Scouting new sigma receptor ligands: Synthesis, pharmacological evaluation and molecular modeling of 1,3-dioxolane-based structures and derivatives

Article abstract of DOI:10.1016/j.ejmech.2016.01.059

Herein we report the synthesis and biological activity of new sigma receptor (σR) ligands obtained by combining different substituted five-membered heterocyclic rings with appropriate σR pharmacophoric amines. Radioligand binding assay, performed on guine

Full text of DOI:10.1016/j.ejmech.2016.01.059

Accepted Manuscript
Scouting New Sigma Receptor Ligands: Synthesis, Pharmacological Evaluation and
Molecular Modeling of 1,3-Dioxolane-Based Structures and Derivatives
Silvia Franchini, Umberto Maria Battisti, Adolfo Prandi, Annalisa Tait, Chiara Borsari,
Elena Cichero, Paola Fossa, Antonio Cilia, Orazio Prezzavento, Simone Ronsisvalle,
Giuseppina Aricò, Carmela Parenti, Livio Brasili
PII:
S0223-5234(16)30069-1
10.1016/j.ejmech.2016.01.059
EJMECH 8349
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 1 October 2015
Revised Date: 13 January 2016
Accepted Date: 30 January 2016
Please cite this article as: S. Franchini, U.M. Battisti, A. Prandi, A. Tait, C. Borsari, E. Cichero, P.
Fossa, A. Cilia, O. Prezzavento, S. Ronsisvalle, G. Aricò, C. Parenti, L. Brasili, Scouting New Sigma
Receptor Ligands: Synthesis, Pharmacological Evaluation and Molecular Modeling of 1,3-Dioxolane-
Based Structures and Derivatives, European Journal of Medicinal Chemistry (2016), doi: 10.1016/
j.ejmech.2016.01.059.
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ACCEPTED MANUSCRIPT
Graphical Abstract

ACCEPTED MANUSCRIPT
Scouting New Sigma Receptor Ligands: Synthesis, Pharmacological Evaluation and
Molecular Modeling of 1,3-Dioxolane-Based Structures and Derivatives.
a
a
a
a
a
Silvia Franchini , Umberto Maria Battisti , Adolfo Prandi , Annalisa Tait , Chiara Borsari , Elena
b
b
c
d
d
Cichero , Paola Fossa , Antonio Cilia , Orazio Prezzavento , Simone Ronsisvalle , Giuseppina Aricò
e
e
a,*
,
Carmela Parenti , Livio Brasili
a
b
Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy.
Dipartimento di Farmacia, Scuola di Scienze Mediche e Farmaceutiche, Università di Genova, Viale Benedetto
.
XV n.3, 16132 Genova, Italy
c
Divisione Ricerca e Sviluppo, Recordati S.p.A., Via Civitali 1, 20148 Milano, Italy
d
Dipartimento di Scienze del Farmaco, Sezione di Chimica Farmaceutica, Università di Catania, Viale A. Doria
6
, 95125 Catania, Italy
e
Dipartimento di Scienze del Farmaco, Sezione di Farmacologia e Tossicologia, Università di Catania, Viale A.
Doria 6, 95125 Catania, Italy
*
Correspondence: Tel +39 059 2058584; Fax +39-059-2055410; livio.brasili@unimore.it
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Abstract
Herein we report the synthesis and biological activity of new sigma receptor (σR) ligands obtained by
combining different substituted five-membered heterocyclic rings with appropriate σR pharmacophoric
amines. Radioligand binding assay, performed on guinea pig brain membranes, identified 25b (1-(1,4-
dioxaspiro[4.5]decan-2-ylmethyl)-4-benzylpiperazine) as the most interesting compound of the series,
displaying high affinity and selectivity for σ R (pKiσ = 9.13; σ /σ = 47). The ability of 25b to
1
1
1
2
modulate the analgesic effect of the κ agonist (−)-U-50,488H and µ agonist morphine was evaluated in
vivo by radiant heat tail-flick test. It exhibited anti-opioid effects on both κ and µ receptor-mediated
analgesia, suggesting an agonistic behavior at σ R. Docking studies were performed on the theoretical
1
σ1R homology model. The present work represents a new starting point for the design of more potent
and selective σ R ligands.
1
Keywords: Sigma receptors ligands; sigma-1; sigma-2; piperidine; piperazine; 1,3-dioxolane; receptor-
mediated analgesia.
2

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1
. Introduction
Sigma receptors (σRs) were discovered in 1976 and initially classified as an additional class of opioid
receptorse [1]. Subsequently, σRs were mischaracterized as PCP/NMDA glutamate receptor complexes,
due to the poor selectivity of the ligands employed [2,3]. However, these hypotheses were disproved
[
4,5]. Today, the σR is recognized as a unique entity with no homology to opioid receptors or other
mammalian proteins[6]. Further radioligand binding studies and biochemical analysis suggested that
sigma receptors exist as two different and distinct subtypes, named sigma-1 receptor (σ R) and sigma-2
1
receptor (σ R) [7,8]. The σ R has been recently characterized and cloned from guinea pig [9], human
2
1
[
(
10], mouse [11,12], and rat tissues [13]. It is present mainly in the endoplasmic reticulum membrane
ER), the mitochondria associated ER membrane (MAM) and the plasma membrane [14]. σ R consists
1
of two transmembrane domains with both the amino and carboxy termini on the cytoplasmic side,
whereas the loop between the transmembrane domains is located within the endoplasmic reticulum [15].
σ1R has been shown to act as a unique ligand-regulated molecular chaperone that modulates the activity
of several proteins, such as the N-methyl-D-aspartate (NMDA) receptor[16] and several ion channels
[
17]. Neurosteroids such as progesterone and dehydroepiandrosterone have been postulated to be the
endogenous σ R ligands[18-20]. Moreover, it has been shown that several exogenous compounds can
1
interact with the σ R. Among them, the dextrorotatory benzomorphans SKF10047 and pentazocine [21-
1
2
5], haloperidol and NE-100 represent relevant σ R ligands [22, 25-27].
1
High affinity σ R ligands have been considered to play an important role in the treatment of various
1
neurological disorders, including depression, schizophrenia, neuropathic pain, and Alzheimer's disease
[
28-34]. Unlike σ Rs, σ Rs have not yet been cloned. This subtype is mainly located in lipid rafts where
1 2
it modulates calcium signalling through sphingolipid products. Very recently it has been proposed that
the progesterone receptor membrane component 1, which binds directly to the heme group and regulates
lipid and drug metabolism and hormone signalling, represents the σ R binding site [35]. Activation of
2
σ2R appears to be involved in the regulation of cellular proliferation and cell death [36]. For these
reasons, the antagonism or inhibition of σ R function could mitigate cell death [37]. Furthermore, it has
2
been reported that σ R ligands can be used as biomarkers for tumour cell proliferation and thus they
2
could be exploited for tumor imaging [37,38]. Therefore, due to the broad diagnostic and therapeutic
potential, the development of potent and selective σ R or σ R ligands is a primary challenge in
1
2
medicinal chemistry.
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In a previously published paper we reported a series of 1,4-benzodioxane-based piperazines and
piperidines as novel σR ligands with a good affinity for both receptor subtypes but lacking in adequate
selectivity among sigma subtypes and sigma /5-HT1A receptors (Chart 1, 1a,b) [39]. Parallel SAR
studies conducted by our research group on α -adrenoreceptor demonstrated the bioequivalence of the
1
1,3-dioxolane moiety with the 1,4-benzodioxane nucleus [40]. This approach has successfully led to the
discovery of a novel class of α -adrenoreceptors antagonists and, more recently, the identification of
1
potent and selective 5-HT receptor agonists and NOP receptor ligands [41, 42].
1
A
Thus, in this work we have applied the same strategy to explore a series of 1,3-dioxolane-based
compounds, obtained by replacing the 1,4-benzodioxane moiety, in order to verify whether the above
mentioned approach could be advantageous also for the class of σR ligands (Chart 1, 8a,b). In addition,
focusing our attention on the 1,3-dioxolane scaffold, we applied the classical medicinal chemistry
approach described in Chart 2, such as annular oxygen bio-isosteric substitutions (Group II and III) and
externalization of the annular oxygen (Group IV) to investigate the effect on activity of a series of five-
membered heterocyclic rings or opened analogues (Group V). Moreover, on the basis of previously
obtained results showing that the phenyl groups at position 2 on the 1,3-dioxolane scaffold are not
essential for the binding to 5-HT R and NOP receptors, we planned the synthesis of the
1
A
conformationally restricted spiro-dioxolanes (Group VI) [41, 43]. All the compounds were tested for
affinity and selectivity at σ and σ R subtypes and detailed SAR studies were drawn up. In addition
1
2
nociceptive effect was evaluated in vivo. In order to rationalize the pharmacological results and support
and guide the chemical exploration, in-silico docking studies were performed on the theoretical σ three-
1
dimensional model.
2
. Results and discussion
2.1. Chemistry
All the compounds (8-25a,b) were prepared by alkylation of the commercially available 4-
benzylpiperidine or 1-benzylpiperidine with the suitable intermediate.
For Group I and II compounds acetalization of the selected ketone with the proper glycerol derivative
provided the corresponding 1,3-dioxolane, oxathiolane and dithiolane-intermediates from which either
the chloro or the tosyl derivatives 3-7 were obtained (Scheme 1). In case of 4, the diastereomeric
mixture was separated by silica gel flash chromatography yielding cis-4 and trans-4. The separated
1
isomers were characterized by means of NOESY experiments and H-NMR studies (Figure 1S, panel a,
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Supporting Informations). The furane derivatives 14a,b (Group III) (Scheme 2) were prepared starting
from the key intermediate 13, obtained in three steps, as recently described (see experimental section).
The cyclopentanone derivatives 16a,b were obtained in good yields by Mannich reaction between
diphenylcyclopentanone (15) in the presence of aqueous paraformaldehyde and 4-benzylpiperidine or 1-
benzylpiperazine as hydrochloride salt to ensure the acidic reaction conditions [44]. Reduction of 16a,b
by NaBH provided the corresponding cyclopentanol derivatives 17a,b (Group IV) (Scheme 2). The
4
cis/trans diastereomeric pairs were separated by using flash column chromatography and their relative
1
stereochemistry was elucidated by NOESY experiments and H -NMR studies (Figure 1S, panel b,
Supporting Informations).
For the 1,3-dioxolane opened analogues 22a,b and 23a,b (Group V), the 3-chloropropane-1,2-diol,
previously protected as tert-butyldiphenylsilyl ether 18, or the 2-chloroethanol was reacted with the
bromodiphenylmethane to yield the alkyl halides 19 and 20 (Scheme 3).
The spiro-dioxolane derivatives 25a,b (Group VI) were readily prepared starting from the key
intermediate 24 (Scheme 2).
2
2
.2. Biological activity
.2.1. Binding affinity
The compounds in Groups I-VI were evaluated for their affinity at both σ R and σ R (Table 1-3). Since
1
2
most of the molecules share the same chemical features with previously published 5-HT R ligands [41,
1
A
4
3, 44] we also evaluated the binding affinities at 5-HT R. Furthermore, the affinity at α
1A 1
adrenoceptors was determined (values not shown) and the compounds showed practically no activity at
these receptors.
Compounds 1a and 1b were our starting points. In a previously published paper we reported that they
display good affinity for both receptor subtypes but lacking in adequate selectivity [39]. Replacing the
1,4-benzodioxane group with the 2,2-diphenyl-dioxolane moiety (8a and 8b) the affinity of both
derivatives was increased by about 5/10-fold while the selectivity remained absent, as in the case of the
parent compounds. However, 8a and 8b show lower affinities for 5-HT R with respect to 1a and 1b
1
A
with good selectivity ratios (σ/5HT ) of 251 and >589, respectively. Replacement of one of the two
1
A
phenyl rings with a cyclohexyl group at position 2 of the 1,3-dioxolane ring led to a different effect for
the two series (piperidine and piperazine), both in terms of affinity and stereoselectivity. Compounds
cis-9a and trans-9a showed a marked decrease in affinity at both receptor subtypes. A decrease in
σ/5HT selectivity was also observed. In this case the stereochemistry seems not to play a significant
1
A
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role. On the contrary, for the piperazine derivatives a certain degree of stereoselectivity at σ R site was
1
observed. Compound trans-9b maintained the affinity at σ subtype while, at σ receptor subtype, the
1
2
value is slightly decreased (7.79 vs 8.38). On the other hand, the cis isomer 9b is more than 10-fold less
active at σ R while having the same affinity at σ subtype with respect to the trans isomer 9b. Moreover,
1
2
for both isomers cis-9b and trans-9b the σ/5HT selectivityis conserved (>56 and >933 respectively).
1
A
With the substitution of the second phenyl ring, to give the 2,2-dicyclohexyl derivatives (10a and 10b),
the affinities of the piperidine series are further decreased, while, in the case of the piperazine series,
they are maintained. However, the very small decrease in affinity at σ R together with the small increase
1
at σ R drastically reduced the selectivity observed with trans-9b. The Piperazine series is confirmed to
2
be more selective towards σ receptors with respect to the 5-HT R.
1
A
Isosteric substitutions oxygen/sulphur/methylene of compound 8a and 8b were also evaluated.
Replacement of oxygen with sulphur, to give the 1,3-oxathiolane 11a and 11b, reduced the affinity at
both σR subtypes of different extent: 4- 5-fold in the case of piperidine 11a and a large reduction of 40-
50-fold in the case of piperazine 11b. The same trend, although to a lesser extent, is also observed with
the introduction of a second sulphur atom to give the 1,3-dithiolane derivatives 12a and 12b. As a result,
the piperidine couple (11a and 12a) is more potent than the piperazine one, at both σR subtypes.
Isosteric substitution of one annular oxygen atom of the 1,3-dioxolane with a methylene unit gave the
tetrahydrofurane derivatives 14a and 14b endowed with lower affinity values. It is a quite large decrease
of about 40 to 70-fold either for piperazine and piperidine, at both σR subtypes.
All isosters of 8a and 8b retain good σ/5HT selectivity displaying low affinity values for 5HT R.
1
A
1A
Replacing the oxygen atom in the tetrahydrofuran ring with a carbonyl group, to give the
cyclopentanones derivative 16a and 16b, a further reduction of affinity is observed, although an increase
of selectivity (20-fold) for the piperazine derivative 16b is observed.
The reduction of the carbonyl group gives two couples of diastereoisomeric cyclopentanols cis-17a
,
trans-17a and cis-17b and trans-17b. For both piparazine and piperidine couples, a recovery of affinity
,
is observed with respect to the parent cyclopentanones, with a clear lack of diastereoselectivity since
each diasteromeric couple shows similar affinity values at both receptor subtypes. It is worth noting that
the least active of the four cyclopentanols, trans-17a, is the only one to show a certain degree of
selectivity (39-fold). Interestingly, all the pentanol derivatives, except trans-17a, show a marked
increase in affinity towards 5HT R, with reversed σ/5HT selectivity.
1
A
1A
Compounds 22a and 22b are open analogues of 8a and 8b while 23a and 23b, obtained by removal of
the hydroxymethylene group, could be considered their molecular simplification. Opening of the 1,3-
dioxolane ring causes a drop in affinity at both σR subtypes: of about 4- 7-fold in the case of piperazine
6

