Heteroadamantyl cannabinoids

Article abstract of DOI:10.1021/jm100390h

The aliphatic side chain plays a pivotal role in determining the cannabinergic potency of tricyclic classical cannabinoids. We have synthesized a series of analogues in which the C3 position is substituted either directly or through a one-carbon atom link

Full text of DOI:10.1021/jm100390h

5656 J. Med. Chem. 2010, 53, 5656–5666
DOI: 10.1021/jm100390h
Heteroadamantyl Cannabinoids
Darryl D. Dixon,† Divakaramenon Sethumadhavan,† Tore Benneche,† April R. Banaag,† Marcus A. Tius,*,†
Ganesh A. Thakur,‡ Anna Bowman,‡ JodiAnne T. Wood,‡ and Alexandros Makriyannis*,‡
†Department of Chemistry, University of Hawaii at Manoa, 2545 The Mall, Honolulu, Hawaii 96822, and ‡Center for Drug Discovery,
Northeastern University, 360 Huntington Avenue, 116 Mugar Life Sciences Building, Boston, Massachusetts 02115
Received March 30, 2010
The aliphatic side chain plays a pivotal role in determining the cannabinergic potency of tricyclic
classical cannabinoids. We have synthesized a series of analogues in which the C3 position is substituted
either directly or through a one-carbon atom linker with an adamantylamine or with an oxa- or an
oxazaadamantane. The oxaadamantane pharmacophore in analogue 16 showed the best binding profile
for both receptors.
Introduction
to accommodate the steric bulk of the 1-adamantyl group
revealed an unanticipated flexibility and furthermore sug-
gested that introducing heteroatomic functionality on the
adamantane structure could be used to interrogate the recep-
tor. Changes in binding affinities of cannabinoids bearing
heteroatom-substituted adamantyl residues might indicate
the close proximity of polar amino acid residues within the
binding pocket. We have reported the synthesis of cannabi-
noids 2 and 310 from known oxazaadamantane I.11-13 Oxaza-
adamantyl cannabinoids 4, 5, 6, and 7, azaadamantyl canna-
binoids 8-15, and oxacannabinoids 16 and 17 were designed
and prepared as ligands with which tointerrogatethe CB1 and
CB2 receptors (Figure 1). The northern aliphatic hydroxyl
group is known to be an important cannabimimetic pharma-
cophore and was introduced at C9 as an R or β hydroxyl group.
Chemistry. To prepare a diverse set of cannabinoid ligands
without preparing each individual alkyl resorcinol, we de-
signed an advanced common intermediate from which all
analogues could be derived. Following an approach that had
been developed in our group,10,13 we prepared bicyclic
intermediate 18a via acid catalyzed condensation between
phloroglucinol 19a and a mixture of diacetates 20 and 21
(Scheme 1). This key step had been developed by a team at
the Eli Lilly company for the synthesis of nabilone.14
Although the condensation works beautifully in chloroform,
the solvent that had been used in the nabilone synthesis,
phloroglucinol is very sparingly soluble in chloroform. To
overcome this problem, we had used dichloromethane/ace-
tone for our earlier synthesis of 18a but were able to isolate
only moderate (40%) yields of the product.10 Part of the
difficulty is associated with the high reactivity of 19a that
leads to condensation with a second molecule of 20 or 21. It
also became apparent that the choice of solvent had a large
effect on the yield. We had explored a variety of solvents,
acids, and conditions in order to overcome this difficulty to
no avail. It is a testament to the skilled efforts of the Lilly
team who carefully optimized this process that chloroform
appears to be uniquely suited for the reaction. Fortunately,
we were able to devise a simple modification of the procedure
to overcome the problems associated with the low solubility
of phloroglucinol in chloroform. Exposure of phloroglucinol
The discovery of the two cannabinoid receptors, CB11,2 and
CB2,3 ushered in a new era in research into the chemistry and
pharmacology of this class of compounds. Both receptors are
membrane-bound and belong to the family of G-protein-
coupled receptors (GPCRs). The structural analysis of CB1a
and CB2 as well as the study of their interactions with their
ligands are hampered by the lack of a crystal structure.
Consequently, there is little direct evidence for the mode(s)
of interaction between ligand and receptor.4 The recognition
of CB1 as an important therapeutic target for, inter alia,
glaucoma,5 pain,6 and appetite modulation,7 indicates a need
for a better understanding of the specific interactions between
the cannabinoid pharmacophore and the key amino acids
associated with the CB1 binding site.
It has long been known that the aliphatic side chain is
important for determining the cannabinergic potency of
classical cannabinoids and also that the presence of a tert-
alkyl appendage at C10 potentiates receptor binding affinity.8
Nevertheless, it was surprising that cannabinoids bearing a
pendant adamantyl group at C3 in place of the n-pentyl group
that is found in naturally occurring materials, such as (-)-
3-(1-adamantyl)-Δ8-tetrahydrocannabinol (1, AM411), were
tolerated in both CB1 and CB2 binding sites.9 Furthermore,
considerable receptor subtype selectivity was observed de-
pending on the relative orientation of the adamantyl group
with respect to the tricyclic nucleus. The ability of the receptor
*To whom correspondence should be addressed. (M.T.) Phone: 808-
956-2779. Fax: 808-956-5908. E-mail: tius@hawaii.edu. (A.M.) Phone:
617-373-4200. Fax: 617-373-7493. E-mail: a.makriyannis@neu.edu.
aAbbreviations: CB1, cannabinoid 1 receptor; CB2, cannabinoid 2
receptor; DCM, dichloromethane; DIBAL, diisobutylaluminum hy-
dride; DIPEA, N,N-diisopropylethylamine; HEK, human embryonic
kidney; L-Selectride, lithium tri-sec-butylborohydride; MOMCl, methyl
chloromethyl ether; OPLS, optimized potentials for liquid simulations;
PdCl2(dppf), 1,10-bis(diphenylphosphino)ferrocene palladium(II) dichlo-
ride; Pd2(dba)3, tris(dibenzylideneacetone)dipalladium(0); PinB-BPin,
bis-pinacolato diborane; rmsd, root-mean-square deviation; SAR, struc-
ture-activity relationship; TBAF, tetrabutylammonium fluoride; TEA,
triethylamine; TESCl, triethylsilyl chloride; TMSBr, trimethylsilyl bro-
mide; TMSCl, trimethylsilyl chloride; TMSOTf, trimethylsilyl trifluoro-
methanesulfonate.
r
pubs.acs.org/jmc
Published on Web 07/01/2010
2010 American Chemical Society

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 15 5657
Figure 1. Adamantyl and heteroadamantyl cannabinoids.
to trimethylsilyl chloride (TMSCl) and triethylamine (TEA)
in dichloromethane (DCM) led to the persilylated derivative
22 (Scheme 1). This hydrolytically sensitive material was not
purified but was used in the condensation with 20 and 21 in
place of phloroglucinol. Masking the phenolic hydroxyl
groups as trimethylsilyl ethers led to a large increase in
solubility in chloroform. This allowed us to perform the
reaction in a mixture of chloroform and acetone (4/1) with
p-toluenesulfonic acid in slight excess. This led to a much
cleaner reaction and more than doubling of the yield of 18a
to approximately 70%. The phenolic trimethylsilyl groups
were hydrolyzed during workup. The separation of 18a from
unreacted phloroglucinol was difficult. Although the separa-
tion can be accomplished by means of careful flash column
chromatography on silica gel, we found that it was more
practical to peracetylate the mixture of 18a and 19a following
workup. The chromatographic separation of acetates 18b
and 19b was straightforward and pure 18a was recovered in
68% overall yield following hydrolytic cleavage of the
acetoxy groups by KOH in methanol. The large improve-
ment in the yield in the first step of the synthesis greatly
increased the pace of progress.
An improvement was made in the yield for the cyclocon-
densation step that converts 18a to tricyclic intermediate 23
as well. In our earlier synthesis of 23, we had used SnCl4 as
the Lewis acid. While on a small scale this procedure was
practical, upon scale-up, the formation of emulsions during
workup led to irreproducible yields of product. Trimethyl-
silyl triflate (TMSOTf ) proved to be a much better choice of
Lewis acid both in terms of the ease of workup as well as the yield
(>95% vs 84%). Treatment of 23 with N-phenyltriflimide15
in dichloromethane led to 24 regioselectively and in 68%
yield (57% overall from 18a). Intermediate 23 was also con-
verted to nonaflate 25 in 57% yield through treatment with
reagent 26 in the presence of CsF in N,N-dimethylformamide
(DMF).
Because it was our goal to produce both diastereomers of
the C9 alcohol, ketone 24 was reduced with NaBH4 in 97%
yield to give a ca. 95/5 mixture of C9-β (equatorial) alcohol
27 and C9-R (axial) diastereomer 28. Alcohol 28 was the
exclusive product of the reduction of ketone 24 with L-Selec-
tride at -78 °C.
The phenolic and aliphatic hydroxyl groups in 27 and 28
were simultaneously protected as the methoxymethyl ether,
leading to 29 and 30 in 93% and 94% yield, respectively,
setting the stage for palladium catalyzed cyanation. Expo-
sure of the aryl triflates to catalytic Pd(PPh3)4 and Zn(CN)2
in DMF led to nitriles 31 and 32, however, the reaction was
not always reproducible. Addition of 10 wt % polymethyl-
hydrosiloxane (PMHS)16 to the reaction mixture as an
oxygen scavenger resulted in a consistent and reproducible
yield of greater than 95% for each of the diastereomers 31
and 32. Nitriles 31 and 32 were hydrolyzed in the next step
with LiOH in aqueous methanol, yielding carboxylic acids 33
(91% yield) and 34 (91% yield), respectively. Condensation
of 33 with I, 1-adamantylamine, or 2-adamantylamine using
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and
4-dimethylaminopyridine (DMAP) led to amides 35 (91%
yield), 37 (90% yield), and 39 (90% yield), respectively.
Condensation of 34 with I, 1-adamantylamine, or 2-ada-
mantylamine under the same conditions led to amides 36
(88% yield), 38 (91% yield), and 40 (91% yield), respectively.
Cleavage of the methoxymethyl ether protecting groups with
17
n-BuSH/ZnBr2 led to amides 4, 5, and 8-11 in yields
ranging from 77% to 92%.
The next task was to prepare compounds 6 and 7 that
incorporate a methylene spacer group between amine I and
the tricyclic cannabinoid nucleus. The synthesis from car-
boxylates 33 and 34 is summarized in Scheme 2. Reduction of
acids 33 and 34 with borane-tetrahydrofuran (THF) com-
plex led to benzylic alcohols 41 and 42, each in 88% yield.
