Structure-affinity studies for a novel series of homochiral naphtho and tetrahydronaphtho analogues of α1 antagonist WB-4101

Article abstract of DOI:10.1016/j.bmc.2004.06.040

A number of enantiomeric pairs of naphthodioxane, tetrahydronaphthodioxane and naphthoxy analogues of WB-4101 (1) were designed and synthesized in order to improve the selectivity profile of the parent compound, hopefully in favour of the α_1a-AR with respect to the other two α₁ subtypes and the 5-HT_1A receptor. The new compounds 2-8 and, in addition, the two enantiomers of 1 were tested in binding assays on the α_1a-AR, α_1b-AR, α_1d-AR, and the 5-HT_1A receptor. Two of them, namely the naphtho- and tetrahydronaphthodioxane derivatives (S)-2 and (S)-3, showed lower, but significantly more specific α_1a affinity than (S)-1, while the two enantiomers of the 2-methoxy-1-naphthoxy analogue 6 maintained most of the very high α_1a affinity of (S)-1 and its α_1a versus α_1b selectivity slightly increasing the α_1a/α_1d and α_1a/5HT _1A affinity ratios. The SAR data were evaluated in the light of known α₁ subtype pharmacophores and of the α_1a-AR binding mode of WB-4101 resultant from literature mutagenesis studies disclosing some interesting consonances with these models.

Full text of DOI:10.1016/j.bmc.2004.06.040

Bioorganic & Medicinal Chemistry 12 (2004) 4937–4951
Structure–affinity studies for a novel series of homochiral
naphtho and tetrahydronaphtho analogues of a1 antagonist
WB-4101
Cristiano Bolchi,a Paolo Catalano,b Laura Fumagalli,a Marco Gobbi,b Marco Pallavicini,a
Alessandro Pedretti,a Luigi Villa,a Giulio Vistolia and Ermanno Valotia,*
a
´
Istituto di Chimica Farmaceutica e Tossicologica, Universita degli Studi di Milano, viale Abruzzi 42, I-20131 Milano, Italy
bIstituto di Ricerche Farmacologiche ÔMario NegriÕ, via Eritrea 62, I-20157 Milano, Italy
Received 30 April 2004; accepted 28 June 2004
Available online 31 July 2004
Abstract—A number of enantiomeric pairs of naphthodioxane, tetrahydronaphthodioxane and naphthoxy analogues of WB-4101
(1) were designed and synthesized in order to improve the selectivity profile of the parent compound, hopefully in favour of the
a1a-AR with respect to the other two a1 subtypes and the 5-HT1A receptor. The new compounds 2–8 and, in addition, the two
enantiomers of 1 were tested in binding assays on the a1a-AR, a1b-AR, a1d-AR, and the 5-HT1A receptor. Two of them, namely
the naphtho- and tetrahydronaphthodioxane derivatives (S)-2 and (S)-3, showed lower, but significantly more specific a1a affinity
than (S)-1, while the two enantiomers of the 2-methoxy-1-naphthoxy analogue 6 maintained most of the very high a1a affinity of
(S)-1 and its a1a versus a1b selectivity slightly increasing the a1a/a1d and a1a/5HT1A affinity ratios. The SAR data were evaluated
in the light of known a1 subtype pharmacophores and of the a1a-AR binding mode of WB-4101 resultant from literature mutagen-
esis studies disclosing some interesting consonances with these models.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
nonsubtype-selective, such as Terazosin, Doxazosin,
Tamsulosin and Alfuzosin.6–8
To date, a1-adrenergic receptors (a1-ARs), which are
members of the G protein-coupled receptor family, are
classified into a1A, a1B and a1D subtypes and the corre-
sponding cloned counterparts a1a, a1b and a1d.1,2 The
design of agents selective for each of these three receptor
subtypes has become an attractive challenge for medici-
nal chemists due to the therapeutic potential of selective
a1A and a1D antagonists in the treatment of some uro-
logic disorders.3 Indeed, relatively recent evidences indi-
cate that a1A- and a1D-ARs, respectively, predominant
in human prostate4 and bladder,3,5 play a role in lower
urinary tract symptoms (LUTS), which have been previ-
ously demonstrated to be relieved by a1 antagonists,
A variety of structurally unrelated compounds interacts
with a1-AR subtypes, which makes it difficult to deter-
mine the structural requisites leading to receptor sub-
type selectivity. Historically, the first a1 antagonist to
be identified was WB-4101 (1),9 a 2-aminomethyl-1,4-
benzodioxane derivative, which was later found to be
slightly selective for a1A- and, to a minor degree, for
a1D-ARs with respect to a1B-AR and 5-HT1A serotonin-
ergic receptor.7,10 Over the past decades, many investi-
gations11–21 have been devoted to improving both
affinity and selectivity of this prototype of a1 antagonists
and our researches22–24 have also contributed to get an
insight into some determinants of its binding capacity
through the study of several homochiral analogues.
OMe
+
O
O
O
Keywords: a1-Antagonist; WB-4101; WB-4101 analogues; a1-Adren-
ergic receptor subtypes; 5-HT1A serotoninergic receptor;
Binding affinity.
*
N
H
H
MeO
Cl-
*
Corresponding author. Tel.: +39-2-50317553; fax: +39-2-
50317565; e-mail: ermanno.valoti@unimi.it
1 (WB 4101)
0968-0896/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.06.040

4938
C. Bolchi et al. / Bioorg. Med. Chem. 12 (2004) 4937–4951
At present, ligand-based approach to design of subtype
selective a1 antagonists can exploit relatively reliable
pharmacophore models,25–27 generated from a number
of different subtype selective antagonists, and be inte-
grated with docking simulations, using the rhodopsin-
based models of the AR subtypes,28 and with the
knowledge of the a1 antagonist binding site resulting
from mutagenesis studies.29,30 These discoveries have
allowed the interactions of 1 with the a1-ARs to be mod-
elled opening new prospects to the rational design of
benzodioxane analogues with an improved pharmaco-
logical profile.
Perez mutagenesis studies, in conferring a1a selectivity
and high a1 affinity.29,30
It is common knowledge that aromaticity/hydrophobic-
ity is more important in antagonist than in agonist bind-
ing: a1 agonists generally have one aromatic ring and
hydrophilic substituents, while a1 antagonists are larger
molecules with multiple aromatic/hydrophobic moieties.
Of all compounds, including 1, both the enantiomers
have been synthesized and tested in radioreceptor bin-
ding assays. Finally, the SAR data have been analyzed
applying the pharmacophore models proposed by Brem-
ner and co-workers27 for the a1-AR subtypes.
On these bases, we have recently undertaken a study
on both the enantiomers of compounds structurally re-
lated to 1 aimed at identifying high affinity ligands for
a1a-AR with a more pronounced selectivity over the
other a1-AR subtypes and 5-HT1A. The following design
approaches have been done: (a) replacement of benzodi-
oxane by a naphthodioxane or a tetrahydronaphthodi-
oxane (compounds 2 and 3); (b) replacement of 2,6-
dimethoxyphenyl by 1- or 2-naphthyl (compounds 4
and 5); (c) replacement of 2,6-dimethoxyphenyl by ortho
methoxy substituted 1- or 2-naphthyl (compounds 6–8).
Though already described in the literature,13 the naph-
thodioxane analogue 2 was included in the series consid-
ering that the reported biological data pertain to its
racemate and are a1 and a2 functional affinities, which
provide little, if any, information about binding affinities
for a1-AR subtypes. The rationale of such approaches
was to increase the steric hindrance and the hydrophob-
icity of the benzodioxane or, alternatively, of the di-
methoxyphenoxy residue of the lead compound
without compromising, but rather modulating the inter-
action capabilities of these two regions of the ligand,
which would be, respectively, involved, according to
2. Chemistry
The S isomers of compounds 4–8 were synthesized as
outlined in Scheme 1. In detail, the reaction sequence
consisted in the following steps: (a) displacement of
mesylate from the mesyl ester of (S)-glycerol acetonide
(R)-9 by 2-(benzyloxy)phenoxide; (b) hydrolysis of the
cyclic ketal (S)-10; (c) mesylation of the resultant vic-
diol (R)-11; (d) removal of the benzyl from the phenoxy
residue of (S)-12; (e) intramolecular nucleophilic substi-
tution of the mesylate at C2 of the glycerol skeleton by
the ortho-phenoxy moiety to give 1,4-dioxane ring
closure [(R)-14]. (S)-4, (S)-5, (S)-7 and (S)-8 were finally
obtained by amination of (R)-14 with 1-(2-aminoeth-
oxy)naphthalene (46), 2-(2-aminoethoxy)naphthalene
(50), 1-methoxy-2-(2-aminoethoxy)naphthalene (37) and
2-(2-aminoethoxy)-3-methoxynaphthalene (42), respec-
tively; (S)-6 was synthesized from the same intermediate
(R)-14, but through three steps: (f) conversion into the
azide (S)-15, (g) reduction with hydrazine to (S)-16
OMe
O
+
O
*
N
H
H
O
MeO
Cl-
2
OMe
+
O
O
+
O
O
O
O
*
*
N
N
H
H
H
H
H
MeO
Cl-
Cl-
3
4
+
O
O
O
O
O
O
+
O
*
*
*
N
N
H
H
H
MeO
Cl-
Cl-
5
6
OMe
+
+
O
O
O
O
O
*
N
N
H H
Cl-
H
H
MeO
Cl-
7
8

