Information to Users

SYNTHESIS OF DELTA-3-CANNABIDIOL AND THE DERIVED RIGID ANALOGS.

Item Type text; Dissertation-Reproduction (electronic)

Authors NAGARAJA, KODIHALLI NANJAPPA.

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 24/09/2021 13:38:47

Link to Item http://hdl.handle.net/10150/184033 INFORMATION TO USERS

While the most advanced technology has been used to photograph and reproduce this manuscript, the quality of the reproduction is heavily dependent upon the quality of the material submitted. For example:

e Manuscript pages may have indistinct print. In such cases, the best available copy has been filmed.

fib Manuscripts may not always be complete. In such cases, a note will indicate that it is not possible to obtain missing pages.

• Copyrighted material may have been removed from the manuscript. In such cases, a note will indicate the deletion.

Oversize materials (e.g., maps, drawings, and charts) are photographed by sectioning the original, beginning at the upper left-hand corner and continuing from left to right in equal sections with small overlaps. Each oversize page is also filmed as one exposure and is available, for an additional charge, as a standard 35mm slide or as a 17"x 23" black and white photographic print.

Most photographs reproduce acceptably on positive microfilm or microfiche but lack the clarity on xerographic copies made from the microfilm. For an additional charge, 35mm slides of 6"x 9" black and white photographic prints are available for any photographs or illustrations that cannot be reproduced satisfactorily by xerography.

8711643

Nagaraja, Kodihalli Nanjappa

SYNTHESIS OF DELTA·3·CANNABIDIOL AND THE DERIVED RIGID ANALOGS

The University of Arizona PH.D. 1987

University Microfilms International 300 N. Zeeb Road, Ann Arbor, MI48106

SYNTHESIS OF DELTA-3-CANNABIDIOL

AND THE DERIVED RIGID ANALOGS

Kodihalli Nanjappa Nagaraja

A Dissertation submitted to the Faculty of the

DEPARTMENT OF PHARMACEUTICAL SCIENCES

in partial fulfillment of the requirements For the Degree of

DOCTOR OF PHILOSOPHY

In the Graduate College

THE UNIVERSITY OF ARIZONA

198 7 THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE

As members of the Final Examination Committee, we certify that we have read

the dissertation prepared by KODIHALLI NANJAPPA NAGARAJA

entitled "SYNTHESIS OF DELTA-3-CANNABIDIOL AND THE DERIVED RIGID ANALOGS"

and recommend that it be accepted as fulfilling the dissertation requirement DOCTOR OF PHILOSOPHY for the Degree of ------

Date' 'J../"lO ( ~ 1 Date

Date )- 2 {)"'~7- Date

Date

Final approval and acceptance of this dissertation is contingent upon the candidate's submission of the final copy of the dissertation to the Graduate College.

I hereby certify that I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation requirement.

Dissertation Director STATEMENT BY AUTHOR

This dissertation has been submitted in partial fulfillment of 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 dissertation are allowable without special permission, provided that accurate acknowledgement of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or on part may be granted by the Dean of the Graduate College when in his or her judgement the proposed use of the material is in the interests of scholarship. In all other instances, however, permission must be obtained from the author. ~ ~)~ SIGNED------~.~--~------SHRI SRINGERI SHARADA

TO MY PARENTS

Smt. K. N. Venkamma and Sri. K. N. Nanjappa

iii ACKNOWLEDGMENTS

The author would like to thank Dr. Arnold R.

Martin for his guidance and constant encouragement.

Special thanks are due to Dr. Sham S. Nikam, Dr. Bhashyam

Iyengar, Dr. Shivanand D. Jolad, and Dr. Vinayak V. Kane, for their invaluable assistance in the compilation of the thesis. This work was supported by funds provided by the

National Institute of Health research grant NIH 15441.

iv TABLE OF CONTENTS page LIST OF ILLUSTRATIONS •••••••••• ...... viii LIST OF TABLES...... x ABSTRACT...... xi CHAPTER 1 INTRODUCTION...... 1

Historical aspects of Cannabis •••••••••••••••••••• 1 Botanical Classification of Cannabis ••••••••••• 5 Chemical Constituents of Cannabis •••••••••••••• 6 Biosynthesis of Cannabinoids •••••••••••••••••••••• 9 Synthesis of THC's and CBD's ••••••••••••••••••• 15 Cannabinoid Nomenclature •••••••••••••••••••••• 19 Cannabis And Health •.••••.•••••.••••••..•••• 21 Cannabis And Cannabinoids as Drugs •••••••••• 22 Cannabinoids As Antiepileptic Agents ••••• .... 26 Rationale ..••.•.... o ••••••••••••••••••••• · . 28

CHAPTER 2 • • • • • • • • • • • • • • • • • • • • • • • • • • e • • • • • • • • • 30 SYNTHESIS OF DELTA-3-CANNABIDIOL ANALOGS...... 30 Pechmann Condensation Reactions •••••••••• · . 34 Incorporation of the Alkyl Sidechain •••••••••••••• 36 Modification of the Terpenoid Portion •••• ...... 37 The Dibenzpyrones ••••••••••••••••••••••••••• 38 Opening of the Dibenzpyrones ••••••••••••• 46 Generation of the Dienes ••••••••••••••••••••••• 50 CHAPTER 3 •••••••• ...... ·. 64 SYNTHESIS OF CONFORMATIONALLY RIGID ANALOGS •• ...... 64

Intermolecular Diels-Alder Reactions •••••••••••••• 64 Isomers from the Lewis acid catalyzed Diels-Alder reaction ••••••••••••••••••• •• 74 Diels-Alder reactions of diene 55A ••••••• • .82 Intramolecular Diels-Alder Reactions •••••••• 89 CHAPTER 4 •••••••••• ...... · . 93 STEREOCHEMICAL ASRECTS OF THE DIENE ••• 93

RESULT AND CONCLUSION ••••••••••••••••••••••••••••••••• 100

v vi TABLE OF CONTENTS--Continued

EXPERIMENTAL. • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •• 103 General procedures •••••••••••••••••••••••••••••••• 103 Exerimental procedures •••••••••••••••••••••••••••• 105 Ia. Ethyl-4-methyl-2-oxo-1-cyclohexanecarboxylate 105 II. Typical procedure for the preparation of benz pyrones .•.•..•..•.••••.•••..••...••.....••••• l05 IIa. 1-Hydroxy-3-n-pentyl-7,8,9,10-tetrahydro- 6H-dibenz[b,d]pyrone ••••••••••••••••••••••••• 106 lIb. 1-Hydroxy-3-n-pentyl-6,7,8,9-tetrahydro- 6 - 0 x 0 - c y c lop e n t a - ben z [b , d ] pyrone • • • • • • • • • • • •• 1 0 7 IIc. I-Hydroxy-3-n-pentyl-9-methyl-7,8,9,10- tetrahydro-6H-dibenz[b,d]pyrone •••••••••••••• 107 lId. 1-Hydroxy-3(1",1"-dimethylheptyl)7,8,9,10- tetrahydro-6H-dibenz[b,d]pyrone •••••••••••••• 108 lIe. I-Hydroxy-3(1",1"-dimethylheptyl)6,7,8,9- tetrahydro-6-oxo-cyclopenta-benz[b,d]pyrone •• 109 IIf. 1-Hydroxy-9-methyl-3( 1",1 "-dimethylheptyl)- 7,8,9,10-tetrahydro-6H-dibenz[b,d]pyrone ••••• 110 III. General method for the preparation of the trihydric alcohols ••••••••••••••••••••••••••• 110 IlIa. 2-[l-Cyclohexene-2-(1-hydroxy-1-methylethyl)- 1-yl]-S-n-pentyl-resorcinol •••••••••••••••••• III IIIb. 2-[l-Cyclopentene-2-(1-hydroxy-1-methylethyl) 1-yl]-S-n-pentyl-resorcinol •••••••••••••••••• 112 IIIc. 2-[1-Cyclohexene-S-methyl-2(1-hydroxy-l methylethyl)-1-yl]-S-n-pentyl-resorcinol ••••• 113 IIId. 2-[1-Cyclohexene-2-(1-hydroxy-1-methylethenyl) 1-yl]-S(1",1"-dimethylheptyl)-resorcinol ••••• 113 IIIe. 2-[I-Cyclopentene-2-(1-hydroxy-1-methylethe nyl)-1-yl]-s-(1",1"-dimethylheptyl)resorcinol 114 IIIf. 2-[1-Cyclohexene-Smethyl-2-(1hydroxy-1- methyl-ethenyl)1-yl]-S(1",1"-dimethylheptyl)- resorcinol ...... •...•.....•..•• 114 IV. 2-[1-Cyclohexene-2-(1-hydroxy-1-methylethyl)- 1-yl]-1,3-diacetyl~S(n-pentyl)-resorcinol •••• 114 V. 2-[1-Cyclohexene-2-(1-methylethenyl)-1-yl]-s (n-pentyl)-1,3-diacetyl-resorcinol ••••••••••• 115 VI. General method for the preparation of delta -3-cannabidiol analog •••••••••••••••••••••••• 116 VIa. 2-[1-Cyclohexene-2-(I-methylethenyl)1-yl] s-(n-pentyl)-1,3-diacetyl-resorcinol ••••••••• 117 Vlb. 2-[I-Cyclopentene-2-(1-methylethenyl)1-yl s(n-pentyl)-1,3-diacetyl-resorcinol •••••••••• 118 VIc. 2-[1-Cyclohexene-S-methyl-2-(lmethylethenyl) l-yl]-S-(n-pentyl)-1,3-diacetyl-resorcinol ••• 119 vii TABLE OF CONTENTS--Continued

VIde 2-[1-Cyclohexene-2-(1-methylethenyl)-1-yl]- 5-(1",1"-dimethylheptyl)-1,3-diacetyl- resorcinol .••.•...•..••....•...••...••••..... 119 VIe. 2-[1-Cyclopentene-2-(1-methylethenyl)1-yl]- 5(1",1"-dimethylheptyl)-1.3-diacetyl- resorcinol •...... •...... •....•...... 120 Vlf. 2-[1-Cyclohexene-5-methyl-2-(1-methyl ethenyl)-1-yl]-5(1",1"-dimethylheptyl)-1,3- diacetyl-resorcinol •••••••••••••••••••••••••• 121 VII. 2-[1-Cyclohexene-2-(1-hydyoxy-1-methyl ethyl)-1-yl]-1,3-dimethoxy-5-(n-pentyl)- resorcinol ...••...... •..•....•...•.....• 122 VIII. 2-[1-Cyclohexene-2-(1-methylethenyl)-lyl] -5-(n-pentyl)-1,3-dimethoxy-resorcinol ••••••• 123 IX. General method for intermolecular Lewis- acid catalysed Diels-Alder reactions ••••••••• 125 Ethyl-l-methyl-10-[1-phenyl-2,6-diacetyl- 4-(n-pentyl)]-2,3,4,5,6,7,8-octahydrb naphthalene-4-carboxylate •••••••••••••••••••• 126 Eyhyl-1-methyl-10-[1-phenyl-2,6-diacetyl- 4-(n-pentyl)]-2,3,4,5,6,7,8-octahydro naphthalene-3-carboxylate •••••••••••••••••••• 126

Appendix 1 ••••.•••••••••.•.•••••••••••••••••••.••.•••• 128 Appendix 2 ••••.•••••••••••••••••••••••••••••••.•..•••• 129 Appendix 3 •....•..•.•••.••..•..•...••.•••••••..••••.•• 130

REFERENCES •••••••••••••••••••••••••••••••••••••••••••• 131 LIST OF ILLUSTRATIONS

Figure page

1. Cannabis sativa L. {female plant) ••••••••••• 2 2. Naturally occuring cannabinoids ••••••••••••• 7 3. Compounds from cannabis origin •••••••••••••• 8 4. Isolation of cannabinoids ••••••••••••••••••• 10 5. Biosynthesis of cannabinoids •••••••••••••••• 1 1 6. Biosynthesis of cannabinoids (contd.,) •••••• 12 7. Formation of cannabinol ••••••••••••••••••••• 13 8. Synthetic cannabinoids •••••••••••••••••••••• 16 9. Principal numbering systems of cannabinoids. 20 10. Structure activity relationship ••••••••••••• 31 11 • Natural and synthetic cannabinoids •••••••••• 33 12. Pechmann condensation reaction •••••••••••••• 34 13. Mechanism of Pechmann reaction •••••••••••••• 35 14. Resorcinols 19 and 19a •••••••••••••••••••••• 36 15. The p-keto esters •••...... •••.•.•...... • 37 16. Pechmann condensation products •••••••••••••• 39 17. Di benz py rones •••••••••••••••••.••••••••••••• 41 18. Cyclization products of Pechmann reaction ••• 43 19. Intermediate trihydric alcohols ••••••••••••• 47 20. Synthetic scheme for delta-3-cannabidiol analog 55...... 51 21. Synthetic scheme for delta-3-cannabidiol analog 58 ••••••••••••••..••••••••••••••• ea. • 52 22. Synthetic scheme for delta-3-cannabidiol ana log 61 ••••••••••.•••••••••••••••••••••••• 53 23. The delta-3-cannabidiol analogs ••••••••••••• 55 24. Numbering for 13C NMR data •••••••••••••••••• 60 25. Intermolecular Diels-Alder reaction ••••••••• 64 26. Regioisomers para-like products •••••••••••• 66 27. Delta-l-CBD a~he rigid bicyclic 8 n Alog ••• 67 28. Regioisomers meta-like products •••••••••••• 69 29. Formation of delta-3-THC anatog ••••••••••••• 73 30. Intermediate tertiary alcohols •••••••••••••• 79 31- Rigid delta-l-CBD analogs~ •••••••••••••••••• 80 32. Stereochemical view of the rigid delta-l-CBD ana logs •••••••• ~ •••••••••••••••••••••••••••• 81 33. Diels-Alder reactions of diene 55A •••••••••• 82 34. Generation of diene diacrylate •••••••••••••• 90 35. Intramolecular Diels-Alder product •••••••••• 91

viii ix

LIST OF ILLUSTRATIONS--Continued

36. Delta-3-THC analog from triol 53 ••••••••••• 92 37. Conformers of diene 55 and 55A •••••••••••••• 95 38. Chemical shift of olefinic protons in conju gated and isolated systems •••••••••••••••••• 99 39. Appendix 1 •••••••••••••••••••••••••••••••••• 128 40. Appendix 2 •••••••••••••••••••••••••••••••••• 129 41. Appendix 3 ••••••••••••••••••••••••••••••.••• 130 LIST OF TABLES

TABLE page

1. Physical characteristics of .benzpyrones •••••••• 42 2. Physical characteristics of triols ••••••••••••• 49 3. Physical characteristics of delta-3-cannabidiol analogs...... 56 4. 13C NMR chemical shift (250MHz DMSO-D ) of diene 55...... 6 61 5. 13C NMR Chemical shifts of the downfield signals(90MHz CDCI 3 ), for compounds 55, 58, a~d 61...... 62 6. 1 C NMR chemical shifts of the downfield signalsand 67...... (90MHz CDCI 3 ) for compounds 65, 66, 63 7. Tgermal vs Catalysed Diels-Alder reaction •••••• 71 8. 1 C NMR chemical shifts (2S0MHz CDCI ) for diene 55A...... 3 88

x ABSTRACT

Synthesis of 2-[1-cyclohexene-5-methyl-2-(1-met hyl-ethenyl)-1-yl]-1,3-diacetyl-5-(n-pentyl)resorcinol and the related delta-3-cannabidiol analogs, with modification of the terpenoid and/or the aliphatic side chain, were successfully carried out to study the structure anticon vulsant activity relationship. Modifications of the terpe noid skeleton and the sidechain were done by the initial condensation of suitable a f3 -keto ester with appropriate resorcinol carrying the required side chain to obtain benzpyrones as the starting compounds. Attempts were made to synthesize the conformationally rigid delta-I-cannabi diol (delta-l-CBD) analogs through inter-and intramolecu lar Diels-Alder strategy. The expected products, ethyl-I methyl-lO-[1-phenyl-2,6-diacetyl-4-(n-pentyl)]-2,3,4,5,6-

7,8-octahydro-naphthalene-4-carboxylate and tn~ correspon ding stereo-and/or regioisomers were observed to form in trace amounts in presence of Lewis acid catalyst. Cycli zation to the corresponding delta-3-THC, in case of diene

55, was a major drawback. The parent dienes 55 and 55A,

xi xii

were seen to decompose and generate high molecular weight products. The diene 55 and 55A were inert to ther~ mal Diels-Alder reactions.

Attempts to obtain the diacrylate of the triol -2-

[1-cyclohexene-2-(1-hydroxy-l-methylethyl)-1-yl]-5-(n-pen tyi)-resorcinol, to setup the molecule for intramolecular

Diels-Alder reaction met with little success.

The delta-3-CBD analogs (55,58,61,65,66, and 67) were submitted for pharmacological activity tests to provide information on the structure-anticonvulsant activity. The anticonvulsant activity was assessed employing the audiogenic seizure (AGS) susceptible rat model of epilepsy and the standard rotorod (ROT) paradigm to evaluate differential neurotoxicity. The results of these tests are encouraging in the n-pentyl analog 55, while the results of analogs 58, 61 with n-pentyl side chain and 65, 66, 67 with dimethylheptyl side chain are awaited. CHAPTER 1

INTRODUCTION

Historical aspects of cannabis

Cannabis sativa L. (Fig 1) represents one of the oldest cultivated plants and is believed to have origi nated in the plains of Central Asia, north of the Himalaya mountains. 1 The Chinese were the firs t to utilize its fiber for cloth and writing materials. Presently this species is found in many parts of the world, both in cultivated and wild forms. Since time immemorial, pre parations from this exotic plant have been used for their peculiar psychoactive effects and medicinal value.

However, the alarming growth and spread of marihuana (also spelled as marijuana) consumption in the early 1960's, and the continuing trend of its abuse by various cultures around the world, caused grave concern both in social as well as political circles. This, in fact, brought a renaissance to cannabis chemical research. For the past two decades many research projects have been aimed at examining the constituents of cannabis and exploring the compounds responsible for its psychoto mimetic activity.

1 2

~ lr F CMf- 4 0 M....

0 G

L ;r MM/ - i· I I oL (D N M 0 ...... J Ca"raols saliva Female olanl. on mary soeclmen-Mary F SoeJ"cer. No 8S7-frUit from Virgin Is H Chase No 13005 In BritiSh Museum 01 Natural History. Lc:'c:m ;.: l=emal9 ,rtlo~escence w,!n lIewer not CrOleCling oeyona :he :eaves G: Fe,....ale '!ower H. J: Bract or calyx wrlcn erwraos the c,.ary I: Pollen·catcnlng stigmas K. L: F'ult . acrenel. M. N: Embryo N'(I" -:cly scors

ILLUSTRAiIml REPqCQUCED FRor~ 1I~IARrHlJA~JA I'I SCr~:rICE ..~~jO II ME:JICINE • G,':;, .':Jhas, Raven Press, ~IY, 1984, ~7

Fig u r e 1. C .l n n 3 b iss a t i vaL. (E e mal e p 1 ant) • 3

General interest in pharmacological, physiological and toxicological properties of the ingredients of marihuana and the related cannabis species has prompted the isolation, structure determination, and study of the synthetic aspects of the major biologically active components and their metabolites.

The ill ici t commercial prepara t ions inges ted for their intoxicating effect consist mostly of an extract from the flowering top of the female plant (Fig 1) which is known as hashish (Middle East), charas and bhang

(India). A combination of the flowering top with the resin is termed ganja (India), kif (North Africa), dagga (South

Africa), maconha (South America), and marihuana (U.S.A.).

