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A novel approach to manipulate cavity size In resorcinarenes

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Title:
A novel approach to manipulate cavity size In resorcinarenes
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Parulekar, Sumedh
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University of South Florida
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Cavitand
Ring closing metathesis
Bromination
Crystal structure
NMR
Dissertations, Academic -- Chemistry -- Masters -- USF   ( lcsh )
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bibliography   ( marcgt )
theses   ( marcgt )
non-fiction   ( marcgt )

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Abstract:
ABSTRACT: Intramolecular ring closing metathesis in the presence of Grubbs' catalyst has been used as an efficient approach to synthesize bridged resorcinarenes. Octaallyl cavitands may undergo conformational changes; however bridge formation by RCM of the allyl groups gives a rigid, enforced, concave cavity capable of holding neutral molecules. This is the first report describing tandem formation of the four bridges on the upper rim of resorcinarenes. Structures of bridged resorcinarenes are confirmed by spectral analysis data.This report also describes the synthesis of polyhydroxy resorcinarenes, which have been used as metal complexing agents, sensors, receptors, molecular reaction vessels and catalytic chambers. They are able to encapsulate small neutral molecules, drug molecules inside the cavity. Such cavitands offer unique molecular platforms for host--guest chemistries, as well as new polymers and self-assembled systems.
Thesis:
Thesis (M.S.)--University of South Florida, 2006.
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Includes bibliographical references.
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by Sumedh Parulekar.
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Title from PDF of title page.
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Document formatted into pages; contains 60 pages.

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usfldc doi - E14-SFE0001810
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ABSTRACT: Intramolecular ring closing metathesis in the presence of Grubbs' catalyst has been used as an efficient approach to synthesize bridged resorcinarenes. Octaallyl cavitands may undergo conformational changes; however bridge formation by RCM of the allyl groups gives a rigid, enforced, concave cavity capable of holding neutral molecules. This is the first report describing tandem formation of the four bridges on the upper rim of resorcinarenes. Structures of bridged resorcinarenes are confirmed by spectral analysis data.This report also describes the synthesis of polyhydroxy resorcinarenes, which have been used as metal complexing agents, sensors, receptors, molecular reaction vessels and catalytic chambers. They are able to encapsulate small neutral molecules, drug molecules inside the cavity. Such cavitands offer unique molecular platforms for host--guest chemistries, as well as new polymers and self-assembled systems.
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A Novel Approach To Manipulate Ca vity Size In Resorcinarenes by Sumedh Parulekar A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science Department of Chemistry College of Arts and Sciences University of South Florida Major Professor: Kirpal Bisht, Ph.D. Edward Turos, Ph.D. Abdul Malik, Ph.D. Date of Approval: November 13, 2006 Keywords: cavitand, ring closing metathes is, bromination, crystal structure, NMR Copyright 2006 Sumedh Parulekar

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DEDICATION This thesis is dedicated to my beloved mother Mrs. Gayatri Parulekar and father Mr. Neenad Parulekar, who motivated me to pursue this degree and accomplish my goals. I present this work as a token of appreciati on and gratitude for all their efforts. I would also like to dedicate this thesis to my sister Ms. Shweta Parulekar for her encouragement.

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ACKNOWLEDGEMENT I wish to express my sincerest thanks to my adviser Dr. Kirpal Bisht, for his wise counsel, viable guidance and constant encour agement and for the su ccessful culmination of this thesis. I would like to thank Dr. Frank Fronczek at the Louisiana State University, for his help in crystallographic analysis. I would like to thank Dr. John Koomen at Moffitt Cancer Research Center and Dr. Ted Gauthier at the University of South Florida for the mass spectral data. I would like to thank Dr. Edwin Rivera for NMR data. I wish to thank Ms Kirti Muppalla for working with me on this project and research work. I would like to acknowledge my committee members, Dr. Edwa rd Turos and Dr. Abdul Malik for their encouragement and assistance. I am thankful to my labmates Pasha Khan, Surbhi Bhatt, Sridhar Kaulagari and Ruizhi Wu for their timely help and support during my research work. Last but not the least I wish to acknowledge my fr iends and roommates for the lighter moments I shared with them. Fina lly, I would like to thank Department of Chemistry and University of South Florida fo r allowing me to carry out this research project successfully.

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TABLE OF CONTENTS LIST OF FIGURES.....ii LIST OF TABLES......vi LIST OF SCHEMES ....vii LIST OF ABREVIATIONS.viii ABSTRACT....x CHAPTER 1. INTRODUCTION 1.1. Introduction to Resorcinarenes.....1 1.2. Introduction to Bridged Resorcinarenes...........3 CHAPTER 2. SYNTHESIS OF BRIDGED RESORCINARE...6 2.1. Synthesis of Octahydroxy Resorcinarene. ... 2.2. Allylation of Octahydroxy Resorcinarene................ 2.3. Ring Closing Metathesis of Allyloxy Resorcinarene......10 2.4. Synthesis of Partially Bridged Resorcinarene by RCM..........16 2.5. Synthesis of Single Bridge d Resorcinarene by RCM.........18 CHAPTER 3. SYNTHESIS OF PO LYHYDROXY RESO RCINARENES.20 3.1. Introduction to Polyhydroxy Resorcinarenes......20 3.2. Synthesis of Polyhydroxy Resorcinarenes......21 CHAPTER 4. EXPERIMENTAL..27 4.1. General Experimental Procedure i

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4.2. Crystal structure data of Resorcinarenes.38 REFERENCES..40 APPENDICES...43 ii

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LIST OF FIGURES Figure 1. Structure of resorcinarene.....2 Figure 2. Conformations in re sorcinarenes (Top view)...3 Figure 3. Structures of br idged resorcinarenes........4 Figure 4. 1 H NMR of compound 12.....9 Figure 5. X-ray crystal structure of compound 7.....9 Figure 6. Ring closing metathesis of allyloxy resorcinarenes.......10 Figure 7. Grubb's genera tion-I catalyst..11 Figure 8. 1 H NMR of compound 14 ..........13 Figure 9. X-ray crys tal structure of 14 (top view).14 Figure 10. X-ray crystal structure of 14 (side view)..4 Figure 11. 13 C NMR of compounds 14 and 8 ...........16 Figure 12. 1 H NMRs of compound 16 and its precursor 11......18 Figure 13. Methylene-bridged Resorcinarene with heptyl substituent......20 Figure 14. Tetraol 24 obtained from tetrabromo resorcinarene ........23 Figure 15. Comparative proton NMRs of compound 25 and its precursor 23......25 iii

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APPENDIX Figure 16. 1 H NMR of compound 1 ....... Figure 17. 1 H NMR of compound 3 ...........44 Figure 18. 1 H NMR of compound 4 ...........45 Figure 19. 1 H NMR of compound 6 ...... 45 Figure 20. 1 H NMR of compound 7 .......46 Figure 21. 13 C NMR of compound 8 .........46 Figure 22. 1 H NMR of compound 9 .......47 Figure 23. 13 C NMR of compound 9 .........47 Figure 24. 1 H NMR of compound 10 .....48 Figure 25. 1 H NMR of compound 11 .....48 Figure 26. 1 H NMR of compound 12 ........49 Figure 27. 13 C NMR of compound 12 ...........49 Figure 28. 1 H NMR of compound 13 .........50 Figure 29. 13 C NMR of compound 13 .......50 Figure 30. 1 H NMR of compound 14 .........51 Figure 31. 13 C NMR of compound 14 ...51 Figure 32. 1 H NMR of compound 15 .........52 Figure 33. 13 C NMR of compound 15 ........... iv

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Figure 34. 1 H NMR of compound 16 .........53 Figure 35. 1 H NMR of compound 17 .........53 Figure 36. 13 C NMR of compound 17 ...........54 Figure 37. 13 C NMR of compound 22 ...........54 Figure 38. 1 H NMR of compound 23 .........55 Figure 39. 13 C NMR of compound 23 .......55 Figure 40. 1 H NMR of compound 25 .....56 Figure 41. 1 H NMR of compound 26 .........56 Figure 42. 1 H NMR of compound 27 .....57 Figure 43. 13 C NMR of compound 27 .......57 Figure 44. gCOSY of compound 13. .....58 Figure 45. gHSQC of compound 13 ..........58 Figure 46. gHSQC of compound 15 ..........59 Figure 47. gCOSY of compound 15 ..........59 Figure 48. DEPT of compound 27 (expanded NMR)............60 Figure 49. DEPT of compound 27.............60 v

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LIST OF TABLES Table 1. Percent yield data of different reso rcinarene cavitands synthesized in the lab by different routes..19 vi

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LIST OF SCHEMES Scheme 1. Condensation reaction be tween resorcinol and aldehydes ........ Scheme 2. Allylation reaction of octahydroxy resorcinarene......8 Scheme 3. Ring closing metathesis of octaallyloxy resorcinarenes 79............12 Scheme 4. Ring closing metathesis of octaallyloxy resorcinarenes 11 and 12 .........17 Scheme 5. Ring closing metathesis of octaallyloxy Resorcinarenes 18 and 19 .......19 Scheme 6. Synthesis of octahydroxy resorcinarene 2........ Scheme 7. Synthesis of met hylene bridged resorcinarene 22.... Scheme 8. Synthesis of tetrabromo resorcinarene 23.... Scheme 9. Formation of octaester 25 from tetrabromo resorcinarene.......24 Scheme 10. Formation of polyhydroxy resorcinarene 26 from octaester resorcinarene ..26 Scheme 11. Glycosyl ation of compound 26 with glucose pentaacetate.... vii

