Further structural exploration of trisubstituted asymmetric pyran derivatives (2S,4R,5R)-2-benzhydryl-5-benzylamino-tetrahydropyran-4-ol and their corresponding disubstituted (3S,6S) pyran derivatives: A proposed pharmacophore model for high-affinity inte

Article abstract of DOI:10.1021/jm0601699

In our previous report, we described a novel series of asymmetric pyran derivatives (2S,4R,5R)-2-benzhydryl-5-benzylamino-tetrahydropyran-4-ol and their enantiomers as blockers of monoamine transporters in the brain. In this report, we describe the furthe

Full text of DOI:10.1021/jm0601699

J. Med. Chem. 2006, 49, 4239-4247
4239
Further Structural Exploration of Trisubstituted Asymmetric Pyran Derivatives
(2S,4R,5R)-2-Benzhydryl-5-benzylamino-tetrahydropyran-4-ol and Their Corresponding
Disubstituted (3S,6S) Pyran Derivatives: A Proposed Pharmacophore Model for High-Affinity
Interaction with the Dopamine, Serotonin, and Norepinephrine Transporters
Shijun Zhang,† Fernando Fernandez,† Stuart Hazeldine,† Jeffrey Deschamps,‡ Juan Zhen,§ Maarten E. A. Reith,§ and
Aloke K. Dutta*,†
Department of Pharmaceutical Sciences, Wayne State UniVersity, Detroit, Michigan 48202, Laboratory for the Structure of Matter, Code 6030,
NaVal Research Laboratory, 4555 OVerlook AVenue SW, Washington, D.C. 20735, and New York UniVersity School of Medicine, Millhauser
Laboratories Department of Psychiatry, New York, New York 10016
ReceiVed February 14, 2006
In our previous report, we described a novel series of asymmetric pyran derivatives (2S,4R,5R)-2-benzhydryl-
5-benzylamino-tetrahydropyran-4-ol and their enantiomers as blockers of monoamine transporters in the
brain. In this report, we describe the further exploration of this series of molecules by incorporating functional
groups in the molecular template, which should promote the formation of H bonds with the transporters. In
addition, a new synthetic scheme for the asymmetric synthesis of disubstituted cis-(6-benzhydryl-tetrahydro-
pyran-3-yl)-benzylamine analogues and their biological characterization is reported. All synthesized derivatives
were tested for their affinities for the dopamine transporter (DAT), serotonin transporter (SERT), and
norepinephrine transporter (NET) in the brain by measuring their potency in inhibiting the uptake of [3H]-
DA, [3H]5-HT, and [3H]NE, respectively. The compounds were also tested for their binding potency at the
DAT by their ability to inhibit binding of [3H]WIN 35, 428. The results indicated that the presence of
functional groups, such as -OH, -NH2, and the bioisosteric 5-substituted indole moiety in both di and
trisubstituted compounds, significantly increased their potencies for the SERT and NET, especially for the
NET. Among the trisubstituted compounds, (-)-4b exhibited the highest potency for the NET and the SERT
(Ki of 2.13 and 15.3 nM, respectively) and was a serotonin norepinephrine reuptake inhibitor (SNRI).
Compound (-)-4a exhibited the highest selectivity for the NET. Among the disubstituted compounds, a
number of compounds, such as (-)-9a, (+)-9b, (-)-9b, and (+)-9d, exhibited significant low-nanomolar
potencies for the SERT and the NET. Interestingly, compound (-)-9d exhibited appreciable potencies at all
three transporters. On the basis of our present and past findings, we propose a qualitative model for the
interaction of these compounds with monoamine transporters, which will be refined further in the future.
Introduction
Structurally diverse molecules have been developed for
targeting monoamine transporter systems in search of medica-
tions for various diseases such as cocaine addiction and
depression. Especially, for the past one and half decades, the
DAT has been a target for developing medications for cocaine
addiction. In this respect, compounds with diverse structures
have been developed as extensively reviewed in recent
articles.15-17 Similarly, various structurally different molecules
have been developed for the inhibition of the SERT known as
SSRIs, for example, fluoxetine (Figure 1).18,19 SSRIs are known
to possess pharmacological activity against depression and are
used extensively as antidepressant agents.19-21 However, selec-
tive agents for the NET are relatively rare, compared to those
for the DAT and the SERT. Recently, the highly selective NET
blocker reboxetine (Figure 1) has been advanced for its strong
antidepressant effect.22-24 Compounds that are potent at both
the SERT and the NET are known as SNRIs. Two well-known
molecules belonging to the SNRI category are duloxetine and
venlafaxine (Figure 1).25 SNRIs such as venlafaxine exhibit
antidepressant activity in clinical trials and produce a somewhat
greater response and remission rates compared to those of
SSRIs.26
Synaptic transmission involves the regulated release of
neurotransmitters into the synaptic cleft for interaction with
postsynaptic receptors.1 The removal of biogenic amine trans-
mitters from the cleft and from the extraneuronal space by their
respective transporters enables the termination of the signal by
its reuptake back into the presynaptic terminal, allowing a high
constant level of neurotransmitters in the neuron and a low
extraneuronal concentration.2 Monoamine transporters, including
the dopamine transporter (DAT), the serotonin transporter
(SERT), and the norepinephrine transporter (NET), play an
important role in maintaining the concentration of biogenic
amine neurotransmitters in the central nervous system (CNS).
These transporters are involved in different pathological pro-
cesses and have been implicated in many neurological
disorders.3-8 DAT is believed to be the main target for mediating
cocaine’s reinforcing and behavioral effects, although several
lines of evidence also implicate the involvement of the sero-
tonergic system in some capacity.9-12 It is believed that
dysfunctional SERT and NET systems in the CNS play an
important role in the etiology of depression.13,14
* Corresponding author. Tel: 313-577-1064. Fax: 313-577-2033. E-
mail: adutta@wayne.edu.
In our effort to design and discover novel templates for
developing pharmacotherapies for cocaine addiction and other
related neuro disorders, we recently developed 3,6-disubstituted
and 2,4,5-trisubstituted tetrahydro-pyran derivatives targeting
† Wayne State University.
‡ Naval Research Laboratory.
§ New York University School of Medicine.
10.1021/jm0601699 CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/16/2006

4240 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14
Zhang et al.
