Asymmetric synthesis of 9-alkyl-2-benzyl-6,7-benzomorphans: Characterization as novel σ receptor ligands

Article abstract of DOI:10.1021/jm990169r

A convenient enantioselective synthesis of (1R,5R,9R)- and (1S,5S,9S)-9- alkyl-2-benzyl-6,7-benzomorphans (2a-c) which starts with naphthaldehyde is described. These compounds were designed to gain additional information on the structure-σ binding relatio

Full text of DOI:10.1021/jm990169r

J . Med. Chem. 1999, 42, 4621-4629
4621
Asym m etr ic Syn th esis of 9-Alk yl-2-ben zyl-6,7-ben zom or p h a n s: Ch a r a cter iza tion
a s Novel σ Recep tor Liga n d s
F. Ivy Carroll,*,‡ Xu Bai,‡ Ali Dehghani,‡ S. Wayne Mascarella,‡ Wanda Williams,† and Wayne D. Bowen†
Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina 27709, and Laboratory of
Medicinal Chemistry, NIDDK, NIH, Bethesda, Maryland 20892
Received April 12, 1999
A convenient enantioselective synthesis of (1R,5R,9R)- and (1S,5S,9S)-9-alkyl-2-benzyl-6,7-
benzomorphans (2a -c) which starts with naphthaldehyde is described. These compounds were
designed to gain additional information on the structure-σ binding relationship of the 6,7-
benzomorphan class of σ ligands. In contrast to pentazocine and most 6,7-benzomorphans, the
(1R,5R,9R)-isomers of 2a -c showed greater affinity for the σ1 receptor than the (1S,5S,9S)-
isomers. Despite reversal of enantioselectivity at the σ1 sites, moderate affinity and enantio-
selectivity at the σ2 sites [greater affinity for (1R,5R,9R)-isomers than (1S,5S,9S)-isomers] were
maintained. A comparison of the binding affinities of 2a -c to the more conformationally flexible
trans-2-alkyl-1-benzaminoethyl-1,2-dihydronaphthalenes (10a -c) suggested that the relatively
rigid structure of 2a -c played an important part in their σ1 binding properties. These
compounds, particularly (1R,5R,9R)-2-benzyl-9-methyl-6,7-benzomorphan [(-)-2a ], which has
a Ki value of 0.96 nM, will be useful in further characterization of the σ1 receptor.
In tr od u ction
to have a much higher affinity than 1a for the receptor.1
The (1R,5R,9R)-(-)-isomers of these racemic drugs are
responsible for their analgesic activity.23,24 The
(1S,5S,9S)-(+)-isomer is responsible for the σ receptor
activity. Usually, it has been concluded that (+)-ben-
zomorphans have comparable affinities for the two
subtypes.1,25-29 The reduction in affinity of (+)-benzo-
morphans at σ2 sites leads to a reversal of enantiose-
lectivity, whereby (-)-isomers have higher affinity than
(+)-isomers. In fact, the opposite enantioselectivity of
the benzomorphans such as 1a ,b played an important
part in defining the σ1 and σ2 receptors.1,30
σ Receptors bind various classes of psychoactive
agents, including opiate-related compounds, phencyli-
dine-related compounds, typical neuroleptics, and some
antidepressants.1,2 However, σ receptors are unique
binding sites, having pharmacological profiles distinct
from other neurotransmitter receptors. Two classes of
σ receptors are now widely accepted,3 and various
biochemical, physiological, and behavioral processes
have been attributed to them. σ1 Receptors have been
implicated in modulation of NMDA-stimulated neu-
rotransmitter release and electrophysiological activity,4,5
modulation of muscarinic receptor-stimulated phospho-
inositide turnover,6 modulation of opiate analgesia,7 and
regulation of learning and memory processes.8,9 σ2
Receptors have been implicated in regulation of move-
ment and posture,10,11 modulation of potassium channel
conductances,12,13 contraction of the electrically stimu-
lated guinea pig ileum,14 modulation of intracellular
calcium levels,15,16 and induction of cell morphology
changes and apoptosis.17-19 The σ1 receptor has been
cloned from guinea pig liver,20 rat brain,21 and human
placenta.22 The sequence revealed a unique protein,
unrelated to any known receptor. Although there was
some sequence homology to an enzyme of fungal sterol
metabolism,20 the significance of this is not yet clear
since the protein has no known enzymatic activity.
σ Receptor binding ligands consist of a variety of
structurally unrelated compounds. 2-Substituted 5,9R-
dimethyl-2′-hydroxy-6,7-benzomorphans were the first
structural class of σ ligands with the 2-allyl analogue
1a , referred to as N-allyl-N-normetazocine, NANM, or
SKF 10,047 by various investigators, being the first σ
ligand.1,2 The well-known analgesic pentazocine (1b),
which is N-dimethylallyl-N-normetazocine, was found
Our search for high-affinity, specific σ receptor ligands
has focused on the benzomorphan class of compounds.
The benzomorphan ring system provides a convenient
rigid backbone for probing the pharmacophoric require-
ments of σ receptor sites. For the purposes of such SAR
‡ Research Triangle Institute.
† NIH.
10.1021/jm990169r CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/05/1999

4622 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 22
Carroll et al.
Sch em e 1a
F igu r e 1. Structure-activity relationship zones for the
benzomorphan structure.
studies, the benzomorphan nucleus can be conceptually
divided into three zones: the aromatic ring (A), the
saturated or morphan segment (B), and the nitrogen
substituent (C) (see structure 3 in Figure 1). In previous
studies from our laboratory, we reported the effects of
changes in zones A and C on σ1 and σ2 binding affinity
and selectivity.25-29 To gain information concerning the
effects of zone B on σ receptor binding properties, we
designed a SAR study to synthesize and evaluate a
series of compounds that involves changes in the 5- and
9R-methyl groups present in the N-normetazocine class
of compounds. In this report, we present novel asym-
metric syntheses of (+)- and (-)-9-alkyl-2-benzyl-6,7-
benzomorphans (2a -c) and show that in contrast to all
previously reported N-substituted N-normetazocine ana-
logues and their 2′-deoxy analogues, the (1R,5R,9R)-
isomers of 2a -c have higher affinity for the σ1 receptor
than the (1S,5S,9S)-isomers. A part of this study has
been reported in a preliminary communication.31
a
(a) (S)-Phenylglycinol, MgSO4, CHCl3, reflux; (b) (R)-phenyl-
glycinol, MgSO4, CHCl3, reflux; (c) RMgCl; (d) 3 M HCl; (e) NaBH4,
MeOH, 0 °C.
drochloride in methanol using sodium cyanoborohydride
provided the desired intermediates (1S,2R)-10a -c.
These intermediates also were prepared from (1S,2R)-
9a -c. Thus, tosylation of (1S,2R)-9a -c with toluene-
p-sulfonyl chloride followed by treatment of the result-
ing tosylate with potassium cyanide in dimethyl sulfoxide
at 105 °C yielded nitriles (1S,2R)-13a -c. Lithium
aluminum hydride reduction of 13a -c in diethyl ether
afforded amines (1S,2R)-14a -c which were benzoylated
with benzoyl chloride to give the amides (1S,2R)-15a -
c. Reduction of 15a -c with lithium aluminum hydride
in tetrahydrofuran gave benzylamines (1S,2R)-10a -c.
Mercuric acetate-assisted cyclization of (1S,2R)-10a -c
in THF at 25 °C followed by reduction with lithium
aluminum hydride or sodium borohydride afforded the
desired 6,7-benzomorphans (1S,5S,9S)-2a -c. The use
of lithium aluminum hydride provided cleaner reactions
Ch em istr y
Inoue and May reported that mercury(II) acetate-
sodium borohydride cyclization of the dihydronaphtha-
lene 4 gave a mixture of 5b,c.32 Compound 5c could be
converted to 5b, and reduction of 5b with palladium in
acetic acid containing perchloric acid gave the desired
(2RS,6RS,11RS)-(()-2,9-dimethyl-2′-methoxy-6,7-ben-
zomorphan (5a ). The synthesis of Inoue and May suffers
the disadvantage of providing racemic material and
requiring several steps to prepare the key intermediate
4.32 In 1992, Pridgen et al.33 reported that either optical
antipode of trans-1-hydroxymethyl-2-alkyl-1,2-dihy-
dronaphthalene [(1S,2R)- or (1R,2S)-9] could be pre-
pared in high chemical and optical purity via the
aldehyde (1S,2R)- or (1R,2S)-8 by the route shown in
Scheme 1. Thus, the addition of the appropriate alkyl-
magnesium halide to the oxazolidine 7, derived from (R)-
or (S)-phenylglycinol and naphthaldehyde 6, followed
by acid-catalyzed cleavage of the chiral auxiliary and
reduction of the resulting aldehyde 8, provided the
required optically active alcohols 9 in either optical form
depending on the phenylglycinol used.
