo (si cn o IO IO IO IO in IO 87 Table 3.5. *H N M R (500 MHz, CDC13) chemical shifts of adamantane protons of S-keto esters 42, 47A, and 47B. 42 47A 47B H-l 2.36(lH,m) 2.41(lH,s) 2.41(lH,s) H-2 part of m(2H) 2.54-2.50(lH) 2.51(lH,m) 2.52-2.51(lH,m) H-3 2.93(lH,s) 2.93(lH,s) 2.92(lH,s) H-4 3.45(lH,s) 3.43(lH,s) 3.44(lH,s) H-5 2.21(lH,s) . 2.22(lH,s) 2.21(lH,s) H-6 1.85-1.81(lH,m) part of m (5H) 1.93-1.83(1H) partofm(5H) 1.94-1.76(1H) H-6' partofm(3H) 1.95-1.86(1H) partofm(5H) 1.93-1.83(1H) partofm(5H) 1.94-1.76(1H) H-7 2.01-2.00(lH,m) 2.02-2.01(lH,m) 2.02(lH,s) H-8 1.74-1.69(lH,m) part of m (3H) 1.75-1.67(1H) 1.75-1.74(lH,m) H-8' part of m(3H) 1.95-1.86(1H) part of m(5H) 1.93-1.83(1H) partofm(5H) 1.94-1.76(1H) H-9 - 1.58-1.54(lH,m) 1.62-1.59(lH,m) part of m (3H) 1.66-1.55(1H) H-9' part of m(2H) 2.54-2.50(lH) 2.57-2.53(lH,m) 2.58-2.55(lH,m) H-10 partofm(3H) 1.95-1.86(1H) part of m(5H) 1.93-1.83(1H) partofm(5H) 1.94-1.76(1H) H-10' 2.13-2.09(lH,m) 2.14-2.11(lH,m) part of m (2H) 2.18-2.11(1H) N O E difference experiments provided information about the stereochemistry of 47B (Fig.3.30). Irradiation of H-4 resulted in moderate enhancements of H-24, H-3 and H-5, and weak enhancements of H-10'and H-6. The spatial proximity of H-4 to H-10' and H-6 proves its equatorial orientation. Irradiation of H-2 resulted in moderate enhancements of H-3 and H - l and weak enhancements H-8, H-10 and H-9. The latter was caused by the partial 88 a) 24 lO'lO b) e) J i i • i • i • • • i i i • • i i i i • < i • • • •• i • i 1 1 1 ' i 1 ' 1 1 1 1 ' • 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ' i 1 ' 1 1 1 1 ' • • i 8.5 8.0 7.5 7.0 6.5 . 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm Figure 3.30. NOE difference experiment on photoproduct 47B a) irradiation at 6=2.92 ppm (H-3), b) irradiation at 6=2.41 ppm fH-1), c) irradiation at 5=3.44 ppm (H-4), d) irradiation at 6=2.51 ppm (H-2), e) off-resonance spectrum. 89 irradiation of H-9' which is slightly overlapped with H-2 in the 400MHz ' H N M R spectrum. The NOE response of H-8 and H-10 confirmed their spatial proximity to H-2 and its equatorial assignment. Figure 3.31. Selected NOE.correlations used for ester 4 7 B stereochemistry determination. 3.2.4. Solid State Photolysis of p-Keto Ester 34 34 47B 48 Figure 3.32. Solid state photolysis of P-keto ester 34. Irradiation of a solid sample of p-keto ester 34 resulted in the formation of diastereomer 47B and photoproduct 48 in a ratio of 93:7 (Fig.3.32). Only traces of diastereomer 47A could be detected by T l N M R analysis. Unfortunately, isolation of 90 compound 48 in pure form was not achieved. Its enriched mixture with 47B was obtained by repeated radial chromatography of the reaction mixture with collection of the selected fractions. GC/MS analysis revealed that compound 48 has the same molecular ion as 47B. The IR spectrum showed two absorption bands corresponding to the ketone and ester carbonyls and no hydroxyl stretching band. Since, in the solid state photolysis of (3-keto ester 28, we observed the formation of ester 44 with the ester group in an equatorial position it was proposed that compound 48 was also a 8-keto ester with the benzoyl group in an axial and the ester group in an equatorial positions. As has been observed for diastereomers 47A/47B and 8-keto ester 42, identical stereochemistry results in a similarity of the chemical shifts of the adamantane protons. The similarity of the adamantane proton chemical shifts for compounds 44 and 48 serves as evidence of their analogous stereochemistry (Table 3.6). Table 3.6. Selected proton chemical shits of adamantane fragments of compounds 44 and 48. 44 48 H-1 2.32(lH,s) part of m (3H) 2.34-2.30(lH) H-2 3.19(lH,s) 3.13(lH,s) H-3 2.73(lH,s) 2.76(lH,s) H-4 3.55(lH,s) 3.55(lH,s) H-5 2.29(lH,s) part of m (3H) 2.34-2.30(lH) 91 3.2.5. Asymmetric Induction in the Solution and Solid State Photolysis of p-Keto Ester 34 Irradiation of an acetonitrile solution of P-keto ester 34 resulted in the formation of two diastereomeric 8-keto esters, 47A and 47B. These photoproducts were formed in a ratio of 57 : 43 as determined from the ^ N M R spectrum of the reaction mixture by comparing the signals of the protons a to oxygen in the norbornane moieties. A drastic change in the diastereoselectivity was observed in the solid state photoreaction, where chiral discrimination is provided by the rigid crystal environment. Diastereomer 47B was mainly formed and only traces of 47A could be detected. The high diastereoselectivity observed in the solid state photoreaction of P-keto ester 34 can be correlated to its crystal structure (Fig.3.33). It was determined from X-ray crystallographic analysis that only one y-hydrogen, H-x (d=2.50A), lies within the abstraction distance (d<2.72 A). The next closest hydrogen, H-y, is too far (d=3.38 A) from the carbonyl oxygen to be abstracted (Appendix I). Assuming that photoproduct 47B is the diastereomer formed by the topochemically favored abstraction of H-x, its absolute stereochemistry can be proposed (Fig.3.34). Surprisingly, the diastereoselectivity observed in the solution photolysis of P-keto ester 34 was the reverse of that observed in the solid state photoreaction, where diastereomer 47B was the major product. When a covalent chiral auxiliary is employed, the asymmetric induction can be governed by several factors including the steric, electronic, and hydrogen 92 bonding interactions in the excited and/or ground states. In the case of optically active P-keto ester 34, irradiation results in an (n,7t*) 1 excitation of the ketone carbonyl. Part of the excited state energy is lost by rapid intersystem crossing and the system passes into a (n,7c*)3 state of lower energy. The next step, y-hydrogen abstraction and 1,4-biradical formation, is highly efficient for aryl ketones. The 1,4-biradical of P-keto ester 34 can either undergo ring closure, forming the corresponding cyclobutanol, or reverse hydrogen transfer leading to the starting material, which by re-excitation joints the reaction cycle again. Thus, the possibilities for diastereoselection can be considered at different stages of the photoreaction. Figure 3.33. X-ray crystal structure of P-keto ester 34. 93 Hx abstraction HO P h COO-(-)-bornyl 'COO-(-)-bornyl HO y P h 'COO-(-)-bornyl cyclization P h . .,OH QO-(-)-bornyl HO. ,,Ph ring-opening .Ph COO-(-)-bornyl 47B ring-opening <\ / P h COO-(-)-bornyl 47A Figure 3.34. The suggested absolute configurations of 47A and 47B. The ground state of P-keto ester 34 in solution is composed of an equilibrium mixture of conformations favorable for H-x abstraction (34B) and conformations favorable for H-y abstraction (34A) (Fig.3.35). Molecular mechanics calculations M M + (HyperChem) predict that the free energy difference between the two lowest energy conformations leading to abstraction of H-x and H-y is only 0.8 Kcal/mol. Photoexcitation produces (instantaneously on the time scale of bond rotation) the mixture of excited conformers 34B* and 34A* in the same ratio as in the ground state. If a new conformational equilibrium is established in the excited state, it may or may not, be the same as the ground state conformational equilibrium. Under these circumstances, the ratio of the two possible biradicals formed (A and B) will depend on the free energy difference between the diastereomeric transition states (Curtin-Hammett principle55). However, if the excited state reaction (hydrogen abstraction) is faster than its conformational change, the ground state conformational equilibrium will control the diastereoselectivity of biradical formation.56 Moreover, the cyclization of the biradicals formed by abstraction of H-x and H-y proceeds via diastereomeric transition states of unequal energy. Thus, the closure may occur with different rates in competition with reverse hydrogen transfer, which leads to the formation of starting P-keto ester 34. The difference in partitioning ratios ^ c y c i . A ^ - H y vs ^ C y c i . B ^ - H x of biradical intermediates A and B can be the factor determining the diastereoselectivity observed in the solution state photolysis of P-keto ester 34. 95 47A 47B Figure 3 . 3 5 . A simplified kinetic scheme for the formation of diastereomers 47A and 47B. In order to remove the chiral auxiliaries, transesterification of 47A and 47B to the corresponding methyl esters by refluxing the reaction mixtures (solution or solid state) with indium iodide in methanol was attempted.57 The reaction was quite slow, taking several days even when a great excess of indium iodide was used. The chiral auxiliary could not be removed without epimerization at the C-4 carbon. A mixture of methyl esters 42 and 43, with the latter being the major product, was formed. Trace amounts of esters 44 and 46, products of epimerization at the C-2 carbon, were also detected. A determination of the enantiomeric composition 42A/42B of methyl ester 42 was possible using chiral GC. This ratio may differ from the ratio of diastereomers 47A/47B, since transesterification as well as epimerization of the diastereomers can occur with different rates. However, chiral GC analyses of methyl ester 42 showed that the enantiomeric ratios of 42A and 42B were the same within experimental error as the corresponding diastereomeric ratios of 47A and 47B (Table 3.7). 96 Table 3.7. Trasesterification of photoproducts obtained by photolyses of keto ester 34. Compound experimental conditions for photolysis conversion of starting material, diastereomeric ratio of photoproducts experimental conditions for transesterification ratio of recovered enantiomers, 42A:42B Ee, % 34 solution in C H 3 C N 2.5 hr 100%, 47A/47B: 57/43 a M 3 , MeOH reflux 3 days 55:45 10 34 solid state 40 min, room temp 100%, 47A/47B: 2/98 a I n l 3 , M e O H reflux 3 days <1:>99 99 a.-Determined by 1 H N M R analysis. 3.3. Photochemical Studies of p-Keto Ester 35 3.3.1. Preparation and Identification of Photoproducts 35 49A 49B Figure 3.36. Photochemistry of p-keto ester 35. Irradiation of an acetonitrile solution, as well as a solid sample of P-keto ester 35 led to the formation of two photoproducts, 49A and 49B (Fig.3.36), which were isolated by radial chromatography. The structures of compounds 49A and 49B were determined on the basis of their analytical and spectral data. Elemental and high resolution mass spectroscopic 97 analyses revealed that 49A and 49B have the same formula as p-keto ester 35, and the IR spectra of these photoproducts showed absorption bands corresponding to ketone and ester carbonyl groups. Since the mechanism of the phototransformation of ester 35 is likely the same as for esters 28 and 34, it can be suggested that photoproducts 49A and 49B are diastereomeric 8-keto esters with both ketone and ester substituents in axial positions. As observed for the ^ N M R spectra of photoproducts 47A and 47B, the proton chemical shifts of the adamantane fragments of 49A and 49B were almost identical and very close to those of S-keto esters 47A, 47B, and 42 (Fig.3.37, Table 3.8). This similarity made the proton and carbon signal assignments predictable and easy. As was done for compounds 47A and 47B, the proton and carbon signals in the *H and 1 3 C N M R spectra of 49A and 49B were assigned starting from methine proton H-12 for norbornane and H-2 and H-4 for the adamantane fragments. The assignment of the remaining protons and carbons was done in a way similar to that for esters 47A, 47B, and 42, and was based on APT, HMQC, H M B C , COSY, and N O E difference data. Selected spectral features of photoproducts 49A and 49B are shown in Fig.3.38 - 3.40 and Fig.3.41 - 3.43, respectively. The absolute configurations of diastereomers 49A and 49B were not determined and were assigned arbitrarily. The axial orientations of the ketone and ester substituents were confirmed by N O E difference experiment data. 98 a) b) i ' 1 1 ' i 1 ' •' i ' ' •' i 1 ' ' ' i ' 1 1 ' i ' ' ' ' i ' ' 1 ' i ' ' 1 ' > 1 1 ' ' i ' 1 ' 1 1 ' • ' ' i ' •' • i • ' ' ' i ' ' •' i ' •' • i • ' ' ' i • •' • i ' 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm Figure 3.37. The ! H NMR spectrum (400 MHz, CDCl 3 ) of a) photoproduct 49A; b) photoproduct 49B. 99 Table 3.8. *H N M R (500 MHz, CDC13) chemical shifts of adamantane protons of 8-keto esters 42, 49A, and 49B. 42 49A 49B H-1 2.36(lH,m) 2.42(lH,s) 2.43-2.42(lH,m) H-2 part of m(2H) 2.54-2.50(lH) 2.53(lH,s) part of m (2H) 2.53-2.51(1H) H-3 2.93(lH,s) 2.84(lH,s) 2.88(lH,s) H-4 3.45(lH,s) 3.44(lH,s) 3.43(lH,s) H-5 2.21(lH,s) 2.23(lH,s) 2.23(lH,s) H-6 1.85-1.81(lH,m) partofm(4H) 1.93-1.84(1H) partofm(4H) 1.92-1.83(1H) H-6' partofm(3H) 1.95-1.86(1H) partofm(4H) 1.93-1.84(1H) partofm(4H) 1.92-1.83(1H) H-7 2.01-2.00(lH,m) 2.02(lH,s) 2.02-2.01(lH,m) H-8 1.74-1.69(lH,m) 1.78-1.75(lH,m) 1.77-1.73(lH,m) H-8' partofm(3H) 1.95-1.86(1H) part of m (4H) 1.93-1.84(1H) partofm(4H) 1.92-1.83(1H) H-9 1.58-1.54(lH,m) partofm(4H) 1.71-1.56(1H) part of m (5H) 1.70-1.57(1H) H-9' part of m(2H) 2.54-2.50(lH) 2.48-2.45(lH,m) part of m (2H) 2.53-2.51(1H) H-10 partofm(3H) 1.95-1.86(1H) partofm(4H) 1.93-1.84(1H) part of m (4H) 1.93-1.84(1H) H-10' 2.13-2.09(lH,m) 2.12-2.10(lH,m) 2.12-2.10(lH,m) 100 Figure 3.38. Partial HMBC spectrum (500 MHz, CDC13) of photoproduct 49 A. 101 Figure 3.39. Partial COSY spectrum (500 MHz, C D C 1 3 ) of photoproduct 49A. 102 I I I • I I • • ' ' I ' ' ' ' I ' ' ' ' I ' ' • ' 1 1 • ' ' I ' 1 • ' I 1 ' 1 ' I • ' ' 1 1 ' ' ' ' I • ' 1 1 I ' 1 1 • I 1 1 • ' 1 1 ' •' I •' •' I 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 45 4.0 .3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm Figure 3.40. NOE difference experiment on photoproduct 49A a) irradiation at 5=3.44 ppm (H-4), b) irradiation at 5=2.53 ppm (H-2), c) off-resonance spectrum. 