Figure 1. Molecular structures of selected dopamine, serotonin, and norepinephrine transporter blockers.
monoamine transporter systems.27-29 In a recent report, we
demonstrated the development of asymmetric trisubstituted
pyran derivatives in different stereo- and regio-selective isomers
with respect to the location of the hydroxyl and amino
substitutions on the pyran ring.29 Biological results indicate that
the regioselective location of the hydroxyl group at the
4-position on the pyran ring, as shown in compounds I and II
in Figure 1, is an important requirement for the binding
interaction with the transporters. In addition, the stereoselective
orientation of the hydroxyl group is important because the (-)-
isomers exhibited higher potency compared to that of the
corresponding (+)-isomers. Our earlier results indicated the
preferential interaction of certain cis-3,6-disubstituted pyran
derivatives with the NET, whereas (2S,4R,5R)-2,4,5-trisubsti-
tuted pyran derivatives bound selectively or nonselectively
mainly to the SERT or NET.28,29 For trisubstituted derivatives,
the selectivity for different transporters could be manipulated
by modifying the substituents in the phenyl ring of the N-benzyl
moiety.29 Thus, compound I exhibited high potency and
selectivity for the NET, whereas compound II exhibited dual
activity by being potent for both the SERT and NET.29 We now
report an extrapolation of this initial result. In the class of
compounds presented here, the moieties capable of hydrogen
bonding have been introduced at the N-benzyl position in both
the di and trisubstituted series. Thus, in one instance, either
hydroxyl or amino groups were introduced in the phenyl ring,
and in another case, the phenyl moiety was replaced by a
5-substituted indole moiety.
Scheme 2 presents the asymmetric synthesis of disubstituted
(-)-9a, (-)-9b, (-)-9c, and (-)-9d. The trans-epoxide deriva-
tive 1a was reduced by lithium aluminum hydride (LAH) in
hexane/ether (100:1) to give 5a and 5c as a mixture of products,
which were mesylated without further separation. Pure mesylate
6a could be separated by column chromatography. The detailed
structural characterization of 6a is included in the Supporting
Information. trans-(3R,6S)-Benzhydryl-tetrahydro-pyran-3-ol
(5a) was converted to 8a through three reaction steps as reported
in our previous publication.28 Thus, mesylation with methane-
sulfonyl chloride in dry dichloromethane produced 6a, which
was then treated with sodium azide in DMF to produce azide
7a with inversion of configuration. This azido displacement
reaction resulted in the production of the cis-isomer 7a from
trans-5a. Finally, the catalytic hydrogenation of azide 7a with
Pd/C produced the amine precursors 8a in good yield. The
reductive amination of 8a with 4-hydroxy-benzaldehyde, 1H-
indol-5-carnaldehyde, and 4-nitro-benzaldehyde produced (-)-
9a, (-)-9b, and (-)-9c, respectively. Compound (-)-9d was
synthesized from (-)-9c via the reduction of the nitro group in
the presence of SnCl2 in ethanol and ethyl acetate.
The synthesis of compounds (+)-9a, (+)-9b, (+)-9c, and (+)-
9d is presented in Scheme 3. The same procedure we have
described in Scheme 2 produced the enantiomeric compounds
(+)-9a, (+)-9b, (+)-9c, and (+)-9d from the starting compound
trans-1b.
In our attempt to synthesize the asymmetric trisubstituted
derivatives, we have followed our previously established
synthetic procedure. In addition, we have developed a novel
asymmetric synthetic procedure for the synthesis of 3,6-
disubstituted derivatives.
Chemistry. The route of synthesis of all final compounds is
presented in Schemes 1-3. Scheme 1 describes the synthesis
of (-)-4a, (+)-4a, (-)-4b, and (+)-4b. The trans-epoxide
derivative 1a,29 was reacted with NaN3 in the presence of NH4-
Cl in CH3OH-H2O to regioselectively give only 2a.30,31
Compound 2a was hydrogenated in the presence of a pal-
ladium-C catalyst in methanol to produce amine 3a in good
yield. The reductive amination of 3a with 4-hydroxy-benzal-
dehyde and 1H-indol-5-carbanaldehyde produced (-)-4a and
(-)-4b, respectively. The same procedure starting with 1b
regioselectively produced enantiomeric compounds (+)-4a and
(+)-4b in good yield.
In our initial article, we extensively characterized the structure
of the final target compounds and the epoxide intermediates by
proton NMR analysis.29 We demonstrated that the highest
activity in the 2-benzhydryl-5-benzylaminotetrahydropyran-4-
ol analogues resides in the (2S,4R,5R) absolute configuration.
Furthermore, we showed by NMR analysis that the equatorial
biphenyl group is in a cis relationship with the axial amino
group. We also demonstrated that the hydroxyl group located
in the 4-position on the pyran ring is oriented in an axial position
and in a trans stereochemistry relationship with the vicinal amino
substitution and in a trans relationship with respect to the benzyl
group at the 2-position. We have now unambiguously confirmed
our proposed structure by a crystal structure of compound II
(Figure 2). The crystal structure confirms the (2S,4R,5R)
absolute configuration stereochemistry that we proposed ear-
lier.29

Trisubstituted Asymmetric Pyran DeriVatiVes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14 4241
Scheme 1a
a (a) NaN3/NH4Cl/CH3OH-H2O (8:1), 80 °C, overnight. (b) H2/Pd-C, MeOH, 4 h. (c) Aldehyde/AcOH/NaCNBH3, ClCH2CH2Cl, room temperature, 4
h.
Scheme 2a
a (a) LiAlH4/hexane/ether (100:1), room temperature, 20 h. (b) (i) MeSO2Cl/Et3N/CH2Cl2, room temperature, overnight. (ii) Separation by chromatography.
(c) NaN3/DMF, 100 °C, overnight. (d) H2/Pd-C, MeOH, 4 h. (e) Aldehyde/AcOH/NaCNBH3, 4 h. (f) SnCl2/EtOH/EtOAc, reflux, 1.5 h.
Results and Discussion
transporters. The design of these compounds was prompted by
our earlier observation that either the introduction of a hydroxyl
and an amino group in the benzyl aromatic ring or the
replacement of the 4-hydroxyphenyl group by a bioisosteric
5-substituted indole ring in 3,6-disubstituted pyran derivatives
produces compounds with potent affinity at the NET.28 Fur-
thermore, in our initial study on trisubstituted compounds, we
In this report, we describe the biological properties of
rationally designed novel asymmetric pyran derivatives as an
extension of our earlier findings.28,29 The current compounds
have been designed with H bond forming functionalities
incorporated in the N-benzyl substitution to explore their effect
on potency and selectivity in interacting with monoamine

4242 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14
Zhang et al.
Scheme 3a
a (a) LiAlH4/pentane, rt, 20 h. (b) (i) MeSO2Cl/Et3N/CH2Cl2, rt, overnight. (ii) Separation by column. (iii) NaN3/DMF, 100 °C, overnight. (iv) H2/Pd-C.
