Classical/nonclassical hybrid cannabinoids: Southern aliphatic chain- functionalized c-6β methyl, ethyl, and propyl analogues

Article abstract of DOI:10.1021/jm960677q

The stereoelectronic requirements for interaction of the southern aliphatic hydroxyl of cannabimimetic pharmacophores with the CB1 and CB2 receptors are explored. The stereoselective syntheses of three series of classical/nonclassical hybrid cannabinoids

Full text of DOI:10.1021/jm960677q

3596
J . Med. Chem. 1998, 41, 3596-3608
Cla ssica l/Non cla ssica l Hybr id Ca n n a bin oid s: Sou th er n Alip h a tic
Ch a in -F u n ction a lized C-6â Meth yl, Eth yl, a n d P r op yl An a logu es
David J . Drake,† Rader S. J ensen,† J akob Busch-Petersen,† J oel K. Kawakami,†
M. Concepcion Fernandez-Garcia,† Pusheng Fan,‡ Alexandros Makriyannis,*,‡ and Marcus A. Tius*,†
Department of Chemistry, University of Hawaii, 2545 The Mall, Honolulu, Hawaii 96822, and Department of Medicinal
Chemistry, School of Pharmacy, University of Connecticut, 372 Fairfield Road, Storrs, Connecticut 06269
Received September 27, 1996
The stereoelectronic requirements for interaction of the southern aliphatic hydroxyl of
cannabimimetic pharmacophores with the CB1 and CB2 receptors are explored. The stereo-
selective syntheses of three series of classical/nonclassical hybrid cannabinoids are described.
These compounds were designed to investigate the importance of the southern aliphatic hydroxyl
(SAH) pharmacophore for cannabimimetic activity. Variation in the chain length of the SAH
moiety in these 6â-(hydroxyalkyl)dihydrobenzopyran analogues, from 6â-hydroxymethyl to 6â-
(ω-hydroxyethyl) and 6â-(ω-hydroxypropyl), and the effects of replacing the hydroxyl functional-
ity by hydride and iodide are reported. Our results indicate that the SAH pharmacophore has
less pronounced effects than the C-3 aliphatic chain on cannabinoid activity. Furthermore, it
appears that this southern molecular component is capable of interacting with two different
subsites on the receptor and that the nature of this interaction is determined by the terminal
substituent on the C-6â alkyl group. One of the subsites can accommodate the relatively polar
SAH pharmacophore, while the second subsite interacts with more hydrophobic C-6â substit-
uents and can accommodate large spherical pharmacophores separated by three methylene
carbons from the tricyclic cannabinoid template.
In tr od u ction
This southern aliphatic hydroxyl (SAH)2 has been
shown to produce a significant increase in activity. This
important region of the molecule is the subject of the
current study.
The broad spectrum of pharmacological properties
exhibited by cannabis is well-known, and a great deal
of effort has gone into the search for therapeutically
useful agents based on the parent structure of ∆9-THC
(Chart 1).1 A large number of analogues have been
synthesized and tested for biological activity and phar-
macological selectivity.2 The recognition of two distinct
cannabinoid receptors (CB1 and CB2), one first identi-
fied in the central nervous system3 (CB1) and the other
exclusively found in the periphery (CB2),4,5 and the
discovery of an endogenous ligand,6 arachidonyl etha-
nolamide (anandamide), has led to efforts to define the
structural requirements for receptor specificity.2
Four principal pharmacophores within the cannab-
inoid structure have been associated with cannabimi-
metic activity.2,7 These include a phenolic hydroxyl at
C-1 and an aliphatic side chain attached to the phenolic
ring at C-3, both of which are present in the natural
tetrahydrocannabinol constituents found in cannabis.
Addition of a ‘northern’ aliphatic hydroxyl (NAH) at the
C-9 or C-11 position leads to increased activity, provid-
ing the hydroxyl or hydroxymethyl at C-9 has a â-equa-
torial configuration, such as in 9-nor-9â-hydroxyhexahy-
drocannabinol (HHC, 1).8 The fourth pharmacophore
was identified from work with nonclassical cannab-
inoids, the best known representative of which is CP-
55,940 (2).7b The analogues in this class of cannabimi-
metic agents do not contain the pyran ring of the
classical cannabinoids but possess a second aliphatic
hydroxyl group in the ‘southern’ portion of the molecule.
An a logu e Design Str a tegy
Earlier work from our group had examined the
stereochemical preference of the SAH pharmacophore
by restricting its spatial orientation through reintroduc-
tion of the pyran B-ring into the nonclassical cannab-
inoid skeleton.9 These compounds combined the dihy-
drobenzopyran structure of 1 with the hydroxyalkyl
chain found in 2, and the resulting classical/nonclassical
hybrid cannabinoids 3 and 4 were tested for their
affinities for the CB1 receptor. Competitive binding
assays, using receptor membrane isolated from rat
forebrain, showed a dose-dependent displacement of the
radioligand [3H]CP-55,940. The â-hydroxyethyl ana-
logue 3 showed an affinity constant (Ki) of 70.5 nM,
compared to a Ki of 1353 nM for the R-epimer 4. This
receptor preference for a â-hydroxyalkyl substituent at
C-6 provided key information for further study of the
SAH pharmacophore.
We chose to investigate the effect of modifying the
functionality of the C-6 alkyl chain with regard to
affinity for the CB1 and CB2 receptors by synthesizing
three series of analogues in which the 6â-alkyl chain
was increased from one to three carbon atoms. In
addition to the parent hydroxymethyl (n ) 1) 5, hy-
droxyethyl (n ) 2) 6, and hydroxypropyl (n ) 3) 7
compounds, we synthesized iodides 8 (n ) 2) and 9 (n
) 3) and hydrocarbons 11 (n ) 2) and 12 (n ) 3). Iodine
was chosen to examine how the size of the southern
aliphatic side chain affected receptor binding. Hydride
† University of Hawaii.
‡ University of Connecticut.
S0022-2623(96)00677-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/22/1998

Classical/ Nonclassical Hybrid Cannabinoids
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19 3597
Ch a r t 1
Sch em e 1. Synthesis of Intermediate 13a
crude product of this oxidation was used in the conden-
sation. All attempts to purify the mixture of diacetates
15 and 16 by vacuum distillation resulted in a sharply
diminished yield of 17. The yield of 17 after recrystal-
lizing to constant optical rotation was 61%.11
Both phenolic hydroxyl groups in 17 were protected
as tert-butyldimethylsilyl (TBS) ethers, and the cyclobu-
tane ring was cleaved using trimethylsilyl iodide. The
unstable tertiary iodide intermediate was treated with
DBU in benzene to generate the required isopropenyl
group in 13.12 This reaction sequence required consid-
erable optimization. Under rigorously anhydrous condi-
tions the cyclobutane ring opening failed to take place,
suggesting that the process was catalyzed by hydroiodic
acid. The finding that 2 mol % tert-butyl alcohol
catalyzed the reaction supports this hypothesis. Higher
concentrations of HI resulted first in loss of the TBS
protecting groups and then decomposition of the resor-
cinol through a number of reaction pathways. Decom-
position of the tertiary iodide also took place on stand-
ing, presumably as a result of the spontaneous elimi-
nation of HI. Heating the tertiary iodide in the presence
of the base led to 13 in good yield. Contamination of
13 even by small amounts of the tertiary iodide resulted
in fairly rapid decomposition of the sample; therefore
it was essential that the conversion to 13 be complete.
a
(a) TsOH‚H2O, CHCl3, rt, 3 days, 61%; (b) TBSCl, imidazole,
DMAP, DMF, rt, 36 h, 83%; (c) i. TMSI, CCl4, cat. t-BuOH, 0 °C,
2 h, ii. DBU, PhH, 50 °C, 3 h, 68%.
provided a nonpolar side chain with which to test the
southern pharmacophoric region. To maximize receptor
affinity, pharmacophores demonstrated to be optimal
at C-3 and C-9 were incorporated into our analogues.
This paper describes the synthesis of 5-7 and the
stereoselective introduction of the SAH moiety. Iodides
8 and 9 and hydrocarbons 11 and 12 were synthesized
from the corresponding alcohols.
Introduction of the C-9 hydroxymethyl group for the
n ) 1 and n ) 2 series was accomplished by treating
13 with (methoxymethylene)triphenylphosphorane
(Scheme 2). Methyl vinyl ether 19 was hydrolyzed with
wet trichloroacetic acid, and the diastereomeric mixture
of C-9 aldehydes was epimerized to produce the â-equa-
torial isomer 20.13 Reduction with sodium borohydride
followed by protection of the C-11 hydroxyl as the TBS
ether led to 22.
Ch em istr y
The n ) 1 and n ) 2 analogues were prepared from
a common advanced intermediate (13)10 and will be
discussed first (Scheme 1). Resorcinol 14 was coupled
with diacetates 15 and 1610 to produce 17 in 61% yield.
The original procedure by Archer et al.,10 which de-
scribed the preparation of 5-(1′,1′-dimethylheptyl)resor-
cinol (14), as well as the coupling reaction, suffered from
low yields (39-41%). Two factors are key to realizing
a high yield of 17. First, the enol acetate derived from
(-)-â-pinene (98% ee; Aldrich) was treated with lead
tetraacetate under gentle reflux for 2 h, and second, the
The SAH group of the n ) 1 series was introduced by
means of an allylic oxidation14 of 22. Removal of all silyl
protecting groups from 23 by treatment with HF in
acetonitrile15 produced tetrol 24 in only modest yield.

3598 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19
Sch em e 2. Synthesis of n ) 1 Alcohol 5a
Drake et al.
a
(a) Ph3PCH2OMe+Cl-, Na tert-amylate, PhH, 70 °C, 3 h, 73%; (b) i. Cl3CCO2H, H2O, CH2Cl2, rt, 10 min, ii. K2CO3, EtOH, rt, 24 h,
73%; (c) NaBH4, EtOH, 0 °C, 2 h, 72%; (d) TBSCl, imidazole, DMF, rt, 17 h, 99%; (e) i. SeO2, salicylic acid, t-BuOOH, CH2Cl2, rt, 2 h, ii.
NaBH4, MeOH, 0 °C, 30 min, 83%; (f) i. Et3N‚HF, MeCN, cat. HF, 0 °C, 4 h, ii. TBAF, THF, 0 °C, 10 min, 80%; (g) Hg(OAc)2, THF, rt, 20
h, then NaBH4, 1 M NaOMe in MeOH, -78 °C, 15 min, 62%.
Sch em e 3. Synthesis of n ) 2 Analoguesa
a
(a) Me3Al, 2,6-diphenylphenol, sym-trioxane, CH2Cl2, 0 °C, 1 h, 82%; (b) TBAF, THF, -78 °C, 2 h, 95%; (c) i. Hg(OAc)2, THF, rt, 24
h, ii. 2.5 N NaOH, n-Bu4NOH, NaBH4, CH2Cl2, 0 °C, 10 min, 43%; (d) Et3N‚HF, MeCN, cat. HF, 0 °C, 1.5 h, 76%; (e) I2, Ph3P, imidazole,
PhH, 45 °C, 45 min, 82%; (f) Et3N‚HF, MeCN, cat. HF, 0 °C, 1.5 h, 73%; (g) LiAlH4, THF, rt, 3 h, 71%.
This compound was particularly sensitive to acid;
therefore the protecting groups were removed in two
steps. Exposure of 23 to triethylamine hydrofluoride
and catalytic HF selectively deprotected the TBS group
on the C-11 hydroxyl.16 Subsequent treatment with
tetra-n-butylammonium fluoride17 gave 24 in 80% over-
all yield for the two steps. Cyclization of 24 to the
tricyclic cannabinoid skeleton was accomplished by
means of the intramolecular oxymercuration-demer-
curation reaction which we developed.9,18 The origins
of the stereoselectivity have been discussed elsewhere.19
Compound 5 was obtained in 62% yield as the major
diastereomer following purification by HPLC.
ide) formaldehyde reagent20 to produce 25 in 82% yield.
The phenolic hydroxyls were selectively desilylated by
exposure to tetra-n-butylammonium fluoride to give 26,
which was cyclized in the same way as 24.9 Deprotec-
tion of 27 with triethylamine hydrofluoride gave 6.
Iodide 8 and hydrocarbon 11 were prepared from 27.
Treatment of 27 with triphenylphosphine, iodine, and
imidazole led to iodide 28,21 which was deprotected
under acidic conditions in order to avoid dehydroiodi-
nation. Iodide 8 was converted to 11 by reduction with
an excess of lithium aluminum hydride.
A concise synthesis of the n ) 3 series of analogues
was implemented by operating simultaneously on the
northern and southern regions of the molecule. Treat-
ment of 13 with Yamamoto’s reagent20 produced the
hydroxybutyl compound 29 in excellent yield (Scheme
4). Deprotection of the phenolic hydroxyl groups led to
The additional carbon atom present in the n ) 2 series
was introduced by means of a Lewis acid-catalyzed ene
reaction (Scheme 3). Intermediate 22 was treated with
Yamamoto’s methylaluminum bis(2,6-diphenylphenox-

