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Asymmetric induction in the solid state photoisomerization of some three-membered ring compounds Chong, Ching Wah (Kenneth) 2003

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A S Y M M E T R I C INDUCTION IN THE SOLID STATE PHOTOISOMERIZATION OF SOME T H R E E - M E M B E R E D RING COMPOUNDS by Ching Wah (Kenneth) Chong  B.Sc. (Hons.), The University o f British Columbia, 1998  A THESIS S U B M I T T E D IN P A R T I A L F U L F I L M E N T OF THE REQUIREMENTS FOR THE D E G R E E OF D O C T O R OF PHILOSOPHY in T H E F A C U L T Y OF G R A D U A T E STUDIES ( D E P A R T M E N T OF CHEMISTRY) W e accept this thesis as conforming to the required standard  T H E UNIVERSITY OF BRITISH C O L U M B I A September 2003 © C h i n g W a h Chong, 2003  In presenting this thesis in partial fulfilment o f the requirements for an advanced degree at the University o f British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying o f this thesis for scholarly purposes may be granted by the head o f my department or by his or her representatives. It is understood that copying or publication o f this thesis for financial gain shall not be allowed without my written permission.  C  Department o f Chemistry The University o f British Columbia Vancouver, Canada  September 23, 2003  Abstract  The ionic chiral auxiliary approach to asymmetric induction was investigated in two types o f photoisomerizations o f cyclopropyl compounds in the solid state.  Three different tri-substituted cyclopropyl carboxylic acids were prepared.  Upon  irradiation, the achiral starting materials undergo cis-trans isomerization to form chiral products.  Salts were formed between the achiral acids and optically pure amines. The  resulting chiral samples were irradiated i n the solid state, and the photoproducts analyzed for enantiomeric purity. Enantiomeric excesses ranging from poor to excellent were obtained. The enantioselectivity observed is controlled by both topochemical and chiral conformational effects.  The same method o f asymmetric induction was applied to study the solid state photochemistry o f two achiral cyclopropyl ketoacids, which underwent the Norrish type II cleavage reactions to give chiral olefins. Enantioselectivities ranging from moderate to excellent were observed when optically active salts o f these acids were irradiated in the crystalline state. The study presents the first successful asymmetric induction in a Norrish type II cleavage reaction. The starting materials are thermally reactive and undergo the enolene rearrangement to give the same chiral olefins. The salts prepared from one o f the ketoacids remained solid at the reactive temperature, and the product showed low to moderate ee.  ii  Table of Contents Abstract  ii  Table o f Contents  iii  List o f Figures  vii  List o f Tables  x  List o f Symbols and Abbreviations  xii  Acknowledgements  .  xiv  Introduction  1  Chapter 1 Introduction  1  1.1  General considerations  1  1.2  Photochemistry  3  1.3  Organic photochemistry — electronic aspects  3  1.4  Photochemistry o f ketones  7  1.5  Solid state photochemical reactions - structure-reactivity correlations  9  1.6  Geometric requirements for the Norrish type II hydrogen atom abstraction  12  1.7  The fate o f the 1,4-biradical  14  1.8  Asymmetric synthesis in the crystalline state  15  1.9  The ionic chiral auxiliary approach  21  1.10 Research objectives  25  Results and Discussion  28  Chapter 2 Asymmetric  synthesis in  the  cyclopropyl compounds  geometric  isomerization  of some 28  iii  2.1 General considerations 28 2.1.1 Early attempts at asymmetric induction in the cis-trans isomerization o f 1,2diphenylcyclopropane 28 2.1.2 The use o f chiral auxiliaries to induce asymmetric isomerization 29 2.2  Photoisomerization o f trans, trans-2, 3-diphenyl-l-cyclopropane carboxylic acid derivatives 30 2.2.1 Synthesis o f substrates 30 2.2.2 Photochemistry o f derivatives o f acid 37 33 2.2.3 Dimorphs o f methyl ester 38 35 2.2.4 Asymmetric photoisomerization o f derivatives o f acid 37 i n the crystalline state '. 37 2.2.5 Structure-reactivity correlations 43 2.2.6 Photochemistry o f derivatives o f acid 53 46 2.2.7 Asymmetric photoisomerization o f derivatives o f acid 53 in the crystalline state 48 2.2.8 Structure-reactivity correlations 54  2.3  Photoisomerization o f A-(trans, fra«5 -2,3-dibenzoylcyclopropyl-l-)benzoic acid derivatives 63 2.3.1 Synthesis o f substrates 63 2.3.2 Photochemistry o f ester 72 66 2.3.3 Asymmetric photoisomerization in the crystalline state 68 2.3.4 Structure-reactivity correlations 71 2.3.5 Conformational enantiomerism 79 2.3.6 Solid state racemization o f the cis,trans-\somevl 80  2.4  ,  Summary  83  Chapter 3 The Norrish type II reaction and enolene rearrangement of cyclopropyl 84  ketones 3.1 General considerations 3.1.1 The Norrish type II reaction of cyclopropyl ketones 3.1.2 The enolene rearrangement o f cyclopropyl ketones 3.1.3 Asymmetric synthesis in the isomerization o f cyclopropyl ketones 3.2  84 84 86 87  Isomerization of cis, cw-2,3-bis(benzyloxymethyl)-l-benzoylcyclopropane derivatives 89 3.2.1 Synthesis o f substrates 89 3.2.2 Solution photolysis 90 3.2.3 Identification o f photoproducts 92 3.2.4 Solid state photochemistry 97 3.2.5 Stereoselectivity in solution and the solid state 98 3.2.6 Asymmetric synthesis in the crystalline state 99 3.2.7 Chiral crystalline state reactivity 104  iv  3.2.8 3.2.9 3.2.10 3.2.11  H P L C peak assignments Stereoselectivities for optically active salts Structure reactivity correlations Thermal reactivity o f derivatives o f acid 85  107 108 110 117  3.3  Isomerization o f 9-tricyclo[4.4.1.0]undecyl 4-carboxyphenyl methanone derivatives 118 3.3.1 Preparation o f substrates 118 3.3.2 Photochemistry o f 9-tricyclo[4.4.1.0]undecyl 4-(carbomethoxyphenyl) ketone 103 119 3.3.3 Photochemical asymmetric synthesis o f derivatives o f acid 102 128 3.3.4 Structure-reactivity correlations 133 3.3.5 Thermal reactivity o f derivatives o f acid 102 136 3.3.6 Structure-reactivity correlations 139 3.3.7 Single crystal-to-single crystal thermal rearrangement o f keto-ester 103... 140  3.4  Summary  146  Experimental  147  Chapter 4 Preparation of Substrates  147  4.1  General Considerations  4.2  Synthesis derivatives  4.3  Synthesis o f trans, Jra«.s-2,3-diphenyl-l-benzoylcyclopropane derivatives  166  4.4  Synthesis of derivatives  acid 187  4.5  Syntheses derivatives  4.6  Synthesis derivatives  of  of  of  trans,  147 trans  4-(trans,  cis,  2,3-diphenylcyclopropane-l-carboxylic  ?ra«5-2,3-dibenzoylcyclopropyl-l-)  benzoic •  czs-2,3-bis(benzyloxymethy)-l-benzoylcyclopropane 201  9-tricyclo[4.4.1.0]undecyl  4-carboxyphenyl  methanone 216  Chapter 5 Photochemical studies 5.1  acid 151  233  General considerations  233  5.2  Photolysis o f trans, trans-2, 3-diphenylcyclopropane-lderivatives 5.2.1 Preparative photolysis o f ester 38 5.2.2 Preparative photolysis o f esters o f acid 53  v  carboxylic  acid 235 235 237  5.3  Photolysis o f A-(trans, /ran.s-2,3-dibenzoylcyclopropyl-l-) derivatives 5.3.1 Photolysis o f esters o f acid 71  benzoic  acid 241 241  5.4  Photolysis of cis, cw-2,3-bisbenzyloxymethyl-l-benzoylcyclopropane derivatives 247 5.4.1 Preparative photolysis o f compound 86 247  5.5 Photolysis o f 9-tricyclo[4.4.1.0]undecyl 4-carboxyphenyl ketone derivatives .. 249 5.5.1 Preparative photolysis o f compound 103 249  vi  List of Figures Figure 1.1.1 (a) an enantioselective  alkylation.  (b) a Simmons-Smith reaction — a  stereoselective addition o f CH2 Figure 1.3.1 H O M O and L U M O in C - C ( c r - > G * ) , C=C  1 (TI—>TT*)  and C = 0  (n->7t*)  4  Figure 1.3.2 Jablonski diagram for molecular photophysical processes  5  Figure 1.3.3 The concept o f triplet energy transfer  6  Figure 1.4.1 A Norrish type I reaction leading to formation of a ketene  7  Figure 1.5.1 Photochemistry of trans-cirmamic acid  10  Figure 1.5.2 [2+2] Photoaddition of /rarcs-stilbene 15 in the pseudorotaxane complex  17a  11  Figure 1.6.1 Four geometric parameters governing solid state y-hydrogen abstraction... 12 Figure 1.7.1 The solid state reactivity o f three spiroketones 19, 20, and 21  15  Figure 1.8.1 Difference i n solid state enantioselectivity in (a) an achiral crystal lattice and (b) a chiral crystal lattice  18  Figure 1.8.2 The first example o f absolute asymmetric synthesis  19  Figure 1.8.3 Examples of photochemical absolute asymmetric syntheses  20  Figure 1.8.4 Application o f a chiral host for solid state asymmetric synthesis  21  Figure 1.9.1 A hypothetical energy diagram o f the solid state reaction o f an optically pure salt formed from an achiral reactive anion and an optically pure ammonium cation auxiliary  22  Figure 1.9.2 Applications of the ionic chiral auxiliary approach  23  Figure 1.10.1 Orbital overlap in cyclopropane  25  Figure 1.10.2 Geometric photoisomerization of three cyclopropyl compounds  26  Figure 1.10.3 Cyclopropyl ketones selected for the study of enantioselective Norrish type II cleavage  27  Figure 2.1.1 Substrates chosen for study  29  Figure 2.2.1 cis, trans-esters 115 and 118  31  Figure 2.2.2 H N M R signals o f the C - H protons on the cyclopropane ring of (a) trans, !  trans-ester 38 and (b) cis, trans-ester 115  vn  32  Figure 2.2.3 H N M R signals o f the C - H protons on the cyclopropane ring of (a) trans, !  trans-ester 52 and (b) cis,frans-ester118 Figure 2.2.4 D S C thermograms of dimorphs o f ester 38  32 36  Figure 2.2.5 Chiral G C trace ofthe crystalline phase photolysis of ester 38 (dimorph A ) 38 Figure 2.2.6 A hypothetical case - the influence of a chiral crystal lattice on  the  enantioselectivity of the system  44  Figure 2.2.7 Crystal structure ofthe prism form of ester 38  45  Figure 2.2.8 Separation ofthe enantiomers o f ester 118  52  Figure 2.2.9 (a) Photochemistry of ketone 144 (b) Chair (i) and boat (ii) conformations of ketone 144  55  Figure 2.2.10 Photochemistry of ketone 149  56  Figure 2.2.11 Overlap o f p-orbital on C = 0 with C 1 - C 2 and C 1 - C 3 bonds at different values o f 9  57  Figure 2.2.12 Crystal structures o f ester 52  58  Figure 2.2.13 Crystal structure of chiral samples 64 and 66  59  Figure 2.2.14 Conformational and lattice effects on the solid state photoisomerization of derivatives of acid 53  61  Figure 2.3.1 Definition o f a i and co  73  Figure 2.3.2 Some possible conformations of geometry 1  73  Figure 2.3.3 Three possible conformations of geometry 2  74  Figure 2.3.4 Some possible conformations o f geometry 3  75  Figure 2.3.5 Overlap o f t h e p-orbital with the p bonds when a i increases form 90° to 180°  76  Figure 2.3.6 Crystal structure of ester 80  78  Figure 2.3.7 O R T E P drawing of ester 81  79  Figure 2.3.8 Conformation enantiomersim o f ester 81  80  Figure 2.3.9 Mechanism o f racemization o f cis, trans-isomer 124 via (a) C 1 - C 2 bond rotation and (b) C 1 - C 2 and C 1 - C 3 two bonds rotation  82  Figure 3.1.1 Substrates chosen for study  88  Figure 3.2.1 H labeling system o f products 129 and 130  92  viii  Figure 3.2.2 H N M R spectra o f a) product 130 and b) product 129  93  Figure 3.2.3 ' H C O S Y of product 129 (cis isomer)  94  Figure 3.2.4 ' H C O S Y o f product 130 (trans isomer)  95  Figure 3.2.5 Possible conformations of 129 and 130  97  !  Figure 3.2.6 H P L C separation ofthe enantiomers of photoproducts 129 and 130  101  Figure 3.2.7 Hypothetical energy-reaction diagram for the Norrish type II reaction of salts of acid 85  105  Figure 3.2.8 A hypothetical case - distribution o f diastereomers 129S,  129R,  130S  and  130R after solid state photolysis of an optically active salts o f acid 85. . 106 Figure 3.2.9 Sample calculation of the selectivity in each ofthe two steps  109  Figure 3.2.10 Crystal structure of ester 86  112  Figure 3.2.11 Three torsion angles that determine the C=O...Hx distance and angular abstraction parameters o f H a and Hb  114  Figure 3.2.12 A "hula-twist" like rotation  115  Figure 3.2.13 Crystalline state racemization of compound 167  116  Figure 3.3.1 IR study ofthe solid state photochemistry of ester 103  120  Figure 3.3.2 H labeling pattern of some hydrogens in the enol intermediate  121  Figure 3.3.3 T w o diastereomers of the D-incorporated ketone 133  122  Figure 3.3.4 Ketonization o f enol 132  123  Figure 3.3.5 ' H N M R spectrum o f ketone 133 i n C D C 1  3  125  Figure 3.3.6 H M Q C spectrum of ketone 133  126  Figure 3.3.7 Separation o f the enantiomers o f ester 133  130  Figure 3.3.8 O R T E P drawing o f the crystal structure of ester 103  133  Figure 3.3.9 D S C thermograms of some derivatives of acid 102  137  Figure 3.3.10 Crystal structure of ketone 103  142  Figure 3.3.11 Crystal structure of the 68 % mixed crystal  142  Figure 3.3.12 Crystal structure of enol 132  143  Figure 3.3.13 Lowest energy conformation of enol 132 calculated by MM+ molecular mechanics  144  ix  List of Tables Table 2.2.1 Ee's obtained from different samples o f the needle dimorph o f ester 38  37  Table 2.2.2 Optically active salts prepared from acid 37  40  Table 2.2.3 Solid state photolysis o f optically active salts o f acid 37  42  Table 2.2.4 Optically active salts prepared from keto-acid 53  48  Table 2.2.5 Optically active esters prepared from keto-acid 53  50  Table 2.2.6 Solid state photolysis o f optically active salts o f keto-acid 53  51  Table 2.2.7 Solid state photolysis o f optically active esters o f keto-acid 53  53  Table 2.2.8 The angles 9 o f some derivatives o f acid 53  60  Table 2.3.1 Optically active salts prepared from acid 71  68  Table 2.3.2 Optically active esters prepared from acid 71  69  Table 2.3.3 Solid state photolyses o f optically active salts 73-77  70  Table 2.3.4 Solid state photolysis o f optically active esters 78-81  71  Table 2.3.5 Effects o f cti and ot2 on selective bond fission and stereoselectivity  76  Table 2.3.6 Torsion angles i n chiral esters 80 and 81  76  Table 3.2.1 Product ratio o f isomers 129, 130 and secondary photoproduct 131a when ester 130 was irradiated i n C H C N 3  Table 3.2.2 H assignments o f products 129 and 130  92 96  Table 3.2.3 Ratio o f photoproducts 129 and 130 obtained in solution and solid state photolyses  97  Table 3.2.4 Optically active salts prepared from keto-acid 85  99  Table 3.2.5 Solid state photolysis o f salts o f acid 85  102  Table 3.2.6 Selectivity o f hydrogen atom abstraction and biradical cleavage  109  Table 3.2.7 Abstraction parameter values o f the four y- Hydrogen atoms o f ester 86 .. 110 Table 3.3.1 Results o f solution photolyses o f compound 103  120  Table 3.3.2 H and C assignments o f 133  124  Table 3.3.3 Optically active salts prepared from keto-acid 102  128  Table 3.3.4 Solid state photolysis o f optically active salts o f keto-acid 102  131  Table 3.3.5 Hydrogen abstraction parameter for H a and Hb o f 103  134  x  Table 3.3.6 Thermolysis o f the optically active salts in the solid state  138  Table 3.3.7 Crystal data and structure refinement for crystals containing 15%, 25%, 68% and 1 0 0 % o f e n o l l 3 2  141  Table 3.3.8 B o n d angles and lengths o f selected atoms in ketone 103 and enol 132  xi  144  List of Symbols and Abbreviations A  angstrom  A  heat  6  chemical shift (ppm)  O  quantum yield  anal.  analysis  APT  attached proton test  aq.  aqueous  bp  boiling point  br  broad  C D 6  6  benzene-Jtf  CI  Chemical ionization  calcd  calculated  cat.  catalytic  CDCI3  chloroform-d  CD3OD  methanol-J^  COSY  l  d  doublet  dd  doublet of doublets  de  diastereomeric excess  DSC  Differential scanning calorimetry  DMF  dimethylformamide  ee  enantiomeric excess  EI  electron impact  ESI  Electrospray ionization  Et 0 2  diethyl ether  EtOAc  ethyl acetate  EtOH  ethanol  GC  gas chromatography  h  hour(s)  rl- H correlation spectroscopy l  xii  hv  light  HMBC  heteronuclear multiple bond connectivity  HMQC  heteronuclear multiple quantum coherence  HPLC  high performance liquid chromatography  HRMS  high resolution mass spectrometry  ER  infrared  IUPAC  International U n i o n o f Pure and Applied Chemistry  J  coupling constant (Hz)  LRMS  low resolution mass spectrometry  LSEMS  liquid secondary ionization mass spectra  M  molarity  Me  methyl  MeOH  methanol  MeCN  acetonitrile  m  multiplet  min  minute  mp  melting point  NMR  nuclear magnetic resonance  OAc  acetate  ORTEP  Oak Ridge Thermal Ellipsoid Program  Ph  phenyl  'Pr  isopropyl  ppm  parts per million  q  quartet  quint  quintet  s  singlet  t  triplet  TFA  trifluoroacetic acid  THF  tetrahydrofuran  TMS  trimethylsilyl  U V / VIS  ultraviolet / visible  xiii  Acknowledgements I would like to express my deepest gratitude to Dr. John Scheffer for his guidance, patience, encouragement, and support over the last five years.  H i s valuable comments  and suggestions were essential for the preparation o f this thesis.  I would like to thank the current and past members o f the Scheffer group for their help and encouragement.  Special thanks go to D r Eugene Cheung and D r Matthew  Netherton, who gave me a lot o f help and advice even after they left the group, and Wayne Chou for proofreading this manuscript.  I am grateful to Dr. Andre B . Charette and M r J.-F. Foumier o f the University o f Montreal for devising a synthetic route for one o f the starting materials. I could not have synthesized the substrate successfully without help from Fourni er.  Finally, I would like to thank D r Brian Patrick in the U B C X - r a y crystallography laboratory, and Carl Scott for their help on X-ray crystal structure determinations.  I  would also like to express my appreciation to the staff in the N M R laboratory, mass spectrometry facilities, and the Chemistry Department at the University o f British Columbia.  xiv  Chapter 1 Introduction 1.1 General considerations The quest for new methods o f stereoselective synthesis is important, especially for the pharmaceutical industry, because stereoisomers usually have different biological properties and chemical reactivities. experiments i n the solution phase.  For many years, chemists have been conducting The molecules are free to undergo conformational  changes i n such a medium, and intermolecular collisions occur in any direction. A s a result, chemical reactions occur v i a different conformations and pathways, and usually lead to the formation o f a mixture o f isomers. A s the medium is isotropic, the reaction environment has little effect on the selectivity o f the reaction. electronic effects determine the reaction selectivities. starting  materials  or  catalysts  carefully, such  Instead, steric and  Chemists have designed the  that highly regio-,  diastereo-,  or  enantioselective reactions can be induced by controlling the steric and electronic effects  Figure 1.1.1 (a) an enantioselective alkylation. (b) a Simmons-Smith reaction — a stereoselective addition o f CH2  o f the reactions.  For example, a highly enantioselective alkylation is achieved by using a  chiral oxazolidone (Figure 1.1.1a).  1  The bulky auxiliary blocks the bottom face o f the  molecule, such that the reaction has to go via the more open top face, leading to the formation o f only one enantiomer. In the Simmons-Smith reaction shown i n Figure  1  1.1.1b, the oxygen atom coordinates with the Z n complex, which leads to a highly 2  stereoselectivite addition o f CH2 to the double bond and avoids an insertion reaction. There are numerous examples o f successful and highly stereoselective reactions, which are obtained by using carefully designed reactants. However, instead o f tailoring the reacting molecules, a stereoselective reaction can also be achieved i f the reaction is carried out i n a more organized and constrained medium. In recent years,  organized media,  such  as  polymer thin  films,  cyclodextrins, and crystals have been utilized to carry out stereoselective  zeolites, reactions.  4  Translational mobility and conformational flexibility are reduced in these anisotropic reaction media. The reactions are therefore more selective because the trajectories that are attainable in solution become inaccessible. Reactions i n the crystalline phase have been studied extensively. One o f the advantages o f studying this kind o f reaction is that no external agent is required.  The constrained medium is made up exclusively o f the  reacting molecules. Problems such as binding efficiency i n a two-component system can be avoided.  In addition, the crystal lattice is constructed by repeating the unit cell.  Therefore, the conformation and environment o f each molecule in the unit cell are uniform  throughout  the  structure.  More importantly,  with the  help  of  X-ray  crystallography, the solid state conformation and the confined environment can be revealed.  This provides useful information to rationalize the solid state reactivity and  mechanism o f the system being studied. There are some disadvantages  in studying solid state reactions.  Since the  molecular movements are more restricted, reaction rates are usually slower than their solution counterparts.  Another problem is that crystals melt and soften as temperature or  conversion increases. A s crystals melt, the reaction is no longer occurring in a confined space and selectivity is lost. Although some high temperature crystalline reactions have been reported, the study o f solid state reactions is still limited due to the melting o f the 5  starting materials. However, as light can induce reaction without heating, photochemical reactions have been studied extensively in the crystalline state. The objective o f this thesis is to study highly enantioselective photochemical reactions in the crystalline state. Before going into detail i n the Results and Discussion  2  section, the concepts o f photochemistry, selectivity i n crystalline state reactions, and crystal structure-reactivity-correlations w i l l be discussed first.  1.2 Photochemistry When a compound absorbs a photon o f appropriate energy, it becomes an excited state species and is highly energetic. This often leads to the formation o f a product that would be kinetically unstable i f formed v i a a ground state reaction.  Because o f this,  photochemistry has become an important tool for chemists to prepare "inaccessible" molecules. However, early studies o f photochemistry were hindered b y a very important factor, the light source. The earliest studies o f a photochemical reaction utilized sunlight as the irradiation source.  6  This light source is relatively weak, and broad wavelengths o f  light are absorbed by the compounds. was limited.  A s a result, the development o f photochemistry  The study has been revolutionized since the beginning o f the twentieth  century, following the invention o f an artificial light source: the mercury broadband arc lamp. This highly intense light source speeds up the rates o f photochemical reactions and led to a rapid development in this area.  1.3  Organic photochemistry — electronic aspects When a molecule absorbs a photon possessing energy equivalent to the energy  difference between the highest occupied molecular orbital ( H O M O ) and the lowest unoccupied molecular orbital ( L U M O ) , transition o f an electron from the H O M O to the L U M O occurs and an excited state is created.  In general, there are four possible  transitions i n organic molecules, which include a—»a*, n—>a*, n—>n* and n—»rr* transitions. The energy difference between the H O M O and L U M O o f a sigma bond is large, and requires very strong excitation energy (far U V region). Therefore, the ci—»CT* transition is not very important i n organic photochemistry. 7i—»7i*  The energy differences in  or n—>n* transitions are near the U V - v i s i b l e region, and therefore compounds  3  possessing double bonds or carbonyl groups are usually more photoactive. In general, functional groups like double bonds that absorb light are called chromophores.  a*  TC*  LUMO  g  LUMO  TC* L U M O n TC a  C-C  HOMO  HOMO  HOMO  c=c  C=0  Figure 1.3.1 H O M O and L U M O in C - C ( C T - X J * ) , C=C (TI-»7I*) and C = 0 (n->7i*).  In the ground state, the two electrons in the H O M O have opposite spins. Therefore, the total spin quantum number, S, equals 0 (+V2 + (-V2)). Hence, the spin multiplicity, which is defined as 25+1, is 1. The spin multiplicity o f the ground state is a singlet, and the ground state is denoted as So, where the subscript 0 indicates the ground state. According to the selection rules for electronic spectroscopy, the change o f spin multiplicity must be zero in a transition. U p o n excitation, the two unpaired electrons must still have opposite spins and the electronic state o f the excited species is still a singlet and is termed S i . The subscript 1 denotes that this is the first excited state. A s a result, direct excitation from the ground state always lead to a singlet excited state, So - » S,. In the excited singlet state, the two unpaired electrons are i n different orbitals, and therefore Pauli's exclusion principle does not apply. The two electrons can possess the same spin state, and the spin mulitplicity can become 3, or a triplet state (T). This spin inversion is known as intersystem crossing (ISC). This is a forbidden process, but occurs to some extent through spin-orbit coupling, most often when a heavy atom is present in  4  the molecule.  9  According to Hund's rule, the triplet state has a lower energy than the  singlet state, and the lifetime ofthe triplet state is longer than that ofthe singlet state. The excited species can relieve its excess energy by undergoing physical or chemical processes. The possible physical processes o f an excited molecule are shown in the Jablonski Diagram (Figure 1.3.2).  10  ic = internal conversion (non-radiative) isc = intersystem crossing (non-radiative) fluor = fluorescence (radiative) phos = phosporescence (radiative)  S = singlet state T = triplet state  Figure 1.3.2 Jablonski diagram for molecular photophysical processes.  In most cases, electrons are excited from So to Si, but promotion to S2 and higher levels is also possible. The excited molecule can return to its ground state by two different kinds o f physical routes: radiative and non-radiative.  The two non-radiative  routes are internal conversion and intersystem crossing. In both cases, the excited state decays without emission o f light. In internal conversion, there is no change in the spin state.  11  The molecule in the Si state drops to So by giving up its energy to the  environment, and hence this is a relatively slow process. In intersystem crossing, the spin state inverts from singlet to triplet. There is no loss in energy in this process. The excess energy ofthe Si state is retained by crossing to a high vibrational level o f Ti and then Ti cascades down to the lowest vibrational level —vibrational relaxation.  The radiative  decay routes are fluorescence or phosphorescence. In both cases, the electron is returned to the ground state from the singlet or triplet state by emission o f a photon.  5  In  fluorescence, the electron usually returns from the lowest singlet state to any vibrational level  i n the  ground  state, while the  electron returns from  the  triple state in  phosphorescence. Both singlet and triplet species can lose their excess energy by undergoing chemical reactions.  However, as the singlet species is very short lived (< 10"  many chemical processes are known to go v i a the longer-lived triplet state.  10  sec),  12  A phenomenon that is important in photochemistry is triplet energy transfer or sensitization.  13  A s most photochemical reactions go v i a the triplet state, i f Si o f a  molecule has poor intersystem crossing efficiency, the triplet state cannot be obtained and the molecule is photochemically inactive. However, the triplet state o f such molecule can be populated by energy transfer from a triplet sensitizer. Sensitizers usually have a low Si energy and undergo ISC efficiently to the triplet state.  If the triplet energy o f the  sensitizer is higher than that o f the acceptor (quencher), then the triplet energy can be transferred (Figure 1.3.3), and the photochemically inactive molecule becomes excited. This technique is essential because it can selectively excite a particular molecule without the use o f short wavelength irradiation, which often causes other unwanted side reactions.  LUMO  °  Triplet Energy Transfer  HOMO  Sensitizer (T,)  Figure 1.3.3  Quencher (S )  Sensitizer (S )  0  0  The concept o f triplet energy transfer.  6  Quencher (T,)  1.4 Photochemistry of ketones A m o n g different kinds o f photochemical reactions, the photochemistry o f ketones has been studied extensively. group.  The chromophore i n saturated ketones is the carbonyl  The H O M O is the n orbital containing the lone pair on the oxygen atom, and  hence the lowest energy transition is the n—>n* transition.  14  Most ketones absorb at  around 290-330 nm, light which is very easy to obtain from a mercury arc lamp. A s the singlet and triplet states o f ketones are very close i n energy, these compounds undergo intersystem crossing efficiently. reactions have been reported.  16  15  For aliphatic ketones, both singlet and triplet state For phenyl ketones, the intersystem crossing is so  efficient that reactions occur exclusively via the triplet state.  17  A n excited saturated ketone can undergo three major kinds o f reaction: the Norrish type I, Norrish type II and photoreduction.  18  In the Norrish type I process,  19  the  molecule undergoes a-cleavage to give an acyl and an alkyl radical. The process is usually followed by hydrogen transfer, which can lead to the formation o f a ketene (Figure 1.4.1) or'an unsaturated aldehyde. Decarbonylation v i a loss o f carbon monoxide from the acyl radical is often observed i n gas phase reactions.  F i g u r e 1.4.1 A Norrish type I reaction leading to formation o f a ketene  In the type II process, six membered  20  the excited ketone undergoes y-hydrogen abstraction via a  transition state, and generates a 1,4-biradical intermediate.  intermediate can react v i a three different routes (Scheme 1.4.1): abstraction to regenerate the ketone starting material; cyclobutanol,  22  21  This  (1) Reverse hydrogen  (2) Cyclization to form a  and (3) cleavage to form an alkene and an enol, which tautomerizes to the  keto form later.  23  In most cases, solution photolyses lead to cleavage. The cleavage is  7  believed to be driven by the overlap between the P-y bond and the two singly occupied porbitals o f the biradical. This process is suppressed i f such an alignment is not possible. Lewis et al. showed that the partitioning between cleavage and cyclization is influenced 24  by the substitution pattern on the alpha carbon. The more substituted this carbon is, the more likely the biradical is to undergo cyclization.  The geometry o f the ketone has a  substantial effect on the Norrish type II process, which w i l l be discussed i n the coming section. Scheme 1.4.1  The third type o f reaction is photoreduction.  The excited species undergoes  intermolecular hydrogen transfer and becomes a saturated compound.  For example,  when benzophenone is irradiated i n the presence o f benzhydrol (8), compound 10 is obtained (Scheme 1.4.2).  17  Scheme 1.4.2 OH  X O  hv  o  Ph^Ph  OH  8  Ph^^Ph  Ph • Ph  9  8  dimerization  Ph Ph Ph-  •F  OH OH 10  1.5 Solid state photochemical reactions - structure-reactivity correlations Because molecules are closely packed in the solid state, atomic and molecular movements Therefore,  are severely restricted by the presence o f the neighbouring molecules. it is believed that solid state reactions undergo  molecular motions.  minimum atomic and  This is known as the topochemical postulate, and was originally  formulated by Kohlshutter  25  and later further described by Schmidt.  26  According to this  postulate, solid state reactions are allowed only when the molecules are packed in such a way that the reaction proceeds with a minimum amount o f motion.  Cohen  27  has  described a similar concept for crystalline state reactions, which is known as the reaction cavity theory, and this has been extended to other organized media reactions by Weiss et a/.  28  In this theory, the reacting molecule is within a cavity formed by the neighboring  molecules in the crystal lattice. A s the reaction proceeds, the geometry o f the molecule changes. However, the overall change o f geometry must fit the cavity or the reactions are not allowed. In other words, the reaction with a minimum change i n geometry w i l l be favoured. Since the development  o f X-ray crystallography, the molecular packing and  conformations o f compounds in the solid state can be determined. This provides a very useful tool to study how the crystal structure determines or affects solid state reactivity* and explains any difference in selectivity observed between solution and solid state reactions.  The very first example o f establishing such an X-ray crystal structure-  reactivity correlation was conducted by Schmidt et al} It is known that when trans6  cinammic acid and its derivatives are irradiated in solution, they undergo cis-trans isomerization only, while exclusive [2+2] cycloaddition is observed i n the solid state. Bernstein and Quimby proposed that the photodimerization o f cinnamic acid is a crystal lattice-controlled reaction.  The acid can crystallize in two dimorphs: a and p, and due  to different packing arrangements, these two dimorphs lead to the formation o f a-truxlic and P-truxinic acid, respectively upon solid state irradiation.  9  hv  Ar.  'COOH  Ar^  ^COOH  Solution  11  Ar. HOOC.  hv s  Ar. Ar^  12  COOH Ar  Ar. HOOC^>—  a form  13 a-truxlic acid hv  COOH 'COOH  Ar Ar  ^ C O O H COOH  N  P form  Ar. Ar.  COOH Ar  14  hv  COOH  y form  P-truxinic acid  No Reaction  COOH  F i g u r e 1.5.1 Photochemistry o f frarcs-cinnamic acid.  The reaction was further investigated by Schmidt et al.,  who discoverd that the  derivatives o f substituted and unsubstituted /ra«5-cinnamic acid crystallize i n three phases - a, P, and y. The y form is unreactive, while the other two phases undergo [2+2] photocycloaddition (Figure 1.5.1).  B y comparing the crystal structures o f these three  different solid phases o f /ra«s-cinnamic acid derivatives, Schmidt came to the following conclusion: in order for the [2+2] cycloaddition to occur, the distance between the center of the two double bonds must be less than 4.2 A, and there should be a parallel alignment between the two reacting double bonds.  The y form is not reactive i n the solid state  because the two reaction centers are too far away from each other (4.7-5.1 A).  The  geometric requirements determined by Schmidt are found to account for other solid state photocycloadditions o f different olefins.  31  Indeed, it has become a guideline for chemists  to study and design solid state photocycloadditions. For example, Garcia-Garibay underwent irradiation.  et al.  reported that  trans-sixVoQne, derivatives 15  cis-trans isomerization in both solution and the solid state exclusively upon The crystalline state packing arrangement o f the molecules does not favor a  [2+2] photocycloaddition o f the stilbene olefin groups. In order to bring the two  10  trans-  stilbenoid units closer, Garcia-Garibay et. al. prepared a supramolecular complex 17a (Figure 1.5.2). Crown ether 16 was chosen because it had an appropriate size to form a doubly threaded 2:2 complex with compound 15 upon co-crystallization i n the solid state. The two /rans-stilbenoid units are forced to align i n a geometry that is suitable for the [2+2] photocycloaddition in pseudorotaxane 17a. X-ray crystal analysis showed that an ideal arrangement had been engineered, in which the centroid-centroid distance o f the two olefin groups is 4.20 A . A s expected, solid state irradiation o f this complex afforded the dimerized product 18.  Figure 1.5.2 17a.  [2+2] Photoaddition o f trans-sttibene 15 i n the pseudorotaxane complex  The pioneering work by Schmidt et al. demonstrates that with the help o f X-ray crystallography, crystalline state reactivity can be related to the crystal structure.  The  importance o f such a correlation is not only to elucidate solid state reaction mechanisms, but it also can provide a model for chemists to design solid state reactions.  11  Several  research groups have conducted studies on establishing structure-reactivity correlations for different chemical processes,  and one o f the well established ones is the Norrish  type Et reaction.  1.6 Geometric requirements for the Norrish type II hydrogen atom abstraction Extensive studies have been performed to determine the geometric requirements for hydrogen atom abstraction in the Norrish type II reaction o f ketones. that there are four important parameters that control abstraction.  34  It was found  These are the O . . . H  distance (d); co, the dihedral angle that the O - H vector makes with respect to the nodal plane o f the n system; A, the C=O...H angle, and 6, the O . . . H - C angle (Figure 1.6.1).  35  F i g u r e 1.6.1 Four geometric parameters governing solid state y-hydrogen abstraction  The distance (d) is probably the most important factor for controlling hydrogen abstractability. Early theoretical studies showed that the upper limit o f such a distance is 1.8 A .  36  However, Scheffer et al.  37  have studied a series o f ketones in the solid state, and  their solid state conformational findings suggested that the abstractable distance is < 2.72 A, which is the sum o f the van der Waals radii for oxygen and hydrogen. abstractable C=O...H distances greater than 2.72 A have been reported, that i n most cases, the distances are within ± 0.2 A o f this limit.  12  39  38  Although  it was found  For hydrogen abstraction to occur, there must be good overlap between the hydrogen atom and the orbital involved on oxygen. In an n—>n* excitation, the nonbonding n orbital on oxygen is responsible for hydrogen abstraction, therefore  the  abstraction should be optimized when there is a direct overlap between this n-orbital and the hydrogen orbital.  This alignment is achieved when both orbitals lie on the same  plane, that is when co equals 0°. B y the same reasoning, the abstraction is least favored when this angle equals 90°, where the two orbitals are perpendicular to each other. However, there are many examples in the literature reporting successful hydrogen abstraction for co angle between 4 0 ° - 6 0 ° . dependency ofthe abstraction rate.  41  40  Wagner has proposed that there is a cos co 2  A s long as the angle is not 90°, the rate w i l l not be  zero and abstraction is possible. In addition to co, A also plays a role i n determining the optimum overlap between the n orbital on oxygen and the hydrogen atom. Depending on the hybridization o f the oxygen atom, the optimum value o f A varies.  I f the oxygen is sp hybridized, the n-  orbital is 120° with respect to the C = 0 bond, and the optimum value o f A is 120°; i f the oxygen is unhybridized, the n-orbital is 90° away from the C = 0 b o n d ,  42  and the optimum  value o f A becomes 90°. Therefore, the ideal value o f A lies between 90° to 120°. The last parameter, 9, measures the C - H . . . 0 alignment. Theoretical study demonstrates that the best orientation for the abstraction to occur is a linear one,  43  and hence the ideal value  o f the angle 9 is 180°. This parameter might be less important than the other ones, as numerous examples have shown that this angle can deviate significantly from the ideal value  4 4  The ideal values o f the four parameters are summarized in Table 1.1.  45  Table 1.6.1 Ideal values o f the geometrical parameters for hygrogen abstraction by an excited carbonyl oxygen  d(A)  co(°)  A(°)  en  <2.72  0  90-120  180  13  1.7 Thefateofthel,4-biradical A s mentioned in section 1.4, the 1,4-biradical obtained from hydrogen abstraction in a Norrish type II process can undergo cleavage, cyclization, or reverse hydrogen abstraction.  In solution, as the triplet biradical has a sufficient lifetime, it can undergo  conformational changes and hence it is inappropriate to correlate the observed reactivity to the initial molecular conformation. However, this problem is eliminated in the solid state.  A s conformational change is at a minimum in a confined, space, the initial  conformation o f the starting molecule w i l l be very similar to that o f the intermediate. A s a result, structure-reactivity correlations for this intermediate can been established by determining the crystal structures o f the starting materials. Scheffer and coworkers have studied various Norrish type II Y a n g cyclization systems. In a recent study o f a homologous series o f spirobenzoyladamantane derivatives (Figure 1.7.1), the fate o f different 1,4-biradicals formed after a Norrish type II hydrogen abstraction were determined and related to their solid state conformations.  