The total synthesis of c1 azacycloalkyl hexahyroccannabinoids the total synthesis of 3 oxaadamantyl hexahydrocannabinoids the synthesis of bicyclic 3 adamantyl cannabinoids

THE TOTAL SYNTHESIS OF C1'-AZACYCLOALKYL HEXAHYDROCANNABINOIDS THE TOTAL SYNTHESIS OF 3-OXAADAMANTYL HEXAHYDROCANNABINOIDS THE SYNTHESIS OF BICYCLIC 3-ADAMANTYL CANNABINOIDS A DISSERTATION SUBMITTED TO THE GRADUATE DIVISION OF THE UNIVERSITY OF HAWAI‘I AT MĀNOA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN CHEMISTRY DECEMBER 2014 By Thanh Chi Ho Dissertation Committee: Marcus A Tius, Chairperson Thomas Hemscheidt Philip Williams Kristin Kumashiro Stefan Moisyadi We certify that we have read this dissertation and that, in our opinion, it is satisfactory in scope and quality as a dissertation for the degree of Doctor of Philosophy in Chemistry DISSERTATION COMMITTEE _ Chairperson _ _ _ _ ii ACKNOWLEDGEMENTS I would like to express sincere gratitude to my advisor, Professor Marcus A Tius for his valuable guidance Instruction of a graduate student from another culture and language does not only require dedication and knowledge but also enthusiasm, patience, sympathy and love This is spoken from my heart I would like to thank Professor Lawrence M Pratt for his recommendation that gave me an opportunity to study at the University of Hawai‘i at Mānoa I also would like to thank all members in Professsor Tius' group in the past and at present for contributions to my chemistry work Especially to Dr Naoyuki Shimada for his initial instructions when he was a postdoctoral fellow and I was a first year graduate student; to members working on similar research projects (Dr Darryl Dixon, Mr Go Ogawa, and Mr Kahoano Wong) for information on their earlier work; and to Dr Francisco Lopez-Tapia and all other members in our lab for helpful suggestions on chemistry and for the time we were together I would like to thank my committee members: Professor Thomas Hemscheidt, Professor Philip Williams, Professor Kristin Kumashiro, and Professor Stefan Moisyadi for their time and wisdom, advice, and help I would like to thank Professors in the Department of Chemistry at the University of Hawai‘i at Mānoa for valuable and enthusiastic instruction in chemistry and help with my studies Thanks also for technical support from Mr Wesley Yoshida, Dr Walt Niemczura, Dr Anais Jolit, Dr Christine Brotherton-Pleiss for NMR and mass spectra I would like to thank my parents, my wife and her family, and my little daughter for their time and love Finally, I would like to thank the Vietnamese Government for the scholarship that supported my study during the first three years I would like to thank Professor Marcus A Tius for his financial support in the form of research assistanships as well as the Department of Chemistry of the University of Hawai‘i at Mānoa for support in the form of teaching assistantships iii ABSTRACT Chapter A brief background on the discovery and pharmacology of cannabinoids and of cannabinoid receptors was described Also, SAR and earlier synthesis approaches to tricyclic cannabinoids were reviewed Chapter The total synthesis of three series of C1'-azacycloalkyl 9-hydroxy hexahydrocannabinoids: 2,2-disubstituted pyrrolidine, 3,3-disubstituted azetidine, and 2,2disubstituted azetidine cannabinoids are described The key steps in the synthesis for each series were the Liebeskind cross coupling, the Pd-catalyzed decarboxylative cross coupling, and the titanium enolate addition to Ellman's imine 3,3-Disubstituted N-methyl azetidine and 2,2disubstituted N-methyl pyrrolidine cannabinoids exhibited high binding affinities for CB1 and CB2 receptors that are similar to (–)-9-THC while evaluation of binding affinities of 2,2disubstituted azetidine cannabinoid is in progress Chapter The total synthesis of a series of 3'-functionalized 3-oxaadamantyl 9hydroxy hexahydrocannabinoids is described The key steps in the synthesis were the nucleophilic addition of aryllithium to epoxide ketone to prepare an 3-oxaadamantyl resorcinol, condensation of resorcinol with a mixture of optically active diacetates followed by cyclization to construct the tricyclic cannabinoid