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UMIA Bell & Howell Infonnation Company
300 North Zeeb Road, Ann Arbor MI 48106-1346 USA313n61-4700 800/521-0600
PART I: THE STEREOSELECTIVE SYNTHESIS OFCANNABINOIDS
PART II: THE TOTAL SYNTHESIS OF SARCOPHYTOL AAND ITS ANALOGS
A DISSERTAnON SUBlVtITIED TO THE GRADUATE DIVISION OF THEUNIVERSITY OF HAWAII IN PARTIAL FULFILLMENT OF THE
REQUIREMENTS FOR TIlE DEGREE OF
DOCTOR OF PHILOSOPHY
IN
CHElVtISTRY
DECEMBER 1995
By
Xianglong Zou
Dissertation Committee:Marcus A. Tius, Chairman
Charles F. HayesCraig M. JensenEdgar F. KieferRobert S. H. Liu
UMI Number: 9615565
UMI Microform 9615565Copyright 1996, by UMI Company. All rights reserved.
This microform edition is protected against unauthorizedcopying under Title 17, United States Code.
UMI300 North Zeeb RoadAnn Arbor, MI 48103
iii
ACKNOWLEDGEMENTS
I would like to thank my advisor, Professor Marcus A. Tius, not
only for guidance but also for his patience and encouragement during
the completion or. this work. I also wish to thank the other members
of my dissertation committee for their assistan~e and
encouragement.
I thank members of the Tius group, past and present, for being
helpful and understanding. Many thanks to Dr. David Drake for
proofreading this dissertation and Dr. Walter Niemczura, Mike Burger
and Wesley Yoshida for their valuable help in obtaining NMR and
mass spectral data.
I would like to thank my wife Ling Cui and my daughter Susan
fer their love and support.
Finally, I would like to thank Professor Marcus A. Tius for his
support in the form of research assistantship and the Department of
Chemistry of the University of Hawaii for support in the form of a
teaching assistantship.
IV
ABSTRACT
Part I: The stereoselective total synthesis of each of the two
diastereomeric C6-hydroxyhexahydrocannabinols is described. The
extension of isopropenyl to hydroxymethyl was accomplished by the
use of an ene reaction with formaldehyde in the presence of
methylalurninum bis(2,6-diphenylphenoxide). Stereochemistry of the
two final products was controlled by an intramolecular mercuration.
Biological testing showed that the analogs exhibit different degrees
of binding to the CB1 cannabinoid receptor.
Part II: The total synthesis of a dienone precursor of sarcophytol A
is described. The conversion of dienone to sarcophytol A has been
reported. Hence, this is the formal total synthesis of sarcophytol A.
Interesting features of this synthesis include an alkynylation of an
allylic halide, macrocyclization, and C-alkylation of a 1,3-diketone
with isopropyl iodide. Selective reduction of diketone to dienone was
accomplished with DIBAL. It is noteworthy that conversion of
sulfoxide directly to the corresponding enone did not succeed
through a Pummerer rearrangement. Attempted conversion of
sulfone to dienone in the target molecule was not successful and
eliminated product was obtained. A synthesis of canventol is also
described. Biological testing has shown that canventol is a more
potent antitumor promotor than sarcophytol A even though
canventol is structurally simpler.
v
TABLE OF CONTENTS
ACKNOWLEDGEMENTS .iiiABSTRACT .i vLIST OF ABBREVIATIONS viii
PART ISTEREOSELECTIVE SYNTHESIS OF CANNABINOIDS
INTRODUCTION 1
1. Background 12. The Structural and Stereochemical Requirements forBiological Activity 33. Previous Synthetic Approaches towards Cannabinoids 7
RESULTS AND DISCUSSION 1 4
1. Retrosynthesis of 1213-Hydroxymethyl-9-nor-913-Hydroxyhexahydrocannabinol. 142. Stereospecific Ring Opening of Cuprate Adduct.. l 53. Formation of Tetraol l 84. Stereoselective Synthesis of 12p-Hydroxymethyl-9-nor-913-Hydroxyhexahydrocannabinol.. 195. Stereoselective Synthesis of 14a-Hydroxymethyl-9-nor-9p-Hydroxyhexahydrocannabinol.. 2 16. Biological Activities of the Synthetic Compounds 2 4
CONCLUSION 2 6EXPERIMENTAL 2 7REFERENCES : 5 2
vi
PART IITOTAL SYNTHESIS OF SARCOPHYTOL A AND ITS ANALOGS
A. SYNTHESIS OF CANVENTOL AND ITS ANALOGS .5 6
INTRODUCTION 5 6
1. Background 5 62. Synthesis of Canventol and Its Analogs 5 63. Biological Activity 60
EXPERIMENTAL 6 1REFERENCES 7 3
B. THE TOTAL SYNTHESIS OF SARCOPHYTOL A 7 4
INTRODUCTION 74
1. Background 742. Previous Approaches to Macrocyclization 75
a. Stabilized Anion Additions 75b. Alkynyl Anion Addition 76
3. Previous Synthetic Approaches to Sarcophytol A 77a. Takayanagi et. al. 77b. Takahashi et. al. 79c. Kodama et. al. 8 0d. Li et. al. 8 0
RESULTS AND DISCUSSION 8 2
1. Retrosynthesis of Sarcophytol A 8 22. Synthesis of Alkynyl Acetate 8 33. Formation of Cyclic Alkynyl Alcohol.. 8 54. Synthesis of Alkylated Sulfoxide 8 8
vii
'5. Pummerer Rearrangement of Alkylated Sulfoxide.Attempted Synthesis of Enone 9 0
a. Model Study 90b. Attempted Conversion of Sulfoxide to Enone 92c. Attempted Synthesis of Ester 93
6. Reevalu,ation of Retrosynthesis 967. Synthesis of Alkylated Diketone 968. Selective Reduction of 1,3-Diketone. Synthesis ofDienone 99
CONCLUSION 10 1EXPERIMENTAL 102REF'ERENCE:S 124
Ac
Ar
br
C
c
cat.
CBD
a:JN
CSCM
6 8
6 9-
d
DBA
DBU
dd
ddd
DIBAL
DMAP
DME
DMF
DMSO
dt
FE
LIST OF ABBREVIATIONS
acetyl
aromatic
broad
Celsius
concentration
catalytic
Cannabidiol
Correlated Spectroscopy
Chemical Shift Correlation Map
Delta-8-
Delta-9-
doublet
Dibenzyl acetone
l,8-diazabicyclo[5.4.0]JJnctec-7 -ene
doublet of doublets
doublet of doublet of doublets
diisobutylaluminum hydride
4-(dimethylamino)pyridine
1,2-dimethoxyethane
N ,N-dimethylformamide
dimethyl sulfoxide
doublet of triplets
ethoxyethyl
VUl
Et
Et20
eV
EVE
g
h
Hz
HHC
HMBC
HMPA
HMQC
HPLC
HRMS
IR
J
KHMDS
LAH
LDA
m
M
mg
MHz
ethyl
diethyl ether
electron volt
ethyl vinyl ether
gram
hour
Hertz
Hydroxyhexahydrocannabinol
Heteronuclear Multiple Bond Correlation
Hexamethylphosphoramide
Heteronuclear Multiple Quantum Correlation
High Pressure Liquid Chromatography
high resolution mass spectrum
infrared
coupling constant
potassium bis(trimethylsilyl)amide
lithium aluminum hydride
lithium diisopropylamide
multiplet
Molar
milligram
megahertz
ix
min
mL
mmol
n-Bu
NMR
nOe
Oxaziridine
Ph
PPTS
p-TSA
pyr.
q
Rf
s
SAR
sat'd
t
tert-B u
TBDM
TEA
TFA
TFAA
me
minutes
milliliter
millimole
normal butyl
nuclear magnetic resonance
nuclear Overhauser effect
2 -(p-toluenesu lfony1)-3 -ary loxaziridine
phenyl
pyridium para-toluenesulfonate
para-toluenesulfonic acid
pyridine
quartet
retention factor
singlet
Structure Activity Relationship
saturated
triplet
tertiary butyl
tertiary-bu tyld imethy Is ilyl
triethylamine
trifluoroacetic acid
trifluoroacetic anhydride
tetrahydrocannabinol
x
THF
TMS
Ts
tetrahydrofuran
trimethylsilyl
toluenesulfonyl
Xl
PART I: THE STEREOSELECTIVE SYNTHESIS OF CANNABINOIDS
INTRODUCTION
1. Background
Cannabis sativa L. was one of the first plants to be used for
fiber, food, medicine and in social and religious rituals.! Its medical
properties have been recognized for thousands of years in different
societies. In Assyria, cannabis, known as azallu, was used for pain
alleviation and its seed was prescribed for treatment of depression,
"evil eye", and kidney stones.2 The medical applications of cannabis
were also well recognized by Chinese in their traditional folk
medicine formulations, some of which are still followed today.
Cannabis was used for alleviation of pain, clearing blood and
treatment of hyperthermia.3 Externally, cannabis was used as a
poultice, or as a constituent of various ointments for swellings and
bruises. The plant ex.tracts were used in Europe for a long time for
treatment of chronic headaches and certain psychosomatic
disorders.4 ,5 Although cannabis has its origins in folk medicine.
considerable interest for its use in standard medical practice was
generated in the early 19th century when the British scientist
O'Shaugnessy applied various cannabis preparations to animal and
human clinical experiments.6 The most important observation made
by O'Shaugnessy was that cannabis was a potent antinauseant agent.
Since then various medical potentials were observed.7•8 Despite these
observations of potential medicinal uses, little progress was made
1
toward practical medical use. The main reason was that no pure
constituents of cannabis had been isolated and the variety of crude
plant preparations made it difficult to obtain reproducible clinical
results. The situation was dramatically changed after a series of
compounds with cannabimimetic activity were synthesized by
Adams and Todd9. 10 and subjected to biological tests)l The most
widely tested compound was parahexyl, ~6a.lOa-THC 1.
2
1 Parahexyl
In 1964, the isolation and elucidation of the major
psychotropically active constituent, ~9-tetrahydrocannabinol, (-)_~9_
THe 2, by Mechoulam12 indicated that the modern era of cannabis
chemistry had arrived for synthesis, pharmacology, metabolism and
clinical investigation. For convenience, the following dibenzopyran
numbering system will be used throughout this dissertation.
3
2. T~e Structural and Stereochemical Requirements for
Biological Activity
Previous studies have shown that alteration of the basic
cannabinoid structure dramatically altered the biological activity.I3
Although the structure activity relationships (SAR) for cannabinoids
are relatively well established, some observations still need to be
clarified. Generally, a classical cannabinoid contains three major
parts: (a) a phenol (A ring) with C-3 side chain, (b) a six-membered
ring (B ring) with oxygen substitution, (c) a six-membered C ring. In
the early 1940's, the SAR of several synthetic cannabinoids were
investigated by Loewe. 14 Since the identification of the structure of
(-)-69-THC in the 1960's, a large amount of biological data has been
recorded for both natural and synthetic cannabinoids. Much of this
data comes from whole animal bioassays, and the methods for
assessment of activities include the overt behavior test in rhesus
monkeys or baboons,14 dog ataxia test,15 spontaneous activity test 10
rats and mice,16 drug discrimination test.!7 Limited data is available
from humafls, for a small number of cannabinoids. Some tentative
rules for SARs formulated by Mechoulam 18 in the early 1970's are
still consistent with what has been observed for newly synthesized
cannabinoids. Most of the active cannabinoids, including (-)_~9_THC,
have a benzopyran structure and cannabinoids in which the pyran
ring has been cleaved, e.g. cannabidiol (CBD, 3), show complete loss of
activity. Although a pyran ring is a requirement for activity. the
4
benzopyran itself does not confer activity. Substitution of oxygen
with nitrogen retains the activity, as illustrated by levonantradol 4.
Surprisingly, some cannabinoids which do not contain the
OH
/'N (CH2bCsHsH
4 Levonantradol
~ "'OH
3 Cannabidiol (CBD)
benzopyran structure, referred to as non-classical cannabinoids, are
more potent than (-)-~9-THC. For example, CP-47,497 Sand CP
55,940 6 are ten times more potent than (-)-~9-THC itself. This
indicates that the benzopyran ring may not be an absolute
requirement for activity ,19
OH (NAH)
OH
5 CP-47,947
OH
(CH20H (SAH)
6 CP·55,940
Furthermore, SAR studies have also shown that the hydroxyl at C-l
has to be free or esterified. Etherification of the phenol led to either
complete loss or reduction in activity, whereas the phenolic ester
5
retains the activity.20 The replacement of hydroxyl by amino or
other ·heteroatoms eliminates the activity. It is also known that the
side chain at C-3 is of considerable importance for cannabinoid
activity. In general, elongation and branching of the side chain
increase the activity . Johnson and Melvin21 reported that compounds
7 and 8 are analgesically more active than (-)-9-nor-9~-
hydroxyhexahydrocannabinol (HHC. 9) and (-)-.19-THC. The most
OH
R
7 A =CH(CH3)(CH2)4CSHS8 A = CH (CH3)CH(CH3)(CH2)4CH3
OH
9 HHC
active side chains identified thus far are l,l-dimethylheptyl and 1,2
dimethylheptyl. It is interesting to note that substitution of an all
carbon chain by one containing oxygen at different positions does not
considerably influence the activity.22...... ,"1'•••
In contrast to the well established structural requirements for
activity, stereochemical aspects of the SAR need more investigation
due to the difficulties in purification of cannabinoids in large
amounts and enantiomeric contamination of cannabinoids used In
early in vivo testing. 23 Considerable efforts have been made to
establish stereochemical SARs. It was found that the stereochemistry
at C-6a, C-IOa should be trans (6aR, IOaR) and that an equatorial
6
substituent at C-9 was more active than an axial one. Molecular
shape:"plays an important part in determining the pharmacology of
cannabinoids. Recently, Makriyannis24 suggested that cannabinoids
with all three rings coplanar are inactive, or have very low activity,
and analogs in which the C-ring deviates from planarity are
pharmacologically' active. Enormous differences in activity between
enantiomeric pairs have been observed. Mechoulam25 reported that
(-)-1l-0H-~8_THC-DMH (HU210) was about 87 times more active
than (-)-~9-THC. Its (+)-enantiomer was inactive in the pigeon drug
discrimination test. Similar results were demonstrated by Johnson
and Melvin26 on other enantiomeric pairs. For example,
levonantradol 4 was active in a series of tests for analgetic and other
natural cannabimimetic responses (spontaneous activity,
hypothermia and catalepsy), however, its enantiomer was inactive in
these tests.