Mesylation followed by immediate displacement of the

5658 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 15
Scheme 1. Synthesis of Amides 4,5 and 8-11a
Dixon et al.
a Reagents and conditions: (a) p-TsOH, CHCl3/acetone (4/1), 0 °C, 1 h; rt, 1 h; ca. 70%; (b) Me3SiCl, Et3N, CH2Cl2, 0 °C to rt; (c) CH2Cl2, DMAP
(cat.), pyr, Ac2O, 0 °C to rt, 12 h; (d) KOH, MeOH, 0 °C, 2 h; 68% overall from 20 and 21; (e) Me3SiOTf, MeNO2, 0 °C, 2.5 h, >95%; (f ) PhNTf2, Et3N,
CH2Cl2, 0 °C to rt; 57% from 18a; (g) CsF, 26, DMF, rt, 12 h; 57%; (h) NaBH4, MeOH, 0 °C, 1 h; 97% 27 þ 28, ca. 95/5; (i) L-Selectride, THF, -78 °C,
2 h; rt, 1 h; 90%; ( j) MeOCH2Cl, (i-Pr)2NEt, CH2Cl2, 0 °C to rt, 2.5 h; 29, 93%; 30, 94%; (k) Zn(CN)2, Pd(PPh3)4 (cat.), 10 wt % PMHS, DMF, 60 °C, 8
h; 31, 96%; 32, 97%; (l) LiOH, MeOH/H2O (4/1), 70 °C, 3 d; 33, 91%; 34, 91%; (m) I, 1-adamantylamine or 2-adamantylamine, EDCI, DMAP, CH2Cl2,
rt, 2 h; from 33: 35, 91%; 37, 90%; 39, 90%; from 34: 36, 88%; 38, 91%; 40, 91%; (k) n-BuSH, ZnBr2, CH2Cl2, 45 °C; 4, 77%; 5, 89%; 8, 89%; 9, 92%; 10,
91%; 11, 90%.
mesylate by bromide gave the diastereomeric benzylic bro-
mides. These were allowed to react in DMF with a slight
excess of amine I at ambient temperature to give oxaza-
adamantylamines 43 and 44 in 75% and 72% yield, respec-
tively. Protecting group removal was carried out as in
(TES) ethers was followed by reduction of the nitrile to the
aldehyde and fluorodesilylation to produce 47 and 48, both
in 61% overall yield for the three steps. Removal of the
methoxymethyl groups in the presence of the aldehyde took
place in poor yield, making the protecting group exchange
necessary. Imine formation with 1- or 2-adamantylamine
was followed by catalytic hydrogenation with 10% Pd/C in
methanol under an atmosphere of hydrogen, resulting in the
clean formation of compounds 12-15.
The synthesis of oxaadamantyl cannabinoids 16 and 17
proved to be a difficult challenge. Our first approach was an
attempt to trap a cannabinoid-derived benzyne with an
appropriate carbon nucleophile, a strategy that had served
us well in the past.10 Ultimately we were unable to define
effective reaction conditions and were forced to abandon this
approach in favor of a cross coupling process. The synthesis
of the required vinyl boronate is summarized in Scheme 4.
Treatment of commercially available 1,3-adamantanediol
with benzenesulfonyl chloride18 in a mixture of pyridine
and benzene at 70 °C led to the Grob fragmentation product
49. Ozonolysis in the next step gave diketone 50 in 66% yield
over the two steps. Selective protection of one of the two
ketone carbonyl groups as the ethylene ketal formed 51 in
17
Scheme 1 by exposure to n-BuSH/ZnBr2 in dichloro-
methane at 45 °C, leading to oxaza adamantylcannabinoids
6 and 7 in 81% and 73% yield, respectively. It should be
noted that all attempts to remove the ether protecting groups
from 43 and 44 by means of trimethylsilyl bromide (TMSBr)
conditions that we found to be satisfactory in molecules
bearing an aromatic nitrogen atom10 led to inferior yields of
6 and 7. This is quite likely due of the buffering effect of the
more basic benzylic nitrogen atom in 6 and 7. In contrast, the
conditions for methoxymethyl ether group cleavage deve-
loped by Rawal and co-workers were optimal in our system
and should be given consideration for similar applications in
synthesis.
We followed a slightly different strategy for the synthesis
of compounds 12-15, all of which were prepared by means
of reductive amination reactions (Scheme 3). Nitriles 31 and
32 were deprotected by treatment with ZnBr2 and n-BuSH.
Temporary masking of the hydroxyl groups as triethylsilyl

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 15 5659
Scheme 2. Synthesis of Benzylamines 6 and 7a
a Reagents and conditions: (a) BH3 THF, THF, 0 °C; 0 °C to rt; 41, 88%; 42, 88%; (b) MsCl, Et3N, THF, 0 °C to rt; LiBr, THF, rt; (c) I, DMF,
3
K2CO3, rt; 43, 75%; 44, 72%; (d) n-BuSH, ZnBr2, CH2Cl2, 45 °C; 6, 81%; 7, 73%.
Scheme 3. Synthesis of Benzylamines 12-15a
moderate to high affinities for the CB1 and CB2 receptors
where the 1-adamantyl analogue 1 exhibited preferential
affinity for CB1 while its 2-adamantyl regioisomer (-)-
3-(2-adamantyl)-Δ8-tetrahydrocannabinol (AM744) had
higher affinity for CB2. Our effort to introduce heteroatoms
within the novel adamantyl cannabinoid structures involved
the use of 9β- and 9R-hydroxy hexahydrocannabinols as
prototypes for the novel ligands. This was motivated by
earlier work in which we have demonstrated that the tricyclic
component in this series of analogues is a very successful
pharmacophore for the two known cannabinoid receptors.21
To probe the stereoelectronic requirements of the ada-
mantyl group and also explore potential opportunities for
improving the polar properties of the adamantyl cannabi-
nergic ligands, we synthesized three groups of heteroada-
mantyl cannabinoids. The first includes analogues in which
heteroatoms are incorporated into the adamantyl group
a Reagents and conditions: (a) n-BuSH, ZnBr2, CH2Cl2, rt; 45, 90%,
either as a 2,6-oxazaadamantyl ring in which the ring nitro-
46, 76%; (b) Et3SiCl, (i-Pr)2NEt, CH2Cl2, 0 °C to rt; (c) DIBAL,
gen is directly attached to the 3-position of the tricyclic ring
CH2Cl2, PhMe, -78 °C; (d) TBAF, THF, rt; 47, 61% from 45; 48,
(2, 3) or alternatively as a 2-oxaadamantyl substituent (16,
17) (see 1 in Figure 1). In the second group, the heteroatom(s)
are incorporated into the carbocyclic 1- or 2-adamantyl
residue appended at C3 through carboxamido (8-11) or
methylamino (12-15) groups. In the third group, the 2,
6-oxazaadamantyl ring is attached to the 3-position either
through carbonyl (4, 5) or methylene groups (6, 7).
˚
61% from 46; (e) PhH, 1- or 2-adamantylamine, 4 A MS, reflux,
Dean-Stark; (f) Pd/C, H2, MeOH, rt; 12, 81% from 47; 13, 78% from
48; 14, 60% from 47; 15, 84% from 48.
94% yield. Sequential treatment of 51 with lithium diisopro-
pylamide (LDA) and N-phenyltriflimide followed by acid
catalyzed exchange of the ketal led to vinyl triflate 52 in 82%
yield over the two steps from 51. Suzuki coupling of 52 with
bis-pinacolato diborane (PinB-BPin) led to keto boronate 53
in good yield.19,20
The SAR of all novel adamantyl analogues was examined
by measuring their respective affinities for the CB1 and CB2
receptors (Table 1). All novel oxazacannabinoids exhibited
reduced affinities for both receptors when compared with the
earlier reported carbocyclic cannabinoids.9 The 9β-OH ana-
logues exhibited more favorable affinities for both receptors
when compared to their 9R-OH isomers. Compounds be-
longing to the second group (8-15) generally had low
affinities for both receptors, although all analogues had
significant CB2 selectivities over CB1. This is congruent with
the earlier data suggesting that the CB2 receptors, either
human or mouse, are capable of accommodating larger side
chain substituents when compared to CB1. The data also
suggest that mCB2 is capable of accommodating larger
groups compared to hCB2.
Analogues from the third group (4-7) carrying an ap-
pended oxazaadamantyl ring exhibited a similar affinity
trend as group I. Again, all analogues showed substantial
CB2 vs CB1 selectivities where the mCB2 had somewhat
more favorable affinities than hCB2. Also, at the CB2
receptors, 9β-OH analogues (12, 14) had slightly more
favorable affinities compared to their 9R-OH analogues.
The first group of heterocannabinoids carries the struc-
turally most compact 3-substituents. Their synthesis was
Vinyl boronate 53 was coupled with aryl triflates 29 and 30
(Scheme 5). Treatment of 29 or 30 with 1,10-bis(diphenylphos-
phino)ferrocene palladium(II) dichloride (PdCl2(dppf)), K2CO3,
and a slight excess of 53 in a mixture of DMF/EtOH (4:1) at
70 °C led to products 54 and 55 in 87% and 67% yield,
respectively. Because 53 is racemic whereas 29 and 30 are
homochiral, products 54 and 55 are formed as diastereomeric
mixtures. For the sake of simplicity, only one diastereomeric
structure is shown in Scheme 5. Exposure of 54 and 55 to
sodium borohydride unsurprisingly led exclusively to the endo
alcohols 56 and 57 in 90% and 82% yield, respectively.
Removal of the methoxymethyl protecting groups from 56
and 57 with ZnBr2 and n-BuSH induced cyclization of the
seco-oxaadamantanes forming 16 and 17 in 95% and 79%
yield, respectively.
Results and Discussion
Structure-Activity Relationships. Earlier work from our
laboratory9 has shown that tetrahydrocannabinol analogues
substituted at the 3-position of the phenolic ring exhibit

5660 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 15
Scheme 4. Synthesis of Ketone 53a
Dixon et al.
a Reagents and conditions: (a) PhSO2Cl, PhH, pyr, 70 °C; (b) O3, CH2Cl2, -78 °C; Me2S; 66% for two steps; (c) HO(CH2)2OH, PhH, TsOH (cat.),
reflux, Dean-Stark; 94%; (d) LDA, THF, -78 °C; PhNTf2, THF, warm to 0 °C; (e) acetone, TsOH (cat.), rt; 82% from 51; (f ) PdCl2(PPh3)2, PPh3,
K2CO3, 1,4-dioxane, PinB-BPin, 70 °C; 73%.
Scheme 5. Synthesis of Oxaadamantane Cannabinoids 16 and 17a
a Reagents and conditions: (a) 53, PdCl2(dppf ), K2CO3, DMF/EtOH (4/1), 70 °C; 54, 87%; 55, 67%; (b) NaBH4, MeOH, 0 °C; 56, 90%; 57, 82%;
(c) n-BuSH, ZnBr2, CH2Cl2, rt; 16, 95%; 17, 79%.