Scheme 2 outlines how either (1S,2R)-8a-c or (1S,2R)-
9a -c were converted to the common intermediate
(1S,2R)-10, which was cyclized to give the desired 6,7-
benzomorphans (1S,5S,9S)-2a -c. The (1R,5R,9R)-2a -c
isomers were prepared in a similar fashion starting with
(1R,2S)-8a-c or (1R,2S)-9a-c. Thus, subjecting (1S,2R)-
8a -c to the Wittig reaction using the ylid prepared from
(methoxymethyl)triphenylphosphonium chloride in tet-
rahydrofuran at -78 °C gave the methoxy vinyl ether
(1S,2R)-11a -c. Acid hydrolysis of vinyl ethers 11a -c
resulted in the formation of aldehydes (1S,2R)-12a -c.
Reductive amination of 12a -c with benzylamine hy-
1
and higher yields than sodium borohydride. H NMR
spectra of the unpurified products obtained using the
sodium borohydride procedure suggested that small
amounts of (1R,5S,9S)-16 were present. The structural
assignment of benzomorphans 2a -c is based on the
elemental analysis of the hydrochloride salts and 1H
NMR, 13C NMR, 2D H-1H correlation NMR, and 2D
1
1H-13C correlation NMR data of the free bases.
The absolute configurations of starting alcohols 9
produced by the method shown in Scheme 1 are
known34,35 and were verified by comparison with the
published optical rotation for each enantiomer.33,36 As
the stereochemistry of all three stereogenic centers in
the product is determined by the stereochemistry of the
alcohol starting material, the absolute stereochemistry
of the benzomorphans 2a -c was established. Optical
purities of 2a ,c were determined to be g99% by HPLC
analysis using a Sumichiral OA-4900 column (Rainin
Instrument, Inc.). Optical purities of 2b,c were also
shown to be g96% by gas chromatography-mass spec-
tral analysis of the (R)-2-methoxy-2-trifluoromethylphen-

9-Alkyl-2-benzyl-6,7-benzomorphans
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 22 4623
Sch em e 2a
a
(a) CH3OCH2P+(C6H5)3Cl-, NaHMDS, THF; (b) 3 N HCl, 25 °C; (c) C6H5CH2NH3+Cl, NaBH3CN, CH3OH; (d) TsCl-pyridine, 0 °C; (e)
KCN-DMS), 105 °C; (f) LiAlH4-Et2O; (g) PhCOCl, triethanolamine-CH2Cl2; (h) LiAlH4-THF, reflux; (i) Hg(OAc)2, Et3N, THF, followed
by LiAlH4; (j) Hg(OAc)2-THF, 50 °C, followed by NaBH4, NaOH (aq); (k) H2, 10% Pd/C, CH3OH; (l) (R)MTPACl, (j) (C2H5)3N, CH2Cl2.
ylacetyl amides 17b,c. The amides 17a -c were pre-
pared by catalytic debenzylation of 2b,c followed by
acylation of the unpurified intermediate N-nor analogue
with (R)-2-methoxy-2-trifluoromethylphenylacetyl chlo-
ride [(R)MTPACl]. The report that the optical purity of
intermediate 9b was g96%33 also shows the optical
purity of 2b must be at least 96%.
noethyl-1,2-dihydronaphthalene (10a -c), and reference
compounds are shown in Table 1.
Resu lts a n d Discu ssion
(+)- and (-)-Pentazocine have Ki values of 3.1 and
83.1 nM, respectively, for the σ1 receptor (see Table 1).
In sharp contrast, (+)- and (-)-pentazocines have Ki
values of 1540 and 36.5 nM for the σ2 receptor. Studies
of several other N-normetazocine analogues showed that
the (+)-(1S,5S,9S)-isomer always possessed higher af-
finity for the σ1 receptor than the (-)-(1R,5R,9R)-
isomer.25 One of the bases for defining two types of σ
receptors (σ1 and σ2) was the opposite enantioselectivity
for the N-normetazocine class of compounds.1,3,30 The
fact that (+)- and (-)-pentazocines as well as several
other benzomorphans bind to the σ receptor with
enantioselectivity suggested that the rigid framework
of this class of compounds imparted directionality to the
lone-pair nitrogen electrons and/or that the steric bulk
of the tricyclic system contributes to the enantioselec-
tivity.26
Additional studies from our laboratory showed that
the rigid cis-5,9-dimethyl-6,7-benzomorphan (cis-N-
normetazocine) could be used as a structural template
to provide useful SAR data for helping establish a
pharmacophore for σ receptors.25-29,31 These SAR stud-
ies involved changes in the N-substituent and the
aromatic ring, zones C and A, respectively, in Figure 1.
The zone C studies revealed that (1S,5S,9S)-N-benzyl-
N-normetazocine [(+)-1c] possessed a 0.67 nM Ki value
Liga n d Bin d in g Stu d ies
σ1 Binding sites were labeled using the σ1-selective
ligand [3H]-(+)-pentazocine37 and guinea pig brain
membranes, as described previously.38 Rat liver mem-
branes have been shown previously to be a rich source
of σ2 sites and are labeled using [3H]DTG in the
presence of dextrallorphan to mask σ1 sites.39
Various concentrations of the test ligand ranging from
0.005 to 1000 nM or from 0.05 to 10000 nM were
incubated with guinea pig brain membranes (σ1) or rat
liver membranes (σ2) and radioligand. Assays were
carried out using the conditions described below: σ1, 3
nM [3H]-(+)-pentazocine; σ2, 5 nM [3H]DTG + 1 µM
dextrallorphan. IC50 values were derived using the
computerized iterative curve-fitting program GraphPAD
InPlot (San Diego, CA). Ki values were calculated from
IC50 values using the Cheng-Prusoff equation40 and Kd
values that were predetermined in independent experi-
ments.
The results expressed as Ki values of the 9-alkyl-2-
benzyl-6,7-benzomorphans (2a -c), 2-alkyl-1-benzylami-

4624 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 22
Carroll et al.
Ta ble 1. σ Binding Data for 6,7-Benzomorphans and Related Compounds
Ki (nM)a
σ1, [3H](+)-
σ2,
σ2,σ1
compd
structure stereochemistry
R
R′
CH3
R′′
X
pentazocine
DTG
ratiob
(+)-pentazocine [(+)-1b]
(-)-pentazocine [(-)-1b]
(+)-1c
A
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
1S,5S,9S
1R,5R,9R
1S,5S,9S
1R,5R,9R
1S,5S,9S
1R,5R,9R
1S,5S,9S
1R,5R,9R
1S,5S,9S
1R,5R,9R
1S,5S,9S
1R,5R,9R
1S,2R
(CH3)2dCHCH2
(CH3)2CdCHCH2 CH3
CH3 OH
3.1 ( 0.3c
1540 ( 313d
36.5 ( 5.76d
500
0.44
2600
5
26
1.8
102
136
18
34
6
CH3 OH 83.1 ( 6.2c
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
C2H5
(CH3)2CH
(CH3)2CH
CH3
CH3
C2H5
C2H5
(CH3)2CH
(CH3)2CH
CH3 OH 0.67 ( 0.10c 1710 ( 407
(-)-1c
CH3 OH 36.5 ( 6.3c
192 ( 36
487 ( 65.6
149 ( 9
(+)-1d
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
18.4 ( 2.13d
82.9 ( 4.6
5.74 ( 0.17
0.96 ( 0.02
26.7 ( 3.47
3.36 ( 0.11
167 ( 11.5
31.7 ( 3.36
19.6 ( 1.73
17.3 ( 0.18
16.6 ( 0.27
14.8 ( 1.8
12 ( 0.33
(-)-1d
(+)-2a
587 ( 57
131 ( 19
478 ( 76.1
115 ( 10.7
944 ( 99
133 ( 4.75
607 ( 38
371 ( 11
759 ( 34
850 ( 52
854 ( 13
785 ( 37
(-)-2a
(+)-2b
(-)-2b
(+)-2c
(-)-2c
4
(+)-10a
(-)-10a
(+)-10b
(-)-10b
(+)-10c
(-)-10c
31
22
46
57
71
67
1R,2S
1S,2R
1R,2S
1S,2R
1R,2S
11.7 ( 0.65
a
b
Values are the average ( SEM of two to three experiments. Each experiment was carried out in duplicate. σ2/σ1 are ratios of Ki
values. c Ki values taken from ref 15. These Ki values are slightly different from those in ref 29 due to the fact that they contain data
d
from additional experiments.
for the σ1 receptor and was highly selective for the σ1
site relative to the σ2 site (σ2/σ1 ratio ) 2600) (see Table
1). In a SAR study of zone A (Figure 1), we found that
replacement of the 2′-hydroxyl group with a hydrogen
to give (1S,5S,9S)-cis-5,9-dimethyl-6,7-benzomorphan
[(+)-1d ] resulted in a 28-fold loss in affinity for the σ1
receptor (0.67 nM compared to 18.4 nM). There was also
a 4-fold increase in affinity at the σ2 receptor.
site relative to the σ2 site (σ2/σ1 ) 136). Unexpectedly
and in sharp contrast to pentazocine (1b ) and cis-N-
benzyl-N-normetazocine (1d ), each of the 9-alkyl-2-
benzyl-6,7-benzomorphans (2a -c) showed enantiose-
lectivity toward the (-)-(1R,5R,9R)-isomers at σ1 sites.
