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Part I. New synthetic approaches to cannabinoids and theiranalogs. Part II. Benzoannelation of ketones

Kannangara, Gallage Sriyant, Ph.D.

University of Hawaii, 1994

V·M·I300 N. Zeeb Rd.Ann Arbor, MI48106

PART I: NEW SYNTHETIC APPROACHES TO CANNABINOIDS

AND THEIR ANALOGS

PART II: BENZOANNELATION OF KETONES

A DISSERTATION SUBMITTED TO THE GRADUATE DIVISION OF THEUNIVERSITY OF HAWAII IN PARTIAL FULFILLMENT OF THE

REQUIREMENTS FOR THE DEGREE OF

DOCTOR OF PHILOSOPHY

IN

CHEMISTRY

AUGUST 1994

By

G. S. Kamali Kannangara

Dissertation Committee:

Marcus A. Tius, ChairmanSheila Conant

Bradley S. DavidsonRobert S. H. Liu

Karl Seff

To Mohan and my parents

iii

ACKNOWLEDGEMENTS

It is with great pleasure that I express my sincere appreciation to my

advisor, Professor Marcus A. Tius, for the valuable guidance and support I

have received from him throughout my career as a graduate student. His

dedication to scientific research and his endless enthusiasm for his work have

been an inspiration to me. I also wish to thank the other members of my

dissertation committee for their assistance and encouragement.

I would like to recognise Dr. Michael A. Kerr, for his contribution on

the halogenated cannabinoid synthesis project and Ms. Krista J. S. Grace,

Pharmacology Research and Teaching Program, U. C. Santa Barbara, for

performing the anti-inflammatory screening assays. In addition, I wish to

thank Joel K. Kawakami for sharing with me his expertise in fluorination of

vinyl stannanes, and for the stimulating discussions regarding his work. I

thank members of the Tius group, past and present, for being helpful,

understanding and accommodating.

Many thanks to Dr. Walter Niemczura, Wesley Yoshida and Mike

Burger for their help rendered in obtaining NMR and mass spectral data.

lowe a special debt to my husband Mohan, for all of his love, support

and endurance.

Finally, I would like to thank Professor Marcus A. Tius for providing

generous financial assistance in the form of a research assistantship; the

Department of Chemistry of the University of Hawaii for the Departmental

Research Fellowship and a teaching assistantship; and East-West Center,

Hawaii for the financial assistance provided in the form of a scholarship.

iv

ABSTRACT

Part I: New Synthetic Approaches To Cannabinoids And Their Analogs

New synthetic approaches to several tetrahydrocannabinoids (THC)

and their analogs are described. The synthesis of ll-hydroxy-~8_THC and

(-)-11-nor-~8-THC-9-carboxylic acid methyl ester proceed through a common

intermediate obtained from the addition of a mixed higher-order cuprate

derived from bis-2-ethoxyethyl ether of olivetol to (+)-apoverbenone in the

presence of BF3·Et20. The cuprate addition is stereospecific and takes place

trans to the geminal dimethyl bearing bridge of (+)-apoverbenone. Further, it

provides an efficient solution to the regiochemistry problem encountered in

some of the earlier cannabinoid syntheses. Another interesting reaction in

the synthetic sequence for (-)-II-nor-~8-THC-carboxylic acid methyl ester is

the cationic cyc1ization of the vinyl triflate derived from cuprate adduct with

excess BF3·Et20 in CH2CIZ. The relief of ring strain attending the cleavage

of four-membered ring of the pinane skeleton is assumed to be the driving

force of the reaction. The palladium catalyzed carbonylation of the ~8_THC­

cyclohexenyl triflate thus obtained led to (-)-II-nor-~8-THC-9-carboxylic acid

methyl ester.

The synthesis of 51-(ZH3)-(-)-II-nor-9-carboxy-~9_THCmethyl ester

methyl ether was accomplished from the u-bromoenone derived from

nopinone. The halogen substituent at CIO acts as a control element to

generate the thermodynamically less stable unsaturation of the ~9-series.

It was necessary to use an oxygen protecting group on olivetol which would

be robust enough to survive the acid-catalyzed conditions for the cleavage of

v

the cyclobutane ring. Hence, bismethoxy olivetol ether was used in the

cuprate reaction. The key steps in the synthesis are the stereocontrolled ring

opening of the cuprate adduct and formation of the benzopyran ring using

iodotrimethylsilane in chloroform leading to the ~9-THC-cyclohexenyl

triflate.

A convenient synthesis of several bicyclic and tricyclic fluoro- and iodo

analogs of cannabinoids has also been reported. A new, mild synthetic

methodology for the synthesis of vinyl fluorides from vinylstannanes has

been demonstrated. These C9 halo- functionalized cannabinoid analogs,

along with (-) and (+)_~9_THCcarboxylic acids, have been screened for anti­

inflammatory activity in the mouse ear edema assay. It is interesting to find

that both enantiomers of ~9_THC carboxylic acid were moderately active as

anti-inflammatories. The bicyclic vinyl iodide also showed appreciable anti­

inflammatory activity.

Part II: Benzoannelation of Ketones

Benzoannelation procedures, the elaboration of aromatic rings from

non-aromatic precursors have offered several advantages such as synthesis of

highly substituted aromatic rings and substitution patterns not easily

accessible through conventional approaches. The synthetic methodology

described herein provides a highly practical route for the benzoannelation of

ketones. The efficacy of the method is demonstrated by its application to both

cyclic and acyclic, a-unsubstituted ketones. Both the methallylmagnesium

chloride reaction and the cyclization take place cleanly. There is no need to

purify the intermediate and the aromatic compounds are obtained in high

overall yield.

vi

TABLE OF CONTENTS

ACKN"OWLEDGEMEN'TS.................................................................................... i v

ABSTRACT.............................................................................................................. v

LIST OF FIGURES..... xi

LIST OF ABBREVIATIONS.................................................................................. xii

PART I: NEW SYNTHETIC APPROACHES TO CANNABINOIDS AND

THEIR ANALOGS

INTRODUCTION................................................................................................... 1

A. Pharmacohistory of Cannabis sativa.................................................... 1

B. Nomenclature of the cannabinoids...................................................... 4

C. Structural and stereochemical requirements for

cannabinoid activity .

D. Some common natural cannabinoids ..

E. Metabolism of cannabinoids .

5

10

12

F. Therapeutic potential of cannabinoids and

synthetic analogs...................................................................................... 13

G. Previous synthetic approaches to cannabinoids

and analogs................................................................................................ 15

RESULTS AND DISCUSSION............................................................................. 29

A. Stereo- and regiospecific condensation of olivetol diether

with (+)-apoverbenone............................................................................ 29

vii

B. Synthesis of ll-hydroxy-~8-tetrahydrocannabinoL........................... 32

a. Retrosynthesis of ll-hydroxy-~8-THC......................................... 32

b. Formation of spiroepoxides........................................................... 33

c. Epoxide ring opening to form the allylic alcohoL.................... 35

d. Formation of the dihydropyran ring from triol........................ 36

C. Synthesis of (-)-11-nor-~8-tetrahydrocannbinol-9-carboxylic acid

methyl ester................................................................................................. 37

a. Formation of ~8-cyclohexenyl triflate.......................................... 37

b. Palladium catalyzed carbonylation of

~8-eyclohexenyl triflate................................................................... 38

D. Synthesis of (-)-11-nor-~9-tetrahydrocannabinol acid methyl ester

methyl ether................................................................................................ 40

a. Retrosynthesis of ll-nor-~9-THC-9-carboxylic acid.................. 40

b. Formation of (-)-11-nor-9-ketohexahydrocannabinol............. 41

c. Mixed higer-order cuprate reaction with

a-bromoenone.................................................................................. 42

d. Attempted cyclization of the bromo ketone.............................. 44

e. Formation of the a-alkoxyenones................................................ 46

f. Reevaluation of the retrosynthesis.............................................. 47

g. Stereospecific ring opening of cuprate adduct........................... 48

h. Regiospecific formation of the cyclohexenyl triflate

followed by Palladium-catalyzed carbonylation......................... 50

viii

i. Attempted cleavage of methyl ether............................................ 51

j. Formation of benzopyran ring and carbonylation of

cyclohexenyl triflate........................................................................... 51

E. Synthesis of halogenated cannabinoids.................................................. 54

a. Bis-fluorination of ketones using methyl-DAST....................... 55

b. Formation of vinyl-fluoride from bis-fluoride.......................... 56

c. Formation of 9-nor-9a-fluoro-hexahydrocannabinol............... 57

d. Formation of 3-[4-pentyl-2,6-bis(acetoxy)phenyl]

4-isopropenyl-cyclohexan-1-one and attempted fluorination

with methyl-DAST........................................................................... 59

e. Formation of vinyl stannanes....................................................... 61

f. Fluorination of vinyl stannanes.................................................... 62

g. Formation of (-)-9-fluoro-L\8-THC.............................................. 63

h. Formation of vinyl iodo cannabinoids........................................ 64

F. Anti-inflammatory activity of several cannabinoids.......................... 64

CONCLUSION......................................................................................................... 66

EXPERIMENTAL SECTION.................................................................................. 69

APPENDIX I: SPECTRA FOR SELECTED COMPOUNDS IN PART 1.......... 171

REFERENCES 274

PART II: BENZOANNELATION OF KETONES

INTRODUCTION 289

ix

RESULTS AND DISCUSSION............................................................................. 293

CONCLUSION......................................................................................................... 299

EXPERIMENTAL SECTION.................................................................................. 300

A. General procedure for the preparation of 2-(hydroxymethylene)ketone 300

B. Reaction of methallylmagnesium chloride with trimethylsiloxy-

methylene ketone......... 301

C. Cyclization of 1-(2-methallyl)-2-(trimethylsiloxy)methylene alcohol to

the methyl-substituted aromatic compound................................................ 302

APPENDIX II: SPECTRA FOR SELECTED COMPOUNDS IN PART II....... 311

REFERENCES 327

x

LIST OF FIGURES

Figure 1: Numbering systems for THCs............................................................. 5

Figure 2: Some of the representative natural cannabinoids......................... 11

Figure 3: Retrosynthesis of II-hydroxy_~8-THC............................................... 32

Figure 4: Retrosynthesis of A9_cyclohexenyl triflate 40

Figure 5: Aromatic compounds obtained from a-unsubstituted ketones 290

xi

LIST OF ABBREVIAnONS

A angstrom

Ac acetyl

Ar aromatic

br broad

Bu butyl

C Celsius

c concentration

cat. catalytic

CBD cannabidiol

CBN cannabinol

COSY correlated spectroscopy

CSCM chemical shift correlation map

d8- delta-8-

d9- delta-9-

D dimensional

d doublet

DAST dialkylaminosulfurtrifluoride

dd doublet of doublets

ddd doublet of doublet of doublets

DIBAH diisobutylaluminum hydride

DIPEA diisopropylethylamine

DMAP 4-(dimethylamino)pyridine

DME l,2-dimethoxyethane

xii

DMF

DMSO

dt

EE

eq

equiv

Et

Et20

eV

EVE

g

GC-MS

h

HETCOR

HETEROCOSY

hv

Hz

HHC

HMBC

HMQC

HPLC

HRMS

IR

LIST OF ABBREVIATIONS (CONTO)

N,N-dimethylformamide

dimethyl sulfoxide

doublet of triplets

ethoxyethyl

equation

equivalent

ethyl

diethyl ether

electron volt

ethyl vinyl ether

gram

gas chromatography-mass spectrometry

hour

heteronuclear chemical shift correlation

heteronuclear correIated spectroscopy

uv-irradiation

hertz

hydroxyhexahydrocannabinol

heteronuclear multiple bond correlation

heteronuclear multiple quantum correlation

high pressure liquid chromatography

high resolution mass spectrum

infrared

xii i

LIST OF ABBREVIATIONS (CONT'D)

J coupling constant

KHMDS potassiurn bis( trimethylsil yl)amide

LAH lithium aluminum hydride

LDA lithium diisopropylamide

m multiplet

M molar

MCPBA mefa-chloroperoxybenzoic acid

Me methyl

mg milligram

MHz megahertz

min minutes

mL milliliter

mmol millimole

MOM methoxymethyl

mp melting point

n-Bu normal butyl

NBS N-bromosuccinimide

NMR nuclear magnetic resonance

n.O.e nuclear Overhauser effect

PIX:: pyridinum dichromate

PET positron emission tomography

Ph phenyl

PMA phorbol-12-myristate-13-acetate

xiv

PPTS

p-TSA

pyr.

q

Rf

s

SAR

sat'd

t

tert-Bu

TBDMS

TEA

TFA

TFAA

THe

THF

TIPS

tIc

TMS

TMSOTf

Ts

UV

U.S.

LIST OF ABBREVIATIONS (CONT'D)

pyridinium para-toluene sulfonate

para-toluenesulfonic acid

pyridine

quartet

retention factor

singlet

structure activity relationship

saturated

triplet

tertiary butyl

tertiary-butyldimethylsilyI

triethylamine

trifluoroacetic acid

trifluoroacetic anhydride

tetrahydrocannabinol

tetrahydrofuran

triisopropylsilyl

thin-layer chromatography

trimethylsilyl

trimethyIsHyltrifluoromethanesulfonate

toluenesulfonyl

ultraviolet

United States

xv

INTRODUCTION

A. Pharmacohistory of Cannabis sativa

Cannabis sativa L. is one of the oldest and most extensively used

plants by man for fiber, food, medicine and social and religious rituals.I It is a

fast-growing, herbaceous annual, propagated by seed. Cannabis sativa is

normally a dioecious plant of which two varieties exist, namely indica and

non indica or typica. The cannabis fiber, better known as "hemp" comes from

the stem. The flowers are small and typically green, greenish yellow or white.

The leaves are distinctive, commonly with five, seven, nine, or other odd

numbers of saw-toothed leaflets arranged palmately.2 The flowering tops of

the female plant are covered with glandular hairs which secrete a resin. The

resin formation usually becomes abundant late in the plant's development

and it is commonly believed that the function of the resin is to prevent

desiccation of the seeds and to protect them during the ripening period. The

choice of cannabis plant parts as drug products and the method of preparation

vary from place to place. In the United States, the two main drug products

from Cannabis sativa are known as marijuana and hashish. "Marijuana"

consists of any part of the plant that has been crudely prepared for smoking,

primarily by drying. "Hashish" essentially is resin from the plant.

Cannabis has been quite prominent as a folk medicine in different

cultures since ancient times.3 The Greek historian Herodotus (ca. 300 B. C.)

reported use of cannabis as an intoxicant by the Scythians which had also

played a central role in their religious rites. 3b A Chinese treatise, about 2000

1

years old, has recorded the use of cannabis mixed with wine as an anesthetic

in surgery.4 Externally, cannabis was used as a poultice, or as a constituent of

various ointments for swellings and bruises. Crushed seeds, either as a drink

or in food, were prescribed for depression. Cannabis fumes were a medication

to alleviate arthritis pain. The plant extracts were used in Europe for a long

period of time for chronic headaches and certain psychosomatic disorders. It

is still quite popular in indigenous medicine especially in India (referred to as

bhang, ganja, Indian hemp etc.) and is used as a spasmolytic, hypnotic,

analgesic and also to increase body resistance to severe physical stress.S

Further, cannabis derived drugs were used in various parts of India as

appetite promoters and a general tonic to improve both the physical and

mental state of the user. Cannabis was also used with considerable success in

dysentery and cholera.

Although the folkloric use of cannabis as a medicine has been around

for a long period of time, it was largely during the 19th century that the

preparations of cannabis were assimilated into the standard medical practice.

In the 1840s the British scientist and physician O'Shaugnessy meticulously

carried out research on various cannabis preparations and observed that

cannabis was a potent antivomiting agent.6 Encouraging results were

also reported when ethanolic extracts (tincture) of cannabis resin were

administered to patients with rheumatism, tetanus, rabies and infantile

convulsions. For example, the painful, tonic muscular spasms of tetanus

and rabies were attenuated.

Despite the widespread long pharmacohistory and the therapeutic

potential of cannabis, its acceptance as a medicine declined in the early

2

decades of the 20th century. The main reason for this was the unavailability

of the constituents of cannabis in pure form. Crude extracts or preparations

of cannabis whose contents were known to vary widely were used instead,

and this resulted in low reproducibility of the clinical results. Another factor

was the unavailability of a reliable animal test which paralleled the activity

in humans and the lack of controlled clinical experiments. The development

of more conveniently administered and more uniform alternative drugs

therefore hampered the biological work and medical use of cannabis.

Interest in cannabis was renewed in the early 1940s as a result of the

identification of the basic structural features and synthesis of compounds

with cannabimimetic activity by Adams? and Todd8. The most widely tested

compound was synhexyl (1). Although initial trials with synhexyl reported

efficacy as an antidepressant and as a treatment for alcohol or opiate

withdrawal, subsequent evaluations proved negative.

1 Synhexyl (pyrahexyl, parahexyl)

In 1964, the modern era of cannabinoid research began with the

isolation and structure elucidation of (_)-&9-tetrahydrocannabinol

«_)-&9_THC, 2), the primary psychoactive constituent of cannabis, by

Mechoulam and Gaoni in Israe1.9 This coincided with an explosion in

3

marijuana use as a drug of leisure by large numbers of young individuals and

evidence of serious health hazards. In 1967, the U. S. Federal government,

responding to the rising concern over the use of marijuana, launched its first

intensive research program on cannabis through the National Institute of

Mental Health. The cannabis preparations once accepted as therapeutically

useful drugs were subjected to strict controls of the U. S. Drug Enforcement

Administration under the Controlled Substances Act (1970). Today, hashish

and marijuana, the best known cannabis preparations, have become the most

widely used illicit drugs in the world. Ironically, the psychoactive effects that

are responsible for its abuse are the same properties that limit its medical use.

Since 1964 an enormous number of research publications on the chemistry,

pharmacology and behavioral effects and metabolism of both natural and

synthetic cannabinoids have appeared. Efforts have also been directed toward

the design of analogs that may serve as probes for identifying the mechanisms

responsible for the behavioral effects of the cannabinoids.

B. Nomenclature of the cannabinoids

Two different numbering systems for cannabinoids with a dibenzo­

pyran ring appear in the literature (Figure 1).10 Most of the American

publications use the dibenzopyran numbering system while most researchers

in Europe use the monoterpenoid numbering system. In this dissertation,

dibenzopyran ring nomenclature will be used for tricyclic cannabinoids.

4

l' 3'

~LTHC

Dibenzopyran numbering

Figure 1. Numbering systems for THCs

Monoterpenoid numbering

C. Structural and stereochemical requirements for cannabinoid activity

In 1973, Mechoulam and Edery formulated tentative rules for

cannabimimetic structure-activity relationships (SAR)11 based on the results

of pharmacological studies carried out following the identification of the

primary active constituent of cannabis in 1964. Most of these rules were

consistent with the observed SARs for both natural and synthetic

cannabinoids.12 The term "cannabimimetic" refers to cannabinoids that

produce human subjective effects in common with (_)_~9_THC,or that

produce (_)_~9-THC-likeactivity in laboratory animals that parallels the

human activity.13 Some of the commonly used animal behavioral

measures14 for assessing the psychoactive component of cannabinoids are

dog ataxia, spontaneous activity and hypothermia in rats and mice, overt

behavior in Rhesus monkeys and baboons, drug discrimination behavior in

rodents, pigeons or in monkeys, and the mouse ring test. But on the basis of

these tests, it is not possible to quantify the extent of separation of psycho-

5

active and other side effects from therapeutic effects. In more recent

years, synthetic compounds with structures apparently unrelated to

the classical cannabinoids, referred to as nonclassical cannabinoids, have

shown promise in SAR studies.IS Although the structural requirements

for cannabimimetic activity have been reasonably well established, the

stereochemical requirements need further investigation.16 The main

reason for the difficulties in establishing the stereochemical requirements

was that the cannabinoids are very often oily compounds which cannot be

recrystallized and obtained in absolute enantiomeric purity.

Considerable effort has been devoted to the SAR of the cannabinoids

in order to develop agents with a selective spectrum of pharmacological

effects. Depending on the specific structural modifications, potency

differences among compounds were substantial, i.e., ranging from hundreds

of times that of (_)_~9_THC to being completely devoid of cannabimimetic

activity. The dihydropyran-type structure, with a hydroxyl group at CI and

an alkyl group at C3 appeared in most of the psychoactive cannabinoids.

When the dihydropyran ring of ~9_THC was opened and the oxygen was

converted to a free hydroxyl group on the aromatic ring, the bicyclic structure

so obtained was the naturally occurring cannabidiol (CBD, 3a) and was

completely devoid of cannabimimetic activity and most other major activities

characteristic of ~9-THC except anticonvulsant activity.17 However, several

major exceptions have been found. The studies of Wilson and May using the

9-nor-9~-hydroxyhexahydrocannabinol (HHC, 4) and the epimeric 9-nor-9a­

HHC (5) led to research in the nonclassical cannabinoid field.I8 Their

findings demonstrated that both isomers of HHC produced cannabimimetic

activity but only the ~-isomer exhibited enhanced analgesic activity in

6

rodents, with potency equal to morphine.18a,b These results represented a

significant step forward in the search for a nonnarcotic, potent analgesic

structurally unrelated to morphine.

3a Cannabidiol (CBD) 4 Rl = H; R2 = OH

5 Rl = OH; R2 = H

In an attempt to delineate the minimum structural requirements of

HHC needed to produce analgesia, it was found that the dihydropyran ring

of HHC was not necessary for activity,19 For example, the bicyclic analogs

CP-47,497 (6)20 and CP-55,940 (7)21 exhibited potent analgesic activity. A wide

variety of analogs were developed based on this simplified cannabinoid

structure to define the pharmacophore of cannabinoid activity.22a,b In fact,

the tritium-labeled nonclassical cannabinoid CP-55,940 was used to identify a

unique cannabinoid receptor in rat brain membranes.22c Autoradiography of

OH

6 CP-47,497

7

OH

7 CP-55,940

tritiated CP-55,940 binding in brain sections from several mammalian species,

including man, revealed a unique and conserved distribution of the

presumptive cannabinoid receptor.23 Recently, Matsuda and co-workers

have reported their results of cloning and expressing the gene which codes for

the cannabinoid receptor.24

Structure-activity relationship studies revealed that the phenolic

hydroxyl group at Cl has to be free or esterified.25 Blocking of the hydroxyl

group as an ether has led to either elimination or considerable reduction

of activity. It is possible that the esters were actually inactive but undergo

hydrolysis in vivo to the free phenols. Further, it was shown that the

orientation of the lone pairs of electrons on the oxygen plays an important

role in the mediation of at least some of the behavioral effects of the

cannabinoids. Adams and co-workers have reported that the replacement

of the n-pentyl side chain of cannabinoids by higher and branched homologs

significantly increases biological activity.26a The removal of the alkyl

side chain at C3 eliminates pharmacological activity. The optimum

pharmacological activity was achieved with l,l-dimethylheptyl and 1,2­

dimethylheptyl side chains.26b It has also been reported that the 9-methyl

substituent of .18-THC might not be essential for activity. Accordingly,9-nor­

.18-THC was synthesized and its pharmacological activity was evaluated.27

It was found that the profile of biological activity of 9-nor-.18-THC is very

similar to that of .18-THC and the two materials are of equal potency.

The synthesis of natural and synthetic cannabinoid enantiomeric pairs

in high optical purity made possible the comparison of their biological and

pharmacological activities. In most cases, the natural trans-(6aR,10aR)-(-)­

cannabinoids showed significant cannabimimetic activity. In general, the (+)-

8

enantiomers exhibited either no activity or very little activity compared to the

(-)-compounds.28 The high enantioselectivity and the degree of potency

demonstrated for (-)-enantiomers were consistent with the existence of a

specific receptor for the cannabinoids. However, there is evidence to suggest

that some of the pharmacological properties, such as the anticonvulsant

activity of both enantiomers of CBD,29 are produced through nonspecific

membrane interactions.

The recent identification of a cannabinoid receptor in the rat brain22

was a major step forward in the understanding of cannabinoid mechanism(s).

This receptor was shown to be more responsive to the psychoactive

cannabinoids than the nonpsychoactive derivatives. The first successful

photoaffinity receptor probe, 5'-azidO-~8-THC (8) was developed by

Makriyannis and co-workers30 and was used to covalently label the

cannabinoid receptor. The photoaffinity labeling of a receptor provides useful

information on receptor distribution and molecular weights of amino acid

residues at or near the active site. The discovery of the cannabinoid receptor

has also led to a search for its endogenous ligandts). More recently,

arachidonylethanolamide (9), an arachidonic acid derivative in porcine brain,

has been identified as a natural ligand for the cannabinoid receptor.31 This

compound, whose structure is totally unrelated to both classical and

~o (CH2)s,N3

8 (-)-5'-N3-A8-THC

9

<X )CCNHCH2CH20H

9 Arachidonylethanolamide (anandamide)

nonclassical cannabinoids, has been characterized by mass spectrometry and

nuclear magnetic resonance spectroscopy and has been confirmed by

synthesis.

D. Some common natural cannabinoids

Cannabis is a complex mixture of about 426 compounds, including

at least 62 cannabinoids.32 The most important of these cannabinoids are

shown in Figure 2. Among cannabinoids, (-)- ~9-THC (2) is the major

psychoactive component present in the plant with its content ranging from

2-14% among plant varieties. The cannabinoids were defined by Mechoulam

and Gaoni33 "as the compounds unique to the cannabis plant with 21 carbon

atoms, their carboxylic acids, analogs and transformation products." These

exist in several homologous series characterized by side chains containing

I, 2, 3, 4, or 5 carbon atoms. The n-pentyl side chain is by far the most

important followed by the n-propyl sidechain. Naturally occurring

cannabinoids not only occur as neutral substances but also as carboxylic acid

derivatives substituted at positions 2 or 4. (10,11) However, these acidic

cannabinoids are unstable and undergo slow spontaneous decarboxylation to

the neutral form. This process is rapid and complete when the material is

smoked. The concentration of cannabinoids in the plant seems to depend

both on climatic factors and on the botanical variety. It is generally accepted

that the resin of Cannabis sativa grown in temperate climates contains more

cannabidiol (3a) and also probably cannabidiolic acid (3b) and less THe and

cannabinol (13) than the resin formed in subtropical and tropical regions.

10

CsHn

R"

2 R'=R"=H;~9_THC 12 ~8_THC

10 R' = COOH, R" = H; ~9 -THC acid A11 R' = H, R" = COOH; ~9-THC acid B

CsHn

R

~HO

3a R = H; Cannabidiol (CBD)3b R = COOH; Cannabidiolic

acid

OH OH

13 Cannabinol (CBN)

14 Cannabigerol 15 Cannabichromene

COOH

16 Cannabielsoic acid A 17 Cannabifuran

Figure 2: Some of the Representative Natural Cannabinoids

11

E. Metabolism of cannabinoids

The metabolism of (_)-L19_THC (2), (_)-L18_THC (12) and the non­

psychoactive cannabinoid, (-)-CBD (3a) and several other major natural

cannabinoids has been investigated in detail, and numerous reviews are

available.34 The major metabolic pathway for L19_THC when marijuana is

smoked involves cytochrome P-450 catalyzed oxidation at the C-ll position

giving rise to the 11-hydroxy-L19-THC (18).35 This metabolite was first

characterized in 1970 and was shown to have a pharmacological profile very

similar to that of L19-THC.36 Allylic hydroxylation also occurs at C-8 (in 1:!.9_

THC) to give both 8a- and 8~-hydroxy-1:!.9_THCand at C-7 (in L18-THC) to give

7a- and 7~-hydroxy-.1.8-THe. The relative amounts of these stereoisomers

showed marked species specificity. Comparable metabolic pathways are

followed for CBD and other natural cannabinoids. Further oxidation of the

monohydroxy metabolites gives rise either to the carbonyl compound or, in

the case of primary alcohols, to the carboxylic acid. The secondary metabolism

involves glucuronidation of the carboxylic acid to give 19.37 The phenolic

R

18 R:: CH20H20 R= COOH

12

OHn~OHH~O-.l.COOH

O~C""O

19 Glucuronide of 11-nor-1:!.9-THC­9-carboxylic add

glucuronide has also been detected in human urine. The major urinary

metabolite of A9·THC, ll-nor-A9.THC-9-carboxylic acid (20), has received

much attention as an internal reference in a number of immunological

screening tests38 which have been developed to ascertain whether an

individual has used marijuana.

F. Therapeutic potential of cannabinoids and synthetic analogs

Although cannabis preparations have been known to produce

beneficial effects in humans, clinical experiences in the early 1900s using

crude extracts of the cannabis plant were not encouraging. This was mainly

because of the complexity and variability of active constituents of the plant

itself and the different methods of preparation of drug products. In the 1960s

the identification of the active principal component of cannabis and the

widespread usage of marijuana as a major recreational drug led to chance

observations concerning some of the beneficial effects. These observations

together with the historical accounts on the medicinal properties of cannabis

therefore provided an impetus for modern investigations on the effects and

potential therapeutic uses of natural cannabinoids and their analogs.

(-)-A9.THC (2) has a broad pharmacological spectrum consisting of

anticonvulsant, analgesic, ocular hypotensive, bronchodilator and antiemetic

effects in animals and humans.39 Both (-)-A9_THC and the synthetic analog,

nabilone (21),40 demonstrated efficacy and safety as oral antiemetics in cancer

chemotherapy and are commercially available as Dronabinol (Unimed, Inc.)

and Cesamet (Eli Lilly and Company) respectively.41 Very recently, it has

13

been clinically observed that considerably higher doses of ~8-THC (12) can be

given as an antiemetic to children undergoing cancer chemotherapy.42 The

side effects observed in this case were negligible.

o

21 Nabilone

(_)_~9_THC was also evaluated for its antispasmodic and antitremor

effects in patients with multiple sclerosis. Additionally, CBD (3a) was tried

experimentally for epilepsy and, more recently, on patients with other

neurological conditions such as Huntington's chorea and dystonia.1 7b The

fact that CBD lacks cannabimimetic activity and possesses only antiepileptic

effects has made it a very attractive candidate for a potential drug. There are

several other nonclassical cannabinoids, Levonantradol (22),43 (-)-CP 55,940

(7)44 and (-)-HU-210 (23)45 for example, that are being evaluated for their

anticonvulsant, analgesic and cannabinoid receptor binding activities.

Another promising therapeutic area for (_)_~9-THC and possibly some other

analogs, is in the treatment of glaucoma,46 which is one of the leading causes

of blindness in the United States. It is a condition characterized by an increase

in intraocular pressure that progressively impairs vision and may lead to

absolute blindness. The psychoactive properties of (_)_~9-THC and its

14

OH

22 Levonantradol 23 (-)-HU-210

inability to penetrate the human eye when administered topically have been

listed as principal deficiencies associated with the drug. The latter property is

related to the fact that THCs are extremely hydrophobic,47 thus presenting

problems with proper formulation.

It is obvious that the realization of the pharmacological potential of

cannabinoids and their analogs will depend on the ability to eliminate

undesirable psychotropic side effects. There are several recent reports on the

separation of cannabimimetic from therapeutic activity in synthetic

molecules, in particular enantiomers, and this discovery may revitalize the

development of cannabinoid related drugs.

G. Previous synthetic approaches to cannabinoids and analogs

There is a huge body of published research on synthetic efforts directed

toward cannabinoids and their analogs. In reviewing some of the past

synthetic research on these compounds, it will, of course be worthwhile to

emphasize some of the important contributions to this field. The synthetic

15

schemes will be discussed briefly, showing only the key reactions and the

intermediates.

Since the identification of the structure of L\9_THC, many hundreds of

analogs of L\9_THC and of other natural and unnatural cannabinoids have

been synthesized. The motivation for the early synthetic work in this area

was to confirm the structures of metabolites and to provide materials for the

evaluation of biological activity. More recently, the interest in these

compounds was driven by the commercial need for metabolites of L\9-THC as

analytical standards in the calibration of assays for the accurate detection of

cannabinoids in urine. Further, much emphasis has also been placed on

designing analogs that may serve as probes for understanding the

mechanisms responsible for cannabinoid drug action in man. In this regard,

a large number of cannabinoid agonists, active and inactive metabolites, and

related structures have been used to characterize the pharmacology of the

receptor. The development of a novel, easily available radiolabeled

cannabinoid type ligand with very high binding affinity to the receptor is

necessary for further work in this field.

A large number of synthetic procedures for cannabinoids show that

most efforts have been focused on reactions of olivetol (24) with an

appropriately functionalized monoterpene derivative. Some of the

drawbacks encountered in previous syntheses of THCs will be discussed.

Firstly, the conjunction of olivetol with an appropriate monoterpene under

cationic cyclization conditions led to a ca. 1/1 mixture of regioisomers derived

from substitution at both C2 and C4 of olivetol (eq, 1).48 The byproduct, in

which hydroxyl and n-pentyl groups are formally transposed, is often referred

to as the "abnormal" cannabinoid. This lack of regiospecificity compromises

16

the efficacy of the synthesis and would lead to unacceptable loss of material if

expensive labeled olivetol derivatives were utilized.

R

OH+

CsHn

R

"abnormal"

(eq.l)

When the 1',l'-dimethylheptyl analog of olivetol (25) was condensed

with monoterpene derivative 26 using p-TSA in benzene at 45 0C, the

reaction proceeded smoothly to give the cyclized cannabinoid 27 in 43% yield

(eq, 2).49 There was no appreciable formation of the other regioisomer. This

is presumably due to the steric effect provided by the l',l'-dimethyl group,

which suppresses the attack of the resorcinol at C4.

p-TSA

benzene45°C

26 25

17

27 (eq.Z)

The chiral cyclic monoterpenoids which have been used to synthesize

A9_THC include cis and trans-p-mentha-2,8-dien-l-ol,50 (+)-trans-2,3-epoxy­

carane,51 (-)-cis- or (-)-trans-verbenol,52 and (+)-(lR,4R)-p-menth-2-ene­

l,8-dio1. 53 Of these, cis and trans-p-mentha-2,B-dien-l-ol and (+)-(lR,4R)­

p-menth-2-ene-l,8-diol appear to offer advantages in terms of fewer

byproducts in the preparation of A9-THC. It should also be emphasized that

these cationic condensations are promoted by Lewis acids, and their

regiochemical course is critically sensitive to reaction conditions. The

cyclization often results in a mixture of trans- and cis-THCs which are quite

difficult to separate. When the reaction was carried out with cis/trans­

p-mentha-2,B-dien-l-ol and olivetol in strong acids (p-TSA, CF3COOH), the

thermodynamically more stable A8-THC (12) was formed which requires

isomerization54 to A9_THC by the addition and elimination of hydrogen

chloride. These processes thus require three steps and involve at least

two very tedious and careful chromatographic separations. Treatment of

equimolar quantities of cis/trans-p-mentha-2,8-dien-l-ol and olivetol with

1% BF3·Et20 and MgS04 in CH2Cl2 at 0 0C produced A9-THC as the major

product and practically no A8_THC was formed.49 Another interesting

synthesis of (-)-A9_THC was reported by Rickards and Ronneberg,55 wherein

a BF3·Et20 catalyzed arylation of (lS,4R)-p-mentha-2,B-dien-l-yl acetate (28)

with the homocuprate derived from lithiated olivetol dimethyl ether

proceeded efficiently with high regio- and stereospecificity (Scheme 1).