46  For the three  ketones studied, compound 19 gave cleavage products only; compound 20 was not reactive and compound 21 underwent cyclization exclusively. X-ray crystal structure analyses showed that the differences i n reactivity were related to the orientation o f the porbital lobe on C l .  (p was defined as the torsion angle between this p-orbital and the C 2 -  C3 bond. This angle can be presented as cos (p because this function is proportional to the overlap between a p-orbital and an adjacent a type orbital. Therefore, the ideal value of (p for cleavage to occur is 0° because the p-orbital overlaps directly with the C2-C3 bond i n this geometry (cos <p = 1). The values for cos <p o f ketones 19-21 were found to be 0.93, 0.05 and 0.34, respectively.  For cyclization, the p-orbital on C l should be  pointing toward the p-orbital lobe on C 4 , which means that it should lie parallel to the C 2 - C 4 vector.  X-ray crystal structures o f the three ketones revealed that ketone 19  deviates from this ideal geometry by 60° and the corresponding deviations i n ketones 20 and 21 are 59° and 39°, respectively. From the crystal data, the geometry o f ketone 19 does not favor cyclization, but does favor cleavage, and hence it underwent cleavage exclusively.  For ketone 21, cos (p suggests a poor alignment for cleavage, but the  orientation o f the p-orbital lobe on C l is very close to that on C 4 , and hence cyclization  14  occurred. The geometry o f ketone 20 does not favor cleavage or cyclization. Hence, it only underwent reverse hydrogen transfer.  This example demonstrates that the solid  state reactivity o f a biradical intermediate is closely related to the initial molecular conformation and illustrates the importance o f X-ray crystallography i n determining solid state structure-reactivity correlations.  19 n = 1 20 n = 2 21 n = 3 F i g u r e 1.7.1 The solid state reactivity o f three spiroketones 19, 20, and 21.  1.8 Asymmetric synthesis in the crystalline state A s the enantiomers  o f chiral molecules often possess different  biological  activities, the demand for optically pure compounds has grown tremendously in the pharmaceutical industry over the last decade.  Chemists have sought new and efficient  methods o f asymmetric synthesis, and have obtained excellent results i n solution ground state reactions by using optically pure catalysts, auxiliaries and reagents. " ' 3b  the results for photochemical processes have not been encouraging  4 8  c  47  However,  One reason is that  the chiral agents employed in ground state reactions may not be suitable i n an excited state process. These auxiliaries usually contain transition metal complexes, which can act as hydrogen donors, electron transfer agents or even quenchers, and interfere with the  15  photochemical reaction.  49  However, the study in section 1.7 shows that reactions can be  highly selective in the rigid crystalline environments.  If one can carefully design a  system, it is possible to utilize the crystal lattice to carry out highly enantioselective reactions or asymmetric syntheses. L i k e molecules, crystal lattices can be classified as chiral or achiral.  If the  molecules are arranged i n a way that there is no mirror symmetry operation in the unit cell, then the crystal lattice is defined as chiral.  There are 230 different ways to pack  molecules in a lattice and these are called space groups. groups, 65 o f them are chiral.  50  O f the 230 possible space  Optically pure compounds must crystallize i n a chiral  space group. However, achiral compounds usually reside in an achiral space group, but that is not always true. H o w can this chiral lattice induce solid state enantioselectivity?  Based on the  topochemial postulate, one can imagine that solid state enantioselectivity can be controlled by two factors: (1) the conformation and (2) the packing arrangement o f the starting molecules.  In fluid media, where bond rotation and atomic motions are not  restricted, the molecules can adopt different conformations and therefore reactions occur via one or more different conformers. However, as molecules have minimum motion i n the solid state, change i n conformation is unlikely.  The reaction w i l l proceed v i a a  transition state that is close in geometry to that o f the starting material. In a chiral crystal lattice, there is no mirror symmetry element, and hence the mirror image o f the conformer does not exist. Therefore, i f the solid state conformation favors the formation of  one  enantiomer,  conformational effect.  enantioselectivity can  be  The packing arrangement  induced.  This is  termed  as  the  o f the molecules also plays an  important role i n solid state enantioselectivity. The molecules in the lattice have close contacts with the cavity or the crystalline environment. Ln a chiral lattice, these contacts are asymmetric.  The crystalline environment may favor the reaction to give one  enantiomer over the other, and the process becomes enantioselective. This is known as the topochemical lattice effect. In general, the selectivity o f solid state organic reactions is influenced by both conformational and topochemical lattice effects.  16  The concept can be illustrated better i f one considers the case o f ketone 21 discussed i n section 1.7. The solid state molecular conformation o f this compound is a chiral one,  44  and the two y-hydrogen atoms H a and H b possess different hydrogen  abstraction parameters. X-ray crystal data reveal that H a is more abstractable i n the solid state conformation (i) and eventually would lead to the formation o f cyclobutanol 22 with an S configuration at the chiral center * (Figure 1.8.1).  However, as ketone 21  crystallized i n one o f the achiral space groups, the mirror image o f conformer i also exists in equal amounts.within the unit cell. The mirror image conformer (ii) would lead to the formation o f the (R) cyclobutanol 22 and therefore irradiation o f crystals o f ketone 21 produces cyclobutanol 22 as a racemate. However, the result would not be the same i f the molecule crystallized in a chiral space group. conformer i would not exist.  In this case, the mirror image o f  Irradiation o f this kind o f crystal would lead to a highly  enantioselective reaction. Therefore, when a compound crystallizes i n one o f the chiral space groups, asymmetric synthesis can be induced. The first example o f an asymmetric synthesis that was induced by crystal chirality was described by Penzien and Schmidt in 1969 (Figure 1.8.2).  51  4,4'-Dimethylchalcone  (23) was found to crystallize i n the chiral space group P2i2i2]. W h e n a single crystal o f this compound was treated with bromine vapor, the resulting brominated product (24) was found to have an enantiomeric excess o f 6 %. It was proposed that the chalcone molecules were packed in a chiral environment and that the bromine vapor approached the two faces o f the double bond with different rates, leading to an enantioselective bromination. molecule  This kind o f asymmetric induction, which resulted from an achiral  spontaneously  crystallized in a chiral space group,  asymmetric synthesis.  17  is called  absolute  (a)  solid, hv conformer ii  Racemic product 22  Compound 21 in an achiral unit cell  (b)  conformer i  solid, hv  conformer i  Compound 21 in a chiral unit cell  Optically active product 22  F i g u r e 1.8.1 Difference in solid state enantioselectivity in (a) an achiral crystal lattice (experimental result) and (b) a chiral crystal lattice (a hypothetical case)  18  p  6  Br Vapor 2  Solid Br  H  o 23  O  24  6 % ee F i g u r e 1.8.2 The first example o f absolute asymmetric synthesis  Examples o f photochemical absolute asymmetric syntheses have been described in many cases and have given high ees for the photoproducts.  In a recent example,  53  diarylethene derivative 25, which crystallizes in the chiral space group P2j, gives the optically active cyclized product 26 with a 99 % ee upon irradiation i n the solid state (Figure 1.8.3a).  54  A more profound example is the solid state photochemistry o f  compound 27, which exists as two dimorphs in the crystalline state (Figure 1.8.3b). One o f the dimorphs crystallizes in a chiral space group, while the other crystallizes in an achiral  one.  Irradiation o f a single crystal o f the  chiral  dimorph affords  enantiomerically enriched di-7t-methane rearrangement product 2 8 .  55  an  However, when a  single crystal o f the achiral crystal is irradiated, no enantiomeric excess was observed for the product. This example highlights the importance o f a chiral environment i n inducing solid state asymmetric synthesis. Although examples o f absolute asymmetric syntheses have been reported quite frequently and have given high ees, the process is unpredictable.  The reasons why  achiral compounds crystallize in chiral space groups are not known, and there is no way to design an achiral molecule to pack in a chiral space group.  Nevertheless, absolute  asymmetric synthesis illustrates that a chiral crystalline lattice is an ideal medium in which to carry out enantioselective reactions.  19  However, i n order to fully utilize this  environment for asymmetric synthesis, a more reliable and predictable method must be used, and this leads to the application o f chiral handles or auxiliaries.  (a)  (b)  27  28  Space Group  ee  P2 2,2 (Chiral) 1  96 %  1  Pbca (Achiral)  0  F i g u r e 1.8.3 Examples o f photochemical absolute asymmetric syntheses, (a) a photocyclization (b) a di-7t methane rearrangement. The space groups o f the two dimorphs are included  Since optically active compounds must crystallize i n a chiral space group, i f the achiral starting material is co-crystallized with an optically pure compound, then a chiral crystalline lattice is guaranteed.  Toda et al.  56  have utilized the idea o f host-guest  inclusion complexes to carry out crystalline state asymmetric syntheses.  The chiral  handle (optically pure host) forms a complex with the reacting guest molecule by hydrogen bonding. The crystals o f the resulting complex are chiral, and thus the solid  20  state reaction occurs in a chiral crystalline environment.  For example, compound 30  undergoes the Norrish type II Yang cyclization to give cyclobutanol 31 upon irradiation. When the crystals formed between compound 30 and an optically pure host (29) are irradiated, a 1 0 0 % ee for cyclobutanol 31 is observed.  57  Various chiral host compounds  have been utilized and this method is found to be successful in inducing ee in different photochemical reactions.  Figure 1.8.4 Application o f a chiral host for solid state asymmetric synthesis.  1.9 The ionic chiral auxiliary approach Another way o f incorporating a chiral handle to achiral substrates has been developed by Scheffer et a / .  58  The auxiliary and the substrate are held together by ionic  salt bridges. In this scenario, the auxiliary and the substrates are acids and bases, and the resulting salts can be prepared easily by mixing the acid and base together in an appropriate solvent.  The role o f the auxiliary is a passive one; it is only used to induce a  chiral crystalline environment. The concept ofthe chiral auxiliary approach is shown in Figure 1.9.1.  The chiral crystalline environment is capable o f differentiating the two  21  diastereomeric transition states o f the substrates, and the pathway with the lowest kinetic barrier proceeds at a faster rate and the resulting product is formed i n excess.  The  auxiliary can be removed easily by acidic or basic work up after the reaction.  coo coo  0  (+)-Chiral product  A ©  (-)-Chiral product  A(±r  A  COO_  ©  COO_  ©  © JS*IH  Z  ©  .NH-,  r  Photolysis in the crystalline state  ©  f  coo  ©  ©  Chiral Crystal  A ' Acid-base reaction  COOH ( ^ ^ —  Achiral acid Photoreactive substrate  )  Optically pure amine Auxiliary  F i g u r e 1.9.1 A hypothetical energy diagram o f the solid state reaction o f an optically pure salt formed from an achiral reactive anion and an optically pure ammonium cation auxiliary  T w o examples o f the utilization o f an optically pure carboxylic acid and amine as the chiral auxiliaries are shown in Figure 1.9.2. In Figure 1.9.2a, the ammonium ion o f optically active salt 32 undergoes the Norrish type H/Yang cyclization and gives a racemic mixture o f cyclobutanol 33 in solution photolysis. irradiation o f this salt affords 98 % ee for photoproduct  33.  59  However, solid state  In Figure 1.9.2b, the ionic  chiral auxiliary is an optically pure amine. U p o n irradiation, the photoactive carboxylate  22  ion rearranges and affords compound 35 with greater than 85 % ee.  When the  photosubstrate is a carboxylic acid, a simple diazomethane work up can convert the compound to the methyl ester, which is easier to analyze than the acid.  Therefore, in  many cases, the photoactive substrate is designed to be an acid rather then a base.  (a)  F i g u r e 1.9.2 Applications o f the ionic chiral auxiliary approach i n (a) a Norrish type JJ cyclization and (b) the photorearrangement of linearly conjugated benzocyclohexadienone  In principle, the concept illustrated in Figure 1.9.1 can be applied to any kind o f solid state asymmetric synthesis utilizing chiral auxiliaries, with the difference being how the auxiliaries are attached.  There are many different ways to achieve this goal. In the  examples shown above, they are attached via an ionic salt bridge. The auxiliaries can also be attached covalently by forming ester (optically pure alcohols) or amide linkages (optically pure amines) with achiral photoactive acids. advantages o f using the ionic chiral auxiliary approach.  23  However, there are several Firstly, organic salts generally  have stronger lattice forces and higher melting points than purely covalent compounds. This makes the crystal more robust upon solid state photoreaction.  Secondly, this  approach requires much less synthetic work and the auxiliary can easily be removed following reaction.  Finally, there are numerous optically pure amines and carboxylic  acids available commercially, and hence there are plenty o f choices for the chiral auxiliary.  It is important to point out that there is no way to predict how the optically  active salts w i l l crystallize. This is a trial-and-error process.  W i t h more choices o f  auxiliaries, the greater the chances are to prepare salts crystallizing in lattices that can differentiate between the two diastereomeric transition states efficiently. The ionic chiral auxiliary approach is similar to the Pasteur method o f resolving chiral compounds by forming diastereomeric salts.  61  However, the ionic chiral auxiliary  approach has its advantages over the Pasteur procedure. If a photoactive substrate is first irradiated and then resolved by the Pasteur method, the maximum yield o f an optically pure enantiomer is 50 % . However, by irradiating an optically active salt, it is possible to achieve a 100 % yield o f an enantiomerically pure product.  The ionic chiral auxiliary  approach can possibly provide twice as much optically pure product as the Pasteur method. To date, the ionic chiral auxiliary approach has been applied i n numerous solid state photochemical reactions, such as the Norrish type II Y a n g cyclization, electrocyclic reactions and the di-Tt-methane rearrangement and has given encouraging results. There is no reason why this method cannot be applied to ground state reactions. A s a result, this process should have great potential to become a useful method o f asymmetric synthesis.  24  1.10 Research objectives The goal o f the present study is to induce solid state asymmetric synthesis in two kinds o f photochemical isomerizations o f cyclopropyl compounds by using the ionic chiral auxiliary approach. It is the first study o f solid state asymmetric synthesis for these kinds o f reactions. The cyclopropane ring system represents a unique class o f organic compounds. 3  62  3  Because o f the ring strain, the C - C bonds in a cyclopropane ring are not the usual sp -sp c bonds.  The bond angle (60°) in the three membered ring is very different from the  ideal angle (109°) o f an sp hybridized carbon. In order to relieve this angle strain, the 3  four orbitals on the cyclopropane carbon have different hybridizations.  A s the bond  angle o f an ordinary p orbital is 90°, which is closer to the actual bond angle o f 60°, the p character  o f the two orbitals involved in ring bonding increases.  hybridization is more like s p , 5  overlap o f two sp orbitals. 5  63  The resulting  and the C - C bond in the cyclopropane ring is formed by  Molecular orbital calculations indicate that this bond is  intermediate in character between a a bond and a rt bond, and the electron density deviates from the inter-nuclear axis ofthe two bonding carbon atoms (Figure 1.10.1).  64  These are called bent bonds. Because o f the n bonding character, the bent bond behaves somewhat like a double bond and can conjugate with an adjacent double bond or n system.  65  This bonding property makes cyclopropyl ring compounds photochemically  and thermally more labile than other ring systems.  F i g u r e 1.10.1 Orbital overlap in cyclopropane .  25  The photochemical reactivity o f cyclopropyl ring compounds is highly sensitive to the substitution pattern. Different kinds o f photoisomerizations have been reported. T w o of these reactions were chosen for study. The first kind is geometric photoisomerization. Acids 37, 53, 71 and their derivatives were selected for study i n this thesis (Figure 1.10.2).  Close analogues  o f these compounds are known to undergo  photoisomerization i n solution.  cis-trans  One o f the objectives o f the study was therefore to  determine i f the reaction proceeds in the crystalline state, where bond rotation is more restricted.  The major goal is to test i f the use o f ionic chiral auxiliaries can induce  enantioselectivity in the isomerization process.  Although enantioselective  cis-trans  isomerization o f 1,2-diphenylcyclopropane have been induced i n solution (see Chapter 2 for details), asymmetric induction in this type o f reaction has never been conducted in the crystalline state.  Therefore, another objective was to establish a crystal-structure-  reactivity correlation for this kind o f solid state reaction.  The compounds chosen for  study differ in the number o f the phenone chromophores. The possible influence o f this structural change on the solid state reactivity w i l l be investigated as well.  X  x  x  Figure 1.10.2 Geometric photoisomerization o f three cyclopropyl compounds  26  The second project involves the study o f the Norrish type II reaction o f cyclopropyl ketones (Figure 1.10.3). One o f the goals o f this project was to correlate the reactivities o f the substrates with their crystal structures, and to determine the hydrogen abstraction parameters for this class o f compounds. The results can be combined with the current data library to contribute further to the well-formulated reactivity model for y-hydrogen abstraction. A more important goal is to induce asymmetric synthesis i n Norrish type II cleavage.  H i g h enantioselective type II Yang cyclizations have been induced in  numerous cases, but such an example o f type II cleavage has not been reported. Because the Norrish type II process o f cyclopropyl ketones is found to give cleavage products (olefins)  exclusively,  it  appeared  that  such  a  process  could  be  carried  out  enantioselectively in the crystalline state by applying the ionic chiral auxiliary approach. A s olefins have diverse functionality, and can serve as precursors in natural product syntheses, preparation o f optically pure olefins is potentially important and useful in the pharmaceutical industry. Successful application o f the ionic chiral auxiliary approach in type II cleavage increases the potential o f the procedure to become a reliable method o f asymmetric synthesis i n natural product synthesis.  86 COOMe  COOMe  103  F i g u r e 1.10.3 Cyclopropyl ketones selected for the study o f enantioselective Norrish type II cleavage.  27  Chapter 2 Asymmetric synthesis in the geometric isomerization of some cyclopropyl compounds 2.1 General considerations 2.1.1 Early attempts at asymmetric induction in the cis-trans isomerization of 1,2-diphenylcyclopropane The  photochemistry  extensively.  of  1,2-diphenylcyclopropane  (135)  has  been  studied  Cis-trans isomerization o f this compound has been observed upon direct  66  or sensitized photolysis.  Direct irradiation usually leads to formation o f other minor  products  67  (Scheme  2.1.1),  while triplet sensitized conditions only give cis-trans  isomerization.  Scheme 2.1.1 H  ^  Ph  Bond rotation,ringclosure  Ph  H 137  u H  \/\/  p  H  |_|  p  n  135  n  , hv  ,.direct .  >  H t  ^  y/\(  cyclohexane Ph  H  1,2 H shift  ~,,r.u  —  -  Ph 1  3  p  h  ^ ^  ^ +  p h  138  ca  6  Rearrangement  C H  2  p h  139  r^^Y^^i  140  ^  "^^  t^x] ph  p  v  h  141  The geometric isomerization o f compound 135 has played a central role in studying photochemical asymmetric synthesis. A chiral compound is generated from an achiral starting material as cis- 1,2-diphenylcyclopropane transforms to its trans isomer. Several research groups have attempted to carry out the isomerization enantioselectively by using chiral singlet and triplet sensitizers. Hammond and Cole in 1965.  68  These  28  The first attempt was reported by  researchers employed an optically pure  naphthalene derivative as a singlet sensitizer, leading to enantiomeric excesses o f 6.7 %. A n ee o f 3% was obtained by Ouannes et al. when an optically active triplet sensitizer 69  was employed as the chiral inductor. different kinds o f chiral inductors, 10%.  This was  arenecarboxylates  70  Similar studies have been performed by using  and the highest ee reported so far is only around  achieved by Inoue as  electron-accepting  et a/.,  71  who  used  photosenitizers.  optically active  In  general,  the  alkyl  use  of  intermolecular chiral inductors in solution does not appear to be an effective method for inducing enantioselective cis-trans isomerization.  2.1.2 The use of chiral auxiliaries to induce asymmetric isomerization A confined environment may serve as a better medium to carry out the reaction enantioselectively.  Ramamurthy  and  co-workers  have  carried  out cis-trans  photoisomerization studies o f derivatives o f compound 135 i n zeolites with the presence of chiral inductors and have observed enantiomenc excesses o f ca. 20 %.  A chiral  crystalline environment may serve for this purpose as well, and such a medium can be achieved by using the ionic chiral auxiliary approach.  In order to apply this method, a  third substituent must be added to the cyclopropyl ring, such that the auxiliary can be attached. A s a result, acid 37 was prepared.  In addition to this compound, two other  compounds (53 and 71), which undergo geometric photoisomerization, were prepared and studied (Figure 2.1.1).  The solution photochemistry o f close analogues o f these  compounds has been studied extensively. '  '  Therefore, the present research w i l l  focus on studying the solid state enantioselectivty o f the geometric isomerizations o f these compounds and on determining the solid state-structure correlation.  COOH 37  53  71  F i g u r e 2.1.1 Substrates chosen for study  29  2.2 Photoisomerization of trans, trans-2, cyclopropane carboxylic acid derivatives  3-diphenyl-l-  2.2.1 Synthesis of substrates Scheme 2.2.1  o  2. H N(OMe)MeCI 2  52  51  The method o f Blatchford et al. was employed for the synthesis o f acid 37. The 73  singlet carbenoid addition reaction was found to be very low yielding and numerous side products were obtained.  Nonetheless, the addition was highly stereoselective.  The  stereoisomer o f ester 36, ethyl cis, £ra«s-2,3-diphenylcyclopropane-l-carboxylate, was not observed. The overall yield o f acid 37 was 52 % (based on recovered cz's-stilbene). The methyl ester (38) o f acid 37 was prepared by reacting the acyl choride o f the acid with methanol.  30  The conversion o f acid 37 to amide 51 was a very important step for the synthesis o f acid 53 because amide 51 ensured a single Grignard addition reaction on the Weinreb amide functional group and led to ketone 52. The yield o f the Grignard reaction was between 70-75 %, which was satisfactory. A c i d 53 was obtained i n an overall yield o f 55-60 % starting from acid 37. The stereoisomers o f esters 38 and 52 (115 and 118) were also prepared from the same synthetic route (Figure  2.2.1),  the only difference being that trans-stiVoene was  employed instead o f the cis isomer 142. For convenience, the isomers possessing the stereochemistry o f acid 37 and 53 are named as the trans, trans-isomer, while those with the stereochemistry o f esters 115 and 118 are named as the cis, trans'-isomer.  COOMe  118  115  F i g u r e 2.2.1 cis, trans-esters 115 and 118.  The stereochemistry o f the cis, trans- and trans, trans-isomers was easily assigned by ' H N M R spectroscopy.  A s the trans, trans-isomers (esters 38 and 52)  possess a plane o f symmetry, the two benzylic hydrogens are equivalent and appear as a single signal in the H N M R spectrum in a non-chiral solvent. Hence the three methine !  hydrogen atoms appear as an A B 2 system, and two different signals are observed. However, the cis, trans-isomers (esters 115 and 118) do not have such a symmetry element, and therefore  the three methine hydrogen on the cyclopropane ring are  31  nonequivalent  ( A B C system),  and  three  different  signals  are  observed  in  the  corresponding *H N M R spectrum (Figure 2.2.2 and 2.2.3 ).  ,  (•J  i—^r-r^———  ppm  (b)  :  1  1  3.0  2.8;  ••  :  I  —  ~  2.6  I  T----  ppm 3.2  —^—  3.0  I ••  —"—""  2.8  TT"  '  2.6  2.4  F i g u r e 2.2.2 ' H N M R signals o f the C - H protons on the cyclopropane ring o f (a) trans, trans-ester 38 and (b) cis, trans-ester 115  PP'"  T  1  3.5  3.4  r —  3.3  ;  PP  m  1  1  1  3.6  3.5  3.4  ;  r  3.3  F i g u r e 2.2.3 ' H N M R signals o f the C - H protons on the cyclopropane ring o f (a) trans, trans-ester 52 and (b) cis, trans-ester 118  32  • —J^-  2.2.2  Photochemistry of derivatives of acid 37  Compound 38 shows a strong U V absorption at 260 nm. W h e n irradiated (A.>190 nm), it underwent photoisomerization to give the cis, trans-isomev as the major product and led to a photostationary state o f 115:38 = 1:2.  Numerous side products, which  accounted for 8-10 % o f total materials, were obtained on extended irradiation.  The  major side product (ca 6 %) was isolated and found to be compound 117 (Scheme 2.2.2).  Scheme 2.2.2  CX^OMe  CK^OMe H  115  38  COOMe +  Minor  117  C2-C3 bond fission -2H, H-Shift  O.^.OMe  1. Bond rotation 2. Cyclization  COOMe  Rearrangement  The photochemistry diphenylcyclopropane (135).  o f compound 38 Griffin et al.  61  is very similar to that o f cis- 1,2-  have shown that when compound 135 is  irradiated, the trans isomer is formed as the major product plus other minor ones  33  including cis- andfrYms-l^-diphenylpropeneand 1-phenyl in dene (Scheme 2.1.1). As both compound 38 and 135 afford 1-phenyl in dene derivatives upon irradiation, it is reasonable to assume that compound 38 undergoes a similar mechanism as that of compound 135. Several research groups have tried to trap the biradical intermediate, but none of them succeeded. It is believed that the rates of bond rotation and ring closure 74  are much faster than the rates of the reactions with radical scavengers. Nevertheless, as this is the most reasonable mechanism to account for the formation of 1-phenylindene derivatives, it is considered to be the correct pathway. When irradiated in acetone, the reactivity of ester 38 was very different from that observed in acetonitrile. With the presence of a sensitizer (acetone), the reaction was found to occur with a Pyrex filter (X> 290 nm). The reaction is very clean with no observation of compound 117 or any other side products. Besides, a substantially different 115:38 photostationary state ratio of 7:3 was observed. Becker et al.' estimated 5  the triplet state energy of trans 1,2-diphenylcyclopropane to be 53 kcal/mol. Therefore, acetone (E = 78 kcal/mol) should be adequate to sensitize the isomerization of compound t  38.  When compound 38 was irradiated in the solid state, it underwent photoisomerization to give the  cis, trans-isomer  115 as well. However, the rate of the  reaction was much slower than that in the solution state. The ratio of 115:38 was 1:6 after 90 min of irradiation, whereas a close to 1:2 ratio was obtained when the compound was irradiated in solution for the same amount of time. Interestingly, the methyl ester crystallizes in two different morphologies. When the other dimorph was irradiated, less than 5 % conversion was observed after 90 min of irradiation.  34  2.2.3 Dimorphs of methyl ester 38 When methyl ester 38 was recrystallized from ethyl acetate, it afforded clear prisms with space group Pbca.  However, recrystallization o f this compound from  methanol afforded a mixture o f prisms and tiny white needles. Owing to their small size, the needles were not suitable for X-ray analysis. The two samples showed significantly different IR spectra, and solid state reactivity. The needle form was found to be more reactive than the prism form. After 90 m i n o f irradiation, 15 % o f the needles reacted, while less than 5 % o f the prisms converted. Therefore it appears that the compound can exist as two different dimorphs.  When the needles (dimorph A ) and prisms (dimorph B )  were subjected to differential scanning calorimetry ( D S C ) analysis, they gave different thermograms (Figure 2.2.4). For the hair-like needles, the D S C showed an endotherm at around 65 °C, followed immediately by an exotherm and then another endotherm at around 74 °C.  For the prisms, only one endotherm at 74 °C was observed on the  corresponding thermogram. This indicates that the needle form o f ester 38 undergoes a monotopic phase transition - the original phase first melts, and then resolidifies into a 76  second phase (prism form). This is in agreement with the observation that when dimorph A melts and is then allowed to resolidify slowly, the new solid sample melts at the same temperature as that o f the prisms. A s the needle form is the more photoreactive dimorph, it is important to determine a way to prepare this form exclusively, and not as a mixture o f two dimorphs. Different solvents (hexanes, pentane, acetonitrile, and acetone) were used for the recrystallization o f ester 38, but none o f them gave the desired needle form exclusively. However, vacuum sublimation was found to induce the formation o f the desired dimorph. When prisms o f ester 38 were sublimed, tiny white needles were deposited on the cold finger. Melting point and IR analyses indicated that the sublimed crystals are dimorph A . The desired crystal form can also be obtainedwhen a melt ofthe prisms, is super cooled by dry i c e .  77  These experiments demonstrate that form A is actually the metastable form,  which agrees with the D S C thermoanalysis. kinetically controlled conditions.  Dimorph A can only be prepared under  When the crystals are allowed to grow slowly, the  35  more stable prism form is produced. It is noteworthy to mention that solidifying the melt of the prisms under different condition can lead to the formation o f the two dimorphs (Chart I).  Chart I Super Cooling /-78 ° C  Morphology A (Needles)  6  (a)  5  °  C  ,  Melt  Solidify  ^ Morphology B (Prisms)  75 ° C  1  -  Solidify R.T.  0 -  :•'  -  l  -  -2 -  (b)  •H ;  ,2v4  -3H  40  60  80  Figure 2.2.4 D S C thermograms o f dimorphs o f ester 38. (a) prism form and (b) needle form. # denotes first melting; * denotes solidification to dimorph B .  36  Melt  2.2.4 Asymmetric photoisomerization of derivatives of acid 37 in the crystalline state 2.2.4.1  Absolute asymmetric synthesis When the needle form o f ester 38 was irradiated, an enantiomeric excess was  observed for the photoisomerized product. However, no ee was obtained from the prism form. In addition, the ee values obtained from different batches o f the needle form varied and ranged from 0 to 60 % (Table 2.2.1). Samples 1-9 were prepared by supercooling the melt o f ester 38; samples 10-12 were obtained by sublimation, while the final four samples were prepared by recrystallization o f the compound from methanol. The enantiomers ofthe the isomerized product were separated by chiral G C (Figure 2.2.5) Table 2.2.1  Ee's obtained from different samples o f the needle dimorph o f ester 38  Sample  % Conversion  ee  Peak  1 2 3 4 5 6 7 8 9  5.5 6.5 8 8 7 8 6 8 6  14 20 0 11 2.5 0 5 5• 9.2  B A  10 11 12  9 8 11  5 3 8  A B A  13 14 15 16  8 13 10 12  22 15 45 60  A B A A  .  3  A B  A A A  The peak of the enantiomerically enriched product shown on chiral GC A l l o f the data indicate an absolute asymmetric synthesis.  3Z  In this phenomenon,  an achiral compound spontaneously crystallizes i n a chiral space group without the addition  of  any  chiral  inductor.  As  the  crystalline  environment  is  chiral,  enantioselectivity can be induced when the reaction is carried out in the solid state. Since the hair-like needles are not suitable for X-ray crystal analysis, their space group could  37  not be determined.  However, it is obvious that, unlike the prism form, they must  crystallize i n one o f the 65 chiral space groups.  (b)  Figure 2.2.5 Chiral G C trace o f the crystalline phase photolysis o f ester 38 (dimorph A ) (a) ee = 41 %, peak A (b) ee = 14 %, peak B  The wide range o f ee values shown i n Table 2.2.1 are what one would expect from photolysis o f a mixture o f enantiomorphous chiral crystals that are formed randomly in varying proportions during the crystallization process, with one enantiomorph forming one enantiomer o f ester 115 (pro R crystal), and the other enantiomorph affording its mirror image (pro S crystal).  In principle, since the formation o f the pro R and pro S  38  crystals is a random process, the chance o f forming mixtures o f nearly a 1:1 ratio o f the two enantiomorphous crystals is the highest.  This explains why low ees were usually  observed when different batches o f ester 38 were photolyzed; for the same reason, the chances o f getting highly pure mixtures o f crystals (high ee) are low.  Because the hair-  like needles are so fine, a single crystal could not be picked up. Hence irradiation o f a single enantiomorphously pure crystal could not be performed, and it is not certain whether the highest ee (60 %) obtained is the result o f a mixture o f pro S and pro R crystals or an enantiomorphously pure polycrystalline sample.  Nevertheless, the study  provides a unique method to induce asymmetric cis-trans  isomerization o f 2,3-  diphenylcyclopropane-l-carboxylic acid derivatives, and demonstrates that a chiral crystalline environment is a good medium for carrying out such a reaction. However, absolute asymmetric synthesis does not always provide reproducible results when a mixture o f pro R and pro S crystals are obtained.  In order to ensure that the samples  crystallize in chiral space groups and provide an enantiomorphously pure crystalline sample, the use o f chiral auxiliaries becomes a better choice.  39  2.2.4.2  The ionic chiral auxiliary approach: preparation of optically active salts Optically active salts o f acid 37 were prepared by mixing equimolar amounts o f  acid 37 and optically pure amines. acetonitrile i n most cases. summarized in Table  The salts were crystallized from methanol or  The amines and recrystallization solvents employed  2.2.2.  Table 2.2.2 Optically active samples prepared from acid 37 Samples  Amines  3  39 NH 40  <CM"  H  H  NH  NH  ME  ~C5^ ^-^  Methanol  168-170  Methanol  163-165  Acetonitrile  143-145  Methanol  183-185  Methanol  130-132  2  H  NH  2  44 ^—y  168-170  2  42  43  Methanol  2  HGM*  B  mp (°C)  2  NH  41  Solvent  N—Ph H  40  are  Table 2.2.2 continued Samples  Solvent  mp(C)  Methanol  150-152  Methanol/water  240-242  Trituration from pet ether  92-94  Methanol  111-114  Methanol  185-188  Methanol  185-187  Amines  3  45 -Ph Fh  H  3  46  )H -Ph Fh  H  3  47 H 48  49  H ^ ^COOMe  C^l H  50  Samples  0  L.J-.. .OH  H  a  OH  39 - 48 are organic  11  0 salts; while samples  41  49-50 are complexes.  2.2.4.3  Solid state photolysis of optically active salts.  Optically active samples 39-50 were crushed between two quartz plates and then irradiated i n the crystalline state. The sample mixtures were then converted to methyl esters 38 and 115 by treatment with diazomethane.  The ee's o f ester 115 were then  analyzed by chiral G C (Table 2.2.3). Table 2.2.3 Solid state photolysis o f optically active samples o f acid 37 Samples  Conversion (%)  ee  Peak  39  44 33 25 41  B  40  10 17 35 13  A  41  4  5  A  42  28 17 58 48 60 57 60 55 14  A  46  6 15 10 27 10 17 6 12 4  47  7  20  B  48  9 17 4 15 20 7  43 41. 79 69 66 72  A  43 44 45  49  50  :  The peak of the enantiomerically enriched product shown on chiral GC (Figure 2.2.5)  42  A A B A  B  A  3  Enantiomeric excesses were observed only when the samples were irradiated i n the crystalline state. solution.  N o ee's were observed when the reactions were carried out in  This is in agreement with the solid state photolysis o f compound 38, as  enantioselectivity can only be induced i n a chiral crystalline environment (dimorph A ) . The highest ee was obtained when proline was used as the chiral auxiliary. A s it is unlikely for acid 37 to form a salt with an amino acid, which usually exists as a zwitterions, samples 49 and 50 are more likely to be hydrogen-bonded complexes. This suggests that the role o f the auxiliary is to induce crystal chirality only. The way it is attached to the substrate does not have a significant effect on the selectivity o f the system.  When the salts and complexes were irradiated, they gave different ee values for the product. A s an optically pure amine was employed i n each case, the variation in ee's cannot be due to the presence o f a mixture o f pro R and pro S crystals as discussed in the section on absolute asymmetric induction. Instead, the variation is related to the different crystal structures adopted by the samples.  2.2.5 Structure-reactivity correlations The enantioselectivity o f the system is highly governed by the chiral crystalline environment. A s the isomerization o f optically pure samples  39-50 is likely to proceed  via C 2 - C 3 bond cleavage (Figure 2.2.6), rotation o f the C 1 - C 2 bond i n the resulting biradical would give one o f the enantiomers ofthe cis, trans-isomQX, while rotation ofthe C 1 - C 3 bond would give the other enantiomer.  Therefore, enantioselectivity can be  achieved i f the rates o f the two different bond rotations are different.  In solution, where  there is little restriction on bond rotation or other movements, one would expect the rates of bond rotations to be approximately equal, leading to a racemic mixture o f the cis, trans-xsomex. However, i n the crystalline state, such rotations are more restricted, and the rates o f the two possible bond rotations would not be the same i n a homochiral crystalline environment. Therefore, one o f the enantiomers would be formed in excess, and lead to an enantiomeric excess for the cis, ^raws-product.  43  The simplest source o f  such selectivity would be the steric hindrance imposed by crystal packing. The rotation o f one o f the benzyl radicals is blocked or disfavored by the presence o f a neighboring molecule (Figure 2.2.6).  This type o f influence is termed as a topochemical effect  because the selectivity is strictly related to the crystalline environment, or i n other words, how the compounds are packed.  79  A s all the optically active salts do not necessarily pack  in the same way, the selectivity varies i n different cases.  Neighboring Molecule: Blocks C1-C2 bond rotation => formation of the resulting enantiomer is unlikely  ring closure  H H  Formation of this enantiomer is favored  Formation of this enantiomer is not favored  Figure 2.2.6 A hypothetical case - the influence o f a chiral crystal lattice on enantioselectivity ofthe system  the  To date, samples 39-50 have resisted attempts to obtain X-ray quality crystals, and hence direct comparisons o f different  crystal lattices could not be achieved.  However, the crystal structure o f methyl ester 38 (prism form) was determined (Figure 2.2.7).  