In the case of 2a where a direct comparison to 1d is
possible, this reverse in enantioselectivity is due to a
38-fold increase in affinity of (-)-2a relative to (-)-1d
and only a 3-fold increase in affinity of (+)-2a relative
to (+)-1d . Even though the binding affinity at the σ2
site for all three compounds is much weaker than
binding to the σ1 site, the (1R,5R,9R)-isomer in each
case has the higher affinity for the σ2 receptor.
Compounds 10a -c are the intermediates used to
prepare compounds 2a -c and thus possess many of the
structural features present in 2a -c. However, since
compounds 2a -c are tricyclic and 10a -c bicyclic, the
latter compounds possess a larger degree of conforma-
tional freedom. The σ1 Ki values for these compounds
are particularly informative. Note that there is es-
sentially no difference in the Ki values at the σ1 receptor
regardless of the stereochemistry or the size of the
9-substituent. The σ1 Ki values range from 11.7 nM for
the (1R,2S)-9-isopropyl analogue (-)-10c to 19.6 nM for
the (1S,2R)-9-methyl analogue (+)-10a . Note that cy-
clization of (1R,2S)-10a and (1R,2S)-10b to (1R,5R,9R)-
2a and (1R,5R,9R)-2b results in an 18- and 4.4-fold
increase in σ1 affinity, whereas cyclization of (1R,2S)-
10c to (1R,5R,9R)-2c results in a 2.7-fold loss in σ1
affinity. These results strongly suggest that the unique
σ1 binding properties of 2a -c are due at least in part
to the rigid framework of the 6,7-benzomorphan struc-
ture. These results are also consistent with our previous
hypothesis that the rigid framework and directionality
imparted to the lone-pair nitrogen electrons are impor-
As a continuation of the SAR study of the 6,7-
benzomorphan class of σ ligands, we have synthesized
the (1S,5S,9S)- and (1R,5R,9R)-isomers of several 9-alkyl-
2-benzyl-6,7-benzomorphans (2a -c) and evaluated their
binding affinities at σ1 and σ2 receptors. The goal of this
study was to gain information involving changes in zone
B (Figure 1) of the 6,7-benzomorphans on σ1 binding
properties. Since the 9-methyl analogue 2a can be
viewed as an analogue of 1d where the 5-methyl group
has been removed, the binding results from this com-
pound allowed the determination of the effect of this
group on σ1 and σ2 binding affinity and selectivity.
Compounds 2b,c, which possess a 9-ethyl and 9-isopro-
pyl substituent, respectively, provided information on
the effect of larger and more lipophilic groups in this
position. Most importantly, a comparison of the σ
binding affinities of the (+)- and (-)-isomers in each
case allowed the determination of the enantioselectivity
of these changes to zone B (Figure 1) of the 6,7-
benzomorphans. The σ1 binding affinities for the 9-alkyl-
6,7-benzomorphans 2a -c range between 0.96 and 167
nM. The (1R,5R,9R)-9-methyl analogue (-)-2a has the
highest affinity, while the (1S,5S,9S)-9-isopropyl ana-
logue (+)-2c has the lowest affinity. The affinities for
2a -c at the σ2 site are lower than those for the σ1 site
with Ki values ranging from 115 to 944 nM. Compound
(1R,5R,9R)-2a shows the greatest selectivity for the σ1

9-Alkyl-2-benzyl-6,7-benzomorphans
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 22 4625
lidine (4R)-7 (2.97 g, 10.9 mmol) afforded 1.31 g (70%) of
(1R,2S)-8a as a pale yellow oil: [R]23D +212° (c 0.415, CHCl3).
(1S,2R)-tr a n s-2-E t h yl-1,2-d ih yd r on a p h t h a len e-1-ca r -
boxa ld eh yd e (8b). To a stirred solution of oxazolidine (4R)-7
(3.53 g, 12.8 mmol) in THF (75 mL) at -78 °C was added
ethylmagnesuim chloride (2 M in THF, 19.5 mL, 39 mmol)
dropwise. After 3 h, the solution was allowed to warm to room
temperature and stirred overnight, then cooled to 0 °C.
Aqueous HCl (3 N, 25 mL, 75 mmol) was added, and the
reaction mixture was stirred for an additional 1 h. The layers
were separated, and the aqueous layer was extracted with
ether (4 × 10 mL). The combined organic extracts were washed
with water and brine, dried over anhydrous MgSO4, and
filtered through Celite. The solvent was removed in vacuo to
give the crude product. Purification by radial PLC (silica gel,
1% Et2O-hexanes) afforded 1.87 g (78%) of (1S,2R)-8b as a
pale yellow oil: [R]23D -252° (c 0.370, CHCl3); 1H NMR (CDCl3)
δ 9.57 (s, 1H), 7.28-7.09 (m, 4H), 6.41 (d, 1H, J ) 9.7 Hz),
6.01 (dd, 1H, J ) 5.7, 9.7 Hz), 3.41 (s, 1H), 2.81-2.73 (m, 1H),
1.56-1.29 (m, 2H), 0.93 (t, 3H, J ) 7.4 Hz); 13C NMR (CDCl3)
δ 204.1, 135.1, 133.6, 129.9, 128.4, 128.2, 127.1, 126.6, 52.6,
44.4, 27.6, 23.0, 19.4, 12.1; IR (neat) 3015, 2865, 2705, 1724,
tant to the σ1 binding properties of 6,7-benzomor-
phans.26 It is also interesting to note that the stereo-
chemical factors governing enantioselectivity at σ1 sites
are separate from those for σ2 sites since the B-zone
alteration which reversed enantioselectivity at σ1 sites
did not change enantioselectivity at σ2 sites.
In summary, we have reported results which show
that 9-alkyl-2-benzyl-6,7-benzomorphans (2a -c) have
a reversed enantioselectivity [i.e. (1R,5R,9S) better than
(1S,5S,9S)] for the σ1 receptor when compared with
pentazocine (1b), 2-benzyl-5,9-dimethyl-2′-hydroxy-6,7-
benzomorphan (1c, cis-N-benzyl-N-normetazocine), and
cis-2-benzyl-5,9-dimethyl-6,7-benzomorphan (1d ). These
compounds will be valuable for the further characteriza-
tion of the σ receptors.
Exp er im en ta l Section
Gen er a l. All reactions were performed in oven-dried glass-
ware under an argon atmosphere and were magnetically
stirred. Tetrahydrofuran (THF) and diethyl ether were dried
by distillation from sodium benzophenone ketyl prior to use.
Methylene chloride was dried by distillation from P2O5. Other
anhydrous solvents and reagents were purchased from Aldrich
Chemical Co., Inc. and were used without further purification.
Melting points were determined in open capillary tubes with
a Meltemp melting point apparatus and are uncorrected.
Optical rotations were determined with an Autopol III auto-
matic polarimeter (Rudolph Research, Flanders, NJ ). Radial
preparative-layer chromatography (radial PLC) was performed
on a chromatotron (Harrison Associates, Palo Alto, CA) using
glass plates coated with 1-, 2-, or 4-mm thicknesses of Kieselgel
60 PF254 coating gypsum. When optical purity was determined
using chiral HPLC, a Sumichiral OA-4900 column (Rainin
Instrument, Inc.) was used. Nuclear magnetic resonance
spectra were recorded on a Bruker AM-250 spectrometer.
Chemical shifts for 1H NMR are reported in parts per million
(δ) downfield from tetramethylsilane (0 ppm). 13C NMR
chemical shifts are reported in parts per million (δ) relative
to CDCl3 (77.0 ppm). IR spectra were recorded on a Shimadzu
infrared spectrometer (IR-460). Elemental analysis was per-
formed by Atlantic Microlabs Inc., Norcross, GA.
