C1′-cycloalkyl side chain pharmacophore in tetrahydrocannabinols

Article abstract of DOI:10.1021/jm070121a

In earlier work we have provided evidence for the presence of a subsite within the CB1 and CB2 cannabinoid receptor binding domains of classical cannabinoids. This putative subsite corresponds to substituents on the C1-position of the C3-alkyl side chain, a key pharmacophoric feature in this class of compounds. We have now refined this work through the synthesis of additional C1′-cycloalkyl compounds using newly developed approaches. Our findings indicate that the C1′-cyclopropyl and C1′-cyclopentyl groups are optimal pharmacophores for both receptors while the C1′-cyclobutyl group interacts optimally with CB1 but not with CB2. The C1′-cyclohexyl analogs have reduced affinities for both CB1 and CB2. However, these affinities are significantly improved with the introduction of a C2′-C3′ cis double bond that modifies the available conformational space within the side chain and allows for a better accommodation of a six-membered ring within the side chain subsite. Our SAR results are highlighted by molecular modeling of key analogs.

Full text of DOI:10.1021/jm070121a

4048
J. Med. Chem. 2007, 50, 4048-4060
C1′-Cycloalkyl Side Chain Pharmacophore in Tetrahydrocannabinols
Demetris P. Papahatjis,*,† Victoria R. Nahmias,† Spyros P. Nikas,‡ Thanos Andreou,† Shakiru O. Alapafuja,‡ Andrew Tsotinis,§
Jianxin Guo,‡ Pusheng Fan,‡ and Alexandros Makriyannis*,‡
Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vass. Constantinou, Athens 116-35 Greece,
Center for Drug DiscoVery, Northeastern UniVersity, 116 Mugar Life Sciences Building, 360 Huntington AVenue, Boston, Massachusetts 02115,
and Faculty of Pharmacy, Department of Pharmaceutical Chemistry, UniVersity of Athens, Panepistimioupoli-Zografou, 15771, Athens, Greece
ReceiVed January 30, 2007
In earlier work we have provided evidence for the presence of a subsite within the CB1 and CB2 cannabinoid
receptor binding domains of classical cannabinoids. This putative subsite corresponds to substituents on the
C1′-position of the C3-alkyl side chain, a key pharmacophoric feature in this class of compounds. We have
now refined this work through the synthesis of additional C1′-cycloalkyl compounds using newly developed
approaches. Our findings indicate that the C1′-cyclopropyl and C1′-cyclopentyl groups are optimal
pharmacophores for both receptors while the C1′-cyclobutyl group interacts optimally with CB1 but not
with CB2. The C1′-cyclohexyl analogs have reduced affinities for both CB1 and CB2. However, these
affinities are significantly improved with the introduction of a C2′-C3′ cis double bond that modifies
the available conformational space within the side chain and allows for a better accommodation of a six-
membered ring within the side chain subsite. Our SAR results are highlighted by molecular modeling of
key analogs.
Introduction
Pfizer and exemplified by the well-known ligand 5-(1,1-
dimethylheptyl)-2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)-
cyclohexyl]phenol (CP-55,940).24 Our continued efforts in
cannabinoid medicinal chemistry have sought to characterize
and optimize all four pharmacophores.14,16-23 It is now well-
established that, among these, the side chain is a key pharma-
cophore in determining a ligand’s affinity and pharmacological
potency for both CB1 and CB2. Previous SAR studies25-29
seeking to probe chain length and substitution pattern require-
ments have suggested that optimal activity is obtained with a
seven or eight carbon chain substituted with 1′,1′-dimethyl (1c,
Table 1) or 1′,2′-dimethyl groups. It has also been reported that
oxygen atoms and unsaturation within the chain or substitution
of the terminal carbon with carboxamido, cyano, azido, and
halogen groups are well-tolerated.16,27,30-36 Furthermore, studies
in which the side chain carries aryl, cycloalkyl, and the bulky
adamantyl groups,37-41 along with the synthesis and biological
testing of conformationally restricted side chain analogs,42 have
added to our understanding of the pharmacophoric features of
this side chain. Earlier work from our laboratories30,40,43-46 has
suggested the existence of district subsites within the CB1 and
CB2 cannabinoid receptor binding domains occupied by ring
substituents at the C1′-position of the (-)-∆8-tetrahydrocan-
nabinol structure [(-)-∆8-THCs, Table 1]. The stereochemical
features of this putative subsite also have been probed through
the synthesis of (-)-∆8-THC analogs bearing variously sized
sulfur- and oxygen-containing heterocyclic rings at C1′-posi-
tion.30,44,46 These earlier results have motivated us to extend
this work and further refine our understanding of the side chain
pharmacophoric requirements, with special attention to the C1′-
subsite. Toward this end, we have now expanded the group of
cyclic C1′-substituents to include the previously unexplored
respective cyclobutyl and cyclohexyl analogs. Additionally, we
have explored the pharmacophoric limits of side chain length
and the effects of conformational restriction at the C2′-C3′ bond
by synthesizing the C1′-cycloalkyl series of n-octyl analogs, as
well as those incorporating the respective C2′-C3′-cis-heptenyl
chains.
CB1a and CB2, currently the two well-characterized cannab-
inoid receptors,1-3 are relatively new members in the G-protein-
coupled receptor (GPCR) superfamily. CB1 is very densely
distributed throughout the central nervous system and in various
tissues in the periphery, whereas CB2 is present in immune cells2
and very recently has also been identified in the brain.4,5 Their
discovery6,7 and cloning,7-10 along with the isolation and
characterization of two families of endogenous cannabinergic
ligands, represented by arachidonoyl ethanolamine11 (ananda-
mide) and 2-arachidonoyl glycerol12,13 (2AG), have opened new
and exciting chapters in biochemistry and pharmacology.
Although the primary sequences for both CB1 and CB2 are
known, their three-dimensional structure and the amino acid
residues involved in ligand recognition, binding, and activation
have not been well-characterized. In the absence of any X-ray
crystallographic and nuclear magnetic resonance (NMR) data,
information about the structural requirements for ligand-
receptor interactions is obtained with the help of suitably
designed molecules that serve as probes in structure-activity
relationship (SAR) studies. Reviews of the existing SAR14-23
recognized four pharmacophores associated with cannabinergic
activity within the tricyclic cannabinoid structure. These include
a phenolic hydroxyl, a lipophilic alkyl side chain, as well as a
northern aliphatic and a southern aliphatic hydroxyl groups. The
first two are encompassed in the plant-derived classical can-
nabinoids, while all four pharmacophores are represented in
some of the synthetic nonclassical cannabinoids developed by
* To whom correspondence should be addressed. D.P.P.: Tel, +302-
10-7273885; fax, +302-10-7273831; e-mail, dpapah@eie.gr. A.M.: Tel,
+1-617-373-4200; fax, +1-617-373-7493; e-mail, a.makriyannis@neu.edu.
† National Hellenic Research Foundation.
‡ Northeastern University.
§ University of Athens.
a Abbreviations: SAR, structure-activity relationship; CB1, cannabinoid
receptor 1; CB2, cannabinoid receptor 2; GPCR, G-protein-coupled receptor;
2AG, 2-arachidonoyl glycerol; NMR, nuclear magnetic resonance; (-)-
∆8-THC, (-)-∆8-tetrahydrocannabinol; DIBAL-H, diisobutylaluminum
hydride; B-I-9-BBN, B-I-9-borabicyclo[3.3.1]nonane; p-TSA, p-toluene-
sulfonic acid.
10.1021/jm070121a CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/02/2007

C1′ Pharmacophore in Tetrahydrocannabinols
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17 4049
Chemistry
Table 1. Affinities (Ki) of ∆8-THC Analogs for CB1 and CB2
Cannabinoid Receptors (95% Confidence Limits)
Cyclo-bis-alkylation40,43,45,46,48 of (3,5-dimethoxyphenyl)ac-
etonitrile46 (2) using the appropriate R,ω-dibromoalkane, after
sequential deprotonation with potassium bis(trimethylsilyla-
mide), afforded the corresponding (3,5-dimethoxyphenyl)-
cycloalkane carbonitriles 3a, 3b, 3c, and 3d (62-93% yield),
bearing cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl
rings, respectively (Scheme 1). Reduction of the cyano group
with diisobutylaluminum hydride46,49 at -78 °C led to aldehydes
4a-4d (87-98% yield), which were further olefinated with
(butylmethylene)triphenylphosphorane or (pentylmethylene)-
triphenylphosphorane, affording intermediates 5a-5d (89-98%
yield) and 5e-5h (78-82% yield), bearing seven and eight
carbon atom side chains, respectively. This Wittig reaction
afforded exclusively the cis-alkene intermediates under the
experimental conditions used. Catalytic hydrogenation of 5b,
5d, 5f, 5g, and 5h led to the respective resorcinol dimethyl ethers
6b, 6d, 6f, 6g, and 6h in 93-99% yields. These were converted
to the corresponding resorcinols 7b, 7d, 7f, 7g, and 7h in 75-
97% yields, by demethylation using boron tribromide.46,50
Because of the sensitive nature of the cyclopropane ring, milder
reaction conditions were used in both the hydrogenation and
demethylation steps in order to obtain resorcinol 7e. Thus,
double bond reduction43,51 of the unsaturated precursor 5e in
the presence of p-toluenesulfonyl hydrazide and sodium acetate
in water/DME afforded the saturated analog 6e (76% yield),
which was then demethylated43,52 using B-I-9-borabicyclo[3.3.1]-
nonane (B-I-9-BBN) to give compound 7e in 95% yield.
Friedel-Crafts allylation30,43,46,53 of resorcinol derivatives 7b,
7d-7h with (+)-cis/trans-p-mentha-2,8-dien-1-ol54 produced
cannabidiols 8b, 8d-8h, respectively, in 46-92% yields.
Treating the latter with catalytic amounts of boron trifluoride
etherate resulted in a clean cyclization reaction, to produce the
respective tricyclic tetrahydrocannabinols 9b, 9d-9h (46-67%
yield). These were obtained as the desirable thermodynamically
more stable (-)-∆8-THC analogs, rather than their respective
(-)-∆9-isomers that can be isolated under controlled condi-
tions.34,55-57
The side chain unsaturated C1′-cylopropyl, C1′-cyclobutyl,
C1′-cyclopentyl, and C1′-cyclohexyl analogs 12a-12d were
synthesized from the respective unsaturated precursors 5a-5d,
as shown in Scheme 2. The phenolic hydroxyl groups in 5a-
5d were deprotected using the bulky B-I-9-BBN reagent (75-
94% yield) in order to avoid double bond bromination.
Subsequently, efficient coupling of the resulting resorcinols
10a-10d with (+)-cis/trans-p-mentha-2,8-dien-1-ol, catalyzed
by p-toluenesulfonic acid, produced the C1′-cyclopropyl-, C1′-
cyclobutyl-, C1′-cyclopentyl-, and C1′-cyclohexylcannabidiols
11a-11d, respectively, in 50-80% yields. Cyclization in the
presence of boron trifluoride etherate gave the corresponding
unsaturated cannabinoid analogs 12a-12d in 67-91% yields.
n-Heptyl-(-)-∆8-THC (1b, Table 1) represents a starting point
in our studies. Although its chemical synthesis and affinity
constant (Ki, value) for the CB1 receptor have been reported,26
the affinity of this compound for the CB2 receptor has not yet
been disclosed. We have now resynthesized 1b through a
modified procedure, shown in Scheme 2. We obtained 1b
following the methodology developed in our laboratory that
involved Wittig olefination of 3,5-dimethoxybenzaldehyde 13
and stepwise Friedel-Crafts allylation/dibenzopyran ring closure
under mild conditions.
a Affinities for CB1 and CB2 were determined using rat brain (CB1) or
mouse spleen (CB2) membranes and [3H]CP-55,940 as the radioligand
following previously described procedures.47 Ki values were obtained from
three independent experiments run in duplicate and are expressed as the
mean of the three values. b Reported previously.27 c Reported previously.19
d Reported previously.43 e Reported previously.46
As with earlier work, we used (-)-∆8-THC (1a) as our
prototype, favoring it over the less stable and almost equipotent
isomer (-)-∆9-THC. All analogs were tested for their respective
affinities for CB1 and CB2.