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derivatives and, a more pronounced decrease, about 44- 90-fold, in the case of piperidine derivatives.
The removal of the hydroxymethylene group does not cause a significant variation in affinites. Once
more, piperazines 22b and 23b highlight good σ/5HT1A selectivity values while the corresponding
piperidines displayed poor or no selectivity.
Considering that the best results, in terms of affinity, were obtained with the 1,3-dioxolane scaffold and
that the phenyl rings in position 2 do not seem to be essential for affinity (see compounds trans-9b and
10b) we planned the synthesis of the conformationally restricted spiro-dioxolanes 25a and 25b.
The piperazine derivative 25b showed the highest affinity at σ R with a pKi value of 9.13 and a
1
selectivity ratio (σ /σ ) of 47 fold. The same profile was observed for the piperidine derivative 25a,
1
2
although the affinity for σ subtype and the selectivity ratio was of a lesser extent. Compound 25b also
1
displays the highest σ/5HT selectivity value (1349) in the whole series.
1
A
As far as the differences in affinity between σ R and σ R subtypes are concerned, in most cases higher
1
2
values are obtained for the former, although the selectivity is quite low. Only compound 25b is
outstanding in this respect (pK σ = 9.13, σ /σ = 47). Furthermore, it is worth noting that, excluding the
i
1
1
2
1
,3-oxathiolane and the 1,3-dithiolane derivatives 11 and 12, it clearly appears that at the σ binding site
2
the piperazine derivatives are more active than the corresponding piperidines, with the exception of
cyclopentanones (16) and spiro derivatives (25). In the case of the sulphur-containing derivatives (1,3-
oxathiolanes and 1,3-dithiolanes), the piperidines show affinity values higher than those seen with the
piperazines, with a reversed trend of activity. Therefore, it seems that the introduction of one or two
sulphur atoms is responsible for this effect. However, as the number of compounds is too limited, more
compounds are needed in order to generalize this observation.
2.2.2. In vivo analgesic activity
Given the implication of σ Rs in opioid-mediated analgesia [45] we analysed the ability of compound
1
25b, on the bases of its affinity (pKi = 9.13) and selectivity (47-fold), to modulate the analgesic effect of
the systemically injected KOP agonist, trans-(1S,2S)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-
cyclohexyl]benzeneacetamide [(−)-U50,488H] [46]. Our results demonstrate that the systemic
administration of 25b (1 mg/kg sc) did not affect tail withdrawal latencies during the entire observation
time (data not shown). Injection of the KOP agonist (−)-U-50,488H, at a dose of 5 mg/kg s.c.,
significantly increased the nociceptive latency by following thermal stimulation, which demonstrated a
clear analgesic effect (* P< 0.05 vs saline treated rats). Pre-treatment with 25b at 1 mg/kg s.c., followed
by (−)-U-50,488H (5 mg/kg s.c.) caused a reduction in the opioid analgesic effect which was significant
only at 30 minutes after the last administration (*P<0.05 vs (−)-U-50,488H treated rats) (Figure 1). In
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the next experimental protocol, the injection of morphine at the dose of 2 mg/kg s.c. (chosen in a dose
*
range of 1 to 10 mg/kg) determined a significant analgesic effect ( P<0.05 vs saline treated rats). The
double treatment with 25b 1 mg/kg s.c. plus morphine 2 mg/kg s.c., diminished MOP-induced analgesia
**
(
Figure 2); values were significant only at 30 minutes of observation ( P<0.05 vs morphine treated
rats). These results are consistent with an agonistic behavior at σ R of compound 25b.
1
2.3. Molecular Modeling
In order to better understand the affinities of the compounds disclosed here, docking studies on the σ R
1
homology model, previously built by us and presented here (see experimental section), were performed.
According to our results, the putative σ binding site was delimited by: (i) one hydrophobic region
1
located inside the protein including F58, A86, V104, L105, L106, L124, Y147, (ii) one hydrophilic core
placed around the polar residues D126, E150, T151, (iii) a region much more exposed outside the
protein showing the F83, V84, F107, I128, S130, T132, F133, H134 residues. The model refinement
was performed exploring the docking mode of known σ ligands and then comparing the results with the
1
literature data. In particular, compound I (1-benzyl-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,4-
c]pyran], Figure 3) [47] was chosen for its high binding affinity at σ R and for a considerable structural
1
similarity with leading members of our series. The docking results highlight the importance of a salt-
bridge with the D126 side-chain and of one H-bond between the spirocyclic oxygen atom and T151
(
Figure 4); the data, being in agreement with the literature, supported the reliability of the obtained σ R
1
homology model [47]. The relevance of the interactions with D126 and T151 was also confirmed by
mutagenesis studies [48], validating, once again, the computational protocol. In addition, the MOE dock
scoring funtions revealed the docking protocol ability to efficiently rank any selected conformer in
accordance with the affinity trend (Table S1, Supporting Information). Among the compounds
investigated here, a number of them displayed a salt-bridge interaction with D126 and some
hydrophobic contacts with V84, A86, V104, L105, L106, L124, I128, while the compounds with the
highest affinity also showed additional H-bonds with T151 and/or S130. In more detail, the dioxolane
derivatives 8a and 8b shared the same docking mode, displaying the key salt-bridge interaction between
the piperidine or piperazine protonated nitrogen atom and D126 and the H-bond interaction between the
dioxolane core and T151, while the diphenyl portion and the benzylic ring were properly engaged in
π−π stacking with F83, F107, F133, and Y147, respectively (Figure 5, the S enantiomers were revealed
by calculations to be the most stable). These results are in agreement with the affinity data showing that
piperidine 8a and piperazine 8b bind equally both σR subtypes. Conversely, the replacement of one or
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two phenyl rings with the cyclohexyl group led to a different effect, the piperazines cis/trans-9b and 10b
showing higher pK values than the corresponding piperidines cis/trans-9a and 10a at both σR subtypes.
i
In particular, it was observed that the most active piperazines trans-9b and 10b displayed a docking
mode comparable with that described for 8a and 8b, maintaining the two driving interactions with the
key residues D126 and T151, although, in this case, both of them are exerted by the two piperazine
nitrogen atoms, while the oxygen ring is not engaged in any H-bond. On the contrary, the piperidine
derivatives 9a and 10a, were characterized by a switched binding mode, orienting the cyclohexyl or
dicyclohexyl portion towards Y147 and therefore lacking the key salt-bridge interaction with D126
(Figure 6, the 10a and 10b S and R enantiomers were revealed by calculations to be the most stable). In
this case, only the H-bond with T151 was maintained. These results could be an indication of the
different affinities observed in the binding experiments for these two series. All the structural
modifications applied to the dioxolane scaffold, leading to the ring-opened derivatives (22a,b; 23a,b:
pK = 6.7-7.9) oxathiolane- (11a,b: pK = 7.9, 7.2), dithiolane- (12a,b: pK = 7.8, 6.5), tetrahydrofuran-
i
i
i
(
14a,b: pK = 6.7, 7.0), cyclopentanone- (16a,b: pK = 5.9, 6.2) or cyclopentanol- (cis/trans-17a, b: pK =
i
i
i
6.5-7.4) analogues, proved to be detrimental for binding to σR . With the exception of oxathiolanes or
dithiolanes, the above-mentioned compounds properly located the diphenyl and the benzyl substituents
towards F83, F107, F133, and Y147, respectively, thus resulting in only the salt-bridge interaction with
D126 or in the H-bond with T151. Conversely, both interactions were maintained in compound 22b
through the piperazine nitrogen atom and the hydroxyl group, respectively.
Interestingly, when the 1,3-dioxolane portion was replaced with a 1,3-oxathiolane or 1,3-dithiolane,
compounds in the piperidine series (11a, 12a) performed better (pK σ = 7.82, 7.92) than the
i
1
corresponding piperazine derivatives (11b, 12b; pK σ = 6.52, 7.20), at both σR subtypes. According to
i
1
our calculation, 11a and 12a oriented the diphenyl and the benzyl substituent inside and quite outside
the protein, respectively, displaying a salt-bridge between the protonated nitrogen atom and D126. On
the contrary, the corresponding piperazine 11b and 12b showed an inversed docking mode which
prevented any contact with D126, exhibiting only a weak H-bond with T151 (data not shown).
Lastly, 25a and 25b, the most interesting members of this series, outstanding for their affinity (pK =
i
8
.70, 9.13) and selectivity (σ / σ = 10, 47) at σ R, shared the by following interactions: (i) a salt-bridge
1 2 1
between the piperidine or piperazine nitrogen atom and D126; (ii) an H-bond between the dioxolane
oxygen atom and S130: (iii) π−π stacking and hydrophobic contacts with Y147 and with V84, I128,
F133. Moreover, compound 25b displayed one additional H-bond between the piperazine nitrogen atom
and T151 (Figure 7; the 25a and 25b S enantiomers were revealed by calculations to be the most stable).
Significantly, the docking pose of 25b was comparable with that of the previously described agonist I
9

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(
pK =9.36), displaying the same hydrophilic contacts with D126 and T151. Notably, the bond distances
i
measured for the two protein-ligand complexes were slightly lower for I, giving an indication for the
slightly greater affinity of I with respect to 25b. On the basis of these results, it could be hypothesized
that the replacement of the piperazine ring with a shorter basic linker between the benzyl group and the
dioxaspiro-core on 25b could efficiently guarantee the proper pattern of an H-bond acceptor and basic
features to interact with D126, T151 and also with S130. Moreover, additional aromatic moieties linked
to the spiro-decane scaffold could be introduced, in order to further stabilize the protein-ligand complex
by means of π−π stacking interactions with both the two aforementioned hydrophobic pockets,
including F58, Y147 and F83, F107, F133. These results could represent a new starting point for the
design of structural analogues of 25b.
3. Conclusions
Starting from 1a and 1b and replacing the 1,4-benzodioxane moiety with a variety of five-membered
heterocyclic rings, a new class of σR ligands was obtained. Structure-affinity studies were performed
leading to these conclusions:
a) all the compounds exhibited a preference for σ R subtype respect to σ R, although the
1
2
selectivity, in most of the cases, is quite low;
b) the best results in terms of affinity and selectivity were obtained with the 1,3-dioxolane scaffold;
c) isosteric substitutions of the dioxolane atoms or molecular simplification led to a general
decrease in affinity;
d) aromatic substituents at position 2 on the 1,3-dioxolane ring do not seem to be essential for σR
affinity;
e) with few exceptions, piperazine-based compounds were more potent than the corresponding
piperidines;
f) the computational results, in agreement with the biological data, proved the reliability of the σ R
1
model.
In particular, compound 25b was outstanding for its high affinity (pK =9.13) and selectivity (σ /σ = 47)
i
1
2
at σ R subtypes. In-vivo studies suggested that 25b acts as a σ R agonist since it is able to reduce both
1
1
(−)-U50,488H- and morphine-mediated analgesia. Therefore, 25b could represent a new starting point
for the development of more active and selective ligands. Further research along this line is in progress
and will be disclosed in due course.
1
0