10 HU 210
OH
CH20H
11 CP-55,244
It should be emphasized that the stereospecificity for classical or
synthetic cannabinoids is consistent with the results for non-classical
cannabinoids. Generally, a conformation in which the southern
7
aliphatic hydroxyl (SAH) is syn to the northern aliphatic hydroxyl
(NAH), is required for activity. The non-classical analog, CP-47,497 5,
includes the minimal structural requirements for activity and is
approximately 10-fold more potent than naturally occurring (_)_.6,9-
THC with respect to analgesic activity. Conversely, CP-55,244 11
which contains a: conformationally more defined sy n SAH group is
50-fold more potent than its simpler congener and shows a high
degree of enantioselectivity.27
3. Previous Synthetic Approaches towards Cannabinoids
Since the isolation and elucidation of the structure of (_)_.6,9 -T HC
in 1964, several hundred papers related to the synthesis of
cannabinoids and their analogs have appeared.28 The main reason for
early synthetic afforts was to understand whether the parent
cannabinoids themselves were biologically active or whether the
activity was derived from one or more biologically active
metabolites. Recently, the interest in these compounds was driven by
the commercial need for metabolites of (_)_.6,9-THC as analytical
standards in the calibration of assays for the accurate detection of
cannabinoids in urine. Further, much effort has been devoted to the
design of analogs that may serve as probes in order to increase the
understanding of the mechanism responsible for cannabinoid
pharmacology in man and also as potential therapeutic agents.29
Several syntheses directed toward .6,9_, .6,8-THC and their analogs have
been reported.3 0 Generally, chiral cyclic monoterpenoids and olivetol
8
were the key starting materials In these syntheses. A facile and
practi~al method to (-)-L\9-THe was developed by Mechoulam and co-
workers in 1972 (scheme 1).31 Therein, (- )-verbenol 12, which itself
SCHEME 1
OH
0 a ..~ +
OH HO
12 13 14
b
d
16
Reagents: (a) p-toluenesulfonic acid. CHZC1Z; (b) BF3·EtZO, room temperature;(c) ZnClz. HCl (g); (d) potassium tert-amylate.
was prepared from p-pinene, was condensed with olivetol 13 in
methylene chloride in the presence of p-toluenesulfonic acid to
produce condensation adduct 14 which was obtained in 60% yield
9
after chromatography. The treatment of adduct 14 with boron
trifluoride etherate in methylene chloride at room temperature for
10 min gave ~8-THC 15 in 80% yield. It should be pointed out that in
the p-toluenesulfonic acid catalyzed condensation, 4-(2
olivetyl)pinene 14 was the only product isolated. No abnormal
isomers were obtained. In 14 the C-6a and C-I0a hydrogens are
trans, presumably due to steric factors. The conversion of 15 to 16
was accomplished in quantitative yield by adding gaseous
hydrochloric acid at low temperature with catalytic zinc chloride.
Treatment of 16 with potassium tert-amylate led to (_)_~9-THC 2 in
90% yield. The overall yield of (_)_~9-THC (2) from (-)-verbenol 12
was ca. 43%. The advantages of the synthesis were the ready
availability of starting materials and the reasonable yields.
The major urinary metabolite of ~9_THC, Il-nor-~9-THC-9-
carboxylic acid 22, has received much attention as an internal
reference in a number of immunological screening tests which have
been developed to ascertain whether an individual has used
marijuana. In the synthesis of (-)_~9_THC metabolites, the principle
was to indentify an available terpene which would provide the
carbon atoms for the C-ring and also establish the absolute sense of
asymmetry of the final product, for example, (-)-1l-nor-~9-THC-9-
carboxylic acid 22. Although a number of synthetic approaches to 22
have been reported,32.33 the shortcomings of these syntheses were
either that they were long, produced racemic product or were low
yielding. A novel, efficient synthesis was reported in our laboratory
(scheme 2),34 Therein, the starting material, monoacetate 18, was
10
SCHEME 2
..OH
b ..~o
I20
COOH
d, e ..~O
I
22
~18
OOCOCH3
HO
I +4 steps
~O I1 9
OH
c
a
~17
CHO
6
Reagents: (a) BF3·Et20; (b) TBSCI. CH2CI2; (c) LAH. THF; (d) Swern oxidation; (e)Sodium chlorite, 2-methylbut-2-ene, CH2 C12.
prepared from R -(+)-perillaldehyde34 17 in 4 steps. The conversion
of 18 to 19 was accomplished by exposure of a dichloromethane
solution of olivetol 13 and 18 to freshly distilled boron trifluoride
etherate at ooC for 2 h. The yield of 19 was ca. 30% and it was
11
subsequently converted to final product 22 by protection as sHyl
ether ~O, reduction to 21, oxidation and deprotection in good yield.
Recently, a convenient synthesis of ~8_THC metabolites was
reported in our labaratory (scheme 3),35 wherein (+)-apoverbenone
SCHEME 3
o
29
HO27
COOCH3
OH
c
0 OEE
8 +~
23 24
OS02CF3
OEEb
•
EEO26
OS02CF3
~ OHd ..
~OI
28
Reagents: (a) Mixed higher-order cuprate; (b) KN(TMS)2 or LOA, thenPhN(S02CF3)2; (c) PPTS, methanol; (d) BF3"Et20. CH2Cl2; (e) PdCI2(PPh3)2,K2C03. CO, THF. methanol.
23, which was prepared from (-)-J3-pinene, was used as a starting
12
material. Olivetol 13 was converted to its bis(ethoxyethyl)ether 24
in 77% yield by treatment in diethyl ether with a small excess of
ethyl vinyl ether in the presence of p-toluenesulfonic acid. The
lithiated olivetol derivative was transferred to 1 equivalent of
lithium 2-thiophenecyanocuprate in THF. The mixed, higher order
cuprate was treat.ed with a THF solution of apoverbenone and boron
trifluoride etherate (1/1) at -780C for 2 h and cuprate adduct 25 was
obtained in 66% yield. Consecutive treatment of adduct 25 with
potassium hexamethyldisilylamide followed by
bis«(trifluoromethyl)sulfonyl)oxy)aniline in THF at OOC led to enol
triflate 26. Exposure enol triflate 26 to pyridinium tosylate in
methanol gave the dihydroxy compound 27 in 65% yield from 26. A
solution of 27 in anhydrous dichloromethane was treated at 25°C
with an excess of boron trifluoride etherate for 8 h and cyclic vinyl
triflate was obtained in 87% yield. Transposition of the double bond
during cyclization leads specifically to the ~8-series. The
stereochemistry of the ring junction was determined by the trans
cuprate addition to the geminal dimethyl bearing bridge. Treatment
of a solution of 28 in methanolic THF with 10% mol PdCI2(PPh3h,
potassium carbonate and a static atmosphere of CO at 250C led to
methyl ester 29 in 72% yield. Although all these syntheses are for
classical cannabinoids, some of these synthetic methods could be
applied to non-classical cannabinoids. For example, the cuprate
addition which forms the trans ring junction and the cleavage of the
ring. Since non-classical cannabinoid CP-55,940 was more active as
an analgesic than morphine, its increase in potency was attributed in
13
part to the introduction of the new hydroxypropyl binding
component in the southern portion of the molecule. Significantly,
both the arylcyclohexyl bond and the hydroxypropyl groups are not
conformationally restricted.
14
RESULTS AND DISCUSSION
The aim of this work was to synthesize non-classical
cannabinoids which combine the structural elements of CP-55,940 6
and HHC 9 and to study the relationships between stereochemistry
and their activity.
1. Retrosynthesis of 1213- H yd roxy m et hyl- 9- nor - 9 ~
hydroxyhexahydrocannabinol
In order to synthesize compound 30, intermediate 32 was
envisioned as a potential precursor to the product 30, because it is
possible to convert 32 to 30 by an ene reaction followed by
stereoselective cyclization (scheme 4).
SCHEME 4
OHOH
:> :>I
HO~OH~
HO 31
0 0
>
RO33
15
Compound 31 would be prepared through an ene reaction on the
intermediate 32. The compound 32 could be obtained from a two
step procedure involving the ring opening of compound 33.
2. Stereospecific Ring Opening of Cuprate Adduct
The starting· material for the synthesis, (+)-apoverbenone 23,
was prepared from cheap and readily available (-)-13-pinene 34
according to Huffman's method36 via ozonolysis of (-)-~-pinene 34 to
nopinone 35, followed by lead tetraacetate oxidation and acetic acid
hydrolysis (scheme 5). Olivetol 13 was converted to its bis-2-
SCHEME 5
80 0
a ~ b, C G.. • /1'
34 35 23
Reagents: (a) 03; (b) isopropenyl acetate; then Pb(OAc)4; (c) aq. HOAc, roomtemperature.
HO
OH
13
a ..EEO
OEE
24
Reagents: (a) p-toluenesulfonic acid, ethyl vinyl ether, CH2 CIZ 00 C.
16
ethoxyethyl ether 24 in 75% yield by treatment with a small excess
of EVE in the presence of a catalytic amount of PPTS.
The cuprate addition was carried out according to a published
procedure37 (scheme 6): Bis-2-ethoxyethyl ether 24 can be
Reagents: (a) Mixed high-order cuprate. BF3·EtZO. THF, -78°C; (b). PPTS,methanol; (c) TBSCI. DMAP; (d) TMSI. CCI4. OOC; (e) DBU. benzene.
deprotonated selectively using n-butyllithium in THF at 25°C. The
lithiated bis-2-ethoxyethyl ether of olivetol was converted to the
17
mixed higher-order cuprate by transferring to a solution of lithium
2-thiophenecyanocuprate in THF at -78°C which was prepared
according to the procedure published by Lipshutz.3 8 The mixed
higher-order cuprate solution was then treated with a THF solution
of (+)-apoverbenone 23 and boron trifluoride etherate (I/l) at
-780C. The progress of the reaction can be monitored by tIc. After 30
min. the reaction was quenched with a solution of saturated
NH4CI/NH40H (9/1) and the product was purified by silica gel column
chromatography. The yield of cuprate adduct 2S was 70-80%.
Treatment of 25 with PPTS in methanol at 250C led to 36 in
quantitative yield. Exposure of resorcinol 36 to
tert-butyldimethylsilyl chloride and imidazole in DMF at 230C
produced bis-tert-butyldimethylsilyl ether 37 in 85% yield. Cleavage
of the cyclobutane ring in adduct 37 under the influence of
trimethylsilyl iodide (generated in situ from allyltrimethylsilane and
iodine) at OOC gave rise to tertiary iodide 38 which was immediately
converted to 39 by treatment with DBU in benzene at 23°C. It should
be emphasized that the regiospecific elimination which forms the
388 3ab
18
isopropenyl substituent of 39 is due to a stereoelectronic effect39
caused by the aryl substituent at C-5: The steric bulk of the aryl
group prevents iodine and H-6a from adopting a trans-anti
conformation which would lead to the undesired elimination product.
3. Formation of Tetraol
The next task was to append a hydroxymethyl group to the
isopropenyl methyl of 39. An obvious approach was to make use of
an acid catalyzed ene reaction with formaldehyde (scheme 7).
SCHEME 7
o
~ ~OTBS
39
OH
- I ~HO~OTBS
41
a
c
o
: I ~HO~OTBS
40
OH
b
Reagents: (a) Trioxane. Me3A1, 2.6-diphenylphenol; (b) NaBH4.THF/isopropanol; (c) n-Bu4N+F-, THF. aoc.
19
Dimethylaluminum chloride was initially used as the Lewis acid, but
the yield of 40 was too low (ca. 20%) and the reaction did not
proceed to completion. A very efficient reagent, methylaluminum
bis(2,6-diphenylphenoxide)formaldehyde, which was prepared from
trimethylaluminum, 2,6-diphenylphenol and trioxane In
dichloromethane at DoC, has been reported by Yamamoto,39a
Exposure of 39 to Yamamoto's reagent in dichloromethane at room
temperature for 1 h followed by quenching with sodium bicarbonate
led to 40 in 55% yield. Treatment of 40 with sodium borohydride in
THF/isopropanol (9/1) at 230C led to equatorial alcohol 41 in 88%
yield. Removal of both TBS protecting groups was accomplished to
produce tetraol 42 in 90-96% yield by simply exposing diol 41 to
tetra-n-butylammonium fluoride in THF at room temperature.
Compound 42 was envisioned as a potential precursor in the
synthesis of both the target molecules 30 and 43.
4. Stereoselective Synthesis of 12~·Hydroxymethyl·9·nor·
9~·Hydroxyhexahydrocannabinol
Several methods for the non-stereoselective cyclization of
tetraol 42 can be imagined. However, control of the stereochemistry
at C-6 posed a difficult challenge, since cyclization of 42a leads to 43
whereas, 42b leads to 30. Also, there was no reason a priori to
expect any conformational preference between 42a and 42 b. In fact,
H
..
HO
20
OH428 42b
treatment of tetraol 42 with p-toluenesulfonic acid in refluxing
toluene led to 1:1 diastereoisomeric mixture of 30 and 43. The
protonation of the isopropenyl group presumably led to a tertiary
planar carbocation which was attacked by the phenolic hydroxyl
OH
30
OH
with a complete lack of stereochemical bias. This result with proton
as the electrophile was disheartening, but it suggested that the
OH
- I ~. ~ A'
HO OH42
a ..
OH
30
Reagents: (a) Hg(OAc)2. NaOH; NaBH4. room temperature,
21
problem might be overcome by altering the mechanism, through the
use of an alternative electrophile. Treatment of tetraol 42 with
mercuric acetate39b in THF at OOC for 30 min, followed by reductive
demercuration with sodium borohydride in aqueous sodium
hydroxide led to a 86: 14 (hplc: 25cm, 10 ~ Econosil column; 80/20
ethyl acetate/heximes) mixture of compounds 30 and 43 in 75%
yield. The determination of stereochemistry in compound 30 was
based on nOe analysis: irradiation of the pseudoaxial methyl group (0
= 1.10 ppm) led to enhancement of the C-I0a benzylic methine signal
(0 = 2.52 ppm). The assignment of stereochemistry is also supported
by the IH-NMR data of various THe derivatives in which the 6a
methyl is always at higher field (1.10 ppm) than that of the 6~
methyl.39 This approach provided the stereoselective route to
compound 30.
5. Stereoselective Synthesis of 14a.-Hydroxymethyl-9.nor9~-Hydroxyhexahydrocannabinol
In order to prepare compound 43, the Swern oxidation of 40
presumably gave the ~,.y·unsaturated aldehyde 44 which underwent
spontaneous isomerization to a single conjugated aldehyde 45
(scheme 8). The E-geometry of the double bond of aldehyde 45 was
determined by examination in 1H-NMR spectrum at 300 MHz: no
coupling between the vinylic methyl and vinylic hydrogen was
observed. Reduction of both carbonyl groups in 4S with sodium
borohydride in a mixed solvent (THF/isopropanol) led to 46 in 80%
yield. Cleavage of the phenolic protecting groups with t etra -n-
22
SCHEME 8
o
..
o
o44
OH
b .. ..
OH
e
OH
..I
)HOHO 47
d
Reagents: (a) Swern oxidation; (b) room temperature 30 h: (c) NaBH4.methanol; (d) n-Bu4N+F-, THF; (e) Hg(OAc)2, NaOH: NaBH4.
butylammonium fluoride led to tetraol 47. Mercuration
demercuration of 47 with sodium borohydride led to a 15:85
mixture of 30 and 43 in 80% yield. The stereochemistry was
23
assigned by nOe analysis: irradiation of the C-14 methylene group m
isomer 43 led to enhancement of the C-IOa benzylic methine signal
(0 = 2.52 ppm).
The results from the above syntheses demonstrated that each of
the two diastereomers was available selectively, however the origin
of the stereoselectivity was not easily rationalized. Some of the
results in this area are contradictory. For example, Sinay40 has shown
that intramolecular oxymercuration of 48 produces 49, in which the
-CH2HgCI group is axial. The stereochemistry in this case was
attributed to coordination by the adjacent benzyloxy group to
~\_O~~BnO~~BnOBnO
48~
Bn
BnO 0
BnO OBn49 HgCI
the incoming mercurio species. On the other hand, Ganem41 reported
only equatorial product 51 from the intramolecular
aminomercuration of 50, even though an adjacent benzyloxy group
was present to direct the axial stereochemistry. In Kozikowski's42
synthesis of dactylomelynes, the high degree of stereoselectivity
~ NHBnBnO~~BnO OBn
50
.. ~~~~rBno~~nBnOBnO
51
24
during the cyclization of 48 was attributed to the equatorial
preference of the bulky alkylmercurial group in a chair-like
transition state. It is perhaps significant that in the solid state of the
HrrHm
~ ·~OH.;
MeO'"! O! ! OHHHH
52
..
product, rotation about the CI-C3 bond in 53 places the
chloromercury group syn to the C7 hydroxyl, suggesting that in this
case, the stereoselectivity may in fact be traced to a directing effect
by hydroxyl. In the case of both 42 and 47, oxymercuration took
place so as to place the alkylmercurial group axial in the developing
dihydrobenzopyran ring. In the absence of any heteroatomic
directing effect, the stereochemical preference may be due to the
anomeric effect of the positively charge mercurio species43 in the
transition state. The mercury is clearly exercising a profound effect
on the stereochemistry, as shown by the observation that
fluorodesilylation of compound 45, followed by reduction with
sodium borohydride, produced a I: I mixture of 30 and 43.