Its crystal packing diagram shows that the molecules are closely packed i n the  crystal lattice, and the resulting environment might not favor the space demanding photoisomerization process, therefore leading to low reactivity as observed. A s different salts adopt different conformations and packing systems i n the crystal lattices, the difference i n ee can tentatively be attributed to these variations.  44  (a)  2.2.6 Photochemistry of derivatives of acid 53 When  trans, trans-ester  52  was  irradiated  in  acetonitrile,  it  underwent  photoisomerization to give the cis, trans-isomer 118 as the only photoproduct (Scheme 2.2.3). The observed photoreactivity o f ketone 52 is very similar to that o f trans, trans2,3-diphenyl-l-benzoylcyclopropane (143), which was first studied by Zimmerman et /.  80  fl  It was found that the photoisomerization o f compound 143 is highly efficient with  O = 0.94. The mechanism o f the photoisomerization o f ester 52 should be similar to that postulated by Zimmerman for ketone 143, and is shown i n Scheme 2.2.3.  Scheme 2.2.3  118 R = Me  46  Although esters 38 and 52 both afford the corresponding cis, trans-isom&cs as the major photoproducts upon irradiation, the photochemistry and the mechanisms o f the two compounds are substantially different. trans,  W i t h the presence o f a phenone chromophore,  frans-2,3-diphenyl-l-benzoylcyclopropane  derivatives  are  photoactive  when  irradiated directly with A>300 nm. The ketone undergoes n—»7t* excitation and generates an excited state, which is able to cause either C 1 - C 2 or C 1 - C 3 bond fission. After bond rotation and ring closure, the cis, trans-i&omQr is formed. When ester 52 was irradiated in the crystalline state, it underwent isomerization as well.  geometric  Interestingly, like ester 38, compound 52 crystallizes into two  different dimorph forms. When the compound was recrystallized from methanol, short clear needles were obtained (space group P ), while recrystallization from ethyl acetate T  afforded colorless prisms, space group Fl\ln.  The two dimorphs o f ester 52 demonstrate  different solid state photoreactivity. The needle form is not photoactive, while the prism dimorph affords about 10 % o f product after 2 h o f irradiation. However, the rate o f conversion o f ester 52 (prism dimorph) in the solid state is slower than that in solution. Irradiation o f this compound in acetonitrile for 2 h afforded 87 % o f the isomerized product.  47  2.2.7 Asymmetric photoisomerization of derivatives of acid 53 in the crystalline state The achiral compounds 52 and 53 do not crystallize i n chiral space groups, and hence absolute asymmetric synthesis could not be studied i n these cases.  The chiral  auxiliary approach was applied to ensure a chiral crystalline environment.  2.2.7.1  The ionic chiral auxiliary approach: optically active salts Optically active salts o f acid 53 were prepared by mixing equimolar amounts o f  acid 53 and optically pure amines. acetonitrile in most cases.  The salts were crystallized from methanol or  The amines and recrystallization solvents employed are  summarized i n Table 2.2.4. Table 2.2.4 Optically active salts prepared from keto-acid 53 Solvent Amines Salts NH  54  NH  55  2  2  56 NH  57  B r  ~0~^  Methanol  203-205  Methanol  203-205  Methanol  185-188  Methanol  185-188  2  H NH  mp (°C)  2  48  Table 2.2.4 continued Amines  Salts 58  Solvent  mp (°C)  Methanol/  237-239  water Ph  H  59 •  N H H N  60  61  Me-\  62  63  rf—(rW v—* NH  "0^"  H  ^ - ^  64  65  NH  204-205  Acetonitrile  201-203  Acetonitrile  146-148  Methanol  175-177  Methanol  183-185  Chloroform/  157-158  2  CP NH  2  ^ ^ j ^ ^ O H NH  Methanol  2  O-C C I  189-190  Ph  OH  2  Methanol  Pet ether  2  49  2.2.7.2  T h e covalent c h i r a l a u x i l i a r y approach: optically active esters A s the role o f the chiral auxiliary is a passive one, the way to attach it to the  substrate can vary. Instead o f forming salt bridges, they can also be attached covalently by forming ester or amide linkages. Three optically active esters were prepared and their solid state reactivities were studied. The esters were prepared by first converting acid 53 to its acid chloride followed by reaction with an optically pure alcohol. The optically active alcohols and the recrystalhzation solvents employed are summarized in Table 2.2.5. T a b l e 2.2.5 Optically active esters prepared from keto-acid 53 Esters  Alcohol  66  Recrystalhzation solvents  mp (°C)  Methanol  153-154  Ethyl acetate  141-142  Ethyl acetate/Pet ether  128-130  OH HO,,  67  >< > 68  / = \  OMe  W  ^ O H  50  2.2.7.3  Solid sate photolysis of optically active salts and esters of acid 53  Salts 54-65 and esters 66-68 were crushed between two microscope slides and then irradiated at room temperature in the crystalline state.  Some o f the crystalline  samples were also irradiated at low temperature (-10 °C).  The organic salts were  converted to methyl esters by treatment with diazomethane after photolysis, and the ee o f ester 118 were then analyzed by chiral H P L C (Figure 2.2.8).  The chiral esters were  analyzed directly by chiral H P L C without any workup after photolysis.  The ee's and  de's observed from solid state photolyses o f the optically active salts and esters are summarized i n Table 2.2.6 and 2.2.7 respectively. Table 2.2.6 Solid state photolysis o f optically active salts o f keto-acid 53 Salt#  % Conversion  ee  a  54  33 50 18 55 63 20 50 73 28 25 38 25 32 18 32 6 23 26 47 60 33* 15 28 36  91 86 92 89 88 99 92 89 94 99 96 77 76 54 52 41 40 51 50 47 56 27 17 13  +  55  56  57 58 59 60 61 62  63  51  a  +  -  -  Table 2.2.6 continued Salt#  % Conversion  64 65 * Photolysis was carried out at -10 °C. at the sodium D line.  a  ee  a  + 7 9 + 33 13 sign of rotation of the enantiomerically enriched priduct  Figure 2.2.8 Separation o f the enantiomers o f ester 118. (a) Chiral H P L C trace o f the product from the crystalline phase photolysis o f salt 55, ee = 89 % (-) (b) Chiral H P L C trace o f the product from the crystalline phase photolysis o f salt 54, ee = 91 % (+). The enantiomers were separated by a Chiralcel O D column. The mobile phase was 9:1 hexanes/iso-propanol, and the flow rate was 1 ml/min.  52  Table 2.2.7 Solid state photolysis o f optically active esters o f keto-acid 53 Sample #  Conversion  %de  Peak  RT. 10 -10 R.T. R.T. -15 -15  33 14 11 7 36 11 40  17 26 39 59 27 70 56  2 2 2 2 2 2 2  R.T.  8  4  1  Temp/ °C  66  67  68  b  a  The peak of the diastereomerical y enriched product shown on chiral H P L C trace. The diastereomers of each ester were separated by H P L C on a Chiralcel O D column. The mobile phase was 9:1 hexanes/2-propanol, and the flow rate was 1.0 ml/min. sample melted a  b  When the salts and esters were irradiated i n acetonitrile or methanol, there was no sign o f any stereoselectivity.  However, asymmetric photoisomerization was induced  when the optically active samples were irradiated in the crystalline state. Some o f the results are excellent. conversion.  For example, salts 54 - 58 gave ee's o f ca. 90 % at over 50 %  A s expected, irradiations o f enantiomeric salts (e.g. salts 54 and 55) gave  rise to enantiomeric ester 118 with similar ee's.  These results indicate that the reacting  system is well-behaved, and can access either enantiomer with a simple substitution o f the ionic chiral auxiliary. A s reduced temperatures can preserve the crystal lattice better, low temperature photolyses were carried out for some o f the samples that gave low or moderate ee's at ambient temperature.  Ester 66 showed a 20 % increase i n de when the  reaction was carried out at - 1 0 °C instead o f ambient temperature.  For salts 60 and 61,  the reaction rates were significantly reduced, and no reaction was observed after 15 h o f irradiation when the reactions were carried out at - 1 0 °. However, a slight improvement in ee was observed when salt 62 was irradiated at low temperature. The variation in ee or de observed from different salts and esters can be attributed to the differences in crystal structures adopted by the chiral samples.  A s discussed in  Section 2.2.5, the chiral crystalline environment, or the topochemical effect, is capable o f inducing selective bond rotations o f the intermediate, leading to enantioselectivity. This effect probably plays a role in governing the solid state enantioselectivity o f the photoisomeriaztion o f derivatives o f acid 53 as well.  53  However, as the reaction  mechanisms o f compounds 38 and 52 are different, the chiral crystalline lattice effect might not be the only factor controlling the stereoselectivity o f the current system.  2.2.8 Structure-reactivity correlations The first step i n the mechanism o f the photoisomerization o f trans, trans-2,3diphenyl-l-benzoylcyclopropane system involves the cleavage o f one o f the P-bonds, which are the carbon-carbon bonds adjacent to the carbonyl group (C1-C2 and C 1 - C 3 , Scheme 2.2.3). I f one looks at this step more carefully, it is easy to realize that rupture o f either one o f these bonds would lead to the formation o f a pair o f diastereomeric biradicals, which give the (+) and (-) enantiomers o f the cis, trans isomer after bond rotation and ring closure.  In other words, the enantioselectivity o f the reaction is  determined i n the very first step, bond cleavage.  If the P-bond cleavage at the excited  state is selective, then the reaction w i l l become enantioselective. " Dauben et a / .  81  found out that the ring opening process o f cyclopropyl ketones is  related to the geometry ofthe starting material. When bicyclo[4.1.0]heptan-2-one  (144a)  and its 1-methyl derivative 144b were irradiated, 2-cyclohexenones (147) were formed. The mechanism involves cyclopropyl ring opening followed by 1,2-hydrogen migration (Figure 2.2.9a).  In principle, the reaction can go either v i a C 1 - C 6 or C 1 - C 7 bond  cleavage, but the experimental result indicated that C 1 - C 7 fission occurred exclusively because the other bond cleavage product, 2-cycloheptenone (148) was not observed. The result is surprising because intermediate 146 is more stable than the primary biradical 145.  This indicates that the reaction is kinetically controlled rather than  thermodynamically controlled. In other words, cleavage o f C 1 - C 7 is faster than that o f C 1 - C 6 . Dauben attributed the selective bond cleavage to the "Tt-assisted" overlap effect the P bond on the three membered ring that has a better overlap with the p orbital on the carbon o f the carbonyl group w i l l be' cleaved preferentially.  D u e to the rigidity o f the  bicyclic ring system i n compound 144, the C 1 - C 6 and C 1 - C 7 bonds have different overlaps with the p-orbitals on the carbonyl group (Figure 2.2.9b).  54  ii  i  Figure 2.2.9 (a)  Photochemistry o f ketone and boat (ii) conformations o f ketone 144  144; the  excited species is  144* (b)  Chair (i)  According to Dauben's idea, the C 1 - C 7 bond has a better overlap with the p orbital on the carbonyl carbon than that o f C 1 - C 6 bond i n the chair form i, while i n the boat conformation ii, the reverse is true. A s the chair form is the major conformation, the reaction goes predominantly v i a C 1 - C 7 bond fission, leading to a selective formation o f the primary biradical 145.  This type o f selectivity is not observed when a non-rigid  55  compound is irradiated. Irradiation o f ketone 149 afforded methyl cycloheptenone (150) as the major product (Figure 2.2.10).  82  In this case, the geometry o f the carbonyl group  relative to the C 1 - C 6 and C 1 - C 7 bonds is not fixed, and the carbonyl group can rotate freely to give the more stable biradical intermediate via C 1 - C 6 bond fission and hence affords the cycloheptenyl ketone as the major product (thermodynamically controlled).  150  149*  F i g u r e 2.2.10 Photochemistry o f ketone 149  The derivatives o f acid 53 are not conformationally rigid, and the resulting biradicals from the two possible bond ruptures are identical in energy and therefore the selective P-bond cleavage as discussed above does not exist when the compounds are irradiated i n solution.  However, bond rotations and molecular movements are more  restricted in the crystalline state.  A s a result, the molecular conformations o f the  compounds become rigid and hence selectivity is possible i f the samples crystallize in a way that the p orbital on the carbonyl carbon atom has a better overlap with one o f the two p bonds.  In other words, the molecular conformation can impose a significant  impact on the enantioselectivity o f the system being studied. However, how good does the overlap have to be i n order for the system to have an efficient selective bond cleavage? Sevin et alP have performed a comprehensive computational study on estimating the differences  in activation energy between the two P bond  fissions  o f methyl  cyclopropyl ketone in different geometries, and showed that the orientation o f the carbonyl group with respect to the cyclopropane ring has a profound effect on the relative activation energy for C 1 - C 2 versus C 1 - C 3 fission along the (n, n*)  potential energy  surface. A s shown i n Figure 2.2.11, the overlap o f the p orbital and C 1 - C 3 bond varies as  56  G increases from 0° to 180°. It was estimated that the difference i n activation energy favoring C 1 - C 2 over C 1 - C 3 cleavage was greatest (29 kcal/mol) when 6 = 30°, where the p-orbital is orthogonal to the C 1 - C 3 bond. In this geometry, there is no overlap between the p-orbital and this bond, while the p-orbital overlaps reasonably well with the C 1 - C 2 bond. When 6 = 0 ° , the p-orbital overlaps equally well with the two bonds, and hence the difference in activation energy is zero.  Although Sevin did not perform any  calculation when 9 > 90°, logic dictates that the greatest difference i n activation energy should also occur when 6 = 150°. However, in this case, C 1 - C 3 cleavage is favored.  F i g u r e 2.2.11 Overlap o f p-orbital on C = 0 with C 1 - C 2 and C 1 - C 3 bonds at different values o f 9  A t this point, we can make a very reasonable hypothesis regarding the effect o f molecular conformation o f derivatives o f acid 53 on the selectivity o f p bond cleavage, as well as the enantioselectivity o f the system. The differentiation is lowest when 9 = 180° (or 90°). A s 9 a p p r o a c h e s l 5 0 ° , a better selectivity in bond rupture is expected, and therefore higher enantioselectivity should result.  In order to validate this hypothesis,  crystal structures o f the substrates must be determined. Most o f the salts and esters have resisted attempts to grow X-ray quality crystals. However, crystal structures o f the two dimorphs o f methyl ester 52, ester 66, and salt 64 were determined (Figure 2.2.12 and Figure 2.2.13). substrates are chiral.  The angles  The conformations o f all these  o f 9 range from 164 to 177°. This finding is very  important because it indicates that the carbonyl group can adopt significantly different  57  . C3  F i g u r e 2.2.12 Crystal structures of ester 52. (a) O R T E P drawing of the needle form of ester 52 and (b) its crystal packing diagram; (c) O R T E P drawing of the prism form of ester 52 and (d) its crystal packing diagram.  58  (a)  (b)  F i g u r e 2.2.13 Crystal structure of chiral samples 64 and 66. (a) O R T E P drawing of salt 64 and (b) its crystal packing diagram; (c) O R T E P drawing of ester 66 and (d) its crystal packing diagram.  59  geometries i n the crystalline state. This agrees with the assumption that the differences in enantioselectivity o f different salts or esters are related to various conformational effects. The angles o f 6 and stereoselectivities o f the substrate ( i f applicable) are summarized in Table 2.2.8.  Table 2.2.8 The  angles 0 o f some derivatives o f acid 53  Compounds  e°  Best ee or de  Ester 52 (Needle form)  164  -  Ester 52 (Prism form)  176  -  Salt 64  177  7  Ester 66  172  39  According to the hypothesis, when 6 is close to 180°, the conformational effect is weakest and hence ee is expected to be low. Both salt 64 and ester 66 possess 9 close to 180°. The stereoselectivites observed from these two substrates are poor (<40%), which agree with the hypothesis.  A s the crystal structures o f the salts that gave high ee could  not be obtained, it cannot be tested i f the high enantioselectivities obtained are related to a 9 close to 150°. Nonetheless, the theoretical and experimental studies indicate that this hypothesis  is  reasonable,  and  enantioselectivities observed.  could  be  used  to  explain  the  difference  in  It is important to emphasize that the major impact o f the  molecular conformation effect is to create a difference in activation energy between two P bond cleavages such that the rate o f rupture o f one bond is faster than the other one. It is not necessary for 0 to be 150° for this influence to be important.  If salts  54-65  possesses an angle close to that o f the prism form o f ester 52 (9 = 164°), then on the basis o f the idea o f Sevin et al,  this angle should be able to account  for the high  enantioselectivities observed. One limitation o f the above hypothesis is that the conformational effect is not the only way to control the overall stereoselectivity o f the reactions.  A s mentioned at the  beginning o f this section, the isomerization process can be affected by a topochemical effect as well.  Therefore, the selectivity o f this system is actually determined by both  lattice and conformational effects (Figure 2.2.14).  60  *0.  /Ar  ki H  H  C1-C2 Cleavage  Ph  Ph  C2-C-3 bond rotation  Ph. . ^? l_l  O^Ar Cv  O^/Ar hv H  H Ph  H  H Ph  Ph  Ph  ^Ar  H  H H  Ph  Ph  H  Ar^.0 Ph  H Ar.  C1-C3 Cleavage  Ar.  ^O*  Ph  \ Ph  Ph  .  H  Ph  .H  H  H  C2-C-3 bond rotation  / H  Ph  F i g u r e 2.2.14 Conformational and lattice effects on the solid state photoisomerization o f derivatives o f acid 53  The conformational effect controls the rates o f C1-C2 and C1-C3 bond cleavage ( k i and k ) , while the topochemical effect affects the rates o f C2-C3 bond rotation o f the 2  two diastereomeric biradicals ( k and Li). When k i and k are comparable (9 = 180°), the 3  2  enantioselectivity is dependent on the difference between k and k . 3  4  Therefore, in the  cases o f salt 64 and ester 66, in which conformational effects are not very significant, the observed stereoselectivity can be attributed mainly to topochemical effects.  The results  o f these two samples suggest that k and k are comparable in these two cases. However, 3  if k » 3  4  Lt, then high ee for the product can still be obtained even i f the angle 9 indicates  low enantioselectivity.  In this case, the conformational effect cannot provide a correct  prediction on enantioselectivity.  Nevertheless, as the topochemical effect is hard to  predict and study in detail, the conformational effect provides a reasonable model, which  61  allows chemists to relate the observed selectivity to the data available from crystal structures and to study the system quantitatively.  62  2.3 Photoisomerization of 4-(trans, cyclopropyl)benzoic acid derivatives  fra«s-2,3-dibenzoyl-  2.3.1 Synthesis of substrates Scheme 2.3.1  o  71  A procedure modified from that o f Bhaskar Reddy et al.  was used to prepare  acid 71. In the literature procedure, chalcone, instead o f compound 69, was employed and therefore the reaction was carried out i n methylene chloride and a phase transfer reagent was added.  W i t h the presence o f the acidic functional group, it appeared that  using two equivalents o f N a O H could convert acid 69 to the corresponding anion and allow the reaction to go i n an aqueous medium. It was found that the reaction worked very well under these conditions and afforded the final product 71 i n an isolated yield o f 79 % . The reaction is highly stereoselective and the stereoisomer o f acid 71, 4-(cis, ^ra«s-2,3-dibenzoyl-cyclopropyi)benzoic acid (123), was produced i n a yield o f 10 % . The stereochemical assignments o f the compounds were based on their N M R spectra. L i k e the compounds discussed i n Section 2.2, the *H N M R spectrum o f the cis, trans-  63  isomer showed three types o f cyclopropane hydrogens, whereas the trans, trans-isomer exhibited two signals (AB2 system) o f these three methine hydrogens. This kind o f highly stereoselective addition reaction was also observed when ylide 70 reacted with chalcone and was studied by Trost et a / .  85  It was found that the  selectivity is determined in the first step o f the reaction, which involves a Michael addition o f ylide 70 to the double bond i n chalcone, affording a dipolar intermediate (Scheme 2.3.2).  Scheme 2.3.2 O  ii  The ylide can approach the chalcone i n two different ways. The first would lead to the pro S intermediate i (at the chiral center *), while the other would lead to the pro R intermediate ii.  A s shown i n the Newman projections i n Scheme 2.3.2, intermediate ii  possesses more unfavorable gauche interaction than intermediate i. Therefore, pathway i should be the preferred mechanism, leading to a higher proportion o f the trans, trans-  64  isomer. This rationale can be applied to the preparation o f compound 71 as well because adding a para-substitutent to chalcone should not affect the selectivity significantly. It was found that the ratio o f acids 71 and 123 was sensitive to the amount o f base present.  When excess sodium hydroxide was used, acid 123 was found to be the  predominant product. A l s o , when acid 71 was treated with excess N a O H and allowed to stir  for 2  days,  it converted  to  isomer  123.  This  shows  that acid  123  is  thermodynamically more stable than acid 71 (Scheme 2.3.3).  The thermodynamically controlled epimerization and the kinetically controlled ylide addition reaction are very important for the study o f the photoisomerization o f acid 71, as the product and the starting material can be prepared readily from these reactions. The corresponding methyl esters o f acids 71 and 123 (72 and 124) were prepared by treatment with a solution o f diazomethane.  These four compounds are new and were  fully characterized by different spectroscopic methods. The details are presented in the Experimental Section.  65  2.3.2 Photochemistry of ester 72 When ester 72 was irradiated i n acetonitrile, it underwent photoisomerization smoothly to give ester 124.  H i g h conversion (ca. 95 %) was observed after 2 h o f  irradiation. The photochemistry o f the compound is similar to that o f trans, trans-\,2dibenzoyl-3-phenylcyclopropane,  which was  first  studied by Chae et al.  86  Upon  irradiation, the O O group probably underwent an n —» n* transition and the excited ketone can undergo C 1 - C 3 (or C 1 - C 2 when the carbonyl on C 2 is excited) and C2-C3 bond fission. Scheme 2.3.4).  Both types o f bond cleavages give rise to stable biradicals (a and b in It was found that both bond fissions occur when A r = P h because  biradicals a and b can be trapped with P h S H .  8 6  Scheme 2.3.4  72  66  In biradical a (from C 1 - C 3 bond rupture), rotation o f the C 2 - C 3 bond affords biradical a', which undergoes intersystem crossing and ring closure to give the cis, transisomer 124. In biradical b (from C 2 - C 3 bond rupture), rotation o f either the C 1 - C 3 or C 1 - C 2 bond yields biradical b', which gives isomer 124 as well.  It is noteworthy to  mention that C 1 - C 2 bond rotation is also possible in intermediates a and a' in principle. However, in biradical a, rotation o f this bond would give an all cis 1, 2, 3-trisubstituted cyclopropane, which is an unfavorable structure as the steric hindrance is large.  In  biradical a', rotation o f this bond is allowed, but it would just give the cis, trans-isomQX again, and does not affect the overall reactivity.  When compound 72 was irradiated i n the solid state, it was slowly converted to the cis, trans-isomtx, however, the yield was only about 25 % after 24 h o f irradiation. Nevertheless, compound 124 was found to be the only photoproduct.  The solid state  photoisomerization o f ester 72 was less efficient than its solution counterpart.  This  probably is due to the fact that bond rotation in the confined crystalline lattice is more restricted and rotation o f a benzoyl group is space demanding, leading to a lower reactivity. Nevertheless, the ionic chiral auxiliary approach was applied to determine i f asymmetric photoisomerization could be induced in the crystalline state.  67  2.3.3 Asymmetric photoisomerization in the crystalline state 2.3.3.1  The ionic chiral auxiliary approach: optically active salts Optically active salts o f acid 71 were prepared by mixing acid 71 with one  equivalent o f an optically pure amine, and the resulting compounds were recrystallized from an appropriate solvent.  The amines and recrystalhzation solvents employed are  summarized i n Table 2.3.1.  The author would like to thank M i s s M a y a Haasz, an  N S E R C Summer Undergraduate Research Fellow, who did a marvelous job on preparing twenty different salts and studying their photochemistry. Five o f these salts are selected and included in this thesis. Table 2.3.1 Optically active salts prepared from acid 71 Recrystalhzation solvents  mp (°C)  Methanol  127-129  Methanol  182-184  75  Methanol  170-173  76  Methanol  204-207  Ethanol  198-200  Amines  Salt 73 i  H  NH  74  2  CO' " 0  \JJ  y  H  77  V ^ / ^ C H  2  O H  68  2.3.3.2  The covalent chiral auxiliary approach: optically active esters The covalent chiral auxiliary approach was also applied to study the solid state  asymmetric photoisomerization o f the target system.  The esters were prepared i n  accordance with Scheme 2.3.5. A c i d 71 was first converted to an acyl chloride and then reacted  with  an optically pure  alcohol.  The optically pure  alcohols and the  recrystallization solvents employed are summarized i n Table 2.3.2. Scheme 2.3.5  R*OH = Optically active alcohol  Table 2.3.2 Optically active esters prepared from acid 71 Recrystallization solvents  mp (°C)  Methanol  164-165  Ethyl acetate  189-190  80  Methanol/Hexane  159-160  81  Methanol/Hexane  136-137  Esters  Alcohol  78  79  HO,  > o  69  2.3.3.3  Solution a n d solid state photolyses of optically active salts a n d esters Salts 73-77 and esters 78-81 were irradiated in solution and the solid state. After  irradiation (A, > 290 nm), the salts were treated with diazomethane and the enantiomeric excesses o f ester 124 were analyzed. N o ee was observed when the salts were irradiated in solution (methanol or acetonitrile). When chiral esters 73 - 77 were irradiated in acetonitrile, the photoproduct o f each ester was separated and characterized.  N o de's  were observed when these esters were irradiated in solution. The enantio- or diastereoselectivity o f the system was studied i n the pure crystalline state in which the optically pure samples were crushed between two microscope slides and then irradiated.  The conversions i n the solid state, like the one o f  the methyl ester, were low. Nevertheless, stereoselectivity could be induced when the reactions were carried out in the chiral crystalline medium. However, the ee's and de's were not outstanding (Table 2.3.3 and 2.3.4). The highest value obtained was 65 %. In order to explain the results, the molecular conformations o f the reactants must be considered. T a b l e 2.3.3 Solid state photolyses o f optically active salts 73-77 Salt  Temp (°C)  Conversion %  ee (%)  73  ambient  74  ambient  75  ambient  76  -5 ambient  77  ambient  4.7 36.0 7.5 16.0 9.4 24 4.5 5.0 6.5 19.0 11.0 15.0 9.0 16.8  6(+) 6(+) 20(+) 25 (+) 33(+) 29(+) 32 (+) 26 (-) 27 (-) 25 (-) 49 (+) 42 (+) 65 (+) 59(+)  -5  a  The sign of rotation of the enantiomerically enriched product is shown in parentheses. The enantiomers were separated by H P L C on a Chiralcel A S column. The mobile phase was 95:5 hexanes/2-propanol, and the flow rate was 1.0 mL/min. 3  70  Table 2.3.4 Solid state photolysis o f optically active esters 78-81 Esters  ee (%)  Conversion %  a  38 (B) 9.0 32(B) 26 6.5 (A) 6.5 79 7.0 (A) 12 12(A) 5.0 80 10(A) 11 5.5 (B) 4.5 81 5.0(B) 8.5 The peak of the diasteredmerically enriched product is shown in parentheses. Thefirstpeak that eluted from the chiral HPLC column is named as A. The diastereomers of each ester were separated by HPLC on a Chiralcel AS column. The mobile phase was 95:5 hexanes/2-propanol, and the flow rate was 1.0 mL/min. 78  a  2.3.4 Structure-reactivity correlations The stereoselectivity observed for the chiral esters and salts is likely to be controlled by both conformational and topochemical effects.  The conformational effect  probably determines which one o f the cyclopropyl bonds w i l l be broken, while the topochemical effect determines which bonds w i l l undergo rotation to give the cis, transisomer. Before going into detail to establish the structure-reactivity correlation, it is important  to  first discuss the possible effects  o f a chiral conformation  on  the  stereoselectivity o f the reaction. For convenience, the three carbons on the cyclopropyl ring, C l , C 2 , and C 3 , w i l l be numbered counter clockwise for the rest o f this chapter. Hence, the configuration o f the starting material at C 2 and C3 would be (2R, 35). A s mentioned before, the isomerization o f the system can go v i a C 1 - C 2 , C 1 - C 3 or C2-C3 bond fission. C 1 - C 2 bond cleavage gives a pro^S, S) biradical intermediate because the cis, trans-isomer is obtainable only by rotating the C 2 - C 3 bond, which w i l l convert the configuration at C 2 to S. Similarly, cleavage o f the C 1 - C 3 bond would give the pro-(i?, R) biradical. However, the biradical resulting from C 2 - C 3 cleavage is achiral and can undergo either C 1 - C 3 or C 1 - C 2 bond rotation to give the (2R, 3R) or (2S,  3S)  diastereomer (Scheme 2.3.6). A s a result, a chiral conformation has its strongest effects on inducing stereoselectivity i f it favors C 1 - C 2 or C 1 - C 3 bond cleavage only. When C 2 -  71  C3 bond fission occurs, the stereoselectivity o f the final product is determined by selective bond rotation around C 1 - C 2 or C 1 - C 3 , which is determined i n turn by the chiral crystalline lattice. A s mentioned in Section 2.2, the torsion angle between the keto group and the Coc-H bond has a significant effect on determining bond cleavage. According to Sevin et al.  83  the difference in activation energy between the fission o f the two P bonds is greatest  when this torsion angles equals 150°, where the p-orbital on the carbon o f the C = 0 group is orthogonal to one o f the p bonds. In acid 71 and its derivatives, there are two benzoyl groups, and either one o f them can be excited.  In other words, the preferred bond  cleavage is related to the geometry o f these two benzoyl groups. There are three possible geometries: 1) Neither o f the benzoyl groups is i n a good position, 2) both ofthe benzoyl groups are i n a good position or 3) Only one o f the benzoyl groups is i n a good position to differentiate the two possible bond cleavages. The two important torsion angles 0 1 C 4 - C 2 - H 2 and 0 2 - C 5 - C 3 - H 3 are defined as a i and a.2 respectively (Figure 2.3.1).  Scheme 2.3.6  'Achiral' biradical  72  H  F i g u r e 2.3.1 Definition o f cti and 0:2  In hypothetical geometry (1), these two angles are close to either 90° or 180°. The p orbital on the carbonyl carbon overlaps equally well with the two adjacent p bonds in the cyclopropyl ring; therefore differentiation in bond cleavage is poor (Figure 2.3.2).  F i g u r e 2.3.2 Some possible conformations o f geometry 1. The p-orbital on the carbonyl carbon o f both C = 0 groups overlap equally well with the P bonds when a i and 0,2 = ± 90° or ± 180°. N o selectivity i n bond cleavage  In hypothetical geometry (2), both a i and 0C2 are close to the ideal value o f 150°. However, there are three possible conformations for both carbonyl groups to possess such an ideal angle (Figure 2.3.3): (i) a i and ai are close to - 1 5 0 ° and +150° respectively. In this case, the p orbitals on the carbons o f both carbonyl groups have good overlap with the C 2 - C 3 bond, highly favoring this bond cleavage. Formation ofthe achiral biradical is favored, and the selective cleavage has no significant influence on stereoselectivity, (ii) a i and 0:2 are close to +150° and -150° respectively. Excitation o f C4=01 favors C 1 - C 2  73  cleavage while the excitation o f C 5 = 0 2 favors C 1 - C 3 rupture.  A s it is likely that the  probability o f exciting.the two benzoyl chromophores is equal, the reaction would afford a pair o f diastereomeric biradicals, leading to the formation o f the (2R, 3R) and (2S, 3S) diastereomers. Therefore, high stereoselectivity w i l l not be induced, (iii) cti and a close to + 1 5 0 ° (or - 1 5 0 ° ) .  2  are  Excitation o f one o f the benzoyl groups favors cleavage o f  either the C 1 - C 2 (or C1-C3) bond, while excitation o f the other benzoyl group favors C 2 C3 bond rupture. This is the only way for geometry (2) to impose a significant influence on stereoselectivity because the reaction favors the formation o f only one o f the diastereomeric biradical.  iii  ii  F i g u r e 2.3.3 Three possible conformations o f geometry 2. (i) Selective cleavage o f C 2 C 3 . (ii) C4=Oi favors C 1 - C 2 cleavage; C 5 = 0 favors C 1 - C 3 cleavage; (iii) C4=Oi favors C 1 - C 2 cleavage; C5=C>2 favors C 2 - C 3 cleavage. 2  Using similar reasoning, for hypothetical geometry (3) to be important in determining stereoselectivity, either a i must be close to +150° while a  2  is around ±90° or  ±180°, or a must be close to -150° when cti is around ±90° or ±180° (Figure 2.3.4). In 2  this case, the geometry o f one o f the benzoyl groups always favors cleavage o f the C 1 - C 2 or C 1 - C 3 bond, while rupture o f C 2 - C 3 is never favored. Nonetheless, this would not lead to high stereoselectivity because when the keto group possessing the torsion angle o f ±90° or ±180° is excited, the two P bonds adjacent to it can be cleaved, leading to the formation o f other biradical intermediates. For example, in case i shown in Figure 2.3.4, excitation o f the C 5 = 0 2 group leads to C 1 - C 3 rupture and the formation o f the pro R biradical intermediate; while excitation o f the other carbonyl group, C 4 = 0 1 , leads to C 2 -  74  C3 or C 1 - C 2 cleavage and the formation o f the achiral and the pro S biradicals. A s the formation  of  a  single  kind  of  diastereomeric  biradical  cannot  be  achieved,  stereoselectivity is limited.  F i g u r e 2.3.4 Some possible conformations o f geometry 3. (i) a i can also be +180° and ± 90°. C4=Oi has no selectivity on p bond cleavage; C5=G>2 favors C 1 - C 3 cleavage, (ii) ct2 can also be -180° and ± 90°. C5=C>2 has no selectivity on p bond cleavage; C4=Oi favors C1-C2 cleavage.  Based on the above analysis, it is difficult for reactants 73-81 to adopt a conformation that can lead to a selective bond cleavage favoring the formation o f one enantiomeric product.  Therefore, the conformational effect alone does not appear to be  capable for inducing high stereoselectivity in this system. It is important to point out that the values o f a discussed above are limiting values, which would have the maximum or minimum effects on differentiating bond fission.  According to the idea o f Sevin, the difference i n activation energy between  rupture o f C1-C2 and C2-C3 increases from 0 to the maximum value as a i increases from 90° to 150°, and decreases from the maximum to 0 again as cti changes from 150° to 180° (Figure 2.3.5). Logic dictates that the activation energy for C 1 - C 2 fission is always lower than that o f C2-C3 rupture when a is within +90° to +180°. Therefore, rupture o f this P bond, which is on the other side o f the carbonyl group, is favored when a is within this range. Based on this analysis, the effects o f a i and 0:2 from ± 9 0 ° to ± 180° on the stereoselectivity of the system are predicted and summarized i n Table 2.3.5.  75  ii  i  iii  Figure 2.3.5 Overlap o f the p-orbital with the (3 bonds when a i increases form 90° to 180°. (i) a = 9 0 ° , the p-orbital overlaps equally well with C 1 - C 2 and C 2 - C 3 . (ii) A s CM increases from 90° t o l 5 0 ° , the overlap between the p-orbital and C 2 - C 3 becomes poorer, cleavage o f C 1 - C 2 is preferred, (iii) A s a i increases from 150° to 180°, the overlap between the p-orbital and C 2 - C 3 increases, the differences in activation energies between the ruptures o f C 1 - C 2 and C 2 - C 3 bonds decreases and becomes zero when cti =180°.  Table 2.3.5 Effects o f a i and oc on selective bond fission and inducing stereoselectivity 2  +90 to+180 -90 to-180 +90 or ± 1 8 0  favor bond fission C1-C2 C2-C3  -  induce de or ee yes no no  a ° 2  +90 to+180 -90 to-180 +90 or ± 1 8 0  favor bond fission C2-C3 C1-C3  -  induce de or ee no yes no  In order to establish a structure-reactivity correlation, and test i f the above hypothesis fits the current system, crystal structures o f the chiral substrates must be determined. Salts 73-77 have resisted attempts to give X-ray quality crystals. However, crystal structures o f esters 80 and 81 were determined (Figure 2.3.6 and 2.3.7).  The  molecular conformations o f these two esters are highly asymmetric. Moreover, there are significant variations i n the values o f oil and ct in the two structures (Table 2.3.6). 2  Table 2.3.6 Torsion angles in chiral esters 80 and 81 Ester  Torsion angle oti (°)  80 81a* 81b* There are two independent units (a) and  Torsion angle a (°)  -104.5 -162.4 -139.9 (b) in the unit cell o f ester 81.  76  2  150.1 132.6 159.5  For ester 80, a i is -105°. The p orbital on the carbon o f C4=01 almost bisects the three membered ring. From Table 2.3.6,, excitation o f this C = 0 group would favor C 2 * C3 bond cleavage, i f there is any selectivity. Angle ct2 is close to the ideal value o f +150°. Therefore, excitation o f C 5 = 0 2 would highly favor C 2 - C 3 cleavage. A s a result, the conformation o f ester 80 overall favors C 2 - C 3 bond cleavage, or the formation ofthe achiral biradical.  The diastereoselectivity i n this ester is likely to be determined by  selective bond rotation in the resulting biradical, which is affected by the packing arrangement o f the crystals. For ester 81, the compound crystallizes i n two independent conformations that are close to mirror images o f one another. In either conformation, cti and ot2 are close to (within 10°) - 1 5 0 ° and +150° respectively.  According to the  predicted values in Table 2.3.6, this pair o f angles favors the rupture o f the C 2 - C 3 bond. L i k e ester 80, low de is expected. This agrees with the observed results i n which the de's of both compounds are <15 %. If the other salts or esters adopt conformations similar to either one o f the two esters, then the chiral molecular conformation would play a very limited role in inducing stereoselectivity. A chiral crystalline lattice effect appears to be the more determining factor. It  is  difficult  to  rationalize  stereoselectivity o f the system.  the  topochemical  effect  imposed  on  the  The actual movement and atomic motions o f the  biradicals are hard to predict, and therefore a quantitative explanation is impossible. However, as low de's were usually observed when the chiral substrates were irradiated, the chiral crystalline environment probably did not differentiate the two diastereomeric transition states very efficiently.  77  (a)  Figure 2.3.6 diagram  Crystal structure of ester 80 (a) O R T E P drawing and (b) crystal packing  78  Figure  2.3.7 O R T E P drawing of ester  81  2.3.5 Conformational enantiomerism The crystal structure of ester 81 demonstrates a special way of crystal packing. If one ignores the presence of the chiral auxiliary and considers only the trans, trans-2,3dibenzoyl-3-arylcyclopropane moiety, it is easy to see that half o f the molecules crystallize in one enantiomeric conformation, while the other half crystallize as its near mirror image. B y inverting one o f the independent conformers and superimposing it on 87  the other computationally, a good overlap is obtained (Figure 2.3.8).  Scheffer et al.  have described this type of behavior in several optically pure organic salts.  However,  ester 81 represents the first case o f a covalent compound possessing this type of packing arrangement.  79  (a)  (b)  Poor  Figure 2.3.8 Conformation enantiomerism o f ester 81. (a) The two conformers found in the crystal lattice o f ester 81 shown in the same orientation (b) Overlap structure o f the two conformers. Full color o f atoms indicate poor overlap (chiral auxiliary).  