1 0 3 1— i 1 1 1 j 1 1 • 1 1 0 1 1 1 j 6 i i -. * f 170 180 190 MO aio 00» ppa 4.0 3 5 3.0 2 5 Figure 3.41. Partial HMBC spectrum (500 MHz, CDC13) of photoproduct 49B. 104 Figure 3.42. Partial COSY spectrum (500 MHz, CDC13) of photoproduct 4 9 B . 105 a) 24 J L b) c) d) J L T 3, 5 Iff 6 5.10* Ln ft I i i • • I i • • i I i i i • I I i i i i I i . i i I i i i i I i i i t I i i i . | i t i i I i i i i I i i i . I i i i i I • i i i ! 6.0 75 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm Figure 3.43. NOE difference experiment on photoproduct 4 9 B a) irradiation at 5=3.43 ppm (H-4). b) irradiation at 5=2.52 ppm (H-2), c) irradiation at 6=1.75 ppm (H-8), d) off-resonance spectrum. 106 3.3.2. Determination of Photoproduct 49A Stereochemistry Irradiation of H-4 resulted in a strong NOE response of H-24, moderate enhancements of H-3 and H-5, and weak responses of H-10' and H-6 (part of multiplet). Irradiation of H-2 resulted in a moderate enhancement of H-3 and weak enhancements of H-8 and H-10 (part of multiplet). The spatial proximity of H-4 to H-10' and H-6, and H-2 to H-8 and H-10 confirms the 1,3-diaxial stereochemistry of 8-keto ester 49A (Fig.3.40, Fig.3.44). 3.3.3. Determination of Photoproduct 49B Stereochemistry Irradiation of H-4 resulted in strong enhancement of H-24, moderate N O E responses of H-3 and H-5, and weak responses of H-10' and H-6 (part of multiplet), thus confirming the spatial proximity of H-4 to H-10' and H-6. Irradiation of H-2 resulted in a strong enhancement of H-9 and weak enhancements of H-5, H-8 and H-10 (part of multiplet). The NOE responses of H-9 and H-5 were the result of the irradiation of H-9', since the latter was Figure 3.44. Selected NOE correlations used for ester 49A stereochemistry determination. 107 not resolved from the H-2 signal. Irradiation of H-8 resulted in a strong enhancement of H-2 and moderate enhancement of H-1 confirming the spatial proximity of H-2 to H-8 and the 1,3-diaxial stereochemistry of 8-keto ester 49B (Fig.3.43, Fig.3.45). 3.3.4. Asymmetric Induction in Solution and the Solid State Photolysis of P-Keto Ester 35 Low asymmetric induction was observed in the solution state photolysis of fenchyl derivative 35, where the ratio of diastereomeric photoproducts, 49A and 49B, was estimated from the *H N M R spectrum of the reaction mixture as 36 : 64 and from chiral GC analysis as 37 : 63. In contrast to p-keto ester 34, low diastereoselectivity was observed in the solid state photolysis of ester 35 (Table 3.9). Figure 3.45. Selected NOE correlations used for ester 49B stereochemistry determination. 108 Table 3.9. Results of solid state photolysis of p-keto ester 35. Conditions of photolysis Conversion of starting material, Ratio of photoproducts % 4 9 A : 4 9 B a Solid state, room t.,1 hr 76 41:59 Solid state, room t., 14 min 10 41:59 Solid state, -20°C, 2 hrs 69 39:61 a. Ratios were estimated from GC analyses using p-Dex-390 chiral column. Examination of the crystal structure of P-keto ester 35 revealed the explanation for such low diastereoselectivity in the solid state. Crystals of ester 35 contain four independent molecules in the asymmetric unit (Appendix II). The X-ray data suggests that only one y-hydrogen in each molecule is at a reasonable distance from the carbonyl oxygen to be abstracted. Molecules 1 and 2 adopt a conformation that favors H-x abstraction, while molecules 3 and 4 are in an opposite conformation, favorable for H-y abstraction (Table 3.10). Nevertheless, the reaction occurs in a chiral environment and may therefore proceed via diastereomeric transition states of different energies, resulting in the formation of unequal amounts of the diastereomeric products (18% de). Table 3.10. y-H abstraction distances in P-keto ester 35 crystals. y-H Molecule 1, Molecule 2, Molecule 3, Molecule 4, d(A) d(A) d(A) d(A) H-x 2.38 2.34 3.24 3.32 H-y 3.16 3.23 2.39 2.42 109 3.4. Photochemistry of P-Keto Ester 33 Figure 3.46. Photochemistry of p-keto ester 33. (-)-Menthyl ester 32 was obtained as an oil and its irradiation in an acetonitrile solution led to the formation of two photoproducts in a ratio of 60:40 as determined by GC analysis (Fig.3.46). Since the photoproducts were not separable by radial chromatography they were analyzed as a diastereomeric mixture. The photoreaction of ester 33 is likely to proceed by the same mechanism as for 28, 34, and 35. It is therefore probable that the two photoproducts formed are the diastereomeric 5-keto esters 50A and 50B, with both substituents in axial positions. Elemental and high resolution mass spectroscopic analyses revealed that 50A and 50B have the same formula as starting P-keto ester 33, and the IR spectra showed two carbonyl absorption bands corresponding to ketone and ester groups. As observed for the pairs of diastereomeric 8-keto esters 47A/47B and 49A/49B, the methine proton chemical shifts of the adamantane fragments of 50A and 50B were identical to each other and very close to those of ester 42 (Table 3.11). The diastereoselectivity observed in the photolysis of menthyl ester 33 (20 de) is similar to the diastereoselectivities observed in the solution state photoreactions of esters 34 and 35. 110 Table 3.11. Methine proton chemical shifts for 5-keto esters 42, 47A/47B, 49A/49B, and mixture of 50A750B. Hz 8-keto ester 50A/50B 42 47A 47B 49A 49B H-l 2.41-2.37(lH,m) 2.36 2.41 2.41 2.42 2.43-2.42 H-2 2.55-2.48 part of m (2H) 2.54-2.50 part of m (2H) 2.51 2.51 2.53 2.53-2.51 partofm(2H) H-3 2.94(lH,s) 2.92 2.93 2.92 2.84 2.88 H-4 3.42(lH,s) 3.45 3.43 3.43 3.44 3.43 H-5 2.21(lH,s) 2.21 2.22 2.21 2.23 2.23 H-7 2.01(lH,m) 2.01-2.00 2.02-2.01 2.02 2.02 2.02-2.01 3.5. Photochemistry of Salt 40 42 43 44 Figure 3.47. Photochemistry of salt 40. Photolysis of salt 40 in the solid state at room temperature for 1 hour (100% conversion), followed by diazomethane workup, resulted in the formation of methyl esters 111 42, 43, and 44 in a ratio of 60:7:33, respectively, according to GC analysis (Fig.3.47). Chiral GC analysis revealed that enantiomer 42B of methyl ester 42 was formed almost exclusively. Unfortunately, analysis of the enantiomeric composition of esters 43 and 44 was not possible. However, according to the mechanism suggested for the formation of compounds 43 and 44, asymmetric induction for these photoproducts should be similar to that observed for ester 42. Therefore, very high enantiomeric excess (>99%) was generated by applying the ionic chiral auxiliary approach to the solid state photoreaction of achiral P-keto acid 36 (Fig.3.48). Since salt 40 decomposed readily in acetonitrile it was not possible to carry out solution state photolysis for this compound. <1 : >99 Figure 3.48. The ratios of enantiomers 42A and 42B formed in: a) photoreaction of p-keto ester 28, b) solid state photoreaction of chiral salt 40, followed by diazomethane work up. 112 3.6. Asymmetric Induction in Solution Versus Solid State. Conclusions and Further Applications The following points summarize the results of the asymmetric induction studies carried out employing covalent and ionic chiral auxiliaries. The solution phase photolyses of chiral esters 33, 34 and 35 proceeded with relatively low diastereoselectivity (14-28% de), reflecting the extent of asymmetric induction due to the direct influence of the chiral auxiliaries. Asymmetric induction in the solid state was studied for the (-)-bornyl and (+)-fenchyl P-keto esters (34 and 35). The solid state photoreaction, in which chiral information is provided by the rigid chiral environment, proceeded with high diastereoselectivity (>95% de) at quantitative conversion for ester 34 and with low diastereoselectivity (18% de) for ester 35. The diastereoselectivity observed in the solid state was correlated with the X-ray crystal structure data for the corresponding compound. The solid state photolysis of the salt of P-keto . acid 36 with optically active R-(+)-a-methylbenzylamine, followed by diazomethane work up, led to the methyl P-keto ester 42 with an excellent enantiomeric excess (>99% ee) at quantitative conversion of the starting material. This result suggests that chiral salt 40 crystallizes in a conformation that permits abstraction of only one of two possible y-hydrogens. Since we could not obtain X-ray quality crystals of chiral salt 40 to confirm this point, investigation of the asymmetric induction in the photoreaction of the salt of P-keto acid 36 with the enantiomeric chiral auxiliary (S)-(-)-methylbenzylamine would be interesting to carry out. If this salt crystallizes in a conformation that favors the abstraction of the other y-hydrogen, the opposite enantiomer of methyl ester 42 should result. 113 Comparison of the asymmetric induction results in the solution and solid state photoreactions of P-keto acid 36 derivatives showed the importance of environmental effects in this system. Therefore, another interesting investigation would be the extension of asymmetric induction studies to other organized media such as zeolites. Such a collaborative project with Professor V. Ramamurthy at Tulane University is under way at the present time. 114 EXPERIMENTAL Chapter 4. Preparation of Starting Materials 4.1. General Procedures Melting Points (MP) Melting points were determined on a Fisher-Johns melting point apparatus and are uncorrected. Infrared Spectra (IR) The Infrared spectra were recorded on Perkin Elmer 1710 and Bomem Michelson 100 Fourier transform infrared spectrometers. The positions of the absorption maxima are reported in cm" 1. Liquid samples were run neat, as thin films between two sodium chloride plates, or as chloroform solutions in sodium chloride cells. Solid samples were prepared by grinding anhydrous potassium bromide (100-150 mg) with solid sample (1-3 mg) and pressing the mixture into pellets in an evacuated die (Perkin-Elmer 186-0002) with a laboratory press (Carver, model B) at 17000 psi. 115 Mass Spectra (MS) Low and high resolution electron ionization (EI) mass spectra were obtained on a Kratos MS 50 mass spectrometer. Desorption chemical ionization (DCI) mass spectra were recorded on a Kratos MS 80 instrument. Liquid secondary ion mass spectra (LSEVIS) were obtained on a Kratos IIHQ hybrid mass spectrometer. Mass to charge ratios im/e) are reported with relative intensities in parentheses. Molecular ions are designated as M + . GC/MS spectra were obtained using a Hewlett Packard HP5890 Series GC/HP 5973 MSD System. Ultraviolet Spectra (UV) Ultraviolet spectra were taken on Hewlett-Packard-8452A Diode Array and Cary 50 Scan UV-Visible Spectrometers. Wavelengths for each absorption maximum ( ^ m a x ) are reported in nanometers (nm) and the corresponding extinction coefficients (s, M 4 c m 4 ) are given in parentheses. Elemental Analyses All elemental analyses were performed by Mr. Peter Borda, Department of Chemistry, University of British Columbia. Proton Nuclear Magnetic Resonance Spectra (*H NMR) Proton spectra were recorded on the following spectrometers as indicated: Bruker AC-200 (200 MHz), Bruker WH-400 (400 MHz), and Bruker AMX-500 (500 MHz). Signal positions (8) are given in parts per million (ppm) with the residual proton signal from the 116 deuterated solvent as the internal reference. The number of protons, signal multiplicities, coupling constants (J) in Hertz (Hz), and assignments are given in parentheses following the signal position. The multiplicities of the signals are abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad. Carbon Nuclear Magnetic Resonance Spectra (* 3C NMR) Carbon spectra were recorded on the following spectrometers: Bruker AC-200 at 50.3 MHz, Varian XL-300 at 75.4 MHz, Bruker AM-400 at 100.6 M H z and Bruker A M X -500 at 125.8 MHz. Al l spectra were determined with broad band 13C-{lH} decoupling. Chemical shifts (8) are reported in ppm with the middle peak of the solvent signal used as an internal reference. Reported chemical shifts are followed in parentheses by the sign determined from the APT (Attached Proton Test) experiments. For APT a positive sign (+) signifies C or CH2, and a negative sign (-) signifies C H or CH3. In some cases, H M Q C (Heteronuclear Multiple Quantum Coherence) and H M B C (Heteronuclear shift correlations via Multiple Bond Connectivities) experiments on the Bruker AMX-500 spectrometer, COSY (Correlated SpectroscopY) on the Bruker WH-400 and the Bruker AMX-500 spectrometers and N O E (Nuclear Overhauser Effect) difference experiments on the Bruker WH-400 spectrometer were carried out in order to verify structures. 