1677, 1481, 1452, 1372, 1052 cm-1
.
(1R,2S)-tr a n s-2-E t h yl-1,2-d ih yd r on a p h t h a len e-1-ca r -
boxa ld eh yd e (8b). The title compound was prepared by a
procedure analogous to that used for (1S,2R)-8b. Oxazolidine
(4R)-7 (2.58 g, 9.4 4 mmol) afforded 1.35 g (77%) of (1R,2S)-
8b as a colorless oil: [R]23 +253° (c 0.320, CHCl3).
D
(1S,2R)-tr a n s-2-Isop r op yl-1,2-d ih yd r on a p h t h a len e-1-
ca r boxa ld eh yd e (8c). Using a procedure analogous to the
one described for the preparation of 8b, 2.10 g (81%) of (1S,2R)-
8c was obtained from 3.59 g (13 mmol) of oxazolidine (4S)-7:
[R]22D -271° (c 0.745, CHCl3); 1H NMR (CDCl3) δ 10.06 (s, 1H),
7.26-6.99 (m, 4H), 6.62 (d, 1H, J ) 9.9 Hz), 5.90 (dd, 1H, J )
5.1, 9.9 Hz), 2.54-2.51 (m, 1H), 2.08-2.01 (m, 1H), 1.36 (s,
3H), 0.96 (d, 3H, J ) 6.88 Hz), 0.68 (d, 3H, J ) 6.7 Hz); 13C
NMR (CDCl3) δ 205.4, 136.6, 133.0, 128.5, 128.2, 127.2, 127.1,
126.0, 125.8, 52.1, 50.0, 29.7, 22.5, 21.7, 17.2; IR (neat) 3055,
2935, 2820, 1719, 1682, 1484, 1463, 1384, 1105, 1034, 928, 824
cm-1
.
(1R,2S)-tr a n s-2-Isop r op yl-1,2-d ih yd r on a p h t h a len e-1-
ca r boxa ld eh yd e (8c). Using a procedure analogous to the
one described for the preparation of (1S,2R)-8c, 1.78 g (80%)
of (1R,2S)-8c was obtained from 3.06 g (11.2 mmol) of oxazo-
lidine (4S)-7: [R]22 +269° (c 0.495, CHCl3).
[3H]-(+)-Pentazocine (51.7 Ci/mmol) was supplied by Dr. K.
C. Rice (Laboratory of Medicinal Chemistry, NIDDK, NIH).
[3H]DTG (39.1 Ci/mmol) was purchased from DuPont/New
England Nuclear (Boston, MA). Haloperidol, Tris-HCl, and
poly(ethylenimine) were purchased from Sigma Chemicals (St.
Louis, MO).
D
(1S,2R)-tr a n s-2-Met h yl-1-(2-m et h oxyvin yl)-1,2-d ih y-
d r on a p h th a len e (11a ). A solution of NaHMDS in THF (1
M, 4.0 mL, 4.0 mmol) was added dropwise to a mixture of
(methoxymethyl)triphenylphosphonium chloride (1.44 g, 4.20
mmol) in THF (13 mL) at -78 °C. After 1 h, aldehyde (1S,2R)-
8a (0.392 g, 2.28 mmol) in THF (10 mL) was added dropwise
and the mixture was stirred at -78 °C for 4 h, then quenched
with water (10 mL). The separated aqueous layer was ex-
tracted with ether (4 × 10 mL) and the combined organic
extracts were washed with brine, dried over anhydrous MgSO4,
and filtered through Celite. The solvent was removed in vacuo
to give the crude product. Purification by radial PLC (silica
gel, 1% EtOAc-hexanes) afforded 0.350 g (77%) of (1S,2R)-
(1S,2R)-tr a n s-2-Meth yl-1,2-d ih yd r on a p h th a len e-1-ca r -
boxa ld eh yd e (8a ). To a stirred solution of oxazolidine (4S)-
733 (1.90 g, 6.95 mmol) in THF (60 mL) at -78 °C was added
methylmagnesuim chloride (3 M in THF, 9.3 mL, 27.3 mmol)
dropwise. After 30 min, the solution was allowed to warm to
room temperature and refluxed for 17 h, then cooled to 0 °C.
Aqueous HCl (3 N, 25 mL, 75 mmol) was added, and the
reaction mixture was stirred for an additional 2 h. The layers
were separated, and the aqueous layer was extracted with
ether (4 × 10 mL). The combined organic extracts were washed
with water and brine, dried over anhydrous MgSO4, and
filtered through Celite. The solvent was removed in vacuo to
give the crude product. Purification by radial PLC (silica gel,
1% Et2O-hexanes) afforded 0.85 g (71%) of (1S,2R)-8a as a
pale yellow oil: [R]23D -212° (c 0.575, CHCl3); 1H NMR (CDCl3)
δ 9.57-9.56 (m, 1H), 7.31-7.11 (m, 4H), 6.39 (d, 1H, J ) 10
Hz), 5.96 (dd, 1H, J ) 5.0, 10.0 Hz), 3.33 (s, 1H), 3.01-2.96
(m, 1H), 1.07 (d, 3H, J ) 7.15 Hz); 13C NMR (CDCl3) δ 200.8,
132.3, 129.6, 128.3, 128.2, 127.8, 126.7, 125.9, 58.3, 28.7, 18.6;
IR (neat) 3015, 2860, 2700, 1726, 1688, 1484, 1452, 1121, 1034,
11a as a colorless oil: [R]23 -231° (c 0.610, CHCl3); 1H NMR
D
(CDCl3) δ 7.28-7.00 (m, 4H), 6.43-6.30 (m, 2H), 5.90-5.81
(m, 1H), 4.78 (dd, 1H, J ) 10.0, 12.5 Hz), 3.56 (s, 3H), 3.02 (t,
3H, J ) 9.25 Hz), 1.11-1.07 (m, 3H); 13C NMR (CDCl3) δ 148.5,
147.2, 137.9, 137.5, 134.2, 134.0, 127.6, 127.2, 126.6, 126.4,
126.0, 108.8, 105.2, 59.6, 56.1, 44.9, 40.4, 35.3, 32.7, 19.6, 19.4;
IR (neat) 3050, 2950, 2820, 1648, 1480, 1451, 1385, 1279, 1204,
1146, 1104, 939, 782 cm-1. Anal. (C14H16O) C, H.
(1R,2S)-tr a n s-2-Met h yl-1-(2-m et h oxyvin yl)-1,2-d ih y-
d r on a p h th a len e (11a ). Using a procedure analogous to that
described for (1S,2R)-11a , aldehyde (1R,2S)-8 (0.479 g, 2.78
mmol) afforded 0.471 g (77%) of (1R,2S)-11a as a colorless oil:
788 cm-1
.
[R]23 +212° (c 0.805, CHCl3). Anal. (C14H16O) C, H.
D
(1R,2S)-tr a n s-2-Meth yl-1,2-d ih yd r on a p h th a len e-1-ca r -
boxa ld eh yd e (8a ). The title compound was prepared by a
procedure analogous to that used for (1S,2R)-8a . The oxazo-
(1S ,2R )-t r a n s-2-E t h yl-1-(2-m e t h oxyvin yl)-1,2-d ih y-
d r on a p h th a len e (11b). Using a procedure analogous to the
one described for the preparation of 11a , 1.29 g (75%) of

4626 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 22
(1S,2R)-11b was obtained from the Wittig reaction of 1.50 g
Carroll et al.
described for the preparation of (1S,2R)-12b, acid hydrolysis
of 0.563 g (2.63 mmol) of vinyl ether (1R,2S)-11a gave 0.436 g
(8.10 mmol) of aldehyde (1S,2R)-8b: [R]23 -210° (c 1.16,
D
1
CHCl3); H NMR (CDCl3) δ 7.17-7.02 (m, 4H), 6.44 (dd, 1H,
(83%) of (1R,2S)-11b as a colorless oil: [R]24 +375° (c 0.635,
D
J ) 1.5, 9.7 Hz), 6.32 (d, 1H, J ) 12.6 Hz), 5.96 (dd, 1H, J )
4.3, 9.7 Hz), 4.83 (dd, 1H, J ) 9.1, 12.6 Hz), 3.52 (s, 3H), 3.21-
3.14 (m, 1H), 2.20-2.16 (m, 1H), 1.57-1.31 (m, 2H), 0.93 (t,
3H, J ) 7.4 Hz); 13C NMR (CDCl3) δ 147.7, 137.6, 132.8, 131.6,
127.7, 126.9, 126.5, 126.3, 125.7, 105.4, 55.7, 41.8, 41.7, 25.7,
10.9; IR (neat) 3010, 2870, 1650, 1478, 1450, 1373, 1230, 1210,
1146, 1119, 945 cm-1. Anal. (C15H18O) C, H.