C. Bolchi et al. / Bioorg. Med. Chem. 12 (2004) 4937–4951
4939
tosylate at C2 of the glycerol skeleton with the naphth-
oxy moiety. The dihydronaphthodioxine (R)-21 was
transformed into iodomethyl derivative (R)-22 and final-
ly submitted to amination with 2-(2,6-dimethoxyphen-
oxy)ethylamine yielding (S)-2.
OBn
OBn
OH
O
O
O
O
O
O
OH
a
b
MsO
(R)-9
(S)-10
(R)-11
OMs
OBn
OMs
OH
The S enantiomer of 3 was synthesized by the strategy
illustrated in Scheme 3. Esterification of 5,6,7,8-tetra-
hydro-2-naphthol with acetyl chloride, followed by Fries
rearrangement, afforded 24, which was benzylated, oxi-
dized to acetate and then submitted to methanolysis to
give 27. Displacement of mesylate substituent of (R)-9
by 27 in the presence of potassium hydroxide and suc-
cessive hydrolysis of the cyclic ketal led to the diol
(R)-28, which was dimesylated and debenzylated to give
(S)-30. This latter was transformed into (R)-2-((mesyl-
oxy)methyl)-2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]-
dioxine [(R)-31] by intramolecular nucleophilic substitu-
tion of mesylate at C2 of glycerol skeleton. Finally, reac-
tion with 2-(2,6-dimethoxyphenoxy)ethylamine yielded
(S)-3.
O
OMs
O
OMs
d
c
(S)-12
(S)-13
h,i
O
O
(S)-4
e
OMs
j,i
(S)-5
(S)-7
(S)-8
l,i
(R)-14
m,i
f
O
O
O
O
k,i
N3
NH2
g
(S)-6
(S)-16
(S)-15
Scheme 1. Reagents and conditions: (a) 2-benzyloxyphenol, KOH,
EtOH. (b) HCl. (c) MsCl, TEA. (d) H2–Pd/C, EtOAc, MeOH. (e)
K2CO3, acetone. (f) NaN3, DMF, H2O. (g) hydrazine, PdO, MeOH.
(h) 1-(2-aminoethoxy)naphthalene, 2-propanol. (i) HCl, EtOH. (j) 2-
(2-aminoethoxy)naphthalene, 2-propanol. (k) 1-(2-bromoethoxy)-2-
methoxynaphthalene, 2-methylpropanol. (l) 1-methoxy-2-(2-aminoeth-
oxy)naphthalene, n-butanol. (m) 2-(2-aminoethoxy)-3-methoxynaph-
thalene, 2-propanol.
The R enantiomers of 2–8 were synthesized by the same
sequence as their antipodes, but using (S)-9.
Amines 46, 50, 42 and 37 were prepared from 1-naph-
thol, 2-naphthol, 2-hydroxy-3-methoxynaphthalene
(38) and 1-methoxy-2-hydroxynaphthalene (33), respec-
tively, by treatment with ethylene carbonate and potas-
sium carbonate, tosylation or mesylation of the resultant
(2-hydroxy)ethyl derivatives 43, 47, 39 and 34, succes-
sive conversion into the corresponding azides 45, 49,
41 and 36 and final reduction with hydrazine (Scheme
4). Compound 38 was obtained by treatment of naph-
thalenediol with dimethyl sulfate, while its position
and (k) N-alkylation with 1-(2-bromoethoxy)-2-meth-
oxynaphthalene (54).
Compound (S)-2 was prepared from (R)-9 as outlined in
Scheme 2. Treatment with 3-benzyloxy-2-hydroxynaph-
thalene (17) in the presence of sodium hydroxide and
successive hydrolysis of the cyclic ketal afforded (R)-
18, which was ditosylated and debenzylated to give
(S)-20. This latter was converted into (R)-2-((tosyl-
oxy)methyl)-2,3-dihydronaphtho[2,3-b][1,4]dioxine [(R)-
21] by intramolecular nucleophilic substitution of the
OH
O
OAc
OBn
O
b
c
a
d
23
24
25
OBn
O
OBn
OBn
OH
e
OH
OH
O
OH
O
OH
a
b
OH
O
26
27
(R)-28
OBn
OBn
17
(R)-18
OBn
O
OH
g
f
h
OTs
OTs
O
OTs
O
OTs
OMs
O
OMs
c
d
OMs
OMs
OBn
OH
(S)-29
(S)-30
(S)-19
(S)-20
O
i , j
OMs
(S)-3
O
O
O
I
OTs
e
f,g
(S)-2
(R)-31
O
O
Scheme 3. Reagents and conditions: (a) AlCl3, 1,2-dichlorobenzene.
(b) 2.5N NaOH, TBAB, benzyl bromide, DCM. (c) m-CPBA, CH2Cl2.
(d) MeOH, 2.5N NaOH. (e) (R)-9, KOH, EtOH; MeOH, HCl. (f)
MsCl, TEA, DCM. (g) H2–Pd/C, EtOAc. (h) K2CO3, acetone. (i) 2-
(2,6-Dimethoxyphenoxy)ethylamine, 2-propanol. (j) HCl, EtOH.
(R)-21
(R)-22
Scheme 2. Reagents and conditions: (a) (R)-9, NaOH, EtOH; HCl. (b)
TsCl, Py. (c) H2–Pd/C, EtOAc. (d) K2CO3, acetone. (e) NaI, acetone.
(f) 2-(2,6-dimethoxyphenoxy)ethylamine, 2-propanol. (g) HCl, EtOH.

4940
C. Bolchi et al. / Bioorg. Med. Chem. 12 (2004) 4937–4951
serotoninergic receptor, and the selectivities for the a1a
OH
O
OMe O
OMe
subtype with respect to the remaining receptors (a1b,
a1d and 5-HT1A).
OH
a
Me
b
32
Considering the binding data, it is possible to observe
that almost all the WB-4101 analogues display from
moderate to high affinities, but lower than the S isomer
of the lead compound, which exhibits about nanomolar
affinity towards the four different receptors. Only the a1a
and a1b affinities (pKia1a 8.80and p Kia1b 7.80) of (S)-6
approximate those of (S)-1 (pKia1a 9.39 and pKia1b
8.24). As a consequence of the generalized affinity de-
crease, the eudismic indexes are relatively small, rarely
exceeding the unity, and lower than for 1, whose S
enantiomer is 28-, 13-, 20- and 17-fold more potent than
the R enantiomer towards a1a, a1b, a1d and 5-HT1A re-
ceptors, respectively. As shown in Table 1, the affinities
of the S isomers of compounds 2–8 are always higher
than those of the corresponding R isomers excepting
the cases of the low a1b and a1d affinities displayed by
the enantiomeric pairs of 2 and 3.
33
OMe
OH
OH
OH
c
38
R
O
R O
R
O
R
O
d
e
f
g
R
OH
OH
NH2
OY
N3
Y = Ts
Y = Ts
Y = Ts
33
38
37
34
39
43
47
35
36
41
45
49
42
46
50
40
44
48
1-naphthol
2-naphthol
Y = Ms
Scheme 4. Reagents and conditions: (a) MeI, KOH, DMSO. (b) m-
CPBA, CH2Cl2; H2SO4, MeOH. (c) Me2SO4, Me3COK, 2-methoxy-
ethanol. (d) Ethylene carbonate, K2CO3, toluene or DMF. (e) TsCl
and Py or MsCl and Et3N. (f) NaN3, DMF. (g) Hydrazine, PdO,
MeOH.
(S)-1 exhibits 14.1 a1a/a1b and 6.0 a1a/5-HT1A affinity
ratios, while its a1a and a1d affinities are nearly equal.
Similar selectivity pattern was found for (R)-1.
The structural modifications performed on the benzodi-
oxane moiety sensibly lowered affinity for a1-AR sub-
types and 5-HT1A receptor, but, what is noteworthy,
improved a1a subtype specificity. Indeed, a1a, a1b and
5-HT1A affinities of (S)-2 and (S)-3 were almost equally
(about 2 orders of magnitude) decreased with respect to
(S)-1, whereas, for a1d, the loss of affinity ranged be-
tween 661-fold and 812-fold. As shown by the affinity
ratios reported in Table 1, such a trend slightly im-
proved the a1a versus a1b and 5HT1A selectivities of
(S)-1, while producing moderate, but undeniable a1a
versus a1d selectivity, of which (S)-1 is virtually devoid.
Therefore, (S)-2 and (S)-3 can be considered ligands
with an only moderate a1a affinity, but a significant selec-
tivity over both the other a1 subtypes and the 5-HT1A
receptor. Furthermore, their almost superimposable
affinity profiles indicate that the addition of an aromatic
or alicyclic residue to the benzodioxane system equally
advantages a1a selectivity.
O
O
H
H
O
OCH3
OCH3
a
b
51
Br
OCH3
OH
O
c
OCH3
53
52
Scheme 5. Reagents and conditions: (a) m-CPBA, CH2Cl2. (b)
LiAlH4, THF. (c) Dibromoethane, NaH, THF, DMSO.
isomer 33 was synthesized by O-methylation of 1-hyd-
roxy-2-acetonaphthone, followed by the Baeyer–Villiger
oxidation of the resultant 1-methoxy-2-acetonaphthone
(32) to the corresponding naphthyl acetate, which was
not isolated, but directly submitted to methanolysis
(Scheme 4).
Otherwise, replacement of 2,6-dimethoxyphenyl with
naphthyl residues (compounds 4–8) led to averagely
higher affinities than those of 2 and 3, but proved to
be detrimental for selectivity, even for that for a1a with
regard to a1b, the most marked subtype selectivity
shown by (S)-1. In this series, (S)-6 and (R)-6, which
exhibit nearly nanomolar a1a affinities, constitute an
exception, because they maintain the a1a/a1b selectivity
of the lead compound while improving the a1a/5-HT1A
and a1a/a1d affinity ratios of this latter.
1-(2-Bromoethoxy)-2-methoxynaphthalene (53) was
obtained by the Baeyer–Villiger oxidation of 2-methoxy-
naphthaldehyde to the corresponding naphthylformiate
51, which was submitted to reduction with LiAlH4 to
give 2-methoxynaphthol (52). This latter was reacted
with dibromoethane in the presence of NaH yielding
53 (Scheme 5).
In summary, SAR analysis indicates that the modifica-
tions performed on the 2,6-dimethoxyphenyl residue
and on the benzodioxane nucleus tend to modulate the
ligand a1-ARs binding affinity and the a1a subtype selec-
tivity, respectively. This trend is consistent with the
model of interaction between 1 and a1a-AR antagonist
3. Results and discussion
Table 1 reports the affinities, expressed as pKi values, at
the three cloned human a1-AR subtypes and 5-HT1A

C. Bolchi et al. / Bioorg. Med. Chem. 12 (2004) 4937–4951
4941
Table 1. Affinity constants, expressed as pKi (ꢀlogKi, M), and selectivities of the enantiomeric pairs of compounds 1–8 for cloned human
a1-adrenoreceptor subtypes and 5-HT1A receptor
Compd
pKi ( SE)
Affinity ratios
a-1a/a-1ba
a-1a/a-1db
a-1a/5-HT1A
c
a-1a
a-1b
a-1d
5-HT1A
(S)-1
(R)-1
(S)-2
(R)-2
(S)-3
(R)-3
(S)-4
(R)-4
(S)-5
(R)-5
(S)-6
(R)-6
(S)-7
(R)-7
(S)-8
(R)-8
9.39 ( 0.06)
7.95 ( 0.04)
7.47 ( 0.05)
6.99 ( 0.08)
7.60 ( 0.15)
7.00 ( 0.07)
7.70 ( 0.02)
6.98 ( 0.03)
7.29 ( 0.04)
6.66 ( 0.05)
8.80 ( 0.09)
8.34 ( 0.05)
7.41 ( 0.05)
6.92 ( 0.04)
7.91 ( 0.02)
5.89 ( 0.06)
8.24 ( 0.04)
7.14 ( 0.06)
6.05 ( 0.04)
6.37 ( 0.04)
6.24 ( 0.03)
6.40 ( 0.05)
7.19 ( 0.03)
<6
9.29 ( 0.11)
7.98 ( 0.08)
6.38 ( 0.04)
6.53 ( 0.04)
6.47 ( 0.06)
6.69 ( 0.04)
8.38 ( 0.07)
6.74 ( 0.06)
7.03 ( 0.09)
6.31 ( 0.03)
8.18 ( 0.13)
7.65 ( 0.05)
7.44 ( 0.07)
6.83 ( 0.11)
7.98 ( 0.05)
6.89 ( 0.05)
8.61 ( 0.04)
7.39 ( 0.03)
6.46 ( 0.04)
6.00 ( 0.04)
6.44 ( 0.03)
6.30 ( 0.03)
8.13 ( 0.04)
7.24 ( 0.04)
7.41 ( 0.06)
<6
14.1
6.5
1.3
0.9
12.3
2.9
13.5
2.0
0.2
1.7
1.8
2.2
4.2
4.9
0.9
1.2
0.8
0.1
6.0
3.6
26.3
4.2
10.2
9.8
22.9
4.0
14.5
5.0
3.2
0.4
0.5
>9.6
2.2
6.95 ( 0.03)
<6
0.8
>4.6
10.0
18.6
1.3
>4.6
7.1
7.80 ( 0.07)
7.07 ( 0.07)
7.28 ( 0.05)
6.57 ( 0.07)
7.58 ( 0.03)
6.76 ( 0.04)
7.95 ( 0.06)
7.17 ( 0.04)
7.90 ( 0.05)
6.97 ( 0.06)
7.75 ( 0.04)
6.51 ( 0.09)
14.8
0.3
2.2
2.1
0.9
1.4
0.1
0.2
a Antilog (pKia1aꢀpKia1b).
b Antilog (pKia1a–pKia1d).
c Antilog (pKia1a–pKi5-HT1A).
binding pocket resulting from Perez mutagenesis stud-
ies.29,30 According to such a model, three consecutive
aminoacid residues (Gln 177, Ile 178 and Asn 179) of
the second extracellular loop (E2) would interact with
the benzodioxane system and account for a1a selectivity,
whereas two phenylalanine residues (Phe 308 and Phe
312), set on transmembrane domain 7 (TM7) and
strictly conserved among all three a1-AR subtypes,
would be responsible for non subtype selective binding
to a1-ARs through interactions with the 2,6-dimethoxy-
phenyl fragment of the ligand. Indeed, both the tetra-
hydronaphthodioxane and naphthodioxane analogues
(S)-3 and (S)-2 have markedly lower affinity, but higher
specificity for a1a-AR than (S)-1, suggesting that sub-
type specific interactions, of apolar nature, with the
above three consecutive aminoacid residues set in E2
play a critical role. Conversely, the derivatives modified
at the 2,6-dimethoxyphenyl moiety by condensation
with an additional benzene maintain a good affinity,
but loose subtype selectivity. However, it is to be noticed
that the enlargement of the aromatic system in this por-
tion of the ligand molecule doesnÕt lead to an undiscrim-
inating enhancement of the a1 affinity as expected on the
basis of the proposed involvement of the two phenylala-
nine residues in the ligand interaction with all the a1-AR
subtypes. The substitution with a 1-naphthyl residue is
preferable to that with a 2-naphthyl, where the para
position to the oxygen atom is not free, as demonstrated
by the higher affinities of (S)- and (R)-4 with respect to
(S)- and (R)-5. Such a trend is confirmed by the series of
compounds 6-8, where the two enantiomers of 6 display
the maximum affinities. These results are in agreement
with previous observations,31 which pointed out the del-
eterious effects of 4-substitution at the 2,6-dimethoxy-
phenyl moiety. Furthermore, it is evident that the
additional presence of an ortho positioned methoxy
group on the 1-naphthyl fragment favourably contrib-
utes to the interaction, as indicated by the fact that
˚
Table 2. Angle (s, °) and distances (d1ꢀd4, A) between the pharmacophore features of compounds 1–8
d1
d2
+
O
O
N
d3
d4
O
Me
Compd
sa
s mina
d1
d2
d3
d4
1
2
3
4
5
6
7
8
125.08
126.21
118.51
109.63
120.99
109.56
109.64
123.41
79.09
3.25
5.50
4.83
4.75
91.903.250.22
89.29
51.60
4.49
4.41
2.92
3.07
2.91
3.06
3.10
3.25
4.98
5.53
5.26
5.43
5.19
5.50
4.54
––
4.56
––
66.27
57.52
––
––
4.61
4.42
4.83
5.02
4.72
4.75
68.48
79.09
a HBA–N–A angle determined by d1 and d2.