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LIST OF ABBREVATIONS RCM ring closing metathesis.5 DMF N,N-Dimethylformamide.7 APCI MS atmospheric pressure chem ical ionization mass spectrometry 13 C NMR carbon nuclear magnetic resonance.8 1 H NMR proton nuclear magnetic resonance..8 NMR nuclear magnetic resonance.8 ORTEP oak ridge thermal ellipsoid plot...9 R f retention factor for chromatography..11 2D NMR two-dimensional nuc lear magnetic resonance...11 DCM dichloromethane.....12 m/z mass/charge for mass spectrometry...12 AIBN 2,2-Azobisisobutyronitrile DEPT NMR distortionless enhancement by polarization transfer nuclear magnetic resonance NBS N-Bromosuccinimide.22 THF tetrahydrofuran... chemical shifts for nuclear magnetic resonance DMSO dimethylsulfoxide..27 J coupling constant for NMR...27 viii

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MALDI MS matrix assisted laser de sorption ionization mass spectrometry.27 gHSQC gradient heteronuclear single quantum correlation ... gCOSY gradient corr elation spectroscopy..32 TLC thin layer chromatography.35 ix

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A Novel Approach to Manipulate Cavity Size in Resorcinarene Sumedh Parulekar ABSTRACT Intramolecular ring closing metathesis in th e presence of Grubbs catalyst has been used as an efficient approach to synthesize br idged resorcinarenes. Octaallyl cavitands may undergo conformational changes; however brid ge formation by RCM of the allyl groups gives a rigid, enforced, concave cavity capable of holding neutral mole cules. This is the first report describing tandem formation of the four bridges on the upper rim of resorcinarenes. Structures of bridged resorc inarenes are confirmed by spectral analysis data. This report also describes the synthesis of polyhydroxy resorcinarenes, which have been used as metal complexing agents, sensors, receptors, molecular reaction vessels and catalytic chambers. They are able to encapsu late small neutral molecules, drug molecules inside the cavity. Such cavitands offer unique molecular platforms for hostguest chemistries, as well as new polymers and self-assembled systems. x

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CHAPTER 1. INTRODUCTION 1.1. Introduction to Resorcinarene Resorcinarenes are compounds made by c ondensation of resorcinol and aldehydes in the presence of acids. Resorcinarenes in a locked conformation result in cavitands, which are defined as compounds that cont ain an enforced cavity large enough to accommodate simple organic compounds or ions. 1 Resorcinarene cavitands have been used for variety of purposes because of thei r rigidity, enforced cavities and synthetic viability. 2 Resorcinarenes have been used as meta l complexing agents, sensors, receptors, molecular reaction vessels and catalytic chambers. 3 They are also able to encapsulate small neutral molecules such as CH 2 Cl 2 CHCl 3 and CS 2 as well as drug molecules, photoactive components. 4 Resorcinarenes also act as precursors to carceplexes, carcerands, hermicarcerands, as binders of neut ral guest molecules and as agents to form monolayers. 5 They can provide novel and efficient receptors with potential complexation towards complicated guests. 6 Resorcinarene cavitands have found applications in nuclear waste treatment because of their ability to bi nd to strontium, cesium and actinides with high efficiency and selectivity. In 1870, Adolf Von Baeyer observed a red-colored solution upon addition of concentrated sulfuric acid to an ethanolic solution of benzaldehyde and resorcinol. 7 The red-colored solution yielded, in several days, a crystalline compound. In 1883, Michael 1

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determined that the crystalline compound form ed from an equal number of benzaldehyde and resorcinol molecules with loss of water molecules. 8 In 1940, Vogel and Niederl 9 prepared the crystalline compound described by Baeyer and its peracetate derivative. Molecular weight determina tions of the crystalline compound and the peracetate derivative led them to establish the ratio of the resorcinol and the aldehyde to be 4:4, i.e., each molecule of the resorcinarene contained fo ur molecules of the resorcinol with four molecules of the aldehyde, of course with loss of 4 molecules of water. 9 The crystal structure of the resorcinarene was first solved by Erdtman and coworkers in 1968, thus proving its structure as in figure 1. D. J. Cram synthesized the first cavitand in 1982 with alkylene bridge on upper rim of resorcinarene. 10 HO HO OH HO OH HO OH OH R' R' R' R' R R R R Figure 1. Structure of Resorcinarene, R' = H, CH 3 Br, OH, etc. R = Aliphatic or Aromatic substituents. In resorcinarenes the m acrocyclic ring can adopt five symmetrical arrangements, namely, crown, chair, boat, diamond and saddle. 1a,4a However, the two major preferred conformations are Crown (C 4v ) and Chair (C 2v ) (Figure 2), depending on reaction conditions, time duration and different R and R substituents on the cavitands. 11 2

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R R R R R' R' R' R' O O O O O O O O H H H H H H H H R R R' R' R' R' HO OH OH HO HO HO OH OH R R C4v (Crown) C2v (Chair) Figure 2. Conformations in Resorcinarene (Top view.) 1.2. Introduction to Bridged Resorcinarenes Intramolecular cyclization leading to conf ormationally locked resorcinarenes, i.e., cavitands, has been a key feature of synthe tic procedure leading up to many of these encapsulating platforms. The covalent linkage of the neighboring phenolic groups on the adjacent phenyl rings is generally exploited for synthesis of the rigid 'bowl' shaped cavity. The treatment of the octahydroxy re sorcinarene with excess of CH 2 ClBr and base results in formation of the methylene bridge d cavitand; the most comm on of the covalent linkage reported. The synthesis of ethylene and propylene bridged cavitands has also been reported. 12 It has been observed that compared to the methylene bridge cavitands, the ethylene and propylene bridged cavitands are somewhat more flexible. There are also reports of the dialkylsilicate-, 13 phosphoryl-, 14 and heterophenylene-bridged cavitands 15 (Figure 3). 3

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The length and nature of th e alkylene bridge has been shown to affect the cavity size of the cavitand. For example, while the heterophenylene bridges deepen the cavity, the alkyl substituents of the silicon bridge considerably narrow the cavity. 16 Clearly, the bridging reaction can be used to manipulate the cavity size and hence can be used to alter the properties of the cavitand. We realize that by the application of ring closing metathesis reaction, very interesting resorc inarene cavitands with unusual properties can be prepared. R2 R2 R2 R2 O O O O O O O O Si Si Si Si CH3 CH3 H3C H3C R1 R1 R1 R1 R2 R2 R2 R2 O O O O O O O O P P P P R R R R R2 R2 R2 R2 O O O O O O O O R1 R1 R1 R1 R2 R2 R2 R2 O O O O O O O O n(H2C) (CH2)n n(H2C) (CH2)n R1 R1 R1 R1 Figure 3. Structure of alkylene bridged reso rcinarenes, dialkylsilicate bridge resorcinarenes, phosphoryl bridge reso rcinarenes and heterophenylene bridge resorcinarenes, respectively. 4

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Ring-closing metathesis (RCM) has been rapidly establ ished as an efficient approach to the synthesis of me dium to large ring systems. Advancement in the design of the catalyst leading to their remarkable functional group tolerance, operational simplicity, high stability and commercial availability ha s greatly contributed to the popularity of the RCM reaction. To the best of our knowledge, th ere are no reports of use of RCM reaction in resocinarenes. However, McKervey 17 and Chen 18 have reported use of RCM in synthesis of bridged, bisand tetracalix[4]arenes. The following chapter describes our effo rts towards utility of the tandem RCM reactions in manipulation of the resorcinarene's cavity size. 5

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CHAPTER 2. SYNTHESIS OF BRIDGED RESORCINARENES 2.1. Synthesis of Octahydroxy resorcinarenes Resorcinarenes, 16 were used as starting mate rial for the preparation of octaallyloxy resorcinarenes. They were pr epared by condensation of resorcinols and aldehydes in the presence of hydrochloric acid and ethanol as a solvent (Scheme 1). The compounds were precipitated from ice-cold water to yield brown-colored solids. The condensation reactions, depending on the su bstrates, were carri ed out at reaction temperature ranging from 45 o C to 78 o C. Low reaction temperature of 45 o C to 50 o C was maintained for resorcinol condensation while the reaction mixture was brought to a reflux (78 o C) for condensation reaction of methyl re sorcinol. Resorcinarenes from methyl resorcinol ( 13) were isolated in 70-90 % yiel d whereas those of resorcinol ( 46 ) in 5080% yield. The condensation of resorcinol at the reflux temperature led to the decomposition of the product and reduced yield of the 46 was obtained. 6

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HO OHHO HO OH HO OH HO OH OH R' R' R' R' R R R R R-CHO, Ethanol, HCl 1 R = CH(CH2CH3)2 R' = CH3 2 R = C6H13 R' = CH3 3 R = C9H19 R' = CH3 4 R = CH(CH2CH3)2 R' = H 5 R = C6H13 R' = H 6 R = C9H19 R' = H R' Scheme 1 Condensation reaction between resorcinol and aldehyde. 2.2. Allylation of Octahydroxy resorcinarenes Resorcinarenes, 16 were subsequently perallylat ed by its reaction with allyl bromide in presence of potassium carbonate as a base in refluxing acetone. Reaction conditions were modified a nd optimized. When DMF and potassium tert-butoxide were used at 60 o C, especially in case of alkyl substitu ents, the reaction resulted in a complex mixture of products in low yield of the pera llylated product. Additionally, the removal of DMF by distillation was tedious and might have attributed to the decomposition or side reactions. Allylation using acetone as a solvent and potassium carbonate as a base were therefore investigated. While the reactions worked well in 7-9 the reaction was extremely slow for compounds 1012. The allylation was therefore investigated in a sealed tube, which allowed higher reaction temperature to be attained (Scheme 2). Reactions in sealed tube c onditions were performed at 120 o C and led to clean products 8 and 9, in 60-76% yield. Compound 7, could be isolated in 36% yield. Although reactions 7