CHCl3).
(1S,2R)-tr a n s-2-Isop r op yl-1,2-d ih yd r on a p h t h a len e-1-
a ceta ld eh yd e (12c). Using a procedure analogous to the one
described for the preparation of 12a , acid hydrolysis of 0.506
g (2.24 mmol) of vinyl ether (1S,2R)-11c gave 0.385 g (80%) of
(1S,2R)-12c as a colorless oil: [R]23 -353° (c 0.710, CHCl3);
D
1H NMR (CDCl3) δ 10.0-9.96 (m, 12H), 7.22-7.02 (m, 4H),
6.61 (dd, 1H, J ) 9.83 Hz), 5.90 (dd, 1H, J ) 5.73, 9.83 Hz),
2.99 (dd, 1H, J ) 2.2, 15.63 Hz), 2.79 (dd, 1H, J ) 2.95, 15.63
Hz), 2.47-2.43 (m, 1H), 2.05-1.93 (m, 1H), 1.43 (s, 3H), 0.93
(d, 3H, J ) 6.9 Hz), 0.46 (d, 3H, J ) 6.7 Hz); 13C NMR (CDCl3)
δ 203.4, 142.8, 133.0, 129.0, 128.2, 127.5, 127.2, 126.8, 123.0,
52.9, 49.5, 48.8, 39.7, 29.5, 29.2, 22.3, 16.7; IR (neat) 3055,
(1R ,2S )-t r a n s-2-E t h yl-1-(2-m e t h oxyvin yl)-1,2-d ih y-
d r on a p h th a len e (11b). Using a procedure analogous to the
one described for the preparation of 11a , 0.795 g (80%) of
(1R,2S)-11b was obtained from the Wittig reaction of 0.863 g
(4.64 mmol) of aldehyde (1R,2S)-8b: [R]23 +280° (c 0.900,
D
CHCl3). Anal. (C15H18O) C, H.
2930, 2730, 1719, 1479, 1449, 1381, 1072, 1040, 809, 788 cm-1
.
(1S,2R)-tr a n s-2-Isopr opyl-1-m eth yl-1-(2-m eth oxyvin yl)-
1,2-d ih yd r on a p h th a len e (11c). Using a procedure analogous
to the one described for the preparation of (1S,2R)-11a , 1.21
g (80%) of (1S,2R)-11a was obtained from the Wittig reaction
of 1.34 g (6.70 mmol) of aldehyde (1S,2R)-18c: [R]22D -304° (c
(1R,2S)-tr a n s-2-Isop r op yl-1,2-d ih yd r on a p h t h a len e-1-
a ceta ld eh yd e (12c). Using a procedure analogous to the one
described for the preparation of (1S,2R)-12c, acid hydrolysis
of 0.722 g (3.16 mmol) of vinyl ether (1R,2S)-11c gave 0.585 g
1
(86%) of (1R,2S)-12c as a colorless oil: [R]23 +345° (c 1.03,
1.11, CHCl3); H NMR (CDCl3) δ 7.31-6.96 (m, 4H), 6.52 (d,
D
1H, J ) 9.89 Hz), 6.05 (d, 1H, J ) 7.16 Hz) 5.87 (dd, 1H, J )
6.0, 9.89 Hz), 4.72 (d, lH, J ) 7.18 Hz), 2.54-2.49 (m, 1H),
2.26-2.13 (m, 1H), 1.49 (s, 3H), 0.90 (d, 3H, J ) 7.07 Hz),
0.39 (d, 3H, J ) 7.07 Hz); 13C NMR (CDCl3) δ 147.7, 145.0,
132.5, 127.9, 127.7, 127.5, 126.5, 125.8, 124.7, 109.8, 59.8, 49.7,
42.3, 30.5, 29.6, 21.6, 16.4; IR (neat) 3055, 2935, 1658, 1474,
1446, 1380, 1281, 1208, 1107, 1073, 1035, 818, 787 cm-1. Anal.
(C16H20O) C, H.
CHCl3).
(1S,2R)-tr a n s-1-[2-(Ben zyla m in o)et h yl]-2-m et h yl-1,2-
d ih yd r on a p h th a len e (10a ). A mixture of aldehyde (1S,2R)-
12a (0.083 g, 0.44 mmol), benzylamine hydrochloride (0.128
g, 0.89 mmol), and NaBH3CN (0.028 g, 0.44 mmol) in MeOH
(6 mL) was stirred at room temperature overnight. The
separated aqueous layer was extracted with ether (4 × 5 mL),
and the combined organic extracts were washed with brine,
dried over anhydrous K2CO3, and filtered through Celite. The
solvent was removed in vacuo to give the crude product.
Purification by radial PLC (silica gel, MeOH-EtOAc-hexanes,
(1R,2S)-tr a n s-2-Isopr opyl-1-m eth yl-1-(2-m eth oxyvin yl)-
1,2-d ih yd r on a p h th a len e (11c). Using a procedure analogous
to the one described for the preparation of 11a , 1.03 g (76%)
of (1R,2S)-11c was obtained from the Wittig reaction of 1.19
0.1:0.9:4) afforded 0.099 g (80%) of (1S,2R)-10a as a colorless
g (5.93 mmol) of aldehyde (1R,2S)-8c: [R]23 +262° (c 0.865,
oil: [R]22 -280° (c 0.325, CHCl3); H NMR (CDCl3) δ 7.35-
1
D
D
CHCl3). Anal. (C16H20O) C, H.
7.00 (m, 9H), 6.34 (d, 1H, J ) 9.5 Hz), 5.91 (dd, 1H, J ) 5.0,
9.5 Hz), 3.73 (s, 2H), 2.63-2.55 (m, 2H), 2.37-2.27 (m, 2H),
(1S ,2R )-t r a n s-2-Me t h yl-1,2-d ih yd r on a p h t h a le n e -1-
a ceta ld eh yd e (12a ). A solution of vinyl ether (1S,2R)-11a
(0.158 g, 0.789 mmol) in THF (7 mL) and 3 N HCl (5 mL) was
stirred at room temperature overnight. The layers were
separated and the aqueous layer was extracted with ether (4
× 5 mL). The combined organic extracts were washed with
saturated K2CO3 solution and brine, dried over anhydrous K2-
CO3, and filtered through Celite. Removal of the solvent in
vacuo yielded the crude aldehyde. Purification by radial PLC
(silica gel, 5-10% EtOAc-hexanes) provided 0.112 g (77%) of
1.75-1.66 (m, 2H), 1.25 (m, 1H), 0.93 (d, 3H, J ) 7.0 Hz); 13
C
NMR (CDCl3) δ 140.6, 137.5, 132.7, 132.3, 129.2, 128.4, 128.2,
126.9, 126.5, 126.2, 125.4, 54.1, 47.2, 42.8, 35.6, 34.1; IR (neat)
3300, 3010, 2865, 1467, 1447, 1358, 1119, 1027, 846 cm-1. The
free base was converted to the tartrate salt: [R]22 143° (c
D
0.275, CHCl3); mp 57.2-60.8 °C. Anal. (C24H29NO6‚0.25H2O)
C, H.
(1R,2S)-tr a n s-1-[2-(Ben zyla m in o)et h yl]-2-m et h yl-1,2-
d ih yd r on a p h th a len e (10a ). Using a procedure analogous to
that used to prepare (1S,2R)-10a , the aldehyde (1R,2S)-12a
(0.125 g, 0.67 mmol) afforded 0.142 g (76%) of (1R,2S)-10a as
aldehyde (1S,2R)-12a as a colorless oil: [R]23 -361° (c 0.740,
D
CHCl3); 1H NMR (CDCl3) δ 9.52-9.48 (m, 1H), 7.32-7.07 (m,
4H), 6.47 (dd, 1H, J ) 2.25, 9.63 Hz), 5.77 (dd, 1H, J ) 3.3,
9.59 Hz), 2.79(dd, 1H, J ) 2.91, 14.23 Hz), 2.54-2.45 (m, 1H),
2.32 (dd, 1H, J ) 3.6, 14.17 Hz), 1.49 (s, 3H), 1.10 (d, 3H, J )
7.33 Hz); 13C NMR (CDCl3) δ 203.6, 140.4, 133.9, 132.9, 127.8,
127.0, 126.5, 126.2, 124.7; IR (neat) 3015, 2865, 2725, 1718,
a colorless oil: [R]22 +271° (c 0.465, CHCl3). The free base
D
was converted to the tartrate salt: [R]22 +106° (c 0.120,
D
CHCl3); mp 46.5-49.0 °C. Anal. (C24H29NO6‚1.25H2O) C, H.