The results were used to explore the binding domain for the
cannabinoid side chain and to outline steric differences that
define receptor subtype recognition using computational mo-
lecular graphics. (-)-∆8-THC analogs carrying a seven-carbon
long side chain substituted with cyclopropyl, cyclobutyl, and
cyclopentyl groups at the C1′-position exhibited remarkably high
affinities for CB1 and CB2. Interestingly, within this series the
cyclobutylhexyl (9b) and the cyclobutylheptyl (9f) analogs
(Table 1) were found to have high affinities and significant
selectivities (8-fold and 20-fold, respectively) for CB1.
Receptor Binding Studies
The abilities of 1b, 9b, 9d-9h and 12a-12d to displace
radiolabeled CP-55,940 from purified rat forebrain synaptosomes

4050 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17
Papahatjis et al.
Scheme 1
and mouse spleen synaptosomes were determined, as described
in the Experimental Section. Ki values calculated from the
respective displacement curves are listed in Table 1 and reflect
the affinities of these tetrahydrocannabinol analogs for the CB1
and CB2 receptors.
length from seven to eight carbons generally leads to substantial
reduction in CB2 affinities, with only small or no effect on CB1
affinities. Thus, the C-8 side chain analogs (9e-9h) generally
exhibit enhanced CB1 selectivity.
(2) It was previously reported that the introduction of C1′-
alkyl substituents, as exemplified by the C1′-dimethyl analog,
leads to substantial enhancement in affinity for both CB1 and
CB2 (1c), when compared to the unsubstituted n-heptyl analog
(1b). We now show that transformation of the gem-dimethyl
substitution into the more compact cyclopropyl ring generally
leads to further enhancement in the ligand’s affinities for CB1
and CB2. Thus, in the substituted heptyl analogs the C1′-
cyclopropyl group distinguishes itself as an optimal pharma-
cophore for the C1′-subsite. Similarly, the conformationally
more expanded C1′-cyclopentyl analog (1e) maintains favorable
affinities for both receptors. This trend for enhancement in
affinity due to C1′-ring substituents is reversed in the respective
bulkier C1′-cyclohexyl analog (9d), an observation that clearly
defines the limits of steric tolerance of this C1′-subsite.
Results and Discussion
The series of (-)-∆8-tetrahydrocannabinol analogs reported
here allows us to further refine the stereochemical features of
the C3-alkyl side chain, the most critical pharmacophore in the
tricyclic cannabinoid structure. As an aid in the interpretation
of the data, we carried out molecular dynamics simulations to
fully explore the available conformational space of the key
analogs while focusing on the C3 side chain with its C1′-cyclic
substituents. To access all possible low-energy conformers, we
first performed high-temperature dynamics simulations followed
by simulated annealing. Such a process allows us to sample
the entire conformational space of the side chain beyond any
local minimum. These models represent families of the most
probable conformers for each analog and thus define the
pharmacophoric space available for interactions with the CB1
and CB2 binding sites. The models also emphasize steric
differences between ligand requirements for interaction with
CB1 and CB2. Our findings can be summarized as follows:
(1) As elaborated in earlier publications, extension of the
n-pentyl group side chain of the natural cannabinoids from five
to seven carbons leads to substantial enhancement of both CB1
and CB2 affinities. However, further extension of the side chain
(3) Unlike the C-3, C-5, and C-6 cyclic congeners, where
there is no distinct preference between CB1 and CB2, introduc-
ing a C1′-cyclobutyl ring clearly produces analogs with CB1
selectivity. Such selectivity can be accounted for, almost
exclusively, by reduced affinities for the CB2 receptor. This
CB1 selectivity holds true for the heptyl side chain analog (9b)
and is further enhanced in its octyl counterpart (9f). However,
the CB1 selectivity disappears in the respective C2′-C3′-cis-
heptene analog (12b), where the ligand’s affinities are now

C1′ Pharmacophore in Tetrahydrocannabinols
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17 4051
Figure 1. (Top row) Representative low-energy conformers for compounds 1d (A), 9b (B), and 1e (C) as determined using molecular mechanics/
molecular dynamics calculations. The two families of conformers in which the tricyclic ring system occupies the equatorial or the axial positions
of the cyclopentane ring in 1e (C) are represented by conformers a (green) and b (cyan), respectively. The models also identify differences between
the three analogs related to the orientation of their respective C3 side chains. (Bottom row) Superimposition results for compounds 1d, 9b, and 1e
using the carbon atoms of their aromatic rings as the superimposition points. All low-energy conformers for the cyclobutane ring of 9b (red) where
superimposed with those for the cyclopropane (D) and cyclopentane (E) rings of compounds 1d and 1e, respectively (green). Only carbon atoms
of the carbocyclic rings are shown here. The white highlighted area represents the different space required to accommodate the C1′ cyclobutyl ring
substituent of the 9b.
Scheme 2
equally high for both receptors. While seeking to interpret this
interesting observation, we have determined the preferred
conformations for the C1′-cyclopropyl- (1d), C1′-cyclopentyl-
(1e), and C1′-cyclobutylheptyl (9b) analogs (Figure 1). Earlier
conformational analysis of different C1′-dimethyl analogs in
classical and nonclassical cannabinoids consistently showed that
the C3 side chain adopts an orientation almost perpendicular to
the aromatic ring.34,58-62 Similar results were also obtained with

4052 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17
Papahatjis et al.
Figure 2. (A and B) Modeling of 9b (cyan) and 12b (green) showing
representative low-energy conformers. The models also incorporate a
family of 100 low-energy conformations for the C1′-cyclobutyl ring
for each analog. (C) Superimposition results of 9b and 12b using the
carbon atoms of their aromatic rings as the superimposition points.
Figure 3. Representative low-energy conformers for compounds 9d
(A) and 12d (B) as determined using molecular mechanics/molecular
dynamics calculations. The two families of conformers in which the
tricyclic ring system occupies the equatorial or the axial position of
the cyclohexane ring are represented by conformers a (green) and b
(cyan), respectively.
the side chains of the C1′-cyclopentyl and C1′-dithiolane
analogs.44,46 To identify any stereochemical differences, the
CB1-selective 9b was superimposed with 1d and 1e. A cursory
examination of the models reveals that the cyclobutyl group in
9b occupies a distinct stereochemical space that is not shared
by the other two. This is clearly seen when comparing each
analog’s preferred conformers. The cyclopropyl ring preferred
conformers are grouped in a space left of the cyclobutyl ring.
On the other hand, the cyclopentyl ring preferred conformers
fall into two families flanking the cyclobutyl ring’s conforma-
tional space. Our modeling exercise allows us to postulate a
subsite at the CB1 receptor in which the three-, four-, and five-
membered carbocyclic ring substituents can be accommodated
equally well. This results in enhanced CB1 affinities, as
compared to the respective unsubstituted analogs. The same
subsite can be invoked with the CB2 receptor. In this case,
however, the stereochemical requirements for optimal ligand-
receptor interaction are more stringent. While the three- and
five-membered ring analogs can interact optimally with the
subsite, the four-membered ring encounters some negative
pharmacophoric space that can be defined within our superim-
position models (see Figure 1). An additional factor that may
explain these observed differences in selectivity is the relative
orientation of the C1′-C2′ bond. Indeed, as can be observed in
Figure 1, the presence of the C1′-cyclobutyl ring with the fully
saturated side chain (9b) orients the side chain somewhat
differently than its respective three- and five-membered ring
congeners. While such variations in chain alignment can be
tolerated at the CB1 receptor, the chain orientation of the C1′-
cyclobutyl analog 9b may impede its optimal interaction with
CB2. Such a postulate can explain the approximately 8-fold
CB1/CB2 selectivity in 9b that is further enhanced in the
respective C-8 analog 9f, where CB1 selectivity is now nearly
20-fold.
the C1′-cyclohexyl analogs. Here, introducing a C2′-C3′ cis-
double bond leads to an analog (12d) with enhanced affinities
for both CB1 and CB2, when compared to its fully saturated
counterpart (9d). This suggests that introducing a cis-double
bond at the C2′-C3′ chain segments leads to improved
interactions with both receptors. We have now shown through
computer modeling that in both 9d and 12d the cyclohexyl ring
assumes two distinct conformations in which the C1′-C7′ chain
is in either the equatorial or axial position. Representative low-
energy conformers for each of these are shown in Figure 3 (the
full cluster simulation is available under Supporting Informa-
tion). According to our models, the C1′-C7′ side chain carbons
for the respective C3-heptyl (9d) and C3-cis-hept-2-enyl (12d)
analogs assume different preferred orientations, with 12d having
the most favorable pharmacophoric conformation. We postulate
that these differences in preferred side chain conformational
space may reflect differences in their affinities for CB1 and
CB2.
Conclusion
This study has helped to define the pharmacophoric elements
of the C3 classical cannabinoid side chain. It also provides
information needed for designing later generation analogs
possessing higher potencies and selectivities for each of the two
known cannabinoid receptors. This careful SAR study has
revealed the pharmacophoric restrictions of the C1′-subsite for
the CB2 receptor. The corresponding subsite in CB1 appears
to be more sterically tolerant. Our data also argue that the
putative groove with which the cannabinoid side chain interacts
is somewhat more confined in the CB2 receptor, in which the
C-8 side chain analogs are subjected to unfavorable steric
constrains. Future work will seek to further define the pharma-
cophoric constraints of the distal region of the classical
cannabinoid side chain.
Interestingly, the CB1 selectivity of the cyclobutyl analog
9b is lost in its C2′-C3′-cis-heptenyl analog 12b, which exhibits
equally high affinities for both the CB1 and CB2 receptors. This
observation can be explained by the superimposition of the
preferred conformers for 9b and 12b so that their respective
aromatic rings overlap (Figure 2). We observed that the
conformational space of the four-membered ring in 9b is distinct
from that of 12b. Additionally, the alignment of the C3 side
chain in 12b is distinctly different than that of 9b (Figure 2). It
can thus be argued that the C1′ substituent in 12b occupies a
more favorable CB2 pharmacophoric space and aligns its side
chain in a more favorable conformation compared to its
congener with the fully saturated side chain (9b).
Experimental Section
Chemistry. All reagents and solvents were purchased from
Aldrich Chemical Co., unless otherwise specified, and used without
further purification. All anhydrous reactions were performed under
a static argon or nitrogen atmosphere in flame-dried glassware using
scrupulously dry solvents. Flash column chromatography employed
silica gel 60 (230-400 mesh). All compounds were demonstrated
to be homogeneous by analytical TLC on precoated silica gel TLC
plates (Merck, 60 F245 on glass, layer thickness 250 µm), and
chromatograms were visualized by phosphomolybdic acid staining.
Melting points were determined on a micro-melting point apparatus
(4) Introducing a C2′-C3′ cis-double bond in the chain of
the cyclopropyl and cyclopentyl congeners (12a, 12c) produces
analogs with equal affinities for the CB1 and CB2 receptors
and quite comparable to those of their congeners carrying a fully
saturated side chain. However, a different trend is observed in
1
and are uncorrected. H NMR spectra were recorded on a Bruker
DMX-500 or on a Bruker AC 300 spectrometer operating at 500
and 300 MHz, respectively. All NMR spectra were recorded in

C1′ Pharmacophore in Tetrahydrocannabinols
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17 4053
CDCl3, unless otherwise stated, and chemical shifts are reported
in units of δ relative to internal TMS. Multiplicities are indicated
as br (broadened), s (singlet), d (doublet), t (triplet), q (quartet),
and m (multiplet), and coupling constants (J) are reported in hertz
(Hz). Low- and high-resolution mass spectra were performed at
the School of Chemical Sciences, University of Illinois at Urbana-
Champaign, or were recorded on Varian Star 3400CX (GC) and
Saturn 2000 (MS) instruments. Elemental analyses were obtained
by Baron Consulting Co., Milford, CT, or carried out by the
Microanalytical Section of the Institute of Organic and Pharma-
ceutical Chemistry, National Hellenic Research Foundation.
