Synthesis of (+)- and (-)-cis-2-[(1-adamantylamino)-methyl]-1-phenylcyclopropane derivatives as high affinity probes for σ1 and σ2 binding sites

Article abstract of DOI:10.1016/S0014-827X(01)01170-3

Selective ligands for either sigma₁ (σ₁) or σ₂ binding sites are potentially useful for gaining a better understanding of the physiological functions of these proteins. Moreover, potent and selective homochiral σ₁

Full text of DOI:10.1016/S0014-827X(01)01170-3

Il Farmaco 57 (2002) 45–53
www.elsevier.com/locate/farmac
Synthesis of (+)- and (−)-cis-2-[(1-adamantylamino)-
methyl]-1-phenylcyclopropane derivatives as high affinity probes
for s1 and s2 binding sites
Agostino Marrazzo a, Orazio Prezzavento a, Maria S. Pappalardo a, Ennio Bousquet a,
Manuela Iadanza a, Victor W. Pike b, Giuseppe Ronsisvalle a,*
a Department of Pharmaceutical Sciences, Uni6ersity of Catania, Viale Andrea Doria, 6-Citta´ Uni6ersitaria, 95125 Catana, Italy
b Molecular Imaging Branch, National Institute of Mental Health, Building 1, Room B3-10, 1 Center Dri6e, Bethesda, MD 20852-0135, USA
Received 22 June 2001; received in revised form 4 August 2001; accepted 13 August 2001
Abstract
Selective ligands for either sigma1 (s1) or s2 binding sites are potentially useful for gaining a better understanding of the
physiological functions of these proteins. Moreover, potent and selective homochiral s1 and s2 binding site ligands represent leads
to potential radioligands for tumour imaging with positron emission tomography (PET). On the basis of their structural similarity
to previous leads, new (+)- and (−)-cis-2-[(1-adamantylamino)-methyl]-1-phenylcyclopropane derivatives were synthesised and
their binding affinities for s1 and s2 binding sites were determined. Each enantiomer showed high affinity for both s1 and s2
binding sites, but only (−)-cis-methyl-2-{[1-adamantyl(methyl)amino]methyl}-1-phenylcyclopropane-carboxylate, (−)-4, showed
appreciable selectivity for binding to s1 versus s2 sites. The enantiomers of cis-(2-{[1-adamantyl(methyl)amino]methyl}-1-phenyl-
cyclopropyl)methanol, 6, expressed the highest affinity for s1 and s2 binding sites. Ligands (−)-4, (+)-6 and (−)-6 might be
rapidly labelled in their N-methyl groups by methylation of the N-desmethyl analogues with [11C]iodomethane to provide
prospective radioligands for PET. The N-desmethyl analogues, which are also high affinity ligands, were prepared and shown to
undergo satisfactory methylation with iodomethane. © 2002 Elsevier Science S.A. All rights reserved.
Keywords: Sigma; Receptors; Ligands; Stereoselectivity; PET
1. Introduction
has a specific distribution in the CNS but at a higher
concentration than the s1 subtype. However, it has a
molecular weight of 18–21 kDa and low affinity for the
aforementioned dextro cis-normetazocine derivatives.
s binding sites are also present in the peripheral
tissues [6]. Recently, the 223 amino acid s1 protein
(Fig. 1) has been purified and cloned from several
animal species and humans [7,8]. This shows no anal-
ogy with other mammalian protein but a homology
sequence with a fungal D-8,7-sterol-isomerase. The
high density of s1 sites in steroid-producing tissues and
CNS provides evidence for their involvement in neu-
roendocrine functions, such as the synthesis and
metabolism of neuroactive steroids [9]. Several other
physiological functions have been reported for s1 sites,
such as modulation of synthesis and release of the
Since the first reports [1,2] on sigma (s) binding sites,
steady progress has been made for their biochemical,
physiological and pharmacological characterisation. At
least two subtypes of s binding site have been identified
through their different pharmacology, anatomical dis-
tributions and molecular weights [3–5].
The s1 subtype, with a specific distribution in the
central nervous system (CNS) and a molecular weight
of 25 kDa, shows high affinity for the dextro-isomers of
cis-normetazocine derivatives, (+)-pentazocine, (+)-
SKF-10,047 and (+)-cyclazocine. The s2 subtype also
* Corresponding author.
E-mail address: ggrmedch@mbox.unict.it (G. Ronsisvalle).