Interestingly, the preparations from cannabis have long been utilized in China, India, and Middle East, for their medicinal properties. In China, the use of cannabis was known as early as 2737 B.C., where a concoction of cannabis with wine was effectively used as a means of inducing anesthesia. 2 ,3 The Indian Hemp Commission Report of 1893 records the use of cannabis preparations for migraine, depression, rheumatism, epilepsy, ulcers, insomnia, withdrawal of opiates, menstrual bleeding, and labor pain. 4

Introduced into Western medicine by an Irish phy sician 0' Shaughnessy in the year 1842, cannabis was hailed as a miracle drug 4 for the relief of pain, muscle spasm, convulsions occuring in tetanus, rabies, rheumatism, and epilepsy. Adding to this seemingly impressive list, cannabis was also indicated 5 as an antipyretic, antitussive, antispasmodic, antiemetic, anti hypertensive, antiglaucoma agent, and an appetite stimulant. With this impressive list of indications the cannabis preparations made an entry into the British and the U.S. Pharmacopoeia, though only for a short time.

Alarming side effects, variability of the potency of batches (both from the same as well as different sources), non specificity of action, and the entry of some useful drugs with less side effects into the market forced the removal of the cannabis preparations from the British

Pharmacopoeia in 1932 and from the U.S. Pharmacopoeia in

1942.

Although the research from the past two decades has compiled a huge amount of data in almost all aspects of marihuana chemistry, overall, it is disappointing to note that none of the natural or synthetic analogs has any outstanding clinical usefulness. Through structural modi- 5

fication, efforts have been made in the development of synthetic analogs with less side effects. Synthetic method is one avenue where therapeutically useful drugs from cannabis may still be a possibility.

Botanical Classification Of Cannabis

In 1753, the hemp plant was christened Cannabis sativa by a Swedish botanist Carl Linnaeus,6 in his species plant arum and it has borne this scientific name ever since. In Latin cannabis means hemp; the name there fore denotes the genus of the hemp family of plants. The species sativa means sown or planted. The adjectives indica, and americana, identify the variety of the species according to their different geographical locations. It is a herbaceous annual plant (Fig 1), belonging to the

Cannabaceae family7 (some botanists still prefer to assign it to the Moraceae family). Cultivated plants grow up to

20 feet in height, and are widely distributed throughout the tropical and the temperate zones of the world.

It is considered to be a single nonstabilized species with more than one hundred varieties. Botanists in general agree on the following classification: 8 6

DIVISION Tracheophyta

SUB DIVISION Pteropsida

CLASS Angiospermae

SUB CLASS Dicotyledoneae

ORDER Urtieales

FAMILY Cannabaceae

GENUS Cannabis

SPECIES Sativa Linne'

Chemical Constituents Of Cannabis

Cannabis and humulus are the only two genera of the cannabaceae family containing "cannabinoids". The term cannabinoids is used for the groups of phenolic compounds containing 21-carbon atoms, their analogs and transforma tion products. 9

The major psychotomimetic component in cannabis preparations is delta-9-tetrahydrocannabinol(L) (delta-9-

THC), and to a small extent, delta-8-tetrahydrocannabinol

(2)(delta-8-THC). Cannabidiols (CBD's), though a major component is nonpsycoactive. As of today about 61 diffe rent cannabinoids have been isolated,lO mostly from leaves and flowering tops. These are characterized and classified 7

1 2 3

.. ..QH H OH

R 5 6 4 OH

7 8

>InHO R 9 10 11 R =C5H11

Figure 2. ~dturally occuring cannabinoids. 8

OH I r

12 13 14

R =-CH-< 15

R =-CH-{ 16

~ H I o I I R = C R= C=O H/ ""OH H ..... ~ C5H11 d5H11 Hd"k...... H 17 18 OH

R = H 19 H R = C02H 20

Figure 3. Compounds from cannabis origin. 9

into Tetrahydrocannabinoids(1,2), Cannabinol (3), Cannabi

diol (delta-l-CBD) (4), Cannabinodiol(5), Cannabitriol

(6), Cannabigeriol (7), Cannabichromene (8), Cannabicyclol

(9), Cannabielison (10), Cannabicitran (11). A new series of compounds including Cannabispirone (12), Cannabispire none (13), and Cannabispirol (14), have been recently

isolated. 11 Among the few other compounds of significance are cannabifurannes (15,16) and the spermidine alkaloids l2,13 [cannabisativine (17), anhydrocannabisati vine (18)] Fig 2 and Fig 3. Apart from these, a large number of non cannabinoid compounds of various classes, have been isolated and characterized. 14

A general procedure for the isolation of delta-9-

THC (1), delta-l-CBD (4), and cannabinol(3), from the leaves and the flowering top of cannabis plant, is given in Fig 4.

Biosynthesis Of Cannabinoids

The biosynthetic scheme for the formation of cannabinoids in the cannabaceae family is based mainly on cannabigeriol (CBC 7).9 Earlier this was considered an inactive cannabinoid. Recent findings 15 that cannabigeriol 10

CRUDe eXTRACT (Hoxane) HASHISH /~ NEUTRAL PORTION ACIDIC PORTION

ChromDtographad

(Florl,lI)

CsH11 TETRAHYDROCANNABINOL

I I ~O H11 :z::: CANNABIDIOL 5" Elher 95,. Pentane CANNABINOL

, 5.,. Ethor 85'l1o Pentano

Fig u r e 4. I <; ,) 1 d t ion ,) f can n a h i n 0 ids • 11

Ml!VALONA TE ACETATE/MALONATE ~ o

COOH 23

OOH 24

,I \ OH OOH ~H ~~ SH11 25 28

Figure 5. Biosynthesis of cannabinoids. 12 1 28 °2H 1 °21-1

H 1 29 5 " 1

27 1 30

Figure 6. Biosynthesis of cannabinoids (contd.). 13 DELTA-9-~ / \a

Figure 7. Formation of cannabinol. 14

can effectively reduce introcular pressure (rOP) have

created renewed interest in utilizing its therapeutic

potential.

Earlier theories on the biosynthesis of cannabi noids envisaged condensation of olivetol (19) or oliveto

lic acid (20) with a cyclic mono-terpene like mentha diene. 14

Theories substantiated by labeling experiments envisage the condensation of geranylpyrophosphate (21) 16 with olivetolic acid (20) or a C 12 -polyketide (22) to give cannibigerolic acid (23) which via hydroxylation (24) and allylic rearrangement (25) goes to cannabidiolic acid

(26) and, ultimately, to delta-9-THC (1) via delta-9-THC acid (27). Alternatively, the intermediate hydroxy canna- bigerolic acid (24) can eliminate a molecule of water to give the corresponding anhydro compound (28),. which cyclises to 29 and ultimately goes to cannabicyclolic acid

(30), Fig 5. and Fig 6.

Cannabinol (3) is mostly produced by oxidation of delta-9-THC (1). The fact that it is present in higher percentage in the aged samples support this theory to a certain extent. It is of interest to note that the inter-

.. 15

mediates 31 and 35 have been found in cannabis extracts which substantiate the proposed theory. A mechanism for its formation based on the work of Garret I7 and Kajima iS is proposed by Turner and Elsohly, Fig 7.

The use of in vitro tissue culture of the cannabis sativa I9 is considered to be useful in elucidating the mechanisms of biosynthesis of cannabinoids.

Synthesis Of THC's And CBD's

Delta-3-cannabidiol (36) (delta-3-CBD) and delta-

6a,IOa-tetrahydrocannabinol (37) (delta-6a,lOa-THC), differ from the natural THC's (1,2), and delta-I-CBD (4) in the relative position of the double bond (FIG S·). The delta-3-CBD (36) and delta-3-THC (37) also exhibit the characteristic psychoactive effect similar to the natural

THC's and CBD's respectively. A considerable amount of work, both synthetic, as well as 0 n t;, est r u c t u r e - activity relationships (SAR) was initiated by Adams 20 in the United States, and Todd 21 in the Great Britain, during early 1940's. Detailed reviews of the analogs have been compiled by Mechoulam 22 ,23 and Pars. 24 16

'fH2 =CH

COCI-I2CH2CH2NC) h

Figure 8. Synthetic cannabinoids. 17

A few of the important synthetic analogs evaluated

to date include delta-3-CBD (36), delta-6a,10a-THC (37), nabilone (38), synhexyl (39), DMHP (40), nabitan (41), and nantradol (42), (Fig 8). Among these, nabilone (38) is commercially available for treating nausea and vomiting secondary to cancer chemotherapy. This is the only clear cut success so far in quest of drugs from cannabis origin.

The general method for the synthesis of the delta-

3-analog is to condense a suitable {3 _keto ester with an appropriate resorcinol derivative. Various analogs that differ in length of th~ alkyl side chain and ring modifi cations have been most commonly studied by various groups.25,26

One of the major difficulties encountered in the cannabinoid field is the insolubility of cannabinoids in water. Water soluble alkyl amino esters of the phenolic hydroxyl group exhibiting both CNS and marihuana like activity are now known. 24

Cannabinoids belong to the catagory of compounds that does not contain nitrogen atom in its framework.

Incorporation of the nitrogen atom in the framework of 18

cannabinoids to make them more hydrophilic in nature has

opened new avenues in analog synthesis. A number of

analogs containing a nitrogen atom (as an isosteric

replacement) at different positions in the terpenoid

portion have been synthesised by various groups.24

Surprisingly, the acid salts of these compounds do not exhibit hydrophilic properties. 24

In a similar fashion incorporation of a sulfur atom in the terpenoid ring has added a number of compounds 27 into literature, which are only of academic interest.

The natural delta-1-CBD (4) was first isolated by

Adams and co-workers. 20 The structure was reported by

Mechoulam,28 and was confirmed through x-ray studies by

Ottersen. 29 Most of the synthetic routes leading to the natural cannabidiol (4) are not of practical value as the yields are poor. A new method using BF 3 -etherate on alu~ina as a condensing agent reported by ~echoulam and co-workers,30 seems to be an attractive approach in the synthesis of the natural cannabidiol (4). The delta-3- cannabidiols are not naturally occuring. These are obtained through synthetic methods. 19

Cannabiboid Nomenclature

Investigations on the synthetic analogs of the tetrahydrocannabinols (THC's) and cannabidiols (CBD's) by suitably modifying the terpenoid portion and/or varying the side chain has been the most common approach. Various research groups have used different system of nomenclature in referring to the same cannabinoid. Five different ring numbering systems have so far bee~ used. Presently however, the most commonly used systems are; a) the formal ring numbering (benzopyran ring numbering), and b) mono-terpenoid ring numbering (Fig 9). The principal psychoactive cannabinoid is referred to as delta-9-THC, by the former and as delta-I-THC, by the latter. Examples of the mono-terpenoid and the formal mode of numbering as applied to THC'S and CBD'S are illustrated in Fig 9.

I nth i s the sis the for mal r i n gnu m J:, .~ r i n g (b e n z 0 - pyran ring numbering) is maintained for the THC'S, and for the delta-3-cannabidiol analogs. The analogs and their corresponding precursors are looked upon as derivatives of the corresponding resorcinols. 20

5 8 5 7 9

10 5 C5H11 DELTA-1-THC DELTA-9-THC

TERPENOID NUMBERING FORMAL NUMBERING

DEL T A-I-CBD DELTA-2-CBD

Figure 9. Principal numbering systems of cannabinoids. 21

Cannabis And Health

Scientific evidence published to date indicates that cannabis preparations have a broad range of influence on biological and physiological behavior in man. 31 The major constituent, delta-9-THC (1), has been found to produce adverse effects on the lungs, the cardiovascular system, and the reproductive systems of both males and females. It also causes mitotic activity, chromosomal abnormalities and impairment of immune response. Another serious consequence supposedly associated with the high lipophilicity and long half life of delta-9-THC (1), is the accumulation of the drug in the adipose tissue which produces secondary effects leading to psychotoxicity.32,33

This may cause deterioration of the mental function~ such as panic reactions,34,35 dysphoric reactions like acute brain syndrome (usually manifested by i~pairment of thinking, memory disorder), perceptual mental disturb ances, and changes in sleep pattern. 33 Cannabis may also trigger underlying psychosis 36 (schizophrenia). prolonged chronic use is known to produce amotivational syndrome,37 characterized by loss of interest, initiative, and overall 22

mental and physiological deteriora:tion. 38 With these frightening consequences the prime concern of any society should be to exercise caution and educate the general public as to the negative effects of the drug.

Cannabis And Cannabinoids As Drugs

The progress made thus far in cannabis research indicates that the traditional use of the preparations on a trial and error basis is neither desirable nor acceptable. The important factor contributing to this failure seems to be the complexity of constitutents and the inseparable side effects. The therapeutic potential of cannabis at this stage was thought to rest mainly on the individual cannabinoids. Based on this assumption the pure cannabinoids were tested as a remedy for anxiety, retardation of tumor growth, alcoholism, depression, pain, neuralgia, rheumatism, asthma, nausea and vomiting, glaucoma, and for epilepsy. By the early 1980's the long list of indications acclaimed by folklore as a miracle drug had dwindled down to just a few. 23

Cannabis was used as a relaxant as it was known to

decrease tension, anxiety, and to induce sleep on smoking

marihuana. Oral ingestion or intravenous (I.V) administra

tion of delta-9-THC (1), however induced anxiety,

dysphoria and sedation. 39 Overall, the sedative-hypnotic

activity of cannabinoids was not disputed, but the

existing medication for these and the side effects of

anxiety and panic prevented recommending cannabis prepara

tions.

Oral preparations of delta-9-THC (1), and delta-8-

THC (2), have been proved to decrease the size of

tumors,40,41 and increase the mean survival time in animal

models. The fact that these were not superior to the

currently used antineoplastic drugs was one of the main

reasons for not using these for this disease state.

The use of cannabis in treating alcoholism was

first suggested by Rosenberg. 42 However, cannabis was

found to be ineffective in treating both alcuholism and

drug dependency.S

As a folk medicine, many cultures had used cannabis for melancholia. Regelson and co-workers 43 found

that delta-9-THC (1) could be used as mood elevator and

tranquilizer. The data available at present is insuffi- 24

cient to convincingly draw any conclusion.

Traditionally, cannabis had been administered for

toothache, dysmenorrhea, difficult childbirth, neuralgia and rheumatism in places where it was abundantly available. The research done so far in this field using delta-9-THC (1), has indicated that it has mild analgesic action,44 but even at a slightly higher dosage it induced prohibitively high sedating and intoxicating effect. It is now established that the analgesic effect is more due to the II-hydroxy metabolite of delta-9-

THC. 45 ,46 (1) The current status is that none of the natural or synthetic cannabinoids can compete as an analgesic with the drugs commercially available.

Smoking of marihuana has been known to produce bronchodilation 47 , however, chronic smoking of marihuana is associated with pulmonary complications. The pure delta-9-THC (1), though a mild bronchodilator, has un reliable effects due to variable absorption from the gas trointestinal tract. An aerosol developed for this reason turned out to be a major drawback as it produced bronchial irritation. 48 25

The nausea and vomiting sensation caused by cancer chemotherapeutic agents is surprisingly not quite controlled by the antiemetic drugs. Delta-9-THC (1), and nabilone (38) have provided pronounced protection against emesis. With the available data it appears that these two cannabinoids have definitely filled a void where the antiemetic drugs had failed, especially in the cancer chemotherapy.49,50 The synthetic analog nabilone (38) has been observed to be more effective 51 compared with delta-

9-THC (1).

A decrease in ocular hypertension observed in glaucoma patients on smoking marihuana 52 encouraged the use of delta-9-THC (1) on human patients, with variable results. Minor psychic side effects with some patients caused concern. Use of this as an eye drop along with mineral oil, did record success on rabbits but proved to be an irritant on human patients. 53 Delta-8-THC (2) and nabilone (38) are indicated as oral and topical drugs to reduce introcular pressure (rOP). The major problem in this area seems to be the choice of administration of the drug. Nonaqueous preparations are found to be undesirable.

As of today, cannabinoids along with the existing anti- 26

glaucoma agents (pilocarpine, acetazolamide), show some

promise as an effective therapeutic regime in glaucoma.54

The anticonvulasnt activity of cannabinoids

especially delta-I-CBD (4) has been demonstrated by

various researchers.55 - 61 In subtoxic doses, delta-9-THC

(1) and delta-8-THC (2) both suppressed kindled

seizures. 62 A recent survey63 suggests a high incidence of

the use of marihuana among epileptics. There are

indications to support this view and to utilize this

therapeutic potential.58

Cannabinoids As Antiepileptic Agents

One of the therapeutic use of cannabinoids is the

management of epileptic seizures. Marihuana and synthetic

homologs of delta-9-THC (1), have been reportedly used in human convulsive disorders. 55 - 58 Support for this came from studies showing anticonvulsant eicects on the

laboratory test animals for delta-9-THC (1).59,60 However,

the therapeutic potential of delta-9-THC (1) and related analogs are limited as they did not eKhibit any marked separation between the anticonvulsant and neurotoKic potencies. 61 - 64 Another possible undesirable chara- 27

cteristic is that they exhibited anticonvulsant tolerance, and paradoxically, induced convulsions in some seizure susceptible anima1s. 59 ,65-68 In humans, delta-9-THC (1) is known to produce undesirable side effects. 69 ,70

The potential of delta-1-CBD (4) as an antiepi leptic drug 71 ,72 was first observed in 1973. Subsequent reports have confirmed its ability to prevent seizures in laboratory anima1s. 64 ,67,73,74 De1ta-l-CBD (4), given acutely, prevents various kinds of convulsions including:

1) tonic (maximal) generalized convulsions in rodents caused by electroshock and gama-aminobutyric acid (GABA) inhibiting drugs, 2) genetically dependent convulsions in epileptic chickens, rodents and rabbits, 3) Cobalt pro duced cor.tica1 focal convulsions in rats. De1ta-l-CBD (4) has good selectivity of anticonvulsant action relative to minimal neurotoxicity. It is also devoid of central nervous system (CNS) excitatory effects (unlike de1ta-9-

THC 1) in seizure susceptible animals. Overall the anti convulsant profile of de1ta-l-CBD (4) is very similar to those of antiepileptic drugs (phenytoin, phenobarbital, carbamazepine) that are useful in partial and generalized seizures of the grandmal type. Clinical trials of de1ta-l

CBD (4) are quite encouraging in terms of effectiveness, 28

toxicity and side effects. 68 ,73,75-77 This encouraging observation has given a new thrust to designing synthetic analogs employing classical SAR techniques to possibly generate a more useful drug for epilepsy.

Rationale

The potential usefulness of delta-I-CBD (4) as an antiepileptic would indicate the importance of studies that define the structure-antiepileptic efficacy. In order to explore this aspect, a rational approach is to analyse the existing data available on model compound (delta-I

CBD), and to suitably modify the molecule retaining the essential functions and appropri'ate stereochemical features.

