2-Amino-2-oxazolines as subtype selective α2 adrenoceptor agonists

Article abstract of DOI:10.1021/jm9905256

Cyclohexylamino oxazoline I (AGN 190837), an analogue of 2 (Bay a6781), is a potent α₂ adrenoceptor agonist. On the basis of a design generated by receptor-ligand modeling, a number of cyclohexyl and norbornyl analogues were synthesized wherein the propyl group of I was replaced by phenylalkyl subsituents. This resulted in compound 6 being an α(2c) selective agonist, as well as 7 and 9 being α(2a)/α(2c) selective.

Full text of DOI:10.1021/jm9905256

J . Med. Chem. 2000, 43, 1699-1704
1699
2-Am in o-2-oxa zolin es a s Su btyp e Selective r2 Ad r en ocep tor Agon ists
Wai C. Wong,*,†,| Wanying Sun,†, Weili Cui,†,+ Yuewen Chen,†,∇ Carlos Forray,‡ Pierre J .-J . Vaysse,§
Theresa A. Branchek,‡ and Charles Gluchowski†,#
Deparments of Chemistry, Pharmacology, and Cell Biology, Synaptic Pharmaceutical Corporation, 215 College Road,
Paramus, New J ersey 07652
Received October 20, 1999
Cyclohexylamino oxazoline 1 (AGN 190837), an analogue of 2 (Bay a6781), is a potent R2
adrenoceptor agonist. On the basis of a design generated by receptor-ligand modeling, a number
of cyclohexyl and norbornyl analogues were synthesized wherein the propyl group of 1 was
replaced by phenylalkyl subsituents. This resulted in compound 6 being an R2c selective agonist,
as well as 7 and 9 being R2a/R2c selective.
In tr od u ction
The R adrenoceptors are members of the diverse
family of G-protein coupled receptors which are cell
membrane proteins consisting of seven putative trans-
membrane helices.1 These receptors have long been
targets for drug development because of their impor-
tance in controlling many physiological functions both
peripherally and centrally.2 Medetomidine,3 brimonidine
(UK 14,304),4 and clonidine5 are examples of R2 adreno-
ceptor agonists which have been developed as antihy-
pertensive, antiglaucoma, analgesic, and veterinary
anesthetic agents. Recent studies in animals with
deletions or overexpression of the genes encoding the
different R2 adrenoceptor subtypes suggest that each of
these subtypes mediates discrete physiological func-
tions.6 In addition, these studies have highlighted the
potential for the development of subtype selective
therapeutic agents with improved efficacy and/or re-
duced side effects when compared to existing drugs.
We are interested in designing novel R2 agonists
which are selective for each of the three R2 adrenoceptor
subtypes.7 These compounds are expected to serve as
useful pharmacological tools to delineate the physiologi-
cal roles of each R2 subtype. Moreover, an R2 subtype
selective agonist may be useful for the treatment of such
conditions as pain, hypertension, and glaucoma with
potentially fewer side effects.6b Cyclohexylamino oxazo-
line 1 (AGN 190837),8 an analogue of 2 (Bay a6781),9
was used as our design lead because it is a potent R2
agonist and its alkyl side chain appears to be important
for receptor activation (Figure 1). By modeling the
molecular interaction of 1 with the human R2c receptor
(Figure 2), we have designed and synthesized two new
series of compounds which showed interesting binding
and functional activities at the cloned human R2 adreno-
ceptors.10 Herein we report our results.
F igu r e 1. Cyclohexylamino and norbornylamino oxazolines.
F igu r e 2. Model of molecular interaction between 1 and the
human R2c receptor (extracellular view showing the seven
transmembrane helices I-VII arranged in a counterclockwise
manner with the side chains of the relevant amino acid
residues highlighted).
Mod el Con str u ction
The three-dimensional model of the human R2c recep-
tor used in this study was built using a homology
modeling procedure similar to that of Hibert,11 with
bacteriorhodopsin as the template. Energy minimization
and constrained molecular dynamics were used for the
refinement of the receptor model. On the other hand,
the 3D structure of ligand 1 was built and optimized
using the Insight II/Discover program (Biosym Tech-
nologies, San Diego). It was docked into the R2c receptor
model using the following computational process: af-
* To whom correspondence should be addressed. Tel: 203-812-3456.
Fax: 203-812-2650. E-mail: WAI.WONG.B@BAYER.COM.
† Department of Chemistry.
‡ Department of Pharmacology.
§ Department of Cell Biology.
| Current address: Bayer Corporation, West Haven, CT.
Current address: Merck Research Laboratories, Rahway, NJ .
+ Current address: MicroSimulations, Mahwah, NJ .
∇ Current address: J ames International Consulting, Inc., Edison,
NJ .
#
Current address: RiboGene, Inc., Hayward, CA.
10.1021/jm9905256 CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/18/2000

1700 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 9
Sch em e 1. Synthesis of Oxazoline 3a
Wong et al.
