7-Spirobenzocyclohexyl derivatives of naltrexone, oxymorphone, and hydromorphone as selective opioid receptor ligands

Article abstract of DOI:10.1021/jm970283e

On the basis of previous structure-activity studies of the highly potent and selective δ-opioid receptor antagonist naltrindole (1) and the spiroindanyl analagues 2 and 3, we have synthesized epimeric pairs of spirobenzocyclohexyl derivatives of naltrexon

Full text of DOI:10.1021/jm970283e

3064
J . Med. Chem. 1997, 40, 3064-3070
7-Sp ir oben zocycloh exyl Der iva tives of Na ltr exon e, Oxym or p h on e, a n d
Hyd r om or p h on e a s Selective Op ioid Recep tor Liga n d s
Xinqin Fang, Dennis L. Larson, and Philip S. Portoghese*
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455
Received April 29, 1997X
On the basis of previous structure-activity studies of the highly potent and selective δ-opioid
receptor antagonist naltrindole (1) and the spiroindanyl anologues 2 and 3, we have synthesized
epimeric pairs of spirobenzocyclohexyl derivatives of naltrexone, oxymorphone, and hydromor-
phone (4-9). Pharmacologic evaluation in smooth muscle assays has revealed that the
oxymorphone derivatives (6, 7) are δ-selective agonists and possess receptor binding profiles
that are consistent with their agonist activity. It is proposed that the spirobenzocyclohexyl
group of 6 and 7 orients its benzene moiety orthogonally with respect to the C ring of the
opiate in a manner similar to that of the spiroindanyl analogue 3. It is suggested that this
orthogonal orientation serves as an “address” to facilitate activation of δ receptors. The finding
that the hydromorphone analogues (8, 9) were full µ agonists and exhibited only partial δ agonist
activity suggests that the 14-hydroxyl group also contributes to the δ agonist activity. The
naltrexone derivatives (4, 5) were µ-selective antagonists and exhibited relatively weak δ
antagonist activity. However, the binding data indicated a very high-affinity δ-selective binding
profile that was not consistent with the pharmacology. This study illustrates the differential
contributions of the δ “address” to agonist and antagonist activity and supports the idea of
different recognition sites for interaction of agonist and antagonist ligands with δ-opioid
receptors.
Ch a r t 1
In tr od u ction
Naltrindole (1) (NTI) is a highly potent and selective
non-peptidic δ-opioid receptor antagonist.1-3 Its high
δ-opioid antagonist potency and selectivity have been
attributed to the indolic benzene “address” moiety which
presumably mimics the Phe4 residue of enkephalin.3 In
an effort to investigate the conformational role of this
moiety in conferring high δ antagonist potency and
selectivity of NTI, a variety of related naltrexone and
oxymorphone derivatives4,5 have been examined. Among
these, the 7-spiroindanyl derivatives 2 (SINTX) and 3
(SIOM) are especially noteworthy. While the naltrexone
derivative 2 is a potent δ-opioid receptor antagonist both
in vitro and in vivo, the N-methyl analogue 3 is
apparently both an agonist and an antagonist in vivo
at the δ1 receptor.4,5 Here we describe the synthesis
and biological activity of a series of 7-spirobenzocyclo-
hexyl derivatives (4-9) that are structurally related to
2 and 3. These compounds were of interest because the
“address” is oriented differently in the 7R and 7â
epimers.
Design Ra tion a le a n d Ch em istr y
pounds that are homologues of 2 and 3. These com-
pounds were of interest because the C-7 epimeric
relationship (4, 6, 8 vs 5, 7, 9) affords two different
preferred orientations of the “address”, as can be seen
in Figure 1. Thus, the preferred conformations of the
aromatic moiety for the 7R epimers (5, 7, 9) are similar
to those in the indanyl series, whereas the correspond-
ing benzene moiety of the 7â epimers (4, 6, 8) is above
and approximately in the same plane as that for the 7R
epimers.
The design rationale for 7-spirobenzocyclohexane
derivatives of naltrexone, oxymorphone, and hydromor-
phone (compounds 4-9) was based on structure-
activity studies of the spiroindanyl series (2 and 3),
where the aromatic moiety is orthogonal to ring C of
the morphinan system. In the present study, we have
further investigated the conformational role of the
address moiety in conferring opioid receptor selectivity
by the synthesis of three pairs of C-7 epimeric com-
The synthetic route to the target compounds 4-9 is
outlined in Scheme 1. Lithium aluminum hydride
* To whom correspondence should be addressed.
X Abstract published in Advance ACS Abstracts, August 15, 1997.
S0022-2623(97)00283-5 CCC: $14.00 © 1997 American Chemical Society

7-Spirobenzocyclohexyls as Opioid Receptor Ligands
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 19 3065
Sch em e 1
reduction of homophthalic acid (10) afforded diol 11,
which was converted to dibromide 12 by treatment with
carbon tetrabromide and triphenylphosphine.6 Naltrex-
This assignment also is consistent with the modeling
studies, which showed that the distance between H-5
and one of the CH2 protons (Hb) in epimer 16 is 3.47 Å,
within the range where the NOE usually is observed.
The distance between H-5 and Ha (4.86 Å) is outside
this range. In contrast, both of these protons in 17 are
too remote (4.75 and 4.77 Å) from H-5 to produce the
corresponding NOE enhancements. The C-7 stereo-
chemistry of the other epimeric pairs (18, 19; 20, 21)
was established in an analogous fashion.
one and oxymorphone were protected as benzyl ethers4,5
(13, 14) prior to cyclization with the dibromide com-
pound 12. The key step in this synthetic route was the
base-promoted double alkylation by 12 of 13-15, to
generate a spiro center at C-7 on the morphinan ring
system. Each of the cyclization reactions produced a
pair of C-7 epimers (16, 17; 18, 19; 20, 21), which were
carefully separated by column chromatography. Cleav-
age of benzyl or methyl ether protective groups from
intermediates 16-21 furnished the target compounds
4-9, respectively.