To determine the structure-anitepileptic efficacy, it seems reasonable to compare the structural features of non-cannabimimetic delta-I-CBD (4), and the c ... nnabimimetic delta-9-THC (1). Mimicking the delta-I-CBD (4), which is a di-phenol (rather than a mono-phenol) and has two rings

(rather than three Lings), seems to be an essential requirement. Varying anyone of these units based on the classical structure activity relationship (SAR) is a 29

possible approach for arriving at new structures for determining structure-anticonvulsant activity. Various parameters that can be altered to determine the SAR., are: a) homologation of the rings and/or side chain; b) isosteric replacement of atoms and functional groups;78 c) synthesis of the prodrug derivatives;79 d) blocking of known sites of bio-transformation; e) modification of the stereochemistry at the chiral centers; and f) synthesis of conformationally rigid analogs.80

The overall objective of this thesis is to synthesize delta-3-cannabidiol, and related analogs and to comprehensively investigate structure-anticonvulsant activity relationship in delta-3-cannabidiols and derived rigid analogs with the goal of optimizing anticonvulsant activity as a function of structure. CHAPTER 2

Synthesis of Delta-3-Cannabidiol Analogs

The major obstacle encountered in cannabis chemi

cal research for the past two decades in pursuit of chemo

therapeutical drugs, is the separation of the cannabi

mimetic effects from the individual cannabinoids. The

delta-I-cannabidiol (4) being devoid of this characteris

tic side effect 85 is a suitable model in developing new

drugs through molecular modifications.

Though delta-I-cannabidiol (4), is one of the

major constituent of cannabis, and is non psychoactive, it

has not been as extensively investigated as delta-9-tetra

hydrocannabinol (1). the fact that delta-I-cannabidiol (4)

was shown to possess anticonvulsant activity86-93 and low

somatic toxicity74 has, of late, evoked interest in the synthetic as well as the pharmacological aspects of delta

I-cannabidiol (4), and related analogs.

Confo~mationally rigid analogs of delta-l-cannabi diol (4) have displayed encouraging ~esults in being active against va~ious convulsive diso~ders.81,82 This has prompted to designing related compounds, anticipating

30 31

that they might be therapeutically more useful.

The current investigations therefore, pertain mainly to the synthesis of the delta-3-cannabidiol analogs

(55, 58, 61, 65, 66, and 67), and the conformationally rigid delta-l-cannabidiols (80), as possible anticonvul sant drugs. The overall basis for the synthesis of these target compounds is the classical structure anticonvulsant activity relationship73,76,94(SAR). The delta-I-cannabi diol (4) is viewed as made of three distinct parts. The terpenoid unit, resorcinol portion, and the alkyl side chain, as shown in Fig 10, is assumed to be responsible for the cannabidiol-like activity.

STRUCTURE ACTIVITY RELATIONS

I I I , I I I I I / I I I

I R4 , I " I I

Figure 10. Structure activity relationships. 32

The carbon-carbon double bond, and the appendage

at the 4-position of the terpenoid unit, the resorcinol

with its phenolic function either as free hydroxy group or

as the corresponding acetate, and the alkyl side chain

with a minimum of 5-carbon atoms are considered essential

for CBD-like activity.

Modification of the side chain has been known to

exert profound influence on the pharmacological activity

of cannabinoids. 95 - 97 In delta-I-cannabidiol (4) the I",

I"-dimethylheptyl, I",2"-dimethylheptyl, I"-ethyl,I"

methylheptyl side chain have been shown to have greater

anticonvulsant activity as compared to the natural delta

I-cannabidiol (4), which has n-pentyl side chain. I3 ,8I

These observations have prompted us to design various delta-3-cannabidiol acetates as representative of a new series of compounds, with possible high efficacy, as anticonvulsant drugs and minimal neurotoxicity.

During the course of this research a series of diene containing delta-3-cannabidiols (55, 58, 61, 65, 66, and 67) have been synthesized and efforts have been made to test their anticonvulsant activity. Entry into the conformationally rigid analogs of delta-I-cannabidiol (4), have been attempted through inter-and intramolecular 33

Diels-Alder strategy, utilizing the delta-3-cannabidiol analog 55 as a diene.

Unlike the natural delta-I-cannabidiol (4), the delta-3-cannabidiol (36), and the related analogs are accessible only through synthetic methods.

o 5 H 11 I ~6_CBD

I ~3_CBD

Figure L1. ~i:ltural and synthetic cannabidiols. 34

Pechmann Condensation Reaction

The pechmann condensation reaction98-101 (Pechmann reaction) is one possible approach to obtain the delta-3- cannabidiol (36), and t,he related analogs. In its simplest form the pechmann reaction is the condensation of a phenol with a P -keto ester to generate a coumarin (benzpyrone), as shown in the Fig 12.

~ ~H + >

Figure 12. Pechmann condensation reaction.

The reaction is known to proceed through trans- esterification, followed by acid catalysed ring closure to the corresponding benz-pyrones 102 • Possible mechanism for 35

> ~Jl ~

'0) ,:>~--cJ

df' r ~....cL P'cL

I I ~~

Figure 13. Mechanism of pechmann reaction. 36

the formation of be,nzpyrone using phosphorus oxychloride is illustrated in Fig 13. A variety of protic acids, like concentrated sulfuric acid, concentrated hydrochloric acid, phosphoric acid, trichloroacetic acid, phosphorus oxychloride 103 , and Lewis acids like anhydrous aluminium- chloride, and anhydrous zinc chloride have been used for cyclization.

The Pechmann reaction has been effectively utilized to generate the desired benzpyrones as the starting compounds.

Incorporation of the Alkyl Sidechain

Incorporation of the required alkyl side chain in the delta-3-analogs are usually accomplished through the initial synthesis of the resorcinol, having the appropriate side chain at the S-position (19 and 19a). Various

19a = =

Figure 14. Resorcinols 19 and 19A. 37

methods are known in the literature,104-107 for the synthesis of resorcinols carrying 5-(1',1'-dimethylheptyl) side chain. Among these, the short and efficient method given by Dominianni and co-workers,108 was used in incor- porating the 1",I"-dimethylheptyl side chain for three of the analogs (65, 66, 67). The resorcinol derivative with the n-pentyl side chain used in the synthesis of analogs

55, 58, 61, was commercially available as olivetol (19).

Modification of the Terpenoid Portion

Modification of the terpenoid portion in the delta-3-cannabidiol analogs has been attained by choosing

Figure IS. j3 -Ketoesters 38

appropriate P -keto esters, like, ethyl-2-cyclohexanone-l carboxylate (43), ethyl-2-cyclopentanone-l-carboxylate

(44), and ethyl-4-methyl-2-cyclohexanone-l-carboxylate

(45). The keto ester 45, was prepared in the laboratory according to the procedure of Adams and co-workers,109 whereas the keto es ters 43 and 44 were obtained from the commercial source (Aldrich Chemical Co.,). These were purified by column chromatography before use.

Dibenzpyrones

Six different pyrones (47-52), with different terpenoid unit and/or the side chain were prepared according to the procedure of Adams,110 using phosphorus oxychloride as the acid catalyst in refluxing benzene medium (Fig 16). 1-Hydroxy-3-n-pentyl-7,8,9,10-tetrahydro-

6H-dibenz[b,d]pyrone (47), I-hydroxy-3-n-pentyl-6,7,8,9- tetrahydro-6-oxo-cyclopenta-benz[b,d]pyrone (48), and 1- hydroxy-3-n-pentyl-9-methyl-7,8,9,10-tetrahydro-6H-di-benz

-[b,dJpyrone (49), are obtained as the condensation products of the respective f3 -keto esters 43, 44, 45 with

5-(n-pentyl)resorcinol(19). Whereas the condensation of 39

+ H

R n H 1 H 0 CH3 1

R' e e' n 47 H Cs H11 1 48 H C5 H11 0 49 CH3 C5 H11 1 50 H CgH19 1 51 H CgH19 0 52 CH3 C9H19 1

Figure 16. P~chmann condensation products. 40

the esters 43, 44, and 45 with 5-(1 ' ,1'-dimethylheptyl)

resorcinol (19a), under similar reaction conditions gave

another set of benzpyrones, 1-hydroxy-3-(1',1 ' -dimethyl -heptyl)-7,8,9,10-tetrahydro-6H-dibenz[b,d]pyrone (50), 1-

hydroxy-3-(1 ' ,1 ' -dimethylheptyl)-6,7,8,9-tetrahydro-6-oxo

cyclopenta-benz [b,d] pyrone (51), and 1-hydroxy-3-( 1 I, 1 '

dimethylheptyl)-9-methyl-7,8,9,10- tetrahydro-6H- di-benz

[b,d]pyrone (52).

The formation of the benzpyrones proceeded smoothly to give colorless crystalline (ethanol) compounds, in moderate yields (53% to 70%). The analogs 48 and 51 containing the cyclopentyl ring, gave lower yields as compared to the benzpyrones containing the six membered ring 47,49,50 and 52 (Table 1). Variation in the react ion conditions did not improve the yields significantly.

Another routine observation on the pyrones 48 an<;l 51 are their polar nature, compared to the benzpyrones 47, 49, 50 and 52 as observed by their Rf-values in TLC (Table 1).

The important feature in all these benzpyrones is the placement of the carbon-carbon double bond across 6a lOa, positions in 47, 49, 50, and 52, and across 6a-9a, positions in 48 and 51. Unlike the natural cannabi- 41

47 50

48 51

Fl~ure 17. Dibenzpyrones. 42 TABLE 1

Physical characteristic of dibenzpyrones.

======~======~======~===Q ==== IH NMR o Compound mp C %y Rf. S(ppm)

Ar-2H

======

47 190 63 0.54 6.56

48 196 53 0.41 6.62

6.56

49 180-181 66 0.64 6.58

185-186

SO 160 67 0.48 6.89

6.72

51 156 58 0.44 6.86

6.77

52 182-183 70 O. SO 6.80

======

a Ethyl acetate/hexane 20:80 43

noids, positioning of this double bond eliminates the possibility of isomers in the pyrones 47, 48, 50, and 51.

However, in case of pyrones 49 and 52, methyl substituent at C 9 position, leads to a mixture of isomers. With the incorporated terpenoid portion and the desired side chain, the individual pyrones look like cyclic-CBD analogs (tetra hydrocannabinols) except for the fact that a carbonyl function is present in place of methyl groups at the 6- position Fig 17.

Another aspect to consider is the reactivity of the resorcinols (19) and (19a). Positions C 2 ' C4 and C6 of the resorcinol are available for cyclization. This can generate different products 47 and 47a (Fig 18).

7 7

470 47

Figure 18. CyclLzation products of pechmann reaction 44

The positions C4 and C6 being in similar environ ment cyclization at anyone of these positions should

.generate 47a, whereas cyclization at C2 position should give compound 47. The exclusive formation of compound 47 was observed in the formation of benzpyrones (47-51).

Higher reactivity of the 2-position of the resorcinols

(19, 19a), and the bulky nature of the alkyl side chain is thought to be mainly responsible 110a for the selective formation of 47.

The benzpyrones were characterized by IR (Nujol), and IH and 13 C NMR. Each pyrone had the characteristic strong stretching band for the hydroxyl function and for the pyrone carbonyl. The -OH stretching absorption of the two pyrones 48 and 51 containing the cyclopentyl moiety occured at higher frequency regions as compared to the other pyrones. The carbonyl stretching frequencies of pyrones were shifted to lower frequency regions compared to the expected C=O stretching frequency of saturated delta-lactone. This is due to the fact that the molecule is conjugated.

The benzpyrones 47, 48, and 49 carrying the n pentyl side chain were insoluble in CDCl 3 • The 1H NMR spectra of these compounds were recorded in dimethyl 45

sulfoxide-D6 (DMSO-D 6 ). However the pyrones SO, 51, and 52 with the 5-(1',I'-dimethylheptyl) side chain had no such solubility problem. This solubility factor was critical in the assignment of some of the absorptions in pyrones 47,

48, and 49, which were masked by the signals due to the impurity in DMSO-D 6 , and the moisture in DMSO-D 6•

The two aromatic protons C2H and C4H in the benzpyrones being in a slightly different environment, were expected to be magnetically nonequivalent. As expected the benzpyrone 48 showed two singlets at" 6.56 and 6.62 ppm.

However, the benzpyrones 47, and 49 showed a singlet at

6.56 and 6.58 respectively, for two protons in the aroma tic region. In case of the pyrones SO, 51, and 52, carrying the 5-(l I, 1 ' -dimethylheptyl) side chain all'three of them exhibited the nonequivalence for the aromatic protons resonating at 6.89, 6.72, (SO), 6.86, 6.77 (51) and 6.80, 6.76 ppm (52), respectively.

The fact that 47 and SO, as well as 49 and 52, differ only in side chain, it is likely that the branched side chain in compounds 50 and 52, to a certain extent is influencing the C2 and C4 protons in these benzpyrones to be nonequivalent. 46

Opening of the Dibenzpyrones

Opening of the benz pyrone ring system to the corre

sponding triols was accomplished through Grignard react

ion. lll The appropriate benzpyrone (47, 48, 49, 50, 51, and 52), in benzene solution on treatment with methyl

magnesium bromide under reflux for 6 h. gave the correspo nding triol, 2-[1-cyclohexene-2-(1-hydroxy-l-methylet hyl)-1-yl]-5-n-pentyl-resorcinol (53), 2-[1-cyclopentene-

2-(1-hydroxy-l-methylethyl)-1-yl] -5-n-pentyl-resorcinol

(56), 2-[1-cyclohexene-5-methyl-2-(1-hydroxy-l-methyl ethyl)-l-yl] -5-n-pentyl-resorcinol (59), 2-[1-cyclopent ene-2-(1-hydroxy-l-methylethyl)-1-yl]-5-(I",I"-dimethylhe ptyl)-resorcinol (62), 2-[I-cyclohexene-2-(I-hydroxy-l methylethyl)-I-yl]-5-(I",I"-dimethylheptyl)-resorinol(63) and 2-[1-cyclohexene-S-methyl-2-(1-hydroxy-l-methylethyl) l-yl]-5-(I",1"-dimethylheptyl)-resorcinol (64), (Fig 19), in good yield (94-98%), as viscous oils. These were puri fied through medium pressure column chromatography using a short column, and eluted out as rapidly as possible using ethyl acetate/hexane, 20:80, as these were sensitive to heat and light, and decompose on exposure to 47

CgH19 53 62

56 63

CgH19

59 (54

Figure 19. Intermediate trihydric alcohols. 48

silica gel and leave residue in TLC when allowed to stand overnight at room temperature.

These observations are in agreement with their polar nature due to the three hydroxyl groups in their framework, they all showed very low Rf-values on TLC

(Table 2). The triols 56 and 63 carrying the cyclopentyl ring, had low Rf-value, compared to the triols, 53, 59,

62, and 64 (Table 2).

Very highly characteristic broad bands were observed in IR spectra (film), due to the overlapping bands of the tertiary-OH and the phenolic-OH functionality in each of the triols prepared. Significantly, the absor ption due to lactone carbonyl of the starting compound was absent. Appearence of doublet at the C-H bending region

1385, and 1360 cm -1 for 53, 1 380, and 1360 cm -1 for 56,

1375, and 1365 cm- 1 for 59, 1 375, and 1365 cm- 1 for 62,

1385, and 1360 cm- 1 for 63, 1 385, and 1360 cm- 1 for 64, indicating the presence of the isopropyl group was an important feature in identifying the triols. 1 12 1H A notable feature in the NMR (CDC1 3) in each of these triols was the magnetic equivalence of the aromatic protons at C4 , and C6 , in 56, and 62-64, whereas the corresponding precursors exhibited nonequivalence. 49

TABLE 2

Physical characteristics of triols.

Compound %y

======~======

53 0.42 81 3400

56 0.26 75 3430

59 0.45 82 3400

62 0.26 84 3400

63 O. 15 78 3430

64 0.35 85 3400

======

a Ethyl acetate/hexane 20:80

.'WI 50

With the opening of the benzpyrone ring, these look more like delta-3-cannabidiol analogs, except for the appendage at the 4-position which required further modification.

Generation of the Diene

The incorporation of the isopropenyl appendage at the 4-position of the terpenoid portion was initially carried out on the triol 53, in two steps. The first step involved acylation of the resorcinolic function at room temperature to get the diacetate of the tertiary alcohol

54. Subsequent step of activating the tertiary alcohol as a better leaving group and generating the carbon-carbon double bond across Cs and Cg carbon atoms, was done by using E-toluenesulfonyl chloride, in presence of pyridine and refluxing toluene. Routine workup gave the key intermediate, 2-[l-cyclohexene-2-(1-hydroxy-l-methylethyl)

-1-yl)]-1,3-diacetyl-5-(n-pentyl)-resorcinol (55), (delta-

3-cannabidiol acetate). Further experiments on the triol

(53), showed that hy warming this in presence of acetic o anhydride and pyridine to gO C gave the required delta-3- cannabirliol acetate (55) in single step. This advantage 51

OAc TsCl, py >

54 55

Figure 20. Synthetic scheme for delta-3-cannabidiol analog (55). 52

CH3M9 Sr Cs H6, .6

57 58

Figure 21. Synthetic scheme for delta-3-cannabidiol analog (58). /

TsCI I PY >

Figure 22. Synthetic scheme for delta-3-cannabidiol analog (61). 54

was utilized in obtaining the remaining analogs without

isolating the corresponding tertiary alcohols 57 and 60

(Fig 21-22). The analogs, 2-[ l-cyclopentene-2-( I-methyl ethenyl)-I-yl]-1,3-diacetyl-5-(n-pentyl)-resorcinol (58),

2-[I-cyclohexene-5-methyl-2-(I-methylethenyl)-1-yl]-I,3-di ace tyl-5-(n-pen t yl )-res ore i no 1 (61), 2- [ I-eye 10 hexene-2-( 1

-methylethenyl)-1-yl]-1,3-diacetyl-5-(1",1"dimethylheptyl)

-resorcinol (65), 2-[1-cyclopentene-2-(1-methylethenyl)-1- yl]-1,3-diacetyl-5-(1",1"-dimethylheptyl)-resorcinol (66),

2-[1-cyclohexene-5-methyl-2-(1-methylethenyl)-1-yl]-1,3-di acetyl-5-(1" , l"-dimethylheptyl)-resorcinol (67), along

with 55, formed a new series of the delta-3-cannabidiols,

(Fig 23).

The six a n a log s 55, 58, 6 1, 65, 66, and 67", ( Fig

23), were light yellow to golden yellow oils. The analogs with 5(1",1"-dimethylheptyl) side chain 65,66,67, were less polar than the corresponding 5-n-pentyl side chain analogs 55, 58, and 61. The analogs 65, 56, 67, were characterized by their IR (film), IH NMR, 13 C NMR, and elemental analysis.

Presence of the stretching band for the C=O, in IR spectra between 1765-1770 em-I, and the disappearence of the -OH stretching bands indicate complete formation of 55

55 65

61 67

Figure 23. The delta-3-cannabidiol analogs 56

TABLE 3

Physical characteristics of the delta-3-CBD analogs.

======~======

%y IH NMR (ppm) 0

Compound Ar-2H =CH 2 ======

55 0.62 78 6.75 4.55

58 0.60 70 6.78 4.88

61 0.66 80 6.75 4.61

65 0.75 80 6.85 4.60

66 0.72 81 6.88 4.85

67 0.85 85 6.85 4.56

======a Ethyl acetate/hexane 20:80 57

the acetate. Compounds 55, 58, 61, and 66, exhibited

absorptions in the regions 3550, 3530, 3520, and 3530,cm- 1

respectively, which were identified as the overtone bands of the the carbonyl stretching frequencies.