Attempts to effect concomitant demethylation and dihydropyran ring

formation by treatment of 29 with boron tribromide gave a complex mixture

containing A9_THC only in low yield. It was necessary to protect the

terpenoid double bonds from the Lewis acid to obtain A9-THC in good yield.

18

The dihydrobromide 30 was prepared through treatment with a saturated

solution of hydrogen bromide in CHZCIZ at -ZO °C. Surprisingly, when the

reaction was left at room temperature for ca. 5 h, the extremely unstable bis­

bromo adduct 30 underwent monodemethylation and dihydropyran ring

SCHEMEl

rn'~Q

A

OMe

+~MeO .# CsHn

a

28 29

b c---....... ..

30 31

d e-----1.._ ..

Reagents: (a) homocuprate (Z equiv.) of dimethyl ether of olivetol, BF3"EtZO

(3.5 equiv.), ether, -76 °C; (b) HBr-saturated CHZCIZ, -ZO 0C; (c) warm up toroom temperature; (d) BBr3, CHZCIZ; (e) potassium tert-butoxide

19

formation to yield 31 in quantitative yield. It is worthy of note that olivetol

dimethyl ether itself was unaffected by HBr under above conditions, therefore

the formation of 31 was attributed to the crowding of the vicinal substituents

in the dihydrobromide 30. Demethylation was completed by reaction of 31

with boron tribromide to afford 32. The bromide 32 was subjected to regio­

specific dehydrobromination with potassium tert-butoxide to give (_)_~9_THC

in 59% overall yield from the acetate 28.

Another, very ingenious method for overcoming the problem of non­

specific condensation at C2 and C4 of resorcinol has been described by Chan,56

wherein 4-carbomethoxyolivetol (33) was used in place of olivetol (eq. 3). The

aromatic carbomethoxy group blocked the undesired cyclization. However,

the introduction of carbomethoxy group and its subsequent removal from the

product detracts somewhat from the overall efficiency.

a ...

33 55% yield (eq. 3)

Reagents: (a) Anhydrous MgS04, CH2CI2, BF3·Et20, 0 0C, 1.5 h.

A problem often encountered with the purification of cannabinoids is

that these compounds are more often than not difficult to crystallize and are

sensitive to oxidation, particularly in basic media. In recent years, several

additional synthetic strategies for ~9_ and ~8_THC have been reported. These

20

address most of the problems encountered in earlier work. A very elegant

synthesis of 88-THC was reported by Kowalski and Sankar Lal (Scheme 2),57

wherein a Diels-Alder reaction between isoprene and ketoester 34 in the

presence of catalytic Lewis acid (TiCI4) afforded the adduct 35, which was

converted to the silyloxyacetylene 36. The homologation and rearrangement

reaction central to this step proceeded with retention of stereochemistry to

afford the trans- substituted product. Heating a mixture of silyloxyacetylene

and 3-pentyl-cyclobutenone in toluene at 80 0C smoothly gave rise to the

desired resorcinol product 37, which was conveniently cyclized to 88-THC

1261% yield over two steps

CsHll

37

Scheme 2

~+~co,Et a ~C~E1 b ~C=C-OTIPS.. •

~O '1'OTMSIsoprene 34 35 36

93% yield 52% yield

c afIPS d OH• •

Reagents: (a) TiCl4, CH2CI2; (b) MeLi, -98 0C, THF; LiCHBr2; BuLi, RT; TIPSCI;

TMSCI; (c) 3-pentyl-cyclobutenone, toluene, 80 0C; (d) HCI, EtOH.

21

(12). This novel four-step synthesis, proceeding in 29% overall yield from the

ester 34 provides an easy access to ~8_THe.

A recent synthetic approach to ~9_THC involves the condensation of

olivetol with cis-p-menth-2-ene-l,8-diol using p-TSA in CH2C12 to give ring

opened intermediate 38 in 68% yield (Scheme 3).58 The purification of 38 was

achieved through crystallization. It is of interest to note that purification of

this intermediate eliminated most of the byproducts which otherwise

contaminate the target molecule and create separation problems. Subsequent

ring closure of 38 with ZnBr2 in CH2Cl2 in the presence of 3A molecular

sieves afforded ~9_THC (2) in 72% yield.

+o/f'

OHcis-p-menth-2-ene-l,8-diol

SCHEME 3

a

>iHO

OH

HO

3868% yield

b

2

72% yield

Reagents: (a) p-TSA, CH2CI2; (b) ZnBr2, CH2CI2, 3A molecular sieves.

22

In the synthesis of ~9_THC metabolites, it was necessary to identify an

available terpene that would provide the carbon atoms for the C-ring and

would establish the absolute sense of asymmetry in the final product. A

convenient synthesis of (-)-11-nor-A9-THC-9-carboxylic acid (20) was reported

in our laboratory by Tius, Gu and Kerr in 1989.59 The conversion of (+)­

limonene oxide (39) to (R)-(+)-perillaldehyde (40) was accomplished in 4 steps

(overall yield 34%) by Tius and Kerr.60 The diol41 was prepared in 3 steps

from 40 as follows: treatment of 40 with a small excess of TBDMSOTf and

triethylamine in CH2Cl2 at OOC provided the silyl enol ether. The crude silyl

enol ether was treated with m-CPBA in a two-phase mixture of ether and

saturated sodium bicarbonate resulting in the consumption of the starting

material. The unpurified reaction mixture was dissolved in THF, and was

treated with a THF solution of lithium aluminum hydride (LAH) to produce

diol 41 as a mixture of diastereomers which was purified (but not separated)

by silica gel column chromatography. The overall yield of diol41 from 40 was

66%. It was thought that the condensation of olivetol with 41 would proceed

in a manner similar to the reported reaction50 with p-mentha-2,8-dien-l-ol.

In the event, the acid catalyzed condensation of 41 with olivetol under a

c5H

(ICHO

HO

64 steps 3 steps

I~~

A A A39 (+)-Limonene 40 (R)-(+)-Perillaldehyde 41

oxide

23

variety of conditions led to a very low yield of Il-hydroxy-.19-THC (18). The

difference in reactivity between 41 and p-menth-2,8-dien-l-01 was attributed

to the destabilizing inductive effect of the primary hydroxy group upon

the putative cationic intermediate. The acetate 42 obtained from the

monoacetylation of the primary hydroxyl group proved to be a suitable

substrate for the condensation with olivetol (Scheme 4). The conversion of

42 to 43 was accomplished by exposure of CH2Cl2 solution of 42 and olivetol

(24) to freshly distilled BF3·Et20 at 0 oc. The yield of the reaction was ca. 30%.

This material was converted to (-)-11-hydroxy-.19-THC (18) and to the

SCHEME 4

42

COOH

20

24

a

43

18

Reagents: (a) BF3·Et20, CH2CI2; (b) LAH, THF

24

corresponding carboxylic acid 20 in good yield. The shortcomings of this

synthetic route were the lack of regiocontrol during the cyclization step and

the difficulty in obtaining the optically active starting material, (R)-(+)­

perillaldehyde (40), from a commercial source.

A convenient synthesis of racemic d9-cis-(6a,10a)-THC-9-carboxylic acid

has also been accomplished in our laboratory by Tius and Gu in 1989 (eq. 4).61

The key intermediate 44 of the synthetic sequence was treated with TFA in

CHCl3 at 0 0C to produce 45 in 69% yield as a mixture of ring junction

isomers (cis/trans: 6/1). The preferred formation of the cis ring fusion

isomer was attributed to a kinetically controlled intramolecular cycloaddition

of an a-quinone methide.62 Under the mild conditions for this reaction,

acid-catalyzed opening of the dihydropyran ring, followed by reclosing to the

thermodynamically favored trans ring fusion, did not take place.63 It is of

interest to note that the kinetically controlled cyclizations of saturated

cannabinoids, under conditions which preclude ring junction isomerization

through reversible opening of the pyranoid ring, gave rise to trans ring fused

products.62 With C8-C9 unsaturated cannabinoids, the same reaction

conditions produced cis ring fused products.

OTBDMS

44

TFA, CHCl3..

25

45

cis/trans: 6/1 (eq.4)

Continued interest in the synthesis of C9 functionalized cannabinoids

has resulted in several efficient procedures. The problem of regiospecificity

has been addressed elegantly by Huffman and co-workers (Scheme 5)64

wherein the bis-MOM ether of olivetol was lithiated with n-butyllithium and

subsequently was reacted with (+)-apoverbenone (46) to give 47. Allylic

oxidation and rearrangement of 47 gave 48 in excellent overall yield. The

cyclization of 48 was carried out by refluxing in P:TSA in CHCl3 or CHCl3 to

which small amount of ethanol had been added. The yield of 49 was 86%.

When dried CHCl3 (4A molecular sieves followed by distillation) was

CsHn

SCHEMES

00

a b6) .. ...»:CsHn CsHn

46 47 48

0 0s02CF3

C d... ..

49 50

trans/cis = 3/1

Reagents: (a) Lithiated bis-MOM ether of olivetol, THF, 20 0C; (b) PDC,CH2CI2; (c) p-TSA, CHCI3, ethanol, reflux; (d) Li, liquid NH3, THF, then

N-phenyltriflimide.

26

used, the cation obtained by opening of the cyclobutane ring underwent

deprotonation rather than reaction with the phenolic hydroxyl. Therefore,

it is probable that the cation formed during the ring opening is trapped by an

external nucleophile such as ethanol and then undergoes cyclization via an

intramolecular SNI reaction to yield 49. Racemization probably would have

occured through the formation of an achiral enol during the prolonged

heating (ca. 26 h) with acid which was needed to effect rearrangement. The

major disadvantage in this scheme was the non-stereospecific nature of the

reduction of cyclized enone 49 which produced a 3/1 ratio of trans/cis ring

junction isomers. Furthermore, this isomeric mixture was inseparable by

chromatography. The mixture of cyclohexenyl triflate isomers was subjected

to palladium catalyzed carbonylation65 to yield a mixture of diastereomeric

acids. A pure sample of acid 20 was obtained in modest yield through

recrystallization. The problem of racemization in scheme 5 was subsequently

solved by using less stringent conditions (3 equiv. of AICl3 in CH2Cl2 at 22

0C) to afford optically active 53 in 68% yield (Scheme 6).66 However, the

formation of the ring junction isomers during the reduction of double bond

could not be avoided. It is worthy of note that the phenol 52 was obtained

through a nucleophilic ether cleavage of 51 using sodium thiopropoxide.67

The carbon atom at the Cll position was introduced via a one-carbon

homologation reaction on the cyclohexenyl triflate 50.65 Although

cyclohexenyl triflates are promising intermediates for the labeled

cannabinoids, the lack of stereospecificity and the resulting diminution of the

chemical yield does not appeal for such syntheses.

27

o

51

o

SCHEME 6

a

o

52

b

53

Reagents: (a) NaSPr, DMF, 120 OC, 3 h; (b) AICl3 (3 equiv.), CH2CI2.

Lately, attention has been focused on development of improved

synthetic methods for the chiral monoterpenoids68 which could be used in

the condensation reaction with olivetol to afford ~9_THC metabolites. For

example, Razdan and co-workers have reported68a,c an improved and

updated version of work done in 1978.48 However, it is disappointing to

note that these synthetic schemes still use the conventional acid-catalyzed

condensation reaction which gave rise to a substantial amount of the

"abnormal" cannabinoid product.

28

RESULTS AND DISCUSSION

Our synthetic strategy was aimed at a methodology for the ~8_THC and

~9-THCmetabolites that would be short, efficient and general enough to be

applied to cannabinoid analogs as well. The cyclohexenyl triflates

corresponding to ~8_ and ~9_THC were envisioned as potential precursors to

CII oxidized metabolites because these not only avoid the difficult oxidation

step for the conversion of the corresponding ell alcohol and/or aldehyde to

acid, but also might provide access to cannabinoids labeled at CII. It is of

considerable interest to develop a synthetic method that would utilize easily

accessible optically active starting materials and would also eliminate the

formation of regioisomers during the cyclization reaction.

A. Stereo- and regiospecific condensation of olivetol diether with

(+)-apoverbenone

The starting material for the synthesis, (+)-apoverbenone (46), was

prepared from cheap and readily available (-)-J3-pinene (54) according to

Grimshaw's method69 via ozonolysis of (-)-J3-pinene to nopinone (55),

followed by bromination and dehydrobromination. Recently, a more reliable

method for the synthesis of (+)-apoverbenone from (-)-J3-pinene has been

reported by Huffman and co-workers.66

54 (-)-p-pinene

a

AIt:J

55 nopinone

29

o

@46 (+)-apoverbenone

Olivetol (24) was converted to its bis-2-ethoxyethyl ether (56) in 77-80%

yield by treatment with a small excess of ethyl vinyl ether in the presence of

catalytic p-TSA in diethyl ether (eq, 5). The bis-2-ethoxyethyl ether of olivetol

(56) can be deprotonated selectively using n-butyllithium in THF at 25 oc.

OH

p-TSA, EVE...

ether,OOC

OEE

24 56 (eq.5)

The lithiated bis-2-ethoxyethyl ether of olivetol was converted to the mixed

higher-order cuprate by transferring to a solution of lithium-2-thienyl­

cyanocuprate70 in THF at -78 oC. The lithium-2-thienylcyanocuprate solution

was initially purchased from Aldrich Chemical Company and later was

prepared according to the published procedure71 by Lipshutz and co-workers

(Scheme 7). The mixed higher-order cuprate solution was next treated with a

SCHEME 7

osThiophene

n-BuLi / THF...-78 DC, 30 min

O-usCuCN / THF ...

-78 DC ~CUCNLi

RLi / THF / -78 DC 0-'... CuCNU2

R = Bis-2-ethoxyethyl ether S Iof olivetol R

"Mixed higher-order cuprate"

30

THF solution of (+)-apoverbenone and BF3·Et20 (1/1) at -78 0C (eq, 6). The

progress of the reaction can be monitored by tlc, After 2 h, the reaction was

quenched with a solution of saturated NH4CI/NH40H (9/l) and the product

was purified by silica gel column chromatography. The yield of the cuprate

adduct 57 was 66%. Lately, this step has been scaled up in our group to afford

3 g of the cuprate adduct. It is of interest to note that in the absence of

BF3·Et20 there was no appreciable formation of cuprate adduct.

a

AIl1J+46

aEE

56

a

57 (eq.e)

Reagents: (a) Mixed higher-order cuprate (see text), BF3·Et20, THF, -78 0C

The cuprate reaction takes advantage of the steric shielding that steers

conjugate arylation of apoverbenone away from the territory dominated by

the geminal dimethyl substituent. This in turn, determines the ring junction

stereochemistry of the final product. Therefore, it not only provided an

efficient solution to the stereochemical problem but also addressed the lack of

regiochemistry discussed in section G. It should, of course, be emphasized

that the conjugate addition strategy has been used very successfully by others

in the past, for both the synthesis of natural,55 as well as nonclassical

cannabinoids?2 The adduct 57 can be envisioned as a promising precursor to

both ~8_ and ~9_THC series.

31

B. Synthesis of ll-hydroxy-~8-tetrahydrocannabinol

a. Retrosynthesis of ll-hydroxy_~8_THC

An attractive method for the formation of allylic alcohol A in Figure 3,

would be through the rearrangement of the cis- or trans-spiroepoxide. Cis­

spiroepoxide B could be obtained from methylenation of the cuprate adduct C

and trans-spiroepoxide could be obtained from a two-step procedure

involving the epoxidation of the exo-methylene group derived from C.

CsHn

ll-Hydroxy-~8-THe

>

>

cis- spiroepoxide

B

>

o

C

Figure 3. Retrosynthesis of ll-hydroxy-~8_THC.

32

b. Formation of spiroepoxides

Cuprate adduct 57 was converted to cis-spiroepoxide 58 by treatment

with dimethylsulfonium methylide73 in THF at 0 0C (eq. 7). Attempts to

catalyze the rearrangement of 58 with BF3·EtzO in ether afforded a mixture of

products. The IH NMR spectrum of the product mixture indicated the

presence of an aldehyde as the major product. Similar reactivity has been

reported for the cis-spiroepoxide derived from (-)-(3-pinene.74 The

mechanism for the formation of aldehyde can be thought of as a concerted

cleavage of the oxirane C-obond with hydride migration?4

o

57 58 (eq.7)

Reagents: (a) Dimethylsulfonium methylide, THF, 0 oC

Since the desired rearrangement to the allylic alcohol was postulated

to be stereoelectronically favored for the trans-spiroepoxide,75 its synthesis

was undertaken. The bridge bearing the geminal dimethyl group in 57 had

directed the entry of the methylide leading to cis-spiroepoxide 58, so it seemed

logical that epoxidation of an exo-methylene group would provide the trans­

spiroepoxide. Cuprate adduct 57 was treated with triphenylmethylene

phosphorane which was generated from freshly sublimed potassium-tert-

33

butoxide and methyltriphenylphosphonium iodide in ether at ca. 45 oC76 to

produce exo-methylene product S9 in 80% yield (Scheme 8). Since the

epoxide rearrangement required acidic conditions, the acid labile ethoxyethyl

protecting groups were first removed by treatment in methanol with PPTS to

produce resorcinol 60 in 85% yield. Acetylation of the hydroxy groups in 60

was carried out in CH2Cl2 with acetic anhydride and pyridine in the presence

of catalytic DMAP to afford 61 in 80% yield. Exposure of 61 to a two-phase

reaction mixture of m-CPBA in CH2Cl2/ether (1/1) and aqueous saturated

NaHC0377 resulted in 62 as a single diastereomer in 85% yield.

SCHEME8

o

57

a

S9 R=EE)b60 R=H

c

61

...

62

Reagents: (a) tert-BuO-K+, Ph3PCH3+I-, ether, 45 °C; (b) PPTS, methanol; (c)

AC20, pyr., cat. DMAP, CH2CI2; (d) m-CPBA, CH2CI2/etherlsat'd. NaHC03

34

c. Epoxide ring opening to form the allylic alcohol

The rearrangement of 62 was surprisingly challenging, and a number

of reaction conditions which have been used for the epoxide ring opening of

13-pinene oxide were examined?5 Treatment of 62 with HgCl2 in aqueous

acetone,75c or aqueous acetone which had been saturated with C02,75d led to

no detectable reaction. The reaction with WCl6 in THF at -78 0C or with

trichloroacetic acid in 1,2-dichloroethane in the presence of Zeolite A-475b

produced complicated mixtures of aldehydes along with modest quantities

(15-35% yield) of the desired allylic alcohol 63. The best conditions for the

rearrangement of 62 were those disclosed by Delay?5e Exposure of 62 to

ammonium nitrate in nitromethane at 25 0C led to the allylic alcohol 63

(eq, 8). The rather low solubility of the ammonium salt in the reaction

solvent was suspected to be responsible for the slow rate of conversion of

62 to 63, however sonication of the reaction mixture did not result in an

appreciable rate acceleration. Examination of the crude reaction mixture by

1H NMR spectroscopy after 3 days indicated the presence of 63 and unreacted

starting material. The yield of 63 was 35-37% and 8-10% of recovered 62.

In an attempt to improve the yield for this reaction, 62 was converted to

a

62

Reagents: (a) ammonium nitrate, nitromethane, 25 0C

35

63 (eq.B)

monoacetate 64 by exposure to solid powdered potassium carbonate in

methanol at 25 0C in quantitative yield Ceq. 9). Since the reactions of 64 were

similar to those of 62, this avenue was not pursued.

K2CD3, methanol...

62 64 (eq.9)

d. Formation of the dihydropyran ring from triol

Exposure of 63 to methanolic potassium carbonate for 3 h at 25 0C gave

65, which was cyclized conveniently with catalytic p-TSA in benzene at 25 0C

SCHEME 9

63 65

p-TSA, benzene...

36

to produce ll-hydroxy-Li8_THC (66) in 65% overall yield from 63 (Scheme 9).

Comparison of the spectral data for 66 obtained from this sequence of

reactions with those obtained in an earlier synthesis78 of II-hydroxy-Li8_THC

confirmed the structural assignment.

C. Synthesis of (-)-11-nor-Li8-THC-9-carboxylic acid methyl ester79

a. Formation of Li8-cyelohexenyl triflate

The ketone 57 was converted to 67 by consecutive treatment in THF

with KHMDS or LOA followed by phenyl triflimide80 (Scheme 10). The

SCHEME 10

o

57

CsHn

a

67

b ..

68

CsHn

c ..

69

Reagents; (a) KHMDS or LOA, THF, 0 0C then PhN(S02CF3)Z; (b) PPTS,methanol; (c) BF3·EtzO, CHZClZ

37

ethoxyethyl groups in 67 were removed by treatment in methanol with PPTS

at 25 0C to give diol68 in 65% overall yield from 57. The cyclohexenyl triflate

68 was robust, as expected, and exposure to a solution of excess BF3'Et20 in

CH2Cl2 produced 69 in 87% yield following flash column chromatography

on silica gel. The reaction proceeded smoothly and progress was easily

monitored by tIc. Transposition of the double bond during cyclization led

specifically to the ~8-series. This cyclization reaction is without precedent and

is undoubtedly a stepwise process which is facilitated by the relief of ring

strain attending the cleavage of the four-membered ring.

b. Palladium catalyzed carbonylation of ~8_cyclohexenyI triflate

The one-carbon homologation of cyclohexenyl triflate was carried out

with a solution of 69 in methanolic THF with 10 mol% of PdCI2(PPh3)2,

potassium carbonate and a static atmosphere of carbon monoxide at 25 oC,81

to give methyl ester 70 in 72% yield as a crystalline solid (mp 142 0C)

following flash column chromatography (eq. 10). In preliminary experiments

to optimize the palladium-catalyzed carbonylation reaction, a strongly UV­

absorbing byproduct was obtained when the ratio of THF-methanol was 6:1.

a ..

69 70 (eq. 10)

Reagents: (a) PdCI2(PPh3)2 10 mol%, K2C03, CO, methanol, THF, 25 oC

38

This byproduct was assigned oxalate structure 71 based on spectroscopic

evidence. No attempt was made to optimize the formation of 71. When the

proportion of methanol in the solvent mixture was reduced, 70 was the only

CsHn

71

product observed. The ester 70 has been conveniently hydrolyzed by

Schwartz and Madan82 using methanolic aqueous NaOH to afford ll-nor-.18­

THC-9-carboxylic acid (72) in quantitative yield (eq, 11). The spectroscopic data

reported therein for Il-nor-.18-THC-9-carboxylic methyl ester is consistent

with that obtained for 70 through this synthetic scheme. Alternatively,

through the use of ammonium formate in the palladium-catalyzed reaction,

acid 72 can be prepared directly from 69.65

CCXXH3 COOH

OH NaOH, methanol..H2O

CsHn CsHn

70 72 (eq.Tl)

39

D. Synthesis of (-)-11-nor·~9·THC acid methyl ester methyl ether 83

a. Retrosynthesis of 11-nor-~9-THC-9-carboxylic acid

Our synthetic strategy for the 8,9.THC metabolites involved the 8,9­

cyclohexenyl triflate (A) as a potential precursor. There are two approaches to

the formation of subunit A (Figure 4). The first was through the regiospecific

enolization of cyclized ketone B (X =H) leading specifically to the 8,9-series.

Cyclic ketone B can be envisioned to arise from the cationic cyclization of

resorcinol C (X = H) which in turn can be prepared through the use of a mixed

higher-order cuprate as described in Section I. Since the ~8_ cannabinoids

represent the thermodynamically more stable isomer series,84 it was evident

that the formation of the 8,9-enolate with specificity would be difficult.

~oA

>

o

>

B

o

~xD

OR

Figure 4: Retrosynthesis of ~9-cyclohexenyl triflate

40

However, the apparent simplicity and directness of the approach suggested

that enolization of B (X =H) was worth examining under both kinetic and

thermodynamic enolization conditions. The second was to utilize a

heteroatomic substituent (X =halogen, alkoxy) at CI0 of ketone B as a control

element to generate the unsaturation leading to the A9-series. The

substitution at CI0 could be introduced either through the use of the

substituted apoverbenone (0; X =halogen, alkoxy) in the cuprate reaction or

by intercepting the enolate formed from the apoverbenone (0; X =H) with a

heteroatomic electrophile.

b. Formation of (-)-11-nor-9-ketohexahydrocannabinol

Hydrolytic cleavage of the ethoxyethyl groups in the cuprate adduct 57

was carried out with PPTS in methanol to afford 73 as a single isomer in 78%

yield?9 Treatment of 73 with stannic chloride in anhydrous CHCl3 at 25 0C

produced optically active ketone 74 in 72% yield (eq, 12). These conditions

are analogous to those described by Archer and co-workers in the synthesis

of nabilone (21).40a In Archer's report, the conjunction of substituted

o

73

..o

74 (eq.12)

resorcinols with (+)-apoverbenone was accomplished under acidic conditions.

Phenol functionality in 74 was protected either as the ethoxyethyl ether (EVE,

41

cat. p-TSA, ether) or as the tert-butyldimethylsilyl ether (Imidazole, DMF,

TBDMSCl). The enolization of these two protected ketones with variety of

bases (LDA, KHMDS, Et3N, diisopropylaminomagnesium bromide, 2,4,6­

trimethyl pyridine) followed by trapping the enolate either as the silyl ether

or as the triflate in all cases resulted in L\8-enol ether with no detectable

formation of the L\9-isomer.

c. Mixed higher-order cuprate reaction with a-bromoenone

Attention was next focused on the alternative strategy for the 8 9­

cyclohexenyl triflate. (+)-Nopinone (55), readily obtainable in large quantities

by ozonolysis of (-)-~pinene, was brominated with excess NBS in CCl4 at

75 0C in the presence of catalytic benzoyl peroxide (Scheme 11).69 Bis-bromo­

nopinone (75) was formed along with mono-bromonopinone as a 3:2 mixture

and was separated by flash column chromatography on silica gel. The

dehydrobromination was carried out in DMF with lithium carbonate and

lithium bromide at 130 oC85 to afford the n-bromoenone 76 as pale yellow

SCHEME 11

0 o B 0

tlfB' b ~B'fiJ a"1'1l' ~ T ~

55 Nopinone 75 76

Reagents: (a) NBS,cat. (PhC02)2, CC14, 75 0C; (b) Li2C03, LiBr, DMF, 130 °C

42

crystals in 76% yield. Attempts to carry out the dehydrobromination reaction

with DBU in CH2Cl286 and potassium tert-butoxide in THF at varying

temperatures resulted in a mixture of products and a lower yield of 76.

The initial synthetic strategy envisioned that the ethoxyethyl ether

would serve as a protecting group for olivetol during cuprate addition. Regio­

specific lithiation of olivetol bis-2-ethoxyethyl ether with n-butyllithium in

THF at 22 oC79 followed by transfer to lithium-2-thienylcyanocuprate70 in

THF at -78 0C afforded the mixed higher-order cuprate solution. After 1.5 h

at -78 oe, cuprate solution was treated with 76 and BF3·Et20 (1/1) in THF to

furnish 77 in 55-60% yield (Scheme 12). The 1H NMR spectrum of 77

indicated a mixture of diastereoisomers, due to the asymmetric center on

each of the ethoxyethyl ether protecting groups. Hydrolytic removal of the

ethoxyethyl ether with catalytic PPTS in methanol produced resorcinol 78

SCHEME 12

o

~Br OEE

76 I

"Mixed higher-ordercuprate"

o

o

77

PPT5, methanol

78

43

as a single isomer in 90% yield. Attack of the cuprate took place trans to the

geminal dimethyl bridge, which was confirmed by reduction of the bromine

substituent in 78 with sodium dithionite (Na2S204) in aqueous DMP87 to

yield 73, with known stereochemistry. The chemical shift assignments of

the protonated carbons in compound 78 were made using 2D NMR (HMQC,

HMBC) techniques. It was interesting to note that the proton on the carbon

bearing the bromine substituent was highly deshielded (0 = 6.30 ppm),

and was coupled to the benzylic proton at 0 4.28 ppm (d, J=8.7 Hz).

The magnitude of the vicinal coupling constant suggests a trans diaxial

relationship between these protons.

d. Attempted cyclization of the bromo ketone

The next phase involved the cyclization of 78, the crucial step in the

synthetic sequence. A number of methods were investigated to effect

cyclization of 78 unsuccessfully, including treatement with stannic chloride in

CHCl340a or aqueous CH2CI2, BP3·Et20 in CH2C12,40a perchloric acid in

aqueous trifluoroethanol, lithium perchlorate in ether88 and zinc bromide in

ether in the presence of lithium bromide. These conditions resulted in no

detectable reaction at lower temperatures (-780C to 22 DC) and partial

o

78

._-------- ....

44

o

l

decomposition of 78 at elevated temperatures (60 0C to 110 0C). When the

reaction was carried out with excess TiCl4 in CHCl3 at 60 0C, 79 was isolated

as the major product in 42% yield (unoptimized). The stereochemistry of

the dihydrofuran derivative 79 was established through n.O.e experiments.

Attempted cyc1ization of 78 with p-TSA in CHCl3 in either ethanol64 or

methanol provided the corresponding ketals 80 and 81 in good yield. These

ketals could not be converted to the cyclized ketone with stannic chloride in

CH2CI2, although the conversion of the corresponding non-halogenated

cannabinoid methyl ketal to the cyclized ketone with cis ring junction hac;

been reported.40a Apparently the electronic effect of the bromine substituent

adversely influences the cationic cyclization process.

o

79

CsHn

80 R =Et

81 R =Me

OR

The electrophile-initiated cyclobutane ring cleavage of 3-methyl

nopinone has been carried out with iodotrimethylsilane.89 When 78 was

treated in acetonitrile with iodotrimethylsilane in the hope of cleaving the

cyclobutane ring, a facile reduction of the bromine substituent took place

instead, giving rise to 73 (eq, 13). This type of reduction of a halogen

45

substituent a to the keto group is well precedented.90 Cyclobutane ring

opening of 3-methyl-nopinone has been achieved by Yoshikoshi and

co-workers91 using BF3·Et20 in the presence of zinc acetate in acetic

anhydride. Treatment of 78 with similar reaction conditions led to acetylation

of the hydroxyls on the aromatic ring.

o

78

TMSI/CHCI3

o

73 (eq.13)

e. Formation of the a-alkoxyenones

The difficulties encountered with 78 suggested that an e-alkoxy

substituent be examined. The formation of 1,2-diketones via ozonolysis of

a-hydroxymethylene ketones is precedented.92 Treatment of (+)-nopinone

with ethyl formate and sodium hydride in ether in the presence of catalytic

ethanol produced the salt of the a-hydroxymethylene ketone93 which was

acidified carefully with IN HCI and extracted with ether to afford 82 in 73%

yield (Scheme 13). Ozonolysis of 82 in CH2Cl2:pyridine (vIv 1:1) at -78 0C

gave a bright yellow solution which was treated with methyl sulfide to afford

83 in 56% yield. Enones 84 and 85 were prepared from 83 by trapping the

enolate formed with potassium tert-butoxide in THF at -50 0C with methyl

iodide and acetic anhydride respectively. The cuprate addition to enone 84

was first studied using methyl homocuprate and mixed cyanocuprate in ether.

46

SCHEME13a

o~OR

~b

o

Cv°It:J

a~OH ~

82 83 84 R= CH3

85 R=COCH3

aReagents: (a) 03, pyridine:CH2CI2, -78 0C then (CH3)2S; (b) K+ -OBut, THF,-50 0C then CH31 to give 84 or (CH3CO)20 to give 85

These studies revealed that prior activation of the enone 84 with TMSCI was

necessary to effect complete addition of the cuprate. On the other hand, the

enone 85, which would serve as a better Michael acceptor than 84, underwent

reaction with the methyl cuprates in the absence of any Lewis acids. However,

the mixed higher-order cuprate reaction of bis-2-ethoxyethyl ether of olivetol

with either 84 or 85 was unsuccessful even in the presence of monodentate

and bidentate Lewis acids such as boron trifluoride etherate or stannic

chloride, respectively.

f. Reevaluation of the retrosynthesis

These failures prompted a rethinking of the chemistry outlined in

Figure 4. Ketals 80 and 81 presumably arise from intramolecular attack of the

phenolic oxygen on the carbonyl carbon. To avoid the ketal formation, it was

therefore necessary to use an oxygen protecting group on olivetol which

would be robust enough to survive the acid-catalyzed conditions for the

cleavage of the cyclobutane ring of the cuprate adduct. 5,-(2H3)-Olivetol

47

- - ._--------------_._-

dimethyl ether (86)94 was metalated with n-butyllithium in THF at Z5 0C and

was converted to the mixed higher-order cuprate as before,79 by transferring

to an equivalent of lithium-Z-thienylcyanocuprate in THF -78 oc. The

cuprate solution was next treated with a solution of e-bromoenone 76 in the

presence of BF3·EtZO (1/1) in THF to produce 87 in 83% yield (eq, 14).

0 0

~r&'" I" OCH3 a

~..

CD3 CD3

86 87 (eq.14)

Reagents: (a) Mixed higher-order cuprate, BF3·EtZO, THF, -78 oC

g. Stereospecific ring opening of cuprate adduct

The stereospecific ring opening of 87 was carried out with excess I,Z­

bis(trimethylsilyloxy)ethane in CHZCIZ at ZZ 0C using an equivalent of

TMSOTf to give 88 in 65% yield (eq, 15). When the reaction was carried out

with catalytic TMSOTf,95 initial ketalization took place, followed by

oa

1\o 0,Br

", OCH3

87 88 (eq.15)

Reagents: (a) I,Z-bis(trimethylsilyloxy)ethane, TMSOTf, CHZCIZ

48

cyclobutane ring opening to 88 upon addition of more TMSOTf. A related

rearrangement of a pinane with ethylene glycol and p-TSA in benzene at

100 0C has also been reported.96 Exposure of 87 to these conditions produced

traces of 88. It is worthy of note that ketalization and cyclobutane ring

opening of a-bromonopinone (89) formed 2-brom0-4-isopropylidene

cyclohexan-l-ethylene ketal (90) exclusively; none of the isopropenyl isomer

could be detected. The formation of the isopropenyl substituent in the case

o

e' Br.,-'".k-..

89

90

of 88 is due to a stereoelectronic effect by the aryl substituent at C4: in the

carbocationic intermediate 91, the steric bulk of the aryl group prevents

the alignment of the 2p orbital on C6 with the C6a-H bonding orbital.

Consequently, proton loss takes place from the methyl group in 92, leading to

the isopropenyl group of the product.