4942
C. Bolchi et al. / Bioorg. Med. Chem. 12 (2004) 4937–4951
(S)-6 displays sensibly higher a1a and a1b affinities
than(S)-4 approximating the values of (S)-1.
to evaluate the affinity for the three a1-AR subtypes and
the 5-HT1A receptor. Thus, little is known about their
selectivity at this level and the possibility to improve
the selectivity of the lead compound, which is just mod-
est excepting the significantly lower a1b affinity com-
pared with those for the other two a1 subtypes and the
5-HT1A receptor. In this context, the present studies
on the enantiomers of WB-4101 and a novel series of
homochiral analogues of the same indicate that it is pos-
sible to significantly modulate the affinity and selectivity
profile of (S)-1 simply fusing a cyclohexane or an addi-
tional benzene ring with its benzodioxane or phenoxy
moiety. In particular, the naphthodioxane and tetra-
hydronaphthodioxane derivatives (S)-2 and (S)-3 dis-
play a good a1a selectivity with respect to the other
two subtypes and the 5-HT1A receptor, while the 2-
methoxy-1-naphthyloxy analogue (S)-6 and (R)-6 a very
high a1a affinity, little lower than that of (S)-1, but
slightly more specific than this latter. These results are
coherent with the a1a-AR binding model for WB-4101
resultant from mutagenesis studies and, to a certain ex-
tent, with previously proposed a1 subtype pharmaco-
phore models.
To further analyze the SAR data of compounds 2-8,
whose S isomers have all Kia1a <100nM and, in the case
of 2 and 3, an appreciable a1a specificity, we have ap-
plied a pharmacophore model for a1a-AR. Out of those
reported in literature, we selected the model developed
by Bremner and co-workers,27 which ensues from four
relatively heterogeneous a1A antagonists with a1A/a1B
and a1A/a1D selectivities comparable to those of (S)-2
and (S)-3 and is claimed to well predict the a1A affinity
of WB-4101, not comprised in the training set. This
a1A pharmacophore model includes three features,
namely a protonated centre (N), a hydrogen bond
acceptor group (HBA) and an aromatic ring (A), defined
˚
˚
by a 7.1A N–HBA distance, a 5.5A N–A distance and a
100° HBA–N–A angle. The fact that the same three fea-
tures, but in a folded disposition with a 47° angle, also
frame the a1D pharmacophore model proposed by the
same authors suggests that the conformational profile
of the considered compounds could be determinant for
the a1A/a1D selectivity. Otherwise, the a1A/a1B selectivity
would rest on more solid bases since the a1B pharmaco-
phore model substantially differs from the two others for
the presence of four features and, in particular, of a
hydrogen bond donor in place of an acceptor.
5. Experimental
5.1. Chemistry
Table 2 reports the calculated values of the distance be-
tween N and dioxane O1 (d1) and between N and the ba-
rycentre of the phenyl linked to the oxyethyl chain (d2)
for compounds 1–8. The same table lists the values of
the distance between N and methoxy O (d3) and be-
tween N and the barycentre of the aromatic ring of
the benzodioxane system (d4). It is evident that both
d1 and d3, which can be assumed as N–HBA distances,
Melting points were measured on Buchi melting point
apparatus and are uncorrected. H NMR spectra were
1
recorded operating at 200 or 300MHz. Chemical shifts
are reported in ppm relative to residual solvent (CHCl3
or DMSO) as internal standard. Signal multiplicity is
designed according to the following abbreviations:
s = singlet, d = doublet, dd = doublet of doublets,
t = triplet, m = multiplet, br s = broad singlet, br
t = broad triplet. Optical rotations were determined by
a Perkin–Elmer 241 Polarimeter at 25°C. Elemental
analyses (CHN) of the new substances are within
0.40% of theoretical values. Purifications were per-
formed by flash chromatography using silica gel (parti-
cle size 40–63lm, Merck).
˚
are far from the 7.1A value proposed by Bremner. On
the contrary, both d2 and d4 acceptably match with
˚
the proposed 5.5A N–A distance. Overall, these results
indicate that d1 and d2, or, alternatively, d3 and d4
are not constructive descriptors to justify the affinity
and selectivity profile of the title compounds, in parti-
cular of (S)-2, (S)-3, (S)-6 and (R)-6, which would not
be able to map the HBA feature of the model. However,
consistently with BremnerÕs models, conformational
analysis shows that the two most a1a/a1d selective com-
pounds, that is, (S)-2 and (S)-3, cannot assume the
folded disposition of the three pharmacophore features
required for the interaction with the a1D subtype (see
the minimum 91.90° and 89.29° HBA–N–A angles in
Table 2), what is instead allowed to the other less or
not a1a/a1d selective ligands. Significantly, (S)-4, whose
minimum HBA–N–A angle (51.60°) is the most similar
to the postulated value of 47°, exhibits a reversed selec-
tivity in favour of a1d with respect to a1a subtype.
(S)- and (R)-glycerol acetonide were prepared by Chemi
S.p.a. (Cinisello Balsamo, Milan, Italy) from racemic
glycerol acetonide according to the method described
in the literature.32
5.1.1. (R)-1-Mesyloxy-2,3-propanediol acetonide [(R)-9].
Prepared from commercially available (S)-glycerol
acetonide as reported by Jeminet.33
5.1.2. (S)-1-Mesyloxy-2,3-propanediol acetonide [(S)-9].
Prepared from commercially available (R)-glycerol
acetonide as described for (R)-9.
4. Conclusions
5.1.3. (S)-3-(2-Benzyloxyphenoxy)-1,2-propanediol aceto-
nide [(S)-10]. A solution of 2-benzyloxyphenol (14.7g,
73.4mmol) and potassium hydroxide (4.12g, 73.4mmol)
in ethanol (100mL) was heated at 70°C for 30min and,
after adding (R)-9 (22.1g, 77.2mmol), refluxed for 24h.
The solvent was evaporated and the residue treated with
Although many analogues, mostly racemic, of the po-
tent a1 antagonist WB-4101 have been investigated over
the past years, drawing conclusions on the features rele-
vant to a1/a2 selectivity, a few of them have been assayed