The 1H NMR, of the analogs 55, 58, 61, 65-67, were all very similar and each showed expected signals for the protons at C8 , C7 , C9 in 55, 58, and 61 respectively for the olefinic methylenes (-C=CH 2 ), and methyl groups of the acetyl function [-C(=O)-CH 3 ], as sharp singlets, and singlets for the newly formed vinylmethyl (C 9 -CH 3) group

( Tab I e 3) • The be n z y 1 i cpr 0 t on s (0 f t he sid e ch a in) w ere seen as broad multiplets, and their coupling constants could not be measured. The broad methylene hump for the aliphatic side chain portions and the ring methylenes accounted for the required number of protons expected for each of these compounds. These were indicative of the formation of expected delta-3-cannabidiol analogs. The structures were further confirmed by 13 C NM~ ~pectral data for each of these compounds.

The 13 C NMR (Table 4), showed the expected resona nces for 24 carbon atoms (C24H3204)' in the diene 55. A total of nineteen peaks were seen, of which nine were in the region 110 to 170 ppm. As C I , and C3 " C4 , and C6 " of 58 the aromatic ring, and the two carbonyl carbons of acetate moiety formed a pair of equivalent carbon atoms, the nine lines observed acccounted for twelve carbon atoms. The remaining twelve carbon atoms are expected to absorb in the region 10 to 40 ppm. A total of ten lines were seen in the upfield region. As the C4 and Cs, and carbon atoms of the methyl group of the acetate could absorb as a single line, the ten signals account for twelve carbon atoms.

The DEPT experiment (Distortionless Enhancement by

Polarization Transfer) indicated that the peaks 168.09,

148.09, 145.32, 141.83, 139.04, 127.40, and 123.42 ppm are quaternary carbons, the signal at 119.73 ppm, is a tertiary carbon, and the one at 113.04 ppm, is a methylene carbon. In the upfield region, signals 21.00, 20.6~, and

13.86 ppm, were due to methyl carbons, and the rest of the signals were due to methylene carbons (Table 4).

13 C Carbon chemical shift for C 1 " , C 2 " , C 3 " ,

C4 " , and Cs" , reasonably agree with the ('!emical shift calculated based on additivity of sunstituent effects. 113

The chemical shift 119.73 ppm was assigned for C4 , and C6' as the signal was seen as a doublet in IH and 13 C off- resonance spectral data. Similarly, the triplet for C8 was helpful in assigning the resonance frequency 113.04. 59

The 13 C spectral data for delta-l-cannabidiol 115 ,116 was helpful in fixing the chemical shift of carbons in the aromatic ring,113-1l6 and the quaternary carbon atoms (Table 4).

In contrast to the observed broad low intensity signal for the C l ' and C 3 ' carbon atoms (156.80 ppm,

CDCI 3 ), in the 13 C NMR of delta-I-cannabidiol dimethyl ether,117 the delta-3-cannabidiol analog (55) showed that these are very sharp singlet at 148.09 ppm. In their study of the internal rotation on C3 ' C2 ' bond in canna bidiol(4), using 1H and 13C dynamic spectroscopy, Kane and coworkers l17 have demonstrated that the broad singlet at

156.80 ppm, can be resolved to a doublet at 157.60, and o 156.40 ppm, at -50 C. The literature cited values for the chemical shift of C I , C3 ' carbon atoms in delta-1-CBD are 155.1 and 154.61 ppm ( CDCI 3)' respectively.115,116 Based on these observations the resonance at 148.09 was assigned to C1 ' and C3 ' carbon atoms. Chemical shifts for the 13 C NMR (250MHz, DMSO-

0 6 ), is given in Table 4. The chemical shifts (90MHz,

CDCl 3 ) of the carbon atoms in the downfield region, for compounds 55,58,61 and for 65,66, and 67 are presented in Table 5, and Table 6 respectively. 60

G 5

R = H, DELTA-I-CBD

R = CH 3 , DELTA-I-CBD DIMETHYL ETHER

4 3

3" 5"

Figure 24. Numbering for 13 C NMR data. 61

TABLE 4

13C NMR chemical shift (2S0MHz, DMSO-D 6) for diene 55.

======~======~======

Signal signal

S(ppm) assignment 6 (p pm) assignment

======

(C=O)a 168.09 34.34 C1"

148.09 ( C 1 I ,C 3 .)a 30.82 C2 " (30.10)*

145.32 C7 30.00 C3

141.83 CS' 29.28 C3" (32.00)*

139.04 C1 28.37 C6

127.40 C2 22.48 (C4' CSo)a

123.42 C2' 21.88 C4" (21.40)*

119.73 (C 4 I , C6 I)a 21.00 CO£H 3

113.04 C8 20.62 C9

13.86 CS" (13.70)* ======:======:===:======:======:======

a Carbon atoms are magnetically equivalent.

* Calculated values are given in parenthesis 62

TABLE 5

13C NMR chemical shifts of the downfield signals

(90MHz CDCl 3 ) for compounds 55, 58, 61.

======~======~======~= signal 55 58 61 assignment 5 (ppm) 6 (ppm) 6 (ppm)

======

(-C=O)a 168.71 168.75 168.80

(C 1 ,)a 148.45 148.87 148.70 (C ,)a 2 148.45 148.87 148.70

C7 145.85 143.50 146.38

C5 ' 142.44 141. 99 142.58

C1 139.57 141.62 139.60

C2 127.05 130.18 128.64 124.02 C2 ' 124.24 124.38 (C4 I) a 119.74 119.77 120.00

I ) 120.00 (C 6 a 119.74 119.77

C8 113.02 114.30 113.25

======~======a Carbon atoms a~e magnatically equivalent 63

TABLE 6

13C NMr chemical shifts of downfield signals

(90MHz, CDC1 3 ) for compounds 65, 66, and 67

=~======signal 65 66 67 assignment o (ppm) o (ppm) o (ppm)

======

(-C=O)a 168.66 168.79 168.75 (C ,)a 1 149.75 150.89 149.79 (C ,)a 2 149.75 150.89 149.79

C7 148.29 148.72 148.32

C5 ' 145.74 141.90 145.62

C1 139.35 141.63 138.90

C2 127.21 130.25 127.50

C2 ' 124.40 124.50 123.89

(C 4 ,)a 117.46 117.52 117.61 (C ,)a 6 117.46 117.52 1 17. 6 1

C8 113.02 114.27 113.17

======~~======a Carbon atoms are magnatLcally equivalent CHAPTER 3

Synthesis of Conformationally Rigid Analogs

Intermolecular Diels-Alder Reactions·

The delta-3-cannabidiol analogs 55, 58, 61, 65-67, as the corresponding acetates, were synthesized with two fold interest. The initial purpose was to test this new series of compounds for their anticonvulsant activity. The ultimate aim however, was to transform one of these (55)

1'~, PhCH Or 3 iO.R + {oEt > 2'A1C13 I Ph H 55

2 AcO 68 69

AR - -p-C SH11 Ac O Figure 25. The intermolecular Diels-Alder reaction

64 65

to the corresponding conformationally rigid delta-I-canna bidiol analog (80, Fig 27). Entry into the rigid analog was attempted through inter-and intramolecular Diels-Alder strategy.

The Diels-Alder reaction,118 is a typical 1,4- cycloaddition reaction, and still remains as one of the useful synthetic method for the formation of six-membered rings. 119 The important aspect of the reaction is that the new six membered ring systems are generated with remark able stereo-and regioselectivity.

Cycloaddition of a unsymetrical 1,3-diene system and a dienophile, which is also unsymmetrical, can give addition products resembling head to head and head to tail orientation. Usually these are formed in unequal amounts. l20 When unsymmetrical reagents participate in

Diels-Alder reaction it is assumed that formation of one of the sigma-bond is more rapid than the other. l21 ,122

The c y c loa d d i t ion rea c t ion 0 f the d',. e n e 5 5, wit h ethyl acrylate as a dienophile, can give compound 68, which is one of the possible regioisomers. The mnemonic used to describe this type of substitution pattern is that they are "ortho-like", "para-like'" products. Since the substitution on the diene 55 is complex, the Diels-Alder 66

product 68 in this thesis is referred to as "para-like"

product, as the vinyl methyl of the diene 55 and ethyl- ester group of dienophile (ethyl acrylate) are para to each other in the Diels-Alder cyclized product 68 (Fig

26).

The regioisomer 68, having the aryl and ester substitution, is capable of existing in cis (70) or trans

(71) conformation. The aryl substituent is forced to occupy axial position at the bridgehead, hence the cis

(70) and trans (71) arise with the ester function occu- pying either equatorial or axial position (Fig 26). Since the carbon atoms C4 and C IO are asymmetric centers,

TRANS

70 71

Figure 26. Regioisomers "para-like" products. 67

each of these (70 and 71) in turn, will have their corresponding enantiomers, rendering the product a complex isomeric mixture. A total of eight isomers are possible.

Important feature of the molecule 68 are: 1) two assymmetric centers are introduced at C 4 and CIa positions; 2) the aryl substituent at the bridgehead is always axially oriented; 3) The newly formed bicyclic system has the carbon-carbon double bond across CI and C9 7 6~1~ 5 AR 4 I J..8 DELTA-1-CBD 10/~g

2 3

R R= AcO a· _C02Et 68 AR = ~5H11 b· -LOH 74 Ac O " vv// c· " 80 Figure 27. Delta-l-CBD, and the rigid bicyclic analog 68

carbon atoms; and 4) the vinyl methyl at C I is placed in the desired position. With these features, the molecule looks like delta-I-CBD analog. The only difference between delta-I-CBD (4) and the rigid delta-3-CBD analog is that the C2 and C3 carbon atoms of the delta-I-CBD are fused to another six-membered ring (Fig 27).

In simple systems the "ortho-like" or the "para- like" may predominate compared to the "meta-like" product. I20 The diene (55) and dienophile (ethyl acrylate), both being unsymmetrical, may give a mixture of regioisomers. I23 It is therefore reasonable to expect min 0 ram 0 u n t 0 f the " ~~ - 1 ike", reg i 0 i s 0 mer (6 9 ) • The

"meta-like" regio-isomer can give another set of cis (72) and trans (73) isomers. In this case also, the aryi substituent is axially oriented, whereas the ester function could be either axial or equatorial. The cis (72) and trans (73) will exist as a mixture of their corresponding enantiomers. The mnemonic used to describe the substitution pattern in these products is, "meta-like" as the ester function in the cyclized product (69) is meta to both the aryl and the vinyl methyl group of the parent diene 55 (Fig 28). 69

Figure 28. Regioisomers "meta-like" products

Essentially, the 1,4-cyclo addition reaction of diene (55) and the ethyl acrylate could be a complex mixture of isomers (70, 71, 72, 73, and their corresponding enantiomers).

Another aspect of the Diels-Alder reaction is the use of the Lewis acid catalyst, especially in the reactions where the dienophile has electron acceptor groups.

Some Diels-Alder reactions are accelerated in presence of catalyst like AICl 3 ' SnCl 2 ' BF 3 -etherate 124 TiCI 4 • ,125 The general advantage of catal.yzed reaction can be classified as: a) increased percent yield; b) milder reacting conditions; and c) enhanced reaction rate.

Apart from these advantages, in some cases the product distribution may dramatically alter, resulting in pronoun ced stereo or regioselective product formation. 124 ,125 70

.Anhydrous aluminium chloride (AICI 3 ) is known to complex with ethyl acrylate (dienophile) and enhance the

electrophilic nature of ethyl acrylate, facilitating the

reaction. 124

The Diels-Alder cycloaddition reaction of the

dienes 55 and 58, with ethyl acrylate were carried out by

thermal, as well as Lewis acid catalysed, reactions. The

uncatalyzed (thermal) Diels-Alder reaction in refluxing

benzene did not give products. However, the reaction in o toluene at 110 C , TLC showed that some transformation is

taking place. The reaction after 7.0 to 8.0 h was incom-

plete, and showed some highly polar material in TLC.

(ethyl acetate/hexane 20:80). Apart from the unreacted

diene (55) two products on TLC 68b (Rf 0.50) and 68c (Rf

0.38) in ethyl acetate/hexane, 20:80, was observed in the

product. Both 68b and 68c showed molecular weight higher

than the one expected for the Diels-Alder product, in the

mass spectra of the respective compounds. Overall, the

thermal reaction was not very encouraging.

In contrast to the thermal reaction the Lewis acid catalysed reaction (anhydrous AICI 3 ), carried out in dry benzene at room temperature was faster. The appearence of

the spots at Rf 0.50 to 0.39 in TLC (ethyl acetate/hexane 71 TABLE 7

Thermal vs Catalyzed Diels-Alder Reactions

~===m=====~======a======a=~======

Toluene, 6 AICI 3 ,(RT) Rf %y Rf %y

======a 0.63 32.0 A 0.68 42.5 b 0.50 20.5 B 0.50 30.0 c 0.38 12.0 C 0.39 15.0

======

ELEMENTAL ANALYSIS

======

C % H ,.~I

A Caled 71.78 8. 3 l

Found 72. 13 8. 51

B Caled 71.87 8. 31

Found 70.43 8.30

======72

20:80), was indicative of transformation taking place. The

disapperence of the parent diene was complete in 4.0 h

In general, the Rf-values of the products of the uncata-

lysed reaction (thermal) coincide with that of the Lewis

acid catalysed reactions. Except for the fact, that the

thermal reaction showed the presence of unreacted diene,

whereas the Lewis acid catalyzed reaction gave consider-

able amount (42.5%) of a compound 68A (Rf 0.68, ethyl

acetate/hexane 20:80). The I R, and IH NMR of 68A was entirely different from the starting diene (55). In terms of product distribution however, the catalysed reaction did not show any marked selectivity. The TLC of the product from the Lewis acid catalysed reaction showed

three spots eluting in ethyl acetate/ hexane (20:80), Rf

0.68 (68A), Rf 0.50 (68B), and Rf 0.39 (68C). The Rf of

the 68A (0.68) was very close to the parent diene 55

(0.62), in the same solvent system (Table 7). The three compounds were separated by preparative TLC (20 X 20

plates eluted in ethyl acetate/hexane, 20:80).

The compound 68A (Rf 0.68) was isolated as a gum, o which crystallized in ethanol (mp 81-82 C). Initially this was thought to be the parent diene 55. However, the IH NMR

(CDCl 3 , 60MHz), did not show the characteristic absorption 73

due to the methylenes at C8 position of the parent diene. The aromatic region showed absorptions at 6.57 and 6.38 ppm (J = 1.35 and 1.36 Hz), as meta coupled doublets. The mass spectra of the compound with the molecular ion at M/z

342 (EI/l1S) indicated the molecular weight to be 342. The

1H NMR and 13 C NMR (250MHz), indicated that 68A is delta-3-THC analog (Fig 29). The observed values of elemental analysis was exactly fitting to the molecular formula C22H3003 (MW 342). Formation of the delta-3-THC o analog was observed even at -78 C. An attempt to procure the Diels-Alder product 68 from the diene 55, using Tita o nium tetrachloride (TiCl 4 ), at -78 C ~dry-ice and ethanol), resulted in the formation of delta-3-THC (50%).

Unreacted diene (45%) was recovered. There was no "indication of any Diels-Alder cyclized product.

G8 A

Figure 29. Formation of delta-3-THC analog 74

To confirm that the diene 55 is cyclizing to the corresponding delta-3-THC, in presence of Lewis acid catalyst (AICI 3 ), a blank experiment was carried out without the dienophile (ethyl acrylate). The isolated product on separation through preparative TLC (Rf 0.68, o ethyl acetate/hexane 20:80) gave solid (mp 82-83 C), which gave a superimposible IR and 1H NMR to that of compound

68A, obtained from the Lewis acid catalyzed Diels-Alder reaction. The blank experiment proved that the cyclization to the corresponding delta-3-THC-analog is taking place in presence of Lewis acid.

Isomers From The Lewis Acid Diels-

Alder Reaction.

The product 68B (Rf 0.50) from the Lewis acid catalyzed Diels-Alder reaction was isolated as viscous light yellow oil by the preparative TLC. IR (neat), showed strong absorptions at 1775 and 1740 cm- 1 due to the acetate and ester carbonyl functions. IH NMR (CDC1 3 , 90MHz) showed singlet at 6.65 ppm for the two aromatic 75

protons. The ester methylenes appeared as multiplets in the 4.20-3.95 ppm region. A Triplet at 2.55 ppm for the benzylic methylenes of the side chain and the absorption due to acetyl methyl at 2.20 ppm indicated the formation of the expected cyclized products (68 and/or 69). The proton count also agreed with the number of H-atoms expected for the molecule C29H4006. However, it was not possible to identify whether compound 68B isolated from preparative TLC is "para-like" or "meta-like" regioisomer.

The methine proton at C 4 -carbon atom should appear as a triplet for the "ortho-like" compound 68, whereas a multiplet should result for the "~-like" compound 69.

However, the signal due to this particular methine proton was buried in the methylene multiplets. Distinct assignment of regioisomers was impossible. IH NMR recorded on higher resolution instrument (250 MHz) was also not further helpful in figuring out the absorption due to this me thine proton. The elemental analysis c~rried out on compound 68B agreed with the theoretical value required for C29H4006 (Table 7). Later by GC/MS, this value was found to be fortuitous.

The compound (68C) isolated from preparative TLC

(Rf 0.3.9) was also viscous light yellow oil. The IR 76

(film) of 68C, was very much similar to the product 68B.

This was highly indicative that 68B and 68C are similar

compounds. The 1H NMR (CDCl 3 , 90MHz), showed the requisite signals for aromatic protons, ester methylenes, acetyl

methyl, benzylic methylene protons, and the characteristic

signals due to the aliphatic side chain. The 1H NMR was

similar to that of the compound 68B. The 1H NMR spectra of

68C on higher resolution (250 MHz), showed extra signals

in 2.30-2.00 ppm region. Overall spectra showed excess

protons, and the elemental analysis was low by 1.4% on

. ca rbon, co mpared to the theore t i.cal val ue.

The major obstacle encountered at this stage was

that the expected products formed by the cyclization

reaction could not be assigned unequivocally to any

particular isomer. The unexpected side reaction in the

formation of the corresponding delta-3-THC analog (Fig 29)

in major amounts was another problem. Even after repeated

separation by preparative TLC, 68B, and 68C (Table 7),

were still possibly a mixture of isomers. These problems

made us believe that the parent diene 55 needed to be

modified. Basically the modification should prevent the

formation of the unwanted side reaction. For this reason

it was thought that the dimethylether of the resorcinol 77

moiety on the parent diene (Fig 33) should be more suit able for the cyclization reaction.

the two compounds separated from preparative TLC

(Rf 0.50 and 0.39), obtained from Lewis acid catalyzed

Diels-Alder reaction (Table 7), were thought to be the regioisomers 68 and 69 along with their corresponding enantiomers. This was only an assumption, these could be the cis (70) and trans (71) isomers along with their corresponding enantiomers.

Further examination of the product 68B (Rf 0.50,

Table 7) by mass spectroscopic technique (GC-EI/MS) showed, that 68B is a mixture of compounds. The chromato gram showed ten peaks, with the retention time (Rt) ranging from 2.90 to 10.50 minutes. The molecular ion at

M/Z 484 expected for the product 68 and/or 69 was not observed in the mass spectrum of any of the major peaks in the chromatogram. The mass spectra of two peaks with retention time 2.90 and 3.25 minut'2s, could be traced to compound 69 and/or 68 respectively. A possible approach for the analysis of major fragments in the mass spectra for each of these two peaks has been included (see Appen dix). However, the peak area measurement showed that both the peaks (Rt 2.90 and 3.25) together accounted for 10% of 78

the total area of all the peaks observed in chromatogram.

