Probes for narcotic receptor mediated phenomena. Part 42: Synthesis and in vitro pharmacological characterization of the N-methyl and N-phenethyl analogues of the racemic ortho-c and para-c oxide-bridged phenylmorphans

Article abstract of DOI:10.1016/j.bmc.2011.04.028

A new synthesis of N-methyl and N-phenethyl substituted ortho-c and para-c oxide-bridged phenylmorphans, using N-benzyl- rather than N-methyl-substituted intermediates, was used and the pharmacological properties of these compounds were determined. The N-

Full text of DOI:10.1016/j.bmc.2011.04.028

Bioorganic & Medicinal Chemistry 19 (2011) 3434–3443
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Probes for narcotic receptor mediated phenomena. Part 42: Synthesis and
in vitro pharmacological characterization of the N-methyl and N-phenethyl
analogues of the racemic ortho-c and para-c oxide-bridged phenylmorphans
Jin-Hee Kim a, , Jeffrey R. Deschamps b, Richard B. Rothman c, Christina M. Dersch c, John E. Folk a,z
,
Kejun Cheng a, Arthur E. Jacobson a, Kenner C. Rice a,
⇑
a Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse and The National Institute on Alcohol Abuse and Alcoholism,
National Institutes of Health, Department of Health and Human Services, 5625 Fishers Lane, Room 4N03, Bethesda, MD 20892-9415, USA
b Centre for Biomolecular Science and Engineering, Naval Research Laboratory, Washington, DC 20375, USA
c Clinical Psychopharmacology Section, Chemical Biology Research Branch, National Institute on Drug Abuse, Addiction Research Center, National Institutes of Health,
Department of Health and Human Services, Baltimore, MD 21224, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 January 2011
Revised 6 April 2011
Accepted 13 April 2011
Available online 22 April 2011
A new synthesis of N-methyl and N-phenethyl substituted ortho-c and para-c oxide-bridged phenylmor-
phans, using N-benzyl- rather than N-methyl-substituted intermediates, was used and the pharmacolog-
ical properties of these compounds were determined. The N-phenethyl substituted ortho-c oxide-bridged
phenylmorphan(rac-(3R,6aS,11aS)-2-phenethyl-2,3,4,5,6,11a-hexahydro-1H-3,6a-methanobenzofuro-
[2,3-c]azocin-10-ol (12)) was found to have the highest
the a- through f-oxide-bridged phenylmorphans. Functional data ([35S]GTP-
mate 12 was more than three times more potent than naloxone as an -opioid antagonist.
Published by Elsevier Ltd.
l
-opioid receptor affinity (Ki = 1.1 nM) of all of
c
-S) showed that the race-
Keywords:
Racemates
Ortho-c and para-c oxide bridged
phenylmorphans
l
N-Phenethyl substituent
Opioid receptor affinity
Functional assays
Molecular shape
Opioid antagonist activity
1. Introduction
more potent than naloxone in the [35S]GTP S assay.7 The ortho-d
c
and para-d isomers were found to have little affinity for any opioid
receptor (Ki > 200 nM)3 and the ortho-a and para-a isomers are in
the process of being evaluated. An insufficient quantity of the
N-methyl-substituted ortho-c and para-c isomers was initially pre-
pared4 to allow pharmacological evaluation, and the N-phenethyl
analogues were not synthesized formerly. We now report the
The syntheses of the 12 racemic ortho-a and para-a through -f
oxide-bridged phenylmorphans (Fig. 1) have been published.1–10
These compounds were prepared to examine the possibility that
spatial characteristics, that is, interatomic distances and shape,11,12
might be related to their ability to interact with particular opioid
receptors and function as agonists or antagonists. Several of the
structurally rigid a–f compounds have been found to have good
affinity for opioid receptors, and most of those display opioid antag-
onist activity. Thus far, only one compound, the (À)-enantiomer of
the N-phenethyl substituted para-e isomer,7 has been found to have
morphine-like agonist activity in vivo. The (+)-enantiomer of the
N-phenethyl substituted ortho-b isomer was found to be a weak
and non-selective antagonist,3 and the (À)-enantiomer of the N-
phenethyl substituted para-f isomer was found to be four times
⇑
Corresponding author. Tel.: +1 301 496 1856; fax: +1 301 402 0589.
E-mail addresses: jheeeee@gmail.com (J.-H. Kim), kr21f@nih.gov (K.C. Rice).
Present address: Korea Food & Drug Administration, Incheon, Korea.
Deceased 12/27/10.
Figure 1. Structures of N-substituted ortho-a and para-a through -f oxide-bridged
phenylmorphans and the ortho-c and para-c oxide-bridged phenylmorphan
isomers.
z
0968-0896/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.bmc.2011.04.028

J.-H. Kim et al. / Bioorg. Med. Chem. 19 (2011) 3434–3443
3435
synthesis of the racemic N-methyl and N-phenethyl analogues of the
ortho-c and para-c isomers (Fig. 1) in sufficient quantities to permit
determination of their binding affinity and efficacy.
intermediate 9 was obtained in 59% yield from 8, with the correct
configuration at C4 to allow cyclization to the ortho-c oxide-
bridged phenylmorphan 10. This was accomplished using boron
tribromide in cold chloroform to cleave the aromatic ether moie-
ties to the bisphenolic compound followed by base-catalyzed ring
closure of 9 to the desired product 10 in 27% yield in a larger scale
run, over two steps from 8. Competing formation of aziridinium ion
intermediate 9b (Scheme 2) led to the undesired five-membered
ring compound 10a, possibly via an initial attack of the unpaired
electrons on nitrogen on the C4-mesylate to displace the mesylate
moiety and form the aziridinium ring.5 The structure of the inter-
mediate 10 was confirmed as the ortho-c isomer (Scheme 2) by
X-ray crystallographic analysis of 10ÁHCl. (Fig. 2).
2. Chemistry
The ortho-c and para-c compounds were initially synthesized
using an N-methyl substituent in a lengthy and low yielding
route.4 Since we sought higher yielding reactions and, as well,
needed a different N-substituent in our final product (the N-phen-
ethyl), we decided to modify the synthetic sequence of Tadic et al.4
by utilizing an N-benzyl substituent. For the initial reactions (for
compounds 2 through 9), the N-benzyl compounds were prepared
in better overall yields than the corresponding N-methyl analogs.
The syntheses of rac-N-methyl (13) and N-phenethyl (12) -ortho-
c compounds were accomplished in 11 and 12 steps, respectively,
as shown in Schemes 1 and 2.
1-Benzyl-4-(2,3-dimethoxyphenyl)piperidin-4-ol (1) was pre-
pared from commercially available materials (Scheme 1), and a
65% yield was obtained after purification by column chromatogra-
phy. The crude alcohol 1 was sufficiently pure for use in the next
reaction in which water was eliminated from the molecule under
acidic conditions to form the 1,2,3,6-tetrahydropyridine 2 in 67%
yield.
Phenylmorphan 4 was prepared using an extension of prior
methodology13 by alkylation of 2 with allyl bromide to give 3 that
was cyclized to enamine 4 with a mixture of formic and phosphoric
acids. The 5-phenylmorphan 4 had the structural requirements
necessary to go forward to the essential intermediate, mesylate
9. Crude 4 was brominated at C4 of the 5-phenylmorphan with
N-bromoacetamide, and the ensuing bromide 5 was reduced with
sodium cyanoborohydride to give the saturated bromo compound
6, in 73% yield from 5, and 60% yield over the three steps from
crude 3. In order to obtain the correct oxide-bridged phenylmor-
phan, the c-isomer, inversion of the configuration at C4 in 6 was
required. This was accomplished by displacement of the bromine
at C4 with potassium benzoate in DMF at 80 °C presumably via
an SN2 mechanism, to give the benzoate 7 in 68% yield. The 2-aza-
bicyclo[3.3.1]nonan-4-ol (8) was obtained by methanolysis of the
ester under alkaline conditions in 66% yield. The essential mesylate
Compound 10 was used as the starting material for conversion
to N-methyl- and N-phenethyl-substituted para-hydroxy com-
pounds 19 and 22, respectively (Scheme 3).4 To accomplish this,
both the phenolic hydroxyl group in 10 and the N-substituent
had to be removed. To remove the phenolic hydroxy group a tetra-
zoyl ether 14 was prepared by reaction of 10 with phenylchlorotet-
razole in DMF at room temperature.14 Column chromatography
gave the pure compound, in 89% yield. Both the tetrazoyloxy moi-
ety and the N-benzyl group were concomitantly cleaved by reduc-
tion with 10% Pd/C and hydrogen in acidic solution, in 45% yield
after chromatography, to give the intermediate 15 that could be
used to prepare the desired N-substituted para-c oxide-bridged
phenylmorphans; the oxide-bridge was undisturbed during this
series of reactions. N-Methylation was carried out in 82% yield
after chromatography using formaldehyde in an atmosphere of
hydrogen at room temperature to give 16. Aromatic nitration in
the para-position (para oriented to the oxide-bridge) to give 17
was achieved using sodium nitrite in trifluoroacetic acid in 39%
yield. It was sufficiently pure for use in the preparation of the
para-amino compound 18. Hydrogenation of 17 using 10% Pd/C
in acidic solution gave the desired amino compound 18, in 68%
yield, which was converted to the desired phenol 19 by sequential
diazotization with sodium nitrite in 30% sulfuric acid followed by
treatment with Cu(NO3)2 and Cu2O. The N-methyl substituted
para-c oxide-bridged phenylmorphan 19 was purified through
recrystallization of its hydrochloride salt. The phenol was pro-
tected by conversion to the acetate 20, in 98% yield, using acetic
Scheme 1. Synthesis of phenylmorphan alcohol 8: Reagents and conditions: (a) n-BuLi, Et2O, 0 °C, 65%; (b) p-TSA, toluene, 67%; (c) sec-BuLi, allyl bromide, THF, 68%; (d) 88%
HCOOH + 85% H3PO4, 20 °C, 4 days; (e) NBA, THF, À78 °C, 30 min; (f) NaCNBH3, 20 °C, 30 min; (g) anhydrous potassium benzoate, DMF, 80 °C, 16 h; (h) NaOMe, MeOH, 40 °C,
3 h.