Ta ble 1. Binding and Functional Activities at Cloned Human
R2 Adrenoceptorsa
R2a
R2b
R2c
compd pKi pEC50 (IA) pKi pEC50 (IA) pKi pEC50 (IA)
1
3
4
5
6
8.53 8.79 (1.0) 8.23 8.03 (1.0) 7.61 8.39 (1.0)
7.74 NA
7.68 NA
8.84 NA
7.82 NA
7.65 NA
7.39 NA
8.16 NA
7.49 NA
7.28 NA
7.18 NA
7.97 NA
7.49 7.57 (0.9)
a
SEM’s are typically within (3% of the mean pKi or pEC50
a
Reagents: (a) NH4OAc, NaCNBH3; (b) Cl(CH2)2NCO; (c)
values.
boiling H2O, or CH3CN, KF/alumina.
Subsequent cyclization in either boiling water or aceto-
nitrile containing KF/alumina7a afforded 3.
finity grid maps, generated by the method of Goodford,12
were used to define the targeted binding site and to
calculate binding energies; the exploration of the posi-
tion and orientation of the ligand was carried out using
Monte Carlo simulated annealing.13
The amine precursors to 4-6 were prepared according
to Scheme 2. Treatment of cyclohexene oxide (14) with
Grignard reagents17 gave trans-alcohol 15. Tosylation
of 15 led to cis-tosylate 16 which was then converted to
azide 17 with overall retention of configuration. Sub-
sequent hydrogenation afforded trans-amine 18 which
was cyclized to the final products according to the
method depicted in Scheme 1.
The synthesis of the amine precursors to norbornyl
7-10 is depicted in Scheme 3 whereby norcamphor (19)
was alkylated with the appropriate halides, and the
resulting exo-ketone 20 was then reduced with lithium
aluminum hydride to give a mixture of two isomeric
alcohols from which trans-alcohol 21 could be isolated
after flash chromatography. Conversion to azide 22 was
accomplished with inversion of configuration by using
diphenylphosphoryl azide. Subsequent transformation
to the final products followed the above-mentioned
processes.
Molecu la r Design
It is generally accepted that the carboxylate anion of
the Asp residue on the transmembrane helix III of R2
receptors forms a salt bridge with the protonated
nitrogen of a substrate such as oxazoline 1.14 However,
while catecholamines (e.g., norepinephrine) activate the
receptors by hydrogen bonding between the aromatic
hydroxyl groups and the Ser and/or Cys residues on
transmembrane helix V, 1 lacks a hydroxyl group and
therefore is likely to activate the receptors by some other
mechanism. By docking 1 in a computer-generated
model of the human R2c receptor (Figure 2), we found
that the propyl side chain of 1 orients itself between
transmembrane helices III and IV. It has previously
been reported that p-azidoclonidine, when photoacti-
vated, labeled the fourth transmembrane helix of the
R2c receptor.15 Therefore, we hypothesized that the
propyl side chain of 1 may be involved in the activation
of the receptors. By aligning the amino acid sequences
of the three human R2 receptor subtypes, we observed
that both helices III and IV are conserved in the area
of the binding pocket. However, while the R2a and R2c
subtypes have a Phe on transmembrane helix IV, the
Resu lts a n d Discu ssion
Equilibrium competition binding assays using [3H]-
rauwolscine were preformed with membrane prepara-
tions from cultured LM(tk-) cells stably transfected with
cloned human R2 adrenoceptor subtypes, except for R2b
which was expressed in Y-1 cells.18 Estimates of equi-
librium inhibition constants (expressed as pKi) were
determined by nonlinear regression analysis. The ago-
nist potency (expressed as pEC50) was measured as a
function of the ability to inhibit forskolin-stimulated
synthesis of cyclic adenosine monophosphate (cAMP).19
Intrinsic activity (IA) is the fraction of maximum
inhibition produced by each test compound relative to
norepinephrine (IA ) 1.0). The tables summarize the
binding and functional activities of the test compounds
(NA ) not active; a compound is considered not active
when IA < 0.3). None of the compounds were evaluated
for antagonist activity.
R2b subtype has a Leu at the corresponding location. As
such, modifying the side chain of 1 so that it selectively
interacts with the Phe of R2a and R2c but not with the
Leu of R2b might yield subtype selective ligands. Hence,
our plan was to prepare compounds 3-6 (Figure 1)
wherein the phenyl group is gradually extended out in
an attempt to reach the Phe on helix IV. In addition,
we also prepared norbornyl analogues 7-10 (Figure 1)
to determine if the six-membered ring conformation
would affect affinity and potency.
Syn th esis
Compound 1 (AGN 190837) clearly binds with high
affinity and activates all three R2 adrenoceptors (Table
1). In contrast, 3 and 4 bind to the receptors but do not
seem to activate them. Interestingly, compound 5 with
a longer ethyl chain has gained some affinity but still
The synthesis of compound 3 is outlined in Scheme
1. Reductive amination of 2-phenylcyclohexanone (11)
gave, after chromatographic purification, trans-amine
intermediate 12 which was then converted to urea 13.