1-(3,5-Dimethoxyphenyl)cyclopropanecarbonitrile45 (3a). The
synthesis was carried out as with 3b (see text below) by using 2
(500 mg, 2.82 mmol), potassium bis(trimethylsilyl)amide (3.38 g,
16.92 mmol), and 1,2-dibromoethane (1.59 g, 8.46 mmol) in dry
THF (28.2 mL). The reaction was completed in 3 h at 0 °C: yield
mixture was stirred at the same temperature for 1 h and then
quenched by dropwise addition of potassium sodium tartrate (10%
solution in water). The resulting mixture was warmed to room
temperature, stirred vigorously for 40 min, and then diluted with
EtOAc. The organic phase was separated and the aqueous phase
extracted with EtOAc. The combined organic layer was washed
with brine and dried over Na2SO4, and the solvent was evaporated
under reduced pressure. The crude product was purified by flash
column chromatography on silica gel using 15% diethyl ether-
petroleum ether as eluent to give compound 4b as a viscous oil in
88% yield (339 mg): 1H NMR (500 MHz, CDCl3) δ 9.50 (s, 1H),
6.37 (t, J ) 2.3 Hz, 1H), 6.28 (d, J ) 2.3 Hz, 2H), 3.80 (s, 6H),
2.72-2.65 (m, 2H of the cyclobutane ring), 2.43-2.35 (m, 2H of
the cyclobutane ring), 2.03-1.93 (m, 1H of the cyclobutane ring),
1.93-1.86 (m, 1H of the cyclobutane ring); mass spectrum m/z
(relative intensity) 220 (M+, 84), 192 (100), 177 (30), 164 (64);
exact mass calcd for C13H17O3 (M+ + 1, FAB), 221.1178, found
221.1171. Anal. (C13H16O3) C, H.
1
62% (355 mg); viscous oil; H NMR (500 MHz, CDCl3) δ 6.44
(d, J ) 2.4 Hz, 2H), 6.38 (t, J ) 2.4 Hz, 1H), 3.80 (s, 6H), 1.71-
1.68 (dd, J ) 7.4 Hz, J ) 5.2 Hz, 2H), 1.41-1.38 (dd, J ) 7.4 Hz,
J ) 5.2 Hz, 2H); mass spectrum m/z (relative intensity) 203 (M+,
100), 188 (22), 172 (37). Anal. (C12H13NO2) C, H.
1-(3,5-Dimethoxyphenyl)cyclopentanecarboxaldehyde45,46 (4c).
The synthetic procedure was reported previously, along with
physical and spectral data.46
1-(3,5-Dimethoxyphenyl)cyclobutanecarbonitrile45 (3b). To
a solution of 2 (500 mg, 2.82 mmol) in dry THF (20 mL) at
-16 °C, under an argon atmosphere, was added potassium bis-
(trimethylsilyl)amide (1.69 g, 8.46 mmol). The mixture was stirred
at the same temperature for 3 min, and then a solution of
1,3-dibromopropane (626 mg, 3.10 mmol) in dry THF (8.2 mL)
was added dropwise. Following the addition, the reaction was stirred
for 2 h at -16 °C and then quenched by the addition of saturated
aqueous NH4Cl. The mixture was diluted with Et2O, the organic
layer was separated, and the aqueous phase was extracted with Et2O.
The combined organic layer was washed with brine and dried over
Na2SO4 and the solvent evaporated under reduced pressure to give
an oily residue. Purification by flash column chromatography (25%
diethyl ether-petroleum ether) afforded 379 mg (62% yield) of
the compound 3b as a viscous oil: 1H NMR (500 MHz, CDCl3) δ
6.53 (d, J ) 2.2 Hz, 2H), 6.40 (t, J ) 2.2 Hz, 1H), 3.80 (s, 6H),
2.82-2.76 (m, 2H of the cyclobutane ring), 2.64-2.56 (m, 2H of
the cyclobutane ring), 2.46-2.35 (m, 1H of the cyclobutane ring),
2.10-201 (m, 1H of the cyclobutane ring); mass spectrum m/z
(relative intensity) 217 (M+, 100), 189 (69), 160 (13), 133 (11);
exact mass calcd for C13H16NO2 (M+ + 1, FAB), 218.1181, found
218.1173. Anal. (C13H15NO2) C, H, N.
1-(3,5-Dimethoxyphenyl)cyclohexanecarboxaldehyde45 (4d).
The synthesis was carried out as described for 4b by using 3d (643
mg, 2.62 mmol) and diisobutylaluminum hydride (6.6 mL, 1 M
solution in CH2Cl2) in dry CH2Cl2 (26.2 mL). The reaction was
completed in 45 min at -78 °C: yield 89% (578 mg); colorless
1
oil; H NMR (300 MHz, CDCl3) δ 9.31 (s, 1H), 6.44 (d, J ) 1.8
Hz, 2H), 6.35 (t, J ) 1.8 Hz, 1H), 3.75 (s, 6H), 2.23 (m, 2H of the
cyclohexane ring), 1.80 (m, 2H of the cyclohexane ring), 1.61 (m,
3H of the cyclohexane ring), 1.45 (m, 2H of the cyclohexane ring),
1.25 (m, 1H of the cyclohexane ring); mass spectrum m/z (relative
intensity) 248 (M+, 7), 220 (100), 151 (37), 81 (13). Anal.
(C15H20O3) C, H.
3,5-Dimethoxy-1-[1-[(1Z)-1-hexenyl]cyclopropyl]benzene43 (5a).
The synthesis was carried out as with 5b (see text below) by using
pentyltriphenylphosphonium bromide (3.53 g, 8.55 mmol) in dry
THF (48 mL), potassium bis(trimethylsilyl)amide (1.67 g, 8.38
mmol), and a solution of 4a (352 mg, 1.71 mmol) in dry THF (5
mL). The reaction was completed in 45 min at 10 °C: yield 96%
(426 mg); colorless liquid; 1H NMR (300 MHz, CDCl3) δ 6.40 (d,
J ) 2.4 Hz, 2H), 6.26 (t, J ) 2.4 Hz, 1H), 5.65 (d, J ) 10.4 Hz,
1H, 2′-H), 5.51 (dt, J ) 10.4 Hz, J ) 7.0 Hz, 1H, 3′-H), 3.75 (s,
6H), 2.07 (m, 2H, 4′-CH2), 1.28 (m, 4H, 5′-CH2, 6′-CH2), 1.08
(half of AA′BB′ system, 2H of the cyclopropane ring), 0.97 (half
of AA′BB′ system, 2H, of the cyclopropane ring), 0.85 (t, J ) 7.0
Hz, 3H); mass spectrum m/z (relative intensity) 260 (M+, 45), 217
(100), 203 (31), 189 (33). Anal. (C17H24O2) C, H.
3,5-Dimethoxy-1-[1-[(1Z)-1-hexenyl]cyclobutyl]benzene (5b).
To a suspension of pentyltriphenylphosphonium bromide (3.18 g,
7.7 mmol) in dry THF (42.7 mL) at 0 °C, under an argon
atmosphere, was added potassium bis(trimethylsilyl)amide (1.5 g,
7.55 mmol). The mixture was warmed to 10 °C and stirred for an
additional 30 min to ensure complete formation of the orange
(butylmethylene)triphenylphosphorane. A solution of 4b (339 mg,
1.54 mmol) in dry THF (4 mL) was added dropwise to the resulting
slurry, at the same temperature. The reaction was stirred for 45
min and upon completion was quenched by the addition of saturated
aqueous NH4Cl. The organic layer was separated and the aqueous
phase was extracted with diethyl ether. The combined organic layer
was washed with brine and dried over Na2SO4, and the solvent
was evaporated under reduced pressure. The residue was purified
through a short column of silica gel using 5% diethyl ether-
petroleum ether as eluent to afford the compound 5b as a colorless
liquid in 98% yield (414 mg): 1H NMR (500 MHz, CDCl3) δ 6.50
(d, J ) 2.1 Hz, 2H), 6.28 (t, J ) 2.1 Hz, 1H), 5.78 (d, J ) 11.1
Hz, 1H, 2′-H), 5.28 (dt, J ) 11.1 Hz, J ) 7.5 Hz, 1H, 3′-H), 3.77
(s, 6H), 2.51-2.45 (m, 2H of the cyclobutane ring), 2.39-2.33
(m, 2H of the cyclobutane ring), 2.02-1.95 (m, 1H of the
cyclobutane ring), 1.92-1.81 (m, 3H, cyclobutane ring, 4′-CH2),
1.24-1.15 (m, 4H, 5′-CH2, 6′-CH2), 0.80 (t, J ) 7.0 Hz, 3H, 7′-
CH3); 13C NMR (CDCl3) δ 160.6, 151.9, 138.6, 130.8, 104.5, 96.9,
1-(3,5-Dimethoxyphenyl)cyclopentanecarbonitrile40,45,46 (3c).
The synthetic procedure was reported previously, along with
physical and spectral data.46
1-(3,5-Dimethoxyphenyl)cyclohexanecarbonitrile40,45 (3d). The
synthesis was carried out as described for 3b by using 2 (500 mg,
2.82 mmol), potassium bis(trimethylsilyl)amide (1.69 g, 8.46 mmol),
and 1,5-dibromopentane (713 mg, 3.10 mmol) in dry THF (28.2
mL). The reaction was completed in 2 h at 0 °C: yield 93% (643
1
mg); viscous oil; H NMR (300 MHz, CDCl3) δ 6.62 (d, J ) 1.8
Hz, 2H), 6.38 (t, J ) 1.8 Hz, 1H), 3.79 (s, 6H), 2.11 (m, 2H of the
cyclohexane ring), 1.85-1.67 (m, 8H of the cyclohexane ring); mass
spectrum m/z (relative intensity) 245 (M+, 100), 190 (93), 165 (31),
152 (29). Anal. (C15H19NO2) C, H.
1-(3,5-Dimethoxyphenyl)cyclopropanecarboxaldehyde43,45 (4a).
The synthesis was carried out as with 4b (see text below) by using
3a (355 mg, 1.75 mmol) and diisobutylaluminum hydride (4.4 mL,
1 M solution in CH2Cl2) in dry CH2Cl2 (17.5 mL). The reaction
was completed in 45 min at -78 °C: yield 98% (352 mg); viscous
1
oil; H NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 6.46 (d, J ) 2.4
Hz, 2H), 6.40 (t, J ) 2.4 Hz, 1H), 3.78 (s, 6H), 1.53 (half of AA′BB′
system, 2H of the cyclopropane ring), 1.37 (half of AA′BB′ system,
2H of the cyclopropane ring); mass spectrum m/z (relative intensity)
206 (M+, 44), 178 (100), 163 (38), 147 (27). Anal. (C12H14O3), C,
H.
1-(3,5-Dimethoxyphenyl)cyclobutanecarboxaldehyde45 (4b).
To a solution of 3b (379 mg, 1.75 mmol) in dry CH2Cl2 (17.5 mL)
at -78 °C under an argon atmosphere was added diisobutylalu-
minum hydride (4.4 mL, 1 M solution in CH2Cl2). The reaction

4054 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17
Papahatjis et al.
55.2, 47.9, 36.3, 31.5, 27.9, 22.4, 16.7, 13.9; mass spectrum m/z
(relative intensity) 274 (M+, 68), 231 (54), 217 (48), 203 (100),
189 (50); exact mass calcd for C18H27O2 (M+ + 1, FAB), 275.2011,
found 275.2011. Anal. (C18H26O2) C, H.
spectrum m/z (relative intensity) 276 (M+, 84), 248 (34), 205 (100),
192 (46), 178 (81), 165 (21), 152 (15); exact mass calcd for
C18H28O2, 276.2089, found 276.2093. Anal. (C18H28O2) C, H.
3,5-Dimethoxy-1-(1-hexylcyclohexyl)benzene (6d). The syn-
thesis was carried out as described for 6b by using 5d (683 mg,
2.26 mmol) and 10% Pd/C (123 mg) in EtOAc (20.6 mL). The
reaction was completed in 4 h at room temperature: yield 95%
(653 mg); colorless liquid; 1H NMR (300 MHz, CDCl3) δ 6.50 (d,
J ) 1.9 Hz, 2H), 6.31 (t, J ) 1.9 Hz, 1H), 3.80 (s, 6H), 2.02 (m,
2H of the cyclohexane ring), 1.55-1.40 (m, 10H, 2′-CH2, 8H of
the cyclohexane ring), 1.22-1.13 (m, 6H, 4′-CH2, 5′-CH2, 6′-CH2),
0.96 (m, 2H, 3′-CH2), 0.83 (t, J ) 6.7 Hz, 3H, 7′-CH3); 13C NMR
(CDCl3) δ 160.5, 150.2, 105.7, 96.3, 55.1, 43.8, 41.5, 36.4, 31.7,
30.0, 26.6, 23.4, 22.7, 22.5, 14.1; mass spectrum m/z (relative
intensity) 304 (M+, 30), 220 (100), 208 (28), 165 (25), 151 (42).
Anal. (C20H32O2) C, H.