91

R -...-- •

49

92

R

h. Regiospecific formation of the cyclohexenyl triflate followed by Palladium­

catalyzed carbonylation

Hydrolysis of ketal 88 with 50% aqueous perchloric acid in acetone97 at

40 0C gave ketone 93 in 66-71% yield (Scheme 14). Formation of the double

bond corresponding to the /i.9_THC series was achieved through the reductive

debromination of 93 with lithium dimethylcuprate in ether98 at 0 0C

followed by trapping of the enolate with N-phenyltriflimide in freshly

distilled DME to produce 94 in 75-81% yield. Palladium-catalysed

carbonylation of 94 gave the methyl ester 95 in 80% yield.65

SCHEME 14

1\o 0.Br••, OCH

3

88

a ..o

93

b ..

94

Reagents: (a) 50% aqueous HCI04, acetone; (b) lithium dimethylcuprate,

ether, 0 0C, then N-phenyltriflimide, DME, 0 0C; (c) Et3N, Pd(OAc>2,

triphenylphosphine, methanol, DMF, CO.

50

i. Attempted cleavage of methyl ether

The next task was to cleave the methyl ether groups in 95 and form

the dihydrobenzopyran ring. As anticipated, cleavage of the methyl ester to

the corresponding carboxylate took place rapidly. When 95 was fused with

pyridine hydrochloride at 200 0C, a clean reaction took place leading to 96, the

carboxy analog of cannabifuran. Other reaction conditions for the cleavage of

the methyl ether groups, such as boron tribromide in CH2Cl2 at -78 0C

followed by warming to 0 0C were accompanied by isomerization of

isopropenyl to isopropylidene. Attempted cleavage of the methyl ether

of 88 with sodium thioethoxide in DMF at 120 oC67 gave only the

dihydrobenzofuran derivative 97 and 98. The stereochemistry of these

dihydrobenzofuran derivatives was established by n.O.e experiments.

COOH

96 97 R=H98 R= CH3

j. Formation of benzopyran ring and carbonylation of cyclohexenyl triflate

Cyclohexenyl triflates are chemically robust, and it was gratifying to

note that 94 was a suitable substrate for the demethylation and cyclization.

Treatment of 94 with excess iodotrimethylsilane99 (purchased from Aldrich

Chemical Co.) in anhydrous CHCl3 at 22 oC, followed by purification by flash

51

column chromatography, gave a mixture of trans (99) and cis stereoisomers

in the approximate ratio of 17:1 (by IH NMR spectral integration of the

proton at CI0) in 47% yield (Scheme 15). The vinylic proton at CI0 for the

trans- stereoisomer appeared at 8 6.78 ppm, whereas in the cis-stereoisomer it

is slightly shielded (8 =6.65 ppm). Attempts to improve the yield using

various methods for in situ generation of iodotrimethysilane, such as

sodium iodide or lithium iodide and trimethylchlorosilane in acetonitrile,

allylsilane100 or hexamethyldisilane101 and iodine, gave either lower

yields of 99 or a higher percentage of the cis stereoisomer. The cis isomer

probably arises from add-catalyzed isomerization of the isopropenyl to the

isopropylidene followed by cyclization. The major reaction byproduct,

SCHEME 15

...

99

b ...

101

Reagents: (a) iodotrimethylsilane, CHCI3, 220C; (b) Et3N, Pd(OAc)2,

triphenylphosphine, methanol, DMF, CO

52

5,_(2H3)olivetol dimethyl ether (86), presumably arises from initial transfer of

a proton to the electron-rich aromatic ring of 94, followed by carbon-carbon

bond cleavage with generation of allylic carbocation 100. It is interesting that

the presence of the electron-withdrawing triflate group on 94 is not sufficient

100

to inhibit this cleavage reaction. Both the side reaction leading to 86 as

well as the cyclization to 99 apparently require catalysis by ill because the

conversion of 94 to 99 did not proceed when iodotrimethylsilane was used in

the presence of an acid scavenger, such as pyridine or methylcyclohexene, or

when excess allylsilane or hexamethyldisilane and iodine were used to form

iodotrimethylsilane in situ. Cyclohexenyl triflate 99 and the cis isomer were

treated with carbon monoxide and methanol under palladium catalysis to

afford trans- (101) and cis- unsaturated methyl esters in 82% combined

yield.81 The trans isomer was separated and purified by HPLC (Phenomenex

Ultracarb 5 ODS 30 column, 250x10 mm, flow rate 2.5 ml/min, methanol).

The specific rotation for 101 was [a]21D =-2370 (c =0.005 glml, ethanol) and

the 1H NMR spectral data closely paralleled those of the racemic,

undeuterated 101 reported earlier.64 The benzylic proton at C10a in 101

appeared at B3.31 ppm as a doublet of doublets (J =11.4, 1.5 Hz), as expected

for a trans relationship of the C6a and C10a protons.

53

E. Synthesis of halogenated cannabinoids102

The discovery of the non-classical cannabinoids and the early

recognition of their activities have shed light on the structural requirements

for activity. The essential features associated with pharmacological activity

appear to be the aromatic ring, an unsubsitituted phenolic hydroxyl group,25

the n-pentyl or 7 carbon aliphatic side chain with small alkyl groups at l' and

2' positions26 and a B/C trans ring fusion.l 03 The substitution of the C ring

with hydroxyl groups has also resulted in enhancement of activity.104

However, there is very little information on the synthesis of halogen

substituted cannabinoids or the effect of halogen substitution on cannabinoid

activity.105 Very recently, the pharmacological activities and relative

cannabinoid receptor site(s) binding affinities of (_)_L\8_THC analogs with a

halogen substituent at Cll and C5' have been described.105c Another analog

with a 18p substituent at the C5' has been used to study the biodistribution of

cannabinoids in primate brain by positron emission tomography (PET).l06

Because of the low binding affinity of (-)-5d 8p-L\8_THC (102), the PET

experiment was unable to distinguish between the specific and the non­

specific binding sites for cannabinoids. Further, (-)-2-iodo-L\8-THC (103)

102 X =18p

54

x

103

was found to be an interesting probe which exhibited the greatest separation

between antinociceptive and sedative cannabinoid properties.105c The

presence of a hydroxy group either at C9 or at Cll in the C ring is a significant

feature in determining the activity.104 Therefore, it would be useful to

prepare halogen substituted THC derivatives because unlike the oxygen

substituted cannabinoids, in which the hydroxyl can act as a donor or an

acceptor of a hydrogen bond, halogens act only as hydrogen bond acceptors.

The steric and electronic effects of halogen substitution on cannabinoid SARs

can be dissected by using fluoro- and iodo substituents.

It should be pointed out that some of the reactions in the synthesis of

halogenated cannabinoids, namely the formation of 106 and 108 from 104,

the reduction of ketones 104 and 116 to yield their respective alcohols 109

and 117 and fluorination reactions using methyl-DAST were carried out by

Dr. Michael A. Kerr of this group.

a. Bis-fluorination of ketones using methyl-DAST

The fluorination of ketones and alcohols with dialkylaminosulfur

trifluoride (DAST) and its analogs is well precedented.107 Therefore, (-)-11­

nor-9-keto-hexahydrocannabinol (74) was an ideal starting material for 9­

fluoro-hexahydrocannabinol analogs. The phenolic hydroxyl in 74 was

protected as the acetate (pyr., cat. DMAP, acetic anhydride, CHZCIZ) to afford

104 in 83% yield (Scheme 16). Treatment of 104 with excess dimethylamino­

sulfur trifluoride (methyl-DAST) in CHZCIZ under nitrogen at ambient

temperature for Z days afforded bis-fluoride 105 in excellent yield along with a

trace of vinyl fluoride. Acetate hydrolysis in 105 with potassium carbonate in

methanol at 22 0C gave 106 in 80% yield. The 13C NMR spectrum of 106

55

SCHEME 16

o

CsHn

b

CsHn

74 R=H )104 R = COCH3 a 105 R=COCH3 ) c

106 R=H

Reagents: (a) pyr., cat. DMAP, AC20i (b) methyl-DAST, CH2CI2, 22 0C, 2 days;

(c) K2C03, methanol.

proved interesting. Fluorine-bearing carbon C9 at 3 =123.6 ppm, showed

not only the expected coupling to the fluorine atoms (t, J = 240.7 Hz) but also

two- and three-bond coupling to C8, CI0 (t, J = 24.4 Hz) and C7, CI0a (d, J=10.4

Hz) respectively. Examination of Drieding models indicated that both C7 and

CI0a form dihedral angles of 1800 and 900 with the equatorial and axial

fluorine respectively. This observation proved to be useful for the

assignment of stereochemistry at C9 for monofluoro hexahydrocannabinols.

b. Formation of vinyl-fluoride from bis-fluoride

The formation of trace amount of vinyl fluoride 107, during the

bis-fluorination of ketones was presumed to occur through the loss of an

a-hydrogen from the fluoro-carbocation. Therefore, the use of polar solvents

was expected to stabilize the polar fluoro-carbocation intermediate which

would eventually increase the yield of vinyl fluoride. However, all attempts

56

..F

105 107 R=COCH3108 R=H (eq.16)

to increase the ratio of vinyl fluoride 107 to 105 during the fluorination of 104

by using a polar solvent, such as THF, DME or N-methylpyrrolidone were

unsuccessful. Therefore, a two step procedure for the synthesis of 107 was

envisioned. Elimination of hydrogen fluoride from 105 using neutral

activated alumina at 120 0C in a sealed tube108 for two days afforded vinyl

fluoride 108 in 37% yield (eq, 16). It should be noted that hydrolysis of the

acetate also took place during the elimination reaction. The formation of the

~8-isomer is not surprising as it is thermodynamically more stable than the

~9-isomer.84

c. Formation of 9-nor-9a.-fluoro-hexahydrocannabinol

In order to prepare 9-nor-9a.-fluoro-hexahydrocannabinol (112), ketone

104 was reduced with sodium borohydride in a 9:1 mixture of THF and

o

104

NaBH,l'22°C..THF : isopropanol

(9:1)

57

109

CsHn

(eq.17)

isopropanol at 22 0C to afford 9-nor-9J3-hydroxy-hexahydrocannabinol (109) in

80% yield (eq. 17).27 Fluorination of the alcohol 109 with methyl-DAST in

CH2Cl2 at -78 0C gave 42% yield of the desired axial monofluoride acetate

110 along with 21% of alkene 111 (Scheme 17).109 The hydrolysis of 110

with potassium carbonate in methanol produced phenol 112 in 88% yield.

SCHEME 17

CsHn

a

H

CsHn

109 110 R=COCH3 ) b112 R=H

111

Reagents: (a) methyl-DAST, CH2Cl2, -78 0C; (b) K2C03, methanol.

The stereochemistry at the fluorine-bearing carbon in 112 was determined by

examination of the 19p spectrum which showed vicinal coupling to each of

the trans diaxial hydrogens. Futhermore, the absence of 3-bond coupling of

C7 and C10a to the fluorine atom in the 13C NMR spectrum is consistent with

an axial fluorine substituent. Attempts to synthesize the other isomer, 9-nor­

9J3-fluoro-hexahydrocannabinol, from 9-nor-9a-OH-hexahydrocannabinol

acetate using methyl-DAST under identical conditions resulted in a mixture

of products. Studies have shown that cyclic alcohols which possess an axial

hydroxyl group and a neighboring anti-periplanar hydrogen often undergo

58

facile elimination reactions and/or rearrangements to give rise to a mixture

of products.110

d. Formation of 3-[4-pentyl-2,6-bis(acetoxy)phenyl]-4-isopropenyl-cyclohexan­

1-one and attempted fluorination with methyl-DAST

Bicyclic C9 halogen substituted cannabinoids were the next targets for

synthesis. Ketone 114 was obtained from the reaction between racemic enone

113 and the mixed higher-order cuprate derived from the bis-2-ethoxyethyl

ether of olivetol (56) and lithium-2-thienylcyanocuprate (Scheme 18).70

SCHEME18

0 0

6 OEE a

+~..

I"A AEEO ~ CsHn CsHn

EEO

113 56 114

RO

b c.. ..CsHn A CsHn

CH3COO

115 116

Reagents: (a) mixed higher-order cuprate, THF, - 78 0C; (b) p-TSA, wet THFto form 115 (R =H); (c) pyr., cat. DMAP, AezO

59

Enone 113 was prepared from commercially available racemic perillaldehyde

according to Razdan's procedure.68c The fluorination of 114 with methyl­

DAST was not successful, perhaps due to the acid-labile ethoxyethyl ether

protecting groups. Hydrolysis of the ethoxyethyl ether groups with PPTS in

methanol gave the methyl ketal (115; R =CH3) cleanly. The use of catalytic

p-TSA in wet THF gave the hemiketal (115; R =H) which was subsequently

rearranged and protected using pyridine and acetic anhydride in CH2Cl2 in

the presence of catalytic DMAP to afford bis acetate 116 in 80% yield. The

formation of the hemiketal, though unexpected, was not surprising as

such acid catalyzed reactions are known. 83 Fluorination of 116 with methyl­

DAST failed to give the desired geminal difluoride. Instead, a complicated

mixture was produced from which no identifiable products were isolated.

Fluorination of the alcohol 117 which was obtained from the reduction of 116

with sodium borohydride afforded only 9% of monofluoride 118 with an

approximately equal amount of the elimination product 119 (eq. 18).

H

a .. +

»< CsHn CsHn.A CsHn

CH3COO CH3COO CH3COO

117 118 119 (eq.18)

Reagents: (a) methyl-DAST, CH2CI2, -78 °C.

60

e. Formation of vinyl stannanes

The difficulty which we encountered in our attempts to prepare these

fluoro analogs in acceptable yield, and the limitations of methyl-DAST as

a fluorination agent for these systems, provided the impetus for the

development of a mild alternative method for the introduction of fluorine.

Exposure of vinyltrimethylstannanes to xenon difluoride in the

presence of silver(I) salts leads to the rapid, stereospecific replacement of tin

by fluorine.111 Recent work in our laboratory by Tius and Kawakami has led

to significant improvement in the yield of this process. This methodology

appeared to be ideal for the synthesis of fluorovinyl cannabinoids. Treatment

of ketone 114 with LDA in THF at 0 0C followed by N-phenyltriflimide in

freshly distilled DME gave cyclohexenyl triflate 120 (Scheme 19).80 The

position of the double bond was determined by 2D-NMR (HMQC, HMBC)

correlations. Hydrolytic cleavage of the ethoxyethyl protection groups with

PPTS in methanol afforded 121 in 57% overall yield from 114. Palladium(O)

SCHEME 19

CsHnARO

120 R=EE)121 R=H a

b ..

ARO

122 R=H ) c123 R=COCH3

Reagents: (a) PPlS, methanol; (b) anhydrous Li2C03, LiCI, cat. (PPh3)4Pd,

hexamethyldistannane, THF, 60 0C, 12 h; (c) pyr., cat. DMAP, AC20, CH2CI2.

61

catalyzed stannylation of the cyclohexenyl triflate 121 with hexamethyl­

distannane in the presence of lithium carbonate and lithium chloride

produced 122 in 73% yield,112 The phenolic hydroxyls in 122 were protected

as the acetates to give 123 in 65% yield.

f. Fluorination of vinyl stannanes

The conversion of vinyl stannane 123 to vinyl fluoride 124113 was

carried out with silver triflate formed in situ from silver carbonate and

trifluoromethanesulfonic acid (triflic acid),114 and xenon difluoride in

CH2Cl2 at 22 0C (Scheme 20).115 Fluorination was fast (ca. 3 min) and gave

rise to a mixture of vinyl fluoride 124 and alkene (5:1 ratio) respectively. The

separation of 124 from alkene using flash column chromatography on

silica gel was difficult. Separation of the free resorcinols was much easier.

Hydrolysis of the acetates in the mixture followed by purification using flash

column chromatography produced 125 contaminated with traces of alkene in

SCHEME 20

CsHn

a

F

ARO

124 R=COCH3 )125 R=H b

Reagents: (a) XeF2, Ag2C03, triflic acid, CH2CI2, 22 0C; (b) K2C03, methanol.

62

57% overall yield. The fluorination of 122 took place in lower yield (ca. 30%),

and the product mixture in this case contained a number of polar byproducts.

Nonetheless, the remarkable fact that 125 could be isolated from the reaction

demonstrates the utility of the method. The survival of the electron rich

resorcinol in the presence of xenon difluoride is unusual and testifies to the

mildness of the method.1 16

g. Formation of (-)-9-fluoro-~8-THC

This methodology was next applied to 69 (Scheme 21). Stannylation of

69 and protection of the phenolic hydroxyl as the acetate gave 127 in 60%

overall yield from 69. The fluorination of 127 using xenon difluoride in the

SCHEME 21

69

CsHn

F

a

126 R=H ) b127 R=COCH3

c ...

128

Reagents: (a) Li2C03, LiCI, hexamethyldistannane, cat. Pd(PPh3)4 THF,60 0C, 12 h; (b) pyr., cat. DMAP, AC20; (c) XeF2,Ag2C03, triflic acid, CH2CI2.

63

presence of silver carbonate and trifluormethanesulfonic acid in CH2Cl2

followed by hydrolysis gave (-)-9-fluoro-L18-THC (128) and the corresponding

alkene as a 5:1 mixture in 62% yield.

h. Formation of vinyl iodo cannabinoids

Vinyl stannanes 122 and 126 are excellent starting materials for the

preparation of vinyl iodides via a metal halogen exchange. Treatment of

vinyl stannanes 122 and 126 separately with a dilute solution of iodine in

CH2Cl2 at 0 °C gave rise to 129 (78% yield) and 130 (83% yield) respectively.

I

A.-HO

129

I

130

F. Anti-inflammatory activity of several cannabinoids

Burstein has suggested that (-)-11-nor-L19-THC-9-carboxylic acid (20)

may act as a non-steroidal anti-inflammatory agent.117 In order to learn

whether other C9-functionalized cannabinoids share this activity, and in

particular whether the halogenated analogs act as anti-inflammatory agents,

several were evaluated in the mouse ear edema assay.lIB The mouse ear

edema assay was performed by Ms. Krista J. S. Grace in Prof. Jacob's research

group, at University of California, Santa Barbara. The results are summarized

in Table 1, and confirm that (-)-11-nor-L19-THC-9-carboxylic acid (20) is in fact

64

eOOH

131

active. It is interesting that 131,119 the enantiomer of 20, was active at

approximately same level. This insensitivity to molecular chirality may

suggest the cell membrane as the drug target, rather than the cannabinoid

receptor which would presumably discriminate between the two enantiomers.

Iodo cannabinoid 129 also showed appreciable activity in this assay.

Table 1. Effect of Topical Application of Various Cannabinoid Analogs onPhorbol-12-myristate-13-acetate-induced Edema of the Mouse Eara

Compound

20

131

130

112

106

129

Percent Inhibition of Inflammation

52%

69%

15%

17%

19%

45%

a Compounds were topically applied in acetone to the inside pinnae of the ears of mice in asolution containing phorbol-12-myristate-13-acetate (PMA). PMA alone (2Ilg/ear) or incombination with 50 Ilg/ear of test compound was applied to the left ears and acetone wasapplied to all right ears. After 3 hours 20 minutes incubation, the mice were sacrificed, the earsremoved, bores taken and the difference in weight between the two ears recorded. Per centinhibition of inflammations relative to the PMA control were calculated and the mean valueswere based on 5 mice.

65

CONCLUSION

In conclusion, the design and execution of new synthetic approaches to

several cannabinoids and analogs have been described. The key step in these

synthetic schemes is the conjunction of olivetol ether with the appropriate

monoterpene using a mixed higher-order cuprate reaction. Some of the

features of the cuprate reaction are noteworthy and are listed below:

(1) (+)-Apoverbenone (46), the starting material for the cuprate reaction, is

derived in high yield from cheap and readily available, (-)-~-pinene (Aldrich

Chemical Company, 92% optical purity) through ozonolysis to nopinone (55),

followed by introduction of the double bond through oxidation. The optical

purity of 46 can be enhanced by recrystallization of reduction product,

followed by re-oxidation to 46. The optically active form of enone 113, on the

other hand, can be prepared through the use of a commercially available,

enantiomerically pure terpene, (+)-limonene oxide.

(2) The mixed higher-order cuprate utilizes one equivalent of the olivetol

ether as the transfer ligand with thiophene acting as the "dummy" ligand.

This is a significant improvement to the earlier homocuprates, and an

important factor that has to be taken into consideration, especially when an

expensive, alkylresorcinol is employed. Also, the fact that lithium-2­

thienylcyanocuprate solution can be prepared conveniently in the laboratory

adds to the utility of the reaction.

(3) Modification of the cannabidiol (CBD) structure has led to analogs with

unique pharmacological profiles. The cuprate adduct 114 is an ideal precursor

for the synthesis of CBD analogs with structural modifications in the

isopropenyl substituent. If the conjunction of olivetol with a ring opened

66

monoterpene derivative were carried out under acid catalysis, it could have

resulted in products containing a dihydrobenzopyran ring.

(4) The regiospecificity problem encountered in most of the earlier

cannabinoid syntheses is completely avoided by using the cuprate reaction

to join the olivetol derivative to the monoterpene fragment. An alternative,

elegant approach to cannabinoids has been developed by Huffman and

co-workers which addresses the lack of regiospecificity. According to

their procedure, the synthesis of natural (-)-cannabinoids requires

(-)-apoverbenone, which is obtained from (+)-13-pinene. (+)-13-Pinene is

commercially unavailable and is prepared from the isomerization of

(+)-a-pinene. Further, Huffman's procedure cannot be applied to the ring

opened enone 113.

(5) The cuprate attack is stereospecific and took place trans to the geminal

dimethyl bridge of 46. This is an important factor because the stereochemistry

of the cuprate addition determines the ring junction stereochemistry of the

final product.

Apart from the mixed higher-order cuprate reaction, it is worthy of note

that some of the other reactions and products obtained through these

synthetic schemes can be employed towards the synthesis of cannabinoid

analogs.

A convenient synthesis of optically active, cyclized ketone 74 has been

accomplished in high yield. It should be emphasized that 74 is a very

versatile intermediate. Recently, analogs of 74 have been prepared in our

laboratory with either dimethyl heptyl or with an unsaturated sidechain.

The synthetic sequence for ll-nor-.18-THC-carboxylic add methyl ester

constitutes one of the shortest enantioselective routes to ~8-cannabinoids and

67

their analogs. An interesting reaction in scheme 10 is the opening of the

cyclobutane ring in 68 followed by transposition of the double bond during

cyclization leading specifically to the 8,8-series. The cyclohexenyl triflates 69

and 121 were key intermediates in the synthesis of vinyl fluoro- and vinyl

iodo- cannabinoids and could also be envisioned as ideal precursors for the

synthesis of radio-labeled cannabinoids.

The synthesis of a deuterium-labeled /},9_THC derivative 101 that is of

interest as a standard for GC-MS analysis of urine samples has also been

accomplished. Of particular interest was the formation of the isopropenyl

substituent during the ring opening reaction of 87 due to a stereoelectronic

effect exerted by the aryl substituent at C4. In our group, this result has led to

the synthesis of CBD structural variants from pinane-type intermediates. The

good site selectivity observed in the formation of the thermodynamically less

stable 8,9-unsaturation is also remarkable. Cleavage of methyl ether in both

95 and 101 without altering the rest of the THC skeleton was challenging.

Attempted cleavage of the methyl ether groups of 88 with sodium

thioethoxide in DMF at 120 0C resulted in dihydrobenzofuran derivative 97

which can be envisioned as an intermediate for the synthesis of 8,9-THC­

carboxylic acid.

68

EXPERIMENTAL SECI10N

General:

1H NMR and 13C NMR spectra were recorded at 300 MHz 1H (75.5

MHz 13C) or 500 MHz 1H (125.8 MHz 13C) in either deuteriochloroform

(COCI3) with chloroform (7.26 ppm 1H, 77.00 ppm 13C) or deuteriobenzene

(C6D6) with benzene (7.15 ppm 1H, 128.00ppm 13C) as an internal reference.

19F NMR spectra were recorded on a Nicolet NT-300 instrument, and

chemical shifts are reported upfield from fluorotrichloromethane (0.00 ppm)

as an external standard. Chemical shifts are given in B; multiplicities are

indicated as br (broadened), s (singlet), d (doublet), t (triplet), q (quartet), m

(multiplet); coupling constants (J) are reported in hertz (Hz). Infrared spectra

were recorded on a Perkin-Elmer IR 1430 spectrometer. Electron impact mass

spectra were performed on a VG-70 SE mass spectrometer.

Thin-layer chromatography (tlc) was performed on EM Reagents

percoated silica gel 60 F-254 analytical plates (0.25 mm), Flash column

chromatography was performed on Brinkmann silica gel (0.040-0.063 mm).

Tetrahydrofuran (THF), diethyl ether, 1,2-dimethoxyethane (DME)

were distilled from sodium-benzophenone ketyl, N,N-dimethylformamide

(OMF), triethylamine (Et3N) and boron trifluoride-etherate (BF3'Et20) from

calcium hydride, carbon tetrachloride (CCI4), dichloromethane (CH2CI2) from

phosphorus pentoxide. Other reagents were obtained commercially and used

as received unless otherwise specified.

All moisture sensitive reactions were performed under a static

nitrogen or argon atmosphere in flame-dried glassaware. The purity and

homogeneity of the products on which the high resolution mass spectral data

are reported were determined on the basis of 300 MHz 1H NMR and multiple

elution tlc analysis, respectively.

69

OH

Olivetol

OEE

56

Procedure:

To a solution of olivetol (Ig, 5.55 mmol) in ether (20 ml.) at 0 0C was

added ethyl vinyl ether (1.35 mL, 13.88 mmol), followed by a catalytic amount

(ca. 50 mg) of p-TSA in ether. The reaction mixture was stirred at 0 0C and

the progress of the reaction was monitored by tIc. After 7 h, the reaction

mixture was diluted with ether, washed with sat'd aqueous NaHC03,

followed by brine, and was dried (Na2S04). Solvent evaporation in vacuo

gave the crude bis-2-ethoxyethyl olivetol which was purified by flash column

chromatography on silica gel eluting with 5% ethyl acetate in hexanes. The

yield of the reaction was 77-80%.

70

56

Bis-2-ethoxyethyl olivetol (56):

IH NMR (CDC13, 300 MHz): B 6.49-6.47 (br s, 2H), 5.35 (q, J = 5.1 Hz, 2H), 3.81­

3.73 (m, 2H), 3.59-3.49 (m, 2H), 2.52 (t, J= 7.5 Hz, 2H), 1.61-1.56 (m, 2H), 1.49 (d,

J=5.4 Hz, 6H), 1.33-1.27 (m, 4H), 1.21 (t, J =6.9 Hz, 6H), 0.89 (t, J=6.3 Hz,3H)

ppm.

l3C NMR (CDC13, 75 MHz): B 157.8,145.3,110.8,103.8,99.5,61.5,36.1,31.4,30.9,

22.5, 20.3, 15.2, 13.9 ppm.

IR (neat): 2990,2920,2850, 1590, 1450, 1380, 1150, 1110, 1080, 1050 em-I

71

o

~46

Procedure:

OEE

56

o

57

To a solution of 311mg (0.956 mmol) of bis-2-ethoxyethyl olivetol (56)

in THF (15 mL) at 0 0C was added n-butyllithium solution in hexane

(0.85 mL, 1.150 mmol) during 20 min. The mixture was stirred at 0 0C for

10 min and then at 25 0C for 2.5 h. In a separate flask 3.85 mL (0.956 mmol) of

a solution of lithium 2-thienylcyanocuprate71 in THF was cooled to -78 oc.

The lithiated olivetol ether was transferred by cannula to the cuprate solution

over a 20-min period. Following addition, the reaction mixture was placed

in an ice bath for 10 min, cooled to -78 0C, and stirred for 1.5 h. To the pale

yellow cuprate solution was added a mixture of 100 mg (0.735 mmol) of

(+)-apoverbenone (46) and 0.10 mL (0.735 mmol) of BF3·Et20 in 1.5 mL of

THF at -78 0C. The mixture was stirred at -78 °C until tIc (10% ethyl acetate

in hexane) showed the disappearance of the starting material (1-2 h). The

reaction was diluted with ether (30 mL), washed with concentrated

NH40H/sat'd NH4CI (1/9) solution, extracted with ether, and dried (MgS04).

Evaporation of the solvent in vacuo and purification of the crude product by

flash column chromatography on silica gel eluting with 5% ethyl acetate in

hexane produced 225 mg (66% yield) as a mixture of diastereomers due to the

asymmetric center on each of the two ethoxyethyl protecting groups.

72

57

4-[4-n-Pentyl-2,6-bis(2-ethoxyethyl)phenyl]-6,6-dimethyl-2-nopinone (57):

IH NMR (CDC13, 300 MHz): a 6.59 (5, IH), 6.55 (5, IH), 5.46-5.39 (m, 2H), 4.16­

4.09 (m, IH), 3.74-3.64 (m, 2H), 3.57-3.46 (m, 2H), 3.38-3.29 (m, IH), 2.56-2.45 (m,

6H), 2.22 (br 5, IH), 1.61-1.56 (m,4H), 1.48 (d, J=5.1 Hz,6H), 1.35 (5, 3H), 1.33­

1.31 (m, 2H), 1.22-1.16 (m, 6H), 0.98 (5, 3H), 0.89 (t, J =6.7 Hz, 3H) ppm.

IR (neat): 2975,2925,2860, 1710, 1605, 1570, 1430, 1380, 1071,1050 em-1.

73

o

57

..

59

Procedure:

To a suspension of freshly sublimed potassium tert-butoxide (275 mg,

2.46 mmol) in 20 mL of ether was added methyltriphenylphosphonium

iodide (989 mg, 2.46 mmol) in a single portion. The reaction mixture

immediately turned bright yellow and was heated to gentle reflux. After 15

min, ketone 57 (225 mg, 0.49 mmol) in 5 mL of ether was added and stirring

was continued until tIc indicated the complete disappearance of starting

material (ca. 6 h). The reaction was quenched with water, extracted with ether

and was dried over MgS04. Solvent evaporation in vacuo and purification of

the crude product by flash column chromatography on silica gel eluting with

5% ethyl acetate in hexanes produced 193 mg (80% yield) of 59 as a colorless

oil.

74

59

Exo-methylene 59:

IH NMR (CDC13, 300 MHz): 8 6.56 (5, IH), 6.53 (5, IH), 5.43-5.36 (m, 2H), 4.68

(5, IH),4.61 (5, IH), 4.02-3.95 (m, IH), 3.76-3.66 (m,2H), 3.59-3.47 (m, 2H), 2.92­

2.79 (m, IH), 2.51 (dd, J=7.8,7.5 Hz, 2H), 2.46-2.25 (m,4H), 1.99 «. J = 5.4 Hz,

IH), 1.61-1.58 (m, 2H), 1.48 (dd, J= 5.2, 2.7 Hz, 6H), 1.34-1.30 (m,4H), 1.28 (5,

3H), 1.20 (d, J=1.8 Hz,3H), 1.18 (d, J=1.8 Hz,3H), 0.89 (t, J= 6.9 Hz, 3H), 0.86 (5,

3H) ppm.

IR (CC14): 2960,2920,2840, 1600, 1570, 1430, 1375, 1070, 1040 em-I.

75

59 60

Procedure:

To a solution of 193 mg (0.42 mmol) of 59 in 30 mL of methanol was

added ca. 15 mg of PPTS. The mixture was stirred at 25 0C until tIc indicated

that both ethoxyethyl groups have been removed (ca. 5 h). The reaction

mixture was diluted with ether, washed with brine and was dried over

MgS04. Evaporation of the solvent in vacuo and purification of the crude

product by flash chromatography eluting with 5% ethyl acetate in hexanes

produced 110 mg (85% yield) of 60 as a white foam.

76

60

Resorcinol 60:

IH NMR (COC13,300 MHz): ~ 6.16 (5, 2H),4.74 (5, 2H, exchangeable with

D20),4.71 (5, IH), 4.63 (5, IH), 3.78 (dd, J =9.3, 8.7 Hz, IH), 2.81-2.71 (m, 1H),

2.61-2.44 (m, 3H), 2.41 (dd, J= 7.8, 7.5 Hz, 2H), 2.19-2.12 (m, 2H), 1.58-1.48 (m,

2H), 1.30 (5, 3H), 1.28-1.22 (m, 4H), 0.87 (5, 3H), 0.86 (t, J=7.5 Hz, 3H) ppm.

13C NMR (COCI3, 75 MHz): s 154.8, 150.9,142.3, 115.5, 108.7, 106.7, 51.1, 45.3,

42.1,35.2,31.5,30.9,30.8,30.7,26.5,26.2,22.5,21.7, 14.0 ppm.

IR (neat): 3410,2900,2830, 1620, 1580, 1430, 1020 em-I.

77

60 61

Procedure:

To a solution of 150 mg (0.46 mmol) of resorcinol 60 in 20 mL of

CH2Cl2 at 0 °C was added 0.20 mL (2.50 mmol) of pyridine and a catalytic

amount of DMAP. After 15 min, 0.12 mL (1.30 mmol) of acetic anhydride was

added. The reaction stirred at 0 0C for 1 h at which time tIc indicated the

complete consumption of starting material. The reaction mixture was diluted

with ether, washed with sat'd aqueous NaHC03, followed by brine. The

organic phase was dried (MgS04) and evaported. Purification of the residue

by flash column chromatography etuting with 15% ethyl acetate in hexanes

produced 153 mg (84%) of 61 as a colorless oil.

78

61

Diacetate 61:

IH NMR (CDC13,300 MHz): (5 6.71 (5, 2H),4.72 (5, IH), 4.64 (5, IH), 3.46 (dd,

J= 10.5,7.5 Hz, IH), 2.65-2.58(m, IH),2.54 (dd, J= 8.1, 7.5 Hz, 2H), 2.49-2.36 (m,

3H), 2.29 (5, 6H), 2.05 (t, J=5.7 Hz, IH), 1.99 (d, J=9.6 Hz, IH), 1.61-1.54 (m, 2H),

1.33-1.30 (m,4H), 1.28 (5,3H), 0.88 (t, J=6.9 Hz, 3H), 0.81 (5,3H) ppm.

13C NMR (CDCI3, 75 MHz): (5 169.4, 150.1, 149.6, 141.9, 126.9, 120.8, 107.3, 50.6,

44.9,41.9,34.9,32.1,31.4 (two coincident signals), 30.3, 26.4, 26.3, 22.4, 21.3, 21.2,

13.9 ppm.

IR (CCI4): 2920,2850,1765, 1565, 1185,1025 cm-1.

Ma55 spectrum (70 ev, m/e): 398 (M+), 289, 247,205, 139 (100%), 111, 75, 57.

HRMS: for C2SH3404 calculated 398.2457, found 398.2479.

79

61 62

Procedure:

To a solution of 200 mg (0.51 mmol) of 61 in 25 mL of CH2Cl2 at 0 0C

was added a sat'd aqueous solution of NaHC03 (7 mL). A solution of 152 mg

(0.88 mmol) of m-CPBA in CH2Cl21ether (1II) was added slowly at 0 0C and

the two-phase mixture was stirred vigorously until tlc indicated the

disappearance of starting material (ca. 8 h). The excess oxidant was quenched

with aqueous sat'd NaHS03 and the reaction mixture was extracted with

ether. The ether extracts were dried (MgS04) and the solvent was evaporated

in vacuo. Flash column chromatography of the residue on silica gel eluting

with 5% ethyl acetate in hexanes produced 176 mg (85% yield) of epoxide 62 as

a single diastereomer.