Sch em e 2. Synthesis of Cyclohexylaminesa
a
Reagents: (a) Ph(CH2)nMgX; (b) Zn(OTs)2, PPh3, DEAD; (c) NaN3, DMF; (d) H2 or PMe3/H2O.

2-Amino-2-oxazolines as R2 Adrenoceptor Agonists
Sch em e 3. Synthesis of Norbornylaminesa
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 9 1701
is probably only one of two or more elements by which
the receptors are activated because compound 7, without
an aromatic ring, also shows functional selectivity.
Further experiments, including the use of mutagenesis
and/or docking of 1 in molecular models of the R2a and
R2b receptors, are necessary to provide better under-
standing of the role Phe plays in the activation of the
R2 receptors. Moreover, these new selective ligands may
be useful for helping elucidate the functions of the R2
receptor subtypes.
Exp er im en ta l Section
a
Reagents: (a) LiN(SiMe3)2, RX; (b) LiAlH4; (c) (PhO)2PON3,
Melting points (uncorrected) were determined on a Mel-
Temp apparatus in open capillary tubes. 1H NMR spectra were
recorded on a GE QE Plus 300 MHz spectrometer with CDCl3
as internal standard unless otherwise noted. Mass spectra
were obtained by Oneida Research Services, Inc. Elemental
analyses were performed at Robertson Microlit Laboratories,
Inc.
PPh3, DEAD; (d) H2 or PMe3/H2O.
Ta ble 2. aBinding and Functional Activities at Cloned Human
R2 Adrenoceptors
R2a
R2b
R2c
compd pKi pEC50 (IA) pKi pEC50 (IA) pKi pEC50 (IA)
tr a n s-2-(2-P h en ylcycloh exyl)a m in o-2-oxa zolin e (3). A
mixture of trans-2-phenylcyclohexylamine (12, 0.1 g, 0.57
mmol) and 2-chloroethyl isocyanate (0.06 mL, 0.68 mmol) in
THF (5 mL) was stirred at room temperature overnight. After
removal of the solvent, water (10 mL) was added, and the
solution was refluxed for 4 h. It was cooled to room temper-
ature and basified to pH 8 with saturated NaHCO3 solution.
The aqueous solution was extracted with ethyl acetate to give
the crude product (0.12 g). Flash chromatography over silica
gel (10:2:1 ethyl acetate-methanol-triethylamine) afforded
pure product (0.072 g, 52% yield): 1H NMR (CD3OD) δ 1.22-
1.51 (6H, m), 1.70-1.81 (3H, m), 2.08 (1H, m), 2.42 (1H, dt,
J ) 11.2, 3.5 Hz), 3.34-3.53 (3H, m), 3.96 (1H, t), 7.05-7.19
(5H, m). The oxazoline in ethanol was treated with 1 equiv of
fumaric acid to give a fumarate salt as white crystals (56%
yield): mp 130-131.5 °C; 1H NMR (CD3OD) δ 1.37-1.48 (3H,
m), 1.61 (1H, m), 1.65-1.90 (3H, m), 2.04-2.08 (1H, m), 2.49
(1H, m), 3.47-3.57 (3H, m), 4.48 (2H, m), 6.63 (2H, s), 7.17-
7.29 (5H, m). Anal. (C15H20N2O‚C4H4O4) C, H, N.
tr a n s-2-(2-Ben zylcycloh exyl)a m in o-2-oxa zolin e (4). A
mixture of trans-2-benzylcyclohexylamine (0.19 g, 1.0 mmol)
and 2-chloroethyl isocyanate (1.1 mL, 10 mmol) in THF (15
mL) was stirred at room temperature overnight. After removal
of the solvent, the residue was purified via flash chromatog-
raphy over silica gel (4:1 ethyl acetate-hexane) to give the
desired intermediate (0.278 g, 94% yield). It was treated with
KF (0.55 g, 40% on alumina) in acetonitrile (10 mL) and heated
at reflux overnight. After removal of the solvent, the residue
was purified via flash chromatography over silica gel (5:1 ethyl
acetate-2M methanolic ammonia) to give the title compound
(0.108 g, 45% yield) as a white solid. It was treated in ethanol
with 1 equiv of fumaric acid to give a fumarate salt as white
crystals: mp 152-153 °C; 1H NMR (CD3OD) δ 1.00-1.40 (4H,
m), 1.59-1.74 (4H, m), 1.92 (1H, m), 2.30 (1H, dd, J ) 13.5,
8.9 Hz), 2.88 (1H, dd, J ) 13.4, 2.7 Hz), 3.10 (1H, m), 3.83
(2H, m), 4.73 (2H, m), 6.64 (2H, s), 7.08-7.25 (5H, m). Anal.
(C16H22N2O‚C4H4O4‚1/4C2H6O) C, H, N.