nucleus, and functional group manipulation It is noteworthy that no functional group protection was employed in the synthesis Ligands with -CH2NCS and CH2N3 as functional groups have affinities for CB1 and CB2 receptors at nanomolar or subnanomolar levels, and they can be used for LAPS studies in the group of Professor Makriyannis Chapter The synthesis of two series of cannabinoids: the bicyclic 3-adamantyl cannabinoids and the 3'-functionalized 3-oxaadamantyl 9-hydroxymethyl hexahydrocannabinoids are described In the synthesis of bicyclic 3-adamantyl cannabinoids, the iv challenging step, oxidation of bicyclic hydroxy isothiocyanate to bicyclic keto isothiocyanate, was accomplished with PDC with the preservation of the phenolic hydroxy groups Evaluation of binding affinities for receptors of bicyclic cannabinoids are currently in progress In the other series, the synthesis related to conversion of the 9-keto group to 9-hydroxymethyl and 3'functional groups Ligands in this series with -CH2NCS and -CH2N3 have affinities for CB1 and CB2 at nanomolar and subnanomolar levels, and they are also used for LAPS studies v TABLE OF CONTENTS ACKNOWLEDGEMENTS iii ABSTRACT iv Table of Contents vi List of Abbreviations viii Chapter INTRODUCTION 1.1 Cannabinoids: Discovery and Pharmacology 1.2 Cannabinoid Receptors 1.3 Bioassay Techniques 1.4 Tricylic Cannabinoids and Structure  Activity Relationships 12 1.5 Earlier Synthesis Approaches Towards Tricyclic Cannabinoids 22 Chapter THE TOTAL SYNTHESIS OF C1'-AZACYCLOALKYL 9-HYDROXY HEXAHYDROCANNABINOIDS 26 2.1 Introduction 27 2.2 Synthesis of Advanced Intermediate Triflate 29 2.3 Non-diastereoseletive Synthesis of 2,2-Disubstituted Pyrrolidine Cannabinoids 31 2.4 Synthesis of 3,3-Disubstituted Azetidine Cannabinoids 40 2.5 Diastereoselective Synthesis of 2,2-Disubstituted Azetidine Cannabinoids 46 2.6 Receptor Binding Studies 59 2.8 Experimental Section - Chapter 63 Chapter THE TOTAL SYNTHESIS OF 3-OXAADAMANTYL 9-HYDROXY HEXAHYDROCANNABINOIDS 98 3.1 Introduction 99 3.2 Total Synthesis of 3-Oxaadamantyl 9-Hydroxy Hexahydrocannabinoids 101 vi 3.3 Receptor Binding Studies 117 3.4 Experimental Section - Chapter 119 Chapter THE SYNTHESIS OF BICYCLIC 3-ADAMANTYL CANNABINOIDS AND 3OXAADAMANTYL 9-HYDROXYMETHYL HEXAHYDROCANNABINOIDS 134 4.1 Synthesis of Bicyclic 3-Adamantyl Cannabinoids 135 4.2 Synthesis of 3-Oxaadamantyl 9-Hydroxymethyl Hexahydrocannabinoids 142 4.3 Receptor Binding Studies 148 4.4 Experimental Section - Chapter 150 CONCLUSION 161 APPENDIX I THE SYNTHESIS AND SOLUTION STRUCTURES OF -LITHIATED VINYL ETHERS 164 APPENDIX II SPECTRA FOR SELECTED COMPOUNDS IN CHAPTER 177 APPENDIX III SPECTRA FOR SELECTED COMPOUNDS IN CHAPTER 204 APPENDIX IV SPECTRA FOR SELECTED COMPOUNDS IN CHAPTER 221 REFERENCES AND NOTES 234 vii LISTS OF ABBREVIATIONS [α] specific rotation Å Angstrom Ac acetyl AIDS acquired immunodeficiency syndrome aq aqueous BC Before Christ br broadened Bn benzyl BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl ca circa (approximately) cAMP cyclic adenosine monophosphate calcd calculated cat catalytic °C degrees Celsius CB1 cannabinoid receptor CB2 cannabinoid receptor log logarithm cm-1 reciprocal centimeters CNS central nervous system δ (ppm) chemical shift (parts per million) d day(s) (length of reaction time) d doublet dba dibenzylideneacetone dd doublet of doublets viii ddd doublet of doublet of doublets DPPA diphenylphosphoryl azide (diphenylphosphorazidate) dppf 1,1’-bis(diphenylphosphino)ferrocene dt doublet of triplets DMAP 4-(dimethylamino)pyridine DMF N,N-dimethylformamide DMP Dess-Martin periodinane DMSO dimethyl sulfoxide dr diastereomeric ratio EDCI 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide EI electron impact e.g exempli gratia (for the sake of example) ESI electrospray ionization EtOAc ethyl acetate g gram(s) GPCR(s) G-protein-coupled receptor(s) GPR18 G-protein-coupled receptor 18 GPR55 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Allevi, P.; Anastasia, M.; Ciuffreda, P A new simple synthesis of 1,3-dideuterated malondialdehyde (3-hydroxy[1,3-2H2]-2-propenal) J Label Compd Radiopharm 1994, 34, 557–563 262 [...]