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J.-H. Kim et al. / Bioorg. Med. Chem. 19 (2011) 3434–3443
Scheme 2. Synthesis of rac-N-methyl and N-phenethyl-ortho-c compounds (2-methyl- and 2-phenethyl-2,3,4,5,6,11a-hexahydro-1H-3,6a-methanobenzofuro[2,3-c]azocin-
10-ol). Reagents and conditions: (a) methanesulfonyl anhydride, triethylamine, NaHCO3, 60%; (b) BBr3, CHCl3, À2 °C, 1 h, 14% (27% 10 in larger scale run; (c) 10% Pd/C, H2,
EtOH, 60 °C, 6 h, 78%; (d) (2-bromoethyl)benzene, NaHCO3, DMF, 80–90 °C, 4 h, 71%; (e) 10% Pd/C, H2, MeOH, 60 °C, 12 h, then 37% HCHO, H2, room temperature, 4 h.
in only moderate7,15 yields (64–77%), and the necessity of an extra
step that is needed to prepare the N-phenethyl-substituted com-
pound from the N-methyl analogue is considered, the route to
compound 13 in Scheme 2 using the alternate method in Scheme
4 appears preferable.
3. Results and discussion
As can be seen in Table 1, there is a considerable difference be-
tween the binding affinities of the N-methyl and the N-phenethyl-
substituted compounds. The N-phenethyl-substituted ortho-c iso-
mer 12 was found to have the highest affinity (Ki = 1.1 nM, two
to three times the affinity of morphine) of all of the a- through
f-oxide bridged phenylmorphans. It was fairly selective for the
l
-receptor, having about 50 fold less affinity for
about 1200-fold less affinity for d-receptors. The para-hydroxy
analogue had 60-fold less affinity for -receptors than the compa-
rable N-phenethyl ortho-hydroxy compound, and it did not have
appreciable affinity for d- or -receptors. The N-methyl analogues
j-receptors and
Figure 2. X-ray crystal structure of the HCl salt of rac-(3R,6aS,11aS)-2-benzyl-
1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocine-10-ol (10). Dis-
placement ellipsoids are shown at the 50% level.
l
j
anhydride at 60 °C for 1 h. The crude phenolic secondary amine 21
was obtained, in 30% yield after chromatography, through
oxidation of the tertiary amine 20 by cupric acetate in an acetoni-
trile–water mixture with ammonium thiosulfate. It was suffi-
ciently pure for reaction with (2-bromoethyl)benzene in DMF to
give the desired N-phenethyl derivative of the para-c oxide-
bridged phenylmorphan 22, in 67% yield after chromatography.
In an alternate synthesis (Scheme 4) of the N-methyl substi-
tuted compound, the conversion of the N-benzyl compound 8 to
its N-methyl analogue 23, was accomplished in 68% yield. The
analogue 23 was converted4 to the mesylate 24 quantitatively.
The mesylate 24, the N-methyl analog of 9, was not isolated. Com-
pound 25 was ring-closed to 13, the N-methyl analogue of 10, in
70% yield (47% over three steps from 8).4 Much less of 26 (in
Scheme 4), comparable to 10a in Scheme 2, was formed, presum-
ably because with the N-methyl substituted compound, much
more so than with the N-benzyl substituent, the SN2 pathway
was favored over formation of the aziridinium ion. The mechanism
by which the different N-substituents influenced the reaction is
uncertain.
of these compounds had little affinity for any opioid receptor
(Table 1).
It is apparent that the position of the phenolic hydroxyl is of
great importance to the affinity of the molecule, and that the
N-phenethyl substituent is necessary for effective interaction with
the
l-receptor. The shape of the ortho-c compound, the inter-
atomic distance between heteroatoms, the tertiary amine and the
phenolic oxygen, are all apparently necessary for high affinity
interaction with
receptor resulted in opioid antagonist activity, as determined by
35S]-GTP-
-S assays (Table 2).
TheN-phenethylortho-c phenylmorphan 12 was more thanthree
times as potent as naloxone as a -opioid antagonist (Table 2), and
had -opioid antagonist activity as well (one tenth the potency of
l-receptors. This interaction with the l-opioid
[
c
l
j
norBNI). We expect that one of the enantiomers of this compound
will have subnanomolar affinity and close to the optimal shape
and the required heteroatom spatial positioning needed by oxide-
bridged phenylmorphans for high potency and selectivity as an
l-opioid antagonist. Future work will be focused on obtaining a
sufficient amount of these enantiomers for pharmacological analy-
ses, and the synthesis will be based on the N-benzyl route modified
by the alternative procedure noted in Scheme 4.
Even if the removal of an N-methyl substituent in an oxide-
bridged phenylmorphan to form the secondary amine proceeds

J.-H. Kim et al. / Bioorg. Med. Chem. 19 (2011) 3434–3443
3437
Scheme 3. Synthesis of rac-N-methyl and N-phenethyl-para-c compounds (2-methyl- and 2-phenethyl-2,3,4,5,6,11a-hexahydro-1H-3,6a-methanobenzofuro[2,3-c]azocin-8-
ol. Reagents and conditions: (a) 5-phenylchlorotetrazole, K2CO3, DMF, 32 h, 89%; (b) 10% Pd/C, glacial acetic acid, H2, 30–50 psi, 72 h, 45%; (c) 10% Pd/C, 37% HCHO, MeOH, H2,
4 h, 82%; (d) NaNO2, trifluoroacetic acid, 5 °C, 2 h, 39%; (e) 10% Pd/C, MeOH, 37% HCl, H2, 1.5 h, 68%; (f) 30% H2SO4, 0 °C, NaNO2, 2 h, then Cu(NO3)2, Cu2O, 0 °C, 1 h, 67%; (g)
Ac2O, 60 °C, 2 h, 98%; (h)14 CH3CN/H2O (5:1), Cu(OAc)2, (NH4)2S2O8, 12 h, aqueous 10% Na2S2O3; (i) (2-bromoethyl)benzene, NaHCO3, DMF, 80–90 °C, 2 h, 67%.
Scheme 4. Alternative higher yielding route to 13. Reagents and conditions: (a) 10% Pd/C, ammonium formate, reflux 2 h, then 88% formic acid, 37% formaldehyde, reflux 3 h,
68%; (b) methanesulfonyl anhydride, triethylamine, NaHCO3, 99%; (c) BBr3, CHCl3, À0 °C, 5 h, 70%, (47% from 8 to 13).
accomplished under UV light or by staining in an iodine chamber.
Flash column chromatography was performed with Fluka Silica Gel
60 (mesh 220–400). Atlantic Microlabs, Inc., Norcross, GA per-
formed elemental analyses, and the results were within 0.4% of
the theoretical values.
4. Experimental
4.1. General
Melting points were determined on a Buchi B-545 instrument
and are uncorrected. Proton and carbon nuclear magnetic reso-
nance (1H and 13C NMR) spectra were recorded in CDCl3 with
tetramethylsilane (TMS) as the internal standard on a Varian
Gemini-300 spectrometer and on a Bruker AVANCE-500. Mass
spectra (HRMS) were recorded on a VG 7070E spectrometer or a
JEOL SX102a mass spectrometer. Thin layer chromatography
(TLC) analyses were carried out on Analtech silica gel GHLF
0.25 mm plates using various gradients of CHCl2/MeOH containing
1% NH4OH or gradients of EtOAc/n-hexane. Visualization was
4.1.1. 1-Benzyl-4-(2,3-dimethoxyphenyl)piperidin-4-ol (1)
Following the general procedure of Burke et al.,5 a solution of
1,2-dimethoxybenzene (36.4 g, 0.26 mol) in anhydrous Et2O
(225 mL) was cooled in an ice bath and stirred under argon while
a 2.5 M solution of n-BuLi (80 mL, 0.20 mol) was added over a
period of 30 min. The ice bath was removed, and the solution was
stirred at room temperature for 19 h. The resulting white suspen-
sion was cooled to 0 °C, and a solution of 1-benzyl-4-piperidinone

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J.-H. Kim et al. / Bioorg. Med. Chem. 19 (2011) 3434–3443
Table 1
62.74, 60.63, 55.84, 53.24, 50.03, 29.67; HRMS calcd for
[3H] Binding data for ortho-c and para-c oxide-bridged phenylmorphans
C
C
20H24NO2 [M+H]+: 310.1807; found: 310.1803. Anal. Calcd for
R2
20H23NO2ÁHCl: C, 69.45; H, 6.99; N, 4.05. Found: C, 69.29; H,
7.04; N, 4.16.