7
8
9
7.55 7.96 (0.9)
7.86 NA
7.51 7.46 (0.98) 6.85 NA
7.80 7.15 (0.5) 6.99 NA
7.04 6.25 (0.4)
7.39 NA
6.91 7.67 (0.9)
7.10 7.86 (0.5)
6.91 7.22 (0.92)
7.07 8.70 (0.45)
10
a
SEM’s are typically within (3% of the mean pKi or pEC50
values.
does not activate the receptors. However, compound 6
with a phenylpropyl side chain selectively activates only
the R2c receptor with an IA close to 1. This appears to
support our hypothesis that the benzene ring on 6 is
able to reach and selectively interacts with the Phe
moiety on helix IV of the R2c receptor but not the
corresponding Leu of R2b. Meanwhile, it is possible that
the R2a receptor is not activated because its binding
pocket has a conformation different from that of R2c such
that compound 6 does not bind to the two receptors in
the same manner.
Data for norbornyl analogue 7 (Table 2) show that
although addition of the methylene bridge lowers af-
finity, it actually improves selectivity relative to 1
because 7 activates only the R2a and R2c receptors and
is at best a partial agonist at R2b. At this point, we
cannot rationalize how compound 7 activates the recep-
tors, but it is likely that 1 and 7 do not bind to the
receptors identically so that the methylene bridge of 7
led to a binding conformation which resulted in selective
activation of only two subtypes.
Benzyl derivative 8 resembles compound 4 in both
affinity and lack of the ability to activate the receptors
although it may be a partial agonist at R2c. However,
compound 9, like compound 7, selectively activates only
the R2a and R2c receptors. This may mean that the
methylene bridge of 9 allows the molecule to bind in
such a way that it can interact with the Phe residue of
both R2a and R2c equally well, in contrast to compound
6 which activates only R2c. Restraining the side chain
of 9 with a double bond as in 10 reduces the ability of
the ligand to activate the receptors although affinity is
not significantly affected.
Similarly prepared were the following compounds:
tr a n s-2-(2-(2-P h en ylet h yl)cycloh exyl)a m in o-2-oxa zo-
1
lin e (5). Fumarate salt (white crystals): mp 160-162 °C; H
NMR (CD3OD) δ 1.03-1.40 (6H, m), 1.67-2.05 (6H, m), 2.48
(1H, m), 2.68 (1H, m), 3.08 (1H, m), 3.78 (2H, t, J ) 9.0 Hz),
4.63 (2H, t, J ) 8.2 Hz), 6.62 (1H, s), 7.07-7.22 (5H, m). Anal.
(C17H24N2O‚1/2C4H4O4) C, H, N.
tr a n s-2-(2-(3-P h en ylp r op -1-yl)cycloh exyl)a m in o-2-ox-
a zolin e (6). Fumarate salt (white crystals): mp 98-99 °C;
1H NMR (CD3OD) δ 1.24-1.48 (7H, m), 1.65 (2H, m), 1.88 (3H,
m), 1.91 (2H, m), 2.53 (2H, m), 3.81 (2H, t, J ) 4.4 Hz), 4.69
(2H, t, J ) 4.9 Hz), 6.64 (2H, s), 7.11-7.23 (5H, m). Anal.
(C18H26N2O‚C4H4O4‚1/4H2O) C, H, N.
2-(3-exo-P r op yl-2-exo-n or bor n yl)a m in o-2-oxa zolin e (7).
Amine 23a (200 mg, 1.30 mmol) was dissolved in dry THF (5
mL), cooled by an ice water bath, and treated with 2-chloro-
Su m m a r y
Therefore, given these data, it is conceivable that the
Phe on transmembrane helix IV interacts with the
aromatic rings on 6 and 9 resulting in selective activa-
tion of the R2a and/or R2c receptors. However, the Phe

1702 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 9
Wong et al.
ethyl isocyanate (170 µL, 1.99 mmol). The solution was stirred
at room temperature for 3 days before it was concentrated to
give a white solid. It was treated with 40% KF on alumina
(755 mg, 5.20 mmol) in acetonitrile (5 mL) and heated at reflux
overnight. Filtration of the reaction mixture through Celite
followed by concentration of the filtrate gave a white solid
which was dissolved in chloroform and purified via flash
chromatography over silica gel (17 g) eluting with EtOAc/
hexane (1:1) and EtOAc/hexane/triethylamine (15:15:1) to
afford a white solid (135 mg, 47% yield). An analytical sample
was obtained by recrystallization from EtOAc: mp 123-125
1.26 (5H, m), 1.41 (1H, d, J ) 4.4 Hz), 1.53-1.93 (7H, m),
2.54-2.63 (2H, m), 3.18 (1H, m), 7.14-7.29 (5H, m).
cis-2-Ben zyl-1-tosyloxy-cycloh exa n e (16a ). A portion of
15a (1.9 g, 10 mmol) was treated with triphenylphosphine
(13.1 g, 50 mmol) and zinc tosylate (2.4 g, 6 mmol) in benzene
(40 mL). To the mixture was added dropwise diethyl azodi-
carboxylate (3 mL, 50 mmol). The resulting clear solution was
stirred at room temperature overnight. After removal of some
solid by filtration, the benzene was evaporated in vacuo. The
residue was purified via flash chromatography over silica gel
(4:1 hexanes-ethyl acetate) to give the desired product (1.02
g, 30% yield): 1H NMR δ 1.23-1.71 (8H, m), 1.95 (1H, m),
2.36 (1H, m), 2.41 (3H, s), 2.53 (1H, dd, J ) 13.7, 5.5 Hz), 4.76
(1H, m), 7.04 (1H, d, J ) 8.3 Hz), 7.14-7.32 (3H, m), 7.80 (1H,
d, J ) 8.3 Hz).
