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 G-protein-coupled receptor 55 GPR119 G-protein-coupled receptor 119 h hour(s) HHC hexahydrocannabinol(s) HMPA hexamethylphosphoric acid triamide HOBT 1-hydroxybenzotriazole HPLC high performance liquid chromatography HRMS high resolution mass spectrum Hz hertz ix i- iso IBX o-iodoxybenzoic acid IC50 half maximal inhibitory concentration IR infrared Pr propyl J coupling constant Ki absolute inhibition constant KD dissociation constant L- levorotation LAPS ligand-assisted protein structure LC liquid chromatography LDA lithium diisopropylamide m multiplet m- meta m-CPBA meta chloroperbenzoic acid M molar (concentration) M+ molecular ion MHz megahertz minute(s) mm Hg millimeters of mercury mg milligram(s) mL milliliter(s) mmol millimole(s) MOM methoxymethyl mp melting point Ms methanesulfonyl x (96) Handrick, G R.; Uliss, D B.; Dalzell, H C.; Razdan, R K Hashish: synthesis of ()delta-9-tetrahydrocannabinol (THC) and its biologically potent metabolite 3'-hydroxy-delta-9THC Tetrahedron Lett 1979, 8, 681684 (97) Archer, R A.; Blanchard, W B.; Day, W A.; Johnson, D W.; Lavagnino, E R.; Ryan, C W.; Baldwin, J E Cannabinoids 3.1 Synthesis approaches to 9-ketocannabinoids Total synthesis of nabilone J Org Chem 1977, 42, 22772284 (98) Tius, M A.; Kannangara, K G S Synthesis of 11-nor-8-tetrahydrocannabinol-9carboxylic acid methyl ester J Org Chem 1990, 55, 57115714 (99) (a) Chu, C.; Ramamurthy, A.; Makriyannis, A.; Tius, M A Synthesis of covalent probes for the radiolabeling of the cannabinoid receptor J Org Chem 2003, 68, 5561 (b) Tius, M A.; Busch-Petersen, J.; Marris, A R Synthesis of a bifunctional cannabinoid ligand J Chem Soc Chem Commun 1997, 19, 18671868 (100) Tius, M A.; Kannangara, K G S.; Kerr, M A.; Grace, K J S Halogenated cannabinoid synthesis Tetrahedron 1993, 49, 32913304 (101) Goanvic, D L.; Tius, M A Oxaza adamantyl cannabinoids A new class of cannabinoid receptor probes J Org Chem 2006, 71, 78007804 (102) Dixon, D D.; Tius, M A.; Zhou, H.; Bowman, A L.; Shukla, V G.; Peng, Y.; Thakur, G A.; Makriyannis, A C3-heteroaroyl cannabinoids as photolabeling ligands for the CB2 cannabinoid receptor Bioorg Med Chem Lett 2012, 22, 53225325 (103) Boger, D L.; Mullican, M D.; Hellberg, M R.; Patel, M Preparation of optically active, functionalized cis -6-l-octalone J Org Chem 1985, 50, 1904–1911 (104) Coxon, J M.; Garland, R P.; Haetshorn, M P Some derivatives of nopinone Aust J Chem 1970, 23, 1069–1071 (105) Robichaud, J.; Oballa, R.; Prasit, P.; Falgueyret, J.-P.; Percival, M D.; Wesolowski, G.; Rodan, S B.; Kimmel, D.; Johnson, C.; Bryant, C.; Venkatraman, S.; Setti, E.; Mendonca, 248 R.; Palmer, J T A novel class of nonpeptidic biaryl inhibitors of human cathepsin K J Med Chem 2003, 46, 37093727 (106) For the original research article on the Miyaura borylation reaction see: Ishiyama, T.; Murata, M.; Miyaura, N Palladium(0)-catalyzed cross coupling reaction of alkoxydiboron with haloarenes: a direct procedure for arylboronic esters J Org Chem 1995, 60, 75087510 (107) Malan, C.; Morin, C Stereospecific synthesis via cross coupling with aromatic amine J Org Chem 1998, 63, 80198020 (108) Song, Y L.; Morin, C Cedranediolborane as a borylating agent for the preparation of boronic acids: synthesis of a boronated nucleoside analogue Synlett 2001, 2, 266268 (109) Yuen, A K L.; Hutton, C A Deprotection of pinacolyl boronate esters via hydrolysis of intermediate potassium trifluoroborates Tetrahedron Lett 2005, 46, 78997903 (110) Molander, G A.; Cavalcanti, L N.; Canturk, B.; Pan, P.