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4
. Experimental Part
4.1. Chemistry
All the reagents, solvents and other chemicals were used as purchased from Sigma-Aldrich without
further purification unless otherwise specified. Air- or moisture-sensitive reactants and solvents were
employed in reactions carried out under nitrogen atmosphere unless otherwise noted. Flash column
chromatography purifications (medium pressure liquid chromatography) were carried out using Merck
silica gel 60 (230-400 mesh, ASTM). The structures of all isolated compounds were ensured by Nuclear
1
13
magnetic resonance (NMR) and Mass spectrometry. H and C-NMR (1D and 2D experiments) spectra
were recorded on a DPX-200 Avance (Bruker) spectrometer operating at 200.13 MHz and on a DPX-
400 Avance (Bruker) spectrometer operating at 400.13 MHz. Chemical shifts are expressed in δ (ppm).
1
13
H NMR chemical shifts are relative to tetramethylsilane (TMS) as internal standard. C-NMR
1
3
chemical shifts are relative to TMS at δ 0.0 or to the C signal of the solvent: CDCl δ 77.04, CD OD δ
3
3
4
9.8, DMSO-d δ 39.5. NMR data are reported as follows: chemical shift, number of protons/carbons,
6
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broadened), coupling constants
Hz) and assignment (Diox = 1,3-Dioxolane; Ar = Phenyl; Cyc = Cyclohexyl; Ts = Tosyl; Piper =
(
Piperidine or Piperazine; Ph = Phenyl ; Bz = Benzyl, Oxath = 1,3-Oxathiolane; Dithio = 1,3-Dithiolane;
Fur = Tetrahydrofurane; Cyclopent = Cyclopentanone or Cyclopentanol; Dosd = 1,4-
1
1
1
13
Dioxaspiro[4.5]decane). H- H Correlation spectroscopy (COSY), H- C heteronuclear multiple
quantum coherence (HMQC) and heteronuclear multiple bond connectivity (HMBC) experiments were
1
1
1
13
recorded for determination of H- H and H- C correlations respectively. NOESY experiments have
been performed to assign the correct stereochemistry. HR-MS experiments were carried out using a LC-
MS mass spectrometer (6520 Accurate-Mass Q-TOF LC/MS - Agilent Technologies) equipped with an
ion spray ionization source (ESI). MS (+) spectra were acquired by direct infusion (5 ml/min) of a
solution containing the appropriate sample as oxalate salt (10 nmol/ml), dissolved in a 0.1% acetic acid
solution, with mobile phase methanol/water 50:50, at the optimum ion voltage of 4800 V. The yields
reported are based on a single experiment and are not optimized. The final compounds were converted
into hydrogen oxalate. Melting points were determined with a Stuart SMP3 and they are uncorrected.
The purity of the salts was confirmed by elemental analysis on a Carlo Erba 1106 Analyzer and the
values obtained are within ±0.4% of the calculated ones. The purity was higher than 97%. The oxalate
salts were tested for the biological activity.
The compounds 3 [40], 6 [43], 7 [43], 13[44], 15 [44], 24 [43] were obtained as previously reported.
1
1

ACCEPTED MANUSCRIPT
4.1.1. (2-Cyclohexyl-2-phenyl-[1,3]-dioxolan-4-yl)methanol (2)
An excess of glycerol (26.56 mmol) and a catalytic amount of p-toluenesulfonic acid (0.53 mmol) were
added to a solution of cylohexylphenyl ketones (13.28 mmol) in toluene (250 mL). The mixture was
refluxed and water was removed in a Dean-Stark trap until the formation of water stopped. After
completion of the reaction a mixture of CH Cl /H O was added. The organic layer was separated and the
2
2
2
aqueous layer was extracted with CH Cl . The organic layers were combined, washed with a saturated
2
2
solution of NaHCO and brine, dried over anhydrous Na SO , filtered and concentrated under vacuum.
3
2
4
The unassigned diastereoisomeric mixture of the title compound was obtained as a yellow oil (3.31 g,
12.61 mmol, 95% yield) and used without further purification.
1
H NMR (DMSO, 200 MHz): δ = 0.91-1.22 (5H, m, Cyc), 1.49-1.72 (7H, m, Cyc, OH), 3.58 (1H, dd, J
=
7.2, 8.9 Hz, CHa-5 Diox), 3.76 (1H, dd, J = 7.2, 8.2 Hz, CHb-5 Diox), 4.00 (2H, m, CH OH), 4.21-
2
+
4
.35 (1H, m, CH-4 Diox), 7.21-7.40 (5H, m, Ar). ESI-HRMS calcd for C H O [M+H] 263.1642,
1
6
23
3
found 263.1645.
4.1.2. (2-Cyclohexyl-2-phenyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (4)
p-Toluenesulfonyl chloride (8.40 mmol) was added at 0°C to a solution of 2 (7.63 mmol) and
triethylamine (1.0 mmol) in dry CH Cl (10 mL). The mixture was stirred at room temperature for 12 h.
2
2
Ice water was added and the mixture was extracted with CH Cl . The organic extracts were collected,
2
2
washed with brine, dried over anhydrous Na SO , filtered, and concentrated in vacuo to yield the title
2
4
compound. Single pure cis/trans diastereomer was obtained by using flash column chromatography
cyclohexane/ethyl acetate 97.5/2.5) as an oil.
(
Cis-4 (1.81 g, 4.35 mmol, 57% yield)
1
H NMR (CDCl , 200 MHz): δ = 0.91-1.12 (5H, m, Cyc), 1.49-1.78 (6H, m, Cyc), 2.48 (3H, s, CH ),
3
3
3
4
.38 (1H, dd, J = 7.4, 8.1 Hz, CHa-5 Diox), 3.71 (1H, dd, J = 2.4, 4.9 Hz, CHaTs), 3.90 (1H, dd, J= 4.7,
.9 Hz CHbTs), 4.01 (1H, dd, J = 6.3, 7.4 Hz, CHb-5 Diox), 4.11 (1H, m, CH-4 Diox), 7.18-7.41 (7H,
m, Ar, CH-3, CH-5 Ts), 7.71 (2H, d, J= 8.2 Hz, CH-2, CH-6 Ts). ESI-HRMS calcd for C H O S
2
3
29
5
+
[
M+H] 417.1730, found 417.1729.
Trans-4 (0.48 g, 1.14 mmol, 15% yield)
1
H NMR (CDCl , 200 MHz): δ = 0.98-1.15 (5H, m, Cyc), 1.43-1.77 (6H, m, Cyc), 2.47 (3H, s, CH ),
3
3
3
.61-3.78 (2H, m, CH -5 Diox), 3.84-4.07 (3H, m, CH Ts, CH-4 Diox), 7.19-7.36 (5H, m, Ar), 7.37
2
2
(2H, d, J= 8.3 Hz, CH-3, CH-5 Ts), 7.82 (2H, d, J= 8.3 Hz, CH-2, CH-6 Ts). ESI-HRMS calcd for
+
C H O S [M+H] 417.1730, found 417.1729.
23
29
5
1
2

ACCEPTED MANUSCRIPT
4.1.3. 4-(Chloromethyl)-2,2-dicyclohexyl-1,3-dioxolane (5)
The title compound was obtained as an oil (1.09 g, 3.80 mmol, 74%) starting from dicyclohexyl ketone
5.14 mmol) and 3-chloro-1,2-propanediol (7.71 mmol), by following the same procedure described for
(
2
.
1
H NMR (CDCl , 200 MHz): δ = 1.04–1.41 (10H, m, Cyc), 1.54–1.87 (12H, m, 2x Cyc.), 3.44 (1H, dd,
3
J = 7.9, 10.6 Hz, CHa-5 Diox), 3.57–3.71 (2H, m, CH Cl), 4.08 (1H, dd, J = 5.3, 10.6 Hz, CHb-5 Diox),
2
3
5
+
4
.30–4.43 (1H, m, CH-4 Diox). ESI-HRMS calcd for C H O Cl [M+H] 287.1772, found 287.1773.
16 28 2
37
2
+
Calcd for C H O Cl [M+H] 289.1743, found 289.1744.
1
6
28
4.1.4. General procedure for the synthesis of the amines 8-12a,b; 14a,b; 21a,b; 23a,b
A large excess of 4-benzylpiperidine or 1-benzylpiperazine (5-10 equiv.) and a catalytic amount of KI
were added to a solution of chloromethyl (3, 5-7) or tosyl derivative (4, 13, 24) (0.34-2.25 mmol) in 2-
methoxyethanol. The resulting mixture was stirred and was refluxed for 20 h. The solvent was
evaporated under vacuum, CHCl was added, and the residue was washed with a solution of 5% NaOH
3
(
2x) and with brine. The organic layer was dried over Na SO and the solvent was evaporated under
2 4
vacuum to give the desired amine as an oil. The residue was purified by using flash column
chromatography.
4.1.5. 4-Benzyl-1-[(2,2-diphenyl-1,3-dioxolan-4-yl)methyl]piperidine (8a)
The title compound was obtained from 3 [40] and 4-benzylpiperidine and was purified by using flash
column chromatography (cyclohexane/ethyl acetate 70/30) to give 8a (0.44 g, 1.06 mmol, 78% yield) as
an oil.
1
H NMR (CDCl , 400 MHz): δ = 1.41-1.63 (5H, m, CH -3, CH-4, CH -5), 1.89-2.16 (2H, m, CHa-2,
3
2
2
CHa-6 Piper), 2.43-2.59 (3H, m, CHaN, CH Ph), 2.61 (1H, dd, J = 6.2, 12.1, CHbN), 2.77-2.94 (1H, m,
2
CHb-2/CHb-6 Piper), 2.99-3.19 (1H, m, CHb-2/CHb-6 Piper), 3.77 (1H, dd, J = 7.2, 7.6 Hz, CHa-5
Diox), 4.15 (1H, dd, J = 7.6, 7.8 Hz, CHb-5 Diox), 4.27-4.50 (1H, m, CH-4 Diox), 7.01-7.37 (11H, m,
13
Ar , Ph), 7.42-7.69 (4H, m, Ar ); C NMR (CDCl , 100 MHz): δ = 31.8 (CH , C-3/C-5 Piper), 32.2
2
2
3
2
(
CH , C-3/C-5 Piper), 37.0 (CH, C-4 Piper), 42.8 (CH , CH Ph), 53.9 (CH , C-2/C-4 Piper), 54.4 (CH ,
2 2 2 2 2
C-2/C-4 Piper), 60.7 (CH , CH N), 68.6 (CH , C-5 Diox), 75.4 (CH, C-4 Diox), 110.1 (C, C-2 Diox),
2
2
2
1
1
25.7 (CH, C-4 Ph), 126.3 (4CH, C-2, C-6 Ar ), 128.0 (2CH, C-3, C-5 Ph), 128.2 (4CH, C-3, C-5 Ar ),
2 2
28.3 (2CH, C-4 Ar ), 128.9 (2CH, C-2, C-6 Ph), 138.3 (C, C-1 Ph), 142.7 (2C, C-1 Ar ). ESI-HRMS
2
2
+
calcd for C H NO [M+H] 414.2428, found 414.2430.
2
8
32
2
1
3

ACCEPTED MANUSCRIPT
The free amine was converted into the corresponding hydrogen oxalate from diethyl ether (0.03 g, 0.07
mmol, yield 44%).
1
mp: 200-202 °C; H NMR (DMSO, 200 MHz): δ = 1.32-1.53 (5H, m, CH -3, CH-4, CH -5), 2.41-2.52
2
2
(
2H, m, CH Ph), 2.71-2.91 (2H, m, CH N), 3.01-3.27 (2H, m, CHa-2,CHa-6 Piper), 3.29-3.39 (1H, m,
2 2
CHb-2/CHb-6 Piper), 3.42-3.53 (1H, m, CHb-2/CHb-6 Piper), 3.74 (1H, dd, J = 7.2, 7.9 Hz, CHa-5
Diox), 4.12 (1H, dd, J = 7.2, 7.5 Hz, CHb-5 Diox), 4.40-4.64 (1H, m, CH-4 Diox), 7.11-7.51 (15H, m,
Ar , Ph).
2
+
ESI-HRMS calcd for C H NO [M+H] 414.2428, found 414.2430. Anal. Calcd. for C H NO : C,
2
8
32
2
30 33
6
71.55; H, 6.61; N, 2.78; Found C, 71.51; H, 6.42; N, 2.63.
4.1.6. 1-Benzyl-4-[(2,2-diphenyl-1,3-dioxolan-4-yl)methyl]piperazine (8b)
The title compound was obtained from 3 [40] and 1-benzylpiperazine and was purified by using flash
column chromatography (cyclohexane/ethyl acetate 95/5) to give 8b (0.75 g, 1.8 mmol, 80% yield) as
an oil.
1
H NMR (CDCl , 400 MHz): δ = 2.52-2.83 (10H, m, CH -2, CH -3 CH -5, CH -6 Piper, CH N), 3.52
3
2
2
,
2
2
2
(
2H, s, CH Ph), 3.79 (1H, dd, J = 7.1, 7.6 Hz, CHa-5 Diox), 4.16 (1H, dd, J = 7.1, 7.9 Hz, CHb-5 Diox),
2
1
3
4
.35-4.48 (1H, m, CH-4 Diox), 7.20-7.41 (11H, m, Ph, Ar ), 7.48-7.69 (4H, m, Ar ); C NMR (CDCl ,
2 2 3
1
00 MHz): δ = 52.7 (2CH , C-2, C-6 Piper) 53.4 (2CH , C-3, C-5 Piper), 61.0 (CH N), 62.8 (CH ,
2
2
2
2
CH Ph) 69.0 (CH , C-5 Diox), 74.9 (CH, C-4 Diox), 60.7 (CH , CH N), 110.1 (C, C-2 Diox), 126.2
2
2
2
2
(
4CH, C-3, C-5 Ar ), 127.5 (CH, C-4 Ph), 120.1 (2CH, C-2, C6 Ar), 128.2 (2CH, C-2, C-6 Ar’), 128.3
2
(2CH, C-3, C-5 Ph), 129.5 (2CH, C-2, C-6 Ph), 137.2 (C, C-1 Ph). 142.4 (C, C-4 Ar), 142.5 (C, C-4
+
Ar’). 142.7, (2C, C-1 Ar Ar’). ESI-HRMS calcd for C H N O [M+H] 415.2380, found 415.2382.
,
27 31
2
2
The free amine was converted into the corresponding hydrogen oxalate from diethyl ether (0.24 g, 0.47
mmol, yield 51%).
1
mp: 228-229 °C; H NMR (DMSO, 200 MHz): δ = 2.61-3.12 (10H, m, CH -2, CH -3 CH -5, CH -6
2
2
,
2
2
Piper, CH N), 3.71 (1H, dd, J = 7.1, 8.0 Hz, CHa-5 Diox), 3.91-4.21 (3H, m, CHb-5 Diox, CH Ph),
2
2
4
.25-4.46 (1H, m, CH-4 Diox), 7.19-7.36 (15H, m, Ar , Ph).
2
+
ESI-HRMS calcd for C H N O [M+H] 415.2380, found 415.2382. Anal. Calcd. for C H N O : C,
2
7
31
2
2
31 34
2
10
62.62; H, 5.76; N, 4.71; Found C, 62.65; H, 5.82; N, 4.82.
4.1.7. Cis-4-benzyl-1-[(2-cyclohexyl-2-phenyl-1,3-dioxolan-4-yl)methyl]piperidine (cis-9a)
1
4