N
R3
4.1.3. (R⁄)-4-Allyl-1-benzyl-4-(2,3-dimethoxyphenyl)-1,2,3,4-
tetrahydropyridine (3)
O
R1
sec-BuLi (1.4 M) in cyclohexane (62 mL, 0.086 mol) was added
dropwise to a solution of 2 (26 g, 0.084 mol) in THF (500 mL) at
À50 °C, allyl bromide (7.44 mL, 0.086 mol) was added, and the
mixture was allowed to warm slowly to room temperature and
stirred overnight. The reaction was quenched by addition of H2O,
diluted with EtOAc, washed with H2O and brine, dried over Na2SO4,
filtered, and concentrated to give a crude enamine 3. Column chro-
matography of the crude material with hexane and EtOAc (5:1)
gave 3 (19.9 g, 67.8%) as a yellow oil. 1H NMR (CDCl3, 300 MHz):
Compd
R1
R2
R3
la
db
jc
13
19
22
12
OH
H
H
H
Me
Me
PhEt
PhEt
619 26
1500 90
67
1.1 0.1
2.6 0.01
>5200
>5200
1250 147
1230 111
>40,000
1080 53
1230 78
OH
OH
H
6
OH
51
3
Morphine
Opiate receptor binding assays were performed using CHO hMOR, CHO hDOR and
CHO hKOR cells, respectively; N = 3.
[3H]-DAMGO.
a
[3H]-DADLE.
b
d
7.20–7.32 (m, 5H), 6.99 (dd, J = 8.1, 2.1 Hz, 1H), 6.95 (t,
[3H]-U69,593.
c
J = 7.5 Hz, 1H), 6.80 (dd, J = 7.5, 2.1 Hz, 1H), 6.13 (d, J = 8.1 Hz,
1H), 5.51 (m, 1H), 4.94 (m, 2H), 4.62 (dd, J = 8.1, 1.8 Hz, 1H), 3.97
(dd, J = 19.5, 15 Hz, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 2.91 (dd,
J = 13.8, 6 Hz, 1H), 2.76 (td, J = 11.4, 3.9 Hz, 1H), 2.56 (dd, J = 12,
2.7 Hz, 1H), 2.45(m, 2H), 1.90 (m, 1H); 13C NMR (CDCl3, 75 MHz):
d 153.08, 147.32, 140.79, 138.73, 136.09, 135.12, 128.26, 127.92,
126.99, 124.04, 122.27, 116.39, 110.71, 103.09, 60.08, 58.92,
55.68, 45.12, 44.02, 40.89, 33.98.
Table 2
Functional data ([35S]GTP- -S)a for N-phenethyl ortho-c oxide-bridged phenylmor-
c
phan (12)
Compd
l-Antagonism Ke (nM)
j
-Antagonism Ke (nM)
1.79 0.51
11
0.11 0.02
12
Naloxone
norBNI
0.71 0.09
2.3 0.3
17
2
4.1.4. (1R⁄,5R⁄)-2-Benzyl-5-(2,3-dimethoxyphenyl)-2-
azabicyclo[3.3.1]non-3-ene (4)
3
a
Ke determinations were conducted as described in Methods in the section ‘Data
Crude 3 (20.6 g, 0.059 mol) was dissolved in a mixture of
152 mL of 88% HCOOH and 152 mL of 85% H3PO4 at 0 °C. The mix-
ture was stirred for 4 days at room temperature. The reaction mix-
ture was diluted with 400 mL of H2O, cooled in ice, and treated
with 40% NaOH solution (to pH ꢀ8) and extracted with EtOAc
(5 Â 40 mL). The organic layer was washed with H2O and brine,
dried over Na2SO4, and concentrated to give crude enamine 4 as
a dark-brown oil (22 g).
analysis and statistics’. Each parameter value is SD (n = 3–4).
(38.2 g, 0.20 mol) in Et2O (38 mL) was added slowly over 20 min.
The solid dissolved, giving a cloudy yellow solution that was
washed with aqueous NaHCO3 and filtered to remove a white solid.
The organic phase was washed with H2O and brine, dried over
Na2SO4, and evaporated to give the crude alcohol 1. Column chro-
matography using hexane and EtOAc (5:1) gave 1 (55.6 g, 65.4%)
as a yellow oil. An HCl salt was prepared and recrystallized from
MeOH. 1H NMR (CDCl3, 300 MHz): d 7.24–7.38 (m, 5H), 7.01 (t,
J = 8.1 Hz, 1H), 6.90 (dd, J = 8.1, 1.5 Hz, 1H), 6.85 (dd, J = 8.1,
1.5 Hz, 1H), 4.24 (s, 1H), 3.95 (s, 3H), 3.85 (s, 3H), 3.58 (s, 2H),
2.76 (d, J = 11.1, 2H), 2.59 (td, J = 11.7, 2.4 Hz), 2.13 (td, J = 12.6,
4.2 Hz), 1.90 (d, J = 13.5 Hz, 2H); 13C NMR (CDCl3, 75 MHz): d
152.64, 147.23, 140.37, 138.61, 129.24, 128.13, 126.87, 123.78,
117.70, 111.71, 71.49, 63.25, 61.07, 55.75, 49.16, 37.29; HRMS calcd
for C20H26NO3 [M+H]+: 328.1913; found: 328.1909. Anal. Calcd for
4.1.5. (1R⁄,5S⁄)-2-Benzyl-4-bromo-5-(2,3-dimethoxyphenyl)-2-
azabicyclo[3.3.1]non-3-ene (5)
The crude 4 (20 g, 0.057 mol) was dissolved in 200 mL of dry
THF, cooled to À78 °C, and N-bromoacetamide (8.76 g, 0.063 mol)
solution in THF (40 mL) was slowly added. After stirring for
30 min at À78 °C, the mixture was allowed to warm up slowly to
room temperature and stirred at room temperature for 20 min.
The solvents were evaporated, and the oily residue was partitioned
between saturated aqueous NaHCO3 and CH2Cl2. The organic layer
was washed with H2O and brine, and dried over Na2SO4. Evapora-
tion of solvent gave crude 5 (24 g).
C
20H25NO3ÁHClÁ0.2H2O: C, 65.37; H, 7.24; N, 3.81. Found: C, 65.18;
H, 7.26; N, 3.96.
4.1.6. (1R⁄,4S⁄,5S⁄)-2-Benzyl-4-bromo-5-(2,3-dimethoxyphenyl)-
2-azabicyclo[3.3.1]nonane (6)
4.1.2. 1-Benzyl-4-(2,3-dimethoxyphenyl)-1,2,3,6-
tetrahydropyridine (2)
The mixture of the crude alcohol 1 (40 g, 0.122 mol) and p-tol-
uensulfonic acid monohydrate (30 g, 0.158 mol) in toluene
(650 mL) was refluxed for 18 h with a Dean-Stark trap to remove
H2O. After removal of toluene, the residual material was diluted
with EtOAc and saturated NaHCO3. The aqueous layer was ex-
tracted with EtOAc. The combined organic phase was washed with
H2O and brine, dried over Na2SO4 and concentrated to dryness. Col-
umn chromatography of the crude material with hexane and EtOAc
(5:1) gave 2 (25.37 g, 67.2%) as a light yellow oil. The HCl salt was
prepared and recrystallized from MeOH. 1H NMR (CDCl3,
300 MHz): d 7.24–7.40 (m, 5H), 6.98 (t, J = 8.1 Hz, 1H), 6.80 (td,
J = 8.1, 1.5 Hz, 2H), 5.79 (m, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 3.64 (s,
2H), 3.16 (dd, J = 6, 2.7 Hz, 2H), 2.68 (t, J = 6.6 Hz, 2H), 2.56 (m,
2H); 13C NMR (CDCl3, 75 MHz): d 152.79, 146.57, 138.26, 137.06,
134.77, 129.24, 128.22, 127.04, 124.24, 123.76, 121.41, 111.09,
Addition of 37% HCl (17.5 mL) to a suspension of crude 5 (21 g,
0.049 mol) in MeOH (250 mL) gave a dark brown solution to which
was added NaCNBH3 (3.74 g, 0.060 mol). The resulting milky mix-
ture was stirred 30 min at room temperature and them diluted
with saturated aqueous NaHCO3 (100 mL). After removal of MeOH,
the residue was extracted with CH2Cl2 (3 Â 50 mL). The combined
organic phase was washed with H2O and brine, and dried over
Na2SO4. Evaporation of solvent gave 6 as a crude oil. Column
chromatography of the crude material with hexane and EtOAc
(10:1) gave 6 (15.4 g, 73.5%; 60% from crude 3) as a white solid.