117 Crystallographic Analysis (X-RAY) All crystal structures were determined on a Rigaku A FC6S 4-circle diffractometer using single crystal X-ray analysis by Eugene Cheung under the supervision of Professor James Trotter, in the Chemistry Department of the University of British Columbia. Spectroscopic diagrams were drawn using the ORTEP program at a 50% probability level. Chromatography Gas-Liquid (GLC) analyses were carried out on a Hewlett-Packard 5890A gas chromatograph with a flame ionization detector using a 30 m x 0.25 mm fused silica capillary column HP-5 (Hewlett-Packard) with a column head pressure maintained at 14 psi (carrier gas: helium). The instrument was equipped with a Hewlett-Packard 3392 A integrator. Gas-liquid chromatographic analyses for enantiomeric and diastereomeric excess determinations were carried out on a Hewlett-Packard 5890 Series II gas chromatograph with a flame ionization detector using a 35 m x 0.25 mm fused silica capillary column coated with 0.25 um of 2.3-di-0-methyl-6-0-TBDMS-p-cyclodextrin solution (50%) in polysiloxane. Column head pressure was maintained between 250-300 kPa (carrier gas: helium). The instrument was equipped with Hewlett-Packard 3393 A integrator. 118 Thin Layer Chromatography (TLC) was carried out on precoated silica gel plates (E. Merck, type 5554/7) with fluorescent indicator (F 254)-Preparative radial thin-layer separations were performed on a Harrison Chromatotron™ Model 7924T. The adsorbent used was Silica Gel 60, P F 2 5 4 with gypsum binder. Column Chromatography was performed using Silica Gel 60, 230-400 mesh (E. Merck) with the appropriate solvent combination. Column size was determined according to the amount of crude material to be purified. Solvents and Reagents. Solvents and reagents were used as supplied (Aldrich Co, Fisher Scientific Inc.) or purified by known methods and procedures.58 119 4.2. Synthesis of Methyl 2-Benzoyltricyclo[3.3.1.1^»7]decane-2-carboxylate (28) 2-Tricyclo[3.3.1.1^'^]decane carboxylic acid (26) COOH 26 The method of Alberts et al. was used to prepare acid 26. A 500 mL three necked round bottom flask and addition funnel were dried in an oven at 120°C overnight, assembled, and allowed to cool with continuing nitrogen flow. The flask was charged with methoxyrnethyltriphenylphosphonium chloride (23.5 g, 68.6 mmol) and dry diethyl ether (150 mL). The addition funnel was charged with adamantanone 23 (8.4 g, 56.0 mmol, Aldrich, mp. 258-260°C) in 85 mL of dry diethyl ether. After cooling the flask to 10°C H-butyllithium (78.0 mmol, 1.6 M solution in hexane) was added dropwise from a syringe to the continuously stirred suspension of methoxymethyltriphenylphosphonium chloride in diethyl ether. The reaction mixture was observed to change from yellow to red in color. This red suspension was stirred for 1 hr under a nitrogen atmosphere. Adamantanone 23 was slowly added (over 1 hr) and the mixture was allowed to stir at room temperature overnight. With vigorous stirring, anhydrous zinc chloride (11.8 g, 86.5 mmol) was added to complex the suspended triphenylphosphine oxide and the yellowish ethereal layer was decanted. The residue was washed with n-pentane. The pentane washings were filtered through Celite and combined with the ethereal layer. The solvent was removed in vacuo to yield enol ether 24 as 120 a yellowish oil which was used without further purification. Enol ether 24 was dissolved in diethyl ether ( 1 2 0 mL) and hydrolyzed with 35% perchloric acid ( 1 0 mL) at reflux over 1 hr with stirring. The mixture was poured in water (170 mL) and the organic layer was separated, washed with water and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo yielded aldehyde 25 as a viscous oil which was used without further purification. Aldehyde 25 was dissolved in acetone (60 mL) and cooled to 10-15°C. Jones' reagent (8 g CrC«3, 23 mL H - 2 O , 70 mL cone. H 2 S O 4 ) was added dropwise until it was in excess. The mixture was allowed to stir at room temperature for 2 .5 hr. Acetone was removed in vacuo and cold water ( 2 0 0 mL) was added. The mixture was then extracted with diethyl ether (3 x 1 0 0 mL). The ethereal fractions were combined, washed with water and extracted with a IN solution of sodium hydroxide (5 x 60 mL). After washing with ether, the aqueous layer was acidified with concentrated hydrochloric acid, causing the precipitation of a white solid. The suspension was extracted with diethyl ether and the ethereal layers were washed with water, saturated sodium chloride solution and dried over anhydrous sodium carbonate. The solvent was removed in vacuo to yield acid 26 as a white solid (5.7 g, 57% yield from adamantanone). Recrystallization from methanol-water mixture gave colorless crystalline plates of acid 26. MP 139-141°C (lit.4 3 M.P. 141-143°C) i H NMR ( C D C I 3 , 2 0 0 MHz): 5 11 .80 (IH, bs), 2.67 (IH, s), 2.35 ( 2 H , s), 1.95-1.61 ( 1 2 H , m). 121 13C N M R (CDCI3, 75 MHz): 6 181.49(+), 49.41(-), 37.99(+), 37.25(+), 33.50(+), 29.30(-), 27.32(-). IR, cm-1: (KBr pellet) 2915, 1685, 1471, 1455, 1421, 1343, 1302, 1278, 1102, 1065, 1050, 986, 947, 833, 822, 800, 738, 657, 575, 519. Methyl 2-benzoyltricyclo[3.3.1.13,7]{jecane-2-carboxylate (28) A long necked distillation flask equipped with an addition funnel and condenser was charged with a solution of potassium hydroxide (3 g) in water (4.5 mL) and ethanol (15 mL, 96%). The mixture was heated in a water bath at 60-65°C and a solution of N-methy\-N-nitrozo-p-toluenesulfonamide (12.8 g, 60 mmol) in diethyl ether (120 mL) was added dropwise from the addition funnel. The rate of addition was adjusted so that it was equal to the rate of distillation. The distillate, containing diazomethane, was passed into a receiving flask, cooled in an ice-salt bath, containing a solution of carboxylic acid 26 (3 g, 16.6 mmol) in diethyl ether (100 ml). Addition of diazomethane was allowed to proceed until the solution retained the pale yellow color of diazomethane and the evolution of nitrogen gas had ceased. Excess diazomethane was allowed to evaporate. The ethereal solution was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield methyl <\/Ph 28 122 2-adamantane carboxylate 27 as a colorless oil (used without further purification). Lithium diisopropylamide was prepared in a 150 mL flame dried round bottomed flask by dissolving diisopropylamine (11 mL, 8.0 mmol) in dry THF (70 mL) under a nitrogen atmosphere and adding 4.8 mL of w-butyllithium (7.7 mmol, 1.6M solution in hexane) dropwise via syringe at -78°C (dry ice - acetone bath). The mixture was stirred at -78°C for 1 hr and a solution of methyl 2-adamantane carboxylate (27) (1.11 g, 5.7 mmol) in dry THF (20 mL) was added dropwise via syringe over 10 minutes. After allowing the mixture to stir at -78°C for 1.5 hr 1.4 mL of N,N-dimethylpropyleneurea (DMPU) were added and stirring was continued for 10 more minutes. Benzoyl chloride (2 mL, 17.6 mmol) was rapidly added and the reaction mixture was stirred at -78°C for 30 minutes. The reaction was quenched at -78°C with 5% hydrochloric acid (35 mL), allowed to warm to room temperature, and extracted with diethyl ether (2 x 150 mL). The combined ethereal layers were washed with water (70 mL), saturated solution of sodium carbonate (2x30 mL), and saturated sodium chloride solution (100 mL) and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to yield the crude product, 28, as a white solid. P-Keto ester 28 was purified by column chromatography (petroleum ether - diethyl ether, 90:10) and recrystallized from a w-pentane - ethyl acetate solution to yield colorless plates (1.3 g, 4.4 mmol, 76.3% yield). MP 106-108°C. Anal. Calcd. for C 1 9 H 2 2 0 3 : C, 76.48; H, 7.43. Found: C, 76.38; H , 7.58. 123 !H NMR (CDCI3, 400 MHz): 8 7.85-7.83 (2H, m, Ar-H), 7.48-7.44 (IH, m Ar-H), 7.38-7.34 (2H, m, Ar-H), 3.71 (3H, s, C 0 2 C r 7 3 ) , 2.94 (2H, s, ring-//), 2.07-2.03 (2H, m, ring-//), 1-83 (IH, m, ring-//), 1.73-1.54 (9H, m, ring-//). 1 3 C NMR (CDCI3, 75 MHz): 8 199.81(+), 172.35(+), 138.05(+), 131.87(-), 129.20(-), 128.11(-), 65.75(+), 52.56(-), 37.33(+), 34.37(+), 33.72(+), 32.85(-), 26.76(-), 26.55(-). LRMS: (DCI+, N H 3 ) m/e (relative intensity), 299(1.7), 298(6.4, M + ) , 267(1.2), 211(2.3), 163(3.9), 162(31.7), 133(1.8), 106(8.4), 105(100.0), 91(2.5), 77(6.4). HRMS: (DCI+, NH3+CH4) Calculated mass for C19H22O3: 298.1569. Found: 298.1568. IR, cm" 1: (KBr pellet) 2911, 2856, 1728, 1677, 1596, 1578, 1445, 1434, 1353, 1340, 1237, 1215, 1199, 1179, 1097, 1062, 1009, 960, 944, 920, 893, 879, 841, 798, 762, 731, 699, 663, 644, 627, 475. U V : (n-pentane) Xmax 208(10.000), 244(13.000), 274(1300), 332(200) nm. X-ray crystallographic analysis: Space group P2xla, monoclinic, a=10.631(2) A, b=19.712(5) A, c=14.825(5) A, p=93.23(2)°, V=3102(1) A3, Z=8, D c a l c=1.280g/cm 3 , R=0.0422, Rw=0.097. 124 4.3. Syntheses of P-Keto Esters 33, 34 and 35 (lR,2S,5R)-(-)-MenthyI tricyclo[3.3.1.13>7]decane-2-carboxylate (30) :00-(-)-menthyl 9^ 3 (1R,2S,5R)-(-)-menthyl= A 25 mL round bottomed flask was flame dried and allowed to cool with continuing nitrogen flow. The flask was charged with 2-adamantane carboxylic acid 26 (0.36 g, 2.0 mmol) in dry methylene chloride (7 mL). Oxalyl chloride (Aldrich, 0.35 mL, 4.0 mmol) was added via syringe. After stirring the mixture for 5 minutes at room temperature a catalytic amount of dry dimethylformamide (5 pL) was added. The reaction mixture was allowed to stir for 2.5 hr. Excess oxalyl chloride and solvent were removed under reduced pressure. The resulting yellow oil was redissolved in dry methylene chloride (13 mL) and added via syringe to a solution of (lR,2S,5R)-(-)-menthol (312mg, 2.0 mmol) and dry triethylamine (0.31 mL, 2.2 mmol) in methylene chloride (10 mL) maintained in a nitrogen atmosphere at ice bath temperature. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was removed in vacuo and the residue was redissolved in 30 mL of diethyl ether and 15 mL of cold water. The mixture was stirred for few more minutes until all solid residue had dissolved. The ethereal layer was separated and washed with 5% hydrochloric acid ( 2 x l 0 m L ) , 5% aqueous sodium bicarbonate solution 125 (2 x 10 mL), water (1x15 mL) and saturated sodium chloride solution (1 x 20 mL). After drying over anhydrous magnesium sulfate the solvent was removed in vacuo. The crude product was purified by column chromatography (petroleum ether - diethyl ether, 20:1) to yield ester 30 as a white solid (508 mg, 1.6 mmol, 80% yield). M P 89-90°C. Anal. Calcd. for C 2 i H 3 4 0 2 : C , 79.18; H , 10.77. Found: C, 79.24; H, 10.82. lB N M R (CDCI3, 400 MHz). 5 4.73-4.66 (IH, m), 2.55 (IH, s, 2-H), 2.32 (2H, m), 2.01-2.14 (16H, m), 1.40-1.32 (IH, m), 1.09-0.80 (10H, m), 0.75-0.73 (3H, d, J=7.0 Hz). 1 3 C N M R (CDCI3, 75 MHz): 5 174.13(+), 73.54(-), 49.63(-), 47.01(-), 40.92(+), 38.16(+), 37.42(+), 34.32(+), 33.50(+), 31.38(-), 29.64(-), 29.46(-), 27.51(-), 27.43(-), 26.13(-), 23.26(+), 22.05(-), 20.82(-), 16.12(-). L R M S : (DCI+, N H 3 ) m/e (relative intensity), 319(0.5, M++1), 181(7.2), 180(18.9), 163(3.8), 162(12.1), 139(17.5), 138(100.0), 135(25.5), 134(9.6), 123(5.5), 95(10.5), 83(16.2), 81(12.0), 79(3.4). H R M S : (DCI+ NH3+CH4) Calculated mass for C21H35O2: 319.2637. Found: 319.2647. IR, cm" 1: (KBr pellet) 2914, 2852, 1805, 1719, 1456, 1371, 1343, 1298, 1266, 1190, 1171, 1102, 1083, 1063, 1047, 1012, 994, 967, 915, 822, 511. 126 (lR,2S,5R)-(-)-Menthyl2-benzoyltricyclo[3.3.1.13'7]decane-2-carboxylate(33) 00-(-)-menthyl 33 A potassium diisopropylamide - lithium terf-butoxide mixture (KDA) was prepared following the procedure described by S. Raucher and G. Koolpe. 4 6 A flame dried 50 mL round bottomed flask equipped with septum and magnetic stirrer was charged with potassium /ert-butoxide (84 mg, 0.75 mmol) and diisopropylamine (0.11 mL, 0.75 mmol) in dry THF (5 mL) under a nitrogen atmosphere. The flask was cooled to -78°C and n-butyllithium (0.34 mL, 0.62 mmol, 1.6M solution in hexane, Aldrich) was added via syringe to form a yellow mixture of potassium diisopropylamide and lithium tert-butoxide. The reaction mixture was allowed to stir for 40 minutes at ^78°C. A solution of ester 30 (161 mg, 0.5 mmol) in THF (5 mL) pre-cooled to -78°C under a nitrogen atmosphere was added via cannula. Upon addition the mixture changed from pale to dark yellow in color. The mixture was stirred for 1 hour, benzoyl chloride (0.17 mL, 1.5 mmol) was added via syringe, and stirring was continued for 30 min. The reaction was quenched with 5% hydrochloric acid (4 mL), allowed to warm to room temperature, and diluted with 20 mL of diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether (2 x 20 mL). The combined ethereal extracts were washed with saturated 127 sodium carbonate solution ( 2 x 4 mL), water (17 mL) and saturated sodium chloride solution (20 mL). After drying over anhydrous magnesium sulfate the solvent was removed in vacuo to give crude product that was purified by column chromatography (petroleum ether - diethyl ether, 400:1), yielding P-keto ester 33 as a viscous oil (171 mg, 0.41 mmol, 81% yield). Anal. Calcd. for C 2 8 H 3 8 0 3 : C, 79.57; H , 9.07. Found: C, 79.53; H , 8.89. *H NMR (CDC13, 400 MHz): 5 7.88-7.86 (2H, m, Ar-H), 7.47-7.43 (1H, m Ar-H), 7.37-7.33 (2H, m, Ar-H), 4.67-4.23 (1H, m), 2.92-2.90 (2H, m), 2.20-2.19 (1H, m), 2.07-2.04 (1H, m), 1.92-1.32 (16H, m), 0.98-0.71(9H, m), 0.52-0.51 (3H, d, J=7 Hz). 