0014-827X/02/$ - see front matter © 2002 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(01)01170-3

46
A. Marrazzo et al. / Il Farmaco 57 (2002) 45–53
Fig. 1. Amino acid sequence of the human s1 receptor showing the amino acid residues (shaded) in the putative transmembrane domain critical
for ligand binding [25].
neurotransmitters, acetylcholine and dopamine [10,11],
neuromodulatory effects on glutamatergic NMDA-type
[12] and opioid systems [13], attenuation of the cocaine-
induced effect [14] and antiamnesic effects [15]. At
present, the molecular mechanism involved in these
effects is not clear but a recent study shows that
modulation of Ca2+ level by s1 receptor–ankirin–
1,4,5-trisphosphate receptor complex is a possible mode
of action [16].
The protein corresponding to s2 sites has not yet
been cloned and this explains a relative paucity of
information. Nevertheless, its anatomical distribution
in the CNS and the typical extrapyramidal side effects
induced by neuroleptic drugs, such as haloperidol,
provide evidence that s2 receptors are involved in
motor control behaviour [17]. Morphology changes or
apoptotic cell death upon chronic exposure to selective
s2 ligands such as CB-64, ibogaine or treatment with
neuroleptic such as haloperidol seem to be responsible
for irreversible motor disorders and typical dyskinesia.
Distonic effects induced by reduced haloperidol (a
metabolite that has been shown to accumulate in the
brain of patients taking haloperidol) might relate to
citotoxicity of this compound in brain areas with high
density of s2 receptors and controlling motor be-
haviour [18]. The very high concentration of s2 sites in
different tumour cell lines, such as breast, lung, prostate
and melanoma, and apoptotic-type cytotoxicicty sug-
gest an important role in cell proliferation and viability
[19].
binding sites may provide potential drugs for psychosis,
neuroprotection, motor control and cancer treatment,
or tumour imaging agents for non-invasive diagnosis or
clinical research in oncology. Besides normetazocine
derivatives, many classes of compound [20] such as the
neuroleptic agents, perphenazine, haloperidol ana-
logues, U50-488 derivatives, guanidines and others,
bind both s sites.
Recently, we have investigated the design and synthe-
sis of selective s1 and s2 binding site ligands. In
particular, we have focused our attention on examining
structure–affinity relationships in a new series of (9)-
cis-2-[(1-adamantylamino)-methyl]-1-phenylcyclopro-
pane derivatives [21] that are structurally related to
(+)-MPCB (Fig. 2). Here we report that the substitu-
tion of the (+)-cis-N-normetazocine nucleus of (+)-
MPCB with 1-adamantanamine or N-methylada-
mantanamine provides ligands with high affinity for s
sites and high selectivity versus binding to opioid and
dopamine-2 (D2) receptors (Table 1). These data also
show that substitution of the adamantanamine moiety
Thus, considering the biochemical and physiological
processes in which s receptors are involved, the synthe-
sis and discovery of selective ligands for s1 and s2
Fig. 2. Structures of the (+)-MPCB and adamantanamine deriva-
tives.

A. Marrazzo et al. / Il Farmaco 57 (2002) 45–53
47
Table 1
Binding affinities [Ki9SEM (nM)] of (+)-MPCB and compounds 3–5
(as in (9)-3) by an N-methyladamantanamine moiety
(as in (9)-4) or reduction of the carboxymethyl ester
(as in (9)-3 or (9)-4) to a hydroxymethyl group (as in
(9)-5 and (9)-6, respectively) gives a substantial im-
provement in binding affinity to s2 sites. Here we also
describe the synthesis of the enantiomers of each of the
new cis-2-[(1-adamantylamino)-methyl]-1-phenylcyclo-
propane derivatives and report their affinities for bind-
ing to s1 and s2 sites.
Considering that s2 binding sites may represent po-
tential biomarkers of proliferation in solid tumours,
radioligands with high affinity and selectivity for s2
receptors may represent useful probes for non-invasive
tumour imaging [22–24]. None of the reported com-
pounds show high selectivity or for binding to s2 sites;
nor do the compounds show enantioselectivity for bind-
ing to this site. However, compound (−)-4, is identified
as having high affinity and selectivity for s1 sites, and is
suitable for labelling with carbon-11 as a prospective
homochiral radioligand for PET. Similarly, compound
6 may be a useful lead to non-subtype selective s
binding site radioligands.
cis-3–5 and of the enantiomers of 3 were reported
previously [21]. In order to obtain the new cis-enan-
tiomers of compounds 4–6, we synthesised the lactones
(+)-1 and (−)-1 starting from phenylacetonitrile and
(S)- or (R)-epichlorohydrin, respectively, as reported by
Shuto et al. [27].