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were carried out at slightly lower temperature about 90 o C for resorcinol-derived resorcinarenes, products 1012 were isolated in 20-22% yield. 7 R = CH(CH2CH3)2 R' = CH3 8 R = C6H13 R' = CH3 9 R = C9H19 R' = CH3 10 R = CH(CH2CH3)2 R' = H 11 R = C6H13 R' = H 12 R = C9H19 R' = H Allyl bromide, K2CO3, Acetone sealed tube, 90-120oCHO HO OH HO OH HO OH OH R' R' R' R' R R R R O OO OOO O O R' R' R' R' R R R R 1 R = CH(CH2CH3)2 R' = CH3 2 R = C6H13 R' = CH3 3 R = C9H19 R' = CH3 4 R = CH(CH2CH3)2 R' = H 5 R = C6H13 R' = H 6 R = C9H19 R' = H Scheme 2 Allylation reaction of octahydroxy resorcinarene Compounds 712 were analyzed by 1 Hand 13 C NMR and APCI MS data. 1 H NMR clearly showed that changes occurred between 4.0 and 6.0 ppm after perallylation reaction. Allylic proton (O-C H 2 ) appeared between 4.0-4.4 ppm, the vinylic proton (CH=C H 2 ) appeared between 5.0-5.4 ppm and the non-terminal vinylic proton (C H =CH 2 ) appeared between 5.8-6.0 ppm (Figure 4). In the 13 C NMR spectrum, the allylic carbon appeared between 65.0-75.0 ppm, the termin al vinylic carbon appeared between 115.0120.0 ppm and the non-terminal carbon peak appeared between 125.0-130.0 ppm. 8

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O O O O O O O O Figure 4. 1 H NMR of compound 12. Compound 7 was crystallized out from an acetone and methanol solvent (50:50) system. The ORTEP plot of 7 is shown in figure 5, which s hows the macrocyclic ring in the preferred crown conformation with th e allyloxy groups on the upper rim and the isopentyl groups on the lower rim. Figure 5. X-ray crystal structure of compound 7 9

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2.3. Ring Closing Metathesis of Allyloxy resorcinarenes: Four bridged cavitands Intramolecular cyclization leading to a bridged structure has been a very important feature of the synt hesis of many of these cavit ands. Ring-closing metathesis (RCM) is becoming a preferred approach to synthesis of medium and large sized macrocycles. Advancement in the design of the catalyst leading their remarkable functional group tolerance, operational simplicit y, high stability and commercial availability has greatly contributed to the popularity of the RCM reaction. However, there have been no reports describing use of RCM reaction for manipulating the cavity size of the resorcinarene cavitands. We realized that ther e exists an opportun ity to exploit the RCM reaction for manipulating the cavity size of the resorcinarene cavitands by utilizing multiple tandem ring closings on the upper ri m (Figure 6). Resorcinarene has two welldefined rims; a lower rim defined by alkyl or phenyl substituents from corresponding aldehyde and an upper rim defined by hydroxyl groups of resorcinol. In this chapter, we describe our results from the st udy of the RCM reaction on compounds 712. O OO OOO O O R' R' R' R' R R R R O OO OOO O O R' R' R' R' R RR R Figure 6. Ring closing metathesis of allyloxy reso rcinarenes to bridged resorcinarenes. 10

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As described in the previous section, upper rim hydroxyl groups in 16 were allylated to synthesize oc taallyloxy resorcinarenes, 712. In this investigation, we utilized the Grubbs catalyst, which has been widely us ed for ring closing metathesis due to its remarkable functional group tolerance, operational simplicity, high stability and commercial availability. Interesting conf ormational dynamics in the octaallyloxy resorcinarene due to its flexibility (Figur e 7) resulted in in teresting observations summarized in the following sections. Figure 7. Grubb's generation I catalyst. The reaction was carried out under a nitrogen atmosphere using dry dichloromethane as a solvent. 5-8 mol % of Grubbs catalyst was used in the reaction. The reaction was continued for 4 days. Thin layer chromatography showed the appearance of compound with lower R f value [R f = 0.4, ethyl acetate and hexane (20:80) solvent system]. It was separated on column chromatography and analyzed by 1 Hand 13 CNMR, 2D NMRs and mass spectral data. In case of compounds 7 9; all four 2-butylene bridges were formed on the upper rim leading to the compounds 1315 (Scheme 3) in 35-61 % yield. 11

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7 R = CH(CH2CH3)2 8 R = C6H13 9 R = C9H19 Grubb's catalyst, Dry DCM R.T., 4 daysO O O OOO O O R RR R 13 R = CH(CH2CH3)2 14 R = C6H13 15 R = C9H19O O O OOO O O R R R R Scheme 3 Ring closing metathesis of octaallyloxy resorcinarenes 79. Compound 13 was obtained in 35% yield after 9 6h stirring the reaction mixture at 25 o C using 5 mol % of grubb's catalyst. Reactio ns were repeated with higher amount of catalyst (8 mole %) or an additional amount of catalyst was added after 48h, but without higher conversion. The compound 13 was the only compound formed and the unreacted substrate 7 was recovered after column chromatogr aphy to be reused in the reaction to increase overall yield of the cavitand 13. The structure of the cavitand 13 was established using 1 Hand 13 CNMR spectral data. Molecu lar weight of the compound 13 was determined to be 1032 g/mol [Observed m/z =1033.7 (M+H + )] from it APCI MS analysis. In the 1 H NMR spectrum of 13, the proton peaks for the (CH=C H 2 ) groups observed in the 1 H NMR of 7 were replaced by the peak of single alkene protons ( H C=C H ) of the bridge. Its 13 C NMR spectrum, resonances that appeared at 116.0-118.0 ppm for terminal vinyl carbons (CH= C H 2 ) in 7 had disappeared while a new resonances for the bridge (H C = C H) formed after ring-closing me tathesis were at 125.0-130.0 ppm. 12

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Compound 14 was isolated in 59% yield from its precursor 8. Its 1 HNMR and 13 CNMR and mass spectral (APCI) analysis were in accordance with the four-bridged structure. In the 1 H-NMR spectrum the alkene protons ( H C=C H ) were at 5.9 ppm while the terminal (=C H 2 ) allylic protons of 8 were not observed (Figure 8). Molecular weight of the compound 14 was determined to be 1088 g/mol [Observed m/z =1089 (M+H + )] from it APCI MS analysis. O O O OOO O O Figure 8. 1 H NMR of compound 14. The compound 14 was crystallized from a meth anol and ethyl acetate (70:30) solvent system. The crystal stru cture shows the formation of all four bridges in the upper rim (Figures 9 and 10). It also confirmed the tetrameric rigid structure with crown conformation (C 4v symmetry) in which all four methyls and four bridges remain in the upper rim and heptyl substituents remain in the lower rim. 13

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Figure 9. X-ray crystal structure of 14 (top view). Figure 10. X-ray crystal structure of 14 (side view). 14

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X-ray diffraction analysis of recrystallized sample of 14 established its molecular conformation in the solid state. 56 % reflections had I > 2 (I) in the range 2.5 o < 2 < 23 o Crystals came out to be monoclinic, colorl ess prism. The dimension of the O4-C41C45-O5 bridge formed between phenyl rings C8-C13 and C15-C20 are: angles C12C11O4, C11O4C41, O4C41C42, C41C42C 43, C11C12C14, C12C14C15 were 119 o 116 o 112 o 132 o 120 o and 113 o respectively; bond length between C42-C43 is 1.32A o and between C43-C44 is 1.5A o The distance between two met hyl groups in phenyl rings on the opposite side of the cavity was 8-13A o while the distance between the two carbons in the opposite bridges was determined to be 13A o This cavity size of the cavitand is considerably larger than the bri dged resorcinarenes reported in the literature with the cavity of 8-10A o 5,12,13,14,15 Thus we were able to manipulate the cavity size in cavitands by intramolecular multiple ring clos ing metathesis reactions on the upper rim of the resorcinarenes. This is the first report de scribing tandem formation of the four bridges on the upper rim of resorcinarenes. The crystal structure of compound 14 also confirmed that RCM reaction involved two allyl groups on the adjacent phenyl rings rather than those on the same phenyl ring. Compound 15 was isolated in 61% yield from its precursor 9. Its 1 HNMR and 13 CNMR and mass spectral data (APCI) were fully consistent with the intramolecular four-bridged-structure. The molecular weight of compound 15 was determined to be 1256 g/mol [Observed m/z =1257 (M+H + )] from it APCI MS analysis. Compound 15 retained a crown cone conformation (C 4v symmetry) in which all four methyls and four bridges remain in the upper rim and decyl chain remains in the lower rim. 15