1 3 C NMR (CDCI3, 75 MHz): 5 199.73(+), 171.48(+), 138.00(+), 131.84(-), 128.38(-), 128.05(-), 75.29(-), 65.75(+), 46.68(-), 40.11(-), 37.51(+), 34.32(+), 34.24(+), 34.13(+), 33.86(+), 33.82(+), 32.96(-), 32.87(-); 31.37(-), 26.94(-), 26.73(-), 25.47(-), 22.78(+), 21.96(-), 20.69(-), 15.44(-). LRMS: (EI+) m/e (relative intensity), 422(0.4, M + ) , 284(2.8), 163(12.2), 162(100.0), 134(2.4), 118(1.7), 105(18.5), 92(2.3), 91(2.6), 83(5.3), 77(5.9), 69(2.7), 55(5.0). HRMS: Calculated mass for C28H38O3: 422.2821. Found: 422.2817. IR, cm' 1 : (neat) 3066, 2911, 1718, 1681, 1598, 1580, 1456, 1371, 1198, 1097, 1060, 1039, 1010, 982, 950, 914, 845, 821, 800, 783, 773, 759, 733, 698, 679, 647, 627, 470. U V : (H-pentane) ? i m a x 195(28000), 240(8400), 275(1100), 330(130) nm. 128 [(lS)-endo]-(-)-Bornyl tricyclo[3.3.1.13'7]decane-2-carboxylate (31) O - r \ / 31 (-)-Bornyl tricyclo[3.3.1.1^,7]decane-2-carboxylate (31) was prepared from acid 26 (0.36 g, 2.0 mmol) and (-)-borneol (0.308 g, 2.0 mmol), using the same procedure as for ester 30. Ester 31 was obtained as a white solid (501 mg, 1.6 mmol, 79% yield). MP 141-144°C. Anal. Calcd. for C21H32O2: C, 79.69; H, 10.20. Found: C, 79.75; H, 10.27. *H NMR (CDCI3, 400 MHz): 8 4.91-4.88 (IH, m), 2.58 (IH, s), 2.39-2.32 (3H, m), 1.95-1.58 (15H, m), 1.31-1.16 (2H, m), 0.96-0.82 (10H, m). 1 3 C NMR (CDCI3, 75 MHz): 5 174.81(+), 79.29(-), 46.69(-), 48r76(+), 47.73(+), 44.89(-), 38.10(+), 37.40(+), 36.97(+), 33.65(+), 33.56(+), 29.63(-), 29.42(-), 28.06(+), 27.47(-), 27.42(-), 27.21(+), 19.67(-), 18.85(-), 13.56(-). LRMS: (EI+) m/e (relative intensity), 317(22.8), 316(100.0, M+<), 163(10.8), 136(10.6), 135(29.7), 93(2.2), 81(2.7). HRMS: (EI+) Calculated mass for C21H32O2: 316.2402. Found: 316.2406. IR, cm" 1: (KBr pellet) 2910, 2652, 1724, 1452, 1389, 1343, 1300, 1265, 1201, 1173, 1114, 129 1099, 1064, 1048, 1021, 998, 886, 831, 756. [(lS)-endo]-(-)-Bornyl 2-benzoyItricyclo[3.3.1.13'^]decane-2-carboxylate (34) 34 [(lS)-endo]-(-)-Bornyl 2-benzoyltricyclo[3.3.1.13>7]decane-2-carboxylate (34)was prepared following the procedure used for the syntheses of P-keto ester 33. Ester 34 was obtained as a white solid (452 mg, 1.1 mmol, 74% yield starting from 31) and recrystallized from ethyl acetate - /?-pentane to give colorless prisms. M P 139-14TC. Anal. Calcd. for C28H36O3: C, 79.95; H , 8.63. Found: C, 80.06; H , 8.73. ! H N M R (CDCI3, 400 MHz): 5 7.87-7.85 (2H, m, Ax-H), 7.46-7.33 (3H, m Ax-H), 4.90-4.86 (1H, m), 2.96 (2H, s), 2.57-2.34 (1H, m), 2.13-2.06 (2H, m), 1.89-1.83 (2H, m), 1.73-1.54 (12H, m), 1.27-1.19 (1H, m), 1.11-1.05 (1H, m), 0.88 (3H, s), 0.81 (3H, s), 0.71 (3H, s). 130 1 3 C NMR (CDCI3, 75 MHz): 5 199.83(+), 171.91(+), 138.15(+), 131.75(-), 128.20(-), 128.08(-), 81.00(-), 66.02(+), 48.90(+), 47.73(+), 44.74(-), 37.42(+), 36.40(+), 34.38(+), 34.27(+),.33.85(+), 33.81(+), 32.95(-), 32.80(-), 27.83(+), 26.97(+), 26.85(-), 26.63(-), 19.54(-), 18.79(-), 13.42(-). LRMS: (DC1+ N H 3 ) m/e (relative intensity), 420(1.7, M + ) , 285(1.9), 284(9.3), 240(4.4), 239(2.5), 211(10.9), 163(11.85), 162(100.0), 137(28.3), 136(5.3), 106(3.0), 105(35.8), 95(4.7), 93(4.3), 92(2.4), 91(3.3), 81(20.6), 79(2.3), 77(6.5). HRMS: (DCI+, NH3+CH4) Calculated mass for C28H36O3: 420.2665. Found: 420.2659. IR, cm" 1: (KBr pellet) 3059, 2898, 2853, 1714, 1681, 1599, 1578, 1475, 1455, 1393, 1370, 1353, 1300, 1243, 1220, 1203, 1163, 1116, 1100, 1067, 1010, 973, 952, 930, 898, 886, 845, 828, 786, 760, 746, 731, 699, 678, 658, 644, 623, 490. U V : (??-pentane) Xmax 204(13000), 246(10000), 276(920), 332(200) nm. X-ray crystallographic analysis: Space group P2 12 12 1(#19), a=10.709(5) A, b=30.209(6) A, c=7.258(l) A, V=2348(l) A3, Z=4, D c a i c=1.19g/cm 3 , R=0.042, Rw=0.043. 131 [(lR)-endo]-(+)-Fenchyl tricyclo[3.3.1.13>7]decane-2-carboxylate (32) Starting from carboxylic acid 26 (0.4 g, 2.2 mmol) and [(lR)-endo]-(+)-fenchyl (377 mg, 2.4 mmol) and following the procedure used for the synthesis of ester 30, ester 32 was obtained as a white solid (434 mg, 1.4 mmol, 62% yield). MP 52-54°C. Anal. Calcd. for C21H32O2: C, 79.70; H, 10.19. Found: C, 79.50; H, 10.06 ! H NMR (CDCI3, 400 MHz): 5 4.37 (1H, d, J=1.8 Hz), 2.61 (1H, s), 2.35 (2H, bs), 1.92-1.57 (16H, m), 1.44-1.41 (lH,m), 1.17-1.03 (8H, m), 0.77 (3H, s). 1 3 C NMR (CDCI3, 100.6 MHz): 5 174.98(+), 85.84(-), 49.92(-), 48.47(+), 48.44(-), 41.40(+), 39.54(+), 38.25(+), 37.47(+), 33.72(+), 33.63(+), 29.79(-), 29.69(-), 29.54(-), 27.59(-), 27.51(-), 26.78(+), 25.87(+), 20.42(-), 19.51(-). LRMS: (EI+) m/e (relative intensity), 316(5.9, M + ) , 2.88(7.6), 236(3.7), 164(4.0), 163(28.0), 153(6.0), 152(3.9), 137(15.3), 136(44.3), 135(100.0), 124(5.6), 107(2.9), 95(2.1), 93(6.0), 91(3.1), 81(9.6), 80(3.1), 79(4.0), 77(1.9), 67(2.4). HRMS: (EI+) Calculated mass for C21H32O2: 316.2402. Found: 316.2396 132 IR, cm" 1: (KBr pellet) 2917, 2852, 1724, 1455, 1337, 1265, 1199, 1173, 1100, 1065, 1052, 1009. [(1 R)-endo]-(+)-Fenchyl 2-benzoyltricyclo[3.3.1.l3'7]decane-2-carboxyIate (35) 35 The procedure used to prepare ester 33 was modified for the synthesis of [(1R)-endo]-(+)-fenchyl 2-benzoyltricyclo[3.3.1.l3,7]decane.2-carboxylate 35. A solution of potassium fert-butoxide in THF (0.1 M , Aldrich) was used instead of solid anhydrous potassium fe7-/-butoxide. The crude product, 35, was purified by column chromatography (petroleum ether -diethylether, 100:1) to yield P-keto ester 35 as a white solid (398 mg, 0.95 mmol, 72% yield starting from 32), which was recrystallized from methanol to give colorless plates. MP 111-112°C. Anal. Calcd. for C28H36O3: C, 79.96; H , 8.63. Found: C, 79.86; H, 8.87. 133 lB N M R (CDCI3, 400 MHz): 6 7.89-7.87 (2H, m, Ar-H), 7.46-7.33 (3H, m, Ar-H), 4.40-4.39 (1H, d, J=1.8Hz), 2.97 (2H, s), 2.21 (1H, m), 2.07 (1H, m), 1.83-1.51 (14H, m), 1.40-1.32 (1H, m), 1.12-0.97 (5H, m), 0.89(3H,s), 0.56 (3H, s). 1 3 C N M R (CDCI3, 75 MHz): 5 199.79(+), 172.22(+), 138.06(+), 131.85(-), 128.40(-), 128.040, 87.29(-), 66.02(+), 48.75(+), 48.28(-), 41.32(+), 39.98(+), 37.41(+), 34.44(+), 34.22(+), 33.85(+), 33.77(+), 33.02(-), 32.92(-), 29.67(-), 26.88(-), 26.66(-), 26.36(+), 25.75(+), 20.42(-), 19.41(-). L R M S : (EI+) m/e (relative intensity), 420(1.1, M + ) , 284(4.0), 240(2.5), 239(2.3), 212(3.0), 211(14.3), 163(14.2), 162(100.0), 138(2.7), 137(27.7), 136(7.1), 106(4.3), 105(46.9), 95(4.0), 93(3.3), 92(3.8), 91(4.6), 81(24.2), 79(4.1), 77(12.1), 69(4.3), 67(3.0), 55(3.6). H R M S : (EI+) Calculated mass for C28H36O3: 420.2665. Found: 420.2660. IR, cm" 1: (KBr pellet) 3070, 2910, 2866, 1723, 1672, 1597, 1580, 1446, 1368, 1338, 1314, 1240, 1217, 1197, 1099, 1064, 1031, 1010, 976, 951, 896, 842, 828, 793, 759, 729, 696, 679, 666, 645, 627, 472. U V : (tt-pentane) ? t m a x 208(14000), 246(15000), 276(1400), 332(250). X-ray crystallographic analysis: Space group PI, triclinic, a=13.432(2) A, b=15.524(4) A, c=12.140(6) A, a=l 10.7(2)°, P=94.16(2)°, y=79.69(2)°, Z=4, R=0.062, Rw=0.2. 134 4.4. Synthesis of Salt 40 terf-Butyl tricyclo[3.3.1.13'7]decane-2-carboxylate (38) A 100 mL round bottomed flask equipped with a condenser and magnetic stirring bar was flame dried and allowed to cool with continuing nitrogen flow. The flask was charged with tert-butyl alcohol (6.7 mL, 71 mmol), freshly distilled from calcium hydride, and triethylamine (1.4 mL, 11 mmol) in methylene chloride (40 mL). The flask was cooled in an ice bath and a solution of 2-adamantane carboxylic acid chloride* (5.6 mmol) in methylene chloride (17 mL) was added via syringe. The mixture was allowed to warm to room temperature and stirred overnight. To ensure a complete reaction the mixture was refluxed for 30 minutes. The solvent was removed in vacuo and a mixture of diethyl ether (100 mL) and cold water (50 mL) was added and stirred until the solid residue had dissolved. The ethereal layer was separated and washed with 5% hydrochloric acid (2x30 mL), 5% sodium bicarbonate solution (1 x40mL) and saturated sodium chloride solution (1 x40mL) . The ethereal solution was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield a crude product 38. Purification by column chromatography (petroleum * 2-adamantane carboxylic acid chloride was prepared following the procedure described in the synthesis of ester 30. 135 ether - diethyl ether, 20.1) gave compound 38 (698 mg, 53% yield) as a yellowish oil, which solidified overnight under vacuum. MP 29-31°C. Anal. Calcd. for C15H24O2: C, 76.23; H, 10.23. Found: C, 76.45; H , 10.27. !H NMR (CDCI3, 400 MHz): 5 2.45 (IH, s), 2.25 (2H, bs), 1.85-1.55 (12H, m, ring-//), 1.42 (9H, s, f-Bu). 1 3 C NMR (CDCI3, 75 MHz): 5 174.03(+), 79.58(+), 50.20(-), 38.22(+), 37.49(+), 33.55(+), 29.65(-), 28.14(-), 27.53(-). LRMS: (EI+) m/e (relative intensity), 236(2.9, M + ) , 182(8.4), 181(73.8), 180(100.0), 179(12.0), 163(13.8), 162(24.1), 146(2.5), 139(2.8), 138(2.1), 137(7.5), 136(5.7), 135(48.8), 134(29.2), 133(8.7), 121(2.0), 120(3.1), 93(3.7), 91(4.0), 81(24.2), 79(2.6). HRMS: (EI+) Calculated mass for C 1 5 H 2 4 0 2 : 236.1776. Found: 236.1781. IR, cm ' 1 : (KBr pellet) 2917, 2853, 1722, 1453, 1389, 1365, 1334, 1298, 1270, 1220, 1158, 1098, 1065, 1048, 988, 855, 833, 821, 797, 476. 136 terf-Butyl 2-benzoyltricyclo[3.3.1.13>7]decane-2-carboxyIate (39) VP h / ^ ^ T ^ / C O O t - B u 39 A flame dried 100 mL round bottomed flask was charged with a 0.1M solution of potassium terf-butoxide in THF (4.7 mmol, 4.7 mL) and diisopropylamine (0.66 mL, 4.7 mmol) in 12 mL of THF under a nitrogen atmosphere. The flask was cooled to -78°C and a 1.6M solution of «-butyllithium (4.0 mmol, 2.4 mL) in n-hexane was added via syringe. After stirring the mixture at -78°C for 1 hr a THF solution of ester 38 (600 mg, 2.6 mmol) was cooled to -78°C and added to the reaction mixture via cannula. The dark yellow mixture was stirred at -78°C for 1 hr before benzoyl chloride (1.2 mL, 10.4 mmol) was added via syringe and stirring was continued for 1 hr. The reaction was quenched with 5% hydrochloric acid (25 mL), allowed to warm to room temperature, and extracted with diethyl ether (2 x 150 mL). The combined ethereal layers were washed with saturated sodium bicarbonate solution (2 x 25 mL), water (70 mL), and saturated sodium chloride solution (80 mL). The solvent was dried over anhydrous magnesium sulfate and removed in vacuo to yield a crude ester 39 that was purified by column chromatography (petroleum ether - diethyl ether, 10:1) to afford 218 mg (0.6 mmol, 25% yield) of P-keto ester 39 as a white solid. 137 MP 139-141°C. Anal. Calcd. for C 2 2 H 2 8 O 3 : C, 77 . 61 ; H , 8.29. Found: C, 77 .27; H , 8 . 3 3 . !H NMR ( C D C I 3 , 400 MHz): 5 7 . 8 9 - 7 . 8 6 ( 2 H , m, Ar-#), 7 . 4 8 - 7 . 4 3 ( 1 H , m Ar-H), 7.48-7 . 3 4 ( 2 H , m, Ar-H), 2.87 ( 2 H , s), 2 . 1 3 - 2 . 1 0 ( 2 H , m), 1.83 ( 1 H , m), 1 . 7 3 - 1 . 4 8 ( 9 H , m), 1 .4 .0 ( 9 H , s). 1 3 C NMR ( C D C I 3 , 7 5 MHz): 5 200.36(+), 170 .88(+) , 138.38(+), 131.71(-), 128.26(-), 128.09(-), 81.60(+), 6 6 . 4 3 ( + ) , 37.51(+), 34.26(+), 3 3 . 9 3 ( + ) , 3 2 . 9 4 ( - ) , 32.80(-), 27.72(-), 26.91(-), 26.72(-). LRMS: ( D C 1 + , N H 3 ) m/e (relative intensity), 359 (2 .9) , 358(13.0, M + ) , 303 (8 .9) , 3 0 2 ( 4 4 . 2 ) , 285(9.3), 284 (4 .0) , 267 (2 .7) , 2 4 1 ( 1 0 . 0 ) , 240 (5 .1) , 2 1 1 ( 4 . 1 ) , 163 (12 .0 ) , 1 6 2 ( 1 0 0 . 0 ) , 134(2.0), 105(6.7) . HRMS: (DCI+, N H 3 + C H 4 ) Calculated mass for C 2 2 H 2 8 0 3 : 358.2382. Found: 358.2385. ER, cm' 1 : (KBr pellet) 2965, 2918, 2887, 2854, 1711, 1678, 1596. U V : («-pentane) X m a x 206(12000), 244(13000), 274(960), 332(160) nm. 138 R-(+)-a-MethylbenzyIammonium 2-benzoyltricyclo[3.3.1.13'7]decane-2-carboxylate (40) The procedure for the preparation of P-keto acids from the corresponding ter/-butyl esters, described by M.W. Logue, 5 3 was modified for the synthesis of acid 36 in situ. A round bottomed flask was flame dried under a nitrogen atmosphere and charged with tert-buty] ester 39 (81.8 mg, 0.24 mmol). The flask was immersed in an ice bath and cold anhydrous trifluoroacetic acid (2.5 mL) was added via syringe. The reaction mixture was stirred for 30 minutes. Trifluoroacetic acid was removed under reduced pressure at 0°C over 1.5 hr and the white residue was re-dissolved in 1 mL of cold diethyl ether. R-(+)-a-methylbenzylamine (4 ul, 0.26 mmol) was added and within 5 minutes the solution was observed to become cloudy white. After allowing the solution to remain at 0°C for an additional hour, the mixture was filtered and the white precipitate was washed repeatedly with diethyl ether and then dried in vacuo to yield salt 40 as a white powder (46 mg, 0.11 mmol, 47% yield). MP 99-100°C. Anal. Calcd. for C 2 6 H 3 i N 1 0 3 : C, 77.01; H, 7.70; N , 3.45. Found: C, 77.02; H, 7.65; N , 3.44. 