-S.; Kennedy, L E Efficient hydrolysis of organotrifluoroborates via silica gel and water J Org Chem 2009, 74, 73647369 (111) Kuivila, H G.; Reuwer, J F.; Mangravite, J A Electrophilic displacement reactions XV Kinetics and mechanism of the base-catalyzed protodeboronation of areneboronic acids Can J Chem 1963, 41, 30813090 (112) Lennox, A J J.; Lloyd-Jones, G C The slow-release strategy in SuzukiMiyaura coupling Isr J Chem 2010, 50, 664674 (113) Lennox, A J J.; Lloyd-Jones, G C Selection of boron reagents for SuzukiMiyaura coupling Chem Soc Rev 2014, 43, 412443 (114) Yu, S.; Saenz, J.; Srirangam, J K Facile synthesis of N-aryl pyrroles via Cu(II)mediated cross coupling of electron deficient pyrroles and arylboronic acids J Org Chem 2002, 67, 16991702 249 (115) (a) Murphy, J M.; Tzschucke, C C.; Hartwig, J F One-pot synthesis of aryl boronic acids and aryl trifluoroborates by Ir-catalyzed borylation of arenes Org Lett 2007, 9, 757760 (b) For the original research article on oxidative cleavage of the pinacol boronic ester see: Coutts, S J.; Adams, J.; Krolikowski, D.; Snow, R J Two efficient methods for the cleavage of pinanediol boronate esters yielding the free boronic acids Tetrahedron Lett 1994, 35, 51095112 (116) Prokopcová, H.; Kappe, C O Palladium (0)-catalyzed, copper(I)-mediated coupling of boronic acids with cyclic thioamides Selective carbon-carbon bond formation for the functionalization of hetereocycles J Org Chem 2007, 72, 44404448 (117) Mehta, V P.; van de Eycken, E V Microwave-assisted CC bond forming crosscoupling reactions: an overview Chem Soc Rev 2011, 40, 49254936 (118) Allred, G D.; Liebeskind, L S Copper-mediated cross-coupling of organostannanes with organic iodides at or below room temperature J Am Chem Soc 1996, 118, 27482749 (119) (a) Neto, B A D.; Lapis, A A M.; Bernd, A B.; Russowsky, D Studies on the Eschenmoser coupling reaction and its insights on its mechanism Application on the synthesis of Norallosedamine and other alkaloids Tetrahedron 2009, 65, 24842496 (b) Thomsen, I.; Clausen, K.; Scheibye, S.; Lawesson, S.-O Thiation with 2,4-bis(4-methoxyphenyl)-1,3,2,4dithiadiphosphetane 2,4-disulfide: N-methylthiopyrrolidone Org Synth 1984, 62, 158 (120) Brook, M A.; Jahangir The activation of imines to nucleophilic attack by Grignard reagents Synth Commun 1988, 18, 893898 (121) Iqbal, M.; Duffy, P.; Evans, P.; Cloughley, G.; Allan, B.; Lledo, A.; Verdaguer, X.; Riera, A The conjugate addition – Peterson olefination reaction for the preparation of crossconjugated cyclopentenone Org Biomol Chem 2008, 6, 4649–4661 (122) McGarrity, J F.; Ogle, C A High-field proton NMR study of the aggregation and complexation of n-butyllithium in tetrahydrofuran J Am Chem Soc 1985, 107, 18051810 250 (123) Crane, S N.; Bateman, K.; Gagne, S.; Levesque, J.