(1S,2R)-tr a n s-1-[2-(Ben zyla m in o)eth yl]-2-eth yl-1,2-d i-
h yd r on a p h th a len e (10b). Using a procedure analogous to
the one described for the preparation of (1S,2R)-10a , reductive
amination of 0.308 g (1.54 mmol) of aldehyde 5b afforded 0.398
1479, 1444, 1368, 1096, 1038, 786 cm-1
.
(1R ,2S )-t r a n s-2-Me t h yl-1,2-d ih yd r on a p h t h a le n e -1-
a ceta ld eh yd e (12a ). Using a procedure analogous to that
used to prepare (1S,2R)-12a , the vinyl ether (1R,2S)-11a (0.20
g, 1.0 mmol) provided 0.148 g (80%) of aldehyde (1R,2S)-12
g (89%) of amine (1S,2R)-10b as a colorless oil: [R]24 -265°
D
1
(c 0.470, CHCl3); H NMR (CDCl3) δ 7.35-6.99 (m, 9H), 6.37
(d, 1H, J ) 9.6 Hz), 5.95 (dd, 1H, J ) 6.0, 9.6 Hz), 3.73 (s,
3H), 2.76 (t, 1H, J ) 7.2 Hz), 2.64-2.56 (m, 2H), 2.10 (q, 1H,
J ) 6.8, 13.6 Hz), 1.76-1.66 (m, 2H), 1.41-1.20 (m, 2H), 0.88
(t, 3H, J ) 7.4 Hz); 13C NMR (CDCl3) δ 140.6, 138.1, 132.6,
131.6, 129.0, 128.4, 128.2, 126.9, 126.5, 126.2, 125.9, 54.1, 47.3,
40.6, 35.7, 26.8, 11.8; IR (neat) 3300, 3010, 2865, 1486, 1448,
1367, 1119, 1026, 903 cm-1. The free base was converted to
the tartrate salt: [R]22D -146° (c 0.165, CHCl3); mp 43.6-47.0
°C. Anal. (C25H31NO6‚0.5H2O) C, H, N.
as a colorless oil: [R]23 +368° (c 1.10, CHCl3).
D
(1S,2R)-tr a n s-2-Eth yl-1,2-d ih yd r on a p h th a len e-1-a cet-
a ld eh yd e (12b). Using a procedure analogous to the one
described for the preparation of (1S,2R)-12a , acid hydrolysis
of 0.456 g (2.13 mmol) of vinyl ether (1S,2R)-11b gave 0.341 g
(80%) of (1S,2R)-12b as a colorless oil: [R]24 -358° (c 0.670,
D
CHCl3); 1H NMR (CDCl3) δ 9.54-9.52 (m, 1H), 7.29-7.05 (m,
4H), 6.5 (dd, 1H, J ) 2.57, 9.66 Hz) 5.93 (dd, 1H, J ) 3.50,
9.66 Hz), 2.75 (dd 1H, J ) 2.78, 14.29 Hz), 2.33 (dd, 1H, J )
3.57, 14.29 Hz), 2.22-2.16 (m, 1H), 1.75-1.66 (m, 1H), 1.50
(s, 3H), 1.34-1.21 (m, 1H), 0.98 (t, 3H, J ) 7.33 Hz); 13C NMR
(CDCl3) δ 203.6, 140.7, 133.0, 131.4, 127.7, 127.5, 127.0, 126.9,
124.5, 48.7, 45.8, 40.0, 24.8, 21.5, 12.2; IR (neat) 3055, 2925,
(1R,2S)-tr a n s-1-[2-(Ben zyla m in o)eth yl]-2-eth yl-1,2-d i-
h yd r on a p h th a len e (10b). Using a procedure analogous to
the one described for the preparation of (1S,2R)-10b, reductive
amination of 0.430 g (2.15 mmol) of aldehyde (1R,2S)-12b
afforded 0.491 g (78%) of amine (1R,2S)-10b as a colorless oil:
2820, 1718, 1480, 1446, 1371, 1101, 1071, 1040, 789 cm-1
.
[R]24 +281° (c 0.895, CHCl3); H NMR (CDCl3) δ 7.35-6.99
1
D
(1R,2S)-tr a n s-2-Eth yl-1,2-d ih yd r on a p h th a len e-1-a cet-
a ld eh yd e (12b). Using a procedure analogous to the one
(m, 9H), 6.37 (d, 1H, J ) 9.6 Hz), 5.95 (dd, 1H, J ) 6.0, 9.6
Hz), 3.73 (s, 3H), 2.76 (t, 1H, J ) 7.2 Hz), 2.64-2.56 (m, 2H),

9-Alkyl-2-benzyl-6,7-benzomorphans
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 22 4627
2.10 (q, 1H, J ) 6.8, 13.6 Hz), 1.76-1.66 (m, 2H), 1.41-1.20
(m, 2H), 0.88 (t, 3H, J ) 7.4 Hz); 13C NMR (CDCl3) δ 140.6,
138.1, 132. 6, 131.6, 129.0, 128.4, 128.2, 126.9, 126.5, 126.2,
125.9, 54.1, 47.3, 40.6, 35.7, 26.8, 11.8; IR (neat) 3300, 3010,
2865, 1486, 1448, 1367, 1119, 1026, 903 cm-1. The free base
the mixture was stirred under argon at 25 °C for 1.5 h. The
cooled reaction mixture was treated with 15% sodium hydrox-
ide solution, the ether layer separated, and the aqueous layer
extracted with ether. The dried (MgSO4) ether extracts were
concentrated to give the amine (1R,2S)-14b. The amine was
dissolved in 8 mL of CH2Cl2 containing 0.5 mL of triethyl-
amine, and 0.25 mL of benzoyl chloride was added. The
reaction mixture was concentrated, and the resulting residue
was purified by flash chromatography with silica gel using
hexanes-EtOAc (75:25) as the eluent to give 301 mg (62%) of
was converted to the tartrate salt: [R]22 +183° (c 0.230,
D
CHCl3); mp 54.8-57.2 °C. Anal. (C25H31NO6) C, H, N.
(1S,2R)-tr a n s-1-[2-(Ben zyla m in o)et h yl]-2-isop r op yl-
1,2-d ih yd r on a p h th a len e (10c). Using a procedure analogous
to the one described for the preparation of (1S,2R)-10b,
reductive amination of 0.940 g (2.29 mmol) of aldehyde
(1R,2S)-15b: [R]22 212° (c 0.125, CHCl3); 1H NMR (CDCl3) δ
D
7.05-7.63 (m, 9H), 6.39 (d, J ) 9.6 Hz, 1H), 6.00 (dd, J ) 6.2,
9.6 Hz, 1H), 5.88 (bs, 1H), 3.22-3.66 (m, 2H), 2.74 (t, J ) 7.2
Hz, 1H), 2.16 (q, J ) 6.8 Hz, 1H), 1.03-1.44 (m, 2H), 0.88 (t,
J ) 7.4 Hz, 3H). Anal. (C21H23NO) C, H, N.
(1S,2R)-tr a n s-1-[2-(Ben zoyla m in o)eth yl]-2-eth yl-1,2-d i-
h yd r on a p h th a len e (15b). Using a procedure analogous to
that described for (1R,2S)-15b, 299 mg (62%) of (1S,2R)-15b
was obtained from 313 mg (1.59 mmol) of (1S,2R)-13.
(1R,2S)-tr a n s-1-[2-(Ben zoyla m in o)et h yl]-2-isop r op yl-
1,2-d ih yd r on a p h th a len e (15c). Using a procedure analogous
to that described for (1R,2S)-15b, 530 mg (70%) of (1S,2R)-
15c was obtained from 500 mg (2.33 mmol) of (1R,2S)-13c:
[R]22D 319 (c 0.215, C2H5OH); 13C NMR (CDCl3) δ 167.2, 138.0,
134.7, 132.9, 131.1, 130.2, 128.4, 127.2, 126.7, 126.6, 126.5,
afforded 0.586 g (84%) of amine (1S,2R)-10c as a colorless oil:
1
[R]23 -279° (c 0.435, CHCl3); H NMR (CDCl3) δ 7.35-6.98
D
(m, 9H), 6.42 (d, 1H, J ) 9.6 Hz), 5.90 (dd, 1H, J ) 6.0, 9.7
Hz), 3.73 (s, 2H), 2.86 (t, 1H, J ) 7.2, Hz), 2.63-2.56 (m, 2H),
1.94 (t, 1H, J ) 6.7 Hz), 1.75-1.48 (m, 2H), 1.38-1.0 (m, 1H),
0.82 (d, 3H, J ) 6.75 Hz); 13C NMR (CDCl3) δ 140.7, 138.8,
132.9, 130.2, 128.4, 128.2, 126.9, 126.5, 126.4, 126.1, 554.2,
47.2, 46.1, 38.6, 36.5, 32.2, 20.5, 20.3; IR (neat) 3305, 3050,
2920, 2810, 1487, 1452, 1378, 1179, 1116, 1027, 816 cm-1. The
free base was converted to the tartrate salt: [R]23 -152° (c
D
0.630, CHCl3); mp 47.6-50.1 °C. Anal. (C26H33NO6‚0.25H2O)
C, H, N.