The effect o f this kind o f crystal packing on the stereoselectivity of the system is significant. A s the substrates crystallize in two conformations, which are enantiomeric to each other, half o f the molecules give the (2S, 3S) diastereomer while the other half give the (2R, 3R) isomer, leading to low diastereoselectivity. The low ee (or de) observed in this project, as well as those found in Section 2 . 2 , are possibly due to some o f the salts adopting this kind of packing arrangement.  2.3.6 Solid state racemization of the cis-trans isomer? It was found that when an optically active sample o f cis, t^-(3«5'-2,3-dibenzoyl-lphenylcyclopropane was irradiated in benzene, it underwent racemization.  80  86  If this kind  o f reaction occurs in the solid state as well, the final de would be affected.  In order to  determine i f racemization affects the stereoselectivity o f the system, two optically active samples o f acid 123 were prepared by the Pasteur resolution procedure.  The amines  employed were brucine and thiomicamine. The salts were irradiated i n the crystalline state, and the ratios o f the two'enantiomers o f the anion were determined before and after irradiation by converting the molecules to methyl ester 124. It was found that the ester obtained from both salts showed no change i n ee before and after irradiation.  This  indicates that racemization did not occur in these two salts. It is important to point out that owing to different crystalline environments, it is not appropriate to make a general conclusion that racemization is impossible i n the crystalline state based only on these experiments.  It is possible that the crystal structures o f these two salts do not favor  racemization. However, i f one considers the mechanism o f the reaction carefully, it appears that this is true for all possible cases.  A s shown in Figure 2.3.9, the cis, /rans-isomer can  undergo C 1 - C 2 (or C1-C3) and C 2 - C 3 cleavage to give two different kinds o f biradicals. For the former kind o f bond cleavage, rotation o f the C 1 - C 3 bond, followed by cyclization gives exactly the same stereoisomer (2S, 3S) as the starting material. Hence, it is impossible for racemization o f the starting material to go v i a C 1 - C 2 cleavage. For C 2 - C 3 cleavage, the only way for the compound to racemize is to go v i a a two bond ( C l C 2 and C2-C3) rotation. This kind o f rotation is possible in the solution state. However, it is unlikely to happen when the reaction is carried out i n the confined crystal lattice where atomic movements  are more restricted.  Based on this hypothesis and the  experimental findings, it is reasonable to assume that racemization o f the cis, transisomer does not happen in the crystalline state.  81  (2S,  3S)  o (2S,  I  ( < ) 2S  3S)  i  o  {2R, 3R)  3S  Figure 2.3.9 Mechanism o f racemization o f cis-trans isomer 124 v i a (a) C 1 - C 3 bond rotation and (b) C 1 - C 2 and C1-C3 two bonds rotation  82  2.4 Summary For the first time, the ionic chiral auxiliary approach has been extended to induce asymmetric cis-trans photoisomerization o f tri-substituted cyclopropanes.  The results  observed from three different systems range from moderate to excellent. However, the rates o f solid state reaction are significantly slower than those i n solution. For the derivatives o f acid 37, a topochemical effect, which causes a selective bond rotation in the biradical intermediate, appears to be the major factor in controlling enantioselectivity.  B y putting a phenone chromophore  on the cyclopropane ring  (derivatives o f acid 53), the compounds are photoactive when irradiated with wavelength > 300 nm.  The enantioselectivity is influenced by a chiral conformational effect in  addition to topochemical control.  If the carbonyl group adopts a proper geometry, a  selective (3 bond cleavage occurs in the excited state, leading to the formation o f only one enantiomer o f the isomerized product. However, with the presence o f two phenone chromophores (derivatives o f acid 71), it is difficult to obtain a geometry that favors a single (3 bond cleavage leading to high stereoselectivity.  Therefore, the impact o f the  conformational effect on derivatives o f acid 71 is less profound than that i n acid 53. The topochemical effect becomes the major influence on the enantioselectivity for these compounds.  83  Chapter 3 The Norrish type II reaction and enolene rearrangement of cyclopropyl ketones 3.1 General considerations 3.1.1 The Norrish type II reaction of cyclopropyl ketones The photochemistry o f cyclopropyl ketones has been studied in vapor and solution phases extensively.  The reactivity o f the ketones  is controlled by the  substituents on the three membered ring. When a methyl cyclopropyl ketone (153), the simplest cyclopropyl ketone, was irradiated at 260 nm i n the vapor phase (Scheme 3.3.1), the major product was methyl propenyl ketone 154 (O = 0.31). The mechanism involves the rupture o f one o f the (3 bonds, followed by a 1,2-hydrogen migration. However, this 88  type o f reaction only proceeds in solution in the presence o f proton donating solvents.  89  Scheme 3.1.1  153  154  When cyclopropyl ketones possess y-hydrogen atoms cis to the carbonyl group, the above reaction is not observed in the vapor or solution phase.  Instead, the excited  ketone undergoes ring opening and rearranges to give a y,8-unsaturated ketone. There are two possible mechanisms to account for such a reaction. The first one (a) is a Norrish type II process, whereas the second mechanism (b) involves a p cleavage followed by an internal 1,4-hydrogen shift (Scheme 3.1.2). Dauben et al  90  have described a very clever  experiment to determine the correct mechanism by studying the photochemistry o f cis and trans methyl 2-methylcyclopropyl ketones (155 and 156) i n proton donating solvents.  84  Scheme 3.1.2  When the trans isomer 156 was irradiated in isopropanol and pentane, a mixture of products including the cis isomer (155), 4-methylpentan-2-one (159), 2-hexanone (160), and l-hexene-5-one (161) were obtained (Scheme 3.1.3). A s there is no methyl group cis to the carbonyl in ketone 156, it is not possible t o have a Norrish type II rearrangement.  Upon irradiation, p cleavage occurred and afforded intermediates 157  and 158. These two intermediates could either undergo intermolecular hydrogen transfer to give ketones 159 and 160 or geometric isomerization to give ketone 155, which further reacts to give ketone 161. When cyclopropyl ketone 155 was irradiated it gave ketone 161 as the only photoproduct. This indicates that ketone 155 did not follow mechanism b because a mixture o f products was expected from this pathway. A s ketone 155 is in a good geometry for intramolecular hydrogen transfer, the rate o f the type II process is very efficient, and formation o f intermediates 157 and 158 does not occur, which leads to a clean photoreaction.  The mechanism was further established by Pitts  et al?  x  In the  photorearrangement o f methyl 2,2-dimethylcyclopropyl ketone to 5-methyl-5-hexene-2one,  an enol, the intermediate that one would expect from the type II process, was  detected by IR. These experiments strongly support that the general reaction shown i n scheme 3.1.2 occurs via a Norrish type II process.  85  Scheme 3.1.3  155  161  When these cyclopropyl ketones undergo the Norrish type II process, no Yang cyclization is observed.  This is probably due to the fact that unlike cleavage, the ring  strain o f the cyclopropyl ring is not relieved by cyclization.  In addition, the resulting  cyclobutanol would possess a bicyclo[2. 1. 0.]pentane ring system, which is much less stable than the cleavage product. A s a result, the Norrish type TJ cleavage process is the only reaction observed.  3.1.2 The enolene rearrangement of cyclopropyl ketones 92  Roberts et al. 3.1.2  under  thermal  have described a similar rearrangement as that shown in scheme conditions.  It  was  found  that  when  l-methyl-2,2-  dimethylcyclopropyl ketone was heated above 150 °C, it converted smoothly to 5methyl-5-hexen-2-one (Scheme 3.1.4). The reaction was found to be first order with a rate constant o f 3.86 x 10" sec" (152 °C) and the activation energy was calculated to be 5  1  33 kcal/mol. The process was termed the enolene rearrangement. The mechanism o f the rearrangement involves a 1,5-hydrogen shift followed by ring opening ofthe cyclopropyl ring, and the formation o f an enol as an intermediate. 86  In general, this ground state  reaction is very similar to the excited state Norrish type II process. The major difference being that the enolene rearrangement does not involve a biradical intermediate, however both processes give the same products.  Therefore, cyclopropyl ketones possessing y-  hydrogen atoms cis to the carbonyl group are a very interesting class o f compound because they allow chemists to investigate ground state as w e l l as excited state processes on a single substrate. Scheme 3.1.4  3.1.3 Asymmetric synthesis in the isomerization of cyclopropyl ketones Norrish type II reactions have been studied extensively by photochemists. The ionic chiral auxiliary approach has been applied to the type II/Yang cyclization and has been successful in inducing formation o f highly enantiomerically enriched cyclobutanols. In principle, this method can also be used to induce enantioselective Norrish type II cleavage reaction., Scheffer et al  93  had studied the photochemistry o f acid 162 and its  derivatives, which undergo type II cleavage to give a chiral olefin 163 upon irradiation (Scheme 3.14). The ionic chiral auxiliary had been applied to determine i f enantiomeric excesses for olefin 163 could be induced when optically active salts o f acid 162 were irradiated i n the solid state. However, the results were not outstanding (ee = ca. 30 %). This is probably because the cleavage product 163 is an oil, and the rigidity o f the crystal . lattice is lost as the product accumulates, leading to poor enantioselectivity. It appeared that this problem could be overcome i f a salt bridge moiety was attached to the olefin, avoiding formation o f a non-crystalline product.  Because o f this, the Norrish type II  chemistry o f cyclopropyl ketones becomes a perfect system for studying this kind o f reaction.  87  Scheme 3.1.5 O  162  163  164  The compounds chosen for study are shown in Figure 3.1.1. L i k e other examples o f the ionic chiral auxiliary approach, these compounds have a plane o f symmetry but give rise to a chiral product upon irradiation. A c i d 85 would give an acyclic olefin that can  exist  in  cis  and  trans  configurations,  while  acid  102  possesses  a  tricyclo[4.4.1.0]undecane ring system and a cyclic olefin would be produced.  85  102  F i g u r e 3.1.1 Substrates chosen for study  A s mentioned above, these compounds are thermally labile, hence the thermal reactivity o f the system could also be studied. The ionic chiral auxiliary approach could be applied to induce enantioselectivity i n this rearrangement i f the crystalline samples survive at the reactive temperatures. This would be the first example ofthe application o f the method i n a thermal reaction.  88  3.2 Isomerization of c/s, c/s-2,3-bis(benzyloxymethyl)-lbenzoylcyclopropane derivatives 3.2.1 Synthesis of substrates Scheme 3.2.1  85  The synthetic route to cyclopropyl ketone 85 was devised by Charette et a l .  y4  Addition reactions o f carbenoids to alkenes usually give the less sterically hindered cyclopropyl compound. However, in this case, with the help o f the diethyl zinc complex and the two ether linkages on olefin 83, an all cis 1, 2, 3-trisubstituted cyclopropyl ketone was formed as the only product in an overall yield o f 30 %. The unreacted starting material, 4-carboxybenzoic acid, was very difficult to separate from the desired product. Repeated attempts at purification resulted in a low yield o f acid 85. The author would like to thank the Charette group for their help on the synthesis o f this compound. Methyl ester 86 was prepared by treating 85 with an ethereal solution o f diazomethane.  89  3.2.2 Solution photolysis When ester 86 was irradiated in acetonitrile, it underwent efficient Norrish type II cleavage reaction to give an enol ether as the primaiy photoproduct (Scheme 3.2.2). The cleavage product can exist i n cis (129) and trans (130) configurations. N M R study showed that the cis:trans isomers were formed in a ratio o f 1:3 when ester 86 was irradiated in solution. Scheme 3.2.2  R = COOMe  The lifetime o f the enol intermediate is very short. The ketonization step is relatively fast and the product undergoes secondary photochemical reactions  90  upon  extended irradiation. There are two types o f secondary photochemical reactions (Scheme 3.2.3): 1. cis:trans isomerization o f photoproduct:  upon irradiation, the two  stereoisomers  isomerize until a photo stationary state o f 0.43:1 (cisi'trans) is obtained. 2. Norrish type II cleavage reaction: the enol ethers were found to undergo another Norrish type II cleavage to give ketone 131. The structure o f this compound was confirmed by G C M S and N M R .  Scheme 3.2.3  130  The secondary photochemical processes were studied in detail. A solution o f ester 130 was irradiated, and the reaction followed by N M R . The product ratios at different irradiation times are summarized i n Table 3.2.1. It appears that the second Norrish Type II reaction is not very efficient (16 % after 75 minutes o f irradiation). One possible explanation is that the triplet state o f the acetophenone moiety is quecnched by the enol ether, ' ' 95  96  97  therefore the Norrish type II reaction becomes less efficient.  91  Table 3.2.1 Product ratio o f isomers 129, 130 and secondary photoproduct 131 when ester 130 was irradiated in C H 3 C N Time  129/130  131 (%)  0  0  0  15  0.11  4  30  0.24  8  45  0.33  11  60  0.42  13  75  0.43  16  3.2.3 Identification of photoproducts Pure  photoproducts  chromatography,  129  and 130  and characterized  were  isolated  by different  b y preparative  spectroscopic  methods.  HPLC Their  spectroscopic data are very similar except for the *H N M R spectra. The cis and trans configurations were determined by comparing the coupling constants o f the vinylic hydrogen, H a (Figure 3.2.1). Since this hydrogen is next to an ether linkage, it is expected to be very deshielded, and should have a strong coupling to H b . Therefore, the N M R signal o f H a must be the doublet at around 6 ppm in the ' H N M R spectra o f products 129 and 130 (Figure 3.2.2).  O  Figure 3.2.1 H labeling system o f products 129 and 130.  92  V i c i n a l protons on a trans double bond usually interact with a coupling constant of J = 12-15 H z , while the cis coupling constant is usually between 6-9 H z .  The  coupling constants o f H a i n products 129 and 130 were found to be 6.2 H z and 12.7 H z , respectively. These two coupling constants agree very well with the reference values, and therefore the stereochemistry o f products 129 and 130 was assigned as cis and trans respectively.  a)  Ha.  JUu b)  Ha  Ik S  ppm  Figure 3.2.2  H N M R spectra o f a) product  130 and b) product 129  93  95  The structures o f photoproducts 129 and 130 were confirmed by 2 D N M R experiments. A s H a has been identified already, the rest o f the aliphatic hydrogens were assigned by C O S Y experiments (Figure 3.2.3 and Figure 3.2.4). The complete proton assignments o f products 129 and 130 are summarized in Table 3.2.2. The assignments o f H d and H d ' in compounds 129 and 130 were based on the fact that H M Q C experiments revealed that these two protons came from the same methylene carbon. Table 3.2.2 H assignments o f products 129 and 130 Chemical  Aliphatic Hydrogens  Shifts (ppm)  129 (cis)  130 (trans)  Ha  6.10  6.40  Hb  4.34  4.76  He  3.40  2.93  Hd, H d '  3.21,2.88  3.19,2.93  He, H e '  3.40  3.42  Hf  4.42  4.44  Hg  4.74  4.64  The chemical shifts o f most o f the hydrogens o f the two isomers are very similar, except for those o f H a , H b and He. H a and H b shift to a higher field while H e shifts to lower field when the configuration switches from trans to cis. This is probably due to the deshielding effect caused by the phenyl rings o f the benzyloxy substituent. The trans isomer can adopt a conformation similar to conformer a (Figure 3.2.5). In this structure, Hb is very close to the deshielding region o f phenyl ring A , while H a is near the deshielding region o f phenyl ring B . There is no way for the cis isomer to adopt this kind of conformation, hence H a and H b are more shielded i n product 129. However, phenyl ring A and He are on the same side in the cis isomer. Therefore, He is deshielded by phenyl ring A , and has a higher chemical shift than H e i n product 130.  96  Ha  Hb  B  b Figure 3.2.5 Possible conformations o f 129 and 130: a) a conformer o f product 130 b) a conformer o f product 129 a  3.2.4  Solid state photochemistry When ester 86 was irradiated in the crystalline state, the ratio o f the cis and trans  photoproducts was different from those in solution photolysis. The ratios o f the cis and trans isomers obtained from the two media are summaried i n Table 3.2.3 Table 3.2.3 Ratios o f photoproducts 129 and 130 obtained in solution and the solid state photolyses Compound  Conversion (%)  cis  trans  Cis:Trans  solid  25  13  12  1.1  46  21.5  24.5  0.88  31  6  25  0.24  57  12  45  0.28  85  21  64  0.33  solution  a  partly melted  97  3.2.5 Stereoselectivity in solution and the solid state A s shown i n Table 3.2.3, the trans isomer was the predominant product when irradiated in C H C N . However, the cis:trans ratio increased from 0.3 in C H 3 C N to ca. 1 3  when the irradiation was carried out in the solid state. In order to explain this observation, one must consider the fate ofthe 1,4-biradical intermediate (Scheme 3.2.4).  Scheme 3.2.4  The biradical intermediate, which can undergo conformational equilibration by rotation around the C 2 - C 4 bond (Scheme 3.2.4), can exist as structure i or ii. If, as seems likely, rotation about this bond is rapid relative to biradical cleavage, the cisltrans ratio w i l l be determined by the relative rates o f cleavage to form cis-129 and trans-130.  Under  these circumstances, cleavage to form the less hindered trans product 130 is likely to be faster than cleavage to form the more hindered cis-129, thus resulting i n a preference for the former, as observed experimentally. In the crystalline state, however, the molecular conformation is rigid, and bond rotation such as that discussed is more restricted.  The  formation o f the pre-cis (i) or pre-trans (ii) intermediate is determined by the initial solid state conformation, and as a result, the cis:trans ratio can differ considerably from that observed i n solution. .  98  3.2.6 Asymmetric synthesis in the crystalline state 3.2.6.1 Preparation of optically active salts Optically active salts o f acid 85 were prepared b y mixing equimolar amounts o f acid 85 and optically pure amines i n E t i O . The precipitate was washed with ether and then recrystallized from acetonitrile or methanol.  In cases where precipitate was not  formed, the solvent was removed in vacuo, and the residue triturated with petroleum ether. The amines and the recrystalhzation solvents employed are summarized i n Table 3.2.4. Table 3.2.4 Optically active salts prepared from keto-acid 85 Amine  Salt  87  Recrystalhzation solvent  mp (°C)  MeOH  126-128  MeOH  126-127  MeCN  139-141  MeOH  183-185  \ ^ r  88  !-NH  2  C OH  89  o 90 H  C) 99  r >NH  91  MeOH  130-132  MeOH  134-136  MeOH/MeCN  122-124  MeOH/MeCN  122-124  MeOH/MeCN  109-111  Trituration from Pet Ether  114-116  Et 0/MeOH  108-109  2  C 92  NH 93  NH  h  {  HO  2  Z  ( 94  H  NH  2  L^ 95  HO-.  H  ..••kl •••••OH H Nf 2  0 96  L ^NH N  0  H  97  2  H ^ ^ N H  2  2  100  3.2.6.2  Separation of the enantiomers of photoproducts 129 and 130 Enantiomeric excesses o f ester 129 and 130 were determined by H P L C on a  Chiralcel O D column. The mobile phase was hexane/ethanol (95:5), and the flow rate was 1.0 m L / m i n ; the monitoring wavelength was 254 nm. The chromatograms o f the separation o f the four diasteremoers are shown in F i g 3.2.6.  Figure 3.2.6 H P L C separation o f the enantiomers o f photoproducts 129 and 130. Peaks 1 and 2 represent the enantiomers o f 129 while peaks 3 and 4 represent the enantiomers of 130. (a) H P L C trace o f the crystalline phase photolysis o f (+)-norephedrine salt (93). (b) H P L C trace o f the crystalline phase photolysis o f (-)-norephedrine salt (94).  101  3.2.6.3  Photolysis of optically active salts  Each optically active salt was sandwiched between two microscope slides and crushed to a powder. Irradiations were carried out at different temperatures, and the salts were converted to methyl ester by treating the crude photolysate with an ethereal solution of  diazomethane.  Moderate  to  high  ees  were  observed.  In  diastereoselectivity in the formation o f products 129 and 130 was  addition,  high  obtained i n some  cases. The results are summarized in Table 3.2.5. N o enantioselectivity was observed when these salts were irradiated in acetonitrile or methanol. The ratios o f photoproducts 129 and 130 obtained from solution photolyses o f the salts were within 0.32-0.40  (cis:trans).  Table 3.2.5 Solid state photolysis o f optically active salts o f acid 85 130 ee  Peak  1  58  4  60  1  55  4  Salt#  Temp/°C  Conversion %  129/130  129 ee  87  -25  23  0.63  62  68  0.68  Peak  1  88  -25  21  0.58  65  2 •  56  3  89  -25  10  0.42  73  2  61  3  18  0.45  74  2  60  3  48  0.56 •  70 '  2  55  3  62  0.53  69  2  58  3  -45  8  0.39  74  2  63  3  25  47*  1.1  22  2  5  3  -25  10  3.1  35  2  14  3  29  3  33  2  13  3  48  2.4  34  2  13  3  23  0.23  74  2  63  4  33  0.25  68  2  55  4  50  0.29  61  2  45  4  26  0.21  73  2  64  4  45  0.26  71  2  58  4  90  91  -25  -40  102  1  Table 3.2.5 cont'd  130 ee  Peak  2  5  3  5  2  5  3  1  6  2  8  3  16  4.0  89  2  72  3  65*  3.1  73  2  59  3  20  4.6  94  2  82  3  40  3.6  91  2  78  3  77  2.5  79  2  57  3  35  5.6  95  2  86  3  50  5  89  2  74  3  81  2.8  80  2  54  3  -25  44  3.3  90  1  72  4  10  21  1.3  57  1  18  4  45  1.1  51  1  13  4  25  1.7  60  1  21  4  57  1.5  54  1  18  4  9  1.1  87  1  88  3  28  0.83  80  1  78  .3  68  0.68  68  1  59  3  16  0.15  0  -  0  -  129/130 129 ee  Salt#  Temp/°C  Conversion %  92  -25  15  1  6  45  1.1  -45  20  10  93  -25  -45  94 95  -25  96  97  -25  -25  Peak  1  1  Peaks 1/2 and 3/4 correspond to the peaks of the enantiomers of photoproducts 129 and 130 respectively on HPLC traces (Figure 3.2.6). The peak shown in this column indicates the major enantiomer of the product. * sample was partially melted 1  From Table 3.2.5, there are several points that should be addressed. 1) The enantiomeric excesses decreased as conversion increased. The percentage o f the trans isomer appeared to increase with conversion in some cases. 2) Cis:trans ratios varied from salt to salt; the major photoproduct (129 or 130) varied in different cases.  103  3) The enantiomeric excesses o f products 129 and 130 were not the same i n most cases. 4) The enriched enantiomers ofthe two photoproducts 129 and 130 were found to have different configurations at the chiral center. For example, in some cases, peaks 1 and 3 predominated, while in other cases; peaks 1 and 4 were the major ones. The first point suggests the crystallinity is lost at higher conversions. L i k e other solid state reactions, the number o f defect sites increases as the reaction proceeds. This may soften the crystal, and the reaction occurs in a less restricted medium. A s the crystal lattice breaks down, the rigidity decreases and this could lead to a change in selectivity. This may explain the increase o f the trans product at higher conversions in some cases. In fact, the melting points o f most ofthe salts are below 150 °C. The crystalline samples are not very robust, thus it is not surprising to see the crystal break down at high conversions. The last two points are more surprising. A s mentioned in the Introduction (Section 1.8), the enantioselectivity ofthe Norrish type II reaction is determined in the initial hydrogen abstraction step. Therefore, one might expect not only that the enriched enantiomers o f products 129 and 130 should have the same absolute configuration, but should also have very close enantiomeric excess values. The experimental results suggest that things are not that simple.  3.2.7 Chiral crystalline state reactivity In order to explain the result that photoproducts 129 and 130 showed different ee values and configurations o f the enantiomerically enriched products, it is necessary to reconsider the mechanism o f the reaction. A hypothetical energy-reaction diagram for this process is shown in Figure 3.2.7.  104  HCk ^ A r  F i g u r e 3.2.7 Hypothetical energy-reaction diagram for the Norrish type II reaction o f salts o f acid 85  The initial step is the abstraction o f one o f the two sets o f diastereotopic yhydrogen atoms H a and H b .  Abstraction o f H a gives the pro-S biradical 165 while  abstraction o f H b gives the pro-R biradical 1 6 6 . " Biradicals 165 and 166 then undergo cleavage to give diastereomers 129S, 130S and 129R, 130R respectively (S and R are the absolute configuration o f the compound in Figure 3.2.7). The cis and trans configurations of the products are determined i n this second step. However, within the chiral crystalline environment, the activation energies for the formation o f cis and trans products from biradicals 165 and 166 are not necessarily the same. A s shown i n Figure. 3.2.7, biradical 165 might be i n a conformation that favors the formation o f the cis product, while  105  biradical 166 might have a lower energy pathway for the formation o f the trans isomer. A s a result, the ratio o f products 129:130 formed from biradical 165 would not be the same as that from biradical 166. Because  o f this, the enantiomeric  excess o f  photoproducts 129 and 130 would be different. This concept is illustrated further in the example shown in Figure 3.2.8. Ar^ ^OH  Hb OBn  BnO  H  .  H  Hb  20 %  Ha OBn  BnO  H  I  H  OBn  BnO  166 (Pro R)  ee of 129 = (74-4)/(74+4) = 90 % (S)  O  BnO  Ha  H  165 (Pro S)  BnO  -Ar  HO.  O ^ A r  80 %  OBn  Ar*  ee of 130 = (6-16)/(6+16) = 45 % (R)  129S (74 %) + BnO  O Ar*  BnO  OBn  130R(16%)  130S (6%)  F i g u r e 3.2.8 A hypothetical case - distribution o f diastereomers 129S, 129R, 130S and 130R after solid state photolysis o f an optically active salts o f acid 85. The percentage o f each product is chosen arbitrarily.  In this example, the initial step gives biradicals 165 and 166 i n a ratio o f 4:1. Therefore, the total amount o f products having the S configuration is 80%. Biradical 165 then undergoes cleavage to give diastereomers 129S and 130S in a ratio o f 74:6 (93 % o f diastereomer  129S).  Biradical 166 undergoes  a different partitioning, and yields  diastereomers 129R and 130R in a ratio o f 4:16 (80 % o f diastereomer 130R). The overall ee o f isomer 129 is 90 % favoring S, while ee o f isomer 130 is 45 % favoring R. This example demonstrates that the final ee values o f final products 129 and 130 are actually affected by two different steps i n the solid state reaction. Unless biradicals 165  106  and 166 have the same selectivity in the formation o f the two final products, the ee o f compounds 129 and 130 w i l l not be equal. This also rationalizes the fact that the configurations o f the enantiomerically enriched product o f 129 and 130 are not always the same. In the example shown above, i f biradical 166 gives isomers 129R and 130R in a ratio o f 16:4 instead o f the one shown, then the enantiomerically enriched products o f both compounds would have the same configuration, S. The observed ee values shown in Table 3.2.5 are therefore the combined result o f two stereoselective processes in the crystalline state. The selectivity o f each process (formation o f biradicals 165 and 167, and formation o f cis and trans isomers 129 and 130 from intermediates 165 and 166) can be calculated from the observed results, i f one can first determine whether H P L C peaks 1 and 3 or peaks 1 and 4 correspond to products 129 and 130 having the same absolute configuration.  3.2.8 H P L C peak assignments A s shown in Figure 3.2.6, four peaks (named as 1, 2, 3, 4), which correspond to the R and S enantiomers o f the two diastereoisomers, were observed when a mixture o f photoproducts 129 and 130 were injected onto the chiral H P L C column. Since the absolute configurations o f the two stereoisomers were not determined, R* and S* w i l l represent the relative configurations o f the enantiomers o f products 129 and 130 for the remainder o f this chapter. When a mixture o f compounds 129 and 130 is irradiated, cis-trans isomerization occurs, and the percentage o f compounds 129 and 130 varies. However, this process should not affect the total number o f molecules having the S (or R) configuration. other words, i f peaks 1 and  3 correspond  to diastereomers  129S* and 130S*  100  In  respectively,  then the sum o f the relative intensities o f these two peaks should remain the same before and after irradiation. Based on this.hypothesis, the peak assignments can be carried out by irradiating an enantiomerically enriched mixture o f compounds 129 and 130 comparing the sum o f the peak areas before and after irradiation.  107  and  A sample with relative intensities o f peaks 1-4 at 4.4, 15.6, 20.2, and 59.8% respectively was irradiated. After irradiation, the four stereoisomers redistributed and the new relative intensities o f peaks 1-4 became 19.8, 13.0, 26.2 and 41.0 % respectively. If peaks 1 and 3 are diastereomers  129S* and 130S*, then  before irradiation, the  sum o f the diastereomers having the S configuration is 24.6 % (i.e. the sum o f peak areas 1 and 3), while the sum o f the diastereomers having the R configuration is 75.4 %. After irradiation, these two values become 46.0 % and 54.0 % respectively. If peak 1 and 4 are diastereomers  129S* and 130S*, then  before irradiation, the  sum o f the diastereomers having the S configuration is 64.2 %; while the sum o f the diastereomers having the R configuration is 35.8 %. After irradiation, these two values become 60.8 % and 39.2 % respectively. It appears that peak 1 and peak 4 correspond to diastereomers  129S* and 130S*  respectively. Although the values before and after irradiation did not match up perfectly with each other, they are within instrumental error. It is important to point out that the assignments o f the relative configuration are arbitrary. Peak 1 and 4 could have the R configuration.  3.2.9 Stereoselectivities for optically active salts W i t h each peak assigned to the corresponding diastereomer, the percentage o f the pro-S intermediate 165 can be obtained by totaling the percentages o f diastereomers  129S*  and  130S*.  The same can be done for pro-R intermediate  166.  The data also  permit the partitioning o f each biradical between photoproduct 129 and 130 to be calculated. A sample calculation using the results for salt 93 is shown in Figure 3.2.9. The same information o f each salt is calculated according to this method and are shown in Table 3.2.6. For each salt the partitioning between (R) and (S) and cis and trans is determined by the crystal structure o f the carboxylate anion moiety. In order to explain the stereoselectivity observed for the salts, as well as the differencec in selectivity observed i n solution and the crystalline state, the initial solid state conformation o f each compound must be considered.  108  % o f 129R = 74.5 (Peak 2)  % o f 1295 = 3.5 (Peak 1)  % o f 130i? - 19.6 (Peak 3)  % o f 1305 = 2.4 (Peak 4)  Selectivity in the 1 step: Differential formation o f Pro S and Pro R biradicals st  Total percentage o f biradical 165  Total percentage o f biradical 166  = 1295 + 1305  = 129i? + 130i?  = 3.5 + 2.4  =(74.5 + 19.6)  = 5.9%  =94.1 %  Selectivity in the 2  n d  step: Cleavage o f biradicals 165 and 166  129S*:130S* from biradical 165 = (3.5/5.9): (2.4/5.9) = 59 : 41 129R*:130R* from biradical 166 = (74.5/94.1) : (19.6/94.1) = 79 : 21 Figure 3.2.9 Sample calculation ofthe selectivity in each o f the two steps  Table 3.2.6 Selectivity o f hydrogen abstraction and biradical cleavage Salt '" 3  Conversion (%)  Hydrogen abstraction  Cleavage o f biradicals  Obs ee°  Obs ee°  165  166  (%)  (%)  165:166  129S*:130S*  129R*:130R*  129  130  87  68  78:22  41:59  38:62  60 (S)  55 (S)  89  62  19:81  27:73  35:65  69 (R)  58 (R)  90  48  35:65  64:36  74:26  34 (R)  13 (R)  91  50  61:39  7:93  46:54  61 (R)  45 (S)  93  40  6:94  59:41  79:21  91 (R)  78 (R)  95  57  70:30  66:34  46:54  54 (S)  18 (S)  96  68  46:54  74:26  12:88  68 (S)  59 (R)  Salts 92 and 97 are not included because they gave <5% ee for the final products; salts 88 and 94 are omitted as they are the enantiomers of salts 87 and 93 respectively. All selected photolyses were carried out at -25 °C. The diastereomers that are formed in excess are shown in parentheses a  b  109  3.2.10 Structure reactivity correlations 3.2.10.1 Cis and trans partitioning of ester 86 in the solid state  A s it was discussed briefly i n section 3.2.2.1, the selectivity observed in the formation o f products 129 and 130 from methyl ester 86 was different i n solution and the solid state. The ratio o f photoproduct 129:130 was ca. 1:3 when the ester was irradiated in acetonitrile but increased to as high as 1:1 when it was irradiated i n the crystalline state. This difference can be attributed to the solid state conformation o f the methyl ester, which was found by crystallography to be chiral (Figure 3.2.10).  In this conformation,  the carbonyl group is pointing toward H a , while the C 4 - 0 2 and C 5 - 0 3 bonds are pointing i n different directions and appear to be perpendicular to each other.  When  irradiated, the ketone undergoes an n —> n* transition and intersystem crossing to give a triplet excited state, which can abstract a y-hydrogen atom.  There are four y-hydrogen  atoms i n ester 86. The C=O...Hx distances and other angular parameters which determine abstraction o f the four y-hydrogens in ester 86 are summarized in Table 3.2.7. Table 3.2.7 Abstraction parameter values o f the four y- Hydrogen atoms o f ester 86 Parameters  d(A) co(°) A(°)  en  Ideal values  <2.72 0 90-120 180  4  Ha  Ha'  Hb  Hb'  2.40 7.54 70.9 110.6  2.90 5.90 66.1 78.2  2.59 57.20 64.1 111.7  3.98 42.5 57.8 41.78  Successful intramolecular hydrogen abstraction has been carried out up to a C=O...H distance o f 3.1 A .  1 0 1  Therefore, in principle, all four y-hydrogens except H b ' are  abstractable. However, H a is closest to the oxygen atom and has a very favorable angular parameter o f co, and therefore should be abstracted i n preference.  The conformation o f  ester 86 indicates that abstraction o f H a w i l l afford the pre-cis biradical (a), which w i l l lead to the cis isomer 129 upon cleavage (Scheme 3.2.5). This explains the increase in the percentage o f product 129 when ester 86 is irradiated i n the crystalline state. This kind o f selectivity obviously does not exist i n solution where bond rotations are not restricted. Following this argument, one might expect that solid state photolysis o f ester  110  Scheme 3.2.5  86 would give product 129 exclusively because H a is preferably abstracted. However, the experimental observation was different, an almost equal amount o f product 130 was obtained. One possible explanation is that abstraction o f H b , which would give a biradical favoring the formation o f product 130, also occurred. The C=O...Hb distance and other angular parameter values for H b are all within favorable ranges. Therefore, the possibility o f H b being abstracted cannot be ruled out, although it is likely to occur at a slower rate than that o f Ha. However, biradical b is in a perfect geometry for C 1 - C 3 bond cleavage, while biradical a is not in such a good geometry for C 1 - C 2 cleavage. A s discussed i n Chapter 2, Sevin et al.  have shown that the geometry ofthe carbonyl group  has a profound effect on selective (3 bond cleavage o f cyclopropyl ketones. According to the idea o f Sevin, the difference in activation energy for cleavage o f bonds C 1 - C 2 and C 1 - C 3 in a compound such as 86 would be greatest when the torsion angle 0 1 - C 6 - C 1 - H 1 is 150° (Figure 3.2.10, H I attached on C l ) . In principle, this idea can be applied to biradical intermediates as well. This torsion angle in ester 86 is exactly 150°. The porbital on the carbonyl carbon is orthogonal to the C 1 - C 2 bond, and rupture o f this bond is not favored. In contrast, the p-orbital overlaps almost perfectly with the C 1 - C 3 bond,  111  (a)  (b)  F i g u r e 3.2.10 Crystal structure o f ester 86 a) O R T E P drawing and b) the crystal packing diagram of ester 86. The oxygen atom o f the carbonyl group is in red.  112  and therefore facilitates the breakage o f this bond.  A s a result, the conformation o f ester  86 favors the abstraction o f H a but favors the cleavage o f C 1 - C 3 , which means that k > a  kb, but kb> > k -. The experimental results suggest that these two effects balance out. a  3.2.10.2 Stereoselectivity of salts 87-97 in the solid state  To date, salts o f acid 85 have failed to give X-ray quality crystals. However, because compounds usually crystallize close to their lowest energy conformations, it is reasonable to assume that the carboxylate ions o f salts 87-97 crystallize i n conformations similar to that o f ester 86.  The stereoselectivity i n the first step is governed by  preferential abstraction o f the more favorably located diastereotopic hydrogen (Ha or H b in Figure 3.2.8). If the carboxylate ions o f the salts adopt a crystalline state conformation similar to that o f 86, then both diastereotopic hydrogen atoms H a and H b are abstractable. This is very likely to be the case for salt 96. When this salt was irradiated, it gave products 129 and 130 i n close to 1:1 ratio at low conversion. The selectivity in hydrogen abstraction was poor (46:54). However, the overall ee's for products 129 and 130 were found to be 68 and 59 % respectively. The most surprising result was that the enantiomerically enriched products configurations at the chiral center.  o f the two stereoisomers  possessed  opposite  A s discussed above for ester 86, abstraction o f H a  would lead to a biradical favoring the formation o f cis isomer 129, while abstraction o f Hb would favor the formation o f trans isomer 130. If salt 96 adopts a conformation similar to that o f ester 86, the reaction would give an almost equal amount o f enantiomerically  enriched  products  o f 129  and 130 but o f opposite  absolute  configurations. This agrees with the observed results. It is important to point out that the C=O...Ha and C=O...Hb distances and other angular parameters for H-abstraction are very sensitive to the torsion angles cti, a and a 2  3  (Figure 3.2.11). For example, as shown i n Figure 3.2.11, a decrease in cti and an increase in ct2 would shorten the C=O...Ha distance and lengthen the C=O...Hb contact. This change increases the abstractability o f Ha, which could make the overall effect o f k + k a  stronger than that o f kb + k ' , leading to higher enantioselectivity (Scheme 3.2.5). A s the b  113  a  F i g u r e 3.2.11 Three torsion angles that determine the C = O . . . H distance and angular abstraction parameters o f H a and H b . x  compounds are not rigid, these angles need not be the same in all salts. It was shown in Chapter 2 that a i i n 2,3-diphenyl-l-benzoylcyclopropane derivatives varied from 164177°. Therefore, it is reasonable to assume that these angles in salt 87-97 can vary by a similar amount.  Since the abstraction parameters are so close (Table 3.2.7), a small  change in these angles could alter the selectivity significantly.  However, the fact that  only one o f the 11 salts (93) gave efficient partitioning in the initial step (Table 3.2.6) suggests that it is difficult for these compounds to adopt a conformation that can differentiate the two H atoms efficiently. The low selectivity i n the initial hydrogen abstraction step could also be due to conformational enantiomerism. In this phenomenon, the carboxylate ions crystallize in 87  conformations that are close to mirror images o f each other. When irradiated, half o f the anions would give the pro-S biradical while the other half would give the pro-R biradical, leading to a low stereoselectivity. However, it is difficult to attribute the results for salts 91 and 96 to this phenomenon. A s discussed above, even though the selectivity in the hydrogen abstraction is poor (61:39 and 46:54 respectively), the overall ee's for products 129 and 130 obtained from both salts were found to be greater than or close to 50 %. If the  poor selectivity in H-abstraction is due to the  presence  o f conformational  enantiomerism, then l o w ee's i n the final products are expected. While the possibility o f the presence o f conformational enantiomerism cannot be ruled out for other salts, this phenomenon does not play a role at least in salts 91 and 96.  