80

62

Epoxide 62:

IH NMR (CDCI3, 300 MHz): B 6.73 (5, 2H), 3.49 (dd, J=10.5,8.1 Hz, IH), 2.81

(d, J=4.8Hz, IH), 2.65 (d, J=4.8 Hz, IH), 2.54 (t, J=7.8 Hz, 2H), 2.42-2.37 (m,

2H), 2.32 (5, 6H), 2.28-2.22 (m, 2H), 2.03 (t, J=5.4 Hz, IH), 1.77 (dd, J=14.7,7.8

Hz, IH), 1.63-1.52 (m, 2H), 1.32-1.28 (m, 4H), 1.29 (5, 3H), 1.01 (5, 3H), 0.88 (t,

J =6.3 Hz, 3H) ppm.

13C NMR (CDCI3, 75 MHz): B 169.3, 149.6, 142.3, 126.1, 120.9,60.6,55.9,48.2,

45.3,41.9,35.0,31.4,31.1,30.3,29.9,26.4,24.7,22.4, 21.2,20.7, 13.9 ppm.

IR (CCI4): 2920,2850, 1770, 1620, 1425, 1365, 1180, 1025 cm-1.

Mass spectrum (70 ev, m/e): 414 (M+), 370, 312, 285, 247, 219, 193 (100%).

HRMS: for C25H3405 calculated 414.2406, found 414.2397.

81

62 63

Procedure:

To a solution of ca. 15 mg of ammonium nitrate in nitromethane (10

mL) at 25 0C was added 100 mg (0.24 mmol) of epoxide 62. The solution was

stirred at 25 0C and was sonicated intermittently until tlc indicated the

disappearance of most of the starting material (ca. 3 d). The reaction mixture

was diluted with ether (20 mL), washed with sat'd aqueous NaHC03 and

brine, and was dried over MgS04. Solvent evaporation in vacuo and

purification of the crude product by flash column chromatography on silica

gel provided the allylic alcohol 63 in 38% yield.

82

63

Allylic alcohol 63:

Note: Some signals in IH NMR and 13C NMR are broadened due to the

hindered rotation of substituted aryl group,120

IH NMR (CDCI3, 300 MHz): B 6.76 (br 5, 2H), 5.75 (5, IH), 4.62 (5, IH), 4.57 (5,

IH), 3.99 (5, 2H), 3.05 (dt, J=11.4,5.4 Hz, IH), 2.94-2.85 (m, IH), 2.54 (dd, J=8.1,

7.5 Hz, 2H), 2.30 (5, 6H), 2.18-2.85 (m, 3H), 1.65-1.56 (m, 4H), 1.53 (5, 3H), 1.32­

1.25 (m, 4H), 0.88 (t, J =6.3 Hz, 3H) ppm.

13C NMR (COCI3, 75 MHz): B 168.9, 149.3, 146.9, 142.1, 137.0, 124.9, 121.5,

121.1-119.8 (br m), 111.7,66.4,45.1,35.9,35.2,32.1,31.5,31.4,30.2,22.4,21.3 (br 5),

18.6, 13.9 ppm.

IR (CCI4): 3495,2920,2850, 1770, 1365, 1195, 1175, 1030 crrrl.

Mass spectrum (70 ev, mz'e): 414(M+), 396, 354,312,231, 193 (100%),91,69.

HRMS: for C25H3405 calculated 414.2406, found 414.2401.

83

63 65

Procedure:

To a suspension of 100 mg of K2C03 in 10 mL of methanol at 25 0C was

added 30 mg (0.07 mmol) of 63. The reaction mixture was stirred for ca. 3h at

25 0C until tlc indicated the disappearance of starting material. The reaction

mixture was diluted with ether, washed with brine and dried over MgS04.

Solvent evaporation in vacuo produced the crude triol. The crude product of

65 was pure enough (by lH NMR) to be used in the cyclization reaction

without any further purification.

84

65

Trio165:

lH NMR (COCI3, 300 MHz): a 6.11 (5, 2H), 5.77 (5, lH), 4.73 (5, lH), 4.69 (s,2H,

exchangeable with D20), 4.54 (5, lH), 4.04 (5, 2H), 3.39 (dt, J=11.4,5.4 Hz, lH),

3.18 (dt, J = 10.8,5.7 Hz, lH), 2.73-2.63 (m, lH), 2.41 (dd, J = 8.1, 7.5 Hz, 2H), 2.22­

2.12 (m, 3H), 1.59 (5, 3H), 1.38-1.25(m, 6H), 0.88 (t, J= 6.6 Hz,3H) ppm.

13C NMR (CDCl3, 75 MHz): a 154.6 (br 5), 148.8, 142.2, 137.4, 122.8, 114.6, 110.4,

108.5,67.2,44.4,35.3,34.4,32.0,31.6,30.8,30.5,22.5, 18.5, 14.0 ppm.

IR (CC14): 3350,2920,2850, 1620, 1580, 1430,1025 cm-1.

85

65

•

66

Procedure:

To the product 65 of the preceding reaction in 10 mL of benzene was

added catalytic p-lSA monohydrate. The solution was stirred for ca. 15 h at

25 0 C. The reaction mixture was diluted with ether (20 mL), washed with

sat'd aqueous NaHC03 followed by brine, and dried over MgS04. Solvent

evaporation in vacuo and purification of the crude product by flash column

chromatography eluting with 10% ethyl acetate in hexanes produced 15 mg of

pure 66. The overall yield of 66 from 63 was 65%.

86

66

ll-Hydroxy-~8-tetrahydrocannabinol (66):

IH NMR (CDCI3, 300 MHz): 0 6.27 (5, IH),6.11 (5, IH),5.74 (d, J=4.2 Hz, IH),

4.91 (br 5, IH, exchangeable with D20), 4.06 (5, 2H), 3.39 (dd, J=15.6,3.9, IH),

2.71 (dt, J= 10.8,4.5 Hz, IH), 2.44 (dd, J= 8.4, 6.9, 2H), 2.26-2.16 (m, IH), 1.92-1.83

(m, 2H), 1.61-1.51 (m, 3H), 1.38 (5, 3H), 1.32-1.25 (m, 4H), 1.11 (5, 3H), 0.88 (t, J =6.6 Hz, 3H) ppm.

13C NMR (CDCI3, 75 MHz): 0 154.9, 154.7, 142.8, 138.2, 121.3, 110.1, 109.9, 107.7,

76.4,67.1,45.0,35.5,31.6 (two coincidental peaks), 31.4, 30.6, 27.6, 27.5, 22.5, 18.4,

14.0 ppm.

IR (CCI4): 3340,2950,2840, 1620, 1570, 1425, 1260, 1180, 1040 crrrl,

Mass spectrum (70 ev, m/e): 330 (M+), 297, 269, 231 (100%),214, 193,69.

HRMS: for C21H3003 330.2195, found 330.2195.

87

o

57 67

Procedure:

To a solution of 1.302 mmol of potassium hexamethyldisilylamide in

8 mL of THF at 0 0C was added a solution of 200 mg (0.434 mmol) of 57 in

2 mL of THF. The solution was stirred for Ih at 0 0C, and 465 mg (1.303

mmol) of solid phenyl triflimide was added to the reaction mixture. The

progress of the reaction was monitored by tIc (ca. 2 h). The reaction mixture

was diluted with ether (20 mL), washed with brine, and dried (MgS04).

Evaporation of the solvent produced the crude vinyl triflate. Separation of

the product from the excess reagent was difficult as both had nearly identical

chromatographic mobilities. The mixture containing the reagent and the

product which was obtained from flash column chromatography, eluting

with 5% ethyl acetate in hexane was used in the next reaction.

88

67

Vinyl triflate (67):

lH NMR (CDC13, 300 MHz): B 6.63-6.58 (m, 2H), 5.82-5.75 (br m, lH), 5.42­

5.37(m, 2H), 4.15 (t, J= 2.6 Hz, lH), 3.73-3.64 (m, 2H), 3.57-3.49 (m, 2H), 2.51

(t, J =7.6 Hz, 2H), 2.41-2.33 (br m, 2H), 2.09-2.05 (m, lH), 1.97-1.94 (m, lH),

1.60-1.56 (m, 2H), 1.47 (d, J =5.4 Hz, 6H), 1.33 (5, 3H), 1.32-1.25 (m, 4H), 1.19

(t, J=8.2 Hz, 6H), 1.07 (5, 3H), 0.89 (t, J=6.9 Hz, 3H) ppm.

IR (CHC13): 2990,2920, 1610, 1585, 1425, 1210, 1150, 1080, 1050, 1040, 930, 865

cm-1.

Mass spectrum (70 ev, m/e): 595 (M+, weak), 448, 405, 315,234, 193, 109,

73(100%).

HRMS: for C29H43S07F3 592.2682, found 595.2730.

89

67

...

68

Procedure:

To the product 67 from the proceding reaction in 15 mL of methanol

was added ca. 15 mg of PPTS. The reaction mixture was stirred vigorously

at 25 0C until tIc indicated that both ethoxyethyl groups have been removed

(ca. 6 h). The reaction mixture was diluted with ether (20 mL), washed with

brine, and dried (MgS04). Solvent evaporation gave the crude diol 68, which

was purified by flash column chromatography on silica gel, eluting with 5%

ethyl acetate in hexane. The overall yield from 57 was 125 mg (65% yield).

90

68

Resorcinol of the vinyl triflate (68):

1H NMR (CDCI3, 300 MHz): B 6.21 (s, 2H), 5.94 (s, IH), 5.20 (s, 2H,

exchangeable with D20), 4.12 (incomplete t, J= 2.4 Hz, 1H), 2.54-2.41 (m,4H),

2.28 (t, J = 5.6 Hz, IH), 1.76 (d, J= 9.3 Hz, 1H), 1.61-1.51 (rn, 2H), 1.38 (s, 3H), 1.32­

1.26 (m, 4H), 1.08 (s, 3H), 0.89 (t, J =6.9 Hz,3H) ppm.

IH NMR (C6D6, 300 MHz): B 5.84 (s, 2H), 5.56 (s, 1H), 4.71 (s, 2H, exchangeable

with D20), 4.05 (br s, 1H), 2.34 (t, J= 7.2 Hz, 2H), 2.22-2.16 (m, 2H), 2.11-2.04 (m,

IH), 1.86 (d, J= 7.2 Hz, 1H), 1.51 (br t, J = 7.2 Hz, 2H), 1.28-1.24 (m, 4H), 0.98 (s,

3H), 0.89 (s, 3H), 0.87 (t, partiall.y obscurred by the peak at 0.89 ppm, J=6.9 Hz,

3H) ppm.

13C NMR (CDCI3, 75 MHz): B156.5, 154.8, 143.7, 113.8,111.0, 108.7, 47.0 (two

coincidental peaks), 42.4, 35.5, 35.4, 31.5, 30.6, 28.6, 25.3, 22.5, 20.7, 13.9 ppm.

13C NMR (C6D6, 75 MHz): B155.6, 155.4, 143.3, 114.8,111.7,108.9,47.4,47.2,

42.2,35.8,35.7,31.7,31.1,28.7,25.2,22.9,20.6, 14.2 ppm.

IR (CHCI3): 3005,2960,2860, 1630, 1580, 1420, 1250,1220, 1140, 1060, 1025 em-I.

Mass spectrum (70 ev, m/e): 448 (M+), 405, 315, 233 (100%), 193, 109,83.

HRMS: for C21H27S05F3 448.1531, found 448.1523.

Specific rotation: [ex]24D =-79.740 (c =0.38, ethanol)

91

68 69

Procedure:

To a solution of 125 mg (0.279 mmol) of diol 68 in 8 mL of anhydrous

CH2Cl2 was added 0.32 mL (2.601 mmol) of boron trifluoride etherate at 25 oc.

The reaction mixture was stirred at 25 0C for 8 h, at which time tIc indicated

the complete consumption of starting material. The reaction mixture was

diluted with ether (20 mL), washed with brine, and dried (MgS04). Solvent

evaporation produced the crude product, which was purified by flash column

chromatography on silica gel, eluting with 10% ethyl acetate in hexane, to

produce 106 mg (87% yield) of cyclic 69.

92

69

(-)-frans-6a,7,lO,lOa-Tetrahydro-l-hydroxy-6,6-dimethyl-3-pentyl-6H­

dibenzo[b,d]-pyran-9-yl-trifluoromethanesulfonate (69):

IH NMR (CDCl3, 300 MHz): 0 6.28 (5, IH), 6.10 (5, IH), 5.81 (br 5, IH), 4.76 (5,

IH, exchangeable with D20), 3.67 (dd, J=8.2,4.5 Hz, IH), 2.86 (dt, J=11.1,4.8

Hz, IH), 2.44 (t, J= 7.8 Hz, 2H), 2.39-2.18 (br m, 2H), 2.05-1.93 (br m, IH), 1.86

(dt, J=9.9, 3.6 Hz, IH), 1.56-1.52 (m, 2H), 1.41 (5, 3H), 1.32-1.28(m, 4H), 1.12 (5,

3H), 0.84 (t, J=6.3 Hz, 3H) ppm.

13C NMR (CDCl3, 75 MHz): 0 154.5 (two coincidental peaks), 149.4, 143.6,

116.5, 110.1, 108.3, 107.7,76.3,43.6,35.4,33.2,31.6,31.5,30.5,27.5,25.8, 22.5, 18.3,

13.9 ppm.

13C NMR (C6D6, 75 MHz): 0 155.3, 155.2, 149.4, 143.5, 116.9, 110.5, 108.6,107.8,

75.9,43.5,35.9,33.4,31.9,31.8,31.1,27.5,25.5,22.9, 18.3, 14.2 ppm.

IR (CHCl3): 3400,2960,2925,2850, 1625, 1585, 1420, 1250, 1210, 1140, 1050 crrrl.

Mass spectrum (70 ev, role): 448(M+), 392, 231, 193, 109, 69(100%).

HRMS: for C21H27S05F3 448.1531, found 448.1514.

Specific rotation: [a] 240 =-206.130 (c =0.31, ethanol)

93

69 70

Procedure:

A solution of 7 mg (0.01 mmol) of PdCI2(PPh)3 in 2.00 mL of THF and

0.12 mL of methanol, containing 42 mg (0.31 mmol) of potassium carbonate,

was purged with carbon monoxide at 25 °C for 5 min. A solution of 45 mg

(0.10 mmol) of cyclohexenyl triflate 69 in 2 mL of THF was added, and purging

was continued for an additional 10 min. The reaction mixture was stirred at

25 0C under an atmosphere of carbon monoxide until tIc indicated complete

dissappearance of starting material (ca. 8 h). The reaction mixture was diluted

with water and extracted with ether. The ether layers were concentrated and

dried (MgS04). Solvent evaporation gave the crude product, which was

purified by flash column chromatography on silica gel, eluting with 10% ethyl

acetate in hexane. The yield of 70 was 26 mg (72% yield).

94

70

(-)-11-Nor-~8-tetrahydrocannabinol-9-carboxylic acid methyl ester (70):

1H NMR (CDCI3, 300 MHz): 0 7.02 (br s, 1H), 6.25 (5, 1H), 6.14 (s, 1H), 5.49 (s.

1H, exchangeable with D20), 3.85 (dd, J= 8.7,3.3 Hz, 1H), 3.76 (s, 3H), 2.67 (dt,

J=16.2, 4.5 Hz, IH), 2.43 (t, J= 7.8 Hz, 2H), 2.41-2.36 (m, partially obscurred by

the peak at 2.43 ppm, 1H) 2.06-1.92 (br m, 3H), 1.82 (dt, J = 11.7,4.2 Hz, 1H),

1.58-1.53 (m, 2H), 1.39 (s, 3H), 1.32-1.26(br m, 4H), 1.12 (s, 3H), 0.88 (t, J = 6.9 Hz,

3H) ppm.

13C NMR (CDCI3, 75 MHz): 0 168.2, 155.3, 154.6,142.9, 138.1, 130.9, 109.6, 109.4,

107.7,76.0,51.8,44.2,35.5,31.5,31.2,30.6,30.1,28.5, 27.5,22.5,18.3, 13.9 ppm.

IR (CHCI3): 3405,2960,2940,2860, 1715, 1695,1630, 1580, 1440, 1270, 1190, 1075

cm-1.

Mass spectrum (70 ev, m/e): 358 (M+, 100%),302,283,231, 193,69.

HRMS: for C22H3004 358.2144, found 358.2165

Specific rotation: [a]23D = -2190 (c = 1.5, ethanol)

Literature82 [a]D = -3020 (ethanol)

95

71

Oxalate (71):

1H NMR (CDCI3, 300 MHz): 0 7.04 (br 5, IH), 6.27 (5, IH), 6.12 (5, 1H), 4.94 (5,

1H, exchangeable with D20), 3.91 (br d, IH, partially obscurred by the peak at

3.89 ppm), 3.89 (5, 3H), 2.67 (dt, J=11.1,4.2 Hz, 1H), 2.59-2.48 (m, IH), 2.45 (t,

J=6.3 Hz, 2H), 2.19-2.05 (m, 1H), 1.98-1.82 (m, 2H), 1.61-1.52 (m, 2H), 1.40 (5,

3H), 1.35-1.21 (m, 4H), 1.13 (5, 3H), 0.88 (t, J=6.6 Hz,3H) ppm.

13C NMR (CDCI3, 75 MHz): 0 187.4, 164.8, 154.8, 154.6, 147.0, 143.3, 136.8, 110.0,

109.0, 107.8, 75.8, 52.5, 44.1,35.4,31.5,30.8,30.6,29.4,28.2,27.5,22.5,18.3, 14.0

ppm.

IR (CHCI3): 3480, 2960,2860, 1745,1675, 1590, 1440, 1265, 1190, 1170, 1020 crrr l.

Mass spectrum (70 ev, m/e): 386 (M+), 330, 231, 205, 85,71,57(100%).

HRMS: for C23H3005 386.2093, found 386.2092.

96

Procedure:

o

~It:J

Nopinone

..o

~r

"" Br

T75

A solution of (+)-nopinone (2.00 g, 14.49 mmol) in CC14 (10 mL) was

added to a stirred solution of recrystallized N-bromosuccinimide (7.74 g, 43.48

mmol) and benzoyl peroxide (0.36 g, 1.49 mmol) in CC14 (20 mL) in a nitrogen

atmosphere. The resulting solution was heated at reflux, and the progress of

the reaction was monitored by tlc, After 2 days, tlc indicated the formation

of both mono- and bis-bromonopinone (ca. 2:3 ratio). The reaction mixture

was cooled, diluted with water, and extracted with CH2CI2. The combined

CH2Cl2 extracts were washed successively with sat'd aqueous NaHC03 and

brine, dried (MgS04), and concentrated under reduced pressure. Bis-bromo­

nopinone (75) was separated from mono-bromonopinone by flash column

chromatography on silica gel, eluting with 5% ethyl acetate in hexane to

afford 2.35g (55% yield).

97

o

~r

"" Br

T75

3,3-Dibromo-6,6-dimethylbicyclo[3.1.1]-heptan-2-one (75):

IH NMR (300 MHz, COC13): 03.57 (dd, J = 15.9,4.2 Hz, 1H), 3.39 (d, J = 15.9 Hz,

1H), 2.99 (t, J=5.7 Hz, 1H), 2.75-2.68 (m, 1H), 2.60 (d, J=1.1 Hz, 1H), 2.27-2.22

(m, 1H), 1.43 (5, 3H), 0.96 (5, 3H) ppm.

I3C NMR (75 MHz, COC13): 0 199.1,59.6,57.3,48.9,44.3,42.3,25.7,25.4,23.8

ppm.

IR (CHC13): 2980,2960,2920, 1730, 1450 crrrl.

Mass spectrum (70 ev, m/e): 296(M+, weak), 217, 215, 173, 136, 110, 95,

83(100%).

HRMS: for C9H120Br (M+-Br) 215.0071, found 215.0063.

98

Procedure:

o

~r

II, Br

l'75

..o~Br

~76

To a suspension of anhydrous lithium carbonate (1.77 g, 23.89 mmol),

anhydrous lithium bromide (l.45 g, 16.74 mmol) in freshly distilled DMF

(20 mL) under nitrogen, equipped with a reflux condenser at 100 0C, was

added a solution of bis-bromonopinone (75) (2.35 g, 7.96 mmol) in DMF

(10 mL) by cannula. The reaction mixture was stirred at 130 0C for 6 h, at

which time tlc indicated the complete consumption of starting material.

The reaction mixture was cooled, diluted with water (50 mL) and extracted

with ether. The combined ether extracts were washed with brine and

dried (MgS04). Solvent evaporation produced the crude product, which was

purified by flash column chromatography on silica gel, eluting with 5%

ethyl acetate in hexane, to afford 1.29 g (76% yield) of the cc-bromoenone 76.

99

o

rdYBr

~76

3-Bromo-6,6-dimethylbicyclo[3.1.1]-hept-3-en-2-one (76):

IH NMR (300 MHz, CDC13): a 7.83 (d, J=7.2 Hz, IH), 2.93 (dd, J=12.6,6.0 Hz,

IH), 2.87 (dd, J =15.0,5.4 Hz, IH), 2.65 (dd, J=12.6, 6.9 Hz, IH), 2.23 (d, J=9.3

Hz, IH), 1.52 (5, 3H), 1.03 (5, 3H) ppm.

13CNMR (75 MHz, CDC13): a195.9, 156.3,119.8,58.3,56.3,45.9,41.6,26.3,22.5

ppm.

IR (CHC13): 2960, 1695, 1580, 1460, 1305,1240 an-I.

Mass spectrum (70 ev, m/e): 216,214,201, 199, 176, 174, 135,83(100%).

100

o~Br

~+

76

Procedure:

OEE

56

o

77

To a solution of the bis-z-ethoxyethyl olivetol (56) (650 mg, 2.20 mmol)

in anhydrous THF (30 mL) was added n-butyllithium in hexane solution

(l.45 mL, 2.20 mmol) at 0 oC during 20 min. The reaction mixture was stirred

at 0 oC for 10 min and then at 25 oC for 2.5 h. In a separate flask, a solution of

lithium-2-thienylcyanocuprate71 (22.00 mL, 2.20 mmol) was cooled to -78 oC.

The lithiated olivetol diether was transferred via cannula to the cuprate

solution over a 15 min period. Following addition, the reaction mixture

was placed in an ice bath for 10 min, cooled to -78 oC, and stirred for 1.5 h.

To this mixed higher-order cuprate solution at -78 oC was added 76 (268 mg,

1.25 mmol) mixed with BF3·Et20 (0.15 mL, 1.25 mmol) in THF (2 mL). The

mixture was stirred at -78 oC until tIc showed the disappearance of starting

material (5-6 h). The reaction was diluted with ether (30 mL), washed with

concentrated NH40H/sat'd NH4CI (1/9) solution, extracted with ether, and

dried (MgS04). Evaporation of the solvent followed by purification by flash

column chromatography on silica gel eluting with 5% ethyl acetate in hexane

produced 375 mg (56% yield) of 77 as a mixture of ethoxyethyl diastereomers.

101

77

3-Bromo-4-[4-pentyl-2,6-bis(2-ethoxyethyl)phenyl))-6,6-dimethylbicyclo[3.1.1]­

hept-2-one (77):

tH NMR (300 MHz, CDC13): B6.59 (br 5, 2H), 6.27 (d, J=9.0 Hz, IH), 5.56-5.35

(br m, 2H), 4.42 (d, J=9.0 Hz, IH), 3.81-3.65 (br m, 2H), 3.59-3.51 (br m, 2H), 2.83

(dd, J = 6.3, 5.4 Hz, IH), 2.61-2.43 (br m, 2H), 2.53 (t, J = 6.9 Hz, 2H), 2.14-2.11 (m,

IH), 1.58-1.56 (m, 2H), 1.49 (d, J=2.7 Hz, 6H), 1.37 (5, 3H), 1.35-1.30 (m, 4H), 1.18

(t, J=6.9 Hz, 6H), 1.01 (5, 3H), 0.88 (t, J=6.6 Hz,3H) ppm.

IR (CC14): 2960,2920,2870, 1725, 1605, 1580, 1440, 1380, 1350, 1080,1050 em-t.

102

o

77

o

78

Procedure:

To a solution of 77 (375 mg, 0.69 mmol) in methanol (20 mL) was added

PPTS (ca. 35 mg). The reaction was strirred vigorously at 22 DC until tIc

indicated that both ethoxy ethyl groups have been removed (ca. 8 h). The

reaction mixture was extracted with ether, and the combined ether extracts

were washed with brine and dried (MgS04). Solvent evaporation, followed

by purification by flash column chromatography on silica gel eluting with

10% ethyl acetate in hexane afforded 246 mg (90% yield) of the resorcinol 78.

103

o

78

3-Bromo-4-[(2,6-dihydroxy-4-pentyI)phenyl]-6,6-dimethylbicyclo[3.1.1]-hept-2­

one (78):

IH NMR (300 MHz, CDCI3): 06.30 (d, J=8.7 Hz, -CHBr, 1H), 6.24 (5, 2H), 5.66

(br 5, 2H, exchangeable with D20), 4.28 (d, J=8.7 Hz, IH), 2.84 (dd, J=5.4, 5.2

Hz, 1H), 2.62 (d, J=11.1 Hz, 1H), 2.49-2.47 (m, 1H), 2.42 (t, J=7.8 Hz, 2H), 2.20

(t, J=5.7 Hz, 1H), 1.59-1.50 (m, 2H), 1.36 (5, 3H), 1.32-1.24 (m, 4H), 1.01 (s,3H),

0.88 (dd, J=6.9, 6.3 Hz,3H)ppm.

I3C NMR (75 MHz, CDCI3): 0208.7,155.2, 143.4,110.8, 108.9,57.7,52.6,48.9,

44.1,42.2,35.3,31.5,30.5,25.5,23.7,22.5,22.5,13.9 ppm.

IR (CHCI3): 3400,2960,2940,2850, 1710, 1620, 1590, 1430, 1350, 1260 crrr].

Mass spectrum (70 ev, m/e): 396(2%),394(2%),314,258,231,204, 148,83(100%).

HRMS: for C20H2703Br 394.1140, found 394.1144.

104

78

Selected long-range connectivities observed in the HMBC experiment

Position 13CNMR (0)

1 57.7 H3, H6, H8, H9

2 208.7 Hl, H3, H6

3 52.6 Hl, H4, H5

4 42.2 H3,H6

5 48.9 Hl, H4, H6, H8, H9

6 23.7 Hl,H4,H5

7 44.1 Hl, H4, H5, H6

8 25.5 Hl, H5, H9

l' 110.8 H5, H4, H3, H3', H5'

105

6

5' 1" 3" 5"

78

Correlation of 1H and 13C Resonances, from HMQC Experiment

25.5 C8

30.5 C2"

31.5 C3"

35.3 Cl"

42.2 C4

44.1 C7

48.9 C5

52.6 C3

57.7 C1

108.9 C3', C5'

110.8 Cl'

143.4 C4'

155.2 C2', C6'

208.7 C2

106

13CNMR (B)

13.9

22.4

22.5

23.7

Assignment

C5"

C9

C4"

C6

IH NMR (B)

0.88 (t, 3H)

1.09 (5, 3H)

1.32-1.24 (m, 2H)

2.62 (d, 1H),

2.49-2.47 (m, IH)

1.36 (5, 3H)

1.59-1.50 (m, 2H)

1.32-1.24 (m, 2H)

2.42 (t, 2H)

4.28 (d, IH)

2.20 (t, 1H)

6.30 (d, IH)

2.84 (dd, 1H)

6.24 (5, 2H)

0 OCH30

~Br'~I +

..CH30 CD3

CD3

76 86 87

Procedure:

To a solution of the 5,-(2H3)olivetol dimethyl ether (86) (1.20 g, 5.77

mmol) in anhydrous THF (50 ml) was added n-butyllithium in hexane (4.50

mL, 7.21 mmol) at 0 °C during 20 min. The reaction mixture was stirred at

o0C for 10 min and then at 25 0C for 1.5 h. In a separate flask, a solution of

lithium-2-thienylcyanocuprate (75.00 mL, 7.50 mmol) was cooled to -78 0C.

The lithiated olivetol diether was transferred via cannula to the cuprate

solution over a 15 min period. Following addition, the reaction mixture was

placed in an ice bath for 10 min, cooled to -78 0C, and stirred for 1.5 h. To

this mixed higher-order cuprate solution at -78 0C was added a mixture of

76 (770 mg, 3.60 mmol) and BF3·Et20 (0.80 mL, 6.50 mmol) in THF (5 mL).

The mixture was stirred at -78 0C until tIc showed the disappearance of

starting material (3-4 h). The reaction was diluted with ether, washed with

concentrated NH40H/sat'd NH4CI (1/9) solution, extracted with ether, and

dried (MgS04). Evaporation of the solvent followed by purification by flash

column chromatography on silica gel eluting with 5% ethyl acetate in hexane

produced 1.27 g (82% yield) of cuprate adduct 87.

107

o

87

3-Bromo-4-[(2,6-dimethoxy-4-(S'-(2H3)pentyl)phenyl]-6,6-dimethyl­

blcyclols.Lfl-hept-z-one (87):

IH NMR (300 MHz, CDC13): a 6.41 (s,2H), 6.14 (d, J=9.0 Hz, -CHBr, IH),

4.37 (d, J=9.0 Hz, 1H), 3.80 (5, 6H), 2.84-2.81 (m, IH), 2.57 (dd, J=8.1,7.5 Hz,

2H), 2.46 (dd, J=4.5,3.0 Hz, 2H), 2.09 (br t, J =4.5 Hz, IH), 1.65-1.58 (m, 2H),

1.41-1.25 (m, 4H), 1.37 (s,3H), 1.01 (5, 3H) ppm.

13C NMR (75 MHz, CDC13): a 206.9, 158.6, 143.4,113.7, 104.7,57.6, 55.7, 52.9,

48.9,43.8,41.2,36.3,31.5,30.9,25.4,23.7,22.4,22.2 ppm.

IR (CC14): 2920,2850, 1725, 1605, 1575, 1450, 1420, 1120 cm].

Mass specturm (70 ev, m/e): 427(4%),425(5%),346, 250,224, 137, 95, 83(100%).

108

o

Procedure:

87

1\o 0

~Br.-' OMe

88

To a solution of l,2-bis(trimethylsilyloxy)ethane (5.75 mL, 23.64 mmol)

in CH2Cl2 (2 mL) at 22 0C was added trimethylsilyl trifluoromethanesulfonate

(TMSOTf, 0.25 mL, 1.26 mmol). After 15 min, a solution of 87 (500 mg, 1.18

mmol) in CH2Cl2 (5 mL) was added and stirred vigorously at 22 oc. The

progress of the reaction was monitored by tIc. After 60 h, the tIc indicated

nearly complete disappearance of the starting material. The reaction mixture

was extracted with CH2Cl2, and the combined CH2Cl2 extracts were washed

successively with sat'd aqueous NaHC03, brine, and dried (MgS04). Solvent

evaporation, followed by separation of the product from the unreacted

starting material by flash column chromatography, eluting with 2% ethyl

acetate in hexane afforded 360 mg (65% yield) of ketal 88.

109

1\o 0"Br

.' OMe

88

2-Bromo-s-I(2,6-dimethoxy-4-(S'-(2H3)pentyl)Iphenyll-d-isopropenyl­

cyclohexan-t-ethylene ketal (88):

IH NMR (300MHz, CDCI3): B 6.32 (5, IH), 6.30 (5, IH), 5.11 (d, J=12.0 Hz, IH),

4.42 (5, IH), 4.37 (5, IH), 4.33-4.29 (m, IH), 4.25-4.16 (m, IH), 4.06-3.99 (m,2H),

3.92 (dd, J= 12.0, 11.4 Hz, IH), 3.79 (5, 3H), 3.76 (5, 3H), 2.97 (ddd, J= 11.4, 11.1,

3.0 Hz, IH), 2.53 (dd, J =8.1, 7.5 Hz, 2H), 2.04-1.99 (m, IH), 1.83-1.71 (m,2H),

1.63-1.56 (m, 3H), 1.55 (5, 3H), 1.32-1.29 (m,4H) ppm.

13C NMR (75 MHz, CDCI3): B158.6, 158.3, 147.8, 142.6, 115.4, 110.6, 108.3,

104.4, 104.1, 66.2, 65.4, 61.9, 56.0, 55.1, 48.4,43.8,36.5,35.4,31.6,30.8,28.5,22.3,

18.7 ppm.

IR (CC14): 2920,2850, 1605, 1575, 1450, 1120 cml.

Mass spectrum (70 ev, m/e): 471(4%), 469(5%), 388, 308, 224, 154,99,86(100%).

110

1"

88

CD33" 5"

Correlation of lH and 13C Resonances, from HMQC Experiment

36.5 Cl"

43.8 C3

48.4 C4

55.1 C6" or C7"

56.0 C6" or C7"

61.9 C2

65.4 C8orC7

13CNMR (0)

18.7

22.3

28.5

30.8

31.6

35.4

66.2

Assignment

Cll

C4"

C5

C2"

C3"

C6

C7 or C8

111

lHNMR (0)

1.55 (s,3H)

1.32-1.29 (m, 2H)

1.83-1.71 (m,lH)

1.63-1.56 (m, 1H)

1.63-1.56 (m, 2H)

1.32-1.29 (m, 2H)

2.04-1.99 (m, IH)

1.83-1.71 (m, IH)

2.53 (dd,2H)

3.92 (dd, IH)

2.97 (ddd, IH)

3.76 (s,3H)

3.79 (s,3H)

5.11 (d, IH)

4.25-4.16 (m, IH)

4.06-3.99 (m, IH)

4.33-4.29 (m, IH)

4.06-3.99 (m, IH)

88Correlation of IH and 13C Resonances, from HMQC Experiment (Cont'd)

13CNMR (8) Assignment

104.1 C3' or C5'

104.4 C3' or C5'

108.3 Cl

110.6 ClO

115.4 Cl'

142.6 C4'

147.8 C9

158.3 C2' or C6'

158.6 C2' or C6'

IH NMR (8)

6.30 (s, IH)

6.32 (s, IH)

4.42 (5, IH)

4.37 (5, IH)

112

5' 1"

88

3"

Selected long-range connectivities observed in the HMBC Experiment

Position 13CNMR (8)

1 108.3 H2, H3, H5, H6, H7, H8

2 61.9 H3,H4,H6

3 43.8 H2, H4,H5

4 48.4 H2,H3,H5,H6,HI0,Hll

5 28.4 H3,H4,H6

6 35.4 H5

I' 115.4 H2, H3, H3', H5'

2', 6' 158.3, 158.6 H3, H3', H5', H6", H7"

4' 142.6 H3', H5', HI", H2"

113

1\o 0~Br

.' OCH3

88

Procedure:

o

93

To a solution of 88 (250 mg, 0.53 mmol) in acetone (100 mL) was added

50% aqueous perchloric acid (10 mL). The reaction mixture was stirred

vigorously at 40 oC, and the progress of the reaction was monitored by

tIc. After 48 h, the reaction mixture was cooled to room temperature and

neutralized carefully with sat'd aqueous NaHC03, extracted with ether, and

dried (MgS04). Evaporation of the solvent followed by purification by flash

column chromatography on silica gel eluting with 5% ethyl acetate in hexane

produced 160 mg (71 % yield) of ketone 93.