Classical/ Nonclassical Hybrid Cannabinoids
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19 3599
Sch em e 4. Synthesis of n ) 3 Analoguesa
a
(a) Me3Al, 2,6-diphenylphenol, sym-trioxane, CH2Cl2, 0 °C, 1.5 h, 80%; (b) TBAF, THF, 0 °C, 20 min, 86%; (c) Hg(OAc)2, THF, rt, 24
h, then NaBH4, 1 M NaOMe in MeOH, -78 °C, 66%; (d) allyl bromide, n-Bu4NOH, CH2Cl2/H2O, rt, 3 h, 80%; (e) Dess-Martin periodinane,
CH2Cl2, rt, 2 h, 90%; (f) Ph3PCH2OCH3+Cl-, Na tert-amylate, PhH, 70 °C, 3 h, 84%; (g) i. Cl3CCO2H, H2O, CH2Cl2, rt, 10 min, ii. K2CO3,
EtOH, rt, 17 h, then NaBH4, 0 °C, 1 h, 61%; (h) (Ph3P)4Pd, NaBH4, THF, rt, 6 h, 92%; (i) I2, Ph3P, imidazole, PhH, 50 °C, 25 min, 80%;
(j) LiAlH4, THF, rt, 3 h, 80%.
the formation of hemiketal 30, by nucleophilic attack
of one of the phenolic hydroxyls on the ketone carbonyl
group. The oxymercuration-demercuration procedure9
produced the desired tricyclic â-hydroxyethyl derivative
31 in 66% yield. The success of this reaction suggests
that 30 is in equilibrium with the corresponding ketone.
The greater acidity of the phenol relative to the two
aliphatic hydroxyl groups in 31 was exploited in a
phase-transfer-catalyzed allylation which produced 32.
Simultaneous oxidation of the two alcohols with freshly
prepared Dess-Martin periodinane22 gave keto alde-
hyde 33 in 90% yield. Homologation with (methoxy-
methylene)triphenylphosphorane produced bis-enol ether
34 as a mixture of geometrical isomers. Hydrolysis of
34 with wet trichloroacetic acid, epimerization of the
C-9 aldehyde to the more stable â-equatorial configu-
ration, and reduction in situ with sodium borohydride
produced diol 35 in 61% overall yield for the three steps.
The next task required the selective functionalization
of the primary alcohol on the C-6 side chain in the
presence of another primary alcohol at C-11. Removal
of the phenolic allyl protecting group under reductive
conditions in the presence of a primary iodo group
represented a potentially serious obstacle. Although the
removal of the protecting group before the functional-
ization step might introduce a different set of problems,
this approach was followed. In the event, palladium-
catalyzed reductive cleavage of the allyl23 took place in
92% yield. By exploiting the subtle difference in sus-
ceptibility toward nucleophilic displacement at the
terminal carbon of the C-6 side chain, it was possible
to convert 7 to monoiodide 9 in 80% yield. A modest
amount of the diiodide (ca. 20%) was also obtained, but
none of the C-11 monoiodide was isolated. The differ-
ence in reactivity between the two primary alcohols can
be attributed to the â-branching at C-9 which hinders
nucleophilic attack at C-11. Reductive cleavage of the
iodo group with lithium aluminum hydride furnished
12.
Ca n n a bin oid Recep tor Bin d in g Assa ys. Ana-
logues 5-12 were tested for their ability to displace
radiolabeled CP-55,940 from purified rat forebrain
synaptosomes (CB1) and mouse spleen synaptosomes
(CB2) as previously described.13,24 The calculated Ki’s
are shown in Table 1.

3600 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19
Drake et al.
Ta ble 1. Ki Values (nM) for Functionalized Cannabinoid Analogues 5-12′ Competing with [3H]CP-55,940 for CB1 (Brain) and CB2
(Spleen) Receptorsa
n ) 1
n ) 2
n ) 3
X
brain
spleen
brain
spleen
brain
spleen
5
6
8
7
9
OH
1.9
1.4
(1.2, 1.7)
2.8
(2.2, 3.6)
2.3
(1.8, 2.9)
2.2
(2.0, 2.4)
3.4
(1.7, 2.0)
(3.1, 3.8)
I
40.7
9.7
2.2
4.3
(36.5, 45.4)
(8.4, 11.1)
(2.0, 2.7)
(3.5, 6.3)
10
11
12
H
2.3
2.3
11.1
21.5
14.4
38.9
(2.0, 2.7)
(2.0, 2.7)
(10.0, 12.2)
(17.7, 26.1)
(13.2, 15.7)
(29.9, 50.6)
a
The reported values are averages of at least three experiments; numbers in parentheses represent extreme values.
Resu lts a n d Discu ssion
inoid component interacts. A more refined topological
examination of this interaction will require the develop-
ment of novel analogues in which the southern aliphatic
chain is further confined.
Three series of functionalized cannabinoids have been
synthesized to investigate the importance of the south-
ern pharmacophoric region of the hybrid classical/
nonclassical cannabinoid molecule with regard to its
affinity for the cannabinoid receptors. To maximize the
affinity of our analogues for the receptor, we optimized
each of the other cannabinoid pharmacophores and
chose the â-11-hydroxyhexahydrocannabinol as the
tricyclic component with a 1′,1′-dimethylheptyl group
in the side chain. This choice was based on earlier work
from our laboratory involving the design and synthesis
of a corresponding highly potent cannabinoid ana-
logue.25,26 The C-6â alkyl side chain was substituted
with hydroxy and iodo functionalities, and the unsub-
stituted alkyl chain was also synthesized in each case.
The series differed in the length of the alkyl side chain,
having one, two, or three carbons in the C-6 side chain.
The synthesis of the materials is notable for several
reasons. Advanced intermediate 13 was prepared in
multigram quantities following improvements in the
protocol of Archer et al.10 The highly stereoselective
cyclization of the pyran ring through an intramolecular
oxymercuration-demercuration has been extended to
several new systems with this work and appears to be
completely general. This method promises to be broadly
applicable in synthesis and not limited to the cannab-
inoid series. Furthermore, the highly chemoselective
transformation of 7 to 9 demonstrates that it is possible
to perform selective functionalizations in this series
without recourse to tedious protecting group manipula-
tions.
6â-Alk yl An a logu es. The prototype in this series
(10) was synthesized earlier in our laboratory,25 as well
as by Mechoulam and co-workers,26 using different
synthetic approaches. Both of these groups showed
that, in vivo, this compound is a very potent classical
cannabinoid with potency approximately 100-fold higher
than that of (-)-∆9-THC. Mechoulam’s group also
reported that this molecule had a very high affinity for
the CB1 receptor with a Ki ) 45 pM. This result differs
from our current data where we show a Ki ) 2.3 nM.
The discrepancy may be due to the use of different
radioligands and different binding assays by the two
groups. Irrespective of this discrepancy, the compound
remains as one of the most potent CB1 ligands available
to date. In this series the increase in chain length from
n ) 1 to n ) 3 results in progressively lower affinities
toward both CB1 and CB2. This observation serves to
define the limits of steric tolerance for hydrophobic
groups at that subsite in both receptors. It thus appears
that the 6â-alkyl pharmacophore within the otherwise
optimized cannabinoid structure exhibits different struc-
ture-activity relationship (SAR) characteristics than
the previously discussed corresponding 6â-hydroxyalkyl
group. This observation implies that the two southern
pharmacophores, namely, the 6-alkyl and 6-hydroxy-
alkyl groups, either interact differently within the same
CB1 and CB2 southern subsite or alternatively interact
with different southern subsites within the CB1 and
CB2 active sites.
Our data on the respective affinities of our analogues
for CB1 and CB2 indicate that the SAH pharmacophore
plays a significant role in determining cannabimimetic
activity, although this role is less prominent than that
of the C-3 side chain. Below we have interpreted these
data in terms of pharmacophoric requirements for the
two cannabinoid receptor subtypes, CB1 and CB2.
6â-(ω-Hyd r oxya lk yl) An a logu es. In this series we
observe relatively insignificant variations in affinity
between the n ) 1, n ) 2, and n ) 3 analogues. There
was also no difference in affinities between CB1 and
CB2. It thus appears that the southern aliphatic
hydroxyl pharmacophore does not discriminate between
the CB1 and CB2 receptors. Furthermore, the alkyl
C-6â chain is flexible enough to apparently allow equally
optimal interactions between the southern hydroxyl and
a corresponding receptor subsite located no further than
2 Å from the subsite with which the tricyclic cannab-
6â-(ω-Iod oa lk yl) An a logu es. Because of the hydro-
phobic character of this southern pharmacophore, the
analogues in this group were expected to exhibit analo-
gous SAR profiles to those characteristic of the corre-
sponding 6â-alkyl analogues. This indeed is the case
with the iodoethyl analogue in the series, where the
introduction of the bulky iodo substituent results in a
decreased affinity for both CB1 and CB2. However, the
most interesting SAR effect in this group of analogues
was observed with the iodopropyl compound (9) which
exhibits increased affinities for both receptors when
compared with its lower homologues. The effect is most
dramatic with the CB1 receptor for which the bulky
iodopropyl analogue exhibits 20-fold higher affinity than
its iodoethyl homologue. Although the same effect is
observed with the CB2 receptor, the effect is much less
stark. Based on the above data, it is tempting to

Classical/ Nonclassical Hybrid Cannabinoids
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19 3601
gel (32-63 µm). Tetrahydrofuran (THF) and diethyl ether
were distilled from sodium-benzophenone ketyl; N,N-dimeth-
ylformamide (DMF), triethylamine, and 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU) from calcium hydride; carbon tetrachloride
(CCl4) and dichloromethane (CH2Cl2) from phosphorus pen-
toxide; benzene from sodium metal; and methanol from
magnesium/iodine. Other reagents were obtained commer-
cially and used as received, unless otherwise stated. All
anhydrous reactions were performed under a static nitrogen
or argon atmosphere in flame-dried glassware. The purity and
the homogeneity of the products on which high-resolution mass
spectral data are reported were determined on the basis of a
combination of chiral HPLC (Chiracel-OD, Bakerbond OD, or
speculate on the existence of a special hydrophobic
cavity at the southern hydrophobic subsite at the
receptor resembling perhaps a “baseball glove” with
which the “baseball”-like iodo group interacts and
significantly enhances the affinity of this analogue for
the receptor. To reach this subsite the iodo group must
be separated by at least three methylene carbons from
the C-6 carbon of the cannabinoid tricyclic system.
Con clu sion s
In this work we have sought to study the SAR of the
southern cannabinoid pharmacophores and to extend
earlier work7b in which the effects of chain length
variation at the SAH group in nonclassical cannabinoids
were described, as well as work from our own laboratory
which showed that the 6â-substitution in tricyclic can-
nabinoids is preferred over the corresponding 6R-
compounds. The present work serves to explore in
greater detail the pharmacophoric requirements of the
southern aliphatic cannabinoid pharmacophores with
respect to the CB1 and CB2 active sites. It should also
serve as a basis for refining existing cannabinoid
receptor models, a task which we are currently pursu-
ing.
It is clear from our results that the effects of varying
the southern aliphatic chain in the classical and non-
classical cannabinoid ring system on biological activity
are not as stark as those observed with the 3-alkyl side
chain where we observe changes in biological activity
and receptor affinity of up to 3 orders of magnitude.
Within a more modest range, the SAR of the southern
pharmacophore is also distinct and will allow us to
pursue the design of more selective CB1 and CB2
receptor probes.
In summary, the present work indicates that the SAH
pharmacophore may interact with a polar subsite at the
receptor situated very near the cannabinoid tricyclic
component (≈2 Å). All three homologues interact
equally with this subsite and show differences between
CB1 and CB2. Transformation of the polar southern
hydroxyalkyl pharmacophore into hydrophobic alkyl or
haloalkyl groups reveals the presence of an additional
binding subsite. Within this subsite a large cavity can
accommodate hydrophobic groups at least as large as
an iodine atom at a distance of at least 4.0 Å from the
cannabinoid template. Currently, we are further refin-
ing the pharmacophoric requirements of the southern
subsites through the design and synthesis of conforma-
tionally more defined analogues.
1
Chiralpak OD), 300 MHz H NMR, and multiple elution TLC
analysis. The materials which were used for the binding
affinity assays were purified by chiral HPLC (multiple injec-
tions and peak-shaving to get the center cut).
(4R)-4-[4-(1′,1′-Dim eth ylh ep tyl)-2,6-d ih yd r oxyp h en yl]-
6,6-d im eth yl-2-n or p in a n on e, 17. To a solution of 8.8 g of
resorcinol 14 (37.0 mmol) and 10.5 g of diacetates 15 and 16
(44.0 mmol, ca. 85% pure by 1H NMR) in 320 mL of CHCl3
was added p-toluenesulfonic acid monohydrate (8.37 g, 44.0
mmol), and the solution stirred at room temperature for 3 days.
The reaction was diluted with ether and washed sequentially
with water, saturated aqueous NaHCO3, and brine. The
organic phase was dried (MgSO4) and solvent removed in vacuo
to give a brown oil. Recrystallization from CH2Cl2 and hexane
gave 17 as a white crystalline solid (8.4 g, 61% yield): mp 174-
176 °C [lit.10 mp 171-174 °C]; [R]20D +57.2° (c 1.0, CHCl3) [lit.10
[R]20D +55.8° (c 1.0, CHCl3)]; 1H NMR (300 MHz, CDCl3) δ 6.27
(s, 2H), 4.87 (s, 2H), 3.94 (t, J ) 8.1 Hz, 1H), 3.49 (dd, J )
18.6, 7.8 Hz, 1H), 2.66-2.44 (m, 4H), 2.30 (t, J ) 5.1 Hz, 1H),
1.52-1.47 (m, 2H), 1.36 (s, 3H), 1.28-1.18 (m, 6H), 1.20 (s,
6H), 1.07 (br s, 2H), 1.00 (s, 3H), 0.85 (t, J ) 6.6 Hz, 3H);13C
NMR (75 MHz, CDCl3) δ 216.9, 154.7, 150.0, 113.5, 106.6, 57.9,
46.8, 44.4, 42.2, 37.9, 37.2, 31.8, 30.0, 29.5, 28.7, 26.2, 24.6,
24.4, 22.7, 22.2, 14.1; IR (neat) 3300, 2920, 1680, 1580, 1420,
1370, 1330, 1265 cm-1; mass spectrum m/z (relative intensity)
372 (M+, 44), 355 (13), 329 (19), 289 (100), 269 (11), 249 (38),
217 (23), 178 (54), 149 (22), 109 (15), 83 (75). Exact mass
calculated for C24H36O3, 372.2655; found, 372.2648. Anal.
Calcd: C, 77.34; H, 9.74. Found: C, 77.19; H, 9.53.
(4R)-4-[4-(1′,1′-Dim eth ylh ep tyl)-2,6-bis(ter t-bu tyld im -
eth ylsilyloxy)p h en yl]-6,6-d im eth yl-2-n or p in a n on e, 18. To
a solution of 5.8 g of imidazole (85.0 mmol, dried at 40 °C/0.1
mmHg for 2 h) and DMAP (275 mg, 2.0 mmol, resublimed) in
25 mL of DMF was added a solution of 8.1 g of 17 (22.0 mmol)
in 20 mL of DMF. To this mixture was added a solution of
tert-butyldimethylsilyl chloride (10.3 g, 68.0 mmol) in 23 mL
of DMF, and the reaction was allowed to stir at room
temperature for 36 h. The reaction was quenched by addition
of saturated aqueous NaHCO3 and extracted with 3 × 200 mL
of ether. The combined ethereal extracts were washed with 2
× 200 mL of water and brine and dried (MgSO4). Solvent
evaporation gave a pale yellow oil which was purified by flash
chromatography (5% ether in hexane) to produce 18 as a
colorless oil (10.9 g, 83% yield): [R]20 +51.6° (c 1.0, CHCl3);
D
1H NMR (300 MHz, CDCl3) δ 6.40 (s, 2H), 3.99 (br t, J ) 8.1
Hz, 1H), 3.79 (dd, J ) 19.0, 7.0 Hz, 1H), 2.56-2.37 (m, 4H),
2.30 (t, J ) 5.1 Hz, 1H), 1.52-1.46 (m, 2H), 1.32 (s, 3H), 1.27-
1.15 (m, 6H), 1.19 (s, 6H), 1.07 (br s, 2H), 0.99 (s, 18H), 0.97
(s, 3H), 0.84 (t, J ) 6.9 Hz, 3H), 0.27 (s, 12H);13C NMR (75
MHz, CDCl3) δ 215.4, 154.7, 148.2, 119.6, 110.0, 57.9, 47.4,
44.6, 41.9, 37.3, 31.8, 30.2, 30.0, 28.9, 26.7, 26.0, 25.7, 24.7,
24.2, 22.7, 22.2, 18.8, 14.1, -3.0, -3.5, -3.6; IR (neat) 2955,
2930, 2860, 1715, 1605, 1560, 1470, 1465, 1415, 1260, 1095,
1070, 830, 785, 670 cm-1; mass spectrum m/z (relative inten-
sity) 600 (M+, 7), 543 (100), 503 (7), 435 (51), 119 (5). Exact
mass calculated for C36H64O3Si2, 600.4377; found, 600.4400.
(3R,4R)-3-[4-(1′,1′-Dim eth ylh eptyl)-2,6-bis(ter t-bu tyldim -
eth ylsilyloxy)ph en yl]-4-isopr open ylcycloh exan -1-on e, 13.
To a solution of 2.1 g of iodine (8.2 mmol) in 61 mL of CCl4 at
0 °C in the dark was added allyltrimethylsilane (1.3 mL, 8.2
mmol), and the reaction was allowed to stir for 2 h at 0 °C.
Exp er im en ta l Section
1H NMR and 13C NMR spectra were recorded on a General
Electric QE 300 spectrometer at 300 MHz H (75 MHz 13C) or
1
a GE Omega 500 at 500 spectrometer MHz H (125 MHz 13C)
1
in deuteriochloroform (CDCl3) with chloroform (7.26 ppm 1H,
77.00 ppm 13C) as internal reference. Chemical shifts are
given in ppm (δ); multiplicities are indicated as br (broadened),
s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet);
coupling constants (J ) are reported in hertz (Hz). Infrared
spectra were recorded on a Perkin-Elmer IR 1430 spectrom-
eter. Electron impact mass spectra were performed on a VG-
70SE mass spectrometer. Mass spectral data are reported in
the form of m/z (intensity relative to base ) 100). Thin-layer
chromatography (TLC) was performed on Sigma precoated
silica gel 60 F-254 glass plates (0.25 mm). Flash column
chromatography was performed using ICN Biomedicals silica