139 !H NMR (CDCI3, 400 MHz): 5 8.14-8.11 (2H, m, Ai-H), 7.51-7.22 (8H, m, Ax-H), 4.12-4.07 (1H, m), 3.10 (3H, bs), 2.57 (2H, s), 2.25-2.21 (2H, m), 1.85-1.58 (10H, m), 1.40-1.37 (3H, d, J=7 Hz). LRMS: (+LSIMS), 406(M+), 378, 285, 267, 240, 211, 181, 123, 122, 106, 105, 91, 77, 73 HRMS: (+LSIMS) Calculated mass for C26H32O3N: 406.2382. Found: 406.2382. IR, cm" 1 : (KBr pellet) 2949, 2866, 1664, 1629, 1552, 1520, 1453, 1383, 1360, 1337, 1254, 1211, 1183, 1149, 1097, 1014, 986, 953, 924, 808, 796, 764, 738, 700, 646, 623, 542. 140 Chapter 5. Photochemical Studies 5.1. General Irradiation Source Irradiations were carried out using Pyrex (X>290 nm) fdtered light from a Hanovia450 Watt medium pressure mercury lamp operated in a water cooled immersion well. Solution State Photolysis Spectral grade solvents (Fisher) were used for irradiations carried out in solution. The solution of the substrate in the appropriate solvent was purged with nitrogen for at least 30 minutes prior to irradiation and a nitrogen atmosphere was maintained throughout the experiment^ The photochemical reactions were monitored by GC analysis. After irradiation, the solvent was removed in vacuo and the residue was chromatographed to isolate the photoproducts. Solid State Photolysis Solid samples were prepared by crushing crystals of the compound to be irradiated between two Pyrex plates. The plates were then taped together at the top and bottom, placed in a polyethylene bag and thoroughly purged with nitrogen. The bag was then sealed under a positive pressure of nitrogen with a heat-sealing device and suspended at a distance of 10 cm from the immersion well. 141 Low temperature solid state photolyses were carried out by mounting the samples in an ethanol cooling bath controlled by a Crycool CC-100-11 immersion cooling system (Neslab Instrument Inc.). The temperature was kept within ±2°C of the designated value. 5.2. Preparation and Characterization of Photoproducts 5.2.1. Photolysis of p-Keto Ester 28 28 42 43 44 Figure 5.1. Photoreaction of p-keto ester 28. Following the general procedure for solution state photolysis, a stirred solution of P-keto ester 28 (110 mg, 0.37 mmol) in acetonitrile (25 mL) was irradiated for 5 hours (93% conversion of starting material). GC analysis of the reaction mixture indicated the formation of major photoproduct 42 accompanied by the minor products, 43 and 44, in a ratio of 86:11:3. After irradiation the solvent was removed in vacuo and the crude mixture was subjected to radial chromatography (petroleum ether - diethyl ether, 40:1). Only compounds 42 (82 mg, 76% yield) and 43 (18 mg, 16% yield) were isolated in pure form, both as clear, colorless oils. Photoproduct 42 crystallized under vacuum and was recrystallized from an ethyl acetate - «-pentane mixture. The photoproduct distribution was found to be affected by changes in the 142 concentration of 28. Irradiation of P-keto ester 28 (20 mg, 0.7 mmol) in 180 mL of acetonitrile for 30 minutes (100% conversion) led exclusively to the formation of 42 and 44 in an approximate ratio of 4:1 according to GC analysis. After removal of the solvent and separation by radial chromatography (petroleum ether - diethyl ether, 40:1), photoproducts 42 (14.4 mg, 72% yield) and 44 (3 mg, 15% yield) were isolated. The general procedure for solid state photolysis was followed for the irradiation of a solid sample of compound 28. Irradiation of 28 for 1 hour led to the formation of the same photoproducts as these from the solution state photolysis. According to GC analysis, one major, 42, and two minor, 43 and 44, photoproducts were formed in an approximate ratio of 88:3:9. re/-(lR,2S,3S,4R,5S,7R)-Methyl 4-benzoyItricyclo[3.3.1.13>7]decane-2-carboxylate (42) M.P. 77-79°C. Anal. Calcd. for C19H22O3: C, 76.48; H , 7.43. Found: C, 76.49; H , 7.51. *H NMR (CDCI3, 500 MHz): 5 7.86-7.84 (2H, m), 7.51-7.47 (1H, m), 7.44-7.40 (2H, m), 3.45 (IH, s), 3.40 (3H, s), 2.93 (IH, s), 2.54-2.50 (2H, m), 2.36 (IH, m), 2.21 (IH, s), 2.13-2.09 (IH, m), 2.01-2.00 (IH, m), 1.95-1.86 (3H, m), 1.85-1.80 (IH, m), 1.74-1.69 (IH, m), 1.58-1.54 (IH, m). 143 1 3 C N M R (CDCI3, 125.8 MHz): 5 202.04(+), 173.70(+), 136.75(+), 132.25(-), 128.33(-), 127.97(-), 50.91(-), 50.58(-), 47.53(-), 39.97(+), 38.95(+), 38.06(+), 32.97(-), 29.02(+), 28.84(-), 28.30(-), 27.50(-). L R M S : (EI+) m/e (relative intensity), 299(3.1), 298(13.9, M + ) , 267(4.9), 266(15.7), 239(5.9), 238(20.9), 193(6.9), 165(2.4), 161(8.6), 158(2.9), 134(3.5), 133(20.4), 117(4.0), 115(4.4), 106(8.3), 105(100.0), 93(3.6), 92(5.5), 91(36.7), 79(15.2), 78(7.0), 77(51.7), 67(6.1), 65(6.0), 51(12.9). H R M S : (EI+) Calculated mass for C 1 9 H 2 2 0 3 : 298.1564. Found: 298.1570. IR, cm" 1: (neat) 3057, 2914, 1732, 1682, 1597, 1581, 1455, 1368, 1347, 1275, 1216, 1104, 1065, 1023, 960, 917, 886, 867, 845, 830, 789, 773, 759, 647, 669, 649, 618. 144 Table 5.1. ] H N M R data (400 and 500 MHz, CDCI3) for major photoproduct 42. Assignment. H-xa *H NMR(500MHZ) 5 ppm (mult., J(tiz)) COSY(500MHz and 400MHz) correlations^ NOE(400MHz) correlations0 H-1 2.36(lH,m) H-9, H-8, H-3, H-2 med H-2, w H-8, w H-9 H-2 part of m(2H) 2.54-2.50(lH) H-3, H-1 med H-3, medH-l,wH-8 H-3 2.93(lH,s) H-4, H-10, H-10', H-2, H-1, H-5 med H-4, med H-2, med H-15, wH-10' H-4 3.45(lH,s) H-5, H-3 str H-15, w H-3, w H-5, w'H-6, wH-lO'-H-5 2.21(lH,s) H-9', H-9, H-6, H-3, H-4 str H-4, w H-9 H-6 1.85-1.81(lH,m) H-5, H-7 str H-4, med H-5 H-6' part of m(3H) 1.95-1.86(1H) H-7 2.01-2.00(lH,m) H-6, H-8, H-10' H-8 1.74-1.69(lH,m) H-7, H-1, H-2, H-8' str H-2, med H-1, med H-7 H-8' partofm(3H) 1.95-1.86(1H) H-8 H-9 1.58-1.54(lH,m) H-1, H-5, H-9' str H-9', w H-1, w H-5 H-9' part of m(2H) 2.54-2.50(1H) H-9, H-5 str H-9, w H-5, w H-1 145 H-10 partofm(3H) 1.95-1.86(1H) H-10', H-3 H-10' 2.13-2.09(lH,m) H-10, H-3, H-7 med H-4, w H-3 H-12 3.40(3H,s) H-15 7.86-7.84(2H,m) H-16 str H-4, med H-3, str H-16 H-16 7.44-7.40(2H,m) H-15, H-17 str H-15 H-17 7.51-7.47(lH,m) H-16 a- H' indicates the hydrogen of a pair which is more downfield (H-6' is more downfield then H-6). b- Only those COSY correlations that could be unambiguously assigned are recorded. c- Only those NOE data that could be unambiguously assigned are recorded (str=strong, med=medium, w=\veak). 146 Table 5.2. 125.8/500 MHz l3C,lU - shift correlations via HMQC (one bond couplings) and H M B C (long-range couplings) for major photoproduct 42. C-x 1 3 C shift (125.8MHz) 5 (ppm), A P T 3 lU shift (500MHz), 1 3 C - J H one bond correlation, H M Q C b -8 C 0 P P m ) > assignment^ ^ C - ^ H long-range correlations, H M B C b , H-x 1 28.30(-ve) 2.36(lH,m) H - l H-2(2 bonds) 2 47.53(-ve) part of m(2H), 2.54-2.50(lH,bs) H-2 H-4(3 bonds), H-9(3 bonds), H-10'(3 bonds) j 32.97(-ve) 2.93(lH,s) H-3 H-4(2 bonds), H-2(2 bonds) 4 50.58(-ve) 3.45(lHs) H-4 H-2(3 bonds), H-9(3 bonds) 5 28.84(-ve) 2.21(lH,s)H-5 H-4(2 bonds) 6 38.95(+ve) 1.85-1.81(lH,m) H-6 partofm(3H), 1.95-1.86(lH,m) H-6' H-8(3 bonds), H-4(3 bonds) 7 27.50(-ve) 2.01-2.00(lH,m) H-7 H-3 (3 bonds) 8 38.06(+ve) 1.74-1.69(lH,m) H-8 part of m(3H), 1.95-1.86(1H) H-8' H-6(3 bonds), H-10'(3 bonds) 9 29.02(+ve) 1.58-1.54(lH,m) H-9 part of m(2H), 2.54-2.50(lH,m) H-9' H-8(3 bonds), H-l(2 bonds) H-6(3 bonds) 147 10 39.97(+ve) partofm(3H), 1.95-1.86(lH,m) H-10 2.13-2.09(lH,m) H-10 H-4(3 bonds) 11 173.70(+ve) H-12(3 bonds), H-2(2 bonds) 12 50.91(-ve) 3.40(3H,s)H-12 13 202.04(+ve) H-15(3 bonds), H-4(2 bonds) 14 136.75(+ve) H-16(3 bonds) 15 127.97(-ve) 7.86-7.84(2H,m) H-15 H-17(3 bonds) 16 128.33(-ve) 7.44-7.40(2H,m) H-16 17 132.25(-ve) 7.51-7.47(lH,m) H-17 H-15(3 bonds) a- The results of the APT experiments: (-ve) for CH and C H 3 , (+ve) for C and C H 2 . b- Only those HMQC and HMBC data that could be unambiguously assigned are reported, c- Reported chemical shifts are followed in parentheses by the number of protons and multiplicity of the peak, d- H' indicates the hydrogen from the pair of methylene hydrogens (-CHH'-) which is more downfield (H-6' is more downfield than H-6). re/-(lR,2S,3S,4S,5S,7R)-Methyl 4-benzoyltricyclo[3.3.1.13'7]decane-2-carboxylate (43) Anal. Calcd. for C 1 9 H 2 2 0 3 : C, 76.48; H , 7.43. Found: C, 76.31; H , 7.42. i H N M R (CDCI3, 500 MHz): 8 8.00-7.97 (2H, m), 7.52-7.41 (3H, m), 3.77 (3H, s), 3.64 (1H, s), 2.76-2.73 (2H, m), 2.42 (1H, s), 2.25-2.18 (2H, m), 1.97-1.94 (1H, m), 1.93-1.88 (1H, m), 1.85-1.82 (2H, m), 1.81-1.77 (1H, m), 1.73-1.70 (1H, m), 1.56-1.53 (1H, m), 1.51-1.48 (1H, m). 1 3 C N M R (CDCI3, 125.8 MHz): 8 203.82(+), 175.00(+), 136.95(+), 132.27(-), 128.40(-), 128.38(-), 51.60(-), 50.50(-), 48.02(-), 37.77(+), 35.03(+), 33.18(+), 32.40(+), 31.76(-), 29.68(-), 28.98(-), 26.80(-). 148 LRMS: (EI+) m/e (relative intensity), 299(17.3), 298(81.5, M + ) , 267(7.2), 266(29.1), 239(13.6), 238(33.0), 193(9.1), 183(4.0), 161(10.0), 159(4.0), 158(3.3), 134(4.2), 133(29.3), 119(3.7), 118(3.7), 117(3.9), 115(3.8), 106(8.9), 105(100.0), 93(6.3), 92(6.2), 91(40.4), 79(20.6), 78(10.2), 77(59.6), 67(8.6), 65(5.8), 59(5.6), 55(7.4), 51(11.2). HRMS: (EI+) Calculated mass for C 1 9 H 2 2 O 3 : 298.1569. Found: 298.1564. ER, cm" 1: (CHC13) 2919, 2857, 1723, 1678, 1598, 1580, 1448, 1344, 1305, 1267, 1231, 1211, 1206, 1103, 1057, 1020, 1002, 940, 921, 725, 717, 701, 490, 479. 149 Table 5.3. lH N M R data (400 and 500 MHz, CDCI3) for photoproduct 43. 17 Assignment H-xa *H NMR(500MHz) 8 ppm (mult., J(Hz)) COSY(500MHz and 400MHz) correlations^ NOE(400MHz) Correlations0 - H-l 2.42(lH,s) H-5, H-2, H-3, H-8, H-8', H-9, H-9' str H-2, med H-8, med H-9, med H-9' H-2 2.73(lH,s) H-9, H-l str H-l , med H-10, med H-8 H-3 2.76(lH,s) H-10, H-10', H-4, H-l , H-5 str H-15, str H-4, med H-10, med H-10' H-4 3.64(lH,s) H-5, H-3, H-10, H-6 str H-15, med H-3, med H-5, med H-9' H-5 2.25(lH,s) H-4, H-3, H-l , H-6', H-9', H-6, H-9 H-6 1.56-1.53(lH,m) H-6', H-5, H-4, H-7 H-6' 2.21-2.18(lH,m) H-9', H-8, H-6, H-5, H-7 H-7 partofm(2H) 1.85-1.82(1H) H-6, H-10, H-6' H-8 1.73-1.70(lH,m) H-9', H-8', H-6', H-l H-8' partofm(2H) 1.85-1.82(1H) H-8, H-10', H-l H-9 1.81-1.77(lH,m) H-9', H-5, H-2, H-l H-9' 1.93-1.88(lH,m) H-9, H-8, H-6', H-5, H-l 150 H-10 1.51-1.48(lH,m) H-10',H-3,H-4,H-7 str H-10', med H-3, med H-2 H-10' 1.97-1.94(lH,m) H-10, H-3, H-8' H-12 3.76(3H,s) H-15 8.00-7.97(2H,m) H-16 med H-4, med H-3, med H-16 H-16 7.45-7.41(2H,m) H-15, H-17 H-17 7.52-7.48(lH,m) H-16 a- H indicates the hydrogen of a pair which is more downfield (H-6' is more downfield then H-6). b- Only those COSY correlations that could be unambiguously assigned are recorded. c- Only those NOE data that could be unambiguously assigned are recorded (str=strong, med=medium, w=weak). 151 Table 5.4. 125.8/500 MHz ^ C ^ H - shift correlations via HMQC (one bond couplings) and HMBC (long-range couplings) for photoproduct 43. 17 C-x 1 3 C shift (125.8MHz) 5 (ppm), APT 3 ] H shift (500MHz), ^ C ^ H one bond correlation, HMQCb> 5 C Oppm), assignment^ ^ C - ^ H long-range correlations, H M B C b , H-x 1 29.68(-ve) 2.42(lH,s)H-l H-2(2 bonds), H-5(3 bonds) 2 50.50(-ve) 2.73(lH,s) H-2 H-l0(3 bonds) 3 31.76(-ve) 2.76(lH,s) H-3 H-4(2 bonds), H-2(2 bonds) 4 48.02(-ve) •3.64(lH;s) H-4 H-2(3 bonds), H-6(3 bonds), H-9(3 bonds) 5 28.98(-ve) 2.25(lH,s) H-5 H-4(2 bonds) 6 32.40(+ve) 1.56-1.53(lH,m) H-6 2.21-2.18(lH,m)H-6' H-8(3 bonds), H-9'(3 bonds), H-10(3 bonds) 7 26.80(-ve) part of m(2H), 1.85-1.82(1H) H-7 H-6(2 bonds) 8 37.77(+ve) 1.73-1.70(lH,m)H-8 part of m (2H), 1.85-1.82(1H) H-8' H-6'(3 bonds), H-10'(3 bonds) 9 35.03(+ve) 1.81-1.77(lH,m) H-9 1.93-1.88(lH,m) H-9' H-2(3 bonds), H-8(3 bonds), H-4(3 bonds), H-6'(3 bonds) 152 10 33.18(+ve) 1.51-1.48(lH,m) H-10 1.97-1.94(lH,m) H-10' H-4(3 bonds), H-6(3 bonds) 11 175.00(+ve) H-12(3 bonds), H-2(2 bonds) 12 51.60(-ve) 3.77(3H,s) H-12 13 203.82(+ve) H-15(3 bonds), H-4(2bonds) 14 136.95(+ve) H-16(3 bonds), H-15(2 bonds) 15 128.40(-ve) or 128.38(-ve) 8.00-7.97(2H,m) H-15 16 128.40(-ve) or 128.38(-ve) 7.45-7.41(2H,m) H-16 17 132.27(-ve) 7.52-7.48(lH,m) H-17 H-15(3 bonds) a- The results of the APT experiments: (-ve) for CH and C H 3 , (+ve) for C and C H 2 . b- Only those HMQC and HMBC data that could be unambiguously assigned are reported, c- Reported chemical shifts are followed in parentheses by the number of protons and multiplicity of the peak, d- H' indicates the hydrogen from the pair of methylene hydrogens (-CHH1-) which is more downfield (H-6' is more downfield than H-6). re/-(lR,2R,3S,4R,5S,7R)-Methyl 4-benzoyItricydo[3.3.1.13'7]decane-2-carboxylate (44) J H NMR (CDC13, 500 MHz): 5 7.84-7.82 (2H, m), 7.53-7.50 (1H, m), 7.45-7.41 (2H, m), 3.66 (3H, s), 3.55 (1H, s), 3.19 (1H, s), 2.73 (1H, s), 2.32 (1H, m), 2.29 (1H, s), 2.07-2.04 (1H, m), 1.97-1.94 (1H, m), 1.92-1.85 (3H, m), 1.82-1.79 (1H, m), 1.75-1.72 (1H, m), 1.68-1.64 (1H, m), 1.60-1.57 (lH,m). 