ACCEPTED MANUSCRIPT
The title compound was obtained from cis-4 and 4-benzylpiperidine and was purified by using flash
column chromatography (cyclohexane/ethyl acetate 95/5) to give cis-9a (0.27 g, 0.65 mmol, 94% yield)
as a yellow oil.
1
H NMR (CDCl , 400 MHz): δ = 0.81-1.26 (5H, m, Cyc), 1.31-1.86 (11H, m, Cyc, CH -3, CH-4, CH -5
3
2
2
Piper), 1.87-2.13 (2H, m, CHa-2, CHa-6 Piper), 2.22-2.39 (1H, m, CHb-2/CHb-6 Piper), 2.41-2.52 (2H,
m, CH N), 2.55 (2H, d, J = 5.6 Hz, CH Ph), 3.01-3.13 (1H, m, CHb-2/CHb-6 Piper), 3.61-3.78 (2H, m,
2
2
CH -5 Diox), 4.23-4.38 (1H, m, CH-4 Diox), 7.11 (2H, d, J = 7.4 Hz, CH-2, CH-6 Ph), 7.23 (1H, t, J =
2
1
3
7
.2 Hz, CH-4 Ph), 7.32-7.49 (7H, m, CH-3, CH-4 Ph, CH-2, XH-3, CH-4, CH-5, CH-6 Ar); C NMR
(
(
CDCl , 100 MHz): δ = 26.1 (2CH , Cyc) 26.2 (CH , Cyc), 26.3 (CH , Cyc), 26.8 (CH , Cyc), 31.3
3
2
2
2
2
CH , C-3/C-5 Piper), 31.9 (CH , C-3/C-5 Piper), 37.1 (CH, C-4 Piper), 42.7 (CH , CH Ph), 47.1 (CH,
2
2
2
2
C-1 Cyc), 52.9 (CH , C-2/C-4 Piper), 54.2 (CH , C-2/C-4 Piper), 60.2 (CH , CH N), 68.6 (CH , C-5
2
2
2
2
2
Diox), 74.6 (CH, C-4 Diox), 112.5 (C, C-2 Diox), 125.8 (CH, C-4 Ph), 126.4 (2CH, C-3, C-5 Ar), 127.7
(2CH, C-2, C-5 Ar), 128.3 (2CH, C-3, C-5 Ph), 128.9 (CH, C-4 Ar), 129.0 (2CH, C-2, C-6 Ph), 139.3
+
(
C, C-1 Ar), 140.6 (C, C-1 Ph). ESI-HRMS calcd for C H NO [M+H] 420.2897, found 420.2895.
2
8
38
2
The free amine was converted into the corresponding hydrogen oxalate from diethyl ether (0.18 g, 0.36
mmol, yield 55%).
1
mp: 205-207 °C; H NMR (DMSO, 200 MHz): δ = 0.71-1.31 (5H, m, Cyc), 1.41-1.81 (11H, m, Cyc,
CH -3, CH-4, CH -5 Piper), 2.44-2.51 (2H, m, CH Ph), 2.52-2.73 (2H, m, CH N), 2.71-3.32 (4H, m,
2
2
2
2
CH - 2/CH -6 Piper), 3.38-3.43 (1H, m, CHa-5 Diox), 4.05-4.13 (1H, m, CHb-5 Diox), 4.23-4.49 (1H,
2
2
m, CH-4 Diox), 7.11-7.42 (10H, m, Ar, Ph).
+
ESI-HRMS calcd for C H NO [M+H] 420.2897, found 420.2895. Anal. Calcd. for C H NO : C,
2
8
38
2
30 39
6
70.70; H, 7.71; N, 2.75; Found C, 70.83; H, 7.77; N, 2.96.
4.1.8. Cis-1-benzyl-4-[(2-cyclohexyl-2-phenyl-1,3-dioxolan-4-yl)methyl]piperazine (cis-9b)
The title compound was obtained from cis-4 and 1-benzylpiperazine and was purified by using flash
column chromatography (cyclohexane/ethyl acetate 85/15) to give cis-9b (0.37 g, 0.88 mmol, 99%
1
yield) as an oil. H NMR (CDCl , 400 MHz): δ = 0.91-1.24 (5H, m, Cyc), 1.32-1.62 (6H, m, Cyc), 2.47
3
(
2H, d, J = 4.8 Hz, CH N), 2.52-2.98 (8H, m, CH -2, CH -3 CH -5, CH -6 Piper), 3.31 (1H, dd, J = 8.3,
2 2 2 , 2 2
8
.6 Hz, CHa-5 Diox), 3.61 (2H, s, CH Ph), 4.19 (1H, dd, J = 6.1, 8.23 Hz, CHb-5 Diox), 4.27-4.41 (1H,
2
m, CH-4 Diox), 7.21-7.45 (10H, m, Ar, Ph).
1
3
C NMR (CDCl , 100 MHz): δ = 25.8 (2CH , Cyc), 25.9 (CH , Cyc), 26.5 (CH , Cyc), 26.7 (CH ,
3
2
2
2
2
Cyc), 47.1 (CH, C-1 Cyc), 51.7 (2CH , C-3,C-5 Piper), 52.5 (2CH , C-2,C-6 Piper), 60.5 (CH , CH N),
2
2
2
2
1
5

ACCEPTED MANUSCRIPT
6
2.1 (CH , CH Ph), 68.2 (CH , C-5 Diox), 75.1 (CH, C-4 Diox), 112.7 (C, C-2 Diox), 125.9 (CH, C-4
2
2
2
Ph), 126.6 (2CH, C-3, C-5 Ar), 127.2 (CH, C-4 Ar), 127.3 (2CH, C-2, C-5 Ar), 127.4 (C, C-1 Ar), 128.2
(2CH, C-3, C-5 Ph), 129.4 (2CH, C-2, C-6 Ph), 142.3 (C, C-1 Ph). ESI-HRMS calcd for C H N O
27 37 2 2
+
[
M+H] 421.2850, found 421.2853.
The free amine was converted into the corresponding hydrogen oxalate from diethyl ether (0.19 g, 0.32
mmol, yield 40%).
1
mp: 225-226 °C; H NMR (DMSO, 200 MHz): δ = 0.79-1.32 (5H, m, Cyc), 1.45-1.77 (6H, m, Cyc),
2
.47-2.71 (10H, m, CH -2, CH -3 CH -5, CH -6 Piper, CH N), 3.21(1H, dd, J= 7.3, 8.2 Hz, CHa-5
2 2 , 2 2 2
diox), 3.95 (2H, s, CH Ph), 4.20-4.41 (2H, m, CHb-5, CH-4 Diox), 7.20-7.48 (10H, m, Ar, Ph).
2
+
ESI-HRMS calcd for C H N O [M+H] 421.2850, found 421.2853. Anal. Calcd. for C H N O : C,
2
7
37
2
2
31 40
2
10
61.99; H, 6.71; N, 4.66; Found C, 61.86; H, 6.56; N, 4.47.
4.1.9. Trans-4-benzyl-1-[(2-cyclohexyl-2-phenyl-1,3-dioxolan-4-yl)methyl]piperidine (trans-9a)
The title compound was obtained from trans-4 and 4-benzylpiperidine and was purified by using flash
column chromatography (cyclohexane/ethyl acetate 90/10) to give trans-9a (0.31 g, 0.74 mmol, 82%
yield) as a yellow oil.
1
H NMR (CDCl , 400 MHz): δ = 0.93-1.23 (5H, m, Cyc), 1.35-1.84 (11H, m, Cyc, CH -3, CH-4, CH -5
3
2
2
Piper), 1.91-2.17 (2H, m, CHa-2, CHa-6 Piper), 2.43-2.72 (4H, m, CH N, CH Ph), 2.72-2.90 (1H, m,
2
2
CHb-2/CHb-6 Piper), 2.97-3.15 (1H, m, CHb-2/CHb-6 Piper), 3.58 (1H, dd, J = 6.5, 7.3 Hz, CHa-5
Diox), 3.83 (1H, dd, J = 7.0, 7.3 Hz, CHb-5 Diox), 4.02-4.21 (1H, m, CH-4 Diox), 7.12-7.46 (10H, m,
1
3
Ar, Ph); C NMR (CDCl , 100 MHz): δ = 25.8 (2CH , Cyc) 25.9 (CH , Cyc), 26.5 (CH , Cyc), 26.7
3
2
2
2
(
CH , Cyc), 31.4 (CH , C-3/C-5 Piper), 32.0 (CH , C-3/C-5 Piper), 37.3 (CH, C-4 Piper), 42.9 (CH ,
2 2 2 2
CH Ph), 46.5 (CH, C-1 Cyc), 53.4 (CH , C-2/C-4 Piper), 54.0 (CH , C-2/C-4 Piper), 60.3 (CH , CH N),
2
2
2
2
2
6
8.1 (CH , C-5 Diox), 73.9 (CH, C-4 Diox), 112.1 (C, C-2 Diox), 125.8 (CH, C-4 Ph), 126.2 (2CH, C-3,
2
C-5 Ar), 127.5 (CH, C-4 Ar), 127.7 (2CH, C-2, C-5 Ar), 127.8 (C, C-1 Ar), 128.5 (2CH, C-3, C-5 Ph),
+
1
29.6 (2CH, C-2, C-6 Ph), 141.4 (C, C-1 Ph). ESI-HRMS calcd for C H NO [M+H] 420.2897,
28
38
2
found 420.2895.
The free amine was converted into the corresponding hydrogen oxalate from diethyl ether (0.10 g, 0.20
mmol, yield 45%).
1
mp: 198-200 °C; H NMR (DMSO, 200 MHz): δ = 0.73-1.26 (5H, m, Cyc), 1.35-1.82 (11H, m, Cyc,
CH -3, CH-4, CH -5 Piper), 2.45-2.59 (2H, m, CH Ph), 2.61-2.92 (2H, m, CH N), 2.71-3.32 (4H, m,
2
2
2
2
1
6