The treatment of lactone 1 and its enantiomers with
HBr–AcOH (33%) and the subsequent esterification of
the bromoacid derivatives with SOCl2 and methanol–
3N HCl provided the respective intermediate 2 (Scheme
1).
Nucleophilic substitution of 1-adamantanamine with
methyl 2-(bromomethyl)-1-phenylcyclopropanecarboxy-
late 2 gave derivatives 3 that were reduced with
EtN(Me)2AlH3 to the new cis-enantiomers 5. The final
N-methylated compounds, 4 and 6, were obtained by
treatment of the respective amines 3 and 5 with
iodomethane in DMF.
3. Results and discussion
Compounds with high affinity and selectivity for s
receptors are useful probes for a better comprehension
of their biochemical and physiological role. PET is a
uniquely sensitive and quantitative technique for imag-
ing cancerous cells as solid tumours or metastases with
molecules labelled with positron-emitting oxygen-15,
carbon-11 or fluorine-18, that target metabolic
2. Chemistry
The final compound in the synthetic path, racemic
cis-6, was obtained from racemic lactone 1, prepared as
reported in the literature [26]. The syntheses of racemic

48
A. Marrazzo et al. / Il Farmaco 57 (2002) 45–53
processes (e.g. glucose utilisation) or over-expressed
protein (e.g. receptors, binding sites) [28]. In view of
the over-expression of s receptors in many tumour cell
lines, suitably radiolabelled s ligands may be useful for
PET as tumour imaging agents or for clinical research
in oncology.
2) showed that N-methylation generally enhanced
affinity for s1 binding sites (as in the enantiomers of 4
and 6), but either reduced (as in the enantiomers of 4)
or slightly increased affinity (as in the enantiomers of
6) for s2 sites. Reduction of the carboxymethyl ester to
a hydroxymethyl group (as in the enantiomers of 5 and
6) improved affinity for s2 sites, while affinity for s1
sites was either increased significantly (as in the dextro
enantiomers of 5 and 6) or little affected (as in the levo
enantiomers of 5 and 6). Previously it was found that
the levo-isomers generally showed a preference for s1
in respect to s2 [21]. Here, only the enantiomers of 6
lacked enantioselectivity for binding to s subtypes.
Compounds 4–6 all display improved binding affinity
for s sites in respect to the enantiomers of 3. However,
only the levo isomer of 4 showed selectivity in binding
to one subtype, the s2 subtype (s2/s1=24).
Thus, considering the binding data obtained, we fur-
ther supported the importance of the substitution of
(+)-cis-N-normetazocine nucleus with 1-adaman-
tanamine or N-methyl-1-adamantanamine in order to
obtain compounds with very high affinity for s1 and
s2 receptors. Moreover, it seems that control of stereo-
chemistry of substituents on the cyclopropyl ring might
improve binding selectivity for either s1 or s2 recep-
tors, but to obtain highly selective s1 and s2 ligands
additional structural modifications will be necessary.
In conclusion, considering the potential PET radioli-
gand 6, both enantiomers showed a very high affinity
for s1 and s2 receptors. Hence, each enantiomer of 6
Recently, in our laboratory we have synthesised a
series of cis-2-[(1-adamantylamino)-methyl]-1-phenylcy-
clopropane derivatives that show high affinity and se-
lectivity for s sites in respect to opioid and dopamine
D2 receptors [21]. In particular, racemic compounds 4
and 5 showed an improved affinity for s2 sites in
respect
to
(9)-cis-methyl-2-[(1-adamantylamino)-
methyl]-1-phenylcyclopropanecarboxylate 3. A PET ra-
dioligand must have a very high affinity (Kd in
nanomolar range), high selectivity, low or moderate
lipophilicity (to avoid high non-specific binding) and
stereoselectivity where enantiomers exist [29]. Among
all the cis-2-[(1-adamantylamino)-methyl]-1-phenylcy-
clopropane derivatives reported previously, a possible
candidate for development as a PET radioligand is the
adamantylamino compound 5 (Table 1), for example,
as either an O-11C-methyl or N-11C-methylated form.
In this study we report a new synthetic strategy in
order to obtain the enantiomers of 4 and 5. We also
synthesised the N-methylated compound 6 and its ena-
tiomers with the aim to test the binding affinity for s
receptors and verify if N-methylation of 5 with
iodomethane occurs in acceptable yield.