(c) Aldehyde/AcOH/NaCNBH3. (d) SnCl2/EtOH/EtOAc, reflux, 1.5 h.
Figure 2. View of ((2S,4R,5R)-5-(4-methoxybenzylamino)-2-benzhydryl-tetrahydro-2H-pyran-4-ol) (II) with the thermal displacement parameters
shown at the 30% level. The bromine atom and water molecule have been omitted for clarity.
Table 1. Affinity of Drugs at the DAT, SERT, and NET in Rat Brain
DAT binding,
Ki, nM,
[3H]WIN
35, 428a
DAT uptake,
Ki, nM,
SERT uptake,
Ki, nM,
NET uptake,
Ki, nM
compd
[3H]DAa
[3H]5-HTa
[3H]NEa
GBR 12909b
8.56 ( 1.5
1500 ( 570
183 ( 32
125 ( 5
10.6 ( 2.2
446 ( 59
115 ( 12
91.5 ( 7.4
172 ( 20
184 ( 16
120 ( 8
91.1 ( 12.8
707 ( 30
25.9 ( 3.6
2540 ( 430
237 ( 12
223 ( 45
15.3 ( 1.3
187 ( 25
37.7 ( 2.6
11.8 ( 1.6
14.5 ( 2.7
64.6 ( 11.8
19.9 ( 1.5
45.7 ( 17.7
16.1 ( 1.6
102 ( 32
4.92 ( 0.92
15.8 ( 5.3
94.4 ( 18.5
10.4 ( 1.0
13.2 ( 4.0
2.13 ( 0.41
40.9 ( 6
5.09 ( 0.92
15.6 ( 2.3
6.56 ( 1.01
81.6 ( 9.7
54.3 ( 9.8
25.6 ( 3.6
12.6 ( 3.7
(-)-I-(D-165)b
(-)-II-(D-142)b
(+)-4a(D-158)
(-)-4a(D-152)
(+)-4b(D-167)
(-)-4b (D-168)
(+)-9a (D-155)
(-)-9a (D-161)
(+)-9b(D-186)
(-)-9b(D-187)
(+)-9c (D-200)
(-)-9c (D-199)
(+)-9d(D-184)
(-)-9d(D-185)
234 ( 18
399 ( 78
570 ( 142
114 ( 2
67.4 ( 4
226 ( 6
85 ( 5.9
467 ( 48
338 ( 40
64.6 ( 12.4
38.4 ( 10.3
118 ( 18
142 ( 18
142 ( 43
214 ( 11
59.9 ( 14.2
34.6 ( 6.5
43.9 ( 5.2
62.4 ( 5.6
a For binding, the DAT was labeled with [3H]WIN 35, 428. For uptake by the DAT, SERT, and NET, the [3H]DA, [3H]5-HT, and [3H]NE accumulation
were measured. Results are average ( SEM of three to eight independent experiments assayed in triplicate. b See ref 29.
observed the significant influence of substituents in the aromatic
ring on affinity and selectivity for the SERT and the NET. Our
model for the qualitative prediction of potency and selectivity
of these compounds for monoamine transporter systems is based
upon the results from the current studies as well as from our
previously published data.29
Compounds (+)-4a, (-)-4a, (+)-4b and (-)-4b incorporate
phenolic hydroxy and 5-substituted indole moieties. Consonant
with our earlier results on disubstituted compounds,28
both (-)-4a and (-)-4b (Scheme 1) exhibited high potency for
the NET (Ki: 10.39 and 2.13 nM, respectively), and additionally,
the indole derivative (-)-4b exhibited high potency for the
SERT (Ki: 15.3 nM) (Table 1). Thus, (-)-4b is a dual active
serotonin-norepinephrine transporter blocker and can be des-
ignated as an SNRI. As we found enantioselective activity in
our earlier study,29 the enantiomeric (+)-4a was much weaker
than (-)-4a at the NET. However, no appreciable enantio-
selectivity was observed for the two indole enatiomers (+)-4b

Trisubstituted Asymmetric Pyran DeriVatiVes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14 4243
Figure 3. Proposed interaction model of pyran derivatives with monoamine transporters molecules.
Table 2: Selectivity of Drugs (Ratio of Ki) in Inhibiting Uptake by
and (-)-4b because both enantiomers exhibited potent affinity
for the NET (Ki: 13.2 and 2.13 nM, respectively). However,
for the interaction with the SERT, an enantioselectivity was
observed because (-)-4b was more potent than (+)-4b (Ki: 15.3
vs 223 nM). It is evident from these results that the potency for
the NET has increased significantly in these molecules compared
to that of the SERT, reflecting a possible contribution of
enhanced H-bonding interaction with the NET.
Monoamine Transporters
DAT uptake/
DAT uptake/
NET uptakea
SERT uptake/
NET uptakea
compd
SERT uptakea
GBR 12909
(+)-4a
(-)-4a
(+)-4b
(-)-4b
(+)-9a
(-)-9a
(+)-9b
(-)-9b
(+)-9c
(-)-9c
(+)-9d
(-)-9d
0.12
0.03
0.72
0.82
7.8
0.10
0.96
17
14
56.
0.89
27
23
17
7.2
0.36
2.2
1.6
17
4.6
7.4
As described in the Chemistry section, we have developed
an asymmetric synthesis pathway for the 3,6-disubstituted
compounds to circumvent our earlier problems related to
resolution. Similar N-benzyl modifications were introduced for
our disubstituted derivatives as described above for the above
trisubstituted compounds. The results indicate potent activity
for the NET in these optically active disubstituted compounds.
The hydroxy compounds (+)-9a and (-)-9a (Scheme 2)
exhibited differential activity for the monoamine transporters
with (-)-9a displaying an SNRI profile (Ki: 37.7 and 5.09 nM
for SERT and NET, respectively). In this context, the counterpart
of disubstituted compound (-)-9a, the trisubstituted compound
(-)-4a, exhibited low-nanomolar potency at the NET and was
weak at the SERT. Evidently, compound (-)-9a without the
hydroxyl group on the pyran ring has increased affinity for the
SERT. However, indole derivatives (-)-9b and (+)-9b were
potent at both the SERT and the NET with (-)-9b being twice
as potent at the NET than (+)-9b (Ki: 6.56 vs 15.6 nM, Table
1); their potencies at the SERT were comparable (Ki: 14.5 and
11.8 nM, respectively). In addition, the potency of (-)-4b and
(-)-9b was also comparable. However, unlike enantiomeric (+)-
4b, compound (+)-9b retained low-nanomolar affinity for the
SERT (223 vs 11.8 nM).