The HCl salt was prepared and recrystallized from MeOH. Mp (free
base) 125.9–126.2 °C; 1H NMR (CDCl3, 300 MHz): d 7.22–7.39 (m,
5H), 6.95–7.03 (m, 2H), 6.87 (dd, J = 7.2, 2.4 Hz, 1H), 5.34 (dd,
J = 11.1, 6.9 Hz, 1H), 3.95 (s, 3H), 3.86 (s, 3H), 3.77 (dd, J = 24.6,
13.5 Hz, 2H), 3.45 (t, J = 11.4 Hz, 1H), 3.18 (dd, J = 12, 6.6 Hz, 1H),

J.-H. Kim et al. / Bioorg. Med. Chem. 19 (2011) 3434–3443
3439
3.00 (br s, 1H), 2.85 (d, J = 12.6 Hz, 1H), 2.57 (m, 1H), 1.81–2.17 (m,
5H), 1.50 (m, 1H); 13C NMR (CDCl3, 75 MHz): d 153.32, 148.48,
140.10, 139.28, 128.51, 128.25, 126.91, 122.69, 120.19, 111.34,
60.51, 58.81, 58.19, 56.89, 55.75, 51.73, 41.21, 37.94, 32.52,
24.45, 22.00; HRMS calcd for C23H29BrNO2 [M+H]+: 430.1382;
to give mesylate 9 (1.29 mg, 59.7%). The HCl salt was prepared and
recrystallized from MeOH. Mp (9ÁHCl) 149.2–149.5 °C; 1H NMR
(CDCl3, 300 MHz): d 7.20–7.42 (m, 5H), 7.00 (t, J = 7.8 Hz, 1H),
6.84–6.89 (m, 2H), 4.60 (dd, J = 9.9, 7.8 Hz, 1H), 4.51 (dd, J = 9.6,
3.9 Hz, 1H), 4.09 (d, J = 14.4 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H),
3.83 (m, 2H), 3.10 (t, J = 5.4 Hz, 1H), 2.80 (s, 3H), 2.58 (m, 1H),
1.99 (m, 3H), 1.66–1.75 (m, 2H), 1.49 (m, 1H), 1.25 (m, 1H); 13C
NMR (CDCl3, 75 MHz): d 153.36, 141.13, 137.29, 128.15, 128.12,
126.69, 123.28, 119.51, 111.39, 71.54, 70.09, 62.48, 60.66, 60.53,
59.88, 55.77, 49.65, 41.36, 37.06, 31.69, 31.12, 20.62; HRMS calcd
for C24H32NO5S [M+H]+: 446.2001; found 446.2000. Anal. Calcd
for C24H31NO5SÁHClÁ0.4H2O: C, 58.92; H, 6.76; N, 2.86. Found: C,
58.71; H, 6.76; N, 2.86.
found:
430.1375.
Anal.
Calcd
for
C
23H28BrNO2Á
HClÁ0.2H2O: C, 58.72; H, 6.30; N, 2.98. Found: C, 58.65; H, 6.31;
N, 3.06.
4.1.7. (1R⁄,4R⁄,5S⁄)-2-Benzyl-5-(2,3-dimethoxyphenyl)-2-
azabicyclo[3.3.1]nonan-4-yl benzoate (7)
The bromo compound 6 (1 g, 2.32 mmol) was dissolved in DMF
(20 mL) and anhydrous potassium benzoate (1.115 g, 6.96 mmol)
was added while stirring. The suspension was gradually heated
under argon in an oil bath to 80 °C (30 min), and maintained at that
temperature for 16 h. It was cooled to room temperature and di-
luted with H2O. The aqueous phase was extracted with Et2O. The
combined organic extracts were washed with H2O dried over
Na2SO4, and the solvent removed in vacuo. Column chromatogra-
phy of the crude material with hexane and EtOAc (5:1) gave the es-
ter 7 (1.58 g, 68.1%). The HCl salt was prepared and recrystallized
from MeOH. Mp (HCl salt) 98.1–99.2 °C; 1H NMR (CDCl3,
4.1.10. (3R⁄,6aS⁄,11aS⁄)-2-Benzyl-2,3,4,5,6,11a-hexahydro-1H-
3,6a-methanobenzofuro[2,3-c]azocin-10-ol (10)
4.1.10.1.
(6aS⁄,8S⁄,11aR⁄)-7-Benzyl-6a,7,8,9,10,11-hexahydro-
6H-8,11a-methanochromeno[3,4-b]azepin-4-ol (10a).
Small scale: A solution of mesylate 9 (655.5 mg, 1.47 mmol) in
CHCl3 (10 mL) was added dropwise to a vigorously stirred solution
of BBr3 (1.4 mL, 14.7 mmol) in CHCl3 (10 mL) that was cooled to
À2 °C. The mixture was stirred for 1 h at 0–5 °C, and quenched
with a mixture of concentrated NH4OH (20 mL) and crushed ice
(1.5 g). The mixture was then brought to room temperature, and
the organic phase was separated. The aqueous layer was saturated
with NaCl, extracted with CHCl3 and MeOH (3:1). The aqueous
solution was re-extracted with CHCl3 and MeOH (3:1). The com-
bined organic phase was dried over Na2SO4 and evaporated to dry-
ness to give 10a (90.1 mg) and 10 (23.3 mg, 4.9%). The
hydrochloride salt of 10 was prepared by adding HCl in ether to
the tertiary amine 10 in ether; the salt that formed was recrystal-
lized from methanol.
300 MHz):
d 7.64 (d, J = 7.5 Hz, 2H), 7.43(d, J = 7.5 Hz, 2H),
7.20–7.31 (m, 6H), 6.96 (m, 2H), 6.83 (dd, J = 6.9, 2.7 Hz, 1H),
4.64 (m, 2H), 4.15 (d, J = 13.8 Hz, 1H), 3.98 (t, J = 6.3 Hz, 1H), 3.89
(s, 3H), 3.88 (m, 1H), 3.84 (s, 3H), 3.11 (t, J = 5.1 Hz, 1H), 2.69 (m,
1H), 1.94–2.22 (m, 3H), 1.45–1.79 (m, 3H), 1.25 (m, 1H); 13C
NMR (CDCl3, 75 MHz): d 166.61, 153.33, 148.43, 141.40, 138.14,
132.53, 130.21, 129.48, 128.37, 128.04, 126.59, 123.20, 119.94,
111.13, 69.98, 65.88, 62.21, 60.63, 60.10, 55.79, 49.33, 41.46,
31.91, 31.34, 20.41; HRMS calcd for
C
30H34NO4 [M+H]+:
472.2488; found: 472.2493. Anal. Calcd for C30H33NO4ÁHClÁ1.1H2O:
C, 68.26; H, 6.91; N, 2.65. Found: C, 68.06; H, 6.82; N, 2.65.
Larger scale, modified conditions for 10: A solution of 9 (2.8 g,
6.28 mmol) in CHCl3 (65 mL) was added dropwise to a vigorously
stirred solution of BBr3 (6.1 mL, 16 g, 64 mmol) in CHCl3
(210 mL) at À2 °C under argon. The temperature was maintained
at 0 to–5 °C for 1 h and the reaction was quenched with a mixture
of concentrated NH4OH (200 mL) and ice (150 g). The reaction was
brought to room temperature and the organic phase was sepa-
rated. The aqueous phase was saturated with NaCl and extracted
with CHCl3 (3Â). The combined organic extracts were washed with
a little H2O, dried over Na2SO4 and the solvent was removed. Silica
gel chromatography using a linear gradient of hexanes to 25%
EtOAc in hexanes provided 10 (0.56 g, 27% in two steps from 8).
Other runs gave yields from 14% to 22% yields (over two steps).
10: 1H NMR (CDCl3, 300 MHz): d 7.24–7.38 (m, 5H), 6.77 (m, 2H),
6.66 (dd, J = 6.9, 1.5 Hz, 1H), 4.29 (dd, J = 11.7, 5.7 Hz, 1H), 3.94
(d, J = 13.8 Hz, 1H), 3.88 (d, J = 13.8 Hz, 1H), 3.40 (dd, J = 11.7,
10.2 Hz, 1H), 3.23 (dd, J = 9.9, 5.4 Hz, 1H), 3.14 (m, 1H), 2.27 (d,
J = 14.7 Hz, 1H), 2.11 (dd, J = 12, 2.1 Hz, 1H), 1.38–2.04 (m, 7H);
13C NMR (CDCl3, 75 MHz): d 145.90, 140.86, 139.61, 139.38,
128.48, 128.29, 127.00, 122.02, 114.89, 113.69, 89.62, 58.68,
52.71, 50.87, 44.65, 36.65, 31.83, 26.59, 21.73; HRMS calcd for
4.1.8. (1R⁄,4R⁄,5S⁄)-2-Benzyl-5-(2,3-dimethoxyphenyl)-2-
azabicyclo[3.3.1]nonan-4-ol (8)
0.5 M NaOMe in MeOH (29 mL, 14.64 mmol) was slowly added
to a vigorously stirred solution of the ester 7 (3.45 g, 7.32 mmol) in
MeOH (40 mL). The reaction mixture was stirred for 3 h at 40 °C.
After removal of MeOH, the oily residue was partitioned between
saturated aqueous NaHCO3 and CH2Cl2. The combined organic
phase was washed with H2O and brine, dried over Na2SO4 and
evaporated to dryness. Column chromatography of the crude mate-
rial with hexane and EtOAc (3:1) gave 8 (1.78 g, 66%) as a white so-
lid. Mp (free base) 154.8–155.2 °C; 1H NMR (CDCl3, 300 MHz): d
7.23–7.41 (m, 5H), 6.98 (t, J = 7.8 Hz, 1H), 6.84 (dd, J = 8.4, 1.5 Hz,
1H), 6.79 (dd, J = 8.4, 1.5 Hz, 1H), 3.96 (m, 3H), 3.89 (s, 3H), 3.85
(s, 3H), 3.76 (d, J = 13.8 Hz, 1H), 3.36 (t, J = 6.3 Hz, 1H), 3.11 (t,
J = 4.5 Hz, 1H), 2.44 (m, 1H), 1.88–2.12 (m, 4H), 1.49–1.67 (m,
2H), 1.29 (m, 1H); 13C NMR (CDCl3, 75 MHz): d 153.35, 148.02,
140.76, 139.03, 128.30, 128.27, 126.87, 123.43, 119.55, 111.18,
73.67, 62.63, 61.45, 60.70, 59.16, 55.76, 50.05, 41.73, 31.70,
31.64, 19.70; HRMS calcd for C23H30NO3 [M+H]+: 368.2226; found:
368.2219. Anal. Calcd for C23H29NO3: C, 75.17; H, 7.95; N, 3.81.
Found: C, 75.36; H, 7.75; N, 3.86.
