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INFORMATION to USERS the Most Advanced Technology Has Been Used to Photo­ Graph and Reproduce This Manuscript from the Microfilm Master Synthesis of cannabidiol stereoisomers and analogs as potential anticonvulsant agents. Item Type text; Dissertation-Reproduction (electronic) Authors Shah, Vibhakar Jayantilal. Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 02/10/2021 14:16:58 Link to Item http://hdl.handle.net/10150/184523 INFORMATION TO USERS The most advanced technology has been used to photo­ graph and reproduce this manuscript from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely eve~~t that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are re­ produced by sectioning the original, beginni'ng at the upper left-hand corner and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. These are also available as one exposure on a standard 35mm slide or as a 17" x 23" black and white photographic print for an additional charge. Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6" x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. U'MI Order Number 8902359 Synthesis of cannabidiol stereoisomers and analogs as potential anticonvulsant agents Shah, Vibhakar JayantiJaJ, Ph.D. The University of Arizona, 1988 U·M-I 300 N. Zceb Rd. Ann Arbor, MI 48106 SYNTHESIS OF CANNABIDIOL STEREOISOMERS AND ANALOGS AS P01ENTIAL ANTICONVULSANT AGENTS BY VIBHAKAR JAYANTILAL SHAH A Dissenation Submitted to the Faculty of the DEPARTMENT OF PHARMACEUI1CALSCJENCES In Partial fulfillment of the Requirements For the Degree of DOCTOROF~SOPHY In the Graduate College TIlE UNIVERSITY OF ARIZONA 1988 THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE As members of the Pinal Examination CCllD.it.tee, we certify that we have read the dissertation prepared by -'V"'ib"hs"k"'"'...,J"o... S"'hs"'h'- __________ entitled Synthesis of Cannabidiol stereoisomers and analogs as potential anticonvulsant agents. and recClllllend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy Date w~ao~ Date i~-ff1 Date Date Date Final approval and acceptance of this dissertation is contingent upon the candidate's subnission of the final copy of the dissertation to the Graduate Colle<Je. I hereby certify that I have read this dissertation prepared under my direction and reCCllllDlend that it be accepted as fulfilling the dissertation requirement. Dissertation Director srATEME)\T BY AlrrHOR This dissenation has been submitted in partial fulfillment of requirement for an advanced degree at the University of Arizona and is deposited in the university Library to be made available to borrowers under rules of the Library. Brief quotations from this dissenation are allowable without special pennission, provided that accurate acknowledgement of somce is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the head of the major department or the Dean of the Graduate College when in his or her judgement the proposed use of the ~terial is in the interest of scholarship. In all other instances. however. permission must be obtained from the author. SIGXED: 7/~ ~. 4 ACKNOWLEDGEMENTS I would like to thank Dr. Arnold R. Martin for his guidance, encouragement, and support in pursuing and completion of this project. Special thanks also go to Dr. Vinayak V. Kane for his constant enthusiasm, interest and suggestions in compilation of this work. I also would like to thank: Drs. Sham S. Nikam. Ratnakar B. Mujumdar, Bhashyam Iyengar, Timothy Wunz and my fellow graduate students for their valuable suggestions, help and friendship which made my stay at Tucson memorable. Among many others, especially Mr. Steven Louie of Microcomputer learning center at Office of Medical Education, College of Medicine must be thanked for letting me use the computer facility as needed. Finally I thank my parents for their encouragement, patience and understanding without which the work would have suffered. This research was supported in part by the National Institute of neurological and communicative disorders and stroke (NINCDS), Grant No. 15441. TABIEOFCONTENTS page LIST OF ILLUSTRATIONS 8 LIST OF TABLES ABSTRACT ....•. to INTRODUCTION . 