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Figure 11. 13 C NMR spectra show that the resonance in octaallyloxy resorcinarene 8 between 116-118 ppm disappears when it unde rgoes ring closing metathesis and the resonance at 122 ppm becomes very prominent in compound 14. 2.4 Synthesis of partially bridged resorcinarenes by RCM: Two bridged resorcinarenes. RCM reaction catalyzed by the Grubb's generation I catalyst in 11 and 12 led to partially bridged products 16 and 17 respectively with 32-35% yield (Scheme 4). Even at higher concentration of the Grubb's catal yst (8-10 mole %), formation of only two bridges was observed after 4 days of reaction monitoring. Unreacted 11 and 12 were recovered by column chromatography and re used to increase th e overall yield. The structures of compounds 16 and 17 were established by 13 Cand DEPT NMR data. 16

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Molecular weights of the compound 16 was determined to be 1088 g/mol [Observed m/z =1089 (M+H + )] and the compound 17 was determined to be 1256 g/mol [Observed m/z =1257 (M+H + )] from it APCI MS analysis. In 1 H NMR spectra (Figure 12) of 16 and 17 two different alkene protons originating from unreacted allyl groups (5.1-5.4 ppm for the =C H 2 ; 6.1 ppm for the =C H ) and the alkene bridge (5.9 ppm ( H C=C H ) were observed. The appearance of only two sets of resonances for the alkenyl protons (unreacted and in the bridge) suggested a two-fold symmetry in compounds 16 and 17. Similar observations were also made from their 13 CNMR data in which the two set of resonances were observed for the alkenyl carbons (115.0 ppm for the = C H 2 ; 133.0 ppm for the = C H form unreacted allyl group; 127 ppm C = C in the bridge) further establishing a two fold symmetry in the compounds. Thus it was concluded that two bridges formed opposite to each other on the same upper rim side. O O O OOO O O R R R R Grubb's catalyst, Dry DCM R.T., 4 daysO O O OOO O O R R R R 16 R = C6H13 17 R = C9H1911 R = C6H13 12 R = C9H19 Scheme 4. Ring closing metathesis of octaallyloxy resorcinarenes 11 and 12. 17

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Figure 12. 1 H NMRs of compound 16 and its precursor 11. 2.5 Synthesis of single br idged compounds by RCM In compounds 18 and 19 RCM reaction led to formation of compounds 20 and 21, respectively (Scheme 5) in 13-16% yield. Starting material was recovered by column chromatography and was reused in the reac tion. Molecular weights of the compounds 20 [Observed m/z = 893 (M+H + )] and 21 [Observed m/z = 837 (M+H + )] from their APCI MS analysis suggested formation of a single bridge by reaction of the two allyl groups on the adjacent phenyl rings. 18

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O OO OOO O O R' R' R' R' Grubb's catalyst, Dry DCM R.T., 4 daysO O O OOO O O R' R' R' R' 20 R' = CH3 21 R'= H 18 R' = CH3 19 R'= H Scheme 5. Ring Closing Metathesis of Octaallyloxy Resorcinarene 18 and 19. Table 1: Following table gives complete idea a bout different resorcinarene cavitands we prepared in our lab with di fferent substituents. It also shows the reactions we tried to get those compounds and percent yield obtained in each case. Octahydroxy Compounds Allyloxy compounds With different routes of allylation RCM products Aldehydes HCl/ Ethanol DMF/ KO t Bu Acetone/ K 2 CO 3 Sealed tube Reaction Grubbs Cat/ DCM Ethanal (67%) -18 (76%) 18 (70%) 20 (13%) 2-Ethylbutanal 1 (80%) -7 (35%) 7 (40%) 13 (35%) Heptanal 2 (88%) -8 (55%) 8 (60%) 14 (59%) 2-Methyl1,3resorcinol Decanal 3 (85%) -9 (54%) 9 (55%) 15 (61%) Ethanal (48%) --19 (78%) 21 (16%) 2-Ethylbutanal 4 (57%) --10 (15%) -Heptanal 5 (78%) --11 (22%) 16 (32%) 1,3Resorcinol Decanal 6 (62%) --12 (20%) 17 (35%) In conclusion, allylation followed by intramolecular ring closing metathesis by Grubbs catalyst gave rigid enforced cavity on novel resorcinarene cavitands. It is the first report that describe s the synthesis of rigid concave resorcinarene cavitands by four tandem ring closing meta thesis reaction on the upper rim. Such resorcinarenes have potential applications as drug carriers, receptors and sensors for ions and neutral molecules. 19

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CHAPTER 3. SYNTHESIS OF POLYHYDROXY RESORCINARENE 3.1. Introduction to Polyhydroxy resorcinarenes Resorcinarene cavitands with heptyl substi tuent and methylene bridge (Figure 13) could be used in the synthesis of bio active compounds, drug carriers, precursors to formation of hemicarplexes, carplexes, capsu les by attaching differe nt functionalities to polyhydroxy cavitands obtained from them. They could also be used for broad range of applications such as metal complexing agen ts, sensors, water soluble cavitands, phase transfer extraction of heavy metals, etc. more over they could generate platforms for metal ligand exchange complexes, polymeric materials, self-assembled systems, enantioselective reaction sites as well as catalytic reactions. 1-6 O OO OOO O O Figure 13. Methylene-bridged resorcinarene with a heptyl substituent. 20

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3.2. Synthesis of Polyhydroxy resorcinares This synthesis began with condensation of 2-methylresorcinol and heptaldehyde in the presence of hydrochloric acid and ethano l as a solvent at refl ux temperature to give octahydroxy resorcinarene 2 with 88% yield after 24 h (Scheme 6). HO OH O OO OOO O O H H H H H H H H + 2 Ethanol, HCl Reflux, 24 hrs 88% yield Scheme 6 Synthesis of octahydroxy resorcinarene 2. Hydroxy groups on adjacent aromatic rings of compound 2 were reacted with bromochloromethane and potassium carbona te in DMF to form methylene (-CH 2 -) bridges in compound 22 The compound 22 was isolated in 73 % yield (Scheme 7). Its spectral data was identical to that reported in literature. 10,12 21

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O OO OOO O O H H H H H H H H O OO OOO O O Bromochloromethane DMF, K2CO3, 65-70oC, 24 hrs 73% yield 22 2 Scheme 7 Synthesis of methylen e bridge resorcinarene 22. Radical bromination of met hyl group of resorcinarene 22 ring in presence of NBS/ AIBN in degassed benzene resulted in the formation of the tetrabromide 23 in 80 % yield (Scheme 8). O OO OOO O O O OO OOO O O Br Br Br B r 22 23 NBS, AIBN, Benzene, Reflux, 24 hrs 80% yield Scheme 8 Synthesis of tetr abromo resorcinarene 23. Once this tetrabromo resorcinarne 23 was in hand, we attempted its alkylation. Reaction of 23 with ethyl chloroformate using butyll ithium as a base and the reduction of 22

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the tetraester formed resulted in the tetraol 24 (Figure 14). The synthesis of tetraol however was marred with low yield and tedi ous work-ups. Synt hesis of a tetraol 24 was also investigated through a Barbier reaction; tetrabromo resorcinarene was treated with Zn, formaldehyde in THFaqueous ammonium chloride solvent system. Besides low yield, the reaction suffered with use of formaldehydea toxic compound. Clearly a modified strategy was needed. O OO OOO O O OH OH OH OH Figure 14. Tetraol 24 obtained from tetrabromo resorcinarene. Tetrabromide 23 was therefore converted to octaester 25 in 75% yield by its reaction with diethyl malonate and sodium hydride in THF (Scheme 9). Compound was extracted in ethyl acetate, washed w ith brine solution and purified by column chromatography. 23

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O OO OOO O O Br Br Br Br O OO OOO O O EtOOC EtOOC COOEt COOEt EtOOC C O O E t COOEt COOEt 23 25 Diethyl malonate, THF, NaH 45oC, 24 hrs 75% yield Scheme 9 Formation of octaester 25 from tetrabromo resorcinarene. Figure 15 shows the compara tive proton NMRs of compound 25 and its starting material 23. It shows that the C H 2 Br resonance (D) at 4.4 ppm moves upfield to approximately 2.85 ppm after ester is formed and ethyl ester (-COOC H 2 CH 3 ) resonance ( A ) appears at around 4.0 ppm. Mol ecular weight of the compound 25 was determined to be 1562 g/mol [Observed m/z = 1562 (M + )] from its APCI MS analysis. 24

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Figure 15. Comparative proton NMRs of compounds 25 and its precursor 23. Octaester 25 was reduced by treating with sodium borohydride and lithium chloride to polyhydroxy resorcinarene 26 with 77% yield (Scheme 10). This compound was characterized from its detailed NMR analysis. 25

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O OO OOO O O EtOOC EtOOC COOEt COOEt EtOOC C O O E t COOEt COOEt O OO OOO O O HO HO OH OH HO OH OH OH 25 26 LiCl, NaBH4, Ether, 3 days, 40oC, 77% Scheme 10. Formation of polyhydroxy resorcinarene 26 from octaester resorcinarene. Glycosylation of the octahydroxy compound 26 with D-glucose pentaacetate in presence of BF 3 -etherate and subsequent removal of the acetates groups using sodium methoxide solution in methanol led to compound 27 with 92% yield (Scheme 11). O OO OOO O O HO HO OH OH HO OH OH OH O OO OOO O O GluO GluO OGlu OGlu GluO OGlu OGlu OGlu 26 27 (1) Glucose penta-acetate, DCM, BF3-Etherate, 2 days, R.T., 84% (2) NaOMe, Methanol 10 hrs, R.T., 92 % Scheme 11. Glycosylation of compound 26 with glucose pentaacetate. 26