Biologica l Resu lts
Sm ooth Mu scle P r ep a r a tion s. The opioid activity
of 4-9 was evaluated on the electrically stimulated
guinea pig ileal longitudinal muscle8 (GPI) and mouse
vas deferens9 (MVD) preparations as reported previ-
ously.10 The antagonists were incubated with the
preparations for 15 min before testing with the standard
agonists. Morphine, ethylketazocine (EK), and [D-Ala2,D-
Leu5]enkephalin11 (DADLE) were employed as µ-, κ-,
and δ-selective agonists, respectively. Morphine and EK
were used in the GPI, and DADLE was employed in the
MVD. Three or more replicate determinations were
carried out for each compound. Ligands that were not
full agonists were tested at a concentration of 1 µM, and
the agonist activity was expressed as percentage of the
maximal response. Opioid antagonism is expressed as
an IC50 ratio, which is the IC50 of the agonist in the
presence of the test compound (100 nM), divided by the
control IC50 in the same preparation.
In the MVD, the cyclopropylmethyl epimers (4, 5)
were found to be considerably less potent than SINTX
(2; Table 1) but were approximately equipotent as
antagonists of DADLE. J udging from the larger IC50
ratios in the GPI, both 4 and 5 may be more potent at
µ receptors. The N-methyl compounds (6-9) all be-
haved as full agonists in the GPI with IC50 values >
100 nM. Of these, only 6 and 7 exhibited full agonist
activity in the MVD, with potencies similar to that of
SIOM (3). Interestingly, the potencies of epimers 6 and
7 were not significantly different.
The stereochemistry at the C-7 center of the epimers
1
was determined by NMR spectroscopy. The H NMR
spectrum of 16 included a singlet for H-5 at 5.03 ppm
and an AB pattern for the CH2 group (J gem ) 16.5 Hz;
Ha, 3.86 ppm; Hb, 3.25 ppm) which directly links the
spiro C-7 center with the benzene moiety. Similarly,
its epimer 17 showed a singlet at 5.00 ppm (H-5) and
two doublets (J gem ) 15.9 Hz) centered at 3.55 and 3.21
ppm. These peaks are well-separated from one another
and from other signals, and therefore they are appropri-
ate for NOE difference studies, in order to assign the
configuration of the spiro center (C-7) for compound 16
and its epimer 17. With compound 16, irradiation of
H-5 gave a positive enhancement (5.1%) for one of the
CH2 protons (Hb). Conversely, irradiation of Hb pro-
duced a positive enhancement (6.5%) for H-5. These
results indicated that this CH2 group and H-5 are on
the same side of ring C (i.e., the â-face of the morphinan
system), and therefore its stereochemistry is as specified
in structure 16. This conclusion was reinforced by the
NOE difference spectrum of epimer 17, which exhibited
no enhancement for the CH2 protons upon irradiation
of H-5. Irradiation of this benzylic CH2 also produced
no enhancement of the H-5 signal. Thus, these data
suggested that 17 contains an R-oriented CH2 group
which directly links the spiro C-7 center and the
benzene ring.
Bin d in g. The opioid receptor affinities of the target
compounds were determined on mouse brain mem-
branes employing the procedure of Werling et al.12
Binding to µ sites was evaluated by competition of the
target compounds with [3H][D-Ala2,MePhe4,Gly-ol6]-

3066 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 19
Fang et al.
Ta ble 1. Opioid Agonist and Antagonist Potencies of 7-Spirobenzocyclohexyl Derivatives of Naltrexone, Oxymorphone, and
Hydromorphone
GPI
MVD
antagonisma IC50 ratio
antagonisma IC50 ratio
agonismb IC50 (nM) or
% max resp
agonismb IC50 (nM) or
compd
DADLE (δ)
M (µ)
EK (κ)
% max resp
2c
3d
4
5
6
7
8
9
130 ( 30
e
6.8 ( 1.3
7.4 ( 1.9
e
-8 ( 6%
22 ( 9 nM
4 ( 2%
24.9 ( 4
1.9 ( 0.5
16 ( 9%
1.2 ( 0.5
1.0 ( 0.3
55 ( 11%
29.1 ( 6.3
15.6 ( 4.0
1.9 ( 0.3
1.7 ( 0.3
2 ( 1%
16 ( 12%
183 ( 79 nM
629 ( 139 nM
130 ( 40 nM
107 ( 64 nM
3 ( 2%
24 ( 9 nM
28 ( 7 nM
42 ( 10%
17 ( 7%
e
e
e
e
e
e
e
e
e
4.7 ( 1.4
3.6 ( 0.9
a
b
The agonist IC50 value in the presence of the test compound divided by the control IC50
.
Partial agonist activity is expressed as the
percent inhibition of contraction at a concentration of 1 µM. Full agonist activity is expressed as an IC50 (nM). c Data from ref 5. Data
d
from ref 4. e Not determined due to full agonist activity.
Ta ble 2. Binding to Mouse Brain Membranes
Ki (nM)a
compd
[3H]NTI (δ)
[3H]DAMGO (µ)
[3H]U69593 (κ)
2b
3c
4
5
6
7
8
9
0.25 ( 0.06
2.8 ( 0.4
1.5 ( 0.6
14 ( 4
0.38 ( 0.12
0.72 ( 0.17
18 ( 3
28 ( 8
2.8 ( 0.4
119 ( 13
>3000
>3000
>1000
147 ( 32
>1000
>3000
88 ( 30
>1000
0.0019 ( 0.0007
0.0041 ( 0.0009
4.6 ( 1.3
9.3 ( 1.1
8.3 ( 1.7
182 ( 39
a
The arithmetic mean of Ki ((SEM) values for n g 3. The Ki
values were calculated from the Cheng-Prusoff equation,19 Ki )
IC50/(1 + [L]/KD), where IC50 is the concentration of competing
ligand producing 50% inhibition of the specific binding of radio-
ligand at concentration [L] and having affinity constant KD. b Data
from ref 5. c Data from ref 4.
F igu r e 1. (A) Superposition of epimeric 7-spirobenzocyclo-
hexylnaltrexones (4, 5), SINTX (2), and NTI (1). (B) Superposi-
tion of 7-spirobenzocyclohexyloxymorphone (6, 7) and 7-spiro-
benzocyclohexylhydromorphone (8, 9) epimers with SIOM (3).
enkephalin ([3H]DAMGO),13 to δ sites with [3H]naltrin-
dole ([3H]NTI),14 and to κ sites with [3H]-5R,7R,8â-(-)-
N-methyl-N-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl-
benzeneacetamide ([3H]U69593).15 The Ki values of the
target compounds 4-9 are presented in Table 2.
activities.4,5 The naltrexone-derived ligands generally
are not as potent or as selective as NTI (1), and it
appears that an aromatic moiety coplanar to ring C is
optimal for δ antagonist activity. However, it was found
that an orthogonal “address” attached to oxymorphone
favors δ agonist activity.