6. Biological Activities of the Synthetic Compounds
Compounds 30 and 43 as well as their uncyclized precursor 42,
were tested for their affinities for the cannabinoid CB 1 receptor
25
using rat brain membranes and [3H]-CP-55,940 as the radioligand.44
Of tht:se, compound 30, in which the hydroxyethyl group has a /3
equatorial relative configuration, was shown to possess considerable
affinity for the CB 1 receptor (ICSO = 100 nM), while compounds 43
and 42 exhibited much weaker affinities (ICSO =3.2 IJ.M; 0.10 IJ.M,
respectively). The above biochemical data demonstrates the strict
stereochemical requirements for a favorable ligand/receptor
interaction imposed by the cannabinoid receptor on the
hydroxypropyl pharmacophore.
26
CONCLUSION
In conclusion, the design and stereoselective synthesis of two
cannabinoids from 39 in high yield have been described.
Several features are noteworthy: (1) compound 39 is a versatile
precursor for the synthesis of other cannabinoids. (2) Stereoselective
cyclization was achieved by intramolecular oxymercuration.
Biological testing has shown that compound 30 had very good
activity whereas compound 43 showed much weaker binding to the
CB 1 receptor than 30. These results showed that the stereochemistry
of the hydroxyethyl sidechain effects activity significantly.
27
EXPERIMENTAL
General:
IH-NMR and 13C NMR spectra were recorded at 300 MHz IH
(75.5 MHz 13C) or 500 Hz IH (125.8 MHz BC) in either
deuteriochloroform (CDCI3) with chloroform (7.26 ppm, 77.00 ppm
13C) or deuteriobenzene (C6D6) with benzene (7.15 ppm IH, 128.00
ppm 13C) as an internal reference. Chemical shifts are given in 0;
multiplicities are indicated as br (broadened), s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet); coupling constants (1) are
reported in hertz (Hz). Infrared spectra were recorded on a Perkin
Elmer IR 1430 spectrometer. Electron impact mass spectra were
recorded on a VG-70 SE mass spectrometer.
Thin-layer chromatography (tic) was performed on EM Reagents
precoated 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 (DMF), 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 glassware. The purity
28
and homogeneity of the products on which the high resolution mass
spectr~l data are reported were determined on the basis of 300 MHz
IH-NMR (>94%) and multiple elution tic analysis, respectively.
OH OEE
29
EEO
Procedure:
13· 24
To a solution of olivetol 13 (lg, 5.55 mmol) in dichloromethane
(20 ml) at 230C was added ethyl vinyl ether (1.35 ml, 13.88 mmol),
followed by a catalytic amount (ca. 50 mg) of PPTS in
dichloromethane. The reaction mixture was stirred at 230C 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 (NaZS04). Solvent evaporation in
vacuo gave the crude bis-2-ethoxyethyl olivetol which was purified
by flash chromatography on silica gel eluting with 5% ethyl acetate in
hexanes. The yield of the reaction was 70-85%.
30
OEE
EEO
24
Bis-2-ethoxyethyl olivetol 24:
IH-NMR (CDC13, 300 MHz, ppm): a 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, 6H), 0.89 (t, J =6.3 Hz, 3H).
13C-NMR (CDC13, 75 MHz, ppm): a 157.8, 145.3, nO.8, 103.8, 99.5,
61.5, 36.1, 31.4. 30.9, 22.5, 20.3, 15.2, 13.9.
IR (neat, em- l ): 2990, 2920, 2850, 1590, 1450, 1380, 1150, lll0,
1080, 1050.
31
0
0 OEE
~..
+EEO
23 24 25
Procedure:
To a solution of 311 mg (0.956 mmol) of bis-2-ethoxyethyl
olivetol 24 in THF (IS ml) at OOC was added n-butyllithium solution
in hexane (0.85 ml, 1.150 mmol) during 20 min. The mixture was
stirred at OOC for 10 min and then at 250C for 2.5 h. In a separate
flask 3.85 ml (0.956 mmol) of a solution of lithium 2
thienylcyanocuprate in THF was cooled to -78°C. 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°C, and stirred for 1.5
h. To the pale yellow cuprate solution was added a mixture of 200
mg (1.470 mmol mmol) of (+)-apoverbenone (23) and 0.20 ml (1.470
mmol) of BF3.Et20 in 1.5 ml of THF at -78°C. The mixture was stirred
at -780C until tic (5% ethyl actate in hexane) showed the
disappearance of the starting material (lh). The reaction was diluted
with ether (30 ml), washed with concentrated NH40H/saturated
32
NH4CI (1/9) solution, extracted with ether, and dried (MgS04).
Evapo~ation of the solvent in vacuo and purification of the crude
product by flash chromatography on silica gel eluting with 5% ethyl
acetate in hexane produced 225 mg (70% yield) as a mixture of
diastereomers due to the asymmetric center on each of the two
ethoxyethyl protecting group.
4 - [4 - n - pentyl- 2,6- bis (2 -ethoxyethyl) phenyl] - 6,6 -d im ethyl
2-nopinone 25:
!H-NMR (CDCI3, 300 MHz, ppm): d 6.59 (s, IH), 6.55 (s, IH), 5.46-5.39
(m, 2H), 4.16-4.09 (m, IH), 3.74-3.64 (m, 2H), 3.38-3.29 (m, IH),
2.56-2.45 (m, 6H), 2.22 (br s, IH), 1.61-1.56 (m, 4H), 1.48 (d, J = 5.1
Hz, 6H), 1.35 (s, 3H), 1.33-1.31 (m, 2H), 1.22-1.16 (m, 6H), 0.98 (s,
3H), 0.89 (t, J = 6.7 Hz, 3H).
IR (neat, cm-!): 2975, 2925, 2860, 1710, 1605, 1570, 1430, 1380,
1070, 1050.
,.
a
25
Procedure:
a
36
33
To a solution of compound 2S (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 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 resorcinol 36 as
single isomer.
34
o
36
Resorcinol 36 :
IH-NMR (CDCI3, 300 MHz, ppm): 0 6.17 (s, 2H), 5.13 (s, 2H,
exchangeable with D20), 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 (s, 3H), 1.31
1.26 (m, 4H), 0.99 (s, 3H), 0.89 (t, J = 6.9 Hz, 3H).
I3C-NMR (CDC13, 75 MHz, ppm): 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.
IR (CC4, em-I): 3350, 2950, 2850, 1680, 1620, 1590, 1430, 1265,
1020.
Mass spectrum (70 eV, m/e): 316 (M+), 310, 273, 247, 233, 219, 206,
193, 150, 83, 69, 57.
o
36
Procedure:
•
o
37
35
To a solution of resorcinol 36 (158 mg. 0.50 mmol) and tert
butydimethylsilyl chloride (453 mg. 3.00 mmol) in 10 ml N.N
dimethylformamide (DMF) at 230C was added imidazole (410 mg.
6.00 mmol). The mixture was stirred at 230C for 16 hand 50 ml
ether was added. The organic phase was washed with water. dried
(MgS04) and evaporated. The crude product was purified by flash
column chromatography on silica gel (5% ethyl acetate in hexane) to
give 231 mg (85% yield) of 37.
36
o
37
Ketone 37:
IH-NMR (CDCI3, 300 MHz, ppm): a 6.27(s, 2H), 3.98 (m, IH), 3.75 (d, J
= 6.9 Hz, IH), 3.68 (d, J = 6.9 Hz, IH), 2.56-2.36 (m, 6H), 2.21 (m, IH),
1.56-1.30 (m, 2H), 1.55 (s, 3H), 1.32 (s, 3H), 0.98 (s, 6H), 0.86 (s,
18H), 0.02 (s, 12H).
IR (neat, em-I): 2960, 2860,1710,1600,1560,1460,1420,1150,
1050.
Mass spectrum (70 eV, role): 544 (M+), 487, 377, 215, 168, 73.
Calculated mass for C32Hs603Si2: 544.3767, found: 544.3748.
o
T880
37
Procdure:
..
o
39
37
A solution of iodine (343 mg, 1.35 mmol) and
allyltrimethylsilane (156 mg, 1.37 mmol) in 5 ml CCl4 was stirred at
DoC for 2 h. Ketone 37 (480 mg, 0.88 mmol) in 3 ml CCl4 was added.
The reaction mixture was stirred at DoC for 30 min, then quenched
by adding aqueous sat'd Na2S203. The mixture was extracted with
ether. The organic solution was dried (MgS04) and evaporated. The
crude product 38 was dissolved in 5 ml benzene at 23°C and excess
DBU (ca. 4 mmol) was added. The solution was stirred for 2 h at 230C
and diluted with 20 ml ether. The organic solution was washed with
water, dried (MgS04) and evaporated. The residue was purified by
flash chromatography (10% ethyl acetate in hexane) on silica gel to
give 250 mg (52% over yield) of 39.
38
a
39
Ketone 39:
IH-NMR (CDCI3, 300 MHz, ppm): () 6.22 (s, IH), 6.20 (s, IH), 4.66 (d, J
= 0.3 Hz, IH), 3.47 (td, J = 12.0, 3.0 Hz, IH), 3.17 (dd, J = 14.1, 13.5 Hz,
IH), 2.48 (m, 3H), 2.33-1.67 (m, 6H), 1.56 (s, 3H), 1.32 (m, 4H), 1.06
(s, 9H), 0.98 (s, 9H), 0.88 (dd, J = 6.9, 6.6 Hz), 0.35 (s, 3H), 0.32 (s, 3H),
0.23 (s, 3H), 0.16 (s, 3H).
IR (neat, em-I): 3010, 2960, 1720, 1610, 1560, 1470.
Mass spectrum (70 eV, role): 544 (M+), 487, 379, 258, 194, 110, 73.
Calculated mass for C32HS603Si2: 544.3767, found: 544.3794.
o
Procedure:
o
~ I ~HO~OTBS
40
39
To a solution of 2,6-diphenylphenol (134 mg, 0.55 mmol) in 2 ml
CH2Clz was added 0.17 ml of a 1.6 M solution of trimethylaluminum
in toluene (0.27 mmol) at 230C. The solution turned light brown and
was stirred for 1 h at 230C, cooled to DoC, and trioxane (11 mg, 0.12
mmol) in 1 ml CHZClz was added. The mixture was stirred for 1 h at
DoC. Ketone 39 in 2 ml CH2CIZ was added and the solution was stirred
for additional 2 h. Sat'd aqueous NaHC03 was used quench the
reaction. The reaction mixture was extracted with CHzClz and the
organic phase was dried (MgS04) and evaporated. The residue was
purified by flash column chromatography on silica gel (20% ethyl
acetate in hexane) to give 58 mg (50-55% yield) of 40.
-- ~--~. -~ ..._ ..
40
o
Compound 40:
IH-NMR (CDCI3, 300 MHz, ppm): a 6.24 (s, IH), 6.20 (s, IH), 4.97 (s,
IH), 4.68 (s, IH), 3.75 (m, IH), 3.58 (q, J = 12.3, 12.0 Hz, 2H), 3.36 (m,
2H), 2.48-2.05 (m, 6H), 1.71-1.50 (m, 3H), 1.55 (s, 3H), 1.30-1.25 (m,
3H), 1.05 (s, 9H), 0.88 (dd, J = 6.9, 6.6 Hz, 3H), 0.36 (s, 3H), 0.32 (s,
3H), 0.24 (s, 3H), 0.16 (s, 3H).
IR (neat, em-I): 3450, 2980,1710,1570,1420,1100.
Mass spectrum (70 eV, m/e): 574 (M+), 487, 379, 73, 69.
Calculated mass for C33HSS04Si2: 574.3957, found: 574.3915.
..
a
40
Procedure:
OH
- I ~HO~OTBS
41
41
To a solution of ketone 40 (80 mg, 0.14 mmol) in 10 ml of a
mixture of THF and isopropanol (9:1) at 230C was added sodium
borohydride (8 mg, 0.21 mmol) portionwise, and the mixture was
stirred for 30 min. The reaction was quenched with water and the
mixture was extracted with ether. The organic layer was dried
(MgS04) and evaporated. The crude product was purified by flash
column chromatography (20% ethyl in hexane) on silica gel to give 70
mg (85-88% yield) of alcohol 41.
42
OH
41
Diol 41:
IH-NMR (CDCh, 300 Hz, ppm): d 6.22 (s, 1H), 6.18 (s, 1H), 4.91 (s, 1H),
4.61 (s, IH), 3.69 (m, IH), 3.54 (tt, 5.7, 5.7 Hz, 2H), 3.35 (m, IH), 2.89
(m, IH), 2.41 (dd, 7.8, 7.5 Hz, 2H), 2.09 (m, 3H), 1.86 (m, 1H), 1.55 (s,
3H), 1.57-1.24 (m, 7H), 1.06 (s, 9H), 1.02 (s, 9H), 0.88 (dd, J = 6.0, 5.7
Hz, 3H), 0.33 (s, 3H), 0.32 (s, 3H), 0.25 (s, 3H), 0.17 (s, 3H).
IR (neat, em-I): 3340, 2970, 2880, 1600, 1420, 1050.
OH
Procedure:
OH
42
43
-- - ---- - ------
To a solution of 41 (40 mg, 0.07 mmol) in 6 ml THF at 23°C was
added tetra-n-butylammonium fluoride hydrate (73 mg, 0.28 mmol)
portionwise. The mixture was stirred for 1 hand 30 ml ether was
added. The organic phase was washed with water, dried (MgS04) and
evaporated. The residue was purified by flash column
chromatography (80% ethyl acetate In hexane) on silica gel to give 23
mg (90-96% yield) of tetraol 42.
44
OH
42
TetraoI 42:
lH-NMR (CD3COCD3, 300 MHz, ppm): 0 8.00 (br, IH, exchangeable with
D20), 6.16 (s, IH), 6.14 (s, IH), 5.61 (s, IH, exchangeable with D20),
4.84 (d, J = 1.5 Hz, IH), 4.47 (s, IH), 3.64 (m, IH), 3.54-3.31 (m, 3H),
3.03 (m, IH), 2.33 (dd, J = 8.1, 6.9 Hz, 2H), 2.15 (m, 2H), 1.79 (m,
2H), 1.55-1.19 (m, 10H), 0.86 (dd, J = 6.9, 6.6 Hz, 3H).
l3C-NMR (CD3COCD3, 75 MHz, ppm): 0 157.6, 156.0, 151.1, 141.7,
115.8, 109.8, 108.5, 107.6, 71.1, 61.6, 46.4, 40.4, 38.6, 37.1, 36.7,
36.0, 32.9, 32.2, 31.5, 23.1, 14.2.
IR (neat, cm- l ): 3350, 2960, 2880, 1620, 1590, 1420, 1040.
Mass spectrum (70 eV, role) 572 (M+): 516, 515, 445, 405, 377, 100,
95, 73.
Calculated mass for C33HS604Sh: 572.3717, found: 572.3741.
o
~I#HO OTBS
40
Procedure:
o
45
Dimethylsulfoxide (0.52 mmol) was added to the solution of
oxalyl chloride (0.35 mmol) in 2 ml CH2Cl2 at -780C. After 8 min, 48
mg of 40 (0.08 mmol) in 1 ml CH2C12 was added slowly. The mixture
was stirred for 15 min, then triethylamine (0.22 mmol) was added at
-780C. The mixture was warmed to 230C and stirring was continued
for 12 h. The reaction was quenched with water. The organic layer
was washed with brine, dried (MgS04) and evaporated. The crude
product was purified by flash column chromatography 20% ethyl
acetate in hexane) on silica gel to give 41 mg in 85% yield of
ketoaldehyde 45.