3,5-Dimethoxy-1-(1-heptylcyclopropyl)benzene (6e). To a so-
lution of 5e (375 mg, 1.37 mmol) in 1,2-dimethoxyethane (38.1
mL) was added p-toluenesulfonhydrazide (3.06 g, 16.44 mmol).
The resulting mixture was refluxed and a solution of sodium acetate
(2.92 g, 35.62 mmol) in water (37 mL) was added over a period of
4 h. Stirring and reflux continued for another 8 h and the mixture
was then allowed to cool at room temperature. Water was added,
followed by dilution with diethyl ether. The organic layer was
separated and the aqueous phase was extracted with diethyl ether.
The combined organic layer was washed with brine and dried over
Na2SO4, and the solvent was evaporated under reduced pressure.
Purification through a column of silica gel using 2% diethyl ether-
petroleum ether yielded compound 6e as a colorless liquid (287
mg, 76% yield): 1H NMR (300 MHz, CDCl3) δ 6.46 (d, J ) 2.4
Hz, 2H), 6.29 (t, J ) 2.4 Hz, 1H), 3.78 (s, 6H), 1.54 (m, 2H, 2′-
CH2), 1.30-1.15 (m, 10H, 3′-CH2, 4′-CH2, 5′-CH2, 6′-CH2, 7′-
CH2), 0.85 (t, J ) 7.1 Hz, 3H, 8′-CH3), 0.76 (half of AA′BB′
system, 2H of the cyclopropane ring), 0.62 (half of AA′BB′ system,
2H of the cyclopropane ring); 13C NMR (CDCl3) δ 160.3, 148.1,
107.1, 97.6, 55.2, 40.3, 31.9, 29.7, 29.3, 27.2, 26.0, 22.6, 14.1, 13.2.
Anal. (C18H28O2) C, H.
3,5-Dimethoxy-1-(1-heptylcyclobutyl)benzene (6f). The syn-
thesis was carried out as described for 6b by using 5f (364 mg,
1.26 mmol) and 10% Pd/C (66 mg) in EtOAc (11.2 mL). The
reaction was completed in 6 h at room temperature: yield 98%
(358 mg); colorless liquid (spectroscopic and elemental analysis
data are available under Supporting Information).
3,5-Dimethoxy-1-(1-heptylcyclopentyl)benzene (6g). The syn-
thesis was carried out as described for 6b by using 5g (517 mg,
1.71 mmol) and 10% Pd/C (93 mg) in EtOAc (15.5 mL). The
reaction was completed in 6 h at room temperature: yield 98%
(511 mg); colorless liquid; 1H NMR (300 MHz, CDCl3) δ 6.43 (d,
J ) 1.8 Hz, 2H), 6.29 (t, J ) 1.8 Hz, 1H), 3.79 (s, 6H), 2.05-1.50
(m, 10H, 2′-CH2, 8H of the cyclopentane ring), 1.25-1.10 (m, 8H,
4′-CH2, 5′-CH2, 6′-CH2, 7′-CH2), 0.99 (m, 2H, 3′-CH2), 0.84 (t, J
) 7.1 Hz, 3H, 8′-CH3); 13C NMR (CDCl3) δ 160.2, 151.8, 105.6,
96.5, 55.2, 51.3, 41.9, 37.7, 31.9, 30.3, 29.2, 25.2, 23.2, 22.6, 14.1.
Anal. (C20H32O2) C, H.
3,5-Dimethoxy-1-[1-[(1Z)-1-hexenyl]cyclopentyl]benzene46 (5c).
The synthetic procedure was reported previously, along with
physical, spectral, and analytical data.46
3,5-Dimethoxy-1-[1-[(1Z)-1-hexenyl]cyclohexyl]benzene (5d).
The synthesis was carried out as described for 5b by using
pentyltriphenylphosphonium bromide (4.82 g, 11.65 mmol) in dry
THF (64.7 mL), potassium bis(trimethylsilyl)amide (2.28 g, 11.42
mmol), and a solution of 4d (578 mg, 2.33 mmol) in dry THF (6
mL). The reaction was completed in 45 min at 10 °C: yield 97%
(683 mg); colorless liquid; 1H NMR (300 MHz, CDCl3) δ 6.58 (d,
J ) 2.5 Hz, 2H), 6.28 (bs, 1H), 5.66 (d, J ) 11.6 Hz, 1H, 2′-H),
5.35 (dt, J ) 11.6 Hz, J ) 7.3 Hz, 1H, 3′-H), 3.77 (s, 6H), 1.94
(m, 2H of the cyclohexane ring), 1.70-1.57 (m, 9H, 4′-CH2, 7H
of the cyclohexane ring), 1.25 (m, 1H of the cyclohexane ring),
1.10 (m, 4H, 5′-CH2, 6′-CH2), 0.74 (t, J ) 6.7 Hz, 3H, 7′-CH3);
13C NMR (CDCl3) δ 160.3, 153.6, 136.3, 132.1, 105.2, 96.8, 55.2,
43.7, 38.9, 31.3, 28.2, 26.1, 22.8, 22.3, 13.9; mass spectrum m/z
(relative intensity) 302 (M+, 38), 259 (27), 245 (49), 219 (100),
194 (78), 177 (35), 151 (57); Anal.(C20H30O2) C, H.
3,5-Dimethoxy-1-[1-[(1Z)-1-heptenyl]cyclopropyl]benzene (5e).
The synthesis was carried out as described for 5b by using
hexyltriphenylphosphonium bromide (3.65 g, 8.55 mmol) in dry
THF (47.5 mL), potassium bis(trimethylsilyl)amide (1.67 g, 8.38
mmol), and a solution of 4a (352 mg, 1.71 mmol) in dry THF (5
mL). The reaction was completed in 45 min at 10 °C: yield 80%
(375 mg); colorless liquid (spectroscopic and elemental analysis
data are available under Supporting Information).
3,5-Dimethoxy-1-[1-[(1Z)-1-heptenyl]cyclobutyl]benzene (5f).
The synthesis was carried out as described for 5b by using
hexyltriphenylphosphonium bromide (3.29 g, 7.7 mmol) in dry THF
(42.8 mL), potassium bis(trimethylsilyl)amide (1.51 g, 7.55 mmol),
and a solution of 4b (339 mg, 1.54 mmol) in dry THF (4 mL). The
reaction was completed in 1 h at 10 °C: yield 82% (364 mg);
colorless liquid (spectroscopic and elemental analysis data are
available under Supporting Information).
3,5-Dimethoxy-1-[1-[(1Z)-1-heptenyl]cyclopentyl]benzene (5g).
The synthesis was carried out as described for 5b by using
hexyltriphenylphosphonium bromide (4.57 g, 10.7 mmol) in dry
THF (59.4 mL), potassium bis(trimethylsilyl)amide (2.09 g, 10.49
mmol), and a solution of 4c (500 mg, 2.14 mmol) in dry THF (7
mL). The reaction was completed in 45 min at 10 °C: yield 80%
(517 mg); colorless liquid (spectroscopic and elemental analysis
data are available under Supporting Information).
3,5-Dimethoxy-1-[1-[(1Z)-1-heptenyl]cyclohexyl]benzene (5h).
The synthesis was carried out as described for 5b by using
hexyltriphenylphosphonium bromide (4.98 g, 11.65 mmol) in dry
THF (64.7 mL), potassium bis(trimethylsilyl)amide (2.28 g, 11.42
mmol), and a solution of 4d (578 mg, 2.33 mmol) in dry THF (7
mL). The reaction was completed in 45 min at 10 °C: yield 78%
(575 mg); colorless liquid (spectroscopic and elemental analysis
data are available under Supporting Information).
3,5-Dimethoxy-1-(1-hexylcyclobutyl)benzene (6b). To a solu-
tion of 5b (414 mg, 1.51 mmol) in EtOAc (13.7 mL) was added
10% Pd/C (75 mg), and the resulting suspension was stirred
vigorously under hydrogen atmosphere overnight at room temper-
ature. The catalyst was removed by filtration through Celite and
the filtrate was evaporated under reduced pressure to afford the
crude product. Purification through a short column of silica gel
using 5% diethyl ether-petroleum ether yielded compound 6b as
a colorless liquid (388 mg, 93% yield): 1H NMR (500 MHz,
CDCl3) δ 6.27 (t, J ) 2.0 Hz, 1H), 6.25 (d, J ) 2.0 Hz, 2H), 3.79
(s, 6H), 2.34-2.26 (m, 2H of the cyclobutane ring), 2.09-1.97
(m, 3H of the cyclobutane ring), 1.83-1.76 (m, 1H of the
cyclobutane ring), 1.74-1.69 (m, 2H, 2′-CH2), 1.26-1.15 (m, 6H,
4′-CH2, 5′-CH2, 6′-CH2), 1.05-0.97 (m, 2H, 3′-CH2), 0.84 (t, J )
7.1 Hz, 3H, 7′-CH3); 13C NMR (CDCl3) δ 160.3, 153.4, 104.2,
96.6, 55.2, 46.8, 42.5, 32.8, 31.8, 29.8, 24.6, 22.7, 15.8, 14.1; mass
3,5-Dimethoxy-1-(1-heptylcyclohexyl)benzene (6h). The syn-
thesis was carried out as described for 6b by using 5h (575 mg,
1.82 mmol) and 10% Pd/C (104 mg) in EtOAc (16.5 mL). The
reaction was completed in 7 h at room temperature: yield 99%
(572 mg); colorless liquid (spectroscopic and elemental analysis
data are available under Supporting Information).
5-(1-Hexylcyclobutyl)resorcinol (7b). To a solution of 6b (388
mg, 1.41 mmol) in dry CH2Cl2 (47 mL) at -78 °C under an argon
atmosphere was added boron tribromide (3.4 mL, 1 M solution in
CH2Cl2). Following this addition, the reaction temperature was
gradually raised over a period of 3 h to 0 °C, and the stirring
continued at that temperature until the reaction was completed (28
h). Unreacted boron tribromide was destroyed by adding methanol
at -78 °C. The resulting mixture was warmed at room temperature
and stirred for 40 min, and the volatiles were removed in vacuo.
The residue was diluted with EtOAc and washed with saturated
NaHCO3 solution, water, and brine. The organic layer was dried

C1′ Pharmacophore in Tetrahydrocannabinols
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17 4055
over Na2SO4, filtered, and concentrated under reduced pressure.
Purification by flash column chromatography (45% diethyl ether-
petroleum ether) afforded 340 mg (97% yield) of the compound
7b as a slightly brown viscous oil: 1H NMR (500 MHz, CDCl3) δ
6.17-6.13 (m, 3H, ArH), 5.84 (br s, 2H, OH), 2.30-2.21 (m, 2H
of the cyclobutane ring), 2.06-1.98 (m, 3H, of the cyclobutane
ring), 1.82-1.77 (m, 1H of the cyclobutane ring), 1.71-1.67 (m,
2H, 2′-CH2), 1.25-1.15 (m, 6H, 4′-CH2, 5′-CH2, 6′-CH2), 1.02-
0.97 (m, 2H, 3′-CH2), 0.84 (t, J ) 6.9 Hz, 3H, 7′-CH3); 13C NMR
(CDCl3) δ 156.2, 154.3, 105.7, 99.7, 46.6, 42.5, 32.7, 31.8, 29.8,
24.6, 22.7, 15.8, 14.1; mass spectrum m/z (relative intensity) 248
(M+, 86), 220 (13), 177 (35), 163 (14), 150 (100), 91 (7), 77 (8);
exact mass calcd for C16H24O2 248.1776, found 248.1779. Anal.
(C16H24O2) C, H.
5-(1-Hexylcyclohexyl)resorcinol (7d). The synthesis was carried
out as described for 7b by using 6d (653 mg, 2.15 mmol) and boron
tribromide (5.2 mL, 1 M solution in CH2Cl2), in anhydrous CH2-
Cl2 (71.6 mL). The reaction was completed in 72 h at -78 °C to
room temperature: yield 96% (569 mg); slightly brown viscous
oil; 1H NMR (300 MHz, CDCl3) δ 6.39 (d, J ) 1.9 Hz, 2H), 6.18
(t, J ) 1.9 Hz, 1H), 5.14 (br s, 2H, OH), 1.93 (m, 2H of the
cyclohexane ring), 1.49-1.36 (m, 10H, 2′-CH2, 8H of the cyclo-
hexane ring), 1.25-1.10 (m, 6H, 4′-CH2, 5′-CH2, 6′-CH2), 0.92
(m, 2H, 3′-CH2), 0.82 (t, J ) 6.7 Hz, 3H, 7′-CH3); 13C NMR
(CDCl3) δ 156.2, 151.4, 106.9, 100.0, 43.6, 41.2, 36.2, 31.7, 30.0,
26.5, 23.4, 22.7, 22.4, 14.1. Anal. (C18H28O2) C, H.