1
°C; H NMR δ 0.86 (3H, t, J ) 7.1 Hz), 0.90-1.55 (10H, m),
1.65 (1H, m), 2.00 (1H, m), 2.13 (1H, m), 3.58 (1H, d, J ) 7.7
Hz), 3.76 (2H, t, J ) 8.3 Hz), 4.28 (2H, t, J ) 8.3 Hz); CIMS
m/e ) 223 (MH+). Anal. (C13H22N2O) C, H, N.
Similarly prepared were the following compounds:
Similarly prepared were the following compounds:
2-(3-exo-Ben zyl-2-exo-n or bor n yl)a m in o-2-oxa zolin e (8).
Fumarate salt (white crystals): mp 127-130 °C; 1H NMR
(DMSO-d6) δ 1.06 (3H, m), 1.38 (2H, m), 1.82 (2H, m), 2.06
(2H, m), 2.44 (2H, m), 3.52 (3H, m), 4.21 (1H, m), 4.39 (1H,
m), 6.46 (2H, s), 7.09 (3H, m), 7.21 (2H, m); CIMS m/e ) 271
(MH+). Anal. (C17H22N2O‚C4H4O4) C, H, N.
2-(3-exo-(3-P h en ylp r op -1-yl)-2-exo-n or bor n yl)a m in o-2-
oxa zolin e (9). Fumarate salt (white crystals): mp 134-136
°C; 1H NMR (DMSO-d6) δ 0.90-1.20 (5H, m), 1.40 (3H, m),
1.57 (3H, m), 1.94 (1H, m), 2.00 (1H, m), 2.46 (3H, m), 3.50
(1H, d, J ) 8.0 Hz), 3.63 (2H, t, J ) 8.3 Hz), 4.45 (2H, m),
6.44 (2H, s), 7.09 (3H, m), 7.20 (2H, m); CIMS m/e ) 299
(MH+). Anal. (C19H26N2O‚C4H4O4) C, H, N.
tr a n s-2-(3-exo-(3-P h en yl-2-p r op en -1-yl)-2-exo-n or bor n -
yl)a m in o-2-oxa zolin e (10). Fumarate salt (white crystals):
mp 150-155 °C; 1H NMR (DMSO-d6) δ 1.00 (1H, m), 1.10 (2H,
m), 1.40 (2H, m), 1.70 (1H, m), 1.82 (1H, m), 2.03 (4H, m),
3.43 (1H, m), 3.55 (2H, m), 4.30 (1H, m), 4.40 (1H, m), 6.17
(1H, m), 6.28 (1H, d, J ) 16.0 Hz), 6.46 (2H, s), 7.10-7.33
(5H, m); CIMS m/e ) 297 (MH+). Anal. (C19H24N2O‚C4H4O4)
C, H, N.
tr a n s-2-P h en ylcycloh exyla m in e (12).16 To a mixture of
2-phenylcyclohexanone (0.87 g, 5 mmol) and ammonium
acetate (3.85 g, 50 mmol) dissolved in methanol (20 mL) under
argon was added sodium cyanoborohydrate (0.22 g, 3.5 mmol).
The solution was stirred at room temperature overnight and
acidified to pH 1 with concentrated HCl. After removal of most
of the solvent, water (30 mL) was added and the solution was
basified to pH 9 with 6 N NaOH solution. The mixture was
extracted with chloroform, and the dried (sodium sulfate)
extract was concentrated in vacuo. The residue was purified
via flash chromatography over silica gel (4:1 ethyl acetate-
hexane) to give the desired product (0.235 g, 27% yield) as a
white solid: 1H NMR δ 0.96 (2H, s), 1.23-1.45 (4H, m), 1.69-
1.78 (3H, m), 1.89-1.94 (1H, m), 2.16 (1H, dt, J ) 11.1, 3.4
Hz), 2.76 (1H, dt, J ) 12.3, 3.8 Hz), 7.11-7.26 (5H, m).
tr a n s-2-Ben zylcycloh exa n ol (15a ).20 To a solution of
cyclohexene oxide (5 g, 50.9 mmol) in THF (20 mL) being cooled
at -78 °C was added benzylmagnesium chloride in THF (2.0
M, 38 mL) under an argon atmosphere. After being stirred
for about 4 h, the mixture was slowly warmed to room
temperature and allowed to stir overnight. After removal of
half of the solvent, water (40 mL) was added. The solution was
adjusted to pH 7 with 3 N HCl solution and extracted with
ethyl acetate. The dried (sodium sulfate) extract was evapo-
rated in vacuo to give the crude product as a white solid (10.86
g): mp 74-75 °C (lit.20a mp 77 °C); 1H NMR δ 0.85-0.90 (1H,
m), 1.19 (1H, m), 1.23 (2H, m), 1.26-1.71 (5H, m), 1.95 (1H,
m), 2.32 (1H, dd, J ) 13.3, 9.2 Hz), 3.14 (1H, dd, J ) 13.3, 4.0
Hz), 3.26 (1H, dt, J ) 9.6, 4.5 Hz), 7.14-7.35 (5H, m).