C
C
21H24NO2 [M+H]+: 322.1807; found 322.1813. Anal. Calcd for
21H23NO2ÁHClÁ0.9H2O: C, 67.42; H, 6.95; N, 3.74. Found: C,
67.45; H, 6.85; N, 3.75.
4.1.9. (1R⁄,4R⁄,5S⁄)-2-Benzyl-5-(2,3-dimethoxyphenyl)-2-
azabicyclo[3.3.1]nonan-4-yl methanesulfonate (9)
Compound 10a: 1H NMR (CDCl3, 300 MHz): d 7.25–7.38 (m, 5H),
6.69–6.76(m, 2H), 6.65–6.54(m, 1H), 4.29 (dd, J = 12, 9.6 Hz, 1H),
3.96 (dd, J = 9.6, 4.8 Hz, 1H), 3.79 (dd, J = 28.5, 13.2 Hz, 2H), 3.35
(t, J = 5.4 Hz, 1H), 3.04 (dd, J = 12, 5.4 Hz, 1H), 2.11–2.21 (m, 1H),
1.94–2.01 (m, 1H), 1.79–1.89 (m, 2H), 1.45–1.64 (m, 3H), 1.23–
Methanesulfonyl anhydride (777.6 mg, 4.33 mmol) was added
to a solution of 8 (795.8 g, 2.16 mmol) in CHCl3 (20 mL) and trieth-
ylamine (0.8 mL, 5.4 mmol). The colorless solution was stirred
under argon at room temperature for 2 h, and the reaction was
quenched with a saturated solution of NaHCO3. The aqueous phase
was extracted with CHCl3. The combined organic solutions were
washed with H2O, dried over Na2SO4 and evaporated to dryness
1.33 (m, 1H); 13C NMR (CDCl3, 75 MHz):
d 144.29, 140.40,
139.50, 132.43, 128.55, 128.22, 127.06, 119.93, 115.57, 112.88,
69.76, 66.96, 63.33, 61.78, 44.06, 38.44, 35.62, 32.28, 18.52; HRMS
calcd for C21H24NO2 [M+H]+: 322.1807; found 322.1805.

3440
J.-H. Kim et al. / Bioorg. Med. Chem. 19 (2011) 3434–3443
4.1.11. (3R⁄,6aS⁄,11aS⁄)-2,3,4,5,6,11a-Hexahydro-1H-3,6a-
methanobenzofuro[2,3-c]azocin-10-ol (11)
rial with hexane and EtOAc (5:1) gave 14 (41.43 mg, 88.9%); 1H
NMR (CDCl3, 300 MHz): d 7.82 (m, 2H), 7.45–7.57 (m, 3H), 7.23–
7.35 (m, 5H), 7.20 (dd, J = 7.8 Hz, 0.9 Hz, 1H), 7.04 (dd, J = 7.2,
0.9 Hz, 1H), 6.96 (dd, J = 8.4, 7.5 Hz, 1H), 4.36 (dd, J = 11.4, 5.4 Hz,
1H), 3.94 (d, J = 13.8 Hz, 1H), 3.78 (d, J = 13.8 Hz, 1H), 3.35 (t,
J = 10.2 Hz, 1H), 3.17 (m, 2H), 2.27 (d, J = 12.9 Hz, 1H), 2.14 (dd,
J = 12.3, 2.1 Hz, 1H), 1.46–2.05 (m, 6H); 13C NMR (CDCl3,
A mixture of 10 (20 mg, 0.06 mmol) and 10% Pd/C (15 mg) in
EtOH (2 mL) was heated at 60 °C for 6 h in an hydrogen atmo-
sphere. After cooling to room temperature, it was basified with
NH4OH (pH ꢀ9), filtered through a pad of Celite, washed with
MeOH, and concentrated to provide the crude product. The residue
was purified by silica gel column chromatography (CH2Cl2/MeOH/
NH4OH, 90:10:1) to give 11 (10.98 mg, 78.3%); 1H NMR (CDCl3,
300 MHz): d 6.78–6.82 (m, 2H), 6.67 (dd, J = 6.6, 1.2 Hz, 1H), 4.23
(dd, J = 12.0, 5.0 Hz, 1H), 3.83 (t, J = 11.1 Hz, 1H), 3.57 (br s, 2H),
1.53–2.25 (m, 8H).
75 MHz):
d 149.33, 142.02, 139.40, 137.88, 133.20, 129.64,
129.24, 128.41, 128.30, 127.01, 122.17, 121.98, 120.18, 119.70,
90.05, 58.67, 52.85, 50.57, 44.59, 36.51, 32.03, 26.56, 21.69; HRMS
calcd for C28H28N5O2 [M+H]+: 466.2243; found 466.2252. Anal.
Calcd for C28H27N5O2Á0.3H2O: C, 71.41; H, 5.91; N, 14.87. Found:
C, 71.32; H, 5.94; N, 14.92.
4.1.12. (3R⁄,6aS⁄,11aS⁄)-2-Phenethyl-2,3,4,5,6,11a-hexahydro-
1H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol (12)
4.1.15. (3R⁄,6aS⁄,11aS⁄)-2,3,4,5,6,11a-Hexahydro-1H-3,6a-
methanobenzofuro[2,3-c]azocine (15)
A
mixture of 11 (40 mg, 0.17 mmol), NaHCO3 (15.98 mg,
0.19 mmol) and (2-bromoethyl) benzene (25.74 L, 0.19 mmol)
l
10% Pd/C catalyst (138.6 mg) was added to a solution of the
phenyltetrazole ether 14 (111.7 mg, 0.24 mmol) in glacial HOAc
(3 mL). The reaction mixture was hydrogenated at room tempera-
ture at 30 psi for 24 h. The hydrogenation was continued for an
additional 48 h at 50 psi until starting material could no longer
be observed on TLC. The reaction mixture was filtered and the cat-
alyst was washed with HOAc and H2O. Ice was added to maintain
the temperature at 5 °C while the combined acidic solution was
carefully neutralized with NH4OH. The basic aqueous solution
was extracted with CHCl3 and then with CHCl3/MeOH (3:1). The
combined organic material was washed with H2O and the wash-
ings were back extracted with CHCl3. The combined organic ex-
tracts were dried over Na2SO4 and the solvent was removed.
Column chromatography (hexane/EtOAc, 5:1) gave 15 (23.6 mg,
45%); 1H NMR (CDCl3, 300 MHz): d 7.06–7.17 (m, 2H), 6.88–6.93
(m, 2H), 4.12 (dd, J = 12.9, 6.3 Hz, 1H), 3.76 (t, J = 12 Hz, 1H), 3.40
(m, 2H), 2.22 (d, J = 12.3 Hz, 1H), 1.45–2.08 (m, 8H); 13C NMR
in DMF (3 mL) was heated at 80–90 °C for 4 h under argon. After
cooling to room temperature, the mixture was diluted with Et2O,
and washed with H2O and brine. The organic layer was dried over
Na2SO4, filtered, and evaporated in vacuo. Column chromatography
of the crude material with hexane and EtOAc (5:1) gave 12
(40.3 mg, 70.6%). The HCl salt was prepared and recrystallized from
MeOH. Mp (HCl salt) 258.6–259.4 °C; 1H NMR (CDCl3, 500 MHz): d
7.22–7.31 (m, 5H), 6.74–6.82 (m, 2H), 6.66 (d, J = 7.5 Hz, 1H), 4.29
(dd, J = 11.5, 5.5 Hz, 1H), 3.43 (m, 2H), 3.23 (br s, 1H), 2.83–2.98 (m,
4H), 2.23 (d, J = 12 Hz, 1H), 2.13 (d, J = 12.0 Hz, 1H), 1.99 (d,
J = 12.0 Hz, 1H), 1.45–1.79 (m, 5H); 13C NMR (CDCl3, 125 MHz): d
145.97, 140.94, 140.31, 139.50, 128.74, 128.35, 126.07, 122.09,
115.17, 113.72, 89.39, 56.53, 52.80, 51.21, 44.59, 36.70, 34.89,
31.70, 26.48, 21.71; HRMS calcd for
C
22H26NO2 [M+H]+:
336.1964; found 336.1969. Anal. Calcd for C22H25NO2ÁHCl: C,
71.05; H, 7.05; N, 3.77. Found: C, 70.89; H, 6.96; N, 3.77.
(CDCl3, 75 MHz):
d 158.72, 138.42, 127.85, 121.68, 121.27,
4.1.13. (3R⁄,6aS⁄,11aS⁄)-2-Methyl-2,3,4,5,6,11a-hexahydro-1H-
3,6a-methanobenzofuro[2,3-c]azocin-10-ol (13)
110.75, 89.31, 47.98, 45.69, 44.01, 38.24, 32.81, 32.16, 21.66;
HRMS calcd for C14H18NO [M+H]+: 216.1388; found 216.1390.