46
o
Ketonealdehyde 45:
IH-NMR (CDC13, 300 MHz, ppm): B9.82 (d, J =7.9 Hz, IH), 6.22 (s, IH),
6.18 (s, IH), 5.86 (d, J = 7.9 Hz, IH), 3.76 (m, IH), 3.56 (m, IH), 3.20
(dd, J = 13.5, 11.2 Hz, IH), 2.41 (m, 3H), 2.05 (m, IH), 1.99 (s, 3H),
1.80-1.57 (m, 5H), 1.25 (m, 4H), 1.06 (s, 9H), 0.99 (s, 9H), 0.88 (t, J =
6.9, 6.6 Hz, 3H), 0.36 (s, 3H), 0.25 (s, 3H), 0.17 (s, 3H).
IR (neat, em-I): 2980,2880,1720,1680,1605,1570,1100.
Mass spectrum (70 eV, role) 572 (M+): 515, 445, 405, 377, 100, 95,
73.
Calculated mass for C33HS604Si2: 572.3717, found: 572.3741.
47
OH
I)'HO
HO47
Tetraol 47:
The same procedure was followed as in the conversion of (41) to
(42). Ketoaldehyde 4S (25 mg) was converted to diol 4S (18 mg,
72% yield). Desilylation produced 10 mg of tetraol 47 in 92% yield.
IH-NMR (CD3COCD3, 300 MHz, ppm): 07.60 (br d, exchangeable with
DzO, 1H), 6.15 (s, 1H), 6.12 (s, 1H), 5.34 (dd, J = 6.6, 6.0 Hz, 1H), 3.88
(m, 1H), 3.76 (m, 1H), 3.64 (m, 1H), 3.33 (td, J = 11.7, 3.3 Hz, 1H), 2.33
(dd, J = 7.8, 7.5 Hz, 2H), 2.17-1.96 (m, 3H), 1.84 (m, 1H), 1.65-1.23
(m, 9H), 1.48 (s, 3H), 0.86 (dd, J = 7.2, 6.6 Hz 3H).
IR (neat, cm- 1): 3400, 3010, 2980, 1600, 1420, 1100.
Mass spectrum (70 eV, m/e) (no M+): 330 (M+-HzO), 312, 217, 194,
193, 150, 79.
OH
42
Procedure:
OH
30
48
Mercuric acetate (28 mg, 0.06 mmol) was added to a solution of
tetraol 42 (20 mg, 0.06 mmol) in 3 ml THF in one portion at 23 0C.
The mixture was stirred for 18 h. Excess sodium borohydride (0.12
mmol) in 0.5 ml 2.5 M aqueous NaOH (0.5 ml) was added, and the
mixture was stirred for additional 10 h. Sat'd aqueous Na2C03 (0.5
ml) was added and the mixture was stirred for another 4 h. The
reaction mixture was decanted from metallic mercury and was
partitioned between water and ether. The organic phase was dried
(MgS04) and evaporated. The residue was purified by flash
chromatography on silica gel to give 15 mg (75% yield) of a 86:14
mixture of products 30 and 43. The pure product was purified by
hplc (80% ethyl acetate in hexane).
49
OH
30
1213- Hydroxym ethyl-9 -nor-9 ~ -hydroxyahydrocannabinol 30:
IH-NMR (CDC13, 500 MHz, ppm): 0 6.21 (d, J = 1.5 Hz, IH), 6.11 (br, IH,
exchangeable with DzO), 6.10 (d, J = 1.5 Hz, IH), 3.97-3.81 (m, 3H),
3.55-3.52 (m, IH), 2.86 (br, 1H, exchangeable with D20), 2.52 (td, J =
11.1, 2.1 Hz, IH), 2.41 (dd, J = 8.5, 7.0 Hz, 2H), 2.16 (m, IH), 1.95 (t,
5.8 Hz, 2H), 1.84 (m, IH), 1.66-1.53 (m, 4H), 1.40-1.26 (m, 5H), 1.14
1.01 (m, IH), 1.10 (s, 3H), 0.88 (t, J = 7.2 Hz, 3H).
13C-NMR (CDC13, 125 MHz, ppm): 0 155.1, 153.9, 142.9, 109.6, 109.0,
108.2, 79.9, 70.9, 58.9, 46.3, 41.1, 38.6, 35.5, 35.4, 33.2, 31.6, 30.6,
25.7, 22.5, 17.8, 14.0.
IR (neat, em-I): 3400, 2980, 1600, 1480, 1350, 1050.
Mass spectrum (70 eV, m/e) 348 (M+): 257, 193, 167, 150, 149.
Calculated mass for C2IH3204: 348.2300, found: 348.2308.
50
~I) HO
HO47
Procedure:
OH
43
Compound 43 (8 mg) was prepared in 80% yield from 10 mg of
47 by the same procedure for 30. The ratio of 43:30 was 85:15.
51
OH
43
14cx- Hyd roxymethyl-9-nor-9~-Hydroxyhexahyd rocanna binol
43:
IH-NMR (CDCI3, 500 MHz, ppm): 0 6.20 (d, J = 0.9 Hz, IH), 6.09 (d, 0.9
Hz, IH), 5.97 (br, IH, exchangeable with DzO), 3.87 (m, 2H), 3.73 (m,
IH), 3.48 (m, IH), 2.53 (td, J = 11.4, 2.0 Hz, IH), 2.44 (m, 2H), 2.18 (m,
IH), 1.97-1.83 (m, 4H), 1.58-1.33 (m, 8H), 1.42 (s, 3H), 1.05 (q, J =
7.2, 6.9 Hz, IH), 0.87 (dd, J = 7.2, 6.9 Hz, 3R).
13C-NMR (CDCI3, 125 MHz, ppm): 0 155.1, 154.2, 143.2, 109.2 (2C),
108.3, 78.5, 70.8, 59.1, 49.7, 38.8, 35.7, 35.4, 32.8, 32.7, 31.5, 30.6,
25.7, 24.7, 22.5, 14.0.
IR (neat, cm- 1): 3400, 2980, 1610, 1450, 1350, 1100.
Mass spectrum (70 eV, m/e) 348 (M+): 285, 257, 231, 217, 193, 149.
Calculated mass for CZIH3204: 348.2300, found: 348.2295.
REFERENCES
1. Schultes, R. E.; Hofmann, A. The Botany and Chemistry of
Halucinogens, 2nd ed., Charles C Thomas, Springfield, 111.,
1980.
2. Campbell Thompson, R. A Dictionary of Assyrian Botany, the
British Academy, London, 1949.
3. (a) Touw, M. J. Psychoactive Drugs, 1981, 13, 23.
(b) Li, C. P. Chinese Herbal Medicine, Pub!. No. 75-732, U. S.
Department of Health, Education and Welfare, Washington,
D. C., 1974.
4. Mechoulam, R. The Pharmacohistory of Cannabis sativa. In:
Cannabinoids as Therapeutic Agents, Mechoulam, R. ed., CRC
Press, Boca Raton, FL, 1986, pp. 1-19.
5. Kabelik, J.; Krejci, S,; Santavy, F. Bull Narc. 1960, 12, 5.
6. O'Shaugnessy, W. B.; Trans. Med. Phys. Soc. Bombay 1839, 8,
421.
7. O'Shaugnessy, W. B. Pharmacol. J. Trans. 1843,2, 594.
8. O'Shaugnessy, W. B. Cannabis. In: The Bengal Dispensatory and
Pharmacopoeia, Bishop's College Press, Calcutta, 1841, 579.
9. Adams, R. Harvey Lect. 1941·1942,37, 168.
10. Todd, A. R. Experientia 1946, 2, 55.
11. Loewe, S. Arch. Exp. Pathol. Pharmacol. 1950,211, 175.
12. Gaoni, Y.; Mechoulam, R. J. Am. Chern. Soc. 1964,86, 1646.
13. Mechoulam, R.; Edery, H. Structure-activity relationships in the
52
53
cannabinoid series, in Marijuana: Chemistry, Pharmacology,
Metabolism and Clinical Effects, Mechoulam, R., Ed., Academic
Press, New york, 1073.
14. 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.
15. Razdan, R. K. Pharmacol. Rev. 1986,38, 75.
16. Little, P. J.; Compton, D. R.; Martin, B. R. J. Pharmacol. Exp. Ther.
1988, 247, 1046.
17. Jarbe, T. U. C.; Hituene, A. J.; Mechoulam, R., Srebnik, M.; Breuer,
A. Eur. J. Pharmacol. 1988, 156, 361.
18. Mechoulam, R.; Devane, W. A.; Glaser, R. Cannabinoid geometry
and biological activity in Marijuana/Cannabinoids
Neurobiology and Neurophysiology, Murphy & Bartke, Ed., CRC
Press, Boca Raton, FL, 1992, 1.
19. (a) Houry, S.; Mechoulam, R.; Fowler, P. J.; Macko, E.; Loev, B. J.
Med. Chem. 1974,17, 287.
(b) Houry, S.; Mechoulam, R.; Loev, B. J. Med. Chern. 1975, 18,
951.
20. Banerjee, S. P.; Mechoulam, R.; Snyder, S. H. J. Pharmacol. Exp.
Ther. 1975,194, 75.
21. Johnson, M. R.; Althuis, T. H.; Bindra, J. S.; Harbert, C. A.; Melvin,
L. S.; Milne, G. M. NIDA Res. Monogr. Ser., 1981,34, 68.
22. Johnson, M. R.; Melvin, L. S.; Althius, T. H.; Bindra, J. S.; Harbert,
C. A.; Milne, G. M.; Weissman, A., J. Clin. Pharmacol. 1981,271s,
54
21.
23. Matsumoto, K.; Stark, P.; Meister, R. G. J. Med. Chem. 1977,20,
17.24. Makriyannis, A.; Rapaka, R. S. Life Science 1990,47, 2173.
25. Mechoulam, R.; Feigenbaum, J. J.; Lander, N.; Segal, M.; Jarbe, T.
U. C.; Hiltuene, A. J.; Consore, P. Experientia 1988,44, 762.
26. Johnson, M. R.; Milne, G. M. J. Clin. Pharmacol. 1981,21, 367.
27. Charalambous, A.; Marciniak, G.; Lin, S. Y.; Friend, F. L.; Compton,
D. R.; Martin, B. R.; Wang, C. L. J.; Makriyannis, A. Neurosci.
Biobehav. Rev. 1991, 40, 471.
28. Kannangara, G. C. K. Ph. D. Dissertation, University of Hawaii,
1994.
29. Razdan, R. K.; Dalzell, H. C.; Handrick, G. R. J. Am. Chem. Soc.
1974, 96, 5860.
30. Tius, M. A.; Kannangara, G. S. K. Tetrahedron 1992,48, 9173.
31. Mechoulam, R.; Braun, P.; Gaoni, Y. J. Am. Chem. Soc. 1972, 94,
6159.
32. Fahrenholtz, K. E.; Lurie, M.; Kierstead, R. W. J. Am. Chem. Soc.
1967, 89, 5934.
33. Pitt, C. G.; Fowler, M. S.; Sathe, S.; Srivastava, S. C.; Williams, D. L.
J. Am. Chem. Soc. 1975,97, 3798.
34. (a) Tius, M. A.; Gu, X. Q..; Kerr, M. A. J. Chem. Soc., Chem.
Commun. 1989, 62. (b) Tius, M. A.; Kerr, M. A. Synth. Commun.
1988, 1905. (c) Tius, M. A.; Gu, X. Q. J. Chem. Soc., Chem.
Commun. 1989, 1171.
35. Tius, M. A.; Kannangara, G. S. K. J. Org. Chem. 1990,51, 5463.
55
36. Huffman, J. W.; Joyner, H. H.; Lee, M. D.; Jordan, R. D.;
pennington, W. T. J. Org. Chern. 1991,56, 2081.
37. Tius, M. A.; Kannangara, G. S. K.; Kerr, M. A.; Grace, K. J. S.
Tetrahedron, 1993,49, 3291.
38. Lipshutz, B. H.; Kozlowski, J. A.; Parker, D. A.; Nguyen, S. L.;
McCarthy, K. E. J. Organornet. Chem. 1985,285, 437.
39. (a) Maruoka, K.; Concepcion, A. B.; Hirayama, N.; Yamamoto, H. J.
Am. Chem. Soc. 1990,112,7422. (b) Brown, H. C.; Geoghegan, P.
J. Jr. J. Org. Chern. 1975,35, 1844.
40. (a) Uliss, D. B.; Razdan. R. K.; Dalzell, H. C. J. Am. Chern. Soc.
1974,96, 7372. (b) Archer, R. A.; Boyd, D. B.; Demarco, P. V.;
Tyminski, I. J.; Allinger, N. L. J. Am. Chem. Soc. 1970,92, 5200.
41. (a) Pougny, J. R.; Nassr, M. A. M.; Sinay, P. J. Chem. Soc., Chern.
Commun. 1981, 375. (b) Bernotas, R. C.; Ganem, B. Tetrahedron
Lett. 1985,26, 4981.
42. Kozikowski, A. P.; Lee, J. J. Org. Chern. 1990,55, 863.
43. Tius, M. A.; Busch-Petersen, J. Tetrahedron Lett. 1994,35,
5181.
44. Tius, M. A.; Makriyannis, A.; Zou, X. L.; Abadji, V. Tetrahedron,
1994,50, 2671.
-- - ---.-._- --
PART II: THE TOTAL SYNTHESIS OF SARCOPHYTOL A AND ITSANALOGS
56
A. SYNTHESIS OF CANVENTOL AND ITS ANALOGS
INTRODUCTION
1. Background
The aim of this project was to synthesize some structurally
simplified analogs of the natural product sarcophytol A 55 and to
subject them to biological testing for cancer preventative activity.
The analogs 56-59, which are structurally related to sarcophytol A,
were designed by Professor Tius and their biological activity was
evaluated in Professor Hirota Fujiki's laboratory.l
55 sarcophytol A 56 canventol
OHR
57
2. Synthesis of Canventol and Its Analogs
The synthesis of analog 56, which has been named canventol by
Dr. Fujiki, was accomplished by following the synthetic route outlined
57
below (scheme 1). The conversion of compound 60 to enone 62 was
carried out by following the published procedure:2 Birch reduction
SCHEME 1
OCH3 cey; if&COOH a.,~ COOLi b
I~ .. III
60 61 62
c ™CY d e ... 65III ...
OMe63 64
g f.. ..
57 65 56
Reagents; (a) Li/NH3, THF. -78°C; (b) isopropyl iodide; aqueous HCI. 600C; (c)FeCI3/CH3MgBr. TMSCI. Et3N. HMPA; (d) 2,2-dimethoxypropane. TiCI4, OOC; (e)HCI04; (t) NaBH4. CeCI3. methanol; (g) MeLi. Et20. OOC.
of anisic acid 60, followed by alkylation with isopropyl
iodide led to carboxylic acid 61. Hydrolysis of 61 in aqueous Hel
produced enone 62 in 45% overall yield. Formation of the
thermodynamic enolate of 62 and trapping with
58
chlorotrimethylsilane led to enol ether 63 which was exposed to 2,2
dimethoxypropane and titanium tetrachloride at OOC to give enone
64 in 49% overall yield.4 ,5 Elimination of methanol from enone 64 in
the presence of perchloric acid produced dienone 65 in 51 % yield.
The reduction of dienone 65 with sodium borohydride and cerous
chloride gave crystalline (d, l)-canventol (56) in 96% yield.
Treatment of dienone 65 with methyllithium led to analog 57 in
quantitative yield. The overall yield in this synthesis of canventol
was 24% from enone 62. Its shortcomings are the use of HMPA and
the low yield for the elimination of methanol from enone 64.