Similarly prepared were the following compounds:
cis-2-(2-P h en ylet h yl)-1-t osyloxy-cycloh exa n e (16b ).
White solid (21% yield): 1H NMR δ 1.24-1.65 (9H, m), 1.9-
2.0 (2H, m), 2.37 (3H, s), 2.48 (2H, t, J ) 7.6 Hz), 4.78 (1H,
m), 7.04-7.26 (4H, m), 7.79 (1H, d, J ) 8.3 Hz).
cis-2-(3-P h en ylp r op -1-yl)-1-tosyloxy-cycloh exa n e (16c).
White solid (29% yield): 1H NMR δ 1.15-1.65 (14H, m), 1.95
(1H, m), 2.41 (3H, s), 2.44 (1H, m), 4.75 (1H, m), 7.06-7.35
(4H, m), 7.75 (1H, d, J ) 8.3 Hz).
tr a n s-1-Azid o-2-ben zylcycloh exa n e (17a ). Tosylate 16a
(1.15 g, 3.3 mmol) was treated with sodium azide (0.33 g, 5.1
mmol) in DMF (10 mL) and heated at 100 °C overnight. After
removal of the solvent, the residue was purified via flash
chromatography over silica gel (10:1 hexanes-ethyl acetate)
to give the desired product as a colorless oil (0.488 g, 68%
yield): 1H NMR δ 0.88-1.79 (8H, m), 2.07 (1H, dd, J ) 12.6,
2.9 Hz), 2.31 (1H, dd, J ) 13.3, 9.4 Hz), 2.92 (1H, dt, J ) 10.7,
6.5 Hz), 3.10 (1H, dd, J ) 13.4, 3.3 Hz), 7.12-7.29 (5H, m).
Similarly prepared were the following compounds:
tr a n s-1-Azid o-2-(2-p h en yleth yl)cycloh exa n e (17b). Col-
orless liquid (50% yield): 1H NMR δ 0.95-1.43 (6H, m), 1.60-
1.80 (2H, m), 1.92-2.07 (3H, m), 2.54 (1H, m), 2.70 (1H, m),
2.91 (1H, dt, J ) 10.3, 3.9 Hz), 7.16-7.28 (5H, m).
tr a n s-1-Azid o-2-(3-p h en ylp r op -1-yl)cycloh exa n e (17c).
Colorless liquid (35% yield): 1H NMR δ 0.90-0.94 (1H, m),
1.13-1.39 (4H, m), 1.52-2.07 (8H, m), 2.54-2.64 (2H, m), 2.88
(1H, dt, J ) 10.4, 4.0 Hz), 7.14-7.29 (5H, m).
tr a n s-2-Ben zyl-cycloh exyla m in e (18a ). Azide 17a (0.488
g, 2.3 mmol) in methanol (50 mL) was subjected to hydrogena-
tion with a hydrogen balloon in the presence of 10% palladium
on carbon. The reaction was carried out at room temperature
overnight. The catalyst was then filtered off, and the solvent
was removed in vacuo. The product was obtained as a white
solid (0.426 g, 99% yield): 1H NMR δ 0.83 (1H, m), 1.00-1.22
(3H, m), 1.38-1.64 (4H, m), 1.89 (1H, m), 2.19 (1H, dd, J )
13.2, 10.0 Hz), 2.46 (1H, dt, J ) 10.1, 3.9 Hz), 3.15 (1H, dd,
J ) 13.2, 3.5 Hz), 3.43 (2H, s), 7.10-7.23 (5H, m).
Similarly prepared were the following compounds:
tr a n s-2-(2-P h en yleth yl)cycloh exyla m in e (18b). White
solid (88% yield): 1H NMR δ 0.9-1.4 (6H, m), 1.5-2.1 (6H,
m), 2.3-2.8 (4H, m), 7.13-7.25 (5H, m); ESMS m/e ) 204
(MH+).
tr a n s-2-(3-P h en ylp r op -1-yl)cycloh exyla m in e (18c). Col-
orless liquid (95% yield): 1H NMR δ 0.8-1.3 (5H, m), 1.5-2.0
(9H, m), 2.3 (1H, m), 2.5-2.7 (2H, m), 7.1-7.3 (5H, m); ESMS
m/e ) 218 (MH+).