Binding data obtained for these compounds (Table
Scheme 1. (a) HBr–AcOH (33%), 80 °C, 2 h; (b) benzene, SOCl2, MeOH–3 N HCl, 5 h; (c) DMF, NaHCO3, 70 °C, 6 h; (d) EtN(Me)2AlH3,
THF an., 2.5 h; (e) MeI, DMF, NaHCO3, 80 °C, 2 h.

A. Marrazzo et al. / Il Farmaco 57 (2002) 45–53
49
Table 2
s1 and s2 binding affinities [Ki9SEM (nM)]
will be labelled by N-11C-methylation of the corre-
sponding enantiomer of 5. 11C-Methylations of amines
with [11C]iodomethane are very common reactions
for preparing PET radioligands [29], and we have
shown here that compounds 3 and 5 are readily
N-methylated by iodomethane. Each labelled enan-
tiomer of 6 will be evaluated as a radioligand for
PET with assessment of any possible differences in
kinetics, biodistribution, metabolism and resultant
brain distribution. Likewise, (−)-4 will be labelled with
carbon-11 and evaluated as prospective s1-selective ra-
dioligand.
4. Experimental
Reagents were purchased from Aldrich Chemicals
Co. Ltd. unless otherwise specified. Melting points were
determined on a Buchi 530 capillary apparatus and
were uncorrected. Analytical thin-layer chromatogra-
phy (TLC) was performed on pre-coated silica gel 60
F254 aluminium sheets (Merck). Visualization was with
accomplished under UV light or in an iodine chamber.
Merck silica gel 60 (230–400 mesh) was used for flash
column chromatography. 1H and 13C NMR spectra
were recorded on a Varian Unity INOVA (200 MHz)

50
A. Marrazzo et al. / Il Farmaco 57 (2002) 45–53
spectrometer with TMS as an internal standard. Optical
rotations were determined in methanol (c=1) with a
Perkin–Elmer 241 polarimeter. Infrared spectra were
recorded on a 1600 FT-IR Perkin–Elmer instrument
and are consistent with the assigned structures. Elemen-
tal analyses were measured with an elemental analyzer
(model 1106, Carlo Erba). Analyses are indicated by
symbols of the elements. Analytical results obtained for
those elements were within 90.4% of the theoretical
values. Molecular weights of the obtained products
were determined by EI MS (70 eV) on a Kratos 2S
RFA spectrometer using a Tektronix 4205 computer
system.
evaluated in the presence of 5 mM DTG. Inhibition
constants (Ki values) for test compounds were calcu-
lated using the EBDA–LIGAND program [34] pur-
chased from Elsevier/Biosoft.
5.3. (9)-Methyl-cis-2-(bromomethyl)-1-phenyl-
cyclopropanecarboxylate ((9)-2)
Compound 1 (1.24 g, 7.11 mmol) was added to a
solution of hydrogen bromide in 33% acetic acid (12
ml) and the resultant mixture was stirred at 80 °C for 2
h. After cooling to 40 °C, the reaction mixture was
poured into an ice-water bath to obtain the (1S,2R)
(1R,2S) - 2 - (bromomethyl) - 1 - phenylcyclopropanecar-
boxylic acid as a white precipitate, which was filtered
and dried in vacuo. [1.66 g, 91%; m.p. 148 °C; IR
5. Radioligand binding assays
1
(KBr): w(CꢀO) 1665; H NMR (CDCl3) l 1.61 (dd, 1H,
J=4.8, 9.0 Hz), 1.88 (dd, 1H, J=4.8, 7.0 Hz), 2.12–
2.22 (m, 1H), 3.72 (dd, 1H, J=10.2, 11.4 Hz), 3.94 (dd,
1H, J=5.6, 11.4 Hz), 5.28 (br s, 1H), 7.29–7.50 (m,
5H)]. Subsequently, SOCl2 (1.24 ml, 16.9 mmol) was
added to a solution of the (1S,2R) (1R,2S)-2-(bro-
momethyl)-1-phenylcyclopropanecarboxylic acid (1.66
g, 6.5 mmol) in anhydrous benzene (8 ml) at 0 °C.
After heating to reflux for 5 h, the reaction was cooled
to 0 °C. A solution of 3N MeOH–HCl (2.76 ml) was
added dropwise and the reaction mixture allowed to stir
overnight at room temperature. The mixture was evap-
orated in vacuo and the residue dissolved in Et2O,
washed with a solution of 4% NaHCO3 and dried over
anhydrous Na2SO4. The solvent was then evaporated in
vacuo to give the desired ester (+)-2 (1.67 g, 88%);
m.p. 53–55 °C; Rf 0.57 (toluene–chloroform, 8:2 v/v);
5.1. |1-Site binding assays
s1-Site binding assays were carried out on guinea pig
brain membranes according to Matsumoto et al. [30].