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CHAPTER 4. EXPERIMENTAL 4.1. General Experimental Procedure All solvents and reagents were commercially available. Heptanal and diethylmalonate were purified by distilla tion. NMR spectra were recorded on 250 MHz, 400 MHz and 500 MHz spectrometer s. Mass spectra were recorded in APCI mode and using MALDI. Synthesis of octahydroxy resorcinarene (1): 2-Methylresorcinol (1.0 g, 8.1 mmol) was dissolved in anhydrous ethanol (6.27 ml, 775 ml/mol) and 37% aqueous HCl (1.51 ml, 185 ml/mol). The solution was cooled in an ice bath and 2-Et hylbutanal (0.81 g, 8.1 mmol) was added to the above solution slowly over a period of 30 min. Then the mixture was allowed to warm to room temper ature. The reaction was then maintained at temperature of 45 o C for nearly 3 hrs. Then the reac tion mixture was poured onto 50 ml of ice cold water. The precipitate was filtered through a Buchner funnel and it was washed several times until it turned neutral to pH paper. It was dried and the NMR spectrum was taken. 1: 80%; 1 H NMR (DMSO) 0.73 (m, 24H), 1.22 (m, 16H), 1.35 (m, 4H), 1.89 (s, 6H) 1.92 (s, 6H), 4.01 (m, 4H), 7.18 (s, 4H), 8.82 (s, 8H). 27

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Synthesis of octahydroxy resorcinarene (2): 2-Methylresorcinol (1.0 g, 8.1 mmol) was dissolved in anhydrous ethanol (6.27 ml, 775 ml/mol) and 37% aqueous HCl (1.51 ml, 185 ml/mol). The solution was cooled in an ice bath and heptanal (1.13 ml, 8.1 mmol) was added to the above solution slowly over a period of 30 min. Then the mixture was allowed to warm to room temperature. The reaction was then maintained at temperature of 80 o C, i.e. reflux for nearly 12 hrs after which we could see yellow colored precipitate. The precipitate was filtered through a Buc hner funnel and it was washed several times until it turned neutral to pH paper. It was dried and the NMR spectrum was taken. The compound 3 was synthesized in same manner. 2: 88%; 1 H NMR (DMSO) 0.84 (m, 12H), 1.23 (m, 32H), 1.93 (s, 12H), 2.21 (s, 8H), 4.18 (m, 4H), 7.21 (s, 4H), 8.69 (bs, 8H). 3: 85%; 1 H NMR (DMSO) 0.82 (m, 12H), 1.22 (m, 56H), 1.97 (m, 8H), 2.23 (s, 12H), 4.28 (m, 4H), 7.15 (s, 4H), 8.64 (bs, 8H). Synthesis of octahydroxy resorcinarene (4): Resorcinol (1.0 g, 9.1 mmol) was dissolved in mixture of 3.5 ml anhydrous etha nol, 3.5 ml of water and 37% aqueous HCl (1.68 ml, 775 ml/mol). The solution was cooled in an ice bath and 2-Et hylbutanal (0.81 g, 8.1 mmol) was added to the above solution slowly over a period of 30 min. Then the mixture was allowed to warm to room temperature and to stir at 45 o C for nearly one day. Then the reaction mixture was poured into 50 ml of ice cold water. The light yellowcolored precipitate was filter ed through Buchner funnel and it was washed several times until it turned neutral to pH paper. It was dried and the NMR spectrum was taken. 4: 57%; 1 H NMR (DMSO) 0.27 (m, 24H), 0.7 (m, 16H ), 1.51 (m, 4H), 3.55 (m, 4H), 6.01 (s, 4H), 7.36 (s, 4H), 9.01 (bs, 8H). 28

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Synthesis of octahydroxy resorcinarene (5): Resorcinol (1.0 g, 9.1 mmol) was dissolved in anhydrous ethanol (7.1 ml, 77 5ml/mol) and 37% aque ous HCl (1.68 ml, 185 ml/mol). The solution was cooled in an i ce bath and heptanal (1.27 ml, 9.1 mmol) was added to the above solution slowly over a period of 30 min. Then the mixture was allowed to warm to room temperature. The reaction was then maintained at temperature of 60 o C for nearly 36 hrs. Then the reaction mixt ure was poured into 50 ml of ice cold water. The precipitate was filtered through Buchner funnel and it was washed several times until it turned neutral to pH paper. It was dried and the NMR spectrum was taken. 5: 78%; 1 H NMR (DMSO) 0.82 (m, 12H), 1.21 (m, 32H) 2.07 (m, 8H), 4.23 (m, 4H), 6.13 (s, 4H), 7.12 (s, 4H), 8.55 (s, 8H). Synthesis of octahydroxy resorcinarene (6): Resorcinol (1.0 g, 9.1 mmol) was dissolved in anhydrous ethanol (7.1 ml, 775 ml/mol) and 37% aque ous HCl (1.68 ml, 185 ml/mol). The solution was cooled in an ice bath and decanal (1.71 ml, 9.1 mmol) was added to the above solution slowly over a period of 30 min. Then the mixture was allowed to warm to room temperature. The reaction was then maintained at temperature of 45 o C for nearly 24 hrs .The reaction mixture was poured into 50 ml of ice cold water which gave dark brown-colored precipitate. The precipitate was filtered through a Buchner funnel and it was washed several times until it turned neutral to pH paper. It was dried and the NMR spectrum was taken. 6: 62%; 1 H NMR (DMSO) 0.78 (m, 12H), 1.12 (m, 56H), 1.95 (m, 8H), 4.17 (m, 4H), 6.13 (s, 4H), 7.01 (s, 4H), 8.85 (bs, 8H). Synthesis of octaallyloxy resorcinarene (7): 1g of Octahydroxy compound (1) was taken in a sealed tube and acetone (20 ml/mmol) was added to it. The reaction 29

PAGE 43

mixture was stirred till homogenous mixture was formed. Then potassium carbonate (30 eq.) was slowly added over a period of half an hour. Here we observed the change in color from brown to purple. Then allyl brom ide (30 eq.) was added into it at room temperature. The reaction mixture was heated to temperature of 120 o C for nearly 48 hrs. The reaction mixture was filtered and then c oncentrated. It was recrystallized using 50% acetone and 50 % methanol mixture. The NMR spectrum of crystals was taken. 13 C NMR and DEPT 135 were taken on this compound since the proton NMR of this compound gave broad peaks. Compounds 8 and 9 were synthesized in same manner. 7: 36%; 1 H NMR (CDCl 3 ) 0.75 (m, 24H), 1.42 (m, 16H), 1.86 (m, 4H), 2.15 (s, 12H), 3.95 (m, 16H), 4.55 (m, 4H), 5.24 (m, 16H), 5.91 (m, 8H), 6.65 (s, 4H) ; 13 C NMR 10.3, 12.7, 22.2, 24.3, 36.4, 37.3, 40.2, 45.1, 48 .2, 73.1, 74.5, 116.2, 16.7, 125.8, 127.3, 134.4, 134.8, 135.6, 135.1. 8: 60%; 13 C NMR (CDCl 3 ) 10.7, 14.2, 22.9, 28.9, 29.8, 32.1, 35.4, 38.4, 73.3, 116.2, 124.0, 124.0, 124.6, 134.6. 9: 55%; 1 H NMR (CDCl 3 ) 0.82 (t, 12H, J = 7.2 Hz), 1.26 (m, 56H) 1.85 (m, 8H), 2.15 (s, 12H), 4.25 (m, 16H), 4.55 (m, 4H), 5.25 (m, 16H), 6.13 (m, 8H), 6.55 (s, 4H); 13 C NMR 10.6, 10.9, 14.2, 22.8, 28.6, 28.9, 29.5, 30.2, 32.1, 33.5, 34.1, 35.4, 36.5, 37.4, 37.9, 38.4, 38.7, 40.0, 73.3, 73.7, 73.9, 74.5, 74.7, 116.2, 116.4, 116.7, 117.0, 117.3, 124.0, 124.5, 124.7, 124.9, 130.2, 131.7, 133.9, 134.4, 134.6, 134.7, 134.8, 136.8, 153.6, 153.9, 154.6, 155.2. Synthesis of octaallyloxy resorcinarene (10): 1.0 g of octahydroxy compound (4) was added to sealed tube and acetone (20 ml/mol) was added to it. The reaction mixture was stirred till homogenous mixture was formed. Then potassium carbonate (30 30