In the present study, we have investigated epimeric
homologues 4-9 whose orthogonal aromatic groups are
displaced from one another but are approximately in
the same plane (Figure 1).
The epimeric oxymorphone derivatives (6,7) showed
some binding selectivity for δ receptors. This was not
the case for the hydromorphone analogues (8,9) which
exhibited a preference for µ receptors. This difference
in selectivity is related more to differences in the affinity
for µ receptors, since the affinity difference for δ
receptors was small and differed only by a factor of 2.
In any case, the finding that the δ receptor affinities of
the spirobenzocyclohexanes 6-8 and that of the spiroin-
dan 3 are similar to one another suggests that the
position of the orthogonally oriented “address” is not
critical for δ agonist activity. It is unclear why 9 binds
substantially less avidly than its epimer 8. However,
this appears to be more of a general phenomenon in
view of the correspondingly lower affinity of 9 for µ and
δ receptors.
Although the Ki values of the naltrexone derivatives
4 and 5 indicate that they have extremely high affinity
for δ receptors, inspection of the binding curves has
revealed that “competition” with [3H]NTI occurred over
a 6-decade concentration range, suggesting a noncom-
petitive binding component. The reason for this dis-
crepancy is not known. Consequently, the Ki values
may not reflect true competitive binding affinities for 4
and 5. The oxymorphone derivatives 6 and 7 have
similar binding profiles to the indan homologue 3 in that
they have 3-4-fold preference for δ over µ receptors,
with virtually no affinity for κ receptors. The hydro-
morphone epimers (8, 9) have 1.5-3-fold greater affinity
for µ over δ receptors. It is noteworthy that the â
epimers (4, 6, 8) have greater affinity for δ receptors
than the corresponding R epimers (5, 7, 9). However, a
parallel difference also is observed for µ receptor bind-
ing. In this regard, 8 binds with greater affinity to µ
and δ receptors by a factor of 20-40 over its epimer 9.
Discu ssion
Prior pharmacologic and binding studies of 7-spiroin-
danyl derivatives of naltrexone and oxymorphone have
revealed that an aromatic ring that is orthogonal to ring
C of the morphinan system confers a preference for
δ-opioid receptors.4,5 Thus, it has been reported that
compounds 2, 3, and a number of related spiroindanyl
structures exhibit potent δ antagonist or δ agonist
The identical agonist potencies of 6 and 7 in the MVD
are consistent with the binding data, which show only
a minor difference in affinity for δ receptors. These

7-Spirobenzocyclohexyls as Opioid Receptor Ligands
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 19 3067
inert atmosphere (oxygen-free dry nitrogen or argon) using
flame-dried glassware. Column chromatography was carried
out on E. Merck silica gel 60 (230-400 mesh), and the eluting
solvents are reported as v/v percent mixture, unless otherwise
stated. Thin layer chromatography was performed on E.
Merck silica gel 60 F-254 0.25 nm plates and visualized with
UV light, phosphomolybdic acid, or iodine impregnated on
silica gel. Solvents used for reactions were purified by
distillation under dry nitrogen atmosphere as follows: dichlo-
romethane, triethylamine, methanol from calcium hydride;
diethyl ether, tetrahydrofuran, benzene from sodium/ben-
zophenone; chloroform from P2O5. Naltrexone, oxymorphone,
and hydrocodone were supplied by Mallinckrodt, St. Louis,
MO. All other commercial reagents were purchased from
Aldrich Co., Milwaukee, WI, and used without further puri-
fication, unless otherwise noted.
ligands are substantially less effective as µ agonists in
view of the 10-20-fold higher IC50 values in the GPI.
The nearly identical δ agonist potencies of the oxymor-
phone derivatives 3, 6, and 7 also support the idea that
an orthogonal aromatic group is important for full δ
agonist activity and that modest displacement of the
aromatic group in the orthogonal position does not
adversely affect agonist potency. However, the finding
that the hydromorphone analogues 8 and 9 are weak δ
antagonists and probable µ agonists indicates that the
14-hydroxyl group contributes significantly to the δ
agonist activity of 3, 6, and 7. This is consistent with
the known potency-enhancing effect of the 14-hydroxyl
group.17
2-(2-Hydr oxyeth yl)-1-(h ydr oxym eth yl)ben zen e (11). To
a stirred solution of homophthalic acid (10) (5.13 g, 28.5 mmol)
in 150 mL of dry THF was added dropwise a 1.0 M solution of
lithium aluminum hydride (90 mL, 90 mmol) over a period of
45 min. After addition was complete, the resulting solution
was refluxed for 20 h under a nitrogen atmosphere. Upon
cooling to room temperature, the reaction mixture was treated
with water (50 mL) added carefully dropwise, followed by the
addition of 15% aqueous NaOH (100 mL). This mixture was
stirred for 1 h, and 10 g of solid NaCl was added in order to
facilitate the subsequent workup. The mixture was then
filtered through a pad of cotton wool and washed through with
Et2O. The filtrate was extracted with Et2O (3 × 100 mL), and
the combined organic layers were washed with brine, dried
over anhydrous MgSO4, filtered, and evaporated in vacuo. The
crude product was purified by flash chromatography on a silica
gel column, eluting with EtOAc-hexane (50:50) to furnish 4.01
g (93%) of diol 11 as a colorless oil: TLC Rf 0.20 (EtOAc-
While 4 and 5 appeared to possess very high affinity
for δ receptors, they paradoxically exhibited only feeble
antagonism against DADLE in the MVD. In fact, the
smooth muscle pharmacological data indicate that both
4 and 5 are most effective as µ antagonists. Since the
binding curves of 4 and 5 were shallow and spanned
over 6 decades of concentration, these data may be due
to a mixed competitive-noncompetitive mechanism.
Thus, a significant noncompetitive component could
explain the anomalous binding data, which is reminis-
cent of the apparent noncompetitive interaction of a
related ligand, 7-benzospiroindanylnaltrexone,18 with
[3H]NTI. In this regard, it appears that 4 and 5 behave
similarly despite the fact that the energetically pre-
ferred conformations of the spirobenzocyclohexane moi-
ety in these epimers differ from one another.