Table 1. Affinities (Ki) for CB1 and CB2 Cannabinoid Receptorsa
compound had a somewhat different pharmacological pro-
file than its reported carbocyclic isomer 1. Unlike 1, which
exhibited selectivity for CB1, 16 had only modest selectivity
Ki ( μM)a
compd
rCB1
0.0068
1.8
mCB2
hCB2
NA
(2-fold) for CB2. The new oxaadamantyl analogues have
more polar properties (clogP) than 1 and may serve as the
basis for the design of novel heteroadamantyl analogues with
improved physicochemical and pharmacological properties.
We have used molecular modeling to explain the observed
high differences in affinities among the heteroadamantyl
cannabinoids described here. Since among the series of
analogues reported the only pharmacophoric variable is
the 3-substituent, we focused our attention on the conforma-
tional and stereoelectronic properties of this moiety and
examined the conformational space available for the C3
substituents in each of the analogues. To explore the ener-
getically favorable conformations in each analogue, we used
force field methods and retained all conformers within
6 kcal/mol from the global minimum. Representative exam-
ples for each of the three groups of analogues are shown in
Figure 2. It is clear that the conformational space for the
3-substituents in the second and third groups covers a
significantly larger volume than that of the first group. It
can thus be argued that the low affinity of these hexahydro-
cannabinol analogues is attributable to steric factors as well
as large desolvation penalties due to their polar linkers.
Accordingly, these bulky substituents are unable to engage
in an optimal interaction at the adamantyl side chain with its
respective pharmacophoric site within the cannabinoid re-
ceptors. This is more accentuated in their interaction with
CB1 compared to CB2. It should be pointed out that three of
the ligands from the second family (8, 10, 12) exhibited the
most favorable Ki values for mCB2 with 8 and 12 having the
highest affinity (Ki = 0.5 μM). Conversely, all three analo-
gues had 10-50-fold lower affinities for CB1. This observed
preference of ligands carrying 3-substituents capable of
assuming larger conformational space for the CB2 vs CB1
receptor is congruent with our earlier work with carbocyclic
adamantyl analogues. In this work, we have argued that the
CB2 selectivity of 2-adamantyl analogues exhibited a larger
19a
2
0.052
1.2
17
1.8
14.9
20
3
22.4
4
no binding
no binding
10
2.5
8.6
8.7
7.5
0.5
7.5
1.2
3.7
0.5
5
5
25
15
6
7
125
80
5
8
8.7
35
9
375
15
10
11
12
13
14
15
16
17
2.7
15
100
150
10
25
100
150
6.2
7.5
0.018
0.54
20
25
no binding
0.023
0.55
0.019
1.3
aAffinities for CB1 and CB2 were determined using rat brain (CB1) or
membranes from HEK293 cells expressing mouse or human CB2 and
[3H]CP-55,940 as the radioligand following previously described proce-
dures. 26 Ki values for compounds 2, 3, 16, and 17 were obtained from
one experiment (8 point) run in triplicate. Ki values for compounds
4-15, which were all in the micromolar range, were derived from a single
experiment (2 points) run in triplicate.
motivated by work with analogues carrying a carbocyclic
adamantyl group which exhibited interesting pharmacologi-
cal profiles.
In earlier work, we synthesized a pair of 2,5-oxazacanna-
binoids (2, 3) in which the ring nitrogen is directly attached to
the 3-phenolic position. Both of these analogues had low
affinities for both CB1 and CB2.10 To further explore the
basis for this somewhat surprising finding, we have now
synthesized the respective 2-oxaadamantyl analogues in
which the 1-adamantyl carbon is directly attached to the
tricyclic cannabinoid 3-position. We were pleased to observe
that both 9β-OH (16) and 9R-OH (17) isomers exhibited
favorable affinities for both receptors. Expectedly the
9β-isomer had the higher affinity. This interesting new

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 15 5661
conformational space for this pharmacophore with the
mCB2 being more accommodating than hCB2.
further explore potential differences in the manner in which the
low affinity oxaza analogue (2) and the high-affinity oxa
analogues (16, 17) interact with the two cannabinoid receptors,
we calculated the energy barriers for rotation of these com-
pounds around the Ph-N (2) or Ph-C (16, 17) respectively
(Figure 3). Our calculations show that while the oxa analogues
have a rotational barrier of ∼6.3 kcal/mol, the oxaza analogue
has a significantly higher barrier of ∼12.3 kcal/mol. We would
thus argue that while both analogues in question occupy
similar conformational spaces, entropic advantages associated
with a more facile rotation for the oxaadamantyl analogues
may improve ligand binding affinity. Alternatively, it can be
argued that in the 3-oxaza compounds (2 and 3) both N and
O heteroatoms undergo unfavorable interactions within its
allowable pharmacophoric space.
Our arguments for the low affinities of analogues for groups
2 and 3 cannot be easily applied tothe compounds belonging to
the first group. A comparison of the pharmacophoric space for
compounds 2 and 16 does not reveal striking differences in the
accessible conformational volumes of the two analogues. To
Methods. Along with entropic factors, the conformational
space available to the analogues may offer insight into the
steric factors required for CB1 and CB2 selectivity. To
explore the permissible rotations of the bulky substituent, a
conformational search was performed using optimized po-
tentials for liquid simulations (OPLS) force field.23,24 The
cannabinoid tricyclic moiety was held fixed and minimi-
zation on the remaining geometric parameters was per-
formed.23 Conformers with greater than 0.5 A root-mean-
˚
square deviation (rmsd) with 6 kcal mol-1 of the global
minimum were retained. All calculations were performed in
Macromodel.25 The entropic factors involved for a ligand
are also important, and compounds 2 and 16 were of
particular interest and higher level calculations were per-
formed at the B3LYP/6-31G** level. In these computation-
ally more demanding calculations, a conformational scan
was performed using dihedral drive around the C3-C10
bond. The dihedral angle was restrained at a value between
0 and 360° in 10° steps, and minimization on the remaining
geometric parameters was performed.
Summary
The 3-phenyl substituents of cannabinoid ligands are an
essential pharmacophore capable of significantly modulating
their affinities for the CB1 and CB2 cannabinoid receptors. In
earlier work, we have shown that the 3-alkyl groups of
Figure 2. Accessible conformers with 6 kcal/mol of the global energy
minimum for 16 (green), 2 (cyan), 7 (orange), and 14 (magenta).
Analogues are shown superimposed at their aromatic rings.
Figure 3. Plot of the QM energy relative to the lowest energy structure calculated at the B3LYP/6-31G** level for 16 (dashed) and 2 (solid)
during a coordinate scan around the C3-C10 bond.

5662 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 15
Dixon et al.
classical cannabinoids can be successfully substituted with an
adamantyl ring. The present work is aimed at further explor-
ing this interesting pharmacophore. In addition to exploring
the steric requirements of the adamantyl ring, we have sought
to introduce heteroatoms within the ring or within the pen-
dant fragment connecting the ring to the tricyclic component
in order to modulate the hydrophobic physical properties of
the ligands.
quenched with saturated NaHCO3 and stirred for 45 min. The
organic layer was separated and dried over MgSO4 while the
aqueous layer was back-extracted with EtOAc (6ꢀ) and dried
over MgSO4. To the crude condensation product 18a and DMAP
(100 mg, 0.82 mmol) in 200 mL of DCM at 0 °C was added
pyridine (13.0 mL, 160.0 mmol) followed by Ac2O (15.1 mL,
160.0 mmol) and stirred for 12 h. The mixture was quenched with
ice cold water, washed with 1 M HCl and brine, and dried over
MgSO4. The crude product was then purified via flash column
chromatography on silica gel eluting with 30% EtOAc/hexanes
affording 18b (4.90 g, 68% yield over 2 steps) as a white solid.
1H NMR (CDCl3, 300 MHz): δ 6.83 (s, 2H), 3.63 (t, J =
8.4 Hz, 1H), 2.84-2.75 (m, 1H), 2.66-2.57 (m, 3H), 2.29-2.25
(m, 10H), 2.15-2.11 (m, 1H), 1.37 (s, 3H), 0.95 (s, 3H). 13C
NMR (CDCl3, 75 MHz): δ 212.4, 168.5, 168.4, 149.5, 148.5,
125.0, 114.6, 57.1, 45.3, 42.0, 38.7, 30.6, 26.0, 24.5, 21.8, 20.9;
mp: 138-140 °C. IR (neat, cm-1): 2947, 1769, 1709, 1608, 1427,
1371, 1185, 1122, 1031, 903. Mass spec calcd for C21H24O7,
388.1522; found, 388.1532. EIþ(amu): 388 (Mþ, 10), 346 (62),
304 (33), 303 (25), 262 (30), 262 (51), 244 (27), 219 (53), 207 (20),
Our results indicate thatoptimal affinitiesare obtainedwith
compounds in which the adamantyl pharmacophore is di-
rectly attached to the 3-position of the phenolic ring. The
ligands’ affinities for both receptors are severely diminished if
the adamantyl unit is attached through a linker, an observa-
tion attributable to the larger pharmacophoric space required
by these compounds. The most successful ligands were the
2-oxaadamantyl analogues, suggesting that the oxygen atom
in the adamantyl ring could be accommodated within the
binding domain of the CB1 and CB2 receptors. However, the
oxaza analogues in which the nitrogen atom is directly
attached to the ring exhibited reduced affinities for both
receptors. This is attributed to entropic factors because of
restricted rotation around the N-Ph bond. The overall SAR
of the new compounds follows trends congruent with earlier
work in the classical cannabinoid field. This includes the
observation that 9β-OH analogues have higher affinities
compared to their 9R-stereoisomers. The work also confirmed
earlier observations suggesting that the space for the adaman-
tyl pharmacophore is most restricted at the CB1 receptor.
Additionally, there appears to be a species difference with the
mCB2 receptor being more accommodating than hCB2.
194 (32), 177 (34), 152 (50), 83 (100); [R]23 -8.0° (c 0.010,
D
EtOAc).
Synthesis of 18a. To a solution of the triacetate 18b (4.90 g,
12.6 mmol) in 50 mL of MeOH at 0 °C was added KOH (2.48 g,
44.2 mmol) under N2. The reaction mixture was stirred at this
temperature for an additional 2 h and then quenched with 1 N
HCl. MeOH was removed under reduced pressure, and the
residue was diluted with EtOAc, washed with brine, and dried
over MgSO4. The crude product was carried on without further
purification. An analytical sample could be purified via flash
column chromatography on silica gel eluting with 50% EtOAc/
hexanes, affording 18a (3.30 g, 100% yield) as an off-white foam
that typically entrains 10-15% ethyl acetate.