The protein concentration of the suspension was mea-
sured by the method of Lowry et al. [31] and generally
ranged from 6.5 to 8.5 mg of protein/ml. Binding assays
were performed as described by DeHaven et al. [32].
Each tube contained 500 mg of membrane protein and
was incubated with 3 nM [3H]-(+)-pentazocine (45
Ci/mmol); the value of the apparent dissociation con-
stant (Kd) was 1.290.3 nM (n=3) in 50 mM Tris–
HCl (pH 7.4). Test compounds were dissolved in
dimethyl sulfoxide, and then diluted in buffer to a total
volume of 1 ml. Test compounds were added to give a
concentration in the range 10−5–10−11 M. Non-spe-
cific binding was assessed in the presence of 10 mM
haloperidol. The reaction was performed for 150 min at
37 °C and terminated by filtering the solution through
a Whatman GF/B glass fiber filter which had been
pre-soaked for 1 h in a 0.5% poly(ethylenimine) solu-
tion. Filters were washed twice with 4 ml of ice-cold
buffer.
IR (KBr): w(CꢀO) 1716 cm−1 1H NMR (CDCl3) l
;
1.52 (dd, 1H, J=4.6, 8.5 Hz), 1.78 (dd, 1H, J=4.6, 7.5
Hz), 2.05–2.12 (m, 1H), 3.72 (dd, 1H, J=10.0, 11.2
Hz), 3.80 (s, 3H), 3.89 (dd, 1H, J=5.6, 11.2 Hz),
7.29–7.50 (m, 5H)]. 13C NMR (CDCl3)
l
22.32, 27.54, 38.36, 38.91, 50.51, 118.30, 125.32, 128.65, 1
38.41, 173.61; MS: m/z 269 [M]+; Anal. C12H13BrO2
(C, H).
The following compounds were prepared using the
above procedure.
5.2. |2-Site binding assays
s2-Site binding assays were carried out on guinea pig
brain membranes, prepared as described by Mach et al.
[33]. The membranes were incubated with 3 nM
[3H]DTG [1,3-di-(2-tolyl)-guanidine] (31 Ci/mM; Kd=
9.990.8 nM; n=3) in the presence of 400 nM (+)-
SKF10,047 to block s1 sites. Incubation was carried
out in 50 mM Tris–HCl (pH 8.0) for 120 min at room
temperature (r.t.). Each assay was terminated by the
addition of ice-cold 10 mM Tris–HCl pH 8.0, followed
by filtration through a Whatman GF/B glass fiber filter
which had been pre-soaked for 1 h in a 0.5%
poly(ethylenimine) solution. Filters were washed twice
with 4 ml of ice-cold buffer. Non-specific binding was
5.4. (−)-(1R,2S)-Methyl 2-(bromomethyl)-1-phenyl-
cyclopropanecarboxylate ((−)-2)
(1.61 g, 85%); m.p. 53–55 °C; [h]D20 −36°; Rf 0.57
(toluene–chloroform, 4:1, v/v); IR (KBr): w(CꢀO) 1716
cm−1; MS: m/z 269 [M]+. Anal. C12H13BrO2 (C, H).
5.5. (+)-(1R,2S)-Methyl-2-(bromomethyl)-1-phenyl-
cyclopropanecarboxylate ((+)-2)
(1.65 g, 87%); m.p. 53–55 °C; [h]D20 +37,6°; Rf 0.57
(toluene–chloroform, 8:2 v/v); IR (KBr): w(CꢀO) 1716
cm−1; MS: m/z 269 [M]+; Anal. C12H13BrO2 (C, H).

A. Marrazzo et al. / Il Farmaco 57 (2002) 45–53
51
5.6. (9)-cis-Methyl-2-[(1-adamantylamino)methyl]-1-
phenylcyclopropanecarboxylate ((9)-3)
5.9. (−)-cis-Methyl-2-{[1-adamantyl(methyl)amino]-
methyl}-1-phenylcyclopropanecarboxylate ((−)-4)
NaHCO3 (168 mg, 2 mmol) and compound 2 (150
mg, 0.66 mmol) were added to a solution of 1-adaman-
tanamine (184 mg, 1,22 mmol) in DMF (7 ml). The
reaction mixture was stirred at 70 °C for 8 h. The
solvent was evaporated under reduced pressure and the
residue was dissolved in CHCl3 and washed with a
solution of 4% NaHCO3. The mixture was dried over
anhydrous Na2SO4, evaporated in vacuo and the crude
product was purified by flash chromatography eluting
with CHCl3–cyclohexane–EtOH (6:4.5:0.5, by vol.).