1
hexane, 50:50); H NMR (CDCl3) δ 7.33-7.20 (m, 4 H, ArH),
4.61 (s, 2 H, CH2), 3.86 (t, 2 H, J ) 6.0 Hz, CH2), 3.63 (br, 1 H,
OH), 2.95 (t, 2 H, J ) 6.0 Hz, CH2), 2.87 (br, 1 H, OH); 13C
NMR (CDCl3) δ 138.63, 137.59, 129.66, 129.04, 127.93, 126.23,
62.51, 62.17, 34.70; HRMS (EI) calcd for C9H12O2 (M+) 152.0837,
found 152.0836.
Su m m a r y a n d Con clu sion s
In summary, the present study shows that the δ
agonist potency and selectivity resulting from the at-
tachment of an orthogonally oriented spirobenzocyclo-
hexane group to the 7-position of oxymorphone (6, 7) is
similar to those reported for the spiroindan derivative
SIOM(3). These results suggest that the orthogonal
orientation of the “address” is important for conferring
δ agonist activity to the opiate and that its position
within the orthogonal plane is not critical. Also, it
appears that the 14-hydroxyl group of the opiate phar-
macophore contributes significantly to the δ agonist
activity.
On the other hand, identical modification of the
7-position of naltrexone led to weak δ antagonists (4,
5) with selectivity for µ receptors, which is unlike the
contribution from the attachment of spiroindanyl group
(2). This apparent inconsistency is observed with the
pharmacological, but not with the binding, data. The
apparent differential pharmacologic contribution of the
spirobenzocyclohexyl group to agonist and antagonist
activities supports the idea of different recognition sites
for agonist and antagonist ligands on δ receptors.5
2-(2-Br om oeth yl)-1-(br om om eth yl)ben zen e (12). To a
stirred solution of the diol 11 (1.61 g, 10.6 mmol) and carbon
tetrabromide (8.96 g, 27.0 mmol) in 50 mL of dry CH2Cl2 at 0
°C and under a nitrogen atmosphere was added a solution of
triphenylphosphine (6.95 g, 26.5 mmol) in 25 mL of CH2Cl2
via syringe. After the addition, the ice bath was removed and
the resulting orange solution was stirred at ambient temper-
ature for 18 h. The solvent was evaporated from the reaction
mixture, and the resulting residue was treated with Et2O (100
mL). The mixture was then filtered, and the filter cake was
washed with Et2O (3 × 320 mL). The combined filtrate and
washings were concentrated in vacuo, and the residual oil was
purified by flash chromatography twice on silica gel (EtOAc-
hexane, 10:90 and 3:97) to yield 2.04 g (70%) of dibromide 12
as a colorless oil: TLC Rf 0.84 (EtOAc-hexane, 10:90); 1H
NMR (CDCl3) δ 7.4-7.2 (m, 4 H, ArH), 4.56 (s, 2 H, CH2), 3.64
(t, 2 H, J ) 7.7 Hz, CH2), 3.30 (t, 2 H, J ) 7.7 Hz, CH2); 13C
NMR (CDCl3) δ 137.33, 135.39, 130.41, 129.72, 128.83, 127.18,
35.13, 31.69, 31.26; HRMS (EI) calcd for C9H10Br2 (M+)
275.9150, found 275.9141.
7r- a n d 7â-Sp ir oben zocycloh exyl-3-O-ben zyln a ltr ex-
on e (17 a n d 16). To a stirred solution of 12-crown-4 (3.52 g,
3.24 mL, 20 mmol) in 10 mL of dry THF at room temperature
and under a nitrogen atmosphere was added lithium bis-
(trimethylsilyl)amide (1.0 M solution in THF, 20 mL, 20 mmol).
After 2 min, 3-O-benzylnaltrexone (13) (2.2 g, 5.1 mmol) was
added via syringe as a solution in 15 mL of THF, and the
resulting solution was stirred at room temperature for an
additional 15 min. A solution of 2-(2-bromoethyl)-1-(bromom-
ethyl)benzene (3.1 g, 11.2 mmol) in 10 mL of THF was
introduced via syringe, and the mixture was then heated at
reflux for 21 h. After cooling to ambient temperature, the
mixture was poured into 150 mL of brine and extracted with
ethyl acetate or chloroform (3 × 100 mL). The combined
organic layers were washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated in vacuo. The crude cy-
Exp er im en ta l Section
All 1H NMR spectra were recorded on a GE 300 MHz
spectrometer in CDCl3, with TMS as reference, and 13C NMR
spectra were recorded on a GE 300 MHz spectrometer at 75
MHz in CDCl3 with TMS or CDCl3 as reference, unless
otherwise noted. Infrared spectra were recorded on a Nicolet
5DXC FT-IR instrument. Mass spectra were obtained on a
VG 7070E-HF instrument. Elemental analyses were per-
formed by M-H-W Laboratories in Phoenix, AZ, and are within
(0.4% of theoretical values. Melting points were determined
in open capillary tubes on a Thomas Hoover apparatus and
are uncorrected. Reactions were generally conducted under

3068 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 19
Fang et al.
clization products were separated and purified by gravity
column chromatography on silica gel, eluting sequentially with
10%, 20%, and 40% EtOAc in hexane, to afford 16 (490 mg,
17.6%) and 17 (120 mg, 4.3%) as white solids.
(129.06, 128.98, 128.57, 128.47, 127.33, 127.12, 127.06, 125.05,
124.69, 120.19, 119.60, 90.10, 65.33), quaternary (209.98,
147.53, 143.95, 142.01, 138.90, 130.66, 126.50, 77.12, 71.05,
58.01, 52.04); HRMS (FAB) calcd for C33H34NO4 (M + H)+
508.2488, found 508.2492.