5-(1-Heptylcyclopropyl)resorcinol (7e). To a solution of 6e (287
mg, 1.04 mmol) in anhydrous hexane (20 mL) under an argon
atmosphere was added B-I-9-borabicyclo[3.3.1]nonane (3.3 mL, 1
M solution in hexanes) at room temperature. The resulting mixture
was stirred for 2 h until the reaction was completed. The reaction
mixture was then concentrated and the residual was diluted with
anhydrous Et2O (3 mL). A solution of ethanolamine (209 mg, 3.43
mmol) in anhydrous THF (1.56 mL) was added, causing spontane-
ous precipitation of a white solid. The resulting suspension was
stirred for 1 h, the white solid was filtered off, and the filtrate was
evaporated. Purification by flash column chromatography (2%
methanol, 18% ethyl acetate-petroleum ether) afforded 246 mg
(95% yield) of the compound 7e as a viscous oil: 1H NMR (300
MHz, CDCl3) δ 6.35 (br s, 2H), 6.17 (br s, 1H), 5.24 (br s, 2H,
OH), 1.47 (m, 2H, 2′-CH2), 1.25-1.20 (m, 10H, 3′-CH2, -4′-CH2,
5′-CH2, 6′-CH2, 7′-CH2), 0.86 (t, J ) 6.7 Hz, 3H, 8′-CH3), 0.72
(half of AA′BB′ system, 2H of the cyclopropane ring), 0.59 (half
of AA′BB′ system, 2H of the cyclopropane ring); 13C NMR (CDCl3)
δ 156.3, 148.9, 108.4, 100.4, 40.1, 31.9, 29.7, 29.3, 27.2, 25.6,
22.6, 14.1, 13.2.
(-)-2-[3-3,4-trans-p-Menthadien-(1,8)-yl]-5-(1-hexylcyclobu-
tyl)resorcinol (8b). To a solution of 7b (340 mg, 1.37 mmol) in
dry benzene (13.7 mL) at 10 °C under an argon atmosphere was
added p-toluenesulfonic acid (49 mg, 0.26 mmol), followed by the
addition of a solution of (+)-cis/trans-p-mentha-2,8-dien-1-ol (292
mg, 1.92 mmol) in dry benzene (4 mL). The reaction mixture was
stirred at 10-20 °C for 1 h, and at which time TLC indicated the
complete consumption of starting material. The reaction mixture
was diluted with ethyl acetate and washed with saturated NaHCO3
solution, water, and brine. The organic layer was dried over Na2-
SO4, filtered, and concentrated under reduced pressure. Purification
by flash column chromatography (7% diethyl ether-petroleum
ether) afforded 329 mg (63% yield) of the title compound 8b as
colorless viscous oil: 1H NMR (300 MHz, CDCl3) δ 6.11 (br s,
2H, ArH), 5.95 (br s, 1H, OH), 5.58 (s, 1H, 2-H), 4.73 (br s, 1H,
OH), 4.65 (s, 1H, >CdCH2), 4.54 (s, 1H, >CdCH2), 3.83 (m,
1H, 3-H), 2.38 (dt, J ) 10.5 Hz, J ) 4.1 Hz, 1H, 4-H), 2.32-1.60
(m, 18H, 2′-CH2, cyclobutane ring, 5-CH2, 6-CH2, and especially
1.79, s, 3H, 7-CH3 and 1.63, s, 3H, 10-CH3), 1.25-1.10 (m, 6H,
4′-CH2, 5′-CH2, 6′-CH2), 0.94 (m, 2H, 3′-CH2), 0.82 (t, J ) 6.8
Hz, 3H, 7′-CH3); mass spectrum m/z (relative intensity) 382 (M+,
97), 355 (28), 339 (25), 325 (17), 311 (72), 299 (83), 271 (100),
261 (43), 243 (35), 229 (22), 201 (40), 119 (35), 91 (45); exact
mass calcd for C26H38O2 382.2872, found 382.2862. Anal. (C26H38O2)
C, H.
(-)-2-[3-3,4-trans-p-Menthadien-(1,8)-yl]-5-(1-hexylcyclohexyl)-
resorcinol (8d). The synthesis was carried out as described for 8b
by using 7d (569 mg, 2.06 mmol), (+)-cis/trans-p-mentha-2,8-dien-
1-ol (438 mg, 2.88 mmol), and p-toluenesulfonic acid (74 mg, 0.39
mmol) in anhydrous benzene (20.6 mL): yield 92% (777 mg);
1
colorless viscous oil; H NMR (300 MHz, CDCl3) δ 6.33 (br s,
2H, ArH), 5.91 (br s, 1H, OH), 5.61 (s, 1H, 2-H), 4.65 (br s, 2H,
>CdCH2, OH), 4.53 (s, 1H, >CdCH2), 3.81 (d, J ) 8.8 Hz, 1H,
3-H), 2.37 (dt, J ) 10.5 Hz, J ) 4.3 Hz, 1H, 4-H), 2.28-2.07 (m,
2H), 2.01-1.75 (m, 7H, especially 1.80, s, 3H, 7-CH3), 1.65-1.10
(m, 19H, 2′-CH2, 4′-CH2, 5′-CH2, 6′-CH2, 8H of the cyclohexane
ring and especially 1.62, s, 3H, 10-CH3), 0.88 (m, 2H, 3′-CH2),
0.81 (t, J ) 6.9 Hz, 3H, 7′-CH3); mass spectrum m/z (relative
intensity) 410 (M+, 33), 395 (11), 368 (5), 327 (100), 289 (9), 257
(7); exact mass calcd for C28H42O2 410.3185, found 410.3185. Anal.
(C28H42O2) C, H.
(-)-2-[3-3,4-trans-p-Menthadien-(1,8)-yl]-5-(1-heptylcyclo-
propyl)resorcinol (8e). The synthesis was carried out as described
for 8b by using 7e (246 mg, 0.99 mmol), (+)-cis/trans-p-mentha-
2,8-dien-1-ol (211 mg, 1.39 mmol), and p-toluenesulfonic acid (36
mg, 0.19 mmol) in anhydrous benzene (9.9 mL): yield 46% (174
mg); colorless viscous oil; 1H NMR (300 MHz, CDCl3) δ 6.34 (br
s, 2H, ArH), 5.99 (br s, 1H, OH), 5.57 (s, 1H, 2-H), 4.66 (br s, 2H,
>CdCH2, ÃΗ), 4.54 (s, 1H, >CdCH2), 3.82 (d, J ) 8.7 Hz, 1H,
3-H), 2.37 (dt, J ) 10.4 Hz, J ) 3.7 Hz, 1H, 4-H), 2.26-2.02 (m,
2H), 1.88-1.74 (m, 5H, especially 1.79, s, 3H, 7-CH3), 1.64 (s,
3H, 10-CH3), 1.45 (m, 2H, 2′-CH2), 1.30-1.18 (m, 10H 3′-CH2,
4′-CH2, 5′-CH2, 6′-CH2, 7′-CH2), 0.85 (t, J ) 6.7 Hz, 3H, 8′-CH3),
0.71 (half of AA′BB′ system, 2H of the cyclopropane ring), 0.57
(half of AA′BB′ system, 2H of the cyclopropane ring); 13C NMR
(CDCl3) δ 149.4, 145.7, 140.2, 124.0, 113.9, 110.8, 46.0, 40.0, 37.4,
31.8, 30.4, 29.7, 29.3, 28.3, 27.2, 25.1, 23.7, 22.7, 20.7, 14.1, 13.3,
13.2; mass spectrum (FAB) m/z (relative intensity) 383 (M+ + 1,
98), 261 (100), 135 (93); exact mass calcd for C26H39O2 (M+ + 1,
FAB) 383.2950, found 383.2950. Anal. (C26H38O2) C, H.
(-)-2-[3-3,4-trans-p-Menthadien-(1,8)-yl]-5-(1-heptylcyclobu-
tyl)resorcinol (8f). The synthesis was carried out as described for
8b by using 7f (303 mg, 1.16 mmol), (+)-cis/trans-p-mentha-2,8-
dien-1-ol (247 mg, 1.62 mmol), and p-toluenesulfonic acid (42 mg,
0.22 mmol) in anhydrous benzene (11.6 mL): yield 76% (349 mg);
colorless viscous oil (spectroscopic and elemental analysis data are
available under Supporting Information).
5-(1-Heptylcyclobutyl)resorcinol (7f). The synthesis was carried
out as described for 7b by using 6f (358 mg, 1.23 mmol) and boron
tribromide (3 mL, 1 M solution in CH2Cl2), in anhydrous CH2Cl2
(41 mL). The reaction was completed in 72 h at -78 °C to room
temperature: yield 94% (303 mg); slightly brown viscous oil
(spectroscopic and elemental analysis data are available under
Supporting Information).
5-(1-Heptylcyclopentyl)resorcinol (7g). The synthesis was
carried out as described for 7b by using 6g (511 mg, 1.68 mmol)
and boron tribromide (4.0 mL, 1 M solution in CH2Cl2), in
anhydrous CH2Cl2 (56 mL). The reaction was completed in 72 h
at -78 °C to room temperature: yield 75% (348 mg); slightly
brown viscous oil; 1H NMR (300 MHz, CDCl3) δ 6.36 (d, J ) 1.8
Hz 2H), 6.19 (bs, 1H), 5.89 (bs, 2H, OH), 1.78-1.43 (m, 10H,
2′-CH2, 8H of the cyclopentane ring), 1.14 (m, 8H, -4′-CH2, 5′-
CH2, 6′-CH2, 7′-CH2), 0.91 (m, 2H, 3′-CH2), 0.83 (t, J ) 6.7 Hz,
3H, 8′-CH3); 13C NMR (CDCl3) δ 156.1, 152.7, 106.8, 99.8, 51.1,
41.8, 37.6, 31.9, 30.3, 29.2, 25.2, 23.2, 22.6, 14.1.
5-(1-Heptylcyclohexyl)resorcinol (7h). The synthesis was car-
ried out as described for 7b by using 6h (572 mg, 1.80 mmol) and
boron tribromide (4.3 mL, 1 M solution in CH2Cl2), in anhydrous
CH2Cl2 (60 mL). The reaction was completed in 72 h at -78 °C to
room temperature: yield 92% (482 mg); slightly brown viscous
oil (spectroscopic and elemental analysis data are available under
Supporting Information).
(-)-2-[3-3,4-trans-p-Menthadien-(1,8)-yl]-5-(1-heptylcyclo-
pentyl)resorcinol (8g). The synthesis was carried out as described
for 8b by using 7g (348 mg, 1.26 mmol), (+)-cis/trans-p-mentha-
2,8-dien-1-ol (268 mg, 1.76 mmol), and p-toluenesulfonic acid (46

4056 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17
Papahatjis et al.
mg, 0.24 mmol) in anhydrous benzene (12.6 mL): yield 90% (463
mg); colorless viscous oil; 1H NMR (300 MHz, CDCl3) δ 6.29 (br
s, 2H, ArH), 5.95 (br s, 1H, OH), 5.59 (s, 1H, 2-H), 4.65 (br s, 2H,
>CdCH2, ÃΗ), 4.54 (s, 1H, >CdCH2), 3.81 (d, J ) 8.5 Hz, 1H,
3-H), 2.37 (dt, J ) 10.4 Hz, J ) 4.3 Hz, 1H, 4-H), 2.32-2.05 (m,
2H), 1.88-1.77 (m, 7H, especially 1.79, s, 3H, 7-CH3), 1.73-1.57
(m, 9H, especially 1.62, s, 3H, 10-CH3), 1.46 (m, 2H, 2′-CH2),
1.25-1.06 (m, 8H, 4′-CH2, 5′-CH2, 6′-CH2, 7′-CH2), 0.93 (m, 2H,
3′-CH2), 0.83 (t, J ) 6.7 Hz, 3H, 8′-CH3); mass spectrum (FAB)
m/z (relative intensity) 411 (M+ + 1, 84), 410 (M+, 68), 342 (58),
327 (100), 289 (67); exact mass calcd for C28H43O2 (M+ + 1, FAB)
411.3263, found 411.3263. Anal. (C28H42O2) C, H.