(1R,2S)-tr a n s-1-[2-(Ben zyla m in o)et h yl]-2-isop r op yl-
1,2-d ih yd r on a p h th a len e (10c). Using a procedure analogous
to the one described for the preparation of (1S,2R)-10c,
reductive amination of 0.553 g (2.58 mmol) of aldehyde
(1R,2S)-12c afforded 0.577 g (73%) of amine (1R,2S)-10c as a
126.2, 46.1, 38.9, 38.7, 36.1, 32.0, 20.7, 20.0. Anal. (C22H25
NO) C, H, N.
-
(1S,2R)-tr a n s-1-[2-(Ben zoyla m in o)et h yl]-2-isop r op yl-
1,2-d ih yd r on a p h th a len e (15c). Using a procedure analogous
to that described for (1R,2S)-15c, 601 mg (69%) of (1S,2R)-
15c was obtained from 572 mg (2.71 mmol) of (1S,2R)-13c.
colorless oil: [R]22 +269° (c 0.745, CHCl3). The free base was
D
converted to the tartrate salt: [R]22 +181° (c 0.335, CHCl3);
D
mp 57.4-60.2 °C. Anal. (C26H33NO6) C, H, N.
(1S,2R)-tr a n s-1-(Cyan om eth yl)-2-eth yl-1,2-dih ydr on aph -
th a len e (13b). To a solution of 7.0 g (0.04 mol) in 17 mL of
anhydrous pyridine was added 6.34 g (0.02 mol) of (1S,2R)-
9b33 in 25 mL of pyridine for 30 min at 0 °C, then kept at 10
°C overnight. The reaction mixture was diluted with water and
extracted with ethyl ether. The ether extracts were washed
three times with 1 N hydrochloric acid and brine and dried
(MgSO4). Concentration of the extracts gave the tosylate. A
mixture of the tosylate and 2.75 g (0.04 mol) of potassium
cyanide in 63 mL of DMSO was stirred for 2 h at 105 °C. The
cooled reaction mixture was diluted with ethyl ether, washed
twice with water, and dried (MgSO4). The residue obtained
on concentration was purified by flash chromatography on
silica gel using hexanes-EtOAc (95:5) as the eluent to give
Gen er a l P r oced u r e for th e Red u ction of 15b,c to 10b,c.
A solution of 1.56 mmol of 15 in 7 mL of THF was added to
3.1 mL of 1 M LiAlH4 in THF in 8 mL of THF, and the mixture
was refluxed for 4 h. The cooled reaction mixture was treated
with 15% sodium hydroxide and sufficient water to form a solid
that could be separated by filtration. Concentration of the
filtrate gave the desired 15b or 15c isomer. The 1H NMR
spectra were identical to the products prepared from 12b,c.
(1S,5S,9S)-2-Ben zyl-9-m eth yl-6,7-ben zom or p h a n (2a ).
To a mixture of Hg(OAc)2 (0.351 g, 1.1 mmol) and Et3N (0.24
mL, 1.727 mmol) in THF (30 mL) at room temperature was
added amine (1S,2R)-10a (0.203 g, 0.73 mmol) in THF (10 mL)
dropwise, and the reaction mixture was stirred at room
temperature overnight. A solution of LiAlH4 (1 M in THF, 2.0
mL, 2.0 mmol) was added dropwise, and the mixture was
stirred for an additional 2 h, then quenched with saturated
K2CO3 solution (10 mL). The separated aqueous layer was
extracted with ether (5 × 10 mL), and the combined organic
extracts were washed with brine, dried over anhydrous K2-
CO3, and filtered through Celite. The solvent was removed in
vacuo to give the crude product. Purification by radial PLC
(silica gel, MeOH/EtOAc/hexanes, 0.1:0.6:1.3) provided 0.112
g (55%) of (1S,5S,9S)-2a as a colorless oil: 1H NMR (CDCl3) δ
7.61-7.01 (m, 9H), 3.71, 3.61 (AB, 2H, J ) 13.5 Hz), 3.06 (d,
1H, J ) 18.5 Hz), 2.94-2.91 (m, 1H), 2.82 (bs, 1H), 2.63 (dd,
1H, J ) 5.9, 18.5 Hz), 2.44-2.39 (m, 1H), 2.24-2.20 (m, 1H),
2.11-2.03 (m, 2H), 1.51-145 (m, 1H), 0.84 (d, 3H, J ) 7.1 Hz);
13C NMR (CDCl3) δ 139.7, 139.0, 137.0, 129.3, 128.8, 128.2,
127.3, 126.8, 125.8, 125.7, 59.7, 56.6, 43.2, 39.7, 35.7, 34.3, 23.7,
17.4. The free base was converted to the hydrochloride salt:
3.65 g (67%) of (1S,2R)-13b as an oil: [R]24 -280° (c 0.125,
D
1
CHCl3); H NMR (CHCl3) δ 7.04-7.25 (m, 4H), 6.45 (d, J )
9.6 Hz, 1H), 5.97 (dd, J ) 6.1, 9.6 Hz, 1H), 3.02 (t, J ) 7.8 Hz,
1H), 2.39-2.57 (m, 2H), 2.32 (q, J ) 6.9 Hz, 1H), 1.22-1.57
(m, 2H), 0.92 (t, J ) 7.3 Hz, 3H). Anal. (C14H15N) C, H, N.
(1R,2S)-tr a n s-1-(Cyan om eth yl)-2-eth yl-1,2-dih ydr on aph -
th a len e (13b). Using a procedure analogous to that described
for (1S,2R)-13b, 590 mg (3.1 mmol) of (1R,2S)-9b33 afforded
380 mg (64%) of (1R,2S)-13b: [R]24 +273 (c 0.16, CHCl3).
D
Anal. (C14H15N) C, H, N.
(1S,2R)-tr a n s-1-(Cya n om et h yl)-2-isop r op yl-1,2-d ih y-
d r on a p h th a len e (13c). Using a procedure analogous to that
described for (1S,2R)-13b, 0.665 g (56%) of (1S,2R)-13c was
obtained from 1.14 g (0.01 mol) of (1S,2R)-9c: [R]21 -319 (c
D
1
0.17, CHCl3); H NMR δ 7.04-7.25 (m, 4H), 6.51 (d, J ) 9.6
Hz, 1H), 5.95 (ddd, J ) 1.2, 6.1, 9.6 Hz, 1H), 3.16 (t, J ) 7.7
Hz, 1H), 2.39-2.56 (m, 2H), 2.15 (t, J ) 6.8 Hz, 1H),1.62 (m,
J ) 6.8 Hz, 1H),0.87 (dd, J ) 2.2, 6.8 Hz, 6H); 13C NMR
(CDCl3) δ 134.7, 132.2, 128.5, 128.3, 127.7, 126.7, 126.5, 118.8,
45.0, 37.9, 31.7, 24.0, 20.2, 20.0. Anal. (C14H15N) C, H, N.
(1R,2S)-tr a n s-1-(Cya n om et h yl)-2-isop r op yl-1,2-d ih y-
d r on a p h th a len e (13c). Using a procedure analogous to that
described for (1S,2R)-13c, 1.22 g (0.0063 mol) of (1R,2S)-9c33
[R]24 +98° (c 0.145, EtOH); mp >210 °C dec. Anal. (C20H24
-
D
ClN‚0.25H2O) C, H, N.
(1R,5R,9R)-2-Ben zyl-9-m eth yl-6,7-ben zom or p h a n (2a ).
To a mixture of Hg(OAc)2 (0.510 g, 1.60 mmol) and Et3N (0.4
mL, 2.87 mmol) in THF (60 mL) at room temperature was
added amine (1R,2S)-10a (0.340 g, 1.23 mmol) in THF (25 mL)
dropwise, and the reaction mixture was stirred at room
temperature for 64 h. A solution of LiAlH4 (1 M in THF, 3.0
mL, 3.0 mmol) was added dropwise, and the mixture was
stirred for an additional 2 h, then quenched with saturated
K2CO3 solution (15 mL). The separated aqueous layer was
extracted with ether (5 × 10 mL), and the combined organic
extracts were washed with brine, dried over anhydrous K2-
was converted to 0.584 g (43%) of (1R,2S)-13c: [R]22 +315 (c
D
0.17, CHCl3).