These problems were largely overcome during a novel, efficient
synthesis of analogs S8 and 59 (scheme 2). Nopinone 35, which was
SCHEME 2
R
58 R = CH359 R = C2 Hs
67
OH
o 0
O~
e
6968
0 0 0
GJ a Gt°~ b.. /i'. •I
35 66
0 0 0
O~R
c d.. R •
Reagents: (a) Diallyl carbonate, NaH, DME; (b) TMSI, CCI4; (c) RX, acetone,K2C03; (d) Pd(OAc)2, THF, 800C; (e) NaBH4, methanol.
59
prepared from (-)-f3-pinene,6 was converted to ketoester 66 in 80%
yield by treatment of 35 with diallyl carbonate in DME. Ring
cleavage of 66 was achieved by treatment with TMSI in CCl4 at OOC
led to tertiary iodide 67 in 60-70% yield.7 Alkylation of 67 with
iodomethane or iodoethane followed by elimination produced ketone
68 in 50-60% yield respectively. Treatment of 68 with catalytic
palladium acetate led to dienone 69 in 80% yield.8 Reduction of
dienone 69 gave products 58 and 59 in 90% yield.9 The advantages
of this synthesis were the cheap, available starting material and its
applicability for larger scale.
This method was applied to the synthesis of canventol. It was
shown that alkylation of 66 with isopropyl iodide led to a (3:2)
mixture of O-alkylated 70 and C-alkylated 71 products. Starting
material 66 was recovered by hydrolysis of 70 under acidic
condition.
0 0 Jo~o~~o~ a GY'0~
~ ... ~ + ~I I I 0
66 70 71
Reagents: (a) acetone, K2C03, isopropyl iodide.
Recently, a novel synthetic method to canventol was developed
by our laboratory 10 and it provides the possibility of production on
kilogram scale. Further investigation of this synthesis will be
undertaken by our group.
60
3. Biological Activity
The testing which was performed in Professor Fujiki's laboratory
in Japan showed that canventol inhibited tumor promotion induced
by okadaic acid on mouse skin initiated with 7,12
dimethylbenz(a)anthracene in the two stage carcinogenesis
experiment. Canventol inhibited tumor promotion more strongly than
sarcophytol A, even though canventol has a simpler structure than
sarcophytol A.II
--- .-------- ...
61
EXPERIMENTAL
Procedure:
OCH3&COOH _60 62
A three-neck flask was charged with 15.2 g (100 mmol) of 0
methoxybenzoic acid and 100 ml of THF. The solution was stirred and
ammonia (400 ml) was distilled in to give a thick white suspension.
The reaction mixture was maintained at reflux under a nitrogen
atmosphere and lithium wire (washed sequentially with hexane,
ethyl ether) was added in 2 cm pieces until a blue solution was
maintained. The reaction vessel was cooled in a dry ice-acetone bath
and 1,2-dibromoethane (2 ml) added, followed by 2-iodopropane 12
ml (120 mmol). The reaction mixture was warmed to room
temperature under nitrogen and the resultant yellow slurry diluted
with 100 ml water, then acidified with 100 ml concentrated aqueous
HCl. Hydroquinone (200 mg) was added and the solution refluxed for
30 min. The solution was cooled to room temperature and extracted
with CH2C12. The solvent was removed and the residue purified by
chromatography to give 3.84 g of enone 62 in 50% yield.
-- - ---------
62
Enone 62:
IH-NMR (CDCI3, 300 MHz, ppm): 6.21 (dd, J =7.2, 6.9 Hz, IH), 2.87
2.78 (sept, IH), 2.40-2.29 (m, 4H), 1.96-1.87 (m, 2H), 0.97-0.96 (d,
6.9 Hz, 6H).
IR (neat, em-I): 3050, 2960, 1660, 1440, 1380, 1100.
62
Procedure:
62if
63
63
To a solution of anhydrous ferric chloride (257 mg, 2.2 mmol) in
15 ml of anhydrous ether at OOC under an atmosphere of N2 was
slowly added an ethereal solution of methylmagnesium bromide (2.2
ml, 6.6 mmol). The resulting slurry was stirred for 1 h at 25°C, then
enone 62 (276 mg, 2.0 mmol) dissolved in 5 ml ethyl ether was
slowly added over a period of 10 min. After 30 min, Me3SiCI (0.84
ml, 6.6 mmol), Et3N (0.95 ml, 6.8 mmol), HMPA (0.38 ml, 2.2 mmol)
were added in that order. The solution was stirred overnight, diluted
with 10 ml ethyl ether and poured into cold saturated NaHC03
solution. The aqueous layer was extracted with 15 ml ether. The
organic layer was dried over anhydrous sodium sulfate, filtered and
concentrated. The resulting colorless oil was filtered through a plug
of silica gel (5% EtOAc/Hexanes) to remove HMPA and Et3N. The
eluant was concentrated to give a colorless oil 63 which was used in
the subsequent reaction without further purification.
Procedure:
6"-----.....63
OMe
64
64
Under nitrogen, 2,2-dimethoxypropane (0.12 ml, 1.0 mmol) was
added slowly to a solution of TiC4 (1.0 mmol) in 10 ml anhydrous
CHzCl2 at -780 C. After 5 min, compound 63 (210 mg, 1.0 mmol)
dissolved in 5 ml CHzCl2 was added. The deep red solution was
stirred for 30 min at -780C and then 5 ml water added and the
mixture was warmed to room temperature. The aqueous layer was
extracted with 10 ml CH2CIZ. The organic layer was dried over
anhydrous MgS04, filtered and concentrated. The residue was
purified by silica gel chromatography to give 126 mg of the desired
product 64 in 60% yield.
Methoxyketone 64:
IH-NMR (CDCI3, 300 MHz, ppm): 6.75 (s, IH), 3.25 (s, 3H), 2.63-2.50
(m, 2H), 2.38-2.26 (m, IH), 2.03-1.96 (m, IH), 1.71-1.56 (m, IH), 1.17
(s, 3H), 1.10 (s, 3H), 1.02 (d, J = 3.0 Hz, 3H), 0.99 (d, J = 2.7 Hz, 3H).
IR (neat, cm- 1): 3050, 2960, 1680, 1450, 1380, 1050.
Procedure:
OMe
64 65
65
To a solution of compound 64 (294 mg, 1.4 mmol) in 12 ml
CF3CH20H, excess perchloric acid was added slowly at 250C. The
solution was heated to 400C for 30 h and then 10 ml water added.
The mixture was extracted with 10 ml ether and the organic layer
dried over anhydrous MgS04, filtered and concentrated. The oily
residue was purified by silica gel chromatography to give 120 mg of
the desired product 65 in 50% yield.
Dienone 65:
IH-NMR (CDC13, 300 MHz, ppm): 7.25 (s, IH), 2.97 (sept, IH), 2.66 (t, J
= 6.9 Hz, 2H), 2.46 (dd, J = 7.5 Hz, J = 6.6 Hz, 2H), 1.93 (s, 3H), 1.07 (s,
3H), 1.04 (s, 3H).
IR (neat, cm- 1): 3050, 2940, 1670, 1450, 1380, 1050.
Procedure:
65 56
66
To a stirring solution of compound 65 (100 mg, 0.56 mmol mg)
in 5 ml CH30H at 25°C, CeC13 (138 mg, 0.56 mmol) was added. After 5
min, NaBH4 (22 mg, 0.56 mmol) was added, the solution was stirred
for 2 min and water added. The mixture was extracted with 10 ml
ethyl ether. The organic layer was dried over anhydrous MgS04,
filtered and concentrated. The residue was purified by
chromatography to give 98 mg crystalline desired product 56 in 95%
yield.
Canventol 56:
IH-NMR (CDCI3, 300 MHz, ppm): 6.32 (s, IH), 4.24 (dd, J =6.9, 6.6 Hz,
IH), 2.52 (sept, IH), 2.37 (m, 2H), 1.81-1.76 (m, 8H), 1.11 (t, J = 7.2
Hz,6H).
13CNMR (CDCI3, 75 MHz, ppm): 127.5, 126.8, 120.9, 66.0, 32.4, 31.79,
22.59, 21.64, 21.32, 20.86, 19.68.
IR (neat, em-I): 3500, 3030, 2980, 1620, 1450, 1380, 1100, 1050.
Procedure:
65 57
67
To a solution of dienone 65 (45 mg, 0.25 mmol) in 10 ml ethyl
ether was added CH3Li (0.3 mmol) at OOC. The mixture was stirred
for 5 min at OOC and 10 ml water was added. The organic layer was
dried over anhydrous MgS04 and solvent removed. The residue was
purified by flash chromatography to give 40 mg of the desired
product 57 in 89% yield.
Alcohol 57:
IH-NMR (CDC13, 300 MHz, ppm): 6.37 (s, 1H), 2.80-2.67 (m, 1H), 2.35
2.26 (m, 1H), 2.15-2.04 (m, 1H), 1.71 (s, 3H), 1.66-1.62 (m, 2H), 1.60
(s, 3H), 1.21-1.19 (d, J = 6.9 Hz, 3H), 1.13 (d, J = 6.9 Hz, 3H).
IR (neat, em-I): 3350, 2980, 1480, 1350. 1100, 1050.
o 0
~.. O~)t'-.. ----i.._
I
66
Procedure:
o 0
O~
I
67
68
To a solution of allyltrimethylsilane (684 mg, 6.0 mmol) in 5 ml
CCl4 at OOC was added iodine (762 mg, 6.0 mmol). The mixture was
stirred for 1 h at ooC. The starting material 66 (1.11 g, 5.0 mmol) in
5 ml CCl4 was added and the solution was stirred for 30 min at OOC.
The solution was washed with sat'd aqueous NazSz03 solution. The
solvent was removed and the residue purified by flash
chromatography to give 950 mg of the desired product 67 in 55%
yield (the compound was not isolated).
o 0
O~
67
Procedure:
o 0
O~R
68 R = CH369 R = C2Hs
69
A mixture of compound 67 (0.68 mmol), 2 ml acetone,
potassium carbonate (280 mg, 2.03 mmol) and 0.5 ml alkyl iodide
was refluxed in a sealed tube for 10 h. The solution was cooled to
room temperature and filtered. The acetone was removed under
reduced pressure. The residue was purified by flash chromatography
to give 120 mg of compounds 68 or 69 in 75-80% yield.
Compound 69:
IH-NMR (CDCI3, 300 MHz, ppm): 5.92-5.72 (m, 1H), 5.31 (d, J = 17.1
Hz, 1H), 5.24 (d, J = 10.5 Hz, 1H), 4.65-4.51 (m, 2H), 3.23 (d, J = 14.4
Hz, 1H), 2.73-2.30 (m, 4H), 2.21 (d, J = 14.4 Hz, 1H), 1.74 (s, 3H), 1.70
(s, 3H), 1.33 (s, 3H).
IR (neat, em-I): 3040, 2980, 1730, 1710, 1640, 1460, 1380, 1140.
o 0
o~
oA
70
Procedure:
68 R=CH369 Ro=C2Hs
A mixture of compound 68 or 69 (0.48 mmol), Pd(OAch (0.1
mmol), diphenylphosphinoethane (dppe) (0.05 mmol), in 5 ml
acetonitrile was refluxed for 1h. The solution was cooled to room
temperature, filtered, and 20 ml water was added. The mixture was
extracted with ethyl ether and the organic layer was dried over
anhydrous MgS04. The crude product was purified by flash
chromatography to give 45 mg of the desired product dienone in 57
60% yield.
Dienone 72:
IH-NMR (CDCI3, 300 MHz, ppm): 7.26 (s, 1H), 2.70 (d, J = 6.9 Hz, 1H),
2.65 (d, J =7.2 Hz, 1H), 2.49-2.44 (m, 2H), 2.32-2.24 (dd, J = 15.0,
14.7 Hz, 1H), 1.92 (s, 3H), 1.87 (s, 3H), 1.05 (t, J = 7.5 Hz, 3H).
IR (neat, cm- l ): 3030, 2980, 1680, 1640, 1450, 1380, 1100.
o OH
71
RII'
R
Procedure:
58 R = CH359 R = C2Hs
To a stirring solution of dienone (0.27 mmol), CeCl3 (0.27 mmol)
in 5 ml CH30H at room temperature was added NaB14 (0.27 mmol).
After 5 min, 20 ml water was added and the mixture was extracted
with ethyl ether. The organic layer was dried over anhydrous MgS04
and the solvent was removed. The crude product was purified by
chromatography to give 10 mg desired products 58 or 59 in 88-90%
yield.
Compound 58:
IH-NMR (CDCI3, 300 MHz, ppm): 6.29 (s, IH), 4.10 (d, J = 2.1 Hz, IH),
2.32 (t, J = 6.3 Hz, 2H), 1.89 (s, 3H), 1.85-1.70 (m, 2H), 1.78 (s, 3H),
1.74 (s, 3H).
IR (neat, cm- l ): 3350, 2980, 1640, 1450, 1380, 1200, 1050.
72
Compound 59:
IH-NMR (CDC13, 300 MHz, ppm): 6.29 (s, IH), 4.18 (m, IH), 2.35 (t, J =
5.1 Hz, 2H), 2.28-2.21 (dd, J = 14.7, 15.0 Hz, 2H), 1.83-1.78 (m, 2H),
1.80 (s, 3H), 1.75 (s, 3H), 1.10 (dd, J = 7.5, 7.2 Hz, 3H).
13C-NMR (CDCh, 75 MHz, ppm): 140.3, 127.0, 126.8, 122.1, 67.2, 31.8,
27.4, 21.7, 20.7, 19.6, 12.7.
IR (neat, em-I): 3350, 2980, 1640, 1450, 1380, 1100, 1050.
73
REFERENCES
1. Professor H. Fujiki, Cancer Prevention Division, National Cancer
Center Research Institute, Tokyo 104, Japan.
2. (a) Taber, D. ,F. J. Org. Chern. 1976,41, 2649.
3. (a) Zank, G. A.; Rauchfuss, T. B.; Wilson, S. R. J. Am. Chem. Soc.
1984, 106, 7620.
4. Mukaiyama, T.; Hayashi, M. Chem. Lett. 1974, 15.
5. (a) Coxon, J. M.; Hydes, G. J.; Steel, P. J. Tetrahedron, 1985,42,
5213. (b) Luche, J. L.; Gemal, A. L. J. Am. Chem. Soc. 1981,103,
5454.
6. Grimshaw, J.; Grimshaw, J. T.; Juneja, H. R. J. Chem. Soc. Perkin
Trans. 1 1972, 50.
7. (a) Kato, M.; Kamat, Y. P.; Tooyama, Y., Yoshikoshi, A. J. Org.
Chem. 1989,54, 1536. (b) Jung, M. E.; Blumenkopf, T. A.
Tetrahedron Lett. 1978,29, 3657.
8. (a) Wilhelm, F. Newer Methods of Preparative Organic chemistry
Vol 2, 1963, Academic Press, New York. (b) Fatiadi, A. J.
Synthesis 1987, 85.
9. Minami, I.; Nisar, M.; Yuhara, M.; Shimizu, I.; Tsuji, J. Synthesis
1987, 992.
10. Tius, M. A.; Zhuo, J. C. Unpublished Result.
11. Komori, A.; Suganuma, Okabe, S.; ZOll, X. L.; Tius, M. A.; Fujiki, H.
Cancer Res. 1993,53, 3462.