A mixture of 10 (20 mg, 0.06 mL) and 10% Pd/C (5 mg) in MeOH
(2 mL) was heated at 60 °C for 12 h in a hydrogen atmosphere. 37%
HCHO (6 lL, 0.07 mmol) was added to the mixture and it was stir-
4.1.16. (3R⁄,6aS⁄,11aS⁄)-2-Methyl-1,3,4,5,6,11a-hexahydro-2H-
3,6a-methanobenzofuro[2,3-c]azocine (16)
red at room temperature for 4 h in a hydrogen atmosphere. The
mixture was filtered through a pad of Celite, washed with MeOH,
and solvent removed in vacuo to provide the crude product. Col-
umn chromatography of the crude material with CH2Cl2/MeOH/
NH4OH (95:5:1) gave 13 (11.03 mg, 72.5%). The HCl salt was pre-
pared and recrystallized from MeOH. Mp (HCl salt) 218.7–
219.3 °C (dec); 1H NMR (CDCl3, 300 MHz): d 6.70–6.81 (m, 2H),
6.63 (dd, J = 6.0, 1.2 Hz, 1H), 4.29 (dd, J = 11.1, 6.0 Hz, 1H), 3.36
(m, 2H), 3.11 (br s, 1H), 2.59 (s, 3H), 2.24 (m, 1H), 2.12 (dd,
J = 12.3, 1.8 Hz, 1H), 2.02 (m, 1H), 0.83–1.79 (m, 6H); 13C NMR
A mixture of 15 (10 mg, 0.05 mL), 10% Pd/C (3 mg), and 37%
HCHO (3 lL, 0.04 mmol) in MeOH (2 mL) was stirred at room tem-
perature for 4 h in a hydrogen atmosphere. The mixture was
filtered through a pad of Celite, washed with MeOH, and concen-
trated to provide the crude product. Column chromatography with
CH2Cl2/MeOH/NH4OH (95:5:1) gave 16 (9.4 mg, 82%) as a white so-
lid. Mp (free base) 59.1–59.3 °C; 1H NMR (CDCl3, 500 MHz): d 7.08–
7.15(m, 2H), 6.88–6.92 (m, 2H), 4.26 (dd, J = 11.5, 5.5 Hz, 1H), 3.40
(t, J = 10 Hz, 1H), 3.27 (dd, J = 9.5, 5.5, 1H), 3.09 (br s, 1H), 2.59 (s,
3H), 2.28 (d, J = 13 Hz, 1H), 2.16 (d, J = 12 Hz, 1H), 2.00 (d,
J = 12 Hz, 1H), 1.72–1.79 (m, 2H), 1.58–1.64 (m, 1H), 1.40–1.46
(m, 2H); 13C NMR (CDCl3, 125 MHz): d 159.34, 138.33, 127.68,
121.71, 121.17, 110.76, 88.44, 54.34, 53.24, 43.60, 42.21, 36.61,
32.01, 25.91, 21.60; HRMS calcd for C15H20NO [M+H]+: 230.1545;
found 230.1545. Anal. Calcd for C15H19NOÁ0.1H2O: C, 77.95; H,
8.37; N, 6.06. Found: C, 78.14; H, 8.46; N, 6.33.
(CDCl3, 75 MHz):
113.54, 88.85, 54.47, 53.10, 42.02, 36.46, 31.58, 29.69, 25.71,
21.42; HRMS calcd for
15H20NO2 [M+H]+: 246.1494; found
d 141.49, 139.51, 137.06, 122.17, 115.63,
C
246.1494. Anal. Calcd for C15H19NO2ÁHClÁ0.3H2O: C, 62.73; H,
7.23; N, 4.88. Found: C, 62.81; H, 7.20; N, 4.81.
4.1.14. (3R⁄,6aS⁄,11aS⁄)-2-Benzyl-10-((1-phenyl-1H-tetrazol-5-
yl)oxy)-2,3,4,5,6,11a-hexahydro-1H-3,6a-
4.1.17. (3R⁄,6aS⁄,11aS⁄)-2-Methyl-8-nitro-1,3,4,5,6,11a-
methanobenzofuro[2,3-c]azocine (14)
hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocine (17)
NaNO2 (360 mg, 5.22 mmol) was slowly added to a solution of
16 (200 mg, 0.87 mmol) in trifluoroacetic acid (4 mL), cooled to
5 °C in an ice bath, and the mixture was stirred for 2 h under argon,
until the starting material was no longer detectable on TLC. The
mixture was diluted with ice water and carefully basified with
NH4OH. The aqueous solution was extracted with CHCl3/MeOH
(3:1). The combined organic phase was washed with H2O, dried
over Na2SO4 and the solvent was removed to give 17 (93.2 mg,
A mixture of the ortho-c oxide-bridged phenylmorphan 10
(33 mg, 0.1 mmol) and K2CO3 (27.64 mg, 0.2 mmol) in DMF
(1 mL) was stirred under argon at room temperature. 5-Phenyl-
chlorotetrazole (21.67 mg, 0.12 mmol) was added and the stirring
continued for 32 h after starting material could no longer be dis-
cerned on TLC. The reaction mixture was diluted with H2O and ex-
tracted with Et2O. The organic phase was dried over Na2SO4 and
solvent was removed. Column chromatography of the crude mate-

J.-H. Kim et al. / Bioorg. Med. Chem. 19 (2011) 3434–3443
3441
39%); 1H NMR (CDCl3 500 MHz): d 8.13 (d, J = 8.5 Hz, 1H), 7.98 (br s,
1H), 6.94 (d, J = 8.5 Hz, 1H), 4.40 (dd, J = 11.0, 5.0 Hz, 1H), 3.44 (t,
J = 10 Hz, 1H), 3.29 (dd, J = 9.0, 5.0 Hz, 1H), 3.12 (br s, 1H), 2.60
(s, 3H), 2.29(m, 1H), 2.21 (d, J = 10 Hz, 1H), 2.03 (d, J = 10 Hz, 1H),
1.65–1.80 (m, 3H), 1.45–1.49 (m, 2H); 13C NMR (CDCl3,
J = 10.5 Hz, 1H), 1.75–1.79 (m, 2H), 1.60–1.63 (m, 1H), 1.42–1.46
(m, 2H); 13C NMR (CDCl3, 125 MHz): d 169.93, 156.87, 144.73,
139.27, 120.35, 115.47, 110.88, 88.81, 54.27, 53.12, 44.01, 42.14,
36.38, 31.93, 25.82, 21.52, 21.08; HRMS calcd for C17H22NO3
[M+H]+: 288.1600; found 288.1590. Anal. Calcd for C17H21NO3: C,
71.06; H, 7.37; N, 4.87. Found: C, 70.92; H, 7.51; N, 4.68.
125 MHz):
d 164.83, 142.40, 139.58, 125.30, 118.23, 110.73,
90.10, 54.11, 52.77, 43.68, 42.15, 36.25, 32.18, 25.64, 21.49; HRMS
calcd for C15H19N2O3 [M+H]+: 275.1396; found 275.1387.
4.1.21. (3R⁄,6aS⁄,11aS⁄)-2,3,4,5,6,11a-Hexahydro-1H-3,6a-
methanobenzofuro[2,3-c]azocin-8-ol (21)
4.1.18. (3R⁄,6aS⁄,11aS⁄)-8-Amino-2-methyl-1,3,4,5,6,11a-
The tertiary amine 20 (54.6 mg, 0.19 mmol) was dissolved in
CH3CN/H2O (5:1). Cu(OAc)2 (69 mg, 0.38 mmol) and (NH4)2S2O8
(176.97 mg, 0.76 mmol) were added to the solution.14 The mixture
was stirred overnight at room temperature and the reaction was
quenched with aqueous 10% Na2S2O3. The reaction mixture was
basified to pH ꢀ9 with concentrated aqueous NH4OH, extracted
with a CHCl3/MeOH (3:1) mixture. The aqueous solution was then
re-extracted with CHCl3/MeOH (3:1). The organic solution was
dried over Na2SO4, filtered, and the solvent removed in vacuo. Col-
umn chromatography with CH2Cl2/MeOH/NH4OH (90:10:1) gave
crude 21 (13.5 mg, 30.5%). The crude product 21 was not purified
but used directly in the next step.
hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocine (18)
The nitrophenyl compound 17 (70 mg, 0.255 mmol) was dis-
solved in MeOH (10 mL) containing 0.18 mL of concentrated
hydrochloric acid. Pd/C catalyst (55 mg) was added and the solu-
tion was hydrogenated at room temperature for 1.5 h, when the
starting material was no longer detectable on TLC. The mixture
was filtered and the catalyst was washed with MeOH. The com-
bined filtrate was concentrated in vacuo, H2O was added, and the
aqueous solution was extracted with CHCl3. The combined organic
phase was dried over Na2SO4 and the solvent removed to afford the
amine 18 (42.4 mg, 68%); 1H NMR (CDCl3, 500 MHz): d 6.70 (d,
J = 8 Hz, 1H), 6.46–6.48 (m, 2H), 4.20 (dd, J = 11.5, 4.0 Hz, 1H),
3.44 (br s, 2H), 3.36 (t, J = 10.5 Hz, 1H), 3.24 (m, 1H), 3.07 (br s,
1H), 2,58 (s, 3H), 2.27 (m, 1H), 2.09 (d, J = 11.5 Hz, 1H), 1.97 (m,
1H), 1.58–1.77 (m, 3H), 1.41–1.45 (m, 2H); 13C NMR (CDCl3,
4.1.22. (3R⁄,6aS⁄,11aS⁄)-2-Phenethyl-2,3,4,5,6,11a-hexahydro-
1H-3,6a-methanobenzofuro[2,3-c]azocin-8-ol (22)
A
mixture of 21 (12 mg, 0.052 mmol), NaHCO3 (4.8 mg,
125 MHz):
d 152.31, 140.52, 139.26, 114.02, 110.83, 109.73,
0.057 mmol) and (2-bromoethyl)benzene (7.7 L, 0.057 mmol) in
l
88.28, 54.38, 53.33, 43.85, 42.21, 36.55, 31.77, 25.89, 21.57; HRMS
DMF (3 mL) was heated at 80–90 °C for 4 h under argon. After cool-
ing to room temperature, it was diluted with Et2O and washed
with H2O and brine. The solvent was dried over Na2SO4, filtered,
and removed in vacuo. Column chromatography of the crude mate-
rial with hexane/EtOAc (5:1) gave 12 (11.7 mg, 67.3%). The HCl salt
was prepared and recrystallized from MeOH. Mp (HCl salt) 252.1–
254.5 °C; 1H NMR (CDCl3, 500 MHz): d 7.19–7.30 (m, 5H), 6.74 (d,
J = 8.5 Hz, 1H), 6.56–6.59 (m, 2H), 4.24 (dd, J = 11.5, 5.5 Hz, 1H),
3.40 (m, 2H), 3.21 (br s, 1H), 2.81–2.97 (m, 4H), 2.22 (d, J = 12 Hz,
1H), 2.09 (d, J = 11.0 Hz, 1H), 1.97 (d, J = 11.0 Hz, 1H), 1.42–1.82
(m, 5H); 13C NMR (CDCl3, 125 MHz): d 153.29, 150.15, 140.33,
139.71, 128.74, 128.36, 126.07, 113.72, 110.81, 109.60, 88.61,
56.55, 52.95, 51.29, 44.37, 36.51, 34.92, 31.84, 26.56, 21.75; HRMS
calcd for C22H26NO2 [M+H]+: 336.1964; found 336.1968. Anal.