(1R,2S)-tr a n s-1-[2-(Ben zoyla m in o)eth yl]-2-eth yl-1,2-d i-
h yd r on a p h th a len e (15b). A solution of 313 g (1.59 mmol)
of (1R,2S)-13b in 6 mL of anhydrous ethyl ether was added to
1.6 mL of 1.0 M LiAlH4 in THF in 15 mL of ethyl ether, and

4628 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 22
Carroll et al.
CO3, and filtered through Celite. The solvent was removed in
vacuo to give the crude product. Purification by radial PLC
(silica gel, MeOH/EtOAc/hexanes, 0.1:0.6:1.3) provided 0.176
g (52%) of (1R,5R,9R)-10a as a colorless oil: 1H NMR (CDCl3)
δ 7.61-7.01 (m, 9H), 3.71, 3.61 (AB, 2H, J ) 13.5 Hz), 3.06
(d, 1H, J ) 18.5 Hz), 2.94-2.91 (m, 1H), 2.82 (bs, 1H), 2.63
(dd, 1H, J ) 5.9, 18.5 Hz), 2.44-2.39 (m, 1H), 2.24-2.20 (m,
1H), 2.11-2.03 (m, 2H), 1.51-145 (m, 1H), 0.84 (d, 3H, J )
7.1 Hz); 13C NMR (CDCl3) δ 139.7, 139.0, 137.0, 129.3, 128.8,
128.2, 127.3, 126.8, 125.8, 125.7, 59.7, 56.6, 43.2, 39.7, 35.7,
34.3, 23.7, 17.4. The free base was converted to the hydro-
fuged at 31000g for 15 min. The pellet was resuspended in 3
mL/g 10 mM Tris-HCl, pH 7.4, by vortexing, and the suspen-
sion was allowed to incubate at 25 °C for 15 min. Following
centrifugation at 31000g for 15 min, the pellet was resus-
pended to 1.53 mL/g in 10 mM Tris-HCl, pH 7.4, and aliquots
were stored at -80 °C until use. Protein concentration of the
suspension was determined by the method of Lowry41 and was
20-25 mg of protein/mL.
σ1 Bin d in g Assa y. Guinea pig brain membranes (325-500
µg of protein) were incubated with 3 nM [3H]-(+)-pentazocine
(51.7 Ci/mmol) in 0.5 mL of 50 mM Tris-HCl, pH 8.0, for 120
min at 25 °C. Nonspecific binding was determined in the
presence of 10 µM haloperidol. Test compounds were added
in concentrations ranging from 0.005 to 1000 nM or from 0.05
to 10000 nM. Assays were terminated by the addition of 5 mL
of ice-cold 10 mM Tris-HCl, pH 8.0, followed by rapid filtration
through glass-fiber filters using a Brandel cell harvester
(Gaithersburg, MD). Filters were then washed twice with 5
mL of ice-cold buffer. Prior to use, filters were soaked in 0.5%
poly(ethylenimine) for at least 30 min at 25 °C.
σ2 Bin d in g Assa y. Rat liver membranes (160-200 µg of
protein) were incubated with 3 nM [3H]DTG (39.4 Ci/mmol)
in the presence of 1 µM unlabeled dextrallorphan. Incubations
were carried out in 0.5 mL of 50 mM Tris-HCl, pH 8.0 for 120
min at 25 °C. Nonspecific binding was determined in the
presence of 10 µM haloperidol. Test compounds were added
in concentrations ranging from 0.005 to 1000 nM or from 0.05
to 10000 nM. Assays were terminated by the addition of 5 mL
of ice-cold 10 mM Tris-HCl, pH 8.0, followed by rapid filtration
through glass-fiber filters using a Brandel cell harvester
(Gaithersburg, MD). Filters were then washed twice with 5
mL of ice-cold buffer. Prior to use, filters were soaked in 0.5%
poly(ethylenimine) for at least 30 min at 25 °C.
chloride salt: [R]24 -97° (c 0.165, EtOH); mp >210 °C dec.
D
Anal. (C20H24ClN‚0.25H2O) C, H, N.
(1S,5S,9S)-2-Ben zyl-9-eth yl-6,7-ben zom or p h a n (2b). A
solution of 152 mg (0.52 mmol) of (1S,2R)-10b and 352 mg
(1.1 mmol) of mercuric acetate in 20 mL of THF was stirred
for 24 h at 25 °C. A solution of 120 mg (3.2 mmol) of sodium
borohydride in 5 mL of 1 N sodium hydroxide was added to
the reaction mixture, and stirring continued for an additional
5 h. The mixture was extracted with ether. The ether extracts
were washed with brine, dried (MgSO4), and concentrated. The
resulting residue was purified by silica gel chromatography
using hexanes/EtOAc (9:1) as the eluent to give 68 mg (43%)
of (1S,5S,9S)-2b: 1H NMR (CDCl3) δ 6.93-7.31 (m, 9H), 3.64
(AB, J ) 13.5 Hz, 2H), 3.54, 2.98 (d, J ) 18.6 Hz, 1H), 2.96 (d,
J ) 6.4 Hz, 1H), 2.87 (d, J ) 2.6 Hz, 1H), 2.52 (dd, J ) 6.0,
18.6 Hz, 1H), 2.32-2.36 (m, 1H), 1.87-2.10 (m, 3H), 1.39-
1.45 (m, 1H), 1.03-1.12 (m, 2H), 0.78 (t, J ) 7.2 Hz, 3H); 13
C
NMR (CDCl3) δ 59.7 (CH2), 55.5 (CH), 43.6 (CH2), 42.9 (CH),
37.4 (CH), 34.1 (CH2) 24.1 (CH2), 24.0 (CH2), 139.7 (C), 139.1
(C), 137.3 (C), 129.1 (CH), 128.7 (CH), 128.2 (CH), 127.3 (CH),
126.7 (CH), 125.7 (CH), 125.6 (CH), 11.6 (CH3). The free base
was converted to the hydrochloride salt. Anal. (C24H26ClN‚H2O)
C, H, N.
All scintillation counting was carried out in Cytoscint
(National Diagnostics, Manville, NJ ) after an overnight extrac-
tion of counts.
(1R,5R,9R)-2-Ben zyl-9-eth yl-6,7-ben zom or ph an (2b). Us-
ing a procedure similar to that described for (1S,5S,9S)-2b,
229 mg (0.78 mol) of (1R,2S)-10b provided 40 mg (18%) of
(1R,5R,9R)-2b. The free base was converted to the hydrochlo-
Ack n ow led gm en t. This work was supported by the
National Institute on Drug Abuse under Grant No.
DA05721.
ride salt: [R]22 -53° (c 0.085, EtOH); mp 147 °C dec. Anal.
D
(C21H26ClN) C, H, N.
(1S,5S,9S)-2-Ben zyl-9-isopr opyl-6,7-ben zom or ph an (2c).
Using a procedure analogous to that described for (1S,5S,9S)-
2b, cyclization of 380 mg (1.24 mol) of (1S,2R)-10c gave 190
mg (50%) of (1S,5S,9S)-2b: 1H NMR (CDCl3) δ 7.04-7.41 (m,
9H), 3.78 (AB, J ) 13.6 Hz, 2H), 3.66, 3.28 (bs, 1H), 3.15 (bs,
1H), 3.08 (d, J ) 18.6 Hz, 1H), 2.65 (dd, J ) 6.1, 18.6 Hz, 1H),
2.40-2.47 (m, 1H), 1.96-2.20 (m, 2H), 1.47-1.70 (m, 2H),
1.11-1.35 (m, 1H), 0.88 (dd, J ) 1.5, 6.6 Hz, 6H); 13C NMR
(CDCl3) δ 59.8 (CH2), 53.8 (CH), 48.2 (CH), 43.2 (CH2), 36.0
(CH), 34.2 (CH2), 26.9 (CH), 24.1 (CH2), 20.7 (CH3), 139.7 (C),
139.1 (C), 137.6 (C), 128.9 (CH), 128.6 (CH), 128.1 (CH), 127.2
(CH), 126.7 (CH), 125.7 (CH), 125.6 (CH). The free base was
converted to the hydrochloride salt: [R]24D +79 (c 0.135, EtOH);
mp 123 °C dec. Anal. (C22H28ClN‚0.5H2O) C, H, N.
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