3602 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19
Drake et al.
Ketone 18 (3.65 g, 6.1 mmol) was dissolved in a 3 mM solution
of tert-butyl alcohol in CCl4 (41 mL) and added slowly to the
TMSI solution. Stirring was continued for 1.5 h at 0 °C. The
reaction was diluted with 200 mL of ether and washed with
saturated aqueous sodium thiosulfate and saturated aqueous
NaHCO3. The organic phase was dried (MgSO4) and evapo-
rated to give a yellow oil. To a solution of this oil in 36 mL of
benzene was added DBU (2.7 mL, 18.1 mmol), and the reaction
was allowed to stir at 50 °C in the dark for 3 h. An aliquot
m/z (relative intensity) 628 (M+, 35), 570 (21), 543 (16), 477
(41), 433 (10), 208 (10), 151 (100). Exact mass calculated for
C
38H68O3Si2, 628.4689; found, 628.4683.
(1R,3R,4R)-3-[4-(1′,1′-Dim et h ylh ep t yl)-2,6-b is(ter t-b u -
t yld im et h ylsilyloxy)p h en yl]-4-isop r op en yl-1-for m ylcy-
cloh exa n e, 20. To a solution of 360 mg of methyl enol ether
19 (0.57 mmol) in 34 mL of CH2Cl2 was added aqueous
trichloroacetic acid (320 mg, 1.96 mmol, 3.4 equiv), and the
solution stirred for 10 min at room temperature. The reaction
was quenched by addition of saturated aqueous NaHCO3,
washed with brine, and dried (K2CO3) and the solvent evapo-
rated. Aldehyde resonances at δ 9.83 (br s) and 9.60 (d, J )
1.5 Hz) in the 1H NMR spectrum of the crude product indicated
that the reaction had taken place. The crude product was
dissolved in 20 mL of absolute ethanol and stirred with 158
mg of anhydrous K2CO3 (1.14 mmol, 2.0 equiv) for 24 h at room
1
was withdrawn and examined by H NMR to ensure that no
tertiary iodide remained. The reaction was diluted with 100
mL of ether, washed with water, and dried (MgSO4) and the
solvent evaporated to give 3.5 g of a brown oil. Purification
by flash chromatography (5% ether in hexane) gave 13 as a
pale yellow oil (2.49 g, 68% yield): Rf ) 0.40 (5% ether in
hexane); [R]20 -18.7° (c 1.0, CHCl3); 1H NMR (300 MHz,
D
1
CDCl3) δ 6.33 (s, 2H), 4.63 (s, 1H), 4.49 (s, 1H), 3.63 (dt, J )
12.3, 4.2 Hz, 1H), 3.39 (dt, J ) 11.6, 3.0 Hz, 1H), 3.19 (t, J )
14.1 Hz, 1H), 2.46 (dd, J ) 9.6, 4.7 Hz, 2H), 2.31 (dd, J ) 14.1,
4.2 Hz, 1H), 2.04-1.98 (m, 1H), 1.84-1.69 (m, 1H), 1.55 (s,
3H), 1.48-1.43 (m, 2H), 1.31-1.25 (m, 2H), 1.25-1.14 (m, 4H),
1.19 (s, 6H), 1.05 (br s, 9H), 1.03-0.95 (m, 2H), 0.99 (br s, 9H),
0.84 (t, J ) 6.9 Hz, 3H), 0.32 (br s, 6H), 0.23 (s, 3H), 0.15 (s,
3H);13C NMR (75 MHz, CDCl3) δ 211.4, 148.3, 147.4, 119.2,
110.7, 109.8, 109.5, 45.8, 45.1, 44.7, 41.6, 38.7, 37.3, 31.9, 31.8,
29.9, 28.6, 26.4, 25.9, 24.5, 22.5, 19.2, 14.0, -3.8, -4.2; IR
(neat) 3065, 2850, 1710, 1640, 1560, 1410, 1250, 1185, 1090,
1045, 830, 775, 665 cm-1; mass spectrum m/z (relative inten-
sity) 600 (M+, 12), 585 (4), 543 (100), 517 (6), 487 (15), 433
(40). Exact mass calculated for C36H64O3Si2, 600.4377; found,
600.4395.
temperature. Examination of an aliquot by H NMR showed
that epimerization was complete. Purification by flash chro-
matography (5% EtOAc in hexane) gave 20 as a colorless oil
(258 mg, 73% yield over 2 steps): Rf ) 0.20 (10% EtOAc in
hexane); [R]20 -18.8° (c 1.0, CHCl3); IR (neat) 2840, 1725,
D
1640, 1600, 1230, 1120, 1000 cm-1; 1H NMR (300 MHz, CDCl3)
δ 9.60 (d, J ) 1.5 Hz, 1H), 6.31 (s, 1H), 6.30 (s, 1H), 4.57 (br
s, 1H), 4.43 (br s, 1H), 3.28 (td, J ) 11.7, 3.3 Hz, 1H), 3.00 (td,
J ) 11.4, 3.0 Hz, 1H), 2.40-2.18 (m, 1H), 2.12 (dd, J ) 12.6,
3.3 Hz, 1H), 2.05-2.00 (m, 1H), 1.88-1.80 (m, 2H), 1.54 (s,
3H), 1.50-1.40 (m, 4H), 1.18 (s, 6H), 1.27-1.13 (m, 8H), 1.04
(s, 9H), 1.02 (s, 9H), 0.83 (t, J ) 7.2 Hz, 3H), 0.30 (s, 6H), 0.24
(s, 3H), 0.15 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 204.3, 155.0,
153.4, 148.9, 147.7, 120.9, 109.9, 109.8, 109.3, 51.1, 46.2, 44.8,
37.5, 37.2, 31.81, 31.8, 29.9, 29.5, 28.9, 28.6, 26.4, 25.9, 24.6,
22.5, 19.4, 18.8, 18.3, 14.0, -3.6, -3.8, -4.5; mass spectrum
m/z (relative intensity) 614 (M+, 2), 585 (7), 557 (7), 477 (24),
107 (14), 73 (100). Exact mass calculated for C37H66O3Si2,
614.4533; found, 614.4553.
(3R,4R)-3-[4-(1′,1′-Dim eth ylh eptyl)-2,6-bis(ter t-bu tyldim -
eth ylsilyloxy)p h en yl]-4-isop r op en yl-1-(m eth oxym eth yl-
en e)cycloh exa n e, 19. To a suspension of (methoxymethyl)-
triphenylphosphonium chloride (1.5 g, 4.3 mmol, dried at 60
°C/0.1 mmHg for 1 h) in 25 mL of benzene was added sodium
tert-amylate (5.0 mL, 4.3 mmol; 0.85 M solution in benzene),
and the mixture stirred at room temperature for 15 min until
a clear, deep red solution was obtained. A solution of 900 mg
of ketone 13 (1.5 mmol) in 15 mL of benzene was added
dropwise to the ylide, and the reaction stirred at 70 °C for 3
h. The reaction was quenched by dropwise addition of
saturated aqueous NH4Cl and diluted with 40 mL of ether and
the organic phase separated. The aqueous phase was ex-
tracted with 3 × 10 mL of ether, the combined ethereal
extracts were dried (MgSO4), and the solvent was evaporated
to give an orange oil. Purification by flash chromatography
(30% benzene in hexane) gave 19 as a colorless oil (684 mg,
73% yield, mixture of geometric isomers): Rf ) 0.22 and 0.25
(30% benzene in hexane); IR (neat) 3065, 2950, 2920, 2850,
1680, 1640, 1600, 1560, 1460, 1410, 1250, 1205, 1125, 1090,
(1R,3R,4R)-3-[4-(1′,1′-Dim et h ylh ep t yl)-2,6-b is(ter t-b u -
t yld im et h ylsilyloxy)p h en yl]-4-isop r op en yl-1-(h yd r oxy-
m eth yl)cycloh exa n e, 21. To a solution of 258 mg of alde-
hyde 20 (0.42 mmol) in 42 mL of absolute ethanol at 0 °C was
added 63 mg of NaBH4 (1.68 mmol, 4 equiv). The mixture was
warmed to room temperature, stirred for 2 h, and then
quenched by dropwise addition of saturated aqueous NH4Cl
and the solvent evaporated. The residual white solid was
dissolved in water and extracted with EtOAc. The combined
organic extracts were washed with brine and dried (MgSO4),
and the solvent was evaporated. Purification by flash chro-
matography (5% EtOAc in hexane) gave 21 as a colorless oil
(186 mg, 72% yield): Rf ) 0.10 (5% EtOAc in hexane); [R]20
D
-15.9° (c 1.0, CHCl3); IR (neat) 3320, 2920, 1565, 1470, 1410,
1
775, 665 cm-1; H NMR (500 MHz, CDCl3) δ 6.31 (d, J ) 1.7
Hz, 1H), 6.30 (d, J ) 1.7 Hz, 1H), 4.57 (d, J ) 1.9 Hz, 1H),
4.41 (d, J ) 1.0 Hz, 1H), 3.47 (br heptet, J ) 5.9 Hz, 2H), 3.26
(td, J ) 11.9, 3.1 Hz, 1H), 3.01 (td, J ) 11.7, 2.9 Hz, 1H), 1.92-
1.86 (m, 1H), 1.84-1.76 (m, 1H), 1.68-1.58 (m, 1H), 1.55-
1.42 (m, 5H), 1.44-1.38 (m, 1H), 1.25-1.00 (m, 12H), 1.19 (br
s, 6H), 1.06 (s, 9H), 1.03 (s, 9H), 0.84 (br t, J ) 6.9 Hz, 3H),
0.31 (s, 6H), 0.24 (s, 3H), 0.16 (s, 3H) [positive NOE from H-1
(δ 1.68-1.58) to H-3 (δ 3.26)]; 13C NMR (125 MHz, CDCl3) δ
154.9, 153.4, 149.7, 147.3, 121.8, 109.9, 109.3, 109.2, 68.8, 46.7,
44.8, 41.1, 37.8, 37.2, 33.0, 32.4, 31.8, 29.9, 29.3, 28.9, 28.6,
26.4, 25.9, 24.6, 22.6, 19.4, 18.8, 18.3, 14.0, -3.5, -3.7, -3.8,
-4.4; mass spectrum m/z (relative intensity) 616 (M+, 21), 598
(3), 585 (7), 557 (7), 477 (24), 437 (13), 73 (100). Exact mass
calculated for C37H68O3Si2, 616.4689; found, 616.4725.
(1R,3R,4R)-3-[4-(1′,1′-Dim et h ylh ep t yl)-2,6-b is(ter t-b u -
t yld im et h ylsilyloxy)p h en yl]-4-isop r op en yl-1-[(ter t-b u -
tyld im eth ylsilyloxy)m eth yl]cycloh exa n e, 22. To a solu-
tion of 233 mg of imidazole (3.43 mmol) in 1 mL of DMF was
added 1.09 g of 21 (1.77 mmol) in 2 mL of DMF followed by
410 mg of tert-butyldimethylsilyl chloride (2.72 mmol) in 2.2
mL of DMF. The reaction was allowed to stir at room
temperature for 17 h, quenched by addition of saturated
aqueous NaHCO3, and extracted with 3 × 20 mL of ether. The
combined ethereal extracts were washed with 2 × 20 mL of
830, 775, 675 cm-1 1H NMR (300 MHz, CDCl3) higher Rf
;
isomer δ 6.30 (s, 1H), 6.29 (s, 1H), 5.77 (s, 1H), 4.57 (d, J )
2.4 Hz, 1H), 4.39 (s, 1H), 3.48 (s, 3H), 3.17-3.14 (m, 2H), 2.67
(dd, J ) 13.5, 2.1 Hz, 1H), 2.37 (t, J ) 12.0 Hz, 1H), 2.10-
1.90 (m, 2H), 1.74 (br d, J ) 13.5 Hz, 1H), 1.53 (s, 3H), 1.48-
1.42 (m, 2H), 1.38-1.27 (m, 1H), 1.25-1.10 (m, 4H), 1.18 (s,
6H), 1.05 (br s, 9H), 1.01 (br s, 9H), 0.98-0.91 (m, 4H), 0.84
(t, J ) 6.7 Hz, 3H), 0.30 (s, 3H), 0.29 (s, 3H), 0.23 (s, 3H), 0.17
(s, 3H); lower Rf isomer δ 6.31 (s, 1H), 6.29 (s, 1H), 5.72 (s,
1H), 4.55 (s, 1H), 4.39 (s, 1H), 3.53 (s, 3H), 3.20-3.11 (m, 2H),
2.84 (br d, J ) 14.0 Hz, 1H), 2.67 (t, J ) 12.0 Hz, 1H), 1.91 (d,
J ) 13.5 Hz, 1H), 1.81-1.74 (m, 2H), 1.51 (s, 3H), 1.48-1.43
(m, 2H), 1.39-1.34 (m, 1H), 1.25-1.12 (m, 4H), 1.18 (s, 6H),
1.05 (br s, 9H), 1.01 (br s, 9H), 1.00-0.94 (m, 4H), 0.84 (t, J )
6.7 Hz, 3H), 0.31 (s, 3H), 0.30 (s, 3H), 0.24 (s, 3H), 0.17 (s,
3H); 13C NMR (125 MHz, CDCl3) higher Rf isomer δ 155.0,
153.5, 149.6, 147.2, 138.9, 121.7, 118.0, 109.9, 109.4, 109.2,
59.0, 47.1, 44.9, 38.8, 37.2, 34.6, 31.8, 30.2, 30.0, 28.9, 28.8,
28.7, 26.5, 25.9, 24.6, 22.6, 19.3, 18.8, 18.3, 14.1, -3.6, -3.7,
-3.8, -4.8; lower Rf isomer δ 155.0, 153.5, 149.4, 147.4, 139.0,
121.5, 118.5, 109.9, 109.3, 109.2, 59.3, 47.1, 44.8, 40.1, 37.2,
33.9, 33.3, 31.8, 29.9, 28.9, 28.6, 26.5, 26.0, 25.2, 24.6, 22.5,
19.3, 18.8, 18.3, 14.0, -3.6, -3.7, -3.8, -4.5; mass spectrum