1 3 C NMR (CDCI3, 125.8 MHz): 8 203.36(+), 174.91(+), 136.71(+), 132.55(-), 128.57(-), 128.14(-), 52.11(-), 51.39(-), 44.53(-), 38.39(+), 34.69(+), 33.45(+), 33.35(+), 30.87(-), 153 30.24(-), 28.93(-), 27.14(-)'. L R M S : (EI+) m/e (relative intensity), 298(3.6, M + ) , 267(6.6), 266(27.3), 239(24.1), 238(100.0), 210(6.6), 196(3.3), 170(3.3), 158(4.2), 133(12.1), 119(2.8), 118(2.5), 117(3.2), 115(3.0), 106(5.1), 105(62.0), 93(4.1), 92(4.8), 91(22.9), 79(13.3), 78(6.9), 77(44.3), 67(5.0), 65(3.9), 59(3.7), 55(4.4), 51(7.8). H R M S : (EI+) Calculated mass for C19H22O3: 298.1569. Found: 298.1566. IR, cm" 1: (CHCI3) 2920, 2857, 1724, 1678, 1598, 1448, 1347, 1265, 1202, 1182, 1104, 1001, 959, 851, 697, 544, 518. 154 Table 5.5. ] H N M R data (400 and 500 MHz, CDC1 3) for photoproduct 44. Assignment H-xa J H NMR(500MHz) 5 ppm (mult., J(Hz)) COSY(500MHz and 400MHz) correlations^ NOE(400MHz) correlations0 H-1 2.32(lH,m) H-2, H-8, H-8', H-9 str H-2, med H-9', w H-8', w H-9 H-2 3.19(lH,m) H-3, H-1, H-8, H-10 str H-3, str H-1, med H-9' H-3 2.73(lH,s) H-4, H-2, H-10, H-10' str H-4, str H-2, med H-10, med H-10', vv H-15 H-4 3.55(lH,s) H-5, H-3, H-9 str H-15, str H-3, med H-5, med H-10 H-5 2.29(lH,s) H-4, H-9 med H-4, w H-9, w H-9' H-6 partofm(3H) 1.92-1 85(1H) H-6' partofm(3H) 1.92-1 85(1H) H-7 part of m (3H) 1.92-1.85(1H) H-8 1.60-1.57(lH,m) H-2, H-1, H-10, H-81 str H-8', med H-1 H-8' 1.82-1.79(lH,m) H-8', H-1 str H-1, med H-8, w H-10' H-9 1.68-1.64(lH,m) H-4, H-5, H-1, H-9' med H-1, med H-5, str H-9 H-9' 1.97-1.94(lH,m) H-9 str H-9, w H-1, w H-5, med H-2 155 H-10 1.75-1.72(lH,m) H-2, H-3, H-10', H-8 str H-10', w H-3, med H-4 H-10' 2.07-2.04(lH,m) H-10, H-3 str H-10, med H-3 H-12 3.66(3H,s) H-15 7.84-7.82(2H,m) H-16 str H-4, w H-3, w H-5, med H-16 H-16 7.45-7.41(2H,m) H-15 H-17 7.53-7.50(lH,m) a- H' indicates the hydrogen of a pair which is more downfield (H-6' is more downfield then H-6). b- Only those COSY correlations that could be unambiguously assigned are recorded. c- Only those NOE data that could be unambiguously assigned are recorded (str=strong, med=medium, w=weak). 156 Table 5.6. 125.8/500 MHz 1 3 C , ! H - shift correlations via H M Q C (one couplings) and H M B C (long-range couplings) for photoproduct 44. C-x 1 3 C shift (125.8MHz) 5 (ppm), APT 3 lH shift (500MHz), 1 3 C - ] H one bond correlation, HMQC b ' 5 C (ppm), assignment^  1 3C-*H long-range correlations, HMBC b , H-x 1 28.93(-ve) 2.32(lH,m)H-l H-2(2 bonds) 2 44.53(-ve) 3.19(lH,s) H-2 H-4(3 bonds), H-9(3 bonds), H-8(3 bonds), H-10(3 bonds) 3 30.87(-ve) 2.73(lHs) H-3 H-2(2 bonds) 4 52.11(-ve) 3.55(lH,s) H-4 H-10'(3 bonds), H-9(3 bonds) 5 30.24(-ve) 2.29(lH,s) H-5 H-4(2 bonds) 6 38.39(+ve) partofm(3H) 1.92-1.85(1H) H-6 part of m (3H) 1.92-1.85(1H) H-6' H-8'(3 bonds), H-4(3 bonds), H-10'(3 bonds) 7 27.14(-ve) part of m (3H) 1.92-1.85(1H) H-7 H-10'(2 bonds), H-8'(2 bonds), H-3 (3 bonds) 8 33.35(+ve) 1.60-1.57(lH,m) H-8 1.82-1.79(lH,m) H-8' H-2(3 bonds) 9 33.45(+ve) 1.68-1.64(lH,m) H-9 1.97-1.94(lH,m) H-9' H-4(3 bonds) 10 34.69(+ve) 1.75-1.72(lH,m) H-10 2.07-2.04(lH,m) H-10' H-4(3 bonds), H-2(3 bonds) H-8(3 bonds) 157 11 174.91(+ve) H-12(3 bonds), H-2(2 bonds) 12 51.39(-ve) 3.66(3H,s)H-12 13 203.36(+ve) H-15(3 bonds), H-4(2 bonds) 14 136.71(+ve) • H-16(3 bonds) 15 128.14(-ve) 7.84-7.82(2H,m)H-15 H-17(3 bonds) 16 128.57(-ve) 7.45-7.41(2H,m)H-16 17 132.55(-ve) 7.53-7.50(lH,m) H-17 H-15(3 bonds) a- The results of the APT experiments: (-ve) for C H and C H 3 , (+ve) for C and C H 2 . b- Only those H M Q C and H M B C data that could be unambiguously assigned are reported, c- Reported chemical shifts are followed in parentheses by the number of protons and multiplicity of the peak, d- H ' indicates the hydrogen from the pair of methylene hydrogens (-CHH'-) which is more downfield (H-6' is more downfield than H-6). 5.2.2. Detection of an Intermediate, 41, by * 3 C NMR COOCH 3 41 A solution of keto ester 28 (33 mg) in CD3CN (0.4 mL) was placed in a 5 mm N M R tube, purged with nitrogen and sealed. After recording a 1 3 C N M R spectrum of the sample the N M R tube was immersed in an ethanol/water bath, cooled to 0°C (Cryocool Immersion Cooler) and irradiated for 130 minutes. The 1 3 C N M R spectrum of the resulting mixture was recorded immediately after irradiation. Analysis of the spectrum showed the presence of 158 eighteen new "c N M R signals among the known signals of starting compound 28 and major photoproduct 42. The N M R tube with the reaction mixture was kept at room temperature for 3 days and a 1 3 C N M R spectrum was recorded on the same spectrometer. Analysis of the spectrum showed only the presence of starting compound 28 and major photoproduct 42. The additional C N M R signals observed immediately after photolysis were identified by comparison with the spectra of authentic samples of 28 and 42 in C D 3 C N and assigned to intermediate 41. 1 3 C N M R ( C D 3 C N , 100.6 MHz): 5 175.60, 146.51, 129.85, 127.77, 126.05, 125.57, 85,45, 58.51, 52.14, 45.84, 36.22, 35.92, 35.00, 34.85, 33.95, 32.12, 29.76, 25.82. 5.2.3. Base-Catalyzed Isomerization of Photoproduct 42 A sodium methoxide solution was prepared by dissolving sodium metal (66 mg, 2.9 mmol) in dry methanol (25 mL) under a nitrogen atmosphere and added via syringe to a solution of photoproduct 42 (93 mg, 0.3 mmol) in methanol (15 mL). The resulting mixture was stirred at room temperature for 2 days. As shown by GC analysis, the resulting equilibrium mixture was comprised of 10 % of compound 42, 82 % of compound 43, 5 % of compound 44, and 3 % of compound 46. The reaction mixture was quenched with 5 % hydrochloric acid and extracted with diethyl ether (2 x 50 mL). The ethereal layers were combined and washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate the solvent was 159 removed in vacuo. Radial chromatography of the residue (petroleum ether - ether , 40:1) resulted in compound 42 (8 mg, 0.03 mmol, (9% yield), compound 43 (47.8 mg, 0.2 mmol, 52% yield), compound 44 (6 mg, 0.02 mmol, 7% yield), and compound 46 (3 mg, 0.01 mmol, 3% yield). N M R and GC/MS analyses of compound 46 support the assumption that it is a stereoisomer of photoproduct 42, although its stereochemistry was not proven. Compound 46 G C / M S : m/e, 298(M+), 266, 238, 105, 91, 7 7 . lB N M R ( C D C 1 3 , 400 MHz): 5 7.80-7.78 ( 2 H , m), 7 . 5 3 - 7 . 4 9 ( 1 H , m As-H), 7 . 4 5 - 7 . 4 1 ( 2 H , m, As-H), 3.69 ( 3 H , s, O - C H 3 ) , 3 . 3 9 ( 1 H , s), 2 . 7 7 - 2 . 7 4 ( 2 H , m, ring-//), 2 . 4 3 ( 1 H , s, ring-H), 2.32 ( 1 H , s, ring-//), 2 . 0 2 - 1 . 7 9 ( 6 H , m, ring-//), 1.67-1.52 ( 3 H , m, ring-//). 1 3 C N M R ( C D 3 C N , 1 0 0 . 6 MHz): 5 198.84, 170.87, 135.04, 130.49, 126.82, 126 .32 ,53 .34 , 52,41, 51 .55, 40 .21 , 34 .89 , 34 .06 , 32.80, 31.78, 30.92, 30 .54, 28 .39 . 46 160 5.2.4. Base-Catalyzed Protium - Deuterium Exchange in Photoproduct 42 A solution of sodium methoxide (66.2 mg, 1.2 mmol) in CD3OD (1.5 mL) was added via syringe to a solution of photoproduct 42 (25.9 mg, 0.08 mmol) in CD3OD (0.5 mL) and stirred at room temperature for 2 days. As shown by GC analysis, the resulting equilibrium mixture contained four isomers in a ratio of 4.3 : 26 : 1.3 : 1 with retention times identical to those of 42, 43, 44, and 46, respectively. The reaction was quenched with I M hydrochloric acid and extracted with diethyl ether (2x10 mL). The combined ethereal layers were washed with water, saturated sodium chloride solution and dried over anhydrous magnesium sulfate, followed by removal of the solvent in vacuo. Radial chromatography of the residue yielded isomer 42D (3 mg, 0.01 mmol, 12 % yield) and isomer 43D (14 mg. 0.05 mmol, 54 % yield) as colorless oils. Compound 42D lB NMR (CDCI3, 400 MHz): 5 7.87-7.84 (2H, m), 7.53-7.48 (IH, m), 7.48-7.41 (2H, m), 2.92 (IH, s), 2.54-2.51 (2H, m), 2.36 (IH, s), 2.20 (IH, s), 2.13-2.10 (IH, m), 2.01 (IH, m), 1.95-1.82 (4H, m), 1,73-1.70 (IH, m), 1.58-1.55 (lH,m). 1 3 C NMR (CDC13, 75 MHz): 8 202.11, 173.75, 136.71, 132.30, 128.37, 127.97, 50.96, 50.58, 47.50, 39.94, 39.93, 38.05, 32.89, 29.02, 28.75, 28.29, 27.50. \ / P h 42D 161 2 H N M R (CHCI3, CDCI3, 46 MHz): 5 3.4 (m). L R M S : (EI+) m/e (relative intensity), 304(2.6), 303(10.1), 302(26.9), 301(5.0), 300(3.8), 299(2.5), 298(2.5), 268(5.2), 267(5.8), 240(7.4), 239(15.6), 238(4.2), 197(7.8), 194(4.6), 162(3.9), 135(4.6), 134(15.5), 133(3.7), 118(3.5), 106(8.8), 105(100.0), 93(4.8), 92(12.9), 91(11.5), 78(6.2), 77(36.0). Compound 43D lB N M R (CDCI3, 400 MHz): 5 8.00-7.98 (2H, m), 7.52-7.48 (1H, m), 7.45-7.41 (2H, m), 2.74-2.72 (2H, m), 2.42 (1H, s), 2.24-2.18 (2H, m), 1.99-1.70 (6H, m), 1.56-1.47 (2H,m). 1 3 C N M R (CDCI3, 75 MHz): 8 203.85, 175.03, 136.87, 132.28, 128.38, 50.45, 47.98, 37.72, 34.98, 33.10, 32.34, 31.63, 29.67, 28.85, 26.76. 2 H N M R (CHCI3, CDCI3, 46 MHz): 5 3.8(m). L R M S : (EI+) m/e (relative intensity), 304(5.7), 303(34.7), 302(88.3), 301(16.6), 299(3.6), 298(2.2), 268(4.7), 267(20.4), 266(47.8), 240(9.6), 239(18.8), 238(32.7), 237(4.4), 197(8.6), 183(3.6), 162(9.2), 161(7.5), 159(4.1), 158(3.1), 135(6.8), 134(22.7), 133(8.6), 118(3.8), 106(8.8), 105(100.0), 93(5.7), 92(18.8), 91(18.1), 80(6.4), 79(8.2), 78(7.5), 77(34.3), 67(3.8), 51(4.5). D C O O C D 3 43D 162 5.2.5. Base-Catalyzed Hydrolysis of Photoproduct 42 Following the procedure of E.J. Corey etal..47 photoproduct 42 (68 mg, 0.23 mmol) was stirred with a methanol - water (3:1) solution of lithium hydroxide (48 mg, 1.14 mmol) for 2 days at room temperature. Excess methanol was removed in vacuo and the residue was extracted with diethyl ether. The combined ethereal layers were acidified with concentrated hydrochloric acid, causing the formation of a cloudy solution which was extracted with a I M solution of sodium hydroxide. The aqueous layer was acidified with concentrated hydrochloric acid and re-extracted with diethyl ether. The ethereal fraction was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo to yield compound 51 (58 mg, 88 % yield) as a yellowish solid. The ethereal layer was washed with water, saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to yield 6.5 mg of colorless oil. The composition of the oil was determined by GC analysis: compound 42 (9%), compound 43 (74%), compound 44 (6%), and compound 46 (4%). 163 re/-(lR,2S,3S,4S,5S,7R)-4-Benzoyltricyclo[3.3.1.13'7]decane-2-carboxylic acid (51) M.P. 148-150°C. Anal. Calcd. for C 1 8 H 2 o03: C, 76.03; H , 7.09. Found: C, 75.98; H, 7.15. lH NMR (CDCI3, 400 MHz): 5 7.98-7.95 (2H, m, Ar-H), 7.51-7.39 (3H, m Ar-H), 3.66 (1H, s, ring-//), 2.81 (2H, s, ring-//), 2.49 (IH, s, ring-//), 2.29 (IH, s, ring-//), 2.18-2.15 (IH, m, ring-//), 2.03-1.73 (6H, m, ring-//), 1.57-1.51 (2H, m, ring-//). 1 3 C NMR (CDCI3, 75 MHz): 5 203.72(+), 180.76(+), 136.80(+), 132.31(-), 128.38(-), 128.34(-), 50.41(-), 48.14(-), 37.67(+), 34.99(+), 33.09(+), 32.30(+), 29.49(-), 29.02(-), 26.66(-). LRMS: (DCI+, N H 3 ) m/e (relative intensity), 303(5.8), 302(30.8), 286(17.4), 285(95.2), 284(100.0, M + ) , 283(3.9), 267(11.9), 266(22.8), 258(4.9), 242(6.6), 241(38.6), 240(39.1), 239(10.6), 238(15.2), 179(3.2), 162(3.0), 135(3.4), 133(3.1), 105(19.8). HRMS: (DCI+, NH3+CH4) Calculated mass for C 1 8 H 2 o 0 3 : 284.1412. Found: 284.1417. IR, cm" 1: (KBr pellet) 2921, 2851, 1709, 1669, 1597, 1578, 1508, 1448, 1422, 1378, 1343, 1307, 1290, 1267, 1250, 1234, 1159, 1102, 1054, 1014, 981, 939, 911, 850, 759, 741, 697, 659, 614, 528. 51 164 U V : («-pentane) X m a x 208(10000), 244(13000), 332(200) nm. 5.2.5. Photolysis of Compound 34 Following the general procedure for solution state photolysis a stirred solution of P-keto ester 34 (45 mg, 0.11 mmol) in acetonitrile (17 mL) was irradiated for 3 hours and 20 minutes (99% conversion of 34). GC analysis of the reaction mixture indicated the formation of two photoproducts. Due to partial overlapping of the chromatographic peaks the ratio of the products could not be determined accurately. The solvent was removed in vacuo and the residue was subjected to radial chromatography (petroleum ether - diethyl ether, 50:1). But the diastereomeric products could not be fully separated. Chromatographic separation was repeated twice (petroleum ether - diethyl ether, 100:1) and the collection of selected chromatography fractions yielded 47A (11 mg, 0.026 mmol, 24% yield) and 47B (14 mg, 0.033 mmol, 31% yield) as white solids (Fig.3.22). Following the general procedure for solid state photolysis a solid sample of compound 34 was irradiated for 1 hr. GC analysis of the reaction mixture indicated 100% conversion of the starting material and formation two photoproducts in a ratio of 93:7 (Fig.3 32). The main photoproduct was identified by N M R and GC/MS as compound 47B. The isolation of the minor photoproduct 48 in pure form was not achieved. It was analyzed by GC/MS and ' H N M R in the mixture of 48 and 47B 165 (1S,2R,3R,4S,5R,7S)- [(lS)-endo]-(-)-BornyI 4-benzoyltricycIo[3.3.1.13>7]decane-2-carboxyIate (47A) M.P. 127-130°C. Anal. Calcd. for C28H36O3: C, 79.96; H , 8.63. Found: (diastereoisomeric mixture 47A+47B) C, 79.79; H , 8.79. !H NMR (CDCI3, 500 MHz): 8 7.83-7.81 (2H, m), 7.49-7.46 (1H, m), 7.43-7.39 (2H, m), 4.64-4.61 (1H, m), 3.43 (1H, s), 3.93 (1H, s), 2.57-2.53 (1H, m), 2.51 (1H, m), 2.41 Q H , s), 2.38-2.32 (1H, m), 2.22 (1H, s), 2.14-2.11 (1H, m), 1.93-1.87 (4H, m), 1.85-1.83 (1H, m), 1.75-1.67 (3H, m), 1.62-1.59 (1H, m), 1.34-1.28 (1H, m), 1.23-1.20 (1H, m), 1.19-1.16 (1H, m), 0.86 (3H, s), 0.84 (3H, s), 0.70 (3H, s). 