-F Preparation of deuteriumlabeled monounsatureated and saturated fatty acids for use as stable isotope metabolic tracers J Label Compd Radiopharm 2006, 49, 1273–1285 (124) Gilman, H.; Beel, J A.; Brannenm, C G.; Bullock, W.; Dunn, G E.; Dunn, G E.; Miller, L S The preparation of n-butyllithium J Am Chem Soc 1949, 71, 14991500 (125) Oriyama, T.; Watahiki, T.; Kobayashi, Y.; Hirono, H.; Suzuki, T A mild and feasible deprotection of alcohol tetrahydropyranyl or methoxymethyl ethers catalyzed by Sc(OTf)3 Synth Commun 2001, 31, 2305–2311 (126) Clarke, H T.; Gillespie, H B.; Weisshaus S Z The action of formaldehyde on amines and amino acids J Am Chem Soc 1933, 55, 4571–4587 (127) Borch, R F.; Hassid, A I A new method for the methylation of amines J Org Chem 1972, 37, 1673–1674 (128) Bhattacharyya, S Titanium (IV) isopropoxide and sodium borohydride: a reagent of choice for reductive amination Tetrahedron Lett 1994, 35, 24012404 (129) For reviews on palladium-catalyzed -arylation see: (a) Bellina, F.; Rossi, R Transition metal-catalyzed direct arylation of substrates with activated sp3-hybridized C-H bonds and some of their synthetic equivalents with aryl halides and pseudohalides Chem Rev 2010, 110, 10821146 (b) Burtoloso, A C B Catalytic enantioselective alpha-arylation of carbonyl compounds Synlett 2009, 2, 320327 (c) Culkin, D A.; Hartwig, J F Palladium-catalyzed alpha-arylation of carbonyl compounds and nitriles Acc Chem Res 2003, 36, 234245 (d) Lloyd-Jones, G C Palladium-catalysed -arylation of esters: ideal new methodology for discovery chemistry Angew Chem Int Ed 2002, 41, 953956 (130) Shang, R.; Ji, D.-S.; Chu, L.; Fu, Y.; Liu, L Synthesis of -aryl nitriles through palladium-catalyzed decarboxylative coupling of cyanoacetate salts with aryl halides and triflates Angew Chem Int Ed 2011, 50, 44704474 251 (131) Jiang, Y Y.; Fu, Y.; Liu, L Mechanism of palladium-catalyzed decarboxylative cross-coupling between cyanoacetate salts and aryl halides Science China Chemistry 2012, 55, 20572062 (132) Tsuji, J.; Yamada, T.; Minami, I.; Yuhara, M.; Nisar, M.; Shimizu, I Palladiumcatalyzed decarboxylation-allylation of allylic esters of -substituted -keto carboxylic, malonic, cyanoacetic, and nitroacetic acids J Org Chem 1987, 52, 29882955 (133) Tunge, J A.; Recio III, A Regiospecific decarboxylative allylation of nitriles Org Lett 2009, 11, 56305633 (134) Culkin, D A.; Hartwig, J F Synthesis, characterization, and reactivity of arylpalladium cyanoalkyl complexes: selection of catalysts for the -arylation of nitriles J Am Chem Soc 2002, 124, 93309331 (135) (a) Bhushan, K R.; Lisi, C D.; Laursen, R A Syntheiss of photolabile 2-(2nitrophenyl)propyloxycarbonyl protected amino acids Tetrahedron Lett 2003, 44, 85858588 (b) For the original research article see: Tsuji, Y.; Kotachi, S.; Huh, K.-T.; Watanabe, Y Ruthenium-catalyzed dehydrogenative N-heterocyclization: indole from 2-aminophenethyl alcohols and 2-nitrophenethyl alcohols J Org Chem 1990, 55, 580584 (136) Meyers, M J.; Muizebelt, I.; Wiltenburg, J V.; Brown, D L.; Thorarensen, A Synthesis of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate Org Lett 2009, 11, 35233525 (137) Frohlich, J.; Sauter, F.; Blasl, K A novel synthesis of 3,3-(spiro)substituted azetidines Heterocycles 1994, 37, 18791891 (138) Blank, N.; Opatz, T Enantioselective synthesis of tetrahydroprotoberberines and bisbenzylisoquinoline alkaloids from a deprotonated -aminonitrile J Org Chem 2011, 76, 97779784 252 (139) (a) Bertus, P.; Szymoniak, J A direct synthesis of 1-aryl and 1- alkenylcyclopropylamines from aryl and alkenyl nitriles J Org Chem 2003, 68, 71337136 (b) Widemann, S.; Frank, D.; Winsel, H.; de