Classical/ Nonclassical Hybrid Cannabinoids
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19 3603
water and brine and dried (MgSO4), and the solvent was
evaporated to give a pale yellow oil. Purification by flash
chromatography (hexane) gave 22 as a colorless oil (1.29 g,
part of ABq), 3.85 (dd, J ) 14.0, 6.3 Hz, 1H, part of ABq), 3.45
(br s, 2H), 3.27 (td, J ) 11.5, 3.6 Hz, 1H), 2.95 (td, J ) 11.5,
2.4 Hz, 1H), 1.86 (br d, J ) 11.5 Hz, 2H), 1.74 (t, J ) 12.5 Hz,
1H), 1.68-1.59 (m, 2H), 1.48-1.43 (m, 2H), 1.35 (t, J ) 6.3
Hz, 1H), 1.25-1.13 (m, 7H), 1.18 (s, 6H), 1.05 (s, 9H), 1.03 (s,
9H), 1.05-0.95 (m, 2H), 0.90-0.85 (m, 1H), 0.84 (t, J ) 6.7
Hz, 3H), 0.30 (s, 6H), 0.22 (s, 3H), 0.15 (s, 3H).
100% yield): Rf ) 0.80 (hexane); [R]20 -80.9° (c 1.0, CHCl3);
D
IR (neat) 2945, 2920, 2845, 1600, 1560, 1190, 1120, 1000, 880
1
cm-1; H NMR (300 MHz, CDCl3) δ 6.30 (s, 1H), 6.29 (s, 1H),
4.55 (d, J ) 1.5 Hz, 1H), 4.39 (d, J ) 0.9 Hz, 1H), 3.40 (br dd,
J ) 6.3, 1.5 Hz, 2H), 3.12 (td, J ) 11.4, 3.9 Hz, 1H), 2.99 (td,
J ) 11.4, 2.7 Hz, 1H), 1.95-1.80 (m, 1H), 1.80-1.60 (m, 1H),
1.60-1.45 (m, 3H), 1.53 (s, 3H), 1.45-1.40 (m, 1H), 1.26-1.18
(m, 3H), 1.18 (br s, 6H), 1.05 (s, 9H), 1.01 (s, 9H), 1.00-0.80
(m, 11H), 0.87 (s, 9H), 0.29 (s, 6H), 0.22 (s, 3H), 0.13 (s, 3H),
0.02 (s, 3H), 0.01 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 154.9,
153.5, 149.9, 147.1, 122.2, 109.9, 109.4, 109.1, 69.0, 46.9, 44.9,
41.2, 37.9, 37.2, 33.3, 32.6, 31.8, 29.9, 29.5, 28.9, 28.6, 26.5,
26.0, 25.9, 24.6, 22.5, 19.4, 18.8, 18.4, 18.3, 14.0, -3.6, -3.8,
-4.5, -5.3, -5.4; mass spectrum m/z (relative intensity) 731
(M+, 6), 585 (12), 477 (18), 281 (9), 189 (20), 147 (82), 73 (100).
Exact mass calculated for C43H82O3Si3, 730.5550; found,
730.5561. Anal. Calcd: C, 70.69; H, 11.31. Found: C, 69.53;
H, 11.11.
The material was dissolved in 2 mL of THF at 0 °C and
treated dropwise with 93 mg of tetra-n-butylammonium
fluoride hydrate (0.34 mmol) in 1 mL of THF. The reaction
was stirred for 10 min at 0 °C, then 1 M aqueous NaHCO3
was added, and the mixture was extracted with EtOAc. The
organic phase was washed with water, dried (Na2SO4), and
evaporated to give a colorless oil. Purification by flash
chromatography (60% EtOAc in hexane + 1% Et3N) gave 24
as a white foam (29 mg, 80% yield over 2 steps): Rf ) 0.65
(80% EtOAc in hexane + 1% NEt3); [R]20 -17.0° (c 1.0,
D
MeOH); IR (neat) 3300 br, 2920, 2850, 1640, 1580, 1450, 1415,
1
1010 cm-1; H NMR (500 MHz, CDCl3) δ 6.31 (d, J ) 1.7 Hz,
1H), 6.19 (d, J ) 1.7 Hz, 1H), 4.81 (s, 1H), 4.80 (s, 1H), 4.12
(d, J ) 12.6 Hz, 1H, part of ABq), 3.96 (d, J ) 12.6 Hz, 1H,
part of ABq), 3.50 (d, J ) 6.2 Hz, 2H), 3.18 (td, J ) 11.6, 3.6
Hz, 1H), 2.95 (td, J ) 11.6, 2.8 Hz, 1H), 1.94-1.86 (m, 3H),
1.76 (br d, J ) 13.0 Hz, 1H), 1.73-1.60 (m, 3H), 1.55 (qd, J )
13.0, 2.8 Hz, 1H), 1.47-1.43 (m, 2H), 1.26-1.12 (m, 7H), 1.17
(s, 6H), 1.02-0.94 (m, 2H), 0.89-0.85 (m, 1H), 0.84 (t, J ) 7.1
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 154.8, 153.6, 151.3,
149.4, 115.4, 112.1, 107.2, 106.9, 68.5, 65.7, 44.5, 44.4, 40.9,
39.3, 37.2, 33.4, 32.3, 31.8, 30.0, 29.4, 28.7, 28.6, 24.6, 22.6,
14.1; mass spectrum m/z (relative intensity) 404 (M+, 24), 371
(25), 320 (29), 287 (16), 249 (100), 229 (8), 163 (38). Exact mass
calculated for C25H40O4, 404.2916; found, 404.2922.
(1R ,3R ,4R )-1-[(t er t -Bu t yld im e t h ylsilyloxy)m e t h yl]-
3-[4-(1′,1′-dimethylheptyl)-2,6-bis(tert-butyldimethylsilyloxy)-
p h en yl]-4-[2′-(3′-h yd r oxyp r op 1′-en yl)]cycloh exa n e, 23. To
a stirred mixture of selenium dioxide (1 mg, 0.009 mmol) and
salicylic acid (3 mg, 0.002 mmol) in 1 mL of CH2Cl2 was added
tert-butyl hydroperoxide (60 mL, 0.41 mmol) at room temper-
ature. After 5 min, 85 mg of 22 (0.11 mmol) in 2 mL of CH2-
Cl2 was added dropwise and the solution allowed to stir at
room temperature for 2 h. Benzene (1 mL) was added to the
reaction and the solvent removed in vacuo. The residue was
dissolved in ether, washed with 1 N aqueous NaOH and brine,
and dried (MgSO4), and the solvent was evaporated. This
material was dissolved in 1 mL of methanol, and 5 mg of
NaBH4 (0.13 mmol) was added at 0 °C. The reaction was
stirred at room temperature for 30 min and then quenched
with saturated aqueous NH4Cl. The methanol was evaporated
and the residual aqueous phase extracted three times with
ether. The combined ethereal extracts were washed with
brine, dried (MgSO4), and evaporated to give a colorless oil.
Purification by flash chromatography (1% EtOAc in hexane)
gave 23 as a colorless oil (68 mg, 83% yield): Rf ) 0.50 (5%
EtOAc in hexane); [R]20D -17.2° (c 1.0, CHCl3); IR (neat) 3460
br, 2950, 2920, 2850, 1600, 1560, 1460, 1410, 1250, 1120, 1095,
12â-Hyd r oxy-9-n or -9â-(h yd r oxym eth yl)h exa h yd r oca n -
n a bin ol DMH, 5. To a solution of 25 mg of 24 (0.06 mmol)
in THF was added 38 mg of mercuric acetate (0.12 mmol), and
the solution was stirred for 20 h at room temperature. The
reaction was cooled to -78 °C, and 36 mg of NaBH4 (0.94
mmol) in 1 M sodium methoxide/methanol (3 mL) was added
in a single portion. The mixture was stirred at -78 °C for 15
min, quenched with degassed saturated aqueous NH4Cl, and
allowed to warm to room temperature. The reaction was
diluted with ether and washed with brine and the aqueous
phase extracted with ether. The combined ethereal phases
were dried (MgSO4), and the solvent was evaporated to give a
yellow oily solid. Elution through a short column of silica (50%
EtOAc in hexane) followed by purification by HPLC (10-mm
× 250-mm Phenomenex silica column, 50% EtOAc in hexane,
1.5 mL/min, RI detection) gave 5 as a white foam (15 mg, 62%
yield) with a retention time of 12 min. Chiral HPLC (1-cm ×
25-cm Chiracel OD column, 10% 2-propanol in hexane, 2.5 mL/
min, UV detection at 254 nm) showed 5 (16.30-min retention
time, 92.66%) and the enantiomer of 5 (22.71-min retention
1
1055, 825, 770, 660 cm-1; H NMR (300 MHz, CDCl3) δ 6.33
(s, 1H), 6.30 (s, 1H), 4.80 (s, 1H), 4.77 (s, 1H), 3.96 (dd, J )
14.0, 6.5 Hz, 1H, part of ABq), 3.85 (dd, J ) 14.0, 6.3 Hz, 1H,
part of ABq), 3.42 (d, J ) 6.3 Hz, 2H), 3.27 (td, J ) 11.5, 3.6
Hz, 1H), 2.95 (td, J ) 11.5, 2.4 Hz, 1H), 1.86 (br d, J ) 11.5
Hz, 2H), 1.74 (t, J ) 12.5 Hz, 1H), 1.68-1.59 (m, 2H), 1.48-
1.43 (m, 2H), 1.35 (t, J ) 6.3 Hz, 1H), 1.25-1.13 (m, 7H), 1.18
(s, 6H), 1.05 (s, 9H), 1.03 (s, 9H), 1.05-0.95 (m, 2H), 0.90-
0.85 (m, 1H), 0.88 (s, 9H), 0.84 (t, J ) 6.7 Hz, 3H), 0.30 (s,
6H), 0.22 (s, 3H), 0.15 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 154.8, 153.5, 153.1, 147.6, 122.1,
110.3, 109.8, 109.2, 68.8, 65.0, 44.8, 43.6, 41.1, 38.8, 37.2, 33.4,
33.2, 30.0, 29.6, 28.9, 28.6, 26.5, 26.0, 25.9, 24.6, 22.6, 18.8,
18.4, 18.3, 14.0, -3.6, -3.8, -4.5, -5.3, -5.4; mass spectrum
m/z (relative intensity) 746 (M+, 11), 731 (6), 689 (63), 601 (52),
557 (47), 477 (100), 435 (95), 73 (95). Exact mass calculated
for C43H82Si3O4, 746.5499; found, 746.5526.
time, 4.12%), 92% ee: Rf ) 0.20 (50% EtOAc in hexane); [R]20
D
-37.5° (c 1.0, CHCl3); IR (neat) 3340 br, 2920, 2850, 1625,
1575, 1420, 1330, 1050, 1035, 965, 840 cm-1 1H NMR (500
;
MHz, CDCl3) δ 6.34 (d, J ) 1.8 Hz, 1H, H-2), 6.25 (d, J ) 1.8
Hz, 1H, H-4), 6.19 (br s, 1H, OH), 3.67 (s, 2H, H-12â), 3.55-
3.47 (m, 2H, H-11), 3.31 (br d, J ) 12.7 Hz, 1H, H-10), 2.52
(td, J ) 11.0, 2.5 Hz, 1H, H-10a), 2.27 (br s, 2H, OH), 1.91-
1.76 (m, 4H, H-6a, H-7, H-8, H-9), 1.50-1.46 (m, 2H, H-2′),
1.27-1.15 (m, 7H, H-8, H-4′, H-5′, H-6′), 1.18 (s, 6H, H-8′,
H-9′), 1.12 (br d, J ) 9.2 Hz, 1H, H-7), 1.10-1.02 (m, 2H, H-3′),
0.92 (s, 3H, H-12R), 0.84 (t, J ) 6.9 Hz, 3H, H-7′), 0.83-0.78
(m, 1H, H-10); 13C NMR (125 MHz, CDCl3) δ 154.8 (C-5), 154.1
(C-1), 150.1 (C-3), 109.6 (C-10b), 107.7 (C-2), 105.9 (C-4), 79.0
(C-6), 68.5 (C-11), 67.9 (C-12â), 44.4 (C-2′), 43.2 (C-6a), 40.4
(C-9), 37.3 (C-1′), 34.4 (C-10a), 33.2 (C-10), 31.8 (C-6′), 30.0
(C-4′), 29.4 (C-8), 28.7 and 28.6 (C-8′, C-9′), 26.8 (C-7), 24.6
(C-3′), 22.7 (C-5′), 14.9 (C-12R), 14.1 (C-7′); mass spectrum m/z
(relative intensity) 404 (M+, 42), 373 (45), 320 (100), 249 (27),
163 (20). Exact mass calculated for C25H40O4, 404.2916; found,
404.2918.
(1R,3R,4R)-1-(Hyd r oxym et h yl)-4-[2′-(3′-h yd r oxyp r op -
1′-en yl)]-3-[4-(1′,1′-d im et h ylh ep t yl)-2,6-d ih yd r oxyp h en -
yl]cycloh exa n e, 24. To a solution of 68 mg of 23 (0.09 mmol)
in 3.5 mL of acetonitrile at 0 °C was added 70 mg of
triethylamine hydrogen fluoride (0.58 mmol) followed by 6
drops of a 20% solution of hydrofluoric acid (49% aqueous) in
acetonitrile. The reaction was stirred at 0 °C for 4 h, quenched
with saturated aqueous NaHCO3, and extracted with EtOAc.
The combined organic extracts were dried (MgSO4), and the
solvent was evaporated to give a colorless oil (54 mg) which
was used without further purification: Rf ) 0.50 (20% EtOAc
in hexane); 1H NMR (300 MHz, CDCl3) δ 6.33 (s, 1H), 6.30 (s,
1H), 4.80 (s, 1H), 4.77 (s, 1H), 3.96 (dd, J ) 14.0, 6.5 Hz, 1H,
(1R,3R,4R)-1-[(ter t-Bu t yld im et h ylsilyloxy)m et h yl]-3-
[4-(1′,1′-d im eth ylh ep tyl)-2,6-bis(ter t-bu tyld im eth ylsilyl-