1H NMR (MeOH-d4, 300 MHz) δ 5.85 (s, 2H), 3.95 (t, J =
8.1 Hz, 1H), 3.67 (dd, J = 18.6 Hz, 7.5 Hz, 1H), 2.62-2.57 (m,
1H), 2.48-2.35 (m, 3H), 2.14 (t, J = 6.0 Hz, 1H), 1.35 (s, 3H),
0.94 (s, 3H). 13C NMR (MeOH-d4, 75 MHz) δ 220.2, 158.5,
157.3, 108.9, 95.9, 59.3, 48.8, 43.2, 38.8, 30.0, 26.6, 24.9, 22.4.
Synthesis of 23. To a solution of 18a (1.02 g, 3.89 mmol; the
mass of pure ketone 18a was 1.20 g; ethyl acetate was present as
an impurity) in 300 mL of MeNO2 at 0 °C was added TMSOTf
(1.76 mL, 9.73 mmol) dropwise. The resulting mixture was
stirred for 2.5 h at 0 °C and then quenched with solid K2CO3
and stirred for 45 min at rt. The solids were filtered off and the
solvent removed under reduced pressure. Crude 23 was used
without further purification in the next step.
Experimental Section
1
Chemistry. H NMR and 13C NMR spectra were recorded
either at 300 MHz (1H) and 75 MHz (13C) or at 500 MHz (1H)
and 126 MHz (13C). Chemical shifts are reported in parts per
million (δ) and are referenced to the solvent, i.e. 7.26/77.0 for
CDCl3. Multiplicities are indicated as br (broadened), s
(singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sept
(septet), or m (multiplet). Coupling constants (J) are reported in
Hertz (Hz). Thin layer chromatography (TLC) was performed
on glass plates 250 μm, particle size 5-17 μm, pore size 60 A.
Flash column chromatography was performed on silica gel,
200-400 mesh, or premium silica gel, 60 A, 40-75 μm. All
moisture sensitive reactions were performed under a static
atmosphere of nitrogen or argon in oven-dried or flame-dried
glassware. Purity and homogeneity of all materials was deter-
mined to be at least 95% from TLC, 1H NMR, 13C NMR, and
HPLC. All optical rotations were measured on a JASCO digital
polarimeter in a 0.1 dL cell.
˚
˚
1H NMR (MeOH-d4, 300 MHz) δ 5.85 (d, J = 2.4 Hz, 1H),
5.76 (d, J = 2.4 Hz, 1H), 3.81 (dd, J = 15.0 Hz, 3.0 Hz, 1H),
2.79-2.70 (m, 1H), 2.47-2.25 (m, 2H), 2.18-2.02 (m, 2H), 1.92
(td, J = 12.3 Hz, 2.4 Hz, 1H), 1.57-1.45 (m, 1H), 1.42 (s, 3H),
1.08 (s, 3H). 13C NMR (MeOH-d4, 75 MHz) δ 214.6, 158.3,
156.6, 111.2, 104.3, 96.7, 96.6, 77.8, 46.8, 41.5, 36.0, 28.1, 27.9,
19.0.
Synthesis of 18b. To a suspension of phloroglucinol 19a (5.50 g,
43.7 mmol) in 300 mL of DCM at 0 °C was added TEA (24.3 mL,
174.6 mmol) followed by TMSCl (22.3 mL, 174.6 mmol). After
20 min, the cooling bath was removed and the mixture was
allowed to stir at room temperature for an additional 2 h. The
salts were removed via filtration and the filtrate was washed with
ice cold water (3ꢀ), dried over Na2SO4, and concentrated afford-
ing persilylated phloroglucinol 22. Crude 22 was then dissolved in
440 mL of a 4:1 mixture of CHCl3:acetone and cooled to 0 °C. In a
separate flask, diacetates 20 and 21 (4.42 g, 18.6 mmol; 5.2 g of
85% pure diacetates 20 and 21 were used) were dissolved in
Synthesis of 24. To crude ketone 23 (1.02 g, 3.89 mmol) in 40 mL
of DCM at 0 °C was added TEA (1.62 mL, 11.7 mmol) followed
by dropwise addition of N-phenyltrifluoromethanesulfonimide
(1.60 g, 4.47 mmol) in 40 mL of DCM via cannula. The reaction
mixture was allowed to warm to room temperature over 12 h, was
quenched with 1 N HCl, and washed with water. The aqueous
layer was back extracted with DCM, washed with brine, and dried
over MgSO4. The crude product was purified via flash column
chromatography on silica gel eluting with 20, 30, and 40% EtOAc/
hexanes affording 24 (874 mg, 57% yield over 2 steps) as a white
semisolid.
1H NMR (CDCl3, 300 MHz): δ 6.39 (d, J = 2.4 Hz, 1H), 6.33
(d, J= 2.4 Hz, 1H), 4.13 (d, J=15.0 Hz, 1H), 2.94-2.84 (m, 1H),
2.73-2.66 (m, 1H), 2.59-2.47 (m, 1H), 2.25-1.95 (m, 3H),
1.62-1.49 (m, 4H), 1.29-1.12 (m, 4H). 13C NMR (CDCl3, 75
MHz): δ 215.9, 156.6, 155.6, 148.8, 110.7, 102.3, 100.9, 77.8,
46.9, 44.2, 40.7, 34.7, 27.6, 26.8, 18.8. IR (neat, cm-1): 3415(br),
150 mL of 4:1 CHCl3:acetone along with TsOH H2O (4.57 g,
3
24.0 mmol). The TsOH H2O and diacetates mixture was then
3
added dropwise to persilylated phloroglucinol 22 at a rate of
approximately 1 drop/s via an addition funnel. The reaction
mixture was then slowly warmed to room temperature. Once the
diacetates were shown to be consumed by TLC, the reaction was

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 15 5663
1617, 1423, 1246, 1211, 1141, 1099. Mass spec calcd for
C16H17F3O6S, 394.0698; found, 394.0681. EIþ(amu): 394
(Mþ, 13), 279 (28), 270 (72), 243 (69), 225 (80), 207 (100), 195
(70); [R]23D -45.0° (c 0.006, CH2Cl2).
2.44 (td, J = 11.3 Hz, 2.4 Hz, 1H), 2.21-2.16 (m, 1H),
1.92-1.86 (m, 1H), 1.55-1.37 (m, 5H), 1.19-1.03 (m, 5H).
13C NMR (CDCl3, 75 MHz): δ 157.1, 155.4, 148.5, 114.2, 104.3,
99.5, 94.8, 94.6, 77.8, 75.5, 56.3, 55.1, 48.1, 36.1, 33.7, 33.0, 27.4,
25.9, 18.8. IR (neat, cm-1): 3197, 3105, 2940, 2789, 1603. Mass
spec calcd for C20H27F3O8S, 484.1379; found, 484.1403. EIþ-
(6aS,9R,10aR)-6a,7,8,9,10,10a-Hexahydro-1,9-dihydroxy-6,6-
dimethyl-6H-benzo[c]chromen-3-yl trifluoromethanesulfonate 27.
To ketone 24 (583 mg, 1.48 mmol) in 15 mL of MeOH at 0 °C was
added NaBH4 (280 mg, 7.40 mmol) in 3 portions over 5 min. The
reaction mixture was then stirred for 1 h, quenched with dropwise
addition of 1 N HCl, and diluted with EtOAc. The organic layer
was washed with brine and dried over MgSO4. The crude product
was then purified via flash column chromatography on silica gel
eluting with 30% then 40% EtOAc/hexanes, affording alcohol 27
and minor alcohol 28 (570 mg, 97% combined yield; the minor
diastereomer is easily removed during column chromatography
after the subsequent protection) as a white foam.
(amu): 484 (Mþ, 7), 379 (33), 378 (100), 335 (25), 245 (19); [R]23
D
-67.6° (c 0.017, CH2Cl2).
(6aS,9R,10aR)-6a,7,8,9,10,10a-Hexahydro-1,9-bis(methoxy-
methoxy)-6,6-dimethyl-6H-benzo[c]chromene-3-carbonitrile 31.
To triflate 29 (435 mg, 0.90 mmol) was added Zn(CN)2
(84 mg, 0.72 mmol), Pd2(dba)3 (82 mg, 0.090 mmol), and PPh3
(188 mg, 0.718 mmol) followed by PMHS (44 mg, 10 wt %) and
27 mL of DMF under an atmosphere of argon. The reaction
mixture was further degassed by bubbling argon through the
mixture for 15 min. The reaction mixture was heated to 60 °C and
stirred for 8 h. The solvent was removed under reduced pressure,
and the residue was adsorbed onto celite. The crude product was
subjected to flash column chromatography on silica gel eluting
with 10%, 20%, and 30% EtOAc/hexanes, affording 31 as a
clear, colorless viscous oil (313 mg, 96% yield).
1H NMR (CDCl3, 300 MHz): δ 8.19 (br s, 1H), 6.27 (s, 1H),
6.18 (s, 1H), 4.00-3.89 (m, 1H), 3.68-3.60 (m, 1H), 2.50-2.42
(m, 2H), 2.20-2.15 (m, 1H), 1.93-1.88 (m, 1H), 1.51-1.42 (m,
2H), 1.37 (s, 3H), 1.20-1.11 (m, 1H), 1.06-0.99 (m, 4H). 13C
NMR (CDCl3, 75 MHz): δ 156.5, 155.9, 148.3, 119.9, 102.3,
100.6, 77.8, 71.5, 47.7, 37.1, 35.7, 33.3, 27.6, 25.8, 18.9. IR (neat,
cm-1): 3245(br), 2937, 2873, 1597, 1420, 1245, 1213, 1141, 989,
857. Mass spec calcd for C16H19F3O6S, 396.0855; found,
396.0863. EIþ(amu): 396 (Mþ, 79), 378 (45), 336 (57), 335
(100), 186 (29), 69 (71); [R]23D -63.9° (c 0.015, CH2Cl2).
(6aS,9S,10aR)-6a,7,8,9,10,10a-Hexahydro-1,9-dihydroxy-6,6-
dimethyl-6H-benzo[c]chromen-3-yl trifluoromethanesulfonate 28.
To ketone 24 (299 mg, 0.76 mmol) in 8 mL of THF at -78 °C was
added a 1 M solution of L-Selectride in THF (3.00 mL, 3.00 mmol).