74B. THE TOTAL SYNTHESIS OF SARCOPHYTOL A
INTRODUCTION
1. Background
Cembranes are fourteen membered, diterpenoid natural
products which were isolated from terrestrial and marine sources in
the 1970's.1 The structures range from the simple hydrocarbon
cembrane 73, found in pine 0leoresins,2 to those containing highly
oxygenated stereocenters such as sinularin 74.3 The biological
activities in the cembrane series have been found to be diverse: from
cytotoxins4-6 to termite allomones.7-9 For example, sarcophytol ASS,
which was isolated from Sarcophyton glaucum,lO inhibits tumor
promotion by teleocidin in the two-stage carcinogenesis model in
73 cembrane 74 sinularin
55 sarcophytol A
75
mouse skin. I I Due to the biological activities and interesting
structu.ral features, cembranes have become attractive targets for
total synthesis. 12 The major obstacles for synthesis are
macrocyclization, the introduction of functionality and asymmetric
centers on the fourteen membered ring.
2. Previous Approaches to Macrocyclization
The development of an efficient method of macrocyclization is
the key step for a successful cembrane synthesis. Unlike small nngs
(e.g. 5, 6), the number of degrees of freedom is much larger in the
open-chain precursor for larger ring (e.g. 14). Therefore, the entropy
barrier can become a problem, and bimolecular reaction can
predominate over the intramolecular cyclization. The bimolecular
processes, which lead to dimeric or oligomeric products, can be
suppressed at high dilution. There are several general methods of
macrocyclization that have been successfully used for cembrane
synthesis which will be discussed next.
a. Stabilized Anion Additions
Sulfur and cyanohydrin stabilized anions have been used for
direct cyclization. For example, a sulfone stabilized carbanion was
reported by Marshall I3 in the synthesis of dl-7(8)-deoxyasperdiol in
which a sulfone iodide 7S was cyclized to 76 in 53% yield by
treatment with KN(TMSh in THF in the presence of 18-crown-6. An
76
ethoxyethyl-protected cyanohydrin-derived anion 77 also
under~ent cyclization to 78 in 83% yield in the synthesis of mukulol
by Takahashi. 14
7877
a ...
I S02Ph
75 R = CH2Ph 76NC 0
OEEb
Reagents: (a) KN(TMS)2. THF. 18-crown-6; (b) NaN(TMS)2. THF, Hel.
b. Alkynyl Anion Addition
The most recent method of cyclization is that of direct addition
of an alkynyl anion to aldehydes (e.g. 79) or allylic halides (e.g. 81).
This method was previously developed for the formation of ten
membered rings 15 and was first used for cembrane synthesis in our
laboratory.16 The yields of the reaction were 30-60%. There are
several other methods for cyclization e.g. intramolecular Horner
Emmons reaction,17 and radical cyclization18 all of which have been
used in the synthesis of cembranes.
77
a
Br
'---====--H b
- HCHO -----1-._
81
Reagents: (a) LiN(TMS)2, THF. 50°C; (b) LiN(TMS)2, LiI, THF.
3. Previous Synthetic Approaches to Sarcophytol A
The geometrical structure and absolute configuration of
sarcophytol A were confirmed to be 2Z, 4£, 8£, 12£ and IS,
respectively.19 So far, several methods have been developed to the
synthesis of sarcophytol A.
a. Takayanagi et. al.
The first total synthesis of sarcophytol A was accomplished by
Takayanagi et. al. in 1990 (scheme 1).20 Therein trans, trans-farnesal
was converted to nitrile 83 by a Wittig reaction. Sharpless oxidation
of compound 83 led to allylic alcohol 84 in 52% yield (based on the
78
consumed starting material 83, which was converted to the chloride
8S by treatment with PPh3 and CC4. Treatment of 8S with DIBAL at
Doe followed by hydrolysis of the intermediate imine led to dienal
86. The unstable conjugated dienal 86 was converted to the
SCHEME 1
,a b
eN .. ..X
83 84 X = OH85 X = CI
, dc ..
CHO..
CI CI
86 87
e .. 55
88
Reagents: (a) SeOz, t-BuOOH, CH2CIZ, OOC; then CCI4, PPh3; (b) DIBAL, THF, OOC;(c) TMSCN; (d) LiN(TMS)Z, THF, 550C; n-Bu4NF, THF, OOC; (e) (S)-Z-(2,6xylidinomethyl)pyrrolidine, LAH, EtZ 0, -78°C.
cyanohydrin trimethysilyl ether 87. The macrocyclization of 87 was
immediately carried out by adding a solution of LiN(TMSh in the
presence of 18-crown-6, followed by n-Bu4NF to give dienone 88 in
79
60% yield. Treatment of 88 with the asymmetric reducing reagent
prepar~d by mixing LAH in ether with (S)-2-(2,6-xylidinomethyl)
pyrrolidine at -78°C led to optically active 55 of 93% ee in 88% yield.
b. Takahashi et. al.
Another new synthesis of sarcophytol A was developed by
Takahashi et. al. (scheme 2).21 Therein compound 89 was prepared
SCHEME 2
89
b
88
a
90
Reagents: (a) LiN(TMS)2, THF, 50°C; (b) LiCu(CH3)2. THF, DoC.
from trans, trans-farnesol in seven steps. Macrocyclization of 89
with NaN(TMSh in THF, followed by deprotection, led to enone 90 in
45% yield. Methyl cuprate addition to the conjugated exocyclic
double bond of 90 was followed by spontaneous 13-elimination of
alkoxide from the cuprate adduct to produce dienone 88 in 50%
yield.
80
c. Kodama et. al.
Recently, a novel synthesis to sarcophytol A was achieved by a
[2,3] Wittig rearrangement (scheme 3).22 Alcohol 92 was prepared
from geranial 91 in seven steps. Cyclization of 92 led to cyclic ether
93 in 9% yield. Rearrangement of 93 with n-BuLi at -78°C produced
sarcophytol A 55· in 90% yield. Obviously, the defect of this synthesis
was the poor yield (9%) of cyclization of 92.
SCHEME 3
91
7 steps...
92
a ...
93
b----1..._ 55
Reagents: (a) CC13CN, NaH; p-toluenesulfonic acid; (b) n-BuLi, THF.
d. Li et. al.
Macrocyclization by titanium-induced coupling of a dicarbonyl
compound was also achieved in the synthesis of sarcophytol A23.
Compound 94 was prepared from acetone in eight steps and
macrocyclization was carried out by treatment of 94 with TiCI3-AICI3
81
(1/3) and Cu-Zn alloy at 55°C in THF. Sarcophytol A SS was obtained
in 63% yield (scheme 4).
SCHEME 4
oA
8 steps ..
94
a---I"~ 55
Reagents: (a) TiCI3-AICI3 (1/3), Cu-Zn alloy, THF, 550 C.
The development of a novel and efficient method of the
synthesis of sarcophytol A will be disussed in the following chapter.
82
RESULTS AND DISCUSSION
1. Retrosynthesis of Sarcophytol A
Sarcophytol A SS was envisioned as being prepared from cyclic
alkynyl alcohol 96 (scheme 5). Our strategy and key steps are: (1)
the preparation of precursor acyclic alkynyl aldehyde 97 for
macrocyclization. (2) the introduction of isopropyl (C-2) and sulfoxide
(C-l) groups on the 14-membered ring (3) the conversion of
sulfoxide 9S to enone 88. The advantages of starting the synthesis
with trans, trans-farnesol are that it contains three trisubstituted
alkenes which fit the pattern for sarcophytol A.
SCHEME S
55
96
88
OH
===>
97
95
CHO
H,
83
2. Synthesis of Alkynyl Acetate
Starting material trans, trans-farnesol 98 was converted to
farnesyl acetate 99 in the presence of acetic anhydride and pyridine
in quantitative yield. Sharpless oxidation24 of 99 led to allylic alcohol
SCHEME 6
98 R= H99 R = Ae
101
a
c ..
100
102
OAe b
OH
OAe
H
Reagents: (a) (CH3CO)20, pyridine, CH2CI2; then Se02, t-BuOOH, DOC; (b) MsCI,LiBr, THF; (c) Acetylene, K2C03, NaI, CuI, acetone.
100 in 25% yield (scheme 6). There are several features of the
Sharpless oxidation which are noteworthy: (l) the regiochemical
preference of the oxidation made it possible to oxidize the E-terminal
CH3 (2) the methylene (-CHZ-) which IS next to the acetyl group was
not oxidized (3) the low yield (25%) of the reaction and the tedious
column chromatography in the initial step made the reaction very
difficult to perform on large scale. Treatment of allylic alcohol 100
with MsCI, NEt3 and lithium bromide at DOC led to allylic bromide
84
101 in 85% yield.25 Because of the instability of this allylic bromide,
101 was purified by short flash chromatography and used for
subsequent acetylene displacement immediately. To complete the
conversion from 101 to 102, acetylene gas was bubbled into a
mixture of CuI, K2C03, NaI and acetone at room temperature for 2 h
and then 101 was added dropwise.26 The mixture was stirred for 2
days and 102 was isolated in 60% yield. Several other conditions
were also examined. Replacement of acetone by DMF led to 102 in
very poor yield (20-30%), even though the reaction time was short (5
h). Direct displacement of bromide 101 with sodium acetylide or
lithium acetylide in THF at OOC did not succeed, the reaction did not
take place and only starting material 101 was isolated. It has to be
pointed out that acetylene displacement of 101 led to some dimeric
and SN2' byproducts (103 and 104 30% yield). The probable
mechanism of dimerization might be as follows:
SN2'
I ~
V~~r102 SN2 100
S~103
y~
104
85
Byproducts 103 and 104 were inseparable from desired product
102. Optimization of the reaction conditions did not give rise to a
yield better than 60%. The reaction was repeated at high dilution
(e.g. 0.005, 0.003, 0.001 M), but this led to no improvement of the
yield.
3. Formation of Cyclic Alkynyl Alcohol
Hydrolysis of 102 with KzC03 in methanol produced 105 in 85%
yield. Swern oxidationZ7 of 105 led to aldehyde 97. The overall yield
SCHEME 7
-::::-- CHO
H,a102
105 97
Reagents: (a) KZC03, methanol, Z30C; (b) DMSO, (COCI)Z, Et3N, CHZCIZ,-78°C.
from 102 to 97 was 60% (scheme 7). Although several methods for
macrocyclization have been applied to cembrane synthesis, only a
few cases of macrocyclization by direct addition of an alkynyl anion
to an aldehyde exist. The method was first used in the synthesis of
sinularin 74 in our laboratory, but the yield was very poor (30%).16
86
As mentioned above, several factors also affect the macrocyclization,
e.g. te"mperature, base and concentration. What we did first was the
use of different bases at the same temperature and highly dilute
concentration. When NaN(TMS)z was used at room temperature in
THF, the reaction proceeded well. Product 96 was obtained in 50
60% yield. Use of LiN(TMS)z resulted in incomplete reaction (10%
yield). When the stronger base KN(TMS)z was used, the cyclic allenic
a ..OH
96
97
106
Reagents: (a) NaN(TMS)2, THF, room temperature; (b) KN(TMS)2, THF, roomtemperature.
alcohol 106 was obtained in 60% yield. A possible mechanism to
account for the formation of allene 106 was by attack of cyclic
alcohol 96 by KN(TMS)z, so that the allene was formed after
cyclization. But when KN(TMSh was added to the solution of 96 in
87
...00
106
THF at room temperature, no allene 106 was isolated. Another
possibility was that the allene 106 was formed from 107 before
SCHEME 8
97 ...~ CHO
107
---.......-106
cyclization (scheme 8), although no evidence has been obtained to
confirm this assumption. Further work needs to be done on this
reaction. Allenic alcohol 106 was characterized by IH-NMR, IR and
mass spectrometry: IR showed a strong allene absorption band at
1960 em-I. Also, the appearance of the allenic protons (5.6-5.8 ppm)
on allene 106 in the IH-NMR spectrum and the exact mass matched
the proposed structure.
88
4. Synthesis of Alkylated Sulfoxide
To prepare the allenic sulfoxide 111, the following conditions
were examined in a model reaction in order to develop optimal
conditions for the real system (scheme 9).28 Compound 108 was
prepared from I-hexyn-3-01. The solution of compound 108 was
added dropwise to the mixture of CuI and isopropyllithium
SCHEME 9
OH a H>=C~ b
~H.. ...
SOPh H
1-Hexyn-3-ol 108 109
Reagents: (a) PhSCI, Et3N, Et20, -78°C; (b) isopropyllithium. lithium-2thienylcyanocuprate. THF, -780C or CuI. isopropylmagnesium chloride, THF.aoc.
or isopropylmagnesium bromide in THF at -780C. The mixture was
stirred for 2 h, the reaction was worked up with saturated NH4CI and
adduct 109 was obtained in 50% yield. Mixed higher-order cuprate
with lithium-2-thienylcyanocuprate led to the same adduct in 58%
yield. For the real system, allenic sulfoxide 111 was prepared by
[2,3] sigmatropic rearrangement of sulfenate ester 110 derived from
alkynol 96. Treatment of 96 with PhSCI at -78°C in diethyl ether led
to 111 in 80% yield (scheme 10).28 The reaction was quenched at
89
-78°C and compound 111 was purified by flash chromatography.
The el.ectrophilicity of the sp carbon (C-2) of the allene III allowed
the use of a cuprate to introduce the isopropyl appendage at C-2. For
the real system, the cuprate addition to the allene 111 did not work
with CuI and isopropyllithium or isopropylmagnesium bromide and
the reaction was· messy. Thus, an alternative mixed higher-order
reagent was examined. Isopropyllithium was prepared from
SCHEME 10
96
OHa
110
111
SOPh
b
95
Reagents: (a) PhSCI. Et3N. Et20, -780C; (b) isopropyllithium. lithium-2thienylcyanocuprate. THF. -78°C.
isopropyl chloride and lithium sand according to the published
procedure: isopropyl chloride and lithium sand were refluxed in
pentane for 10 h.29 The solution was transferred to another flask to
get it away from the excess lithium sand and was titrated under
90
nitrogen. The mixed higher-order cuprate reagent was prepared by
addition of isopropyllithium to a solution of lithium-2
thienylcyanocuprate30 in THF at -780C. The mixture was stirred for
10 min and then the solution of 111 in THF was added. The mixture
was stirred for 2 h and the reaction was worked up with saturated
NH4Cl. The crude mixture was purified by flash chromatography.
Alkylated sulfoxide 95 was isolated in 60% yield as a diastereomeric
mixture. Sulfoxide 95 was characterized by JR, IH-NMR and HRMS.
The chemical shift of the methine proton at C-I was 3.5 ppm in the
1H-NMR spectrum.
5. Pummerer Rearrangement of Alkylated Sulfoxide.Attempted Synthesis of Enone
a. Model Study
The Pummerer rearrangement, the conversion of a sulfoxide to
the carbonyl group of aldehyde, is well known,31 but very few
reactions have been carried out for conversion to a ketone. The
reason is not clear. It might be due to elimination during
rearrangement or during hydrolysis. Before we worked on the real
system, several conditions were examined in the following model
system (scheme 11). Sulfoxide 113 was prepared from
perillaldehyde 112 in 5 steps. Treatment of 113 with trifluoroacetic
anhydride at -78°C followed by hydrolysis with aqueous NaHC03 did
not give ketone 115 and the reaction was messy. Oxidation of
compound 114 with m-CPBA led to sulfoxide 116 followed by
hydrolysis in aqueous NaHC03 and no ketone 115 was isolated. An
9 1
SCHEME 11
CHO
112
117
5 steps ..
d
115
OCOCF3
SPh~
116
Reagents: (a) TFAA. CH2CI2. -780C; (b) aqueous NaHC03, room temperature; (c)H202. THF. room temperature; (d) n-BuLi, then TMSOOTMS. THF. -78°C; (e) m
CPBA. CH2CI2. (lOC.
alternative method which oxidizes the carbon next to the sulfoxide
group was also considered. Treatment of 113 with different bases
(e.g. LDA, n-BuLi, KN(TMSh, Na(TMSh, sec-BuLi etc.) in THF at -780C,
followed by oxidants (e.g. TMSOOTMS. oxaziridine, H20Z, Oz etc.) did
not produce the desired ketone 115. Since the conversion of sulfone
to the corresponding ketone by oxidation was previously reported,32
sulfoxide 113 was oxidized to sulfone 117 with H20Z in 40% yield in
THF at room temperature. Treatment of 117 with n-BuLi in THF at
92
-78°C followed by TMSOOTMS or oxaziridine led to ketone in 40% and
20% yield respectively. Replacement of n-BuLi with other different
bases (e.g. LDA, KN(TMS)2) did not improve the yield.
b. Attempted Conversion of Sulfoxide to Enone
Since there were significant structural differences between the
real and model systems, direct conversion of sulfoxide 95 to the
corresponding ketone 88 was attempted~ even though the model
reaction did not work well. Treatment of sulfoxide 95 with
trifluoroacetic anhydride at -780C followed by hydrolysis with
aqueous NaHC03 led to several compounds and the reaction was
messy (scheme 12). The crude compounds were characterized by
SCHEME 12
c ..