3604 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19
Drake et al.
oxy)ph en yl]-4-[2′-(4′-h ydr oxybu t-1′-en yl)]cycloh exan e, 25.
To a solution of 2.1 g of 2,6-diphenylphenol (8.4 mmol) in 28
mL of CH2Cl2 was added Al(CH3)3 (4.2 mmol; 1.7 mL of a 2.5
M solution in hexane) at room temperature, and the solution
was stirred for 1 h. The reaction was cooled to 0 °C, 140 mg
of trioxane (1.6 mmol) in 5 mL of CH2Cl2 added, and stirring
continued at 0 °C for 1 h. A solution of 940 mg of 22 (1.4 mmol)
in 28 mL of CH2Cl2 was added to the reaction, and stirring at
0 °C was continued for 2 h. The reaction was quenched with
saturated aqueous NaHCO3 and extracted with CH2Cl2. The
aqueous layer was stirred with potassium sodium tartrate for
30 min and extracted with CH2Cl2. The combined organic
phases were dried (MgSO4), and the solvent was evaporated
to give a yellow solid. Purification by flash chromatography
(50% benzene in hexane) gave 25 as a colorless oil (872 mg,
the combined organic phases were washed with brine, dried
(MgSO4
), and evaporated. Purification by flash chromatog-
raphy (10% EtOAc in hexane) gave 27 (13 mg, 43% yield): Rf
) 0.45 (15% EtOAc in hexane); [R]20 -34.0° (c 1.0, CHCl3);
D
IR (neat) 3250, 2920, 2850, 1620, 1565, 1410, 1260, 1040, 830,
1
735 cm-1; H NMR (300 MHz, CDCl3) δ 6.31 (d, J ) 1.8 Hz,
1H), 6.22 (d, J ) 1.8 Hz, 1H), 4.72 (s, 1H), 3.94-3.91 (m, 2H),
3.52-3.41 (m, 2H), 3.15 (br d, J ) 13.2 Hz, 1H), 2.84-2.82
(m, 1H), 2.50 (td, J ) 11.1, 2.4 Hz, 1H), 1.98-1.95 (m, 2H),
1.83 (br d, J ) 8.4 Hz, 1H), 1.76-1.57 (m, 2H), 1.51-1.45 (m,
2H), 1.25-1.10 (m, 9H), 1.19 (s, 6H), 1.12 (s, 3H), 1.07-1.03
(m, 2H), 0.93-0.80 (m, 4H), 0.90 (s, 9H), 0.04 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 154.9, 153.5, 150.1, 109.7, 107.8, 106.0,
80.1, 68.5, 59.1, 47.3, 44.4, 41.0, 40.6, 37.3, 34.8, 33.3, 31.8,
31.6, 30.1, 30.0, 29.8, 28.7, 27.3, 26.0, 24.6, 22.7, 18.0, 14.1,
-5.3; mass spectrum m/z (relative intensity) 532 (M+, 100),
448 (91), 323 (84), 249 (88), 164 (32). Exact mass calculated
for C32H56O4Si, 532.3933; found, 532.3974.
82% yield): Rf ) 0.13 (50% benzene in hexane); [R]20 -10.5°
D
(c 1.0, CHCl3); IR (neat) 3490 br, 3070, 2950, 2920, 2850, 1600,
1560, 1460, 1410, 1250, 1120, 1095, 1055, 825, 770, 665 cm-1
;
1H NMR (300 MHz, CDCl3) δ 6.33 (s, 1H), 6.30 (s, 1H), 4.92
(s, 1H), 4.59 (s, 1H), 3.50 (q, J ) 6.0 Hz, 2H), 3.42 (d, J ) 6.3
Hz, 2H), 3.27 (td, J ) 11.4, 3.6 Hz, 1H), 2.87 (br t, J ) 11.4
Hz, 1H), 2.18-2.03 (m, 2H), 1.86 (br d, J ) 10.5 Hz, 2H), 1.76
(t, J ) 12.0 Hz, 1H), 1.68-1.59 (m, 2H), 1.48-1.43 (m, 2H),
1.35-1.12 (m, 7H), 1.17 (s, 6H), 1.08-0.97 (m, 2H), 1.05 (s,
9H), 1.03 (s, 9H), 0.88 (s, 9H), 0.86-0.78 (m, 1H), 0.83 (t, J )
6.9 Hz, 3H), 0.31 (s, 3H), 0.30 (s, 3H), 0.23 (s, 3H), 0.14 (s,
3H), 0.02 (s, 3H), 0.01 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
154.7, 153.5, 149.7, 147.6, 122.1, 110.6, 110.1, 109.6, 68.8, 60.0,
45.5, 44.7, 41.2, 38.2, 38.0, 37.2, 33.9, 31.8, 33.1, 30.0, 29.6,
28.9, 28.7, 26.5, 26.0, 25.9, 24.6, 22.6, 18.8, 18.4, 18.3, 14.1,
-3.5, -3.6, -3.8, -4.5, -5.3, -5.4; mass spectrum m/z
(relative intensity) 760 (M+, 21), 730 (66), 673 (52), 585 (91),
477 (100), 433 (46), 294 (23), 147 (37), 121 (57), 73 (81). Exact
mass calculated for C44H84O4Si3, 760.5655; found, 760.5672.
12â-(Hydr oxym eth yl)-9-n or -9â-(h ydr oxym eth yl)h exah y-
d r oca n n a bin ol DMH, 6. To 10 mg of silyl ether 27 (0.019
mmol) in 0.5 mL of acetonitrile at 0 °C was added triethyl-
amine hydrogen fluoride (12 mg, 0.1 mmol) followed by 2 drops
of a 20% solution of HF (49% aqueous) in acetonitrile. The
reaction was stirred at 0 °C for 1.5 h, diluted with Et2O,
washed with saturated aqueous NaHCO3 and brine, and dried
(MgSO4), and the solvent was evaporated. Purification by
flash chromatography (25% EtOAc in hexane) gave 6 as a
white foam (6 mg, 76% yield). Chiral HPLC (1-cm × 25-cm
Chiracel OD column, 10% 2-propanol in hexane, 2.5 mL/min,
UV detection at 254 nm) showed 6 (22.17-min retention time,
92.09%) and the enantiomer of 6 (36.45-min retention time,
5.35%), 90% ee: [R]20 -51.2° (c 0.04, CHCl3); IR (neat) 3550
D
br, 2960, 2920, 2850, 1620, 1570, 1420, 1260, 1080, 1040, 790
1
cm-1; H NMR (500 MHz, CDCl3) δ 6.32 (d, J ) 1.7 Hz, 1H,
H-2), 6.22 (d, J ) 1.7 Hz, 1H, H-4), 4.88 (br s, 1H, OH), 3.97-
3.89 (br m, 2H, H-13), 3.56-3.49 (m, 2H, H-11), 3.22 (d, J )
12.2 Hz, 1H, H-10), 2.78 (br s, 1H, OH), 2.53 (td, J ) 11.1, 2.7
Hz, 1H, H-10a), 1.98-1.96 (m, 3H, H-12â, H-8), 1.86 (dt, J )
8.3, 2.7 Hz, 1H, H-7), 1.80-1.76 (m, 1H, H-9), 1.67 (td, J )
11.1, 2.0 Hz, 1H, H-6a), 1.48 (ddd, J ) 10.8, 5.9, 1.9 Hz, 2H,
H-2′), 1.25-1.10 (m, 8H, H-7, H-8, H-4′, H-5′, H-6′), 1.19 (s,
6H, H-8′, H-9′), 1.13 (s, 3H, H-12R), 1.07-1.02 (m, 2H, H-3′),
0.85 (q, J ) 12.2 Hz, 1H, H-10), 0.85 (t, J ) 7.3 Hz, 3H, H-7′);
13C NMR (125 MHz, CDCl3) δ 154.4 (C-5), 153.6 (C-1), 150.2
(C-3), 109.5 (C-10b), 108.0 (C-2), 106.0 (C-4), 80.0 (C-6), 68.5
(C-11), 59.0 (C-13), 47.3 (C-6a), 44.4 (C-2′), 41.0 (C-12â), 40.5
(C-9), 37.3 (C-1′), 34.7 (C-10a), 33.2 (C-10), 31.8 (C-6′), 30.0
(C-4′), 29.6 (C-8), 28.7 and 28.6 (C-8′, C-9′), 27.2 (C-7), 24.6
(C-3′), 22.6 (C-5′), 18.0 (C-12R), 14.1 (C-7′); mass spectrum m/z
(relative intensity) 418 (M+, 45), 334 (100), 277 (42), 249 (31),
164 (30). Exact mass calculated for C26H42O4, 418.3072; found,
418.3100.
12â-(Iod om et h yl)-9-n or -9â-[(ter t-b u t yld im et h ylsilyl)-
oxym eth yl]h exa h yd r oca n n a bin ol DMH, 28. A screw cap
vial was charged with 10 mg of 27 (0.019 mmol), 0.2 mL of
benzene, 5 mg of triphenylphosphine (0.019 mmol), 4 mg of
imidazole (0.059 mmol), and 5 mg of iodine (0.020 mmol). The
solution was blanketed with argon and capped and the reaction
stirred for 45 min at 45 °C. The mixture was cooled to room
temperature, diluted with ether, washed with water, aqueous
sodium thiosulfate, and brine, dried (MgSO4), and evaporated.
Purification by flash chromatography (2-5% ether gradient
in hexane) gave 28 as a colorless oil (10 mg, 82% yield): Rf )
0.60 (10% EtOAc in hexane); 1H NMR (300 MHz, CDCl3) δ
6.31 (d, J ) 1.5 Hz, 1H), 6.20 (d, J ) 1.5 Hz, 1H), 4.66 (s, 1H),
3.52-3.40 (m, 2H), 3.38-3.32 (m, 2H), 3.16 (br d, J ) 12.6
Hz, 1H), 2.48 (td, J ) 11.1, 2.4 Hz, 1H), 2.36-2.28 (m, 2H),
1.95 (br d, J ) 10.0 Hz, 1H), 1.83-1.80 (m, 1H), 1.76-1.67
(m, 1H), 1.52-1.46 (m, 2H), 1.25-1.12 (m, 7H), 1.19 (s, 6H),
1.11-1.02 (m, 4H), 1.05 (s, 3H), 0.93-0.73 (m, 1H), 0.90 (s,
9H), 0.85 (t, J ) 6.9 Hz, 3H), 0.04 (s, 6H).
(1R,3R,4R)-1-[(ter t-Bu t yld im et h ylsilyloxy)m et h yl]-3-
[4-(1′,1′-d im et h ylh ep t yl)-2,6-d ih yd r oxyp h en yl]-4-[2′-(4′-
h yd r oxybu t-1′-en yl)]cycloh exa n e, 26. To a solution of 860
mg of 25 (1.13 mmol) in 10 mL of THF at -78 °C was added
dropwise 1.0 g of tetra-n-butylammonium fluoride hydrate (3.8
mmol) in 10 mL of THF. After 2 h the solution was allowed
to slowly warm to 0 °C, then diluted with EtOAc, washed with
water and brine, dried (MgSO4), and evaporated. Purification
by flash chromatography (10% EtOAc in hexane) gave 26 as a
white solid (570 mg, 95% yield): Rf ) 0.25 (10% EtOAc in
hexane); mp 138-139 °C; [R]20D -9.7° (c 1.0, CHCl3); IR (neat)
3330 br, 2920, 2860, 1620, 1590, 1470, 1420 cm-1 1H NMR
;
(300 MHz, CDCl3) δ 6.26 (s, 1H), 6.20 (s, 1H), 5.36 (br s, 2H),
4.93 (s, 1H), 4.64 (s, 1H), 3.66-3.57 (m, 2H), 3.50-3.39 (m,
2H), 3.24-3.15 (m, 1H), 2.85 (br t, J ) 11.4 Hz, 1H), 2.24-
2.16 (m, 2H), 1.90 (br d, J ) 10.8 Hz, 2H), 1.81-1.74 (m, 2H),
1.69 (br s, 1H), 1.48-1.43 (m, 2H), 1.35-1.09 (m, 8H), 1.17 (s,
6H), 1.05-0.96 (m, 2H), 0.89 (s, 9H), 0.86-0.78 (m, 1H), 0.83
(t, J ) 6.9 Hz, 3H), 0.03 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
155.1, 153.9, 149.4, 149.2, 115.4, 111.0, 106.7, 105.9, 68.8, 60.4,
45.9, 44.7, 41.0, 38.0, 37.8, 37.2, 33.6, 33.3, 31.8, 30.0, 28.7,
26.0, 24.6, 22.6, 18.5, 14.1, -5.2; mass spectrum m/z (relative
intensity) 532 (M+, 17), 514 (6), 502 (51), 445 (33), 418 (81),
355 (19), 323 (100), 249 (99), 135 (32), 109 (72), 73 (89). Exact
mass calculated for C32H56O4Si, 532.3933; found, 532.3967.
12â-(Hyd r oxym eth yl)-9-n or -9â-[(ter t-bu tyld im eth ylsi-
lyloxy)m eth yl]h exa h yd r oca n n a bin ol DMH, 27. To a flask
containing 21 mg of mercuric acetate (0.067 mmol) was added
30 mg of 26 (0.056 mmol) in 3.6 mL of THF, and the solution
was stirred at room temperature for 24 h. The solvent was
evaporated under
a stream of nitrogen and the residue
dissolved in 2 mL of CH2Cl2. The solution was cooled to 0 °C,
and to it were added 0.5 mL of 2.5 N degassed aqueous NaOH
and 2 drops of tetra-n-butylammonium hydroxide (40% aque-
ous solution). After stirring for 5 min, 0.5 mL of 2.5 N
degassed aqueous NaOH and 10 mg of NaBH4 (0.265 mmol)
were added dropwise. After 5 min, the mixture was diluted
with 5 mL of CH2Cl2 and neutralized with degassed 1 N
aqueous H2SO4. The mixture was extracted with CH2Cl2, and
12â-(Iod om et h yl)-9-n or -9â-(h yd r oxym et h yl)h exa h y-
d r oca n n a bin ol DMH, 8. The same procedure which was
used to convert 27 to 6 was followed: 10 mg of iodide 28 (0.016