Compound 3 was then dissolved in THF and treated
with a solution of oxalic acid in THF to give the salt as
a white solid. The analytically pure sample was ob-
tained by recrystallization from methanol–diethyl
ether.
Iodomethane (0.05 ml, 0.792 mmol) was added to a
mixture of NaHCO3 (84 mg, 1 mmol) and compound
(−)-3 (150 mg, 0.66 mmol) in DMF (6 ml). The
reaction vessel was sealed and heated at 80 °C for 2 h.
After recovering of reaction mixture, the solvent was
evaporated under reduced pressure and the residue was
dissolved in CHCl3 and washed with brine. The mixture
was dried over anhydrous Na2SO4, evaporated in vacuo
and the crude product was purified by flash chromatog-
raphy
eluting
with
CHCl3–cyclohexane–EtOH
(6:4.5:0.2, by vol.). Compound 4 was then dissolved in
THF and treated with a solution of HCl in (C2H5)2O to
give the respective salt. The pure sample was obtained
by recrystallization from methanol–diethyl ether.
1
(Yield: 62%); m.p. 180–182 °C; [h]D20 −54°; H NMR
1
(Yield: 15%); m.p. 248–250 °C; H NMR (DMSO-
(DMSO-d6) l 1.51 (dd, 1H, J=4.1, 8.8 Hz), 1.60–1.78
(m, 7H), 1.82–2.23 (m, 10H), 2.75 (s, 3H), 3.25–3.50
(m, 2H), 3.58 (s, 3H), 5.40 (br s, 2H), 7.22–7.45 (m,
d6) l 1.48 (dd, 1H, J=4.0, 9.2 Hz), 1.51–198 (m, 14H),
2.05–2.20 (m, 4H), 3.12 (dd, 1H, J=7.5, 12.6 Hz), 3.50
(dd, 1H, J=5.5, 12.6 Hz), 3.60 (s, 3H), 4.80 (br s, 2H),
5H); 13C NMR (DMSO-d6)
l 20.65, 23.75, 28.92,
7.20–7.45 (m, 5H); 13C NMR (DMSO-d6)
l
32.38, 34.10, 35.07, 35.52, 46.81, 52.62, 62.97, 127.31, 128
.19, 130.07, 139.31, 164.63, 172.04; MS: m/z 353 [M]+;
Anal. C23H31NO2·HCl (C, H, N).
Enantiomer (+)-4 was prepared using the above
procedure.
19.85, 23.31, 28.35, 34.22, 35.88, 38.08, 46.25, 52.98, 61.0
1, 127.41, 128.61, 130.80, 139.35, 165.50, 172.19;
MS:
m/z 339 [M]+; Anal. C22H29NO2·0.5H2C2O4·1.5H2O (C,
H, N).
Enantiomers (−)-3 and (+)-3 were prepared using
the above procedure.
5.10. (+)-cis-Methyl-2-{[1-adamantyl(methyl)amino]-
methyl}-1-phenylcyclopropanecarboxylate ((+)-4)
5.7. (−)-(1S,2R)-Methyl-2-[(1-adamantylamino)-me-
thyl]-1-phenylcyclopropanecarboxylate ((−)-3)
(Yield: 61%); m.p. 183–186 °C; [h]D20 +56°; 1H
NMR (DMSO-d6) l 1.53 (dd, 1H, J=4.1, 8.8 Hz),
1.62–1.80 (m, 7H), 1.83–2.25 (m, 10H), 2.78 (s, 3H),
3.27–3.53 (m, 2H), 3.60 (s, 3H), 6.50 (br s, 2H), 7.24–
(Yield: 22%); m.p. 248–250 °C; [h]D20 −50°; 1H
NMR (DMSO-d6) l 1.45 (dd, 1H, J=4.0, 9.1 Hz),
1.50–2.00 (m, 14H), 2.08–2.25 (m, 4H), 3.14 (dd, 1H,
J=7.2, 12.1 Hz), 3.53 (dd, 1H, J=5.4, 12.1 Hz), 3.61
(s, 3H), 5.5 (br s, 2H), 7.27–7.45 (m, 5H); 13C NMR
7.47
(m,
5H);
13C
NMR
(DMSO-d6)
l
20.66, 23.77, 28.94, 32.39, 34.14, 35.10, 35.54, 46.83, 52.6
4, 62.99, 127.34, 128.21, 130.10, 139.33, 164.65, 172.05;
MS: m/z 353 [M]+; Anal. C23H31NO2·HCl (C, H, N).