(-)-2-[3-3,4-trans-p-Menthadien-(1,8)-yl]-5-(1-heptylcyclo-
hexyl)resorcinol (8h). The synthesis was carried out as described
for 8b by using 7h (482 mg, 1.67 mmol), (+)-cis/trans-p-mentha-
2,8-dien-1-ol (356 mg, 2.34mmol), and p-toluenesulfonic acid (61
mg, 0.32 mmol) in anhydrous benzene (16.7 mL): yield 86% (611
mg); colorless viscous oil (spectroscopic and elemental analysis
data are available under Supporting Information).
(6aR-trans)-3-(1-Hexylcyclobutyl)-6a,7,10,10a-tetrahydro-
6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol (9b). To a solution of
8b (329 mg, 0.86 mmol) in anhydrous CH2Cl2 (24.6 mL) at 0 °C
under an argon atmosphere was added boron trifluoride etherate
(0.75 mL, 6.02 mmol). Following the addition the mixture was
stirred at 0 °C for 1 h and then at room temperature for 7 h. The
reaction was quenched by the addition of saturated NaHCO3
solution, and the volatiles were removed under reduced pressure.
The crude residual was diluted with EtOAc and the organic layer
was washed with water and brine and dried over Na2SO4. Solvent
evaporation and purification by flash column chromatography on
silica gel (5% diethyl ether-petroleum ether) afforded 168 mg (51%
yield) of the title compound 9b as viscous oil: 1H NMR (300 MHz,
CDCl3) δ 6.18 (d, J ) 1.9 Hz, 1H, 4-H), 6.01 (d, J ) 1.9 Hz, 1H,
2-H), 5.43 (br s, 1H, 8-H), 4.69 (s, 1H, OH), 3.20 (dd, J ) 16.2
Hz, J ) 4.0 Hz, 1H, 10R-H), 2.68 (m, 1H, 10a-H), 2.32-2.13 (m,
3H, 7R-H, 2H of the cyclobutane ring), 2.02-1.59 (m, 12H, 2′-
CH2, 4H of the cyclobutane ring, 10â-H, 7â-H, 6a-H, especially
1.70, s, 9-CH3), 1.38 (s, 3H, 6â-CH3), 1.32-1.13 (m, 6H, 4′-CH2,
5′-CH2, 6′-CH2), 1.11 (s, 3H, 6R-CH3), 1.01 (m, 2H, 3′-CH2), 0.84
(t, J ) 6.7 Hz, 3H, 7′-CH3); mass spectrum m/z (relative intensity)
382 (M+, 100), 354 (22), 311 (51), 298 (25), 271 (14), 200 (6);
exact mass calcd for C26H38O2 382.2872, found 382.2865. Anal.
(C26H38O2) C, H.
CH2), 1.10 (s, 3H, 6R-CH3), 0.85 (t, J ) 6.7 Hz, 3H, 8′-CH3), 0.72
(half of AA′BB′ system, 2H of the cyclopropane ring), 0.56 (half
of AA′BB′ system, 2H of the cyclopropane ring); 13C NMR (CDCl3)
δ 154.5, 154.4, 145.4, 134.7, 119.3, 110.6, 110.3, 107.7, 44.8, 39.9,
35.9, 31.9, 31.5, 29.8, 29.3, 27.9, 27.6, 27.2, 25.0, 23.5, 22.7, 18.5,
14.1, 13.5, 13.2; mass spectrum (FAB) m/z (relative intensity) 383
(M+ + 1, 100), 261 (17); exact mass calcd for C26H39O2 (M+ + 1,
FAB) 383.2950, found 383.2950. Anal. (C26H38O2) C, H.
(6aR-trans)-3-(1-Heptylcyclobutyl)-6a,7,10,10a-tetrahydro-
6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol (9f). The synthesis was
carried out as described for 9b by using 8f (349 mg, 0.88 mmol)
and boron trifluoride etherate (0.55 mL, 4.4 mmol) in anhydrous
CH2Cl2 (25.1 mL): yield 65% (227 mg); colorless viscous oil
(spectroscopic and elemental analysis data are available under
Supporting Information).
(6aR-trans)-3-(1-Heptylcyclopentyl)-6a,7,10,10a-tetrahydro-
6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol (9g). The synthesis
was carried out as described for 9b by using 8g (463 mg, 1.13
mmol) and boron trifluoride etherate (0.71 mL, 5.65 mmol) in
anhydrous CH2Cl2 (32.3 mL): yield 52% (241 mg); colorless
1
viscous oil; H NMR (300 MHz, CDCl3) δ 6.33 (d, J ) 1.8 Hz,
1H, 4-H), 6.16 (d, J ) 1.8 Hz, 1H, 2-H), 5.42 (d, J ) 4.3 Hz, 1H,
8-H), 4.62 (s, 1H, OH), 3.18 (dd, J ) 16.2 Hz, J ) 3.4 Hz, 1H,
10R-H), 2.69 (ddd as dt, J ) 10.4 Hz, J ) 4.9 Hz, 1H, 10a-H),
2.14 (m, 1H, 7R-H), 1.93-1.58 (m, 14H, 8H of the cyclopentane
ring, 10â-H, 7â-H, 6a-H, especially 1.70, s, 9-CH3), 1.48 (m, 2H,
2′-CH2), 1.38 (s, 3H, 6â-CH3), 1.25-1.11 (m, 8H, 4′-CH2, 5′-CH2,
6′-CH2, 7′-CH2), 1.10 (s, 3H, 6R-CH3), 0.97 (m, 2H, 3′-CH2), 0.83
(t, J ) 6.7 Hz, 3H, 8′-CH3); mass spectrum (FAB) m/z (relative
intensity) 411 (M+ + 1, 100) 312 (47); exact mass calcd for
C28H43O2 (M+ + 1, FAB), 411.3263, found 411.3263. Anal.
(C28H42O2) C, H.
(6aR-trans)-3-(1-Heptylcyclohexyl)-6a,7,10,10a-tetrahydro-
6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol (9h). The synthesis
was carried out as described for 9b by using 8h (611 mg, 1.44
mmol) and boron trifluoride etherate (0.90 mL, 7.2 mmol) in
anhydrous CH2Cl2 (41.1 mL): yield 67% (409 mg); colorless
viscous oil (spectroscopic and elemental analysis data are available
under Supporting Information).
5-[1-[(1Z)-1-Hexenyl]cyclopropyl]resorcinol (10a). The syn-
thesis was carried out as described for 7e by using 5a (426 mg,
1.64 mmol) and B-I-9-borabicyclo[3.3.1]nonane (5.25 mL, 1 M
solution in hexanes) in anhydrous hexane (32.8 mL). The reaction
was completed in 2 h at room temperature: yield 89% (339 mg);
slightly brown viscous oil; 1H NMR (300 MHz, CDCl3) δ 6.27 (d,
J ) 2.4 Hz, 2H), 6.13 (t, J ) 2.4 Hz, 1H), 5.63-5.48 (m, 2H,
2′-H, 3′-H), 4.42 (br s, 2H, OH), 2.04 (m, 2H, 4′-CH2), 1.26 (m,
4H, 5′-CH2, 6′-CH2), 1.03 (half of AA′BB′ system, 2H of the
cyclopropane ring), 0.95 (half of AA′BB′ system, 2H of the
cyclopropane ring), 0.84 (t, J ) 6.7 Hz, 3H, 7′-CH3); 13C NMR
(CDCl3) δ 156.5, 149.1, 135.0, 131.9, 105.9, 99.9, 31.4, 28.2, 22.8,
22.5, 17.9, 13.9.
5-[1-[(1Z)-1-Hexenyl]cyclobutyl]resorcinol (10b). The synthesis
was carried out as described for 7e by using 5b (414 mg, 1.51
mmol) and B-I-9-borabicyclo[3.3.1]nonane (4.8 mL, 1 M solution
in hexanes) in anhydrous hexane (30.2 mL). The reaction was
completed in 2 h at room temperature: yield 89% (331 mg); slightly
brown viscous oil; 1H NMR (500 MHz, CDCl3) δ 6.40 (d, J ) 2.1
Hz, 2H), 6.16 (t, J ) 2.1 Hz, 1H), 5.76 (d, J ) 11.0 Hz, 1H, 2′-H),
5.29 (dt, J ) 11.0 Hz, J ) 7.5 Hz, 1H, 3′-H), 4.84 (br s, 2H, OH),
2.47-2.41 (m, 2H of the cyclobutane ring), 2.36-2.30 (m, 2H of
the cyclobutane ring), 2.01-1.93 (m, 1H of the cyclobutane ring),
1.90-1.79 (m, 3H, 1H of the cyclobutane ring, 4′-CH2), 1.21-
1.15 (m, 4H, 5′-CH2, 6′-CH2), 0.81 (t, J ) 7.0 Hz, 3H, 7′-CH3);
13C NMR (CDCl3) δ 156.3, 148.7, 135.0, 131.9, 105.8, 99.5, 34.5,
34.2, 31.4, 28.2, 22.8, 22.5, 18.2; mass spectrum m/z (relative
intensity) 246 (M+, 57), 218 (17), 203 (19), 189 (56), 175 (100),
161 (43), 110 (33), 91 (13); exact mass calcd for C16H22O2
246.1620, found 246.1620.
(6aR-trans)-3-(1-Hexylcyclohexyl)-6a,7,10,10a-tetrahydro-
6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol (9d). The synthesis
was carried out as described for 9b by using 8d (777 mg, 1.90
mmol) and boron trifluoride etherate (1.19 mL, 9.5 mmol), in
anhydrous CH2Cl2 (54.3 mL): yield 63% (492 mg); colorless
1
viscous oil; H NMR (300 MHz, CDCl3) δ 6.37 (d, J ) 1.7 Hz,
1H, 4-H), 6.20 (d, J ) 1.7 Hz, 1H, 2-H), 5.42 (d, J ) 4.5 Hz, 1H,
8-H), 4.70 (s, 1H, OH), 3.19 (dd, J ) 16.3 Hz, J ) 4.1 Hz, 1H,
10R-H), 2.69 (m, 1H, 10a-H), 2.13 (m, 1H, 7R-H), 1.93-1.72 (m,
5H, 2H of the cyclohexane ring, 10â-H, 7â-H, 6a-H), 1.70 (s, 3H,
9-CH3), 1.48-1.30 (m, 13H, 8H of the cyclohexane ring, 2′-CH2,
especially 1.38 s, 3H, 6â-CH3), 1.20-1.00 (m, 9H, 4′-CH2, 5′-
CH2, 6′-CH2, especially 1.11 s, 3H, 6R-CH3), 0.93 (m, 2H, 3′-CH2),
0.81 (t, J ) 6.7 Hz, 3H, 7′-CH3); mass spectrum m/z (relative
intensity) 410 (M+, 46), 368 (5), 326 (100), 314 (17), 271 (9); exact
mass calcd for C28H42O2 410.3185, found 410.3182. Anal. (C28H42O2)
C, H.
(6aR-trans)-3-(1-Heptylcyclopropyl)-6a,7,10,10a-tetrahydro-
6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol (9e). The synthesis was
carried out as described for 9b by using 8e (174 mg, 0.46 mmol)
and boron trifluoride etherate (0.29 mL, 2.3 mmol) in anhydrous
CH2Cl2 (13.1 mL): yield 46% (81 mg); viscous oil; 1H NMR (300
MHz, CDCl3) δ 6.34 (br s, 1H, 4-H), 6.19 (br s, 1H, 2-H), 5.41 (d,
J ) 3.9 Hz, 1H, 8-H), 4.66 (s, 1H, OH), 3.18 (dd, J ) 15.6 Hz, J
) 4.0 Hz, 1H, 10R-H), 2.68 (ddd as dt, J ) 10.8 Hz, J ) 4.9 Hz,
1H, 10a-H), 2.12 (m, 1H, 7R-H), 1.90-1.73 (m, 3H, 10â-H, 7â-
H, 6a-H), 1.69 (s, 3H, 9-CH3), 1.45 (m, 2H, 2′-CH2), 1.37 (s, 3H,
6â-CH3), 1.28-1.14 (m, 10H, 3′-CH2, 4′-CH2, 5′-CH2, 6′-CH2, 7′-
5-[1-[(1Z)-1-Hexenyl]cyclopentyl]resorcinol (10c). The syn-
thesis was carried out as described for 7e by using 5c (500 mg,

C1′ Pharmacophore in Tetrahydrocannabinols
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17 4057
1.74 mmol) and B-I-9-borabicyclo[3.3.1]nonane (5.60 mL, 1 M
solution in hexanes) in anhydrous hexane (34.8 mL). The reaction
was completed in 2 h at room temperature: yield 75% (339 mg);
1H, 3′-H), 4.64 (br s, 2H, >CdCH2, OH), 4.53 (s, 1H, >CdCH2),
3.82 (dd, J ) 11.0 Hz, J ) 1.8 Hz, 1H, 3-H), 2.38 (dt, J ) 11.0
Hz, J ) 4.3 Hz, 1H, 4-H), 2.26-2.06 (m, 2H) 1.93-160 (m, 18H,
especially 1.80, s, 3H, 7-CH3 and 1.63, s, 3H, 10-CH3), 1.10 (m,
4H, 5′-CH2, 6′-CH2), 0.77 (t, J ) 6.9 Hz, 3H, 7′-CH3); 13C NMR
(CDCl3) δ 149.6, 149.4, 139.9, 138.7, 131.9, 124.1, 113.4, 110.7,
51.7, 46.1, 40.9, 40.5, 37.4, 31.5, 30.4, 28.4, 28.2, 23.7, 23.6, 22.3,
20.6, 13.9; mass spectrum m/z (relative intensity) 394 (M+, 35),
311 (100), 273 (26), 243 (20); exact mass calcd for C27H38O2
394.2872, found 394.2866. Anal. (C27H38O2) C, H.