ACCEPTED MANUSCRIPT
CH - 2/CH -6 Piper), 3.62 (1H, dd, J = 6.1, 7.8 Hz, CHa-5 Diox), 3.76 (1H, dd, J = 7.3, 7.8 Hz, CHb-5
2
2
Diox), 4.11-4.26 (1H, m, CH-4 Diox), 7.10-7.48 (10H, m, Ar, Ph).
+
ESI-HRMS calcd for C H NO [M+H] 420.2897, found 420.2895. Anal. Calcd. for C H NO : C,
2
8
38
2
30 39
6
70.70; H, 7.71; N, 2.75; Found C, 70.65; H, 7.58; N, 2.59.
4.1.10. Trans-1-benzyl-4-[(2-cyclohexyl-2-phenyl-1,3-dioxolan-4-yl)methyl]piperazine (trans-9b)
The title compound was obtained from trans-4 and 1-benzylpiperazine and was purified by using flash
column chromatography (cyclohexane/ethyl acetate 90/10) to give trans-9b (0.37 g, 0.88 mmol, 99%
yield) as an oil.
1
H NMR (CDCl , 400 MHz): δ = 0.91-1.27 (5H, m, Cyc), 1.49-1.79 (6H, m, Cyc), 2.62 (2H, br s,
3
CH N), 2.41-2.70 (8H, m, CH -2, CH -3 CH -5, CH -6 Piper), 3.59 (1H, dd, J = 6.4, 7.1 Hz, CHa-5
2
2
2
,
2
2
Diox), 3.72-3.91 (3H, m, CHb-5 Diox, CH Ph), 4.12-4.32 (1H, m, CH-4 Diox), 7.21-7.48 (10H, m, Ar,
2
1
3
Ph); C NMR (CDCl , 100 MHz): δ = 25.8 (2CH , Cyc), 25.9 (CH , Cyc), 26.5 (CH , Cyc), 26.7 (CH ,
3
2
2
2
2
Cyc), 46.2 (CH, C-1 Cyc), 51.1 (2CH , C-3,C-5 Piper), 51.9 (2CH , C-2,C-6 Piper), 60.2 (CH , CH N),
2
2
2
2
6
1.6 (CH , CH Ph), 67.8 (CH , C-5 Diox), 73.5 (CH, C-4 Diox), 113.2 (C, C-2 Diox), 125.9 (CH, C-4
2 2 2
Ph), 126.1 (2CH, C-3, C-5 Ar), 127.4 (CH, C-4 Ar), 127.5 (2CH, C-2, C-5 Ar), 127.7 (C, C-1 Ar), 128.6
(2CH, C-3, C-5 Ph), 129.4 (2CH, C-2, C-6 Ph), 142.4 (C, C-1 Ph). ESI-HRMS calcd for C H N O
27 37 2 2
+
[
M+H] 421.2850, found 421.2851.
The free amine was converted into the corresponding hydrogen oxalate from diethyl ether (0.16 g, 0.26
mmol, yield 35%).
1
mp: 230-232 °C; H NMR (DMSO, 200 MHz): δ = 0.83-1.22 (5H, m, Cyc), 1.49-1.76 (6H, m, Cyc),
2
.69-3.05 (10H, m, CH -2, CH -3 CH -5, CH -6 Piper, CH N), 3.56 (1H, dd, J= 6.6, 8.1 Hz, CHa-5
2 2 , 2 2 2
Diox), 3.73 (2H, dd, J = 6.6, 7.7 Hz, CHb-5 Diox), 3.91-4.22 (3H, m, CH Ph, CH-4 Diox), 7.22-7.48
2
(10H, m, Ar, Ph).
+
ESI-HRMS calcd for C H N O [M+H] 421.2850, found 421.2851. Anal. Calcd. for C H N O : C,
2
7
37
2
2
31 40
2
10
61.99; H, 6.71; N, 4.66; Found C, 61.92; H, 6.72; N, 4.73.
4.1.11. 4-Benzyl-1-[(2,2-dicyclohexyl-1,3-dioxolan-4-yl)methyl]piperidine (10a)
The title compound was obtained from 5 and 4-benzylpiperidine and was purified by using flash column
chromatography (cyclohexane/ethyl acetate 90/10) to give 10a (0.37 g, 0.87 mmol, 71% yield) as a
yellow oil.
1
7

ACCEPTED MANUSCRIPT
1
H NMR (CDCl , 200 MHz): δ = 0.92-1.39 (10H, m, Cyc ), 1.51-1.86 (17H, m, Cyc , CH -3, CH-4,
3
2
2
2
CH -5 Piper), 2.31-2.49 (2H, m, CHa-2, CHa-6 Piper), 2.59 (2H, J= 6.1 Hz, CH Ph), 2.63-2.83 (2H, m,
2
2
CH N), 2.99-3.12 (1H, m, CHb-2/CHb-6 Piper), 3.13-3.39 (1H, m, CHb-2/CHb-6 Piper), 3.43 (1H, dd, J
2
=
7.6, 9.0 Hz, CHa-5 Diox), 4.17 (1H, dd, J = 6.3, 7.4 Hz, CHb-5 Diox), 4.38-4.56 (1H, m, CH-4 Diox),
7
7
.17 (2H, dd, J = 1.5, 7.4 Hz, CH-2, CH-6 Ph), 7.23 (1H, t, J = 7.1 Hz, CH-4 Ph), 7.32 (2H, dd, J = 7.1,
1
3
.4 Hz, CH-3, CH-5 Ph); C NMR (CDCl , 100 MHz): δ = 26.0 (4CH , Cyc ) 26.1 (2CH , Cyc ) 26.8
3
2
2
2
2
(
2CH , Cyc ), 26.9 (2CH , Cyc ), 31.6 (CH , C-3/C-5 Piper), 32.0 (CH , C-3/C-5 Piper), 36.9 (CH, C-4
2 2 2 2 2 2
Piper), 42.9 (CH , CH Ph), 44.2 (2CH, C-1 Cyc), 53.8 (CH , C-2/C-4 Piper), 54.6 (CH , C-2/C-4 Piper),
2
2
2
2
6
0.7 (CH , CH N), 70.6 (CH , C-5 Diox), 75.9 (CH, C-4 Diox), 116.9 (C, C-2 Diox), 125.8 (CH, C-4
2 2 2
Ph), 128.2 (2CH, C-3, C-5 Ph), 128.9 (2CH, C-2, C-6 Ph), 140.6 (C, C-1 Ph). ESI-HRMS calcd for
+
C H NO [M+H] 426.3367, found 426.3368.
28
44
2
The free amine was converted into the corresponding hydrogen oxalate from diethyl ether (0.06 g, 0.12
mmol, yield 40%).
1
mp: 210-212 °C; H NMR (DMSO, 200 MHz): δ = 0.88-1.23 (10H, m, Cyc ), 1.43-1.81 (17H, m, Cyc ,
2
2
CH -3, CH-4, CH -5 Piper), 2.41-2.52 (2H, m, CH Ar), 2.52-2.73 (2H, m, CH N), 2.71-3.32 (4H, m,
2
2
2
2
CH - 2/CH -6 Piper), 3.40 (1H, dd, J = 7.4, 8.1 Hz, CHa-5 Diox), 4.11 (1H, dd, J = 7.1, 7.4 Hz, CHb-5
2
2
Diox), 4.20-4.49 (1H, m, CH-4 Diox), 7.11-7.39 (5H, m, Ar).
+
ESI-HRMS calcd for C H NO [M+H] 426.3367, found 426.3368. Anal. Calcd. for C H NO : C,
2
8
44
2
30 45
6
69.87; H, 8.80; N, 2.72; Found C, 69.91; H, 8.93; N, 2.82.
4.1.12. 1-Benzyl-4-[(2,2-dicyclohexyl-1,3-dioxolan-4-yl)methyl]piperazine (10b)
The title compound was obtained from 5 and 1-benzylpiperazine and was purified by using flash column
chromatography (cyclohexane/ethyl acetate 90/10) to give 10b (0.47 g, 1,10 mmol, 90% yield) as a
yellow oil.
1
H NMR (CDCl , 200 MHz): δ = 0.91-1.44 (10H, m, Cyc ), 1.50-1.81 (12H, m, Cyc ), 2.49-2.72 (10H,
3
2
2
m, CH -2, CH -3 CH -5, CH -6 Piper, CH N), 3.43 (1H, dd, J = 7.5, 9.0 Hz, CHa-5 Diox), 3.60 (2H, s,
2
2
,
2
2
2
CH Ar), 4.12 (1H, dd, J = 6.0, 7.5 Hz, CHb-5 Diox), 4.22-4.41 (1H, m, CH-4 Diox), 7.17-7.41 (5H, m,
2
1
3
CH-2, CH-3, CH-4, CH-5, CH-6 Ph); C NMR (CDCl , 100 MHz): δ = 26.1 (4CH , Cyc ), 26.3 (2CH ,
3
2
2
2
Cyc ), 26.8 (2CH , Cyc ), 26.9 (2CH , Cyc ), 43.0 (CH, C-1 Cyc), 44.0 (CH, C-1 Cyc’), 52.2 (2CH , C-
2
2
2
2
2
2
3
7
,C-5 Piper), 53.1 (2CH , C-2,C-6 Piper), 60.5 (CH , CH N), 62.5 (CH , CH Ph), 70.7 (CH , C-5 Diox),
2 2 2 2 2 2
5.6 (CH, C-4 Diox), 116.1 (C, C-2 Diox), 127.1(CH, C-4 Ph), 128.0 (2CH, C-3, C-5 Ph), 129.1 (2CH,
+
C-2, C-6 Ph), 136.4 (C, C-1 Ph). ESI-HRMS calcd for C H N O [M+H] 427.3319, found 427.3322.
2
7
43
2
2
1
8

ACCEPTED MANUSCRIPT
The free amine was converted into the corresponding hydrogen oxalate from diethyl ether (0.28 g, 0.47
mmol, yield 50%).
1
mp: 226-228 °C; H NMR (DMSO, 200 MHz): δ = 0.89-1.27 (10H, m, Cyc ), 1.45-1.78 (12H, m, Cyc ),
2
2
2
3
.67-3.04 (10H, m, CH -2, CH -3 CH -5, CH -6 Piper, CH N), 3.33-3.40 (1H, m, CHa-5 Diox), 3.80-
2 2 , 2 2 2
.93 (2H, m, CH Ar), 4.01-4.12 (1H, m, CHb-5 Diox), 4.18-4.37 (1H, m, CH-4 Diox), 7.26-7.44 (5H,
2
m, Ar).
ESI-HRMS calcd for C H N O [M+H] 427.3319, found 427.3322. Anal. Calcd. for C H N O : C,
+
2
7
43
2
2
31 46
2
10
61.37; H, 7.64; N, 4.62; Found C, 61.45; H, 7.71; N, 4.44.
4.1.13. 4-Benzyl-1-[(2,2-diphenyl-1,3-oxathiolan-5-yl)methyl]piperidine (11a)
The title compound was obtained from 6 [43] and 4-benzylpiperidine and was purified by using flash
column chromatography (cyclohexane/ethyl acetate 90/10) to give 11a (0.12 g, 0.28 mmol, 82% yield)
as a colorless oil.
1
H NMR (CDCl , 400 MHz): δ = 1.31-1.53 (5H, m, CH -3, CH-4, CH -5 Piper), 1.91-2.27 (2H, m,
3
2
2
CHa-2, CHa-6 Piper), 2.54 (2H, d, J = 6.5 Hz, CH Ph), 2.62-3.22 (6H, m, CH N, CHb-2, CHb-6 Piper,
2
2
CH -4 Oxath), 4.22-4.44 (1H, m, CH-5 Oxath), 7.04-7.42 (13H, m, Ar , Ph), 7.62 (2H, d, J = 7.1 Hz,
2
2
1
3
Ar ); C NMR (CDCl , 100 MHz): δ = 32.1 (CH , C-3/C-5 Piper), 32.2 (CH , C-3/C-5 Piper), 34.7
2
3
2
2
(
CH , C-4 Oxath), 37.5 (CH, C-4 Piper), 43.1 (CH , CH Ph), 54.1 (CH , C-2/C-4 Piper), 55.0 (CH , C-
2 2 2 2 2
2
/C-4 Piper), 62.4 (CH , CH N), 70.3 (CH, C-5 Oxath), 89.3 (C, C-2 Oxath), 125.7 (CH, C-4 Ph), 127.0
2 2
(
4CH, C-2, C-6 Ar ), 127.6 (2CH, C-4 Ar ), 128.1 (2CH, C-3, C-5 Ph), 128.3 (4CH, C-3, C-5 Ar ),
2
2
2
1
29.1 (2CH, C-2, C-6 Ph), 140.5 (C, C-1 Ph), 143.4 (2C, C-1 Ar ). ESI-HRMS calcd for C H NOS
2 28 32
+
[
M+H] 430.2199, found 430.2201.
The free amine was converted into the corresponding hydrogen oxalate from diethyl ether (0.04 g, 0.08
mmol, yield 48%).
1
mp: 182-184 °C; H NMR (DMSO, 200 MHz): δ = 1.31-1.97 (5H, m, CH -3, CH-4, CH -5 Piper), 2.39-
2
2
2
3
7
.64 (2H, m, CH Ph), 2.67-2.99 (2H, m, CHa-2, CHa-6 Piper), 3.02-3.19 (2H, m, CH -4 Oxath), 3.32-
2
2
.64 (4H, m, CHb-2, CHb-6 Piper, CH N),4.31-4.50 (1H, m, CH-5 Oxath), 7.10-7.43 (13H, m, Ar , Ph),
2
2
.60 (2H, d, J = 7.0 Hz , Ar2).
+
ESI-HRMS calcd for C H NOS [M+H] 430.2199, found 430.2201. Anal. Calcd. for C H NO S: C,
2
8
32
30 33
5
69.34; H, 6.40; N, 2.70; Found C, 69.51; H, 6.61; N, 2.83.
1
9