3-exo-P r op yl-2-n or bor n a n on e (20a ). Norcamphor (5.00
g, 45.4 mmol) was dissolved in dry THF (17 mL) and added
dropwise to 1 M lithium bis(trimethylsilyl)amide in THF (50
mL, 50 mmol) being cooled by a dry ice-acetone bath. Then
1-iodopropane (4.5 mL, 46.1 mmol) was added dropwise. The
solution was allowed to slowly warm to room temperature and
stirred overnight. Ice water (20 mL) was added. Extraction
with EtOAc (2 × 25 mL) gave a yellow oil (13.50 g). It was
dissolved in chloroform and purified via flash chromatography
over silica gel (390 g) eluting with EtOAc/hexane (1:20) to
afford a colorless oil (5.18 g, 75% yield): 1H NMR δ 0.88 (t,
3H), 1.10-1.90 (11H, m), 2.40 (1H, m), 2.50 (1H, m).
tr a n s-2-(2-P h en yleth yl)cycloh exa n ol (15b). Yellow liq-
uid (55% yield): 1H NMR δ 0.96-1.43 (6H, m), 1.65-1.76 (2H,
m), 1.92-1.97 (2H, m), 2.05-2.14 (2H, m), 2.54-2.60 (1H, m),
2.75 (1H, dt, J ) 11.0, 2.5 Hz), 3.20 (1H, dt, J ) 9.5, 4.2 Hz),
7.16-7.32 (5H, m).
tr a n s-2-(3-P h en ylp r op -1-yl)cycloh exa n ol (15c). Color-
less liquid (59% yield): 1H NMR δ 0.80-0.95 (1H, m), 1.09-

2-Amino-2-oxazolines as R2 Adrenoceptor Agonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 9 1703
Similarly prepared were the following compounds:
3-exo-Ben zyl-2-n or bor n a n on e (20b). Colorless oil (83%
yield): 1H NMR δ 1.30 (1H, m), 1.40-1.60 (2H, m), 1.75 (2H,
m), 1.89 (1H, m), 2.01 (1H, dt, J ) 11.6, 3.7 Hz), 2.38 (2H, m),
2.58 (1H, m), 2.96 (1H, dd, J ) 14.0, 4.2 Hz), 7.14-7.30 (5H,
m).
then concentrated. The residue was dissolved in chloroform
and purified via flash chromatography over silica gel (70 g)
eluting with EtOAc/MeOH/triethylamine (20:1:1) to afford a
colorless oil (723 mg, 85% yield): 1H NMR δ 0.88 (3H, t, J )
7.0 Hz), 0.90-1.55 (11H, m), 1.66 (2H, br), 1.94 (2H, m), 2.87
(1H, d, J ) 7.8 Hz).
Similarly prepared were the following compounds:
2-exo-Am in o-3-exo-ben zyln or bor n a n e (23b). White solid
(96% yield): 1H NMR (CD3OD) δ 0.95-1.25 (3H, m), 1.39 (1H,
m), 1.54 (1H, m), 1.74 (1H, m), 1.92 (1H, m), 2.00 (1H, m),
2.13 (1H, m), 2.30 (1H, m), 2.76 (1H, dd, J ) 13.4, 4.5 Hz),
3.08 (1H, d, J ) 7.8 Hz), 7.10-7.26 (5H, m).
2-exo-Am in o-3-exo-(3-ph en ylpr op-1-yl)n or bor n an e (23c).
Colorless oil (101% yield): 1H NMR δ 0.95-2.00 (15H, m), 2.59
(2H, m), 2.89 (1H, d, J ) 7.6 Hz), 7.15 (3H, m), 7.23 (2H, m).
2-exo-Am in o-3-exo-(3-p h e n yl-2-p r op e n -1-yl)n or b or -
n a n e (23d ). Used without purification for the preparation
of 10.
3-exo-(3-P h en ylp r op -1-yl)-2-n or bor n a n on e (20c). Color-
less oil (28% yield): 1H NMR δ 1.20-1.80 (11H, m), 2.38 (1H,
m), 2.50 (1H, m), 2.58 (2H, m), 7.15 (3H, m), 7.23 (2H, m).
t r a n s-3-exo-(3-P h e n y l-2-p r o p e n -1-y l)-2-n o r b o r n a -
n on e (20d ). Yellow oil (41% yield): 1H NMR δ 1.40-1.62 (3H,
m), 1.78-1.89 (4H, m), 2.01-2.12 (1H, m), 2.46-2.56 (3H, m),
6.16 (1H, ddd, J ) 15.8, 8.2, 6.0 Hz), 6.38 (1H, d, J ) 15.9
Hz), 7.16-7.34 (5H, m).
3-exo-P r opyl-2-en do-n or bor n an ol (21a). Ketone 20a (4.91
g, 32.3 mmol) was dissolved in dry THF (45 mL), cooled by an
ice water bath, and treated with lithium aluminum hydride
(1.10 g, 29.0 mmol). The mixture was stirred at room temper-
ature for 4 h before sodium sulfate decahydrate (4.7 g, 14.6
mmol) was slowly added. Filtration of the mixture followed
by concentration of the filtrate gave a colorless oil (2.69 g).