Meijere, A Primary 1-arylcyclopropylamines from aryl cyanides with diethyl zinc and titanium alkoxides Org Lett 2003, 5, 753755 (140) (a) Harnisch, J.; Szeimies, G Darstellung und thermisches verhalten von azidocyclopropanen Chem Ber 1979, 112, 39143933 (b) For the original research article see: Levy, A B.; Hassner, A Pyrolysis of cyclopropyl azides A route to 1-azetines J Am Chem Soc 1971, 93, 20512053 (141) Semmelhack, M F.; Harrison, J J.; Young, D C.; Gutierres, A.; Rafii, S.; Clardy, J [3.3]Metacyclophane: a novel synthesis and a study of the structure through X-ray diffraction, molecular mechanics, and solution NMR analysis J Am Chem Soc 1985, 107, 75087514 (142) For the original research article of the oxidative decyanation of -aryl nitriles see: Selikson, S J.; Watt, D S The oxidative decyanation of secondary nitriles via hydroperoxynitriles J Org Chem 1975, 40, 267268 (143) For the original research article see: Liu, G.; Cogan, D A.; Owens, T D.; Tang, T P.; Ellman, J A Synthesis of enantiomerically pure N-tert-butanesulfinyl imines (tertbutanesulfinimines) by the direct condensation of tert-butanesulfinamide with aldehydes and ketones J Org Chem 1999, 64, 12781284 (144) (a) Robinson, P D.; Hua, D H.; Shan, J S.; Saha, S Structure of (+)-[S-(E)]-N-(methylbenzylidene)-p-toluenesulfinamide Acta Crystallogr 1991, C47, 594596 (b) David, F A.; Reddy, R E.; Szewczyk, J M.; Reddy, G V.; Portonovo, P S.; Zhang, H.; Fanelli, D.; Reddy, R T.; Zhou, P.; Carroll, P J Asymmetric synthesis and properties of sulfinimines (thiooximes S-oxides) J Org Chem 1997, 62, 25552563 253 (145) For the original research article see: Tang, T P.; Ellman, J A The tert-butanesulfinyl group: an ideal chiral directing group and boc-surrogate for the asymmetric synthesis and applications of -amino acids J Org Chem 1999, 64, 1213 (146) Davis, F A.; Reddy, T.; Reddy, R E Asymmetric synthesis of sulfinimines: application to the synthesis of nonracemic -amino acids and -hydroxyl--amino acids J Org Chem 1992, 57, 63876389 (147) (a) For a disclose account of Ellman on enolate addition to tert-butanesulfinimines, see: Tang, T P.; Ellman J A Asymmetric synthesis of -aminoacid derivative incorporating a broad range of substitution patterns by enolate additions to tert-butanesulfinyl imines J Org Chem 2002, 67, 78197832 (b) For a review of chiral sulfinimines see: Davis, F A.; Zhou, P.; Chen, B.-C Asymmetric synthesis of amino acids using sulfinimines (thiooxime S-oxides) Chem Soc Rev 1998, 27, 1318 Morton, D.; Stockman, R A Chiral non-racemic sulfinimines: versatile reagents for asymmetric synthesis Tetrahedron 2006, 62, 88698905 (c) For a review of tert-butanesulfinimines see: Ferreira, F.; Botuha, C.; Chemla, F.; Perez-Luna, A tert-Butanesulfinimines: structure, synthesis and synthetic applications Chem Soc Rev 2009, 38, 11621186 (148) Siegel, C.; Thornton, E R Asymmetric aldol reactions A titanium enolate giving very high diastereofacial selectivities J Am Chem Soc 1989, 111, 57225728 (149) Fujisawa, T.; Kooriyama, Y.; Shimizu, M Switchover of diastereofacial selective in the condensation reaction of optically active N-sulfinimine with ester enolate Tetrahedron Lett 1996, 37, 38813884 (150) For the original research article see: Cogan, D A.; Liu, G.; Ellman, J A Asymmetric synthesis of chiral amines by highly diastereoselective 1,2-additions of organometallic reagents to N-tert-butanesulfinyl imines Tetrahedron 1999, 55, 88838904 254 (151) Olofsson, B.; Wijtmans, R.; Somfai, P Synthesis of N-H vinylaziridines: a comparative study Tetrahedron 2002, 58, 59795982 (152) Fukuyama, T.; Jow, C.