(DMSO-d6)
20.58, 23.31, 27.98, 34.50, 35.66, 38.40, 45.91, 51.02, 60.9
l
2, 126.33, 128.03, 131.00, 139.02, 166.48, 172.20;
MS:
5.11. (9)-cis-{2-[(1-Adamantylamino)methyl]-1-phe-
nylcyclopropyl}methanol ((9)-5)
m/z 339 [M]+; Anal. C22H29NO2·0.6H2C2O4 (C, H, N).
5.8. (+)-(1R,2S)-Methyl-2-[(1-adamantylamino)-me-
thyl]-1-phenylcyclopropanecarboxylate ((+)-3)
A solution of compound (9)-3 (1 g, 2.95 mmol) in
anhydrous THF (10 ml) was added dropwise to a 0.5 M
solution of alane-N,N-dimethylethylamine complex (6
ml, 3 mmol) in anhydrous THF (10 ml) at 0 °C under
a nitrogen atmosphere. The reaction mixture was
stirred for 2.5 h and quenched with a water–THF (1:1
v/v) solution to give a white precipitate. The mixture
was dissolved in 1N NaOH and extracted with Et2O
(3×30 ml); the organic extracts were dried with anhy-
drous Na2SO4 and concentrated under reduced pres-
sure. The crude product was purified by flash
chromatography eluting with cyclohexane–ethyl acetate
(1:1 v/v) to afford compound (9)-5.
(Yield: 18%); m.p. 105–112 °C; [h]D20 +49°; 1H
NMR (DMSO-d6) l 1.47 (dd, 1H, J=4.1, 9.1 Hz),
1.50–2.00 (m, 14H), 2.08–2.25 (m, 4H), 3.14 (dd, 1H,
J=7.2, 12.1 Hz), 3.50 (dd, 1H, J=5.4, 12.1 Hz), 3.59
(s, 3H), 6.2 (br s, 2H), 7.28–7.50 (m, 5H); 13C NMR
(DMSO-d6)
l
19.98, 23.10, 28.01, 33.98, 35.00, 39.65, 46.00, 51.32, 61.2
2, 126.15, 128.32, 131.50, 139.10, 165.98, 172.50; MS:
m/z 339 [M]+. Anal. C22H29NO2·0.7H2C2O4·2H2O (C,
H, N).

52
A. Marrazzo et al. / Il Farmaco 57 (2002) 45–53
1
(Yield: 76%); m.p. 280–283 °C; H NMR (DMSO-
5.15. (−)-cis-(2-{[1-Adamantyl(methyl)amino]-
methyl}-1-phenylcyclopropyl)methanol ((−)-6)
d6) l 1.05 (dd, 1H, J=5.0, 8.6 Hz), 1.11 (dd, 1H,
J=5.5, 8.6 Hz), 1.46 (m, 1H) 1.58 (m, 6H), 1.87 (m,
6H), 2.14 (m, 3H), 3.11 (dd, 1H, J=6.4, 12.2 Hz), 3.29
(dd, 1H, J=5.1, 12.2 Hz), 3.53 (d, 1H, J=11.6 Hz),
4.10 (d, 1H, J=11.6 Hz) 5.60 (br s, 3H), 7.15–7.45 (m,
5H); 13C NMR (DMSO-d6) l 17.51, 20.28, 28.42, 31.72,
35.21, 37.79, 40.12, 55.94, 64.74, 126.29, 128.01, 128.72, 1
43.93; MS: m/z 311 [M]+; Anal. C21H29NO2·HCl (C, H,
N).
(Yield: 75%); m.p. 282–283 °C; [h]D20 −70°; 1H
NMR (DMSO-d6) l 1.10 (dd, 1H, J=5.0, 8.3 Hz), 1.14
(dd, 1H, J=5.5, 8.3 Hz), 1.48 (m, 1H) 1.61 (m, 6H),
1.92 (m, 6H), 2.15 (m, 3H), 2.78 (s, 3H), 3.42 (dd, 1H,
J=4.4, 12.8 Hz), 3.48 (dd, 1H, J=7.1, 12.8 Hz), 3.72
(d, 1H, J=11.5 Hz), 4.10 (d, 1H, J=11.5 Hz), 5.60 (br
s, 3H), 7.13–7.43 (m, 5H), 7.60 (br s, 3H); 13C NMR
Enantiomers (−)-5 and (+)-5 were prepared using
the above procedure.