PAGE 44

eq.) was added to the reaction mixture. Here we observed the change in color from brown to purple. Then allyl bromide (30 eq.) wa s added. The reaction mixture was heated to temperature of 90 o C for nearly 48 hrs. The reaction mixture was filtered and then concentrated. It was recrystallized using acetone and methanol mixture. 13 C NMR, 1 H NMR spectrums of crystals were taken Compounds 11 and 12 were also synthesized in same fashion. 10: 15%; 1 H NMR (CDCl 3 ) 0.65 (m, 24H), 1.19-1.25 (m, 16H), 1.42 (m, 4H), 4.21 (m, 16H), 4.33 (m, 4H), 5.22 (m, 16H), 5.9 4 (m, 8H), 6.22 (s, 4H), 6.95 (s, 4H). 11: 22%; 1 H NMR (CDCl 3 ) 0.73 (t, 12H, J = 7.2 Hz), 1.12-1.23 (m, 32H,), 1.72 (m, 8H), 4.11 (d, 8H, J = 12.0 Hz), 4.28 (dd, 8H, J = 12.0 Hz), 4.51 (t, 4H, J = 4.0 Hz), 5.11 (d, 8H, J = 8.0 Hz), 5.29 (d, 8H, J = 16.0 Hz), 5.82 (m, 8H), 6.11 (s, 4H,), 6.52 (s, 4H). 13 C NMR 14.1, 21.0, 22.8, 28.3, 29.7, 31.9, 34.7, 35.8, 69.6, 99.3, 116.1, 125.9, 134.1, 154.8. 12: 20%; 1 H NMR (CDCl 3 ) 0.81 (t, 12H, J = 7.2 Hz), 1.23-1.31 (m, 56H), 1.85 (m, 8H), 4.13 (d, 8H, J = 12.0 Hz), 4.31 (d, 8H, J = 12.0 Hz), 4.59 (t, 4H, J = 4.0 Hz), 5.13 (d, 8H, J = 8.0 Hz), 5.31 (d, 8H, J = 16.0 Hz), 5.94 (m, 8H), 6.35 (s, 4H), 6.65 (s, 4H). Synthesis of bridged-resorcinarene (13) : To a stirred solution of octa-allyloxypentyl-methylresorcinarene (7) (1.0 gm, 0.86 mmole) in dry methylene chloride (90 ml) was added grubbs catalyst (10 mole %, 0.071 gm, 0.086 mmole) in dry methylene chloride (20 ml) at room temperature. The reaction was continued for 4 days. The reaction mixture was then concentrated ove r rotavapor and column chromatography was run using 10% ethyl acetate and 90% hexane so lvent system to separate two spots. The 31

PAGE 45

second spot (fraction) proved to be desired ring closed compound with 35% yield. The compound was confirmed by 13 C, DEPT, HSQC, Mass spectroscopy. 1 H NMR (CDCl 3 ) 0.21 (m, 24H), 1.02-0.71 (set of m, 16H), 1.31 (m, 4H), 2.23 (s, 12H ), 4.81-4.21 (set of m, 16H), 5.22 (m, 4H), 6.235.92 (set of m, 8H), 7.02 (s, 4H); 13 C NMR (CDCl 3 ) in ppm 9.9, 10.1, 10.3, 10.8, 10.9, 11.5, 12.0, 14.3, 22.3, 23.1, 37.5, 39.8, 41.5, 42.1, 42.7, 43.4, 47.5, 49.8, 51.6, 60.5, 69.5, 123.8, 124.0, 124.3, 124.5, 125.0, 125.7, 126.0, 126.7, 127.1, 127.4, 127.8, 128.2, 130.5, 131.0, 132.0, 132.4, 132.7, 132.9, 133.1, 133.2, 133.5, 134.5, 134.6, 150.9, 155.0, 156.5, 171.3; APCI m/z 1033.7 (M+H + ). Synthesis of bridged-resorcinarene (14) : To a stirred solution of octa-allyloxyheptyl-methylresorcinarene (8) (1.0 gm, 0.83 mmole) in dry methylene chloride (87 ml) was added grubbs catalyst (8 mole %, 0.054 gm, 0.066 mmole) in dry methylene chloride 920ml) at room temperature. The reaction was conti nued for 4 days. The reaction mixture was then concentrated ove r rotavapor and column chromatography was run using 10% ethyl acetate and 90% hexane so lvent system to separate two spots. The second spot (fraction) proved to be desired ring closed compound. Recrystallization from methanol-ethyl acetate yielded 27 (59%) as a white crystalline solid. It was confirmed by 1 H NMR, COSY, 13 C, DEPT, HSQC, Mass spectrosc opy and X-ray diffraction method. 1 H NMR (CDCl 3 ) in ppm 0.82 (t, 12H, J = 6.8 Hz), 1.27-1.20 (set of m, 32H), 1.85 (m, 8H), 2.18 (s, 12H), 4.45 (d, 8H, J = 12.4 Hz), 4.73 (dd, 8H, J = 2.4 Hz, J = 12.8 Hz), 4.82 (t, 4H, J = 8.0 Hz), 5.88 (bs, 8H), 7.03 (s, 4H); 13 C NMR (CDCl 3 ) in ppm 11.5, 14.2, 22.9, 28.0, 29.6, 32.1, 36.1, 37.2, 71.0, 123.7, 129.14, 133.5, 154.9; APCI m/z 1089.7 (M+H + ). 32

PAGE 46

Synthesis of bridged-resorcinarene (15) : To a stirred solu tion of octa-allyloxy decyl methylresorcinarene (9) (1.0 gm, 0.73 mmole) in dry me thylene chloride (77 ml) was added grubbs catalyst (8 mole %, 0.048 gm, 0.058 mmole) in dry methylene chloride (17 ml) at room temperature. The reaction was continued for 4 days. The reaction mixture was then concentrated ove r rotavapor and column chromatography was run using 10% ethyl acetate and 90% hexane so lvent system to separate two spots. The second spot (fraction) proved to be desired ring closed compound with 61% yield. It was confirmed by 1 H NMR, COSY, 13 C, DEPT, HSQC, Mass spectroscopy. 1 H NMR (CDCl 3 ) 0.83 (t, 12H, J = 6.8 Hz), 1.24-1.12 (set of m, 32H), 1.82 (m, 8H), 2.14 (s, 12H), 4.41 (d, 8H, J = 12.0 Hz), 4.68 (dd, 8H, J = 3.4 Hz, J = 12.5 Hz), 4.76 (t, 4H, J = 7.6 Hz), 5.85 (bs, 8H), 7.01 (s, 4H); 13 C NMR (CDCl 3 ) in ppm 10.3, 13.0, 21.6, 26.9, 28.3, 28.6, 28.7, 28.8, 30.9, 34.9, 35.9, 69.7, 122.5, 127.9, 132.3, 153.6; APCI m/z 1257.9 (M+H + ). Synthesis of bridged-resorcinarene (16) : To a stirred solution of octa-allyloxyheptyl-resorcinarene (11) (1.0 gm, 0.87 mmole) in dry methylene chloride (91 ml) was added grubbs catalyst (8 mole %, 0.057 gm, 0.0 7 mmole) in dry methylene chloride (20 ml) at room temperature. The reaction was continued for 4 days. The reaction mixture was then concentrated over rotavapor a nd column chromatography was run using 10% ethyl acetate and 90% hexane solvent system to separate two spots. The second spot (fraction) showed that four allyl groups were closed fo rming two bridges with 32% yield. It was confirmed by 1 H NMR, COSY, 13 C, DEPT, HSQC, Mass spectroscopy. 1 H NMR (CDCl 3 ) 0.77 (t, 12H, J = 6.2 Hz), 1.13-1.73 (set of m, 32H), 1.85 (m, 8H), 4.25 (m, 16H), 4.55 (d, 2H, J = 2.5 Hz), 4.62 (s, 2H), 5.18 (dd, 4H, J = 1.2 Hz, J = 10.5 Hz), 5.41 33

PAGE 47

(dd, 4H, J = 1.5 Hz, J = 17.5 Hz), 5.86 (s, 2H), 5.93 (s, 2H), 6.12 (m, 4H), 6.45 (s, 4H), 7.12 (s, 4H); 13 C NMR (CDCl 3 ) in ppm 13.0, 21.7, 27.2, 28.7, 30.9, 33.4, 34.5, 63.6, 68.9, 96.8, 98.2, 115.3, 125.3, 125.6, 123, 127.0, 129, 133.3, 152, 153 ; MALDI m/z 1090.039 (M + ), 1112.068 (M+Na + ). Synthesis of bridged-resorcinarene (17) : To a stirred solu tion of octa-allyloxy decyl resorcinarene (12) (1.0 gm, 0.76 mmole) in dry met hylene chloride (80 ml) was added grubbs catalyst (8 mole %, 0.05 gm, 0.06 1 mmole) in dry methylene chloride (17 ml) at room temperature. The reaction was continued for 4 days. The reaction mixture was then concentrated over rotavapor a nd column chromatography was run using 10% ethyl acetate and 90% hexane solvent system to separate two spots. The second spot (fraction) showed that four allyl groups were closed fo rming two bridges with 35% yield. It was confirmed by 1 H NMR, COSY, 13 C, DEPT, HSQC, Mass spectroscopy. 1 H NMR (CDCl 3 ) 0.79 (t, 12H, J = 6.2 Hz), 1.12-1.73 (set of m, 32H), 1.98 (m, 8H), 4.34 (m, 16H), 4.68 (s, 2H), 4.77 (s, 2H), 5.19 (dd, 4H, J = 1.2 Hz, J = 10.2 Hz), 5.43 (dd, 4H, J = 1.5 Hz, J = 17.0 Hz), 5.88 (s, 2H), 5.95 (s, 2H), 6.11 (m, 4H), 6.45 (s, 4H), 7.12 (s, 4H); 13 C NMR (CDCl 3 ) in ppm 13.0, 21.6, 27.2, 28.3, 28.7, 28.7, 29.0, 30.9, 33.4, 34.4, 34.5, 63.5, 68.9, 96.8, 98.1, 115.3, 122.7, 125.3, 125.6, 127.0, 128.7, 133.3, 152.0, 153.2; MALDI m/z 1257.676 (M +H + ). Synthesis of bridged-resorcinarene (20) : To a stirred solution of octa-allyloxymethyl-methylresorcinarene (18) (1.0 gm, 1.086 mmole) in dry methylene chloride (114 ml) was added grubbs catalyst (8 mole%, 0.071 gm, 0.087 mmole) in dry methylene chloride (25 ml) at room temperature. The reaction was continued for 4 days. The reaction mixture was then concentrated ove r rotavapor and column chromatography was 34