88
119
Reagents: (a) TFAA, ·78oC; aq. NaHC03; (b) 30% H202, THF, 23°C; (c) n-BuLi,(TMSO)2, THF, -780C.
93
IR. IR did not show any evidence of carbonyl group absorption. The
difficu~ty of this Pummerer rearrangement made us consider an
alternative approach. Compound 9S was oxidized to sulfone 118
with HZ02 in 40% yield. Attempted optimization of the reaction
conditions did not increase the yield. The conversion of 118 to
ketone 88 with n-BuLi/ TMSOOTMS did not succeed. Only compound
119 was isolated due to elimination. ~-Elimination probably took
place under the influence of the strong base (n-BuLi) and compound
119 was formed. Compound 119 was characterized by IR and 1H
NMR. There was no sulfoxide absorption in IR. Disappearance of the
methine proton at C-I (3.8 ppm) and the appearance of vinylic
protons (5.6-5.8 ppm) matched the structure of compound 119.
Other conditions were also attempted: When NaN(TMS)z and
TMSOOTMS were used, only starting material 118 was isolated. The
formation of the anion of compound 118 from deprotection by
Na(TMS)z was confirmed by trapping with D20. Different oxidants
(e.g. 02, oxizaridine) were also tried with NaN(TMS)z; none of these
conditions gave the desired dienone 88. These results made
necessary a change in strategy, therefore, substituents other than
sulfoxide and sulfone were considered.
c. Attempted Synthesis of Ester
The conversion of alkynyl carbonate to allenic ester has been
reported by Tsuji in good yield.33 The model study was carried out in
the following system (scheme 13). Compound 120 was prepared
94
from l-hexyn-3-01. Allenic ester 121 was obtained In 80% yield
SCHEME 13
OCOOCH3
~H
120
a ~ ~C=<OO_C_H_b.--1.._H~H7 'cOaCH.
121 122
Reagents: (a) Pd2(DBA)3. PPh3. CO. CH30H. 40oC; (b) isopropyllithium. lithium2-thienylcyanocuprate. THF. -780C.
by treatment of 120 with a catalytic amount of Pd2(DBAh and CO in
methanol. Cuprate addition to 121 with the mixed higher-order
reagent led to ester 122 in 55% yield. It was hoped that the same
chemistry could be applied to our system. Therefore, cyclic alcohol
96 was converted to carbonate 123 by treatment with methyl
chloroformate and DMAP at room temperature (scheme 14).
Compound 123 was treated with the conditions which were
developed for the model reaction, but the reaction only gave the
isomerized ester 125 in 20% yield rather than allenic ester 124.43
Compound 125 was characterized by IH-NMR, IR and HRMS. A
possible mechanism for the formation of 125 from 124 was by a
[1,5] sigmatropic rearrangement. The ease with which 124
rearranged to 125 suggests that the conjugated triene 125 is
thermodynamically more stable than allene 124. These results made
it very difficult to continue our synthesis using the current route,
althou~h enone 88 might be prepared from intermediate 125 by
SCHEME 14
95
96a
125
OCOOCH3
b
c._------
126
d-------
e._----- .....
127
f._------ .....
88
Reagents: (a) CH30COCI, DMAP. El20, DoC; (b) Pd2(DBA)3. PPh3. CO. CH30H. 4QoC;(c) cuprale; (d) hydrolysis; (e) oxidation; (0 isomerization.
cuprate addition, hydrolysis, oxidation and isomerization. Therefore,
on the basis of all of these results, we decided on a more reliable
alternative route.
96
6. Reevaluation of Retrosynthesis
We considered that the difficulties encountered in the above
synthetic routes might be avoided by the following the pathway
which is summarized in scheme 15. The key steps are: (1) selective
reduction of 128 followed by dehydration to enone 88 (2) C
alkylation of diketone 129 with isopropyl iodide
(3) conversion of cyclic alkynyl alcohol 96 to diketone 129. The
reactivity difference between the conjugated carbonyl and
nonconjugated carbonyl groups is well-documented.3 4
SCHEME 15
88
128
7. Synthesis of Alkylated Diketone
129
Oxidation of the cyclic alkynyl alcohol 96 with manganese
dioxide in CH2Cl2 at room temperature led to alkynyl ketone 130 in
60% yield (scheme 16). Compound 130 was characterized by IR, IH
NMR, 13C-NMR, and HRMS. Conjugate addition of methanol to 130,
97
SCHEME 16
OH
ao
b ...
96 130
129
mediated by K2C03, followed by hydrolysis with concentrated
CF3COOH in acetone, produced diketone 129 in 50-60% overall yield
from 130.35 It should be pointed out that the yield for the conjugate
addition of methanol depends on the reaction temperature. The
reaction produced the desired product at ooC. But at higher
temperature (e.g. room temperature) the reaction resulted in several
uncharacterized compounds. To perform the alkylation step, several
conditions in a model system were examined. Generally, alkylation of
a 1,3-diketone with a secondary halide produces both 0- and C
alkylated products.36 For the model system, 5,5-dimethyl-l,3-
+ 133
98
o o-lJio--a·~o
132 133
~
134
Reagents: (a) NaN(TMS)2. THF. 2-iodopropane; (b) DMSO. K2C03. 2-iodopropane.40°C.
cyclohexanedione 132 was chosen as the starting material. When
strong base (e.g. LOA, NaH, KN(TMS)2, Na(TMS)z, LiN(TMSh) was
used, reaction led to either O-alkylated product 133 or some
uncharacterized compounds regardless of solvent. Based on these
results, a weak base (e.g. K2C03) and a more polar solvent (e.g. DMF,
DMSO) were considered. It was found that only DMSO was the solvent
which gave minor C-alkylation 134 and major O-alkylated products
133. The ratio of C-alkylated to O-alkylated product was 2:8. Other
solvents (acetone, THF, DMF) led only to O-alkylated products. Thus,
OMSO was our first choice for the real reaction.
99
a ..
128
Reagent: (a) K2C03, DMSO, 2-iodopropane, 40°C.
Treatment of diketone 129 with isopropyl iodide in DMSO at
400C only produced C-alkylated diketone 128 in 50% yield without
any O-alkylated product, and this material was used for the
subsequent selective reduction step. The problem of the alkylation
was that we were unable to reproduce this reaction and got 50%
yield only three times. Attempted optimization of the conditions of
the reaction with other solvents was not successful.
8. Selective Reduction of 1,3·Diketone. Synthesis ofDienone
A reactivity difference between the two carbonyl groups (C-l &
C-4) of compound 128 was predicted. It has been reported that a
conjugated ketone could be selectively reduced by sodium
borohydride and cerium(lIl) chloride in the presence of a saturated
ketone in good yield.34 Treatment of diketone 128 with sodium
borohydride and cerium (III) chloride produced diol 135 in 65%
100
128
a
135
..
88
Reagents: (a) DIBAL, OOC, CHZC1Z; (b) NaBH4, CeC13, CH30H.
yield. Other reducing reagents (e.g. L-selectride, LAH) were also
tried. None of these reagents gave the desired product. Addition of
DIBAL to a solution of 117 at DOC in CHzClz produced dienone 88 in
20% yield. Enone 88 was characterized by IR, 1H-NMR and mass
spectrometry. The spectral data were identical to the published data
for 88.z0 Reduction of dienone 88 to 55 has been accomplished in
previous syntheses,ZO,21 hence our methodology represents an
effective synthetic pathway to sarcophytol A.
101
CONCLUSION
The total synthesis of dienone 88 has been accomplished in ten
steps from farnesol. The conversion of 88 to sarcophytol A has been
reported during previous syntheses. Hence, this work provides a
formal total synthesis of sarcophytol A.
There are several reactions which are noteworthy:
1. Acetylene displacement of 101 produced 102 10 60% yield.
The polarity of the solvent affects the yield of the reaction and so far
acetone has proved to be the best solvent for the reaction.
2. The macrocyclization of 97 to 96 took place in 50-60% yield.
When KN(TMSh was used, allenic product 106 was isolated in 60%
yield. The mechanism for formation of allene 104 is not clear at this
time.
3. Alkylation of 1,3-diketone 129 with a secondary halide in
DMSO only gave C-alkylated product 128 in 50% yield, without any
observed O-alkylated product.
4. Selective reduction of 128 to dienone 88 was achieved by
DIBAL in moderate yield.
102
EXPERIMENTAL
Procedure:
99
OAe .. OAe
OH
100
To stirred a mixture of 1 mi CHZCIZ, SeOz (5 mg, 0.05 mmol) and
salicylic acid (32 mg, 0.23 mmol) was added TBHP (0.82 mI, 8.2
mmol) at OOC. Farnesyl acetate 99 (600 mg, 2.14 mmol) in 2 ml
CHzClz was added dropwise. After 4 h, the mixture was washed with
NaOH followed by brine. The crude product was purified by column
chromatography in 20% EtOAc/hexanes to give 174 mg of the desired
product 100 in 27% yield.
103
OAe
OH
100
Allylic alcohol 100:
IH-NMR (CDC13, 300 MHz, ppm): 5.34 (m, 2H), 5.10 (dd, J =6.0, 5.4 Hz,
IH), 4.57 (d, J = 7.2 Hz, 2H), 3.97 (s, 2H), 2.10-2.00 (m, 8H), 2.05 (s,
3H), 1.70 (s, 3H), 1.61 (s, 3H), 1.60 (s, 3H).
IR (neat, em-I): 3030, 2980,1740,1620,1450,1380,1100,1050.
Mass spectrum (70 eV, m/e): 280 (M+), 262, 237, 220, 189, 135, 121,
93, 81, 68.
Calculated mass for CI7H2803: 280.2039, found: 280.2050.
Procedure:
100·
OAe ..
101
Br
OAe
104
To alcohol 100 (28 mg, 0.10 mmol) in 5 ml THF was added NEt3
(0.04 ml, 0.29 mmo!) and the mixture was brought to OOC. MsCI (0.02
ml, 0.21 mmol) and LiBr (67 mg, 0.77 mmol) were added. The
solution was warmed to room temperature. Sat'd NaHC03 solution
was added and the mixture was extracted with Et20. The solvent was
dried and removed in vacuo. The crude product was purified by
chromatography to give 31 mg bromide 101 in 90% yield.
105
OAe
101
Bromide 101:
IH-NMR (CDCI3, 300 MHz, ppm): 5.6-5.5 (dd, J = 7.2, 6.9 Hz, IH), 5.34
5.32 (dd, J = 7.2, 6.9 Hz, IH), 5.10-5.08 (dd, J = 6.6, 5.4 Hz, IH), 4.60
4.58 (d, J = 7.2 Hz, 2H), 3.97 (s, 2H), 2.20-2.00 (m, 8H), 2.05 (s, 3H),
1.75 (s, 3H), 1.70 (s, 3H), 1.60 (s, 3H).
IR (neat, cm- 1): 2950, 1740, 1620, 1450, 1380, 1100, 1050.
Mass spectrum (70 eV, m/e): 263, 203, 187, 159, 135, 119, 107, 93,
79.
106
101
Procedure:
OAc ...
H105
Acetylene was passed through a mixture of 5 ml acetone, KzC03
(28 mg, 0.20 mmol), CuI (21 mg, 0.22 mmol) and NaI (30 mg, 0.20
mmol) at room temprature. Allylic bromide 101 (34 mg, 0.1 mmol)
was added to the mixture and stirred at room temperature for 48 h.
The mixture was filtered and the solvent removed. The residue was
added to a mixture of K2 CO 3 and methanol, stirred for 1 h at room
temperature, then water was added and the mixture was extracted
with EtzO. The solvent was dried and removed. The crude product
was purified by chromatography to give 12 mg of lOS in 50% overall
yield.
107
H105
Alcohol lOS:
IH-NMR (CDC13, 300 MHz, ppm): 5.44-5.37 (m, 2H), 5.17 (dd, J =6.9,
6.6 Hz, IH), 4.15 (d, J = 6.6 Hz, 2H), 2.87 (s, 2H), 2.10-2.00 (m, 9H),
1.68 (s, 3H), 1.60 (s, 3H), 1.55 (s, 3H).
IR (neat, cm- 1): 3350, 3300, 2980, 2100, 1630, 1450, 1380, 1100.
Mass spectrum (70 eV, m/e): 246 (M+), 231, 213, 199, 189, 171, 159,
119, 91, 77.
105
Procedure:
97
108
To oxalyl chloride (0.69 ml, 0.79 mmol) in 1.0 ml CH2C12 at -78°C
was added DMSO (0.065 ml, 0.92 mmol). The solution was stirred for
5-8 min and alcohol 105 (60 mg, 0.26 mmol) in 2.0 ml CH2CIZ was
added over a period of 5 min. After 15 min, Et3N (0.18 ml, 1.32
mmol) was added and the solution was allowed to warm to room
temperature. The solution was extracted with CH2Ch. The crude
product was purified by chromatography to give 50 mg of aldehyde
97 in 80% yield.
109
97
Aldehyde 97:
IH-NMR (CDCI3, 300 MHz, ppm): 10.00 (d, J = 8.1 Hz, IH), 5.90 (m,
1H), 5.40 (m, IH), 5.10 (m, IH), 2.80 (s, 2H), 2.40-2.00 (m, 9H), 1.68
(s, 3H), 1.60 (s, 3H), 1.57 (s, 3H).
IR (neat, cm- l ): 3300, 2980, 2960, 2100, 1670, 1630, 1450, 1380.
Mass spectrum (70 eV, m/e): 244, 229, 215, 211, 205, 201, 197, 145,
119, 91, 77.
Calculated mass for C17H240: 244.1850, found: 244.1838.
Procedure:
97
CHO
Ha ..
96
OH
110
To a solution of aldehyde 97 (30 mg, 0.12 mmol) in 20 ml THF
was added 0.37 ml, 1.0 N, NaN(TMSh in a :;iugie porLion at room
temperature. After 5 min, IN Hel was added and the solution was
extracted with Et20. The combined ethereal extracts were washed
with brine dried and solvent was removed in vacuo. The crude
product was purified by chromatography to give 18 mg of alkynyl
alcohol 96 in 50-60% yield.
111
OH
96
Alkynyl alcohol 96:
IH-NMR (CDCI3, 300 MHz, ppm): 5.61 (m, 1H), 5.40 (d, J = 8.4 Hz, 1H),
5.10-5.00 (m, 2H), 2.83 (s, 2H), 2.40-2.00 (m, 8H), 1.65 (s, 3H), 1.59
(s, 3H), 1.58 (s, 3H).
I3C-NMR (CDCI3, 125 MHz, ppm): 136.8, 133.9, 128.8, 126.7, 125.7,
123.3, 85.1, 82.5, 59.3, 38.7, 38.4, 27.4, 24.6, 23.4, 17.5, 15.8, 15.0.
IR (neat, em-I): 3350, 3010, 2960, 2210, 1620, 1480, 1350, 1200.