114  From Table 3.2.8, the selectivity o f each biradical in the formation o f cis and trans isomers was not outstanding. One possible rationale is that biradicals 165 and 166 undergo bond rotation. Ideally, there should be least motion in the solid state. However, it has been shown that a benzyl radical can undergo bond rotation in the crystalline state. In fact, for the current system, a "hula-twist"-like volume-conserving two-bond rotation can invert the radical center in the confined space o f a crystal (Figure 3.2.12).  F i g u r e 3.2.12 A "hula-twist" like rotation  L i u et a / .  103  have shown that this type o f bond rotation is responsible for the  isomerization o f dienes i n organized media such as frozen solvents. In a recent study, Ohashi et al.  m  have applied the "hula-twist" mechanism to rationalize the crystalline  state racemization o f [(i?)-l,2-bis(ethoxycarbonyl)ethyl](pyridine)bis(dimethylgloximato) cobalt (III) (167).  When crystals o f compound (i?)-167 were irradiated, the chiral 1,2-  bis(ethoxycarbonyl)ethyl group was converted to the opposite configuration (Figure 3.2.13). X - r a y crystal analysis revealed that the atomic movement o f the chiral ligand in this process is relatively small, leading to the conclusion that a 180° one bond rotation around the C 2 - C 3 bond i n radical I does not occur. Based on the X-ray crystallographic data, Ohashi suggested that the radical undergoes a "hula-twist" rotation along the alkyl chain, such that the configuration o f the radical center is inverted, but the overall atomic movements are minimized.  115  The study by Ohashi demonstrates that radicals can undergo isomerization v i a hula-twist motion i n the crystalline state. Therefore, it is possible that there w i l l be some C 2 - C 4 bond rotations o f the biradical intermediates 165 and 166 i n the solid state (Figure 3.2.12). The degree o f rotation w i l l be determined b y the chiral crystalline environment and can differ in different crystal lattices.  ^  t4o-  o rn  O  D  3  H  H  0  i  N  C D  i  OH  H  X  9  v"  ° 3  C  0  . C D ,  Co 'N =  Co  i  h 3  Step  N =  CD'  CD  ,CD,  *  H  OH Py  C  3  D  Py  (R)-167 Step 2  hv  .0  D  *0' O CD,  r=N :  CD'  H  HO Co. N i  H  i  OH  ,CD,  O  D  O Step 3  C D 3,  CD'  CD,  HO H "\ N = NN r N Co."  r  n  V  i H  OH  C  D  3  Py  Py  (S)-167  F i g u r e 3.2.13 Crystalline state racemization o f compound 167. Step 1: Homolytic C o - C bond cleavage. Step 2: Hula-twist motion o f t h e 1,2-disubstituted ethyl radical I. The configuration o f the chiral center is inverted i n this step. Step 3: Recombination o f radicals.  116  3.2.11 Thermal reactivity of derivatives of acid 85  When methyl ester 86 was heated at 110-120 °C under an atmosphere o f nitrogen for 6-8 h, the compound underwent the enolene rearrangement and gave products 129 and 130 i n a ratio o f 1:9. Similar observations were obtained when salts 87-97 were heated. However, all samples melted before or concomitant with the reaction.  N o pure  crystalline sample was observed at the end o f the reaction. A sticky o i l was obtained. This is not surprising because the melting points o f most o f the salts are below 140 °C. The crystal lattice is not robust, and crystallinity is lost at high temperatures.  A s the  reactions did not take place in the confined crystal lattices, no ee was observed i n the thermal rearrangement for optically pure salts 87-97. Thermolyses were also carried out at 85-90 °C, but the samples were not reactive at this temperature.  A s crystallinity  cannot be preserved at the reactive temperature, the ionic chiral auxiliary approach could not be applied to induce enantioselective enolene rearrangement for derivatives o f acid 85.  117  3.3 Isomerization of 9-tricyclo[4.4.1.0]undecyI phenyl methanone derivatives  4-carboxy-  3.3.1 Preparation of substrates The following synthetic route was employed in the preparation o f the tricyclo[4.4.1.0] undecane ring compound 102 (Scheme 3.3.1). Scheme 3.3.1  ^  102  The yield o f the first step is highly dependent on the catalyst employed for the carbenoid addition reaction. When CuSCU or R h ( O A c ) was used, the yield was very low 4  (< 15 %) and numerous products were obtained. In the case where Ar3NSbCl6 was employed,  105  compound 99 was produced as the only product in an isolated yield of 56  %, A c i d 102 was prepared in an overall yield o f ca 50 % starting from ester 99. It is important to mention that this catalyst is only reactive toward tetrasubstituted alkenes and other  electron-rich alkenes. Compounds 99-102 are new, and were fully characterized  by spectroscopic and analytical methods. The methyl ester o f 102 (103) was prepared by treating amide 101 with a Grignard reagent prepared from methyl 4-iodobenzoate.  118  3.3.2 Photochemistry of 9-tricyclo[4.4.1.0]undecyl 4-(carbomethoxyphenyl) ketone 103  When keto-ester 103 was irradiated ( X > 290 nm) i n benzene or acetonitrile (Table 3.3.1), it underwent an efficient Norrish type II reaction to give enol 132, which ketonized to give ketone 133 as the primary photoproduct. U p o n extended irradiation, secondary cleavage products 131 and 134 were observed. G C M S analyses indicated that product 134 was a mixture o f hexahydronaphthalenes.  The photoreaction o f keto-ester  103 was very facile. It was completely reacted in less than 20 minutes o f irradiation. The secondary photochemical reaction was efficient. A s a result, extended irradiation o f ester 103 in solution led to a mixture o f products.  119  Table 3.3.1 Solution photolyses o f compound 103 Time (min)  Solvent  103  132  a  133  a  131  a  a  0 0 22 78 5 3 6 0 91 15 8 14 78 60 0 0 3 80 17 5 C D 7 78 15 0 15 16 23 61 55 0 The proportion of the compound in the mixture. Photolyses were followed by H NMR spectroscopy CD CN 3  6  a  6  When keto-ester 103 was irradiated in the solid state, the formation o f secondary photoproducts was much less than that in the solution state. There are two possible explanations: 1) the solid state conformation o f the primary photoproduct 133 does not favor another Norrish type TJ reaction, or 2) the enol intermediate 132 does not undergo ketonization i n the solid state. In order to rationalize this result, the fate o f enol 132 was followed by solid state IR and is shown in Figure 3.3.1.  %T  3550  3200'  2800  2400  2000  1800  1600  1400  1200  1000  .800 cm-1  Figure 3.3.1 TR study o f the solid state photochemistry o f ester 103. a) TR o f a K B r pellet o f ester 103 before irradiation, b) TR o f the sample after irradiation at 0 °C for 45 minutes, x denotes an O H stretch, c) IR o f samples after heating at 50 °C for 5 hrs; y denotes a new C = 0 stretch, d) TR o f ketone 133 that was prepared by independent synthesis.  120  When a K B r pellet o f compound 103 was irradiated, the ketone stretch at 1666 cm" disappeared and a new peak was observed at -3400 cm" , which corresponds to the 1  1  O H stretch o f enol 132.  There was no significant change in the JR spectrum over a  period o f days at room temperature under nitrogen, but upon heating, the enol O H stretch diminished and a new absorption at - 1 6 8 0 cm" corresponding to the ketone stretch o f 1  compound 133 was observed.  These experiments explain the absence o f secondary  photochemistry i n the crystalline state. In solution, the enol undergoes ketonization, and therefore a secondary photochemical reaction is observed. However, in the crystalline state, the rate o f ketonization is relatively slow, hence, no further type II reaction is possible, and the photochemistry is much cleaner. The structure o f enol 132 was confirmed by *H N M R spectrometry. A crystalline sample o f methyl ester 103 was dissolved in CeD6 immediately after irradiation. A clean ]  H N M R spectrum o f enol 132 was obtained.  There are three distinct signals at 4.81,  5.44, and 7.05 ppm, which correspond to H b , He, and H a o f enol 132 respectively (Figure 3.3.2).  COOMe  Figure 3.3.2 H  labeling pattern o f some hydrogens in the enol intermediate  The multiplet at 5.44 ppm must correspond to the vinylic hydrogen He, which couples with H d and H d ' . The signal observed at 7.05 ppm corresponds to the enolic hydrogen H a .  The O H signal for ethenol, propen-l-ol, and propen-2-ol have been  reported to have chemical shift between 7.0-8.5 p p m .  121  106  Therefore, the enolic proton in  enol 132 probably resonate in this range. The ketonization process was followed by H !  N M R experiments. To a pure sample o f enol 132 in CeD6 was added a trace amount o f T F A , and the H N M R spectrum o f the resulting sample showed a mixture o f compounds !  in which there were two new signals at 5.35 (multiplet) and 2.88 (doublet o f doublets) ppm. The *H N M R spectrum o f the sample after leaving it at room temperature for five minutes showed a clean spectrum with only one multiplet between 4.50 and 7.00 ppm. The three signals o f the enol mentioned above disappeared. A strong signal at 2.88 ppm (2H) was observed, which corresponds to the two hydrogen atoms on the newly formed alpha carbon in ketone 133 (Figure 3.3.4). The ketonization was also followed by a deuterium labelling experiment. A pure  sample o f enol 132 was allowed to sit i n a solution o f C D O D . The H N M R spectrum o f !  3  this sample showed two new singlets between 3.10-3.12 ppm.  These two signals  correspond to the diastereotopic protons in the two diastereomers o f the D-incorporated ketone (Figure 3.3.3).  Figure 3.3.3 T w o diastereomers  of the D-incorporated ketone  122  133  (a) 7,05  5.44  4.81  F i g u r e 3.3.4 Ketonization o f enol 132 a) H N M R spectrum o f pure enol b) ' H N M R spectrum o f sample after addition o f T F A - c ) *H N M R spectrum o f sample after five minutes. * denotes signal o f T F A ]  123  3.3.3 Identification of photoproduct 133 The structure o f product 133 was confirmed by ' H , A P T , H M Q C , and H M B C N M R experiments. Assignments o f the hydrogen and carbon signals are summarized in Table 3.3.2. The structure o f ketone 133 was characterized by the multiplet at 5.40 ppm and the two doublet signals at 3.10 and 3.20 ppm in the ' H N M R spectrum (sample dissolved i n CDCI3, Figure 3.3.5).  The signal at 5.40 ppm corresponds to the vinylic  hydrogen H 4 in ketone 133. The simple coupling pattern ofthe two signals at 3.10-3.20 ppm indicates that they are the alpha hydrogens.  This was confirmed by the H M Q C  experiment (Figure 3.3.6), which revealed that the two protons came from the same methylene carbon. T a b l e 3.3.2 H and C assignments o f 133 Carbon  C signals  Hydrogen  Cl  35.72  HI, H I '  1.23, 1.90  C2  18.93  H2, H 2 '  1.50-1.56  C3  25.60  H3,H3'  1.90  C4  121.41  H4  5.40  C5  32.68  H5,H5'  2.01,2.20  C6  28.25  H6, H 6 '  1.20, 1.75  C7  22.35  H7, H 7 '  1.50-1.56  C8  38.24  H8, H 8 '  1.22,2.01  C9  142.27  Quaternary Carbon  C10  39.08  Quaternary Carbon  Cll  41.02  C12  200.50  Quaternary Carbon  C13  133.44  Quaternary Carbon  C14  142.24  H16  8.00  C15  127.81  H15  7.95  C16  129.80  Quaternary Carbon  C17  166.44  Quaternary Carbon  C18  52.42  HI 8  124  1 J  Hll.Hir  ]  H signals  3.15,3.25  3.89  F i g u r e 3.3.5 H N M R spectrum o f ketone 133 in CDC1 !  125  3  H11, H1V  C11  # ppm  4.0  i  3.8  3.6  F i g u r e 3.3.6 H M Q C spectrum o f ketone 133  126  3.4  3.2  3.0  The assignments o f the aromatic atoms are straightforward.  The keto carbon  showed long range coupling with the H atoms at 8.00 ppm, and hence this hydrogen and the carbon it is attached to were assigned to be H I 4 and C14 respectively.  The  quaternary carbon at 133.44 ppm showed correlation with H l l / H l l ' on H M B C and therefore it was assigned to be C 1 3 . Similarly, assignments o f H I 5 and C15 were made based on the long range coupling between H I 5 and C17 shown on H M B C . The assignment o f the atoms i n the decalinl ring system is more complicated. It was made possible by starting from C 4 , which showed a clear correlation with H 4 from the H M Q C experiment. Assignment o f H3 and H 3 ' was based on their C O S Y correlation with H 4 , and led to the assignment o f C3 by H M Q C correlation. A s the carbon atom at 18.93 ppm showed a long range coupling with both H 4 and H 3 , it was assigned to be C 2 , and led to the assignment o f H 2 and H 2 ' . H l l / H l l ' showed long range couplings to two methylene carbons, which have chemical shifts o f 35.72 ppm and 38.24 ppm repectively. A s the signal at 35.72 ppm also showed long range coupling with H 2 and H 3 , it was assigned to be C l , and hence the signal at 38.24 ppm must correspond to C 8 . H I / H I ' and H 8 / H 8 ' were assigned from the corresponding H M Q C correlations. long range couplings with three different methylene carbons.  H 4 showed  T w o o f them have been  assigned as C 2 and C 3 , and therefore the remaining one (32.68 ppm) was assigned to be C5.  H 4 was also found to couple with a vinyl carbon and a quaternary carbon, hence  these two carbon atoms were assigned to be C 9 and C I O respectively.  HMQC  experiments revealed that the methylene carbon at 28.25 ppm possessed two H atoms at 1.75 and 1.20 ppm, and these two H atoms showed long range coupling with C 9 . A s a result, these H atoms were assigned to be H 6 / H 6 ' and the carbon they are attached to was assigned to be C 6 .  The assignments o f the decalin ring system were completed by  assigning the remaining methylene carbon and its hydrogen atoms as C 7 and H 7 / H 7 ' respectively.  127  3.3.3 Photochemical asymmetric synthesis of derivatives of acid 102 3.3.3.1  P r e p a r a t i o n of optically active salts. A l l optically active salts were prepared by the reaction o f carboxylic acid 102  with different optically pure amines. The identities, melting points, and the solvent used for recrystalhzation o f these compounds are summarized in Table 3.3.3. The carboxylate moiety o f the salts are not thermally stable. Attempts to recrystallize the salts from hot solvents usually resulted in partially reacted samples. Therefore, the salts i n most cases were obtained by dissolving the samples at room temperature and allowing the solvent to evaporate slowly or recrystalhzation at 4 °C.  T a b l e 3.3.3 Optically active salts prepared from keto-acid 102 Amine  Salt 104  Recrystalhzation solvent  mp(°C)  Triturated from pet ether  176-178  Triturated from pet ether  176-178  Ether  196-198  MeOH/Ether  186-187  MeOH/Ether  183-184  — N ''H  105 —N* H  106 '  N  NH  2  107 N  '  NH  2  108 ^ — ^  ^JH  2  128  Table 3.3.3 continued Amine  Salt 109  '  N  no  NH  MeOH/Ether  183-184  MeOH/Ether  129-131  Ether  165-167  Triturated from pet ether  114-115  MeOH  198-201  Ether  88-90  2  OH  111  mp °C  2  H ^j^"^NH  Recrystallization solvent  H N^^v^ 2  OH  112 HN  I H J \ ^ O H  2  113  WO 6  114  OH| H„ l^\'H  j  N  H  2  129  3.3.3.2  Separation of the enantiomers of photoproduct 133 The  enantioselectivity  o f the reaction  is determined  by measuring the  enantiomeric excess o f product 133 obtained from each salt. The two enantiomers o f ketone 133 were separated by H P L C on a.Chiralcel A S column (Figure 3.3.7). The mobile phase was hexane/isopropanol (99:1), and the flow rate was 1.0 m L / m i n ; the monitoring wavelength was 254 nm.  n 15  i—  1—•—=i 20'  125  . (™)  Figure 3.3.7 Separation o f the enantiomers o f ester 133 (a) H P L C trace o f the crystalline phase photolysis o f salt 109 ee = (+) 63%. (b) H P L C trace o f the crystalline phase photolysis o f salt 108 ee o f (-) 65%.  130  3.3.3.3  Photochemistry of optically active salts  After irradiation, salts 104-114 were converted to methyl ester 133 by treating the crude photolsyate with etheral diazomethane, and analyzed by chiral H P L C to determine enantiomeric excesses. When the salts were irradiated i n methanol or acetonitrile, no enantiomeric excesses were observed for the photoproduct. When crystalline samples o f salts 104-114 were sandwiched between two microscope slides and then irradiated, the resulting methyl ester showed signs o f enantioselectivity. The results o f the solid-state photolysis o f the salts are summarized in Table 3.3.4. Table 3.3.4 Solid state photolysis o f optically active salts o f keto-acid 102 Salt  Temp /°C  % Conv.  ee  a  104  106  -25 RT  >98 >98 45 >98 >98 28 90 80 >98 40 75 >98 22 >98 28 >98 37 62 >98 98 >98  89 95 90 87 94 89 87 91 90 74 69 59 73 74 57 61 65 68 65 60 63  +  105  RT -25 RT  -25 107  RT  -25 108  RT -25  109  RT -25  131  -  -  -  +  Table 3.3.4 continued Salt  % Conv.  88 (melted) 35 72 >98 RT >98 111 >98 -25 RT >98 112 52 -25 >98 RT >98 113 44 -25 >98 RT 68 114 56 -25 Sign of rotation of the enantiomerically enriched product at the sodium D line 110  a  Temp /°C RT -25  ee 17 68 69 70 <5 8 12 19 16 10 11 13 <5 <5  -  +  -  +  L o w to excellent ee's were observed from solid state photolysis o f salts. Excellent ees (>90 %) were obtained when salts 103 and 105 were irradiated in the solid state, whereas some salts gave less than 10 % ee upon irradiation. L i k e other solid state reactions, lowering the temperature increased the enantioselectivity o f the reaction. significant improvement was found i n salt 110.  A  A s the sample melted at ambient  temperature, the reaction did not occur in the crystalline state and therefore a low ee was observed. However, when the reaction was carried out at - 2 5 °C, the crystal lattice was preserved and this ensured that the reaction occurred in a chiral environment. Selectivity in the Norrish type II process is highly controlled by conformational factors. Hence, the molecular conformation o f the anions i n the crystalline state should play a very important role in determining the enantioselectivity o f the reaction.  132  3.3.4 Structure-reactivity correlations To date, salts 104-114 have resisted attempts to form X-ray quality crystals. However, the crystal structure o f ester 103 was determined (Figure 3.3.8).  It is  reasonable to assume that the carboxylate ions would adopt a conformation similar to that o f compound 103. Therefore, the rationale of the enantioselectivity o f the salts is based on the solid state molecular conformation o f the ester.  F i g u r e 3.3.8 O R T E P drawing of the crystal structure o f ester 103  The conformation o f the ester is chiral with the keto group pointing toward Ha. Therefore, the two abstractable the  crystalline state. The  y-hydrogen atoms, Ha and Hb, become diastereotopic in  H-abstraction  parameters for these two hydrogen  summarized in Table 3.3.5.  133  are  Table 3.3.5 Hydrogen abstraction  parameter for H a and H b o f 103  Ideal values  Abstraction parameters  45  Ha  Hb  d (C=O...H) (A)  <2.72.  2.23  2.37  co(°)  0  19.7  42.8  A(°)  120  98.8  88.8  9(°)  180  136.2  136.1  Table 3.3.5  shows that the difference  in distance between  C=O...Ha and  C=O...Hb is very small (0.14 A), and both hydrogen atoms possess similar angular parameters and are very favorable for abstraction. The major difference between H a and H b is the parameter co. In the ideal situation, the y-hydrogen should lie i n the same plane as the n-orbital on oxygen, i.e., co= 0°. For H a , co = 19°, which is closer to the ideal value than that for H b (co = 42°). Wagner has suggested that the rate o f H-abstraction is proportional to the value o f cos co. When co = 0° (the ideal value), the rate o f abstraction 2  41  is at its maximum which is 1. When co = 19°, cos co is 0.89, and abstraction can occur at 89 % o f the maximum rate. The rate o f abstraction drop to 55 % o f maximum when co = 42°, which is the case for H b . This difference i n rate might be enough to differentiate whether H a or H b is abstracted.  Together with the fact that the C=O...Ha distance is  slightly shorter than that o f C=O...Hb, H a is more likely to be abstracted. In a recent study by Scheffer et a / .  107  it was found that a difference in C = O . . . H distance o f 0.27 A  (2.72 A vs 2.99 A) led to exclusive abstraction o f the nearer hydrogen. If the salts adopt a conformation similar to that o f ester 103, the enantioselectivity can be explained by preferential abstraction o f the more favorably located y hydrogen i n the initial step o f the photoreaction. There is quite a variation in ee among the 11 salts studied. Almost half o f them gave ee's less than 20 %, while two o f them provided > 90% ee upon irradiation.  One  possible explanation is that they adopted slightly different conformations, which show different  abilities in differentiating the two y-hydrogens i n H-abstraction.  If the  conformations o f the salts are similar to that o f ester 103, the H-abstraction parameters o f  134  H a and H b are very similar. These parameters are highly sensitive to the 0 1 - C 4 - C 1 - H 1 angle (Figure 3.3.8, H I attached to C l ) , which was found to be 170° i n ester 103. A s it has been discussed in Section 3.2, this angle is not fixed, and a few degrees o f variation is not impossible. If this angle approaches 180°, the keto group would almost bisect the three membered ring. The conformation would be more symmetrical and the type II abstraction parameters o f H a and H b become very close to each other, leading to low enantioselectivity. O n the other hand, as the torsion angle decreases, the carbonyl oxygen moves away from H b and becomes closer to H a , and this makes H a more abstractable than H b . A s a result, the variation in ee could be attributed to the differences in torsion angles, or molecular conformations in different salts. The low ee's could also be related to conformational enantiomerism.  However, because o f the lack o f crystal structures,  there is no evidence bearing on the presence o f this phenomenon. It is important to point out that the 0 1 - C 4 - C 1 - H 1 angle (170°) i n compound 103 is close to 180°. According to the idea o f Sevin,  for cyclopropyl ketones possessing  such an angle, the difference in activation energy between the cleavage o f the two p bonds is small.  Therefore, the rates o f rupture o f the two P bonds i n the 1,4-biradical  from ester 103 should be close.  A s a result, the enantioselectivity o f the reaction is  influenced by the difference in rates o f the two possible y-hydrogen abstractions.  The  effect o f P bond cleavage on stereoselectivity for ester 86 as discussed i n Section 3.2.10 becomes less important.  135  3.3.5  T h e r m a l r e a c t i v i t y o f d e r i v a t i v e s o f a c i d 102  The tricyclo[4.4.1.0]undecyl ketone is thermally reactive.  When derivatives o f  acid 102 were heated, they underwent the enolene rearrangement and gave ester 133 as the only product after treatment with diazomethane (Scheme 3.3.3). Scheme 3.3.3  103  132  133  In some cases, the substrates melted, but in other case the solid samples appeared to be intact.  A s the challenge o f carrying out thermal asymmetric induction in the  crystalline state is that reaction should occur prior to crystal melting, this encouraging observation suggested that asymmetric synthesis might be possible i n this thermal rearrangement by the use o f the ionic chiral auxiliary approach. The thermal behavior of derivatives o f acid 102 was analyzed by differential scanning calorimetry, which showed two distinct patterns o f behavior (Figure 3.3.8). The first type, shown by salts 110, 112 and 114, is one in which melting ofthe reactant precedes or is concomitant  with rearrangement  crystallization event and a second endotherm  and  is followed by a  due to the melting o f the  product  (Thermogram I i n Figure 3.3.9). The possibility that the first endothermic process shown in this case is a non-melting solid phase transition is eliminated because melting o f the sample was observed at the same temperature on a hot stage melting point apparatus. The second, characteristic o f acid 102, salts 104-9, 111 and 113, consists o f an exothermic  136  process (enolene rearrangement plus crystallization o f the products) followed by an endothermic event (melting o f products) (Thermograms II and III in Figure 3.3.9).  "  '  50  '  100  150  200  '  W  F i g u r e 3.3.9 D S C thermograms o f some derivatives o f acid 102.1) salt 110, II) salt 104, and n i ) acid 102. Endothermic process is denoted by a negative heat flow, while a positive heat flow indicates a exothermic process.  In principle, asymmetric induction is possible in compounds showing the second type o f thermal behavior because there is no obvious damage to the crystallinity when the rearrangement occurs.  Optically active salts 104-114 were sealed in a vial under an  atmosphere o f nitrogen and then heated at various temperatures.  After treatment with  diazomethane, the enantiomeric excess o f product 133 was determined by chiral H P L C . The results are summarized i n Table 3.3.6.  137  Table 3.3.6 Thermolysis o f the optically active salts in the solid state Salt  Temp/°C  Time  % Conv.  ee (a)  104  90-95  0.3 h 2h lOh  22 83 >98  31 (+) 22 (+) 20 (+)  70-74  0.5 h / ' 3h 15h  10 57 94  43 (+) 36(+) 27 (+)  52-56  15 h 4 days  15 >98  42 (+) .36 (+)  ambient  7 days  no rxn  -  90-95  0.5 h 0.75 h 2h lOh  52 55 78 >98  48 43 41 41  68-72  1 h 3h 8h 48 h  47 80 >98 42  59(-) 54(-) 49 (-)  90-95  1.5 h 3h lOh  22 42 >98  55 (-) 48 (-) 30(-)  66-70  15 h 48 h  27 73  44 (-)  45-50  40 h 4 days  11 32  66 (-) 58 (-)  ambient  7 days  no rxn  -  110-120 85-90 45-50  15h 12 h 2 days  >98 28 no rxn  lO(-) 16(-)  90-95 50-55 ambient  4h 4h 7 days  Melted Melted no rxn  <5 <5  111  90-95 75-80  lOh lOh  >98 77  <5 <5  112  75-80 ambient  4h 7 days  Melted no rxn  <5  113  75-80  lOh  64  8(-)  114  70-75  3h  Melted  <5  106  45-50 107  108  110  138  (-) (-) (-) (-)  56(-)  57(-)  -  -  Reactions o f compounds 104-108, which show the second type o f thermal behavior, gave low to moderate ee's, whereas the first type o f reaction (e.g. salt 110) led to a racemic mixture o f product 133. This is not surprising because enantioselectivity can only be induced in the chiral crystalline environment.  The conformational integrity no  longer exists i n a molten sample.  3.3.6 Structure-reactivity correlations  The enolene rearrangement is likely to be governed by conformational factors similar  to  those discussed  for  the  photochemcial process.  The  fact  that  the  enantiomerically enriched product obtained thermally and photochemically have the same sign o f optical rotation suggests that the two pathways are quite similar. When comparing the results in Table 3.3.4 and 3.3.6, in every case, the ee for the photochemical Norrish type II cleavage reaction is greater than that observed in the thermal enolene rearrangement.  The lower ee obtained in the thermal reaction can be attributed to an  increase i n conformational flexibility accompanying the softening o f the crystal lattice at elevated temperatures.  A t higher temperatures, atomic and molecular motions are  enhanced, the rigidity o f the crystal lattice is reduced and the reaction becomes less selective. A s we have assumed that salts 104-114 adopt a conformation similar to that o f ester 103, increasing conformational freedom o f the molecules would likely cause the keto group to oscillate between H a and H b . This would obviously make it more difficult to differentiate two already closely located hydrogen atoms, and would therefore lead to a lower enantioselectivity. In agreement with this picture, the ee obtained by heating salt 104 to >98 % conversion at 52-56 °C (36 %) was nearly twice that obtained at 90-95 °C (20%).  This indicates the enantioselectivity o f the reaction decreases at higher  temperatures.  139  3.3.7 Single crystal-to-single crystal thermal rearrangement of ketoester 103 When a single crystal o f keto-ester 103 was subjected to X-ray crystal structure analysis, the X-ray diffraction patterns contained, residual peaks component.  from  a second  B y allowing the crystals o f ketone 103 to stand i n the dark for extended  periods o f time at room temperature, the compound smoothly converted to the second component.  Crystals that had been treated in this manner remained transparent and  appeared unchanged to the naked eye, suggesting the occurrence o f a single crystal-tosingle crystal reaction.  109  The conversion was efficient at room temperature, and the  crystal structure o f ketone 103 free o f the "impurity" could not be obtained.  X-ray  diffraction data were collected for three different single crystals o f ketone 103. The first showed the presence o f 25 % o f "impurity". The second showed a similar composition as the first and the structure was not refined. This sample was allowed to stand at room temperature and X-ray diffraction data were collected after five days and twelve days, leading to the crystal structures containing 68 % and 100 % o f rearranged product respectively. The X-ray data o f the third sample showed the presence o f about 15 % o f the rearranged product, which was the highest purity achieved. B y solving the structure o f the crystal, it was found that the rearranged product was enol 132. This was also shown by H N M R spectroscopy. ' H N M R identical to that !  shown in Figure 3.3.4a was obtained when the 100 % converted crystals were dissolved in C6D6. When a sample was left under ambient light for five days, it was found to have the same conversion as that standing in the dark. Therefore, the enol was being produced thermally. The experimental data suggested that methyl ester 103 underwent a single crystal-to-single crystal thermal (enolene) rearrangement.  A single crystal was irradiated  in order to determine i f the sample would undergo a single crystal Norrish type H/cleavage. However, photolysis o f single crystals o f ketone 103 caused them to become brittle and opaque.  140  Table 3.3.7 shows the change in unit cell dimensions as a function o f conversion for the thermal reaction. The data indicate a smooth transformation o f ketone 103 into enol 132. The space group remains P2i/n, and the number o f molecules in the unit cell is constant at Z = 4. There is a gradual increase in the length o f the a and c axes, while there is a decrease in b in going from reactant to product. Overall, the unit cell volume increased by approximately 1.5%.  Even though the increase in c (5.3%) seems rather  large for a single crystal-to-single crystal reaction, other single crystal-to-single crystal reactions involving cell dimension changes o f up to 5% have been reported.  110  Table 3.3.7 Crystal data and structure refinement for crystals containing 15%, 25%, 68% and 100% o f enol 132 100 % 68% 25 % 15 % Crystal system Monoclinic Space group p/°  a/A b/A c/A V/A  3  Z D fc./ g/cm" Residuals ( F , all data): R ; R Residuals (F, I>2o-I): R ; R 3  Cfl  2  97.478 (5) 6.2110(5) 14.239(1) 18.531(2) 1625.0 (9) 4 1.277 0.075; 0.118  P2i/n 98.126(4) 6.2079(5) 14.227(1) 18.651(2) 1630.8(2) 4 1.272 0.077; 0.143  101.976(6) 6.2664(7) 14.040(1) 19.227(2) 1654.7(3) 4 1.254 0.087; 1.76  102.924(5) 6.2762(7) 13.811(2) 19.528(3) 1649.8(3) 4 1.258 0.067; 0.114  0.046; 0.108  0.051; 0.131  0.060; 0.164  0.038; 0.052  w  w  Figure 3.3.10 provides O R T E P drawings o f the molecular and crystal structures of cyclopropyl ketone 103, and Figure 3.3.11 depicts the superposition o f the two structures in the mixed crystal containing 68% o f enol 132 and 32% o f ketone 103. It is apparent from Figure 3.3.11 that the correspondence between reactant 103 and product 132  is  rather poor,  rearrangement.  indicating that  significant motions  take  place  during  the  This is not surprising when one considers the large relief o f strain  accompanying opening o f the 3-membered ring. The mechanism o f the reaction is seen to involve transfer o f hydrogen atom H a to O l accompanied by cleavage o f the C 1 - C 6 bond ofthe cyclopropane ring.  141  F i g u r e 3.3.10 Crystal structure of ketone 103. a) O R T E P drawing and b) crystal packing diagram. The oxygen atoms of the keto groups are in red.  Figure 3.3.11 Crystal structure o f t h e 68 % mixed crystal, a) O R T E P drawing: blue enol 132; red = ketone 103 b) crystal packing diagram of the crystal. The oxygen atoms of the keto and enol groups are in red  142  F i g u r e 3.3.12 Crystal structure o f enol 132: a) O R T E P drawing and b) crystal packing diagram. The oxygen atoms o f the enol groups are in red.  Figure 3.3.12 shows the O R T E P drawings of the molecular and crystal structures o f enol 132. The structural changes involved in the transformation o f ketone 103 to enol 132 are evidenced by the changes in bond angles and bond lengths given in Table 3.3.8. A s the reaction proceeds, cleavage o f the C6-C11 bond occurs, leading to an increase o f the C6-C1-C11 bond angle from 60.1° in 103 to 110.7° in compound 132. This causes a significant shift in the position o f C l 1, C l 2, 0 1 and the aryl group. A t the same time, the C 1 1 - C 1 2 bond length decreases as it is transformed from a single to a double bond, and the C12-01 bond length increases as it changes from a double to a single bond.  While  these motions are significantly greater than those accompanying other unimolecular single crystal-to-single crystal reactions,  111  the overall packing arrangement remains  constant, and as a result the process can still occur in a topochemical fashion.  143  Table 3.3.8 Bond angles and lengths o f selected atoms in ketone 103 and enol 132 132 bond length ( A ) 103 132 103 bond angles (°) C12 C l l H l l  113.4  117.2  C12 0 1  1.22  1.38  C6C1 C l l  61.4(3)  110.7(1)  C l l C12  1.49  1.34  C6 C7 H7*  110.0  117.6  C6 C7  1.48  1.34  O l HI  n/a  0.85  * H 7 is the "equatorial" hydrogen on C 7 . The axial hydrogen on this carbon is Ha, which is transferred in the reaction.  Attempts to recrystallize enol 132 in order to obtain a thermodynamically more stable crystal modification were unsuccessful, as tautomerization led exclusively to ketone 133. energy  However, molecular mechanics calculations showed that the minimum  conformation  of enol  132  is very similar to that determined  by  X-ray  crystallography (Figure 3.27), a factor that might have facilitated the single crystal-tosingle crystal transformation.  Attempts were made to determine i f the enol would  undergo topochemical ketonization.  However, tautomerization  occurred only when  crystals of enol 132 were heated above their melting point (82-84 °C).  F i g u r e 3.3.13 Lowest energy conformation of enol 132 calculated by M M + molecular mechanics.  Homogenous or topochemical crystalline state reactions have remained as a rare but important type of solid state reaction. Such processes not only allow chemists to follow the reaction mechanism, but also provide access to the crystal structure of some  144  intermediates that are difficult to isolate and recrystallize as pure compounds. In the present study, the crystal structure o f a simple enol is obtained via a novel single crystalto-single crystal enolene rearrangement.  Simple enols are defined as species derived  from the tautomerization o f monofunctional aldehydes and ketones in which the enol is  112 the only functional group present.  • In solution, simple enols ketonize rapidly unless  kinetically stabilized by the presence o f nearby bulky substituents. A s a result, crystal structures o f simple enols can rarely be determined, since they tend to ketonize before they crystallize o u t .  113  In the solid state enolene rearrangement o f keto-ester 103, the enol  is generated in the crystalline state. Ketonization is not catalyzed under these conditions, and the enol can be analyzed by X-ray crystallography.  145  3.4  Summary The present study demonstrates that the ionic chiral auxiliary method was  successful i n inducing asymmetric synthesis i n the Norrish Type U cleavage reactions o f the salts o f acids 85 and 102. The results indicate that the method can be used to synthesize optically active acyclic or cyclic olefins. For the derivatives o f acid 85, the final ee's for the products were determined by two crystalline state processes:  (1)  formation o f biradicals 165 and 167, and (2) formation o f cis and trans isomers 129 and 130 from the intermediates. The study showed that a low selectivity i n the initial step could still give high ee's in the final products. For the fused ring compounds (salts o f acid 102),  the product has no cis/trans isomers, and the reaction mechanism is less  complicated. The enantioselectivity o f the system is controlled by differential hydrogen abstraction. In order to fully interpret the results, it is necessary to obtain the crystal structures o f the salts, which cannot be achieved at this time. Nevertheless, the study shed light in an area for designing and studying crystalline state asymmetric synthesis in the Norrish type II cleavage reaction. The study also demonstrates the first application o f the ionic chiral auxiliary approach i n a thermal reaction. The thermal reactivity o f salts o f acid 85 and 102 are very different.  The fused ring compounds are thermally more reactive than the  derivatives o f acid 85 (e.g. ester 103 reacted at room temperature).  This is probably  related to the strain associated with the tricyclo[4.4.1.0]undecane ring system.  A s the  reaction can be carried out at a lower temperature, enantioselectivity can be induced i n the reaction o f salts o f acid 102, while the derivatives o f acid 85 melted at the reactive temperature, leading to zero ee.  Nonetheless, the present study shows that the ionic  chiral auxiliary approach can be applied to a ground state reaction.  This increases the  potential o f the procedure to become a more general method for asymmetric synthesis.  146  Chapter 4 Preparation of Substrates 4.1 General Considerations Melting points (mp) Melting points were determined on a Fisher-Johns hot stage apparatus and are uncorrected. Nuclear Magnetic Resonance ( N M R ) spectra !  H and  1 3  C N M R Spectra were recorded i n deuterated solvents as denoted. The  spectrometers used were a Bruker A V 300 and a Bruker A V 4 0 0 . Signal positions are given in parts per million (ppm) with the solvent signal as the internal reference. The proton N M R spectra were either recorded at 300 M H z or at 400 M H z . Chemical shifts (5) are reported in ppm and are referenced to the centre o f the solvent multiplet, with tetramethylsilane (8 0.0) as an external reference: chloroform (7.24 ppm), benzene  (7.15  ppm),  acetonitrile  (1.93  ppm),  methanol  (3.30  ppm),  and  dimethylsulfoxide (2.49 ppm). The signal multiplicity, coupling constants, and number o f hydrogen atoms are given in parentheses following the signal position. The multiplicities o f the signals have been abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, qu = quintet, and broad = br. ' H - ' H correlation spectroscopy ( C O S Y ) was conducted on the Bruker A V - 4 0 0 or Bruker A V - 3 0 0 spectrometers A l l carbon N M R spectra were recorded at 75 or 100 M H z . A l l spectra were run under broad band  13  C - { H } decoupling. Chemical shifts (5) are reported i n ppm and are  referenced to the centre o f the solvent multiplet, with tetramethylsilane (8 0.0) as an external reference: chloroform (77.0 ppm), benzene (128.0 ppm), acetonitrile (29.8 ppm), methanol (49.0 ppm), and dimethylsulfoxide (39.5 ppm). For A P T (attached proton test) 1 3  C N M R spectra, positive (+) signifies C or C H while negative (-) signifies C H or CH3. 2  Two-dimensional spectrometer  using  1 3  the  C - ' H correlation spectra were obtained on the Bruker A V 400 Heteronuclear  Multiple  147  Quantum  Coherence  (HMQC)  experiment for one-bond correlations and the Heteronuclear Multiple B o n d Connectivity (HMBC) experiment for long-range connectivities.  Mass spectra H i g h and low Resolution Mass Spectra ( L R M S / H R M S ) were recorded on a Kratos M S 50 instrument using electron impact (EI) ionization at 70 e V , or chemical ionization (CI) with the ionizing gas noted. Electrospray impact spectra were recorded on a Bruker Esquire L C mass spectrometer.  The masses o f some organic salts were  determined on a Kratos ITHQ hybrid mass spectrometer by recording liquid secondary ionization mass spectra (LSEVIS). Molecular ions are designated as M  +  (for EI), M + l +  (for C I and ESI) or M + N a (for ESI). Analyses were performed by the technicians o f +  2 3  the U B C Mass Spectroscopy laboratory under the supervision o f D r . G . Eigendorf / D r Y u n Ling.  