PAGE 48

run using 10% ethyl acetate and 90% hexane solvent system to separate four spots. The fourth spot (fraction) showed that two allyl groups we re closed forming one bridge. It was confirmed by Mass spectroscopy. MALDI m/z 893.796 (M+H + ), 915.843 (M+Na + ), 933.844 (M+K + ). Synthesis of bridged-resorcinarene (21) : To a stirred solution of octa-allyloxymethyl-resorcinarene (1.0 gm, 1.156 mmole) in dry methylene chloride (121 ml) was added grubbs catalyst (8 mole %, 0.075 gm, 0.092 mmole) in dry methylene chloride (26 ml) at room temperature. The reaction was continued for 4 days. The reaction mixture was then concentrated over rotavapor a nd column chromatography was run using 10% ethyl acetate and 90% hexane so lvent system to separate f our spots. The fourth spot (fraction) showed that two a llyl groups were closed forming one bridge. It was confirmed by Mass spectroscopy. APCI m/z 837.4 (M+H + ), 854.5 (M+H 2 O). Synthesis of methylene-bridged heptyl resorcinarene (22): Octahydroxyheptyl-methylresorcinarene (2) (1.0 g, 1.1 mmol) was diss olved in DMF (11 ml, 10 lit/mol) at room temperature. Potassium carbonate (2.43 g, 17 .6 mmol) was added to it at 0 o C. It was stirred for 30 min., then adde d bromochloromethane (1.54 ml, 17.6 mmol) and heated upto 65-70 o C. After 24 hrs, TLC showed th e appearance of top spot and starting material was totally consumed. The reaction mixture was filtered off and DMF was distilled. The residue was taken in DC M and extracted with brine solution. DCM was then concentrated over rotavapor and com pound was separated by column in 10% ethyl acetate and 90% hexane solvent system to give 73% yield. It was confirmed by 1 H NMR, 13 C, DEPT. 13 C NMR (CDCl 3 ) in ppm 10.5, 14.2, 14.3, 22.8, 18.12, 29.72, 30.16, 30.31, 32.08, 37.04, 37.08, 37.18, 60.54, 98.7, 117.77, 123.79, 138.12, 153.43. 35

PAGE 49

Synthesis of Tetrabromo resorcinarene (23): Methylene bridged heptyl resorcinarene (22) (1.0 g, 1.1 mmol) was dissolved in (20.9 ml, 19 lit/mol) degassed benzene. NBS (1.17 g, 6.6 mmol) and AIBN (0.018 g, 0.11 mmol) were added to reaction mixture at room temperature. The reaction mi xture was refluxed for 24 hrs. After 24 hrs, observing TLC to make sure that starting materi al is consumed and new spot appeared at higher R f value, the reaction mixture was taken fo r work-up. It was firs t filtered off to separate succinimide and then benzene was concentrated over rotavapor. The Column was run in 10% ethyl acetate and 90 % he xane solvent system and the compound was crystallized out from acetone with 80% yield. It was confirmed by 1 H NMR, 13 C NMR and DEPT. 1 H NMR (CDCl 3 ) 0.87 (t, 12H, J = 6.8 Hz), 1.28 (set of m, 24H), 1.41 (q, 8H, J = 5.2 Hz), 1.97 (s), 2.17 (q, 8H, J = 6.4 Hz), 4.39 (s, 8H), 4.52 (d, 4H, J = 6.4 Hz), 4.75 (t, 4H, J = 7.6 Hz), 6.02 (d, 4H, J = 6.0 Hz), 7.11 (s, 4H); 13 C NMR (CDCl 3 ) in ppm 22.7, 23.0, 27.9, 29.5, 30.2, 31.9, 37.0, 98.3, 121.1, 124.6, 138.2, 153.7. Synthesis of Octa-ester resorcinarene (25): To a stirred solution of distilled diethyl malonate (0.74 ml, 4.8 mmole) in dry THF (8 ml, 10 lit/mol) at 0 o C was added NaH (0.1152 g, 4.8 mmole) portionwise under ni trogen atmosphere. The reaction was stirred for 20 min and solution of tetrabromo resorcinarene (23) (1.0 g, 0.8 mmol) was added over a 90 min period. The reaction mixtur e was then warmed to room temperature and the reaction was continued for 24 hrs. It was also heated to 45 o C for 12 more hrs. TLC was checked to make sure that starti ng material was consumed and a new spot appeared at lower R f value, the reaction mixture was taken for work-up. It was first concentrated under reduced pressure and the viscous liquid was taken up in ethyl acetate, extracted with brine solution. An organic layer was dried over sodium sulfate and 36

PAGE 50

concentrated. The column was run in a 30% ethyl acetate and 70% he xane solvent system to get the product in 75 % yield. The compound was confirmed by 1 H NMR, 13 C NMR and DEPT. 1 H NMR (CDCl 3 ) 0.82(t, 12H, J = 5.0 Hz), 1.04 (t, 24H, J = 6.2 Hz), 1.13 (t, 8H, J = 7.5 Hz), 1.33-1.27 (set of m, 24H), 2.11 (bs, 8H), 1.55 (s), 2.85 (d, 8H, J = 5.5 Hz), 3.52 (t, 4H, J = 7.5 Hz), 4.02 (p, 16H, J = 6.7 Hz), 4.12 (d, 4H, J = 6.2 Hz), 4.63 (t, 4H, J = 7.5 Hz), 5.76 (d, 4H, J = 6.5 Hz), 6.95 (s, 4H). MALDI m/z 1562.174 (M + ), 1584.264 (M+Na + ). Synthesis of Octahydroxy resorcinarene (26): Octa-ester resorcinarene (25) (1.0 g, 0.64 mmol) was solublized in ether (12.8 ml, 20 lit/mol) and LiCl (0.435 g, 10.2 mmole) was added to it at 0 o C. the reaction mixture was then stirred for additional 10 minutes. NaBH 4 (0.386 g, 10.2 mmole) was then adde d portionwise over 30 minutes period. The reaction mixture was warmed to ro om temperature and allowed to stir for 48 hrs at 40 o C. TLC was checked to make sure that starting material was consumed and a new spot appeared at lower R f value, the reaction mixture was taken for work-up. It was first quenched with methanol. It was concen trated over rotavapor. The residue was taken in DCM and extracted with aqueous NH 4 Cl. An organic layer was dried over sodium sulfate and concentrated to get product in 77% yield. The compound was confirmed by 1 H NMR, 13 C NMR and DEPT. 1 H NMR (DMSO) 0.8 (t, 12H, J = 7.0 Hz), 1.21-1.18 (set of m, 24H), 1.28 (s, 8H), 1.33 (bs, 8H ), 2.28 (m, 4H), 3.18 (s, 8H), 3.35 (s, 16H), 3.51 (s, 4H), 4.51 (bs, 4H), 5.71 (d, 4H, J = 2.0 Hz), 7.39 (bs, 8H). Synthesis of Glycosilate d resorcinarene (27): Octa-acid resorcinarene (26) (1.0 g, 0.8 mmol) and D-glucose pent aacetate (2.5 g, 6.4 mmol) were solublized in DCM (16 ml, 20 lit/mol) and the reaction mixture was cooled to 0 o C. BF 3 -etherate (4.5 ml, 32.0 37

PAGE 51

mol) was added to the reaction mixture. The reaction mixture was warmed upto room temperature and allowed to stir for 48 hrs at room temperature. TLC was checked to make sure that starting material was consum ed and a new spot appeared at higher R f value, the reaction mixture was taken for work -up. It was first neut ralized with sodium bicarbonate solution. It was concentrated over rotavapor. The residue was then extracted with ethyl acetate and washed with water till neutral pH. An organic layer was dried over sodium sulfate and concentrated to ge t product with 84% yield. The product was subsequently deacetylated by 0.022N sodium methoxide solution (1.6 ml, 60 lit/mol) in methanol (16 ml, 20 lit/mol). After 10 hrs, TLC was checked and appearance of lower spot was observed. The starting material was completely deacetylated. It was neutralized by proton exchange Dowex resi n. The reaction mixture was filtered and methanol was evaporated to give compound 30 in 92% yield. It was confirmed by 1 H NMR, 13 C NMR and DEPT. 13 C NMR (CDCl 3 ) in ppm 20.7, 20.8, 20.9, 61.6, 67.9, 68.0, 69.4, 70.0, 70.4, 72.9, 89.2, 91.9, 169.1, 169.4, 169.6, 170.3, 170.8. 4.2. Crystal structure data of Resorcinarenes (1) Crystal data of allyloxy-methy l-methylresorcinarene (18): Colorless parallelepiped, C 60 H 72 O 8 F.W.= 921.18, triclinic, space group P1, a= 9.774(3), b= 15.987(4), c= 17.049(4) A 0 = 84.594(16) 0 V= 2582(12) A 0 3 Z= 2, D = 1.185 Mg m -3 T= 110 K. Data were collected on Kappa CCD diffractometer (2.5 0 < < 38