ACCEPTED MANUSCRIPT
4.1.14. 1-Benzyl-4-[(2,2-diphenyl-1,3-oxathiolan-5-yl)methyl]piperazine (11b)
The title compound was obtained from 6 [43] and 1-benzylpiperazine and was purified by using flash
column chromatography (cyclohexane/ethyl acetate 65/35) to give 11b (0.22 g, 0.51 mmol, 88% yield)
as a colorless oil.
1
H NMR (CDCl , 400 MHz): δ = 2.48-2.89 (10H, m, CH -2, CH -3, CH -5, CH -6 Piper, CH -4 Oxath),
3
2
2
2
2
2
3
.12-3.28 (2H, m, CH N), 3.54 (2H, s, CH Ph), 4.20-4.45 (1H, m, CH-5 Oxath), 7.16-7.44 (13H, m, Ar ,
2
2
2
13
Ph), 7.63 (2H, d, J = 7.1 Hz, Ar ); C NMR (CDCl , 100 MHz): δ = 34.8 (CH , C-4 Oxath), 52.1
2
3
2
(
2CH , C-3,C-5 Piper), 52.9 (2CH , C-2,C-6 Piper), 60.6 (CH , CH N), 62.6 (CH , CH Ph), 70.5 (CH,
2 2 2 2 2 2
C-5 Oxath), 89.8 (C, C-2 Oxath), 126.2 (CH, C-4 Ph), 127.1 (4CH, C-2, C-6 Ar ), 127.5 (2CH, C-4
2
Ar ), 128.0 (2CH, C-3, C-5 Ph), 128.3 (4CH, C-3, C-5 Ar ), 129.0 (2CH, C-2, C-6 Ph), 139.8 (C, C-1
2
2
+
Ph), 143.2 (2C, C-1 Ar ). ESI-HRMS calcd for C H N OS [M+H] 431.2152, found 431.2154.
2
27 31
2
The free amine was converted into the corresponding hydrogen oxalate from diethyl ether (0.10 g, 0.16
mmol, yield 50%).
1
mp: 210-212 °C; H NMR (DMSO, 200 MHz): δ = 2.71-3.12 (11H, m, CH -2, CH -3, CH -5, CH -6
2
2
2
2
Piper, CH -4 Oxath, CHaN), 3.28 (1H, dd, J = 2.2, 4.5 Hz, CHbN), 4.03 (2H, s, CH Ph), 4.17-4.34 (1H,
2
2
m, CH-5 Oxath), 7.16-7.44 (13H, m, Ar , Ph), 7.59 (2H, d, J = 7.0 Hz, Ar ).
2
2
+
ESI-HRMS calcd for C H N OS [M+H] 431.2152, found 431.2154. Anal. Calcd. for C H N O S:
2
7
31
2
31 34
2
9
C, 60.97; H, 5.61; N, 4.59; Found C, 61.12; H, 5.76; N, 4.31.
4.1.15. 4-Benzyl-1-[(2,2-diphenyl-1,3-dithiolan-4-yl)methyl]piperidine (12a)
The title compound was obtained from 7 [43] and 4-benzylpiperidine and was purified by using flash
column chromatography (cyclohexane/ethyl acetate 98/2) to give 12a (0.24 g, 0.55 mmol, 68% yield) as
a colorless oil.
1
H NMR (CDCl , 400 MHz): δ = 1.30-1.54 (5H, m, CH -3, CH-4, CH -5 Piper), 1.91-2.21 (2H, m,
3
2
2
CHa-2, CHa-6 Piper), 2.53 (2H, d, J = 6.1 Hz, CH Ph), 2.70-3.12 (4H, m, CH -5 Dithio, CHb-2, CHb-6
2
2
Piper), 3.16-3.40 (2H, m, CH N), 3.99-4.17 (1H, m, CH-4 Dithio), 7.04-7.42 (11H, m, Ar , Ph), 7.58
2
2
1
3
(
2H, d, J = 7.1 Hz, Ar ), 7.62 (2H, d, J = 7.1 Hz, Ar ); C NMR (CDCl , 100 MHz): δ = 31.9 (CH , C-
2 2 3 2
3
/C-5 Piper), 32.0 (CH , C-3/C-5 Piper), 37.7 (CH, C-4 Piper), 44.6 (CH , C-5 Dithio), 43.0 (CH ,
2
2
2
CH Ph), 54.0 (CH , C-2/C-4 Piper), 54.8 (CH , C-2/C-4 Piper), 56.5 (CH, C-4 Dithio), 62.6 (CH ,
2
2
2
2
CH N), 68.5 (C, C-2 Dithio), 125.7 (CH, C-4 Ph), 127.2 (4CH, C-2, C-6 Ar ), 127.9 (2CH, C-4 Ar ),
2
2
2
1
1
28.2 (2CH, C-3, C-5 Ph), 128.4 (4CH, C-3, C-5 Ar ), 129.2 (2CH, C-2, C-6 Ph), 140.6 (C, C-1 Ph),
2
+
43.8 (2C, C-1 Ar ). ESI-HRMS calcd for C H NS [M+H] 446.1971, found 446.1972.
2
28 32
2
2
0

ACCEPTED MANUSCRIPT
The free amine was converted into the corresponding hydrogen oxalate from diethyl ether (0.12 g, 0.22
mmol, yield 40%).
1
mp: 164-166 °C; H NMR (DMSO, 200 MHz): δ = 1.26-1.41 (2H, m, CHa-3, CHa-5 Piper), 1.52-1.76
(
3H, m, CHb-3, CH-4, CHb-5 Piper), 2.39-2.64 (2H, m, CH Ph), 2.81-4.04 (1H, m, CHa-2/CHa-6
2
Piper), 3.32-3.64 (7H, m, CHa-2/CHa-6 Piper, CHb-2, CHb-6 Piper, CH N, CH-5 Dithio), 4.27-4.50
2
(
1H, m, CH-3 Oxath), .704-7.38 (11H, m, Ar , Ph), 7.52 (2H, d, J = 7.0 Hz, Ar ), 7.63 (2H, d, J = 7.0
2
2
Hz, Ar2).
+
ESI-HRMS calcd for C H NS [M+H] 446.1971, found 446.1972. Anal. Calcd. for C H NO S : C,
2
8
32
2
30 33
4 2
67.26; H, 6.21; N, 2.61; Found C, 67.33; H, 6.28; N, 2.52.
4.1.16. 1-Benzyl-4-[(2,2-diphenyl-1,3-dithiolan-4-yl)methyl]piperazine (12b)
The title compound was obtained from 7 [43] and 1-benzylpiperazine and was purified by using flash
column chromatography (cyclohexane/ethyl acetate 98/2) to give 12b (0.16 g, 0.36 mmol, 42% yield) as
a colorless oil.
1
H NMR (CDCl , 400 MHz): δ = 2.34-2.84 (10H, m, CH -2, CH -3, CH -5, CH -6 Piper, CH -5
3
2
2
2
2
2
Dithio), 3.12-3.34 (2H, m, CH N), 3.55 (2H, s, CH Ph), 3.91-4.17 (1H, m, CH-4 Dithio), 7.13-7.41
2
2
1
3
(
11H, m, Ar , Ph), 7.56 (2H, d, J = 7.2 Hz, Ar ) 7.66 (2H, d, J = 7.2 Hz, Ar ); C NMR (CDCl , 100
2 2 2 3
MHz): δ = 44.5 (CH , C-5 Dithio), 52.1 (2CH , C-3, C-5 Piper), 53.0 (2CH , C-2,C-6 Piper), 56.7 (CH,
2
2
2
C-4 Dithio), 61.3 (CH , CH N), 62.7 (CH , CH Ph), 68.6 (C, C-2 Dithio), 125.5 (CH, C-4 Ph), 127.3
2
2
2
2
(
4CH, C-2, C-6 Ar ), 127.8 (2CH, C-4 Ar ), 128.1 (2CH, C-3, C-5 Ph), 128.5 (4CH, C-3, C-5 Ar ),
2
2
2
1
29.3 (2CH, C-2, C-6 Ph), 140.7 (C, C-1 Ph), 143.6 (2C, C-1 Ar ). ESI-HRMS calcd for C H N S
2 27 31 2 2
+
[
M+H] 447.1923, found 447.1925.
The free amine was converted into the corresponding hydrogen oxalate from diethyl ether (0.1 g, 0.16
mmol, yield 50%).
1
mp: 211-213 °C; H NMR (DMSO, 200 MHz): δ = 2.59-3.12 (10H, m, CH -2, CH -3, CH -5, CH -6
2
2
2
2
Piper, CH -5 Dithio), 3.11-3.35 (2H, m, CH N), 3.96-4.27 (3H, m, CH Ph, CH-4 Dithio), 7.16-7.52
2
2
2
(
13H, m, Ar , Ph), 7.63 (2H, d, J = 7.1 Hz, Ar ).
2
2
+
ESI-HRMS calcd for C H N S [M+H] 447.1923, found 447.1925. Anal. Calcd. for C H N O S :
2
7
31
2
2
31 34
2
8 2
C, 59.41; H, 5.47; N, 4.47; Found C, 59.77; H, 5.69; N, 4.45.
4.1.17. 4-Benzyl-1-[(5,5-diphenyltetrahydrofuran-2-yl)methyl]piperidine (14a)
2
1

ACCEPTED MANUSCRIPT
The title compound was obtained from 13 [44] and 4-benzylpiperidine and was purified by using flash
column chromatography (cyclohexane/ethyl acetate 70/30) to give 14a (0.21 g, 0.52 mmol, 90% yield)
as a colorless oil.
1
H NMR (CDCl , 400 MHz): δ = 1.30-1.54 (5H, m, CH -3, CH-4, CH -5 Piper), 1.73-1.89 (1H, m,
3
2
2
CHa-3 Fur), 1.99-2.24 (3H, m, CHb-3 Fur, CHa-2, CHa-6 Piper), 2.53 (2H, d, J = 6.1 Hz, CH Ph), 2.61-
2
3
.19 (3H, m, CHa-4 Fur, CHb-2, CHb-6 Piper), 3.21-3.42 (3H, m, CHa-4 Fur, CH N), 4.31-4.49 (1H, m,
2
1
3
CH-2 Fur), 7.09-7.49 (15H, m, Ar , Ph); C NMR (CDCl , 100 MHz): δ = 25.6 (CH , C-3 Fur), 31.3
2
3
2
(
CH , C-3/C-5 Piper), 32.1 (CH , C-3/C-5 Piper), 36.8 (CH, C-4 Piper), 38.8 (CH , C-4 Fur), 42.8 (CH ,
2 2 2 2
CH Ph), 53.7 (CH , C-2/C-4 Piper), 54.8 (CH , C-2/C-4 Piper), 60.6 (CH , CH N), 67.6 (CH, C-2 Fur),
2
2
2
2
2
8
8.2 (C, C-5 Fur), 125.7 (CH, C-4 Ph), 125.9 (4CH, C-2, C-6 Ar ), 126.85(2CH, C-4 Ar ), 128.2 (2CH,
2 2
C-3, C-5 Ph), 128.4 (4CH, C-3, C-5 Ar ), 128.8 (2CH, C-2, C-6 Ph), 140.7 (C, C-1 Ph), 146.6 (2C, C-1
2
+
Ar ). ESI-HRMS calcd for C H NO [M+H] 412.2635, found 412.2636.
2
29 34
The free amine was converted into the corresponding hydrogen oxalate from diethyl ether (0.04 g, 0.08
mmol, yield 42%).
1
1
mp: 206-208 °C; H NMR (DMSO, 200 MHz): δ = H NMR (DMSO, 200 MHz): δ = 1.28-1.81 (5H, m,
CH -3, CH-4, CH -5 Piper), 1.92-2.05 (1H, m, CHa-3 Fur), 2.62 (2H, d, J = 6.2 Hz, CH Ph), 2.63-2.75
2
2
2
(
1H, m, CHb-3 Fur), 2.78-3.21 (4H, m, CH -2, CH -6 Piper), 3.38-4.02 (4H, m, CH N, CH -4 Fur),
2 2 2 2
4
.32-4.47 (1H, m, CH-2 Fur), 7.09-7.49 (15H, m, Ar , Ph).
2
+
ESI-HRMS calcd for C H NO [M+H] 412.2635, found 412.2636. Anal. Calcd. for C H NO : C,
2
9
34
31 35
5
74.23; H, 7.03; N, 2.79; Found C, 74.41; H, 7.33, N, 2.89.
4.1.18. 1-Benzyl-4-[(5,5-diphenyltetrahydrofuran-2-yl)methyl]piperazine (14b)
The title compound was obtained from 13 [44] and 1-benzylpiperazine and was purified by using flash
column chromatography (cyclohexane/ethyl acetate 70/30) to give 14b (0.03 g, 0. 07 mmol, 20% yield)
as a colorless oil.
1
H NMR (CDCl , 400 MHz): δ = 1.01-1.22 (1H, m, CHa-3 Fur), 1.28-1.41 (1H, m, CHb-3 Fur), 1.61-
3
1
.83 (1H, m, CHa-4 Fur), 1.96-2.13 (1H, m, CHb-4 Fur), 2.41-2.87 (10H, m, CH N, CH -2, CH -3,
2 2 2
CH -5, CH -6 Piper), 3.51 (2H, s, CH Ph), 4.33-4.49 (1H, m, CH-2 Fur), 7.09-7.49 (15H, m, Ar , Ph);
2
2
2
2
1
3
C NMR (CDCl , 100 MHz): δ = 25.6 (CH , C-3 Fur), 38.8 (CH , C-4 Fur), 52.1 (2CH , C-3,C-5
3
2
2
2
Piper), 53.0 (2CH , C-2,C-6 Piper), 60.5 (CH , CH N), 62.1 (CH , CH Ph), 65.2 (CH, C-2 Fur), 88.5 (C,
2
2
2
2
2
C-5 Fur), 125.8 (CH, C-4 Ph), 125.8 (4CH, C-2, C-6 Ar ), 127.0 (2CH, C-4 Ar ), 128.1 (2CH, C-3, C-5
2
2
2
2