The reaction was maintained at -78 °C for 2 h and then stirred at
room temperature for 1 h. The flask was cooled to -78 °C and solid
NaHCO3 (930 mg, 11.1 mmol) was added followed by dropwise
addition of a 30% aqueous solution of H2O2 (1.60 mL). After the
addition of 30% H2O2 was complete, the cooling bath was removed
and the reaction mixture was stirred for 1 h at rt. A saturated
solution of sodium thiosulfate (5 mL) was added and the reaction
mixture was stirred for an additional 30 min. Ether was added and
the organic layer was separated, then washed with brine and dried
over MgSO4. The crude product was purified via flash column
chromatography on silica gel eluting with 40% EtOAc/hexanes,
affording alcohol 28 (269 mg, 90% yield) as a white solid. Alcohol
27 was not observed in the 1H NMR at 300 MHz.
1H NMR (CDCl3, 300 MHz): δ 6.90 (d, J = 1.6 Hz, 1H), 6.77
(d, J = 1.6 Hz, 1H), 5.21 (d, J = 6.8 Hz, 1H), 5.16 (d, J = 6.8 Hz,
1H), 4.73 (dd, J = 8.0 Hz, 7.1 Hz, 2H), 3.79-3.68 (m, 1H), 3.49
(s, 3H), 3.40-3.30 (m, 4H), 2.49 (td, J = 11.4 Hz, 2.4 Hz, 1H),
2.23-2.18 (m, 1H), 1.94-1.89 (m, 1H), 1.57-1.39 (m, 5H),
1.20-1.03 (m, 5H). 13C NMR (CDCl3, 75 MHz): δ 156.7, 155.2,
119.8, 118.8, 115.6, 110.9, 108.7, 94.9, 94.5, 77.8, 75.5, 56.4, 55.2,
48.2, 36.1, 34.1, 33.0, 27.5, 25.9, 18.7. IR (neat, cm-1): 2939,
2880, 2228, 1565, 1423, 1369, 1336, 1207, 1155, 1103, 1058. Mass
spec Calcd for C20H27NO5, 361.1889; found, 361.1880. EIþ
(amu): 361 (Mþ, 11), 285 (19), 255 (100), 240 (25), 212 (75), 69
(10); [R]23D -77.9° (c 0.007, CH2Cl2).
(6aS,9R,10aR)-6a,7,8,9,10,10a-Hexahydro-1,9-bis(methoxy-
methoxy)-6,6-dimethyl-6H-benzo[c]chromene-3-carboxylic Acid
33. To nitrile 31 (52 mg, 0.15 mmol) in a screw cap vial was
added MeOH:H2O (4:1, 1 mL) and LiOH (61 mg, 1.45 mmol)
and the mixture was heated to 70 °C in an oil bath for 3 days.
Conc HCl was added to the reaction mixture, and the resultant
milky solution was extracted with CHCl3, washed with satu-
rated brine, and dried over Na2SO4. Acid 33 was obtained as a
clear, colorless oil (50 mg, 91% yield). No purification was
necessary.
1H NMR (CDCl3, 300 MHz): δ 7.29 (s, 1H), 7.24 (s, 1H), 5.26
(d, J = 6.6 Hz, 1H), 5.20 (d, J = 6.6 Hz, 1H), 4.74 (dd, J = 9.3
Hz, 6.9 Hz, 2H), 3.81-3.70 (m, 1H), 3.51 (s, 3H), 3.47-3.40 (m,
4H), 2.51 (td, J = 11.1 Hz, 1.8 Hz, 1H), 2.25-2.18 (m, 1H),
1H NMR (CDCl3, 300 MHz): δ 7.66 (br s, 1H), 6.30 (d, J =
2.5 Hz, 1H), 6.26 (d, J = 2.5 Hz, 1H), 4.35 (s, 1H), 3.24 (d, J =
14.1 Hz, 1H), 2.93-2.86 (m, 1H), 2.54 (br s, 1H), 1.99-1.94 (m,
1H), 1.77-1.68 (m, 2H), 1.56-1.46 (m, 2H), 1.37-1.26 (m, 4H),
0.99 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ 156.1, 148.3, 112.8,
102.9, 101.3, 77.7, 67.5, 48.8, 35.3, 33.5, 28.9, 27.2, 22.5, 18.8;
mp: 188.5-192.5 °C. IR (neat, cm-1): 3210 (br), 2938, 1597,
1506, 1419, 1245, 1212, 1140, 1102, 987, 879, 839, 735. Mass spec
calcd for C16H19F3O6S-H2O, 378.0749; found, 378.0743. EIþ
(amu): 396 (Mþ, 8), 378 (64), 335 (56), 309 (31), 202 (14), 151
(42), 101 (39), 92 (19), 69 (100); [R]23D -57.7° (c 0.014, CH2Cl2).
(6aS,9R,10aR)-6a,7,8,9,10,10a-Hexahydro-1,9-bis(methoxy-
methoxy)-6,6-dimethyl-6H-benzo[c]chromen-3-yl trifluoromethane-
sulfonate 29. Alcohol 27 (430 mg, 1.08 mmol) was dissolved in
10 mL of DCM, was cooled to 0 °C, and was treated with DIPEA
(1.13 mL, 6.48 mmol) and dropwise addition of MOMCl (492 μL,
6.48 mmol). After 45 min, the cooling bath was removed and the
reaction mixture was stirred at room temperature for another 1 h
45 min. Saturated NaHCO3 was added to quench the reaction, and
the resulting mixture was diluted with Et2O. The organic layers were
washed with CuSO4 and brine and then dried over MgSO4. The
crude product was purified via flash column chromatography on
silica gel eluting with 20% EtOAc/hexanes, affording 29 (487 mg,
93% yield) as a clear, colorless oil.
1.92-1.87 (m, 1H), 1.60-1.40 (m, 5H), 1.25-1.04 (m, 5H). 13
C
NMR (CDCl3, 75 MHz): δ 171.2, 156.3, 154.8, 128.7, 120.1,
113.7, 106.5, 94.8, 94.5, 77.4, 75.7, 56.4, 55.2, 48.4, 36.2, 34.3,
33.1, 27.6, 26.1, 18.7. IR (neat, cm-1): 2939, 1719, 1690, 1574,
1424, 1375, 1211, 1149, 1100, 1051. Mass spec calcd for
C20H28O7, 380.1835; found, 380.1827. EIþ(amu): 380 (Mþ,
3), 293 (11), 149 (100), 71 (26); [R]23D -86.0° (c 0.014, CH2Cl2).
β-C9 Oxaza Amide 35 (Procedure for Amidation Reaction). To
a solution of 33 (30 mg, 0.079 mmol) in 2 mL of DCM was added
amine I (30 mg, 0.12 mmol) followed by DMAP (39 mg, 0.32
mmol) and EDCI (30 mg, 0.16 mmol). The flask was sealed with
a Teflon cap and stirred overnight at rt. The mixture was diluted
with EtOAc, washed with 1 N HCl and brine and dried over
MgSO4. The crude product was directly adsorbed onto celite
and purified via flash column chromatography eluting with 80%
EtOAc/hexanes, affording amide 35 as a clear, colorless oil
(36 mg, 91% yield).
1H NMR (CDCl3, 300 MHz): δ 6.66 (s, 1H), 6.49 (s, 1H), 5.21
(d, J = 6.6 Hz, 1H), 5.12 (d, J = 6.6 Hz, 1H), 5.05 (br s, 1H), 4.72
(dd, J = 9.6 Hz, 6.9 Hz, 2H), 4.24-4.18 (m, 3H), 3.78-3.68 (m,
1H), 3.47 (s, 3H), 3.43-3.34 (m, 4H), 2.47 (td, J = 11.2 Hz, 2.0
Hz, 1H), 2.21-1.75 (m, 10H), 1.57-1.37 (m, 5H), 1.21-1.02 (m,
5H). 13C NMR (CDCl3, 75 MHz): δ 169.1, 156.6, 154.8, 135.4,
1H NMR (CDCl3, 300 MHz): δ 6.56 (d, J = 2.5 Hz, 1H), 6.40
(d, J = 2.5 Hz, 1H), 5.19-5.12 (m, 2H), 4.74-4.69 (m, 2H),
3.75-3.67 (m, 1H), 3.47 (s, 3H), 3.69 (s, 3H), 3.35-3.30 (m, 1H),

5664 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 15
Dixon et al.
115.5, 109.4, 103.9, 94.7, 94.5, 77.2, 75.6, 66.7, 56.2, 55.1, 49.0,
48.4, 42.9, 36.3, 35.1, 34.3, 33.9, 33.1, 27.6, 26.0, 18.8. IR (neat,
cm-1): 2937, 1626, 1566, 1424, 1370, 1148, 1101, 1048. Mass spec
calcd for C28H39NO7, 501.2727; found, 501.2702. EIþ(amu):
501 (Mþ, 28), 457 (23), 395 (100), 380 (13), 352 (20), 257 (30),
167 (17), 149 (44), 95 (21), 71 (24), 69 (30); [R]23D -33.3° (c 0.011,
CH2Cl2).
Procedure for Deprotection of MOM Ethers (4-11). β-C9
Oxaza Amide 4. To a solution of amide 35 (36 mg, 0.072 mmol)
and n-BuSH (180 μL, 1.68 mmol) in 2 mL of DCM was added
ZnBr2 (81 mg, 0.36 mmol) all in one portion. The reaction flask
was placed in an oil bath and heated at 45 °C for 8 h. The flask
was then cooled to room temperature, diluted with EtOAc, and
quenched with saturated NaHCO3. The organic layer was
washed with brine and dried over Na2SO4. The crude product
was adsorbed onto Celite and subjected to column chromatog-
raphy on silica gel using a gradient elution of 2.5, 5, 10% MeOH/
DCM. Amide 4 is a white glass obtained in 77% yield (23 mg).
Chiral HPLC (0.46 cm ꢀ25 cm Chiralcel AD-H, 50% 2-propa-
nol in hexanes, 1 mL/min, UV detection at 280 nm) 7.50 min and
98.6% pure.
The solvent was removed under vacuum and then diluted with
EtOAc, washed with water and brine and dried over Na2SO4. The
crude product was subjected to column chromatography on silica
gel eluting with 50% then 80% EtOAc/hexanes, affording amine
43 (55 mg, 75% yield over 2 steps) as a clear, colorless oil.
1H NMR (MeOH-d4, 300 MHz): δ 6.70 (d, J = 1.5 Hz, 1H),
6.47 (d, J = 1.5 Hz, 1H), 5.21 (d, J = 6.5 Hz, 1H), 5.16 (d, J =
6.5 Hz, 1H), 4.71 (s, 2H), 4.22-4.06 (m, 3H), 3.80 (s, 2H),
3.78-3.67 (m, 1H), 3.51-3.43 (m, 4H), 3.37 (s, 3H), 3.06-3.00
(m, 2H), 2.49 (td, J = 11.3 Hz, 2.4 Hz, 1H), 2.24-2.03 (m, 5H),
1.96-1.85 (m, 5H), 1.52-1.36 (m, 5H), 1.20 (td, J = 12.6 Hz, 3.5
Hz, 1H), 1.02 (s, 3H). 13C NMR (MeOH-d4, 126 MHz): δ 158.0,
156.0, 114.5, 112.9, 107.7, 95.9, 95.8, 77.9, 77.4, 68.9, 57.7, 56.6,
55.5, 50.9, 50.3, 38.2, 35.2, 34.4, 33.5, 32.8, 28.1, 27.1, 19.0.