7â Ep im er 16: mp 218-219 °C; TLC Rf 0.20 (EtOAc-
1
hexane, 20:80); IR (KBr pellet) 1718.5 cm-1 (CdO); H NMR
7r Ep im er 19: yield 140 mg (4.3%); mp 224-225 °C; TLC
Rf 0.25 (EtOAc-hexane, 40:60); IR (CHCl3) 1719.8 cm-1 (CdO);
1H NMR (CDCl3) δ 7.6-7.0 (m, 9 H, ArH), 6.74 (d, 1 H, J )
8.1 Hz, H-1), 6.57 (d, 1 H, J ) 8.1 Hz, H-2), 5.35 (d, 1 H, J )
12.5 Hz, OCHHPh), 5.3 (br, 1 H, OH), 5.20 (d, 1 H, J ) 12.5
Hz, OCHHPh), 5.10 (s, 1 H, H-5), 3.56 (d, 1 H, J ) 15.9 Hz,
Ha of C(spiro)-CHaHb-Ar), 3.28 (d, 1 H, J ) 15.9 Hz, Hb of
C(spiro)-CHaHb-Ar), 2.88 (d, 1 H, J ) 6.0 Hz, H-9), 2.75-2.25
(m, 9 H), 2.41 (s, 3 H, CH3), 2.08 (d, 1 H, J ) 14.3 Hz, H-8),
1.88 (d, 1 H, J ) 14.3 Hz, H-8), 1.62-1.52 (m, 1 H); NOE
difference expt, irradiation of H-5 gave no enhancement for
either Ha or Hb of C(spiro)-CHaHb-Ar, irradiation of either Ha
or Hb gave no enhancement for H-5; molecular modeling
calculations showed internuclear distances of 4.75 Å between
H-5 and Hb, 4.76 Å between H-5 and Ha; 13C NMR-DEPT
(CDCl3) δ CH3 (42.60), CH2 (73.45, 46.20, 42.48, 42.30, 41.73,
41.53, 30.92, 21.85), CH (128.27, 128.09, 127.78, 127.67,
126.54, 126.30, 126.05, 124.25, 123.89, 119.38, 118.81, 89.06,
64.56), quaternary (208.74, 145.32, 141.82, 141.75, 140.30,
137.47, 129.67, 125.55, 69.89, 56.30, 50.67); HRMS (FAB) calcd
for C33H34NO4 (M + H)+ 508.2488, found 508.2485.
(CDCl3) δ 7.50-7.12 (m, 9 H, ArH), 6.76 (d, 1 H, J ) 7.8 Hz,
H-2), 6.56 (d, 1 H, J ) 7.8 Hz, H-2), 5.44 (br, 1 H, OH), 5.35
(d, 1 H, J ) 11.9 Hz, OCHHPh), 5.21 (d, 1 H, J ) 11.9 Hz,
OCHHPh), 5.03 (s, 1 H, H-5), 3.86 (d, 1 H, J ) 16.5 Hz, Ha of
C(spiro)-CHaHb-Ar), 3.25 (d, 1 H, J ) 16.5 Hz, Hb of C(spiro)-
CHaHb-Ar), 3.13 (d, 1 H, J ) 5.7 Hz, H-9), 2.79-1.24 (m, 14
H), 0.83 (m, 1 H, H-19), 0.56 (m, 2 H, cyclopropyl), 0.15 (m, 2
H, cyclopropyl); NOE difference expt, irradiation of H-5 gave
a positive enhancement (+5.1%) for Hb of C(spiro)-CHaHb-Ar,
irradiation of Hb gave a positive enhancement (+6.5%) for H-5
and a strong geminal enhancement (+21.5%) for Ha; computer
molecular modeling of 16 using Biosym software7 for energy
minimization calculated internuclear distances of 3.47 Å
between H-5 and Hb, 4.86 Å between H-5 and Ha; 13C NMR-
DEPT (CDCl3) δ CH2 (73.09, 59.87, 44.29, 43.15, 42.51, 42.45,
42.39, 30.99, 23.48, 4.66, 4.55), CH (129.09, 129.04, 128.54,
128.43, 128.39, 127.30, 127.06, 125.04, 124.67, 120.08, 119.51,
89.89, 62.97, 10.75), quaternary (209.01, 146.96, 142.86,
141.02, 138.25, 131.06, 126.83, 118.05, 70.18, 58.09, 52.74);
HRMS (FAB) calcd for C36H38NO4 (M + H)+ 548.2801, found
548.2806.
7r- a n d 7â-Sp ir oben zocycloh exylh yd r ocod on e (21 a n d
20). These were prepared from hydrocodone (15) (2.20 g, 7.35
mmol) using a 3-fold molar excess of dibromide 12. The two
C-7 epimers were separated and purified by gravity column
chromatography using 1-3% methanol and 1% triethylamine
in chloroform as the eluting solvent.
7r Ep im er 17: mp 212-213.5 °C; TLC Rf 0.27 (EtOAc-
1
hexane, 20:80); IR (KBr pellet) 1719.1 cm-1 (CdO); H NMR
(CDCl3) δ 7.48-7.06 (m, 9 H, ArH), 6.78 (d, 1 H, J ) 7.5 Hz,
H-1), 6.58 (d, 1 H, J ) 7.5 Hz, H-2), 5.38 (d, 1 H, J ) 12.4 Hz,
OCHHPh), 5.19 (d, 1 H, J ) 12.4 Hz, OCHHPh), 5.00 (s, 1 H,
H-5), 3.55 (d, 1 H, J ) 15.9 Hz, Ha of C(spiro)-CHaHb-Ar), 3.21
(d, 1 H, J ) 15.9 Hz, Hb of C(spiro)-CHaHb-Ar), 3.12 (m, 1 H,
H-9), 2.70-1.20 (m, 15 H), 0.85 (m, 1 H, H-19), 0.55 (m, 2 H,
cyclopropyl), 0.12 (m, 2 H, cyclopropyl); NOE difference expt,
irradiation of H-5 gave no enhancement for either Ha or Hb of
C(spiro)-CHaHb-Ar, irradiation of either Ha or Hb gave no
enhancement for H-5; molecular mechanics calculations7 on
an energy-minimized structure of 17 gave internuclear dis-
tances of 4.75 Å between H-5 and Hb, 4.77 Å between H-5 and
Ha; 13C NMR-DEPT (CDCl3) δ CH2 (72.38, 59.15, 43.55, 43.52,
42.41, 41.80, 41.67, 30.28, 22.56, 3.90, 3.81), CH (128.31,
128.26, 127.85, 127.81, 127.70, 126.57, 126.33, 124.31, 123.93,
119.35, 118.86, 89.16, 62.18, 9.36), quaternary (208.80, 145.39,
141.83, 140.35, 137.54, 129.90, 125.64, 69.76, 56.41, 51.35);
HRMS (FAB) calcd for C36H38NO4 (M + H)+ 548.2801, found
548.2798.
The following compounds 18-21 were prepared using the
same methodology as described above, except for the differ-
ences noted.