C. Bolchi et al. / Bioorg. Med. Chem. 12 (2004) 4937–4951
4943
diethyl ether (100mL). The resulting suspension was fil-
tered and the filtrate washed with water, 5% potassium
hydroxide, and water again. The organic layer was dried
and concentrated to give a residue, which was chroma-
tographed on silica gel. Elution with cyclohexane/ethyl
acetate (90:10) afforded 13g (56%) of (S)-10 as a white
1H NMR (CDCl3) d 3.08 (s, 3H), 3.14 (s, 3H) 4.10–
4.29 (m, 2H), 4.51 (m, 2H), 5.26 (m, 1H), 6.27 (br s,
1H), 6.84–6.94 (m, 4H).
5.1.10. (R)-3-(2-Hydroxyphenoxy)-1,2-bis(tosyloxy)pro-
pane [(R)-13]. Prepared from (R)-12 as described for
25
25
(S)-13: ½aŠ ¼ þ4:5 (c 1, CHCl3); 1H NMR identical
1
solid: mp 36–37°C; ½aŠ ¼ þ17:4 (c 0.5, ethanol); H
D
D
to that of (S)-13.
NMR (CDCl3) d 1.38 (s, 3H), 1.42 (s, 3H), 3.89–4.07
(m, 2H), 4.08–4.21 (m, 2H), 4.42–4.58 (m, 1H), 5.18 (s,
2H), 6.85–7.00 (m, 4H), 7.32–7.58 (m, 5H).
5.1.11. (R)-2-((Mesyloxy)methyl)-1,4-benzodioxane [(R)-
14]. A mixture of (S)-13 (9.5g, 27.9mmol) and potas-
sium carbonate (3.9g, 30mmol) in acetone (120mL)
was refluxed for 5h. After cooling, the reaction mixture
was concentrated and the residue treated with ethyl ace-
tate (100mL) and 10% HCl (60mL). The organic phase
was separated, washed with water, dried, and concen-
trated to yield a residue, which was crystallized from
5.1.4. (R)-3-(2-Benzyloxyphenoxy)-1,2-propanediol aceto-
nide [(R)-10]. Prepared from (S)-9 as described for (S)-
25
10: mp 36–37°C; ½aŠ ¼ ꢀ17:4 (c 0.5, ethanol); 1H
D
NMR identical to that of (S)-10.
diisopropyl ether/ethanol (7:1) to give 5.1 g (75%) of
5.1.5. (R)-3-(2-Benzyloxyphenoxy)-1,2-propanediol [(R)-
11]. A suspension of (S)-10 (13g, 41.3mmol) in 1N HCl
(65mL) was heated at 75°C for 5h and, after removing
acetone by vacuum distillation, cooled to 5°C and fil-
tered to isolate the precipitate, which was rinsed with
water several times and then dissolved in carbon tetra-
chloride (60mL). Residual water was removed by azeo-
tropic distillation. After slow cooling to 5°C, 8.8g
25
(R)-14: mp 85.4°C; ½aŠ ¼ ꢀ17:2 (c 1, CHCl3); 1H
D
NMR (CDCl3) d 3.09 (s, 3H), 4.20 (dd, 1H), 4.32 (dd,
1H), 4.43–4.55 (m, 3H), 6.89 (s, 4H).
5.1.12. (S)-2-((Mesyloxy)methyl)-1,4-benzodioxane [(S)-
14]. Prepared from (R)-13 as described for (R)-14:
25
D
of (R)-14.
1
½aŠ ¼ þ17:3 (c 1, CHCl3); H NMR identical to that
(78%) of (R)-11 crystallized as a white solid: mp 94–
25
95°C; ½aŠ ¼ ꢀ6:7 (c 0.5, ethanol); 1H NMR
(CDCl3) d D2.5 (t, 1H), 3.21 (d, 1H), 3.89–4.07 (m, 2H),
4.08–4.21 (m, 2H), 4.42–4.58 (m, 1H), 5.10 (s, 2H),
6.85–6.90(m, 4H), 7.35–7.42 (m, 5H).
5.1.13. (S)-2-((Azido)methyl)-1,4-benzodioxane [(S)-15].
A mixture of (S)-14 (3.0g, 12.2mmol) and sodium azide
(8g, 123mmol) in DMF (130mL) was heated at 90 °C
for 3h. At the end, the reaction mixture was extracted
with dichloromethane for three times. The organic
phases were combined, washed with water, dried and
concentrated to give the crude product, which was puri-
fied by chromatography on silica gel. Elution with cyclo-
hexane/ethyl acetate 80:20 afforded 2.1g of [(S)-15] as a
5.1.6. (S)-3-(2-Benzyloxyphenoxy)-1,2-propanediol [(S)-
11]. Prepared from (R)-10 as described for (R)-11: mp
25
D
cal to that of (R)-11.
1
94–95°C; ½aŠ ¼ þ5:8 (c 0.5, ethanol); H NMR identi-
25
D
1
yellow oil (91%): ½aŠ ¼ ꢀ16:1 (c 1, CHCl3); H NMR
5.1.7. (S)-3-(2-Benzyloxyphenoxy)-1,2-bis(mesyloxy)pro-
pane [(S)-12]. Mesyl chloride (7.4g, 65mmol) was added
dropwise to a stirred solution of (R)-11 (8.8g, 32mmol)
and TEA (10mL) in dichloromethane at 0 °C. After 2h
at room temperature, the reaction mixture was washed
with 5% NaHCO3, dried and concentrated to give the
crude product, which was crystallized from diisopropyl
(CDCl3) d 3.45–3.61 (m, 2H), 4.05 (m, 1H), 4.14 (dd,
1H), 4.38 (m, 1H), 6.81–6.90(m, 4H).
5.1.14. (R)-2-((Azido)methyl)-1,4-benzodioxane [(R)-15].
Prepared from (R)-14 as described for (S)-15: ½aŠ
25
D
¼
þ15:6 (c 1, CHCl3); 1H NMR identical to that of (S)-15.
ether yielding 12.4g (90%) of (S)-12 as a white solid:
25
D
mp 103°C; ½aŠ ¼ ꢀ24:3 (c 1, CHCl3); 1H NMR
5.1.15. (S)-2-((Amino)methyl)-1,4-benzodioxane [(S)-16].
Hydrazine hydrate (6.35mL) was added dropwise to a
stirred mixture of (S)-15 (2.1g, 10.9mmol) and PdO
(50mg) in methanol (20mL). After refluxing for 2h,
the reaction mixture was cooled to room temperature
and filtered. The filtrate was concentrated and the resul-
ting crude product treated with 10% HCl until pH = 1.
The aqueous layer was alkalized with 40% NaOH until
pH = 9 and extracted with dichloromethane. The org-
anic phase was separated, washed with water, dried
(CDCl3) d 2.90(s, 3H), 3.30 (s, 3H), 4.24 (m, 2H),
4.48 (m, 2H), 5.03 (s, 2H), 5.15 (m, 1H), 6.90–7.05 (m,
4H), 7.35–7.45 (m, 5H).
5.1.8. (R)-3-(2-Benzyloxyphenoxy)-1,2-bis(mesyloxy)pro-
pane [(R)-12]. Prepared from (S)-11 as described for (S)-
25
D
identical to that of (S)-12.
1
12: mp 10 2.5°C; ½aŠ ¼ þ23:0 (c 1, CHCl3); H NMR
5.1.9. (S)-3-(2-Hydroxyphenoxy)-1,2-bis(mesyloxy)pro-
pane [(S)-13]. A solution of (S)-12 (13g, 30.2mmol) in
ethyl acetate (170mL) and methanol (70mL) was added
with 10% Pd/C (1.2g) and vigorously shaken under
hydrogen at room temperature for 3h. The catalyst
was removed by filtration and the filtrate concentrated
and concentrated to give 1.59g of (S)-16 as a yellow
25
oil (88%): ½aŠ ¼ ꢀ55:4 (c 1, CHCl3); 1H NMR (CDCl3)
D
d 1.4 (br s, 1H), 2.94 (m, 2H), 4.0 (m, 1H), 4.12 (m, 1H),
4.28 (dd, 1H), 6.81–6.90 (m, 4H).
5.1.16. (R)-2-((Amino)methyl)-1,4-benzodioxane [(R)-16].
Prepared from (R)-15 as described for (S)-16:
to give (S)-11 (9.8g) as a colourless oil, which was
used without purification: ½aŠ ¼ ꢀ5:3 (c 1, CHCl3);
25
D

4944
25
D
(S)-16.
C. Bolchi et al. / Bioorg. Med. Chem. 12 (2004) 4937–4951
½aŠ ¼ þ53:7 (c 1, CHCl3); 1H NMR identical to that of
5.1.22. (S)-3-(3-Hydroxy-2-naphthoxy)-1,2-bis(tosyloxy)-
propane [(S)-20]. Prepared from (S)-19 as described for
(S)-13 and isolated, after chromatography on silica gel
(cyclohexane/ethyl acetate, 70:30), as an orange solid
5.1.17. 3-Benzyloxy-2-hydroxynaphthalene (17). Potas-
sium carbonate (43.1g, 0.31mol) was added in small
portions to a solution of 2,3-dihydroxynaphthalene
(50g, 0.31mol) in DMF (120mL). The mixture was
heated at 50°C for 30min. Benzyl chloride (35.7mL,
0.31mol) was added dropwise. After heating at 85°C
for 20h, the solvent was evaporated and the residue
treated with dichloromethane and 10% HCl. The organ-
ic phase was separated, washed with 10% HCl again and
then with water, dried, and concentrated. The resulting
residue was purified by chromatography on silica gel.
Elution with cyclohexane/ethyl acetate 95:5 afforded
25
(53%): mp 134–135°C; ½aŠ ¼ þ7:2 (c 1, chloroform);
D
1H NMR (CDCl3) d 2.42 (s, 6H), 4.25 (m, 4H), 5.09
(m, 1H), 5.99 (br s, 1H), 6.97 (s, 1H), 7.26 (m, 7 H),
7.63 (m, 2H), 7.75 (m, 4H). Anal. Calcd for
C27H26O8S2 (542.62).
5.1.23. (R)-3-(3-Hydroxy-2-naphthoxy)-1,2-bis(tosyloxy)-
propane [(R)-20]. Prepared from (R)-19 as described
25
D
form); H NMR identical to that of (S)-20.
for (S)-20: mp 133–135°C; ½aŠ ¼ ꢀ7:1 (c 1, chloro-
1
5.1.24. (R)-2-((Tosyloxy)methyl)-2,3-dihydronaphtho[2,3-
b][1,4]dioxine [(R)-21]. Obtained from (S)-20 as a white
solid (99%) following the procedure described for (R)-
1
51.45g (66%) of 17 as a yellow oil: H NMR (CDCl3)
d 5.25 (s, 2H), 5.90 (s, 1H), 7.10–7.58 (m, 9H), 7.60–
7.75 (m, 2H). Anal. Calcd for C17H14O2 (250.30).
25
D
1
14: mp 113–115°C; ½aŠ ¼ ꢀ9:5 (c 1, chloroform); H
NMR (CDCl3) d 2.43 (s, 3H), 4.15 (m, 1H). 4.20–4.37
(m, 3H), 4.49 (m, 1H), 7.16 (s, 1H), 7.23–7.35 (m, 5H),
7.61 (m, 2H), 7.80(d, 2H). Anal. Calcd for C 20H18O5S
(370.42).
5.1.18. (R)-3-(3-Benzyloxy-2-naphthoxy)-1,2-propanediol
[(R)-18]. A solution of 17 (13g, 51.9mmol) and sodium
hydroxide (2.07g, 51.9mmol) in ethanol (270mL) was
heated at 70°C for 15min and, after adding (R)-9
(14.6g, 51mmol), refluxed for 24h. 5% HCl (150mL)
was added and boiling continued for 4h. Ethanol was
evaporated and the residue treated with ethyl acetate.
The aqueous layer was separated and extracted with
ethyl acetate again. The combined organic extracts were
washed with water, dried, and concentrated. The brown-
5.1.25. (S)-2-((Tosyloxy)methyl)-2,3-dihydronaphtho[2,3-
b][1,4]dioxine [(S)-21]. Prepared from (R)-20 as
25
D
chloroform); H NMR identical to that of (R)-21.
described for (R)-21: mp 109–111°C; ½aŠ ¼ þ8:9 (c 1,
1
5.1.26. (R)-2-(Iodomethyl)-2,3-dihydronaphtho[2,3-b][1,4]-
dioxine [(R)-22]. A mixture of (R)-21 (3.05g, 8.2mmol)
and sodium iodide (13.6g, 90mmol) in acetone
(40mL) was refluxed for 18h. The solvent was evapo-
rated and the residue treated with 10% HCl and ethyl
acetate. The aqueous layer was separated and extracted
with ethyl acetate. The organic phases were combined,
washed with a saturated aqueous solution of sodium
metabisulfite (50mL), dried, and concentrated to give
ish solid residue was crystallized from methanol yielding
25
D
8.1g (48%) of (R)-18: mp 127–128°C; ½aŠ ¼ ꢀ6:45 (c
1
0.5, ethanol); H NMR (CDCl3) d 2.50(br s, 1H), 3.20
(br s, 1H), 3.80(m, 2H), 4.05–4.35 (m, 3H), 5.20(s,
2H), 7.10–7.55 (m, 9H), 7.60–7.70 (m, 2H). Anal. Calcd
for C20H20O4 (324.38).
5.1.19. (S)-3-(3-Benzyloxy-2-naphthoxy)-1,2-propanediol
[(S)-18]. Prepared from (S)-9 and 17 as described for
2.43g (91%) of (R)-22 as a pale yellow solid: mp 73–
25
D
74°C; ½aŠ ¼ ꢀ7:3 (c 1, chloroform); 1H NMR (CDCl3)
25
D
(R)-18: mp 131–132°C; ½aŠ ¼ þ7:0 (c 0.5, ethanol);
d 3.38 (d, 2H), 4.24 (dd, 1H), 4.35–4.50(m, 2H), 7.30(m,
4H), 7.66 (m, 2H).
1H NMR identical to that of (R)-18.
5.1.20.
(S)-3-(3-Benzyloxy-2-naphthoxy)-1,2-bis(tosyl-
5.1.27. (S)-2-(Iodomethyl)-2,3-dihydronaphtho[2,3-b][1,
4]dioxine [(S)-22]. Prepared from (S)-21 as described
oxy)propane [(S)-19]. Tosyl chloride (12.37g, 65mmol)
was added in small portions to a stirred solution of
(R)-18 (8.1g, 25mmol) in pyridine (18mL) at 0°C. The
resulting mixture was stirred at room temperature for
20h. Ethyl acetate (100mL) and 10% HCl (90mL) were
added. The organic phase was separated, washed with
water, dried, and concentrated to give the crude prod-
uct, which was crystallized from diethyl ether yielding
11.63g (74%) of (S)-19 as a white solid: mp 93–96°C;
25
D
for (R)-22: mp 66–68°C; ½aŠ ¼ þ6:9 (c 1, chloroform);
1H NMR identical to that of (R)-22.
5.1.28. 2-Acetoxy-5,6,7,8-tetrahydronaphthalene (23).
Acetyl chloride (28.9mL, 0.37mol) was added stepwise
to a cool solution of 5,6,7,8-tetrahidro-2-naphthol
(50g, 0.337mol) and pyridine (29.9mL) in dichloro-
methane (250mL) keeping the temperature under 5 °C.
The reaction mixture was stirred at room temperature
for 2h, treated with 10% HCl (150mL), washed with
water (100mL), dried, and concentrated to give 64g of
23 as an oil, which was used for the subsequent step
25
1
½aŠ ¼ þ16:0 (c 0.5, ethyl acetate); H NMR (CDCl3)
D
d 2.30(s, 3H), 2.38 (s, 3H), 4.15–4.40(m, 4H), 4.95
(m, 1H), 5.18 (s, 2H), 7.02 (s, 1H), 7.15–7.50 (m, 12H),
7.60–7.80 (m, 6H). Anal. Calcd for C34H32O8S2
(632.74).
1
without further purification: H NMR (CDCl3) d 1.80
(m, 4H), 2.29 (s, 3H), 2.77 (m, 4H), 5.28 (s, 2H), 6.82
(m, 2H), 7.07 (m, 1H).
5.1.21. (R)-3-(3-Benzyloxy-2-naphthoxy)-1,2-bis(tosyloxy)-
propane [(R)-19]. Prepared from (S)-18 as described for
25
D
tate); H NMR identical to that of (S)-19.
(S)-19: mp 95–95.4°C; ½aŠ ¼ ꢀ15:8 (c 0.5, ethyl ace-
5.1.29. 3-Acetyl-5,6,7,8-tetrahydro-2-naphthol (24). A
solution of 23 (64g) in 1,2-dichlorobenzene (64mL)
1