ACCEPTED MANUSCRIPT
Ph), 128.5 (4CH, C-3, C-5 Ar ), 128.9 (2CH, C-2, C-6 Ph), 140.6 (C, C-1 Ph), 145.1 (2C, C-1 Ar ). ESI-
2
2
+
HRMS calcd for C H N O [M+H] 413.2587, found 413.2586.
2
8
33
2
The free amine was converted into the corresponding hydrogen oxalate from diethyl ether (0.03 g, 0.05
mmol, yield 51%).
1
mp: 222-224 °C; H NMR (DMSO, 200 MHz): δ = 1.49-1.71 (1H, m, CHa-3 Fur), 1.83-2.01 (1H, m,
CHb-3 Fur), 2.32-2.51 (1H, m, CHa-4 Fur), 2.55-2.71 (1H, m, CHb-4 Fur), 2.74-3.31 (10H, m, CH -2,
2
CH -3, CH -5, CH -6 Piper, CH N), 3.82 (2H, s, CH Ph), 4.38-4.45 (1H, m, CH-2 Fur), 7.03-7.58 (15H,
2
2
2
2
2
m, Ar , Ph).
2
+
ESI-HRMS calcd for C H N O [M+H] 413.2587, found 413.2586. Anal. Calcd. for C H N O : C,
2
8
33
2
32 36
2
9
64.85; H, 6.12; N, 4.73; Found C, 64.98; H, 6.35; N, 4.64.
4.1.19. 5-[(4-benzylpiperidin-1-yl)methyl]-2,2-diphenylcyclopenta-1-one (16a)
4-Benzylpiperidin-1-ium chloride (1.85 g, 8.75 mmol) and aqueous paraformaldehyde (0.08 g, 2.7 mol)
were added to a solution of 15 [44] (0.51 g, 2.16 mmol) in 5 mL of anhydrous ethanol. The reaction
mixture was refluxed for 1 h and then an additional amount of paraformaldehyde (0.06g, 2.0 mol) was
added. The mixture was refluxed for further 12 h. After cooling to room temperature, the solvent was
removed under reduced pressure. The crude, dissolved in CH Cl , was washed with a solution of 5%
2
2
NaOH and brine and dried over anhydrous Na SO . The crude extract was purified by using flash
2
4
column chromatography on silica gel (cyclohexane/ethyl acetate 70/30) to give the title compound (0.64
g, 1.51 mmol, 70% yield) as an oil.
1
H NMR (CDCl , 400 MHz): δ = 1.21-1.49 (2H, m, CHa-3, CHa-5 Piper), 1.52-2.05 (5H, m, CH-4,
3
CHb-3, CHb-5 Piper, CH -4 Cyclopent), 2.15-2.41 (4H, m, CHa-2, CHa-6 Piper, CH -3 Cyclopent),
2
2
2
.51-2.99 (7H, m, CHb-2, CHb-6 Piper, CH N, CH Ph, CH-5 Cyclopent), 7.04-7.44 (15H, m, Ar ,
2
2
2
13
Ph); C NMR (CDCl , 100 MHz): δ = 19.2 (CH , C-4 Cyclopent), 31.9 (CH , C-3/C-5 Piper), 32.2
3
2
2
(CH , C-3/C-5 Piper), 37.7 (CH, C-4 Piper), 39.5 (CH, C-5 Cyclopent), 40.1 (CH , C-3 Cyclopent.) 42.6
2 2
(
CH , CH Ph), 53.7 (CH , C-2/C-4 Piper), 55.1 (CH , C-2/C-4 Piper), 61.3 (CH , CH N), 62.9 (C, C-2
2
2
2
2
2
2
Cyclopent), 125.5 (CH, C-4 Ph), 126.8 (2CH, C-4 Ar ), 128.0 (4CH, C-3, C-5 Ar ), 128.2 (2CH, C-3, C-
2
2
5
2
Ph), 128.5 (4CH, C-2, C-6 Ar ), 129.1 (2CH, C-2, C-6 Ph), 140.6 (C, C-1 Ph) 142.3 (2C, C-1 Ar ),
2 2
+
14.2 (C, C-1 Cyclopent). ESI-HRMS calcd for C H NO [M+H] 424.2635, found 424.2637.
3
0
34
The free amine was converted into the corresponding hydrogen oxalate from diethyl ether (0.08 g, 0.15
mmol, yield 85%).
2
3

ACCEPTED MANUSCRIPT
1
mp: 163-165 °C; H NMR (DMSO, 200 MHz): δ = 1.28-1.81 (6H, m, CH -3, CH-4, CH -5 Piper, CHa-
2
2
4
Cyclopent), 2.12-2.37 (1H, m, CHb-4 Cyclopent), 2.61 (2H, d, J = 6.1 Hz, CH Ph), 2.65-3.39 (9H, m,
2
CH -2, CH -6 Piper, CH N, CH -3, CH-5 Cyclopent), 7.08-7.41 (15H, m, Ar , Ph).
2
2
2
2
2
+
ESI-HRMS calcd for C H NO [M+H] 424.2635, found 424.2637. Anal. Calcd. for C H NO : C,
3
0
34
32 35
5
74.83; H, 6.87; N, 2.73; Found C, 74.94; H, 7.03; N, 2.72.
4.1.20. 5-[(4-benzylpiperazin-1-yl)methyl]-2,2-diphenylcyclopenta-1-one (16b)
The title compound was obtained from 15 [44] and 4-benzylpiperazinium chloride (1.85 g, 8.75 mmol)
by following the same procedure described for 16a. The crude extract was purified by using flash
column chromatography on silica gel (cyclohexane/ethyl acetate 70/30) to give 16b (0.59 g, 1.39 mmol,
66% yield) as a yellow oil.
1
H NMR (CDCl , 400 MHz): δ = 1.75-1.91 (1H, m, CHa-4 Cyclopent), 2.21-2.35 (1H, m, CHb-4
3
Cyclopent), 2.42-2.91 (13H, m, CH N, CH -2, CH -3, CH -5, CH -6 Piper, CH -3, CH-5 Cyclopent),
2
2
2
2
2
2
1
3
3
.53 (2H, s, CH Ph), 7.05-7.40 (15H, m, Ar , Ph); C NMR (CDCl , 100 MHz): δ = 19.9 (CH , C-4
2 2 3 2
Cyclopent), 39.7 (CH, C-5 Cyclopent), 40.3 (CH , C-3 Cyclopent), 52.2 (2CH , C-3,C-5 Piper), 53.2
2
2
(
2CH , C-2,C-6 Piper), 60.5 (CH , CH N), 61.9 (CH , CH N), 62.9 (C, C-2 Cyclopent), 125.8 (CH, C-4
2 2 2 2 2
Ph), 126.8 (2CH, C-4 Ar ), 128.1 (4CH, C-3, C-5 Ar ), 128.2 (2CH, C-3, C-5 Ph), 128.6 (4CH, C-2, C-6
2
2
Ar ), 129.1 (2CH, C-2, C-6 Ph), 140.7 (C, C-1 Ph), 142.4 (2C, C-1 Ar ), 216.1 (C, C-1 Cyclopent). ESI-
2
2
+
HRMS calcd for C H N O [M+H] 425.2587, found 425.2589.
2
9
33
2
The free amine was converted into the corresponding hydrogen oxalate from diethyl ether (0.13 g, 0.22
mmol, yield 74%).
1
mp: 220-222 °C; H NMR (DMSO, 200 MHz): δ = 1.53-1.72 (1H, m, CHa-4 Cyclopent), 2.12-2.39 (1H,
m, CHb-4 Cyclopent), 2.54-3.11 (13H, m, CH N, CH -2, CH -3, CH -5, CH -6 Piper, CH -3, CH-5
2
2
2
2
2
2
Cyclopent), 3.52 (2H, s, CH Ph), 7.05-7.40 (15H, m, Ar , Ph).
2
2
+
ESI-HRMS calcd for C H N O [M+H] 425.2587, found 425.2589. Anal. Calcd. for C H N O : C,
29
33
2
33 36
2
9
65.55; H, 6.00; N, 4.63; Found C, 65.87; H, 6.31; N, 4.71.
4.1.21. 5-[(4-Benzylpiperidin-1-yl)methyl]-2,2-diphenylcyclopenta-1-ol (17a)
The title compound was obtained as diastereomeric mixture from 16a (1.18 mmol) using an excess of
NaBH (1.8 mmol) at 0 °C in ethanol. The resulting mixture was stirred for 30 minutes at room
4
temperature, then concentrated under reduced pressure. The residue was partitioned between CH Cl2
2
and water. The organic layer was separated and the aqueous one was extracted with CH Cl . The organic
2
2
2
4

ACCEPTED MANUSCRIPT
layers were combined, washed with water, dried over anhydrous Na SO , filtered, and concentrated
2
4
under vacuum. The cis/trans diastereomeric mixture was separated by using flash column
chromatography (cyclohexane/ethyl acetate 90/10).
Cis-17a (0.04 g, 0.10 mmol, 9 % yield) as a colorless oil.
1
H NMR (CDCl , 400 MHz): δ = 1.20-1.97 (11H, m, CH -3 Cyclopent, CHa-2, CHa-6 Piper, CH -3,
3
2
2
CH-4, CH -5 Piper, CH -4 Cyclopent), 2.15-2.31 (3H, m, OH, CHb-2, CHb-6 Piper), 2.37-2.72 (2H, m,
2
2
CH Ph), 2.74-2.89 (2H, m, CH N), 3.12-3.24 (1H, m, CH-5 Cyclopent), 4.99 (1H, d, J = 5.9 Hz, CH-1
2
2
1
3
Cyclopent), 7.01-7.46 (15H, m, Ar , Ph); C NMR (CDCl , 100 MHz): δ = 20.0 (CH , C-4 Cyclopent),
2
3
2
3
1.8 (CH , C-3/C-5 Piper), 32.4 (CH , C-3/C-5 Piper), 37.6 (CH, C-4 Piper), 29.8 (CH , C-2
2
2
2
Cyclopent), 35.1 (CH, C-3 Cyclopent), 42.6 (CH , CH Ph), 53.7 (CH , C-2/C-4 Piper), 55.1 (CH , C-
2
2
2
2
2/C-4 Piper), 59.0 (C, C-1 Cyclopent), 61.6 (CH , CH N), 63.5 (C, C-2 Cyclopent), 125.5 (CH, C-4 Ph),
2 2
1
26.9 (2CH, C-4 Ar ), 128.2 (4CH, C-3, C-5 Ar ), 128.4 (2CH, C-3, C-5 Ph), 128.6 (4CH, C-2, C-6
2
2
Ar ), 129.2 (2CH, C-2, C-6 Ph), 140.4 (C, C-1 Ph) 142.6 (2C, C-1 Ar ). ESI-HRMS calcd for C H NO
2
2
30 36
+
[
M+H] 426.2791, found 426.2793.
The free amine was then converted into the corresponding hydrogen oxalate from diethyl ether (0.02 g,
0.04 mmol, yield 65%).
1
mp: 187-189 °C; H NMR (DMSO, 200 MHz): δ = 1.31-2.01 (7H, m, CH -3 Cyclopent, CH -3, CH-4,
2
2
CH -5 Piper), 2.11-2.44 (2H, m, CH -4 Cyclopent, CHa-2/CHa-6 Piper), 2.41-2.58 (3H, m, CHa-2/CHa-
2
2
6
5
Piper CH Ph), 2.63-2.92 (3H, m, CHa-2/CHa-6, CHb-2, CHb-6 Piper), 3.10-3.45 (3H, m, CH N, CH-
2 2
Cyclopent), 4.31 (1H, m, OH), 4.90 (1H, d, J = 3.3 Hz, CH-1 Cyclopent), 7.03-7.48 (15H, m, Ar , Ph).
2
+
ESI-HRMS calcd for C H NO [M+H] 426.2791, found 426.2793. Anal. Calcd. for C H NO : C,
3
0
36
32 37
5
74.54; H, 7.23; N, 2.72; Found C, 74.60; H, 7.31; N, 2.88.
Trans-17a (0.22 g, 0.53 mmol, 45 % yield) as a colorless oil.
1
H NMR (CDCl , 400 MHz): δ = 1.14-1.71 (7H, m, CH -3 Cyclopent, CH -3, CH-4, CH -5 Piper),
3
2
2
2
1
.83-2.18 (5H, m, OH, CHa-2, CHa-6 Piper, CH -4 Cyclopent), 2.40-2.88 (7H, m, CHb-2, CHb-6 Piper,
2
CH Ph, CH N, CH-5 Cyclopent), 4.36 (1H, d, J = 9.3 Hz, CH-1 Cyclopent), 7.01-7.49 (15H, m, Ar ,
2
2
2
13
Ph). C NMR (CDCl , 100 MHz): δ = 20.1 (CH , C-4 Cyclopent), 31.7 (CH , C-3/C-5 Piper), 32.4
3
2
2
(
(
(
CH , C-3/C-5 Piper), 37.7 (CH, C-4 Piper), 29.9 (CH , C-2 Cyclopent), 35.2 (CH, C-3 Cyclopent), 42.6
2
2
CH , CH Ph), 53.8 (CH , C-2/C-4 Piper), 55.2 (CH , C-2/C-4 Piper), 59.1 (C, C-1 Cyclopent), 61.4
2
2
2
2
CH , CH N), 63.3 (C, C-2 Cyclopent), 125.4 (CH, C-4 Ph), 126.8 (2CH, C-4 Ar ), 128.1 (4CH, C-3, C-
2
2
2
2
5