7r- a n d 7â-Sp ir oben zocycloh exyl-3-O-ben zyloxym or -
p h on e (19 a n d 18). These were prepared from 3-O-benzyl-
oxymorphone (14) (2.5 g, 6.4 mmol), using potassium bis-
(trimethylsilyl)amide and 18-crown-6 as base. The two epimers
were separated and purified by gravity column chromatogra-
phy, eluting sequentially with 20%, 40%, and 45% ethyl acetate
in hexane and a trace amount of ammonia.
7â Ep im er 18: yield 680 mg (21%); mp 235-236 °C; TLC
Rf 0.18 (EtOAc-hexane, 40:60); IR (CHCl3) 1720.2 cm-1 (CdO);
1H NMR (CDCl3) δ 7.5-7.1 (m, 9 H, ArH), 6.77 (d, 1 H, J )
8.4 Hz, H-1), 6.61 (d, 1 H, J ) 8.4 Hz, H-2), 5.40 (d, 1 H, J )
12.0 Hz, OCHHPh), 5.24 (d, 1 H, J ) 12.0 Hz, OCHHPh), 5.30
(br, 1 H, OH), 5.05 (s, 1 H, H-5), 3.87 (d, 1 H, J ) 17.4 Hz, Ha
of C(spiro)-CHaHb-Ar), 3.24 (d, 1 H, J ) 17.4 Hz, Hb of C(spiro)-
CHaHb-Ar), 3.15 (d, 1 H), 2.84 (d, 1 H, J ) 5.4 Hz, H-9), 2.7-
2.1 (m, 8 H), 2.44 (s, 3 H, CH3), 2.04 (d, 1 H, J ) 14.1 Hz, 1 H,
H-8), 1.84 (d, 1 H, J ) 14.1 Hz, H-8), 1.58 (m, 1 H); NOE
difference expt, irradiation of H-5 gave a positive enhancement
(+5.9%) for Hb of C(spiro)-CHaHb-Ar, irradiation of Hb gave a
positive enhancement (+6.8%) for H-5 and a strong enhance-
ment (+25.6%) for the geminal proton Ha; molecular modeling
calculations7 for the energy-minimized structure furnished
internuclear distances of 3.47 Å between H-5 and Hb, 4.85 Å
between H-5 and Ha; 13C NMR-DEPT (CDCl3) δ CH3 (43.40),
CH2 (73.10, 45.97, 43.29, 43.20, 42.53, 42.33, 31.68, 22.62), CH
7â Ep im er 20: yield 461 mg (15%); mp 230-231 °C; TLC
Rf 0.26 (3% methanol and 1% triethylamine in CHCl3); IR
(CHCl3) 1720.2 cm-1 (CdO); 1H NMR (CDCl3) δ 7.28-7.03 (m,
4 H, ArH), 6.75 (d, 1 H, J ) 7.9 Hz, H-2), 6.58 (d, 1 H, J ) 7.9
Hz, H-1), 4.83 (s, 1 H, H-5), 3.98 (d, 1 H, J ) 17.0 Hz, Ha of
C(spiro)-CHaHb-Ar), 3.85 (s, 3 H, OMe), 3.66 (d, 1 H, J ) 17.0
Hz, Hb of C(spiro)-CHaHb-Ar), 3.3-3.2 (m, 2 H), 3.2-2.8 (m, 4
H, CH2CH2), 2.64 (m, 1 H, H-16), 2.44 (s, 3 H, NMe), 2.5-1.6
(m, 6 H), 1.43 (t, 1 H, J ) 12.9 Hz, H-8a); NOE difference expt,
irradiation of H-5 gave a positive enhancement (+5.8%) for
Hb, irradiation of Hb gave a positive enhancement (+6.6%) for
H-5 and a strong enhancement (+27.4%) for the geminal
proton Ha; molecular mechanics calculations7 on the energy-
minimized structure of 20 gave internuclear distances of 3.32
Å between H-5 and Hb, 4.75 Å between H-5 and Ha; 13C NMR-
DEPT (CDCl3) δ CH3 (57.48, 43.49), CH2 (69.94, 45.51, 45.22,
43.51, 40.02, 37.21, 20.18), CH (129.05, 127.72, 127.30, 126.78,
126.60, 124.09, 123.98, 120.01, 115.06), quaternary (209.02,
145.80, 143.91, 141.46, 139.01, 127.08, 89.56, 59.69, 58.07);
HRMS (FAB) calcd for C27H30NO3 (M + H)+ 416.2226, found
416.2230.
7r Ep im er 21: yield 159 mg (5.1%); mp 237-238 °C; TLC
Rf 0.35 (3% MeOH and 1% of triethylamine in CHCl3); IR
(CHCl3) 1720.0 cm-1 (CdO); 1H NMR (CDCl3) δ 7.25-7.08 (m,
4 H, ArH), 6.77 (d, 1 H, J ) 7.7 Hz, H-2), 6.60 (d, 1 H, J ) 7.7
Hz, H-1), 4.86 (s, 1 H, H-5), 3.89 (s, 3 H, OMe), 3.60 (d, 1 H,
J ) 16.3 Hz, Ha of C(spiro)-CHaHb-Ar), 3.35 (d, 1 H, J ) 16.3
Hz, Hb of C(spiro)-CHaHb-Ar), 3.3-3.2 (m, 2 H, H-9, H-10),
3.1-2.7 (m, 4 H, CH2CH2), 2.64 (m, 1 H, H-16), 2.42 (s, 3 H,
NMe), 2.4-1.6 (m, 6 H), 1.40 (t, 1 H, J ) 13.1 Hz, H-8a); NOE
difference expt, irradiation of H-5 gave no enhancement for
either Ha or Hb of C(spiro)-CHaHb-Ar, irradiation of either Ha
or Hb gave no enhancement for H-5; molecular modeling
calculations7 for distances between H-5 and Hb and between
H-5 and Ha were found to be 4.83 and 5.54 Å, respectively;
13C NMR-DEPT (CDCl3) δ CH3 (56.67, 42.59), CH2 (70.24,
46.61, 46.30, 42.59, 39.84, 35.03, 19.51), CH (127.15, 126.61,
126.25, 126.18, 126.00, 124.27, 124.18, 119.43, 114.96), qua-
ternary (207.82, 144.95, 142.53, 141.46, 138.41, 128.28, 90.02,
58.66, 56.57); HRMS (FAB) calcd for C27H30NO3 (M + H)+
416.2226, found 416.2225.