114

o

932-Bromo-3-[(2,6-dimethoxy-4-(S'-(2H3)pentyl)phenyl]-4-isopropenyl-

cyclohexan-t-one (93):

IH NMR (300 MHz, CDC13): 0 6.33 (5, 2H), 5.48 (d, J=11.4 Hz, -cns-, IH), 4.51

(5, IH), 4.45 (5, IH), 3.98 (dd, J= 11.4, 11.1 Hz, IH), 3.83 (5, 3H), 3.73 (5, 3H), 3.33

(ddd, J= 11.7, 11.4,4.2 Hz, IH), 2.77 (ddd, J= 14.1,3.6,3.1 Hz, IH), 2.62 (dd, J=13.5,6.6 Hz, IH), 2.54 (dd, J=8.1, 7.5 Hz, 2H), 2.03-1.82 (br m, 2H), 1.63-1.57 (m,

2H), 1.52 (5, 3H), 1.32-1.29 (m,4H) ppm.

13C NMR (75 MHz, CDC13): s 201.9, 158.2, 157.9,146.2, 143.4, 114.5, 111.6, 104.4,

104.1,60.1,55.9,55.1,48.1,47.0,40.2,36.4,31.5,30.8, 30.6, 22.2,18.5 ppm.

IR (CC14): 2920,2850, 1725, 1605, 1580, 1450, 1420,1230, 1120 em-I.

Mass spectrum (70 ev, m/e): 427(11%),425(12%),346(100%),317.

115

a

93

...

94

Procedure:

A solution of methyllithium (0.59 mL, 0.71 mmol) was added dropwise

to a suspension of anhydrous cuprous iodide (68 mg, 0.36 mmol) in ether

(6 mL) at 0 oc. The reaction mixture was stirred at 0 0C 10 min. A solution

of ketone 93 (l05 mg, 0.25 mmol) in ether (4 mL) was added to the lithium

dimethylcuprate solution at 0 °C during 30 sec. The reaction mixture turned

bright yellow after ca. 10 sec. A solution of N-phenyltriflimide (176 mg,

0.49 mmol) in freshly distilled DME (3 mL) was added immediately after

the appearance of the bright yellow color. The solution was stirred at 0 °C

for 5 h. The reaction was diluted with ether, washed with sat'd NH4CI

concentrated NH40H (9/1) solution, extracted with ether, and dried (MgS04).

Evaporation of the solvent followed by purification by flash column

chromatography on silica gel by eluting with 5% ethyl acetate in hexane

produced 90 mg (76% yield) of the cyclohexenyl triflate 94.

116

94

3[(2,6-dimethoxy-4-(S'-(2H3)pentyl)Iphenyll-d-Isopropenyl-I­

«(trifluoromethyl)sulfonyl)oxy)-cyclohex-l-ene (94):

IH NMR (500 MHz, COC13): B 6.32 (5, 2H), 5.67 (dd, J=2.3, 2.1 Hz, IH), 4.49

(dd, J=2.9, 1.5 Hz, IH), 4.39 (br d, J=1.5 Hz, IH), 4.15 (dm, J=10.1 Hz, IH), 3.74

(5, 6H), 2.84 (dd, J=15.5,7.8 Hz, IH), 2.67-2.58 (br m, IH), 2.54 (dd, J=7.9, 7.7

Hz, 2H), 2.37 (dm, J =15.5 Hz, IH), 1.91-1.86 (br m, 2H), 1.62-1.58 (br m, 2H),

1.61 (5, 3H), 1.34-1.30 (m, 4H) ppm.

13C NMR (125 MHz, CDC13): B 158.5,158.4,147.1,146.9, 143.1,124.0, 115.1,

103.9,55.5,44.5,36.5,34.8,31.6,31.0,28.8,28.1,22.3, 18.8 ppm.

IR (CHC13): 2920,2860, 1605, 1580, 1450, 1420, 1210, 1150, 1120, 1050, 980 em-I.

Mass spectrum (70 ev, m/e): 479(M+), 411, 329, 278(lOO%), 224, 205, 190, 152,

119.

117

7"

94

Correlation of lH and 13C Resonances, from HMQC Experiment

28.8 C5

31.0 C2"

31.6 C3"

34.8 C3

36.5 C1"

44.5 C4

55.5 C6", C7"

13C NMR (0)

18.8

22.3

28.1

Assignment

C9

C4"

C6

118

lHNMR(o)

1.61 (s,3H)

1.34-1.30 (m, 2H)

2.67-2.58 (br m, 1H)

2.37 (dm, 1H)

1.91-1.86 (br m, 2H)

1.62-1.58 (br m, 2H)

1.34-1.30 (m, 2H)

4.15 (dm, 1H)

2.54 (dd, 2H)

2.84 (dd, 1H)

3.74 (5, 6H)

7"

94

Correlation of lH and 13C Resonances, from HMQC Experiment (Cont'd)

13CNMR (8) Assignment lH NMR (8)

103.9 C3', C5' 6.32 (5, 2H)

111.2 C8 4.49 (dd, IH)

4.39 (br d, 1H)

115.1 Cl'

124.0 C2 5.67(dd, 1H)

143.1 C4'

146.9 C7

147.1 C1

158.4 C2' or C6'

158.5 C2' or C6'

119

7"

94

Selected long-range connectivities observed in the HMBC Experiment

Position 13CNMR (0)

1 147.4 H2, H3, H5, H6

2 124.0 H3,H4,H6

3 34.8 H2,H4,H5

4 44.5 H2,H3,H5,H6,H8,H9

5 28.8 H4,H6

6 28.1 H2,H4,H5

7 146.9 H3,H4,H5,H8,H9

l' 115.1 H2, H3, H4, H3', H5'

2', 6' 158.4, 158.5 H3, H3', H5', H6", H7"

4' 143.1 H3', H5', HI"

120

94 99

Procedure:

To a solution of 94 (100 mg, 0.21 mmol) in distilled CHCl3 (10 mL) was

added iodotrimethylsilane (purchased from Aldrich Chemical Co., 0.45 mL,

3.14 mmol) at 22 oc. After stirring for 12 h at 22 0C, more iodotrimethylsilane

(0.45 mL, 3.14 mmol) was added as the tic of the reaction mixture indicated

the presence of starting material. After 10 h, the reaction was quenched with

sat'd aqueous sodium sulfite, and extracted with CH2CI2. The combined

CH2Cl2 extracts were washed successively with sat'd aqueous NaHC03, brine

and dried (MgS04). The solvent was evaporated and the crude product was

purified by flash column chromatography on silica gel eluting with 2% ethyl

acetate in hexane to afford 46 mg (47% yield) of cyclized enol triflate. The

major by-product was 5'_(2H3)-olivetol dimethyl ether. Examination of the

IH NMR spectrum of the product showed the presence of both trans (99) and

cis ring junction isomers tirans.cis, 17:1). The mixture was used in the

succeeding step without further separation.

121

99

I-Methoxy-3-(5'-(2H3)penlyl)-6a,7,8,lOa-letrahydro-6,6-dimethyl-9­

«(trifluoromethyl)sulfonyl)oxy)-6H-dibe:azo[b,d]-pyran (99):

IH NMR (500 MHz, CDC13): a6.78 (br s, IH), 6.32 (5, IH),6.27 (5, IH), 3.82

(s,3H),3.39 (dd, J=10.9, 2.1 Hz,lH), 2.56-2.52 (m, 2H), 2.51 (dd, J=8.1, 7.5 Hz,

2H), 2.06 (br d, J= 12.6 Hz, IH), 1.78 (dt, J= 11.7, 2.1 Hz, IH), 1.61-1.49 (m,3H),

1.43 (5, 3H), 1.31-1.28 (m, 4H), 1.09 (5, 3H) ppm.

13c NMR (125 MHz, CDC13): 0157.9, 154.2, 148.5, 143.6, 122.5, 110.3, 107.4,

102.9,76.6,55.1,44.3,36.0,32.9,31.5,30.8,28.3,27.6, 24.3, 22.3, 19.1 ppm.

IR (CDC13): 2920,2850, 1615, 1570, 1410, 1205, 1140 em-I.

Mass spectrum (70 ev, m/e): 465(M+), 406, 332, 211, 152(100%), 69.

HRMS: for C22H26D3F305S 465.1876, found 465.1890.

122

99Correlation of 1H and 13C Resonances, from HMQC Experiment

13CNMR (0)

19.1

22.3

24.3

Assignment

C12orC13

C4'

C7

1HNMR (0)

1.09 (s,3H)

1.31-1.28 (m, 2H)

2.06 (br d, lH)

1.61-1.49 (m, lH)

27.6 C8

28.3 C12or C13

30.8 C2'

31.5 C3'

32.9 Cl0a

36.0 Cl '

44.3 C6a

55.1 C6'

76.6 C6

123

2.56-2.52 (m, 2H)

1.43 (s,3H)

1.61-1.49 (m, 2H)

1.31-1.28 (m, 2H)

3.39 (br d, lH)

2.51 (dd, 2H)

1.78 (dt, lH)

3.82 (s,3H)

99

Correlation of IH and 13C Resonances, from HMQC Experiment (Cont'd)

13CNMR (B) Assignment IHNMR (B)

102.9 C2 6.27 (5, 1H)

107.4 ClOb

110.3 C4 6.32 (5, 1H)

122.5 ClO 6.78 (br 5, 1H)

143.6 C3

148.5 C9

154.2 C4a

157.9 C1

124

99

Selected long-range connections observed in the HMBC Experiment

Position 13CNMR (8)

1 157.9 H2, H6'

2 102.9 H4, HI'

3 143.6 H2, H4, HI', H2'

4 110.3 HZ, HI'

4a 154.2 H4,HI0a

6 76.7 H7, H6a, H12, H13

6a 44.3 H7, H8, HI0, HlOa, H12,

H13

7 24.3 H6a, H8, HI0a

8 28.3 H6a,H7,HI0

10 122.5 H6a, H8, HI0a

lOa 32.9 H6a, H7

1 ' 36.0 H2, H4, H2', H3'

2' 30.8 HI " H3', H4'

3' 31.5 HI" H2', H4'

4' 22.3 H2', H3'

125

99 101

Procedure:

A solution of 46 mg (0.10 mmol) of the mixture of trans (99) and cis

ring junction isomers of the cyclohexenyl triflate, 0.03 mL of Et3N, 1.0 mg of

Pd(OAc)2, 2.0 mg of triphenylphosphine, 0.2 mL of methanol in 0.5 mL of

DMF was purged with carbon monoxide for 5 min. and then stirred under a

carbon monoxide atmosphere. The progress of the reaction was monitored by

tIc. After 12 h, the reaction mixture was poured into water, and extracted with

ether. The ether extracts were dried (MgS04) and solvent was evaporated.

The purification of the crude product by flash column chromatography on

silica gel eluting with 5% ethyl acetate in hexane afforded 30 mg of a mixture

of trans (101) and cis methyl esters. These stereoisomers were separated by

HPLC (Phenomenex Ultracarb 5 ODS 30 column, 250 x 10 mm, flow rate 2.5

mL/min, methanol),

126

101

(-)-trans-l-methoxy-3-(S'-(2H3)pentyl)-6a,7,8,10a-tetrahydro-6,6-dimethyl-9­

carbomethoxy-6H-dibenzo[b,dl-pyran (101):

IH NMR (500 MHz, CDCI3): a 7.81(br S, IH), 6.31(s, IH), 6.28 (s, IH), 3.87 (5,

3H), 3.73 (5, 3H), 3.31 (dd, J=11.4, 1.5 Hz, 1H), 2.59-2.53 (br m, 1H), 2.50 (dd,

J=8.1, 7.2 Hz, 2H), 2.47-2.39 (m, IH), 2.00 (dd, J= 12.6, 7.5 Hz, 1H), 1.71 (ddd,

J=12.6, 11.4, 1.8 Hz, IH), 1.63-1.54 (br m, 2H), 1.43 (5, 3H), 1.41-1.36 (m,lH),

1.33-1.28 (br m, 4H), 1.09 (5, 3H) ppm.

13c NMR (75 MHz, CDCI3): a168.2, 158.2, 154.4, 143.3, 143.2, 128.9, 110.3, 108.2,

102.9,77.6,55.3,51.5,44.5,36.0,34.6,31.5,30.8,27.5, 25.4, 24.4,22.3, 18.9 ppm.

IR (CHCI3): 2980,2915,2860,1720, 1620, 1575,1420, 1120, 1100 crrrt.

Mass spectrum (70 ev, m/e): 375(M+), 360, 356, 316, 272, 258, 229, 210(100%),

185.

HRMS: for C23H29D304 375.2489, found 375.2492.

Specific rotation: [a]210 =-2370 (c =0.005 g/ml, ethanol).

127

o

113

Procedure:

56 114

To a solution of the bis-2-ethoxyethyl olivetol (56, 765 mg, 2.35 mmol)

in anhydrous THF (30 mL) was added n-butyllithium in hexane (1.5 mL, 2.21

mmol) at 0 0C during 20 min. The reaction mixture was stirred at 0 0C for

10 min and then at 25 0C for 2.5 h. In a separate flask, a solution of lithium-2­

thienylcyanocuprate (23.5 mL, 2.35 mmol) was cooled to -78 0c. The lithiated

olivetol diether was transferred via cannula to the cuprate solution over 15

min. Following addition, the reaction was placed in an ice bath for 10 min,

cooled to -78 °C, and stirred for 1.5 h. To this mixed higher-order cuprate

solution at -78 0C, was added a mixture of 113 (200 mg, 1.47 mmol) and

BF3·Et20 (0.2 mL, 1.63 mmol) in THF (3 mL). The progress of the reaction

was monitored by tIc. After 4 h, the reaction mixture was diluted with ether,

washed with concentrated NH40H/sat'd NH4CI (l/9) solution, extracted

with ether, and dried (MgS04). Evaporation of the solvent followed by

purification by flash chomatography on silica gel eluting with 10% ethyl

acetate in hexane produced 500 mg (74% yield) of 114 as a mixture of

diastereomers due to the asymmetric center on each of the two ethoxyethyl

protecting groups.

128

o

114

HO

115

Procedure:

To a solution of ketone 114 (60 mg) in THF (5 mL) and H20 (1 mL) at

23 0C was added catalytic p-TSA and was stirred at 23 0C until tIc showed

complete consumption of starting material (10 h). The reaction mixture was

diluted with ether, washed with sat'd aqueous NaHC03, and dried (MgS04).

Evaporation of the solvent followed by purification by flash chromatography

on silica gel eluting with 10% ethyl acetate in hexane produced the hemiketal

115 (97% yield):

129

HO

115

Hemiketal 115:

IH NMR (CDCI3, 300 MHz): 3 6.29 (5, IH), 6.15 (5, IH), 5.01 (5, IH), 4.94 (5, IH),

4.73 (5, IH, exchangeable with D20), 3.62 (br 5, IH), 2.83 (5, IH, exchangeable

with D20), 2.46 (dd, J=7.8,7.5 Hz, 2H), 2.34 (br 5, IH), 2.09 (t, J= 12.6 Hz, IH),

2.05-1.91 (br m, 2H), 1.88 (5, 3H), 1.67-1.52 (m, 4H), 1.35-1.26 (m,5H), 0.88 (dd,

J =6.9, 6.6 Hz, 3H) ppm.

13C NMR (CDCI3, 75 MHz): 3 156.4,152.2,145.4,143.2,111.1,110.5,107.6,

106.8,98.7,42.7,35.7,35.3,31.5,31.2,30.8,30.4,22.5, 21.6, 14.0 ppm.

IR (neat): 3470, 2950, 2920, 2850, 1625, 1585, 1435, 1140, 1070 em -1

Mass 5pectrum(70 ev, m/e): 316(M+), 248,233(100%),204, 150.

HRMS: for C20H2803 316.2038, found 316.2013.

130

o

HO

115

...

116

Procedure:

To a solution of hemiketal 115 (130 mg, 0.41 mmol) in CHZCIZ (20 mL)

at 0 0C was added pyridine (0.10 mL, 1.23 mmol), catalytic DMAP and acetic

anhydride (0.10 mL, 1.03 mmol). The reaction mixture was stirred at 0 0C for

30 min and warmed to ambient temperature. The progress of the reaction

was monitored by tlc for the disappearance of the starting material (5 h). The

reaction was diluted with CHZCIZ, washed with brine, and dried (MgS04).

Evaporation of the solvent and purification of the crude product by flash

chromatography on silica gel eluting with 5% ethyl acetate in hexane gave

116 in 80% yield.

131

o

116

3-[4-Pentyl-2,6-bis(acetoxy)phenyl]-4-isopropenyl-cyclohexan-1-one (116):

Note: Some of the peaks in 1H NMR and 13C NMR are broadened due to

hindered rotation of the aryl 5ub5tituent.120

IH NMR (CDCI3, 300 MHz): B 6.78 (br 5, 2H), 4.62 (5, IH), 4.59 (5, IH), 3.25 (td,

J=12.0,4.8 Hz, IH), 2.96 (td, J=11.4,3.3 Hz, IH), 2.76 (t, J=14.4 Hz, IH), 2.54

(dd, J =8.1, 7.8 Hz, 2H), 2.51-2.39 (m, 2H), 2.32 (br 5, 6H), 2.10-2.02 (m, IH), 1.78

(qd, J=13.2,4.8 Hz, IH), 1.63-1.57 (m, IH), 1.54 (s,3H), 1.32-1.25 (m,6H), 0.88

(t, J=6.6 Hz, 3H) ppm.

13C NMR (CDCI3, 75 MHz): B209.7, 168.5 (br 5), 149.3 (br 5), 145.5, 142.8, 123.0,

120.9,119.9, 112.4,47.4,45.0,41.4,39.1,35.2,31.6,31.5,30.2,29.7, 29.4, 22.4, 19.2,

14.0 ppm.

IR (neat): 2920,2850, 1765, 1720, 1570, 1195, 1175 em-I.

Mass spectrum (70 ev, m/e): 400(M+), 341,298,272,231,206, 150, 117(100%).

HRMS: for C24H3205 400.2250, found 400.2234.

132

o

57

o

73

Procedure:

To a solution of 57 (150 mg, 0.33 mmol) in 25 mL of methanol was

added ca. 25 mg of PPTS. The reaction mixture was stirred at 25 °C until tIc

indicated that both ethoxyethyl groups had been removed (ca. 5-8 h). The

reaction mixture was diluted with ether, washed with brine and was dried

over MgS04' Evaporation of the solvent followed by flash chromatography

eluting with 15% ethyl acetate in hexane produced 80 mg (78% yield) of 73

as a single isomer.

133

o

73

Resorcinol (73):

IH NMR (COCI3, 300 MHz): 0 6.17 (5, 2H), 5.13 (5,2H, exchangeable with 020),

3.95 (t, J = 8.1 Hz, IH), 3.47 (dd, J = 18.9,7.8 Hz, IH), 2.68-2.39 (m, 5H), 2.30 (t,

J=5.4 Hz, IH), 1.36 (5,3H), 1.31-1.26 (m,4H), 0.99 (5,3H), 0.89 (t, J =6.9 HZ,3H)

ppm.

13C NMR (COCI3, 75 MHz): 0 217.2, 155.3, 142.6,113.7, 108.6,57.9,46.8,42.3,

37.9,35.2,31.5,30.6,29.5,26.2,24.4,22.5,22.1,14.0 ppm.

IR (CCI4): 3350,2950,2850, 1680, 1620, 1590, 1430, 1265, 1020 em-I

Mass spectrum (70 eV, m/e): 316 (M+), 310, 273,247,233 (100%),219,206, 193,

150,83,69,57.

Specific rotation: [a]24o =+69.10 (c =0.4, ethanol)

134

o

73

..o

74

Procedure:

To a solution of 125 mg (0.40 mmol) of resorcinol 73 in anhydrous

CHCl3 (12 mL) was added 0.42 mL (3.60 mmol) of stannic chloride at 25 oc.

The resulting mixture was stirred at 25 0C for ca. 24 h at which time tIc

(double elution using 10% ethyl acetate in hexanes) indicated the complete

consumption of the starting material. The reaction mixture was poured onto

ice and extracted with ether. The combined ether extracts were washed with a

sat'd aqueous solution of NaHC03 followed by brine, dried (MgS04), and

concentrated in vacuo. The purification of the crude product by flash column

chromatography eluting with 10% ethyl acetate in hexane produced 90 mg

(72% yield) of 74 as a white foam.

135

o

74

(->-trans-3-Pentyl-6,6a,7,8,lO,lOa-hexahydro-l-hydroxy-6,6-dimethyl-9H­

dibenzo[b,d]pyran-9-one (74):

IH NMR (CDCI3, 300 MHz): 0 6.26 (1H), 6.22 (5, IH, exchangeable with D20),

6.18 (5, IH), 3.99 (br d, J=15.0 Hz, IH), 2.88 (ddd, J= 11.7, 11.4,3.0 Hz, IH), 2.64­

2.48 (m, 2H), 2.44 (dd, J=8.1, 7.5 Hz, 2H), 2.18-2.09 (m, 3H), 1.96 (t, J=12.3 Hz,

IH), 1.59-1.53 (m, 2H), 1.47 (5, 3H), 1.31-1.26 (m, 4H), 1.12 (5, 3H), 0.88 (t, J=6.7

Hz,3H) ppm.

13C NMR (CDCI3, 75 MHz): 0 214.7, 155.3, 154.5, 143.6, 109.1, 107.9, 107.8, 76.4,

47.3,44.9,40.8,35.5,34.8,31.6,30.7,27.8,26.9,22.5, 18.9, 14.0 ppm.

IR (CCI4): 3260,2940,2920,2840, 1685, 1615, 1570, 1420, 1350, 1250, 1175, 1090,

1030 em-I.

Mass spectrum (70 ev, m/e): 316(M+), 301, 273, 260,245,233 (100%), 150, 95, 83,

69,57.

HRMS: for C20H2803 316.2038, found 316.2034.

Specific rotation: [a]D25 -43.70 (c =2.40, CHCI3)

136

o

74

o

104

Procedure:

To a solution of cyc1ized ketone 74 (150 mg, 0.48 mmol) in CH2Cl2

(5 mL) at 0 0C was added pyridine (0.06 mL, 0.72 mmol), catalytic DMAP and

acetic anhydride (0.06 mL, 0.63 mmol), The reaction mixture was stirred at

o0C for 30 min and warmed to ambient temperature. The progress of the

reaction was monitored by tIc for the disappearance of the starting material

(4 h). The reaction was diluted with CH2CI2, washed with brine, and dried

(MgS04). Evaporation of the solvent and purification of the crude product

by flash chromatography on silica gel eluting with 5% ethyl acetate in hexane

gave 104 in quantitative yield.

137

o

104

(-)-trans-3-Pentyl-6,6a,7,8,10,10a-hexahydro-1-acetoxy-6,6-dimethyl-9H­

dibenzo-lb,d]-pyran-9-one (104):

1H NMR (CDC13, 300 MHz): B6.58 (5, 1H), 6.41 (5, 1H), 3.28 (dt, J= 14.7,2.7 Hz,

1H),2.71 (td, J =11.6,3.3 Hz, IH), 2.60-2.54 (m, 1H), 2.49 (t, J =7.8 Hz, 2H), 2.45­

2.36 (m, 1H), 2.32 (5, 3H), 2.29-2.11 (m,3H), 1.95 (td, J= 12.0,2.4 Hz, IH), 1.60­

1.49 (m, 2H), 1.47 (5, 3H), 1.36-1.25 (m, 4H), 1.11 (5, 3H), 0.88 (t, J =6.6 Hz, 3H)

ppm.

13C NMR (CDC13, 75 MHz): B 209.6, 169.0, 154.3, 149.3, 143.7, 115.4, 114.6,

114.0,76.4,47.5,45.9,40.6,35.4,34.9,31.5,30.4,27.7, 26.7, 22.5,21.2, 18.8, 14.0

ppm.

IR (neat): 2940,2910,2840, 1760, 1705, 1620, 1560, 1420, 1360, 1195, 1175 crrr l.

Mass spectrum (70 ev, m/e): 358(M+), 316{100%), 299, 260, 233, 206, 150,69.

HRMS: for C22H3004 358.2144, found 358.2113.

138

o

104 105

Procedure:

To a solution of ketone 104 (12 mg, 0.033 mmol) in dry CH2Cl2 under a

static atmosphere of nitrogen was added methyl-DAST (0.04 mL, 0.330 mmol)

and the mixture was stirred at ambient temperature. The progress of the

reaction was monitored by tIc. Upon complete disappearance of the starting

material (l-2 d), water was added and the reaction was stirred for a few

minutes. The organic layer was separated and the aqueous layer was

extracted with several portions of CH2CI2. The combined organic extracts

were washed once with distilled water and dried (MgS04). Evaporation of

the solvent gave the crude product of 105 which was purified by flash column

chromatography on silica gel eluting with 2-5% ethyl acetate in hexane. The

yield of the reaction was 12 mg (96%).

139

105

9-Nor-9,9-bis-fluoro-hexahydrocannabinol acetate (105):

IH NMR (CDC13,300 MHz): 8 6.56 (s, IH), 6.41 (s, IH), 3.12-2.99 (m, 1H), 2.62

(t, J= 11.4 Hz, 1H), 2.50 (t, J= 8.1 Hz, 2H), 2.32 (s, 3H), 2.30-2.23 (m, IH), 1.93­

1.69 (m, 2H), 1.60-1.49 (m, 4H), 1.41 (s, 3H), 1.35-1.25 (m, 5H), 1.08 (s, 3H), 0.88

(t, J=6.6 Hz,3H) ppm.

13C NMR (CDC13, 125 MHz): 8 168.8, 154.6, 149.5, 143.5, 123.1 (t, J=241.4 Hz),

115.4,114.5,113.7,76.9,47.9,38.6 (t, J=23.1 Hz), 35.4, 34.1 (t, J= 24.0 Hz), 32.3 (d,

J=11.1 Hz), 31.5, 30.4,27.6, 24.2 (d, J=11.1 Hz), 22.5, 21.0, 18.9, 13.9 ppm.

19F NMR (CDC13, 283 MHz): 8 -91.1 (d, J=236.6 Hz),-99.1 (dm, J=238.0 Hz).

140

105 106

Procedure:

A stream of argon was bubbled through a solution of 105 (7 mg,

0.018 mmol) in methanol (5 mL) at 23 0C (15 min) followed by rapid addition

of powdered potassium carbonate. The reaction mixture was stirred at

ambient temperature for 15 min during which time tIc showed complete

disappearance of starting material. The mixture was filtered into a separatory

funnel with ether (20 mL), washed with IN Hel (2xlO mL) and sat'd aqueous

NaHC03 before drying over MgS04. Evaporation of the solvent in vacuo

followed by purification by flash chromatography on silica gel with 5% ethyl

acetate in hexane gave 5 mg (80% yield) of 106.

141

106

9-Nor-9,9-b isfluoro-hexahydrocannabinol (106):

IH NMR (CDCI3, 500 MHz): B 6.26 (d, J=1.3 Hz, IH), 6.08 (d, J=1.3 Hz, IH),

4.73 (s, IH, exchangeable with D20), 3.66-3.59 (m, IH), 2.77 (tt, J= 11.5,2.6 Hz,

IH), 2.43 (td, J =7.1, 2.2 Hz, 2H), 2.29-2.23 (m, IH), 1.92-1.87 (m, IH), 1.81 (dtt,

J=35.7, 13.4, 4.9 Hz, IH), 1.59-1.26 (series of multiplets, 9H), 1.41 (s,3H), 1.10

(s, 3H), 0.88 (t, J=6.3 Hz, 3H) ppm.

13C NMR (CDC13, 125 MHz): B 155.0,154.4,143.3,123.6 (t, J =240.7 Hz), 110.2,

108.0, 107.7, 76.6,47.7,37.9 (t, J=24.4 Hz), 35.4, 34.3 (t, J=24.4 Hz), 32.0 (d,

J=10.4 Hz), 31.5, 30.5, 27.8, 24.2 (d, J=10.5 Hz), 22.5, 19.0, 13.9 ppm.

19p NMR (CDCI3, 283 MHz): B-91.4 (d, J =238.1 Hz), -99.8 (dm, J=247.7 Hz)

ppm.

IR (neat): 3390,2950,2920,2870,2850, 1620, 1575, 1425, 1365, 1090 em-I.

Mass spectrum (70 ev, m/e): 338(M+), 318, 295, 282(100%), 262,235, 193.

HRMS: for C20H28P202 338.2057, found 338.2063.

142

o

114

2 stepsII'

121

Procedure:

To a solution of LDA at 0 0C, prepared from 0.37 mL (2.60 mmol) of

diisopropylamine, 2.43 mmol of n-butyllithium and 20 mL of THF, was

added a solution of 400 mg (0.87 mmol) of 114 in 5 mL of THF. The solution

was stirred at 0 0C for 45 min and treated with N-phenyltriflimide (930 mg,

2.60 mmol) in DME (4 mL). After stirring at 0 0C for 30 min, the reaction

mixture was diluted with ether (15 mL) and washed with sat'd aqueous

NaHC03, and extracted with ether. The organic layer was dried (MgS04)

and concentrated to give crude 120, in which the ethoxyethyl groups were

removed hydrolytically by treatment with catalytic PPTS in methanol at

23 0C. The crude diol121 was purified by flash column chromatography on

silica gel, eluting with 7% ethyl acetate in hexane. The overall yield of 121

from 114 was 57%.

143

121

4-[2,6-Dihydroxy-4(penlyl)phenyl]-5-isopropenyl-2-«(trifluoromethyl)

sulfonyll-oxyl-cyclohex-f-ene (121):

IH NMR (CDCI3, 300 MHz): B 6.10 (5, 2H), 5.82 (br 5, IH), 4.74 (5, IH), 4.62 (5,

2H, exchangeable with D20), 4.56 (5, IH), 3.58 (td, J = 11.3,5.4 Hz, IH), 3.24 (td,

J=11.3,5.4 Hz, IH), 3.06 (br t, J=12.6 Hz, IH), 2.41 (dd, J= 8.1, 7.5 Hz, 2H), 2.34­

2.17 (br m, 3H), 1.57 (5, 3H), 1.54-1.52 (m, 2H), 1.31-1.25 (br m, 4H), 0.89 (dd, J =6.9,6.6 Hz, 3H) ppm.

13C NMR (CDCI3, 75 MHz): B 154.7 (br 5), 148.5,146.9, 143.0, 117.7, 112.5, 111.6,

108.5,43.1,35.3,34.4,31.9,31.5,30.5,29.9,22.5, 18.3, 14.0 ppm.

IR (CC14): 3450,2960,2920,2850,1620,1590, 1410,1240, 1205, 1140, 1035 crrrl.

Mass spectrum (70 ev, role): 448(M+), 392, 299,247,231, 193(100%), 149, 109,

81.

HRMS: for C21H27F305S 448.1531, found 448.1522.

144

121

..

122

Procedure:

To a suspension of anhydrous lithium carbonate (0.22 mmol) and

lithium chloride (1.56 mmol) in THF (5 mL) under a static nitrogen

atmosphere, was added a solution of 121 (0.22 mmol) in THF (2 mL). The

mixture was heated to a gentle reflux. After 30 min, hexamethyldistannane

(0.22 mmol) in THF (2 mL) was added via cannula followed by catalytic

tetrakis(triphenylphosphine)palladium(O) in THF (1 mL). The reaction

mixture was heated at 60 0C for 12 h, during which time tlc indicated the

complete consumption of starting material. The reaction was diluted with

ether (20 mL), washed with sat'd aqueous NaHC03 and dried (Na2S04).

Solvent evaporation produced the crude product, which was purified by

flash chromatography on silica gel eluting with ethyl acetate: hexane:triethyl

amine (86:10:4 ratio) to give 122 (73% yield).

145

122

4-[2,6-Dihydroxy-4-(pentyl)phenyl]-5-isopropenyl-2-trimethylstannyl­cyclohex-1-ene (122):

1H NMR (CDC13, 300 MHz): B 6.13 (s,2H), 5.93 (br 5, 1H), 4.72 (5, 1H), 4.54 (5,

1H), 3.38 (td, J=11.1,5.1 Hz, 1H), 3.18 (td, J=11.1,5.1 Hz, IH), 2.83-2.71 (m,1H),

2.42 (dd, J=8.1, 7.5 Hz, 2H), 2.34-2.13 (br m, 3H), 1.59 (5, 3H), 1.55-1.50 (m, 2H),

1.31-1.25 (m,4H), 0.89 (dd, J= 6.9, 6.6 Hz, 3H), 0.08 (5, 9H) ppm.

13C NMR (C6D6, 75 MHz): B 149.1, 141.7, 140.6, 136.7, 115.3, 110.8, 108.5 (br 5),

44.9,36.8,35.8,35.7,34.8,31.9,31.0,22.9, 18.8, 14.2, -10.4 ppm.

IR (CC14): 3450, 2960,2920,2850,1620,1585, 1425 em-1.

146

122 123

Procedure:

To a solution of 122 (230 mg, 0.50 mmol) in CH2Cl2 at 0 0C was added

pyridine (0.14 mL, 1.75 mmol), catalytic DMAP and acetic anhydride (0.14 mL,

1.50 mmol), The reaction mixture was stirred a 0 0C for 30 min and warmed

to ambient temperature. The progress of the reaction was monitored by tIc

for the disappearance of the starting material (4 h). The reaction was diluted

with CH2CI2, washed with brine, and dried (Na2S04). Evaporation of the

solvent and purification of the crude product by flash chromatography on

silica gel eluting with ethyl acetate:hexane:triethylamine (86:10:4 ratio) gave

123 in 87% yield.

147

123

4-[4-Pentyl-2,6-bis(acetoxy)phenyl]-5-isopropenyl-2-trimethylstannyl-cyclohex­l-ene (123):

IH NMR (C6D6, 300 MHz): B 6.98 (br 5, IH), 6.77 (br 5, IH), 5.98 (5, IH), 4.95 (5,

IH), 4.73 (5, IH), 3.38 (td, J = 10.5,6.6 Hz, IH), 3.21 (td, J= 10.5,5.7 Hz, IH), 2.74­

2.66 (m, 2H), 2.42-2.31 (m, 2H), 2.28 (dd, J=8.1, 7.2 Hz, 2H), 1.79 (br 5, 6H), 1.69

(5, 3H), 1.39-1.32 (m, 2H), 1.12-1.08 (m, 4H), 0.77 (t, J=6.3 Hz, 3H), 0.09 (5, 9H)

ppm.