1 3 C NMR (CDCI3, 125 MHz): 8 202.31(+), 173.55(+), 137.37(+), 132.03(-), 128.26(-), 128.10(-), 80.32(-), 50.56(-), 48.56(+), 48.00(-), 47.47(+), 44.93(-), 40.10(+), 39.02(+), 38.22(+), 36.35(+), 33.18(-), 29.18(-), 28.72(-), 28.50(-), 27.92(+), 27.63(-), 27.33(+), 19.65(-), 18.90(-), 13.41(-). LRMS: (EI+) m/e (relative intensity), 420(6.9, M + ) , 285(2.9), 284(14.3), 283(7.6), 269(4.5), 268(30.0), 267(100.0), 266(5.4), 240(6.7), 239(25.9), 238(7.9), 137(13.6), 136(4.9), 134(6.5), 121(3.4), 107(3.1), 106(5.0), 105(54.4), 95(7.4), 93(8.4), 92(4.4), 91(8.8), 84(4.2), 81(19.8), 79(7.7), 77(15.3), 69(6.2), 67(5.6), 55(4.8). HRMS: (EI+) Calculated mass for C28H36O3: 420.2665. Found: 420.2666. IR, cm" 1: (KBr pellet) 2921, 2850, 1719, 1679, 1598, 1581, 1448, 1376, 1347, 1330, 1308, 166 Table 5.7. ] H NMR data (400 and 500 MHz, CDC1 3) for photoproduct 47A. Assignment H-xa ] H NMR(500MHz) 8 ppm (mult., J(Hz)) COSY(500MHz and 400MHz) correlations'5 NOE(400MHz) correlations0 H-l 2.41(lH,s) H-2, H-9, H-3 w H-8, w H-8', H-9 H-2 2.51(lH,m) H-3, H-l str H-3, w H-8, w H-10 H-3 2.93(lH,s) H-4, H-2, H-l, H-5, H-10' med H-4, str H-2, w H-10', w H-10, med H-24 H-4 3.43(lH,s) H-5, H-3, H-9, H-10' str H-24, med H-3, med H-5, w H-10', w H-6 H-5 2.22(lH,s) H-9, H-4, H-3, H-9', H-6 str H-4, w H-9, w H-6 H-6 1.85-1.83(lH,m) H-5, H-7 H-6' part of m (4H) 1.93-1.87(1H) H-7 2.02-2.01(lH,m) H-10', H-6 H-8 part of m(3H) 1.75-1.67(1H) str H-2, med H-l, med H-7 H-8' part of m (4H) 1.93-1.87(1H) 167 H-9 1.62-1.59(lH,m) H-4, H-5, H-l, H-9' w H-l, med H-5, str H-9' H-9' 2.57-2.53(lH,m) H-9, H-5 str H-9, w H-l, med H-5 H-10 partofm(4H) 1.93-1.87(1H) H-10' 2.14-2.11(lH,m) H-7, H-3 str H-4, str H-3, str H-10 H-12 4.65-4.61(lH,m) H-17, H-17' H-14 1.23-1.20(lH,m) H-15 med H-20, med H-14' H-14' partofm(4H) 1.93-1.87(1H) H-15 1.34-1.28(lH,m) H-15' part of m (3H) 1.75-1.67(1H) H-16 part of m (3H) 1.75-1.67(1H) H-17 1.19-1.16(lH,m) H-17', H-12 med H-17' H-17' 2.38-2.32(lH,m) H-17, H-12 H-19 0.86(3H,s) med H-12, w H-17' H-20 0.84(3H.s) H-21 0.70(3H,s) medH-12 H-24 7.83-7.81(2Hm) H-25 H-25 7.42-7.38(2H,m) H-24, H-26 H-26 7.49-7.46(lH,m) H-25 a- H' indicates the hydrogen of a pair which is more downfield (H-6' is more downfield then H-6). b- Only those COSY correlations that could be unambiguously assigned are recorded. c- Only those NOE data that could be unambiguously assigned are recorded (str=strong, med=medium, w=weak). 168 Table 5.8. 125.8/500 M H z 1 3 C , ] H - shift correlations via H M Q C (one bond couplings) and H M B C (long-range couplings) for photoproduct 47A. C-x 1 3 C shift (125.8MHz) 8 (ppm), APT 3 lH shift (500MHz), 1 3 C - J H one bond correlation, HMQCD> 8C (ppm), assignment'* 1 3 C - * H long-range correlations, H M B C 0 , H-x 1 28.50(-ve) 2.41(lH,s) H-l 2 48.00(+ve) 2.51(lH,s)H-2 H-4(3 bonds), H-9(3 bonds), H-l(2 bonds), H-10'(3 bonds) 3 33.18(-ve) 2.93(lH,s)H-3 H-2(2 bonds), H-4(2 bonds) 4 50.56(-ve) 3.43(lH,s) H-4 H-2(3 bonds), H-9(3 bonds) 5 28.72(-ve) 2.22(lH,s) H-5 H-4(2 bonds), H-3 (3 bonds) 6 39.02(+ve) part of m (4H) 1.93-1.87(1H) H-6' 1.85-1.83(lH,m) H-6 H-4(3 bonds), H-10'(3 bonds) 7 27.63(-ve) 2.02-2.01(lH,m) H-7 8 38.22(+ve) part of m (4H) 1.93-1.87(1H) H-8 part of m (3H) 1.75-1.67(1H) H-8' H-10'(3 bonds), H-6(3 bonds) 9 29.18(+ve) 1.62-1.59(lH,m)H-9 2.57-2.53(lH,m) H-9' H-2(3 bonds) 169 10 40.10(+ve) part of m (4H) 1.93-1.87(1H) H-10 2.14-2.11(lH,m)H-10' H-4(3 bonds) 11 173.55(+ve) H-2(2 bonds) 12 80.32(-ve) 4.65-4.6 l(lH,m) H-12 13 or 18 48.56(+ve) H-12, H-21,H-19, H-20 13 or 18 47.47(+ve) H-21, H-19, H-20 14 27.33(+ve) part of m (2H) 1.23-1.20(1H) H-14 part of m (4H) 1.93-1.87(1H) H-14' H-12(3 bonds), H-21(3 bonds) 15 27.92(+ve) 1.34-1.28(lH,m) H-15 part of m (3H) 1.75-1.67(1H) H-15' 16 44.93(-ve) partofm(3H) 1.75-1.67(1H) H-16 17 36.35(+ve) 1.19-1.16(lH,m) H-17 2.38-2.32(lH,m) H-17' H-12(2 bonds) 19 18.90(-ve) 0.86(3H,s) 20 19.65(-ve) 0.84(3H,s) 21 13.41(-ve) 0.70(3H,s) H-21 H-12(3 bonds) 22 202.3 l(+ve) H-24(3 bonds), H-4(2 bonds) 23 137.37(+ve) 24 or 25 128.26(-ve) 7.42-7.38(2H,m) H-25 or 7.83-7.8l(2H,m) H-24 24 or 25 128.10(-ve) 7.42-7.38(2H,m) H-25 or7.83-7.81(2H,m) H-24 26 132.03(-ve) 7.49-7.46(lH,m) H-26 a- The results of the APT experiments: (-ve) for CH and C H 3 , (+ve) for C and C H 2 . b- Only those HMQC and HMBC data that could be unambiguously assigned are reported, c- Reported chemical shifts are followed in parentheses by the number of protons and multiplicity of the peak, d- H' indicates the hydrogen from the pair of methylene hydrogens (rCHH1-) which is more downfield (H-6' is more downfield than H-6). 1 7 0 (1R,2S,3S,4R,5S,7R)- [(lS)-endo]-(-)-Bornyl 4-benzoyltricyclo[3.3.1.13>7]decane-2-carboxylate (47B) M.P. 124-128°C. Anal. Calcd. for C28H36O3: C, 79.96; H , 8.63. Found: (diastereoisomeric mixture 47A+47B) C, 79.79; H , 8.79. i H NMR (CDCI3, 500 MHz): 5 7.84-7.82 (2H, m), 7.50-7.45 (IH, m), 7.42-7.38 (2H, m), 4.86-4.85 (IH, m), 3.44 (IH, s), 2.92 (1H, s), 2.59-2.55 (IH, m), 2.52 (IH, s), 2.41 (IH, s), 2.21 (IH, s), 2.18-2.11 (2H, m), 1.94-1.76 (5H, m), 1.75-1.74 (IH, m), 1.66-1.53 (3H, m), 1.26-1.18 (1H, m), 1.03-0.97 (IH, m), 0.87 (3H, s), 0.86 (3H, s), 0.83 (3H, s), 0.81-0.78 (1H, m). 1 3 C NMR (CDCI3, 125 MHz): 5 202.05(+), 173.43(+), 137.34(+), 132.06(-), 128.29(-), 128.13(-), 79.32(-), 50.58(-), 49.03(+), 48.23(-), 47.82(+), 44.85(-), 40.16(+), 39.04(+), 38.26(+), 36.17(+), 32.78(-), 29.20(+), 28.84(-), 28.56(-), 27.85(+), 27.66(-), 27.22(+), 19.70(-), 18.94(-), 13.53(-). LRMS: (EI+) m/e (relative intensity), 420(4.3, M + ) , 285(1.9), 284(9.3), 283(6.2), 269(4.3), 268(31.6), 267(100.0), 266(4.3), 240(6.7), 239(26.9), 238(6.4), 153(5.0), 137(6.7), 136(2.7), 134(3.4), 121(2.3), 105(20.8), 95(2.2), 93(3.0), 91(3.1), 81(5.1), 77(3.5). HRMS: (EI+) Calculated mass for C 2 8 H 3 6 0 3 : 420.2665. Found: 420.2661. IR, cm" 1: (KBr pellet) 2917, 2854, 1727, 1680, 1599, 1581, 1447, 1378, 1337 1306, 1273, 1256, 1206, 1161, 1114, 1074, 1058, 1041, 1024, 984, 959, 845, 766, 754, 692, 649, 620. 171 Table 5.9. *H N M R data (400 and 500 MHz, CDCI3) for photoproduct 47B. 7 Assignment H-xa lH NMR(500MHz) 8 ppm (mult., JQHz)) COSY(500MHz and 400MHz) correlationsb NOE(400MHz) correlations0 H-1 2.41(lH,s) H-2, H-9', H-4, H-9 med H-2, w H-8, w H-8', w H-9 H-2 2.51(lH,m) H -3, H-1 med H -3 , med H-1, w H-10, w H-8 H-3 2.92(lH,s) H-4, H-2, H-5, H-10', H-1 med H-24, med H-4, med H-2, w H-10', w H-10 H-4 3.44(lH,s) H-5, H -3, H-1 str H-24, med H -3 , med H-5, w H-10', w H-6 H-5 2.21(lH,s) H-9, H-9', H -3, H-4 med H-4, w H-9' H-6 partofm5H 1.94-1.76(1H) H-6' part of m 5H 1.94-1.76(1H) H-7 2.02(lH,s) H-8 1.75-1.74(lH,m) str H-2, med H-1, med H-7 H-8' partofm5H 1.94-1.76(1H) 172 H-9 partofm(3H) 1.66-1.55(1H) H-l, H-9', H-5 H-9' 2.58-2.55(lH,m) H-l, H-5, H-9 str H-9, med H-5 H-10 part of m (5H) 1.94-1.76(1H) H-10' H-10' partofm(2H)2.18-2.11(lH) H-3, H-10 H-12 4.86-4.82(lH,m) H-17', H-17 str H-19, med H-21, w H-17' H-14 1.25-1.19(lH,m) H-15 str H-=14',w H-20 H-14' partofm(5H) 1.94-1.76(1H) H-15 1.03-0.97(lH,m) H-14 str H-15', med H-16, w H-17, w H-14' H-15' part of m (3H) 1.66-1.55(1H) H-16 partofm(3H) 1.66-1.55(1H) H-17 0.81-0.78 (lH,m) H-17', H-12 str H-17', w H-16 H-17' partofm(2H)2.18-2.11(lH) H-17, H-12 H-19 0.86(3H,s) str H-12, wH-17' H-20 0.84(3H,s) w H-15', w H-14 H-21 0.87(3H,s) med H-12 H-24 7.84-7.82(2H,m) H-25 str H-25, str H-4, med H-3 H-25 7.42-7.39(lH,m) H-24, H-26 H-26 7.50-7.45(2H,m) a- H indicates the hydrogen of a pair which is more downfield (H-6' is more downfield then H-6). b- Only those COSY correlations that could be unambiguously assigned are recorded. c- Only those NOE data that could be unambiguously assigned are recorded (str=strong, med=medium, w=weak). 173 Table 5.10. 125.8/500 MHz ^ C ^ H - shift correlations via HMQC (one bond couplings) and H M B C (long-range couplings) for photoproduct 47B. 7 C-x 1 3 C shift (125.8MHz) 5 (ppm), APT3 lU shift (500MHz), 1 3 C - ! H one bond correlation, HMQCb> 5 C Oppm), assignment^  ^C-^H long-range correlations, HMBC0, H-x 1 28.56(-ve) 2.41(lH,s) H-1 H-9(2 bonds), H-7(3 bonds) 2 48.23(-ve) 2.51(lH,s) H-2 H-4(3 bonds), H-10'(3 bonds) H-9'(3 bonds), H-9(3 bonds) 3 32.78(-ve) 2.92(lH,s) H-3 H-2(2 bonds), H-4(2 bonds) 4 50.58(-ve) 3.43(lH,s) H-4 H-2(3 bonds), H-10(3 bonds) H-3(2 bonds) 5 28.84(-ve) 2.21(lH,s)H-5 6 39.04(+ve) partofm(5H) 1.94-1.76(2H) H-6 H-7(2 bonds), H-10'(3 bonds) 7 27.66(-ve) 2.02(lH,s) H-7 8 38.26(+ve) part of m (H) 1 • 94-1.76(2H) H-8' 1.75-1.74(lH,m) H-8 H-10'(3 bonds) 9 29.20(+ve) part of m (3H) 1.66-1.55(1H) H-9 2.58-2.55(lH,m) H-9' H-2(3 bonds), H-1 (2 bonds) 174 10 40.16(+ve) partofm(5H) 1.94-1.76(1H) H-10 part of m (2H) 2.18-2.11(1H) H-10' H-2(3 bonds) 11 173.55(+ve) H-2(2 bonds) 12 79.32(-ve) 4.86-4.82(lH,m) H-12 13 49.03(+ve) H-14(2 bonds) 14 27.22(+ve) 1.25-1.19(lH,m) H-14 partofm(5H) 1.94-1.76(1H) H-14' H-12(3 bonds), H-21(3 bonds) 15 27.85(+ve) 1.03-0.97(lH,m) H-15 partofm(3H) 1.66-1.55(1H) H-15' 16 44.85(-ve) partofm(3H) 1.66-1.55(1H) H-16 H-19(3 bonds), H-20(3 bonds) 17. 36.17(+ve) 0.81-0.78(lH,m) H-17 part of m (2H)2.18-2.11(1H) H-17' H-12(2 bonds) 18 47.82(+ve) H-14'(3 bonds), H-16(2 bonds) 19 18.90(-ve) 0.86(3H,s)H-19 20 19.65(-ve) 0.84(3H,s) H-20 21 13.53(-ve) 0.87(3H,s) H-21 H-12(3 bonds) 22 202.05(+ve) H-25(3 bonds) 23 137.34(+ve) H-25(3 bonds), H-4(3 bonds) 24 128.13(-ve) 7.84-7.82(2H,m) H-24 H-26(3 bonds) 25 128.29(-ve) 7.42-7.39(2H,m) H-25 26 132.06(-ve) 7.50-7.45(lH,m) H-26 H-24(3-bonds) a- The results of the APT experiments: (-ve) for CH and C H 3 , (+ve) for C and C H 2 . b- Only those HMQC and HMBC data that could be unambiguously assigned are reported, c- Reported chemical shifts are followed in parentheses by the number of protons and multiplicity of the peak, d- H' indicates the hydrogen from the pair of methylene hydrogens (-CHH1-) which is more downfield (H-6' is more downfield than H-6). 175 Compound 48 V I /^COO-(-)-bornyl 48 GC/MS: m/e, 420(rvf), 284, 267, 266, 240, 239, 238, 210, 207, 195, 179, 170, 158, 147, 137, 133, 129, 121, 119, 117, 115, 109, 108, 107, 106, 105, 95, 93, 92, 91, 81, 79, 77, 69, 67, 57, 55. \ lB NMR (CDCI3, 400 MHz)*: 8 7.84-7.82 (2H, m), 7.53-7.49 ( I H , m), 7.45-7.41 (2H, m), 4.86-4.83 ( I H , m), 3.55 ( I H , s), 3.13 ( IH , s), 2.76 ( I H , s), 2.34-2.30 (m). 5.2.7. Photolysis of Compound 35 A solution of keto ester 35 (25 mg, 0.06 mmol) in acetonitrile (32 mL) was irradiated for 1 hour (98% conversion). GC analysis of the reaction mixture indicated the formation of two photoproducts in an approximate ratio of 37:63. After removal of the solvent in vacuo radial chromatography (petroleum ether - diethyl ether, 400:1) of the mixture yielded diastereomers 49A (5 mg, 0.012 mmol) and 49B (8 mg, 0.019 mmol) (Fig.3.36). Irradiation of a solid sample of compound 35 for 1 hour (76% conversion) led to formation of diastereomers 49A and 49B in a ratio of 41:59 as shown by GC and N M R analyses. * Resolved 'H NMR signals attributed to the compound 46 in its mixture with 8-keto ester 45B. 176 (1S,2R,3R,4S,5R,7S)- [(lR)-endo]-(+)-Fenchyl 4-benzoyltricyclo[3.3.1.13>7]decane-2-carboxylate (49A) M.P. 119-123°C. Anal. Calcd. for C28H36O3: C, 79.96; H, 8.63. Found: (diastereoisomeric mixture 49A+49B) C, 79.83; H, 8.61. !H NMR (CDCI3, 500 MHz): 6 7.84-7.82 (2H, m), 7.49-7.46 (1H, m), 7.42-7.39 (2H, m), 4.29 (1H, d, J=1.8Hz), 3.44 (IH, s), 2.84(1H, s), 2.53 (IH, s), 2.48-2.42 (2H, m), 2.21 (IH, s), 2.23 (IH, s), 2.12-2.10 (IH, m), 2.02 (lH,s), 1.93-1.84 (4H, m), 1.78-1.75 (1H, m), 1.71-1.56 (4H, m), 1.53-1.50 (IH, m), 1.43-1.37 (lH,m), 1.12-1.09 (4H, m), 1.00-0.95 (IH, m), 0.86-0.85 (3H, s). 1 3 C NMR (CDCI3, 125 MHz): 6 201.80(+), 173.97(+), 137.54(+), 131.91(-), 128.21(-), 128.09(-), 85.78(-), 50.49(-), 48.35(-), 48.33(+), 48.19(-), 41.34(+), 40.13(+), 39.45(+), 38.91 (+), 38.38(+), 32.63(-), 29.57(-), 29.24(+), 28.80(-), 28.75(-), 27.70(-), 26.61(+), 25.97(+), 20.49(-), 19.33(-). LRMS: (EI+) m/e (relative intensity), 420(6.0, M+), 285(2.6), 284(14.3), 283(2.8), 269(4.0), 268(27.6), 267(100.0), 266(4.7), 240(6.3), 239(27.0), 238(4.9), 153(9.4), 137(6.3), 134(3.2), 105(24.0), 91(2.5), 81(4.8), 77(2.6). HRMS: (EI+) Calculated mass for C28H36O3: 420.2665. Found: 420.2658. IR, cm" 1: (KBr pellet) 2925, 2850, 1727, 1677, 1446, 1378, 1339, 1273, 1259, 1242, 1202, 1162, 1104, 1077, 1045, 1032, 1010, 962, 845, .758, 694. 