7â-Sp ir oben zocycloh exyln a ltr exon e (4). To a rapidly
stirred solution of the benzyl ether 16 (600 mg, 1.09 mmol) in
30 mL of dry chloroform (freshly distilled over P2O5) at room

7-Spirobenzocyclohexyls as Opioid Receptor Ligands
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 19 3069
temperature was added boron tribromide (1.0 M solution in
hexanes, 4.4 mL, 4.4 mmol) via syringe. After the addition,
stirring of the reaction mixture was continued at room
temperature for 2 h. Methanol (10 mL) was added via syringe
to quench the reaction, and the resultant white cloudy mixture
was stirred for another 10 min. Saturated aqueous sodium
bicarbonate solution (20 mL) was added, and the mixture was
stirred for an additional 10 min before being extracted with
chloroform (3 × 40 mL). The organic extracts were combined,
washed with brine, dried over anhydrous Na2SO4, filtered, and
evaporated in vacuo. The residue was purified by flash column
chromatography on silica gel, eluting with 2% methanol in
chloroform and a trace amount of ammonia, to afford 310 mg
(62%) of the desired product 4 as white needles after crystal-
lization from ethyl acetate-chloroform: mp 232-233 °C; TLC
Rf 0.37 (5% methanol in chloroform with a trace amount of
Hz); 13C NMR (DMSO-d6, TMS as reference) δ 208.94, 146.01,
145.19, 142.71, 141.95, 140.12, 130.05, 127.24, 127.01, 125.21,
124.63, 124.11, 120.00, 117.98, 88.51, 70.08, 65.07, 57.10,
49.83, 45.04, 42.35, 42.28, 41.66, 41.53, 30.12, 21.02; HRMS
(FAB) calcd for C26H28NO4 (M + H)+ 418.2018, found 418.2025.
Anal. (C26H27NO4) C, H, N.
7â-Sp ir ob en zocycloh exylh yd r om or p h on e (8). To a
stirred solution of 20 (500 mg, 1.2 mmol) in 30 mL of
dichloromethane at 0 °C was added boron tribromide (1.0 M
solution in hexanes, 3.61 mL, 3.61 mmol) via syringe under a
nitrogen atmosphere. The reaction mixture was stirred at 0
°C for 30 min and then for 90 min at ambient temperature.
Hydrochloric acid (2 N, 24 mL) was added, and the resulting
mixture was then refluxed for 1 h. After cooling to room
temperature, the reaction mixture was adjusted to pH 8.5 with
aqueous sodium bicarbonate solution and then extracted with
chloroform (3 × 80 mL). The combined organic layers were
washed with brine, dried over anhydrous sodium sulfate,
filtered, and evaporated. The residual powder was chromato-
graphed on silica gel, eluting with a mixture of 5% methanol
and 1% ammonia in chloroform. Crystallization from metha-
nol-chloroform furnished 210 mg (44%) of 8 as light yellow
rods: mp 249-250 °C; TLC Rf 0.20 (5% methanol in chloro-
form); 1H NMR (CDCl3) δ 8.24 (br, 1 H, OH), 7.3-7.0 (m, 4 H,
ArH), 6.72 (d, 1 H, J ) 8.1 Hz, H-2), 6.60 (d, 1 H, J ) 8.1 Hz,
H-1), 4.81 (s, 1 H, H-5), 3.94 (d, 1 H, J ) 16.9 Hz, C(spiro)-
CHH-Ar), 3.67 (d, 1 H, J ) 16.9 Hz, C(spiro)-CHH-Ar), 3.3-
3.2 (m, 2 H), 3.2-2.8 (m, 4 H), 2.63 (dd, 1 H, J ) 7.5, 1.0 Hz,
H-16), 2.42 (s, 3 H, CH3), 2.5-1.6 (m, 6 H), 1.44 (t, 1 H, J )
13.0 Hz, H-8a); 13C NMR (CDCl3) δ 209.56, 144.82, 142.54,
140.42, 139.47, 127.63, 127.49, 127.30, 127.15, 125.26, 125.13,
120.80, 119.11, 90.71, 78.15, 59.45, 57.34, 47.54, 47.23, 43.11,
40.85, 40.31, 38.72, 37.17, 35.61, 20.66; HRMS (FAB) calcd
for C26H28NO3 (M + H)+ 402.2069, found 402.2075. The base
was converted to its hydrochloride salt. Anal. (C26H27NO3‚
HCl) C, H, N.
1
ammonia); H NMR (CDCl3) δ 7.15-7.08 (m, 4 H, ArH), 6.74
(d, 1 H, J ) 8.4 Hz, H-1), 6.60 (d, 1 H, J ) 8.4 Hz, H-2), 5.8
(br, 1 H, ArOH), 3.85 (d, 1 H, 17.1 Hz, C(spiro)-CHH-Ar), 3.22
(d, 1 H, J ) 17.1 Hz, C(spiro)-CHH-Ar), 3.14 (d, 1 H, J ) 5.4
Hz, H-9), 3.06 (d, 1 H, H-10a), 2.65 (m, 1 H, H-16e), 2.54 (dd,
1 H, H-10e), 2.5-2.1 (m, 10 H), 2.00 (d, 1 H, J ) 13.5 Hz, H-8),
1.83 (d, 1 H, J ) 13.5 Hz, H-8), 1.50 (dd, 1 H, J ) 10.8, 1.5
Hz, H-15a), 0.9-0.7 (m, 1 H, H-19), 0.6-0.4 (m, 2 H, H-21,
H-20), 0.14 (m, 2 H, H-21, H-20); 13C NMR (CDCl3) δ 210.29,
143.32, 141.83, 140.36, 138.99, 128.94, 126.49, 126.25, 124.21,
123.91, 123.88, 119.64, 118.14, 89.16, 69.84, 62.18, 59.07,
59.23, 56.23, 51.56, 43.53, 42.41, 41.69, 41.61, 30.10, 22.43,
9.31, 3.90, 3.75; HRMS (FAB) calcd for C29H32NO4 (M + H)+
458.2331, found 458.2327. The base was converted to its
hydrochloride salt. Anal. (C29H31NO4‚HCl) C, H, N.