IR (neat, cm-1): 2930, 1573, 1429, 1335, 1154, 1106, 1057.
Mass spec calcd for C28H41NO6, 487.2934; found, 487.2950.
EIþ(amu): 487 (Mþ, 61), 364 (19), 258 (100), 215 (62), 152 (35),
95 (51), 69 (73); [R]23D -60.3° (c 0.029, MeOH).
(6aS,9R,10aR)-6a,7,8,9,10,10a-Hexahydro-1,9-dihydroxy-
6,6-dimethyl-6H-benzo[c]chromene-3-carbonitrile 45. To nitrile 31
(132 mg, 0.365 mmol) in 3.5 mL of DCM at rt was added n-BuSH
(390 μL, 3.65 mmol) followed by ZnBr2 (544 mg, 2.41 mmol) allat
once. The reaction mixturewas stirred for 15min andthen diluted
with EtOAc, washed with saturated NaHCO3 and brine, and
dried over Na2SO4. The crude product was subjected to flash
column chromatography on silica gel eluting with 50% then 80%
EtOAc/hexanes, resulting in nitrile 45 (90 mg, 90% yield) as a
white solid.
1H NMR (MeOH-d4, 500 MHz): δ 6.33 (d, J = 1.8 Hz, 1H),
6.29 (d, J = 1.8 Hz, 1H), 4.96 (br s, 1H), 4.20 (br s, 3H),
3.77-3.71 (m, 1H), 3.53-3.49 (m, 1H), 2.50 (td, J = 11.3 Hz, 2.5
Hz, 1H), 2.18-2.09 (m, 3H), 2.06-2.00 (m, 2H), 1.93-1.80 (m,
5H), 1.46 (td, J = 11.8 Hz, 2.3 Hz, 1H), 1.42-1.33 (m, 4H),
1.24-1.15 (m, 1H), 1.04 (s, 3H), 0.98-0.91 (m, 1H). 13C NMR
(MeOH-d4, 126 MHz): δ 171.7, 158.4, 156.7, 136.0, 115.4, 107.7,
105.8, 78.4, 71.3, 68.2(2), 51.0, 50.1, 44.8, 39.6, 36.6, 36.0, 35.9,
35.2, 35.1, 28.1, 27.2, 19.1. IR (neat, cm-1): 3454 (br), 2932,
1738, 1727, 1604, 1572, 1441, 1381, 1240, 1057. Mass spec calcd
for C24H31NO5, 413.2234; found, 413.2322. EIþ(amu): 413
(Mþ, 100), 395 (26), 352 (20), 275 (30), 149 (56); [R]23D -92.6°
(c 0.007, MeOH).
1H NMR (MeOH-d4, 300 MHz): δ 6.55 (s, 2H), 4.62 (br s, 1H),
3.80-3.70 (m, 1H), 3.52-3.44 (m, 1H), 2.50 (td, J = 11.2 Hz, 2.4
Hz, 1H), 2.17-2.08 (m, 1H), 1.94-1.86 (m, 1H), 1.52-1.31 (m,
5H), 1.22-1.16 (m, 1H), 1.03 (s, 3H), 1.00-0.89 (m, 1H). 13C
NMR (MeOH-d4, 75 MHz): δ 158.7, 157.0, 119.8, 119.6, 113.6,
111.3, 110.6, 78.8, 71.1, 49.7, 39.2, 36.4, 35.2, 28.0, 27.0, 19.1; mp:
212.1 °C (dec). IR (neat, cm-1): 3234 (br), 2982, 2972, 2864, 2224,
1711, 1568, 1424, 1344, 1270, 1057. HRMS calcd for C16H19NO3,
273.1365; found, 273.11360. EIþ(amu): 273 (Mþ, 72), 240 (53),
212 (100), 186 (18), 69 (36); [R]23D -152.6° (c 0.010, MeOH).
(6aS,9R,10aR)-6a,7,8,9,10,10a-Hexahydro-1,9-dihydroxy-
6,6-dimethyl-6H-benzo[c]chromene-3-carbaldehyde 47. To an ice
cold solution of nitrile 45 (140 mg, 0.51 mmol) in 5 mL of DCM
was added DIPEA (460 μL, 2.56 mmol) followed by dropwise
additionofTESCl(300 μL, 1.31 mmol). The reaction mixturewas
stirred for 20 min and then quenched with ice cold saturated
NaHCO3, diluted with Et2O, washed with brine, and dried over
Na2SO4. The crude nitrile was dissolved in 5 mL of DCM, cooled
to -78 °C, and stirred for 10 min. DIBAL in PhMe (1.10 mL,
1.32 mmol, 1.2 M) was added dropwise, and the resulting mixture
was stirred for 1 h. Excess DIBAL was quenched with acetone at
-78 °C, and the reaction mixture was stirred with saturated
Rochelle’s salt at room temperature until the biphasic mixture
was clear. EtOAc was added and the organic layer was separated,
washed with brine, and dried over Na2SO4. The crude product
was purified on a plug of silica gel eluting with 5% EtOAc/
hexanes with 2% TEA present. The silylated aldehyde was
dissolved in 5 mL of THF, treated with TBAF (550 mg, 1.74
mmol) at rt, and stirred until the reaction was shown to be
complete by TLC analysis. Solid CaCO3 was added to the flask
and stirred for 15 min. EtOAc was added and the organic layer
was separated, washed with brine, and dried over Na2SO4. The
crude product was purified via flash column chromatography on
silica gel eluting with 50% then 80% EtOAc/hexanes, resulting in
aldehyde 47 (44 mg, 61% yield over 3 steps) as a white foam.
1H NMR (CDCl3, 300 MHz): δ 9.76 (s, 1H), 6.85 (d, J = 1.4
Hz, 1H), 6.79 (d, J = 1.4 Hz, 1H), 4.01-3.90 (m, 1H), 3.67-3.63
(m, 1H), 2.55 (td, J = 11.1 Hz, 2.1 Hz, 1H), 2.25-2.16 (m, 1H),
1.97-1.86 (m, 1H), 1.57-1.41 (m, 5H), 1.25-1.15 (m, 2H), 1.07
(s, 3H). 13C NMR (CDCl3, 75 MHz): δ 193.9, 158.7, 157.0,
137.4, 120.8, 112.5, 107.2, 78.4, 71.2, 49.9, 39.3, 36.5, 35.5, 28.1,
27.1, 19.1. IR (neat, cm-1): 3338 (br), 2976, 2934, 2872, 1716,
((6aS,9R,10aR)-6a,7,8,9,10,10a-Hexahydro-1,9-bis(methoxy-
methoxy)-6,6-dimethyl-6H-benzo[c]chromen-3-yl)methanol 41. To
carboxylic acid 33 (12 mg, 0.032 mmol) in 0.1 mL of THF was
added excess BH3 THF (100 μL, 1 mmol, 1 M) at 0 °C, and the
3
mixture was allowed to warm to room temperature overnight. Six
N HCl was added slowly and carefully at 0 °C, and the mixture
was diluted with CHCl3. The organic layers were washed with
brine and dried over Na2SO4. The crude product was purified via
flash column chromatography on silica gel using 50% EtOAc/
hexanes as the eluent which resulted in alcohol 41 (10 mg, 88%
yield) as a clear, colorless oil.
1H NMR (CDCl3, 500 MHz): δ 6.63 (s, 1H), 6.50 (s, 1H), 5.21
(d, J = 6.3 Hz, 1H), 5.16 (d, J = 6.3 Hz, 1H), 4.72 (dd, J = 13.3
Hz, 6.8 Hz, 2H), 4.57 (br s, 2H), 3.77-3.71 (m, 1H), 3.50 (s, 3H),
3.44-3.39 (m, 4H), 2.47 (td, J = 11.3 Hz, 2.5 Hz, 1H), 2.23-
2.17 (m, 1H), 1.93-1.88 (m, 1H), 1.56-1.40 (m, 2H), 1.39 (s,
3H), 1.18-1.06 (m, 2H), 1.04 (s, 3H). 13C NMR (CDCl3, 126
MHz): δ 156.7, 154.9, 140.8, 113.3, 109.8, 104.2, 94.8, 94.4, 76.9,
75.7, 65.2, 56.3, 55.2, 48.6, 36.5, 33.9, 33.2, 27.7, 26.1, 18.8. IR
(neat, cm-1): 3409 (br), 2918, 2849, 1577, 1431, 1056, 1042. Mass
spec calcd for C20H30O6, 366.2042; found, 366.2035. EIþ(amu):
366 (Mþ, 26), 260 (100), 245 (28), 217 (34), 177 (10); [R]23
D
-65.8° (c 0.012, CH2Cl2).
β-C9 Oxaza Benzyl Amine 43. Alcohol 41 (55 mg, 0.15 mmol)
was dissolved in 2 mL of THF under N2, was cooled to -40 °C,
and was treated with NEt3 (125 μL, 0.90 mmol) and MsCl
(50 μL, 0.65 mmol). The reaction mixture was allowed to stir at this
temperature for 45 min and then was warmed to 0 °C and stirred
for an additional 30 min. A solution of LiBr (130 mg, 1.50 mmol) in
2 mL of THF was added via cannula, and the reaction mixture was
allowedtowarmtoroomtemperature andwas stirred for 4 h. The
reaction mixture was quenched with ice cold saturated NaHCO3,
extracted with Et2O, washed with brine, and dried over
Na2SO4. The crude bromide and amine I (24 mg, 0.17 mmol)
were dissolved in 1 mL of DMF under N2. K2CO3 (124 mg,
0.90 mmol) was added, and the mixture was stirred overnight.

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 15 5665
1684, 1577, 1558, 1338, 1144, 1057. Mass spec calcd for
C16H20O4, 276.1362; found, 276.1375. EIþ(amu): 276 (Mþ,
2.20-1.81 (m, 5H), 1.68 (dt, J = 14.7 Hz, J = 5.1 Hz, 1H),
1.57-1.22 (m, 8H), 0.96 (s, 3H), 0.82-0.69 (m, 1H). IR (neat,
cm-1): 3566 (br), 2974, 2923, 2825, 1610, 1561, 1153, 1106, 1055,
1042. Mass spec calcd for C28H40O6, 472.2825; found, 472.2823.
EIþ(amu): 472 (Mþ, 100), 366 (94), 360 (14), 279 (14), 149 (44),
91 (31), 79 (30), 69 (35).