Calcd for C22H25NO2ÁHCl: C, 71.05; H, 7.05; N, 3.77. Found: C,
70.79; H, 7.04; N, 3.80.
calcd for C15H21N2O [M+H]+: 245.1654; found 245.1641.
4.1.19. (3R⁄,6aS⁄,11aS⁄)-2-Methyl-1,3,4,5,6,11a-hexahydro-2H-
3,6a-methanobenzofuro[2,3-c]azocine-8-ol (19)
The amine 18 (30 mg, 0.12 mmol) was cooled in an ice-salt bath
and dissolved in 30% H2SO4 (15 mL). Ice (6 g) was added to the
solution, followed by a solution of NaNO2 (10.2 mg, 0.14 mmol)
in H2O (3 mL). The mixture was stirred for 2 h under argon, main-
taining the temperature at 0 °C. This mixture was added over
15 min to
a
cooled aqueous mixture of Cu(NO3)2Á2.5 H2O
(720 mg, 3.09 mmol) and Cu2O (24 mg, 0.17 mmol). The stirring
was continued for 1 h at 0 °C, and the reaction mixture was poured
into an aqueous solution of 10% KOH (60 mL) and ice. The pH was
adjusted to 9 by the addition of a saturated solution of NH4Cl and
the aqueous solution was extracted with CHCl3/MeOH (3:1) to give
19 (20 mg, 67%). An HCl salt was prepared and recrystallized from
acetone. Mp (HCl salt) 202.9–203.7 °C (dec); 1H NMR (CD3OD,
300 MHz): d 6.50–6.66 (m, 3H), 4.10 (dd, J = 11.7, 5.4 Hz, 1H),
3.37 (dd, J = 12, 10.5 Hz, 1H), 3.17 (dd, J = 10.5, 5.4 Hz, 1H), 3.06
(br s, 1H), 2.56 (s, 3H), 2.29 (d, J = 14.4 Hz, 1H), 2.19 (dd, J = 12.6,
2.4 Hz, 1H), 1.44–1.94 (m, 6H); 13C NMR (CD3OD, 75 MHz): d
153.84, 153.27, 140.49, 114.77, 111.75, 110.39, 89.42, 56.16,
54.46, 45.24, 42.44, 37.23, 32.82, 26.73, 22.59; HRMS calcd for
4.1.23. ((1R⁄,4R⁄,5S⁄)-5-(2,3-dimethoxyphenyl)-2-methyl-2-
azabicyclo[3.3.1]nonan-4-ol (23). Alternative route to
(3R⁄,6aS⁄,11aS⁄)-2-methyl-2,3,4,5,6,11a-hexahydro-1H-3,6a-
methanobenzofuro[2,3-c]azocin-10-ol (13)
To a solution of 8 (3.67 g, 10 mmol) in MeOH (300 mL) was
added 10% Pd/C (2 g) and the mixture was heated to boiling. To this
was added a solution of ammonium formate (2.9 g, 46 mmol) in
H2O (3 mL) and the mixture was stirred and refluxed for 2 h, at
which time 88% formic acid (1 mL) and 37% formaldehyde (2 mL)
were added. After stirring at reflux temperature for another 3 h
the mixture was filtered and washed with MeOH. The solvents
were removed in vacuo and the residual material dissolved in
H2O, basified with 28% NH4OH and extracted with CHCl3 (2Â).
The combined extracts were washed with H2O and dried over
Na2SO4. The solvent was removed in vacuo to give 23 as an orange
crystalline solid. Recrystallization from 2-propanol gave 23 (1.85 g)
as fine white crystals, mp 163–165 °C (lit.4 163–164 °C). An addi-
tional 0.11 g was obtained from the mother liquor (68% total yield).
Compound 24 was prepared4 similarly to 9 and the crude 24 was
used to prepare 13 as a crystalline free base (46–50% yield from
8), mp 192–193 °C (lit.4 195–196 °C).
C
C
15H20NO2 [M+H]+: 246.1494; found 246.1487. Anal. Calcd for
15H19NO2ÁHClÁ0.1H2O: C, 63.53; H, 7.18; N, 4.94. Found: C,
63.20; H, 7.18; N, 4.97.
4.1.20. (3R⁄,6aS⁄,11aS⁄)-2-Methyl-2,3,4,5,6,11a-hexahydro-1H-
3,6a-methanobenzofuro[2,3-c]azocin-8-yl acetate (20)
The phenol 19 (70 mg, 0.28 mmol) in acetic anhydride (2 mL)
was heated at 60 °C for 1 h under argon. After cooling to room tem-
perature, it was diluted with CH2Cl2, washed with H2O and brine.
The organic layer was dried over Na2SO4, filtered, and evaporated
in vacuo. Column chromatography of the crude material with hex-
ane and EtOAc (5:1) gave 20 (80 mg, 98%); 1H NMR (CDCl3,
500 MHz): d 6.81–6.86 (m, 3H), 4.30 (dd, J = 11.5, 5.5 Hz, 1H),
3.39 (t, J = 11.5 Hz, 1H), 3.26 (dd, J = 10.0, 5.5 Hz, 1H), 3.09 (br s,
1H), 2.58 (s, 3H), 2.27 (br s, 4H), 2.11 (d, J = 12.5, 1H), 2.01 (d,

3442
J.-H. Kim et al. / Bioorg. Med. Chem. 19 (2011) 3434–3443
4.1.24. Opioid binding assays
MgCl2, 1 mM EDTA, 1 mM DTT, 40
tions proceeded for 3 h at 25 °C. Nonspecific binding was deter-
mined using GTP- -S (40 -S
M). Bound and free [35S]-GTP-
were separated by vacuum filtration (Brandel) through GF/B filters.
The filters were punched into 24-well plates to which was added
0.6 mL LSC-cocktail (Cytoscint). Samples were counted, after an
overnight extraction, in a Trilux liquid scintillation counter at
27% efficiency.
lM GDP and 0.1% BSA. Incuba-
As described,16 the recombinant CHO cells (hMOR-CHO, hDOR-
CHO and hKOR-CHO) were produced by stable transfection with
the respective human opioid receptor cDNA, and provided by Dr.
Larry Toll (SRI International, CA). The cells were grown on plastic
flasks in DMEM (90%) (hDOR-CHO and hKOR-CHO) or DMEM/ F-
12 (45%/45%) medium (hMOR-CHO) containing 10% FetalClone II
(HyClone) and Geneticin (G-418: 0.10–0.2 mg/mL) (Invitrogen) un-
der 95% air/5% CO2 at 37° C. Cell monolayers were harvested and
frozen in À80 °C. The hKOR-CHO, hMOR-CHO and hDOR-CHO cells
c
l
c
4.1.26. Data analysis and statistics
are used for opioid binding experiments. For the [35S]-GTP-
c
-S
These methods are described elsewhere.16 For opioid binding
experiments, the pooled data of three experiments (typically 30
data points) are fit to the two-parameter logistic equation for the
best-fit estimates of the IC50 and N values: Y = 100/(1 + ([INHIBI-
TOR]/IC50)N), where ‘Y’ is the percent of control value. Ki values
for test drugs are calculated according to the standard equation:
Ki = IC50/(1+[radioligand]/Kd]). For the [3H]radioligands, the follow-
ing Kd values (nM SD, n = 3) were used in the Ki calculation:
[3H]DAMGO (0.93 0.04), [3H]DADLE (1.9 0.3) and [3H](À)-
U69,593 (11 0.6). The corresponding Bmax values were (fmol/
mg protein SD, n = 3): [3H]DAMGO (1912 68), [3H]DADLE
(3655 391) and [3H](À)-U69,593 (3320 364).
binding experiments, we use hKOR-CHO and hMOR-CHO cells for
assaying KOR and MOR receptor function. Currently, we use the
NG108–15 neuroblastoma  glioma cell for the DOR [35S]-GTP-
c-
S binding assay, and obtain an excellent signal-to-noise ratio. In
summary, we use the hDOR-CHO cells for DOR binding assays,
and the NG108–15 cells for the DOR [35S]-GTP-
c
-S binding assay.
-Ala2-MePhe4,Gly-ol5]enkephalin
([3H]DAMGO, SA = 44–48 Ci/mmol) to label MOR, [3H][ -Ala2,
-Leu5]enkephalin ([3H]DADLE, SA = 40–50 Ci/mmol) to label DOR
We currently use [3H][
D
D
D
and [3H](À)-U69,593 (SA = 50 Ci/mmol) to label KOR binding sites.