Ultraviolet-Visible spectra (UV / VIS) Electronic absorption spectra were recorded on a Perkin-Elmer Lambda-4B U V / VIS spectrometer in the solvents and concentrations indicated using spectral grade solvents. Absorption maxima  (^  m a  x)  are reported i n nanometers (nm), with molar  extinction coefficients (s) reported i n parentheses i n units o f M ^ c m " . 1  Infrared spectra (IR) Infrared spectra were recorded on a Perkin-Elmer model 1710 Fourier transform spectrometer. L i q u i d samples were analyzed neat as thin films between two sodium chloride plates. Solid samples (about 2 mg) were ground with IR grade K B r (100-200 mg) i n an agate mortar and pelleted i n an evacuated die (Perkin-Elmer 186-0002) with a laboratory press (Carver, model B ) at 17,000 psi. The positions o f selected absorption maxima ( v  ) are reported i n units o f cm" . 1  m a x  148  Microanalysis ("Anal. C a l d . ) Elemental analyses were performed by the U B C microanalytical laboratory on a Carlo Erba C H N M o d e l 1106 analyzer.  Crystallography Single crystal X-ray analysis was performed on either a Rigaku A F C 6 S fourcircle diffractometer diffractometer  ( C u - K a or M o - K a radiation) or a Rigaku A F C 7 four-circle  equipped with a D S C Quantum C C D detector  ( M o - K a radiation).  Structures were determined by Dr. Brian Patrick or D r Eugene Cheung under the supervision o f D r . James Trotter. Structures are represented as O R T E P drawings at the 50% probability level.  Optical Rotations Optical rotation data were recorded on a Jasco-J710/ORD-M instrument at room temperature at the sodium D-line (589.3 nm).  Differential Scanning Calorimetry ( D S C ) D S C thermograms were recorded on a 910 D S C system ( T A instrument).  Gas Chromatography ( G C ) Gas chromatographic analyses in a helium carrier gas were performed on a Hewlett-Packard 5890A or a 5890 Series II Plus gas chromatograph, each equipped with a flame ionization detector. The following fused silica capillary columns were used: HP-5 (30 m x 0.25 m m ID, Hewlett-Packard), HP-35 (15 m x 0.25 m m ID, Hewlett-Packard) and  a  chiral  column  B-DEX™  350/1701(50% 6-0-TBDMS-2,3-0-dimethyl-P-  cyclodextrin dissolved in SPB-20 poly(20% phenyl/65% dimethylsiloxane, 30 m x 0.25 m m ID, S U P E L C O ) . Analyses were run with a split injection port (split ratios between  149  25:1 and 100:1) with column head pressures o f 100 k P a (DB-5) or 250 k P a (chiral columns).  Gas Chromatography-Mass Spectroscopy ( G C M S ) G C - M S data were recorded on an Agilent 6890 plus G C system connected to an Agilent 5973 network mass selective detector with an H P - 5 M S (30 m x 0.25 m m ID, Hewlett-Packard) column. Analyses were run with a split injection port (split ratios 100:1) and an electron impact ionization source o f 70 e V was employed.  H i g h Pressure L i q u i d Chromatography (HPLC") H P L C analyses were performed on a Waters 600E system coupled to a tunable U V absorbance detector (Waters 486). The Chiralcel column: A S (250 m m x 4.6 m m ID), and O D (250 m m x 4.6 m m ID) employed were obtained from Chiral Technologies Incorporated.  Silica gel chromatography Analytical thin layer chromatography ( T L C ) was performed on commercial pre-coated (silica gel on aluminum) plates (E. Merck, type 5554). Preparative chromatography was performed using either the flash column method with Merck 9385 silica gel (particle size 230-400 mesh) or radial elution chromatography on a Chromatotron (Harrison Research).  Solvents and reagents T H F and E t 2 0 were refluxed over the sodium ketyl o f benzophenone under an atmosphere o f argon and distilled prior to use. Anhydrous dichloromethane, benzene, and hexanes were obtained by refluxing the commercial solvent (Fisher Scientific) over calcium hydride and distilling prior to use. Unless otherwise noted, all reactions were conducted under an atmosphere o f nitrogen in oven-dried glassware.  150  4.2 Synthesis of trans, trans 2,3-diphenylcyclopropane-lcarboxylic acid derivatives Ethyl trans, trans 2,3-diphenylcyclopropane-l-carboxylate (36)  O.  OEt  The compound was prepared according to the method employed by Blatchford et al.  To  a three necked round bottom flask was added 20 g o f cw-stilbene (111 m m o l Aldrich), 2 g o f anhydrous copper (II) sulfate (12.5 mmol, Eastman), and 50 m L o f anhydrous benzene. To the center neck was fitted a pressure-equalizing dropping funnel. The other two necks were fitted with a condenser and a stopper respectively. The mixture was brought to reflux and kept at 75 °C in an o i l bath. Ethyl diazoacetate  114  (32 m L , 280  mmol) was added over a period o f 4.5 h. The yellow solution was cooled to room temperature, stirred for another 30 min, and  allowed to stand overnight. The black  residue was filtered. The yellow filtrate was concentrated in vacuo. A small amount o f this yellow residual o i l (110 mg) was chromatographed over silica gel (10 % Et20/Pet ether) to give 40 mg (0.15 mmol) o f ester 36 as a white solid. The spectroscopic data for 72  this compound agree with previous published results, ' H N115-116 M R (300° CM( E HtzO, ACcD) C 1 ) 5 1.32 (3H, d 7 = 7.2 H z ) , 2.54 ( I H , t, J = 5.2 H z ) , 3.05 mp: (2H, d,J= 5.2 H z ) , 4.22 (2H, q, J= 7.2 H z ) , 6.93-7.20 (10 H , m) 3  C N M R (75 M H z , C D C 1 ) 8 175.31, 137.62, 130.89, 129.90, 128.53, 62.89, 35.22, 29.34, 16.30 1 3  3  I R f K B r pellet): 3061, 1709, 1434, 1188, 1022, 771,700 cmL R M S (EI) m/z ( M ) : 266, 221, 193, 178, 115 +  151  1  trans, trans 2,3-Diphenylcyclopropane-l-carboxylc acid (37) O.  OH  H  To the yellow residual o i l prepared above (30 g) was added 17.0 g o f sodium hydroxide and 150 m L o f 95 % ethanol. The mixture was refluxed with stirring overnight. The solution was concentrated in vacuo, dissolved i n water, and then washed with pet ether. The organic layer was concentrated in vacuo to give 12.0 g (66.7 mmol) o f unreacted cisstilbene. The aqueous layer was acidified with 6 M HC1, and then extracted with E t 2 0 twice. The combined organic layer was successively washed with water (2 X 30 m L ) , brine (30 m L ) , and then dried over sodium sulfate. The solution was concentrated in vacuo. Recrystalhzation from ethanol/water (twice) gave 5.5 g off white needles (23.1 mmol, 52 % based on recovered starting material).  mp: 154-155 °C (EtOH/water, l i t m p 152.5-154.5 ° C )  7 3  ' H N M R (300 M H z , C D C 1 ) 5 2.55 (1H, t, J= 5.2 H z ) , 3.12 (2H, d, J= 5.2 H z ) , 6.93 7.15 ( 1 0 H , m ) 3  1 3  C N M R (75 M H z , C D C 1 ) 5 179.21, 135.08, 128.91, 128.01, 126.57, 33.82, 27.02 3  I R ( K B r pellet): 3400, 3032, 1681, 1462, 1445, 1283, 1209, 950, 764, 769 cm" L R M S (EI) m/z ( M + l ) : 238, 193, 178, 115, 91 +  152  1  Methyl trans, trans 2,3-diphenylcyclopropane-l-carboxylate (38)  To a solution o f acid 37 (250 mg, 0.99 mmol) in 10 m L o f anhydrous methylene chloride was added 252 m g (1.98 mmol) o f oxalyl chloride (Across). The solution was allowed to stir for 5 min, and 5 u L o f D M F was added. The resulting mixtiure was allowed to stir for 2 h at room temperature. The solvent was removed in vacuo, and the yellow residue was dried under vacuum for 30 m i n . The residue was dissolved i n 10 m L o f methylene chloride, and cooled to 0 °C. T o this was added 3 m L o f dry methanol, and the solution was stirred for 2 h. The reaction was quenched by adding 5 m L o f water, and extracted with ether twice. The combined organic layers were washed successively with 5% sodium bicarbonate (5 m L ) , water ( 2 X 5 m L ) , dried over sodium sulfate, and the solvent removed in vacuo. Silica gel chromatography (15 % Et.20 i n pet ether) followed by recrystallization from methanol afforded 233 m g (0.92 mmol) o f the desired product (88%). The compound was found to exist as clear prisms and fine white needles.  mp: 74-75 °C ( E t O A c , prisms, lit mp: 71-72 ° C ) ; 66-67 ° C ( M e O H , needles). 73  ' H N M R (300 M H z , CDC1 ) 8 2.54 ( I H , t, J= 5.2 H z ) , 3.10 (2H, d, J= 5.2 H z ) , 3.81 (3H,s), 6.93-7.15 ( 1 0 H , m ) 3  C N M R (75 M H z , CDC1 ) 6 173.52, 135.56, 128.48, 127.88, 126.50, 52.12, 33.03, 27.98 1 3  3  IR ( K B r pellet): (prisms) 3060, 1716, 1439, 1309, 1293, 1195, 1174, 772, 700 cm"  1  (fine needles) 3023, 1724, 1443, 1311, 1293, 1196, 1172, 764, 698 cm" U V (hexanes): 214 (697), 264 (9163) L R M S : (EI): 252, 221, 193, 178, 115, 91 153  1  This structure was confirmed by X-ray crystallographic analysis:  Habit  colourless prisms  Space group  Pbca  a, A  17.648(5)  b, A  16.540(5)  c A  9.679(5)  a(°)  90  P(°)  90  Y(°)  90  Z  8  R {onF)  0.051  (if)-(+)-l-Phenylethylamine salt (39)  N  H  v .  H  ,  1 ^ 1  To a solution o f 75 mg (0.31 mmol) o f acid 37 in 8 m L o f diethyl ether was added a solution o f 38 mg (0.31 mmol) o f (i?)-(+)-l-phenylethylamine i n 1 m L o f diethyl ether. The solution was allowed to stand for overnight. The white precipitate was filtered and washed with diethyl ether. Recrystalhzation from methanol gave 88 m g (78 %) o f thin colorless needles.  mp 168-170 ° C ( M e O H )  154  H N M R (400 M H z , C D O D ) 5 1.58-1.60 (3H, d J = 6.9 H z ) , 2.47 ( I H , t, J = 5.4 H z ) , 2.88 (2H, d,J= 5.4 H z ) , 4.28 ( I H , q,J= 6.9 H z ) , 6.93-7.09 (10 H , m), 7.37-7.45 (5H, m). J  3  C N M R (75 M H z , D M S O ) 5 174.86, 144.32, 136.71, 128.73, 128.18, 127.71, 127.09, 126.18,125.81,50.12,32.13,27.50,23.48.  1 3  I R ( K B r pellet): 2979, 1602, 1570, 1526, 1527, 1497, 1385, 759, 711, 697 cm"  1  L R M S (LSHMS) m/z ( M + l ) : 360, 336, 221, 193, 105. +  H R M S (LSTMS) m/z ( M + l ) : Calculated mass for C24H26NO2 = 360.19635, found: 360.19631. +  A n a l . C a l c d . : C , 80.19; H , 7.01; N , 3.90. Found: C , 79.89; H , 7.13; N , 3.79  (5)-(-)-l-Phenylethylamine salt (40)  To a solution o f 65 mg (0.27 mmol) o f acid 37 i n 8 m L o f diethyl ether was added a solution o f 33 m g (0.27 mmol) o f (S)-(-)-l-phenylethylamine i n 1 m L o f diethyl ether. The solution was allowed to stand for overnight. The white precipitate was filtered and washed with diethyl ether. Recrystallization from methanol gave 78 mg (80 %) o f thin colorless needles. m p 168-170 °C ( M e O H ) * H N M R (400 M H z , C D O D ) 5 1.58-1.60 (3H, d J= 6.9 H z ) , 2.47 ( I H , t, J= 5.4 H z ) , 2.88 (2H, d,J= 5.4 H z ) , 4.28 ( I H , q, J= 6.9 H z ) , 6.93-7.09 (10 H , m), 7.37-7.45 (5H, m). 3  155  C N M R (75 M H z , D M S O ) 5 174.86, 144.32, 136.71, 128.73, 128.18, 127.71, 127.09, 126.18, 125.81, 50.12, 32.13, 27.50, 23.48.  , 3  I R ( K B r pellet): 2979, 1602, 1570, 1526, 1527, 1497, 1385,759,711,697 c m '  1  L R M S (LSLMS) m/z ( M + l ) : 360, 336, 221, 193, 105. +  Anal. Calcd.: C , 80.19; H , 7.01; N , 3.90. Found: C , 79.89; H , 7.13; N , 3.79  (S)-l-(4-Bromophenyl)ethylamine salt (41)  O.  O  +  To a solution o f 75 mg (0.31 mmol) o f acid 37 i n 8 m L o f diethyl ether was added a solution o f 62 mg (0.31 mmol) o f (S)-l-(4-bromophenyl)ethylamine in 1 m L o f diethyl ether. The solution was allowed to stand for overnight. The white precipitate was collected and washed with diethyl ether. Recrystalhzation from methanol gave 115 mg (84 %) o f thin white plates. mp 163-165 °C ( M e O H ) ' H N M R (300 M H z , C D O D ) 8 1.58-1.60 (3H, d J= 6.9 H z ) , 2.46 (1H, t, J= 5.4 H z ) , 2.89 (2H, d, J= 5.4 H z ) , 4.31 (1H, q, J= 6.9 H z ) , 6.93-7.12 (10 H , m), 7.36 (2H, d, J = 8.5 H z ) , 7.57 (2H, d,J= 8.5 H z ) . 3  C N M R (75 M H z , C D O D ) 5 181.14, 139.91, 138.40, 133.28, 130.66, 129.72, 128.94, 126.88, 123.67, 51.23, 33.64, 30.60, 21.11  1 3  3  I R ( K B r pellet): 2936, 1532, 1496, 1427, 1377, 774, 699 L R M S (LSEVIS) m/z ( M + l ) : 440, 378, 360, 336, 221, 193, 105. +  H R M S (LSLMS) m/z ( M + l ) : Calculated mass for C 2 4 H 2 5 N O 2 B r = 438.10687, found: 438.10641. +  79  156  A n a l . C a l c d . : C , 65.76; H , 5.52; N , 3.20. Found: C , 65.53; H , 5.44; N , 3.07  (i?)-l-(4-Chlorophenyl)ethylamine salt (42)  To a solution o f 75 mg (0.31;'mmol) o f acid 37 i n 8 m L o f diethyl ether was added a solution o f 48 mg (0.31 mmol) o f (i?)-l-(4-chlorophenyl)ethylamine i n 1 m L o f diethyl ether. The solution was allowed to stand for overnight. The white precipitate was collected and washed with diethyl ether. Recrystallization from acetonitrile gave 100 mg (81 %) o f thin white plates. m p 143-145 °C ( M e C N ) H N M R (300 M H z , C D O D ) 5 1.59-1.62 (3H, d J = 6.9 H z ) , 2.44 ( I H , t, J = 5.4 H z ) , 2.90 (2H, d, J= 5.4 H z ) , 4.35 ( I H , q, J= 6.9 H z ) , 6.92-7.14 (10 H , m), 7.30 (2H, d, J = 8.5 H z ) , 7.47 (2H, d, J= 8.5 H z ) . !  3  C N M R (75 M H z , C D O D ) 5 178.14, 140.06, 138.22, 134.31, 130.88, 130.10, 129.02, 126.85, 123.77, 51.35, 33.20, 30.11, 21.92  1 3  3  I R ( K B r pellet): 2979, 1602, 1524, 1496, 1383, 790, 767, 697 c m  -1  L R M S (LSEVIS) m/z ( M + l ) : 394, 331, 248, 156, 139 +  A n a l . C a l c d . : C , 73.18; H , 6.14; N , 3.56. Found: C , 73.18; H , 6.31; N , 3.15  157  (5)-(-)-l-(4-Tolyl)ethylamine salt (43)  O. H  +  O  NH  H  3  TC H  3  To a solution o f 60 mg (0.25 mmol) o f acid 37 in 6 m L o f diethyl ether was added a solution o f 34 mg (0.25 mmol) o f (5)-l-(4-tolyl)ethylamine i n 1 m L o f diethyl ether. The solution was allowed to stand for overnight. The white precipitate was filtered and washed with diethyl ether. Recrystalhzation from methanol gave 82 mg (87 %) o f thin colorless needles. mp 183-185 ° C ( M e O H ) U N M R (400 M H z , C D O D ) 5 1.61 (3H, d / = 6.9 H z ) , 2.49 (1H, t, J= 5.4 H z ) , 2.91 (2H, d, J = 5.4 H z ) , 4.39 ( l H , q , J= 6.9 H z ) , 6.93 7.36 (14 H , m). l  3  C N M R (75 M H z , C D O D ) 8 180.14, 140.22, 138.11, 136.78, 130.84, 130.15, 128.84, 127.62,127.03,52.14,33.65,29.87,21.10,20.73  1 3  3  I R ( K B r pellet): 2942, 1603, 1531, 1496, 1417, 1381,818,771,699 cm"  1  L R M S ( L S M S ) m/z ( M + l ) : 374,331, 136, 119 +  H R M S (LSLMS) m/z ( M + l ) : Calculated mass for C25H28NO2 = 374.21220, found: 374.21225. +  Anal. Calcd.: C , 80.40; H , 7.29; N , 3.75. Found: C , 80.51; H , 7.32; N , 3.64.  158  (if)-(+)-a Benzyl-l-phenylethylamine salt (44) L  O  O  2  H  V.  To a solution o f 60 mg (0.25 mmol) o f acid 37 in 6 m L o f diethyl ether was added a solution o f 53 mg (0.25 mmol) o f (i?)-(+)-A -benzyl-l-phenylethylamine in 1 m L o f /  diethyl ether. The solution was allowed to stand overnight. The white precipitate was filtered and washed with diethyl ether. Recrystallization from methanol gave 88 mg (78 %) o f thin white plates. mp 130-132 °C ( M e O H ) *H N M R (400 M H z , C D O D ) 5 1.60 (3H, d J= 6.8. H z ) , 2.48 ( I H , t, J = 5.4 H z ) , 2.90 (2H, d,J= 5.4 H z ) , 3.75-3.83 ( I H , d, J= 3.1 H z ) , 3.93-3.97 ( I H , d, J= 3.1 H z ) , 4.24 ( I H , q, J= 6.8 H z ) , 6.93-7.06 (10 H , m), 7.31-7.48 (10H, m). 3  C N M R (75 M H z , C D O D ) 6 180.48, 140.31, 140.07, 138.22, 130.54, 130.31, 130.12, 130.02, 129.89, 128.78, 128.54, 127.01, 59.28, 51.00, 33.67, 30.28, 21.06.  , 3  3  I R ( K B r pellet): 3029, 1602, 1542, 1497, 1377, 1210, 767, 697 cm"  1  L R M S ( L S I M S ) m/z ( M + l ) : 450, 212, 105 +  H R M S ( L S I M S ) m/z ( M + l ) : Calculated mass for C i H 450.24318. +  3  3 2  N0  2  = 450.24330, found:  A n a l . C a l c d . : C , 82.82; H , 6.95; N , 3.12. Found: C , 82.65; H , 7.02; N , 3.18.  159  (5)-(-)-2-(Diphenylmethyl)pyrrolidine salt (45)  To a solution o f 60 mg (0.25 mmol) o f acid 37 in 6 m L o f diethyl ether was added a solution o f 60 mg (0.25 mmol) o f (.S)-(-)-2-(diphenylmethyl)pyrrolidine in 3 m L o f methanol. The solution was allowed to stand for overnight. The white precipitate was filtered and washed with diethyl ether. Recrystalhzation from methanol gave 97 mg (80 %) o f colorless small prisms. mp 150-152 ° C ( M e O H ) * H N M R (300 M H z , C D O D ) 5 1.66-1.71 (1H, m), 1.96-2.07 (3H, m), 2.44-2.48 (1H, i,J = 5.4 H z ) , 2.88 (2H, d, J = 5.4 H z ) , 3.25 (2H, m), 4.10 (1H, d, J= 11.5 H z ) , 4.45-4.48 (1H, m), 6.93-7.06 (10 H , m), 7.29-7.45 (10H, m). 3  C N M R (75 M H z , C D O D ) 5 181.12, 142.78, 142.22, 138.45, 130.32, 130.07, 130.02, 128.87, 128.82, 128.73, 128.65, 128.41, 126.92, 64.43, 56.45, 47.07, 33.62, 31.44, 30.73, 24.6 1 3  3  I R ( K B r pellet): 3028, 1530, 1497, 1453, 1374, 774, 760, 744, 699 cm"  1  L R M S ( L S I M S ) m/z ( M + l ) : 476, 238, 70. +  A n a l . C a l c d . : C , 83.33; H , 6.99; N , 2.94. Found: C , 83.18; H , 6.77; N , 2.90.  160  (5)-(-)-2-(Diphenylhydroxymethyl)pyrrolidine salt (46)  To a solution o f 60 mg (0.25 mmol) o f acid 37 i n 6 m L o f diethyl ether was added a solution o f 63 mg (0.25 mmol) o f (,S)-(-)-2-(diphenylhydroxymethyl)pyrrolidine in 3 m L of methanol. The solution was allowed to stand for overnight. The white precipitate was filtered and washed with diethyl ether. Recrystallization from methanol/water gave 105 mg (85 %) o f white powder. mp 240-242 °C (MeOH/water) ' H N M R (400 M H z , C D O D ) 5 1.95-2.18 (4H, m), 2.45 ( I H , t,J= 5.4 H z ) , 2.89 (2H, d, J= 5.4 H z ) , 3.25-3.31 (2H, m), 4.77 ( I H , m), 6.90-7.08 (10 H , m), 7.24-7.35 (6H, m), 7.-7.48-7.61 ( 4 H , m ) . 3  C N M R (75 M H z , D M S O ) 5 174.33, 147.18, 146.27, 136.01, 128.47, 127.62, 127.54, 127.48, 126.02, 125.86, 125.80, 125.21, 77.22, 63.91, 46.66, 32.15, 26.54, 26.40, 25.12.  1 3  I R ( K B r pellet): 3063, 1547, 1496, 1426, 1385, 774, 747, 698 c m  -1  L R M S ( L S I M S ) m/z ( M + l ) : 493, 254 +  A n a l . Calcd.: C , 80.62; H , 6.77; N , 2.85. Found: C , 80.47; H , 6.90; N , 2.94.  161  (5)-(+)-2-(Methoxymethyl)pyrrolidine(47)  To a solution o f 60 mg (0.25 mmol) o f acid 37 i n 6 m L o f diethyl ether was added a solution o f 29 mg (0.25 mmol) o f (5)-(+)-2-(methoxymethyl)pyrrolidine  in 1 m L of  methanol. The solution was allowed to stand overnight, and then concentrated in vacuo to give a sticky oil. To this was added 5 m L o f pet ether. Slow evaporation o f solvent gave 47 mg (53 %) o f colorless small prisms. mp 92-94 °C (pet ether) ' H N M R (400 M H z , C D C N ) 5 1.59 (1H, m), 1.80-1.87 (3H, m), 2.50-2.54 (1H, t, J = 5.4 H z ) , 2.88 (2H, d, J = 5!4 H z ) , 3.08-3.17 (2H, m), 3.33 (3H, s), 3.42-3.50 (2H, m), 3.58-3.62 (1H, m), 7.00-7.12 (10 H , m). 3  C N M R (75 M H z , C D C N ) 5 178.28, 138.31, 129.89, 128.74, 126.81, 73.58, 59.24, 58.47, 46.11, 33.24, 29.02, 28.04, 25.08 1 3  3  I R ( K B r pellet): 3028, 2936, 1543, 1498, 1418, 1375, 772, 698 cm"  1  L R M S ( L S M S ) m/z ( M + l ) : 354, 116 +  H R M S ( L S M S ) m/z ( M + l ) : Calculated mass for C 2 2 H N 0 354.20699. +  2 8  3  = 354.20692, found:  A n a l . C a l c d . : C , 74.76; H , 7.70; N , 3.96. Found: C , 74.53; H , 7.83; N , 3.89.  162  L - P h e n y l a l a n i n e methyl ester salt (48)  To a solution o f 60 mg (0.25 mmol) o f acid 37 i n 6 m L o f diethyl ether was added a solution o f 45 mg (0.25 mmol) o f L-phenylalanine methyl ester in 1 m L o f diethyl ether. The solution was allowed to stand overnight and then concentrated in vacuo. The white precipitate was collected and washed with diethyl ether. Recrystallization from methanol gave 85 m g (81 %) o f thin white needles. mp 1 1 1 - 1 1 4 ° C ( M e O H ) * H N M R (400 M H z , C D O D ) 8 2.51 ( I H , t, J= 5.4 H z ) , 2.92 (2H, d, J= 5.4 H z ) , 3.003.08 ( I H , dd, J= 14.0 H z , J= 3.9 H z ) , 3.10-3.15 ( I H , dd, J= 14.0 H z , J= 6.2 H z ) , 3.76 (3H, s), 4.03 ( I H , dd, J= 6.9 H z , J= 7.2 H z ) , 6.94-7.38 (15 H , m) 3  C N M R (75 M H z , C D O D ) § 179.19, 173.23, 137.77, 136.75, 130.36, 130.01, 129.87, 128.83, 128.44, 127.13, 55.87, 49.98, 39.52, 33.89, 29.22  , 3  3  I R ( K B r pellet): 2947, 1746, 1603, 1559, 1497, 1384, 1221, 697 cm"  1  L R M S ( L S I M S ) m/z ( M + l ) : 418, 359, 221, 180, 120 +  H R M S ( L S I M S ) m/z ( M + l ) : Calculated mass for C26H28NO4 = 418.20183, found: 418.20164. +  A n a l . C a l c d . : C , 74.80; H , 6.52; N , 3.35. Found: C , 75.08; H , 6.60; N , 3.40.  163  L - P r o l i n e complex (49) O.  OH OH H  H  H  O  To a solution o f 60 mg (0.25 mmol) o f acid 37 in 6 m L o f diethyl ether was added a solution o f 29 mg (0.25 mmol) o f L-proline in 4 m L o f methanol. The solution was allowed to stand for overnight. The white precipitate was filtered and washed with diethyl ether. Recrystalhzation from methanol gave 72 mg (80 %) o f thin white needles. mp 185-188 °C ( M e O H ) ' H N M R (300 M H z , C D O D ) 8 1.95 (2H, m), 2.12 (1H, m), 2.20-2.31 (1H, m), 2.59 (1H, t, J= 5.4 H z ) , 2.98 (2H, d,J= 5.4 H z ) , 3.20-3.28 (1H, m), 3.37-3.46 (1H, m), 3.98 (1H, dd, J= 6.2 H z , J = 8.3 H z ) , 6.94-7.10 (10 H , m). 3  C N M R (75 M H z , C D O D ) 8 177.08, 174.04, 137.98, 133.99, 129.05, 127.47, 62.60, 47.02, 34.33, 30.41, 27.45, 25.08 1 3  3  I R ( K B r pellet): 3028, 2936, 1543, 1498, 1418, 1375, 772, 698 c m '  1  L R M S ( L S I M S ) m/z ( M + l ) : 354, 347, 330, 116 +  H R M S ( L S M S ) m/z ( M + l ) : Calculated mass for C i H 354.17033. +  2  3 3  N0  4  = 354.17053, found:  A n a l . C a l c d . : C , 71.37; H , 6.56; N , 3.96. Found: C , 71.39; H , 6.57; N , 4.15  164  D - P r o l i n e complex (50)  O. H  OH H  H  O  3 To a solution o f 60 mg (0.25 mmol) o f acid 37 i n 8 m L o f diethyl ether was added a solution o f 29 mg (0.25 mmol) o f D-proline i n 3 m L o f methanol. The solution was allowed to stand for overnight. The white precipitate was filtered and washed with diethyl ether. Recrystallization from methanol gave 75 mg (84 %) o f thin white needles. mp 185-188 °C ( M e O H ) * H N M R (300 M H z , C D O D ) 5 1.95 (2H, m), 2.12 ( I H , m), 2.20-2.31 ( I H , m), 2.59 ( I H , t, J= 5.4 H z ) , 2.98 (2H, d,J= 5.4 H z ) , 3.20-3.28 ( I H , m), 3.37-3.46 ( I H , m), 3.98 ( I H , dd, J = 6.2 H z , J= 8.3 H z ) , 6.94-7.10 (10 H , m). 3  C N M R (75 M H z , C D O D ) 5 177.08, 174.04, 137.98, 133.99, 129.05, 127.47, 62.60, 47.02, 34.33, 30.41, 27.45, 25.08 1 3  3  I R ( K B r pellet): 3028, 2936, 1543, 1498, 1418, 1375, 772, 698 cm"  1  L R M S ( L S I M S ) m/z ( M + l ) : 354, 347, 330, 116 +  H R M S ( L S I M S ) m/z ( M + l ) : Calculated mass for C i H 354.17042. +  2  3 3  N0  4  = 354.17053, found:  A n a l . C a l c d . : C , 71.37; H , 6.56; N , 3.96. Found: C , 71.52; H , 6.63; N , 4.09  165  4.3 Synthesis of trans, propane derivatives  fra«s-2,3-diphenyl-l-benzoyIcyclo-  trans, trans 2,3-diphenylcyclopropane-l-(A -methyl-A -methoxy)amide (51) 7  /  r  OMe  A solution o f acid 37 (2.00 g, 8.40 mmol) in 30 m L o f dichloromethane was cooled to 0 °C and treated with l,l'-carbonyldiimidazole (Aldrich, 1.63 g, 10.1 mmol). The solution was stirred for 30 min.  O-dimethylhydroxylamine hydrochloride (Aldrich, 2.05 g, 21.0  mmol) was then added and the mixture was allowed to warm to room temperature, stirred for 24 h, and filtered. The residue was washed with ether. The filtrate was washed with 0.5 M HC1, water (2x5mL), and brine. The organic layer was then dried and concentrated in vacuo. The residual o i l was chromatographed on silica gel and eluted with 30 % ethyl acetate/pet ether. Removal o f the solvent in vacuo followed by recrystalhzation from ethyl acetate afforded 1.98 g (84 %) o f off white prisms.  mp 94-95 ° C ( E t O A c ) H N M R (300 M H z , C D C 1 ) 5 3.07 (3H, m), 3.30 (3H, s), 3.78 (3H, s), 6.94-7.12 (10H, m) !  3  C N M R (75 M H z , C D C 1 ) 5 174.89, 138.27, 130.89, 129.91, 128.24, 63.84, 34.92, 34.67, 26.56 1 3  3  I R ( K B r pellet): 3070, 2970, 1638, 1603, 1443, 1380, 1163, 992, 762, 735, 697cm"  1  L R M S ( E I ) m / z ( M ) : 281,221, 193, 178, 144, 115,91 +  H R M S (EI) m/z ( M ) : Calculated mass for C i H +  8  1 9  N 0 = 281.14158, found: 281.14146 2  Anal. Calcd.: C , 76.84; H , 6.81; N , 4.98. Found: C , 76.68; H , 6.84; N , 4.64. 166  l-(trans, rra«s-2,3-Diphenyl)cyclopropyI 4-carbomethoxyphenyl methanone (52)  A solution o f methyl 4-iodobenzoate (1.98 g, 6.73 mmol) i n 30 m L o f anhydrous T H F was cooled to - 4 0 °C. Isopropyl magnesium chloride (2.0 M i n T H F , Aldrich, 3.53 m L , 7.05 mmol,) was added, and the resulting solution was stirred for 1.5 h. A m i d e 51 (1.80 g, 6.41 mmol) was then added and the reaction mixture was stirred for 6 h at - 2 0 °C. The reaction was quenched and worked up as a standard Grignard reaction. The white residue was chromatographed on silica gel (10 % ether in pet ether). Recrystallization from ethyl acetate gave 1.62 g (72 %) o f colorless prisms. Clear needles were obtained when methanol was used for recrystallization. mp 133-134 °C ( E t O A c , prisms), 137-138 °C ( M e O H , needles) ' H N M R (400 M H z , CDC1 ) 5 3.32 (2H, d / = 5.2 H z ) , 3.51 ( I H , \, J = 5.2 H z ) , 3.95 (3H, s), 6.99 (4H, m), 7.15 (6H, m), 8.01-8.17 (4H, dd, J = 7.0 H z , 17.4 H z ) 3  C N M R (75 M H z , CDCI3) 8 198.18, 166.31, 140.87, 135.82, 133.90, 129.86, 128.92, 128.17, 128.04, 126.73, 52.55, 36.78, 32.80  1 3  I R ( K B r pellet): Prism: 3027, 1727, 1667, 1603, 1420, 1279, 1105, 756, 736, 696 cm" Needle: 3028, 1722, 1651, 1420, 1278, 1108, 764, 731, 692 cm"  1  1  U V ,hanoi): 260 (11800), 322 (me  (280)  L R M S (EI) m/z ( M ) : 356, 325, 193, 163, 115 +  H R M S (EI) m/z ( M ) : Calculated mass for C 2 4 H 2 0 O 3 = 356.14124, found: 356.14122. +  A n a l . Calcd.: C , 80.88; H , 5.66 Found: C , 80.78; H , 5.59  167  The structures o f the two dimorphs were confirmed by X-ray crystallographic analysi  Habit  Colourless prisms  Space group  P2 ln  a, A  8.278(4)  x  b,k  21.253(7)  c,k  11.227(2)  a(°)  90  P(°)  104.62(3)  y(°)  90  z  4  R(onF)  0.048  Habit  colourless needles  Space group a, A  5.8902(8)  b,k  8.634(2)  c,k  18.365(3)  a(°)  84.51 (1)  P(°)  80.79 (1)  Y(°)  83.76 (1)  Z  2  R(onF)  0.047  168  \-{trans, frans-2,3-diphenyl)cyclopropyl 4-carboxyphenyl methanone (53)  O OH O.  H  A mixture o f ester 52 (1.5 g, 4.3 mmol), sodium hydroxide (0.68 g, 17.0 mmol), methanol (15 m L ) , and water (60 m L ) was refluxed with stirring for 24 h. The mixture was then cooled, extracted with ether, acidified, and again extracted with ether. The solvent was removed in vacuo, and the residue was recrystallized from methanol to give 1.35 g (91%) o f colorless prisms.  mp 190-192 ° C ( M e O H ) H N M R (400 M H z , C D C 1 ) 5 3.36 (2H, d J= 5.1 H z ) , 3.54 ( I H , t, J = 5.2 H z ) , 8.17 (2H, d, J= 8.5 H z ) , 8.27 (2H, d, J= 8.5 H z ) !  3  C N M R (75 M H z , C D C 1 ) 5 198.17, 171.24, 141.74, 135.67, 132.89, 130.56, 128.91, 128.11, 126.67,36.90, 32.88  1 3  3  I R ( K B r pellet): 3027, 1694, 1668, 1416, 1287, 1213, 1008, 751,694 cm-  1  L R M S (EI) m/z ( M ) : 342, 193, 149, 115 +  H R M S (EI) m/z ( M ) : Calculated mass for C H 2 8 N 0 = 342.12559, found: 342.12544. +  23  3  Anal. Calcd.: C , 80.68; H , 5.30. Found: C , 80.75; H , 5.42.  169  (1R, 25)-(+)-c/s-l-Amino-2-indanol salt (54) O  To a solution o f 75 mg (0.22 mmol) o f acid 53 in 5 m L o f diethyl ether was added a solution o f 33 mg (0.22 mmol) o f (IR, 25)-(+)-czs-l-amino-2-indanol i n 5 m L o f diethyl ether. The solution was allowed to stand overnight. The white precipitate was collected and washed with diethyl ether. Recrystalhzation from methanol gave 94 m g (87 %) o f long colorless needles. mp 203-205 °C ( M e O H ) * H N M R (300 M H z , C D O D ) 5 2.85-2.95 (1H, dd J= 4.7, 16.4 H z ) , 3.08-3.19 (3H, m), 3.63 (1H, t J= 5.2 H z ) , 4.40 (1H, dJ= 6.3 H z ), 4.58 (1H, q 4.7 H z ) , 6.92-7.05 (9 H , m), 7.14-7.38 (4H, m), 7.98-8.09 (4H, dd 8.3, 22.7 H z ) 3  C N M R (75 M H z , C D O D ) 8 200.28, 174.78, 142.67, 139.88, 137.32, 130.61, 130.54, 129.90, 129.08, 128.86, 128.44, 127.50, 126.62, 126.14, 72.28, 58.84, 40.11, 37.42, 32.45. 1 3  3  I R ( K B r pellet): 3029, 1652, 1537, 1497, 1397, 758, 697 cm"  1  L R M S (ESI) m/z ( M + l ) : 492, 365, 298, 150 +  H R M S (ESI) m/z ( M + l ) : Calculated mass for C H N O = 492.2175, found: 492.2162. +  3 2  3 0  4  A n a l . C a l c d . : C , 78.19; H , 5.95; N , 2.85. Found: C , 77.99; H , 5.96; N , 2.99.  170  (15, 2it)-(-)-c/s-l-Amino-2-indanol salt (55)  O o o.  HO +  To a solution o f 50 m g (0.15 mmol) o f acid 53 in 5 m L o f diethyl ether was added a solution o f 23 mg (0.15 mmol) o f (15, 25)-(-)-m-l-amino-2-indanol i n 5 m L o f diethyl ether. The solution was allowed to stand for overnight. The white precipitate was collected and washed with diethyl ether. Recrystallization from methanol gave 62 mg (85 %) o f long colorless needles.  mp 203-205 °C ( M e O H ) H N M R (300 M H z , C D O D ) 5 2.85-2.95 ( I H , ddJ= 4.7, 16.4 H z ) , 3.08-3.19 (3H, m), 3.63 ( I H , t J= 5.2 H z ) , 4.40 ( I H , d J= 6.3 H z ), 4.58 ( I H , q 4.7 H z ) , 6.92-7.05 (9 H , m), 7.14-7.38 (4H, m), 7.98-8.09 (4H, dd 8.3, 22.7 H z ) J  3  C N M R (75 M H z , C D O D ) 8 200.28, 174.78, 142.67, 139.88, 137.32, 130.61, 130.54, 129.90, 129.08, 128.86, 128.44, 127.50, 126.62, 126.14, 72.28, 58.84, 40.11, 37.42, 32.45. 1 3  3  I R ( K B r pellet): 3029, 1652, 1537, 1497, 1397, 758, 697 c m  -1  L R M S (ESI) m/z ( M + l ) : 492, 365, 298, 150 +  A n a l . C a l c d . : C , 78.19; H , 5.95; N , 2.85. Found: C , 78.12; H , 5.92; N , 2.91.  171  (S)-l-(4-Bromophenyl)ethylamine salt (56) O  To a solution o f 75 mg (0.22 mmol) o f acid 53 in 7 m L o f diethyl ether was added a solution o f 44 mg (0.22 mmol) o f (S)-l-(4-bromophenyl)ethylamine i n 2 m L o f diethyl ether. The solution was allowed to stand overnight. The white precipitate was collected and washed with diethyl ether. Recrystalhzation from methanol gave 98 m g (82 %) o f white powder. mp 185-188 °C ( M e O H ) * H N M R (400 M H z , C D O D ) 5 1.59 (3H, d,J= 6.9 H z ) , 3.22 (2H, d, J= 5.2 H z ) , 3.83 (1H, t, J= 5.2 H z ) , 4.42 (1H, q, J. = 6.9 H z ) , 7.06-7.16 (16H, m), 7.37 (2H, d, J= 8.4 H z ) , 7.57 (2H, d, J= 8.5 H z ) , 8.07 (2H, d, J= 8.5 H z ) , 8.17 (2H, d, J= 8.5 H z ) . 3  C N M R (75 M H z , D M S O ) § 197.56, 168.13, 142.45, 138.11, 135.56, 131.27, 129.30, 128.78, 128.72, 127.94, 127.76, 126.32, 120.45, 49.51, 35.78, 29.66, 22.65  1 3  I R ( K B r pellet): 2765, 1662, 1581, 1379, 1217, 754, 696 cm"  1  L R M S (ESI) m/z ( M + l ) : 544, 542, 365, 185, 183 +  H R M S (ESI) m/z ( M + l ) : Calculated mass for C 3 i H 9 B r N 0 542.1335. +  7 9  3  3  = 542.1331, found:  A n a l . C a l c d . : C , 68.64; H , 5.20; N , 2.58. Found: C , 68.79; H , 5.11; N , 2.72.  172  (/?)-l-(4-Bromophenyl)ethylamine salt (57)  O  To a solution o f 50 mg (0.15 mmol) o f acid 53 in 5 m L o f diethyl ether was added a solution o f 29 mg (0.15 mmol) o f (i?)-l-(4-bromophenyl)ethylamine i n 2 m L o f diethyl ether. The solution was allowed to stand overnight. The white precipitate was collected and washed with diethyl ether. Recrystallization from methanol gave 67 m g (83 %) o f white powder. m p 185-188 °C ( M e O H ) * H N M R (400 M H z , C D O D ) : 1.59 (3H, d, J= 6.9 H z ) , 3.22 (2H, d, J= 5.2 H z ) , 3.83 ( I H , t,J= 5.2 H z ) , 4.42 ( I H , q, J= 6.9 H z ) , 7.06-7.16 (16H, m), 7.37 (2H, d, J= 8.4 H z ) , 7.57 (2H, d, J= 8.5 H z ) , 8.07 (2H, d, J= 8.5 H z ) , 8.17 (2H, d, J= 8.5 H z ) . 3  C N M R (75 M H z , D M S O ) : 197.56, 168.13, 142.45, 138.11, 135.56, 131.27, 129.30, 128.78, 128.72, 127.94, 127.76, 126.32, 120.45, 49.51, 35.78, 29.66, 22.65  1 3  I R ( K B r pellet): 2765, 1662, 1581, 1379, 1217, 754, 696 cm"  1  L R M S (ESI) m/z ( M + l ) : 544, 542, 365, 185, 183 +  A n a l . C a l c d . : C , 68.64; H , 5.20; N , 2.58. Found: C , 68.53; H , 5.16; N , 2.64.  173  (5)-(-)-2-(Diphenylhydroxymethyl)pyrrolidine salt (58) O  o o  +  ^ H To a solution o f 75 mg (0.22 mmol) o f acid 53 i n 8 m L o f diethyl ether was added a solution o f 56 mg (0.22 mmol) o f (5)-(-)-2-(diphenylhydroxymethyl)pyrrolidine i n 4 m L o f methanol. The solution was allowed to stand for 2 h. The white precipitate was collected and washed with diethyl ether. Recrystalhzation from methanol/water gave 105 mg (80 %) o f white powder. mp 237-239 °C (MeOH/water) H N M R (400 M H z , D M S O ) 5 1.55-1.60 (3H, m), 3.05 (2H, m), 3.18 (2H, t, 7= 5.3 H z ) , 4.05 (1H, t,J= 5.3 H z ) , 4.63 (1H, m), 7.08-7.31 (16J, m), 7.48 (2H, d,J= 7.3 H z ) , 7.62 (2H, d, J= 7.3 H z ) , 8.04 (2H, d, J= 8.4 Hz), 8.23 (2H, d, J= 8.4 H z ) . J  C N M R (75 M H z , D M S O ) 5 197.72, 168.45, 146.11, 145.88, 138.07, 135.56, 129.45, 128.91, 128.10, 128.05, 127.91, 127.82, 126.67, 126.55, 126.40, 126.03, 125.36, 77.18, 64.28, 46.71, 35.82, 29.71, 26.33, 24.68. 1 3  I R ( K B r pellet): 3027, 1660, 1639, 1583, 1547, 1397, 1215, 753, 696 cm"  1  L R M S (ESI) m/z ( M + l ) : 596, 507, 365, 236, 158, +  H R M S (ESI) m/z ( M + l ) : Calculated mass for C40H38NO4 = 596.2801, found: 596.2794. +  A n a l . C a l c d . : C , 80.64; H , 6.26; N , 2.35. Found: C , 80.42; H , 6.20; N , 2.47  174  CR)-(+)-N-Benzyl-l-ethylamiiie salt (59)  To a solution o f 75 mg (0.22 mmol) o f acid 53 in 8 m L o f diethyl ether was added a solution o f 47 mg (0.22 mmol) o f (i?)-(+)-A^-benzyl-l-ethylamine i n 2 m L o f diethyl ether. The solution was allowed to stand overnight. The white precipitate was collected and washed with diethyl ether. Recrystallization from methanol gave 94 mg (77 %) o f thin white needles, mp 189-190 °C ( M e O H ) H N M R (400 M H z , C D O D ) 5 1 . 6 3 (3H, d, / = 6.8 H z ) , 3.22 (2H, d, J = 5.2Hz), 3.783.86 (2H, m), 4.00 ( I H , d, J= 13.0Hz), 4.27 ( I H , q, J= 6.8 H z ) , 7.01-7.16 (10 H , m), 7.32-7.48 (10H, m), 8.08 (2H, d, J= 8.5 H z ) , 8.17 (2H, d, J = 8.5 H z ) . l  3  C N M R (75 M H z , C D O D ) 5 200.19, 173.24, 140.18, 139.01, 138.88, 130.71, 130.56, 130.52, 130.44, 130.29, 130.20, 130.07, 129.14, 129.01, 128.82, 127.48, 59.42, 50.90, 37.34,32.41,20.52 1 3  3  I R ( K B r pellet): 3031, 1661, 1581, 1538, 1497, 1377, 1303, 1214, 740, 698 c m  -1  L R M S (ESI) m/z ( M + l ) : 554, 503, 381, 365, 236, 212 +  H R M S (ESI) m/z ( M + l ) : Calculated mass for C +  3 8  H  3 6  N 0 = 554.2685, found: 554.2698. 3  A n a l . C a l c d . : C , 82.42; H , 6.38; N , 2.53. Found: C , 82.68; H , 6.38; N , 2.68.  175  (15, 25)-(+)-2-Amino-l-phenylpropanediol salt (60)  O OH  O O  +  NH 3  HO H  H  3 To a solution o f 75 mg (0.22 mmol) o f acid 53 in 8 m L o f diethyl ether was added a solution o f 37 mg (0.22 mmol) o f (IS, 2S)-(+)-2-amino-l-phenylpropanediol in 5 m L o f diethyl ether. The solution was allowed to stand for overnight. The white precipitate was collected and washed with diethyl ether. Recrystalhzation from methanol gave 88 mg (78 %) o f clear long needles. mp 204-205°C ( M e O H ) ' H N M R (300 M H z , C D O D ) 5 3.21 (2H, d, J= 5.2Hz), 3.38-3.57 (2H, m), 3.81 (1H, t, J= 5.2 H z ) , 4.74 (1H, d, J= 8.6 H z ) , 7.05-7.18 (10 H , m), 7.32-7.41 (5H, m), 8.09 (2H, d, J= 8.5 H z ) , 8.15 (2H, d, J= 8.5 H z ) . 3  C N M R (75 M H z , C D O D ) 5 200.28, 174.67, 142.21, 140.04, 137.18, 130.82, 130.14, 129.82, 129.64, 129.01, 128.89, 127.78, 127.54, 72.41, 60.32, 59.87, 37.44, 32.42.  1 3  3  I R ( K B r pellet): 3252, 1661, 1581, 1529, 1397, 1219, 1036, 757, 698 cm"  1  L R M S (ESI) m/z ( M + l ) : 510, 365, 335, 298, 168 +  H R M S (ESI) m/z ( M + l ) : Calculated mass for C +  3 2  H  3 2  N 0 = 510.2280, found: 510.2275 5  A n a l . C a l c d . : C , 75.44; H , 6.09; N , 2.75. Found: C , 75.20; H , 6.12; N , 2.85.  176  (5)-(-)-l-(4-Tolyl)ethylamine salt (61) O  To a solution o f 75 mg (0.22 mmol) o f acid 53 in 8 m L o f diethyl ether was added a solution o f 30 mg (0.22 mmol) o f (5)-(-)-l-(4-tolyl)ethylamine in 2 m L o f diethyl ether. The solution was allowed to stand overnight. The white precipitate was collected and washed with diethyl ether. Recrystallization from acetonitrile gave 83 mg (79 %) o f thin white needles.  m p 201-203 °C ( M e C N ) H N M R (400 M H z , C D O D ) 8 1.58 (3H, d,J= 6.9 H z ) , 2.33 (3H, s), 3.22 (2H, d, J = 5.2 H z ) , 3.81 ( I H , t, J= 5.2 H z ) , 4.33-4.40 ( I H , q,J= 6.9 H z ) , 7.04-7.15 (10 H , m), 7.25 (2H, d, J 8 . 0 H z ) , 7.32 (2H, d, J= 8.0 H z ) , 8.08 (2H, d,J= 8.5 H z ) , 8.14 (2H, d,J= 8.5 Hz). J  3  C N M R (75 M H z , C D O D ) 5 200.28, 174.10, 141.30, 140.22, 139.92, 137.24, 136.97, 130.82, 130.56, 130.08, 129.04, 128.88, 127.53, 52.1, 37.39, 32.38, 21.13, 20.84.  , 3  3  I R ( K B r pellet): 2936, 1661, 1582, 1537, 1378, 1282, 753,696 cm"  1  L R M S (ESI) m/z ( M + l ) : 478, 365, 303, 136 +  H R M S (ESI) m/z ( M + l ) Calculated mass for C 2 H N 0 = 478.2382, found: 478.2384. +  :  3  3 2  3  A n a l . C a l c d . : C , 80.47; H , 6.54; N , 2.93. Found: C , 80.28; H , 6.50; N , 2.96  177  (ic)-(+)-2-Phenylpropylamine salt (62) O  To a solution o f 75 mg (0.22 mmol) o f acid 53 i n 8 m L o f diethyl ether was added a solution o f 30 mg (0.22 mmol) o f (K)-(+)-2-phenylpropylamine i n 2 m L o f diethyl ether. The solution was allowed to stand overnight. The white precipitate was collected and washed with diethyl ether. Recrystallization from M e C N gave 86 mg (82 %) o f thin white plates. mp 146-148°C ( M e C N ) N M R (300 M H z , C D O D ) 5 1.31 (3H, d, J= 6.6 H z ) , 3.02-3.12 (3H, m), 3.22 (2H, d, J= 5.2 H z ) , 3.80 ( I H , t,J= 5.2 H z ) , 7.01-7.12 (10 H , m), 7.23-7.33 (5H, m), 8.07 (2H, d, J= 8.4 Hz), 8.15 (2H, d,J= 8.4 H z ) 3  C N M R (75 M H z , C D O D ) 5 200.19, 174.02, 143.52, 143.36, 139.92, 137.16, 130.45, 130.10, 130.0, 130.03, 129.01, 128.47, 128.19, 127.51, 46.82, 39.70, 37.39, 32.34, 19.88  1 3  3  I R ( K B r pellet): 3028, 1662, 1584, 1499, 1386, 1219, 1010, 735, 698 cm"  1  L R M S (ESI) m/z ( M + l ) : 478, 343, 228, 136 +  H R M S (ESI) m/z ( M + l ) : Calculated mass for C +  3 2  H  3 2  N 0 = 478.2382, found: 478.2377 3  A n a l . C a l c d . : C , 80.47; H , 6.54; N , 2.93. Found: C , 80.47; H , 6.54; N , 2.92.  178  (S)-l-(4-Chlorophenyl)ethylamine salt (63)  O  To a solution o f 75 mg (0.22 mmol) o f acid 53 i n 8 m L o f diethyl ether was added a solution o f 34 mg (0.22 mmol) o f (S)-l-(4-chlorophenyl)ethylamine i n 2 m L o f diethyl ether. The solution was allowed to stand overnight. The white precipitate was collected and washed with diethyl ether. Recrystalhzation from methanol gave 83 mg (76 %) o f white powder.  mp 175-177 ° C ( M e O H ) * H N M R (400 M H z , C D O D ) 5 1.59 (3H, d, J = 6.9 H z ) , 3.21 (2H, d, J= 5.2 H z ) , 3.82 (1H, t, J= 5.2 H z ) , 4.42 (1H, q, J= 6.9 Hz)), 7.06-7.16 (16H, m), 7.43 (4H, s), 8.07 (2H, d, J= 8.5 H z ) , 8.15 ( 2 H , d,J= 8.5 H z ) . 3  C N M R (75 M H z , C D O D ) § 200.23, 180.50, 140.00, 139.1, 138.31, 137.22, 130.55, 130.32, 130.06, 129.41, 129.02, 128.89, 127.52, 51.60, 37.41, 32.37, 20.82  1 3  3  I R ( K B r pellet): 2618, 1661, 1583, 1379, 1287, 1097, 753, 695 cm"  1  L R M S (ESI) m/z ( M + l ) : 500, 498, 365, 298, 156. +  H R M S (ESI) m/z ( M + l ) : Calculated mass for C H 9 C 1 N 0 498.1827. +  3 5  3 1  2  5  = 498.1836, found:  A n a l . C a l c d . : C , 74.76; H , 5.67; N , 2.81. Found: C , 74.40; H , 5.62; N , 2.77  179  (S)-(+)-l-Aminoindane salt (64)  O O O.  +  NH. 3  H  To a solution o f 75 mg (0.22 mmol) o f acid 53 in 8 m L o f diethyl ether was added a solution o f 29 mg (0.22 mmol) o f (5)-(+)-l-aminoindane in 2 m L o f diethyl ether. The solution was allowed to stand overnight. The white precipitate was collected and washed with diethyl ether. Recrystalhzation from methanol gave 78 m g (75 %) o f tiny colorless neddles. mp 183-185 °C ( M e O H ) U N M R (300 M H z , C D O D ) 5 2.01-2.13 (1H, m), 2.52-2.64 (1H, m), 2.91-3.02 (1H, m), 3.08-3.18 (1H, m), 3.22 (2H, d,J= 5.2 H z ) , 3.81 (1H, t,J= 5.2 H z ) , 4.73 (1H, dd, J. = 7.7 H z , J= 5.1 H z ) , 7.06-7.16 (10H, m), 7.25-7.49 (4H, m), 8.08 (2H, d, J= 8.5 H z ) , 8.16 (2H, d, .7=8.5 H z ) . l  3  C N M R (75 M H z , C D O D ) 5 200.29, 173.87, 145.37, 143.51, 140.16, 139.94, 137.24, 130.60, 130.54, 130.07, 129.03, 128.86, 128.24, 127.52, 126.34, 125.42, 56.98, 37.38, 32.41,31.91,31.00. 1 3  3  I R ( K B r pellet): 2947, 1653, 1581, 1521, 1499, 1384, 1219, 1008,761,736, 697 cm"  1  L R M S (ESI) m/z ( M + l ) : 552, 453, 323, 122, 105, 91. +  H R M S (ESI) m/z ( M + l ) : Calculated mass for C H N O = 476.2226, found: 476.2219. +  3 2  3 0  3  A n a l . C a l c d . : C , 80.82; H , 6.15; N . 2.95. Found: C , 80.58; H , 5.91; N , 2.95  180  This structure was confirmed by X-ray crystallographic analysis:  Habit  colourless needles  Space group  P2i2i2i  a, A  6.3759(4)  b,k  12.6024(8)  c A  31.137(2)  a(°)  90  PC)  90  Y(°)  90  Z  4  R(on F)  0.077  (5)-(+)-2-Amino-l-butanol salt (65) O  To a solution o f 90 mg (0.26 mmol) o f acid 53 in 10 m L o f diethyl ether was added a solution o f 24 mg (0.26 mmol) o f (5)-(+)-2-amino-l-butanol i n 3 m L o f diethyl ether. The solution was allowed to stand overnight. The white precipitate was collected and washed with diethyl ether. Recrystallization from a solution o f chloroform/pet ether gave 93 mg (83 %) o f thin needles.  181  mp 157-158 °C (CHC1 /Pet ether) 3  H N M R (300 M H z , C D O D ) § 0.97-1.06 (3H, t,J = 7.5 H z ) , 1.61-1.68 (2H, m), 3.083.11 ( I H , m), 3.22 (2H, d,J = 5.2 H z ) , 3.50-3.52 (1 H , m), 3.74-3.78 ( I H , m). 3.79-3.82 ( I H , t, J= 5.2 H z ) , 7.04-7.14 (10 H , m), 8.08 (2H, d, J= 8.4 H z ) , 8.16 (2H, d, J= 8.4 H z ) !  