Deprotection and Cyclization Reaction. β-C9 Oxaadamantane
16. To alcohol 56 (26 mg, 0.055 mmol) in 2 mL of DCM was
added n-BuSH (135 μL, 1.27 mmol) at rt followed by ZnBr2
(62 mg, 0.28 mmol) all at once. The reaction mixture was stirred
for 20 min and then diluted with EtOAc and saturated NaHCO3.
The organic layer was washed with brine and dried over Na2SO4.
The crude product was purified via flash column chromatogra-
phy eluting with 40% and then 50% EtOAc/hexanes, affording
oxaadamantane 16 (20 mg, 95% yield) as a white glass. Chiral
HPLC (0.46 cm ꢀ25 cm Chiralcel AD-H, 50% 2-propanol
in hexanes, 1 mL/min, UV detection at 280 nm) 7.50 min and
98.1% pure.
75), 258 (42), 243 (33), 215 (100), 189 (54), 142 (66); [R]23
D
-154.4° (c 0.007, MeOH).
Procedure for Reductive Amination (12-15). β-C9 1-Adaman-
tyl Benzylamine 12. To a round-bottom flask equipped with a
stir bar, reflux condenser, and Dean-Stark trap was added
aldehyde 47 (10 mg, 0.036 mmol), 1-adamantanamine (6 mg,
˚
0.040 mmol), and two 4 A molecular sieve beads in benzene. The
reaction mixture was heated at reflux overnight. The progress of
the reaction was followed by IR, monitoring the disappearance
of the carbonyl absorption. The solvent was removed under
vacuum, and the crude imine was dissolved in dry MeOH and
was treated with a spatula tip of 10% Pd/C. The reaction flask
was purged with H2 gas three times and the mixture was allowed
to stir at room temperature overnight. The Pd/C was filtered off
through a plug of celite. The crude product was purified on silica
gel using 2.5, 5, 10% MeOH/DCM as the eluent resulting in
amine 12 as a brown oil (12 mg, 81% yield over the 2 steps).
HPLC (0.10 cm ꢀ25 cm Luna C8(2) 5 μ, 20-60% MeCN in
water (both containing 0.1% HCO2H) over 30 min, 3 mL/min,
UV detection at 280 nm) 15.87 min and 96.1% pure.
1H NMR (C6D6, 500 MHz): δ 8.51 (br s, 1H, OH), 6.87 (s,
1H), 6.79 (s, 1H), 4.24 (br s, 1H), 4.01-3.99 (m, 1H), 3.85-3.80
(m, 1H), 2.56 (br t, J = 10.8 Hz, 1H), 2.15-1.87 (m, 8H),
1.63-1.15 (m, 12H), 0.97 (s, 3H), 0.81-0.74 (m, 1H). 13C NMR
(C6D6, 126 MHz): δ 156.8, 155.6, 147.6, 111.0, 105.8, 104.3,
76.6, 73.0, 71.6, 69.2, 48.5, 42.3, 41.9, 38.6, 35.8, 35.7, 35.2, 34.2,
28.0, 26.4, 19.3. IR (neat, cm-1): 3336 (br), 2975, 2928, 2852,
1622, 1577, 1418, 1051. Mass spec calcd for C24H32O4 þ Hþ,
385.2380; found, 385.2379. [R]23D -98.7° (c 0.008, MeOH)
Binding Assays: Rat brain CB1, mouse and human CB2
binding assays. Compounds were tested for their affinities for
the CB1 and CB2 receptors using membrane preparations from
rat brain or HEK293 cells expressing either mCB2 or hCB2, res-
pectively, and [3H]CP-55,940, as previously described.22,26-29
Results from the competition assays were analyzed using non-
linear regression to determine the IC50 values for the ligand; Ki
1H NMR (MeOH-d4, 500 MHz): δ 6.26 (d, J = 1.0 Hz, 1H),
6.24 (d, J = 1.0 Hz, 1H), 3.77-3.70 (m, 1H), 3.52 (br s, 3H), 2.44
(td, J = 11.2 Hz, 2.3 Hz, 1H), 2.14-2.06 (m, 4H), 1.92-1.88 (m,
1H), 1.81-1.63 (m, 13H), 1.47-1.29 (s, 5H), 1.19 (td, J = 12.8
Hz, 3.3 Hz, 1H), 1.01 (s, 3H), 0.95-0.88 (m, 1H). 13C NMR
(MeOH-d4, 126 MHz): δ 158.1, 156.3, 140.8, 112.2, 109.8, 108.6,
77.7, 71.3, 52.4, 50.3, 45.3, 42.8, 40.0, 37.7, 36.7, 35.0, 31.0, 28.2,
27.2, 19.1. IR (neat, cm-1): 3282 (br), 2976, 2906, 2844, 1576,
1363, 1232, 1134, 1054. Mass spec calcd for C26H37NO3,
411.2773; found, 411.2760. EIþ(amu): 411 (Mþ, 10), 207 (23),
151 (82), 135 (28), 94 (100), 77 (30), 67 (23); [R]23 -109.5° (c
D
0.008, MeOH).
Procedure for Suzuki-Miyaura Coupling. β-C9 Styrenyl ke-
tone 54. A 4:1 solution of DMF/EtOH(abs) over 4 A molecular
30
values were calculated from the IC50 (Prizm by GraphPad
Software, Inc.). Each experiment was performed in triplicate
and Ki values determined from one experiment.
˚
sieves was degassed by bubbling Ar through the solution for
20 min. In a separate flask equipped with a stir bar was added
triflate 29 (65 mg, 0.13 mmol), boronate 53 (45 mg, 0.17 mmol),
Acknowledgment. We thank The National Institute on
Drug Abuse (DA07215, 2 P01 DA09158, 5 R01 DA03801)
for generous support of this research. The contributions of Yan
Peng, Shivangi Joshi, and Han Zhou in performing the binding
assays are also acknowledged by the authors. We thank
Dr. David Le Goanvic for supplying compounds 2 and 3.
K2CO3 (62 mg, 0.45 mmol), and PdCl2(dppf ) DCM (12 mg,
3
0.015 mmol). The reaction flask was evacuated and purged with
Ar three times, then 2 mL of the DMF/EtOH mixture was added
and the reaction mixture was heated at 70 °C for 6 h. The flask
was cooled to room temperature; the mixture was filtered
through cCelite and concentrated directly onto celite. The crude
product was purified via flash column chromatography on silica
gel eluting with 10, 20, 30, and 40% EtOAc/hexanes, resulting in
ketone 54 as a clear, colorless oil as a mixture of diastereomers
(55 mg, 87% yield).
Supporting Information Available: Optimized experimental
procedures for the synthesis of I. Preparation of vinyl boronate
53. Spectroscopic data for 30, 32, 36-40, 5, 7-11, 42, 44, 46, 48,
1
13-15, 55, 57, 17, 49-53; reproductions of H and 13C NMR
1H NMR (CDCl3, 300 MHz): δ 6.63 (d, J = 6.0 Hz, 1H),
6.51-6.47 (m, 1H), 6.12 (d, J = 5.7 Hz, 1H), 5.22-5.12 (m, 2H),
4.73 (dd, J = 10.5 Hz, 6.9 Hz, 1H), 3.79-3.68 (m, 1H), 3.49 (s,
3H), 3.43-3.34 (m, 4H), 2.91-2.83 (br s, 1H), 2.80-1.84 (m,
13H), 1.55-1.25 (m, 5H), 1.20-1.03 (m, 5H). IR (neat, cm-1):
2924, 2853, 1712, 1608, 1564, 1422, 1367, 1209, 1141, 1105, 1056,
1041. Mass spec calcd for C28H38O6, 470.2668; found, 470.2667.
EIþ(amu): 470 (Mþ, 26), 85 (100), 83 (51), 69 (26), 67 (21).
Procedure for NaBH4 Reduction of Styrenyl Ketones. β-C9
endo-Alcohol 56. Ketone 54 (55 mg, 0.117 mmol) in 2 mL of
MeOH was cooled to 0 °C and NaBH4 (22 mg, 0.58 mmol) was
added all at once and stirred for 30 min. The reaction was
quenched with brine and the crude product was extracted with
EtOAc and dried over Na2SO4. The crude product was quickly
purified via flash column chromatography eluting with 50%
EtOAc/hexanes, affording a diastereomeric mixture of endoal-
cohol 56 as a clear, colorless oil (50 mg, 90% yield).
spectra of 4-17, 24, 25, 27-50, 52, 53. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) Devane, W. A.; Dysarz, F. A., III.; Johnson, M. R.; Melvin, L. S.;
Howlett, A. C. Determination and characterization of a cannabi-
noid receptor in rat brain. Mol. Pharmacol. 1988, 34, 605–613.
(2) Matsuda, L. A.; Lolait, S. J.; Brownstein, M. J.; Young, A. C.;
Bonner, T. I. Structures of a cannabinoid receptor and func-
tional expression of the cloned cDNA. Nature (London) 1990,
346, 561–564.
(3) Munro, S.; Thomas, K. L.; Abu-Shaar, M. Molecular character-
ization of a peripheral receptor for cannabinoids. Nature 1993, 365,
61–65.
(4) For leading references see: (a) Huffman, J. W.; Miller, J. R. A.;
Liddle, J.; Yu, S.; Thomas, B. F.; Wiley, J. L.; Martin, B. R.
Structure-activity relationships for 10,10-dimethylalkyl-Δ8-tetra-
hydrocannabinols. Bioorg. Med. Chem. 2003, 11, 1397–1410. (b)
Papahatjis, D. P.; Nikas, S. P.; Kourouli, T.; Chari, R.; Xu, W.; Pertwee,
R. G.; Makriyannis, A. Pharmacophoric requirements for the cannabi-
noid side chain. Probing the cannabinoid receptor subsite at C10.
J. Med. Chem. 2003, 46, 3221–3229. (c) Papahatjis, D. P.; Nikas,
1H NMR (C6D6, 300 MHz): δ 6.99-6.95 (m, 2H), 6.43 (d, J =
6.0 Hz, 1H), 5.03-5.00 (m, 1H), 4.92-4.90 (d, J = 6.6 Hz, 1H),
4.77-4.70 (dd, J = 14.6 Hz, 6.8 Hz, 2H), 3.93 (br s, 1H),
3.74-3.67 (m, 2H), 3.28-3.23 (m, 7H), 2.60-2.48 (m, 4H),

5666 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 15
Dixon et al.