Furthermore, we synthesized two enantiomeric amino deriva-
tives as shown in structures (+)-9d and (-)-9d. The profile of
the interaction with the monoamine transporters of these two
derivatives bears similarities to that for (+)-9b and (-)9b. All
molecules exhibited potent interaction with the NET and SERT,
indicating the potential involvement of an H-bonding interaction
with the amino moiety. In this regard, compound (-)-9d
exhibited activity for all three transporters and was thus a triple
acting molecule. Interestingly, much of the potency for the NET
was decreased when the electron withdrawing substituent nitro
was introduced in compounds (+)-9c and (-)-9c. Thus,
compound (-)-9c was more than 4- and 8-fold less potent than
(-)-9d and (-)-9b (54.3 vs 12.6 and 6.56 nM, Table 1). An
interesting observation was that the disubstituted derivatives
compared to their trisubstituted counterpart exhibited a relative
lack of discrimination between respective enantiomers for
interaction with the three transporters.
12.
15
9.1.
33
0.73
0.63
1.7.
5.0
0.75
2.2.
0.79
0.36
1.8
0.92
1.7.
0.96
3.9
1.3
a Ratio of Ki values.
monoamine transporter targets. This is shown in Figure 3. The
biphenyl moiety in this model may represent a common
pharmacophoric element that is important for all three transport-
ers. In both disubstituted and trisubstituted compounds, the
substituents on the phenyl moiety dictate selectivity and potency
mainly for the SERT and NET. Increasing interaction with the
NET was observed when H-bonding substitution was introduced.
In the trisubstituted compounds, the stereoselective orientation
of the hydroxyl group is important for interaction with both
SERT and NET, more so with NET. The interaction of the same
hydroxyl group with the DAT appears to be unfavorable.
Conclusion
In this report, we describe the successful completion of the
asymmetric synthesis of both disubstituted and trisubstituted
pyran derivatives. In vitro binding results indicate that the
presence of H bond forming moieties increases the potencies
of these molecules for the SERT and the NET, especially for
the NET. Several compounds from this latest series, for example,
(-)-4b, (-)-9a, (+)-9b, (-)-9b, and (+)-9d, can be considered
as dual acting SNRIs because they exhibited appreciable
potencies at both the SERT and NET (Table 1 and Table 2).
Compound (-)-4a exhibited the highest selectivity for the NET
in the current series (Table 2). However, compound (-)-9d was
triple acting because it was active at all three transporters. On
the basis of the information available so far on this novel class
of molecules, we propose a preliminary model for the interaction
with the three monoamine transporters. This model will be
refined further in the future when more SAR results become
available. These compounds will have strong potential to act
as antidepressants.
Experimental Details
Model of Interaction. On the basis of our current results
and the results from our previous publication,29 we propose a
model for the interaction of these pyran derivatives with
Reagents and solvents were obtained from commercial suppliers
and used as received unless otherwise indicated. The dry solvent

4244 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14
Zhang et al.
was obtained according to the standard procedure.32 All reactions
were performed under inert atmosphere (N2) unless otherwise noted.
Analytical silica gel-coated TLC plates (Si 250F) were purchased
from Baker, Inc. and were visualized with UV light or by treatment
with phosphomolybdic acid (PMA). Flash chromatography was
pressure, and the residue was purified by flash chromatography
(hexane/ethyl acetate/triethylamine, 3:2:0.2) to give, (-)-4a: 0.03
g (80%, [R]D (-)72.6, c)1, MeOH).
1HNMR (CDCl3, 400 MHz): 1.40 (m, 1H, H-3eq), 1.66 (dt, J
) 2.8 Hz, 14.0 Hz, 1H, H-3ax), 2.45 (m, 1H, H-5), 3.23 (bs, NH,
OH), 3.58 (d, J ) 12.4 Hz, 1H, (OH)PhCH2), 3.70-3.80 (m, 2H,
H-6, (OH)PhCH2), 3.84-4.00 (m, 3H, H-4, H-6, Ph2CH), 4.49 (dt,
J ) 2.0 Hz, 10.0 Hz, 1H, H-2), 6.57, 7.03, 7.10-7.36 (m, 14H,
aromatic-CH).
1
carried out on Baker Silica Gel 40 mM. H NMR spectra were
routinely obtained using a Varian 400 MHz FT NMR spectrometer.
The NMR solvent used was CDCl3 as indicated. TMS was used as
an internal standard. Elemental analyses were performed by Atlantic
Microlab, Inc. and were within ( 0.4% of the theoretical value.
[3H]WIN 35,428 (87.0 Ci/mmol), [3H]dopamine (59.4 Ci/mmol),
[3H]serotonin (30.0 Ci/mmol), and [3H]norepinephrine (52.0 Ci/
mmol) were obtained from Dupont-New England Nuclear (Boston,
MA). (-)-Cocaine hydrochloride, WIN 35,428 naphthalene sul-
fonate, and GBR 12909 dihydrochloride (1-[2-[bis(4-fluorophenyl)-
methoxy]ethyl]-4-[3-phenylpropyl]piperazine) were purchased from
SIGMA-Aldrich (St. Louis, MO).
Procedure A. Synthesis of (2S,4R,5R)-5-Azido-2-benzhydryl-
tetrahydropyran-4-ol (2a). A solution of 1a (0.05 g, 0.19 mmol)
in an 8:1 MeOH/H2O (2 mL) mixture was treated with NaN3 (0.06
g, 0.94 mmol) and NH4Cl (0.02 g, 0.41 mmol), and the resulting
reaction mixture was stirred at 80 °C overnight. The reaction
mixture was diluted with ether, and the organic layer was separated.
The ether extract was washed with saturated aqueous NaHCO3 and
water and dried over Na2SO4. The ether was removed in vacuo to
afford a crude solid product. Purification of the product by flash
chromatography (hexane/ethyl acetate ) 4:1) yielded 2a: 0.05 g
(95%, [R]D (-)109.3, c)1, MeOH).
The free base was converted into oxalate: mp 202-205 °C. Anal.
[C25H27NO3‚(COOH)2 0.4H2O] C, H, N.
Synthesis of (2R,4S, 5S)-2-Benzhydryl-5-(4-hydroxy-benzyl-
amino)-tetrahydro-pyran-4-ol ((+)-4a). Compound 3b (0.02 g,
0.07 mmol) was reacted with 4-hydroxybenzaldehyde (0.01 g, 0.07
mmol), glacial acetic acid (0.004 g, 0.07 mmol), and NaCNBH3
(0.01 g, 0.09 mmol) (Procedure C) to give (+)-4a: 0.02 g (85%,
[R]D (+)72.4, c)1, MeOH).