C. Bolchi et al. / Bioorg. Med. Chem. 12 (2004) 4937–4951
4945
was added with aluminium trichloride (45g) and heated
at 100°C for 5h. After cooling, dichloromethane
(200mL) was added and the resulting mixture was
poured into frozen 10% HCl (250mL). The organic
phase was separated, washed with water, dried, and con-
centrated. After distillation of dichlorobenzene under
vacuum, the green residue was crystallized from metha-
nol (300mL) to give 42.1g (66%) of 24 as a light yellow
uum and the residue was extracted with dichlorometh-
ane. The organic phase was dried and concentrated to
give the crude product, which was purified by chroma-
tography on silica gel. Elution with dichloromethane/
methanol 98/2 afforded 11.4g (59%) of (R)-28 as a solid:
25
D
mp 95–96°C; ½aŠ ¼ ꢀ6:5 (c 0.5 ethanol); 1H NMR
(CDCl3) d 1.76 (m, 4 H), 2.35 (t, 1H), 2.66 (m, 4H),
3.17 (d, 1H), 3.68 (m, 2H), 4.02 (m, 2H), 4.12 (dd,
1H), 5.04 (s, 2H), 6.65 (s, 2H), 7.31–7.45 (m, 5H).
1
solid: mp 71–72°C; H NMR (CDCl3) d 1.78 (m, 4H),
2.58 (s, 3H), 2.75 (m, 4H), 6.68 (s, 1H), 7.40(s, 1H),
11.96 (s, 1H).
5.1.34. (S)-3-(3-benzyloxy-5,6,7,8-tetrahydro-2-naphth-
oxy)-1,2-propanediol [(S)-28]. Prepared from (S)-9 and
25
D
(c 0.5, ethanol); H NMR identical to that of (R)-28.
5.1.30. 2-Benzyloxy-3-acetyl-5,6,7,8-tetrahydronaphtha-
lene (25). At room temperature, 2, 5N NaOH
(440mL) was added to a stirred solution of benzyl bro-
mide (39.4mL, 0.33mol), TBAB (9.2g) and 24 (42.1g,
0.22mol) in dichloromethane (400mL). The reaction
mixture was stirred at room temperature for 4h. After-
wards, the organic phase was separated, treated with
10% HCl (100mL), washed with water (50mL), dried,
and concentrated to give the crude product. Crystalliza-
tion from methanol (250mL) afforded 44.1g (71%) of 25
as a white solid: mp 94–95°C; 1H NMR (CDCl3) d 1.78
(m, 4H), 2.58 (s, 3H), 2.76 (m, 4H), 5.11 (s, 2H), 6.72 (s,
1H), 7.34–7.45 (m, 5H), 7.50(s, 1H).
27 as described for (R)-28: mp 123–124°C; ½aŠ ¼ þ5:2
1
5.1.35. (2S)-3-(3-Benzyloxy-5,6,7,8-tetrahydro-2-naphth-
oxy)-1,2-bis(mesyloxy)propane [(S)-29]. Prepared from
(R)-28 as described for (S)-12 and isolated after crystal-
lization from diisopropyl ether as a white solid (87%):
25
D
mp 126–127°C; ½aŠ ¼ ꢀ16:1 (c 1, chloroform); 1H
NMR (CDCl3) 1.75 (m, 4H), 2.64 (m, 4H), 2.90(s,
3H), 3.05 (s, 3H), 4.20 (m, 2H), 4.40–4.55 (m, 2H),4.98
(m, 2H), 5.05 (m, 1H), 6.58 (s, 1H), 6.65 (s, 1H).
5.1.36. (R)-3-(3-Benzyloxy-5,6,7,8-tetrahydro-2-naphth-
oxy)-1,2-bis(mesyloxy)propane [(R)-29]. Prepared from
(S)-28 as described for (S)-29: mp 125–126°C;
5.1.31. 2-Benzyloxy-3-acethoxy-5,6,7,8-tetrahydronaph-
thalene (26). 3-Chloroperbenzoic acid (62.8g) was added
to a solution of 25 (44g, 160mmol) in dichloromethane
(400mL) at 0°C. The reaction mixture was stirred at
room temperature for 20h. The progress of the reaction
was monitored by 1H NMR analysis observing the shift-
ing of the acetyl signal from 2.58 to 2.26d. At the end of
the reaction, the mixture was filtered and washed with a
saturated solution of sodium bicarbonate and with
water. The organic phase was dried and concentrated
to give 46.5g of 26 as a yellow oil, which was used for
the subsequent step without further purification: 1H
NMR (CDCl3) d 1.78 (m, 4H), 2.26 (s, 3H), 2.70(m,
4H), 5.04 (s, 2H), 6.71 (s, 1H), 6.76 (s, 1H), 7.35–7.47
(m, 5H).
25
1
½aŠ ¼ þ15:7 (c 1, chloroform); H NMR identical to
D
that of (S)-29.
5.1.37. (S)-3-(3-Hydroxy-5,6,7,8-tetrahydro-2-naphth-
oxy)-1,2-bis(mesyloxy)propane [(S)-30]. Prepared from
(S)-29 as described for (S)-13 and isolated as a white
25
solid (95%): mp 114°C; ½aŠ ¼ þ4:7 (c 1, chloroform);
D
1H NMR (CDCl3) d 1.75 (m, 4H), 2.64 (m, 4H), 3.10
(s, 3H), 3.14 (s, 3H), 4.18–4.22 (m, 2H), 4.48–4.53 (m,
2H), 5.25 (m, 1H), 6.53 (s, 1H), 6.63 (s, 1H).
5.1.38. (R)-3-(3-Hydroxy-5,6,7,8-tetrahydro-2-naphth-
Prepared
oxy)-1,2-bis(mesyloxy)propane
[(R)-30].
from (R)-29 as described for (S)-30: mp 112–113°C;
25
½aŠ ¼ ꢀ4:8 (c 1, chloroform); 1H NMR identical to
D
that of (S)-30.
5.1.32. 3-Benzyloxy-5,6,7,8-tetrahydro-2-naphthol (27).
A solution of crude 26 (46g, 0.155mol) in methanol
(240mL) was added with 2, 5N NaOH (80mL) and stir-
red at room temperature for 5h. After addition of HCl
10% until pH1, a brownish solid was formed, which
was isolated by filtration. The solid was crystallized
twice from cyclohexane to give 29g of 27 as a yellow
5.1.39. (R)-2-((Mesyloxy)methyl)-2,3,6,7,8,9-hexahydro-
naphtho[2,3-b][1,4]dioxine [(R)-31]. Prepared from (S)-30
as described for (R)-14 and isolated as a white solid
25
(78%): mp 81°C; ½aŠ ¼ ꢀ13:8 (c 1, chloroform); 1H
D
NMR (CDCl3) d 1.67 (m, 4H), 2.58 (m, 4H), 3.02 (s,
3H), 4.02 (dd, 1H), 4.19 (dd, 1H), 4.34 (m, 3H), 6.52
(s, 2H).
1
solid: mp 75–76°C; H NMR (CDCl3) d 1.78 (m, 4H),
2.68 (m, 4H), 5.06 (s, 2H), 6.63 (s, 1H), 6.66 (s, 1H),
7.37–7.45 (m, 5H).
5.1.40. (S)-2-((Mesyloxy)methyl)-2,3,6,7,8,9-hexahydro-
naphtho[2,3- b][1,4]dioxine[(S)-31]. Prepared from (R)-
5.1.33. (R)-3-(3-Benzyloxy-5,6,7,8-tetrahydro-2-naphth-
oxy)-1,2-propanediol [(R)-28]. A solution of 3-benzyl-
oxy-2-naphthol 27 (15g, 59.0mmol) and potassium
hydroxide (3.9g, 60mmol) in ethanol (200mL) was
heated at 70°C for 30min and, after adding (2R)-1-me-
syloxy-2,3-propanediol acetonide [(R)-9] (12.6g,
60mmol), refluxed for 24h. The solvent was evaporated
and the residue treated with methanol (70mL) and HCl
1N (70mL). The resulting suspension was heated at
75°C for 3h. The methanol was evaporated under vac-
25
D
1, chloroform); H NMR identical to that of (R)-31.
30 as described for (R)-31: mp 79.0°C; ½aŠ ¼ þ13:5 (c
1
5.1.41. 1-Methoxy-2-acetonaphthone (32). Iodomethane
(16.2mL, 260mmol) was added dropwise to a solution
of 1-hydroxy-2-acetonaphthone (24.2g, 130mmol) and
potassium hydroxide (8g, 143mmol) in DMSO
(250mL) at room temperature. After 18h, water
(200mL) and diethyl ether (50mL) were added. The