177 Table 5.11. ] H N M R data (400 and 500 MHz, CDC1 3) for photoproduct 49A. Assignment H-xa lU NMR(500MHz) 5 ppm (mult., J(Hz)) COSY(500MHz and 400MHz) correlations0 NOE(400MHz) correlations0 H-1 2.42(lH,s) H-8, H-3 w H-8, w H-9 H-2 2.53(lH,s) H-3 med H-3, w H-8, w H-10 H-3 2.84(lH,s) H-4, H-2, H-5, H-10', H-1 med H-24, med H-4, med H-2, w H-10' H-4 3.44(lH,s) H-5, H-3, H-9 str H-24, med H-3, med H-5 w H-10', w H-6 H-5 2.23(lH,s) H-3, H-9, H-9', H-4 med H-4, w H-9 H-6 part of m(4H) 1.93-1.84(1H) H-61 part of m(4H) 1.93-1.84(1H) H-7 2.02(lH.s) H-8 H-8 1.78-1.75(lH,m) H-1, H-9',H-7 str H-8', med H-2, w H-1, w H-7 H-8' partofm(4H) 1.93-1.84(1H) 178 H-9 1.59-1.56(lH,m) H-4, H-9', H-5 H-9' 2.48-2.45(lH,m) H-8, H-5, H-9 str H-9, w H-5 H-10 partofm(4H) 1.93-1.84(1H) H-10' 2.12-2.10(lH,m) H-3 str H-10, str H-4, med H-3' H-12 4.29(lH,d,J=1.8Hz) H-16 w H-21, w H-19, w H-18' H-14 partofm(3H) 1.71-1.62(1H) H-15 1.43-1.37(lH,m) H-16 w H-18, w H-16 H-15' part of m (3H) 1.71-1.62(1H) H-16 1.00-0.95(lH,m) H-15, H-12, H-18' H-16' part ofm(3H) 1.71-1.62(1H) H-18 part of m (4H) 1.12-1.09(1H) H-18' 1.53-1.50(lH,m) H-16, H-18 H-19 0.86(3H,s) H-20 0.85(3H,s) H-21 part ofm(4H) 1.12-1.09(3H) str H-12, w H-20 H-24 7.84-7.82(2H,m) H-25 str H-25, str H-4, med H-3 H-25 7.42-7.39(2H,m) H-24 H-26 7.49-7.46(lH,m) a- H' indicates the hydrogen of a pair which is more downfield (H-6' is more downfield then H-6). b- Only those COSY correlations that could be unambiguously assigned are recorded. c- Only those NOE data that could be unambiguously assigned are recorded (str=strong, med=medium, w=\veak). 179 Table 5.12. 125.8/500 MHz 1 3 C , ] H - shift correlations via HMQC (one bond couplings) and HMBC (long-range couplings) for photoproduct 49A. C-x 1 3 C shift (125.8MHz) 5 (ppm), APT3 • ] H shift (500MHz), 1 3 C - ! H one bond correlation, HMQC0' 5C 0PPm), assignment'* ^ C - ' H long-range correlations, HMBC0, H-x 1 28.80(-ve) 2.42(lH,s) H-l 2 48.19(-ve) 2.53(lH,s) H-2 H-4(3 bonds) 3 32.63(-ve) 2.84(lH,s) H-3 H-2(2 bonds), H-4(2 bonds) 4 50.49(-ve) 3.44(lH,s) H-4 H-2(3 bonds) 5 28.75(-ve) 2.23(lH,s) H-5 6 38.91(+ve) part of m (4H) 1.93-1.84(2H) H-6, H-6' 7 27.70(-ve) 2.02(lH,s) H-7 8 38.26(+ve) 1.78-1.75(lH,m) H-8 part of m (4H) 1.93-1.84(1H) H-8' H-2(3 bonds) 9 29.24(+ve) part of m (4H) 1.59-1.56(1H) H-9 2.48-2.45(lRm) H-9' H-4(3 bonds), H-2(3 bonds) 180 10 40.13(+ve) part of m (4H) 1.93-1.84(1H) H-10 2.12-2.10(lH,m)H-10' H-2(3 bonds) 11 173.97(+ve) H-l2(3 bonds), 2(2 bonds) 12 85.78(-ve) 4.29(lH,d,J=1.8Hz) H-12 13 39.45(+ve) H-l5(3 bonds), H-21(2 bonds) H-20(2 bonds), H-12(2 bonds) 14 48.35(-ve) partofm(3H) 1.71-1.62(1H) H-14 15 25.97(+ve) 1.43-1.37(lH,m) H-15 part of m (3H) 1.71-1.62(1H) H-15' 16 17 26.61(+ve) 48.33(+ve) 1.00-0.95(lH,m) H-16 part of m (3H) 1.71-1.62(1H) H-16' H-12(3 bonds), H-19(3 bonds) 18 41.34(+ve) part ofm(4H) 1.12-1.09(1H) H-18 1.53-1.50(lH,m)H-18' HI9(3 bonds) 19 19.33(-ve) 0.86(3H,s) H-19 H-12(3 bonds) 20 20.49(-ve) 0.85(3H,s) H-21 H-21(3 bonds) 21 29.57(-ve) part of m (4H) 1.12-1.09(1H) H-20 H-12(3 bonds), H-20(3 bonds) 22 201.80(+ve) H-24(3 bonds), H-4(2 bonds) 23 137.54(+ve) H-25(3 bonds) 24 128.09(-ve) 7.84-7.82(2H,m) H-24 25 128.21(-ve) 7.42-7.39(2H,m) H-25 26 131.91(-ve) 7.49-7.46(lH,m) H-26 H-24(3 -bonds) a- The results of the APT experiments: (-ve) for CH and C H 3 , (+ve) for C and C H 2 . b- Only those HMQC and HMBC data diat could be unambiguously assigned are reported, c- Reported chemical shifts are followed in parentheses by the number of protons and multiplicity of the peak, d- H' indicates the hydrogen from the pair of methylene hydrogens (-CHH'-) which is more downfield (H-6' is more downfield than H-6). 181 r<?/-(lR,2S,3S,4R,5S,7R)- [(lR)-endo]-(+)-FenchyI 2-benzoyltricyclo[3.3.1.13>7]decane-2-carboxylate (49B) M.P. 78-82°C. Anal. Calcd. for C 2 8 H 3 6 0 3 : C, 79.96; H : 8.63. Found: (diastereoisomeric mixture 49A+49B) C, 79.83; H , 8.61. ! H NMR (CDC1 3 , 500 MHz): 6 7.82-7.80 (2H, m), 7.49-7.45 (1H, m), 7.42-7.39 (2H, m), 4.34 (1H, d, J=1.9Hz), 3.43 (1H, s), 2.88(1H, s), 2.53-2.51 (2H, m), 2.43-2.42 (1H, m), 2.23 (1H, s), 2.13-2.10 (1H, m), 2.02-2.01 (1H, m), 1.92-1.83 (4H, m), 1.77-1.73 (1H, m), 1.70-1.57 (5H, m), 1.46-1.35 (1H, m), 1.18 (3H,s), 1.16-1.14 (1H, m), 1.10-1.04 (1H, m), 0.99 (3H, s), 0.64 (3H, s). 1 3 C NMR (CDC1 3 , 125 MHz): 5 202.17(+), 173.45(+), 137.44(+), 131.93(-), 128.21(-), 128.14(-), 85.37(-), 50.54(-), 48.65(+), 48.28(-), 48.19(-), 41.49(+), 40.05(+), 39.54(+), 38.99(+), 38.27(+), 32.70(-), 29.57(-), 29.34(+), 28.71(2C)(-), 27.62(-), 26.77(+), 25.82(+), 20.13(-), 19.55(-). LRMS: (EI+) m/e (relative intensity), 420(2.3, M + ) , 284(4.4), 283(3.6), 269(4.0), 268(28.3), 267(100.0), 266(1.6), 240(3.5), 239(15.0), 238(2.9), 153(9.9), 137(6.9), 134(3.3), 106(2.8), 105(33.1), 95(3.0), 91(4.4), 81(13.9), 77(7.9), HRMS: (EI+) Calculated mass for C 2 8 H 3 6 0 3 : 420.2665. Found: 420.2675. IR, cm" 1: (KBr pellet) 2927, 1723, 1674, 1446, 1368, 1338, 1256, 1218, 1078, 1044, 1010, 960,757,695. 182 Table 5.13. ! H N M R data (400 and 500 MHz, CDCI3) for photoproduct 49B. Assignment H-x a J H NMR(500MHz) 5 ppm (mult., J0Hz)) COSY(500MHz and 400MHz) correlations'3 NOE(400MHz) correlations0 H-l 2.43-2.42(lH,m) H-8, H-9 w H-8, w H-9 H-2 part of m (2H) 2.53-2.51(lH) H-3 wH-8, wH-10 H-3 2.88(lH,s) H-2, H-4, H-5, H-10' med H-4, str H-2, w H-10 w H-10' med H-24 H-4 3.43(lH,s) H-5, H-3, H-9 med H-3, med H-5, med H-10', w H-6 str H-24 H-5 2.23(lH,s) H-3, H-4, H-9 str H-4, w H-9, w H-9', w H-6 wH-6' H-6 H-6' part of m (4H) 1.92-1.83(1H) H-7 2.02-2.01(lH,m) wH-8 H-8 1.77-1.73(lH,m) H-l str H-2, med H-l H-8' partofm(4H) 1.92-1.83(1H) H-9 partofm(5H) 1.70-1.57(1H) H-l , H-4, H-5, H-9' H-9' partofm(2H) 2.53-2.51(lH) H-5, H-9 183 H-10 part of m (4H) 1.93-1.84(1H) H-10' 2.12-2.10(lH,m) H-3 str H-4, med H-3, str H-10 H-12 4.34(lH,d,J=1.9Hz) H-16 med H-20, str H-19, str H-21 H-14 part ofm(5H) 1.70-1.57(1H) H-15 1.45-1.35(lH,m) H-16 med H-18 H-15' partofm(5H) 1.70-1.57(1H) H-16 1.10-1.04(lH,m) H-15, H-12 H-16' part of m (5H) 1.70-1.57(1H) H-18 1.16-1.14(lH,m) H-18' part ofm(5H) 1.70-1.57(1H) H-19 1.18(3H,s) str H-12 H-20 0.64(3H,s) wH-12, str H-21 H-21 0.99(3H,s) med H-20, str H-12 H-24 7.82-7.80(2H,m,J=7.2Hz) H-25 str H-25, str H-4, med H-3 H-25 7.42-7.39(2H,m) H-24 H-26 7.49-7.45(lH,m) a- H' indicates the hydrogen of a pair which is more downfield (H-6' is more downfield then H-6). b- Only those COSY correlations that could be unambiguously assigned are recorded. c- Only those NOE data that could be unambiguously assigned are recorded (str=strong, med=medium, w=weak). 184 Table 5.14. 125.8/500 M H z l3C,lU - shift correlations via H M Q C (one bond couplings) and H M B C (long-range couplings) for photoproduct 4 9 B . C-x 1 3 C shift (125.8MHz) 5 (ppm), APT3 J H shift (500MHz), 1 3 C - r H one bond correlation, HMQC0' 5C (ppm), assignment^  ^ C - ' H long-range correlations, HMBC0, H-x 1 28.71(-ve) 2.43-2.42(lH,m)H-l 2 48.19(-ve) part of m (2H) 2.53-2.51(IH) H-2 -> J 32.70(-ve) 2.88(lH,s) H-3 H-4(2 bonds), H-2(2 bonds) 4 50.54(-ve) 3.43(lH,s)H-4 5 28.71(-ve) 2.23(lH,s) H-5 6 38.99(+ve) part of m (4H) 1.93-1.83(2H) H-6 7 27.62(-ve) 2.02-2.01(lH,m)H-7 8 38.27(+ve) 1.77-1.73(lH,m) H-8 part of m (4H) 1.92-1.83(1H) H-8' 9 29.34(+ve) part of m (5H) 1.70-1.57(1H) H-9 H-4(3 bonds) part of m (2H) 2.53-2.51(lH) H-9' 185 10 40.05(+ve) partofm(4H) 1.92-1.83(1H) H-10 2.13-2.10(lH,m)H-10' 11 173.45(+ve) H-12(3 bonds), -2(2 bonds) 12 85.37(-ve) 4.34(lH,d,J=1.9Hz)H-12 H-19(3 bonds), H-20(3 bonds) H-21(3 bonds) 13 39.54(+ve) H-21(2 bonds), H-12(2 bonds) H-20(2 bonds) 14 48.28(-ve) part of m (5H) 1.70-1.57(1H) H-14 H-20(3 bonds), H-21(3 bonds) 15 25.82(+ve) 1.45-1.35(lH,m) H-15 part of m (4H) 1.70-1.57(1H) H-15' 16 26.77(+ve) 1.00-0.95(lH,m) H-16 part of m (4H) .1.70-1.57(1H) H-16' H-12(3 bonds), H-19(3 bonds) 17 48.65(+ve) H-12(2 bonds), H-19(2 bonds) 18 41.49(+ve) 1.16-1.14(lH,m) H-18 part of m (5H) 1.70-1.57(1H) H-18' HI9(3 bonds) 19 19.55(-ve) 1.18(3H,s) H-19 H-12(3 bonds) 20 20.13(-ve) 0.99(3H,s) H-20 H-21(3 bonds) 21 29.57(-ve) 0.64(3H,s) H-21 H-12(3 bonds), H-20(3 bonds) 22 202.17(+ve) H-24(3 bonds), H-4(2 bonds) 23 137.44(+ve) H-25(3 bonds) 24 128.14(ve) 7.82-7.80(2H,m) H-24 25 128.2 l(-ve) 7.42-7.39(2H,m) H-25 26 131.93(-ve) 7.49-7.45(lH,m) H-26 H-24(3-bonds) a- The results of the APT experiments: (-ve) for CH and C H 3 , (+ve) for C and C H 2 . b- Only those HMQC and HMBC data that could be unambiguously assigned are reported. c- Reported chemical shifts are followed in parentheses by the number of protons and multiplicity of the peak. d- H' indicates the hydrogen from the pair of methylene hydrogens (-CHH'-) which is more downfield (H-6' is more downfield than H-6). 186 5.2.8. Photolysis of Compound 33 Irradiation of compound 33 in acetonitrile for 3 hours (97% conversion) led to formation of photoproducts 50A and 50B in a ratio of 60:40, as determined by GC analysis (Fig.3.46). These photoproducts were not separable by radial chromatography and were analyzed as a diastereomeric mixture. Photoproducts 50A and 50B. M.P. 96-100°C. Anal. Calcd. for C 2 8 H 3 8 O 3 : C, 79.57; H, 9.07. Found: C, 79.43; H, 9.05. !H NMR ( C D C I 3 , 500 MHz): 5 7.88-7.83 (2H, m), 7.50-7.39 (3H, m), 4.59-4.50 (IH, m), 3.42 (IH, s), 2.94(1H, bs), 2.55-2.48 (2H, m), 2.41-2.37 (IH, m), 2.21 (IH, s), 2.15-2.11 (IH, m), 2.01 (IH, m), 1.92-1.72 (6H, m), 1.67-1.47 (4H, m), 1.36-1.33 (IH, m), 1.09-0.62 (13H, m). 1 3 C NMR ( C D C I 3 , 125 MHz): 5 202.06(+), 201.55(+), 172.91(+), 172.76(+), 137.32(+), 137.20(+), 132.03(-), 131.96(-), 128.27(-), 128.23(-), 128.06(-), 74.07(-), 73.98(-), 50.60(-), 50.55(-), 48.41(-), 47.99(-), 46.95(-), 40.31(+), 40.17(+), 40.00(+), 39.01(+), 38.25(+), 38.19(+), 34.38(+), 34.25(+), 33.11(-), 32.83(-), 31.35(-), 31.26(-), 29.26(+), 28.69(-), 28.62(-), 28.57(-), 27.66(-), 27.59(-), 26.23(-), 25.90(-), 23.54(+), 23.00(+), 22.21(-), 22.01(-), 20.91(-). 187 LRMS: (EI+) m/e (relative intensity), 423(14.2), 422(45.9, M + ) , 297(11.9), 286(8.3), 285(49.1), 284(86.4), 283(56.9), 269(3.4), 268(24.8), 267(100.0), 266(25.5), 250(3.7), 241(4.0), 240(24.1), 239(41,0), 238(59.3), 237(3.9), 211(3.5), 192(3.7), 180(3.5), 179(20.7), 163(7.0), 162(33.5), 139(3.6), 138(13.0), 136(4.5), 135(18.0), 134(55.5), 133(11.5), 123(4.4), 120(3.7), 119(3.8), 107(3.4), 106(7.5), 105(80.5), 95(8.3), 93(5.7), 92(4.9), 91(11.2), 83(6.6), 81(6.3), 79(6.7), 77(13.5), 55(3.4). HRMS: (E1+) Calculated mass for C28H38O3: 422.2821. Found: 422.2820. IR, cm" 1: (KBr pellet) 2916, 2852, 1724, 1682, 1598, 1581, 1446, 1369, 1347, 1306, 1274, 1259, 1206, 1162, 1103, 1078, 1059, 1023, 1011, 974, 957, 916, 846, 767, 754, 694, 650, 621. 5.2.9. Photolysis of Salt 40 In accordance with the general procedure for solid state photolysis, salt 40 was irradiated for 1 hour. The irradiated sample was removed from the slides, cooled to 0°C, and an excess of ethereal diazomethane was added. GC analysis of the resulting mixture showed a 100% conversion of the starting material and formation of methyl esters 42, 43 and 44 in a ratio of 60:7:33. Chiral GC analysis of methyl ester 42 revealed that one enantiomer (42B) was formed almost exlusively (>99% ee). 188 5.2.10. Transesterification of Photoproducts Obtained by Photolyses of Keto Ester 34 Following the modified procedure of B.C.Ranu et al}1 indium triiodide was prepared in situ under a nitrogen atmosphere by stirring indium metal (2.4 eq) and iodine (3.6 eq) in methanol at room temperature for 30 minutes. A mixture of diastereomers (1 eq), obtained by photolysis of keto ester 34 (in solution or in the solid state) was dissolved in dry methanol under a nitrogen atmosphere and added to the indium triiodide solution. The mixture was heated at reflux and monitored by TLC and GC. After completion, methanol was removed by distillation and the residue was extracted with diethyl ether. The extract was washed successively with saturated solution of sodium thiosulfate, saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. Evaporation of diethyl ether in vacuo resulted in a mixture of transesterification products. 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Stereochemistry of Organic Compounds, John Wiley and Sons, Inc.: New York, 1994, pp 647-655. 56. Lewis, F. D.; Johnson, R. W. J. Am. Chem. Soc. 1 9 7 2 , 94, 8915. 57. Ranu, B. C ; Dutta, P.; Sarkar, A. J. Org. Chem. 1998, 63, 6027. 58. Perrin, D. D., Armarego, W. L . F.; Perrin, D. R. Purification of Laboratory Chemicals, 2 n d Edition, Pergamon Press: Oxford, 1980. 194 Appendix I Geometric Data from X - R a y Structure Analysis of P-Keto Ester 34. Table 1. Geometrical parameters for y-hydrogen abstraction in P-keto ester 34. y-H d, (A) ©, (°) A, O e, (°) H x 2.50. 58.01 83.61 116.90 Hy 3.38 44.02 44.14 110.93 Table 2. Crystallographically derived biradical parameters for p-keto ester 34. a-p bond < P 4 : O < P i , ( ° ) D , (A) C 2 - C 3 -29.8 68.3 3.01 195 Appendix II Geometric Data from X-Ray Structure Analysis of p-Keto Ester 35 Table 1. Geometrical parameters for y-hydrogen abstraction in P-keto ester 35. y-H d, (A) co, (°) A, (°) molecule 1 H x 2.38 47.11 93.30 118.70 H v 3.16 52.24 53.20 114.00 molecule 2 H x 2.34 47.85 93.34 118.78 H v 3.23 51.81 53.09 111.97 molecule 3 H x 3.24 51.28 52.47 112.02 H v 2.39 47.64 92.45 118.70 molecule 4 H x 3.32 48.41 48.91 110.56 H v 2.42 51.72 90.45 117.96 196 

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