1HNMR (CDCl3, 400 MHz): 1.42 (m, 1H, H-3eq) 1.68 (dt, J )
2.8 Hz, 12.0 Hz, 1H, H-3ax), 2.46 (m, 1H, H-5), 3.52 (bs, NH,
OH), 3.60 (d, J ) 12.8 Hz, 1H, (OH)PhCH2), 3.72-3.82 (m, 2H,
H-6, (OH)PhCH2), 3.86-4.00 (m, 3H, H-4, H-6, Ph2CH), 4.50 (dt,
J ) 2.4 Hz, 10.4 Hz, 1H, H-2), 6.58, 7.05, 7.10-7.36 (m, 14H,
aromatic-CH).
The free base was converted into oxalate: mp 196-199 °C. Anal.
[C25H27NO3‚(COOH)2 0.4H2O] C, H, N.
Synthesis of (2S,4R,5R)-2-Benzhydryl-5-[(1H-indol-5-yl-
methyl)-amino]-tetrahydro-pyran-4-ol ((-)-4b). Compound 3a
(0.03 g, 0.11 mmol) was reacted with 1H-indol-5-carbaldehyde
(0.02 g, 0.11 mmol), glacial acetic acid (0.01 g, 0.11 mmol), and
NaCNBH3 (0.01 g, 0.21 mmol) (Procedure C) to give 4b: 0.04 g
(92%, [R]D (-)69.90, c)1, acetone).
1HNMR (CDCl3, 400 MHz): 1.44 (m, 1H, H-3eq), 1.80 (ddd, J
) 14 Hz, 11.2 Hz, 2.8 Hz, 1H, H-3ax), 1.91 (s, 1H, OH), 3.26 (m,
1H, H-5), 3.82-4.04 (m, 4H, H-4, H-6, Ph2CH), 4.49 (dt, J ) 2.4
Hz, 10.0 Hz, 1H, H-2), 7.00-7.40 (m, 10H, aromatic-CH).
Synthesis of (2R,4S,5S)-5-Azido-2-benzhydryl-tetrahydropy-
ran-4-ol (2b). Compound 1b (0.04 g, 0.15 mmol) was treated with
NaN3 (0.05 g, 0.75 mmol) and NH4Cl (0.02 g, 0.33 mmol)
(Procedure A) to yield 2b: 0.04 g (95%, [R]D (+)108, c)1, MeOH).
1HNMR (CDCl3, 400 MHz): 1.45 (m, 1H, H-3eq), 1.80 (ddd, J
) 14 Hz, 11.2 Hz, 2.8 Hz, 1H, H-3ax), 2.0 (bs, 1H, OH), 3.27 (m,
1H, H-5), 3.84-4.05 (m, 4H, H-4, H-6, Ph2CH), 4.50 (dt, J ) 2.4
Hz, 10.0 Hz, 1H, H-2), 7.00-7.40 (m, 10H, aromatic-CH).
Procedure B. Synthesis of (2S,4R,5R)-5-Amino-2-benzhydryl-
tetrahydropyran-4-ol (3a). Compound 2a (0.05 g, 0.18 mmol),
dissolved in methanol (20 mL), was hydrogenated in the presence
of 10% Pd/C (0.01 g). The mixture was filtered through a short
bed of cellite, and the evaporation of the solvent gave 3a: 0.05 g
(97%, [R]D (-)66, c)1, MeOH), which was pure enough for the
next reaction.
1HNMR (DMSO, 400 MHz): 1.24 (m, 1H, H-3eq), 1.63 (dt, J
) 2.8 Hz, 12.0 Hz, 1H, H-3ax), 2.35 (m, 1H, H-5), 3.35 (bs, NH,
OH), 3.61 (d, J ) 10.4 Hz, 1H, H-6), 3.68-3.90 (m, 4H, H-4,
H-6, indol-CH2), 3.97(d, J ) 10.0 Hz, 1H, Ph2CH), 4.45 (dt, J )
2.0 Hz, 10.0 Hz, 1H, H-2), 6.40, 7.00-7.60 (m, 15H, aromatic-
CH).
The free base was converted into oxalate: mp 221-224 °C. Anal.
[C27H28N2O2‚(COOH)2 0.5H2O] C, H, N.
Synthesis of (2R,4S,5S)-2-Benzhydryl-5-[(1H-indol-5-ylmethyl)-
amino]-tetrahydro-pyran-4-ol ((+)-4b). Compound 3b (0.05 g,
0.18 mmol) was reacted with 1H-indol-5-carbaldehyde (0.03 g, 0.18
mmol), glacial acetic acid (0.01 g, 0.18 mmol), and NaCNBH3 (0.02
g, 0.35 mmol) (Procedure C) to give (+)-4b: 0.05 g (69%, [R]D
(+)70.9, c)1, acetone).
1HNMR (acetone, 400 MHz): 1.27 (td, J ) 2.8 Hz, 14.0 Hz,
1H, H-3eq), 1.61 (dt, J ) 2.8 Hz, 14.0 Hz, 1H, H-3ax), 2.34 (m,
1H, H-5), 3.58 (d, J ) 12.0 Hz, 1H, H-6), 3.68-3.90 (m, 5H, H-4,
H-6, indol-CH2, Ph2CH), 4.41 (dt, J ) 2.4 Hz, 10.0 Hz, 1H, H-2),
6.28, 6.94-7.44 (m, 15H, aromatic-CH).
1HNMR (CDCl3, 400 MHz): 1.40 (m, 1H, H-3), 1.70 (m, 1H,
H-3), 2.73 (s, 1H, H-5), 3.20 (m, 3H, NH, OH), 3.60 (m, 1H, H-6),
3.80-4.00 (m, 3H, H-4, H-6, Ph2CH), 4.46 (t, J ) 10.0 Hz, 1H,
H-2), 7.00-7.40(m, 10H, aromatic-CH).
The free base was converted into oxalate: mp 224-228 °C. Anal.
[C27H28N2O2‚(COOH)2 ] C, H, N.
Synthesis of (2R,4S,5S)-5-Amino-2-benzhydryl-tetrahydro-
pyran-4-ol (3b). Compound 2b (0.05 g, 0.14 mmol) was hydro-
genated (Procedure B) to yield 3b: 0.04 g (97%, [R]D (+)66.2,
c)1, MeOH).
Procedure D. Synthesis of (3R,6S)-6-Benzhydryl-tetrahydro-
pyran-3-ol (5a). To compound 1a (0.3 g, 1.13 mmol) in hexane
(20 mL) and ether (0.2 mL) was added LiAlH4 (0.21 g, 5.64 mmol).