7r-Sp ir oben zocycloh exyln a ltr exon e (5). Following the
methodology as that described for 4, the benzyl ether 17 (80
mg, 0.146 mmol) furnished 61 mg (91%) of 5: mp 227-228
°C; TLC Rf 0.24 (2% MeOH and a trace amount of NH3 in
chloroform); 1H NMR (CDCl3) δ 7.13-7.10 (m, 4 H, ArH), 6.71
(d, 1 H, J ) 8.0 Hz, H-2), 6.57 (d, 1 H, J ) 8.0 Hz, H-1), 5.7
(br, 1 H, ArOH), 3.50 (d, 1 H, J ) 15.6 Hz, C(spiro)-CHH-Ar),
3.17 (d, 1 H, J ) 15.6 Hz, C(spiro)-CHH-Ar), 3.10-3.00 (m, 2
H, H-9, H-10), 2.75-2.25 (m, 11 H), 2.04 (d, 1 H, J ) 14.0 Hz,
H-8), 1.84 (d, 1 H, J ) 14.0 Hz, H-8), 1.53 (dd, 1 H, J ) 11.0,
1.7 Hz, H-15a), 1.23 (br, 1 H, OH), 0.9-0.7 (m, 1 H, H-19),
0.57-0.51 (m, 2 H, H-21, H-20), 0.12 (m, 2 H, H-21, H-20);
13C NMR (CDCl3) δ 209.85, 145.10, 142.02, 140.44, 139.02,
129.06, 126.53, 126.45, 124.37, 124.01, 123.98, 119.35, 117.97,
89.02, 70.04, 61.97, 59.67, 55.95, 51.09, 43.62, 42.31, 41.88,
41.81, 29.89, 22.53, 9.69, 3.82, 3.69; HRMS (FAB) calcd for
C29H32NO4 (M + H)+ 458.2331, found 458.2335. The base was
converted to its hydrochloride salt. Anal. (C29H31NO4‚HCl)
C, H, N.
7r-Sp ir oben zocycloh exylh yd r om or p h on e (9). Follow-
ing the procedure as described for 8, methyl ether 21 (110 mg,
0.265 mmol) furnished 44 mg (42%) of 9 as light yellow crystals
from methanol-chloroform: mp 242-243 °C; 1H NMR (CDCl3)
δ 7.2-7.0 (m, 4 H, ArH), 6.75 (d, 1 H, J ) 7.8 Hz, H-2), 6.62
(d, 1 H, J ) 7.8 Hz, H-1), 4.84 (s, 1 H, H-5), 3.62 (d, 1 H, J )
16.2 Hz, C(spiro)-CHH-Ar), 3.38 (d, 1 H, J ) 16.2 Hz, C(spiro)-
CHH-Ar), 3.30-3.23 (m, 2 H, H-9, H-10), 3.08-2.75 (m, 4 H,
CH2CH2), 2.65 (m, 1 H, H-16), 2.45 (s, 3 H, CH3), 2.4-1.6 (m,
7 H), 1.40 (t, 1 H, J ) 13.3 Hz, H-8a); 13C NMR (CDCl3) δ
208.82, 145.08, 141.80, 139.68, 138.73, 126.88, 126.75, 126.59,
126.41, 124.52, 124.39, 120.06, 118.37, 89.97, 78.41, 58.71,
56.60, 46.80, 46.49, 42.37, 40.11, 39.57, 37.98, 36.43, 34.87,
19.92; HRMS (FAB) calcd for C26H28NO3 (M + H)+ 402.2069,
found 402.2064. The base was converted to its hydrochloride
salt. Anal. (C26H27NO3‚HCl) C, H, N.
7â-Sp ir oben zocycloh exyloxym or p h on e (6). The benzyl
ether 18 (600 mg, 1.18 mmol), treated in the same way as
described for 4, afforded 420 mg (85%) of 6 as a white solid:
mp 242-244 °C; TLC Rf 0.29 (5% MeOH and 1% NH3 in
1
chloroform); H NMR (DMSO-d6) δ 9.22 (br, 1 H, OH), 7.14-
Ack n ow led gm en t. We thank Michael Powers and
Veronika Phillips for capable technical assistance and
the NIDA for support of this research.
7.05 (m, 4 H, ArH), 6.59 (d, 1 H, J ) 8.1 Hz, H-1), 6.56 (d, 1
H, J ) 8.1 Hz, H-2), 5.22 (br, 1 H, OH), 5.19 (s, 1 H, H-5), 3.68
(d, 1 H, J ) 17.2 Hz, C(spiro)-CHH-Ar), 3.28 (d, 1 H, J ) 17.2
Hz, C(spiro)-CHH-Ar), 3.08 (d, 1 H), 2.82 (d, 1 H, J ) 5.4 Hz),
2.6-2.1 (m, 6 H), 2.36 (s, 3 H, CH3), 2.01-1.91 (m, 3 H), 1.76
Refer en ces
(d, 1 H, J ) 14.1 Hz, H-8), 1.30 (dd, 1 H, J ) 11.4, 3.0 Hz); 13
C
(1) Portoghese, P. S.; Sultana, M.; Nagase, H.; Takemori, A. E.
Application of the Message-Address Concept in the Design of
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NMR (DMSO-d6, TMS as reference) δ 209.31, 144.07, 143.11,
141.76, 140.68, 139.42, 129.21, 126.19, 125.96, 124.12, 123.54,
123.15, 118.93, 117.26, 87.92, 69.52, 63.71, 55.32, 50.16, 44.88,
42.17, 42.10, 41.33, 41.24, 29.63, 21.20; HRMS (FAB) calcd
for C26H28NO4 (M + H)+ 418.2018, found 418.2022. Anal.
(C26H27NO4) C, H, N.
7r-Sp ir oben zocycloh exyloxym or p h on e (7). Using the
same methodology as described above, benzyl ether 19 (95 mg,
0.19 mmol) afforded 71 mg (90%) of 7: mp 238-239 °C; TLC
1
Rf 0.32 (5% MeOH and 1% NH3 in CHCl3); H NMR (DMSO-
d6) δ 9.4-9.1 (br, 1 H, OH), 7.18-6.96 (m, 4 H, ArH), 5.22 (br,
1 H, OH), 5.16 (s, 1 H, H-5), 3.42 (d, 1 H, J ) 16.4 Hz, C(spiro)-
CHH-Ar), 3.15 (d, 1 H, J ) 16.4 Hz, C(spiro)-CHH-Ar), 2.84
(d, 1 H, J ) 5.6 Hz), 2.76-2.14 (m, 12 H), 2.05-1.82 (m, 3 H),
1.72 (d, 1 H, J ) 14.3 Hz, H-8), 1.26 (dd, 1 H, J ) 11.6, 3.2

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