IR (CCLt): 2960,2920,2840,1765,1195, 1175 crrrl,

148

123

F

124

Procedure:

To a suspension of silver carbonate (20 mg, 0.072 mmol) in CH2CI2,

(2.0 mL) under a static atmosphere of nitrogen at 22 0C was added triflic acid

(trifluoromethanesulfonic acid, 16 mg, 1.5 equiv., ca. 8.7 mg/drop) and stirred

for 30 min.114 The solution of vinyl stannane 123 (38 mg, 0.059 mmol) in

CH2C12 (2.0 mL) and an equimolar amount of xenon difluoride (12 mg) in

CH2C12115 (1.0 mL) was added in rapid succession via cannula using positive

nitrogen pressure. The progress of the reaction was monitored by tlc for the

complete disappearance of starting material (ca. 3 min). The reaction mixture

was diluted with CH2Cl2 and washed with saturated aqueous NaHC03. The

organic layer was dried (MgS04) and filtered through a short pad of silica gel.

After solvent evaporation, the product was purified by flash chromatography

on silica gel eluting with 2% ethyl acetate in hexane to give 57% yield (16 mg)

of 124.

149

F

124

4-[2,6-Bis(acetoxy)4(pentyl)phenyl]-5-isopropenyl-2-fluoro-cyclohex-1-ene

(124):

IH NMR (CDC13, 300 MHz): S 6.78 (br s, 2H), 5.25 «a. J=16.5, 1.8 Hz, IH),

4.63 (5, IH), 4.58 (5, 1H), 3.15 (td, J=11.4,5.7 Hz, IH), 2.86 (td, J=11.1,6.6 Hz,

IH), 2.55 (dd, J=8.1, 7.5 Hz, 2H), 2.52-2.45(m, IH), 2.33 (5, 6H), 2.31-2.24 (m,

IH), 2.14-2.12 (m, 2H), 1.63-1.58 (m,2H), 1.52 (5, 3H), 1.33-1.25 (m, 4H), 0.88

(dd, J =6.9,6.6 Hz, 3H) ppm.

19p NMR (CDC13, 283 MHz): S -104.04 (m) ppm.

IR (CC14): 2920,2850,1770, 1370, 1200, 1180em -1.

Mass spectrum (70 ev, m/e): 402(M+), 384, 360, 318,263,235, 193(100%).

HRMS: for C24H31P04 402.2206, found 402.2202.

150

F

124

F

125

Procedure:

A stream of argon was bubbled through a solution of 124 (16 mg) in

methanol (3 mL) at 23 0C followed by rapid addition of powdered potassium

carbonate. The reaction mixture was stirred at ambient temperature for 15

min during which time tlc showed complete disappearance of starting

material. The mixture was filtered into a separatory funnel with ether,

washed with IN HCI and sat'd aqueous NaHC03 before drying over MgS04.

Evaporation of the solvent in vacuo followed by purification by flash

chromatography on silica gel with 5% ethyl acetate in hexane gave 10 mg of

125 in quantitative yield.

151

F

125

4-[2,6-Dihydroxy-4(pentyDphenyl]-5-isopropenyl-2-fluoro-cyclohex-l-ene(125):

IH NMR (CDCI3,300 MHz): a 6.11 (5, 2H), 5.25 (dd, J= 16.5, 5.4 Hz, IH), 4.73

(s, IH), 4.62 (5, 2H, exchangeable with D20), 4.54 (5, IH), 3.52 (td, 11.7, 5.7 Hz,

IH), 3.18 (td, J=11.1,5.1 Hz, IH), 2.89 (br t, J=14.4 Hz, IH), 2.42 (dd, J =8.1,7.5

Hz, 2H), 2.28-2.05 (br m,3H), 1.57 (5, 3H), 1.55-1.51 (m, 2H), 1.31-1.26 (m,4H),

0.89 (dd, J=6.9, 6.0 Hz,3H) ppm.

IR (CCI4): 3420,2960,2920,2840, 1620, 1580, 1430,1120 em -1.

Mass spectrum (70 ev, m/e): 319,318,300,263,231(100%), 199.

HRMS: for C20H27F02 318.1995, found 318.2005.

152

69 126

Procedure:

To a suspension of anhydrous lithium carbonate (5 mg, 0.07 mmol)

and lithium chloride (20 mg, 0.49 mmol) in THF (5 mL) under a static

nitrogen atmosphere, was added a solution of 69 (30 mg, 0.07 mmol in THF

(5 mL). The mixture was heated to a gentle reflux. After 30 min, a solution

of hexamethyldistannane (23 mg, 0.07 mmol) in THF (l mL) was added via

cannula followed by catalytic tetrakis<triphenylphosphine)palladium(O) in

THF (l mL). The reaction mixture was heated at 60 0C for 6 h, during which

time tIc indicated the complete consumption of starting material. The

reaction was diluted with ether (5 mL), washed with sat'd aqueous NaHC03

and dried (Na2S04). Solvent evaporation produced the crude product, which

was purified by flash chromatography on silica gel eluting with ethyl

acetate:hexane:triethylamine (86:10:4) to give 12678% (25 mg) yield.

153

126

1-Hydroxy-6a,7,10,10a-tetrahydro-6,6-dimethyl-9-trimethylstannyl-6H­

dibenzo[b,d]-pyran (126):

IH NMR (CDCI3, 300 MHz): s 6.27 (5, IH), 6.10 (5, IH), 5.87 (br 5, IH), 4.67

(5, IH, exchangeable with D20), 3.50 (br d, J=16.2 Hz, IH), 2.70 (td, J=10.5,

4.2 Hz, IH), 2.43 (dd, J=8.1,6.9 Hz, 2H), 2.26-2.20 (m, IH), 2.06-1.81 (br m, 3H),

1.58-1.52 (m, 2H), 1.36 (5, 3H), 1.32-1.25 (m, 4H), 1.09 (5, 3H), 0.88 (t, J= 6.9 Hz,

3H), 0.10 (5, 9H) ppm.

154

126 127

Procedure:

To a solution of cyclized ketone 126 (115 mg, 0.25 mmol) in CH2Cl2 at

o0C was added pyridine (0.14 mL, 0.85 mmol), catalytic DMAP and acetic

anhydride (0.06 mL, 0.75 mmol). The reaction mixture was stirred at 0 0C for

30 min and warmed to ambient temperature. The progress of the reaction

was monitored by tIc for the disappearance of the starting material. The

reaction was diluted with CH2CI2, washed with brine, and dried (Na2S04).

Evaporation of the solvent and purification of the crude product by flash

chromatography on silica gel with ethyl acetate:hexane:triethylamine (86:10:4

ratio) gave 127 in 80% yield.

155

127

t-Acetoxy-6a,7,10,tOa-tetrahydro-6,6-dimethyl-9-trimethyIstannyl-6H­

bibenzolb.dl-pyran (127):

IH NMR (C6D6, 300 MHz): 0 6.87 (d, J= 1.5 Hz, IH), 6.58 (d, J=1.5 Hz, IH),

5.78 (br s, IH), 3.25 (dd, J=17.1,2.1 Hz, IH), 2.76 (td, J=10.8,4.5 Hz, IH), 2.39

(dd, J =7.9, 7.5 Hz, 2H), 2.14-2.03 (m, IH), 1.93 (s,3H), 1.86-1.76 (m, 2H), 1.65­

1.60 (m, IH), 1.53-1.43 (m, 2H), 1.25(5,3H), 1.19-1.14 (m, 4H), 1.03 (5, 3H), 0.79

(t, J=6.9 Hz, 3H), 0.15 (5, 9H) ppm.

13C NMR (C6D6, 75 MHz): 0 168.0, 155.4, 150.7, 143.0, 140.3, 135.5, 116.7, 115.8,

114.9,76.4,45.2,37.3,35.7,33.0,31.7,31.0,30.4,27.4, 22.8, 20.8, 18.5, 14.2, -10.5

ppm.

IR (C6D6): 2950,2920,2850, 1765, 1620, 1565, 1420, 1365, 1200, 1175 cmr].

156

127

2 steps

F

7'0

107 R=COCH3

128 R= H

Procedure:

To a suspension of silver carbonate (0.042 mmol) in CH2Cl2 (1 mL)

under a static atmosphere of nitrogen at 22 0C was added trifluoromethane­

sulfonic add (0.059 mmol) and stirred for 30 min. 114 The solution of vinyl

stannane 127 (0.039 mmol) in CH2Cl2 0.5 mL) and an equimolar amount

of xenon difluoride in CH2Cl2115 (1.0 mL) was added in rapid succession

via cannula using positive nitrogen pressure. The progress of the reaction

was monitored by tIc for the complete disappearance of starting material

(ca. 3 min). The reaction mixture was diluted with CH2Cl2 and washed

with sat'd aqueous NaHC03. The organic layer was dried (MgS04) and

filtered through a short pad of silica gel. After solvent evaporation, the

products were purified by flash chromatography on silica gel eluting with

2% ethyl acetate in hexane gave a mixture of 107 and alkene (5:1 ratio based

on 1H NMR integration of the vinylic protons). The hydrolysis of the ester

group in 107 according to the procedure described for the preparation of 125

followed by purification using flash chromatography on silica gel eluting

with 5% ethyl acetate in hexane gave 128 contaminated with a small amount

of alkene (17:1).

157

F

128

1-Hydroxy-6a,7,10,10a-tetrahydro-6,6-dimethyl-9-fluoro-6H-dibenzo[b,d]pyran

(128):

IH NMR (CDC13, 500 MHz): a 6.28 (d, J=1.3 Hz, IH), 6.09 (d, J =1.6 Hz, IH),

5.23 (ddt, J= 16.1,5.7,2.0 Hz, IH), 4.69 (5, IH, exchangeable with D20), 3.50

(dddd, J =16.7,8.1,4.8,1.6 Hz, IH), 2.83 (td, J =11.3,5.2 Hz, IH), 2.44 (td, J=7.5,

3.2, 2H), 2.22-2.17 (m, IH), 2.12-2.05 (m, IH), 1.90-1.85 (m, IH), 1.80 (td, J =11.5,

3.9 Hz, IH), 1.59-1.53 (m,2H), 1.40(5,3H), 1.34-1.25 (m, 4H), 1.12 (5, 3H), 0.88

(t, J=7.0 Hz, 3H) ppm.

13e NMR (CDC13,125 MHz): a 159.5 (d, J=255.3 Hz), 154.4, 154.2, 142.9, 109.7,

108.8,107.2,99.7 (d, J = 16.7 Hz), 76.1, 43.9, 35.0, 31.1, 31.0, 30.9 (d, J = 16.7 Hz),

30.2,27.3,24.1 (d, J = 9.7 Hz), 22.2, 18.1, 13.6 ppm.

19p NMR (CDC13,283 MHz): a -103.1 (m).

IR (neat): 3399,2957,2930,2871,2856, 1706, 1625, 1580, 1427, 1366, 1257, 1185,

1132, 1129, 1081, 1007, 811 em-I.

Mass spectrum (70 ev, m/e): 319, 318(M+, 100%), 275, 262, 246, 231, 193.

HRMS: for C20H27F02 318.1995, found 318.1982.

158

128

Correlation of 1H and 13C Resonances, from HMQC Experiment

13CNMR(o) Assignment 1H NMR(o)

159.5 C9

154.4 Cl

154.2 C4a

142.9 C3

109.7 C4orC2 6.28 (d, IH)

108.8 CI0b

107.2 C4orC2 6.09 (d, IH)

99.7 C8 5.23 (ddt, IH)

76.1 C6

43.9 C6a 1.80 (td, IH)

35.0 Cl' 2.44 (td, 2H)

31.1 C3' 1.34-1.25 (m, 2H)

159

128

Correlation of IH and 13C Resonances, from HMQC Experiment (Cont'd)

13CNMR (8) Assignment IH NMR (8)

31.0 CI0a 2.83 «a, IH)

30.9 CI0 3.50 (dddd, IH)

2.12-2.05 (m, IH)

30.2 C2' 1.59-1.53 (m, 2H)

27.3 C12or C13 1.40 (s,3H)

24.1 C7 2.22-2.17 (m, IH)

1.90-1.85 (m, 1H)

22.2 C4' 1.34-1.25 (m, 2H)

18.1 C120r C13 1.12 (s, 3H)

13.6 C5' 0.88 (t,3H)

160

o

104

OH

109

Procedure:

To a solution of ketone 104 (0.06 mmol) in THF and isopropanol (9:1)

at ambient temperature under a static atmosphere of nitrogen was added

sodium borohydride (1.05 mmol) portionwise and the mixture was stirred for

10 min, during which time tlc indicated the complete consumption of

starting material. The reaction was quenched with water, acidified carefully

with IN HCI and extracted with ether. The combined ether extracts were

washed once with IN HCI, sat'd aqueous NaHC03, and brine and dried

(MgS04). Evaporation of the solvent gave the crude alcohol which was

purified by flash chromatography on silica gel eluting with 20% ethyl acetate

in hexane to give the alcohol 109 as a single isomer (9f3-hydroxy isomer).

161

OH

109

9-Nor-9~-hydroxy-hexahydrocannabinol acetate (109):

1H NMR (CDC13, 300 MHz): B 6.55 (5, 1H), 6.38 (5, 1H), 3.74 (tt, J =11.4,4.2 Hz,

IH), 2.90 (br d, J=12.3, IH), 2.49 (t, J =7.8 Hz, 2H), 2.37 (td, J=11.7,2.4 Hz, IH),

2.30 (5, 3H), 2.16 (br d, J=9.9 Hz, IH), 1.88 (dd, J=12.6,3.0 Hz, IH), 1.62-1.42 (m,

5H), 1.38 (5, 3H), 1.35-1.09 (m, 6H), 1.06 (5, 3H), 0.88 (t, J =6.6 Hz, 3H) ppm.

IR (neat): 3388,2932,2871,2860, 1767, 1626, 1426, 1371, 1208, 1184, 1136, 1052,

1038 em-l .

Mass spectrum (70 ev, m/e): 360(M+), 342, 319, 318(100%), 300, 262, 257, 193.

HRMS: for C22H3204 360.2300, found 360.2304.

162

OH

109

..F

110

To the solution of 109 (0.05 mmol) in CH2Cl2 (3 mL) under a static

atmosphere of nitrogen at -78 0C was added methyl-DAST (5.10 mmol) and

was stirred at -78 oc. The reaction was monitored by tIc. Upon completion of

the reaction (ca. 4h), water was added and reaction mixture was warmed to

23 DC. The organic layer was separated and the aqueous layer was extracted

with CH2CI2. The combined organic extracts were washed once with distilled

water and dried (MgS04). Evaporation of the solvent followed by

purification by flash chromatography on silica gel eluting with 5% ethyl

acetate in hexane gave 2:1 mixture of 110 (42% yield) and elimination product

111 (21 % yield).

163

F

110

9-Nor-9a-fluoro-hexahydrocannabinol acetate (110):

1H NMR (CDCI3, 300 MHz): S 6.55 (d, J=1.5 Hz, IH), 6.39 (d, J=1.5 Hz, IH),

4.95 (d, J= 46.5 Hz, IH), 3.04-2.94 (m, IH), 2.79-2.71 (m, IH), 2.49 (t, J= 7.5 Hz,

2H), 2.30 (5, 3H), 2.23-2.14 (m, IH), 1.74-1.66 (m, IH), 1.64-1.41 (m, 5H), 1.39

(5, 3H), 1.32-1.27 (m, 5H), 1.09 (5, 3H), 0.88 (t, J=6.6 Hz,3H) ppm.

13c NMR (COC13, 125 MHz): 0 169.2, 154.8, 149.5, 143.0, 115.3, 115.1, 114.3,89.0

(d, J=168.4 Hz), 77.2, 48.6, 35.7 (d, J=19.7Hz), 35.4, 31.5, 31.2 (d, J = 21.1 Hz),

30.4,29.7,27.3, 22.9, 22.5, 21.0, 18.9, 14.0 ppm.

19p NMR (CDC13, 283 MHz): S -181.4 (br q, J=44.2 Hz) ppm.

IR (neat): 2932,2872,2858, 1769, 1568, 1427, 1367, 1206 em -1.

Mass spectrum (70 ev, m/e): 362(M+), 343, 342, 321, 320, 300(100%), 283, 257,

244,231.

HRMS: for C22H31P03 362.2257, found 362.2297.

164

F

112

9-Nor-9a-fluoro-hexahydrocannabinol (112):

Hydrolysis of the ester group was carried out according to the

procedure described for 124.

1H NMR (CDCI3, 300 MHz): a 6.26 (5, IH), 6.08 (5, IH), 4.98 (br d, J=47.4 Hz,

IH), 4.70 (5, IH, exchangeable with D20), 3.55-3.45 (m, IH), 2.91 (td, J=10.9,

2.7 Hz, IH), 2.43 (t, J=7.2 Hz, 2H), 2.24-2.16 (m, IH), 1.74-1.69 (m, IH), 1.61-1.51

(m, 4H), 1.39 (5, 3H), 1.32-1.26 (m, 6H), 1.10 (5, 3H), 0.88 (t, J=6.6 Hz, 3H) ppm.

13C NMR (CDCI3, 125 MHz): a 155.2,154.5,142.8, 110.2, 109.3, 107.7, 89.4 (d,

J=167.3 Hz), 76.6, 48.6, 35.4,35.2 (d, J=21.1 Hz), 31.5, 31.4 (d, J=22.6 Hz), 30.4,

29.4,27.5,22.8, 22.4, 19.0, 13.9 ppm.

19p NMR (CDCI3, 283 MHz): a -180.7 (qt, J=46.6,11.3 Hz) ppm.

IR (neat): 3532,3410,2932,2858, 1624,1578, 1427, 1133, 1039 cnrl.

Mass spectrum (70 ev, m/e): 320(M+), 300, 281(100%), 257, 244, 231.

HRMS: for C20H29P02 320.2151, found 320.2184.

165

OH

117

3-[4-Pentyl-2,6-bis(acetoxy)phenyl]-4-isopropenyl-1j3-hydroxy-eyclohexane

(117):

Reduction of the ketone in 116 was carried out according to the

procedure described for 104.

IH NMR (CDC13,300 MHz): a 6.79 (5, IH), 6.69 (5, IH),4.58-4.47 (m, 2H), 3.68­

3.58 (m, IH), 2.80 (td, J= 11.9,3.0 Hz, IH), 2.61-2.41 (m, IH), 2.53 (t, J = 8.4 Hz,2H), 2.34 (5, 3H), 2.30 (5, 3H), 2.11-1.96 (m, 2H), 1.83-1.25 (m, llH), 1.51 (s,3H),

0.88 (t, J=6.6 Hz, 3H) ppm.

IR (neat): 3489,3348,2954,2932,2859, 1770, 1645, 1624, 1573, 1450, 1370, 1201,

1180, 1029, 888 em-I.

Mass spectrum (70 ev, m/e): 402 (M+), 384, 360,342,318,300,261,219, 193, 150,

118,83 (100%).

HRMS: for C24H3405 402.2407, found 402.2384.

166

F

118

3-[4-Pentyl-2,6-bis(acetoxy)phenyl]-4-isopropenyl-la-fluoro-cyclohexane (118):

Alcohol 117, when subjected to the same conditions employed for the

synthesis of 110, afforded 118 in poor yield (9%) along with an approximately

equivalent amount of alkene.

IH NMR (CDCI3, 500 MHz): s 6.78 (br 5, IH), 6.71 (br s, IH), 4.90 (br d, J = 48.7

Hz, IH), 4.58 (5, IH), 4.53 (m, IH), 3.25 (td, J = 12.3,3.6 Hz, IH), 2.65 (tm, J =11.8

Hz, IH), 2.54 (t, J = 8.7 Hz, 2H), 2.33 (5, 6H), 2.17-2.12 (m, 1H), 2.08-2.02 (m, IH),

1.87-1.72 (m, 2H), 1.64-1.57 (m, 3H), 1.56 (5, 3H), 1.31-1.25 (m, SH), 0.88 (t, J =6.5

Hz, 3H) ppm.

13C NMR (COCI3, 125 MHz): () 169.4, 168.5, 149.7, 149.2, 147.4, 142.2, 124.7,

121.0,119.7,111.1,88.6 (d,J = 169. Hz), 48.0, 35.4 (d,J =23.8 Hz), 35.2, 33.1, 31.5,

31.0 (d, J =20.6 Hz), 30.2, 26.9, 22.5, 20.8, 19.0, 14.0 ppm.

19p NMR (COC13, 283 MHz): () -186.1 (qt, J=47.8,9.6 Hz) ppm.

IR (neat): 3075,2952,2930,2856, 1771, 1646, 1625, 1574,1457, 1440, 1429, 1368,

1199, 1181, 1033 em -1.

Mass spectrum (70 ev, m/e): 404(M+), 384, 362, 342, 341,320, 299,277.

HRMS: for C24H33P04 404.2363, found 404.2380.

167

122

I

129

Procedure:

To a solution of vinyl stannane 122 in CH2Cl2 (5 mL) under a static

nitrogen atmosphere at 0 °C was added a dilute solution of iodine in CH2Cl2

dropwise with vigorous stirring until a permanent light pink color remained

in the reaction mixture. The reaction mixture was diluted with CH2Cl2 and

washed with sat'd aqueous NaHC03 followed by brine and dried (Na2S04).

Solvent evaporation produced the crude product, which was purified by flash

chromatography on silica gel eluting with 2% ethyl acetate in hexane to give

129 in 78% yield.

168

I

129

4-[2,6-Dihydroxy-4-(pentyI)phenyl]-5-isopropenyl-2-iodo-cyclohex-1-ene (129):

lH NMR (CDCI3, 300 MHz): B 6.37 (br 5, lH), 6.09 (5, 2H), 4.72 (5, lH),4.64 (5,

2H, exchangeable with D20), 4.54 (5, lH), 3.58 (td, J=11.1,5.1 Hz, lH), 3.26 (td,

J= 11.1,5.1 Hz, lH), 3.14 (m, lH), 2.61 (dd, J=17.1,4.2 Hz, lH), 2.40 (dd, J = 8.1,

7.5 Hz, 2H), 2.34-2.24 (m, lH), 2.17-2.05 (m, lH), 1.57 (5, 3H), 1.56-1.51 (m,2H,

partially obscurred by the peak at 1.57 ppm), 1.30-1.26 (m,4H), 0.88 (dd, J =6.9,

6.3 Hz, 3H) ppm.

13C NMR (CDCI3, 125 MHz): B 155.0, 147.9, 142.7, 136.8, 122.9, 113.3, 111.1,

108.6,95.7,43.9,42.9,36.9,35.535.3,31.5,30.5,22.5, 18.4, 14.0 ppm.

IR (CCI4): 3450,2950,2920,2840, 1620, 1580, 1420 cm-1.

Mass spectrum (70 ev, m/e): 426(M+), 370, 299, 231, 193,71,69(100%).

HRMS: for C20H27I02 426.1056, found 426.1025.

169

I

130

1-Hydroxy-6a,7,10,10a-tetrahydro-6,6-dimethyl-9-iodo-6H-dibenzo[b,dlpyran

(130):

Iodination of 126 was carried out according to the procedure described for 122

to give 130 in 83% yield.

1H NMR (CDCI3, 300 MHz): B 6.36 (br s, IH), 6.26 (5, 1H), 6.09 (5, IH), 4.79 (5,

1H, exchangeable with D20), 3.87 (td, J = 17.7,4.2 Hz, IH), 2.89 (td, J =10.8, 4.5

Hz, IH), 2.43 (dd, J=8.4, 6.9 Hz, 2H), 2.36-2.28 (m, IH), 2.27-2.16(m, 1H), 1.99­

1.72 (m, 2H), 1.57-1.53 (m, 2H), 1.36 (5, 3H), 1.31-1.28 (m, 4H), 1.09 (5, 3H), 0.88

(dd, J=6.0, 6.9 Hz,3H) ppm.

IR (CCI4): 3390,2950,2920,2850,1620, 1570, 1425 cm-l.

Mass spectrum (70 ev, m /e): 426(M+), 370,300,231, 169, 111,69(100%).

HRMS: for C20H27I02 426.1056, found 426.1040.

170

APPENDIX 1: SPECTRA FOR SELECfED COMPOUNDS IN PART I,-- .~-----------_.- - -------------..,

,----j,.,

56

IH NMR SpectrumlCD03 ji

,I....----/

I

__j~! ~'!!'Ii I 0

-- j ·1I' \1.

I j, ,'i 0;10-;;" i.:»'~j: '. '_) \...-.-I' '~'-----.)'---.,.-,----r-------'""=, ._- ,.-r- r-- ,- , .... i - , .- ,--- ,-- 1'- ,-- ,---' ,-1- I

8 G 4 2. 0 1 " 0.1

13C NMR spectrumlCD03

" r- ,--r I i

oj 30 160

I ~r-I I I

140 12C

171

It..

ii

i1-

L1'1"

172

G 7 8 9 10 12

57IH NMR Spectrum/C0 03

(

I~-'r

----

f!

.-1 ~l_.---

L----- .l_LI I I I I I I8 6 4 2 0 PPM

2 :1 3 4 5 6 i 8 9 10 12

iiI

60tI!

L- ~_._~~. _1

173

lH NMR Spectrum/CD03

..i

p,

100

"....

~ 60­Z

"VI

~.."z~ 40-

20': ,. - .... i

Ib

I',.1

174

I I4 ?

HO(\

~Io PPM

10 12

60

IH NMR SpectrumlC003

r

!

-

L1LAl~.-

Ir--j , , , I

, , , r-' , , ,0-'--.' r-r-8 6 4 2 0 fTM

13C NMR spectrumlCD03

jI

:~I , j , , , I

, , , I' I ,I

, , , I , , , I I , , I , ,140 120 10(' ,u, II bO 40 ;Jr. PPM

175

m' ---:~

1'\'1. :••.•.:-. . • • •_. - .... -j,,;, '

)t".

i;..;.................i'i,I,

I:

II,,!.

IIi

I......~:,

I' .

,.1

176

6 7

61

IH NMR Spectrum/CD03

-rI

I)

t-_·,_.._-~.

'-1 I I I

8I6

11I I I

4

~lLc~. __ ~cI I I I .---.--- r--

2 0 PPM

,13C NMR spectrum/C003

I i i I I I I I I i i I I i i i I i i i I i I i I i i I I I I i I I I I I160 140 120 100 80 60 40 <'0 0 PPM

177

;Jr,

;060!

z ,-;" I;~

1:.,40,r.:,

!"

,

JIIi ._ .... _.•. _.;- ..

iI : .'

..... ,., ... , .• ! ''''''''''''''''''

Mass spectrum

6 8 9- 10

~T05223'44 xl Bgd=31 22-mAY-89 15:40+e:0S'24BpM~b9 I=16mvs Hm=743 TIC=b84S~~~

KRMRLI KK -2-10 C25H3404? 398le~. 1. S

90

80

70

60

50

40

30

20

10

o

178

7e-SERent:

PT= eO

350

El·Sys:IlIWBS0eCaL:PFKsee

*44 1.055366000

IlIASS CACC)400

........,r--..~~

I~CH3COO

62IH NMR SpectrumlC003

--_/

-.--,8

LI

/!

--:=~~ tld__I ,----, I" I I I 'r-'6 4 2 0 P~M

13C NMR spectrum/CDCl3

160 140 120 100

179

80 60

6:>I

20i

.,., •••• "f".-. •.•I, '

I·i··

III

.:..1.! .,

I:.,I':!

: . L 1

5 6

t "t ,i.·' '" . l> .1,,11 . :~:~.lOO

8 9

I. ,

10 12

'~i.:. i

II

Msss spectrum

1'''' ;.'

fTlTu::'2 ... -nt:£ ' ~gO=l'j =::-I.t"'I-~'":.'

Bp~l=l' I=~ •blD"'s h'n-~ T: .:-=-lS480COOOKAl1IHI ! •• 2 11 Ci:.G;';;'405? .. 1..

1€""i~tl !

l~·L&·~·~;·4; 7u-3EHcr,t '

Pi= 111';

EI+S~5 . ('lIdE>80u.:at . t=·ri~:;;lt-'

1131;; ! . :14"'601 ~.)"

219 2 '/

7&

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9 lJLU,JlijlMlJU~U~UaMLIlwU~lI..l,4LJw....I.---.li-

180

ll1ASS

Jl lOCH3 /--.! IA -- f

0I3COO 63

IH NMR SpectrumlCD03

--I

I

(-

--- -- -

f,------(

l~!

r~,tj.. _--------

! A A.--, i i I I I , , I , i , I i i , I 1

;... b 4 ') I PPMc

13C NMR spectrumlCOO3

,..1 .•. _.1, ~ ,I ~" j'T "/ ''fIHl "T~

--r-r-'I i , ,

", , I

,~rr-'

I I i 1 i I , I , I I I I r-o-'l~O 140 120 100 80 60 4-0 20 I'r'M

181

I"

I.

!..•,

: ! '1 ;

" .

,..

5

Mass. spectrum

6 11.

EI·Sys : IIIWB900Cal :PF1<Se9

149 1.064271000

?,~

80

70

sa513

40 69

813

213

I~'

O.50 le0

3 2

182

l'IASS

%OH rI

i IA

HO' '?

·651H NMR SpectrumlCDCl3 I)

~ I,

il-I

\JUlUc JlI I

I

! ~: I .l._.~ \1 ',

'v . .....-'

I........

I I I I I I i I I I I I I I I I I I8 6 4 ? 0 PPM

I

13C NMR spectrum/CDCl3

i

,l...... ~l. .» IL

" 'T 'T 'T1'-'---'--,----,.-, i i 1 i 1 i 1 1 i I I I. "-"-r

200 150 100 50 0 rr'.1

183

184

Infra-red spectrum

OH -_. _. _..

r (

~1"lo .....,

66 (IH NMR SpectrumlCn03 I

J(

(,--

/-

-----I'---

,---r-- l ~-

=LL. .UJ. il.l . '" \..i I i i i I I i I I I i I I i i i I

,''':, b 4 ;; I' pprv,

13C NMR spectrum/CD03

\

.1 .I

I~ I,. ~.\,

" .,,' '"'.', n~

i I I I I I I I I I I I I I I I I I I I I I I I i I I I I I I I I I IltiO 140 12o 100 80 bO 4(' ( (I (I PPM

185

OH

OH

Mass spectrum

2S9

2 4

193ss

~ S)

~: ~"tl IIILlb:U~~WlJ,~ln~:9"IIW""J.WIlall!iL4I.1Wl&~~1..JhlJt!·Sl!J!YJ'!t,.AA.!.U..JILA-513 1013 150 200

Il1T052221189 xl BgcP74 22-PIAV-S9 15:06·e: 18:43 79-SEBpl'l=0 1=8.9aws HIl=8 TIC=l35629999 Acnt.:KAI'lALI KK-2-35 C21H3e03? "" 1 PT- eo

1130- c;.

S0

B0

70

80

50

40

186

67

IH NMR Spectrum/CD03

/I'

I

I8

--_._-~

I

25

~ f 1 -·-'---·~"-1·

o·Vi

(j)

~(j)

·z<{0::I-

I6

187

I4

I2

Io

68

1H NMR SpectrumlC6D6 (I

Io PPM

I2

I

4I6

I8

,

/r:

.'f

(/

!,.....-._----,

-' I

-'-' I

-----..

LJ ~ ll.u_- I iI I I I I i I i i i

1H NMR SpectrumlCD03

--_...-

B 6

188

I Iii. I

I I I

160I I i

1+0iii

120I I

1QOI I i

80I I i

60iii

4-0I I

20Io PPM

13C NMR spectrumlCO03

II .I

I200

I150

189

I100

I50

Io PPM

Mass spectrum

~Te8111*4e xl Bgd=l? 8-RUG-B9 19'36·9'11:14 ?9-SEBp~=e 1=64mvs Hmc8 TIC=894984999 Rent'.KK 4 9 C21H2?05SF3 PT- eo

lee- 2:13

913

613

EI·S\jS' IUl889C& ·Pf1(899

fo48 1.99436?8016

213

113

a

1 '3 193 4 B

4 5

83 315

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58 lea 158 21313 2513 300 359 400 450I

190

QSOP3

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(0

69IH NMR SpectrumlCDCl3

(

,/,--;--~ I

r-'--/

I,--

.~ kll!,:!-~-L,Ll ;,1

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v "': \

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13C NMR spectrumlCDCl3 IIIIII

;

:

;

i I ""'"'!

~ ,,.~

I i i I i Ii i I i I I i i i I i i I i i I I i t r

160 ''''0 1.20 100 80 60 40 20 0 f'fM

191

Mass spectrum

~T0~lb~*48 xl Bgd=J9 13-AUG-8SBpfll=,-' 1=1.3t"I')sHm=e TIC=14S02eeeKA~~L) KK~4-11 C21H2705SF3 448

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14:413·0:12:43 7e-SEAcnt:

PT= 00

3' 2

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148 1.018727eee

448

40 11 S

100 150 200

192

350 4ee~ASS

450

i . I ~>'0 #

70lH NMR SpectrumlC003

("(

/

!/

»->:(

/r--- .>

!r-

J~llL Iv~ J\~ '//1 .... ..)-

I I", l, 4 ')

(

j

13C NMR spectrumlCD03

l' PPMI

;nI

4(1I

bOI

f',(JI

100I

120I

140I

IhO

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180

193

Mass spectrum

~T091~1#42 xl Bgd=33 14-AUG-8909'52·9=11:14 79-SE EI·BpIQ=O 1=6.5mvs Hm=0 TIC=47304000 Acnt:. Sys:P1L1B800~,Afl1fiILI KK-4-23 II C22H3004 358 PT- eo .......Cal :PF"K800

lAR. ~po 14295e9~

2 1

3E 2

174

•.1 lit. ,I " MASS390 350250

.1, 1 IoJ II2S0

1 3

15050

I;;19 91 1\9

Ill, 11J. T..~ ,1.• .11 I

90

80

7~

80

'5"

4'1.