Major drawbacks encountered in the Diels-Alder

reaction of the diene 55 could be summarized as follows:

a) Diene 55 is inert for' thermal Diels-Alder reaction; b)

The Lewis acid catalyzed Diels-Alder reaction gives delta-

3-THC analog as the major product; c) Expected Diels-Alder

product 68 and/or 69 was observed to form in very minor

amounts; d) Small percentage of the Diels-Alder product

formed is a mixture of isomeric compounds, along with

other higher molecular weight compounds (as evidenced by

mass spectra (GC-EI/MS).

Based on the observations listed above, further

attempts to obtain the target compound, rigid delta-3-CBD analog (80) starting from the rigid bicyclic compound 68 as shown in Fig 30 and Fig 31, were not pursued. A Stereo

chemical view of the rigid delta-l-CBO is given in Fig 32. 79

68 74

76 77

Figure 30. Intermediate tertiary alcohols. 80

74 90

82 83

Figure 31. Rigid delta-1-CBD analogs. 81

-- -- H

OAe AR --

R = COOEt 68 R ~ 80

Figure 32. Stereochemical view of the rigid"

delta-1-CBD analogs. 82

Diels-Alder reactions of diene 55A

In an attempt to avoid the formation of delta-3-

THe analog in the Lewis acid catalyzed Diels-Alder reaction of diene 55, diene 55A (dimethyl ether) was prepared by methylating the triol 53 (Fig 33).

(1) CH3COCH3, CH3I K2C03 , ~

(2) Ac 20 I Py , ~

C5 H1T 53 (y~R UCOOEt

lLCOOEt CGH6,AICI3 RT ~AR

Ll""COOEt

Figure 33. Diels-Alder reaction of diene 55A. 83

Triol (53), dissolved in acetone (dry) was treated with potassium carbonate and methyl iodide and the mixture refluxed for 8 h. The resulting tertiary alcohol (54A) was purified by column chromatography. The alcohol eluted in ethyl acetate/hexane (3:97) on silica as colorless oil

(73% yield). TLC Rf, 0.50 (ethyl acetate/hexane, 20:80).

The IR (film), of the tertiary alcohol (54A) showed the characteristic absorption at 3485 (-OH stretch), 3050 to

2860 (CH stretch), 1600 and 1590 (C=C stretch), 1230 (C-O

C stretch). The 1H NMR (250MHz), showed singlet for the two aromatic protons at 6.36 ppm. The methoxy signal at

3.76 ppm, gem-dimethyl at 1.16 ppm appeared as sharp singlets. Benzylic methylenes of the side chain appeared as triplet at 2.55 ppm. The broad signal at 2.20 ppm exchangeable with D2 0 was due to the -OH of tertiary alcohol. Subsequent generation of the diene 55A from tertiary alcohol (54A) was done by warming the tertiary alcohol in presence of pyridine and acetic anhydride for o 4h at 70-80 C. After removing the excess pyridine and acetic anhydride under vacuum, the product was extracted into diethyl ether. Successive washing with sodium bicarbonate (10% solution), distilled water, saturated sodium chloride, and drying over sodium sulfate, gave a 84

brownish oil. Purification of this material by column chromatography (ethyl acetate/hexane 1:99), afforded a colorless oil, in 85% yield. TLC, Rf 0.78 (ethyl ace tate/hexane 10:90), was characterized by IR (neat), 1H NMR

(250 MHz), 13C NMR, and mass spectral data (EI/MS). The analysis ·showed that the compound is the required diene,

2-[l-cyclohexene-2-(1-methylethenyl)-1-yl]-5-(n-pentyl)-1,

-3-dimethyl-resorcinol (55A).

The diene (55A) showed a single peak in GC (Rt o 8.16 min, 280 C OV, 17 column). The -OH stretching band of the starting compound (53A) was absent, indicating the possible formation of the diene (55A). IR (neat), cm- 1 ,

3090 to 2840 (CH, stretch), 1610 and 1585 (C=C, stretch),

1230 (C-O-C, asymmetric stretch), bands were seen. ~H NMR

(250 MHz) in CDC1 3 , gave a singlet due to aromatic protons at 6.31 ppm. The two olefinic methylenes were seen as a broad singlet at 4.47 ppm. signal at 3.72 ppm accounting for six protons indicated the -OH of resorcl&lol is still protected as methyl ether. A singlet due to vinyl methyl at 1.60 ppm, and a triplet due to benzylic methylenes of the side chain appeared at 2.55 ppm (J= 7.63 and 8.10 Hz).

Signals of the cyclohexene ring and methylenes of the side chain were seen as broad multiplets. The molecular 10n at 85

M/Z 328 in the mass spectrum confirmed the expected mole-

cular weight required for the diene (ssA).

The 13 C NMR (250 MHz, CDC1 3 ) showed a total of 18 lines, with 8 of these lines in the downfield region. As

the carbon atoms at Cl" C3 , and C4 " C6 , are magnetically equivalent, the 8 lines in the downfield region account

for 10 carbon atoms. In the upfield region, methyl carbons of the methoxy groups, as well as the carbon atoms at C4 and Cs , were seen as single line for each pair of carbons. The 10 lines seen account for the 12 carbon atoms. Assig- nment for the individual lines was made based on the DEPT experiment (Distortionless Enhancement by Polarization

Transfer), and the reported chemical shift data of the delta-l-CBD and the corresponding dimethyl ether analog,11s,116,117(Table 8)

The diene (ssA) was subjected to thermal as well as the Lewis acid catalyzed intermolecular Diels-Alder reaction, using ethyl acrylate as the dienophile.

The thermal reaction was done by warming the diene o (ssA) and ethyl acrylate to 100 C without solvent, and at o 110 C with toluene as solvent, failed to give the desired 86

product 68 and/or 69. Further reactions by heating the diene (55A) and dienophile (ethyl acrylate) in a stoppered o pressure bottle in presence of toluene at 180 C (silicone oil bath), as well as heating the reaction mixture directly over a heating mantle did not give the desired

Diels-Alder product. The diene was recovered unreacted.

Lewis acid catalyzed Diels-Alder reactions in presence of anhydrous aluminium chloride (AlCI3)' BF 3 - etherate (BF 3 -OEt), and Titanium tetrachloride("TiCI4)' were attempt~d to examine if any of the catalyst could be useful in generating the required Diels-Alder product.

I n pre sen ceo fan h y d r 0 usa 1 u.m i n i u m chI 0 rid e

(AlC1 3 ), at room temperature there was no indication of any product after 4 h duration (TLC). Warming the reaction o mixture to 45 C , for 8 h, the TLC (ethyl acetate/hexane

5 : 9 5) , s howe d a con tin u m 0 f s pot s fro m R f O. 2 toO. 7· 5. The crude product, after extraction in diethyl ether and solvent removal, was passed through a colu!i,,1. The yellow oil obtained was subjected to preparative TLC (ethyl acetate/hexane 5:95). Two major fractions at Rf, 0.55 and

Rf 0.25, which showed strong absorption due to ester carbonyl (1745 cm- 1 in the IR spectra, were examined 87

through mass spectroscopic technique (EI/MS). Both showed

ions at M/Z higher than 600 mass units. IH NMR (250 MHz)

indicate, that each are mixtures of compounds.

Diels-Alder reactions in presence of BF 3-etherate gave results similar to what was observed in the case of

reactions with anhydrous aluminium chloride (AIC1 3 ). o With Titanium tetrachloride (TiC1 4 ) at -78 C, in

dichloromethane (CH 2 C1 2 ) as solvent, after 6 h the diene 55A was intact. When the reaction mixture was allowed to

warm to room temperature, only decomposition products were

seen.

Apparently the diene is inert for thermal Diels-

Alder reaction, and is undergoing some sort of decomposi-

tion in presence of Lewis acid catalyst. It was concluded

that both the dienes 55 and 55A, are not suitable for

Diels-Alder reaction with ethyl acrylate, either thermally

or in presence of Lewis acid catalysts AICI 3 , BF 3-etherate

or TiCI 4 • 88

TABLE 8

13C NMR chemical shifts (250MHz CDCl 3 )·for diene 55A

======~======

signal signal

5 (ppm) assignment 5 (p pm) assignment

======

157.04 (C 1 I , C 2 I) a 36.02 C1"

147.27 C7 31.74 C2 "

142.22 CS' 31.07 C3

136.78 C1 30.21 C3 "

125.48 C2 28.88 C6 C )a 119.53 C2, 23.05 (C4' 5

110.55 C8 22.56 C4 "

103.87 (C 4 I , C6 I) a 21.30 C9

14.04 C5 "

55.50 (-OCH 3 )a ======

a carbon atoms are magnetically equivalent 89

Intramolecular Diels-Alder Reactions

In the intramolecular Diels-Alder rreaction, the diene and the dienophile form part of the same molecule.

Since the diene and the dienophile are chained together the cycloaddtion product will have two or more rings, depending on the nature of the parent molecule. The product can be either fused or bridged ring system.

Usually the product formed through ring fusion (91) pre dominates. 123

Starting from triol (53), an attempt was made to generate 2-[1-cyclohexene-2-(1-methyl-ethenyl)1-yl]-5-(n pentyl)1,3-diacryloylresorcinol (90, Fig 34). The compound has both the diene and the dienophile constrained in the same molecule. Thermal or Lewis acid catalyzed intra molecular cyclization of 90, should give the lactone 91

(Fig 35), as the preferred regioisomer. Molecular model shows that the aryl substituent is forced tu occupy axial position. Stereochimically the lactone 91 can form only when it is cis-fust:!d ["ingsystem (Fig 35).

Attempts to obtain compound 90, by reacting the triol 53, with ac["yloyl chloride in presence of pyridine HO"',' R -?-'O . (Jb y~ 53 ~6.PY.",

~'\. o ~

v D R 55 HO',' ,OUR ~XiR K2C03.AQ . ~ ~ ;.~ 0 88 a AC20 90 ~ py L__ ~~~: __ ~6~~~~j' t , I ',~

R R =C5H 11

Figure 34. Generation of diene diacrylate 90.

\0 o 91

A1C'3' Ph-H or >

90 91 C 1' H3MgBr: C6Ho, ~ 2· TsCI . py. ~ .

HO L-.

Af< = -./ ,,>-C S H11 Hj=~

Figure 35. Intramolecular Diels-Alder product. 92

failed to generate 90. The major product (70%), was the cyclic delta-3-THC analog (Fig 36). IR of the compound showed bands at 3450 (-OH, str.), 1620 and 1610 (C=-C, str.), 1380 and 1365 cm- 1 (CH-bending of gem-dimethyl groups). IH NMR (250 MHz), showed the metacoupled doublets

(6.29 and 6.12 ppm, J = 1.40 Hz), benzylic methylenes due to side chain at 2.43 ppm (J :: 7.36 and 7.93 Hz), the gem dimethyl appeared as a singlet at 1.31 ppm, and the methyl of the side chain was seen as a triplet at 0.87 ppm.

Further attempts to obtain compound 90 through other methods also failed (Fig 34). The intramolecular

Diels-Alder reaction of 90 to get lactone 91, and subse quent reactions of lactone 91 to the corresponding rigid delta-l-CBD analog (82) could not be accomplished.

Figure 36. Delta-3-THC analog from triol 53· CHAPTER 4

Stereochemical aspects ~ the dienes

The fact that the dienes 55 and 55A failed to undergo Diels-Alder cyclization indicate that these dienes have restricted reactivity. The reason for the restricted reactivity may be due to electronic factors or may be due to steric and/or conformational rigidity of the molecule.

Taking the electronic factors into consideration the dienes (55 and 55A) lack the presence of strong elec tron donating groups like O-alkyl, OSiMe3. Furthermore the substituents on the aromatic ring (-OAc in 55 and -OMe in

55A) are probably too remote to exert any significant influence on the reactivity of the dienes (55 and 55A). In fact the dienes (55 and 55A) did not undergo Diels-Alder reaction even with an electron poor dienophile, under forcing conditions (refluxing with ethyl acrylate in a closed vessel). Overall, it would appear that steric and/or conformational factors, rather than the electronic factors, are responsible for the inert behavior of the dienes (55 and 55A).

93 94

Closer examination of the dienes 55 and 55A show that one of the double bond of the conjugated diene is frozen in the six-membered alicyclic system, whereas the other double bond is located in the isopropenyl appendage on the C2-carbon. Free rotation about C2 , C7 bond, renders this part of the diene mobile (Fig 37).

Depending on the barrier to rotation, the dienes

(55 and 55A), can exist in three principal conformations, i.e., a) cisoid conformation (s-cis, FIg 37a); b) transoid conformation (s-trans Fig 37b); c) molecular models

(Dreiding) of the dienes 55 and 55A, show that the aroma tic ring and the isopropenyl appendage are non coplanar.

Stable conformations result, when ,the aromatic ring and the cyclohexene ring are orthogonal to each other, and the isopropenyl appendage is at an angle with respect to the cyclohexene ring (Fig 37c).

IH NMR (250MHz) of the dienes 55 and 55A showed marked difference in the olefinic proton absorptions.

Diene 55 showed the olefinic protons as two separate signals 0.09 ppm apart (4.63 and 4.54 ppm). The absorption of the olefinic protons of the diene 55A was seen as a broad singlet at 4.47 ppm.

The absorption of the olefinic protons in 55 as two individual lines can be interpreted as a possible 95 5 5 4 3

9 a= RO AR = i-)-c 5 H11 RO

/ ff /

Figure 37. Conformers of diene SS and 55A. 96

contribution from the s-cis and s-trans (Fig 37a and 37b) conformers. If disproportionate amounts of s-cis and s trans conformers are present, the IH NMR probably should show separate signals due to vinyl methyl, acetyl methyl, and aromatic protons~ However, IH NMR (500MHz), shows a sharp singlet for the aromatic protons (6.73 ppm), acetyl methyl (2.21 ppm), and vinyl methyl (1.65 ppm).

Another explanation for two different signals seen for olefinic protons in diene 55 could be attributed to the proximity of one of the vinyl protons to the aromatic ring and is shielded or deshielded (ring current effect) depending on the orientation of the aromatic ring with respect to the isopropenyl appendage carrying the olefinic protons. In this conformation (Fig 37c), the olefinic protons can be nonequivalent.

At higher temperature IH NMR DMSQ-D 6 , (250MHz) of the diene 55 show that the two peaks 0.09 ppm apart at o room temperature (24 C), exhibit coalesence behavior, and o are only 0.01 ppm apart (4.53 and 4.52) at 60 C. Whether this is dui to solvent effect at higher temperature, or due to conformational effect is still uncertain.

The absorption of of the olefinic protons in diene

55 as two lines (Fig 38) can also be attributed to the 97

"cone effect" of the carbonyl groups of the acetate moiety. One of the olefinic protons ~an be deshielded or shielded depending on whether the proton is in the plane of the carbonyl group (of the acetate moiety) or in the shielding zone of the carbonyl group.

A broad singlet observed in diene 55A (4.47 ppm) which has methyl ether instead of acetyl group support this view. At lower temperature it may be possible that in diene 55A, the broad signal at 4.47 ppm may resolve as two separate signals (similar to the behavior of the o olefinic signals of diene 55 at 24 C). This is evidenced by the fact, that the dimethyl ether analog of delta-l-CBD

(F i g 38) 's how s two s epa rat e s i g n a 1 s -for the ole fin i c protons at lower temperature. The broad singlet at 4.37 ppm (CD 3 -CO-CD 3), resolves into two peaks as the tempera ture is decreased. 126 At -80°C, the peaks were at 4.36 and

4.30 ppm (0.06 ppm apart).

Temperature dependence of the chemical shifts associated with the benzene moiety of delta-l-CBD «C4' 127 and C6 , protons), have been reported by Weiner and Meyer. 128 Rotational nonequivalence as a function of temperature has been observed in 13C NMR spectra of delta 129 l-CBD analogs for C1 , , C3 ' and C4 , , C6 , carbon pairs. 98

However the temperature dependence of the olefinic protons either in delta-i-CBD or in delta-3-CBD (Fig 38) are not

reported in the literature to the best of our knowledge.

The reason for the difference in behavior of the olefinic protons in diene 55 and 55A may be dynamic or fortuitous. Detailed studies by molecular mechanics with structure optimization may be necessary to understand what is happening in these molecules.

Comparision of the chemical shift of the olefinic protons of the dienes 55 and 55A (conjugated dienes) with delta-i-CBD, and limonene (isolated olefins), did not lead to any specific conclusion. The chemical shift of the olefinic protons observed in conjugated and isolated molecules is given in Fig 38.

The ultra violet spectra of the dienes 55 and 55A in cyclohexane showed a shoulder at 235nm for diene 55 and

237nm for diene 55A. This is possibly due to the absor ption of aromatic ring. From 235nm to 20(1,·;;. the optical density increases continuously. The peak due to the diene part of the molecule is possibly beyond 200nm region, and was not useful in determining whether 55 and 55A behave like conjugated diene or isolated olefin. 99

DIENE 55 DELTA-I-CBD 6 4.63 and 4.54 6 4.39 (CD3COCD3) (CDC!3)

DIENE 55A LEMONENE (CDC!3) 6 4.47 (CDCl 3 ) 6 4.70

Figure 38. Chemical shift of olefinic protons

in conjugated and isolated systems. 100

Results and Conclusion

The designing of new drugs can frequently be traced back to the modification of biologically active natural products. Compounds from cannabis origin have been an attractive source for the past two decades. Despite the polarized opinions, either for or opposing the use of ingredients from the cannabis origin, delta-9-THC (1) and nabilone (38), are commercially available in Canada and

Switzerland as an antiemetic drug.

Cannabidiols (CBD) have in recent years gained much attention as anticonvulsant drugs. Synthesis of delta-3-cannabidiol (61), and the related analogs S5, 58,

65, 66, and 67, were successfully completed and characterized by IR, IH NMR, and 13 C NMR. The main aim of synthesizing delta-3-CBD analogs was to test these for their anticonvulsant activity. The delta-j-cannabidiol analog (55), has shown encouraging results, in the initial audiogenic seizure (AGS) susceptible rats and rotorod

(ROT) neurotoxicity tests. Result of these tests on the other analogs of delta-3-cannabidiol (58, 61, 65, 66, and

67) are awaited. 101

The dienes S5 and 55A were inert to intermolecular

thermal Diels-Alder reaction. In the presence of Lewis

acid (AICI 3 ), the major product of intermolecular Diels Alder reaction was cyclization of the diene (55) to the

corresponding delta-3-THC. The minor amount of Diels-Alder

product formed was a mixture of various isomeric compounds of the expected bicyclic product, along with some high

molecular weight compounds. Formation of the cyclic delta

Q 3-THc is so facile that even at -78 C, in the presence of

TiCI 4 , the diene 55 cyclized to delta-3-THC analog. In the intermolecular Diels-Alder reactions of the diene 5SA, formation of the expected Diels-Alder product was seen only in trace amounts. Decomposition products, with molecular weight higher than 600 (EI/MS), were major drawback. Similar results were seen when the reaction was carried out in presence of BF 3-etherate, and TiCl 4 • Attempts to obtain the rigid delta-l-CBD analog 82 through intramolecular Diels-Alder reaction also failed, as triol 53, in presence of acryloyl chloride, cyclized to the corresponding delta-3-THC analog.

Closer examination of the dienes 55 and SSA show that these have complex substitution pattern. Beca.use of steric reasons it was thought that the diene may ristrict 102

the approach of the dienophile (ethyl acrylate), so that

selective formation of 68 or 69 is favoured. However, the

fact that the Diels-Alder reaction did not go even under

forced conditions, indicates that steric and/or conforma

tional factors play a key role in preventing the dienes 55 and 55A to undergo Diels-Alder reaction.