The filtered solid was treated with MeOH to give more
colorless oil (1.45 g). Each oil was dissolved in carbon tetra-
chloride and purified via flash chromatography over silica gel
eluting with EtOAc/hexane (1:10) to afford a colorless oil (2.94
g, 59% yield): 1H NMR δ 0.88 (3H, t), 0.93 (1H, m), 1.10-1.60
(10H, m), 1.75 (1H, m), 1.87 (1H, m), 2.20 (1H, m), 3.66
(1H, m).
Ack n ow led gm en t. The authors thank Vincent J or-
gensen and Raisa Nagorny for performing binding and
functional assays, and Anastasia Kokkinakis for work
on cell cultures and membrane preparation.
Su p p or tin g In for m a tion Ava ila ble: Elemental analysis.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Similarly prepared were the following compounds:
3-exo-Ben zyl-2-en do-n or bor n an ol (21b). White solid (64%
yield): mp 71-73 °C; 1H NMR δ 1.20-1.60 (7H, m), 1.78 (1H,
m), 1.94 (1H, m), 2.24 (1H, m), 2.57 (2H, d), 3.78 (1H, m), 7.10-
7.30 (5H, m).
3-exo-(3-P h en ylp r op -1-yl)-2-en d o-n or b or n a n ol (21c).
Colorless oil (84% yield): 1H NMR δ 0.90-1.90 (12H, m), 2.20
(1H, m), 2.59 (2H, t, J ) 7.7 Hz), 3.66 (1H, m), 3.72 (1H, m),
7.15 (3H, m), 7.23 (2H, m).
tr a n s-3-exo-(3-P h en yl-2-p r op en -1-yl)-2-en d o-n or b or -
n a n ol (21d ). Colorless oil (57% yield): 1H NMR δ 1.12-1.60
(7H, m), 1.79 (1H, m), 1.97 (1H, m), 2.18 (2H, t, J ) 7.4 Hz),
2.23 (1H, m), 3.76 (1H, m), 6.18 (1H, dt, J ) 15.8, 7.0 Hz),
6.38 (1H, d, J ) 15.7 Hz), 7.14-7.34 (5H, m).
2-exo-Azid o-3-exo-p r op yln or bor n a n e (22a ). Alcohol 21a
(2.00 g, 13.0 mmol) was dissolved in dry THF (27 mL), cooled
by an ice water bath, and treated with triphenylphosphine
(3.77 g, 14.4 mmol), diethyl azodicarboxylate (2.2 mL, 14.0
mmol), and diphenylphosphoryl azide (3.1 mL, 14.4 mmol). The
solution was stirred at room temperature overnight and then
concentrated to give an orange oil. It was dissolved in dichlo-
romethane and purified via flash chromatography over silica
gel (160 g) eluting with EtOAc/hexane (1:50) to afford a
colorless oil (2.22 g, 95% yield): 1H NMR δ 0.88 (3H, t, J )
7.1 Hz), 1.00-1.60 (11H, m), 1.97 (1H, m), 2.29 (1H, m), 3.50
(1H, d, J ) 7.5 Hz).
Similarly prepared were the following compounds:
2-exo-Azid o-3-exo-ben zyln or bor n a n e (22b). Colorless oil
(101% yield): 1H NMR δ 1.00-1.20 (3H, m), 1.30-1.70 (3H,
m), 1.96-2.01 (2H, m), 2.37 (2H, dd, J ) 14.2, 10.3 Hz), 2.78
(1H, dd, J ) 14.2, 5.6 Hz), 3.61 (1H, d, J ) 7.2 Hz), 7.10-7.28
(5H, m); ESMS m/e ) 200 (MH+ - N2).
2-exo-Azido-3-exo-(3-ph en ylpr op-1-yl)n or bor n an e (22c).
Colorless oil (91% yield): 1H NMR δ 1.00-1.25 (4H, m), 1.40-
1.70 (7H, m), 1.97 (1H, m), 2.30 (1H, m), 2.59 (2H, m), 3.50
(1H, d, J ) 7.3 Hz), 7.16 (3H, m), 7.25 (2H, m).
tr a n s-2-exo-Azid o-3-exo-(3-p h en yl-2-p r op en -1-yl)-2-n or -
bor n a n e (22d ). Colorless oil (65% yield): 1H NMR δ 1.16 (3H,
m), 1.60 (3H, m), 1.80 (1H, m), 2.10 (2H, m), 2.40 (2H, m),
3.63 (1H, d, J ) 7.6 Hz), 6.22 (1H, ddd, J ) 15.8, 7.8, 6.0 Hz),
6.42 (1H, d, J ) 15.8 Hz), 7.19-7.39 (5H, m).
2-exo-Am in o-3-exo-p r op yln or bor n a n e (23a ). Azide 22a
(1.00 g, 5.58 mmol) was dissolved in EtOAc (10 mL), cooled
by an ice water bath, and treated with 1 M trimethylphosphine
in THF (10 mL, 10 mmol) and water (0.4 mL, 22.22 mmol).
The solution was stirred at room temperature overnight and
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