The resulting reaction mixture was stirred under N2 for 20 h at
room temperature. The reaction was next quenched with 10% NaOH
and diluted with ethyl acetate (30 mL), and the precipitate was
removed by filtration. The organic phase was washed with brine
and dried over anhydrous Na2SO4. The removal of the solvent gave
a crude product mixture (1:1.3) of 5a and trans-4-hydroxy isomer
5c (0.24 g).
1HNMR (CD3OD, 400 MHz): 1.43 (m, 1H, H-3), 1.72 (m, 1H,
H-3), 2.65 (m, 1H, H-5), 3.57 (m, 1H, H-6), 3.82 (m, 1H, H-4),
3.92-4.00 (m, 2H, H-6, Ph2CH), 4.52 (dt, J ) 2.0 Hz, 10.4 Hz,
1H, H-2), 7.00-7.40 (m, 10H, aromatic-CH).
Procedure C. Synthesis of (2S,4R,5R)-2-Benzhydryl-5-(4-
hydroxy-benzylamino)-tetrahydropyran-4-ol ((-)-4a). Into a
solution of 3a (0.02 g, 0.09 mmol), 4-hydroxybenzaldehyde (0.01
g, 0.09 mmol) and glacial acetic acid (0.01 g, 0.09 mmol) in 1,2-
dichloroethane (5 mL) was added portionwise NaCNBH3 (0.01 g,
0.11 mmol) followed by methanol (1 mL). The reaction was
continued for 4 h. Water was added to quench the reaction, and
the mixture was stirred for 30 min at 0 °C. The reaction mixture
was stirred with saturated aqueous NaHCO3, and the product was
extracted with methylene chloride (3 × 10 mL). The combined
organic phase was washed with brine and water and dried over
anhydrous Na2SO4. The solvent was removed under reduced
1HNMR (CDCl3, 400 MHz): 1.29-1.46 (m, 2H, H-5), 1.50-
1.60 (m, 1H, H-4), 2.00-2.12 (m, 1H, H-4), 3.08-3.18 (t, J )
10.4 Hz, 1H, H-2), 3.64-3.74 (m, 1H, H-3ax), 3.83-3.92 (d, J )
9.2 Hz, 1H, Ph2CH), 3.92-4.04 (m, 2H, H-2, H-6), 7.10-7.40
(aromatic-CH).
Synthesis of (3S,6R)-6-Benzhydryl-tetrahydro-pyran-3-ol (5b).
Compound 1b (0.30 g, 1.1 mmol) was reduced by LiAlH4 (0.22 g,
5.5 mmol) (Procedure D) in 1% ether-hexanes to yield a mixture
(1:1.3) of 5b and trans-4-hydroxy isomer 5d (0.25 g).

Trisubstituted Asymmetric Pyran DeriVatiVes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14 4245
1HNMR (CDCl3, 400 MHz): 1.34-1.43 (m, 2H, H-5), 1.54-
1.62 (m, 1H, H-4), 2.03-2.12 (m, 1H, H-4), 3.10-3.19 (t, J )
10.4 Hz, 1H, H-2), 3.62-3.73 (m, 1H, H-3ax), 3.87-3.93 (d, J )
9.2 Hz, 1H, Ph2CH), 3.94-4.04 (m, 2H, H-2, H-6), 7.10-7.40
(aromatic-CH).
3.62-3.74 (m, 2H, H-2), 3.93-3.99 (d, J ) 9.2 Hz, 1H, Ph2CH),
4.05-4.19 (m, 1H, H-6), 7.02-7.40 (m, 10H, aromatic-CH).
Syntheis of cis-(3S,6S)-(6-Benzhydryl-tetrahydropyran-3-yl)-
(4-hydroxy-benzyl)-amine ((-)-9a). Compound 8a (0.02 g, 0.07
mmol) was reacted with 4-hydroxybenzaldehyde (0.01 g, 0.07
mmol) in the presence of glacial acetic acid (0.005 g, 0.075 mmol)
in 1,2-dichloroethane (10 mL), followed by treatment with NaC-
NBH3 (0.006 g, 0.09 mmol) (Procedure C) to give (-)-9a: 0.02 g
(72%, [R]D (-) 38.3, c)1, MeOH).
Procedure E. Synthesis of Methanesulfonic Acid trans-
(3R,6S)-6-Benzhydryl-tetra-hydropyran-3-yl Ester (6a). To a
mixture of 5a, trans-4-hydroxy isomer 5c (0.23 g, 0.85 mmol), and
triethylamine (0.13 g, 1.3 mmol) in dry methylene chloride (10
mL) was added methanesulfonyl chloride (0.15 g, 1.3 mmol). The
reaction mixture was stirred under N2 at room temperature overnight
and then diluted with ethyl ether (50 mL). The organic phase was
washed in turn with saturated NaHCO3, brine, and water and then
dried over anhydrous Na2SO4. The removal of the solvent and
purification by chromatography (hexane/ethyl acetate: 4:1) gave
6a (eluting first) as a white solid (0.12 g) ([R]D (-)54, c)1, MeOH).
1HNMR (CDCl3, 400 MHz): 1.38-1.53 (m, 1H, H-5), 1.60-
1.78 (m, 2H, H-5, H-4), 2.16-2.30 (m, 1H, H-4), 2.93 (s, 3H, CH3-
SO2), 3.28-3.42 ((t, J ) 10.4 Hz, 1H, H-2ax), 3.84-3.94 (d, J )
8.8 Hz, 1H, Ph2H), 3.94-4.07 (dt, J ) 2.0 Hz, 9.6 Hz, 1H- H-6),
4.06-4.19 (m, 1H, H-2eq), 4.52-4.68 (m, 1H, H-3ax), 7.16-7.38
(m, 10H, aromatic-CH).
1H NMR (400 MHz, CDCl3): 1.36 (m, 1H, H-5), 1.51 (m, 1H,
H-5), 1.68 (m, 1H, H-4), 2.00 (m, 1H, H-4), 2.71 (s, 1H, H-3),
3.56 (dd, J ) 1.6 Hz, 11.6 Hz, 1H, H-2), 3.64 (m, 2H, (HO)Ph-
CH2), 3.96 (d, J ) 8.4 Hz, 1H, Ph2CH), 4.02-4.16 (m, 2H, H-6,
H-2), 6.52 (m, 2H, aromatic-CH), 6.98-7.38 (m, 12H, aromatic-
CH).
The free base was converted into oxalate: mp 136-138 °C. Anal.
[C25H27NO2‚(COOH)2 0.6H2O] C, H, N.