... the structure of cannabinoid ligand is the enhancement of water solubility For example, O-1057 (57) behaves as an agonist at both receptor subtypes with high potency at CB1 matching that of ()-CP-55,940.92 21 1.5 Earlier Synthesis Approaches Towards Tricyclic Cannabinoids The first synthesis of cannabinoids was initiated in the early 1940s with reports on the synthesis of cannabinol (2) and some of. .. 3( 1',2'-dimethylheptyl)-6a,10a-tetrahydrocannabinols (35 ) is 512 times more potent than the npentyl analogue (36 ). 73 Among all isomers of 3- (1',2'-dimethylheptyl) cannabinoids, the (1'S,2'R) (37 ) and (1'R,2'S) are considerably more potent than the other isomers.74 Although the 3- (1',2'16 dimethylheptyl) cannabinoids are extremely potent, the 3- (1',1'-dimethylheptyl) analogs have been investigated more extensively because their precursor 1 ,3- dimethoxy-5-(1,1-... cannabinol (2) and some of its isomers in the laboratories of Rodger Adams in the US and Lord Todd in the UK.11b,12a However, it was not until 1967 that the first stereospecific synthesis of cannabinoids was reported by Raphael Mechoulam, the synthesis of (–)-9-THC, the major psychoactive constituent of Cannabis sativa, and its isomer ()-8-THC.16b The structure of tricylic cannabinoids such as 9-THC and... analysis and sequencing of the fragments by mass spectrometry to identify the sites of interaction of the ligand with specific amino acids The location of the receptor pocket can then be deduced from the known primary amino acid sequence Site-directed protein mutations can then be used to obtain additional data to support the location of the binding site The information revealed from these experiments can... being composed of an aromatic part and an alicyclic part, therefore they were first constructed by the condensation of olivetol with a monoterpene, such as verbenol. 93 Figure 17 General structure of a classical tetrahydrocannabinoid, Razdan et al 1981. 93 The distinction of the Mechoulam synthesis is that the bulky dimethylmethylene bridge of verbenol provided stereochemical control of the reaction to... and CB2.69 The second pharmacophore, the phenolic hydroxyl group at C1, is essential for CB1 affinity When it is replaced by a methoxy (e.g 29 vs 30 ), hydrogen (e.g 20 vs 31 ),70 or fluorine atom (e.g 32 vs 33 ),71 CB1 affinity is strongly diminished while lesser effects on CB2 are observed These characteristics serve as the basis for the synthesis of CB2 selective cannabinoids. 72 Figure 11 Cannabinoids. .. homology throughout the total protein, and 68% homology within the transmembrane domains .30 Autoradiography34 and positron emission tomography35 experiments revealed that the CB1 receptors are predominant in the brain with the highest density in the hippocampus, cerebellum and striatum ,36 that correlates well with the observed effects of cannabinoids on cognitive and motor functions .37 Outside the central... duration of action.82 In addition to the C1' -tert-alkyl or C1' -alicyclic side chain substituents, bulky subtituents at C3, such as C1' -2-bornyl (endo), -2-isobornyl (exo), 83 -adamantyl, 84 or -heteroadamantyl85 can easily be tolerated within the CB1/CB2 binding sites Furthermore, the relative orientation of these bulky groups with respect to the tricyclic cannabinoid structure strongly affects the CB1/CB2... that the C1' cyclopropyl (e.g 47) and C1' -cyclopentyl (e.g 49) are optimal pharmacophores for both receptors The C1' -cyclobutyl (48) was close in CB1 affinity, but much better in CB1/CB2 selectivity than the 3- and 5-membered rings The C1' -cyclohexyl (e.g 50) had reduced affinities for both CB1 and CB2.81 This structural feature has been developed by the Makriyannis group in the synthesis of AM- 238 9 (51),... AM-2 233 and WIN-55212-2, Deng, H et al 2005.49 In order to describe the binding affinity of the ligand to its receptors in a way that is independent of the concentration of radioligand used in the assays, the absolute inhibition constant Ki is determined using the Cheng-Prusoff equation: Ki = IC50 / (1 + [L]/KD), in which [L] is the fixed concentration of radioligand and dissociation constant KD is the