-K.; Cheung, M 2- and 4-Nitrobenzenesulfonamides: exceptionally versatile means for preparation of secondary amines and protection of amines Tetrahedron Lett 1995, 36, 63736374 (153) Testa, E.; Fontanella, L.; Aresi, V Auf das zentralnervensystem wirkende substanzen, XXXVI Weitere untersuchungen uber die 2-substituierten azetidine Justus Liebigs Ann Chem 1964, 673, 6070 (154) Cativiela, C.; Diaz-de-Villegas, M D.; Galvez, J A Asymmetric synthesis of lactams Highly diastereoselective alkylation of chiral 2-cyano esters J Org Chem 1994, 59, 24972505 (155) (a) Zoidis, G.; Fytas, C.; Papanastasiou, I.; Foscolos, G B.; Fytas, G.; Padalko, E.; Clercq, E D.; Naesens, L.; Neyts, J.; Kolocouris, N Heterocyclic rimantadine analogs with antiviral activity Bioorg Med Chem 2006, 14, 33413348 (b) Hassner, A.; Wiegand, N Synthesis and ring expansion of vinylazetidines A synthesis of hydroazocines J Org Chem 1986, 51, 36523656 (156) (a) Wells J N.; Tarwater, O R Synthesis of azetidines J Pharm Sci 1971, 60, 156157 (b) Jackson, M B.; Mander, J N.; Spotswood, T M Reduction of N-substituted azetidin-2-ones to azetidines Aust J Chem 1983, 36, 779788 (157) (a) For the original research article on the use of thiol see: Sohn, J.-H.; Waizumi, N.; Zhong, H M.; Rawal, V H Total synthesis of mycalamide A J Am Chem Soc 2005, 127, 72907291 (b) For the mechanism on the use of thiol see: Han, J H.; Kwon, Y E.; Sohn, J.-H.; Ryu, D H A facile method for the rapid and selective deprotection of methoxymethyl (MOM) ethers Tetrahedron 2010, 66, 16731677 (c) For the use of acidic ion-exchange resin see: Seto, H.; Mander, L M A refined method for the removal of the methoxymethyl (MOM) protecting 255 group for carbinols with acidic ion-exchange resin, Synth Commun 1992, 22, 28232828 (d) For the use of LiBF see: Ireland, R E.; Varney, M D Approach to the total synthesis of chlorothricolide: synthesis of (±)-19, 20-dihydro-24-O-methylchlorothricolide, methyl ester, ethyl carbonate J Org Chem 1986, 51, 635641 (158) Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y 2-Azaadamantane N-oxyl (AZADO) and 1-Me-AZADO: highly efficient organocatalysts for oxidation of alcohols J Am Chem Soc 2006, 128, 8412–8413 (159) Muraoka, O.; Wang, Y.; Okumura, M.; Nishiura, S.; Tanabe, G.; Momose, T A facile synthesis of 7-methylenebicyclo-[3.3.1]nonan-3-one and its transformation leading to the novel tricylic system, protoadamantane Synth Commun 1996, 26, 1555–1562 (160) Mori, T.; Yang, K H.; Kimoto, K.; Nozaki, H Photochemistry of bicyclo [3.3.1] nonanes having two functional groups at 3,7-positions Tetrahedron Lett 1970, 28, 2419–2420 (161) Momose, T.; Atarashi, S Bicyclo[3.3.1]nonanes as synthetic intermediates V The Baeyer-Villiger oxidation of bicyclo[3.3.1]nonane-3,7-dione and its congeners Chem Pharm Bull 1979, 27, 824–828 (162) Anderson, W K.; Veysoglu, T A simple procedure for the epoxidation of acidsensitive olefinic compounds with m-chloroperbenzoic acid in an alkaline biphasic solvent system J Org Chem 1973, 38, 2267–2268 (163) For the preparation of aryllithium by bromine/lithium exchange see: Muller, D.; Guenee, L.; Alexakis, A Practical synthesis of simplephos ligands: further development of alkyl-substituted phosphanamines Eur J Org Chem 2013, 28, 6335–6343 (164) Mlinaric-Majerski, K.; Kragol, G.; Ramljak, T S Transannular cyclization with Grignard reagents: facile synthetic routes to oxaadamantane and protoadamantane derivatives Synlett 2008, 3, 405–409 256 (165) Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita, T.; Hatanaka, Y.; Yokoyama, M Carbon-carbon bond-forming reactions using cerium metal or organocerium(III) reagents J Org Chem 1984, 49, 3904–3912 (166) For a review of organocerium reagents see: Molander, G A Application of lanthanide reagents in organic synthesis Chem Rev 1992, 92, 29–68 (167) Takeda, N.; Imamoto, T Use of cerium(III) chloride in the reactions of carbonyl compounds with organolithiums or Grignard reagents for the suppression of abnormal reactions: 1-butyl-1,2,3,4-tetrahydro-1-naphthol Org Synth 1999, 76, 228–233 (168) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya, Y Reactions of carbonyl compounds with Grignard reagents in the presence of cerium chloride J Am Chem Soc 1989, 111, 4392–4398 (169) Krasovskiy, A.; Kopp, F.; Knochel, P Soluble lanthanide salts (LnCl32LiCl) for the improved addition of organomagnesium reagents to carbonyl compounds Angew Chem Int Ed 2006, 45, 497–500 (170) Hatano, M.; Suzuki, S.; Ishihara, K Highly efficient alkylation to ketones and aldimines with Grignard reagents catalyzed by Zinc(II) chloride J Am Chem Soc 2006, 128, 9998–9999 (171) For the preparation of Grignard reagent on small scale see: Sivaraman, B.; Aidhen, I S Weinred amide based building blocks for convenient access to analogues of phenstatin Eur J Org Chem 2010, 26, 4991–5003 (172) (a) Jiang, Z.-X.; Yu, Y B The synthesis of a geminally perfluoro-tert-butylated amino acid and its protected forms as a potential pharmacokinetic modulator and reporter for peptide-based pharmaceuticals J Org Chem 2007, 72, 1464–1467 (b) For the preparation of Jones reagent see: Eisenbraun, E J Cyclooctanone Org Synth 1965, 45, 28–31 (c) For the original research article see: Bowden, K.; Heilbron, I M.; Jones, E R H.; Weedon, B C L 257 Researches on acetylenic compounds Part I The preparation of acetylenic ketones by oxidation of acetylenic carbinols and glycols J Chem Soc 1946, 39–45 (173) Mariampillai, B.; Alberico, D.; Bidau, V.; Lautens, M Synthesis of polycyclic benzonitriles via a one-pot aryl alkylation/cyanation reaction J Am Chem Soc 2006, 128, 14436–14437 (174) Nikitenko, A.; Alimardanov, A.; Afragola, J.; Schmid, J.; Kristofova, L.; Evrard, D.; Hatzenbuhler, N T.; Marathias, V.; Stack, G.; Lenicek, S.; Potoski, J First scale-up synthesis of WAY-262398, a novel, dual-acting SSRI/5HT1 antagonist Org Proc Res Dev 2009, 13, 91– 97 (175) Campagna, F.; Carotti, A.; Casini, G A convenient synthesis of nitriles from primary amides under mild conditions Tetrahedron Lett 1977, 18, 1813–1816 (176) Lewis, F W.; Eichler, M C.; Grayson, D H Synthesis of -amino alcohols via the reduction of lactamides derived from ethyl (2S)-lactate with borane–methyl sulfide Synlett 2009, 12, 1923–1928 (177) Cavender, C J.; Shiner Jr, V J Trifluoromethansulfonyl azide Its reaction with alkyl amines to form alkyl azide J Org Chem 1972, 37, 3567–3569 (178) (a) Alper, P B.; Hung, S.-C.; Wong, C.