Syntheis of cis-(3R,6R)-(6-Benzhydryl-tetrahydropyran-3-yl)-
(4-hydroxy-benzyl)-amine ((+)-9a). Compound 8b (0.02 g, 0.09
mmol) was reacted with 4-hydroxybenzaldehyde (0.01 g, 0.09
mmol) in the presence of glacial acetic acid (0.005 g, 0.09 mmol)
in 1,2-dichloroethane (10 mL), followed by reduction with NaC-
NBH3 (0.012 g, 0.18 mmol) (Procedure C) to give (+)-9a: 0.024
g (71%, [R]D (+) 40.1, c)1, MeOH).
Synthesis of Methanesulfonic Acid trans-(3S,6R)-6-Benzhy-
dryl-tetra-hydropyran-3-yl Ester (6b). A mixture of compound
5b and trans-4-hydroxy isomer 5d (0.25 g, 0.93 mmol) was reacted
with methanesulfonyl chloride (0.15 g, 1.3 mmol) (Procedure E)
to yield 6b (0.13 g) ([R]D (+)54.8, c)1, MeOH).
1H NMR (400 MHz, CDCl3): 1.34 (m, 1H, H-5), 1.51 (m, 1H,
H-5), 1.65 (m, 1H, H-4), 1.96 (m, 1H, H-4), 2.67 (m, 1H, H-3),
3.56 (dd, J ) 1.6 Hz, 11.6 Hz, 1H, H-2), 3.66 (m, 2H, (HO)Ph-
CH2), 3.96 (d, J ) 8.8 Hz, 1H, Ph2CH), 3.98-4.12 (m, 2H, H-6,
H-2), 6.65 (m, 2H, aromatic-CH), 7.06-7.38(m, 12H, aromatic-
CH).
1HNMR (CDCl3, 400 MHz): 1.38-1.52 (m, 1H, H-5), 1.62-
1.78 (m, 2H, H-5, H-4), 2.20-2.29 (m, 1H, H-4), 2.96 (s, 3H, CH3-
SO2), 3.32-3.40 ((t, J ) 10.4 Hz, 1H, H-2ax), 3.88-3.92 (d, J )
8.8 Hz, 1H, Ph2H), 3.97-4.06 (dt, J ) 2.0 Hz, 9.6 Hz, 1H- H-6),
4.10-4.18 (m, 1H, H-2eq), 4.55-4.66 (m, 1H, H-3ax), 7.16-7.38
(m, 10H, aromatic).
The free base was converted into oxalate: mp 136-138 °C. Anal.
[C25H27NO2‚(COOH)2 1.8H2O] C, H, N.
Synthesis of cis-(3S-6S)-(6-Benzhydryl-tetrahydropyran-3-yl)-
(1H-indol-5-ylmethyl)amine ((-)-9b). Compound 8a (0.05 g, 0.19
mmol) was reacted with indole-5-carboxaldehyde (0.03 g, 0.19
mmol) in the presence of glacial acetic acid (0.05 mL) in
1,2-dichloroethane (5 mL) for 1 h. NaCNBH3 (0.02 g, 0.37 mmol)
in MeOH (1 mL) was added, and the reaction mixture was stirred
at room temperature for 4 h (Procedure C) to give (-)9b: 0.04 g
(60%, [R]D (-) 70.7, c)1, acetone).
Procedure F. Synthesis of cis-(3S,6S)-3-Azido-6-benzhydryl-
tetrahydropyran (7a). NaN3 (0.13 g, 2.03 mmol) was added into
a mixture of 6a (0.23 g, 0.68 mmol) in dry DMF (10 mL). The
reaction was stirred under N2 at 100°C overnight. Ethyl ether (50
mL) was added, and the organic phase was washed in turn with
saturated NaHCO3, brine, and water and then dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure, and the
crude product was purified on silica gel using hexanes-ethyl acetate
(7:3) to give, 7a: 0.17 g (86%, [R]D (-)78.2, c)1, MeOH).
1HNMR (CDCl3, 400 MHz): 1.34-1.42 (m, 1H, H-5), 1.60-
1.84 (m, 2H, H-5, H-4), 1.94-2.03 (m, 1H, H-4), 3.52-3.58 (m,
1H, H-3), 3.60-3.67 (dd, J ) 2.0 Hz, 12.4 Hz, 1H, H-2), 3.98-
4.12 (m, 3H, H-2, H-6, Ph2CH), 7.15-7.45 (m, 10H, aromatic-
CH).
1H NMR (300 MHz, CDCl3): 1.28-1.33 (m, 1H), 1.48-1.68
(m, 2H), 1.90-1.98 (m, 2H), 2.69 (bs, 1H), 3.50-3.57 (dd, J )
1.6 Hz, 12.0 Hz, 1H), 3.92-4.14 (m, 5H), 6.48 (s, 1H), 7.08-7.38
(m, 13H), 7.54 (s, 1H), 8.34 (bs, 1H).
The free base was converted into oxalate. mp 201-205 °C. Anal.
[C27H28N2O (COOH)2 0.7H2O] C, H, N.
Synthesis of cis-(3R-6R)-(6-Benzhydryl-tetrahydropyran-3-
yl)-(1H-indol-5-ylmethyl)amine ((+)-9b). Compound 8b (0.02 g,
0.07 mmol) was reacted with indole-5-carboxaldehyde (0.01 g, 0.07
mmol) in the presence of glacial acetic acid (0.05 mL) in
1,2-dichloroethane (5 mL) for 1 h. NaCNBH3 (0.01 g, 0.14 mmol)
in MeOH (1 mL) was added, and the reaction mixture was stirred
at room temperature for 4 h (Procedure C) to give (+)-9b: 0.01 g
(37%, [R]D (+) 72.0, c)1, acetone).
Synthesis of cis-(3R,6R)-3-Azido-6-benzhydryl-tetrahydro-
pyran (7b). Compound 6b (0.03 g, 0.08 mmol) was reacted with
NaN3 (0.016 g, 0.25 mmol) (Procedure F) to yield cis-azide 7b:
0.02 g (quantitative yield, [R]D (+)77.6, c)1, MeOH).
1HNMR (CDCl3, 400 MHz): 1.30-1.40 (m, 1H, H-5), 1.52-
1.85 (m, 2H, H-5, H-4), 1.92-2.02 (m, 1H, H-4), 3.52-3.58 (m,
1H, H-3), 3.59-3.67 (dd, J ) 2.4 Hz, 17.2, Hz, 1H, H-2), 3.94-
4.10 (m, 3H, H-2, H-6, Ph2CH), 7.14-7.42 (m, 10H, aromatic-
CH).