12 Chemical constituents of Cannabis sativa 14 Numbering systems of cannabinoids 19 Cannabinoids as a therapeutic agents 22 Delta-9-1HC as a therapeutic agent 22 An overview of seizure disorders 26 Cannabinoids in seizure disorders 29 Cannabidiol in seizure disorders 31 Cannabidiol in movement disorders 33 Cannabidiol as an antianxiolytic agent 33 Metabolism of cannabidiol (CBD) 34 Rationale and structure-anticonvulsant relationships of CBD and its analogs 37 Objective ....... 44 SYNTHESIS OF CANNABIDIOL 46 Syntheses of racemic cannabidiol 46 Stereospecific syntheses of (-)-cannabidiol 49 SYNTHESIS OF (+)-CANNABIDIOL . 56 SYNTHESIS OF CONFORMA TIONALL Y RESTRICIED CBDANALOGS 64 Synthesis of (+)·carenadiol . 64 Synthesis of (+)-carenadiol diacetate . 69 Synthesis of l",l"-dimethylheptyl carenadiol 69 SYNTHESIS OF 7·HYDROXY CANNABIDIOL 73 EXPERIMENTAL. 84 2·Cyclohexen-l-one, 3-methyl·6-(1·methylethenyl)·,(6S)·, (66.): 85 TAN E OECONDNJ'S CCONTINlTEP! PIll" EXPERIMENTAL (CONTINUED) 2-Cyclohexen-I-o~ 3-metbyl-6-(I-methy1ethenyl)-, mixt of (IR)- and (lS)- isomers, (67): .......•..•.... • • . 85 I, 3-BenzenediDl, 2-[3-metbyl-6-(I-methylethenyl)-2-cycIobexen-l-yl]-5- pentyl-, (IS, trans)-, (Ib): . 86 7-Oxabicyclo[4.1.0]heptane, l-metbyl4-(I-methyl-ethenyl)-, [(mixt of (IR,zs,4S)- and (IS.2R,4S)-isomers, (68a and 69.): • 87 2-Cyclohexen-l-o~ l-metbyl4-(l-methyletbenyl)-, (lR,4S)-, (70): 88 4-0xatricyclo[5.I.O.03,5]octane. 3,8,8-trimetbyl, [IR-(1a,3~,5~,7a)-, (77)]:. • . • . 89 Bicyclo[4.1.0]hept4-en-3-oI, 3,7,7-trimetbyl-, [IS-(Ia,3a,6a)]-, (80)]: 90 1,3-Ben=ediol,2-(bicyclo[4.1.O]hept-3-en-3,8,8-trimethYI-I-yl)-5-pentyl-, (lS, trans)-, (45.): . 91 Diacetateof(+)-Carenadiol(45b): ...... 92 2-Methyloctane-2-o1 (82): 93 4-(I',I'-dimetbylheptyl)-2,6-dimethoxypbenol (84): 93 4-(1',1' -dimetbylheptyl)-2,6-dimetboxyphenyldiethylphosphate (85): 93 1-(l',l'-dimetbylheptyl)-3,5-dimetboxyb=e (86): . 95 5-(l',l'-dimetbylheptyl)resorcinol (87): . • • 95 1,3-b=edio~ 2-(bicyclo[4.1.0]hept-3-en-3,8,8-trimetbyl-I-yl)-, 5-(1",I"-dimetbylheptyl)-, (lS, trans)-, (45<):. 96 7-0xabicyclo[ 4.1.0]heptane-I-methaaol, 4-(I-metbyl-ethenyl)-, (93): . 97 7-Oxabicyclo[4.1.0]heptane. I-[[[(I,I-dimethyletbyl)dlmethyletbylsilyl]-, oxy]methyl]4-(l-methyletbenyl)-, (94):. 98 Cyclohexaao~ 1 [[(I,I-dimethyletbyl)dimethyletbyl-silyl]oxy] metbyl]- 4-(I-metbylethenyl)-2-(phenylseleno)-, [mixt of [(lR)-1a,2b,4b]-,(97.) aad (lS)-la,2b,4a)-, (97b)]): . • 98 Cyclohexaaemetbaaol, l-hydroxy4-(I-metbylethenyl)-2-(pbenyl seleno)-, (mixt of [(IR)-Ia,2~,4~)-, (95.)] and [(lS)-Ia,2~,4")-, (95b)]): . 100 1,3-Dioxaspiro[4.5]decan-2-one,8-(I-metbylethenyl)-6-(phenylseleno)­ (mixt of [(IR)-la,2~,4~)-, (990)1 and [(IS)-Ia,2~,4")-, (99b):]] 100 TAW,E OF CONTENTS (CONTlN!!EDl page EXPERIMENTAL (CONTINUED) I, 3-Dioxaspiro[4.5]dec-6-en-2-one, 8-(I-methyl-ethenyl)-, [(IR,4S)-, (100a)]: .."..., ......... 102 I, 3-Dioxaspiro[4.5]dec-6-en-2-one, 8-(I-methylethenyl)-, [(1S,4R)-, (l00b)]: ... 102 General method for decarbonylation: . 103 2-Cyclohexen-I-oI, I-methanol, 4-(I-methylethenyl)-, [(IR,4S)-, (lOla)]: 103 2-Cyclohexen-I-oI, I-methanol, 4-(I-methylethenyl)-, [(IS,4S)-, (101b)]: 103 General procedure for monoacetylation of diol (101): . • . • • 104 2-Cyclohexen-I-oI, 1-[(I-acetyloxy)methyl]-4-(I-methylethenyl)-, [(IR,4S)-, (102a)]: ...................... 104 2-Cyclohexon-I-oI, 1-[(I-acetyloxy)methyI]-4-(I-methylethenyl)-, [(IS,4S)·, (102b)]: .••... 104 Condensation of diol (101) and olivetol (51): . 105 Condensation of acetate (102) and olivetol (51): 106 7-Acetoxycannabidiol (46b):. 106 7-Acetoxytetrahydrocannabinol (104): 107 Condensation of acetate (102) and olivetol dimethyl ether (52): 106 7-Acetyloxycannabidiol dimethyl ether (46d): 107 Dernethylation of dimethyl ether (46d): 107 Olivetol dimethyl ether (52): 108 LIST OF REFERENCES . 109 LlSIOFDJ,J5TRATIM"S Flgure 1. NlUUl'al Cannabinoids 17,18 2. Numbering systems used for cannabinoids. 20,21- 3.. Antiemetic Canabinoids. 24 3b. Cannabinoids as antiglaucoma agents 25 4. Standard antiepileptic drugs (<:OllIIIIl:I1:ial) . 28 5. Cannabinoids of interest as anticonvulsants 30 6. Metabolic sites and imponant metabolites in man 35 7. Metabolic sites anti important metabolites of CBD 36 8. CBD molecule from SAR point of view 38 9. Proposed CBD analogs 45 10. Scb=el 47 II. Scb=e2 48 12. Scheme 3 50,52 13. Scheme 4 53 14. Scheme 5 55 15. Scb=e6 57 16. Scheme 7 58 17. Scheme 8 60,62-63 18. Scheme 9 66 19. Scheme IO 67-68 20. Scheme II 70 21. Scheme 12 74 22. Scheme 13 75 23. Scheme 14 77,79 24. Scheme 15 81,83 9 IJSfOFTAill ES Table Page I.
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