Classical/ Nonclassical Hybrid Cannabinoids
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19 3605
mmol) gave 8 as a white foam (6 mg, 73% yield). Chiral HPLC
(1-cm × 25-cm Bakerbond OD column, 10% 2-propanol in
hexane, 2.5 mL/min, UV detection at 254 nm) showed 8 (9.69-
min retention time, 96.84%) and the enantiomer of 8 (7.00-
2865, 1720, 1650, 1640, 1610, 1570, 1420, 1260, 1190, 1100,
1050, 830 cm-1; mass spectrum m/z (relative intensity) 630
(M+, 1), 612 (2), 600 (6), 573 (11), 555 (18), 543 (100), 487 (27),
433 (96), 246 (44). Exact mass calculated for C37H66O4Si2,
630.4482; found, 630.4498.
min retention time, 2.11%), 96% ee; [R]20 -26.0° (c 1.0,
D
CHCl3); IR (neat) 3320 br, 2950, 2920, 2850, 1620, 1570, 1410,
(3R,4R)-3-[4-(1′,1′-Dim eth ylh ep tyl)-2,6-d ih yd r oxyp h e-
n yl]-4-[2′-(4′-h yd r oxybu t-1′-en yl)]cycloh exa n -1-on e Ket-
a l, 30. To 3.7 g of 29 (5.8 mmol) in 40 mL of THF at 0 °C was
added dropwise a solution of 6.3 g of tetra-n-butylammonium
fluoride hydrate (24.0 mmol) in 20 mL of THF. The solution
turned pale green and was allowed to stir at 0 °C for 20 min.
The reaction was diluted with ether and washed with water.
The organic layer was dried (MgSO4), and solvent was
evaporated to give a yellow oil. Purification by flash chroma-
tography (30-50% EtOAc gradient in hexane) gave 30 as a
white foam (2.0 g, 86% yield): Rf ) 0.05 (20% EtOAc in
1
1165, 1030 cm-1; H NMR (500 MHz, CDCl3) δ 6.33 (d, J )
2.0 Hz, 1H), 6.21 (d, J ) 2.0 Hz, 1H), 5.32 (br s, 1H), 3.56-
3.49 (m, 2H), 3.40-3.31 (m, 2H), 3.26 (br d, J ) 12.6 Hz, 1H),
2.49 (td, J ) 11.1, 2.8 Hz, 1H), 2.38-2.25 (m, 2H), 1.96-1.94
(m, 1H), 1.85-1.82 (m, 1H), 1.80-1.75 (m, 1H), 1.71-1.62 (br
m, 2H), 1.57-1.45 (m, 3H), 1.26-1.10 (m, 7H), 1.19 (s, 6H),
1.09-1.03 (m, 2H), 1.04 (s, 3H), 0.85 (t, J ) 7.0 Hz, 3H), 0.81
(q, J ) 12.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 154.4,
154.2, 150.2, 109.2, 107.8, 105.6, 79.4, 68.4, 46.2, 45.1, 44.4,
40.4, 37.2, 34.6, 33.2, 31.7, 30.0, 29.9, 28.7, 28.6, 27.0, 24.6,
22.6, 17.7, 14.0, -1.0; mass spectrum m/z (relative intensity)
528 (M+, 49), 444 (87), 400 (12), 316 (25), 249 (70), 164 (59),
128 (100). Exact mass calculated for C26H41IO3, 528.2089;
found, 528.2137.
hexane); [R]20 -28.2° (c 1.0, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 6.41 (s, 1H; an OH overlaps this signal), 6.34 (s, 1H),
5.08 (s, 1H), 5.04 (s, 1H), 4.06-3.99 (m, 1H), 3.81 (br t, J )
9.0 Hz, 1H), 3.60 (br s, 1H), 2.89 (s, 1H, OH), 2.76-2.67 (m,
1H), 2.58 (br s, 1H), 2.42 (ddd, J ) 15.0, 6.0, 3.5 Hz, 1H), 2.20
(s, 1H, OH), 2.07-2.01 (m, 2H), 1.96-1.84 (m, 2H), 1.77-1.65
(m, 2H), 1.53-1.48 (m, 2H), 1.23-1.19 (m, 6H), 1.21 (s, 6H),
1.08-1.05 (m, 2H), 0.84 (t, J ) 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 155.9, 152.4, 150.7, 147.1, 113.1, 109.5, 105.3, 104.4,
98.3, 62.4, 44.5, 40.4, 38.3, 37.5, 34.9, 31.8, 31.0, 30.5, 30.0,
28.8, 24.6, 22.7, 21.4, 14.1; IR (neat) 3360 br, 3085, 2955, 2925,
2850, 1625, 1585, 1415, 1140, 1070, 1045, 905, 735 cm-1; mass
spectrum m/z (relative intensity) 402 (M+, 13), 372 (9), 318
(17), 304 (13), 289 (100), 249 (26), 219 (25), 178 (46). Exact
mass calculated for C25H38O4, 402.2760; found, 402.2771.
12â-Met h yl-9-n or -9â-(h yd r oxym et h yl)h exa h yd r oca n -
n a bin ol DMH, 11. To 10 mg of LiAlH4 (0.26 mmol) under
argon was added a solution of 4 mg of iodide 8 (0.007 mmol)
in 0.4 mL of THF, and the reaction was allowed to stir at room
temperature for 3 h. The reaction was quenched by dropwise
addition of saturated aqueous NH4Cl and extracted with ether.
The combined ethereal extracts were dried (MgSO4), and the
solvent was evaporated to give a colorless oil. Purification by
flash chromatography (50% EtOAc in hexane) gave 11 as a
white foam (2 mg, 71% yield). Chiral HPLC (1-cm × 25-cm
Chiralpak OD column, 10% ethanol in hexane, 2.5 mL/min,
UV detection at 254 nm) showed 11 (13.01-min retention time,
94.68%) and the enantiomer of 11 (15.98-min retention time,
12â-(Hyd r oxym eth yl)-9-n or -9â-h yd r oxyh exa h yd r oca n -
n a bin ol DMH, 31. To 380 mg of 30 (0.95 mmol) in 55 mL of
THF was added 759 mg of mercuric acetate (2.36 mmol), and
the solution was allowed to stir at room temperature for 24 h.
The reaction was cooled to -78 °C, and a solution of 359 mg
of NaBH4 (9.50 mmol) in 15 mL of 1 M sodium methoxide/
methanol was added in a single portion. The mixture was
stirred at -78 °C for 15 min, quenched with degassed
saturated aqueous NH4Cl, and allowed to warm to room
temperature. The reaction was diluted with 100 mL of ether
and washed with brine and the aqueous phase extracted with
3 × 50 mL of ether. The combined ethereal phases were dried
(MgSO4), and solvent was evaporated to give a gray/white oily
solid. Purification by flash chromatography (60% EtOAc in
hexane) gave 31 as a white solid (253 mg, 66% yield). Chiral
HPLC (1-cm × 25-cm Chiracel OD column, 10% 2-propanol in
hexane, 2.5 mL/min, UV detection at 254 nm) showed 31 to
be 95% of a single enantiomer with retention time of 22.17
min (minor enantiomer retention time ) 36.45 min): Rf ) 0.30
0.52%), 99% ee: [R]20 -61.0° (c 1.0, CHCl3); IR (neat) 3330
D
br, 2950, 2920, 2850, 1615, 1565, 1460, 1450, 1410, 1330, 1035,
1
965, 840 cm-1; H NMR (500 MHz, CDCl3) δ 6.35 (d, J ) 1.9
Hz, 1H), 6.21 (d, J ) 1.9 Hz, 1H), 3.56-3.49 (m, 2H), 3.27 (br
d, J ) 12.8 Hz, 1H), 2.50 (td, J ) 11.0, 2.5 Hz, 1H), 1.94-1.91
(m, 1H), 1.87-1.82 (m, 1H), 1.81-1.76 (br m, 2H), 1.75-1.64
(m, 2H), 1.59-1.54 (m, 1H), 1.51-1.47 (m, 2H), 1.26-1.15 (m,
7H), 1.19 (s, 6H), 1.13-1.03 (m, 4H), 1.02 (s, 3H), 1.00 (t, J )
7.3 Hz, 3H), 0.85 (t, J ) 7.0 Hz, 3H), 0.82 (q, J ) 12.0 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 155.0, 154.5, 149.9, 109.6,
107.9, 105.3, 78.0, 68.6, 45.7, 44.4, 40.5, 37.3, 34.7, 33.3, 32.3,
31.8, 30.0, 29.7, 28.7, 28.6, 27.1, 24.6, 22.7, 18.7, 14.1, 7.0; mass
spectrum m/z (relative intensity) 402 (M+, 32), 345 (10), 318
(100), 249 (32), 164 (57), 84 (92). Exact mass calculated for
C26H42O3, 402.3123; found, 402.3142.
(3R,4R)-3-[4-(1′,1′-Dim eth ylh ep tyl)-2,6-bis(ter t-bu tyld i-
m eth ylsilyloxy)ph en yl]-4-[2′-(4′-h ydr oxybu t-1′-en yl)]cyclo-
h exa n -1on e, 29. To 2.0 g of 2,6-diphenylphenol (8.1 mmol)
in 21 mL of CH2Cl2 was added trimethylaluminum (2.13 mL,
4.04 mmol; 1.9 M solution in hexane) at room temperature,
and the solution was stirred for 1 h. The reaction was cooled
to 0 °C, and 122 mg of trioxane (1.35 mmol) in 2.5 mL CH2Cl2
was added. Stirring was continued at 0 °C for 1 h. A solution
of 13 (485 mg, 0.77 mmol) in 9 mL of CH2Cl2 was added to the
reaction, and stirring at 0 °C was continued for 1.5 h. The
reaction was quenched with saturated aqueous NaHCO3 and
extracted with CH2Cl2. The aqueous layer was stirred with
potassium sodium tartrate for 30 min and further extracted
with EtOAc. The combined organic phases were dried (Mg-
SO4), and the solvent was evaporated to give a yellow solid
(2.1 g). Purification by flash chromatography (10-30% EtOAc
gradient in hexane) gave 29 as a pale yellow oil (388 mg, 80%
(60% EtOAc in hexane); mp 153-154 °C; [R]20 -59.4° (c 1.0,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.31 (s, 1H), 6.22 (s, 1H),
5.92 (br s, 1H), 3.96-3.87 (m, 2H), 3.90-3.81 (m, 1H), 3.48
(br d, J ) 10.2 Hz, 1H), 2.78 (br s, 1H), 2.53 (td, J ) 10.2, 2.0
Hz, 1H), 2.16 (br d, J ) 10.2 Hz, 1H), 1.97 (t, J ) 5.7 Hz, 2H),
1.84 (br d, J ) 10.2 Hz, 1H), 1.68 (br t, J ) 11.5 Hz, 1H), 1.51-
1.43 (m, 2H), 1.48-1.35 (m, 2H), 1.27-1.18 (m, 6H), 1.19 (s,
6H), 1.16-0.99 (m, 4H), 1.12 (s, 3H), 0.84 (t, J ) 6.9 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 154.8, 153.4, 150.3, 108.7, 107.5,
106.0, 79.9, 70.9, 58.9, 46.3, 44.4, 41.1, 38.7, 37.3, 35.6, 33.2,
31.8, 30.0, 28.6, 25.8, 24.6, 22.7, 17.9, 14.1; IR (neat) 3340 br,
2960, 2930, 2860, 1625, 1575, 1460, 1420, 1050, 975, 845 cm-1
;
mass spectrum m/z (relative intensity) 404 (M+, 48), 386 (10),
320 (100), 302 (22), 249 (35), 178 (49). Exact mass calculated
for C25H40O4, 404.2916; found, 404.2935.
yield): Rf ) 0.05 (5% ether in hexane); [R]20 -22.6° (c 1.0,
1-(Allyloxy)-12â-(h yd r oxym et h yl)-9-n or -9â-h yd r oxy-
h exa h yd r oca n n a bin ol DMH, 32. Stock solutions of allyl
bromide (160 µL) in CH2Cl2 (2 mL) and tetra-n-butylammo-
nium hydroxide (TBAH) (723 µL, 40% aqueous) in water (7.5
mL) were prepared. To a mixture of 162 mg of 31 (0.40 mmol),
5.4 mL of CH2Cl2, and 2.7 mL of water was added 2.7 mL of
the TBAH stock solution (1 equiv) and 538 µL of the allyl
bromide stock solution (1 equiv), and the reaction was stirred
at room temperature. The reaction was monitored closely by
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.38 (s, 1H), 6.33 (s, 1H),
4.96 (s, 1H), 4.67 (s, 1H), 3.68 (dt, J ) 12.3, 4.2 Hz, 1H), 3.53
(br t, J ) 5.4 Hz, 2H), 3.33-3.20 (m, 2H), 2.47-2.42 (m, 2H),
2.33 (dd, J ) 14.4, 3.6 Hz, 1H), 2.20-1.99 (two m, 3H), 1.76-
1.62 (m, 1H), 1.49-1.44 (m, 2H), 1.31-1.25 (m, 2H), 1.20-
1.18 (m, 4H), 1.18 (s, 6H), 1.05 (s, 9H), 0.99 (s, 9H), 0.88-0.81
(m, 2H), 0.84 (t, J ) 6.9 Hz, 3H), 0.35 (s, 3H), 0.32 (s 3H),
0.23 (s, 3H), 0.15 (s, 3H); IR (neat) 3500 br, 3080, 2960, 2940,