(-)-2-[3-3,4-trans-p-Menthadien-(1,8)-yl]-5-[1-[(1Z)-1-hexenyl]-
cyclohexyl]resorcinol (11d). The synthesis was carried out as
described for 8b by using 10d (581 mg, 2.12 mmol), (+)-cis/trans-
p-mentha-2,8-dien-1-ol (451 mg, 2.97 mmol), and p-toluenesulfonic
acid (77 mg, 0.40 mmol) in anhydrous benzene (21.2 mL): yield
80% (692 mg); colorless viscous oil; 1H NMR (300 MHz, CDCl3)
δ 6.41 (br s, 2H, ArH), 5.91 (br s, 1H, OH), 5.62 (d, J ) 11.6 Hz,
1H), 5.56 (br s, 1H, 2-H), 5.29 (dt, J ) 11.6 Hz, J ) 7.3 Hz, 1H),
4.63 (br s, 2H, >CdCH2, OH), 4.53 (s, 1H, >CdCH2), 3.82 (d, J
) 8.5 Hz, 1H, 3-H), 2.38 (dt, J ) 10.4 Hz, J ) 4.3 Hz, 1H, 4-H),
2.26-2.05 (m, 2H), 1.88-1.55 (m, 20H, especially 1.78, s, 3H,
7-CH3 and 1.63, s, 3H, 10-CH3), 1.08 (m, 4H, 5′-CH2, 6′-CH2),
0.76 (t, J ) 6.7 Hz, 3H, 7′-CH3); 13C NMR (CDCl3) δ 151.3, 149.4,
139.9, 136.4, 131.9, 124.2, 113.2, 110.7, 65.9, 46.1, 42.9, 38.8,
38.5, 37.3, 31.4, 30.4, 28.4, 28.1, 26.0, 23.6, 22.8, 22.3, 20.6, 15.2,
13.9; mass spectrum m/z (relative intensity) 408 (M+, 45), 340 (40),
325 (100), 287 (25); exact mass calcd for C28H40O2 408.3028, found
408.3032. Anal. (C28H40O2) C, H.
(6aR-trans)-3-[1-[(1Z)-1-Hexenyl]cyclopropyl]-6a,7,10,10a-tet-
rahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol (12a). The
synthesis was carried out as described for 9b by using 11a (305
mg, 0.83 mmol) and boron trifluoride etherate (0.5 mL, 4.15 mmol)
in anhydrous CH2Cl2 (23.7 mL): yield 67% (204 mg); viscous oil;
1H NMR (300 MHz, CDCl3) δ 6.23 (d, J ) 1.8 Hz, 1H, 4-H), 6.16
(d, J ) 1.8 Hz, 1H, 2-H), 5.61 (d, J ) 11.0 Hz, 1H, 2′-H), 5.49
(dt, J ) 11.0 Hz, J ) 6.7 Hz, 1H, 3′-H), 5.42 (br s, 1H, 8C-H),
4.59 (s, 1H, OH), 3.17 (m, 1H, 10R-H), 2.65 (m, 1H, 10a-H), 2.38
(m, 1H, 7R-H), 2.09 (m, 2H, 4′-CH2), 1.90-1.62 (m, 6H, 10â-H,
7â-H, 6a-H, especially 1.69, s, 3H, 9-CH3), 1.38-1.15 (m, 7H,
5′-CH2, 6′-CH2, especially 1.36, s, 3H, 6â-CH3), 1.12-0.98 (m,
5H, half of AA′BB′ system, 2H of the cyclopropane ring, especially
1.08, s, 3H, 6R-CH3), 0.92-0.78 (m, 5H, half of AA′BB′ system,
2H of the cyclopropane ring, 7′-CH3); 13C NMR (CDCl3) δ 154.9,
145.5, 134.7, 132.1, 124.3, 119.3, 107.6, 105.9, 104.8, 76.5, 44.8,
35.9, 31.5, 29.7, 28.2, 27.9, 27.5, 23.5, 22.5, 18.5, 17.6, 13.9; mass
spectrum m/z (relative intensity) 366 (M+, 100), 323 (38), 283 (35),
149 (20); exact mass calcd for C25H34O2 366.2559, found 366.2558.
Anal. (C25H34O2) C, H.
(6aR-trans)-3-[1-[(1Z)-1-Hexenyl]cyclobutyl]-6a,7,10,10a-tet-
rahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol (12b). The
synthesis was carried out as described for 9b by using 11b (256
mg, 0.67 mmol) and boron trifluoride etherate (0.42 mL, 3.35 mmol)
in anhydrous CH2Cl2 (19.1 mL): yield 83% (211 mg); viscous oil;
1H NMR (300 MHz, CDCl3) δ 6.44 (d, J ) 1.2 Hz, 1H, 4-H), 6.20
(d, J ) 1.2 Hz, 1H, 2-H), 5.74 (d, J ) 11.0 Hz, 1H, 2′-H), 5.43 (br
s, 1H, 8-H), 5.26 (dt, J ) 11.0 Hz, J ) 7.3 Hz, 1H, 3′-H), 4.70 (s,
1H, OH), 3.18 (m, 1H, 10R-H), 2.68 (m, 1H, 10a-H), 2.46-2.26
(m, 6H of the cyclobutane ring), 2.12 (m, 1H, 7R-H), 1.90-1.80
(m, 5H, 4′-CH2, 10â-H, 7â-H, 6a-H), 1.69 (s, 3H, 9-CH3), 1.38 (s,
3H, 6â-CH3), 1.25-1.10 (m, 4H, 5′-CH2, 6′-CH2), 1.10 (s, 3H, 6R-
CH3), 0.80 (t, J ) 6.7 Hz, 3H, 7′-CH3); 13C NMR (CDCl3) δ 154.6,
138.8, 134.7, 130.6, 125.5, 119.3, 110.2, 107.9, 105.6, 64.9, 47.2,
44.9, 36.0, 31.5, 30.3, 29.7, 27.9, 27.6, 23.5, 22.4, 18.5, 16.7, 13.9;
mass spectrum m/z (relative intensity) 380 (M+, 100), 352 (25),
297 (32), 269 (20); exact mass calcd for C26H36O2 380.2715, found
380.2717. Anal. (C26H36O2) C, H.
1
colorless viscous oil; H NMR (300 MHz, CDCl3) δ 6.42 (d, J )
1.8 Hz, 2H), 6.16 (t, J ) 1.8 Hz, 1H), 5.64 (d, J ) 11.0 Hz, 1H,
2′-H), 5.52 (br s, 2H, OH), 5.25 (dt, J ) 11.0 Hz, J ) 7.9 Hz, 1H,
3′-H), 1.88 (m, 4H, 4′-CH2, 2H of the cyclopentane ring), 1.67 (m,
6H of the cyclopentane ring), 1.09 (m, 4H, 5′-CH2, 6′-CH2), 0.75
(t, J ) 6.7 Hz, 3H, 7′-CH3); 13C NMR (CDCl3) δ 156.5, 147.9,
134.8, 131.9, 105.4, 100.1, 37.9, 37.9, 31.4, 28.2, 22.8, 22.5; mass
spectrum m/z (relative intensity) 260 (M+, 55), 217 (32), 203 (74),
191 (17), 177 (100), 166 (41), 149 (25), 123 (62).
5-[1-[(1Z)-1-Hexenyl]cyclohexyl]resorcinol (10d). The synthesis
was carried out as described for 7e by using 5d (683 mg, 2.26
mmol) and B-I-9-borabicyclo[3.3.1]nonane (7.23 mL, 1 M solution
in hexanes) in anhydrous hexane (45.2 mL). The reaction was
completed in 2 h at room temperature: yield 94% (581 mg);
1
colorless viscous oil; H NMR (300 MHz, CDCl3) δ 6.28 (d, J )
2.5 Hz, 2H), 6.16 (t, J ) 2.5 Hz, 1H), 5.60 (d, J ) 11.6 Hz, 1H,
2′-H), 5.35 (dt, J ) 11.6 Hz, J ) 7.3 Hz, 1H, 3′-H), 4.77 (br s, 1H,
OH), 4.43 (br s, 1H, OH), 1.90 (m, 2H, 4′-CH2), 1.71-1.60 (m,
9H, of the cyclohexane ring), 1.31 (m, 1H, of the cyclohexane ring),
1.07 (m, 4H, 5′-CH2, 6′-CH2), 0.74 (t, J ) 6.7 Hz, 3H, 7′-CH3);
13C NMR (CDCl3) δ 156.8, 148.1, 134.6, 132.3, 105.4, 99.7, 38.9,
38.6, 31.4, 28.1, 27.1, 23.0, 21.5.
(-)-2-[3-3,4-trans-p-Menthadien-(1,8)-yl]-5-[1-[(1Z)-1-hexenyl]-
cyclopropyl]resorcinol (11a). The synthesis was carried out as
described for 8b by using 10a (339 mg, 1.46 mmol), (+)-cis/trans-
p-mentha-2,8-dien-1-ol (311 mg, 2.04 mmol), and p-toluenesulfonic
acid (53 mg, 0.28 mmol) in anhydrous benzene (14.6 mL): yield
57% (305 mg); colorless viscous oil; 1H NMR (300 MHz, CDCl3)
δ 6.24 (br s, 2H, ArH), 5.93 (br s, 1H, OH), 5.59 (d, J ) 10.4 Hz,
1H, 2′-H), 5.54 (br s, 1H, 2-H), 5.48 (dt, J ) 10.4 Hz, J ) 6.7 Hz,
1H, 3′-H), 4.65 (s, 2H, >CdCH2, -OH), 4.55 (s, 1H, >CdCH2),
3.82 (d, J ) 9.8 Hz, 1H, 3-H), 2.38 (dt, J ) 10.4 Hz, J ) 3.7 Hz,
1H, 4-H), 2.20-2.11 (m, 2H), 2.03 (m, 2H) 1.80-1.75 (m, 5H,
especially 1.78, s, 3H, 7-CH3), 1.64 (s, 3H, 10-CH3), 1.25 (m, 4H,
5′-CH2, 6′-CH2), 1.03 (half of AA′BB′ system, 2H of the cyclo-
propane ring), 0.91 (half of AA′BB′ system, 2H of the cyclopropane
ring), 0.84 (t, J ) 7.0 Hz, 3H, 7′-CH3); 13C NMR (CDCl3) δ 149.3,
145.8, 140.0, 134.6, 132.3, 124.1, 113.5, 110.8, 46.1, 37.2, 31.4,
30.3, 28.3, 28.1, 23.7, 22.6, 22.5, 20.5, 17.8, 17.6, 13.9; mass
spectrum m/z (relative intensity) 366 (M+, 65), 299 (50), 283 (100),
245 (32); exact mass calcd for C25H34O2 366.2559, found 366.2556.
Anal. (C25H34O2) C, H.