4946
C. Bolchi et al. / Bioorg. Med. Chem. 12 (2004) 4937–4951
aqueous layer was separated and extracted with diethyl
ether twice. The organic phases were combined, dried,
and concentrated to give the crude product, which was
purified by chromatography on silica gel. Elution with
cyclohexane/ethyl acetate (95:5) afforded 24.1g (93%)
of 32 as a yellow oil: H NMR (CDCl3) d 2.78 (s, 3H),
4.13 (s, 3H), 7.49–7.65 (m, 3H), 7.74 (d, 1H), 7.86 (m,
1H), 8.23 (m, 1H).
5.1.45. 1-Methoxy-2-(2-azidoethoxy)naphthalene (36). A
mixture of 35 (8.95g, 24mmol) and sodium azide
(15.6g, 240mmol) in DMF (130mL) was heated at
90°C for 2h. After cooling, water (30mL) and ethyl ace-
tate (150mL) were added. The aqueous layer was sepa-
rated and extracted with ethyl acetate twice. The organic
phases were combined, washed with water, dried, and
concentrated to give the crude product, which was puri-
fied by chromatography on silica gel. Elution with cyclo-
hexane/ethyl acetate (70:30) afforded 5.37g (92%) of 36
1
5.1.42. 1-Methoxy-2-hydroxynaphthalene (33). 3-Chloro-
perbenzoic acid (61.75g) was added to a solution of
32 (24g, 120mmol) in dichloromethane (400mL) at
0°C. The reaction mixture was stirred at room tempera-
ture for 20days, repeating the addition of 3-chloroper-
benzoic acid (10g) every five days. The progress of the
1
as a yellow oil: H NMR (CDCl3) d 3.66 (t, 2H), 4.06
(s, 3H), 4.31 (t, 2H), 7.27 (d, 1H), 7.38–7.56 (m, 2H),
7.60(d, 1H), 7.81 (d, 1H), 8.17 (d, 1H).
5.1.46. 1-Methoxy-2-(2-aminoethoxy)naphthalene (37).
Hydrazine hydrate (22.4mL) was added dropwise to a
stirred mixture of 36 (7.47g, 30.7mmol) and PdO
(86mg) in methanol (160mL) at 65degrC. After reflux-
ing for 2h, the reaction mixture was cooled to room
temperature and filtered. The filtrate was concentrated
and the resulting crude product purified by chromatog-
raphy on silica gel. Elution with dichloromethane/meth-
1
reaction was monitored by H NMR analysis observing
the shifting of the acetyl signal from 2.8 to 2.4 d. At the
end of the reaction, the mixture was washed with a sa-
turated solution of sodium bicarbonate. The organic
phase was dried and concentrated. The residue was dis-
solved in methanol (120mL) and concentrated sulfuric
acid (4mL) was added. After stirring over-night at room
temperature, the solvent was removed and the residue
treated with brine and diethyl ether. The aqueous layer
was separated and extracted with diethyl ether twice.
The organic phases were combined, dried, and concen-
trated to give the crude product, which was purified by
chromatography on silica gel. Elution with cyclohex-
ane/ethyl acetate (95:5) afforded 13.5g (65%) of 33 as
1
anol (98:2) gave 4.46g (67%) of 37 as an oil: H NMR
(CDCl3) d 1.95 (br s, 2H), 3.15 (t, 2H), 4.01 (s, 3H),
4.19 (t, 2H), 7.24 (d, 1H), 7.41 (t, 1H), 7.49 (t, 1H),
7.57 (d, 1H), 7.78 (d, 1H), 8.11 (d, 1H).
5.1.47. 2-Hydroxy-3-methoxynaphthalene (38). 95%
Potassium tert-butoxide (14.8g, 125mmol) was added
in small portions to a solution of 2,3-dihydroxynaphtha-
lene (20g, 125mmol) in 2-methoxyethanol (100mL).
After dimethyl sulfate (15.8g, 125mmol) was added
dropwise, the reaction mixture was heated at 80°C
over-night. 40% NaOH (15mL) and water (25mL) were
added dropwise at 80°C. After cooling to room temper-
ature, the solvent was removed and the residue treated
with 10% HCl (50mL) and dichloromethane (20mL).
The aqueous layer was separated and extracted with di-
chloromethane twice. The organic phases were com-
bined, washed with water, dried, and concentrated to
give the crude product, which was purified by chroma-
tography on silica gel. Elution with cyclohexane/ethyl
acetate (85:15) afforded 18.2g (84%) of 38 as a white
solid: mp 108–109°C; 1H NMR (CDCl3) d 4.03 (s,
3H), 5.92 (br s, 1H), 7.12 (s, 1H), 7.33 (m, 3H), 7.65
(m, 2H). Anal. Calcd for C11H10O2 (174.20).
1
a yellow solid: mp 92–93°C; H NMR (CDCl3) d 3.98
(s, 3H), 5.80(s, 1H), 7.23 (d, 1H), 7.30(d, 1H), 7.48
(t, 1H), 7.57 (d, 1H), 7.79 (d, 1H), 7.94 (d, 1H). Anal.
Calcd for C11H10O2 (174.20).
5.1.43. 1-Methoxy-2-(2-hydroxyethoxy)naphthalene (34).
A mixture of 33 (8.5g, 48.8mmol), ethylene carbonate
(8.53g, 96.9mmol) and potassium carbonate (13.5g,
97mmol) in toluene (160mL) was refluxed over-night.
After cooling to room temperature, water was added.
The aqueous layer was separated and extracted with
toluene twice. The organic phases were combined, dried,
and concentrated to give a brown oil (10g), which was
purified by chromatography on silica gel. Elution with
cyclohexane/ethyl acetate (80:20) yielded 8g (75%) of
1
34 as a solid: mp 64–65°C; H NMR (CDCl3) d 1.80
(br s, 1H), 3.95 (m, 2H), 4.03 (s, 3H), 4.28 (t, 2H),
7.28 (d, 1H), 7.44 (m, 2H), 7.60(d, 1H), 7.79 (d, 1H),
8.10(d, 1H). Anal. Calcd for C 13H14O3 (218.25).
5.1.48. 2-(2-Hydroxyethoxy)-3-methoxynaphthalene (39).
Prepared from 38 as described for 34 but replacing tol-
uene with DMF. After chromatography on silica gel (cy-
clohexane/ethyl acetate 60:40), the product was isolated
as a yellow oil (70%): 1H NMR (CDCl3) d 3.61 (m, 1H),
3.99 (s, 3H), 4.02 (m, 2H), 4.15 (m, 2H), 7.08 (s, 1H),
7.11 (s, 1H), 7.31 (m, 2H), 7.64 (m, 2H).
5.1.44. 1-Methoxy-2-(2-tosyloxyethoxy)naphthalene (35).
Tosyl chloride (6.8g, 35.7mmol) was added in small
portions to a stirred solution of 34 (7.8g, 35.7mmol)
in pyridine (9mL) at 0°C. The resulting mixture was
stirred at room temperature over-night, diluted with di-
chloromethane (30mL), and washed with 10% HCl. The
aqueous layer was separated and extracted with dichlo-
romethane twice. The organic phases were combined,
dried, and concentrated. The resulting crude product
(13g) was crystallized from diethyl ether yielding 9.05g
5.1.49. 2-(2-Tosyloxyethoxy)-3-methoxynaphthalene (40).
Prepared from 39 as described for 35 and isolated, after
chromatography on silica gel (cyclohexane/ethyl acetate
1
70/30), as a white solid (51%): mp 88–89 °C; H NMR
1
(68%) of 35 as a white solid: mp 78–79°C; H NMR
(CDCl3) d 2.40(s, 3H), 3.95 (s, 3H), 4.32 (m, 2H),
4.46 (m, 2H), 7.05 (s, 1H), 7.11 (s, 1H), 7.33 (m, 4H),
7.65 (m, 2H), 7.84 (d, 2H). Anal. Calcd for C20H20O5S
(372.44).
(CDCl3) 2.42 (s, 3H), 3.93 (s, 3H), 4.38 (m, 4H), 7.14
(d, 1H), 7.26–7.55 (m, 5H), 7.80(m, 3H), 8.10(d, 1H).
Anal. Calcd for C20H20O5S (372.44).

C. Bolchi et al. / Bioorg. Med. Chem. 12 (2004) 4937–4951
4947
5.1.50. 2-(2-Azidoetoxy)-3-methoxynaphthalene (41).
Prepared from 40 as described for 36. After chromato-
graphy on silica gel (cyclohexane/ethyl acetate 80:20),
the product was isolated as a white solid (98%): mp
65–66°C; H NMR (CDCl3) d 3.65 (m, 2H), 3.95 (s,
3H), 4.25 (m, 2H), 7.05 (s, 1H), 7.09 (s, 1H), 7.34 (m,
2H), 7.65 (m, 2H). Anal. Calcd for C13H13N3O2
(243.27).
2H), 4.65 (m, 2H), 7.15 (m, 2 H), 7.41 (m, 2H), 7.76
(m, 3H). Anal. Calcd for C13H14O4S (266.31).
5.1.58. 2-(2-Azidoethoxy)naphthalene (49). Prepared
from 48 as described for 36 and isolated, after chroma-
tography on silica gel (cyclohexane/ethyl acetate 85/15),
1
1
as a white solid (83%): mp 75–76°C; H NMR (CDCl3)
d 3.67 (t, 2H), 4.27 (t, 2H), 7.10(m, 2H), 7.44 (m, 2H),
7.77 (m, 3H). Anal. Calcd for C12H11N3O (213.24).
5.1.51. 2-(2-Aminoethoxy)-3-methoxynaphthalene (42).
Hydrazine hydrate (25mL) was added dropwise to a
stirred mixture of 41 (9.07g, 37.3mmol) and PdO
(96mg) in methanol (100mL) at 65°C. After refluxing
for 90min, the reaction mixture was filtered and the fil-
trate concentrated. The residue was treated with dichlo-
romethane (30mL) and 10% HCl (20mL). The organic
layer was separated and extracted with 10% HCl twice.
The acidic aqueous phases were combined, made alka-
line with 10% sodium hydroxide (100mL), and extracted
with dichloromethane several times. The organic ex-
tracts were combined, dried, and concentrated to give
4.9g (60%) of 42 as a viscous yellow oil: 1H NMR
(CDCl3) d 1.90(br s, 2H), 3.21 (t, 2H), 3.98 (s, 3H),
4.15 (t, 2H), 7.13 (br s, 2H), 7.33 (m, 2H), 7.65 (m, 2H).
5.1.59. 2-(2-Aminoethoxy)naphthalene (50). Prepared
from 49 as described for 37 and isolated, after chroma-
tography on silica gel (dichloromethane/methanol
90:10), as a low-melting solid (75%): H NMR (CDCl3)
d 1.74 (s, 2H), 3.09 (t, 2H), 4.04 (t, 2H), 7.12 (m, 2H),
7.45 (m, 2H), 7.75 (m, 3H).
1
5.1.60. 2-Methoxynaphthoformiate (51). 3-Chloroper-
benzoic acid (16.7g, 96mmol) was added to a solution
of 2-methoxynaphthaldeyde (9g, 48.3mmol) and ethyl-
acetate (90mL) at 0 °C. The reaction mixture was stirred
at room temperature for 40h. The progress of the reac-
1
tion was monitored by H NMR analysis observing the
lost of the aldehyde signal. At the end of the reaction the
ethylacetate was evaporated under vacuum. The residue
was diluted with dichloromethane filtrated and washed
twice with a saturated solution of sodium bicarbonate
and with water. The organic phase was dried and con-
5.1.52. 1-(2-Hydroxyethoxy)naphthalene (43). Prepared
from 1-naphthol as described for 34 and isolated as a
1
yellow oil (83%): H NMR (CDCl3) d 2.95 (br s, 1H),
4.08 (m, 2H), 4.17 (m, 2H), 6.77 (d, 1H), 7.35 (t, 1H),
7.52 (m, 3H), 7.85 (m, 1H), 8.35 (m, 1H).
1
centrated to give 9.0g of 51 (91.8%) as violet oil. H
NMR (CDCl3) d 3.96 (s, 3H), 7.36–7.40(m, 2H), 7.52
(t, 1H), 7.76–7.87 (m, 1H), 8.45 (s, 1H).
5.1.53. 1-(2-Tosyloxyethoxy)naphthalene (44). Prepared
from 43 as described for 35 and isolated as a white solid
1
(64%): mp 99–100°C; H NMR (CDCl3) d 2.42 (s, 3H),
5.1.61. 2-Methoxynaphthol (52). LiAlH4 (1.9g, 50mmol)
was suspended in anhydrous THF (20mL) under N2 and
a solution of 51 (10g, 50mmol) in THF was added drop-
wise. After 4h, the reaction was quenched into frozen
10% HCl (50mL) and extracted with dichloromethane
(100mL). The organic phase was separated, washed with
water, dried and concentrated to give 8.53g of crude 52
as a yellow oil, which was purified by chromatography
on silica gel. Elution with toluene afforded 4.0g of 52
4.33 (m, 2H), 4.53 (m, 2H), 6.69 (d, 1H), 7.20–7.60 (m,
6H), 7.59 (d, 1H), 7.84 (d, 2H), 8.02 (d, 1H). Anal. Calcd
for C19H18O4S (342.41).
5.1.54. 1-(2-Azidoethoxy)naphthalene (45). Prepared
from 44 as described for 36. Hexane/water extraction
and concentration of organic phases gave 45 as a yellow
oil (92%): 1H NMR (CDCl3) d 3.65 (t, 2H), 4.21 (t, 2H),
6.77 (d, 1H), 7.46 (t, 1H), 7.60(m, 3H), 7.92 (m, 1H),
8.45 (m, 1H).
1
(47%)as green solid: mp 53.38°C; H NMR (CDCl3) d
4.0(s, 3H), 6.05 (s, 1H) 7.27 (d, 1H) 7.41 (m, 3H) 7.75
(d, 1H) 8.15 (d, 1H).
5.1.55. 1-(2-Aminoethoxy)naphthalene (46). Prepared
from 45 as described for 37 and identically isolated as
1
5.1.62. 1-(2-Bromoethoxy)-2-methoxynaphthalene (53).
Sodium hydride (1g, 39.6mmol) was suspended in
THF anhydrous (5mL) under N2 atmosphere, and the
mixture was cooled at 0°C. DMSO (5mL) was joined
and 52 (5.5g, 31.5mmol) diluted with THF/DMSO (1/
1; 30mL) was added dropwise keeping the temperature
under 20°C. At the end, the reaction mixture was
quenched into frozen 10% HCl and dichloromethane
was added (100mL). The organic phase was separated,
washed with water, dried and concentrated to give the
crude product, which was purified by chromatography
on silica gel. Elution with cyclohexane/ethylacetate
an oil (56%): H NMR (CDCl3) d 1.65 (br s, 2H), 3.21
(t, 2H), 4.14 (t, 2H), 6.80(d, 1H), 7.40–7.60(m, 4H),
7.81 (m, 1H), 8.29 (m, 1H).
5.1.56. 2-(2-Hydroxyethoxy)naphthalene (47). Prepared
from 2-naphthol as described for 34 and isolated, after
chromatography on silica gel (cyclohexane/ethyl acetate
1
60:40), as a yellow solid (62%): mp 76–77 °C; H NMR
(CDCl3) d 2.36 (br s, 1H), 4.11 (m, 2H), 4.19 (m, 2H),
7.22–7.26 (m, 2H), 7.32–7.50(m, 2H), 7.72–7.80(m,
3H). Anal. Calcd for C12H12O2 (188.23).
1
(70:30) afforded 1.78g (30%) of 53 as a yellow oil. H
5.1.57. 2-(2-Mesyloxyethoxy)naphthalene (48). Prepared
from 47 as described for (S)-12. Crystallization from
methanol yielded 48 (96%) as a white solid (96%): mp
NMR (CDCl3) d 3.73 (t, 2H), 3.98 (s, 3H), 4.47 (t,
2H), 7.25 (d, 1H), 7.38 (t, 1H), 7.50(t, 1H), 7.63 (d,
1H) 7.79 (d, 1H), 8.25 (d, 1H).
1
114–115°C; H NMR (CDCl3) 3.12 (s, 3H), 4.37 (m,