(DMSO-d6)
l
18.36, 19.57, 28.87, 32.09, 35.04, 35.43, 48.63, 63.21, 64.9
0, 126.17, 127.99, 128.42, 143.91; MS: m/z 325 [M]+;
Anal. C21H29NO2·HCl (C, H, N).
5.12. (−)-cis-{2-[(1-Adamantylamino)methyl]-1-phenyl-
cyclopropyl}methanol ((−)-5)
5.16. (+)-cis-(2-{[1-Adamantyl(methyl)amino]-methyl}-
1-phenylcyclopropyl)methanol ((+)-6)
(Yield: 76%); m.p. 282–283 °C; [h]D20 −48°; 1H
NMR (DMSO-d6) l 1.05 (dd, 1H, J=5.0, 8.6 Hz), 1.11
(dd, 1H, J=5.5, 8.6 Hz), 1.46 (m, 1H) 1.58 (m, 6H),
1.87 (m, 6H), 2.14 (m, 3H), 3.11 (dd, 1H, J=6.4, 12.2
Hz), 3.29 (dd, 1H, J=5.1, 12.2 Hz), 3.53 (d, 1H,
J=11.6 Hz), 4.10 (d, 1H, J=11.6 Hz) 5.60 (br s, 3H),
(Yield: 75%); m.p. 282–283 °C; [h]D20 +70°; 1H
NMR (DMSO-d6) l 1.10 (dd, 1H, J=5.0, 8.3 Hz), 1.14
(dd, 1H, J=5.5, 8.3 Hz), 1.48 (m, 1H) 1.61 (m, 6H),
1.92 (m, 6H), 2.15 (m, 3H), 2.78 (s, 3H), 3.42 (dd, 1H,
J=4.4, 12.8 Hz), 3.48 (dd, 1H, J=7.1, 12.8 Hz), 3.72
(d, 1H, J=11.5 Hz), 4.10 (d, 1H, J=11.5 Hz) 6.60 (br
s, 3H), 7.13–7.43 (m, 5H); 13C NMR (DMSO-d6) l
18.34, 19.57, 28.87, 32.09, 35.03, 35.41, 48.63, 63.21, 64.9
0, 126.17, 127.99, 128.42, 143.91; MS: m/z 325 [M]+;
Anal. C21H29NO2·HCl·0.2H2O (C, H, N).
7.15–7.45 (m, 5H); 13C NMR (DMSO-d6)
l
17.51, 20.28, 28.42, 31.72, 35.21, 37.79, 40.12, 55.94, 64.7
4, 126.29, 128.01, 128.72, 143.93; MS: m/z 311 [M]+;
Anal. C21H29NO2·HCl·0.2H2O (C, H, N).
5.13. (+)-cis-{2-[(1-Adamantylamino)methyl]-1-phe-
nylcyclopropyl}methanol ((+)-5)
(Yield: 76%); m.p. 282–283 °C; [h]D20 +46°; 1H
NMR (DMSO-d6) l 1.05 (dd, 1H, J=5.0, 8.6 Hz), 1.11
(dd, 1H, J=5.5, 8.6 Hz), 1.46 (m, 1H) 1.58 (m, 6H),
1.87 (m, 6H), 2.14 (m, 3H), 3.11 (dd, 1H, J=6.4, 12.2
Hz), 3.29 (dd, 1H, J=5.1, 12.2 Hz), 3.53 (d, 1H,
J=11.6 Hz), 4.10 (d, 1H, J=11.6 Hz) 5.60 (br s, 3H),
Acknowledgements
We are grateful to ChiRex and Dr Ian Walker for
their gift of R- and S- epichlorohydrins. We thank
Italian MURST for financial support. The authors
would also like to thank Dr Salvatore Di Marco for the
elemental analyses.
7.15–7.45 (m, 5H); 13C NMR (DMSO-d6)
l
17.51, 20.28, 28.42, 31.72, 35.21, 37.79, 40.12, 55.94, 64.7
4, 126.29, 128.01, 128.72, 143.93; MS: m/z 311 [M]+;
Anal. C21H29NO2·HCl (C, H, N).
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