On the day of the assay, cell pellets were thawed on ice for 15 min-
utes then homogenized with a polytron in 10 mL/pellet of ice-cold
10 mM Tris–HCl, pH 7.4. Membranes were then centrifuged at
30,000g for 10 min, resuspended in 10 mL/pellet ice-cold 10 mM
Tris–HCl, pH 7.4 and again centrifuged 30,000g for 10 min. Mem-
branes were then resuspended in 25 °C 50 mM Tris–HCl, pH 7.4
(ꢀ100 mL/pellet hMOR-CHO, 50 mL/pellet hDOR-CHO and
120 mL/pellet hKOR-CHO). All assays took place in 50 mM
Tris–HCl, pH 7.4, with a protease inhibitor cocktail [bacitracin
For the [35S]GTP-
tion of [35S]GTP-
-S binding was calculated according to the fol-
lowing formula: (S À B)/B Â 100, where B is the basal level of
35S]GTP- -S binding and S is the stimulated level of [35S]GTP-
-S
c-S binding experiments, the percent stimula-
c
[
c
c
binding. Agonist dose-response curves (ten points/curve) are gen-
erated, and the data of several experiments, 3 or more, are pooled.
The EC50 values (the concentration that produces fifty percent
maximal stimulation of [35S]GTP-
c-S binding) and Emax are deter-
(100
statin (2
tion curves were made up with buffer containing 1 mg/mL BSA.
Nonspecific binding was determined using 20 M levallorphan
([3H]DAMGO and [3H]DADLE) and
(À)-U69,593 (for
l
g/mL), bestatin (10
l
g/mL), leupeptin (4
l
g/mL) and chymo-
mined using either the program MLAB-PC (Civilized Software,
Bethesda, MD), KaleidaGraph (Version 3.6.4, Synergy Software,
Reading, PA) or Prism 4.0 (GraphPad Software, Inc, San Diego,
CA). In most cases, the percent stimulation of the test compound
is reported as a percent of the maximal stimulation of 1000 nM
DAMGO, 500 nM SNC80 or 500 nM (À)-U50,488 in the appropriate
cell type. For determination of Ke values using the ‘shift’ experi-
mental design, agonist (DAMGO, (À)-U50,488 or SNC80) dose–re-
sponse curves are generated, using the appropriate cell type, in
the absence and presence (ten points/curve) of a test compound.
The data of several experiments, 3 or more, are pooled, and the
Ke values are calculated according to the equation: [Test Drug]/
(EC50-2/EC50-1 À 1), where EC50-2 is the EC50 value in the presence
of the test drug and EC50-1 is the value in the absence of the test
drug.
lg/mL)], in a final assay volume of 1.0 mL. All drug dilu-
l
1 lM
[3H]U69,593 binding). [3H]Radioligands were used at ꢀ2 nM con-
centrations. Triplicate samples were filtered with Brandel Cell Har-
vesters (Biomedical Research & Development Inc., Gaithersburg,
MD), over Whatman GF/B filters, after a 2 h incubation at 25 °C.
The filters were punched into 24-well plates to which was added
0.6 mL of LSC-cocktail (Cytoscint). Samples were counted, after
an overnight extraction, in a Trilux liquid scintillation counter at
44% efficiency. Opioid binding assays had ꢀ30
lg protein per assay
tube. Inhibition curves were generated by displacing a single con-
centration of radioligand by 10 concentrations of drug.
4.1.25. [35S]GTP-
The [35S]-GTP-
c
c
-S binding assays
-S assays were conducted as described else-
4.1.27. X-ray crystal structure of 10
Single-crystal X-ray diffraction data on 10 (HCl salt of rac-
(3R,6aS,11aS)-2-benzyl-1,3,4,5,6,11a-hexahydro-2H-3,6a-metha-
nobenzofuro[2,3-c]azocine-10-ol) were collected at 173 K using
where.16 In this description, buffer ‘A’ is 50 mM Tris–HCl, pH 7.4,
containing 100 mM NaCl, 10 mM MgCl2, 1 mM EDTA and buffer
‘‘B’’ is buffer A plus 1.67 mM DTT and 0.15% BSA. On the day of
the assay, cells were thawed on ice for 15 min and homogenized
MoKa radiation (k = 0.71073 Å) and a Bruker APEX 2 CCD area
detector. The samples were prepared for data collection by coating
with high viscosity microscope oil (Paratone-N, Hampton Re-
search). The oil-coated crystal was mounted on a MicroMesh
mount (MiTeGen, Inc.) and transferred immediately to the diffrac-
tometer. The 0.233 Â 0.161 Â 0.063 mm3 crystal of 10 was triclinic
in space group PÀ1 with unit cell dimensions a = 7.783(3) Å,
using a polytron in 50 mM Tris–HCl, pH 7.4, containing 4
l
g/mL
leupeptin, 2 g/mL chymostatin, 10 g/mL bestatin and 100
l
l
lg/
mL bacitracin. The homogenate was centrifuged at 30,000g for
10 min at 4 °C, and the supernatant discarded. The membrane pel-
lets were resuspended in buffer B and used for [35S]GTP-
c
-S bind-
-S binding was determined as described
previously. Briefly, test tubes received the following additions:
50 L buffer A plus 0.1% BSA, 50 L GDP in buffer A/0.1% BSA (final
concentration = 40 M), 50 L drug in buffer A/0.1% BSA, 50
35S]GTP-
-S in buffer A/0.1% BSA (final concentration = 50 pM),
and 300 L of cell membranes (50 g of protein) in buffer B. The
final concentrations of reagents in the [35S]GTP-
-S binding assays
were: 50 mM Tris–HCl, pH 7.4, containing 100 mM NaCl, 10 mM
ing assays. [35S]GTP-
c
b = 10.028(4) Å, c = 12.657(5) Å,
a
= 103.490(5), b = 107.365(5),
and
c
= 93.687(6). Data were 98% complete to 26.38° h (approxi-
l
l
mately 0.80 Å) with an average redundancy of 2.07. The asymmet-
ric unit contains a single molecule. Corrections were applied for
Lorentz, polarization, and absorption effects. All structures were
solved by direct methods and refined by full-matrix least squares
on F2 values using the programs found in the SHELXTL suite
(Bruker, SHELXTL v6.10, 2000, Bruker AXS Inc., Madison, WI).
l
l
lL
[
c
l
l
c

J.-H. Kim et al. / Bioorg. Med. Chem. 19 (2011) 3434–3443
3443
Parameters refined included atomic coordinates and anisotropic
References and notes
thermal parameters for all non-hydrogen atoms. Hydrogen atoms
on carbons were included using a riding model [coordinate shifts
of C applied to H atoms] with C–H distance set at 0.96 Å. Atomic
coordinates for 10 have been deposited with the Cambridge Crys-
tallographic Data Centre (deposition number 806,302). Copies of
the data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge, CB2 1EZ, UK [fax: +44(0)-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk.
1. Burke, T. R., Jr.; Jacobson, A. E.; Rice, K. C.; Weissman, B. A.; Silverton, J. V. In
Problems of Drug Dependence 1983; Harris, L. S., Ed.; National Institute on Drug
Abuse Research Monograph 49; DHHS ((ADM) 84-1316): Washington DC,
1984; Vol. 49, pp. 109.
2. Yamada, K.; Flippen-Anderson, J. L.; Jacobson, A. E.; Rice, K. C. Synthesis-
Stuttgart 2002, 2359.
3. Kurimura, M.; Liu, H.; Sulima, A.; Przybyl, A. K.; Ohshima, E.; Kodato, S.;
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4. Tadic, D.; Linders, J. T. M.; Flippen-Anderson, J. L.; Jacobson, A. E.; Rice, K. C.
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5. Burke, T. R., Jr.; Jacobson, A. E.; Rice, K. C.; Weissman, B. A.; Huang, H. C.;
Silverton, J. V. J. Med. Chem. 1986, 29, 748.
Acknowledgments
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The work of the Drug Design and Synthesis Section, CBRB, NIDA,
& NIAAA, was supported by the NIH Intramural Research Programs
of the National Institute on Drug Abuse (NIDA) and the National
Institute of Alcohol Abuse and Alcoholism NIAAA). The Clinical
Psychopharmacology Section, CBRB, NIDA, was supported by the
NIH Intramural Research Program of NIDA. The X-ray crystallo-
graphic work was supported by NIDA through an Interagency
Agreement #Y1-DA1101 with the Naval Research Laboratory
(NRL). We thank Dr. Klaus Gawrisch and Dr. Walter Teague
(Laboratory of Membrane Biochemistry and Biophysics, NIAAA,
for NMR spectral data. The authors also thank Noel Whittaker
and Wesley White, Laboratory of Analytical Chemistry, NIDDK,
for mass spectral data.
14. Carroll, R. J.; Leisch, H.; Scocchera, E.; Cox, D. P. Adv. Synth. Catal. 2008, 350,
2984.
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Aceto, M. D.; May, E. L.; Harris, E. M.; Coop, A.; Dersch, C. M.; Partilla, J. S.;
Rothman, R. B.; Jacobson, A. E.; Rice, K. C. J. Med. Chem. 2007, 50, 3765.
16. Fontana, G.; Savona, G.; Rodriguez, B.; Dersch, C. M.; Rothman, R. B.; Prisinzano,
T. E. Tetrahedron 2008, 64, 10041.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2011.04.028.