PAGE 52

29.5 0 ) using Mo K radiation, ( = 0.71073A 0 ). From the 9131 reflections measured, 4539 (I > 2 (I)) were used in the refinements. (2) Crystal data of allyloxy-pentyl-methylresorcinarene (7): Colorless parallelepiped, C 76 H 104 O 8 F.W.= 1145.59, triclinic, space group P1, a= 12.0664(10), b= 15.9274(12), c= 20.1225(15) A 0 = 96.660(5) 0 V= 3369(5) A 0 3 Z= 2, D = 1.129 Mg m -3 T= 115 K. Data were collecte d on Kappa CCD diffractometer (2.5 0 < < 29.5 0 ) using Mo K radiation, ( = 0.71073 A 0 ). From the 14249 reflections measured, 11348 (I > 2 (I)) were used in the refinements. (3) Crystal structure of bridged-heptyl-methylr esorcinarene (14): Colorless prism, C 72 H 96 O 8 .0.5 (C 4 H 8 O 2 ), F.W.= 1133.54, monoclinic, space group P2 1 /c, a= 17.333(2), b= 34.347(4), c= 23.388 (2) A 0 = 110.586(6) 0 V= 13035(2) A 0 3 Z= 8, D = 1.155 Mg m -3 T= 115 K. Data were collected on Kappa CCD diffractometer (2.5 0 < < 23 0 ) using Mo K radiation, ( = 0.71073 A 0 ). From the 18119 reflections measured, 10173 (I > 2 (I)) were used in the refinements. 39

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References 1. (a) Hgberg, A. G. S. J. Am. Chem. Soc. 1980, 102, 6046. (b) Hgberg, A. G. S. J. Org. Chem. 1980, 45, 4498. 2. Cram, D. J.; Karbach, S.; Kim, H.; Knobler, C. B.; Maverick, E. F.; Ericson, J. L.; Halgeson, R. C. J. Am. Chem. Soc. 1988, 110, 2229. (b) Cram, D. J.; Stewart, K. D.; Goldberg, I.; Trueblood, K. N. J. Am. Chem. Soc 1985, 107, 2574. 3. (a) Cram, D.J.; Cram, J. M. Container Mo lecules and their Guests, Stoddart, J. F. Eds.; Royal Society of Chemistry; Cambridge, 1994. (b) Timmerman, P.; Verboom, W.; Reinhoudt, D. N. Tetrahedron 1996, 52, 2663. (c) Asfari, Z.; Bohmer, V.; Harrowfield, J.; Vicens, J.; Saadioui, M.; Eds.; Kluwer Academic Publishers: Dordrecht, Calixarenes, 2001. 4. (a) Middel, O.; Verboom, W.; Hulst, R.; K ooijman, H.; Spek, A. L.; Reinhoudt, D. N J. Org. Chem. 1998, 63, 8259. (b) Rumboldt, G.; Bohmer, V.; Botta, B.; Paulus, E. F. J. Org. Chem 1998, 63, 9618. (c) Cram, D. J.; Karbach, S.; Kim, Y. H.; Baczynskyj, L.; Kalleymeyn, G. W. J. Org. Chem. Soc. 1985, 107, 2575. 5. (a) For general reviews on macroc yclic cavities see: Szejtli, J. Chem. Rev. 1998, 98, 1743. (b) Seel, C.; Vgtle, F. Angew. Chem. Int. Ed. Engl. 1992, 31, 528. (c) Roman, 40

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E.; Peinador, C.; Mendoza, S.; Kaifer, A. E J. Org. Chem 1999, 64, 2577. (d) Mezo, A. R.; Sherman, J. C. J. Org. Chem. 1998, 63, 6824. (e) Rudkevich, D. M.; Rebek, J. microview Jr. Eur. J. Org. Chem. 1999, 1991. 6. (a) Gibb, B. C.; Chapman, R. G.; Sherman, J. C. J. Org. Chem. 1996, 61, 1505. (b) Sherman, J. C. Tetrahedron 1995, 51, 3395. (c) Gutsche, C.D. Calixarenes; Royal Society of Chemistry: Cambridge, 1989. 7. Baeyer, A. Ber. Disch. Chem. Ges. 1872, 5, 25. 8. Michael, A. J. Am. Chem. Soc 1883, 5, 338. 9. Niederl, J. B.; Vogel, H. J. J. Am. Chem. Soc. 1940, 62, 2512. 10. (a) Cram, D. J. Science 1983, 219, 1177. (b) Moran, J. R.; Karbach, S.; Cram, D. J. J. Am. Chem. Soc. 1982, 104, 5826. 11. Tunstad, L. M.; Tucker, J. A.; Dalcanale, E. ; Weiser, J.; Bryant, J. A.; Sherman, J. C.; Helgeson, R. C.; Knobler, C. B.; Cram, D. J. J. Org. Chem. 1989, 54, 1305. 12. (a) Timmerman, P.; Boerrigter, H.; Verboom W.; Van Hummel, G. J.; Harkema, S.; Reinhoudt, D. N J. Inclusion Phenom. 1995, 18 1. (b) Cram, D. J.; Tunstad, L. M.; Knobler, C. B. J. Org. Chem. 1992, 57, 528. (c) Sorrell, T. N.; Pigge, F. C. J. Org. Chem. 1993, 58, 784. 13. Tucker, J. A.; Knobler, C. B.; Trueblood, K. N.; Cram, D. J. J. Am. Chem. Soc. 1989 111, 3688. 14. (a) Xu, W.; Jadagese, J. V.; Puddephatt, R. J. J. Am. Chem. Soc. 1993, 115, 6456. (b) Xu, W.; Vittal, J. J.; Puddephatt, R. J. J. Am. Chem. Soc. 1995, 117 8362. (c) Lippmann, T.; Wilde, H.; Dalcanale, E.; Mi nlla, L.; Mann, G.; Heyer, U.; Spera, S. J. Org. Chem. 1995, 60, 235. 41

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15. (a) Cram, D. J.; Choi, H. J.; Bryant, J. A.; Knobler, C. B. J. Am. Chem. Soc. 1992 114, 7748. (b) Vincenti, M.; Dalcanale, E.; Soncini, P.; Guglielmetti, G. J. Am. Chem. Soc. 1990, 112, 445. (c) Moran, J. R.; Ericson, J. L.; Dalcanale, E.; Bryant, J. A.; Knobler, C. B.; Cram, D. J. J. Am. Chem. Soc. 1991, 113, 5707. (d) Bryant, J. A.; Ericson, J. L.; Cram D. J. J. Am. Chem. Soc. 1990, 112, 1255. 16. Tucci, F. C.; Rudkevich, D. M.; Rebek, J. Jr. J. Org. Chem. 1999, 64, 4555. 17. (a) Pitarch, M.; Mckee, V.; Nieu wenhuyzen, M.; McKervey, M. A. J. Org. Chem. 1998, 63, 946. (b) Zuercher, W. J.; Hashimoo, M.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 6634. (c) McKervey, M. A.; Pitarch, M. Chem. Commun. 1996 1689. 18. Chen, C. F.; Lu, L. G.; Hu, Z. Q.; Peng, X. X.; Huang, Z. T. Tetrahedron 2005, 61 3853. 42

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APPENDICES 43

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HO HO OH HO OH HO OH OH Figure 16. 1 H NMR of compound 1. HO HO OH HO OH HO OH OH Figure 17 1 H NMR of compound 3. 44

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HO HO OH HO OH HO OH OH Figure 18. 1 H NMR of compound 4. HO HO OH HO OH HO OH OH Figure 19. 1 H NMR of compound 6. 45

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O O O OOO O O Figure 20. 1 H NMR of compound 7. O O O OOO O O Figure 21. 13 C NMR of compound 8. 46

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O OO OOO O O Figure 22. 1 H NMR of compound 9. Figure 23. 13 C NMR of compound 9. 47

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Figure 24. 1 H NMR of compound 10. O OO O O O O O Figure 25 1 H NMR of compound 11. 48

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O O O O O O O O Figure 26. 1 H NMR of compound 12. Figure 27. 13 C NMR of compound 12. 49

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O O O OOO O O Figure 28. 1 H NMR of compound 13. O O O OOO O O Figure 29. 13 C NMR of compound 13. 50

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O O O OOO O O Figure 30. 1 H NMR of compound 14. Figure 31. 13 C NMR of compound 14. 51

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O O O OOO O O Figure 32. 1 H NMR of compound 15. Figure 33. 13 C NMR of compound 15. 52

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O O O OOO O O Figure 34. 1 H NMR of compound 16. O OO OOO O O Figure 35 1 H NMR of compound 17. 53

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Figure 36. 13 C NMR of compound 17. Figure 37. 13 C NMR of compound 22. 54

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Figure 38. 1 H NMR of compound 23. Figure 39. 13 C NMR of compound 23. 55

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Figure 40. 1 H NMR of compound 25. Figure 41. 1 H NMR of compound 26. 56

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Figure 42. 1 H NMR of compound 27. Figure 43. 13 C NMR of compound 27. 57

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Figure 44. gCOSY of compound 13. Figure 45. gHSQC of compound 13. 58

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Figure 46. gHSQC of compound 15. Figure 47. gCOSY of compound 15. 59

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Figure 48. DEPT of compound 27 ( expanded NMR). Figure 49. DEPT of compound 27. 60