3606 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19
Drake et al.
TLC, and after 1 h an additional 54 µL of the allyl bromide
stock solution (0.1 equiv) was added. After another 1 h at room
temperature, additional portions of TBAH stock solution (540
µL, 0.2 equiv) and allyl bromide stock solution (54 µL, 0.1
equiv) were added and the reaction stirred for 1 h, at which
time negligible starting material remained as judged by TLC.
The reaction was quenched with saturated aqueous NH4Cl,
extracted with 3 × 30 mL of CH2Cl2, and dried (MgSO4), and
the solvent was evaporated to give a brown oil. Purification
by flash chromatography (40-60% EtOAc gradient in hexane)
gave 32 as a colorless oil (142 mg, 80% yield): Rf ) 0.45 (60%
EtOAc in hexane); [R]20D -64.4° (c 1.0, CHCl3); IR (neat) 3340
(br), 3080, 2930, 2850, 1610, 1565, 1460, 1450, 1410, 1130,
geometrical isomers): Rf ) 0.2 (30% benzene in hexane); IR
(neat) 3050, 2920, 2850, 1680, 1665, 1650, 1610, 1565, 1450,
1
1410, 1375, 1330, 1200, 1130, 1095, 990, 930 cm-1; H NMR
(300 MHz, CDCl3) δ 6.41 (s), 6.35 (s,), 6.22-6.04 (m), 6.02 (d,
J ) 6.3 Hz), 5.84 (br s), 5.50 (td, J ) 15.6, 1.5 Hz), 5.28 (dd, J
) 10.5, 6.3 Hz), 4.99-4.90 (m,), 4.70-4.62 (m), 4.53 (br d, J )
3.0 Hz), 4.26 (dd, J ) 13.5, 2.4 Hz), 3.60, 3.58, 3.57 & 3.56
(four s), 3.47 (dd, J ) 13.5, 1.2 Hz), 2.89 (br d, J ) 13.5 Hz),
2.58-2.14 (m), 2.05-1.60 (m), 1.54-1.49 (m), 1.42-1.30 (m),
1.25-1.14 (m), 1.23 (s), 1.11-1.04 (m), 1.03 (s), 1.00 (s), 0.84
(t, J ) 6.5 Hz); mass spectrum m/z (relative intensity) 496 (M+,
4), 425 (100), 385 (11), 339 (8), 262 (11), 183 (18), 137 (5), 84
(19). Exact mass calculated for C32H48O4, 496.3540; found,
496.3561. Anal. Calcd: C, 77.36; H, 9.74. Found: C, 77.56;
H, 9.66.
1-(Allyloxy)-12â-(2-h yd r oxyet h yl)-9-n or -9â-(h yd r oxy-
m eth yl)h exa h yd r oca n n a bin ol DMH, 35. To a solution of
75 mg of bis-enol ether 34 (0.15 mmol) in 10 mL of CH2Cl2
was added aqueous trichloroacetic acid (98 mg, 0.60 mmol),
and the mixture stirred at room temperature for 10 min. The
reaction was quenched by addition of saturated aqueous
NaHCO3, washed with brine, and dried (MgSO4) and the
solvent evaporated to give a pale yellow oil: Rf ) 0.54 and
0.59 (20% EtOAc in hexane); 1H NMR (300 MHz, CDCl3)
aldehyde resonances at δ 9.87 (br s, C-13 and C-9a aldehydes),
9.63 (br s, C-9b aldehyde).
1080, 1050, 985, 925, 850, 730 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 6.38 (s, 1H), 6.36 (s, 1H), 6.12-6.03 (m, 1H), 5.40
(dd, J ) 17.3, 1.2 Hz, 1H), 5.28 (dd, J ) 10.8, 1.2 Hz, 1H),
4.54 (d, J ) 5.1 Hz, 2H), 3.99-3.85 (m, 2H, an OH overlaps
this signal), 3.87-3.78 (m, 1H), 3.42 (dt, J ) 11.7, 1.8 Hz, 1H),
2.79 (br s, 1H), 2.53 (td, J ) 11.1, 2.1 Hz, 1H), 2.17 (br d, J )
10.8 Hz, 1H), 1.97 (t, J ) 5.7 Hz, 2H), 1.84 (br d, J ) 12.6 Hz,
1H), 1.68 (br t, J ) 11.4 Hz, 2H), 1.53-1.48 (m, 2H), 1.29-
1.13 (m, 6H), 1.21 (s, 6H), 1.13-1.00 (m, 4H), 1.10 (s, 3H), 0.85
(t, J ) 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 157.2, 153.1,
149.8, 133.6, 117.0, 110.3, 108.2, 102.5, 79.7, 70.5, 68.8, 58.8,
46.6, 44.3, 41.1, 39.5, 37.6, 35.6, 33.2, 31.7, 29.9, 28.7, 25.7,
24.5, 22.6, 17.7, 14.0; mass spectrum m/z (relative intensity)
444 (M+, 100), 402 (7), 360 (92), 313 (16), 289 (34), 218 (28),
175 (20). Exact mass calculated for C28H44O4, 444.3228; found,
444.3236.
This oil was dissolved in 10 mL of absolute ethanol and
stirred with 176 mg of anhydrous K2CO3 (1.28 mmol) at room
1
temperature for 17 h. Examination by H NMR of an aliquot
1-(Allyloxy)-12â-for m yl-9-n or -9-oxoh exa h yd r oca n n a b-
in ol DMH, 33. To a suspension of 859 mg of Dess-Martin
periodinane (2.03 mmol) in 8 mL of CH2Cl2 was added 300
mg of 32 (0.68 mmol) in 8 mL of CH2Cl2, and the resulting
mixture was stirred at room temperature for 2 h. The reaction
was diluted with 20 mL of ether and stirred for 10 min with
20 mL of saturated aqueous NaHCO3 containing a 7-fold excess
of sodium thiosulfate (750 mg). The organic layer was
separated, washed with saturated aqueous NaHCO3 and
water, and dried (MgSO4), and the solvent was evaporated to
give an orange oil. Purification by flash chromatography (25%
EtOAc in hexane) gave 33 as a colorless oil (269 mg, 90%
taken from the reaction showed epimerization had occurred:
Rf ) 0.54 (20% EtOAc in hexane); H NMR δ 9.87 (br s, 1H),
1
9.63 (br s, 1H), 6.37 (s, 1H), 6.36 (s, 1H), 6.11-6.00 (m, 1H),
5.40 (d, J ) 16.2 Hz, 1H), 5.27 (d, J ) 10.5 Hz, 1H), 4.54 (d,
J ) 5.1 Hz, 2H), 3.49 (br d, J ) 13.5, 1H), 2.85-2.75 (m, 1H),
2.68 (t, J ) 6.9 Hz, 1H), 2.60-2.45 (m, 2H), 2.13-1.91 (m, 3H),
1.70 (br s, 1H), 1.54-1.41 (m, 4H), 1.25-1.10 (m, 8H), 1.15 (s,
6H), 1.09-0.97 (m, 2H), 1.07 (s, 3H), 0.84 (m, 3H).
To the ethanolic solution of the dialdehyde was added 67
mg of NaBH4 (1.76 mmol) at 0 °C. The reaction was warmed
to room temperature, stirred for 1 h, and then quenched by
dropwise addition of saturated aqueous NH4Cl, and the solvent
was evaporated. The residual white solid was dissolved in 10
mL of water and extracted with 3 × 30 mL of EtOAc. The
combined organic phases were dried (MgSO4), and the solvent
was evaporated to give a yellow oil. Purification by flash
chromatography (40-60% EtOAc gradient in hexane) gave diol
35 as a white foam (43 mg, 61% yield over 3 steps): Rf ) 0.37
(40% EtOAc in hexane); [R]20D -69.7° (c 1.0, CHCl3); IR (neat)
3350 (br), 3075, 2920, 2850, 1610, 1565, 1410, 1130, 1075, 1045
yield): Rf ) 0.73 (60% EtOAc in hexane); [R]20 -59.1° (c 1.0,
D
CHCl3); IR (neat) 2950, 2920, 2850, 1720, 1710, 1610, 1565,
1415, 1115, 1095, 930, 830, 760, 700 cm-1; 1H NMR (300 MHz,
CDCl3) δ 10.07 (t, J ) 2.7 Hz, 1H), 6.45 (s, 1H), 6.40 (s, 1H),
6.12-5.99 (m, 1H), 5.40 (dd, J ) 16.8, 0.9 Hz, 1H), 5.29 (dd, J
) 10.5, 0.9 Hz, 1H), 4.54 (d, J ) 5.1 Hz, 2H), 3.83 (br d, J )
15 Hz, 1H), 2.91 (dt, J ) 11.7, 3.6 Hz, 1H), 2.80 (dd, J ) 14.7,
2.1 Hz, 1H), 2.70 (dd, J ) 14.7, 3.6 Hz, 1H), 2.59 (td, J ) 11.1,
2.1 Hz, 1H), 2.45-2.35 (m, 1H), 2.17-2.03 (m, 3H), 1.55-1.49
(m, 2H), 1.33-1.14 (m, 7H), 1.23 (s, 6H), 1.20 (s, 3H), 1.11-
0.99 (m, 2H), 0.84 (t, J ) 6.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 210.2, 201.9, 157.0, 153.0, 150.7, 133.2, 117.5, 109.2,
108.2, 102.5, 77.8, 68.8, 52.4, 46.1, 45.6, 44.3, 40.3, 37.7, 34.1,
31.7, 29.9, 28.7, 25.9, 24.5, 22.6, 18.1, 14.0; mass spectrum m/z
(relative intensity) 440 (M+, 43), 356 (100), 315 (25), 287 (14).
Exact mass calculated for C28H40O4, 440.2916; found, 440.2945.
1
cm-1; H NMR (300 MHz, CDCl3) δ 6.37 (s, 1H), 6.35 (s, 1H),
6.13-6.01 (m, 1H), 5.42 (dd, J ) 17.1, 1.2 Hz, 1H), 5.26 (dd, J
) 10.5, 1.2 Hz, 1H), 4.52 (d, J ) 4.8 Hz, 2H), 3.73 (br s, 2H),
3.49 (t, J ) 5.5 Hz, 2H), 3.22 (br d, J ) 12.3 Hz, 1H), 2.52 (td,
J ) 10.8, 2.4 Hz, 1H), 2.00-1.92 (m, 1H), 1.92-1.82 (m, 1H),
1.83-1.70 (br m, 3H), 1.65-1.57 (m, 2H), 1.53-1.48 (m, 2H),
1.25-1.03 (br m, 12H), 1.19 (s, 6H), 1.07 (s, 3H), 0.84 (t, J )
6.9 Hz, 3H), 0.82-0.71 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
157.5, 154.0, 149.7, 133.8, 116.7, 111.2, 108.3, 102.2, 77.9, 68.9,
68.6, 63.3, 46.6, 44.5, 40.7, 37.6, 36.0, 35.0, 33.6, 31.7, 30.0,
29.8, 28.8, 28.7, 27.2, 26.0, 24.6, 22.6, 18.3, 14.1; mass
spectrum m/z (relative intensity) 472 (M+, 67), 388 (99), 347
(31), 289 (100), 249 (44), 203 (54), 163 (71). Exact mass
calculated for C30H48O4, 472.3540; found, 472.3577. Anal.
Calcd: C, 76.28; H, 10.24. Found: C, 76.35; H, 10.40.
1-(Allyloxy)-12â-(2-m eth oxyeth en yl)-9-n or -9-(m eth oxy-
m et h ylen e)h exa h yd r oca n n a b in ol DMH , 34. (Methoxy-
methyl)triphenylphosphonium chloride was dried overnight at
60 °C/0.1 mmHg. To a suspension of 1.19 g of this salt (3.46
mmol) in 8 mL of benzene was added sodium tert-amylate (4.07
mL, 3.46 mmol; 0.85 M solution in benzene), and the mixture
stirred at room temperature for 15 min until a clear, deep red
solution was obtained. A solution of 254 mg of keto aldehyde
33 (0.58 mmol) in 3 mL of benzene was added dropwise to the
ylide and the reaction stirred at 70 °C for 3 h. The reaction
was quenched by dropwise addition of saturated aqueous NH4-
Cl and diluted with 25 mL of ether and the organic phase
separated. The aqueous phase was extracted with 3 × 25 mL
of ether, the combined ethereal extracts were dried (MgSO4),
and the solvent was evaporated to give an orange oil. Puri-
fication by flash chromatography (30% benzene in hexane)
gave 34 as a colorless oil (240 mg, 84% yield) (mixture of
12â-(2-Hydr oxyeth yl)-9-n or -9â-(h ydr oxym eth yl)h exah y-
d r oca n n a bin ol DMH, 7. To a solution of 38 mg of allyl ether
35 (0.08 mmol) in 1.5 mL of THF was added tetrakis-
(triphenylphosphine)palladium(0) (2 mg, 0.002 mmol, 0.02
equiv), and the solution stirred at room temperature for 5 min.
Sodium borohydride (12 mg, 0.32 mmol) was added, and the
reaction was allowed to stir for 6 h. The reaction was
quenched by dropwise addition of saturated aqueous NH4Cl,
extracted with 3 × 30 mL of EtOAc, and dried (MgSO4), and
the solvent was evaporated to give a brown oil. Purification