30

2'3

10

0

\

194

~

>l I ~o71

1H NMR SpectrumlCDCl3

-~I I-- ----

;~-'

I I ~

llL-~u t lll!\J :'. \~ i

~~~ '.' \' ..... 'J ,",--,

I. ~ , -'_.'

I i I I i I i I8 6 4 2 0 r> f' tv1

13C NMR spectrumlCO03

I200

I II

150

II

100

195

I50

Io pp/v1

Mass spectrum

MTII0~5~19 xl 8gd=15 S-HOV-89BpM=el I=37mvs Hm=fl TIC=348324992KAMAL I C23H3e05 KI< -4 -23A

113(1. 5:'

80

80

70

S071

50

41385

313

20

Infra-red spectrum

14:136·13:136:28 7B-SEAcnt :

PT= 13°

EI·Sys:MLlB8eeCaL:PFKseB

119 i .e551113131332

2~5 ~31I J 2/2e0

196

250

o(

73

IH NMR spectrum/CD03(

(

f/

_._------,-

~-~- . ------'

I8

/ '-._-' '--- --I I

6I4

I2

Io PPM

In PPM

I')(1

I10(1

I150

I200

13C NMR spectrumlCDQ3

L ,j'W~,-

j I j j j j j j j i I j j I j

197

5! I ! 'I' r, I L I I I

Infra-red spectrum

Msss spectrum

xl BgcP1 8-JU.-98I=1991lvs HP644 TIC-Bl8484992

- 45 SYHTI£TIC C2eH2803?

PlASS <ACe)

316.

233. 288

193. 23783.

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30

28

10

o

198

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I

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13C NMR spectrum/C0 03

...,.,j L

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?OOI I

1'10

I I

199

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11I I I I I. i i

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25 3 4 5 6 (I 9 10 12100 lltl j.! ,·1, I II ,I., ", Ij. , ...... , ,,, "

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Mass spectrum

11111I

46•

xl Bgd-l 29-.ll.-88 99:53+8:93:2] 79-~

I=l8evs HPe TIC=432944992 Rent :PT= eo

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EI·StjS : JIII36e8cal :PFl<689'1~

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200

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IH NMR Spectrum/CD03~

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-_.-.

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13C NMR spectrum/COO3

-

,II l ,',J~~_~~~~ ~~i1'11~1 ,~, 'r~~I' '1'1'

-I' , , , I I I I ~'I'-', ,

I I , I '-1? r, (\ 1':>0 100 r l (1 r, pp~

201

Mass spectrum

:~gI22ij9 xl Bgd=l 12-SEP-91 16:24·9:92:47 79-SE"I"'~ 1=57mvs Hm=0 TIC=221S9300S Acnt:"~ALl KK-V-105 C9H120BR2 296 PT= 0°11)1)- 83

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lH NMR Spectrum/C003

I4

13C NMR spectrum/C003

If

L .1,1.. <1 .r . L. I .. .J '.L '" .. ... ... .1

r 1 ..... TW" q"T' T n '~ '" "I'If" I'

I I I I I I I1'jO 100 r,O

203

I

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Msss spectrum

17.2

1 9

I.d100

Ii ...150

I I. 1250 300 400 459

204

o

)

78IH NMR spectrum/CD03

r/

r~

I I j i

hI4

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13C NMR spectrumlCn03

I

r--r---r-,-,---r--'-', ,-_. r- r--r--" I

I i.' r·.r'~

205

.".

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'IM.b:.:.I:i:mL!:I:';:':~:(;L::r.::~· 1'.1.' '." ":"'"

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34

1Iffet5892.34 xl Bgd=lS 9-RAY-91BpR-0 IaUIWS . HP8 TICa14lR561898KAlR.I KK-VI II -4!S 394

leeseee7e

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BJ.l.lajlltMllWl••&a.l~~L.d"""........L""0...4""'---..----. MSS4BB

206

207

ppm

-... IV"."- '" '"I I I , I , II , I ,I , I I1 I I, I

t - - -- - -

L¢r'Br,.' OH"~

8-~ )JC

HO~

78

HMQC Experiment

- ~

.'~- i

-

-j

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=

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208

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13C NMR spectrum/CD03

,

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209

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210

36

350

t.•• •. I•. ,J.• I I"

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160 140 120 100 80 60 40 20 0 I i 1·1

211

Infra-red spectrum'. " ~ _' ••1..L

Mass spectrum

4 9

460

PlASS400

388

EI·Sys 11lII.dB809Cal IPF'K8S9

19 1.9931094916

29489990

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10e

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100

90

80

70

60

50

40

30

20

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0.IWIl~rMllI.""..............................L..""""-",,,,-----JL,-_.............:A:

212

88n.O.e

GE ~:l-1R Instruments /home/xenon lIgroups/tius!kk·noe.I TueAug 612:52:54 1991 Page I

500.11 ppm

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II

500.11 ppm

500.11 ppm

500.11 ppm

,) HII. /.. "....... _.\-. '.JJ,J

rrm

213

ppm

8 ~00 -.I a- u. "" .... ....,

Q Q Q Q Q '" Q '"I I I I I I I I I I , I I , I I

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88

HMQC Experiment

-:::l-:::l3

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.:..:::=.=:.",

. ...

I100

I60

ppm

214

I20

ppmU; - ~

.... '" "" Q"" Q 0 = =

0 0

s- e O· 'I!)- e 0

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r--\e- o 0

.....Br

"0

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111 =

- .~ . . - . - . -~ .

<> & ..: -e

·Il,

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ppm

215

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IH NMR spectrum/CD03!

((I

(

rr

L 1... .. L ~ Ll J)~I \., ~.L.

1 I I I I I I i I I I I Ic- b 4 2 (1 PPM

13C NMR spectrum/CO03

216

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Infra-red spectrum

Mass spectrum

217

.;

tu

EI·Sys .l1li3890eM. I PFIC868

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IH NMR spectrumJCDCl3

ppm

13C NMR spectrum/CDCl3

I",,-rtfo'_J\ U_r~_ .

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218

rptvl

flU

1.'1

Infra-red spectrum

2 4

Mass spectrum

~09295'l5 xl Bgd=9 29-SEP-9l 23:48·0:94:37 70-5(BpA=8 1=76avs HM=0 TIC=562197998 Rent:KfIIllAlI KK-IX-69 C23H28D3F"305S 479 PT= eo

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S=~-----------------~_II 7,' c.- __r

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120 100

220

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-----------~-'''---J'----~~

I

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-"----''- -J--, __1-----------'"-1___

0.00 ppm

0.00 ppm

0.00 ppm

0.00 ppm

Jc JJ,iI....

ppm

222

95lH NMR spectrum/CDCI.3

,-

I8

LI6

LIo PPM

1r rr~

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I150

13C NMR spectrum/COO3

.,Jl L. 11 • I, ,J 1.1 ,.I. II J ,'~

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223

co, Infra-red spectrum

224

enm

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97

IH NMR spectrum/COO3

'I11

III'

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13CNMR spectrum/COOS

225

I.I

Mass spectrum

1 4

·r~4e61.21 xl Bgd=13 6-APR-92 15:13+0:05:38 70-SEf,rQ=0 I=71mvs Hm--e TIC=Ii'26370es Acnt:flPlALI KK-IX-71 C22H270403 361 PT= eO1001 8

80

83

70

60

50

40

EI+Sys :1'IIdB800CaL :PFKSS0

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HMQC Experiment

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99

lH NMR spectrumlCOQ3

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IH NMR spectrumIC6D6

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13C NMR spectrumJCDQ3

732

lee

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Mass spectrum

233

EI·Sys : III.IB8OO~1Pfl(860.36 1.13

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HMQC Experiment

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o.

ppm

235

n.O.e

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236

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IH NMR spectrumlCDCl3

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13C NMR spectrum/CDCl3

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I100

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140I

160

" ..... ~ .a, • I I II.. I~ It

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237

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1lIT99131.18 xl Bgd=13 13-SEP-91Bp~=e I=39mvs Hm=9 TIC=5443829/6KA~ALI KK-I-48 C22H3004 358

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98

80

70

60

50

40

30

28

10

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241

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I'rn12122153 xl Bgc:P44 8-FEB-91BpJII=0 I=35lIvs HIl-e TIC=318428090KERR "'-29-33 C2eH28f'202 338

100.

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Wavanulllbar (cm-i)1000

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99

80

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244

110

lH NMR spectrum/CDCl3

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110

Infra-red spectrum

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3000 21:500 2000Wevenumb.,. (cm-s)

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Mass spectrum

2

350

2

32111283

2 72 1

246

1lIT11l5103118 xl Bgd=12 10-\l1AV-91 16'57+8: l1l4 :33 7l1l-SEBpIlI=11I 1=6.4mvs HM=0 TIC=129877l1l89 Rent :1lIK-211l-85 C22H3103F' 3S2 PT::a 111°

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249

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100- 2 3

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60

50

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Infra-red spectrum

OH

15:06·0:06:18 70-SE EI.Aent:

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26120729

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100 93

90

80

70

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255·

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118

lH NMR spectrumlCDCl3

u . _--;,,--i t

ppm

13C NMR spectrumlCDCl3

256

oIII

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362

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342

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300250

2 2

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120

100

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90

89

70

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13C NMR spectrum/COCl3

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REFERENCES

1. Schultes, R. E.; Hofmann, A. The Botany and Chemistry of

Hallucinogens, 2nd ed., Charles C. Thomas, Springfield, Ill. 1980.

2. Jones, H. c, Lovinger, P. W. The Marijuana Question, Dodd, Mead and

Co., Inc., New York, 1985, pp. 249-252.

3. (a) Bouquet, R. J. Cannabis. Bull. Narcotics, 1950, 2, 14.; 1951,3, 22.

(b) Brunner, T. F. Marijuana in ancient Greece and Rome? The literary

evidence, Bull. Hist. Med., 1973, 47, 344.

(c) Mechoulam, R. The Pharmacohistory of Cannabis sativa. In:

Cannabinoids as Therapeutic Agents, Mechoulam, R. ed., CRC Press,

Boca Raton, FL, 1986, pp. 1-19.

4. (a) Harris, L. S.; Dewey, W. L.; Razdan, R. K. Cannabis. Its Chemistry,

Pharmacology, and Toxicology. In: Handbook of Experimental

Pharmacology, Martin, W. R. ed., New York, Springer, 1977, pp. 371-429.

(b) Abel, E. L. Marijuana: The First Twelve Thousand Years"

Plenum Press, New York and London, 1980, pp. 11-12.

5. Chopra, I. c, Chopra, R. N. Bull. Narc. 1957, 9, 4.

6. (a) O'Shaugnessy, W. B. Trans. Med. Phys. Soc. Bombay. 1839,8,421.

(b) O'Shaugnessy, W. B. Cannabis. In: The Bengal Dispensatory and

Pharmacopoeia, Bishop's College Press, Calcutta, 1841, 579.

(c) O'Shaugnessy, W. B. Pharmacol. ]. Trans. 1843,2, 594.

7. Adams, R. Marihuana, Harvey Leet. 1941-1942,37, 168.

8. Todd, A. R. Experientia, 1946, 2, 55.

9. Gaoni, Y.; Mechoulam, R. I. Am. Chern. Soc. 1964, 86, 1646.

274

10. Mechoulam, R; McCallum, N. K.; Burstein, S. Chem. Rev. 1976, 76, 75.

11. Mechoulam, R; Edery, H. Structure-Activity Relationships in the

Cannabinoid Series. In: Marijuana: Chemistry, Pharmacology,

Metabolism and Clinical effects, Mechoulam, Red., Academic Press,

New York, 1973.

12. (a) Razdan, R K. Pharmacol. Rev. 1986,38, 75.

(b) Martin, B. R; Compton, D. R; Little, P. J.; Martin, T. J.; Beardsley, P.

M. Pharmacological Evaluation of Agonistic and Antagonistic Activity of

Cannabinoids. In: Structure-Activity Relationships of the Cannabinoids,

Rapaka, R S.; Makriyannis, A. eds., NIDA Research Monograph No. 79,

Rockville, MD. 1987, pp. 108-122.

13. Weissman, A. J. cu« Pharmacol. 1981,21, 159.

14. Mechoulam, R; Devane, W. A.; Glaser, R Cannabinoid Geometry and

biological Activity. In: Marijuana/Cannabinoids, Neurobiology and

Neurophysiology, Murphy, L.; Bartke, A. eds., eRC Press, Boca Raton,

Florida. 1992, pp. 1-3 and references cited therein.

15. (a) Leite, J. R; Carlini, E. A.; Lander, N.; Mechoulam, R Pharmacology,

1982,124, 141.

(b) Johnson, M. R; Melvin, L. S. The Discovery of Nonclassical

Cannabinoid Analgetics. In: Cannabinoids as Therapeutic Agents,

Mechoulam, Red., Boca Raton, CRC Press, 1986, pp. 121-146.

(c) Compton, D. R; Johnson, M. R; Melvin, L. S.; Martin, B. R t.

Pharmacol. Exp. Ther. 1992,260, 201.

(d) Melvin, L. S.; Johnson, M. R Structure-Activity Relationships of

Tricyclic and Nonclassical Bicyclic Cannabinoids. In: Structure-Activity

275

Relationships of the Cannabinoids, Rapaka, R 5.; Makriyannis, A. eds.,

NIDA Research Monograph No. 79, Rockville, MD. 1987, pp. 31-47.

16. (a) Dewey, W. L.; Martin, B. R; May, E. L. Cannabinoid stereoisomers:

pharmacological effects. In: Handbook of Stereoisomers: Drugs in

Psychopharmacology, Smith, D. F. ed., CRC press, Boca Raton, FL. 1984,

317.

(b) Mechoulam, R; Lander, N.; Srebnik, M.; Breuer, A.; Segal, M.;

Feigenbaum, J. J.; [arbe, T. U. c, Consroe, P. Stereochemical

requirements for cannabimimetic activity. In: Structure-Activity

Relationships of the Cannabinoids, Rapaka, R 5.; Makriyannis, A.

eds., NIDA Research Monograph No. 79, Rockville, MD. 1987, pp. 15-30.

(c) Also see references 11 and 13.

17. (a) Cunha, J. M.; Carlini, E. A.; Pereira, A. E.; Ramos, O. L.; Pimentel, c,Gagliardi, R; Sanvito, W. L.; Lander, N.; Mechoulam, R Pharmacology,

1980,21, 175.

(b) Consroe, P.; Snider, S. R Therapeutic potential of cannabinoids in

neurological disorders. In: Cannabinoids as Therapeutic Agents,

Mechoulam, Red., CRC Press, Boca Raton, FL, 1986, pp. 21-49.

18. (a) Wilson, R 5.; May, E. L.; Martin, B. R; Dewey, W. L.]. Med. Chern.

1976, 19, 1165.

(b) Bloom, A. 5.; Dewey, W. L.; Harris, 1. 5.; Brosius, K. K. ]. Pharmacol.

Exp. Ther. 1977,200,263.

(c) Wilson, R 5.; May, E. L.; Dewey, W. L. t. Med. Chern. 1979,22, 886.

19. (a) Johnson, M. R; Melvin, L. 5.; Milne, G. M. Life Sci. 1982,31, 1703.

276

(b) Weissman, A.; Milne, G. M.; Melvin, L. S. ]. Pharmacol. Exp. Ther.

1982,223,516.

(c) Melvin, L. S.; Johnson, M. R; Harbert, C. A.; Milne, G. M.; Weissman,

A. ]. Med. Chern. 1984, 27, 67.

(d) Reggio, P. H.; McGaughey, G. B.;Odear, D. F.; Seltzman, H. H.i

Compton, D. R; Martin, B. R Pharmacol. Biochern. Behav. 1991,40, 479.

20. (a) Johnson, M. R; Althuis, T. H.; Bindra, J. S.; Harbert, C. A.; Melvin,

L. S.; Milne, G. M. Potent analgesic derived from 9-nor-9f3-hydroxy­

hexahydrocannabinol, In: Problems of Drug Dependence 1980, Harris, 1.

S. ed. NIDA Research Monograph, No. 34, 1981, pp. 68-74.

(b) Johnson, M. R; Melvin, L. S.; Althuis, T. H.; Bindra, J. S.; Harbert, C.

A.; Milne, G. M.; Weissman, A. [. Clin. Pharmacol. 1981,21, 271s

21. (a) Little, P. J.; Compton, D. R; Johnson, M. R; Melvin, L. S.; Martin, B.

R t. Pharmcol. Exp. Ther. 1988,247, 1046.

22. (a) Howlett, A. c, Johnson, M. R; Melvin, L. S. Classical and

Nonclassical Cannabinoids: Mechanism of Action-Brain Binding. In:

Drugs of Abuse: Chemistry, Pharmacology, Immunology and AIDS,

Pham, P. T. K; Rice, K. eds., NIDA Research Monograph No. 96,

pp.l00-l11.

(b) Richardson, S.; Mirasadeghi, S.; Lynn, A.; Johnson, M. R; Melvin,

L. S.; Herkenham, M.; Rice, K C. Synthetic and Biological Studies of

Potential Affinity Ligands for the Cannabinoid Receptor Based on

CP-55,244. In: Problems of Drug Dependence 1990. Harris, L. ed.,

NIDA Research Monograph No. 105, Rockville, MD, 1990, pp. 140-146.

277

(c) Devane, W. A.; Dysarz III, F. A.; Johnson, M. R; Melvin, L. S.;

Howlett, A. C. Mol. Pharmacol. 1988,34, 605.

23. (a) Herkenham, M.; Lynn, A. B.; Little, M. D.; Johnson, M. R; Melvin, L.

S.; de Costa, B. R; Rice, K. C. Proc. Natl. Acad. Sci. U.S.A. , 1990, 87, 1932.

(b) Herkenham, M.; Lynn, A. B.; Johnson, M. R; Melvin, L. S.; de Costa,

B. R; Rice, K. C. J. Neurosci. 1991,11,563.

24. Matsuda, L. A.; Lolait, S. J.; Brownstein, M. J.; Young, A. c, Bonner, T. I.

Nature (London), 1990, 346, 561.

25. (a) Matsumoto, K.; Stark, P.; Meister, R G. J. Med. Chern. 1977,20, 17.

(b) Johnson, M. R; Melvin, L. S.; Althuis, T. H.; Bindra, J. S.; Harbet, S.

A.; Milne, G. M.; Weissman, A. J. Clin. Pharrnacol. 1981,21, 271?

(c) Reggio, P. H.; Seltzman, H. H.; Compton, D. R; Prescott, W. R Jr.;

Martin, B. R Mol. Pharrnacol. 1990,38, 854.

(d) Compton, D. R; Prescott, Jr., W. R; Martin, B. R; Siegel, c, Gordon,

P. M.; Razdan, R. K. J. Med. Chern. 1991,34, 3310.

(e) Seltzman, H,. H.; Hsieh, Y. -A.; Pitt, C. G.; Reggio, P. H. J. Org. Chern.

1991,56, 1549.

26. (a) Adams, R.; Harfenst, M.; Lowe, S. J. Arn. Chern. Soc. 1924,71, 1624.

(b) Loev, B.; Bender, P. E.; Dowalo, F.; Macko, E.; Fowler, P. J. J. Med.

Chern. 1973, 16, 1200.

(c) Martin, B. R; Compton, D. R; Thomas, B. F.; Prescott, W. R; Little, P.

J.; Razdan, R K; Johnson, M. R.; Melvin, L. S.; Mechoulam, R.; Ward, S.

J. Pharrnacol. Biochern. Behav. 1991,40, 471.

27. Wilson, R. S.; May, E. L. J. Med. Chern. 1975, 18, 700.

278

28. (a) Jones, G; Pertwee, R G.; Gill, E. W.; Paton, W. D. M.; Milsson, I. M.;

Widman, M.; Agurell, S. Biochem. Pharmacol. 1974,23,439.

(b) Hollister, L. E.; Gillespie, H. K; Mechoulam, R; Srebnik, M.

Psychopharmacology, 1987,92, 505.

(c) Mechoulam, R K.; Feigenbaum, J. J.; Lander, N.; Segal, M.; [arbe, T. U.

c, Hiltunen, A. J.; Consroe, P. Experientia, 1988,44, 762.

(d)Little, P. J.; Compton, D. R.; Mechoulam, R; Martin, B. R Pharmacol.

Biochem. Behan. 1989,32, 661.

29. (a) Leite, J. R; Carlini, E. A.; Lander, N.; Mechoulam, R Pharmacology,

1982,24, 141.

(b) Consroe, P.; Martin, A.; Mechoulam, R Anticonvulsant effects of

Cannabinoid stereoisomers and analogs in rats. In: Harvey, D. J. ed.,

Marijuana '84. Proceedings of the Oxford Symposium on Cannabis.

Oxford, IRLPress, 1985.pp. 705-712.

30. Charalambous, A.; Yan, G.; Houston, D. B.; Howlett, A. c.; Compton, D.

R; Martin, B. R; Makriyannis, A.]. Med. Chern. 1992,35,3076.

31. Devane, W. A.; Hanus, L.; Breuer, A.; Pertwee, R G.; Stevenson, L. A.;

Griffin, G.; Gibson, D.; Mandelbaum, A.; Etinger, A.; Mechoulam, R.

Science, 1992, 258, 1946.

32. Turner, C. E.; Elsohly, M. A.; Boeren, E. G.]. Natural Prod. 1980,43, 169.

33. Mechoulam, R; Gaoni, Y. 'Recent Advances in the Chemistry of

Hashish'. Fortsch. Chern. Org. Naturst. 1967,25, 175.

34. (a) Watanabe, K; Yamamoto, I.; Oguri, K; Yoshimura, H. Biochem.

Biophys. Res. Commun. 1979, 88, 178.

279

(b) Harvey, D. J. Chemistry, Metabolism and Pharmacokinetics of the

Cannabinoid, In: Marihuana in Science and Medicine, Nahas, G. G. ed.,

Paven Press, New York, 1984, pp. 37-107.

(c) Agurell, S.; Halldin, M.; Lindgren, J.-E.; Ohlsson, M.; Widman, M.;

Gillespie, H.; Hollster, L. Pharmacol. Rev. 1986,38,21-43.

(d) Harvey, D. J.; Samara, E.; Mechoulam, R]. Chromatogr. 1991,562,

299.

35. Pitt, C. G.; Hauser, F.; Hawks, R L.; Sathe, S.; Wall, M. E. J. Am. Chem.

Soc. 1972,94,8578 and references cited therein.

36. (a) Watanabe, K.; Yamamoto, I.; Oguri, K.; Yoshimura, H. Euro.].

Pharmacol. 1980,63, 1-

(b) Watanabe, K.; Kijima, T.; Narimatsu, S.; Nishikami, J.; Yamamoto, I.;

Yoshimura, H. Chern. Pharm. Bull. 1990,38, 2317.

37. Agurell, S.; Halldin, M.; Lindgrenm J.; Ohlsson, A.; Widman, M.].

Pharmacol. Rev. 1986,38, 21.

38. (a) GC/MS Assays for Abused Drugs in Body Fluids, Foltz, R L.;

Fentiman, Jr,. A. F.; Foltz, R B. eds., Chap. 6, NIDA Research

Monograph, No. 32, Rockville, MD. 1980, pp. 62-89.

(b) The Analysis of Cannabinoids in Biological Fluids, Hawks, R. L.

ed. NIDA Research Monograph, No. 42, Rockville, MD, 1982.

(c) Whiting, J. D.; Manders, W. W. J. Anal. Toxicol. 1982,6, 49.

(d) Baker, T. S.; Harry, J. V.; Russell, J. W.; Myers, R. L. t. Anal. Toxicol.

1984,8, 255.

(e) EISohly, M. A.; Standford, D. F.; Little, Jr., T. L. ]. Anal. Toxicol. 1988,

12,54.

280

39. (a) Dewey, W. L. Pharmacol. Rev.1986,38, lSI.

(b) Mechoulam, R.; Feigenbaum, J. J. Towards Cannabinoid Drugs. In:

Progress in Medicinal Chemistry, Ellis, G. P.; West, G. B. eds., Elsevier,

1987,24, 159.

40. (a) Archer, R. A.; Blanchard, W. B.; Day, W. A.; Johnson, D. W.;

Lavagnino, E. R.; Ryan, C. W.; Baldwin, J. E. J. Org. Chem. 1977,42,

2277.

(b) Archer, R. A.; Stark, P.; Lemberger, L. Nabilone. In: Cannabinoids as

Therapeutic Agents, Mechoulam, R. ed., Boca Raton, eRC Press, 1986,

pp.85-104.

41. (a) SaIlan, S. E.; Zinberg, N. E.; Frei, III., E. N. Engl.]. Med. 1975,293, 795.

(b) Jones, S. E.; Durant, J. R.; Greco, A.; Roberstone, A. Cancer Treat. Rev.

1982,9,45.

(c) Levitt, M. Cancer Treat. Rev. 1982,9,49.

(d) Plasse, T. F.; Gorter, R. W.; Krasnow, S. H.; Lane, M.; Shepard, K. V.;

Wadleigh, R. G. Pharmacol. Biochem. Behav. 1991,40, 695.

42. Mechoulam, R; Abramov, A.; Shohami, E. New observations on

cannabinoids as Potential Therapeutic Agents, In: International Cannabis

Research Society Abstracts, Session I, Clinical Pharmacology and

Therapeutic Potential, June 19-20, 1992,

43. Milne, G. M.; Johnson, M. R ]. Clin. Pharmacol. 1981,21, 367s.

44. Howlett, A.c.; Bidaut-Russell, M.; Devane, W. A.; Melvin, L. S.; Johnson,

M. R; Herkenham, M. Trends Neurosci. 1990,13,420.

45. [arbe, T. U. c, Hiltunen, A. J.; Mechoulam, R. t. Pharmacol. Exp. Ther.

1989,250, 1000.

281

46. (a) Hollister, L. E. Pharmacol. Rev. 1986/38/ pp. 1-20.

(b) Adler, M. W.; Geller, E. B. Ocular Effects of Cannabinoids. In:

Cannabinoids as Therapeutic Agents, Mechoulam, Red., Boca Raton,

CRC Press, 1986, pp. 51-70.

47. Garrett, E. R; Hunt, C. A.]. Pharm. Sci. 1974,63, 1056.

48. DUss, D. B.; Handrick, G. R; Dalzell, H. c, Razdan, R K]. Am. Chern.

Soc. 1978,100,2929.

49. Razdan, R K; Dalzell, H. c, Handrick, G. R ]. Am. Chem. Soc. 1974,

96,5860.

50. (a) Petrzilka, T.; Haefliger, W.; Sikemeir, C. Helv. Chim. Acta. 1969,52,

1102.

51. (a) Razdan, R K; Handrick, G. R.]. Am. Chern. Soc. 1970,92,6061.

(b) Baxter, R L.; Crombie, L.; Simmonds, D. J.; Whiting, D. A. t. Chem.

Soc., Perkin Trans. 1,1979, 2972.

52. Mechoulam, R; Braun, P.; Gaoni, Y.]. Am. Chern. Soc. 1972,94,6159.

53. Handrick, G, R; DUss, D. B.; Dalzell, H. c, Razdan, R K Tetrahedron

Lett. 1979/681.

54. (a) Fahrenholtz, K. E.; Lurie, M.; Kierstead, R W. ]. Am. Chem. Soc.

1967,89,5934.

(b) Razdan, R K; Puttick, A. J.; Zitko, B. A.; Handrick, G. R Experientia,

1972,28, 121.

55. Rickards, R. W.; Ronneberg, H.]. Org. Chem. 1984,49,572.

56. Chan, T. H.; Chaly, T. Tetrahedron Lett. 1982,23,2935.

57. Kowalski, C. J.; Sankar Lal, G. ]. Am. Chern. Soc. 1988, 110,3693.

58. Stoss, P.; Merrath, P. Synlett, 1991, 553.

282

59. Tius, M. A.; Gu, X-q.; Kerr, M. A. J. Chern. Soc., Chem. Commun. 1989,62.

60. Tius, M. A.; Kerr, M. A. Synth. Commun. 1988, 1905.

61. Tius, M. A.; Gu, X-q, J. Chern. Soc., Chern. Commun. 1989, 1171.

62. (a) Marino, J. P.; Dax, S. L. J. argo Chern. 1984,49,3671.

(b) Talley, J. J. J. argo Chern. 1985,50, 1695.

63. Moore, M.; Rickards, R W.; Ronneberg, H. Aust. J. Chern. 1984,37, 2339.

64. Huffman, J. W.; Zhang, X.; Wu, M. -J.; Joyner, H. H.; Pennington, W.

T. J. argo Chern. 1991,56, 1481.

65. (a) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 482l.

(b) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1985, 1109.

(c) Cacchi, S.; Lupi, A. Tetrahedron Lett.1992, 3939.

66. Huffman, J. W.; Joyner, H. H.; Lee, M. D.; Jordon, R D.; Pennington,

W. T. J. Org. Chern. 1991,56, 208l.

67. (a) Feutrill, G. I.; Mirrington, R N. Aust. J. Chern. 1972,25, 1731.

(b) Sher, F. T.; Berchtold, G. A. J. argo Chern. 1977, 42, 2569.

68. (a) Siegel, c, Gordon, P. M.; Razdan, R K. J. Org. Chern. 1989,54, 5428.

(b) Baek, S.-H.; Szirmai, M.; Halldin, M. M. Pharmacol. Biochem. Behav.

1991,40,487.

(c) Siegel, c, Gordon, P. M.; Dliss, D. B.; Handrick, G. R; Dalzell, H. c,Razdan, R K. J. argo Chern. 1991,56, 6865.

69. Grimshaw, J.; Grimshaw, J. T.; [uneja, H. R J. argo Chem., Perkin Trans.

1 1972,50.

70. Lipshutz, B. H.; Kozlowski, J. A.; Parker, D. A.; Nguyen, S. L.; McCarthy,

K. E. J. Organomei. Chern. 1985,285,437.

283

71. The solution of the cuprate was prepared according to Lipshutz's

procedure: Lipshutz, B. H.; Koerner, M.; Parker, D. A. Tetrahedron Lett.

1987,28,945.

72. (a) Melvin, L. S.; Johnson, M. R; Harbert, C. A.; Milne, G. M.; Weissman,

A. J. Med. Chem.1984, 27,67.

(b) Harbert, C. A.; Johnson, M. R; Melvin, L. S. US Patent 1983, 4,391,827.

(c) Johnson, M. R.; Melvin, L. S.; US Patent 1984, 4,486,609.

73. Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965,87, 1353.

74. Coxon, J. M.; Dansted, E.; Hartshorn, M. P.; Rochards, K. E. Tetrahedron,

1969,25,3307.

75. (a) Surburg, H.; Mondon, A. Chem. Ber. 1981, 114, 118.

(b) Nomura, M; Fujihara, Y. Nippon Kagaku Kaishi, 1985, 990.

(c) Bluthe, N.; Ecoto, J.; Fetizon, M.; Lazare, S. Eur. Pat. 21,952,June 19,

1979.

(d) Pellegata, R; Ventura, P.; Villa, M.; Palmisana, G.; Lesma, G. Synth.

Commun. 1985,15, 165.

(e) Delay, F. Chern. Abstr. 1986,105,97053.

76. Fitjer, L.; Quabeck, U. Synth. Commun. 1985, 15, 855.

77. Imuta, M.; Ziffer, H. J. Org. Chern. 1979,44, 1351.

78. Petrzilka, T.; Demuth, M. Helv. Chim. Acta. 1974,57, 121.

79. Tius, M. A.; Kannangara, G. S. K. J. Org. Chern. 1990,55,5711.

80. (a) Hendrickson, J. B.; Bergeron, R Tetrahedron Lett. 1973, 4607.

(b) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 979.

81. Pirrung, M. c, Thomson, S. A. J. Org. Chern. 1988,53,227.

82. Schwartz, A.; Madan, P. J. Org. Chem. 1986,51,5463.

284

83. Tius, M. A.; Kannangara, G. S. K Tetrahedron, 1992, 48, 9173.

84. Dalzell, H. c, Dliss, D. B.; Handrick, G. R; Razdan, R K J. argo Chern.

1981,46, 949.

85. Ando, M.; Wada, T.; Kusaka, H.; Takase, K; Hirata, N.; Yanagi, Y.]. argo

Chern. 1987, 52, 4792.

86. Martin, S. F.; Davidsen, S. K; Puckette, T. A. J. argo Chern. 1987,52, 1962.

87. Chung, S. K; Hu, Q. Y. Synth. Commun. 1982,12,261.

88. Grieco, P. A.; Nunes, J. J.; Gaul, M. D. J. Am. Chern. Soc. 1990, 112, 2277.

89 Miller, R D.; McKean, R J. argo Chern. 1981,46, 2412.

90. Olah, G. A.; Arvanaghi, M.; Vankar, Y. D.]. argo Chern. 1980,45,3531.

91. Kato, M.; Kamat, V. P.; Tooyama, Y.; Yoshikoshi, A.; J. argo Chem.1989,

54,1536.

92. Yang, D.; Pelletier, S. W. Chem. Cornmun.1968, 1055.

93. Corey, E. J.; Cane, D. E. J. argo Chern. 1971,36, 3070.

94. A sample of 5,-(2H3)olivetol dimethyl ether prepared previously

according to the published procedure (Girard, M.; Moir, D. B.; ApSimon,

J. W. Can. ]. Chern. 1987,65, 189) was used in this project.

95. Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980,21, 1357.

96. Liu, H-J.; Chew, S. Y.; Browne, E. N. C. Tetrahedron Lett. 1991,32,2005.

97. Corey, E. J.; Tius, M. A.; Das, J.]. Am. Chem. Soc. 1980, 102, 1742.

98. Alkylation of a-bromo ketones and a,a'-dibromo ketones by treatment

with lithium dialkykuprate followed by trapping of the enolate with an

alkyl halide had been reported.

(a) Posner, G. H.; Sterling, J. J. J. Am. Chern. Soc. 1973,95,3076.

(b) Dubois, J-E.; Lion, C: Moulineau, C. Tetrahedron Lett. 1971, 177.

285

99. [ung, M. E.; Lyster, M. A. ]. Org. Chern. 1977,42,3761.

100. [ung, M. E.; Blumenkopf, T. A. Tetrahedron Lett. 1978, 3657.

101. Sakurai, H.; Shirahata, A.; Sasaki, K.; Hosomi, A. Synthesis, 1979, 740.

102. Tius, M. A.; Kannangara, G. S. K.; Kerr, M. A.; Grace, K. J. S. Tetrahedron,

1993,49,3291.

103. Edery, H.; Grunfeld, Y.; Porath, G.; Ben-Zvi, Z.; Shani, A.; Mechoulam, R.

Arzneimittelforshung, 1972,22, 1995.

104. (a) Hollister, L. E. Pharmacology, 1974, 11, 3.

(b) Wilson, R S. J. Med. Chem. 1979,22,879.

(c) Watanabe, K.; Yamamoto, I.; Oguri, K.; Nishikami, J.; Yamamoto, I.;

Yoshimura, H. European ]. Pharmcol. 1980, 63, 1

(d) Watanabe, K.; Kijima, T.; Narimatsu, S.; Nishikami, J.; Yamamoto, I.;

Yoshimura, H. Chern. Pharm. Bull. 1990,38(8), 2317.

105. (a) Mechoulam, R; Varconi, H.; Ben-Zvi, Z.; Edery, H.; Grunfeld, Y.].

Am. Chern. Soc. 1972,94, 7930.

(b) Pitt, C. G.; Selzman, H. H.; Setzer, S. R; Williams, D. L. t. Lab. Camp.

1979, XVIII, 681.

(c) Charalambous, A.; Lin, S.; Marciniak, G.; Banijamali, A.; Friend, F.

L.; Compton, D. R; Martin, B. R Makriyannis, A. Pharmacal. Biochem.

Behav. 1991,40, 509.

106. (a) Marciniak, G.; Charalambous, A.; Shiue, C. -Y.; Dewey, S. L.; Schyler,

D. J.; Makriyannis, A.; Wolf, A. P. ]. Labelled Compd. Radiopharm. 1991,

30,415.