4948
C. Bolchi et al. / Bioorg. Med. Chem. 12 (2004) 4937–4951
5.1.63. (S)-2-[((2-(2,6-Dimethoxyphenoxy)ethyl)amino)-
methyl]-2,3-dihydronaphtho[2,3-b][1,4]dioxine hydrochlo-
ride [(S)-2]. A solution of (R)-22 (1.2g, 3.7mmol) and
2-(2,6-dimethoxyphenoxy)ethylamine (1.47g, 7.45mmol)
in 2-propanol (30mL) was refluxed for 48h. After cool-
ing to room temperature, 10% NaOH and ethyl acetate
were added. The aqueous layer was separated and
extracted with ethyl acetate again. The organic phases
were combined, dried, and concentrated to give a resi-
due, which was purified by chromatography on silica gel.
Elution with dichloromethane/methanol (95:5) afforded
0.89g (61%) of (2S)-2-[((2-(2,6-dimethoxyphenoxy)-
(m, 4 H), 3.76 (s, 6H), 4.03 (dd, 1H),4.12 (m, 2H),
4.30(dd 1H), 4.65 (m, 1H), 6.57 (s, 2H), 6.69 (d, 2H),
7.04 (t, 1H), 9.05 (br s, 1H), 9.52 (br s, 1H). Anal. Calcd
for C23H30ClNO5 (435.94).
5.1.66. (R)-2-[((2-(2,6-Dimethoxyphenoxy)ethyl)amino)-
methyl]-2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]dioxine
hydrochloride [(R)-3]. Prepared from (S)-31 and 2-(2,6-di-
methoxyphenoxy)ethylamine as described for (S)-3: mp
25
25
202.5°C; ½aŠ ¼ þ43:2 (c 1, methanol) (½aŠ ¼ þ22:9
D
D
(c 1, chloroform) for the free amine); 1H NMR identical
to that of (S)-3. Anal. Calcd for C23H30ClNO5 (435.94).
ethyl)amino)methyl]-2,3-dihydronaphtho[2,3-b][1,4]di-
25
D
oxine as an oil: ½aŠ ¼ ꢀ43:0 (c 1, chloroform);); 1H
5.1.67. (S)-2-[((2-(1-Naphthoxy)ethyl)amino)methyl]-1,4-
benzodioxane hydrochloride [(S)-4]. A mixture of (R)-14
(880mg, 3.60mmol) and 46 (678mg, 3.62mmol) in 2-
propanol (10mL) was refluxed for 36h. The solvent
was evaporated and the residue treated with 10% NaOH
(30mL) and ethyl acetate (30mL). The aqueous layer
was separated and extracted with ethyl acetate. The or-
ganic phases were combined, washed with water, dried,
and concentrated to give a residue, which was purified
by chromatography on silica gel. Elution with dichloro-
methane/methanol (98:2) afforded 600mg of (2S)-2-[((2-
(1-naphthoxy)ethyl)amino)methyl]-1,4-benzodioxane as
NMR (CDCl3) d 2.20(br s, 1H), 2.93–3.10(m, 4H),
3.85 (s, 6H), 4.15 (m, 3H), 4.40(m, 2H), 6.61 (d, 2H),
7.00 (t, 1H), 7.29 (m, 4H), 7.64 (m, 2H). The secondary
amine was dissolved in ethanol (20mL) and 2N HCl/
EtOH (4mL) was added. The solution was filtered and
the filtrate concentrated to give a residue, which was
crystallized from 2-propanol yielding 0.53g (33%, based
on the starting amount of (R)-22) of (S)-2 as a white
25
D
solid: mp 161°C; ½aŠ ¼ ꢀ60:5 (c 1, ethanol); 1H
NMR (DMSO-d6) d 3.38 (m, 2H), 3.56 (m, 2H), 3.83
(s, 6H), 4.19–4.40(m, 3H), 4.55 (m, 1H), 4.90(m, 1H),
6.75 (d, 2H), 7.11 (t, 1H), 7.36 (m, 2H), 7.45 (m, 2H),
7.78 (m, 2H), 9.20(br s, 1H), 9.40(br s, 1H). Anal. Cal-
cd for C23H26ClNO5 (431.91).
25
1
a yellow oil: ½aŠ ¼ ꢀ21:8 (c 1, chloroform); H NMR
D
(CDCl3) d 2.01 (br s, 1H), 3.05 (m, 2H), 3.23 (t, 2H),
4.06 (dd, 1H), 4.20–4.40 (m, 4H), 6.82–6.92 (m, 5H),
7.34–7.52 (m, 4H), 7.82 (m, 1H), 8.27 (m, 1H). The sec-
ondary amine was dissolved in a mixture of ethanol
(5mL) and ethyl acetate (5mL), and 4.6 N HCl/EtOH
(1mL) was added. The resulting precipitate was isolated,
rinsed with ethanol, and dried yielding 360mg (27%,
5.1.64. (R)-2-[((2-(2,6-Dimethoxyphenoxy)ethyl)amino)-
methyl]-2,3-dihydronaphtho[2,3-b][1,4]dioxine hydrochlo-
ride [(R)-2]. Prepared from (S)-22 and 2-(2,6-dimethoxy-
phenoxy)ethylamine as described for (S)-2: mp 160°C;
based on the starting amount of (R)-14) of (S)-1 as a
25
25
25
D
½aŠ ¼ þ59:0 (c 1, ethanol) (½aŠ ¼ þ43:3 (c 1, chloro-
white solid: mp 191.2–192.5°C; ½aŠ ¼ ꢀ58:4 (c 1, meth-
D
D
form) for the free amine); H NMR identical to that
1
1
anol); H NMR (DMSO-d6) d 3.44 (m, 2 H), 3.65 (m,
2H), 4.16 (dd, 1H), 4.47–4.57 (m, 3H), 4.87 (m, 1H),
6.94 (m, 4H), 7.04 (d, 1H), 7.43–7.61 (m, 4H), 7.92
(dd, 1H), 8.49 (d, 1H), 9.99 (br s, 2H). Anal. Calcd for
C21H22ClNO3 (371.86).
of (S)-2. Anal. Calcd for C23H26ClNO5 (431.91).
5.1.65. (S)-2-[((2-(2,6-Dimethoxyphenoxy)ethyl)amino)-
methyl]-2,3,6,7,8,9-hexahydro naphtho[2,3-b][1,4]dioxine
hydrochloride [(S)-3]. A solution of (R)-31 (1.2g,
4.0mmol) and 2-(2,6-dimethoxyphenoxy)ethylamine
(0.79g, 4.0mmol) in 2-methyl-1-propanol (6mL) was
refluxed for 48h. After cooling to room temperature,
10% NaHCO3 and ethyl acetate were added. The aque-
ous layer was separated and extracted with ethyl acetate
again. The organic phases were combined, dried, and
concentrated to give a residue, which was purified by
chromatography on silica gel. Elution with cyclohex-
ane/ethyl acetate (80:20) afforded 0.940g (58.8%) of
(2S)-2-[((2-(2,6-dimethoxyphenoxy)ethyl)amino)methyl]-
5.1.68. (R)-2-[((2-(1-Naphthoxy)ethyl)amino)methyl]-1,4-
benzodioxane hydrochloride [(R)-4]. Prepared from (S)-
14 and 46 as described for (S)-4: mp 190.5–191.5°C;
25
25
½aŠ ¼ þ58:4 (c 1, methanol) ð½aŠ ¼ þ22:6 (c 1, CHCl3)
D
D
1
for the free amine); H NMR identical to that of (S)-4.
Anal. Calcd for C21H22ClNO3 (371.86): C, 67.83; H,
5.96; N, 3.77; Cl, 9.53. Found: C, 67.71; H, 5.91; N,
3.71; Cl, 9.59.
5.1.69. (S)-2-[((2-(2-Naphthoxy)ethyl)amino)methyl]-1,4-
benzodioxane hydrochloride [(S)-5]. A mixture of (R)-14
(2.42g, 9.89mmol) and 50 (1.85g, 9.89mmol) in 2-pro-
panol (10mL) was refluxed for 48h. (2S)-2-[((2-(2-
Naphthoxy)ethyl)amino)methyl]-1,4-benzodioxane was
isolated as described for (2S)-2-[((2-(1-naphth-
2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]dioxine as
a
25
solid: mp 75–76°C; ½aŠ ¼ ꢀ24:3 (c 1, chloroform););
D
1H NMR (CDCl3) d 1.74 (m, 4H), 2.55 (br s, 1H) 2.65
(m, 4H), 2.88–3.00 (m, 4H), 3.84 (s, 6H), 3.98–4.05 (m,
1H), 4.14 (m, 2H), 4.27 (m, 2H), 6.58 (m, 4H), 6.99 (t,
1H). The secondary amine was dissolved in ethanol
(5mL) and 2N HCl/EtOH (4mL) was added. The
resulting precipitate was isolated, rinsed with ethanol,
and dried yielding 0.634g (62%, based on the starting
oxy)ethyl)amino)methyl]-1,4-benzodioxane in 46% yield
25
D
(1.51g) as a white solid: mp 111–112°C; ½aŠ ¼ ꢀ34:4 (c
1
1, CHCl3); H NMR (CDCl3) 1.68 (br s, 1H), 3.01 (m,
2H), 3.14 (t, 2H), 4.06 (dd, 1H), 4.19–4.34 (m, 4H),
6.85 (m, 4H), 7.17 (m, 2H), 7.38 (m, 2H), 7.75 (m,
3H). The secondary amine was dissolved in ethyl acetate
(10mL), and 2N HCl/EtOH (4mL) was added. The
amount of (R)-31) of (S)-3 as a white solid: mp 203–
25
204°C; ½aŠ ¼ ꢀ43:7 (c 1, methanol); 1H NMR
D
(DMSO-d6) d 1.65 (m, 4H), 2.59 (m, 4H), 3.30–3.45