Interesting aspect of the dienes 55 and 55A, were temperature dependence of the chemical shift of olefinic protons. 1H NMR data of the olefinic protons of diene 55 and 55A, imply that this may be a dynamic p~oblem. The data on hand was not enough to prove conclusively the conformational aspect of the dienes 55 and 55A.

The overall conclusion is that the Diels-Alder reaction is not a suitable synthetic approach to attain the target molecule, the rigid delta-1-CBD analog (80). EXPERIMENTAL

General procedure

Melting points were determined on Electrothermal melting point apparatus and are uncorrected. Infrared spectra were taken on Beckman IR-33 and Beckman FT 1100 spectrometers, with samples prepared as Nujol or as a film on NaCl plates. The IH NMR and 13 C NMR spectra ~Y'ere recorded on a Jeol FX 90Q spectrometer or for higher resolution on Brucker WM 250MHz or 500MHz spectrometer in deuteriochloroform (CDCl 3) or dimethyl sulfoxide-D6 (OMSO-

0 6 ) with tetramethylsilane (TMS) as an internal standard. Mass spectra were recorded on Varian MAT 311A, with SS 300 data system or Hewlett Packard model 5970. The elemental analysis were performed by Mic Anal (Tucson, Arizona).

Routine thin layer chromatography (TLC), analysis were done using silica gel GF, prescored 10 X 20 cm, 250 micron plates supplied by Analtech. Preparative thin layer chromatography (TLC) was performed on 20 X 20 em plates,

1.5 mm thick, prepared by using silica gel GF-254 (type

103 104

60) supplied by E. Merck. Column chromatography was conducted with E. Merck silica gel (70-230 mesh ASTM). o All glassware were oven dried at 120 C overnight prior to use.

Tetra~ydrofuran (THF) and diethyl ether were distilled over lithium aluminum hydride under nitrogen and stored over SA molecular sieves. Benzene* and toluene were distilled over metallic sodium.

Chemicals were used as suppli,ed from commercial chemical companies, when necessary they were purified by standard methods.

Solvents used in reactions, and for eluting preparative TLC, were of reagent grade and were distilled before use by standard methods.

* Hazardous vapour and known carcinogen, handle with care. 105

Experimental Procedure

I. (a). Ethyl-4-methyl-2-oxo-l-cyclohexane

carboxylate (45)

Prepared by reacting 3-methylcyclohexanone with

diethyl oxylate as reported by Adams and coworkers. l09 The

yellow oil (l.lB g. 65%) obtained was chromatographed

using silica gel (20 g, 3/4" 10, column, 10" column leng

th). Fraction eluting in hexane (Rf, 0.75 ethyl acetate/ hexane 20:BO), was used for cyclization. IR(film), i/ 3350

(OH, str.),1740 and 1730(C=O, str.),1610 cm- 1 (C=C, str.);

lH NMR(CC1 4 ), S 4.20(q,2H,CH 2 of ester,J=7.00 and 6~BOHz),

3.75(s,lH,enol-OH),2.70-1.55(bm,BH,CH and CH 2 of the ring)

1.35(s,3H,CH3 of ester,J=6.BO and 6.64Hz),1.03(d,3H,C 4 CH 3 , J=5.BOHz).

II. Typical procedure for the preparation £! ~

marins (benzpyrones) 47, ~~~1.h 52).

To a stirred solution of resorcinol 19 or 19a (11 mmol) and f3 -keto ester 43, 44, or 45, (10 mmol), in dry 106

benzene (15 mL), under nitrogen, was added phosphorus oxychloride (10 mmol), and refluxed for 4 h. The resulting dark colored solution was allowed to stir overnight at room temperature. Two volumes of ice-cold water was added to remove most of the phosphorus oxychloride. The resulting benzene layer was taken up in diethyl ether (100 mL).

The combined ether-benzene layer was successively washed with sodium bicarbonate (3 X 15 mL, 10% solution), saturated sodium chloride (3 X 15 mL), and dried over sodium sulfate. Solvent removal at reduced pressure gave yellow or brown colored solids, which were crystallized in ethanol to obtain colorless crystalline compound.

(a). 1-Hydroxy-3-n-Pentyl-7,8,9,10-tetrahL~E~~~H-

dibenz[b,d]pyrone, (47).

Colorless crystals (ethanol), 1.8 g. (63%); mp, o 190 C; TLC Rf, 0.54 (ethyl acetate/hexane, 20:80);IR:(Nu- j 0 1 ), ;) 3 2 3 0 ( 0 H, s t r .), 2 9 0 0 and 2 8 4 0 ( C H, s.: r • ) , 1 6 6 0 ( C = 0 , str.), and 160S cm- 1 (C=C, str.); A max(EtOH),2S6,314 nm;

GC Rt, 2.7 min (OV17 6'co1.27SoC);I H NMR(DMSO-D 6 ), S 10.

30(bs,1H,Ar-OH),6.S6(s,2H,ArH),3.7S(bs,2H,C 7CH 2 ),3.07(bs, 107

. 13 C 2 "C 3 "C 4 ,CH 2 ),0.85(t,3H,J=5.58Hz and 6.20Hz,C 5 ,CH 3 ); C N MR (D MS 0 - D 6)' S 1 59. 79, 1 55.2 1 , 1 52.69, 148.55, 144.89, 118.97,

111.01,106.56,106.24,34.13,30.01,28.80,28.39,23.51,21.13,

21.02,20.24,12.76.

(b). 1-Hydroxy-3-n-pentyl-6,7,8,9-tetrahydro-6-

oxo-cyclopenta-benz[b,d]pyrone, (48).

o Color 1 e s s cry s tal s , 1 • 4 5 g. (5 3 %) ; m p • 1 9 6 C; T L C R f ,

0.41(ethyl acetate/hexane 20:80); IR(Nujol), ii 3350(OH, str)

2940 and 2860(CH, str.),1680(C=0, str.),1615 cm- 1 (C=C, str.); A max(EtOH),256 and 307nm; GLC Rt,3.25 min. (OVI7

6'col.

6.62(s,IH,ArH),6.56(s,IH,ArH),3.27(t,2H,J=7.50Hz,C7 CH 2),

2.54(m,4H,C 9 CH 2 and C 1 ,benzylic),2.09(quintet,2H,J=7.

80Hz, C 8 C H2) , 1 • 80- 1 • 15 ( bm, 6 H , C 2 ' , C 3 ' , C 4 ' C H2) , O. 86 ( t , 3 H , J =

5.85 and 6.15Hz,C5,CH3);13C NMR(DMSO-D 6 ), 5 159.01,155.48, 155.37,155.15,146.65,123.89,110.78,106.83, :55.70,35.26,30.

82,29.68,29.30,22.48,21.77,13.54.

(c). I-Hydroxy-3-n-pentyl-9-methyl-7,8,9,10-tetra-

hydro-6H-dibenz[b,d]pyrone, (49). o Colorless crystals, 2.0 g. (66%); mp. 180-181 C and 108

o 185-186 C;TLC Rf, 0.64(ethyl acetate/hexane 20:80); >. max o (EtOH),261 and 315 nm;GC Rt, 2.75 min.(OV17 6"col. 275 C);

IR(Nujol), " 3260(OH, str.),2930 and 2860 (CH, str.), 1670 1 (C=O, str.),1625 and 1600 cm- (C=C, str.);lH NMR(DMSO-D 6 ),

o 10.28(s,lH,Ar-OH),6.58(s,2H,ArH),3.55-3.20(bm,2H,C7 CH 2 )

2.52(m,4H,C 10 CH 2 and C 1 ,benzylic),1.85-1.15(bm,10H,C8 '9'

C2 "C 3 "C4 ,CH 2 ),0.85(t,3H,J=5.75 and 6.10Hz,C5,CH3);13CNMR (D MS 0 - 0 6)' 0 160.20, 155.65, 153.04, 148.7 1 , 145.46, lIS. SI ,

Ill. 18, 106.56, 37.22, 34.56, 30. 50, 29. 53,28.55, 27. 36,24.00,

21.62, 21.18,13.60.

(d). I-Hydroxy-3-(I',1'-dimethylheptyl)-7,8,9,10-

tetrahydro-6H-dibenz[b,d]pyrone, (50). o Crystalline solid, 2.3 g. (67%); mp. 160 C; TLC

Rf, 0.4S(ethyl acetate/hexane, 20:S0);IR(Nujol), ii 3230

(OH, str.), 2960, 2920, and 2860 (CH, str.), 1670 (C=O, str), 1610 and 1595 (C=C, str.), 13S0 and 1365 cm- 1

(l',1',CH 3 ,bending);l H NMR (CDCI 3 ), 0 6.S9(.1,lH,ArH),6.72

(s,lH,ArH),6.55(s,lH,Ar-OH),3.39(t,2H,C 7 CH 2 ),2.S4(t,2H,C 10

CH 2 ),2.21(bm,2H,CS or C9 CH 2 ),1.25(s,6H,C 1 ',1,CH 3 ), 1.65-

1.16(bm,12H,methylene hump, C2 ,-C 6 ,CH 2 and Cs or C9 pro tons),0.S2(t,3H,J=5.S0 and 6.10Hz,C 7 ,CH 3 );13 C NMR(CDCI 3 ), 109

8 162.50,156.23,155.48,154.55,153.20,125 •. 35,108. 72,106.66

106.94,44.36,38.24,36.02,31.74,29.95,29.63,29.36,28.71,

24.70,22.91,22.64,13.97.

(e). 1-Hydroxy-3-(1',1'-di~ethylheptyl)-6,7,8,9-

tetrahydro-6-oxo-cyclopenta-benz[b,d]-

pyrone, ii.!l.

o Cry s t a 11 in e sol i d, 1.9 g. (58.5 %); m p. 156 C; T L C,

Rf, 0.44(ethyl acetate/hexane, 20:80);IR(Nujol), v 3380

(OH,str.),2980,2940, and 2880(CH,str.),1690 (C=-O, str.), I 1610 (C=C, str.),1390 and 1375 cm- (1',1', CH 3 , bending);

1H NMR (CDCI 3 ), 5 7.15(bs,IH,Ar-OH), 6.86(s,lH,ArH),6.77

(s,IH,ArH),3.40(t,2H,J=6.10 and 5.98Hz,C 7 CH 2 ),2.85(t,2H,J=

6.2sHz and 6.00Hz,C 9 CH 2 ),2.12(quintet,2H,C 8 CH 2 ),1.35-I.00

(bm,IOH,C 2 ,C 3 ,C4,C 5 ,C6' side chain CH 2 ), 1.2s(s,6H,I.'CH 3 ),

0.82(t,3H,J=5.9Hz and 6.10Hz,7'CH 3 );13 C NMR(CDC1 3 ), 0.161. 72,157.39,155.22 154.68,153.87,124.67,108.96,106.63,106.30

44.28,38.21,36.04,31.65,29.86,29.43,28.89,28.62,24.61,

22.88,22.55,13.78. 110

(f). 1-Hydroxy-9-methyl-3-( 1 ',1 '-dimethyl heptyl)-

7 ,8,9,10-tetrahydro-6H-dibenz [b,d]pyrone, (52).

o Crystalline solid, 2.5 g. (70%); mp. 182-183 C; TLC

Rf,0.50(ethyl acetate/hexane 20:80);IR(Nujol), 0 3250(OH,

str.),2970,2920, and 2860(CH, str.),1670 (C=O, str.),1610, 1 1600(C=C, str.),1390 and 1380 cm- (C 1 ',1,CH 3 bending); IH 7.50(bs,1H,Ar-OH), 6.80(s,2H,ArH),3.6(bs,

2H,C7CH2),2.8-2.5(bm,2H,Cl0CH2),1.90-1.00(bm,13H,C8 andC 9 protons with C2 ',3',4',5',6,CH2 ),1.25(s,6H,C 1 ,CH 3 ),1.05(d,

3H,J=8.8Hz,C 9 CH 3 ),0.85(t,3H,J=5.80Hz and 6.20Hz,C7,CH 3 );

13C NMR(CDCl 3 ), S 163.00,154.57,153.71,150.56,120.23,109.93 106.75,106.68,44.22,37.99,31.71,29.92,29.38,28.56,28.29,

24.66,24.55, 22.60,21.63,13.94.

III. General method for the preparation of triols

53,56,59,62,63, and 64.

To a stirred solution of pyrone (10 mmol), dissolved in benzene (25 mL), taken in a 100 mL three-neck flask, fitted with a condensor, an addition funnel, and maintained under nitrogen atmosphere, methylmagnesium bromide (4.5 mL, 2.7 molar solution in diethyl ether), was 111

slowly added. The resulting mass was refluxed for 6 h. and allowed to stand overnight with constant stirring, at room

temperature. Cooling the reaction mixture in an ice bath,

the exess Grignard reagent was quenched by adding satu

rated ammonium chloride solution, and the product was extracted into diethyl ether. The ethereal layer was successively washed with ice-cold water (3 X 20 mL), saturated sodium chloride (3 X 20 mL), and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure resulted in a viscous, deep brownish colored oil. The crude product was purified by column chromatography, usinga short glass column, (silica gel

20 g, 1" ID, 6" column length), eluted rapidly using ethyl acetate/hexane, to get brownish oil.

(a). 2-[1-Cyclohexene-2-(I-hZ~~~~Z~!=~~~~zl=

ethyl)-I-yl]-5-(n-pentyl)-resorcinol, (53).

Viscous, brownish oil, eluting in ethyl acetate/ hexane (15:85); 2.6 g. (81%); TLC Rf,0.42 (ethyl acetate/ hexane, (20:80);IR(film), 2400(OH, str.),2950,2860(CH, 1 str.),1615(C=C,str.),1380 and 1360 cm- (C 8 ,C 9 ,CH 3 , ben- 112

ding);lH NMR(CDCl 3 ), S 6.23(s,2H,ArH),S.90(s,2H,Ar-OH),S.lS

(bs,2H,tert-OH),2.60(bs,2H,C 1 u benzylic CH 2 ),2.40(bm,2H,C6

CH 2 ), 1.9S-1.S0(bm,6H,C3,C4,C S CH 2 ),1.28(s,6H,C8,C9 ,CH 3 ),

1.40-1.10(bm,6H,C 2 "C 3 "C 4 ,CH 2 ),0.84(t,3H, J=S.S8Hz and

6.10Hz,C S ,CH 3 );13 C NMR(DMSO-D 6 ), s lS3.49,147.86,145.36, 129.6S,124.S6,117.52,109.39,75.02,37.12,33.87,32.90,31.92,

30.1S, 28.25,2S.46, 25.01,24.85,14.40.

(b). 2-[I-Cyclopentene-2-(I-hydroxy-l-methyl

ethyl)-I-yl]-5-(n-pentyl)-resorcinol, (56).

Viscous, dark brown oil, eluting in ethyl acetate/ hexane, (20:80); 2.3 g. (75%); TLC Rf, 0.26 (ethyl ace tate/hexane, 20:80); IR(film), 0 3420(OH, str.),2960,2940, and2860(CH, str.),l620(C=C, str.),l380, andl 360 cm- l

(C 7 ,C 8 CH 3 bending);lH NMR(CDCl 3 ), S 6.26(s,2H,ArH),6.06(s,

2H,Ar-OH),S.20(bs,lH,tert-OH),2.85(t,2H,C l u b"enzylic CH 2 ), 2. 50 - 2 • 30 (b m , 4 H , C 3 ' C 5 C H 2 ) , 2. 1 5 - 1 • 80 ( bm , 2 H , C 4 -::: H2 ), l. 30 ( s ,

6H,C7,C8CH3),l.7-1.10(bm,6H,C2"C3"C4,CH2),0.87(t,3H, J=

5.80Hz and 6.00Hz,5'CH 3 ). 113

(c). 2- [ l-Cyclo hexene -5-me t hyl-2-( I-hyd roxy-l-me t hyl

ethyl)-I-yl]-5-(n-penty)-resorcinol, (59).

Viscous, brown oil, eluting in ethylacetate/hexane

(15:85); 2.7 g. (82%); TLC, Rf, 0.45 (ethyl acetate/hexane

20:80); IR(nujol), v 3400(OH, str.),2960,2940,and2860 (CH, 1 str.),1600 (C=C,str.),1360 and 1380 cm- (C 9 ,C 10 ,bending);

IH NMR(CDC1 3 ), 6 6.29(s,2H,ArH),6.09(s,2H,Ar-OH),5.29(bs,

IH,tert-OH),2.70-2.00(bm,4H,C 1"benzylic and C3 , or C6 CH 2 ),

1.41(s,3H,C g or C 10 CH 3 ),1.20(s,3H,C 9 or C 10 CH 3 ),1.91-1.0

(d,3H,J=8.00Hz,C 7 CH 3 ),0.86(t,3H,J=5.58Hz,C 5 "CH 3 )·

(d). 2-[I-Cyclohexene-2~(1-hydroxy-l-methylethyl)-I-yl]-

5-( 1",1 "-dimethylheptyl)-resorcinol, (62).

Viscous, Deep brown oil, eluting in ethyl acetate/ hexane (15:85), 3.0 g. (84%); TLC Rf, 0.26 (ethyl acetate/ hexane (20:80); IR(film), ii 3400(OH, str. 2960,2920,and

2880(CH, str.),1620(C=O, str.),1380and1360 cm-1(isopropyl and gem-dimethyl bending). 114

(e). 2- [1-Cyclopentene-2-( 1-hydroxy-1-methyl

ethyl)-1-yl]-5-(1",1"-dimethylheptyl)-resorcinol, (63)

Viscous, light brown oil, eluting in ethyl acetate/

hexane (20:80), 2.8 g. (78%); TLC Rf, 0.15 (ethyl ace

tate/hexane, 20:80); IR(nujol), f) 3400(OH, str.),2960,

2920, and 2860 (CH, str.), 1620 (C=C, str.), 1375, and

1360 cm- 1(isopropyl and gem-dimethyl bending).

(f). 2-[1-Cyclohexene-5-methyl-2-(1-hydroxy-1-methyl

e t hy 1) -l-y 1] - 5 -( 1" , 1 .. -d i met hy 1 he p t y 1) - res 0 r c in 01, (64).

Viscous brown oil. eluting in ethylacetate/hexane

(15:85); 3.2 g.(85%);TLC Rf,0.3S(ethyl acetate/hexane,

20:80);IR(film), ii 3400(OH, str.),2950,2900 and 2860(CH,

str.),1620(C=O, str.),1360and1375 cm-1(isopropyl and' gem dimethyl bending).

IV. 2-[1-Cyclohexene-2-(1-hydroxy-1-methyl

ethyl)-1-yl]-1,3-diacetyl-S-(n-pentyl)-resorcinol, (54).

2-[1-Cyclohexene-2-(1-hydroxy-l-methylethyl)-1-yl]-

5-(n-pentyl)-resorcinol, (0.945 g. 3 mmol), treated with 115

acetic anhydride (5.1 g. 50 mmol), and pyridine (4.3 g. 55

mmol), was stirred at room temperature for 24 h. The

resulting product was poured over crushed ice, extracted

with diethyl ether (100 mL). The organic layer was washed

thrice with cold water (3 X 25 mL), and stirred overnight with sodium bicarbonate (25 mL, 25% solution). Extraction, washing, drying, and solvent removal gave a brownish gum, which on chromatography (glass column I" 10, silica gel,

30 g. 10" column length) eluting in 5:95, ethyl ace tate/hexane, to give a light brown colored oil, 1.10 g.