Mass spectrum (70 eV, m/e): 244, 226, 211, 205, 197, 183, 169, 157.
Calculated mass for C17H240: 244.1827, found: 244.1849.
112
OH
SOPh
11196
Procedure:
To a solution of alkynyl alcohol 96 (20 mg, 0.08 mmol) and
(0.04 ml, 5.6 mmol) Et3N in 3 ml EtzO at -780C was added very
slowly PhSCI (25 mg, 0.16 mmol) in 2 ml EtzO. The solution was
stirred for 5 min at -78°C. Water was added and the reaction mixture
was warmed to room temperature. The solution was extracted with
EtzO and the organic layer was dried over MgS04. The solvent was
removed and the residue was purified by chromatography to give 23
mg of desired product sulfoxide 111 in 80% yield.
113
SOPh
111
Sulfoxide 111:
lH-NMR (CDCI3, 300MHz, ppm): 7.50-7.27 (m, 5H), 6.40-6.35 (m, IH),
5.57-5.53 (d, J = 10.8 Hz, IH), 5.16-5.11 (ro, IH), 4.98-4.94 (m, IH),
2.90-2.84 (d, J = 16.8 Hz, IH), 2.50-2.45 (d, J = 16.8 Hz, IH), 2.19-2.11
(ro, 8H), 1.74 (d, J = 0.9 Hz, 3H), 1.52 (s, 3H), 1.48 (s, 3H).
IR (neat, cm- l ): 3030, 1940, 1640, 1560, 1440, 1380, 1080, 1050.
Mass spectrum (70 eV, role): 352 (M+), 336, 275, 267, 243, 236, 226,
185, 143, 109.
Calculated mass for C23H2SS0: 352.1869, found: 352.1841.
114
111'
Procedure:
SOPh
95
To 2.8 ml of a 0.1 M solution of Cu(CN)(Th)Li in THF was added
0.78 ml of a 0.36 M solution of isopropyllithium in pentane dropwise
at -780C. The mixture was stirred for 5 min and sulfoxide 111 (20
mg. 0.057 mmol) in 2 ml THF was added. The mixture was further
stirred for 1 h and the sat'd NH4CI was added. The mixture was
extracted with Et20. The solvent was dried and removed in vacuo.
The crude product was purified by chromatography to give 12 mg of
alkylated sulfoxide 9S in 57% yield.
115
95
Alkylated sulfoxide 95:
IH-NMR (CDC13, 300 MHz, ppm): 7.66-7.42 (m, 5H), 6.32 (d, J = 11.7
Hz, 1H), 5.64 (d, J = 11.7 Hz, IH), 4.97-4.87 (m, 2H), 4.21 (dd. J = 10.8,
3.0 Hz, IH). 2.50-2.45 (m, 2H), 2.18-1.83 (m, 9H), 1.67 (s, 3H), 1.54 (s,
3H), 1.35 (s, 3H), 1.12 (d, J =6.6 Hz, 3H), 0.97 (d, J = 6.9 Hz, 3H).
IR (neat. cm- 1): 3030, 2980, 1600, 1580, 1450, 1380, 1280, 1050.
Mass spectrum (70 eV, m/e): 270, 255, 227, 187, 159, 120, 105, 84.
96
Procedure:
OH
130
o
116
To a solution of alkynyl alcohol 96 (12 mg, 0.05 mmol) in 5 ml
CH2Cl2 at OOC was added 90 mg (3x30 mg, 1.03 mmol) manganese
dioxide in 15 min. The mixture was stirred until tic showed no
starting material remaining. The mixture was filtered and the CH2Cl2
was removed in vacuo. The crude product was purified by
chromatography to give 7 mg of desired product ketone 130 in 50
60% yield.
1 17
o
130
Ketone 130:
IH-NMR (CDC13, 300 MHz, ppm): 6.29 (s, lH), 5.72 (dd, J = 5.7, 5.1 Hz,
IH), 5.11 (d, J = 0.9 Hz, lH), 2.97 (s, 2H), 2.31 (s, 4H), 2.23-2.18 (m,
4H), 2.06 (s, 3H), 1.60 (s, 3H), 1.57 (s, 3H).
13C-NMR (CDC13, 125 MHz, ppm): 177.9, 155.7, 134.8, 128.3, 127.3,
126.1, 124.0,93.1, 87.6, 38.4, 38.3, 27.5, 24.3, 23.6, 19.7, 17.7, 14.8.
IR (neat, em-I): 3030, 2970, 2250, 1660, 1620, 1450, 1380, 1200.
Mass spectrum (70 eV, m/e): 242 (M+), 227, 199, 173, 159, 145, 115,
91, 77.
Calculated mass for C17H2Z0: 242.1646, found: 242.1658.
118
Procedure:
130
o
129
A mixture of (10 mg, 0.04 mmol) ketone 130 and 1 mg K2C03 in
2 ml methanol was stirred at OOC for 30 min and then warmed to
room temperature for 1 h. The mixture was filtered and the
methanol was removed in vacuo. The residue was dissolved in 5 ml
acetone and 2 drops of CF3COOH was added. The solution was stirred
for 3 h and water was added. The mixture was extracted with Et20
and dried over anhydrous MgS04. The solvent was removed and the
crude product was purified by chromatography to give 6 mg of
desired product diketone 129 in 60% overall yield.
119
129
Diketone 129:
lH-NMR (CDCI3, 300 MHz, ppm): 5.97 (s, IH), 5.06 (t, J =6.3 Hz, 1H),
4.91 (t, J = 6.0 Hz, IH), 3.50 (s, 2H), 3.20 (s, 2H), 2.28-2.14 (m, 8H),
2.11 (s, 3H), 1.66 (s, 3H), 1.57 (s, 3H).
IR (neat, cm- l ): 3030, 2950, 1720, 1680, 1440, 1380, 1150, 1050.
Mass spectrum (70 eV, m/e): 260 (M+), 192, 163, 134, 121, 107, 95,
82.
Calculated mass for Cl7H2402: 260.1772, found: 260.1783.
129
Procedure:
128
120
A mixture of (10 mg, 0.04 mmol) diketone 129 and 30 mg K2C03
in 2 ml DMSO was heated to 400C in a sealed tube. The color of the
solution changed to yellow in 10 min and (0.05 ml, 5.00 mmol)
isopropyl iodide was added. The mixture was stirred for 1 hand
cooled down to room temperature. Water was added, the solution
was extracted with Et20 and the organic layer was dried over
anhydrous MgS04. The solvent was removed and the residue was
purified by chromatography to give 6 mg of desired product 128 in
50% yield.
------ --- ----_.- ~.-.-_.._-
121
128
Alkylated diketone 128:
IH-NMR (CDCI3, 300 MHz, ppm): 5.96 (s, IH), 4.98 (dd, J = 6.9, 6.3 Hz,
IH), 4.86 (dd, J = 6.4, 5.4 Hz, IH), 3.40 (d, J = 10.2 Hz, IH), 2.96 (s,
2H), 2.51-2.23 (m, 9H), 2.11 (s, 3H), 1.65 (s, 3H), 1.56 (s, 3H), 0.89
0.84 (dd, J = 6.6, 6.0 Hz, 6H).
I3C-NMR (CDCI3, 125 MHz, ppm): 205.4, 194.9, 160.7, 134.6, 129.0,
128.6, 123.9, 123.7, 76.3, 52.0, 40.5, 38.8, 28.1, 24.8, 24.3, 21.2, 20.4,
19.3, 17.3, 15.4.
IR (neat, em-I): 3030, 2950, 1720, 1680, 1440, 1380, 1150, 1050.
Mass spectrum (70 eV, m/e): 302 (M+), 259, 234, 203, 163, 150, 135,
121, 95, 82.
Calculated mass for C20H3002: 302.2232, found 302.2238.
128
Procedure:
88
122
To a solution of alkylated diketone 128 (15 mg 0.05 mmol) in
2 ml CHzC1z was added highly dilute DIBAL solution (0.5 eq, 0.025
mmol, 0.3 rol) in CHzClz at aoc. The mixture wqS stirred for 10 min
and IN HCI was added. The solution was extracted with CHzClz and
dried over anhydrous MgS04. The solvent was removed and the
residue was purified by chromatography to give 4 mg of desired
dienone 88 in 30% yield.
123
88
Dienone 88:
IH-NMR (CDCI3, 300 MHz, ppm): 6.23-6.20 (dd, ] = 12.0, 1.5 Hz, IH),
5.90-5.88 (d, ] = 11.5 Hz, IH), 5.02-4.99 (td, ] = 5.5, 1.0 Hz, IH), 4.96
4.93 (t, 6.5 Hz, IH), 3.15 (s, 2H), 2.70-2.65 (sept, IH), 2.20-2.07 (m,
8H), 1.75 (d, ] = 1.0 Hz, 3H), 1.72 (s, 3H), 1.47 (s, 3H), 1.08 (d, ] = 7.0
Hz,6H).
IR (neat, em-I): 3030, 3010, 2980, 1680, 1620, 1380, 1250.
Mass spectrum (70 eV, m/e): 286 (M+), 271, 243, 203, 175, 150, 135,
121, 107, 91, 81.
Calculated mass for C20H300: 286.2334, found: 286.2316.
124
REFERENCES
1. (a) Weinheimer, A. J.; Chang, C. W.; Matson, J. A. Fortschr. Chern.
Org. Naturst. 1979,36, 285.
2. Tursch, B.; Braeckman, J. C.; Daloze, D.; Kaisin, M. In Marine
Natural Products; Scheuer, P. J., Ed.; Academic: New York,
1978; Vol. II, p 247.
3. (a) Kobayashi, H.; Akiyoshi, S. Bull. Chern. Soc. lpn. 1962,35,
1044. (b) Scheuer, P. J. Bioorganic Marine Chemistry, Springer
Verlag, Berlin, 1987, Vol. III, p 99. (c) Takashi, M.; Niwa, M.;
Fukaura, Y.; Fujiki H. Cancer Res. 1989,49, 3287.
4. Weinheimer, A. J.; Matson, J. A.; Hossain, M. B.; Van der Helm, D.
Tetrahedron Lett. 1977,28,34, 2923.
5. Tursch, B.; Braekman, J. C.; Daloze, D.; Herin, M.; Karlsson, R.;
Losman, D. Tetrahedron 1975,31, 129.
6. Culver, P.; Burch, M.; Potenza, C.; Wasserman, L.; Fenical, W.;
Taylor, P. Mol. Pharrnacol. 1985,28, 436.
7. Kobayashi, M.; Nakagawa, T.; Mitsuhashi, H. Chern. Pharm.
Bull. 1979,27, 2382.
8. (a) Fujiki, H.; Suganuma, M.; SU5ud, R.; Yoshizawa, S.; Takagi, K.;
Kobayashi, M. l. Cancer Res. Clin. Oncol. 1989,115, 25.
9. Fujiki, H.; Sugimura, T. Cancer Surveys 1983,2, 539.
10. Fujiki, H.; Suganuma, M.; Takagi, K.; Nishiwaki, S.; Yoshizawa, S.;
Okabe, S.; Yatsunami, J.; Frenkel, K.; Troll, W.; Marshall, J. A.;
125
Tius, M. A. In Phenolic Compounds in Food and Their Effects on
Health II; Huang, M.; Ho. C.; Lee, C. Eds.; ACS Symposiurn Series
507; ACS: Washington, DC, 1992, 380.
11. Narisawa, T.; Takahashi, M.; Niwa, M.; Fukaura, Y.; Fujiki, H.
Cancer Res. 1989, 49, 3287.
12. Tius, M. A:. Chern. Rev. 1988,88, 719.
13. Marshall, J. A.; Cleary, D. G. J. Org. Chern. 1986,51,858.
14. (a) Takahashi, T.; Nemoto, H.; Tsuji, J.; Miura, I. Tetrahedron
Lett. 1983,24, 3485.
(b) Takahashi, T.; Nagashima, T.; Tsuji, J. Tetrahedron Lett.
1981,22, 1359.
15. (a) Danishefsky, S.; Mantlo, N. B.; Yamashita, D. S.; Schulte, G. J.
Arn. Chern. Soc. 1988, 110, 6890. (b) Kende, A. S.; Smith, C. A.;
Tetrahedron Lett. 1988,29, 4217.
16. (a) Tius, M. A.; Cullingham, J. M. Tetrahedron Lett. 1989,30,
3749. (b) Tius, M. A.; Reddy, K. Tetrahedron Lett. 1991,32,
3605.
17. (a) Tius, M. A.; Fauq, A. H. J. Arn. Chern. Soc. 1986, 108, 1035.
(b) Nicolaou, K. C.; Seitz, S. P.; Pavia, M. R.; Petasis, N. A. J. Org.
Chern. 1979,44, 4011. (b) Crombie, L.; Kneen, G.; Pattenden, G.;
Whybrow, D. J. Chern. Soc. Perkin Trans. 1 1980, 1711. (b)
Crombie, L.; Kneen, G.; Pattenden, G. J. Chern. Soc., Chern.
Cornrnun. 1976, 66.
18. (a) Wender, P. A.; Holt, D. A. J. Am. Chern. Soc. 1985, 107,
7771. (b) Marshall, J. A.; Jenson, T. M.; DeHoff, B. S. J. Org. Chern.
1986,51, 4316.
126
20. Takayanagi, H.; Kitano, Y.; Morinaka, Y. Tetrahedron Lett. 1990,
31,3317.
21. Takahashi, T.; Yokoyama, H.; Haino, T.; Yamada, H. J. Org. Chem.
1992,57, 3521.
22. Kodama, M.; Yoshio, S.; Yamaguchi, S.; Fukuyama, Y.;
Takayanagi,.. H.; Morinaka, Y.; Usui, S.; Fukazawa, Y. Tetrahedron
Lett. 1993,34, 8453.
23. Li,W.; Li, Y.; Li, Y. Chin. Chem. Lett. 1994,5, 101.
24. Sharpless, K. B.; Umbreit, M. A. J. Am. Chem. Soc. 1977,99,
5526.
25. Collington, E. W.; Meyers, A. I. J. Org. Chem. 1976,36, 3044.
26. Bumagin, N. A. Bull. Acad. Sci. USSR Engl. (Transl.) 1987,36,
1445.
27. Swern, D.; Mancuso, A. J.; Huang, S. J. Org. Chem. 1978,43,
2480.
28. (a) Van Kruchten, E. M. G. A.; Okamura, W. H. Tetrahedron Lett.
1982,23, 1019. (b) Bulter, P. E.; Mueller, W. H.; J. Am. Chem.
Soc. 1968, 90, 2075. (c) Seliger, H.; Gortz, H. Syn. Comm. 1980,
10, 175.
29. (a) Gilman, H.; Langham, W.; Moore, F. W.; Sugihara, H.;
Tanikaga, R.; Kaji, A. J. Am. Chem. Soc. 1940, 62, 2334. (b)
Luche, J.; Damiano, J. J. Am. Chern. Soc. 1980,102, 7926.
30. Lipshutz, B. H.; Koerner, M.; Parker, D. A. Tetrahedron Lett.
1987,28,945.
127
31. Lucchi, O. D.; Miotti, U.; Modena, G. Organic Reactions 1991,40,
157.
32. (a) Hwu, J. R. J. Org. Chern. 1983,48, 4432. (b) Babin, P.;
Bennetau, B.; Dunogues, J. Syn. Cornm. 1992,22, 2849.
33. Tsuji, J.; Sugiura, T.; Minami, I. Tetrahedron Lett. 1986,27,
731.
34. (a) Paradisi, M. P.; Zecchini, G. P.; Romo, A. Tetrahedron Lett.
1977, 18, 2369. (b) Gemal, A. L.; Luche, J. L. J. Org. Chern.
1979,44, 4187.
35. Walia, J. S.; Walia, A. S. J. Org. Chem. 1976,41, 3765.
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