3  C N M R (75 M H z , C D O D ) 5 200.25, 173.91, 143.39, 139.97, 137.20, 130.48, 130.05, 129.03, 128.49, 127.53, 61.84, 55.96, 37.40, 32.32, 23.58, 10.16  1 3  3  I R ( K B r pellet): 3421, 2963, 1651, 1584, 1551, 1499, 1388, 1219, 1011, 760, 736, 699 cm" 1  L R M S (ESI) m/z ( M + l ) : 432, 365, 303. +  H R M S (ESI) m/z ( M + l ) : Calculated mass for C27H30NO4 = 432.2175, found: 432.2166. +  A n a l . C a l c d . : C , 75.15; H , 6.77; N , 3.25. Found: C , 75.27; H , 6.72; N , 3.03.  (+)-Borneol ester (66)  To a solution o f acid 53 (150 mg, 0.44 mmol) in 10 m L o f anhydrous T H F was added 252 mg (0.88 mmol) o f oxalyl chloride (Acros). The solution was allowed to stir for five minutes, and 5 u L o f D M F was added. The resulting mixture was allowed to stir for 2 h at room temperature. The solvent was removed in vacuo, and the yellow residue was dried under vacuum for 0.5 h. The residue was dissolved i n 10 m L o f methylene chloride, and cooled to 0 °C. To this was added (+)-borneol (68 mg, 0.53 m m o l , Aldrich), and the solution was stirred for 2 h. The reaction was quenched by adding 5 m L o f water, and extracted with ether twice. The combined organic layers were washed successively with  182  5% sodium bicarbonate (5 m L ) , water ( 2 X 5 m L ) , dried over sodium sulfate, and the solvent removed in vacuo. Radial chromatography (15 % Et20 i n pet ether), followed by recrystallization from methanol afforded 103 mg (49 %) o f t h e desired product as fine colorless prisms, mp 153-154 °C ( M e O H ) * H N M R (400 M H z , C D C 1 ) 5 0.81-0.96 (10H, m), 1.15 ( I H , m), 1.30 ( I H , m), 1.721.82 (2 H . m), 2.10 ( I H , m), 2.47 ( I H , m), 3.32 (2H, d, 5.2 H z ) , 3.50-3.52 (1 H , t, J= 5.2 Hz), 5.12 ( I H , m), 7.04-7.14 (10 H , m), 8.13 (2H, d, J= 8.4 H z ) , 8.19 (2H, d, J= 8.4 H z ) 3  C N M R (75 M H z , C D C 1 ) 5 198.14, 165.93, 140.82, 135.84, 134.63, 129.85, 128.87, 128.09, 128.03, 126.67, 81.18, 49.15, 47.9, 44.97, 36.88, 36.72, 32.82, 28.07, 27.40, 19.70, 18.90, 13.62  1 3  3  I R ( K B r pellet): 2952, 2876, 1704, 1673, 1421, 1283, 1126, 1011,755,727, 694 cm"  1  L R M S (CI, N H ) m/z ( M + l ) : 479, 285, 193, 180, 137. +  3  H R M S (CI, N H ) m/z ( M + l ) : Calculated mass for C 479.25703. +  3  3 3  H  3 5  A n a l . C a l c d . : C , 82.81 H , 7.16. Found: C , 82.85, H , 7.21 This structure was confirmed by X-ray crystallographic analysis: Habit  colourless block  Space group  P2i2i2i 10.647(2) 11.3118(5) 22.104(1) 90 90 90  Z  4 0.066  183  0  3  = 479.25862, found:  (IR, 2S, 5it)-(-)-Menthol ester (67)  To a solution o f acid 53 (150 mg, 0.44 mmol) in 10 m L o f anhydrous T H F was added 252 mg (0.88 mmol) o f oxalyl chloride (Acros). The solution was allowed to stir for five minutes, and 5 u L o f D M F was added. The resulting mixture was allowed to stir for 2 h at room temperature. The solvent was removed in vacuo, and the yellow residue was dried under vacuum for 0.5 h. The residue was dissolved i n 10 m L o f methylene chloride, and cooled to 0 °C. To this was added (IR, 2S, 5i?)-(-)-menthol (69 mg, 0.53 mmol, Aldrich), and the solution stirred for 2 h. The reaction was quenched by adding 5 m L o f water, and extracted with ether twice. The combined organic layers were washed successively with 5% sodium bicarbonate (5 m L ) , water ( 2 X 5 m L ) , dried over sodium sulfate, and the solvent removed  in vacuo. Radial chromatography (15 % Et20 i n pet  ether), followed by recrystallization from E t O A c afforded 97 mg (46 %) o f the desired product as fine white needles. mp 141-142 ° C ( E t O A c ) ' H N M R (300 M H z , C D C 1 ) 5 0.79 (3H, d, J= 6.9 H z ) , 0.91 (7H, m), 1.13 (2H, m), 1.54 (2H, m), 1.73 (2 H . m), 1.93 ( I H , m), 2.11 ( I H , m), 3.32 (2H, d, 5.2 H z ) , 3.50-3.52 (1 H , t,J= 5.2 H z ) , 4.92 ( I H , m), 6.98-7.15 (10 H , m), 8.10-8.18 (4H, dd, J= 8.4, 14 H z ) 3  C N M R (75 M H z , C D C 1 ) 5 198.13, 165.19, 140.75, 135.82, 134.58, 129.88, 128.85, 128.06, 128.00, 126.63, 75.49 , 47.21, 40.89, 36.67, 34.23, 31.42, 26.55, 23.63, 21.99, 20.70, 16.52 , 3  3  I R ( K B r pellet): 2941, 1709, 1667, 1499, 1421, 1276, 1107, 747, 732, 695 c m  184  -1  L R M S (CI, N H ) m/z ( M + l ) : 481, 287, 193, 149, 91 +  3  H R M S (CI, N H ) m/z ( M + l ) : Calculated mass for C 481.27433. +  3  3 3  H  3 6  0  3  = 481.27427, found:  A n a l . C a l c d . : C , 82.46; H , 7.55. Found: C , 82.58; H , 7.68  (i?)-(-)-2-Methoxy-2-phenylethanol ester (68)  0  To a solution o f acid 53 (100 mg, 0.29 mmol) i n 10 m L o f anhydrous T H F was added 74 m g (0.58 mmol) o f oxalyl chloride (Acros). The solution was allowed to stir for five minutes, and 5 u L o f D M F was added. The resulting mixture was allowed to stir for 2 h at room temperature. The solvent was removed in vacuo, and the yellow residue was dried under vacuum for 0.5 h. The residue was dissolved in 10 m L o f methylene chloride, and cooled to 0 °C. To this was added (i?)-(-)-2-methoxy-2-phenylethanol (53 mg, 0.35 mmol, Aldrich), and the solution was stirred for 2 h. The reaction was quenched by adding 5 m L o f water, and extracted with ether twice. The combined organic layers were washed successively with 5% sodium bicarbonate (5 m L ) , water ( 2 X 5 m L ) , dried over sodium sulfate, and the solvent removed in vacuo. Radial chromatography (15 % Et20 i n pet ether), followed by recrystalhzation from EtOAc/pet ether afforded 86 mg (62 %) o f the desired product as fine white needles.  mp 118-120 °C (EtOAc/pet ether) * H N M R (300 M H z , C D C 1 ) § 3.32 (5H, m), 3.50-3.52 (1 H , t, J= 5.2 H z ) , 4.46 (2H, m), 4.57 (1H, m), 6.98-7.15 (10 H , m), 7.34-7.39 (5H, m), 8.10-8.17 (2H, dd, J= 8.4, 13 H z ) 3  185  C N M R (75 M H z , C D C 1 ) 5 198.09, 165.52, 140.96, 137.88, 135.80, 133.81, 130.03, 128.86, 128.64, 128.40, 128.07, 127.00, 126.95, 126.65, 81.52, 68.54, 57.14, 36.77, 32.77  , 3  3  I R ( K B r pellet): 3029, 1723, 1657, 1273, 1099, 760, 697 cm" L R M S (CI, N H ) m/z ( M + l ) : 477, 283, 193 +  3  A n a l . C a l c d . : C , 80.65; H , 5.92. Found: C , 80.78; H , 6.02  186  1  4.4 Synthesis of 4-(trans, *raws-2,3-dibenzoylcyclopropyl-l-) benzoic acid derivatives Chalcone 4'-carboxylic acid ( 6 9 )  115  O  HOOC To a solution o f N a O H (1.0 g, 25 mmol) i n 10 m L o f water was added a solution o f 4carboxybenzaldehyde  (1.5 g, 10 mmol, Aldrich) in 6 m L o f D M F and a solution o f  acetophenone (1.15 g, 9.6 mmol, Eastman) in 5 m L o f E t O H . The mixture was allowed to stir for 5 h at 25 °C, during the time the solution turned yellow. The solution was then washed with ether (25 m L ) , acidified with 6 M HC1, and extracted with 20 % THF/ether (3 x 30 m L ) . The combined organic layers were washed with brine (2 x 40 m L ) and dried over magnesium sulfate. The solvent was removed in vacuo, and the light yellow solid residue was recrystallized from ethanol to give 1.91 g (82 %) o f light yellow flakes. The spectroscopic data agree with previos published result.  115  R N M R (300 M H z , D M S O ) : 7.49 - 7.76 (4H, m), 7.95-8.02 (5H, m), 8.13 (2H, m)  l  S u l f o n i u m salt (70) O  This compound was prepared according to the method employed by Speziale et.  al.  ue  Dimethyl sulfide (620 mg, 10.0 mmol, Aldrich) and a-bromoacetophenone (2.0 g, 10.0 mmol, Aldrich) were dissolved in benzene (5 m L ) and stirred at room temperature for 24 h. The precipitate was filtered and dried under vacuum to give 1.6 g (62%) o f sulfonium salt 34. This compound was used without characterization.  187  4-(trans, *rans-2,3,-Dibenzoylcyclopropyl-l-)benzoic acid (71)  COOH  A  A procedure modified from that employed by Reddy et. a/.  S4  was used. To a solution of  acid 69 (1.07 g, 4.25 mmol) and N a O H (0.338 g, 8.45 mmol) i n 50 m L o f water was added sulfonium salt 70 (1.10 g, 4.25 mmol). The solution was stirred overnight, and then washed with ether (2 x 25 mL). The aqueous layer was then acidified with 6 M HC1, and extracted with ether (2 x 50 m L ) . The combined organic layer was washed with water (2 x 50 m L ) , brine (1 x 50 m L ) , and then dried over sodium sulfate. Removal o f the solvent in vacuo afforded a white powder. Recrystalhzation from ethyl acetate gave 1.24 g (79 %) o f clear long needles. mp 204-207 °C (EtOAc) ' H N M R (300 M H z , D M S O ) 6 3.37 (1H, t, J = 6 . 1 H z ) , 3.87 (2H, d, J = 6 . 1 H z ) , 7.467.58 (8H, m), 7.92 (6H, m), 12.90 (1H, s) C N M R (75 M H z , D M S O ) 8 193.65, 167.07, 144.05, 136.53, 133.34, 129.51, 128.62, 128.15, 126.82,37.42, 30.27  1 3  I R ( K B r pellet): 3012, 1687, 1657, 1610, 1574 cm"  1  L R M S (EI) m/z ( M ) : 370, 353 +  H R M S (EI) m/z ( M ) : Calculated mass for C H i 0 4 = 370.12051, found: 370.12051 +  24  8  A n a l . C a l c d . : C , 77.82; H , 4.90. Found: C , 77.85; H , 4.88  188  Methyl 4-(trans, *ra«s-2,3,-dibenzoylcyclopropyl-l-)benzoate (72)  COOMe  A solution o f acid 71 (150 mg, 0.41 mmol) i n 8 m L o f ethanol was treated with an excess o f an ethereal solution o f diazomethane. The solvent was removed in vacuo, and the residue was recrystallized from methanol to give 142 mg (90 %) o f fine white needles. mp 110-112 °C ( M e O H ) ' H N M R (300 M H z , C D C 1 ) 5 3.43 (2H, d, J = 6.0 H z ) , 3.56 ( I H , t, J= 6.0 H z ) , 3.90 (3H, s), 7.34- 7.54 (8H, m), 7.96 (6H, m) 3  C N M R (75 M H z , C D C 1 ) 6 194.02, 166.91, 144.32, 137.42, 133.64, 130.34, 129.57, 129.00, 128.59, 126.92, 52.35, 37.48, 31.09  1 3  2  2  IR ( K B r pellet): 2923, 1717, 1656, 1611, 1596, 1578 c m  -1  L R M S (EI) m/z ( M ) : 370, 353 +  H R M S (EI) m/z ( M ) : Calculated mass for +  C25H20O4  = 384.13616, found: 384.13589  Anal. Calcd.: C , 78.11; H , 5.24. Found: C , 77.95; H , 5.62  189  (i?)-(+)-A -Benzyl-l-phenylethylamine salt (73) /  To a solution o f acid 71 (75 mg, 0.20 mmol) in 4 m L o f methanol was added a solution o f (i?)-(+)-A^-benzyl-l-phenylethylamine (42 mg, 0.20 mmol) in 1 m L o f methanol. Slow evaporation o f solvent gave 26.0 mg (22 %) o f white powder. mp 127-129 °C ( M e O H ) ' H N M R (300 M H z , C D O D ) : 1.61 (3H, d, J= 6.8 H z ) , 3.47 (1H, t, J= 6.2 H z ) , 3.71 (2H, d, J= 6.2 H z ) , 3.82 (1H, d, J= 13.0 H z ) , 3.97 (1H, d,J = 13.0 H z ) , 4.24 (1H, t, J = 6.8 H z ) , 7.32-7.45 (18H, m), 7.98 (6H, m), 3  C N M R (75 M H z , C D O D ) : 196.41, 174.02, 143.33, 140.12, 138.39, 134.89, 134.55, 131.04, 130.52, 130.31, 130.03, 129.91, 129.67, 128.45, 127.30, 59.31, 51.12, 38.64, 32.20,21.01 , 3  3  I R ( K B r pellet): 3437, 1678, 1609, 1542, 1376 cm"  1  L R M S ( L S M S ) m/z ( M + l ) : 582, 371, 212 +  HRMS (LSMS) found:.582.26455  m/z  (M +l): +  Calculated  mass  for  C  3 9  H  3 6  N0  4  =  A n a l . C a l c d . : C , 80.53; H , 6.06; N , 2.41. Found: C , 80.19; H , 6.18; N , 2.45.  190  582.26443,  (IS, 2R) (-)-c/s-l-Amino-2-indanol salt (74)  COO  To a solution o f acid 71 (93 mg, 0.25 mmol) i n 4 m L o f methanol was added a solution o f (IS, 2R) (-)-czs-l-amino-2-indanol (38 mg, 0.25 mmol) i n 1 m L o f methanol. Slow evaporation o f solvent gave 63 mg (48 %) o f thin white plates. mp 182-184 °C ( M e O H ) H N M R (300 M H z , C D O D ) 5 3.01 ( I H , dd, J = 4.9, 16.4 H z ) , 3.21 ( I H , dd, J= 6.3, 16.3 H z ) , 3.43 ( I H , t,J= 6.2 H z ) , 3.69 (2H, d, J= 6.2 H z ) , 4.52 ( I H , d, J= 5.9 H z ) , 4.69 ( I H , q, J= 6.0 H z ) , 7.24 - 7.57 (12H, m). 7.98-8.05 (6H, m) J  3  C N M R (75 M H z , C D O D ) 5 196.52, 174.61, 142.78, 142.56, 138.44, 137.23, 131.31, 131.02, 130.67, 129.89, 129.71, 129.32, 128.40, 127.21, 127.14, 126.73, 126.24, 72.15, 58.71,40.10,38.34, 32.32 1 3  3  I R ( K B r pellet): 3053, 1684, 1586, 1519, 1396 c m  -1  L R M S ( L S I M S ) m/z ( M + l ) : 520, 371, 150 +  H R M S (LSIMS) found:.520.21300  m/z  (M +l): +  Calculated  mass  for  C H NO 3 3  3 0  5  =  A n a l . C a l c d . : C , 76.28; H , 5.63; N , 2.70. Found: C , 75.99; H , 5.78; N , 2.80.  191  520.21240,  (if)-(+)-2-Phenylpropylamine salt (75)  COO H  To a solution o f acid 71 (75 mg, 0.20 mmol) i n 4 m L o f methanol was added a solution o f (i?)-(+)-2-phenylpropylamine  (27 mg, 0.20  mmol) i n  1 m L o f methanol.  Slow  evaporation o f solvent gave 58 mg (56 %) o f long white needles. mp 170-173 °C ( M e O H ) * H N M R (300 M H z , C D O D ) 5 1.32 (3H, d,J= 6.7 H z ) , 3.08-3.28 (3H, m), 3.45 (1H, t, J= 6.2 H z ) , 3.70 (2H, d, J= 6.2 H z ) , 7.26-7.56 (13 H , m), 7.95 - 8.02 (6H, m) 3  C N M R (75 M H z , D M S O ) 5 193.89, 174.02, 144.03, 140.89, 136.67, 133.28, 129.34, 128.62, 128.49, 128.14, 127.12, 126.50, 125.97, 48.56, 39.22, 37.34, 30.54, 19.15,  1 3  I R ( K B r pellet): 2965, 1682, 1582, 1508, 1376 cm"  1  L R M S ( L S M S ) m/z ( M + l ) : 506, 371, 136 +  HRMS (LSMS) found:.506.23291  m/z  (M +l): +  Calculated mass  for  C33H32NO4  A n a l . C a l : C , 78.39; H , 6.18; N , 2.83. Found: C , 78.16; H , 6.28; N , 2.83.  192  =  506.23313,  (15,2i?)-(+)-Norephedrine salt (76)  COO +  NH:'" 3  l  ^ A  To a solution o f acid 71 (75 mg, 0.20 mmol) in 4 m L o f methanol was added a solution o f (15, 2i?)-(+)-norephedrine (30 mg, 0.20 mmol) i n 1 m L o f methanol. Slow evaporation o f solvent gave 80 m g (76 %) o f thin white plates. mp 204-207 °C ( M e O H ) H N M R (300 M H z , D M S O ) 5 0.90 (3H, d, J= 6.5 H z ) , 3.30-3.38 (3H, m), 3.82 (2H, d, J= 6.2 H z ) , 4.97 ( I H , s, br), 7.24-7.61 (13 H , m), 7.89-8.02 (6H, m) !  C N M R (75 M H z , D M S O ) 5 193.88, 173.65, 141.96, 141.02, 136.64, 132.27, 129.36, 128.62, 128.15, 127.97, 126.91, 125.99, 125.92, 71.86, 51.80, 37.34, 30.52, 12.40  I 3  I R ( K B r pellet): 3229, 1683, 1654, 1608, 1559, 1531, 1374 cm"  1  L R M S (LSLMS) m/z ( M + l ) : 522, 371, 152 +  H R M S (LSLMS) found:.522.22846  m/z  (M +l): +  Calculated mass  for  C33H32NO5  =  A n a l . C a l c d . : C , 75.99; H , 5.99; N , 2.69. Found: C , 76.22; H , 6.01; N , 2.68.  193  522.22805,  (15, 25)-(+)-Thiomicamine salt (77)  COO  OH + 3 u  SCH  3  To a solution o f acid 71 (75 mg, 0.20 mmol) in 3 m L o f ethanol was added a solution o f (15, 25)-(+)-thiomicamine (43 mg, 0.20 mmol) i n 1 m L o f ethanol. Slow evaporation o f solvent gave 86 mg (73%) o f white powder. mp 198-200 °C (EtOH) U N M R (300 M H z , D M S O ) 5 2.45 (3H, s), 2.99 (1H, m), 3.22 (1H, dd, J= 5.6, 11.5 Hz), 3.32 (1H, t, 6.2 H z ) , 3.43 (1 H , dd, J= 3.0, 11.4 H z ) , 3.82 (2H, d, 6.2 H z ) , 4.60 (1H, d, J= 8.0 H z ) , 7.12-7.61 (13 H , m), 7.89-8.02 (6H, m) l  C N M R (75 M H z , D M S O ) 5 193.86, 173.54, 141.24, 139.31, 137.01, 136.64, 133.30, 129.40, 128.63, 128.16, 127.41, 126.05, 125.77, 70.92, 59.86, 58.64, 37.37, 30.51, 14.78  1 3  I R ( K B r pellet): 3063, 1683, 1655, 1583, 1524, 1398 cm"  1  L R M S ( L S M S ) m/z ( M + l ) : 584, 371, 214 +  HRMS (LSMS) found:.584.21012  m/z  (M +l): +  Calculated mass  for  C33H34NO6S  =  A n a l . C a l c d . : C , 69.96; H , 5.70; N , 5.49. Found: C , 69.89; H , 5.64; N , 2.44.  194  584.21068,  (IR, 2R, 3R, 55)-(-)-Isopinocampheol ester (78)  O  V o  To a solution o f acid 71 (150 mg, 0.41 mmol) i n 10 m L o f anhydrous T H F was added 103 m g (0.81 mmol) o f oxalyl chloride (Across). The solution was allowed to stir for five min, and 5 u L o f D M F was added. The resulting mixture was allowed to stir for 2 h at room temperature. The solvent was removed in vacuo, and the yellow residue was dried under vacuum for 0.5 h. The residue was dissolved i n 10 m L o f methylene chloride, and cooled to 0 °C. T o this was added (IR, 2R, 3R, 55)-(-)-isopinocampheol (75 mg, 0.49 mmol, Aldrich), triethylamine (50 u L ) , and the solution was stirred for 4 h. The reaction was quenched by adding 5 m L o f water, and extracted with ether twice. The combined organic layers were washed successively with 5% sodium bicarbonate (5 m L ) , water (2 X 5 m L ) , dried over  sodium sulfate,  and the solvent removed  in vacuo. Radial  chromatography (40 % E t 2 0 i n pet ether), followed by recrystalhzation from methanol afforded 120 m g (53 %) o f the desired product as colorless fine needles.  mp 164-165 °C ( M e O H ) * H N M R (300 M H z , C D C 1 ) 8 1.00 (3H, s), 1.16, (4H, d, J= 7.5 H z ) , 1.66 (3H, s), 1.791.91 (2H, m), 1.98 (1H, m), 2.30 (1 H , m), 2.43 (1H, m), 2.68 (1H, m), 3.42 (1H, d, J = 6.1 H z ) , 3.52 (2H, d J= 6.1 H z ) , 5.28 (1H, qu, J= 7.8 H z ) , 7.34-7.44 (6H, m), 7.52 (2H, m), 7.96 (4H, m), 8.04 (2H, d, J= 8.3 H z ) 3  C N M R (75 M H z , CDCI3) 8 193.67, 165.54, 143.56, 136.96, 133.29, 130.08, 129.81, 128.58, 128.34, 126.34, 75.22, 47.25, 40.96, 37.05, 34.29, 31.42, 30.70, 25.54, 24.56, 23.01, 19.72, 16.53 1 3  195  I R ( K B r pellet): 2905, 1704, 1682, 1664, 1277, 763, 724, 688 cm' L R M S (ESI) m/z ( M + l ) : 507, 261 +  A n a l . C a l c d . : C , 80.60; H , 6.70. Found: C , 80.51; H , 6.72.  (11?, 2S, 5i?)-(-)-Menthol ester (79)  To a solution o f acid 71 (150 mg, 0.41 mmol) i n 10 m L o f anhydrous T H F was added 126 mg (0.81 mmol) o f oxalyl chloride (Across). The solution was allowed to stir for five min, and 5 u L o f D M F was added. The resulting mixture was allowed to stir for 2 h at room temperature. The solvent was removed in vacuo, and the yellow residue was dried under vacuum for 0.5 h. The residue was dissolved i n 10 m L o f methylene chloride, and cooled to 0 °C. To this was added (IR, IS, 5i?)-(-)-menfhol (77 mg, 0.49 m m o l , Aldrich), triethylamine (50 u L ) , and the solution was stirred for 3 h. The reaction was quenched by adding 5 m L o f water, and extracted with ether twice. The combined organic layers were washed successively with 5% sodium bicarbonate (5 m L ) , water ( 2 X 5 m L ) , dried over sodium sulfate, and the solvent removed in vacuo. Radial chromatography (25 % Et20 in  196  pet ether), followed by recrystallization from ethyl acetate afforded 92 m g (44 %) o f the desired product as a fine white powder.  mp 189-190 ° C ( E t O A c ) * H N M R (400 M H z , C D C 1 ) 8 0.78 (3H, d, J= 6.9 H z ) , 0.92, (7H, m), 1.01-1.28 (2H, m), 1.52 (2H, m), 1.72 (2H, m), 1.96 ( I H , m), 2.13 (1 H , m), 3.42 ( I H , d, J= 6.1 H z ) , 3.56 (2H, d J= 6.1 H z ) , 5.28 ( I H , qu, J= 7.8 H z ) , 7.34-7.44 (6H, m), 7.52 (2H, m), 7.96 (4H, m), 8.04 (2H, d, J= 8.3 H z ) 3  C N M R (75 M H z , CDCI3) 5 193.77, 165.68, 143.58, 136.96, 133.26, 130.12, 129.81, 128.60, 128.32, 126.36, 74.94, 47.25, 40.96, 37.04, 34.29, 31.42, 30.79, 26.53, 23.65, 22.01,20.73,16.53 1 3  I R ( K B r pellet): 2954, 1714, 1676, 1275, 763. 719, 688 cm"  1  L R M S (ESI) m/z ( M + l ) : 509, 249 +  A n a l . Calcd.:for C 3 4 H 3 6 O 4 : C , 80.28; H , 7.13. Found: C , 80.45; H , 7.19.  (5)-2-Methylbutanol ester (80)  To a solution o f acid 71 (150 mg, 0.41 mmol) in 10 m L o f anhydrous T H F was added 126 mg (0.81 mmol) o f oxalyl chloride (Across). The solution was allowed to stir for five minutes, and 5 u L o f D M F was added. The resulting mixture was allowed to stir for 2 h at room temperature. The solvent was removed in vacuo, and the yellow residue was dried under vacuum for 0.5 h. The residue was dissolved i n 10 m L o f methylene chloride, and cooled to 0 °C. The residue was dissolved i n 10 m L o f methylene chloride, and  197  cooled to 0 °C. To this was added 0S)-2-methylbutanol (77 mg, 0.49 m m o l , Aldrich), triethylamine (50 u L ) , and the solution was stirred for 2 h. The reaction was quenched by adding 5 m L o f water, and extracted with ether twice. The combined organic layers were washed successively with 5% sodium bicarbonate (5 m L ) , water ( 2 X 5 m L ) , dried over sodium sulfate, and the solvent removed in vacuo. Radial chromatography (30 % E t 2 0 in pet ether), followed by recrystallization from MeOH/hexane afforded 101 mg (56 %) o f the desired product as thin colorless needles.  mp 159-160 °C (MeOH/hexane) ' H N M R (300 M H z , C D C 1 ) 5 0.97 (6H, m), 1.27 ( I H , m), 1.49 ( I H , m), 1.84 ( I H , m), 3.42 ( I H , d, J= 6.1 H z ) , 3.57 (2H, d J = 6.1 H z ) , 4.15 ( I H , m), 7.34-7.55 (8H, m), 7.96 8.04 ( 6 H , m ) 3  C N M R (75 M H z , CDCI3) 8 193.74, 166.26, 143.71, 136.97, 133.25, 130.08, 129.49, 128.59, 128.31, 126.41, 69.60, 37.05, 34.29, 30.77, 26.14, 16.51, 11.26  1 3  I R ( K B r pellet): 2966, 1709, 1682, 1269, 763, 721, 696 cm"  1  L R M S (ESI) m/z ( M + l ) 441 +  :  A n a l . C a l c d . : C , 79.07 H ; 6.41. Found: C , 79.32; H , 6.42. This structure was confirmed by X-ray crystallographic analysis: Habit  colourless block  Space group  P2i2i2i  a, A  10.8383(4)  b, A  16.1783(7)  cA  27.0471(1)  <x(°)  90  P(°)  90  Y(°)  90  Z  8  R(onF)  0.050  198  (S)-2-butanol ester (81)  O  o To a solution o f acid 71 (150 mg, 0.41 mmol) i n 10 m L o f anhydrous T H F was added 126 mg (0.81 mmol) o f oxalyl chloride (Across). The solution was allowed to stir for five minutes, and 5 JLIL o f D M F was added. The resulting mixture was allowed to stir for 2 h at room temperature. The solvent was removed in vacuo, and the yellow residue was dried under vacuum for 0.5 h. The residue was dissolved i n 10 m L o f methylene chloride, and cooled to 0 ° C . To this was added (S)-2-butanol (37 mg, 0.49 m m o l , Aldrich), triethylamine (50 uL), and the solution was stirred for 2 h. The reaction was quenched by adding 5 m L o f water, and extracted with ether twice. The combined organic layers were washed successively with 5% sodium bicarbonate (5 m L ) , water ( 2 X 5 m L ) , dried over sodium sulfate, and the solvent removed in vacuo. Radial chromatography (30 % E t 2 0 i n pet ether), followed by recrystalhzation from MeOH/hexane afforded 75 mg (43 %) o f the desired product as tiny colorless platelets  mp 136-137 ° C (MeOH/hexane) * H N M R (300 M H z , CDCI3): 0.96 (3H, d J= 6.8 H z ) , 1.30 (3H, d J= 6.8 H z ) , 1.71 (2H, m), 3.42 (1H, d,J= 6.1 H z ) , 3.57 (2H, d J= 6.1 H z ) , 5.05 (1H, m), 7.34-7.55 (8H, m), 7.96 - 8.04 (6H, m) C N M R (75 M H z , CDCI3): 193.77, 165.84, 143.55, 136.97, 133.25, 130.06, 129.88, 128.59, 128.32, 126.34, 72.96, 37.05, 30.77, 28.92, 19.53, 9.7.  1 3  199  IR ( K B r pellet): 3029, 1723, 1657, 1273, 1099, 760, 732, 697 cm' L R M S (ESI) m/z ( M + l ) : 427 +  A n a l . C a l c d . : C , 78.85; H , 6.14. Found: C , 79.02; H , 6.15. This structure was confirmed by X-ray crystallographic analysis: Habit  colourless platelet  Space group a, A  13.412(1)  b,A cA  5.6984(5)  <x(°)  90  P(°)  95.911(5)  Y(°)  90  Z  2  R(on F)  0.042  14.543(1)  200  4.5 Syntheses of cis, c/s-2,3-bis(benzyloxymethy)-l-benzoylcyclopropane derivatives Compounds 82 - 84 were prepared according to the procedure reported by Charette et.  al.  ni  (Z)-l,4-Dibenzyloxy-2-butene (82)  To a solution o f (Z)-but-2-'ene-l,4-diol (2.02 g, 22.9 mmol, Aldrich) i n dry D M F (60 m L ) at 0 °C was added N a H (4.04 g, 45.8 mmol, Aldrich) in small portions. The reaction was cooled to 0 °C before addition o f benzyl chloride (6.77 g, 48.2 mmol). This solution was allowed to warm to room temperature and stirred overnight. The reaction was then quenched by adding water (40 m L ) . The mixture was diluted with diethyl ether and then acidified with 10 % HC1. The aqueous layer was extracted with ether (2 X 150 m L ) , and the combined organic layer was washed successively with water (5 X 100 m L ) , dried over magnesium sulfate and the solvent removed  in vacuo. Silica gel chromatography (0-  20 % EtOAc/pet ether) afforded 5.60 g (82 %) colorless oil. The spectral data agreed with previously published results.  117  *H NMR (400 M H z , C D C 1 ) : 1.98 (2H, m), 2.80 ( I H , t, J= 8.4 H z ) , 3.72 (2H, m), 3.88 (2H, m), 4.40 (4H, s), 7.08-7.17 (10 H , m), 7.89 (2H, d J = 8.2 H z ) , 7.99 (2H, d,J= 8.2 Hz) 2  2  E t h y l z i n c iodide (83) To a solution o f iodine (2.87 g, 11.3 mmol, 3.0 eq) in dichloromethane (10 m L ) at 0 °C was added ether (2.4 m L , 22.6 mmol, 6.0 eq.) and diethyl zinc (1.2 m L , 11.3 mmol, 3.0  201  eq) slowly. The ice bath was removed and the reaction mixture stirred for 10 m i n before being used.  '  . '  Cyclopropylzinc (84)  ZnR  BnO To a solution o f the dibenzyl ether 82 (1.00 g, 3.75 mmol, 1.0 eq.) i n dry C H C 1 (8 m L ) 2  2  at 0 °C was first added the E t Z n l solution (83) (13 m L , 11.3 m m o l , 3.0 eq), then a solution o f iodoform (2.21 g, 5.62 mmol, Aldrich) i n C H C 1 (25 m L ) by cannula. The ice 2  2  bath was removed and the reaction mixture was stirred until T L C analysis showed the complete consumption o f starting material.  cis, cj's-2,3,-Bis(benzyloxymethyl)cyclopropyl 4-carboxyphenyl methanone (85)  94  O  A solution o f compound 84 i n C H C 1 was evaporated to dryness under vacuum and T H F 2  2  (10 m L ) was added to the residue. This solution was cooled to -78 °C and freshly prepared C u C N - 2 L i C l ( C u C N : 1.01 g, 11.3 mmol, Aldrich; L i C l : 0.953 g, 22.5 mmol, Aldrich) in T H F (35 m L ) at -30 °C was added by cannula. The resulting mixture was 202  allowed to slowly warm to 0 °C over 2 h, and then cooled to - 7 8 °C. To this was added a solution o f terephthaloyl chloride (3.81 g, 18.8 mmol, 5.0 eq.) in T H F (60 m L , slowly cool the solution to - 7 8 °C while adding) by cannula. The reaction was allowed to warm to room temperature slowly over 3 h. The reaction vessel was then cooled to 0 °C, and 10 m L o f water was added. The ice bath was removed and the reaction stirred for 30 min. The resulting biphasic solution was filtered on a flash column and eluted with 50% EtOAc/pet ether. The filtrate was concentrated and the residue was chromatographed on silica gel and eluted with 10-50 % EtOAc/pet ether. The solvent was removed in vacuo. Recrystalhzation from E t O Ac/pet ether gave 571 mg (35%) o f fine white needles. mp 130-132 °C (EtOAc/pet ether) ' H N M R (400 M H z , C D C 1 ) 5 1.98 (2H, m), 2.80 (1H, t, J= 8.4 H z ) , 3.72 (2H, m), 3.88 (2H, m), 4.40 (4H, s), 7.08-7.17 (10 H , m), 7.89 (2H, d 7 = 8.2 H z ) , 7.99 (2H, d,J = 8.2 Hz) 2  2  C N M R (75 M H z , C D C 1 ) 5 198.67, 170.32, 143.78, 139.01, 132.92, 130.66, 128.74, 128.46, 128.20, 128.01, 73.40, 65.04, 27.55, 25.72  1 3  2  2  I R ( K B r pellet): 2859, 1686, 1664, 1411, 1288, 1212, 1114, 1006, 730, 696 cm"  1  L R M S (ESI) m/z ( M + l ) : 431, 323 +  H R M S (ESI) m/z ( M + l ) : Calculated mass for C +  2 7  H  2 7  N 0 = 431.1859, found: 431.1857 5  A n a l . C a l c d . : C , 75.33; H , 6.09. Found: C , 75.48; H , 6.24.  cis,  ci's-2,3,-Bis(benzyIoxymethyI)cyclopropyl 4-carbomethoxyphenyl  (86) O OMe  203  methanone  A solution o f acid 85 (150 mg, 0.35 mmol) i n 10 m L o f methanol was treated with ethereal diazomethane until a permanent yellow colour was observed. The solution was concentrated in vacuo and the resulting residue was purified by radial chromatography (35 % ether/pet ether). Recrystallization from hexanes afforded 118 m g (76%) o f fine needles. m p 67-68 °C (hexanes) H N M R (300 M H z , C D C N ) § 1.93 (2H, m), 2.96 ( I H , t, J= 8.6 H z ) , 3.77 (2H, m), 3.89 (5H, m), 4.40 (4H, dd, J= 11.8 H z , 16.5 H z ) , 7.16-7.26 (10 H , m), 7.98-8.06 (4H, ddJ = 8.7 H z , 16.1 H z ) !  3  C N M R (75 M H z , C D C N ) 5 199.11, 167.02, 143.45, 139.78, 134.43, 130.30, 129.24, 129.00, 128.51, 128.28, 73.31, 73.14, 65.25, 53.03, 27.64, 25.89  1 3  3  I R ( K B r pellet): 2863, 1718, 1663, 1279, 1110, 1010, 728, 698 cm"  1  L R M S (ESI) m/z ( M + l ) : 445, 337 +  H R M S (ESI) m/z ( M + l ) : Calculated mass for +  C28H29O5  = 445.2015, found: 445.2011.  A n a l . C a l c d . : C , 75.65; H , 6.35. Found: C , 75.71; H , 6.42  Habit  colourless platelet  Space group  P2i/n 17.271(2) 5.7140(5) 23.476(3) 90 98.234(5)  Y(°)  90  Z  4 0.062  204  (^)-(+)-l-Phenylethylamine salt (87) O  To a solution o f 19 mg (0.16 mmol) o f (7?)-(+)-l-phenylethylamine i n 1 m L o f diethyl ether was added a solution o f 70 mg (0.16 mmol) o f acid 85 in 3 m L o f methanol. The solution was allowed to stand overnight, and the solvent was removed in vacuo. The solid residue was suspended in Et20, filtered and washed with Et20. Recrystallization from methanol gave 75 mg (85 %) o f thin white plates. mp 126-128 °C ( M e O H ) ' H N M R (300 M H z , C D O D ) 5 1.58-1.60 (3H, d J= 7.0 H z ) , 2.02 (2H, m), 3.04 ( I H , t,J = 8.6 H z ) , 3.80-3.94 (4H, m), 4.40 (5H, m), 7.18-7.42 (15 H , m), 7.96-7.98 ( 4 H , ' d d / = 8.3, 19.0 H z ) 3  C N M R (75 M H z , C D O D ) 5 200.56, 174.02, 141.78, 140.33, 139.62, 130.31, 130.12, 129.34, 128.87, 128.67, 128.62, 127.56, 73.91, 65.72, 52.33, 27.67, 26.00, 21.04  1 3  3  I R ( K B r pellet): 2853, 1665, 1586, 1396, 1076, 736, 699 c m  -1  L R M S (LSLMS) m/z ( M + l ) : 552, 453, 323, 122, 105, 91. +  H R M S (LSLMS) m/z ( M + l ) : Calculated mass for C 552.27488. +  3 5  H  3 8  N0  5  = 552.27500, found:  A n a l . C a l c d . : C , 76.20; H , 6.76; N , 2.54. Found: C , 76.18; H , 6.84; N , 2.44  205  ( S M - ) - l - P h e n y l e t h y l a m i n e salt (88)  To a solution o f 16 mg (0.13 mmol) o f (S)-(-)-l-phenylethylamine in 2 m L o f diethyl ether was added a solution o f 55 mg (0.13 mmol) o f acid 85 in 2 m L o f methanol. The solution was allowed to stand overnight, and the solvent removed in vacuo. The solid residue was suspended i n E t 0 , filtered and washed with Et20.Recrystallization from 2  methanol gave 51 m g (71 %) o f thin white plates m p 126-128 °C ( M e O H ) H N M R (300 M H z , C D O D ) 8 1.58-1.60 (3H, dJ= 7.0 H z ) , 2.02 (2H, m), 3.04 (1H, t, J = 8.6 H z ) , 3.80-3.94 (4H, m), 4.40 (5H, m), 7.18-7.42 (15 H , m), 7.96-7.98 (4H, dd J = 8.3, 19.0 H z ) !  3  C N M R (75 M H z , C D O D ) 8 200.56, 174.02, 141.78, 140.33, 139.62, 130.31, 130.12, 129.34, 128.87, 128.67, 128.62, 127.56, 73.91, 65.72, 52.33, 27.67, 26.00, 21.04  1 3  3  I R ( K B r pellet): 2853, 1665, 1586, 1396, 1076, 736, 699 cm"  1  L R M S ( L S I M S ) m/z ( M + l ) : 552, 453, 323, 122, 105, 91. +  A n a l . C a l c d . : C , 76.20; H , 6.76; N , 2.54. Found: C , 76.18; H , 6.84; N , 2.44  206  (IR, 25)-(+)-c/s-l-Amino-2-indanol salt (89)  O  To a solution o f 24 mg (0.16 mmol) o f (IR, 2S)-(+)-cj's-l-amino-2-indanol in 8 m L o f diethyl ether was added a solution o f 70 mg (0.16 mmol) o f acid 85 i n 3 m L o f methanol. The solution was allowed to stand overnight, and the solvent removed in vacuo. The solid residue was suspended in Et20, filtered and washed with Et20. Recrystallization from acetonitrile gave 64 mg (68 %) o f fine white plates.  mp 139-141 °C ( M e C N ) H N M R (400 M H z , C D O D ) 5 2.05 (2H, m), 2.90-3.10 (2H, m), 3.21 ( I H , m), 3.76 (2H, m), 3.93 (2H, m). 4.40 (4H, S), 4.52 ( I H , d J= 5.8 H z ) , 4.68 ( I H , m), 7.15-7.46 (15H, m), 7.92-8.05 (4H, dd J= 11.2 H z , J= 8.4 H z ) . !  3  C N M R (75 M H z , C D O D ) 5 200.62, 174.51, 142.76, 141.92, 139.63, 130.81, 130.30, 129.27, 128.85, 128.70, 128.69, 128.42, 126.67, 126.11, 73.91, 72.08, 65.74, 58.75, 40.12,27.67,26.07 1 3  3  I R ( K B r pellet): 3410, 2857, 1665, 1585, 1542, 1389, 1209, 1075, 739, 697 c m  -1  L R M S (ESI) m/z ( M + l ) : 580, 453, 323, 150. +  H R M S (ESI) m/z ( M + l ) : Calculated mass for C H48N0 = 580.2699, found: 580.2712 +  36  6  A n a l . C a l c d . : C , 74.59; H , 6.43; N , 2.42. Found: C , 74.65; H , 6.61; N , 2.39  207  (5>(-)-2-(Diphenylhydroxymethyl)pyrrolidine salt (90)  O  To a solution o f 29 mg (0.12 mmol) o f (5)-(-)-2-(diphenylhydroxymethyl)pyrrolidine in 3 m L o f methanol was added a solution o f 50 mg (0.12 mmol) o f acid 85 i n 3 m L o f methanol. The solution was allowed to stand overnight, and the solvent removed in vacuo. The solid residue was suspended i n Et20, filtered and washed with Et20. Recrystalhzation from M e O H gave 53 mg (68 %) o f fine white powder.  mp 183-185 °C ( M e O H ) *H N M R (300 M H z , C D O D ) 5 1.95-2.11 (6H, m), 3.05 (1H, t, 8.6 H z ) , 3.12-3.28 (2H, m), 3.72-4.00 (4H, m), 4.81 (1H, m), 4.42 (4H, s), 7.09-7.32 (16H, m), 7.17-7.39 (15 H , m), 7.48 (2H, m), 7.58 (2H, m), 7.92-8.05 (4 H , dd J= 14.5 H z , 7 = 8.5 H z ) . 3  C N M R (75 M H z , C D O D ) 5 200.58, 174.41, 145.83, 145.56, 141.78, 139.61, 130.27, 129.78, 129.54, 129.28, 128.86, 128.61, 126.90, 126.74, 125.43, 78.38, 73.89, 68.01, 65.71, 47.93, 27.65, 27.19, 26.01, 25.52 1 3  3  IR ( K B r pellet): 3540, 3013, 1672, 1635, 1585, 1544, 1387, 1075, 750, 697 cm"  1  H R M S ( L S M S ) m/z ( M + l ) : Calculated mass for C44H46NO6 = 684.33251, found: 684.33243 +  Anal. Calcd.: C , 77.28; H , 6.63; N , 2.05. Found: C , 76.92; H , 6.75; N , 2.07.  208  (/?)-(-)-!-Cyclohexylethylamine salt (91)  O  o  +  H  O.  O H  H  H  o  To a solution o f 20 mg (0.16 mmol) o f (R)-(-)- 1-cyclohexylethylamine i n 5 m L o f diethyl ether was added a solution o f 70 mg (0.16 mmol) o f acid 85 i n 3 m L o f methanol. The solution was allowed to stand overnight, and the solvent removed in vacuo. The solid residue was suspended i n Et20, filtered and washed with Et20. Recrystallization from methanol gave 70 mg (78 %) o f fine white needles. mp 130-132 °C ( M e O H ) ' H (400 M H z , C D O D ) 5 1.02-1.38 (8H, m), 1.52 ( I H , m), 1.72-1.88 (5H, m), 2.09 (2H, m), 3.02-3.08 (2H, m), 3.78-3.99 (4H, m), 4.41 (4H, s), 7.12-7.35 (10 H , m), 8.00 (4H, dd, J = 8 . 5 H z , 10 H z ) 3  C (75 M H z , CD3OD) 5 200.62, 174.13, 143.04, 141.74, 139.64, 130.24, 129.31, 128.89, 128.70, 128.62, 73.91, 65.78, 53.42, 42.78, 30.02, 28.85, 27.67, 27.10, 27.02, 26.95, 26.04, 16.07 1 3  I R ( K B r pellet): 2922, 1664, 1585, 1539, 1372, 1095, 732 c m  -1  L R M S (LSLMS) m/z ( M + l ) : 558, 453, 323, 128, 91 +  H R M S (LSLMS) m/z ( M + l ) : Calculated mass for C35H44NO5 = 558.32195, found: 558.32209. +  A n a l . C a l c d . : C , 75.37; H , 7.77; N , 2.51. Found: C , 74.98; H , 7.62; N , 2.48.  209  (l?)-(+)-Bornylamine salt (92)  O  To a solution o f 25 m g (0.16 mmol) o f (i?)-(+)-bornylamine i n 5 m L o f diethyl ether was added a solution o f 70 m g (0.16 mmol) o f acid 85 in 3 m L o f methanol. The solution was allowed to stand overnight, and the solvent was removed in vacuo. The solid residue was suspended i n Et20, filtered and washed with Et20. Recrystallization from methanol gave 72 m g (77 %) o f thin white needles.  mp 134-136 °C ( M e O H ) H N M R (300 M H z , C D O D ) : 5 0.92 (3 H , s), 0.94 (3 H , s), 0.95 (3 H , s), 1.12 ( I H , dd J = 13.5 H z , J= 4.4 H z ) , 13.1 ( I H , m), 1.54 (2H, t J= 7.5 H z ) , 1.75 ( I H , tJ= 14.5 H z ) , 1.89 ( I H , m), 2.05 (2H, m), 2.27-2.36 ( I H , m), 3.06 ( I H , t, 8.2 H z ) , 3.23 ( I H , dd J= 2.6, J= 12.2 H z ) , 3.78-3.99 (4 H , m), 4.42 (4H, s), 7.16-7.24 (10 H , m), 7.95-8.05 (4H, dd, J = 15.2 H z , J= 8.6 H z ) . ]  3  C N M R (75 M H z , C D O D ) 5 200.60, 174.04, 142.93, 141.74, 139.62, 130.24, 129.29, 128.86, 128.69, 128.60, 73.90, 65.74, 57.98, 50.08, 45.85, 35.60, 28.56, 27.95, 27.64, 26.0, 19.84, 18.72, 13.32. 1 3  3  I R ( K B r pellet): 2954, 1672, 1528, 1398, 1097, 741, 697 c m  -1  L R M S (LSLMS) m/z ( M + l ) : 584, 323, 154, 137, 91, 81. +  H R M S (LSLMS) m/z ( M + l ) : Calculated mass for C 7 H N 0 584.33789. +  3  4 6  5  = 584.33760, found:  A n a l . C a l c d . : C , 76.13; H , 7.77; N , 2.40. Found: C , 76.08; H , 8.02; N , 2.32.  210  (15, 2J?)-(+)-Norephedrine salt (93) O +  o H  O.  O H  H  H  o  To a solution o f 25 mg (0.16 mmol) o f (IS, 2i?)-(+)-norephedrine in 10 m L o f diethyl ether was added a solution o f 70 mg (0.16 mmol) o f acid 85 in 3 m L o f methanol. The solution was allowed to stand overnight, and the solvent was removed in vacuo. The solid residue was suspended i n E t 0 , filtered and washed with Et20. Recrystalhzation from a 2  solution o f methanol and acetonitrile gave 74 mg (78 %) o f thin white plates. mp 122-124 °C ( M e O H / M e C N ) H N M R (400 M H z , C D O D ) 5 1.03 (3H, d, J= 6.8 H z ) , 2.05 (2H, m), 3.07 (1H, t, J = 8.6 H z ) , 3.46 (1H, m), 3.78-3.96 (4H, m), 4.42 (4H, s), 4.91 (1H, d, J= 6.2 H z ) , 7.177.39 (15 H , m), 7.95 (4H, dd) !  3  C N M R (75 M H z , C D O D ) 5 207.65, 178.41, 151.38, 149.00, 148.01, 138.50, 137.56, 137.50, 136.80, 136.75, 136.48, 135.44, 81.47, 81.23, 73.53, 61.30, 35.47, 33.77, 21.93.  1 3  3  I R ( K B r pellet): 3609, 2873, 1663, 1625, 1532, 1374, 1090, 1052, 748, 730 cm"  1  L R M S (LSLMS) m/z ( M + l ) : 582, 323, 152, 134, 91. +  H R M S (LSLMS) m/z ( M + l ) Calculated mass for C H o N 0 6 = 582.28556. Found: 582.28543. +  :  3 6  4  A n a l . C a l c d . : C , 74.33; H , 6.76; N , 2.41. Found: C , 74.09; H , 6.70; N , 2.38.  211  (IR, 2S)-(-)-Norephedrine salt (94) O  To a solution o f 19 mg (0.13 mmol) o f (IR, 2,S)-(-)-norephedrine i n 8 m L o f diethyl ether was added a solution o f 55 mg (0.13 mmol) o f acid 85 i n 3 m L o f methanol. The solution was allowed to stand overnight, and the solvent was removed in vacuo. The solid residue was suspended in Et20, filtered and washed with Et20. Recrystalhzation from a solution of methanol and acetonitrile gave 53 mg (72 %) o f thin white plates. mp 122-124 °C ( M e O H / M e C N ) * H N M R (400 M H z , C D O D ) 5 1.03 (3H, d, J= 6.8 H z ) , 2.05 (2H, m), 3.07 (1H, t,J = 8.6 H z ) , 3.46 (1H, m), 3.78-3.96 (4H, m), 4.42 (4H, s), 4.91 (1H, d, J = 6.2 H z ) , 7.177.39 (15 H , m), 7.95 (4H, dd, J= 8.5 H z , J= 17.0 H z ) 3  C N M R (75 M H z , C D O D ) 5 207.65, 178.41, 151.38, 149.00, 148.01, 138.50, 137.56, 137.50, 136.80, 136.75, 136.48, 135.44, 81.47, 81.23, 73.53, 61.30, 35.47, 33.77, 21.93.  1 3  3  I R ( K B r pellet): 3609, 2873, 1663, 1625, 1532, 1374, 1090, 1052, 748, 730 cm" L R M S ( L S I M S ) m/z ( M + l ) : 582, 323, 152, 134, 91. +  A n a l . C a l c d . : C , 74.33; H , 6.76; N , 2.41. Found: C , 74.20; H , 6.82; N , 2.48.  212  1  (11?, 21?)-(-)-2-Amino-l-phenyl-l,3-propanediol salt (95) O  To a solution o f 22 mg (0.13 mmol) o f (IR, 2i?)-(-)-2-amino-l-phenyl-l,3-propanediol in 8 m L o f diethyl ether was added a solution o f 55 mg (0.13 mmol) o f acid 85 in 3 m L o f methanol. The solution was allowed to stand overnight, and the solvent was removed in vacuo. The solid residue was suspended i n Et20, filtered and washed with Et20. Recrystallization from a solution o f methanol and acetonitrile gave 58 m g (76 %) o f fine white plates. m p 109-111 °C ( M e O H / M e C N ) ' H N M R (300 M H z , C D O D ) 5 1.98 (2H, m), 30.5 ( I H , t,J= 8.5 H z ) , 3.43 ( I H , dd, J = 6.1, 11.8 H z ) , 3.58 ( I H , dd, J= 4.4, 11.8 H z ) , 3.80-4.01 (4H, m), 4.42 (4H, s), 5.72 ( I H , d, J= 8.6 H z ) , 7.21-7.53 (15, H ) , 7.93-8.01 (4H, dd, J= 8.5 H z , 17.0 H z ) . 3  C N M R (75 M H z , C D O D ) 5 200.60, 173.91, 142.17, 141.80, 139.61, 130.26, 129.77, 129.56, 129.29, 128.56, 128.70, 128.61, 127.89, 73.90, 72.41, 65.72, 60.29, 60.05, 27.65, 26.02 1 3  3  I R ( K B r pellet): 2857, 1664, 1585, 1519, 1382, 1208, 1073, 698 c m  -1  ' L R M S (LSLMS) m/z ( M + l ) : 598, 431, 323, 169, 91 +  H R M S ( L S I M S ) m/z ( M + l ) : Calculated mass for C H 4 o N 0 598.28086 +  3 6  7  = 598.28048, found:  A n a l . C a l c d . ( C H N 0 ) : C , 72.34; H , 6.58; N , 2.34. Found: C , 72.18; H , 6.70; N , 2.38. 3 6  3 9  7  213  L - P r o l i n a m i d e salt (96) O  To a solution o f 20 mg (0.17 mmol) o f L-prolinamide in 3 m L o f methanol was added a solution o f 75 mg (0.17 mmol) o f acid 85 in 3 m L o f methanol. The solvent was removed in vacuo, and gave a colorless o i l . To this was added 8 m L o f pet ether and the resulting solution was allowed to evaporate to give 47 mg (49 %) o f fine white neddles. mp 114-116°C (pet ether) H N M R (300 M H z , C D O D ) 6 1.96-2.06 (5H, m), 2.36 ( I H , m), 3.00 ( I H , t / = 8.6 H z ) , 3.10-3.24 (2H, m), 3.76-3.97 (4H, m), 4.16 ( I H , m), 4.40 (4H, s), 7.15-7.24 (10H, m), 7.93-8.01 (4H, dd, 8.5 H z , 17.0 H z ) !  3  C N M R (75 M H z , C D O D ) 8 200.54, 174.52, 168.58, 142.00, 139.61, 130.30, 129.28, 128.86, 128.75, 128.61, 73.89, 65.71, 60.95, 47.34, 31.27, 27.68, 26.03, 25.42.  1 3  3  I R ( K B r pellet): 3320, 2939, 1673, 1594, 1554, 1372, 1211, 1074, 734, 698 cm"  1  L R M S ( L S I M S ) m/z ( M + l ) : 545, 323, 122, 105, 91. +  H R M S (LSLMS) m/z ( M + l ) : Calculated mass for C 545.26516. +  3 2  H  3 7  N 0 2  6  = 545.26520, found:  A n a l . C a l c d . : C , 70.57; H , 6.60; N , 5.14. Found: C , 70.19; H , 6.84; N , 5.44.  214  (i?)-(+)-2-PhenyIpropylamine salt (97) O  To a solution o f 22 mg (0.16 mmol) o f (i?)-(+)-2-phenylpropylamine i n 3 m L o f diethyl ether was added a solution o f 70 mg (0.16 mmol) o f acid 85 i n 3 m L o f methanol. The solvent was removed in vacuo, and gave a white solid residue. Recrystalhzation from a solution o f diethyl ether and methanol gave 49 mg (53 %) o f white powder, mp 108-109 °C ( E t 0 / M e O H ) 2  *H N M R (300 M H z , C D O D ) 6 1.32 (3H, d J = 6.5 H z ) , 2.02 ( 2 H , m), 3.02-3.10 (4H, m), 3.78-3.97 (4H, m), 4.41 (4H, s), 7.15-7.35 (15H, m), 7.93-8.03 (4H, ddJ= 8.3, 17.5 Hz) 3  C N M R (75 M H z , C D O D ) 5 200.58, 174.41, 143.40, 141.78, 139.62, 130.23, 130.16, 129.29, 128.85, 128.72, 128.60, 128.54, 128.23, 73.89, 65.73, 46.90, 39.83, 27.67, 26.03, 19.91  1 3  3  I R ( K B r pellet): 2866, 1671, 1619, 1583, 1524, 1453, 1394, 1208, 1107, 736, 698 cm"  1  L R M S (ESI) m/z ( M + l ) : 566, 453, 323. +  H R M S (ESI) m/z ( M + l ) : Calculated mass for C36H40NO5 = 566.2907, found: 566.2909. +  A n a l . C a l c d . : C , 76.43; H , 6.95; N , 2.48. Found: C , 76.28; H , 6.89; N , 2.49.  