(90%); TLC Rf, 0.50 (ethyl acetate/hexane, 20:80);lR

(film), fj 3500(OH, str.),2940, 2860(CH, str.),1770,1740

(C=O, str.), 1615(C=C, str.),1190(O-C::C, assym str.), 1 1215 cm- [C-C(=O)-O,sym. str.j;l H NMR(COC1 3 ), 0 6:72(s,

2H,ArH),2.70(s,lH,OH,D 2 0 exchangeable),2.65-2.40(m,4H,C 1 " benzylic and C or C CH ),2.2l(s,6H,COCH ),2.08(bm,6H, of 3 6 2 3 r i n g) , 1. 50 ( bm , 6 H , C 2" , C 3" , C 4" C H2) , 1 • 25 ( s , 6 H , C 8 ' C 9 ' C H 3) •

V. 2-[1-Cyclohexene-2-(1-methylethenyl)-I-ylj-5-

(n-pentyl)-1,3-diacetyl-resorcinol i11l.

To a solution of 0.8 g. (2 mmol), 1,3-diacetyl resorcinol (54), in toluene (15 mL), pyridine (4.80 g. 6 116

mmol), p-toluenesulfonyl chloride (0.76 g. 4 mmol), was added and ref!uxed for 6 h. The ether extract of the crude product was washed with Hel (0.1 N), and with sodium bicarbonate 3 X 20 mL, 10% solution). Washing, drying, and solvent removal gave a dark oil. Column chromatography, eluting with ethyl acetate/hexane, (2:98), gave a golden yellow oil, 0.S1 g. (72%); TLC Rf, 0.64 (ethyl acetate/hex ane, 20:80);IR(film), fi 1770(C=O, str.),1615 cm- 1 (C=C, str.);l H NMR (CDC!3)' 5 6.76(s,2H,ArH),4.S4(d,2H,=CH 2 ),

2.S0-2.40(bm,4H,C 1" benzylic, and ring-protons),2.21(s,6H,

COCH 3 ),1.64(s,3H,=-CH 3 ),2.2-1.00(bm,12H, ring and side chain protons),0.87(t,3H,C S "CH 3 );Anal. Calcd for C24H3204: C, 74.96, H, 8.38, Found: C, 75.01 H, 8.3S;mass spectrum

(GC-EI/MS), Rt, 9.40 min (S% phenyl methyl silicone, column), M/Z(relative intensity),341(0.70),324(7.08),283

(100),282(76.85),226(16.4S),213(32.96).

V 1. g e n e I' aIm e tho d for the pre p a I' at:;. uno f

delta-3-cannabidiol analog.

S mmol of triol (53,56,59,62,63,64), was taken in a flask (100 mL), fitted with a condensor and a drying tube.

Acetic anhydride (50 mmol) and pyridine (50 mmo!), was 117

o added, and the reaction mixture heated to 90 C, for 6 h.

After allowing the mixture to stir overnight at room

temperature, it was extracted into ether (50 mL). Washing

with water (3 X 25 mL), sodium bicarbonate (3 X 25 mL) and

solvent removal afforded a brownish oil, which was puri-

fied through column chromatography (30 g. silica gel, 12"

column length), eluting in 2-5% ethyl acetate/hexane. The light yellow colored oil was characterized by IR, NMR, and elemental analysis.

(a). Z-[1-Cyclohexene-2-(1-methylethenyl)-

1-yl]-5-(n-pentyl)-1,3-diacetyl-resorcinol (55).

Viscous, golden yellow oil, eluting in ethyl acetate/hexane(3:97); 1.5 g. (78%);TLC Rf,0.6Z (ethyl acetate/ hexane 20:80);IR(film), j) 3080(CH, aromatic str.),Z930,

2860(CH, str.),16Z0(C=O, str.), 1360(sym. bending CH 3 ), 1Z10[C-C(=O)-O, str.],1185 cm- 1(O-C::C,assym. str.);l H NMR

(CDC1 3 ), 5 6.75(s,ZH,ArH),4.55(m,2H, =CH Z),Z.55-Z.40(bm,

4H,C 1 " benzylic and ring protons),Z.ZZ(s,6H,COCH 3 ),Z.Zl-1.

15(bm,lZH, sidechain and ring CH Z),1.66(s,3H,=-CH 3 ),0.88 ( t , 3 H , 5 ' C H 3 ) ; 1 3 C N ~t R ( D MS 0 - D 6 ), 5 1 6 8. 7 1 , 1 4 8 • 4 5 , 1 4 5 • 8 5 , 1 4 2 •

44,139.57,lZ7.05,124.Z4,119.74,113.0Z,35.40,31.69,30.50, 118

3 0 • 0 6 , 2 9 • 4 1 , 2 3. 3 S , 2 2 • 5 9 , 2 1 • SO, 2 1 • 0 7 , 1 4'. 0 3 ; A n a 1. Cal cd. for

C24H3204: C, 74.96 H, 8.38, Found: C 7S.22, H 8.48

(b). 2-[I-Cyclopentene-2-(I-methylethenyl)-I-yl]-

5-(n-pentyl)-1,3-diacetyl-resorcinol (58).

Viscous, bright yellow oil, eluting in ethyl acetate/hexane (4:96), 1.3 g. (70%); TLC Rf, 0.61 (ethyl acetate /hexane 20:80);IR(film),O 30S0(CH, str. aromatic),

2940,2860(CH, str.aliphatic),176S(C=O, str.)1620,1600(C=C, str.),1360(CH 3 , sym. bending),1180(O-C::C assym. str.), 1 120S cm- [C-C(=O)-O, sym, str. of acetate); 1H NMR(CDCl 3 ),

o 6.78(s,2H,ArH),4.88(s,2H,=CH 2 ),2.61(bm,6H,benzylic and C3,CSCH2),2.17(s,6H,COCH3),1.9-1.7(bm,2H,C4CH2),1.60(s,3H,

=-CH3),1.40-1.20(bm,6H,C2",C3",C4"CH2),0.89(t,3H,J=S.1Oand

S.80Hz,C S"CH 3 );13 C NMR(DMSO-d 6 ), S 168.7S,148.87,143.S0, 141.99,141.61,130.18,126.93,124.38,119.77,114.30,38.62,36.

3 S , 3 S. 43, 3 1. 4 7 , 30. 33, 2 3.02, 22.42 , 2 1. 1 8 , 20.64 , 1 3.92 ; A n a 1.

Calcd. for C23H3004: C,74.S6 H,8.16, Found: C, 74.S4, H,

8.33. 119

(c). 2- [ l-Cyclo hexe ne-5-me t hyl-2-( I-me thy 1 ethenyl)-I-yl]-5-(n-pentyl)-1,3-diacetyl-resorcinol, (61)

Viscous pale yellow oil, eluting in ethyl acetate/hexane, 2:98, 1.6 g. (80%);TLC Rf, 0.66 (ethyl ace tate/hexane, 20:80);IR(fi1m), ii 3520(overtone of C=0),3060

(CH, str. aromatic), 2920, 2860(CH, str. aliphatic), 1760,

1745(C=0, str.), 1610(C=C, str.), 1360(CH 3 , sym. bending), 1210, C[C(=O)-O, str.], 1175 cm- 1 (O-C::C asym. str.),

IH NMR(CDC1 3 ), 0 6.75(s,2H,ArH),4.61(bd,2H,=CH 2 ),2.7-2.48

(bm,4H,C 1 "benzylic and ring CH 2 ),2.22(s,3H,COCH 3 ),2.20(s, 3H, COCH3),1.66(s,3H,=-CH3),1.9-1.20(bm,IIH,side chain and ring CH 2 ),0.96(d,3H, J= 6.40Hz,C 7 CH 3 ),0.88(t,3H,C 5 ",CH 3 );

13 C NMR(CDC1 3 ), 0 168 • 8 0,148.70,146.00,142.58,139.60, 128.65,124.02,120.00,113.25,38.02,36.16,32.06,31.52,30.05,

29.08,22.65,21.60,21.58,20.05,14.05. Anal. Calcd~ for

C25H3404: C, 75.34, H, 8.69, Found: C, 75.51, H, 9.04.

(d). 2-[I-Cyclohexene-2-(1-methylethenyl)-I-yl]-5-

(1",1 "-dimethy1heptyl)-1,3-diacety1-resorcinol, (65)

Viscous pale yellow oil, eluting in ethyl ace- 120

tate/hexane,3:97, 1.7 g. (80%); TLC Rf, 0.75 (ethyl ace-

tate:hexane, 20:80);IR:(film), j) 3060(CH, str. aromatic),

2950,2850(CH, str. aliphatic),1765,17S0 (C=O, str),1621

(C=C,str.),1368(CH 3 ,sym. bending),1210[C-C(=O)-,str.), 1 1199 cm- (O-C::C,asym. str.);I H NMR(CDCl 3 ), S 6.85(s,3H,

=-CH 3 ),4.60(d,2H,=CH 2 ),2.65-1.00(bm,ISH,side chain and

ring CH 2 ),2.22(s,6H,COCH 3 ),1.65(s,3H,=-CH 3 ),1.24(s,3H,C 1 "

CH 3 ),1.1S(s,3H, ,Cl"CH3),0.S5(t,3H'C7"CH3);13CNMR(CDCl3)' S 16S.66,149.75,14S.29,145.74,139.35,127.21,124.40,117.46,

113.02,44.49,37.67,31.60,29.S1,29.65,29.27,2S.46,24.39,

23.09,22.60,22.50,21.30,20.07,13.94.; Anal. Cal cd. for

C2SH4004: C, 76.32, H, 9.14, Found: C, 76.47, H, 9.29.

(e). 2-[I-Cyclopentene-2-(I-methylethenyl)-I-yl]~5-

(1", l"-dimethylheptyl)-1 ,3-diacetyl-resorcinol, (66).

Viscous pale yellow oil, eluting in ethyl .ace-

tate/hexane (5:95), 1.70 g. (Sl%); TLC Rf, G.72, (ethylacetate/hexane 20:S0);IR(film), j) 3520(overtone of C=O, str.),30S4(CH, str. aromatic),2950,2933,2864(CH, str. ali-

phatic),1760(C=O, str.),1621(C=C, str.),1367(CH 3 , sym. 121

bending),120S[C-C(=O)-O, str.],1188 cm- 1 (O-C::C, assym.

H str.);l NMR(CDC1 3 ), 6 6.88(s,2H,ArH),4.8S(s,2H,=CH2 ),2.70

-2.48(m,4H,C 3 ,C S CH 2 ), 2.30-1.20(bm,12H,sidechain and C4

CH 2 ),2.17(s,6H,COCH3 ),1.Sl(s,3H,=-CH3 ),1.26(s,3H,C 1 "CH3)

1.18(s,3H,C 1"CH 3 ),0.84(t,3H,C 7 "CH 3 ); 13 C NMR(CDC1 3 ) 6 168.79 lS0.89,8.72,141.90,141.63,130.2S,124.S0,117.52,114.27,44.

49,38.42,37.03,36.31,31.6S,29.06,28.51,24.50,23.04,22.55,

21.09,20.6S,13.99.; Anal. Calcd. for C27H3804: C, 76.01,

H, 8.97, Found: C, 75.74, H, 9.11.

(f). 2-[1-Cyclohexene-5-methyl-2-(1-methylethyl)-1-yl]

S - ( 1" , 1 "-dim e thy 1 he p t y 1) -1 ,3-d i ace t y 1 - res 0 rei no 1, (67) •

Viscous pale yellow oil, eluting in ethyl acetate/ hexane, (2:98), 1.95 g. (85%); TLC Rf, 0.78(ethyl acetate/hexane, 20:80);IR:(film), ii 3059(CH, str. aromatic),2953,2928(CH, str. aliphatic), 1765(C=O, str.),1621

( C = C , s t r • ) , 1 3 6 7 ( C H 3 ' s y m • ben din g ) , 1 2 (, 5 ( [ C - C ( = °) - °, 1 str.],1190 cm- (O-C::C, assym. str.); 1H NMR(CDC1 3 ),

6 6.85(s,2H,ArH),4.56(d,2H,=CH 2 ),2.21(s,6H,COCH 3 ),1.64(s, 3 H , = - C H3) , 1 • 24 ( s , 3 H , C 1 .. C H3) , 1 • 1 8 ( s , 3 H , C 1 "C H 3) , 2 • 60- 1 • 00 ( bm

17H,side chain and ring CH 2 ),0.96(d,3H,J=7.5Hz,C 7CH 3 ),O.83

(t,3H,C 7 "CH 3 );13 C NMR(CDC1 3 ), 6 168.75,149.79,148.32, 122

145.62,138.90,127.50,123.89,117.61,113.13,44.53,38.19,37.

75,31.69,31.20,29.90,29.74,29.09,28.92,28.76,28.54,24.48,

22.69,22.59,22.42,21.45,21.23,21.01.; Analc. Calcd.for

C29H4204: C, 76.61, H, 9.31, Found: C, 76.79, H, 9.51.

VII. 2-[1-Cyclohexene-2(1-hydroxy-1-methyl

ethyl)-1-yl]-1,3-dimethoxy-5-(n-pentyl)

resorcinol(54A).

To a stirred mixture of triol 53 (0.31 g. 1 mmol), in dry acetone (10 ml) and potassium carbonate (0.56 g. 4 mmol), was added methyl iodide (0.62 ml, 10 mmol), and refluxed in anhydrous condition s for 8 h. Potassium carbonate was filtered off and the compound was taken in diethyl ether (2 X 15 ml). The organic layer was washed with water (3 X 15 ml), saturated sodium chloride (2 X 15 ml). The organic layer was dried over anhydrous sodium sulfate. Removal of solvent offered a bro~uish colored oil, which was purified by column chromatography (20 g. silica gel, 6" column length, 1" ID glass column). The fraction eluting in ethyl acetate/hexane (3:97), as pale 123

yellow oil (0.25 g. 73%). TLC Rf, 0.50 (ethyl acetate/hexane 20:80);IR(film), Ii 3485(OH, str.),3050,2860(CH, str.),

1600,IS90(C=C, str.),1230 cm- 1(C-O-C, asym. str.);lH NMR

(CDC1 3 ), 5 6.36(s,2H,ArH),3.76(s,6H,OCH 3 ),2.5S(t,2H,C 1 "

CH 2 ),2.2S-2.10(m,2H,C6 CH 2 ),2.20(bs,lH,OH),1.80-1.60(bm,6H,

C4 CS ,C 6 CH 2 ),1.4S-1.30(bm,6H,CH 2 ,side chain),1.16(s,6H, gem-dimethyl),0.90(t,3H,CS "CH 3 )·

VIII. 2-[1-Cyclohexene-2-(I-methylethenyl)-1-yl]

S-(n-pentyl)-1,3-dimethoxy-resorcinol (S5A).

1.73 g (2 mmol) of the tertiary alcohol (S4A) was mix e d wit h dry p y r,i din e (4.0 m L , 10m mol), and ace tic anhydride (3.0 g. 6 mmol) in a 50 ml flask maintained in o nitrogen atmosphere. the contents were warmed to 70 C with constant stirring for 4 h. Excess pyridine and acetic anhydride were removed under reduced pressure and the resulting dark colored oil was extracted in 1iethyl ether

(2 X50 mL). The ether solution was treated with crushed ice (20 g.), and stirred with sodium bicarbonate solution

(20 mL, 10% solution) for 4 h. Organic layer was separated 124

washed to neutral with water (3 X 20 mL) and saturated sodium chloride solution (2 X 25 mL). The organic layer was dried over sodium sulfate. Solvent removal afforded a brownish colored oil, which was purified by column chromatography (20 g. silica gel, 6" column length, I" 10, column). Eluent collected from ethyl acetate/hexane (1:99) on solvent removal afforded a colorless oil (1.45 g. 88%),

TLC Rf, 0.78 (ethyl acetate/hexane 10:90); GC Rt, 8.16 o min. (OVI7, 6 1 co!., 280 C);IR(film), ii 3090-2840(CH, str.),1610,IS8S(C=C, str.),1230 cm- 1 (C-O-C, asym. str.);

IH NMR(CDC1 3 ), 0 6.31(s,2H,ArH),4.47(bs,2H,=CH 2 ),3.72(s,

6H,OCH 3 ),2.S5(t,2H,C 1"benzylic CH 2 ,J=7.63 and 8.00Hz),2.2S

-2.0S(bm,4H,C 6 and C3CH2)1.78-1.52(bm,6H,C4,CS,C2"CH2),I.

60(s,3H,=-CH 3),1.40-1.30(bm,4H,C 3 ",C4 "CH 2 ),0.90(t,3H,C5"

CH 3 );13 NMR(CDCl 3 ), 0157.04,147.27,142.22,136.78,125.48, 119.53,110.55,103.87,55.50,36.62,31.74,31.07,30.21,28.88,

23.05,22.56,21.30,14.04;mass spectrum,EI/MS, M/Z (relative intensity)329(13.45),328(M+·S7.48),313(31.uo),298(49.59),

297(100),241(5.85),228(11.90),227(65.67),226(19.20),212

(14.30);Anal. Caled. for C22H3202:C 80.44, H, 9.81, Found:

C, 80.04, H, 9.73. 125

VII. General method for lew-is acid catalyzed

Intermolecular Diels-Alder Reaction.

To a stirred solution of diene 55 (0.76g. 2.0 mmol) in dry benzene was added ethyl acrylate (0.40 g. 4.0 mmol), and Lewis acid (ALCl 3 ) (3.0 mmo!). The mixture was allowed to stand at 40 C with stiring for 5 to 6h and allowed to stirr overnight at room temperature. the mixture was extracted in diethyl ether (3 X 25 mL), the crude product (1.00 g.) was washed in ice-cold water (3 X

20 mL), saturated sodium chloride (3 X 15 mL), and dried over anhydrous sodium sulfate. solvent removal gave a light yellow oil, which was subjected to preparative thin layer chromatography (20 X 20 em plates). Bands ~t Rf,

0.68 (fraction A), Rf, 0.50 (fraction B), Rf, 0.39 (frac tion C) were separated and extracted individually using e thy lac eta' t e (3 X 20m L ). F i 1 t e r i n g the s iIi c age 1, and solvent removal gave 0.42 g. of fraction A, 0.28 g. of fraction B, and 0.14 g. of fraction C.

Fraction A was identified as delta-3-THC analog, 1-

-acetoxy-3-n-pentyl-6,6-dimethyl-7,8,9,10-tetrahydro-6H dibenzo[b,d]pyran. Crystalline solid 0.42 g. (61%); mp 81- 126

o 82 C (ethanol);IR(Nujol), f) 29S4-282S(CH, str.),176S(C=O, 1 str.),161S cm- (C=C, str.);1 H NMR(CDC1 3 ), 6 6.S7and6.38

(dd,2H,ArH,J=1.SSandl.78Hz),2.S0(t,2H,benzylic CH 2 ,J=7.49 and8.00Hz),2.4S-2.32(bm,2H,C10CH2),2.27(s,3H,COCH3),2.1S-

2.03(bm,2H,C 7 CH 2 ),1.70-1.SS(bm,6H,ring and side chain CH 2 )

1.32(s,6H,C 6 gem-dimethyl),1.3S-1.25(bm,4H,side chain CH 2 ),

0.87(t,3H,CS"CH 3 ,J=6.80 and 6.76Hz);mass spectrum,M/Z(rel. intensity)342(M+· 12.56),328(24.05),327(100),286(15.84),

285(77.16),228(11.28);Analo Calcd. for C22H3003: C, 77.16,

H,8.82, Found: C, 77.24, H, 8.79.