286

(b) Charalambous, A.; Marciniak, G.; Shiue, C. -Y.; Dewey, S. L.; Schyler,

D. J.; Wolf, A. P.; Makriyannis, A. Pharmacal. Biochem. Behav. 1991,40,

503.

107. Middleton, W. J. ]. Org. Chern. 1975, 40, 574.

108. Strobach, D. R; Boswell, G. A. Jr.]. Org. Chern. 1971,36,818.

109. The majority of the nonfluorination side reactions are dehydrations to

olefins. These accompany conversion of alcohols into fluorides and may

become the only reaction in certain hydroxy compounds.

110. Hudlicky, M. "Fluorination with Diethylaminosulfur Trifluoride and

related Aminofluorosulfuranes." In: Organic Reactions, 1988,35,513.

111. (a) Tius, M. A.; Kawakami, J. K. Synthetic Commun. 1992,22(10), 1461.

(b) Tius, M. A.; Kawakami, J. K. Synlett, 1993, 207.

See also, Hodson, H. F.; Madge, D. J.; Widdowson, D. A. Synlett, 1992,

831.

112. (a) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron, K. L.;

Gilbertson, S. R; Kaesler, R W.; Yang, D. c, Murray, C. K. ]. Org. Chem.

1986,51,277.

(b) Scott, W. J.; Crisp, G. T.; Stille, J. K. ]. Am. Chem. Soc. 1984, 106, 4630.

113. The conditions for the fluorination have been improved by Joel K.

Kawakami and will be published in the near future.

114. The flask was covered with aluminum foil to prevent decomposition of

silver carbonate and silver triflate.

115. Xenon difluoride was weighed in a glove box, and dissolved in CH2Cl2

using sonication.

287

116. Anand, S. P.; Quarterman, L. A.; Hyman, H. H.; Migliorese, K. G.; Filler,

R. J. Org. Chern. 1975,40,807.

117. (a) Burstein, S. H. "Inhibitory and Stimulatory Effects of Cannabinoids

on Eicosanoid Synthesis". In: Structure-Activity Relationships of the

Cannabinoids, Rapaka, R S.; Makriyannis, A. eds., NIDA Research

Monograph 79,1987, pp. 158-172.

(b) Burstein, S. H. U. S. Patent 4,847,290; Chern. Abstr.1990, 112, 677g.

(c) Burstein, S. H.; Audette, C. A.; Breuer, A.; Devane, W. A.; Colodner,

S.; Doyle, S. A.; Mechoulam, R t. Med. Chern. 1992,35, 3135.

118. Van Arman, C. G. cu« Pharm. Ther. 1974,16,900.

119. We thank Dr. Xue-qin Gu for providing a sample of (+)-11-nor-~9-THC­

9-carboxylic acid (131) which had been prepared according to the

published procedure (reference 59) using (S)-(-)-perillaldehyde.

120. A similar rotational non-equivalence of carbon resonances as a function

of the temperature has been reported earlier for the 13C nmr of

cannabidiol. Kane, V. V.; Martin, A. R; Jaime, c, Osawa, E.

Tetrahedron, 1984, 40, 2919.

288

INTRODUCTION

The classical approach to the synthesis of functionalized aromatic

compounds has been to start with a commercially available, cheap aromatic

hydrocarbonls) and make use of traditional substitution reactions to

introduce appendages and functionality. This strategy has served well, but it

is limiting for multistep organic synthesis because it normally requires that

the aromatic substitutions (nucleophilic and/or electrophilic) be carried out

at the very beginning of a sequence. Further, these substitution strategies

generally require protecting/deprotecting sequences which result in

diminution of overall yield. The formation of aromatic rings from non­

aromatic precursors, aromatic annelation, is therefore an important objective

in organic synthesis) The use of annelation procedures has advantages, such

as the synthesis of highly substituted aromatic rings in relatively few steps

and the formation of compounds with substitution patterns not easily

accessible through conventional routes. Also, the greater availability of

labeled acyclic precursors would provide easy access to labeled aromatic

compounds.

General methods for the preparation of phenols, pyridines and

substituted benzene rings from non-aromatic precursors have been reported.

The two most commonly employed methods for the construction of six­

membered rings, the Robinson annelation- and the Diels-Alder reaction,3

involve the union of a two-carbon unit with a four-carbon fragment.

Another approach involving the condensation of two three-carbon units, one

with two nucleophilic sites and the other containing two electrophilic sites

has been reported.f The regiochemistry of the reaction was controlled by the

289

differential reactivities of nucleophilic and electrophilic sites. G. S. Krishna

Rao and co-workers1k have reported a one-pot general procedure for

benzoannelation of homoallylic alcohols using the Vilsmeier reagent to

afford biphenyls and dihydrophenanthrenes.

Studies on benzoannelation of non-aromatic precursors by Tius and

co-workers have led to the elaboration of a-unsubstituted ketones into

phenols,S catechol monoethers,6 pyridines,7 hydroxy-p-quinones,8 m­

terphenyls'[, 2,3-disubstituted naphthalenes and phenanthreneslv and

unsymmetrical biphenylal l (Figure 5). The substituted biphenyls whose

preparation through classical methodology is often not straightforward are

potentially useful materials for liquid crystal synthesis.

OH OH o»ORo

(')Ar'Y

R

Figure 5: Aromatic compounds obtained from a-unsubstituted ketones

290

Further, an efficient general procedure for the synthesis of methyl­

substituted aromatic compounds from ketones was reported by Tius and Ali

in 1982.12 This synthetic sequence involves three steps: addition of the

methallylmagnesium chloride in ether at 0 0C to trimethylsilyl vinylogous

ester I, dehydration to form the ~-methallylic unsaturated aldehyde 2

and add-catalyzed intramolecular Prins reaction and dehydration to yield the

methyl-substituted aromatic compound 3. The cydization of 2 has been

carried out using p-TSA in refluxing benzene (Scheme 21). The mechanism

for the cyclization is believed to involve a cationic intermediate, a view

supported by the need for a cation stabilizing substituent (methyl group in the

above reaction). In the absence of a cation stabilizing group at C-2 of the

Grignard reagent, the yield of the cydization is low. A similar effect has been

SCHEME 21

a

2

b

3

Reagents: (a) methallylmagnesium chloride, ether, 0 0C and then 1Naqueous HCI, 3 h; (b) p-TSA, benzene, reflux.

291

observed by [unjappa and co-workers in related work. 13 Unsubstituted,

benzoannelated products are nevertheless accessible from cyclization of the

adducts of [2-(trimethylsilyl-2-propenyl]magnesium chloride.12 Further,

the conditions for the cationic cyclization step have been modified (PPTS

in benzene at 23 0C for 12 h) to accomodate add-sensitive functionality.1 4

This benzoannelation methodology is general enough to be applied

to both cyclic and acyclic ketones. In order to submit a large-scale (10 g of

3,4-cyclododeceno-l-methylbenzene) experimental procedure to Organic

Syntheses 15, it was necessary to identify potentially hazardous steps in the

published procedure and any safety measures taken during the reaction.

Further, it was desirable to avoid as much as possible the handling of large

quantities of potentially dangerous or carcinogenic materials.

292

RESULTS AND DISCUSSION

The sodium salt of 2-hydroxymethylene ketone 5 was prepared by

mixing an ether solution of ethyl formate and cyc1ododecanone (4) with a

suspension of sodium hydride in ether in the presence of a small amount

of methanol as a catalyst.16 Sodium hydride was washed with hexane to

remove mineral oil and ethyl formate was distilled from phosphorus

pentoxide. On large-scale, stirring of the heterogenous reaction mixture

required the use of a mechanical stirrer. A pressure-equalizing dropping

funnel was used to ease the addition of large volumes of reagents. The salt

obtained was washed once with ether to remove unreacted ketone and

residual mineral oil. Careful acidification of the sodium salt with IN HCI to

pH 6 afforded 5, which was used in the next reaction without purification.

o o OH

4

a

5

Reagents: (a) HC02CH2CH3, sodium hydride, ether, cat. methanol

The Grignard reagent, methallylmagnesium chloride, was prepared

from methallyl chlorideI 7 and magnesium turnings18 in anhydrous ether at

ooc. This reaction was exothermic and care should be exercised to add the

methallyl chloride at a moderate rate with adequate stirring and cooling of

293

the reaction mixture. In a separate flask, 5 was treated with a 1/1 (v/v)

mixture of chlorotrimethylsilane and triethylamine19 to produce the

hydrolytically labile trimethylsilyl vinylogous ester 6 which was immediately

added20 to an excess of methallylmagnesium chloride at 0 0c. The reaction

mixture was quenched by slow addition of saturated brine until the reaction

mixture becomes clear. The ether layer was decanted from the sodium salt

and unreacted magnesium. The crude product 7 which was obtained after

drying over magnesium sulfate, followed by concentration, was used in the

cyclization step without purification.

o

6

a ...

7

Reagents: (a) methallylmagnesium chloride, ether, a0C, then sat'd. brine

It was necessary to find conditions for the cyclization of 7 which did not

utilize large amounts of carcinogenic solvents, such as benzene. During the

benzoannelation reaction, a highly UV-active product was observed by

thin-layer chromatography (tlc) which underwent conversion to the final

product 9 on standing.21 The IH NMR spectrum of the UV-active product

revealed that it was the p-methallylic unsaturated aldehyde 8. When catalytic

294

BF3·Et20 was used in CH2Cl2 at low temperatures (-780C), the product

mixture consisted primarily of 8. The use of one equivalent of BF3·Et20 at

o0C for 20 min afforded a moderate yield of 9. The best conditions for the

reaction were obtained through the use of p-TSA (0.4 equiv. with respect to 5)

in toluene22 at 80 0C for 3h. The overall yield of the reaction was 86% from 5.

7

a ..

9

8

Reagents: (a) p-TSA, toluene, 80 0C, 3 h.

Several related methods for benzoannelation have been reported.23

Most provide aromatic sulfides or phenols that require additional

manipulation. The efficacy of the present benzoannelation methodology has

been demonstrated (Entries 1-7, Table 2) by its application to both cyclic and

acyclic ketones with one methylene group flanking the carbonyl. This

295

method is not limited to the preparation of methyl-substituted aromatics. By

using benzylmagnesium bromide instead of methallyl Grignard reagent, a

naphthalene can be appended onto the ketone.10 Similarly, phenanthreneslv

and m-terphenyls9 have been obtained conveniently and in high yield.

296

Table 2: Benzoannelation of Ketones

Entry 2-Hydroxymethylene ketone Product Overall yield (%)

1

2

3

4

~OH

t-Bu

o OH

(jo

297

t-Bu

52

76

79

74

Table 2: Benzoannelation of Ketones (Cont'd)

Entry 2-Hydroxymethylene ketone Product Overall yield (%)

5

6

CI a

66

89

o OH

7 65

8

o

298

86

CONCLUSION

This preparation describes a highly practical and efficient method

for the synthesis of structurally diverse aromatic compounds from non­

aromatic precursors. It is applicable to a wide variety of ketones and gives

rise to high yields of benzoannelated products. It is worthy of note that there

are no intermediate purification steps; both the nucleophilic addition of

methallymagnesium chloride and the aromatic cyclization take place cleanly.

The cyclization process is fast and avoids the use of benzene as a solvent. The

ease of the reactions, the high yields, and the convenience recommend its

use.

299

EXPERIMENTAL SECTION

A. General Procedure for the preparation of 2-(hydroxymethylene)ketone:

To a l-L, three-necked, round-bottomed flask equipped with a septum

inlet, mechanical stirrer, nitrogen inlet, and pressure equalizing dropping

funnel was added 92 mmol of sodium hydride (obtained from Aldrich

Chemical Company, Inc.). The mineral oil was removed from the sodium

hydride by washing with hexane, ether was added (250 mL) and the reaction

mixture cooled to 0 oc. A mixture of 77 mmol of ketone and 85 mmol of

ethyl formate (obtained from Aldrich Chemical Company, Inc., and distilled

from phosphorus pentoxide) in ether (75 mL) was added through the

dropping funnel over 45 min. Next methanol (4 mL) was cautiously added.

After 30 min the reaction became heterogenous. Further addition of

methanol (4 ml.) allowed stirring to take place. The reaction mixture was

then stirred of 4 h at 0 oc. The cooling bath was removed and stirring was

continued for 8 h at 23 oc. The reaction was worked up by collecting the

solid and dissolving it in water (150 mL). The aqueous layer was washed once

with ether to remove unreacted ketone and residual mineral oil. Careful

acidification with lN hydrochloric acid to pH 6 was followed by extraction

with ether (6 x 50 mL). The ether extracts were washed with brine (2 x 50 mL),

dried (MgS04) and concentrated to produce 2-(hydroxymethylene)ketone,

which was used in the next step without purification.

300

B. Reaction of methallylmagnesium chloride with trimethylsiloxymethylene

ketone:

A dry, 2-L, three-necked, round-bottomed flask connected to a nitrogen

bubbler and equipped with a mechanical stirrer with ground shaft and

bearing a 100-mL pressure equalizing dropping funnel and a septum inlet was

charged with 1.89 mol of magnesium turnings and flushed for 5 min with

nitrogen. Anhydrous ether (450 mL) was added and the flask was cooled to

o0C in an ice bath. Methallyl chloride (0.65 mol) was added dropwise from

the addition funnel to the stirred magnesium turnings during 45 min. The

reaction is exothermic and care must be exercized to add the methallyl

chloride at a moderate rate with adequate stirring and cooling of the reaction

mixture. During this time the reaction mixture turns to a gray heterogeneous

slurry. Stirring was continued at 0 0C for 1.5 h and at 22 0C for 1.5 h.

In a separate, dry, I-L, two-necked, round-bottomed flask fitted to a

nitrogen bubbler and equipped with a magnetic stirring bar and a septum

inlet was added a solution of 2-(hydroxymethylene)ketone in anhydrous

ether (500 mL). The stirred ethereal solution of the hydroxymethylene ketone

was treated at 22 0C with a freshly prepared mixture (I /1, v / v) of

chlorotrimethylsilane and triethylamine. An immediate reaction took place

with deposition of a white precipitate. The mixture was stirred thoroughly at

22 0C for 15 min to insure complete conversion to the silyl enol ether.

The heterogenous mixture of the silyl ether and triethylamine

hydrochloride was transferred to the solution of the Grignard reagent at 0 °C

by means of a large cannula during 5 min. The efficient transfer of the silyl

enol ether was accomplished with the aid of nitrogen pressure. The flask

containing the silyl enol ether was rinsed with 50 mL of ether and was

301

transferred to the Grignard solution. Stirring at DoC was continued for 15

min. The reaction was then quenched by slow addition of saturated aqueous

sodium chloride solution until the reaction mixture becomes clear. The septa

were removed from the flask in order to vent the pressure. The solution was

allowed to warm to 22 0C and the ethel layer was decanted from the

magnesium salt and the unreacted magnesium. The residue was diluted

with saturated aqueous sodium chloride solution (100 mL) and extracted with

ether (3 x 50 mL). The combined ether extracts were washed with saturated

aqueous sodium chloride solution (2 x 50 mL), dried over anhydrous

magnesium sulfate and concentrated at reduced pressure. The product that

was obtained was used in the cyclization reaction without purification.

c. Cyclization of 1-(2-methallyl)-2-(trimethyysiloxy)methylene alcohol to the

methyl-substituted aromatic compound:

A 1-L, two-necked, round-bottomed flask equipped with a reflux

condenser, septum inlet, and a magnetic stirring bar is fitted to a nitrogen

bubbler. The flask in charged with 200 mL of toluene and 24 mmol of

p-toluenesulfonic add monohydrate. The solution is warmed to 80 0C in

a heating mantle. Tertiary alcohol from the preceding step is dissolved in

150 mL of toluene and transferred to the flask by cannula. The progress of

the reaction was monitored by silical gel tlc, After 3 h, the reaction mixture

was cooled to 22 0C and washed with saturated aqueous sodium bicarbonate

(2 x 100 mL). The aqueous phase was extracted with ether (4 x 100 mL) and

the combined organic extracts were dried (MgS04). The solvents were

removed under reduced pressure and the residue was purified by flash

column chromatography on silica gel eluting with hexane.

302

3,4-Cyclopenteno-t-methylbenzene (10):

1H NMR (300 MHz, CDCI3): S 7.13-6.94(m, 3H), 2.87 (t, J=7.5 Hz, 4H),2.33 (5,

3H), 2.06 (q,J=7.5 Hz, 2H) ppm.

13C NMR (75 MHz, CDCI3): S 144.3,141.1,135.5,126.7, 125.1, 124.1, 32,8, 32.4,

25.6, 21.2 ppm.

IR (neat): 3000,2950,2820, 1490, 1430,800 crrr l.

Mass spectrum (70 eV, m/e): 132 (M+), 117 (100%),91, 131.

HRMS: for C10H12 132.0939, found 132.0957

Physical appearance: colorless oil.

303

t-Bu

3,4-(4'-fert-butylcyc!ohexeno)-1-methylbenzene (11):

IH NMR (300 MHz, CDC13): a 7.02-6.92 (m, 3H), 2.82-2.69 (m, 3H), 2.57-2.47

(m, IH), 2.31 (s, 3H), 2.03-1.97 (m, IH), 1.52-1.26 (m, 2H), 0.96 (s,9H) ppm.

13C NMR (75 MHz, CDC13): a 136.8, 134.7, 134.5, 129.2, 129.1, 126.2, 44.9, 32.4,

30.6 (2 coincidental peaks), 27.3, 24.6, 20.9 ppm.

13C NMR (75 MHz, C6D6): a 136.8, 134.6, 134.5, 129.6, 129.5, 126.7,45.2,32.4,

30.9,30.8,27.3,25.0,21.2 ppm.

IR (neat): 2960,2870, 1500, 1470, 1430, 1390, 1360,800 crrrl.

Mass spectrum (70 eV, m/e): 202(M+), 187, 159, 145(100%), 131, 118, 105.

HRMS: for C15H22 calculated 202.1722, found 202.1732.

Physical appearance: colorless oil

304

3,4-Cyclohepteno-1-methylbenzene (12):

IH NMR (300 MHz, CDCI3): B 7.00-6.89 (m,3H), 2.77-2.74 (rn,4H), 2.29 (s, 3H),

1.87-1.79(m, 2H), 1.65-1.63 (m, 4H) ppm.

13C NMR (75 MHz, CDCI3): B 143.2, 140.3, 135.2,129.9, 128.9, 126.4, 36.7,36.2,

32.8, 28.5, 28.4, 20.9 ppm.

IR (neat): 3000,2920,2840,1500, 1450,810 em-I.

Mass spectrum (70 eV, m/e): 160(M+, 100%), 145(100%),131, 118, 105,91,77

HRMS: for C12H16 160.1252, found 160.1244.

Physical appearance: light yellow crystalline solid.

305

Cl

3-(4'-Chlorophenyl)-1,4-dimethylbenzene (13):

1H NMR (300MHz, CDCI3): B 7.39 (d, J= 8.4 Hz, 2H), 7.26 (d, J= 8.4 Hz, 2H),

7.19-7.03 (m, 3H), 2.36 (5, 3H), 2.23 (5, 3H) ppm.

13c NMR (75 MHz, CDCI3) B 140.5,135.3,132.7, 132.1, 130.5, 130.3, 128.2, 128.1,

20.9, 19.9 (2 peaks coincidental in the aromatic region) ppm.

13C NMR (75 MHz, DMF-d7): B 141.4,140.9,135.9,132.8,132.5, 131.6, 131.1,

130.8,129.0, 128.9, 20.7, 19.9 ppm.

IR (neat): 3020,3000,2960,2920,2860,1480, 1450, 1390, 1090, 1010,830 em-I.

Mass spectrum (70 eV, rrr/e): 216(M+, 100%),210, 181, 165,89,76.

HRMS: for C14H13CI 216.0706, found 216.0713.

Physical appearance: light yellow oil.

306

3-(4'-Meth.ylphenyI)-1-methylbenzene (14):

IH NMR (300 MHz, CDCI3): 3 7.54-7.17 (br m, 8H), 2.45 (5, 3H), 2.43 (s,3H)

ppm.

13C NMR (75 MHz, CDCI3): 3 141.1,138.4,138.2, 136.9, 129.4, 128.6, 127.7, 127.6,

126.9, 124.1,21.5,21.1 ppm.

IR (neat): 3100,2920,2860, 1600, 1510, 1480,1450,820 em-I.

Mass (70 eV, m/e): 182 (M+, 100%), 167, 152,90,76,40,28.

HRMS: for C14H14 182.1096, found 182.1099.

Physical appearence: light yellow oil.

307

3-Ethyl-l,4-dimethylbenzene (15):

IH NMR (300 MHz, CDCI3): 6 7.05-6.91 (m, 3H), 2.60 (q, J =7.5 Hz, 2H), 2.31 (5,

3H), 2.27 (5, 3H), 1.21 (t, J =7.5 Hz,3H) ppm.

13C NMR (75 MHz, CDCI3): 6 142.1, 135.3, 132.5, 129.9, 128.7, 126.3,26.2,20.9,

18.7,14.5 ppm.

IR (neat): 2960,2920,2870, 1460, 1380, 1360, 1130 em-I.

Mass spectrum (70 eV, rrr/e): 134 (M+), 119 (100%), 105,91.

HRMS: for CI0H14 134.1096, found 134.1103.

Physical appearance: light yellow oil.

308

3-Methyl-7-methoxy-9,10-dihydrophenanthrene (16):

IH NMR (300 MHz, CDCI3): 0 7.68(d, J=8.4 Hz, IH), 7.51 (5, IH), 7.11 (d, J=7.5

Hz, IH), 7.00 (d, J=7.5 Hz, IH), 6.86-6.78 (m, 2H), 3.85 (5, 3H), 2.83 (5, 4H), 2.39

(s,3H) ppm.

13C NMR (75 MHz, CDCI3): 0 =158.9, 139.1, 136.3, 134.2, 133.5, 127.9, 127.5,

127.2, 124.8, 123.7, 113.5, 112.3, 55.2, 29.7, 28.6, 21.4 ppm.

IR (CCI4): 3000,2930,2830, 1610, 1500, 1430, 1270, 1240, 1105, 1040, 1030,860,

810 crrr].

Mass spectrum (70 eV, m/e): 224(M+, 100%),209, 194, 178, 165.

HRMS: for C16H160 224.1201, found 224.1194.

Physical appearance: Light yellow crystalline solid

309

3,4-Cyclododeceno-l-methylbenzene (9):

IH NMR (300 MHz, CDCI3): a 7.09-6.93 (m, 3H), 2.62 (t, J -7.5 Hz, 4H), 2.29 (5,

3H), 1.76-1.65 (m, 4H), 1.54-1.51 (m,4H), 1.44-1.39 (m, 8H) ppm.

13C NMR (75 MHz, CDCI3): a 140.8, 137.9, 134.9, 130.2, 129.5, 126.5,30.0,29.9,

29.3,28.9,26.3,26.3,26.2,25.6,22.9,20.9 ppm.

Note: 2 peaks are coincidental in the aliphatic region.

IR (neat): 2940,2880, 1510, 1475,1450,830,810 em-l .

Mass spectrum (70 eV, m/e): 230 (M+), 215, 173, 159, 145, 119 (100%), 105,91,

40.

HRMS: for C17H26 230.2035, found 230.2026.

Physical appearance: light yellow oil.

310

APPENDIX II: SPECTRA FOR SELECfED COMPOUNDS IN PART II

c1~9

1H NMR spectrum/CDCl3

r--

----_.

F- a , . -- --- '-.-d.L__ ~ ~ .. -I I I I I I i I I I I I I I I I I I

8 6 4 2 0

13C NMR spectrum/CD03

I II I I I I I I I I I I I I I I I I I I I I I I I I I I I I i I I I

140 120 100 e.O bO 40 ?O (1 ·PPM

311

-_.,~.~-------------------

Mass spectrum

"lTAlIP2.~ '.1

1 IS

312

B' ,(

10

/'

lH NMR spectrum/CD03

r(I

'- L\. ~-I I I I I I I I I I I I I j I I I I 1

8 b 4 2 (, PPM

13C NMR spectrumlCDCl3

I I I I I I I I I I I I I I I I I I I I I I I I I I i i I I I Il-PYM

I fj o 140 120 100 80 bO 40 ?(' ('

lllTlil1121t7 ,1 Bgd=1BpN=117 1=14~,","=- HII1=ElI7KAMAlI KI<.-4-115 ChlH12

HIe!

Mass spectrum

&'10

12-JAH-ge 09'54·0'01'32 /0-SETIC.407934016 Rent,

PT= eo1 7

El·SYS'~CaL,PFK8ee

17 1.92137945984

1 ~

80

se7lL

60

50

<40 6930.

20 9

10 .I9 I I~I

60 80 189

.11,120

314

1<415 168

MSS CACe)200

§'t-Bu

11

IH NMR spectrum/CDC13

(

(

!/

_..--.._----_.

- -- -- ._-----....- - _.._._---_.

I8iii I

6

i I I4

_~'-- I'L. ..M\....J.J. \..__ ._ .. _1- I I I I I I I

2 0 PPM

13C NMR spectrum/CD03

.11 ..I••. ,.' rt ' I" 'I' "i I I I I I I I I I I I I I I i i I I I I I 1I I I I I I i

140 120 100 80 60 40 ?0 o

315

,'I'

316

8't-Bu

11 ,~.

... j .

. 1I

I!It

II.-c,« ,'.j IJI;fllH-II/l;M I HUll-_ ..__ . -." -._~-----

."

8' r(12

1H NMR spectrum/CtrClg

rr - ..

I

........ •. L ~L -'--- . "- c ~'-,I I I I I I I I I I I I [ I [ I [ !

8 6 4 2 (' PPM

r·i

13C NMR spectrum/CD03

-_.. - . 1'-'"l_ vw..1l. _

~ I I I I I I I I I i I I I [ I I i i i I I I I I I I I I i I I I160 140 12o 100 Be' 60 4() ?C, (I . p. 'tvl

317

Mass spectrum

79-5£Rent'

PT.. eo145 1

28-NOY-S9 10'21·O'02'41TICcB35156992

xl Bgd=1I=194mvs Hm=743

VK-4-105 C12H16 160

I'lTll2821lBBpl'l=69f(ArrJALI

I~l)

80

e.·1 1 1

1 S

I'lASS CACe)

318

p (:,

cllf~313

1H NMR spectrum/CDCl3

I

-_. ._'.'-~

--'---18

1

6I4

I

l. \,r--'--'--' 1

? I~ prM

13C NMR spectrum/C003

~ II ~- , 'jI , I i1

i ,I I I

1I I

1I I I I I I i i

1I I

160 140 120 100 80 60 40 ? (1 0

319

'11AI 1~ I .. P xl BQd=1"1'1'1"0 J=18mvs Htn=l,'l'Il1'1ALI KK-5-41 C14H13Cl 216

1£108

~~

1::(:\

5~

40

:;l0 89

213

10

969 813

Mass spectrum

320

181

I \' \ , . I I'" ~ , ., I I' ., .

[J.S\,IS, 1'ftdB990Cal.,PF'K889

'l~l94W

~3~ ~

~ICH3

141H NMR spectrum/CDC13

-- ..

. -- 1 j \ • LI I I I I I i I I I i i i I i i i r-

8 6 4 " (' ['f'M(

13C NMR spectrumlCn03

I

j L ,

i i I I i I i I I I i I I i i I i i i ~'-Ii i i I i i I II I

140 120 1(l (1 f'·(1 be' 4~1, C'lbO (

321

Mass spectrum

~T01181'11 xl Bgd-lBpAa0 I=7Smvs HM--eK~ALI KK-5-19 C14H14 182

100·

99

eei'9

69

sa49

39

29

19

929 4l1' 60 120

322

149

1 '7

PlASSJS8. '.' .189

lH NMR spectrum/Cl'rClg

r

r

r1Lt - ij L

L_

Ii I I4

.,I.' rcr>t\1,~

I) r"

13C NMR spectrumlCD03

I I

1 fj ()

I I i

140

..I

I I120

I I I I

100

323

I I I

?, (!

I I I

bOI I I

40

I I I r I I I:.' 1'. (.

CH3

H3C~CH3

15

Mass spectrum

'H"t,"_4 :--1 Rgd=1 12-jAH-se 10'28·9'01'31 70-S[ [I·, 'pN-fl !=112m'.'s HIIl'"0 TIC=538148032 Rent' S\,Is'PlLIBLOW' ....mllL! Kk-'5-~5 CHlH14 134 PTc v!' Cal,PfK340

'~Il. 1 9 14 ~')11 r 809276

. ,.,

~:A

"'n

.21-' -":'\., 1/'f

.....1.1 9

.''fll :r T510 109 IIII J!I0 ·1 i .. I111 I I. flIASSN. 90 ~ ii.,- . 119 120 ,~ 1,40

324

IH NMR spectrum/CDC13

r(r

r

ll,JtI I I , i I I

Q b('

13C NMR spectrum/CDCl3

r

- ~WtI' \. ~l&V ....~.._........'i i I I I I I i I I I I I I I I I i I I I i I I I , rr-""'-r-r- T '-1

160 14C 120 1'.' l' .-:, ' I ( 4' , ,

325

"'j';',1 ..

Mass spectrum

I Il~'

....~~!::;._ ..,

.i:.._·t~o;:·!I .. !:·::·;..,

;::':1':" .

.. ··Ii.... ··:..;·;:.!.....,.,......

i

11111 t , 0":II J ~ ~.J- I ,t;. ,_:) 14· +j~lI: \h~ >52 ;l~I-SE [I·

I:ipPI"o J .:... J.: t1111 " ; HIU';:U III '.~ -t "_ ;\t~lll"8 Aor,t . Sys'Il1WBSee1<.f1111.Ii 1 II.' ~-'., I itA \I t .•) ;, <::24 PT"- eO CaL :PFK800

1\:,'·2'4 .16 ~

-\ 1773380

::'.... -i..:C.LI •

71:1

bl1

5u

4U

36

,oJ10

e PlASS

8~ 188 120 148 168 180 289 220

326

REFERENCES

1. (a) Barnfield, P.; Gordon, P. F. Chern. Soc. Rev. 1984, 13, 441.

(b) Reed, M. W.; Moore, H. W. J. argo Chern. 1987,52,3491.

(c) Stossel, D.; Chan, T. H.; J. argo Chern. 1987,52,2105.

(d) Kozikowski, A. P.; Sato, K.; Basu, A.; Lazo, J. S. ]. Arn. Chern. Soc. 1989,

11,6228.

(e) Corey, E. J.; Carpino, P.]. Arn. Chern. Soc. 1989, 111,5472.

(f) Roush, W. R.; Michaelides, M. R.; Tai, D. F.; Lesur, B. M.; Chong, W. K

M.; Harris, D. J.]. Am. Chern. Soc. 1989, 111,2984.

(g) Broka, C. A.; Chan,S.; Peterson, B. l- argo Chern. 1988,53, 1584.

(h) Boger, D. L.; Mullican, M. D. ]. argo Chern. 1984,49, 4045.

(i) Magnus, P.; Gallagher, T.; Schultz, J.; Or, Y.; Ananthanarayan, T. P.

J. Am. Chern. Soc. 1987,109,2706.

(j) Asokan, C. V.; Ila, H.; [unjappa, H. Synthesis, 1987, 284.

(k) Rao, M. S. C.; Rao, G. S. K. Synthesis, 1987, 231.

(1) Fu, J. M.; Sharp, M. J.; Snieckus, V. Tetrahedron Lett. 1988,29, 5459.

(m) Siddiqqui, M. A.; Snieckus, V. Tetrahedron Lett. 1988, 29,5463.

(n) Gupta, A. K; Ila, H.; [unjappa, H. Tetrahedron Lett.1987, 28, 1459.

(0) Sibi, M. P.; Dankwardt, J. W.; Snieckus, V. ]. argo Chern. 1986,51,271.

2. Boger, D. L.; Mullican, M. D. l- argo Chern. 1980, 45,5002 and references

cited therein.

3. (a) Danishefsky, S.; Yan, C.-F.; Singh, R. K; Gammill, R. B.; McCurry, Jr., P.

M.; Fritsch, N.; Clardy, J.]. Am. Chern. Soc. 1979, 101,7001.

(b) Danishefsky, S.; Harayama, T.; Singh, R. K ]. Am. Chern. Soc. 1979,

101,7008.

327

4. Chan, T.-H.i Brownbridge, P. ]. Am. Chern. Soc. 1980, 102, 3534.

5. Tius, M. Ai Thurkauf, A.i Truesdell, J. W. Tetrahedron Lett. 1982,23,

2823.

6. Tius, M. A.i Thurkauf, A t. Org. Chern. 1983,48, 3839.

7. Tius, M. Ai Thurkauf, A.; Truesdell, J. W. Tetrahedron Lett. 1982,23,

2819.

8. Tius, M. A.i Cullingham, J. M.i Ali, S. J. Chem. Soc. Chem. Commun.

1989,867.

9. Tius, M. A; Savariar, S. Synthesis, 1982, 467.

10. Tius, M. Ai Gomez-Galeno, J. Tetrahedron Lett.1986, 27, 2571.

11. Tius, M. A Tetrahedron Lett. 1981,22, 3335.

12. Tius, M. Ai Ali, S. ]. Org. Chern. 1982,47, 3163.

13. Singh, c, Ila, H.; [unjappa, H. Tetrahedron Lett.1984, 25,5095.

14. Tius, M. Ai Thurkauf, A. Tetrahedron Lett. 1986,27, 4541.

15. Tius, M. Ai Kannangara, G. S. K. Organic Syntheses, 1992,71, 158.

16. Also see, Ainsworth, C. Org. Synth. Coil. Vol. IV, 1963,536 and

Woodward, R. B.i Scheinbaum, M. L. Org. Synth. Coil. Vol. VI, 1988, 590.

17. Methallyl chloride obtained from Aldrich Chemical Company, Inc., was

distilled (bp 71-72 0C) from phosphorus pentoxide.

18. Magnesium turnings (98%) from Aldrich Chemical Company, Inc., were

used after drying in a beaker at 110 °C overnight. The Grignard reaction

took place without need of an initiator.

19. Chlorotrimethylsilane obtained from Aldrich Chemical Company, Inc.,

and triethylamine (Aldrich Chemical Company, Inc.,) were mixed in

equal volumes in dry, stoppered tubes. These were centrifuged briefly

and the supernatant was transferred through a septum by syringe.

328

20. A suitable cannula was made by filing the ends of a 45-cm long

aluminum tube of 2-mm internal diameter to points.

21. The reaction was most easily monitored by noting the disappearance of

the highly UV absorbing unsaturated aldehyde intermediate by tlc,

22. Reagent grade toluene (Fisher Scientitic Company) was degassed with a

nitrogen stream.

23. (a) Dieter, R. K.; Lin, Y. J. Tetrahedron Lett. 1985, 26, 39.

(b) Datta, A.; Ila, H.; Iunjappa, H. Tetrahedron Lett. 1988,29,497.

and also see references 4 and 1(k).

329