ACCEPTED MANUSCRIPT
5
Ar ), 128.4 (2CH, C-3, C-5 Ph), 128.5 (4CH, C-2, C-6 Ar ), 129.1 (2CH, C-2, C-6 Ph), 140.3 (C, C-1
2
2
+
Ph) 142.5 (2C, C-1 Ar ). ESI-HRMS calcd for C H NO [M+H] 426.2791, found 426.2792.
2
30 36
The free amine was converted into the corresponding hydrogen oxalate from diethyl ether (0.13 g, 0.20
mmol, yield 49%).
1
mp: 219-221 °C; H NMR (DMSO, 200 MHz): δ = 1.24-2.01 (7H, m, CH -3 Cyclopent, CH -3, CH-4,
2
2
CH -5 Piper), 2.53-3.38 (11H, m, CH -2, CH -6 Piper, CH Ph, CH N, CH -4, CH-5 Cyclopent), 4.23
2
2
2
2
2
2
(
1H, d, J = 9.3 Hz, CH-1 Cyclopent), 4.33 (1H, m, OH), 7.10-7.44 (15H, m, Ar , Ph).
2
+
ESI-HRMS calcd for C H NO [M+H] 426.2791, found 426.2792. Anal. Calcd. for C H NO : C,
3
0
36
32 37
5
74.54; H, 7.23; N, 2.72; Found C, 74.67; H, 7.44; N, 2.93.
4.1.22. 5-[(4-Benzylpiperazin-1-yl)methyl]-2,2-diphenylcyclopenta-1-ol (17b)
The title compound was obtained as diastereomeric mixture from 16b (12.3 mmol) by following the
same procedure described for 17a.
Cis-17b (0.16 g, 0.37 mmol, 3 % yield) as a colorless oil.
1
H NMR (CDCl , 400 MHz): δ = 1.41-1.53 (1H, m, CHa-4 Cyclopent), 1.68-1.89 (1H, m, CHb-4
3
Cyclopent), 2.23-2.88 (14H, m, OH,CH N, CH -2, CH -3, CH -5, CH -6 Piper, CH -3, CH-5
2
2
2
2
2
2
Cyclopent), 3.51 (2H, s, CH Ph), 4.99 (1H, d, J = 4.8 Hz, CH-1 Cyclopent), 7.01-7.47 (15H, m, Ar ,
2
2
1
3
Ph); C NMR (CDCl , 100 MHz): δ = 20.0 (CH , C-4 Cyclopent), 29.7 (CH , C-2 Cyclopent), 35.1
3
2
2
(
CH, C-3 Cyclopent), 52.2 (2CH , C-3,C-5 Piper), 53.4 (2CH , C-2,C-6 Piper), 59.1 (C, C-1 Cyclopent),
2 2
6
0.3 (CH , CH N), 61.6 (CH , CH N), 63.5 (C, C-2 Cyclopent), 125.5 (CH, C-4 Ph), 126.9 (2CH, C-4
2 2 2 2
Ar ), 128.2 (4CH, C-3, C-5 Ar ), 128.4 (2CH, C-3, C-5 Ph), 128.6 (4CH, C-2, C-6 Ar ), 129.2 (2CH, C-
2
2
2
+
2
, C-6 Ph), 140.4 (C, C-1 Ph) 142.6 (2C, C-1 Ar ). ESI-HRMS calcd for C H N O [M+H] 427.2744,
2 29 35 2
found 427.2743.
The free amine was converted into the corresponding hydrogen oxalate from diethyl ether (0.04 g, 0.06
mmol, yield 62%).
1
mp: 210-212 °C; H NMR (DMSO, 200 MHz): δ = 1.35-1.61 (1H, m, CHa-4 Cyclopent), 1.69-1.87 (1H,
m, CHb-4 Cyclopent), 2.08-2.20 (1H, m, CHa-3, Cyclopent), 2.17-3.02 (12H, m, CH N, CH -2, CH -3,
2
2
2
CH -5, CH -6 Piper, CHb-3, CH-5 Cyclopent), 3.62 (2H, s, CH Ph), 4.28 (1H, m, OH), 4.99 (1H, d, J =
2
2
2
3
.3 Hz, CH-1 Cyclopent), 7.01-7.47 (15H, m, Ar , Ph).
2
+
ESI-HRMS calcd for C H N O [M+H] 427.2744, found 427.2743. Anal. Calcd. for C H N O : C,
2
9
35
2
33 38
2
9
65.33; H, 6.31; N, 4.62; Found C, 65.56; H, 6.59; N, 4.65.
2
6

ACCEPTED MANUSCRIPT
Trans-17b (0.31 g, 0.74 mmol, 6 % yield) as a colorless oil.
1
H NMR (CDCl , 400 MHz): δ = 1.23-1.42 (2H, m, CH -4 Cyclopent), 1.83-2.16 (3H, m, OH, CH -3
3
2
2
Cyclopent), 2.25-2.90 (11H, m, CH N, CH -2, CH -3, CH -5, CH -6 Piper, CH-5 Cyclopent), 3.54 (2H,
2
2
2
2
2
13
s, CH Ph), 4.38 (1H, d, J = 6.7 Hz, CH-1 Cyclopent), 7.05-7.51 (15H, m, Ar , Ph). ). C NMR (CDCl ,
2
2
3
1
00 MHz): δ = 20.2 (CH , C-4 Cyclopent), 29.8 (CH , C-2 Cyclopent), 35.1 (CH, C-3 Cyclopent), 42.6
2 2
(
CH , CH Ph), 52.1 (2CH , C-3, C-5 Piper), 53.3 (2CH , C-2, C-6 Piper), 59.1 (C, C-1 Cyclopent), 61.3
2 2 2 2
(
CH , CH N), 63.3 (C, C-2 Cyclopent), 125.4 (CH, C-4 Ph), 126.8 (2CH, C-4 Ar ), 128.1 (4CH, C-3, C-
2
2
2
5
Ar ), 128.4 (2CH, C-3, C-5 Ph), 128.5 (4CH, C-2, C-6 Ar ), 129.1 (2CH, C-2, C-6 Ph), 140.2 (C, C-1
2 2
+
Ph) 142.6 (2C, C-1 Ar ). ESI-HRMS calcd for C H N O [M+H] 427.2744, found 427.2745.
2
29 35
2
The free amine was converted into the corresponding hydrogen oxalate from diethyl ether (0.07 g, 0.12
mmol, yield 56%).
1
mp: 224-226 °C; H NMR (DMSO, 200 MHz): δ = 1.37-1.54 (1H, m, CHa-4 Cyclopent), 1.78-2.05 (1H,
m, CHb-4 Cyclopent), 2.05-2.22 (1H, m, CHa-3, Cyclopent), 2.41-3.12 (12H, m, CH N, CH -2, CH -3,
2
2
2
CH -5, CH -6 Piper, CHb-3, CH-5 Cyclopent), 3.66 (2H, s, CH Ph), 4.11 (1H, m, OH), 4.22 (1H, d, J =
2
2
2
9
.2 Hz, CH-1 Cyclopent), 7.01-7.47 (15H, m, Ar , Ph).
2
+
ESI-HRMS calcd for C H N O [M+H] 427.2744, found 427.2745. Anal. Calcd. for C H N O : C,
29
35
2
33 38
2
9
65.33; H, 6.31; N, 4.62; Found C, 65.41; H, 6.42; N, 4.70.
4.1.23. 1-[(Tert-butyldiphenylsilyl)oxy]-3-chloropropan-2-ol (18)
Tert-butyldiphenylsilyl chloride (3.50 ml, 13.56 mmol) and imidazole (1.20 g, 17.18 mmol) were added
to a solution of 3-chloropropane-1,2-diol (1.00 g, 9.04 mmol) in dry DMF (15 mL). The mixture was
stirred at room temperature for 5 h. The reaction was quenched with saturated aqueous NH Cl and
4
extracted with EtOAc (3 ×30 mL). The combined organic layer was washed with 1.0 M aqueous HCl for
three times and brine. The organic layer was dried over anhydrous MgSO and concentrated under
4
reduced pressure. The residue was purified by flash column chromatography to give the corresponding
silyl ether as a colorless oil (2.21 g, 6.33 mmol, 70% yield).
1
H-NMR (200MHz, CDCl ): δ 1.09 (9H, s, t-Bu), 2.54 (1H, d, J = 6.2; OH), 3.64 (1H, dd, J = 5.7, 11.0
3
Hz, CHa-Cl), 3.71 (1H, dd, J = 5.3, 11.0 Hz, CHb-Cl), 3.74 (1H, dd, J= 5.4, 10.2 Hz, CHa-O), 3.81 (1H,
dd, J = 4.6, 10.2 Hz, CHb-O), 3.92 (1H, m, CHOH), 7.32-7.51 (6H, m, CH-3, CH-4, CH-5 Si-Ar2),
3
5
+
7
3
.56-7.76 (4H, m, CH-2, CH-6 Si-Ar ). ESI-HRMS calcd for C H ClO Si [M+H] 349.1386, found
2 19 26 2
3
26
7
+
49.1388. Calcd for C H ClO Si [M+H] 351.1356, found 351.1358.
1
9
2
2
7

ACCEPTED MANUSCRIPT
4.1.24. (2-(Benzhydryloxy)-3-chloropropoxy)(tert-butyl)diphenylsilane (19)
Bromodiphenylmethane (0.51 g, 2.05 mmol) was added to a solution of 18 (2.1 g, 6.2 mmol ) in toluene
10 mL). The mixture was stirred under reflux for 24 h. The solvent was evaporated under reduced
(
pressure and the solid residue obtained was taken up with EtOAc (30 mL). The organic layer was
washed with brine, dried over anhydrous MgSO and concentrated under reduced pressure. The residue
4
was purified by flash column chromatography to give the title compound as a dark oil (0.65 g, 1.27
mmol, 62% yield).
1
H-NMR (200MHz, CDCl ): δ 1.05 (9H, s, t-Bu), 3.69-3.85 (5H, m, Cl-CH , CH -O, CHOH), 5.58 (1H,
3
2
2
s, CHAr ), 7.25-7.48 (16H, m, Ar , CH-3, CH-4, CH-5 Si-Ar ), 7.61-7.69 (4H, m, CH-2, CH-6 Si-Ar ).
2
2
2
2
+
ESI-HRMS calcd for C H ClO Si [M+H] 515.2168, found 515.2169.
3
2
36
2
4
.1.25. [(2-Chloroethoxy)methylene]dibenzene (20)
The title compound was obtained from bromodiphenylmethane (0.47 g, 1.92 mmol) and 2-chloroethanol
0.4 g, 5.0 mmol) as an oil (0.1 g, 0.5 mmol, 26% yield) by following the same procedure described for
(
19.
1
H NMR (CDCl , 200 MHz): δ = 3.74 (2H, t, J = 6.2 Hz, OCH ), 3.80 (2H, t, J=6.2 Hz, CH Cl), 5.5
3
2
2
3
5
+
(
1H, s, CHAr ), 7.21-7.49 (10H, m, Ar ). ESI-HRMS calcd for C H ClO [M+H] 247.0885, found
2
2
15 16
3
16
7
+
2
47.0883. ESI-HRMS calcd for C H ClO [M+H] 249.0855, found 249.0853.
1
5
4.1.26. 1-{2-(Benzhydryloxy)-3-[(tert-butyldiphenylsilyl)oxy]propyl}-4-benzylpiperidine (21a)
The title compound was obtained from 19 and 4-benzylpiperidine as a yellow oil (0.28 g, 0.43 mmol,
74% yield) by following the general procedure described in the 4.1.4. section.
1
H NMR (CDCl , 400 MHz): δ = 1.02-1.38 (14H, m, t-Bu, CH -3, CH-4, CH -5 Piper), 1.81-2.11 (2H,
3
2
2
m, CHa-2, CHa-6 Piper), 2.56-2.94 (6H, m, CH N, CH Ph, CHa-2, CHb-6 Piper), 3.61-3.83 (3H, m,
2
2
CH -O, CHOH), 5.58 (1H, s, CHAr ), 7.23-7.72 (25H, m, Si-Ar , Ar , Ph). ESI-HRMS calcd for
2
2
2
2
+
C H NO Si [M+H] 654.3762, found 654.3764.
44
52
2
4
.1.27. 1-{2-(Benzhydryloxy)-3-[(tert-butyldiphenylsilyl)oxy]propyl}-4-benzylpiperazine (21b)
The title compound was obtained from 19 and 1-benzylpiperazine as a colorless oil (0.32 g, 0.49 mmol,
0% yield) by following the general procedure described in the 4.1.4. section.
9
2
8