Fraction B Colorless oil, 0.28 g. (30%); IR(film),

f) 2950 - 2 860 ( C H, s t r. ) , 1 7 7 5 , 1 740 ( C = 0, s t r. ) , 16 10 c m-1 (C =C , str);1 H NMR(CDCl 3 ), 66.65(bs,2H,ArH),4.91(t,1H,impurity),

4.20-3.95(m,2H,CH 2 of ester),2.55(t,2H,benzylic CH 2 ),2.20 (s,6H,COCH3),1.57(s,3H,=-CH3),2.19-1.12(broad multiplets),

0.88(t,3H,CH 3 of side chain);mass spectra of fraction B, showed that it is a mixture of compounds. T~.e GC-EI/MS of two peaks Rt, 2.90 and 3.25 min is given in appendix 1.

Analysis of the fragmentation pattern indicate that the two compounds with Rt, 2.90 and 3.25 min may possibly be the Diels-Alder products, ethyl-1-methyl-10-[1-phenyl-2,6- 127

diacetyl-4-(n-pentyl)]-2,3,4,S,6,7,8-octahydro-naphthalene

-4-carboxylate (68), or ethyl-1-methyl-10-[1-phenyl-2,6- diacetyl-4-(n-pentyl)]-2,3,4,5,6,7,8-octahydro-naphthalene

-3-carboxylate (appendix 2 and appendix 3).

Fraction C Colorless oil, TLC Rf, 0.39 (ethyl acetate/hexane 20:80). Repeated elemental analysis of this fraction showed that it has 1.44% low on carbon, calculated for C29H40060 Mass spectrum (EI/MS) of the fraction C, show that it is possibly a mixture of compounds having molecular weight higher than 600 mass units. APPENDIX 1

411 369

400 450

GC-EI/MS of compound with Rt, 2.90 minutes.

4494('5

450 50~)

GC-EI/MS of compound with Rt, 3.25 minutes.

128 APPENDIX 2

m/z.t47

t -ARH I ACO~(C5H" cv9- -C:)CC2H5 _2§A'_- D. OAe (:OOC2H5 mil. 464(M+;not 5e(m~

j-AoOH

rr'll' 369

rr/z.327

) - :3 M 9

/ I

m1Z·253 m/Z, 309 I

('-...., ;)Ac

X'~~i CH=Ci-l 2 .?, m/:.263 mil' 3C7

Fragmentation of compound with Rt, 2.90 minutes.

129 APPENDIX 3

mIl, 309 • - AcOH ~ - CH2CO. mll.327 f -CH) ,"

mil. 484 (M") not 5~n - CH3'

mil' )00 L.~I'.'('

mIl. 282([305'"

mn,2'13

Fragmentation of compound with Rt, 3.35 minutes.

130 REFERENCES

1. Shultes, R. E. In "The Botany ~ Chemistry .Q!. Cannabis" Joyce, C.R.B., Curry, S. H.; Eds.; Churchill Inc.: London, 1970, pp 11-38.

2. Li, H. L. Economic Botany 1974, 28 293.

3. Li, H. 1. Economic Botany 1974, 28 437.

4. Nahas, G. G. "Marihuana In Science And Medicine" Raven Press: New Yo r k , 1 984 , p p 247.--

5. Bhargava, H. N. Gen. Pharmac. 1978, 2" 195.

6. Abel, E. L. "Marihuana" Plenum Press: New York, 1980, pp 120.

7. Nahas, G. G. "Marihuana In Science And Medicine" Raven Press: New Yo r k , 1 984, p p 3 - 3 5-.-

8. Quimbly, M. W• Arch. INVEST. Med. 5. Suppl. 1974, .!.,127.

9. Mechoulam, R.; Gooni, Y. Fortsch. Chern. 2.!:..a. Naturst. 1967, 25, 175.

10. Nahas, G. G. "Marihuana In Science And Medicine" Raven Press: New Yo r k , 1 984, p p 2 6. ll. Shoyarna, Y.; Nishioka, I. Chern. Pharm. Bull. 1978 3641.

13 1 132

12. Turner, C. E.; Hsu, M. F. H.; Knapp, J. E.; Schiff, P.L., Jr.; Slatkin, D. J. J. Pharm. Sci. 1976, 65, 1084.

13. Elsohly, M. A.j Turner, E. C.; Phoebe, C. H., Jr. ; Knapp, J. E. J. Pharm. Sci. (1978), 2l.., 124.

14. Turner, C. E.; Elsohly, M. A.; Boeren, F. G. J. Nat. Prod. (1980), 43, 170.

15. Colasanti, B. K. ~.~. Res. (1984), 39, 251.

16. Mechoulam, R.; Ben-Zvi, Z.; Varconi, H.; Samuclov, Y. Tetrahedron (1973), ~, 1615.

17. Garrett, E. R.; Tsau, J. J. Pharrn. Sci. (1974), 63, 1563.

18. Kajima, M.; Piraux, M. Phytochemistry (1982), ll, 67.

19. Braut-Boucher, F.; Lenoble, M.; Braemer, R.; Fisse, J.; Cosson, 1.; Paris, M. (Poster Session), Third colloque section, Francaise Association. Inter national de culture de tissue et de Cellules de plantes (LA.P.T.C) Toulouse, France, 1981.

20. Adams, R.; Baker, B. R.; Wearn, R. B • .,J. Amer. Chern. Soc. (1940), .£1., 2201, 2204, 2401, 2405:

21. Todd, A. R.; Gosh, R.; Wilkinson, S. J. Chern. Soc. (1940), 1121, 1393.

22. Mechoulam, R. Ed.; In "Pharmacology, Metabolism, And Clinical Effects" Academic Press: New York,1973. 133

23. Mechoulam, R.; Mc Callum, N. K.; Burstein, S. Chern. Re v. 1976, 76, 75.

24. Pars, H. G.; Razdan, R. K.; Howes, J. F. In "Advances In Drug Research" B. Simmonds, N. J. Harper, Eds.; Academic Press: London, 1977, Vol II.

25. Razdan, R. K. ; Pars, H. G. ; Granchilli, F. E.; Harris, L. S. J. --Med. ---Chern. 1968, l...!.., 377.

26. Razdan, R. K. Pars, G. ; Dodge, P. w. ; Kyneyl, J. ; Somani, P. J. Med. Che rn., 1976, .l2., 454.

27. Razdan,R. K.; Zitko-Terris, B.; Handrick, G. R.; Dalzell, H. C.; Pars, H. G. :!... Med. Chern., 1976, .l2., 549.

28. Mechoulam, R. Tetrahedron 1963, .l2., 2073.

29. Ottersen, T. Acta. Chern. Scand. B31, 1977, 807.

30. Mechoulam, R.; Srebink, S.; Baek, S. H. Tetrahedron. Lett. 1985, ~, 1083.

31. Nahas, G. G. "Marihuana In Science And Medicine" Raven Press: New York, 1984, pp 124-126.

32. Keeler, M. H. Am. J. Psychiatry .• 1967, 124, 674.

33. Kaplan, H. S. NY. State. J. Med. 1971, 2..!.., 433.

34. Melges, F. T.; Tinklenberg, J. R.; Deardorff, C. M. Arch. Gen. Psychiatry. 1974, lQ, 855.

35. Arne s, F. J. Ment. Sci. 1958, 104, 972. 134

36. Nahas, G. G. "Marihuana In Science And Medicine" Raven Press: New York, 1984, pp 248.

37. Smith, D. E. J. Psychedelic Drugs 1968, !, 37.

38. Miller, L. L. In "The Ca.nnabinoids Chemical Pharmacologic And Tii:"erapeutic Aspects". S. Agurell, W. L. Dewey, R. E. Willette, Eds.; Academic Press: New York, 1984, pp 21.

39. Neu,C.;DiMascio,A.;Zwllling,G. In "The Therapeutic Potential Q!. Marijuana" S. Cohen, R. C. Stillman, Eds.; New York, Plenum Press: 1976.

40. Carchman, R. A.; Harris, L. S.; Munson, A. E. Cancer Res. 1976, l§., 95.

41. Friedman, M. A. Cancer Biochem. Biophy. 1977, !, 51.

42. Rosenberg,C. M.; Schnell,C. Journal Of Studies In Alcohol 1978, 1l, 1955.

43. Regelson, W.; Butler, J. R.; Schultz, J.; Kirk, T.; Peck, L.; Green, M. L.; Zakis, o. In "Pharmacology Of Marijuana". New York, Raven Press: 1976.

44. Noyes, R.; Brunk, S. F.; Baram, D. A.; Canter, A. J. Clio Pharmacol. 1975, .!2., 139.

45. Wilson, R. S.; May, E. L. J. Med. Chern. 1974, .!l., 475.

46. Harris, L. S.; In "The Therapeutic Potential Of Marijuana" S. Cohen R. Stillman Eds. Plenum Press: New York, 1976.

47. Tashkin, B. J.; Shapiro, I. M.; Frank, 1. M. Am. Rev. Resp. Dis. 1974, 109, 420. 135

48. Lodge, J. W. Am. Rev. Reap. Dis. 1977, 115, 57.

49. Regelson, W.; Butler, J. R.; Schultz, J.; Kirk, T.; Peck, L.; Green, M. L.; Zakis, 0.; In "Phar!!!acology .2..f Mar i j u a n a" M• C. Bra u d e, S • S. Z al: g, E d a • ; Raven Press: New York, 1976.

50. Gross, H. A.; Ebert, M.; Goldberg, W. K.; Caine, E.; Faden, V.; Hawks, R.; Zinberg, N. Am. Psychiatric Association 1980,

51. Archer, A. R.; Hanason, G. K.; Lemberger, L.; Sullivan, H. R.; In "Treatment .Q!. Cancer Chemotherapy Induced Nausea And Vomiting",D. S. Poster, J. S.Penta, S. Bruno, Eds.; Moser Inc: New York, 1981, pp 119-127.

52. Helper, R. S.; Frank, I. M., J. Am. med. Assocn. 1971, 217, 1392.

53. Green, X. Journal of psychedelic drugs 1978, lQ, 207.

54. Cohen, S. In NIDA Marijuana Research Findings R.C. Peterson Ed.; 1980, Vol II, pp 199.

55. 0' Shaughnessy, W. B. Trans. Med. Phr s • Soc. !.2..!!l~, 1842, l!., 421.

56. Reynolds, J. R. , Lancet 1870, 1, 637.

57. Davis, J. P.; Ramsey, H. H. Federation Proc. 1949, l!., 284.

58. Consroe,P. F.; Wood, G. C,; Buchsbaum, H., J. Amer. Med. Assoc. 1975, 234, 306.

59. Consroe, P. F.; Jones, B.; Laird, H.; Reinking, J. In "The Therapeutic Potential Of Marihuana, " 136

S.Cohen, R. C. Stillman Eds.; Plenum Press: New York, 1976, pp 363.

60. Corcoran, J. A.; Mc Coughran, J. A., Jr.; Wade, J. A., Epilepsia 1978, ~, 47.

61. Consroe, P. F.; Man, D. P. Life Sci. 1973, .!1., 429.

62. Consroe, P. F.; Wolkin, A. J. Pharmacol. Expt. Ther. 1976, 201, 26.

63. Feeney, D. M., J. Am. Med. Assoc. 1976, 235, 1105.

64. Karler, R.j Turkanis, S. A., In "Marihuana Biological Effects G. G. Nahas, W. D. M. Paton, Eds.; Pergamon Press: New York, 1979, pp 619.

65. Karler, R.j Turkanis, S. A., J. Clin. Pharmacol. 1981, l..!., 437s.

66. Feeney, D. M. In "Marihuana Biological Effects," G. G. Nahas,W. D. M. Paton,Eds.; Pergamon Press: Ne wY 0 r k, 1979, p p 643.

67. Turkanis, S. A.j Karler, R. J. Clin. PharmacoL 1981, l..!., 449s.

68. Consroe, P. F.j Martin, A. R.j Fish, B. S., J. Med. Chern. 1982, ~, 596.

69. Hollister, L. E. Pharmacology, 1974, .!...!., 3.

70. Jones, R. T. Ann. Rev. Med. 1983, li, 247. 137

71. Carlini, E. A.; Leite, J. R.; Tannhauser, M.; Bernardi A. C. J. Pharm. Pharmacol. 1973, 11, 664.

72. Karler, R.; Cely, W.; Turkanis, S. A., Life.Sci. 1973, 13, 1527.

73. Consroe, P.; Martin, A. R.; Singh, v. J. Clin. Pharmacol. 1981, ll, 428s •

. 74. Cunha, J. M.; Carlini, E. A.; Pereira, A. E.; Ramos, O. L.; Pimentel, C.; Gagliardi, R.; Sanvito, W. L.; Lander, N.; Mechoulam, R. Pharmacology, 1980, ll, 175.

75. Carlini, E. A.; Mechoulam, R.; Lander, N. Res. Comma Chem. Path. 1975, g, 1.

76 Martin, A. R.; Kane, V. V.; Singh, V.; Consroe, P. F. J. Med. Chem.

77. Leite, J. R.; Carlini, E. A.; Lander, N. mechoulam, R. Pharmacol. 1982, ~, 141.

78 Thornber, C. W., Chem. Rev. 1979, ~, 563.

79. Sinkula, A. A.; Ann. Rer. Med. Chern. 1975, l:..Q., 306.

80. Bentley, K. W.; Hardy, D. G. J. Amer. Chem. Soc. 1967, 89, 3267.

81. Consroe, P.; Martin, A. R.; Mechoulam, R., In "Marihuana '84," D.J. Harvey Ed.; IRL Pres's: Oxford, 1985 , p p 7 AS. 138

82. Shah, V. J.; Martin, A. R. Unpublished results Department of Pharmaceutical Sciences, University Of Arizona.

83. Consroe, P.; Kudray, K.; Schmitz, R. !!..E.. Neurol. 1980, 70, 626.

84. Dunham, N. W.; Miya, T. S. J. Amer. Pharm. Assocn. 1957, 46, 208.

85. Nahas, G. G. Marihuana In Science And Medicine Raven press: New York, 1984, pp 25~

86. Karler, R.; Celey, W.; Turkanis, S. A. Life.Sci. 1973, 13, 1527.

87. Izquierdo, I.; Orsingher, o. A.; Berardi, A. C.; Psychopharmacologia,1973. ~, 102.

88. Karler, R.; Cely, W.; Turkanis, S.A. Life. Sci. 1974, U' 931.

89. Turkanis, S. A.; Cely, W.; Olsen, D. M.; Karler, R. Res. Commun. Chem. Pathol. Pharmacol. 1974, .!!' 231.

90. Turkanis, S. A.; Chiu, P.; Borys, H. K.; Karler, R. Psychopharmacology, 1977, g, 207.

91. Turkanis, S. A.; Smiley, K. A.; Borys, H. K.; Chiu, P. Epilepsia, 1979, 20, 351.

92. Carlini, E. s.; Cunha, J. M. J. Clin.Pharmacol. 1981, ~, 417s.

93. Cunha, J. M.; Carlini, E. A.; Mechoulam, R. Pharmacology, 1980,~, 175. 139

94. Cavallito. "Structure Activity Relationships" Pergamon press: Elmsford, Vol!, 1973, pp 77.

95. Adams, R.; Herfenist, M.; Loewe, S. J. Am~. Che!!!.. !2..£. 1949, 71, 1624.

96. Loev, B.; Bender, P. E.; Dowalo, F.; Macko, E. J. Med. Chem. 1973,.!,!, 1200.

97. Mochulam, R.; Edery, H. In, "Marihuana: Chemistry, Pharmacology, metabolism, and Clinical Effects. Mechoulam Ed., Academic press: New York, 1973, pp 101.

98. Pechmann, V. Ber. 1884, 16, 2119.

99. Sethna, S. Chem. Rev. 1945, 1..£., 10.

100. Sethna, S.; Phadka, R • .Q.E..a. Reactions, 1953, I, 1.

101. Kappe, T.; Zeigler, E. £..!:.£. Prep. Proced. 1969, 1., 61.

102. March, J. "Advanced Organic Chemistry" Reaction, Mechanisms, Abd Structure, Second ed., McGraw-Hill: New York, 1977, pp 501.

103. Naik, and Desai. J. Ind. Che!!!.. Soc. 1929, ,§., 83.

104. Adams, R.; Mackenzi, S. Jr.; Loewe, S. J. Amer. Chern. Soc. 1948, !..2.., 664.

105. Marmor, R. S. J • .2..!:.£. Che.!!!.. 1987, 37,2901.

106. Petrzilka, T.; Haeflinger, W.; Sikrneir, C. Helv. Chi!!!.. Acta. 1969, 52, 1109. 140

107. Matsumoto, K.; Stark, P.; Meisrer, R. G. J. Med. Che.!!. 1977, 20,17.

108. Dominianni. S. J.; Ryan, C.W.; DeArmitt, C. W. J • .Q..E..[. Chem. 1977, 42, 334.

109. Adams. R.; Smith, C. M.; Loewe, S. J. Amer. Chem. Soc. 1942, ~, 2087.

110. Adams, R.; Baker. B. R • .1. Am~. Che.!!. Soc. 1940, 21., 2405.

110a Pars, H.G.; Granchelli, F. E.; Razdan. R. K.; Keller, J.K. J. Med. Chem. 1976, 1..2., 445.

Ill. Razdan, R. K.; U1iss, D. B.; Handrick, R. G. J • .Q.!..[. Chem. 1977, i1, 2563.

112. Silverstein, R. M.; Bassler, G. C.; Morri1, T. C. "Spectroscopic identification £!.. Organic Compounds" Forth Ed., John Wiley and Sons: New York,1981, pp 107.

113. Silverstein, R. M.; Bassler, G. C.; Morril, T. C. "Spectroscopic identification £!.. Organic Compounds" Forth Ed., John Wiley and Sons: New York,1981, pp 259.

114. Lindman, L. P.; Adams, J. Q. Anal. Chel!\. 1971, il, 1245.

115. Kurth, H. J.; Bieniek, D.; korte, F. Z. Naturforsch B: Anorg. Chern. OrgChem. 1981, 36B, 275.

116. Whwrli, F. W.; Nishida, T. Fortschr. che!!!. • .2...!:.Jl. Naturstaffe. 1979, l2., 1. 141

117. Kane, V. V.; Martin, A. R.; Jaime, C.; asawa, E. Tetrahedron, 1984, ~, 2919.

118. Diels, 0.; Alder, K. Liebigs. Ann. Chern. 1928 2.!!., 460.

119. Wassermann, A. "Diels Alder Reactions" Elsevier Publishing Co., London, 1965.

120. Saver, J. Angew. Chern. Int. Ed. Engl. 1967, i, 16.

121. Eisenstein, 0.; Lepour, J. M.; Anh, N. T. Hudson, R. F. Tetrahedron 1977, ri, 523.

122. Woodward, R. B.; Katz, T. J. Tetrahedton 1959 1, 70.

123. "The Intra Molecular Diels Alder Reaction" Organic Reactions, 1984, 1!, pp 17.

124. Inukai, T. ; Kojima, T. Jor. .Q!.K • Chern. 1967, 1!, 872.

125. Inukai, T. ; KOjima, T. Jor. ~. Chern. 1966, ~, 1121.

126. Martin, A. R. unpublished results, College of Pharmacy University of Arizona. Tucson, Arizona, U.S.A.

127. Weinner, B. Z.; Meyer, A. Y.; unpublished results, Department of Organic Chemistry, Hehrew University Jerusalem, Israel.

128. Tamir, 1.; Mechoulam, R.; Meyer, A. Y. J. Med. Chern. 1980, Q, 220.

129. Kane, V. V.; Martin, A. R.; Jamie, C.; asawa, E. Tetrahedron, 1984, ~, 2919.