S. P.; Andreou, T.; Makriyannis, A. Novel 10,10-chain substituted Δ8-
tetrahydrocannabinols. Bioorg. Med. Chem. Lett. 2002, 12, 3583–
3586. (d) Khanolkar, A. D.; Lu, D.; Fan, P.; Tian, X.; Makriyannis, A.
Novel conformationally restricted tetracyclic analogs of Δ8-tetrahydro-
cannabinol. Bioorg. Med. Chem. Lett. 1999, 9, 2119–2124. (e)
Huffman, J. W.; Liddle, J.; Duncan, S. G., Jr.; Yu, S.; Martin, B. R.;
Wiley, J. L. Synthesis and pharmacology of the isomeric methylheptyl-
Δ8-tetrahydrocannabinols. Bioorg. Med. Chem. 1998, 6, 2383–2396.
(f ) Papahatjis, D. P.; Kourouli, T.; Abadji, V.; Goutopoulos, A.;
Makriyannis, A. Pharmacophoric requirements for cannabinoid side
chains: multiple bond and C10-substituted Δ8-tetrahydrocannabinols.
J. Med. Chem. 1998, 41, 1195–1200. (g) Busch-Petersen, J.; Hill,
W. A.; Fan., P.; Khanolkar, A.; Xie, X.-Q.; Tius, M. A.; Makriyannis,
A. Unsaturated side chain β-11-hydroxyhexahydrocannabinol analogs.
J. Med. Chem. 1996, 39, 3790–3796.
(15) Modified procedure of: Chittiboyina, A. G.; Reddy, C. R.;
Watkins, E. B.; Avery, M. A. First synthesis of antimalarial
Machaeriols A and B. Tetrahedron Lett. 2004, 45, 1689–1691.
(16) (a) Kubota, H.; Rice, K. C. Palladium-catalyzed cyanation
of hindered, electron-rich aryl triflates by zinc cyanide. Tetrahedron
Lett. 1998, 39, 2907–2910. (b) Martin, M. T.; Liu, B.; Cooley,
B. E., Jr.; Eaddy, J. F. Open air palladium catalyzed cyanation-the use
of PMHS to protect from oxygen. Tetrahedron Lett. 2007, 48, 2555–
2557.
(17) Sohn, J.-H.; Waizumi, N.; Zhong, H. M.; Rawal, V. H. Total
synthesis of mycalamide A. J. Am. Chem. Soc. 2005, 127, 7290–
7291.
(18) Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y. 2-Azaada-
mantane N-oxyl (AZADO) and 1-Me-AZADO: highly efficient
organocatalysts for oxidation of alcohols. J. Am. Chem. Soc. 2006,
128, 8412–8413.
(19) Ishiyama, T.; Takagi, J.; Kamon, A.; Miyaura, N. Palladium-
catalyzed cross-coupling reaction of bis(pinacolato)diboron with
vinyl triflates β-substituted by a carbonyl group: efficient synthesis
of β-boryl-R,β-unsaturated carbonyl compounds and their syn-
thetic utility. J. Organomet. Chem. 2003, 687, 284–290.
(20) Ghosh, S.; Kinney, W. A.; Gauthier, D. A.; Lawson, E. C.;
Hudlicky, T.; Maryanoff, B. E. Convenient preparation of aryl-
substituted nortropanes by Suzuki-Miyaura methodology. Can.
J. Chem. 2006, 84, 555–560.
(21) (a) Tius, M. A.; Makriyannis, A.; Zou, X. L.; Abadji, V. Con-
formationally restricted hybrids of CP-55,940 and HHC: stereo-
selective synthesis and activity. Tetrahedron 1994, 50, 2671–2680.
(b) Tius, M. A.; Hill, W. A. G.; Zou, X. L.; Busch-Petersen, J.;
Kawakami, J. K.; Fernandez-Garcia, M. C.; Drake, D. J.; Abadji, V.;
Makriyannis, A. Classical/nonclassical cannabinoid hybrids; stereo-
chemical requirements for the southern hydroxyalkyl chain. Life Sci.
1995, 56, 2007–2012.
(22) Dodd, P. R.; Hardy, J. A.; Oakley, A. E; Edwardson, J. A.; Perry,
E. K; Delaunoy, J. P. A rapid method for preparing synaptosomes:
comparison, with alternative procedures. Brain Res. 1981, 226,
107–118.
(23) Jorgensen, W. L.; Tirado-Rives, J. The OPLS [optimized potentials
for liquid simulations] potential functions for proteins, energy
minimizations for crystals of cyclic peptides and crambin. J. Am.
Chem. Soc. 1988, 110, 1657–1666.
(5) (a) Roesch, S.; Ramer, R.; Brune, K.; Hinz, B. R(þ)-Methananda-
mide and other cannabinoids induce the expression of cyclooxy-
genase-2 and matrix metalloproteinases in human nonpigmented
ciliary epithelial cells. J. Pharm. Exp. Ther. 2006, 316, 1219–1228.
(b) Jarvinen, T.; Pate, D. W.; Laine, K. Cannabinoids in the treatment of
glaucoma. Pharmacol. Ther. 2002, 95, 203–220.
(6) (a) Huang, S. M.; Walker, J. M. In Cannabinoids as Therapeutics;
€
Raphael, M., Ed.; Birkhauser Verlag: Basel, 2005; p 149. (b) Mbvundula,
E. C.; Rainsford, K. D.; Bunning, R. A. D. Cannabinoids in pain and
inflammation. Inflammopharmacology 2004, 12, 99–114. (c) Smith, P. F.
Cannabinoids in the treatment of pain and spasticity in multiple sclerosis.
Curr. Opin. Invest. Drugs 2002, 3, 859–864.
(7) (a) Barth, F.; Rinaldi-Carmona, M. In Cannabinoids as Therapeu-
€
tics; Raphael, M., Ed.; Birkhauser Verlag: Basel, 2005; p 219. (b) Koch,
J. E. Δ9-THC stimulates food intake in Lewis rats: effects on chow,
high-fat and sweet high-fat diets. Pharmacol., Biochem. Behav. 2001,
68, 539–543.
(8) (a) Adams, R. Marihuana. Harvey Lect. 1942, 37, 168–197. (b)
Adams, R.; Harfenist, M.; Lowe, S. New analogs of tetrahydrocanna-
binol. XIX. J. Am. Chem. Soc. 1949, 71, 1624–1628.
(9) (a) Lu, D.; Meng, Z.; Thakur, G. A.; Fan, P.; Steed, J.; Tartal,
C. L.; Hurst, D. P.; Reggio, P. H.; Deschamps, J. R.; Parrish, D. A.;
€
George, C.; Jarbe, T. U. C.; Lamb, R. J.; Makriyannis, A.
Adamantyl cannabinoids: a novel class of cannabinergic ligands.
J. Med. Chem. 2005, 48, 4576–4585. See also: (b) McLaughlin, P. J.;
Lu, D.; Winston, K. M.; Thakur, G.; Swezey, A.; Makriyannis, A.;
Salamone, J. D. Behavioral effects of the novel cannabinoid full agonist
(24) Kaminski, G. A.; Friesner, R. A.; Tirado-Rives, J.; Jorgensen,
W. L. Evaluation and reparametrization of the OPLS-AA force
field for proteins via comparison with Accurate quantum chemical
calculations on peptides. J. Phys. Chem. B 2001, 105, 6474–6487.
(25) Macromodel, version 9.5; Schrodinger, LLC: New York, NY, 2007.
(26) Abadji, V.; Lucas-Lenard, J. M.; Chin, C.; Kendall, D. A. Involve-
ment of the carboxyl terminus of the third intracellular loop of the
cannabinoid receptor in constitutive activation of Gs. J. Neuro-
chem. 1999, 72, 2032–2038.
€
AM 411. Pharmacol., Biochem. Behav. 2005, 81, 78–88. (c) Jarbe,
T. U. C.; DiPatrizio, N. V.; Lu, D.; Makriyannis, A. (-)-Adamantyl-Δ8-
tetrahydrocannabinol (AM-411), a selective cannabinoid CB1 receptor
agonist: effects on open-field behaviors and antagonism by SR-141716
in rats. Behav. Pharmacol. 2004, 15, 517–521.
(10) Le Goanvic, D.; Tius, M. A. Oxaza adamantyl cannabinoids. A
new class of cannabinoid receptor probes. J. Org. Chem. 2006, 71,
7800–7804.
(11) (a) Stetter, H.; Heckel, K. Compounds with the adamantane struc-
ture synthesized by cyclization reactions with N,N-dibromo-p-
toluenesulfonamide. Tetrahedron Lett. 1972, 13, 801–804. (b) Stetter,
H.; Heckel, K. Compounds with urotropine structure. LII. Cyclization
reactions with cis,cis-1,5-cyclooctadiene as the precursor. Chem. Ber.
1973, 106, 339–348.
(12) (a) Portmann, R. E.; Ganter, C. Heterotricyclodecane. XVI. 2-Oxa-
6-azaadamantane and derivatives. Helv. Chim. Acta 1973, 56, 1962–
1985. (b) Ganter, C.; Portmann, R. E. Synthesis of 2-thia-6-azaadaman-
tanes and derivatives. Helv. Chim. Acta 1971, 54, 2069–2077.
(13) An improved synthesis of oxazaadamantane I is described in the
Supporting Information.
(27) Lan, R.; Lui, Q.; Fan, P.; Lin, S.; Fernando, S. R.; McCallion, D.;
Pertwee, R.; Makriyannis, A. Structure-activity relationships of
pyrazole derivatives as cannabinoid receptor antagonists. J. Med.
Chem. 1999, 42, 769–776.
(28) Morse, K. L.; Fournier, D. J.; Li, X.; Grzybowska, J.; Makriyannis,
A. A novel electrophilic high affinity irreversible probe for the
cannabinoid receptor. Life Sci. 1995, 56, 1957–1962.
(29) Guo, Y.; Abadji, V.; Morse, K. L.; Fournier, D. J.; Li, X.;
Makriyannis, A. (-)-11-Hydroxyl-70-isothiocyanato-10,10-dimethyl-
heptyl-D8-THC: a novel, high-affinity irreversible probe for the
cannabinoid receptor in the brain. J. Med. Chem. 1994, 37, 3867–
3870.
(14) Archer, R. A.; Blanchard, W. B.; Day, W. A.; Johnson, D. W.;
Lavagnino, E. R.; Ryan, C. W.; Baldwin, J. E. Cannabinoids. 3.
Synthetic approaches to 9-ketocannabinoids. Total synthesis of
nabilone. J. Org. Chem. 1977, 42, 2277–2284.
(30) Cheng, Y.; Prusoff, W. H. Relationship between the inhibition
constant (K1) and the concentration of inhibitor which causes 50%
inhibition (IC50) of an enzymatic reaction. Biochem. Pharmacol.
1973, 22, 3099–3108.