C. Bolchi et al. / Bioorg. Med. Chem. 12 (2004) 4937–4951
4949
resulting precipitate was isolated, rinsed with ethyl ace-
tate, and dried yielding 1.2g (33%, based on the starting
amount of (R)-14) of (S)-5 as a white solid: mp 244–
amine was dissolved in ethanol (10mL), and 2N HCl/
EtOH (5mL) was added. The solvent was evaporated
and the resulting residue crystallized from ethyl acetate
(20mL) yielding 450mg (36%, based on the starting
amount of (R)-14) of (S)-7 as a white solid: mp 154–
25
1
245°C; ½aŠ ¼ ꢀ46:1 (c 1, DMSO); H NMR (DMSO-
D
d6) d 3.37 (m, 2H), 3.57 (m, 2H), 4.14 (dd, 1H), 4.43
(m, 3H), 4.72 (m, 1H), 6.94 (m, 4H), 7.26 (m, 1H),
7.51 (m, 3H), 7.89 (m, 3H), 9.32 (br s, 2H): Anal. Calcd
for C21H22ClNO3 (371.86).
25
1
155°C; ½aŠ ¼ ꢀ44:3 (c 1, ethanol); H NMR (DMSO-
D
d6) d 3.40(m, 2H), 3.57 (m, 2H), 3.97 (s, 3H), 4.18 (m,
1H), 4.40–4.60 (m, 3H), 4.76 (m, 1H), 6.95 (br s, 4H),
7.35–7.60(m, 3H), 7.75 (d, 1H), 7.93 (d, 1H), 8.06 (d,
1H), 9.50(br s, 1H), 9.70(br s, 1H). Anal. Calcd for
C22H24ClNO4 (401.89).
5.1.70. (R)-2-[((2-(2-Naphthoxy)ethyl)amino)methyl]-1,4-
benzodioxane hydrochloride [(R)-5].. Prepared from (S)-
14 and 50 as described for (S)-5: mp 244–245°C;
25
25
½aŠ ¼ þ46:1 (c 1, DMSO) (½aŠ ¼ þ33:9 (c 1, CHCl3)
5.1.74. (R)-2-[((2-(1-Methoxy-2-naphthoxy)ethyl)amino)-
methyl]-1,4-benzodioxane hydrochloride [(R)-7]. Prepared
from (S)-14 and 35 as described for (S)-7: mp 155–
D
D
1
for the free amine); H NMR identical to that of (S)-
5. Anal. Calcd for C21H22ClNO3 (371.86).
25
25
156°C; ½aŠ ¼ þ44:7 (c 1, ethanol) ð½aŠ ¼ þ24:6 (c 1,
D
CHCl3) for the free amine); H NMR identical to that
D
1
5.1.71.
methyl]-1,4-benzodioxane hydrochloride [(S)-6]. A mix-
ture of S-14, 2-aminomethyl-1,4-benzodioxane,
(S)-2-[((1-Naphthoxy-2-methoxy)ethyl)amino)-
of (S)-7. Anal. Calcd for C22H24ClNO4 (401.89).
(401.6mg, 1.99mmol) and 54 (280mg, 0.996mmol) in
2-methylpropanol (4mL) was refluxed for 4h. The sol-
vent was evaporated and the residue treated with 10%
HCl (5mL) and dichloromethane (10mL). The aqueous
layer was separated and extracted with dichloromethane.
The organic phases were combined, washed with water,
dried and concentrated to give a residue, which was puri-
fied by chromatography on silica gel. Elution with
cyclohexane/ethylacetate/2-methyl-1-propanol (1:1:0.3)
afforded 320mg of (2S)-2-[((1-naphthoxy-2-meth-
5.1.75. (S)-2-[((2-(3-Methoxy-2-naphthoxy)ethyl)amino)-
methyl]-1,4-benzodioxane hydrochloride [(S)-8]. A mix-
ture of (R)-14 (884mg, 3.62mmol) and 42 (787mg,
3.62mmol) in 2-propanol (10mL) was refluxed for
36h. Crude (2S)-2-[((2-(3-methoxy-2-naphthoxy)ethyl)-
amino)methyl]-1,4-benzodioxane was isolated as
described for (2S)-2-[((2-(1-naphthoxy)ethyl)amino)-
methyl]-1,4-benzodioxane and purified by chromatogra-
phy on silica gel. Elution with dichloromethane/metha-
nol (95:5) afforded 365mg (28%) of the secondary
25
oxy)ethyl)amino)methyl]-1,4-benzodioxane as
a
yel-
amine as a white solid: mp 107–108°C; ½aŠ ¼ ꢀ29:0
D
25
D
1
low oil: ½aŠ ¼ ꢀ27:5 (c 1, CHCl3); H NMR (CDCl3)
(c 1, CHCl3); 1H NMR (CDCl3) d 1.80(br s, 1H),
3.01 (t, 2H), 3.18 (t, 2H), 3.99 (s, 3H), 4.06 (dd, 1H),
4.23–4.34 (m, 4H), 6.86 (m, 4H), 7.13 (s, 1H), 7.16 (s,
1H), 7.34 (m, 2H), 7.67 (m, 2H). Anal. Calcd for C22
H23 NO4 (365.43). (2S)-2-[((2-(3-Methoxy-2-naphth-
oxy)ethyl)amino)methyl]-1,4-benzodioxane was dis-
solved in ethyl acetate (10mL), and 2N HCl/EtOH
(2mL) was added. The resulting precipitate was isolated,
rinsed with ethyl acetate, and dried yielding 395mg
d 2.19 (br s, 1H), 2.96–3.13 (m, 4H), 3.98 (s, 3H), 4.07
(q, 1H), 4.25–4.38 (m, 4H), 6.82–6.93 (m, 4H), 7.27–
7.38 (m, 2H), 7.46 (t, 1H), 7.60(d, 1H), 7.78 (d, 1H),
8.12 (d, 1H). The secondary amine was dissolved in
EtOH (5mL) and 1.39N HCl/EtOH (3mL) was added.
The resulting precipitate was isolated, rinsed with etha-
nol, and dried yielding 120mg (15% based on the starting
amount of (S)-14) of (S)-6 as a white solid: mp 164°C;
25
½aŠ ¼ ꢀ46:5 (c 1, ethanol); 1H NMR (DMSO-d6) d
(27%, based on the starting amount of (R)-14) of (S)-8
D
25
D
3.35–3.50(m, 4H), 3.92 (s, 3H), 4.80–4.14 (m, 1H),
4.31–4.42 (m, 3H), 4.74–4.77 (m, 1H), 6.85–6.95 (m,
4H), 7.38 (m, 1H), 7.50(m, 2H), 7.74 (d,1H), 7.86 (d,
1H), 8.10(d, 1H), 9.46 (br s, 1H), 9.76 (br s, 1H).
as a white solid: mp 155–156°C; ½aŠ ¼ ꢀ45:2 (c 1, eth-
1
anol); H NMR (DMSO-d6) d 3.41 (m, 2H), 3.55 (m,
2H), 3.93 (s, 3H), 4.15 (dd, 1H), 4.43 (m, 3H), 4.78
(m, 1H), 6.64 (m, 4H), 7.39 (m, 4H), 7.80(m, 2H),
9.73 (br s, 2H). Anal. Calcd for C22H24ClNO4 (401.88).
5.1.72. (R)-2-[((1-Naphthoxy-2-methoxy)ethyl)-amino)-
methyl]-1,4-benzodioxane hydrochloride[(R)-6]. Prepared
from (R)-14 and 54 as described for (S)-6: mp 162°C;
5.1.76. (R)-2-[((2-(3-Methoxy-2-naphthoxy)ethyl)amino)-
methyl]-1,4-benzodioxane hydrochloride [(R)-8]. Prepared
from (S)-14 and 42 as described for (S)-8: mp 154–
25
25
½aŠ ¼ þ43:5 (c 1, ethanol) (½aŠ ¼ þ25:4 (c 1, CHCl3)
D
D
for the free amine); H NMR identical to that of (S)-6.
25
25
1
155°C; ½aŠ ¼ þ45:2 (c 1, ethanol) (½aŠ ¼ þ27:9 (c 1,
D
CHCl3) for the free amine); H NMR identical to that
D
1
5.1.73. (S)-2-[((2-(1-Methoxy-2-naphthoxy)ethyl)amino)-
methyl]-1,4-benzodioxane hydrochloride [(S)-7]. A solu-
tion of (R)-14 (769mg, 3.15mmol) and 37 (1.37g,
6.3mmol) in n-butanol (30mL) was refluxed for 48h.
(2S)-2-[((2-(1Methoxy-2-naphthoxy)ethyl)amino)methyl]-
1,4-benzodioxane was isolated as described for (2S)-2-
of (S)-8. Anal. Calcd for C22H24ClNO4 (401.88).
5.2. Biology
Binding assays. The pharmacological profile of both the
S and R enantiomers of compounds 1–8 was assessed by
measuring their affinities for a1a, a1b, a1d AR-subtypes
and 5-HT1A serotoninergic receptor with in vitro bind-
ing studies.
[((2-(1-naphthoxy)ethyl)amino)methyl]-1,4-benzodiox-
25
D
ane in 50% yield (570mg) as a viscous oil: ½aŠ ¼ ꢀ25:3
1
(c 1, CHCl3); H NMR (CDCl3) d 1.75 (br s, 1H), 3.01
(t, 2H), 3.15 (t, 2H), 4.02 (s, 3H), 4.05–4.11 (m, 1H),
4.25–4.40(m, 4H), 6.86 (m, 4H), 7.2–07.55 (m, 3H),
7.58 (d, 1H), 7.78 (d, 1H), 8.12 (d, 1H). The secondary
Briefly, membranes derived from Chinese Hamster
Ovary (CHO) cells expressing a1-AR subtypes (prepared

4950
C. Bolchi et al. / Bioorg. Med. Chem. 12 (2004) 4937–4951
as described by Testa et al.34) were resuspended in Tris–
HCl, 50mM, pH = 7.7 containing 10 lM pargyline and
0.1% ascorbic acid, and incubated for 30min at 25°C
with 0.5nM [3H]-Prazosin (NEN, 80.5Ci/mmol) in the
absence or presence of different concentrations of the
tested compounds. Prazosin 1lM was used to determine
nonspecific binding.
Acknowledgement
Financial support provided by the Italian Ministero
`
dellÕIstruzione, dellÕUniversita e della Ricerca Scientifica
is gratefully acknowledged.
References and notes
Binding studies at 5-HT1A receptors were carried out
using crude membrane preparations from rat hippocam-
pus, which were resuspended in Tris–HCl 50mM
(pH = 7.7, 10lM pargyline and 4mM CaCl2) and incu-
bated for 30min at 25 °C with 1nM [3H]-8-OH-DPAT,
in the absence or presence of different concentrations
of the tested compounds. 5-HT1A1lM was used to
determine nonspecific binding.
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obtained in the different experiments were pooled to-
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`
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`
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etries are considered as ÔdifferentÕ if they differ more than
60° in one torsion). For each group the lowest energy
geometry was considered only. The d1–d4 distances
and the s angle of pharmacophore models were calcu-
lated averaging the corresponding measures of all the
lowest energy conformers for each analyzed compound,
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each compound in this analysis.
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