(-)-2-[3-3,4-trans-p-Menthadien-(1,8)-yl]-5-[1-[(1Z)-1-hexenyl]-
cyclobutyl]resorcinol (11b). The synthesis was carried out as
described for 8b by using 10b (331 mg, 1.35 mmol), (+)-cis/trans-
p-mentha-2,8-dien-1-ol (287 mg, 1.89 mmol), and p-toluenesulfonic
acid (49 mg, 0.26 mmol) in anhydrous benzene (13.5 mL): yield
50% (256 mg); colorless viscous oil; 1H NMR (300 MHz, CDCl3)
δ 6.31 (br s, 2H, ArH), 5.97 (br s, 1H, OH), 5.78 (d, J ) 11.0 Hz,
1H, 2′-H), 5.57 (br s, 1H, 2-H), 5.26 (dt, J ) 11.0 Hz, J ) 7.3 Hz,
1H, 3′-H), 4.68-4.57 (br s, 2H, > CdCH2, OH), 4.55 (s, 1H, >Cd
CH2), 3.83 (d, J ) 9.2 Hz, 1H, 3-H), 2.42-2.23 (m, 7H, 4-H,
cyclobutane ring), 2.16-2.05 (m, 2H), 1.94-1.83 (m, 7H, especially
1.79, s, 3H, 7-CH3), 1.64 (s, 3H, 10-CH3), 1.15 (m, 4H, 5′-CH2,
6′-CH2), 0.81 (t, J ) 6.7 Hz, 3H, 7′-CH3); 13C NMR (CDCl3) δ
149.5, 140.1, 138.9, 130.8, 124.1, 113.4, 110.8, 64.9, 47.1, 46.0,
37.4, 36.2, 36.1, 31.5, 30.4, 28.3, 27.9, 23.7, 22.4, 20.7, 16.7, 13.9;
mass spectrum m/z (relative intensity) 380 (M+, 100), 312 (35),
297 (82), 269 (85); exact mass calcd for C26H36O2 380.2715, found
380.2711. Anal. (C26H36O2) C, H.
(-)-2-[3-3,4-trans-p-Menthadien-(1,8)-yl]-5-[1-[(1Z)-1-hexenyl]-
cyclopentyl]resorcinol (11c). The synthesis was carried out as
described for 8b by using 10c (339 mg, 1.30 mmol), (+)-cis/trans-
p-mentha-2,8-dien-1-ol (277 mg, 1.82 mmol), and p-toluenesulfonic
acid (47 mg, 0.25 mmol) in anhydrous benzene (13 mL): yield
76% (390 mg); colorless viscous oil; 1H NMR (300 MHz, CDCl3)
δ 6.37 (br s, 2H, ArH), 5.92 (br s, 1H, OH), 5.65 (d, J ) 11.0 Hz,
1H, 2′-H), 5.56 (br s, 1H, 2-H), 5.23 (dt, J ) 11.0 Hz, J ) 7.3 Hz,
(6aR-trans)-3-[1-[(1Z)-1-Hexenyl]cyclopentyl]-6a,7,10,10a-tet-
rahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol (12c). The
synthesis was carried out as described for 9b by using 11c (390
mg, 0.99 mmol) and boron trifluoride etherate (0.62 mL, 4.95 mmol)
in anhydrous CH2Cl2 (28.3 mL): yield 91% (355 mg); viscous oil;

4058 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17
Papahatjis et al.
1H NMR (300 MHz, CDCl3) δ 6.42 (d, J ) 1.8 Hz, 1H, 4-H), 6.24
(d, J ) 1.8 Hz, 1H, 2-H), 5.63 (d, J ) 11.0 Hz, 1H, 2′-H), 5.42 (d,
J ) 3.7 Hz, 1H, 8-H), 5.23 (dt, J ) 11.0 Hz, J ) 7.3 Hz, 1H,
3′-H), 4.60 (s, 1H, OH), 3.17 (dd, J ) 16.5 Hz, J ) 4.3 Hz, 1H,
10R-H), 2.68 (dt, J ) 11.0 Hz, J ) 4.3 Hz, 1H, 10a-H), 2.14 (m,
1H, 7R-H), 1.94-1.66 (m, 16H, 4′-CH2, 10â-H, 7â-H, 6a-H, 8H
of the cyclopentane ring and especially 1.69, s, 3H, 9-CH3), 1.37
(s, 3H, 6â-CH3), 1.08 (br s, 7H, 6R-CH3, 5′-CH2, 6′-CH2), 0.73 (t,
J ) 6.7 Hz, 3H, 7′-CH3); 13C NMR (CDCl3) δ 154.3, 149.2, 138.7,
134.8, 131.8, 119.3, 110.2, 108.7, 106.6, 51.8, 44.9, 40.7, 40.6,
36.0, 31.5, 31.3, 28.1, 27.9, 23.6, 23.5, 22.3, 18.4, 13.9; mass
spectrum m/z (relative intensity) 394 (M+, 100), 351 (30), 311 (87);
exact mass calcd for C27H38O2 394.2872, found 394.2865. Anal.
(C27H38O2) C, H.
(6aR-trans)-3-[1-[(1Z)-1-Hexenyl]cyclohexyl]-6a,7,10,10a-tet-
rahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol (12d). The
synthesis was carried out as described for 9b by using 11d (692
mg, 1.70 mmol) and boron trifluoride etherate (1.1 mL, 8.5 mmol)
in anhydrous CH2Cl2 (49 mL): yield 71% (492 mg); viscous oil;
1H NMR (300 MHz, CDCl3) δ 6.46 (d, J ) 1.2 Hz, 1H, 4-H), 6.27
(d, J ) 1.2 Hz, 1H, 2-H), 5.59 (d, J ) 11.6 Hz, 1H, 2′-H), 5.41 (br
s, 1H, 8-H), 5.30 (dt, J ) 11.6 Hz, J ) 7.3 Hz, 1H, 3′-H), 4.60 (s,
1H, OH), 3.17 (dd, J ) 16.5 Hz, J ) 4.9 Hz, 1H, 10R-H), 2.68
(dt, J ) 11.0 Hz, J ) 4.3 Hz, 1H, 10a-H), 2.12 (m, 1H, 7R-H),
1.92-1.77 (m, 5H, 4′-CH2, 10â-H, 7â-H, 6a-H), 1.69 (s, 3H,
9-CH3), 1.56 (m, 10H of the cyclohexane ring), 1.37 (s, 3H, 6â-
CH3), 1.08 (s, 3H, 6R-CH3), 1.04 (m, 4H, 5′-CH2, 6′-CH2), 0.71 (t,
J ) 6.7 Hz, 3H, 7′-CH3); 13C NMR (CDCl3) δ 154.3, 150.8, 136.5,
134.7, 131.9, 119.3, 110.1, 108.5, 106.3, 65.8, 44.9, 43.0, 38.8,
38.5, 36.0, 31.5, 31.2, 29.7, 28.1, 27.9, 27.6, 26.1, 23.5, 22.8, 22.3,
18.4, 13.9; mass spectrum m/z (relative intensity) 408 (M+, 100),
365 (25), 351 (30), 325 (87), 300 (40); exact mass calcd for
C28H40O, 408.3028, found 408.3032. Anal. (C28H40O2) C, H.
1.65 (s, 3H, 10-CH3), 1.58-1.51 (m, 2H, 2′-CHC), 1.34-1.23 (m,
8H, 3′-CH2, 4′-CH2, 5′-CH2, 6′-CH2), 0.87 (t, J ) 7.1 Hz, 3H, 7′-
CH3).
(6aR-trans)-3-Heptyl-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-
6H-dibenzo[b,d]pyran-1-ol (1b). The synthesis was carried out as
described for 9b by using 17 (72 mg, 0.21 mmol) and boron
trifluoride etherate (0.1 mL, 0.80 mmol) in anhydrous CH2Cl2 (5
mL): yield 53% (38 mg); colorless viscous oil; spectral and
analytical data were reported previously.26
Radioligand Binding Assays. Forebrain synaptosomal mem-
branes were prepared from frozen rat brains by the method described
by Dodd et al.64 and were used to assess the affinities of the novel
analogs for the CB1 binding sites, while affinities for the CB2 sites
were measured using a membrane preparation from frozen mouse
spleen using a similar procedure.47 The displacement of specifically
tritiated CP-55,940 from these membranes was used to determine
the IC50 values for the test compounds. The assay was conducted
in a 96-well microfilter plate. The samples were filtered using a
Packard Filtermate Harvester and Whatman GF/B unifilter-96
plates, and 0.5% BSA was incorporated into the wash buffer.
Radioactivity was detected using MicroScint 20 scintillation cocktail
added to the dried filter plates and was counted using a Packard
Instruments Top Count. Data were collected from three independent
experiments between 100% and 0% specific binding for [3H]CP-
55,940, determined using 0 and 100 nM CP-55,940. The normalized
data from three independent experiments were combined and
analyzed using a four-parameter logistic equation to yield IC50
values that were converted to Ki values using the assumptions of
Cheng and Prussoff.65
Molecular Modeling. Computational calculations were per-
formed on the cannabinoid analogs using the Biosym InsightII/
Discover molecular modeling software package66 on a SGI Fuel
workstation. The Biosym integrated CVFF force field was employed
in the calculation. Each cannabinoid analog was first constructed
with bond angles and bond distances supplied by the molecule
builder module and then underwent constrained molecular dynamics
performed by heating it to 1000 K (or 1500K for analogs 9d and
12d) and recording 100 atomic coordinate trajectories every 10 000
iterations (1 fs per iteration). A restraint file was incorporated in
each dynamics run in order to prevent possible cis/trans isomer-
izations at the B/C ring junction and/or C2′-C3′ double bond. Next,
each trajectory was subjected to simulated annealing followed by
energy minimization with the steepest descent method for 100
iterations. This in turn was followed by the conjugate gradient
method until the maximum derivative was less than 0.001 kcal/
mol. The resulting structures were then superimposed by minimum
rmsd alignment of the analogs.
3,5-Dimethoxy-1-(1-heptenyl)benzene (14, mixture of Z and
E isomers in 91:9 ratio respectively, according to 1H NMR data).
The synthesis was carried out as described for 5b by using
hexyltriphenylphosphonium bromide (12.9 g, 30.2 mmol) in dry
THF (120 mL), potassium bis(trimethylsilyl)amide (5.9 g, 29.6
mmol), and a solution of 13 (1 g, 6.02 mmol) in dry THF (30
1
mL): yield 92% (1.30 g); colorless liquid; H NMR (500 MHz,
CDCl3, Z-isomer) δ 6.43 (d, J ) 2.2 Hz, 2H, ArH), 6.35 (t, J )
2.2 Hz, 1H, ArH), 6.33 (d, J ) 11.5 Hz, 1H, 1′-H), 5.65 (dt, J )
11.5, J ) 7.0 Hz, 1H, 2′-H), 3.97 (s, 6H, OMe), 2.32 (qd, J ) 7.3
Hz, J ) 1.7 Hz, 2H, 3′-CH2), 1.46 (quintet, J ) 7.3 Hz, 2H, 4′-
CH2), 1.40-1.21 (m, 4H, 5′-CH2, 6′-CH2), 0.88 (t, J ) 7.1 Hz,
1
3H, 7′-CH3); H NMR (500 MHz, CDCl3, E-isomer) δ 6.50 (d,
2H, J ) 2.2 Hz, ArH), 6.21 (dt, J ) 15.8 Hz, J ) 6.8 Hz, 1H,
2′-H), the remaining protons are overlapping with those of the
Z-isomer.
Acknowledgment. This work was supported by the National
Hellenic Research Foundation and by grants from the National
Institute on Drug Abuse, P01-DA09158, R37-DA03801, and
R01-DA07215.
3,5-Dimethoxy-1-heptylbenzene (15). The synthesis was carried
out as described for 6b by using 14 (1.25 g, 5.34 mmol) and 10%
Pd/C (0.19 g) in EtOAc (50 mL): yield 95% (1.20 g); colorless
liquid; spectral and analytical data were reported previously.26
5-Heptylresorcinol (16). The synthesis was carried out as
described for 7b by using 15 (1.18 g, 5 mmol) and boron tribromide
(11 mL, 11 mmol, 1 M solution in CH2Cl2) in anhydrous CH2Cl2
(40 mL): yield 91% (0.95 g); slightly brown solid; mp 53-54 °C
(lit.63 mp 55-56 °C); spectral and analytical data were reported
previously.26
Supporting Information Available: Experimental details and
spectroscopic data, elemental analysis results, and whole cluster
simulations of the side chains of 9d and 12d. This material is
available free of charge via the Internet at http://pubs.acs.org
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mg, 4.9 mmol), and p-toluenesulfonic acid (76 mg, 0.45 mmol) in
anhydrous benzene (45 mL): yield 32% (489 mg); colorless viscous
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