215  4.6 Synthesis of 9-(tricyclo [4.4.1.0]undecyl) 4-carboxylphenyl methanone derivatives A ' - O c t a l i n (98) 9  10  A procedure o f Benkese et a / .  118  was employed. Naphthalene (12.8 g, 0.100 mole) was  dissolved i n a mixture o f 125 m L o f anhydrous ethylamine and 125 m L o f anhydrous dimethyamine in a 500 m L three-necked flask fitted with a dry ice condenser and cooled in an ice bath. To this solution was added, piecewise, 5.75 g. (1.674 g-atoms) o f lithium wire (0.5 cm lengths). After the addition was complete, the cooling bath was removed and the blue solution was stirred for 14 h. The dry ice condenser was replaced by a water condenser and the mixture was allowed to stand overnight, during which time the volatile amine solvents evaporate. The top o f the condenser was protected with an anhydrous calcium sulfate drying tube, maintaining anhydrous conditions in the reaction vessel during the evaporation o f solvent. The reaction flask was placed i n an ice bath and the white residue was hydrolyzed by dropwise addition o f 300 m L o f water, with occasional stirring. After the resulting suspension had been filtered with suction, the residual solid was washed with four 25 m L portions o f diethyl ether. The ether layer was separated, and the aqueous phase o f the filtrate was extracted with four additional 25 m L portions o f ether. The combined ethereal solutions were dried over calcium sulfate and concentrated in vacuo. The residual liquid was distilled under reduced pressure, separating 10.3 g (76%) o f colorless o i l , b.p. 7 2 - 7 7 ° (14 mm). Analysis o f this product by G C M S shows the presence o f two kinds o f octalin in a ratio o f 84:16. According to previous report, the major component is the desired product, A ' - o c t a l i n , while the minor one is A ^ - o c t a l i n . 9  l0  This mixture was used without further purification.  216  E t h y l tricyclo[4.4.1.0]undecyl-9-carboxylate (99)  OEt  A solution o f A  9,10  - o c t a l i n (98) (1.0 g, 7.4 mmol) and ethyl diazoacetate  114  (3.35 g, 29.5  mmol) in 25 m L o f freshly distilled dichloromethane was cooled to - 7 0 °C under nitrogen. Tris(2,4-dibromophenyl)aminium hexachlorantimonate  105  (3.11 g, 2.96 mmol)  was added in small portions, and the mixture was allowed to warm to 0 °C. The solution was quenched  by adding 5 m L o f 10 % sodium methoxide  i n methanol. M o r e  dichloromethane was added to dissolve the products and the organic layer was washed with water and brine. The solution was dried and then concentrated. The yellow residual oil was chromatographed on silica gel (0-5 % diethyl ether i n pet ether) to give 920 mg (56 %) o f a colorless o i l with a pleasant smell.  H N M R (400 M H z , CDCI3): 5 1.23-1.47 (14 H , m), 1.61 (2H, m), 1.84 (2 H , m), 1.94 (2H, m), 4.05 (2H, q, J= 7.1 H z ) J  C N M R ( A P T , 75 M H z , CDCI3): 5 172.3 (+), 59.6 (+), 33.2 (+), 31.5 (-), 28.4 (+),27.5 (+),21.4 (+), 20.5 (+), 14.4 (-) 1 3  H R M S (EI) m/z ( M ) : 222, 177, 148, 134 +  H R M S (EI) m/z ( M ) : calculated mass for C14H22O2: 222.16198, found: 222.16214 +  I R : (neat) 2929, 1727, 1453, 1158, 1050 c m . -1  217  A mixture o f ester 99 (1.5 g, 6.8 mmol), sodium hydroxide (1.08 g, 27.0 mmol), ethanol (15 m L ) , and water (60 m L ) was reflux ed with stirring for 24 h. The mixture was then cooled, extracted with ether, acidified, and again extracted with ether. The solvent was removed in vacuo, and the residue was recrystallized from ether/pet ether to give 1.2 g (88%) o f colorless prisms. mp 146-147 °C (Et 0/pet ether). 2  H N M R (400 M H z , CDCI3): 5 1.25-1.32 (6H, m), 1.39-1.51 (5H, m), 1.63 (2H, m), 1.84 (2H, m), 1.97 ( 2 H , m ) ; !  1 3  C N M R (75 M H z , CDCI3): 5 178.8, 33.1, 31.4, 30.2, 27.2, 21.4, 20.3  I R ( K B r pellet): 2931, 1687, 1453, 1317, 1231, 1185,934,719, 642 cm" . 1  L R M S : (CI, N H ) m/z ( M + 1): 195, 177, 149, 135 +  3  H R M S : (CI, N H ) m/z ( M + 1) calculated mass for 195.13847. +  3  C12H19O2  = 195.13851, found:  A n a l . C a l c d . C , 74.19; H , 9.34. Found: C , 74.35; H , 9.52.  Tricyclo[4.4.1.0] undecyl-9-(/V-methyl-/V-hydroxylmethyl) amide (101)  MeO  N  Me  218  A solution o f acid 100 (1.15 g, 5.94 mmol) in 30 m L of dichloromethane was cooled to 0 °C and treated with l,l'-carbonyldiimidazole (Aldrich, 1.15 g, 7.11 mmol), and the solution was stirred for 30 min. N , O-dimethylhydroxylamine hydrochloride (Aldrich, 1.45 g, 14.8 mmol) was then added and the mixture was allowed to warm to room temperature, stirred for 24 h, and filtered. The residue was washed with ether. The filtrate was washed with I M HC1, water (x2), and brine. The organic layer was then dried and concentrated to give 1.32 g (93%) of a colorless residual o i l . The compound was used without any further purification. ' H N M R (400 M H z , CDCI3): 5 1.15-1.48 (11H, m), 1.58-1.69 (2H, m), 1.78-1.84 (2H, m), 1.95-2.03 (2H, m), 3.18 (3H, s), 3.67 (3H, s) 1 3  C N M R (75 M H z , CDC1 ) § 173.8, 61.1, 36.1, 33.4, 30.1, 28.6, 26.5, 21.5, 20.9 3  IR(neat) 2927, 1662, 1451, 1178, 1111, 1024, 976, 845 cm" ; 1  L R M S (CI, N H ) mlz ( M + 1): 238, 208, 177 +  3  H R M S (CI, N H ) mlz ( M + 1): calculated mass for C i H N O = 238.18070, found: 238.18079. +  3  2  2 4  9-(Tricyclo[4.4.1.0]undecyl) 4-carboxylphenyl methanone (102)  A solution of 4-iodobenzoic acid (Aldrich, 1.5 g, 6.07 mmol) i n 50 m L o f anhydrous T H F was cooled to - 4 0 °C. Isopropyl magnesium chloride (2.0 M in T H F , Aldrich, 6.70 m L , 13.3 mmol) was added, and the resulting solution was stirred for 1.5 h. A m i d e 101 (1.20 g, 5.06 mmol) was then added and the reaction mixture was stirred overnight. The  219  reaction was quenched by adding 20 m L o f 1 M HC1. The mixture was extracted with ether twice, and the combined organic layer was washed with 10% N a O H . The aqueous phase was acidified, and extracted with ether again. The organic phase was then washed with  water  and brine, dried over M g S 0 4 ,  filtered, and concentrated  in vacuo.  Recrystallization from ether/ pet ether gave 1.09 g (60 %) o f small white needles. mp 192-194 °C ( E t 0 / pet ether). 2  H N M R (400 M H z , C D C 1 ) 8 1.33-1.65 (10H, m), 1.77 (2H, m), 1.98-2.03 (4H, m), 2.12 ( I H , s), 7.95 (2H, d, J = 8.5 H z ) , 8.16 (2H, d, J= 8.5 H z ) !  3  C N M R (75 M H z , CDCI3) 5 200.0, 171.0, 143.8, 132.2, 130.4, 127.8, 37.4, 33.6, 31.9, 28.2,21.5,20.8 1 3  L R M S (CI, N H ) m/z ( M + 1): 299, 255, 135 +  3  H R M S (CI, N H ) m/z ( M + 1) calculated mass for 299.16548 +  3  C19H23O3:  299.16472, found:  IR: ( K B r pellet) 2936, 1693, 1668, 1607, 1570, 1289, 1218, 802, 769, 555 cm" . 1  Anal Cald.: C , 76.48; H , 7.43. Found: C , 76.18; H , 7.32.  9-(Tricyclo-[4.4.1.0]-undecyl) 4-carbomethoxylphenyl methanone (103)  MeO^ / O  A solution o f methyl 4-iodobenzoate (250 mg, 1.0 mmol) i n 8 m L o f anhydrous T H F was cooled to - 4 0 ° C . Isopropyl magnesium chloride (2.0 M i n T H F , A l d r i c h , 550 u L , 1.1 mmol,) was added, and the resulting solution was stirred for 1.5 h. A m i d e 101 (200 mg, 0.84 mmol) was then added and the reaction mixture was stirred for 6 h at - 2 0 °C. The reaction was quenched and worked up as a standard Grignard reaction. The white residue  220  was chromatographed on silica gel (10 % ether in pet ether). Recrystallization from hexane gave 160 mg (61 %) o f colorless prisms. mp 68-69 °C (hexanes). H NMR (400 M H z , C D C 1 ) 5 1.28-1.49 (l'OH, m), 1.97 (4H, m), 2.11 ( I H , s), 3.93 (3H, s), 7.92 (2H, d, J= 8.7 H z ) , 8.10 (2H, d, J= 8.7 H z ) !  3  C NMR (75 M H z , CDCI3) 5 199.95, 166.42, 143.00, 133.08, 129.73, 129.47, 52.34, 37.23,33.61,31.61,28.17,21.53,20.82 1 3  LRMS: (ESI) m/z ( M + 1): 313 +  HRMS: (ESI) m/z ( M + 1) calculated mass for C20H25O3: 313.1804, found 313.1810 +  IR ( K B r pellet) 2927, 1720, 1666, 1445, 1278, 1224, 1109, 742 c m . -1  Anal Calcd. C , 76.89; H , 7.74. Found: C , 76.97; H , 7.60.  Habit  colourless block  Space group  P2]/n 6.211(5) 14.2393(1) 18.531(2) 90 97.478(5)  Y(°)  90  Z  4 0.046  221  (IS,  25)-(+)-Pseudoephedrine  Salt (104)  To a solution o f 42 mg (0.25 mmol) o f (IS, 25)-(+)-pseudoephedrine in 2 m L o f methanol was added a solution o f 75 mg (0.25 mmol) o f acid 102 in 8 m L o f diethyl ether. Slow evaporation o f solvent gave a sticky oil. To this was added 8 m L o f pet ether and the resulting solution was allowed to evaporate to give 93 mg (80 %) o f thin white plates. mp 176-178 °C (pet ether). H N M R (400 M H z , C D O D ) 5 1.05 (2H, d,J= 6.7 H z ) , 1.28- 1.49 (10H, m), 1.75 (2H, m), 1.85-2.05 (4H, m), 2.18 (1H, s), 2.67 (3H, s), 4.40 (1H, d, J= 9.1 H z ) , 7.32-7.49 (5H, m), 7.81 ( 2 H , d, J= 8.2 H z ) 8.05 (2H, d, J= 8.2 H z ) J  3  C N M R (75 M H z , C D O D ) 5 202.30, 174.19, 142.93, 142.01, 130.33, 129.80, 129.71, 128.64, 128.44, 128.18, 75.74, 61.75, 38.23, 34.77, 31.78, 30.56, 29.53, 22.56, 22.05, 12.75  1 3  3  L R M S (ESI) mlz ( M + 1): 464, 331, 299, 166 +  H R M S (ESI) mlz ( M + 1) calculated mass for C 2 H N 0 : 464.2801, found: 464.2793 +  9  3 8  4  I R ( K B r Pellet), 2933, 1665, 1592, 1552, 1493, 1376 cm" . 1  A n a l . C a l c d . C , 75.13; H , 8.04; N , 3.02. Found: C , 74.97; H , 8.33; N , 3.12.  222  To a solution o f 28 mg (0.17 mmol) o f (IR, 2 K)-(-)-pseudoephedrine 1 m L o f methanol J  was added a solution o f 50 mg (0.17 mmol) o f acid 102 i n 8 m L o f diethyl ether. Slow evaporation o f solvent gave a sticky o i l . To this was added 8 m L o f pet ether and the resulting solution was allowed to evaporate to give 57 mg (73 %) o f thin white plates.  mp 176-178 °C (pet ether). H NMR (400 M H z , C D O D ) 5 1.05 (2H, d, J= 6.7 H z ) , 1.28-1.49 (10H, m), 1.75 (2H, m), 1.85-2.05 (4H, m), 2.18 ( I H , s), 2.67 (3H, s), 4.40 ( I H , d,J = 9.1 H z ) , 7.32-7.49 (5H, m), 7.81 (2H, d, J= 8.2 H z ) 8.05 (2H, d,J= 8.2 H z ) ]  3  C NMR (75 M H z , C D O D ) 5 202.30, 174.19, 142.93, 142.01, 130.33, 129.80, 129.71, 128.64, 128.44, 128.18, 75.74, 61.75, 38.23, 34.77, 31.78, 30.56, 29.53, 22.56, 22.05, 12.75  1 3  3  LRMS (ESI) m/z (M + 1): 464, 331, 299, 166 +  IR ( K B r Pellet), 2933, 1665, 1592, 1552, 1493, 1376 cm" . 1  Anal. Calcd. C , 75.13; H , 8.04; N , 3.02. Found: C , 75.12; H , 8.24; N , 3.08.  223  (i?)-(-)-l-Cyclohexylethylamine Salt (106):  To a solution o f 32 mg (0.25 mmol) o f (i?)-(-)-l-cyclohexylethylamine i n 1 m L o f diethyl ether was added a solution o f 75 mg (0.25 mmol) o f acid 102 i n 8 m L o f diethyl ether. Slow evaporation o f solvent gave 72 mg (68 %) o f tiny white needles.  mp 196-198 °C ( E t 0 ) 2  H N M R (400 M H z , C D O D ) 5 1.12 (2H, m), 1.33-1.72 (16H, m), 1.73-1.81 (7H, m), 1.85-20.3 (4H, m), 2.13 (1H s), 3.02 (1H, m), 7.85 (2H, d, J= 8.3 H z ) , 8.03 (2H, d, J = 8.3 H z )  !  3  C N M R (75 M H z , C D O D ) 5 200.78, 174.52, 141.55, 140.48, 128.84, 126.96, 53.91, 43.26, 38.74, 35.31, 32.23, 30.53, 30.06, 29.34, 27.60, 27.53, 27.45, 23.10, 22.58, 16.57 , 3  3  L R M S (ESI) mlz ( M + 1): 426, 299 +  H R M S (ESI) mlz ( M + 1): calculated mass for C 7 H o N 0 : 426.3008, found: 426.3003. +  2  4  3  I R ( K B r Pellet), 2927, 1666, 1637, 1582, 1535, 1373 cm" . 1  A n a l . C a l c d . C , 76.20; H , 9.24; N , 3.29. Found: C , 75.90; H , 9.18; N , 3.22.  224  (5)-(-)-l-(4-Methylphenyl)ethylamine (107)  To a solution o f 34 mg (0.25 mmol) o f (.S)-(-)-l-(4-methylphenyl)ethylamine in 1 m L o f methanol was added a solution o f 75mg (0.25 mmol) o f acid 102 in 8 m L o f diethyl ether. Slow evaporation o f solvent gave 80 mg (75 %) o f thin white plates, mp 186-187 °C ( E t 0 / M e O H ) 2  * H N M R (400 M H z , C D O D ) 5 1.33-1.49 (10H, m), 1.60 (2H, d,J= 6.9 H z ) , 1.77 (2 H , m), 1.82-2.01 (4H, m), 2.19 ( I H , s), 2.33 (3H, s), 4.39 ( I H , q,J= 6.9 H z ) , 7.25 (2H, d, J = 8.1 H z ) , 7.32 (2H, d, J= 8.1 H z ) , 7.87 (2H, d, J= 8.4 H z ) , 8.01 (2H, d, J= 8.4 H z ) ; 3  C N M R (75 M H z , C D O D ) 5 202.28, 174.12, 142.83, 142.04, 140.17, 137.04, 130.81, 130.35, 128.45, 127.56, 52.08, 38.25, 34.79, 31.78, 29.54, 22.58, 22.06, 21.15, 20.88  1 3  3  L R M S (ESI) m/z ( M + 1): 434, 299 +  H R M S (ESI) m/z ( M + 1) calculated mass for C H N 0 : 434.2695, found: 434.2699. +  2 8  3 6  3  I R (KBr pellet): 2931, 1667, 1613, 1579, 1519, 1390, 1223, 816, 750 c m . -1  A n a l . C a l c d . C , 77.56; H , 8.14; N 3.23. Found: C , 77.18; H , 8.24; N , 3.15.  225  (!?)-(+)-l-Phenylethylamine (108) O.  o NH  3  A ^  To a solution o f 30 mg (0.25 mmol) o f (i?)-(+)-l-phenylethylamine i n 1 m L o f methanol was added solution o f 75mg (0.25 mmol) o f acid 102 in 8 m L o f diethyl ether. Slow evaporation o f solvent gave 76 mg (72 %) o f small needles, mp 183-184 °C ( E t 0 / M e O H ) . 2  H NMR (300 M H z , C D O D ) 5 1.25-1.45 (9H, m), 1.61 (3H, d J = ,6.9 H z ) , 1.82 (2H, m), 1.91-2.05 (4H, m), 2.20 (1H, S), 4.52 (1H, q, J = 6.9 H z ) , 7.38-7.45 (5H, m), 7.92 (2H, d, J= 8.4 Hz), 8.02 (2H, d, J= 8.4 H z ) J  3  C NMR (75 M H z , C D O D ) 5 202.26, 174.07, 142.78, 142.02, 140.15, 130.33, 130.26, 130.05, 128.50, 127.60, 52.31, 38.23, 34.78, 31.75, 29.54, 22.57, 22.05, 21.97  1 3  3  LRMS (ESI) mlz ( M + 1): 420, 299 +  HRMS (ESI) mlz ( M + 1) calculated mass for C H N 0 : 420.2539, found: 420.2543. +  2 7  3 4  3  IR: ( K B r pellet): 2933, 1673, 1624, 1581, 1525, 1381 cm" . 1  Anal. Calcd. C , 77.29; H , 7.93; N , 3.34. Found: C , 77.00; H , 7.86; N 3.33.  226  (S)-(-)-l-Phenylethylamine Salt (109):  O.  O  To a solution o f 20 mg (0.17 mmol) o f (/S)-(-)-l-phenylethylamine i n 1 m L o f methanol was added a solution o f 50 mg (0.17 mmol) o f acid 102 i n 6 m L o f diethyl ether. Slow evaporation o f solvent gave 49 mg (70 %) o f small needles. mp 183-184 °C ( E t 0 / M e O H ) 2  *H N M R (300 M H z , C D O D ) 81.25-1.45 (9H, m), 1.61 (3H, d, J= 6.9 H z ) , 1.82 (2H, m), 1.91-2.05 (4H, m), 2.20 ( I H , S), 4.52 ( I H , q, J = 6.9 H z ) , 7.38-7.45 (5H, m), 7.92 (2H, d,J= 8.4 Hz), 8.02 (2H, d, J = 8.4 H z ) 3  C N M R (75 M H z , C D O D ) 5 202.26, 174.07, 142.78, 142.02, 140.15, 130.33, 130.26, 130.05, 128.50, 127.60, 52.31, 38.23, 34.78, 31.75, 29.54, 22.57, 22.05, 21.97  , 3  3  L R M S (ESI) m/z ( M + 1): 420, 299 +  H R M S (ESI) m/z ( M + 1) calculated mass for C H N 0 : 420.2539, found: 420.2540. +  2 7  3 4  3  I R : ( K B r pellet): 2933, 1673, 1624, 1581, 1525, 1381 cm" . 1  A n a l . C a l c d . C , 77.29; H , 7.93; N , 3.34. Found: C , 77.10; H , 8.04; N 3.26.  227  (/?)-(+)-2-Phenylpropylamine (110)  To a solution o f 34 mg (0.25 mmol) o f (i?)-(+)-2-phenylpropylamine i n 1 m L o f methanol was added a solution o f 75mg (0.25 mmol) o f acid 102 i n 8 m L o f diethyl ether. Slow evaporation o f solvent gave 78 mg (72 %) o f white powder. mp 129-131 °C ( E t 0 / M e O H ) 2  * H N M R (300 M H z , C D O D ) 5 1.32-1.49 (13H, m), 1.72-1.77 (2H, m), 1.94-2.01 (4H, m), 2.19 (1H, s), 3.10-3.13 (3H, m), 7.26-7.35 (5H, m), 7.86 (2H, d, J= 8.4 H z ) , 8.01 (2H, d, 7 = 8 . 4 H z ) 3  C N M R (75 M H z , C D O D ) 5 202.26, 174.09, 143.41, 142.80, 142.05, 130.33, 130.15, 128.53, 128.45, 128.23, 46.92, 39.89, 38.23, 34.77, 31.77, 29.52, 22.56, 22.04, 19.90  1 3  3  L R M S (ESI) mlz ( M + 1):434, 299, 136 +  H R M S (ESI) mlz ( M + 1) calculated mass for C H N 0 : 434.2695, found: 434.2693 +  2 8  3 6  3  I R : ( K B r pellet): 2930, 1670, 1581, 1536, 1220, 1015, 820, 779, 703 cm" . 1  A n a l . C a l c d . C , 77.56; H , 8.14; N , 3.23. Found: C , 77.29; H , 8.27; N , 3.24.  228  (IR, 2S)-(+)-c/s-l-Amino-2-indanol (111)  To a solution o f 37 mg (0.25 mmol) o f (IR, 2S)-(+)-c/s-l-arnino-2-indanol i n 4 m L o f diethyl ether was added solution o f 75mg (0.25 mmol) o f acid 102 in 8 m L o f diethyl ether. Slow evaporation o f solvent gave 69 mg (62 %) o f white powder. mp 165-169 °C ( E t 0 ) 2  ' H N M R (400 M H z , C D O D ) 5 1.21-1.39 (10H, m), 1.75 (2H, m), 1.92-2.05 (4H, m), 2.18 (1H, s), 3.02 (1H, dd, J= 5.0, 16.4 H z ) , 3.28 (1H, dd, J= 6.4, 16.4 H z ) , 4.55 (1H, d, J= 5.9 H z ) , 4.69 (1H, q,J= 5.9 H z ) , 7.20-7.38 (4 H , m), 7.85 (2H, d, J= 8.3 H z ) , 7.85 (2H, d, J= 8.4 Hz), 8.05 (2H, d, J= 8.4 H z ) 3  C N M R (75 M H z , C D O D ) 5 202.19, 174.11, 141.57, 140.32, 130.21, 129.89, 129.12, 128.78, 128.41, 126.91, 126.18, 72.11, 58.67, 40.13, 38.22, 34.76, 31.75, 29.50, 22.58, 22.06 1 3  3  L R M S (ESI) mlz ( M + 1): 448, 299 +  H R M S (ESI) mlz ( M + 1) calculated mass for C28H24NO4: 448.2488, found: 448.2496; +  I R : ( K B r pellet): 2926, 1671, 1580, 1540, 1396, 741 cm" . 1  A n a l . C a l c d . C , 75.14; H , 7.43; N 3.13. Found: C , 75.16; H , 7.53; N , 2.97.  229  (IS, 2S)-(+)-2-Amino-l-phenyl-l,3-propanediol (112)  To a solution o f 42 mg (0.25 mmol) o f (IS, 2S)-(+)-2-amino-l-phenyl-l,3-propanediol in 5 m L o f diethyl ether was added solution o f 75mg (0.25 mmol) o f acid 102 i n 8 m L o f diethyl ether. Evaporation o f solvent gave a sticky o i l .  Triturating from pet ether  afforded 74 mg (63 %) o f white powder. mp 114-115 °C (Trituration from Pet ether) * H N M R (400 M H z , C D O D ) 8 1.25-1.49 (10 H , m), 1.75 (2H, m), 1.93-2.05 (4H, m), 2.19 ( I H , s), 3.41 ( I H , dd, .7=6.4 H z , J= 11.5 H z ) , 3.51 (1H, .7=3.8 Bz,J= 11.5 H z ) , 4.73 ( I H , d,J= 8.4 H z ) , 7.36-7.40 (5H, m), 7.86 (2H, d, J= 8.4 H z ) , 8.00 ( I H , d, J= 8.4 Hz). 3  C N M R (75 M H z , C D O D ) 8 202.32, 174.03, 142.23, 142.08, 130.36, 129.78, 129.54, 128.62, 128.43, 127.89, 72.55, 60.25, 38.25, 34.70, 33.76, 31.78, 29.52, 22.56, 22.03  1 3  3  L R M S (ESI) m/z ( M + 1): 466, 299, 168 +  H R M S (ESI) m/z ( M + 1) calculated mass for C28H36NO5: 466.2593, found: 466.2599; +  I R : ( K B r pellet): 2928, 1670, 1593, 1542, 1395, 1221, 1051, 763, 699 cm" . 1  A n a l . C a l c d . : C , 72.23; H , 7.58; N , 3.01. Found: C , 71.86; H , 7.88; N , 2.83.  230  (5)-(-)-2-(Diphenylhydroxymethyl)pyrroIidine (113)  To a solution o f 63 mg (0.25 mmol) o f (5)-(-)-2-(diphenylhydroxymethyl)pyrrolidine in 3 m L o f methanol was added solution o f 75mg (0.25 mmol) o f acid 102 i n 8 m L o f diethyl ether. Slow evaporation o f solvent gave 80 mg (56%) o f white powder. mp 198-201 ° C ( M e O H ) ' H N M R (400 M H z , C D O D ) 5 1.22-1.49 (10H, m), 1.76 (2H, m), 1.94-2.03 (8H, m), 2.19 ( I H , s), 3.13-3.26 (2H, m), 4.80 ( I H , dd, J= 9.0, 10.1 H z ) , 7.21-7.35 (10H, m), 7.85 (2H, d, J= 8.2 H z ) , 7.99 (2H, d, J= 8.2 H z ) 3  C N M R (75 M H z , C D O D ) 8 202.29, 174.11, 145.87, 145.62, 142.92, 141.99, 130.34, 129.78, 128.64, 128.56, 128.43, 126.89, 126.77, 78.45, 67.93, 47.96, 38.22, 34.77, 31.74, 29.52, 27.23, 25.55, 22.56, 22.04 1 3  3  L R M S (ESI) m/z ( M + 1): 552, 254, 178 +  H R M S (ESI) m/z ( M + 1) calculated mass for C ^ r L ^ N C U : 552.3114, found: 552.3123; +  IR: ( K B r pellet): 2928, 1671, 1633, 1584, 1545, 1390, 1221, 750, 701cm" . 1  Anal. Calcd. C , 78.37; H , 7.49; N , 2.54. Found: C , 78.15; H , 7.38; N , 2.51.  231  (IR, 2S)-(-)-Norephedrine Salt 11 (114)  To a solution o f 38 mg (0.25 mmol) o f (IR, 2 S>(-)-norephedrine i n 4 m L o f diethyl ether 1  was added solution o f 75mg (0.25 mmol) o f acid 102 i n 8 m L o f diethyl ether. Slow evaporation o f solvent gave 73 mg (65 %) o f white powder. mp 88-90 °C ( E t 0 ) 2  N M R (300 M H z , C D O D ) 5 1.07 (3H, d,J= 6.8 H z ) , 1.28-1.49 (10H, m), 1.77 (2H, m), 1.93-2.00 (4H, m), 2.19 ( I H , s), 3.48 ( I H , m), 4.93 ( I H , d,J = 3.5 H z ), 7.22-7.38 (5 H , m), 7.86 (2H, d, J= 8.4 H z ) , 8.01 (2H, d, J= 8.4 H z ) 3  C N M R (75 M H z , C D O D ) 5 202.29, 174.07, 142.05, 141.16, 130.34, 129.53, 129.00, 128.63, 128.44, 127.19, 73.76, 53.68, 38.23, 34.77, 31.78, 29.52, 22.56, 22.04, 12.56  1 3  3  L R M S (ESI) m/z (M + 1): 450, 299, 152 +  H R M S (ESI) m/z ( M + 1) calculated mass for C ^ H ^ N C U : 450.2648, found: 450.2635; +  I R : ( K B r pellet): 2928, 1671, 1589, 1543, 1391, 1222, 1054, 743, 701 c m . -1  A n a l . C a l c d . C , 74.80; H , 7.85; N , 3.12. Found: C , 74.62; H , 7.77; N , 3.09.  232  Chapter 5 Photochemical studies 5.1 General considerations Light sources and filters Both solution and solid state photolyses were carried out by using a 450 W Hanovia medium-pressure mercury lamp in a water-cooled immersion well. Light from the lamp was filtered through a Pyrex (k > 290 nm), or a quartz (A. > 200 nm) immersion well.  ,  Solution state photolyses Samples were dissolved i n H P L C grade or spectral grade (Fisher Chemical) solvents and were purged with nitrogen for at least 15 minutes prior to irradiation. The reactions were performed either in sealed reaction vessels or under a positive pressure o f nitrogen. For preparative scale photolyses, yields and conversions were calculated based on the mass o f the isolated products. For analytical reactions, these values were based on N M R spectroscopy or the average integration o f at least two G C analyses.  Analytical solid state photolyses Solid  samples (2-5 mg) were sandwiched between two quartz plates  microscopic slides.  or  The sample plates were then fixed to one another with tape and  placed i n a polyethylene bag, and heat-sealed under a positive pressure o f nitrogen. Following irradiation, the sample was quantitatively washed from the plates with an appropriate solvent, and concentrated in vacuo. For neutral molecules, the sample was  233  analyzed directly by G C and/or N M R spectroscopy. Photolysates o f the salts derived from keto-acid 38, 53, 71, 80, 102 were treated with diazomethane, and subsequent analysis based on the corresponding methyl esters. Yields and conversions o f the solid state reactions were determined as mentioned above for solution photolyses.  Low-temperature studies A low temperature ethanol bath contained in an unsilvered Dewar vessel (Pyrex) was maintained at a temperature indicated by means o f a Cryocool C C - 1 0 0 II Immersion Cooling System (Neslab Instrument Inc.). Samples sealed i n poly(ethylene) bags were suspended in the cold liquid and irradiated through the transparent walls o f the Dewar vessel.  234  5.2 Photolysis of trans, trans-2, 3-diphenylcyclopropane-lcarboxylic acid derivatives 5.2.1 Preparative photolysis of ester 38  A solution o f ester 38 (60 mg, 0.24 mmol) in acetonitrile (20 m L ) was irradiated (quartz filter, 450 W Hanovia lamp) for 5 h at room temperature. The solvent was removed in vacuo and the residue chromatographed  (Chromatotron, 5 % E t 0 in 2  petroleum ether) to afford starting material 38 (33 mg, 55%), its epimer 115 (14 mg, 23 %), and 1 -phenylindene derivative 117 (oil, 4 mg, 6.5 %). compound  117  (ethyl  1-phenylindene  carboxylate)  spectroscopic data are similar to those o f compound 117.  has  A close analogue o f  been  reported  and  its  119  Compound 115 mp: 68-69 °C ( M e O H , lit 67-68 ° C )  73  H N M R (300 M H z , CDC1 ) 5 2.39-2.43 (1H, dd, J= 5.3 H z , J = 9.50 H z ) , 2.90 (1H, dd, J = 7.1 H z , J = 9.50 H z ) , 3.20 (1H, dd, / = 5.3 H z , J = 7.1 H z ) , 3.50 (3H, s), 7.20-7.34 (10H,m) J  3  C N M R (75 M H z , CDC1 ) 8 170.41, 139.49, 135.99, 129.06, 128.60, 128.10, 126.94, 126.71, 126.65, 51.65, 34.42, 31.0, 29.51  1 3  3  235  I R ( K B r pellet): 3030, 1731, 1174, 700 cm"  1  L R M S : (EI) mlz ( M ) 252, 221, 193, 178, 115, 91 +  Compound 117 H N M R (400 M H z , C D C 1 ) 8 3.68 (3H, s,) 4.11 (2H, s), 8.65-8.75 (2H, m), 7.80-80.5 ( 2 H , m ) , 7.55-7.66 (10 H , m). !  3  C N M R (100 M H z , C D C 1 ) 8 172.03, 131.55, 130.74, 130.24, 128.98, 128.88, 128.38, 126.91, 126.76, 126.68, 124.40, 123.22, 122.51, 52.18, 39.61 ( C H ) .  1 3  3  2  L R M S : (EI) mlz ( M ) : 250, 191 +  H R M S : (EI) mlz ( M ) Calculated mass for C i H 0 2 = 250.09938, found: 250.09952 +  7  1 4  A n a l . C a l c d . : C , 81.58; H , 5.64. Found: C , 81.21; H , 5.67  Independent svsthesis o f ester 115 The procedure for preparing ester 38 described in Chapter 4 was employed, with the difference being that trans stilbene (15 g, 83 mmol, Aldrich) was used instead ofthe cis isomer. Following the procedure afforded 4.3 g o f cis, zra/ts-2,3-diphenylcyclopropane1-carboxylic acid (116). The compound was converted to ester 115 by treatment with diazomethane.  The compound showed identical spectroscopic data as those o f the  isolated product. Data for acid 116 mp: 159-160 °C ( M e O H , lit mp 157-158.5 ° C )  7 3  * H N M R (300 M H z , CDCI3): 2.38-2.43 ( I H , dd, J= 5.3 H z , J= 9.50 H z ) , 2.95-3.00 ( I H , dd, J= 7.1 H z , J= 9.50 H z ) , 3.15-3.20 ( I H , dd, J= 5.3 H z , J= 7.1 H z ) , 3.50 (3H, s), 7.18-7.34 ( 1 0 H , m ) I R ( K B r pellet): 3029-2643, 1684, 1445, 1232, 698 cm" . 1  L R M S (EI) mlz ( M ) : 238, 193, 178, 115 +  236  5.2.2 Preparative photolysis of esters of acid 53 1. Photolysis o f ester 52  o  O OMe  OMe  o. hv  6 H  CH CN 3  52  118  A solution o f ester 52 (42 mg, 0.12 mmol) in acetonitrile (15 m L ) was irradiated (Pyrex filter, 450 W Hanovia lamp) for 1 h at room temperature. The solvent was removed in vacuo and the residue chromatographed (Chromatotron, 10% Et20 in petroleum ether) to afford starting material 53 (4 mg, 10%), and its epimer 118 (31 mg, 74 %). The three methine hydrogens on the cyclorpopane ring o f the isomerized product showed a A B C coupling system on *H N M R spectroscopy as opposed to a A B  2  system  demonstrated by the starting material. mp 170-172 °C (EtOAc) ' H N M R (400 M H z , C D C 1 ) 8 3.29-3.37 (2H, m), 3.67 (1H, t,J= 6.8 H z ) , 3.92 (3H, s), 6.10-7.41 (10 H , m), 7.98 (2H, d, / = 8.0 H z ) , 8.11 (2H, d, J= 8.0 H z ) 3  C N M R (75 M H z , C D C 1 ) § 194.56, 166.23, 141.46, 139.60, 135.14, 133.50, 129.75, 129.03, 128.65, 128.15, 127.95, 127.06, 126.81, 52.42, 38.22, 36.86, 30.18  1 3  3  L R M S (EI) m/z ( M ) : 356, 325, 193, 163, 115 +  H R M S (EI) m/z ( M ) : Calculated mass for +  C24H20O3  = 356.14124, found: 356.14164.  Anal. Calcd.: C , 80.88; H , 5.66 Found: C , 80.63; H , 5.58  237  Independent synthesis o f ester 118 The procedure described in Chapter 4 for preparing ester 52 was employed, with the difference being that cis, rra«s-2,3-diphenylcyclopropane-l-carboxylic acid (116) (2.0g, 8.4 mmol) was used as the starting material. Following the procedure afforded 1.7 g o f ester 118  (57 %). The compound showed identical spectroscopic data as that o f the  isolated product.  2. Photolysis o f ester 66  120  O D  A solution o f ester 66 (30 mg, 0.06 mmol) in acetonitrile (10 m L ) was irradiated (Pyrex filter, 450 W Hanovia lamp) for 1 h at room temperature. The solvent was removed in vacuo and the residue chromatographed (Chromatotron, 5% E t 2 0 i n pet ether) to afford starting material 66 (3 mg, 10%), and its epimer 120 (22 mg, 73 %) as a solid.  Spectroscopic data o f ester 120 H N M R (400 M H z , C D C 1 ) 5 0.89-0.98 (10 H , m), 1.15 (1H, m), 1.31 (1H, m), 1.701.80 ( 2 H , m), 2.11 (1H, m), 2.48 (1H, m), 3.33-3.35 (1H, dd, J = 7.0 H z , J= 9.6 H z ) , 3.54-3.57 (2H, m), 5.06-5.10 (1H, m), 7.13-7.38 (10 H , m), 7.98 (2H, d,J = 8.0 H z ) , 8.08 ( 2 H , d , .7=8.0 H z ) !  3  238  C N M R (75 M H z , C D C 1 ) 5 194.52, 166.25, 141.48, 139.62, 135.10, 133.48, 129.77, 129.00, 128.67, 128.11, 127.98, 126.99, 126.78, 81.17, 49.22, 47.91, 44.92, 38.22, 36.89. 36.84, 30.18, 28.01, 27.43, 19.67, 18.88, 13.60. 1 3  3  L R M S (CI, N H ) m/z ( M + 1): 479, 285, 193, 180, 137 +  3  A n a l . C a l c d : C , 82.81; H , 7.16 Found: C , 82.70; H , 7.23  3. Photolysis o f ester 67  121  A solution o f ester 67 (30 mg, 0.07 mmol) in acetonitrile (10 m L ) was irradiated (Pyrex filter, 450 W Hanovia lamp) for 1.5 h at room temperature. The solvent was removed in vacuo and the residue chromatographed (Chromatotron, 5% Et20 i n petroleum ether) to afford ester 121 (23 mg, 77 %) as a solid.  Spectroscopic data o f ester 121  * H N M R (300 M H z , C D C 1 ) 5 0.76 (3 H , d, 7 = 6.8 H z ) , 0.90 (7H, m), 1.12 (2H, m), 1.55 (2H, m), 1.76 (2H, m), 1.95 (1H, m), 2.14 (1H, m), 3.35-3.37 (1H, m), 3.53-3.58 (2H, m), 4.87-94 (1H, m), 7.14-7.40 (10 H , m), 7.99-8.05 (4H, dd, 7 = 8.2 H z , J= 16.2 Hz). 3  C N M R (75 M H z , CDCI3) 5 194.49, 166.29, 141.52, 139.60, 135.12, 133.46, 129.79, 129.05, 128.71, 128.14, 127.96, 127.95, 126.82, 75.52, 47.22, 40.91, 38.25, 36.84, 34.25, 31.38, 30.18, 26.55, 23.56, 22.04, 20.72, 16.53 1 3  239  L R M S (CI, N H ) m/z ( M ) : 481, 287, 193, 149, 91 +  3  A n a l . C a l c d . : C , 82.46; H , 7.55 Found: C , 82.18; H , 7.48 4. Photolysis o f ester 68  A solution o f ester 68 (20 mg, 0.04 mmol) in acetonitrile (8 m L ) was irradiated (Pyrex filter, 450 W Hanovia lamp) for 1.5 h a t room temperature. The solvent was removed in vacuo and the residue chromatographed (Chromatotron, 10 % Et20 i n petroleum ether) to afford ester 122 (16 mg, 80 %) as a sticky oil.  Spectroscopic data o f ester 122  YL N M R (300 M H z , C D C 1 ) 5 3.26 (3H, s), 3.65 ( I H , dd, J= 6.8 H z , J= 10.0 H z ) , 4.48 (2H, m), 3.52-3.57 (2H, m), 7.14-7.48 (15H, m), 7.99-8.04 (4H, dd, J= 8.0 H z , J= 16.1 Hz) l  3  C N M R (75 M H z , CDCI3) 5 194.56, 166.23, 141.46, 139.60, 137.91, 135.14, 133.50, 129.75, 129.03, 128.71, 128.65, 128.43, 128.15, 127.95, 127.06, 126.99, 126.81, 81.59, 68.50, 57.18, 38.22, 36.86, 30.18 1 3  L R M S (CI, N H ) m/z ( M + 1): 477, 283, 193 +  3  240  5.3 Photolysis of 4-{trans, fra«s-2,3-dibenzoylcyclopropyl-l-) benzoic acid derivatives 5.3.1 Photolysis of esters of acid 71 1. Photolysis o f ester 72 O  o  o  o  hv CH CN  H  3  O  O  72  124  A solution o f ester 72 (32 mg, 0.08 mmol) in acetonitrile (10 m L ) was irradiated (Pyrex filter, 450 W Hanovia lamp) for 1.5 h at room temperature. The solvent was removed in vacuo and the residue chromatographed (Chromatotron, 30 % Et20 in petroleum ether) to afford starting material 72 (3 mg, 9 %), and its epimer 124 (25 mg, 78 %).  The three methine hydrogens on the cyclopropane ring o f the isomerized product showed an A B C coupling system on ' H N M R spectroscopy, as opposed to an A B  2  system demonstrates by the starting material. A n additional carbonyl carbon signal was observed in the  1 3  C spetrum o f the isomerized product.  m p 110-112 °C ( M e O H ) U NMR (400 M H z , C D C 1 ) 5 3.56 ( I H , dd, J= 6.20 H z , J= 10.0 H z ) , 3.77-3.81 ( I H , dd, J= 4.9 H z , J= 10.0 H z ) , 3.84 (3H, s), 4.26 ( I H , m), 7.10 (2H, d,J = 8.20 H z ) , 7.407.68 (6H, m), 7.89 (2H, d, J= 8.20 H z ) , 7.96 (2H, d, J = 7.44 H z ) , 7.92 (4H, m), 8.14 (2H, d, 7 = 7 . 4 2 H z ) . l  3  241  C N M R (75 M H z , C D C 1 ) 5 196.86, 193.29, 166.67, 139.66, 137.21, 136.89, 133.67, 133.42, 130.56, 129.52, 129.23, 128.82, 128.77, 128.67, 128.44, 128.27, 51.99, 37.42, 37.27, 29.77 1 3  3  I R ( K B r pellet): 2923, 1717, 1656, 1611, 1596, 1578 cm-  1  L R M S (EI): 384, 353, 279, 105, 77  A n a l . C a l c d . : C , 78.11; H , 5.24. Found: C , 77.95, H ; 5.52  Independent synthesis o f acid 123 and ester 124 The procedure described in Chapter 4 for preparing ester 71 was employed, with the difference being that excess sodium hydroxide (4 eq) was used and the reaction mixture was stirred for 3 days. A c i d 123 was prepared in a yield o f 90 %. The acid was then converted to methyl ester 124 by treatment with diazomethane. The spectroscopic data o f the compound are identical with the isolated product.  Data for A c i d 123 mp 163-167 ° C ( M e O H ) K N M R (400 M H z , C D O D ) 5 3.56 (1H, dd, J= 6.20 H z , J= 10.0 H z ) , 3.77-3.81 (1H, dd, J= 4.9 H z , 7 = 10.0 H z ) , 3.84 (3H, s), 4.26 (1H, m), 7.10 (2H, d, J= 8.20 H z ) , 7.407.68 (6H, m), 7.89 (2H, d, J= 8.20 H z ) , 7.96 (2H, d, J = 7.44 H z ) , 7.92 (4H, m), 8.14 (2H, d, .7=7.42 H z ) . l  3  C N M R (75 M H z , C D O D ) 5 195.99, 192.94, 166.98, 139.59, 136.81, 136.47, 133.79, 133.51, 129.91, 129.43, 129.96, 128.35, 128.07, 126.90, 28.73, 25.47, 18.54  1 3  3  I R ( K B r pellet): 2923, 1717, 1656, 1611, 1596, 1578 c m  -1  L R M S (EI) m/z ( M ) : 370, 353 +  H R M S (EI): Calculated mass for  C24H20O3  = 370.12051, found: 370.12098  242  2. Photolysis o f ester 78  125 A solution o f ester 78 (40 mg, 0.08 mmol) in acetonitrile (25 m L ) was irradiated (Pyrex filter, 450 W Hanovia lamp) for 1 h at room temperature. The solvent was removed in vacuo and the residue chromatographed (Chromatotron, 30 % E t 0 i n petroleum ether) to 2  afford starting material 78 (3 mg, 8 %), and its epimer 125 (solid, 33 mg, 82 %).  Spectroscopic data o f ester 125  * H N M R (400 M H z , C D C 1 ) 5 0.98 ( I H , m), 1.12 (4H, m), 1.23 (3H, s), 1.77-1.89 (3H, m), 2.29 (1 H , m), 2.41 ( I H , m), 2.68 ( I H , m), 3.58-3.62 ( I H , dd, J= 6.3 H z , J= 10.1 Hz), 3.62-3.79 ( I H , J= 5.0 H z , J= 10.1 H z ) , 4.25-4.28 ( I H , dd, J= 5.0 H z , J= 6.3 H z ) , 5.15-5.19 ( I H , m), 7.39-7.60 (8H, m), 7.86 (2H, d, J= 7.3 H z ) , 8.00 ( I H , d,J= 7.2 H z ), 8.19 (2H, d, 7 = 7 . 2 H z ) . 3  C N M R (75 M H z , CDCI3) 5 196.86, 193.29, 166.67, 139.66, 137.21, 136.89, 133.67, 133.42, 130.56, 129.52, 129.23, 128.82, 128.77, 128.67, 128.44, 128.27, 75.22, 47.25, 40.96, 37.45, 34.29, 31.42, 29.90, 29.85, 25.54, 24.56, 23.01, 19.72, 16.53 1 3  L R M S (ESI) m/z ( M + N a ) : 529 +  23  A n a l . C a l c d . : C , 80.60; H , 6.70 Found: C , 80.46; H , 6.68  243  3. Photolysis o f ester 79  126  79  A solution o f ester 79 (40 mg, 0.08 mmol) in acetonitrile (15 m L ) was irradiated (Pyrex filter, 450 W Hanovia lamp) for 2 h at room temperature. The solvent was removed in vacuo and the residue chromatographed  (Chromatotron, 40 % E t 0 in 2  petroleum ether) to afford ester 126 (solid, 34 mg, 85 %).  Spectroscopic data o f ester 126  H N M R (300 M H z , C D C 1 ) 5 0.78 (3H, d, J = 6.9 H z ) , 0.92, (7H, m), 1.01-1.28 (2H, m), 1.52 (2H, m), 1.72 (2H, m), 1.96 - 2.09 (2H, m), 3.55 (1H, m), 3.76 (1H, dd J= 4.9 H z , / = 10.1 H z ), 4.25 (1H, t,J= 4.9 H z ) , 4.86 (1H, m), 7.25-7.60 (8H, m), 7.82-8.00 ( 4 H , m ) , 8.19 ( 2 H , m ) . !  3  C N M R (75 M H z , CDCI3) § 196.88, 193.42, 165.65, 139.35, 137.23, 136.84, 133.40, 130.09, 129.48, 129.48, 128.79, 128.70, 128.65, 128.40, 128.27, 41.18, 40.86, 37.40, 34.23, 31.35, 29.90, 29.85, 26.28, 23.44, 23.47, 21.95, 20.71, 16.32. 1 3  L R M S (ESI) m/z ( M + N a ) : 531 +  23  A n a l . C a l c d . : C , 80.28; H , 7.13 Found: C , 80.46; H , 7.22  244  4. Photolysis o f ester 80  A solution o f ester 80 (35 mg, 0.08 mmol) in acetonitrile (15 m L ) was irradiated (Pyrex filter, 450 W Hanovia lamp) for 1.5 h at room temperature. The solvent was removed in vacuo and the residue chromatographed  (Chromatotron, 40 % Et20 in  petroleum ether) to afford starting material 80 (3 mg, 8.5 %), and its epimer 127 (29 mg, 83 %).  Spectroscopic data o f ester 127 >H N M R (300 M H z , C D C 1 ) 8 0.51-1.00 (6H, m), 1.27 (1H, m), 1.40-1.50 (1H, m), 1.75-1.84 (1H, m), 3.55 (1H, m), 3.79 (1H, dd .7=4.9 H z , J= 10.1 H z ), 4.00-4.15 (1H, m), 4.25 (1H, t, J= 4.9 H z ) , 7.25-7.60 (8H, m), 7.82-8.00 (4H, m), 8.15 (2H, m). 3  C N M R (75 M H z , C D C 1 ) 8 196.92, 193.38, 166.28, 139.54, 137.27, 136.91, 133.68, 133.45, 129.51, 128.85, 128.77, 128.71, 128.47, 128.31, 69.48, 37.40, 34.27, 29.87, 26.12, 16.50, 11.25 1 3  3  L R M S (ESI) m/z ( M + N a ) : 463 +  23  245  5. Photolysis o f ester 81  O  o  81  o  0  hv  So  CH CN 3  H 128  A solution o f ester 81 (25 mg, 0.06 mmol) in acetonitrile (15 m L ) was irradiated (Pyrex filter, 450 W Hanovia lamp) for 1.5 h at room temperature. The solvent was removed in vacuo and the residue chromatographed (Chromatotron, 30 % E t 2 0 i n petroleum ether) to afford ester 128 (solid, 22 mg, 87 %).  Spectroscopic data o f ester 128  R N M R (400 M H z , C D C 1 ) 5 0.92 (3H, t, J= 7.5 H z ) , 1.27 (3H, d, J= 6.3 H z ) , 1.611.69 (2H, m), 3.57 ( I H , dd, J.= 5.0 H z , J= 10.1 H z ) , 3.80 ( I H , dd J= 5.0 H z , J= 10.1 H z ), 4.25 ( I H , J= 5.0 H z ) , 5.00 ( I H , m), 7.28-7.63 (8H, m), 7.84 (2H, d J= 8.3 H z ) , 7.95 ( 2 H , d J = 7 . 6 H z ) , 8.13 (2H, dJ= 7.4 H z ) . X  3  C N M R (75 M H z , C D C 1 ) 5 196.96, 193.42, 165.88, 139.41, 137.30, 136.94, 133.74, 133.46, 129.93, 129.51, 128.86, 128.72, 128.48, 128.35, 72.83, 37.42, 29.89, 28.92, 19.50,9.69.  1 3  3  L R M S (ESI) m/z ( M + N a ) : 449 +  2 3  A n a l . C a l c d . : C , 78.85, H , 6.14 Found: C , 78.61; H , 6.29  246  5.4 Photolysis of cis, as-2,3-bisbenzyloxymethyl-l-benzoylcyclopropane derivatives 5.4.1 Preparative photolysis of compound 86  e  131  A solution o f ester 86 (33 mg, 0.07 mmol) in acetonitrile (10 m L ) was irradiated (Pyrex filter, 450 W Hanovia lamp) for 75 m i n at room temperature. The solvent was removed in vacuo and the residue chromatographed (Chromatotron, 20 % Et20 in petroleum ether) to afford a mixture o f compounds 129 and 130 (23 mg, 70 %), and a trace amount o f compound 131. N M R spectroscopy and G C analysis revealed a ratio o f 0.3 o f  129/130.  The isolation o f pure isomers  129 and 130  was difficult. Repeated  attempts at purification by preparative H P L C (3 % E t O A c i n hexanes) afforded pure compound 129 (ca. 2 mg, oil) and 10 mg o f pure compound 130 as a sticky oil. The structure o f compound 131 was assigned based on G C M S analysis and H N M R ]  spectroscopy.  120  247  cis isomer 129 * H N M R (400 M H z , C D C N ) 5 2.86-2.91 ( I H , dd, J= 5.9 H z , J= 15.7 H z ) , 3.29-3.25 ( I H , dd, J= 5.9 H z , J= 15.7 H z ) , 3.36-3.43 (3H, m), 3.89 (3H, s), 4.34 ( I H , dd, J= 6.1 H z , J= 8.3 H z ) , 4.42 (2H, s), 4.74 (2H, dd, 7 = 11.3 H z , J= 15.7 H z ) , 6.09 ( I H , d,J = 6.1 H z ) 7.20-7.29 (10 H , m), 7.94 (2H, d, J= 8.6 H z ) , 8.01 (d, 2 H , J= 8.6 H z ) . 3  C N M R (100 M H z , C D C N ) 5 200.06, 166.94, 146.81, 141.52, 139.52, 134.51, 130.33, 129.23, 129.14, 129.08, 128.73, 128.42, 128.30, 107.59, 74.37, 73.82, 73.28, 52.95, 42.56, 33.33 1 3  3  L R M S (ESI) m/z ( M + N a ) : 467 +  23  H R M S (ESI) m/z ( M + 467.1847 +  23  N a ) : Calculated mass for C 8 H 0 2  2 8  2 3 5  N a = 467.1834, found  trans isomer 130 * H N M R (400 M H z , C D C N ) 5 2.93-2.98 (2H, m), 3.18-3.21 ( I H , m), 3.40-3.44 (2H, m), 3.89 (3H, s), 4.39 (2H, s), 4.64 (2H, s), 4.75-4.80 ( I H , dd, J= 8.3 Uz,J= 12.4 H z ) , 6.39 ( I H , d,J= 12.4 H z ) 7.20-7.29 (10 H , m), 7.96 (2H, d, J= 8.6 H z ) , 8.05 (d, 2 H , J = 8.6 H z ) . 3  C N M R (100 M H z , C D C N ) 6 200.14, 167.02, 148.47, 141.52, 139.90, 138.35, 134.60, 130.47, 129.31, 129.16, 129.04, 128.69, 128.51, 128.32, 105.85, 74.88, 73.47, 71.93, 53.02,42.78,36.41 1 3  3  IR: 2923, 1724, 1687, 1279, 737, 698 cm L R M S (CI + N H ) m/z ( M + 1): 445, 337, 247 +  3  H R M S (CI + N H ) m/z ( M + l ) : Calculated mass for C H 2 9 0 445.20159. +  3  2 8  5  = 445.20150, found  A n a l . C a l c d . : C , 75.65; H , 6.35 Found: C , 75.42; H , 6.32  Spectroscopic data o f compound 131 H N M R (300 M H z , C D C 1 ) : 2.64 (3 H , s), 3.95 (3H, s), 8.01-8.08 (4 H , dd, J= 7.8 H z , J = 16.5 H z ) ]  3  L R M S (EI) m/z ( M ) 178, 163, 147, 135 +  248  5.5 Photolysis of derivatives  9-tricyclo [4.4.1.0]undecyl  phenyl  ketone  5.5.1 Preparative photolysis of compound 103  A solution o f ester 103 (25 mg, 0.08 mmol) in acetonitrile (5 m L ) was irradiated (Pyrex filter, 450 W Hanovia lamp) for 20 m at room temperature. In addition to the desired product, G C M S analysis o f the crude photosylate also indicated the presence o f compound 131 and another substance, which showed identical mass spectroscopic data to hexahydronaphthalene (134).  The G C peak area ratio o f these two compounds to the  desired product was found to be 3:3:94. The solvent o f the crude sample was removed in vacuo and the residue chromatographed (Chromatotron, 5 % Et20 in petroleum ether) to afford compound 133 (18 mg, 72 %).  C o m p o u n d 133 mp 79 -80 °C (ether/pet ether) 'H (400 M H z , CDC1 ): 5 8.08 (2H, d J = 7.0 H z ) , 7.95 (2H, d J = 7.0 H z ) , 5.40 (1H, m), 3.90 (3H, s), 3.23 (1H, d J = 15.0 H z ) , 3.13 (1H, d J = 15.0 H z ) , 2.23 (1H, m), 1.98-2.05 (1H, m), 1.87-1.92 (3 H , m), 1.76 (1H, m) 1.43-1.65 (4H, m), 1.14-1.31 (3H, m) 3  249  C ( A P T , 75 M H z , C D C 1 ) 5 200.50 (+), 166.28 (+), 142.39 (+), 142.26 (+), 133.43 (+), 129.76 (-), 127.81 (-), 121.40 (-), 52.40 (-), 41.67 (+), 39.07 (+), 38.23 (+), 35.71 (+), 32.67 (+), 28.24 (+), 25.55 (+), 22.34 (+), 18.92 (+) 1 3  3  H R M S : (CI, N H ) m/z ( M + l ) : calculated mass for 313.25115. +  3  C20H25O3:  313.25085. Found  I R ( K B r pellet) 2925, 1718, 1685, 1438, 1281, 1109, 957, 761,666 cm" . 1  A n a l . C a l c d . C , 76.89; H , 7.74. 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Comm. 1988,18, 343.  1 2 0  The 'FI N M R o f compound 131 agree with that o f methyl 4-acetylbenzoate recorded in the Integrated Spectra Data Base System for Organic Compound, created b y Hayamizu, K . ; Yanagisawa, M . ; Yamamoto, O.; Wasada, N . ; Someno, K . ; Tanabe, K . ; Tamura, T.; Hiraishi, J. the National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan. SDBSWeb: http://www.aist.go.jp/RIODB/SDBS/ (March 3, 2003).  261  

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