-H Metal catalyzed diazo transfer for the synthesis of azides from amines Tetrahedron Lett 1996, 37, 6029–6032 (b) Nyffeler, P T.; Liang, C.-H.; Koeller, K M.; Wong, C.-H The chemistry of amine-azide interconversion: catalytic diazotransfer and regioselective azide reduction J Am Chem Soc 2002, 124, 10773– 10778 (179) Wong, R.; Dolmabn, S J Isothiocyanates from tosyl chloride mediated decomposition of in situ generated dithiocarbamic acid salts J Org Chem 2007, 72, 3969– 3971 258 (180) For excess CS2 or excess TEA affects the reaction see: Li, G.; Tajima, H.; Ohtani, T An improved procedure for the preparation of isothiocyantes from primary amine by using hydrogen peroxide as the dehydrosulfurization reagent J Org Chem 1997, 62, 4539–4540 (181) (a) Blanco, J L J.; Barria, C S.; Benito, J M.; Mellet, C O.; Fuentes, J.; SantoyoGonzalez, F.; Fernadez, J M G A practical amine-free synthesis of symmetric ureas and thioureas by self-condensation of iso(thio)cyanates Synthesis 1999, 11, 1907–1914 (b) For other conditions to prepare symmetrical thioureas see: Perveen, S.; Hai, S M A.; Khan, R A.; Khan, K M.; Afza, N.; Sarfaraz, T B Expeditious method for synthesis of symmetrical 1,3disubstituted ureas and thioureas Synth Commun 2005, 35, 1663–1674 (182) Lu, D.; Vemuri, V K.; Duclos Jr, R I.; Makriyannis, A The cannabinergic system as a target for anti-inflammatory therapies Curr Top Med Chem 2006, 6, 1401–1426 (183) Makriyannis, A.; Nikas, S P.; Khanolkar, A D.; Thakur, G A.; Lu, D Novel bicylic cannabinoids US20070135388 A1, 14 Jun 2007 (184) Hanus, L.; Breuer, A.; Tchilibon, S.; Shiloah, S.; Goldenberg, D.; Horowitz, M.; Pertwee, R G.; Ross, R A.; Mechoulam, R.; Fride, E HU-308: a specific agonist for CB2, a peripheral cannabionoid receptor Proc Natl Acad Sci U.S.A 1999, 96, 14228–14233 (185) (a) Yeoh, S D.; Skene, C E.; White, J M Hyperconjugation involving strained carbon−carbon bonds Structural analysis of ester and ether derivatives and one-bond 13 C−13C coupling constants of α- and β-nopinol J Org Chem 2013, 78, 311–319 (b) Malek, J Reductions by metal alkoxyaluminum hydrides In Organic Reactions; Kende, A S., Ed.; Wiley & Sons: New York, 1985; Vol 34, pp 1–317 (186) Yacovan, A.; Grynszpan, F.; Aizikovich, A.; Brody, M S.; Bar-Joseph, A.; Meilin, S A Benzofuran derivatives as cannabinoid receptor ligands and their preparation, pharmaceutical compositions, and their use in treatment of diseases WO2006129318 A3, 07 Dec 2006 (187) (a) Magdziak, D.; Rodriguez, A A.; Water, R W V D.; Pettus, T R R Regioselective oxidation of phenols to o-quinones with o-iodoxybenzoic acid (IBX) Org Lett 259 2002, 4, 285–288 (b) LuO, H B.; Xie, Y Y Regioselective oxidation of phenols to o-quinones with Dess-Martin periodinane (DMP) Chinese Chemical Letters 2003, 14, 555–556 (188) For the original research article see: Corey, E J.; Schmidt, G Useful procedures for the oxidation of alcohols involving pyridinium dichromate in aprotic media Tetrahedron Lett 1979, 20, 399–402 (189) Czernecki, S.; Vijayakumaran, K.; Ville, G Convenient synthesis of hex-1-enopyran3-uloses: selective oxidation of allylic alcohols using pyridinium dichromate J Org Chem 1986, 51, 5472–5475 (190) (a) Benchikh, E.; Fitzgerald, S P.; Innocenzi, P J.; Lowry, P A.; McConnell, I R Detection of synthetic cannabinoids US20130065323 A1, 14 Mar 2013 (b) Morikawa, T.; Chaipech, S.; Matsuda, H.; Hamao, M.; Umeda, Y.; Sato, H.; Tamura, H.; Kon'i, H.; Ninomiya, K.; Yoshikawa, M.; Pongpiriyadacha, Y.; Hayakawa, T.; Muraoka, O Antidiabetogenic oligostilbenoids and 3-ethyl-4-phenyl-3,4-dihydroisocoumarins from the bark of Shorea roxburghii Bioorg Med Chem 2012, 20, 832–840 (191) For the use of 0.6 equivalent of PDC see: Czernecki, S.; Georgoulis, C.; Stevens, C L.; Vijayakumaran, K Pyridinium dichromate oxidation Modifications enhancing its synthetic utility Tetrahedron Lett 1985, 26, 1699–1702 (192) Fitjer, L.; Quabeck, U The Wittig reaction using potassium-tert-butoxide high yield methylenations of sterically hindered ketones Synth Commun 1985, 15, 855–864 (193) Conia, J.-M.; Limasset, J.-C L’utilisation du t-amylate de sodium dans les re´actions de Wittig Bull Soc Chim Fr 1967, 6, 1936–1938 (194) (a) Schollkopf, U.; Hanssle, P 1-Athoxyvinyllithium als reagens zur nucleophilen acetylierung Justus Liebigs Ann Chem 1972, 763, 208–210 (b) Baldwin, J E.; Hofle, G A.; Lever, O W J -Methoxyvinyllithium and related metalated enol ethers Practical reagents for nucleophilic acylation J Am Chem Soc 1974, 96, 7125–7127 260 (195) Harrington, P E.; Li, L.; Tius, M A Difluorocyclopentenone synthesis J Org Chem 1999, 64, 4025–4029 (196) Dixon, D D.; Tius, M A.; Pratt, L M Gas phase and solution structures of 1methoxyallenyllithium J Org Chem 2009, 74, 5881–5886 (197) (a) Tius, M A Cationic cyclopentannelation of allene ethers Acc Chem Res 2003, 36, 284–290 (b) Harrington, P E.; Tius, M A Asymmetric cyclopentannelation Chiral auxiliary on the allene Org Lett 2000, 2, 2447–2450 (c) delos Santos, D B.; Banaag, A R.; Tius, M A An improved chiral auxiliary for the allene ether version of the Nazarov cyclization Org Lett 2006, 8, 2579–2582 (d) Banaag, A R.; Tius, M A Traceless chiral auxiliaries for the allene ether Nazarov cyclization J Org Chem 2008, 73, 8133–8141 (198) For a review see: Friesen, R W Generation and reactivity of -metalated vinyl ethers J Chem Soc., Perkin Trans 1, 2001, 1969–2001 (199) Tamao, K.; Nakagawa, Y.; Arai, H.; Higuchi, N.; Ito, Y Intramolecular hydrosilation of -hydroxy enol ethers: a new highly stereoselective route to polyhydroxylated molecules J Am Chem Soc 1988, 110, 3712–3714 (200) Tamao, K.; Nakagawa, Y.; Ito, Y Regio- and stereoselective intramolecular hydrosilylation of -hydroxy enol ethers: 2,3-syn-2-methoxymethoxy-1,3-nonanediol Org Synth 1998, 9, 539–547 (201) (a) For compound with the -MEM protecting group see: Patel, S T.; Percy, J M.; Wilkes, R D New fluorine-containing building blocks from trifluoro ethanol Tetrahedron 1995, 51, 9201–9216 For compounds with the -OBn and -OTs see: (b) Ramachandran, P V.; Chatterjee, A Gem-difluorinated homoallyl alcohols, -hydroxy ketones, and syn- and anti-1,2diols via ,-difluoroallylboronates Org Lett 2008, 10, 1195–1198 (c) Gogsig, T M.; Sobjerg, L S.; Lindhardt, A T.; Jensen, K L.; Skrydstrup, T Direct vinylation and difluorovinylation of 261 arylboronic acids using vinyl- and 2,2-difluorovinyl tosylates via the Suzuki–Miyaura cross coupling J Org Chem 2008, 73, 3404–3410 (202) Soderquist, J A.; Hsu, G J.-H Pure, unsolvated (-methoxyvinyl)lithium and related acyl anion equivalents via the transmetalation of organotin compounds Organometallics 1982, 1, 830–833 (203) 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