Classical/ Nonclassical Hybrid Cannabinoids
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19 3607
by flash chromatography (30-50% EtOAc gradient in hexane)
gave 7 as a white solid (32 mg, 92% yield). Chiral HPLC (1-
cm × 25-cm Chiracel OD column, 10% 2-propanol in hexane,
2.5 mL/min, UV detection at 254 nm) showed 7 (22.47-min
retention time, 82.97%) and the enantiomer of 7 (32.57-min
retention time, 5.78%), 88% ee: Rf ) 0.28 (60% EtOAc in
hexane); mp 175-176 °C; [R]20D -44.5° (c 1.0, CHCl3); IR (neat)
(12), 128 (100). Exact mass calculated for C27H42I2O2, 652.1262;
found, 652.1285.
11-Hyd r oxy-3-(1,1′-d im eth ylh ep tyl)h exa h yd r oca n n a b-
in ol (10) was prepared according to the procedure of Yan et
al.25 Chiral HPLC (1-cm × 25-cm Chiralpak OD column, 10%
ethanol in hexane, 2.5 mL/min, UV detection at 254 nm)
showed 10 (13.69-min retention time, 91.73%) and the enan-
tiomer of 10 (18.29-min retention time, 5.86%), 88% ee.
12â-Eth yl-9-n or -9â-(h ydr oxym eth yl)h exah ydr ocan n ab-
in ol DMH, 12. To 28 mg of LiAlH4 (0.74 mmol) under argon
was added 10 mg of 9 (0.018 mmol) in 1 mL of THF, and the
reaction was allowed to stir at room temperature for 3 h. The
reaction was quenched by dropwise addition of saturated
aqueous NH4Cl and extracted with ether. The combined
ethereal extracts were dried (MgSO4), and solvent was evapo-
rated to give a colorless oil. Purification by HPLC (10-mm ×
250-mm Phenomenex silica column, 30% EtOAc in hexane, 3
mL/min, UV detection at 254 nm) gave 12 as a white foam (6
mg, 80% yield, 90.3% pure) with a retention time of 25 min:
Rf ) 0.25 (60% EtOAc in hexane); [R]20D -95.5° (c 1.0, CHCl3);
IR (neat) 3320 br, 2950, 2920, 2860, 1620, 1565, 1460, 1450,
3340 br, 2920, 2850, 1620, 1570, 1410, 1040 cm-1 1H NMR
;
(500 MHz, CDCl3) δ 6.33 (d, J ) 1.8 Hz, 1H, H-2), 6.20 (d, J )
1.8 Hz, 1H, H-4), 5.08 (br s, 1H, OH), 3.74-3.71 (m, 2H, H-14),
3.52 (m, 2H, H-11), 3.23 (br d, J ) 12.5 Hz, 1H, H-10), 2.52
(td, J ) 11.0, 2.6 Hz, 1H, H-10a), 1.88-1.86 (m, 1H, H-8),
1.82-1.73 (m, 8H, H-7, H-9, H-12â, H-13, 2xOH), 1.57 (td, J
) 11.1, 2.2 Hz, 1H, H-6a), 1.50-1.46 (m, 2H, H-2′), 1.25-1.13
(m, 8H, H-7, H-8, H-4′, H-5′, H-6′), 1.16 (s, 6H, H-8′, H-9′),
1.10-1.04 (m, 2H, H-3′), 1.01 (s, 3H, H-12R), 0.83 (t, J ) 6.8
Hz, 3H, H-7′), 0.77 (q, J ) 12.0 Hz, 1H, H-10); 13C NMR (125
MHz, CDCl3) δ 154.5 (C-5), 154.4 (C-1), 150.0 (C-3), 109.5 (C-
10b), 107.8 (C-2), 105.5 (C-4), 78.0 (C-6), 68.5 (C-11), 63.4 (C-
14), 46.3 (C-6a), 44.4 (C-2′), 40.5 (C-9), 37.3 (C-1′), 36.0 (C-
12â), 34.8 (C-10a), 33.2 (C-10), 31.8 (C-6′), 30.0 (C-4′), 29.6 (C-
8), 28.7 and 28.6 (C-8′, C-9′), 27.1 (C-7), 26.0 (C-13), 24.6 (C-
3′), 22.7 (C-5′), 18.4 (C-12R), 14.1 (C-7′); mass spectrum m/z
(relative intensity) 432 (M+, 34), 348 (100), 249 (65), 163 (49).
Exact mass calculated for C27H44O4, 432.3228; found, 432.3226.
1
1410, 1330, 1035, 960, 840 cm-1; H NMR (500 MHz, CDCl3)
δ 6.34 (d, J ) 2.0 Hz, 1H), 6.19 (d, J ) 2.0 Hz, 1H), 4.84 (br s,
1H), 3.52 (dd, J ) 6.5, 1.0 Hz, 2H), 3.23 (br d, J ) 12.8 Hz,
1H), 2.50 (td, J ) 11.0, 2.7 Hz, 1H), 1.95-1.91 (m, 1H), 1.86-
1.83 (m, 1H), 1.80-1.72 (br m, 1H), 1.68-1.64 (m, 1H), 1.64-
1.60 (m, 2H), 1.58-1.51 (m, 2H), 1.50-1.47 (m, 2H), 1.48-
1.43 (m, 1H), 1.25-1.17 (m, 7H), 1.19 (s, 6H), 1.12-1.04 (m,
3H), 1.03 (s, 3H), 0.96 (t, J ) 6.7 Hz, 3H), 0.88-0.78 (m, 1H),
0.84 (t, J ) 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 155.0,
154.5, 150.0, 109.5, 108.0, 105.3, 78.2, 68.6, 46.3, 44.5, 42.2,
40.6, 37.3, 34.8, 33.4, 31.8, 30.1, 29.7, 28.7, 28.6, 27.2, 24.6,
22.7, 18.5, 15.7, 14.6, 14.1; mass spectrum m/z (relative
intensity) 416 (M+, 31), 345 (17), 332 (100), 249 (57), 164 (21),
85 (38), 71 (66). Exact mass calculated for C27H44O3, 416.3279;
found, 416.3313.
P h a r m a cologica l Meth od s. Rat forebrain synaptosomal
membranes were prepared by the method of Dodd et al.27 and
were used to assess the affinity of 5-12 for the CB1 binding
sites. Mouse spleen membranes were used as the source
material for CB2 receptors. The displacement of specifically
bound tritiated CP-55,940 from these membranes using a
standard filtration assay was used to determine the IC50 for
the test compounds. Briefly, 40 µg of protein was incubated
for 1 h at 30 °C in the presence of 0.76 nM [3H]CP-55,940 and
various concentrations of test compound, final volume 200 µL.
Nonspecific binding was defined by 100 nM cold CP-55,940.
The incubation was terminated by rapid filtration and wash-
ing, and the amount of specifically bound [3H]CP-55,940 was
determined. Data normalized between 0 and 100% specific
binding were plotted against log concentration of test com-
pound, and IC50 values were determined from the average of
at least three experiments run in duplicate, by fitting to a four-
variable nonparametric equation, holding the maximum to 100
and the minimum to 0. IC50 values were converted to Ki values
according to the method of Cheng and Prusoff.28
12â-(2-Iod oet h yl)-9-n or -9â-(h yd r oxym et h yl)h exa h y-
d r oca n n a bin ol DMH, 9. Stock solutions of iodine (123 mg
in 500 µL of benzene) and triphenylphosphine (123 mg in 500
µL of benzene) were prepared. To a dry septum-capped vial
containing 7 mg of imidazole (0.093 mmol) was added 10 mg
of 7 (0.023 mmol) in 200 µL of benzene followed by 50 µL
(0.046 mmol) of the triphenylphosphine stock solution. The
iodine stock solution was added dropwise to the stirred
reaction mixture until a yellow coloration persisted. The
reaction was stirred at 50 °C for 25 min, at which time TLC
showed the absence of starting material. After cooling to room
temperature, the reaction was diluted with ether/EtOAc,
washed with water, saturated aqueous sodium thiosulfate, and
brine, dried (MgSO4), and evaporated to give a pale yellow oil.
Purification by flash chromatography (40% EtOAc in hexane)
gave 9 as a white foam (10 mg, 80% yield). Chiral HPLC (1-
cm × 25-cm Bakerbond OD column, 10% 2-propanol in hexane,
2.5 mL/min, UV detection at 254 nm) showed 9 (9.73-min
retention time, 93.27%) and the enantiomer of 9 (7.04-min
retention time, 2.14%), 96% ee: Rf ) 0.56 (80% EtOAc in
hexane); [R]20 -35.2° (c 1.0, CHCl3); IR (neat) 3320 br, 2920,
D
2850, 1620, 1570, 1410, 1040 cm-1; 1H NMR (500 MHz, CDCl3)
δ 6.32 (d, J ) 1.75 Hz, 1H), 6.20 (d, J ) 1.75 Hz, 1H), 4.74 (br
s, 1H), 3.52 (d, J ) 6.5 Hz, 2H), 3.31-3.20 (m, 3H), 2.51 (td,
J ) 11.0, 2.6 Hz, 1H), 2.13-2.05 (m, 1H), 2.03-1.98 (m, 1H),
1.97-1.93 (m, 1H), 1.89-1.83 (m, 1H), 1.79-1.69 (m, 3H),
1.70-1.58 (br m, 2H), 1.51-1.46 (m, 2H), 1.25-1.05 (m, 10H),
1.19 (s, 6H), 1.06 (s, 3H), 0.89-0.78 (m, 1H), 0.84 (t, J ) 7.0
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 154.6, 154.4, 150.1,
109.3, 107.9, 105.4, 77.7, 68.5, 46.4, 44.4, 40.7, 40.5, 37.3, 34.8,
33.2, 31.8, 30.0, 29.6, 28.7, 28.6, 27.1, 27.0, 24.6, 22.7, 18.4,
14.1, 7.7; mass spectrum m/z (relative intensity) 542 (M+, 61),
458 (100), 414 (6), 330 (25), 249 (55), 164 (54), 128 (65). Exact
mass calculated for C27H43IO3, 542.2245; found, 542.2266.
Ack n ow led gm en t. NIDA (Grants DA 09158 and
DA 07215) is thanked for generous support of this work.
We also thank Dr. Liu Dai for experimental assistance.
In addition to 9, 12â-(2-iodoethyl)-9-nor-9â-(iodomethyl)-
hexahydrocannabinol DMH (3 mg, 20%) was isolated: Rf )
0.84 (80% EtOAc in hexane); IR (neat) 3400 br, 2920, 2850,
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1H), 3.32-3.27 (m, 2H), 3.25-3.20 (m, 2H), 3.14 (dd, J ) 9.8,
6.7 Hz, 1H), 2.53 (td, J ) 11.0, 2.6 Hz, 1H), 2.14-2.04 (m,
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