Procedure G. Synthesis of cis-(3S,6S)-(6-Benzhydryl-tetrahy-
dropyran-3-yl)-amine (8a). Compound 7a (0.17 g, 0.58 mmol) in
methanol (25 mL) was hydrogenated under a 10% Pd-C (0.02 g,
10wt %) catalyst for 4 h to give cis-amine 8a: 0.12 g (78%, [R]D
(-)74.3, c)1, MeOH).
1H NMR (300 MHz, CDCl3): 1.28-1.33 (m, 1H), 1.48-1.68
(m, 2H), 1.90-1.98 (m, 2H), 2.69 (bs, 1H), 3.51-3.57 (dd, J )
2.0 Hz, 12.0 Hz, 1H), 3.94-4.16 (m, 5H), 6.50 (s, 1H), 7.12-7.38
(m, 13H), 7.55 (s, 1H), 8.18 (bs, 1H).
The free base was converted into oxalate. mp 206-211 °C. Anal.
[C27H28N2O (COOH)2 0.5H2O] C, H, N.
1HNMR (CDCl3, 400 MHz): 1.22-1.36 (m, 1H, H-5), 1.45-
1.59 (m, 1H, H-5), 1.62-1.84 (m, 2H, H-4), 2.78 (bs, 1H, H-3),
3.56-3.70 (m, 2H, H-2), 3.92-3.99 (d, J ) 8.8 Hz, 1H, Ph2CH),
4.06-4.13 (m, 1H, H-6), 7.04-7.40 (m, 10H, aromatic-CH).
Synthesis of cis-(3R,6R)-(6-Benzhydryl-tetrahydropyran-3-
yl)-amine (8b). Compound 7b (0.02 g, 0.08 mmol) was hydroge-
nated under a 10% Pd-C (0.002 g, 10wt %) catalyst (Procedure
G) to yield cis-amine 8b: 0.02 g (92%, [R]D (+)74.0, c)1, MeOH).
1HNMR (CDCl3, 400 MHz): 1.25-1.36 (m, 1H, H-5), 1.47-
1.61 (m, 1H, H-5), 1.68-1.88 (m, 2H, H-4), 2.90 (bs, 1H, H-3),
Synthesis of cis-(3S,6S)-(6-Benzhydryl-tetrahydropyran-3-yl)-
(4-nitrobenzyl)amine ((-)-9c). Compound 8a (53.0 mg, 0.198
mmol) was reacted with 4-nitrobenzaldehyde (30.5 mg, 0.202
mmol) in the presence of glacial acetic acid (15 µL) in 1,2-
dichloroethane (2 mL) for 1 h. NaCNBH3 (20.5 mg, 0.31 mmol)
in MeOH (0.5 mL) was added, and the reaction mixture was stirred
at room temperature for 4 h (Procedure C) to give (-)-9c: 68.3
mg (86%, [R]D (-) 57.7, c)1.01, acetone).
1H NMR (400 MHz, CDCl3): 1.33 (bd, 1H), 1.45-1.57 (m, 1H),
1.66 (tt, J ) 13.6, 4.0 Hz, 1H), 1.80 (bs, 1H), 1.88-1.95 (m, 1H),

4246 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14
Zhang et al.
2.60 (s, 1H), 3.57 (dd, J ) 11.6 Hz, 1.6 Hz, 1H), 3.80-4.10 (m,
5H), 7.14-7.36 (m, 10H), 7.49 (d, J ) 8.8 Hz, 2H), 8.16 (d, J )
8.8 Hz, 2H).
The free base was converted into the oxalate salt: mp 218-220
°C. Anal. [C25H26N2O3 (COOH)2] C, H, N.
a Bruker SMART 1000 CCD detector on a four-circle goniometer
using SMART (1a). Lattice parameters were determined using
SAINT(2b) from 5058 reflections within 1.38 < 2θ < 27.10. Data
were collected to 2θ ) 27.10°. A set of 9111 reflections was
collected using a combination of φ and 2θ/ω scans. There were
5058 unique reflections. Corrections were applied for Lorentz,
polarization, and absorption effects. The structure was solved with
SHELXTL (3a) and refined with the aid of the SHELX system of
programs. The full-matrix least-squares refinement on F2 used four
restraints and varied 297 parameters: atom coordinates and
anisotropic thermal parameters for all non-H atoms. H atoms on
carbon atoms were included using a riding model (coordinate shifts
of C applied to attached H atoms, C-H distances set to 0.96-0.93
Å, H angles idealized, Uiso-(H) were set to 1.2 to 1.5 Ueq(C)).
Final residuals were R1 ) 0.0460 for the 3978 observed data with
Fo > 4σ(Fo) and 0.0663 for all data. Final difference Fourier
excursions were 0.533 and -0.322 eÅ-3. The absolute configuration
was determined using anomalous diffraction (absolute structure
parameter ) 0.078(10)). The asymmetric unit contains one molecule
of the title compound, plus a bromine counterion and one water
molecule. Tables of coordinates, bond distances and bond angles,
and anisotropic thermal parameters have been deposited with the
Crystallographic Data Centre, Cambridge, CB2, and 1EW, England.
Synthesis of cis-(3R,6R)-(6-Benzhydryl-tetrahydropyran-3-
yl)-(4-nitrobenzyl)amine ((+)-9c). Compound 8b (77.8 mg, 0.275
mmol) was reacted with 4-nitrobenzaldehyde (42 mg, 0.28 mmol)
in the presence of glacial acetic acid (20 µL) in 1,2-dichloroethane
(2 mL) for 1 h. NaCNBH3 (25 mg, 0.38 mmol) in MeOH (0.5 mL)
was added, and the reaction mixture was stirred at room temperature
for 4 h (Procedure C) to give (+)-9c: 90.3 mg (82%, [R]D (+)
56.2, c)1.015, acetone).
The free base was converted into oxalate: mp 215-218 °C. Anal.
[C25H26N2O3 (COOH)2] C, H, N.
1H NMR (400 MHz, CDCl3): 1.33 (bd, 1H), 1.45-1.57 (m, 1H),
1.66 (tt, J ) 13.6, 4.0 Hz, 1H), 1.80 (bs, 1H), 1.88-1.95 (m, 1H),
2.60 (s, 1H), 3.57 (dd, J ) 11.6 Hz, 1.6 Hz, 1H), 3.80-4.10 (m,
5H), 7.14-7.36 (m, 10H), 7.49 (d, J ) 8.8 Hz, 2H), 8.16 (d, J )
8.8 Hz, 2H).
Procedure H. Synthesis of cis-(3S-6S)-(6-Benzhydryl-tetrahy-
dropyran-3-yl)-(4-aminobenzyl)amine ((-)-9d). A mixture of
(-)-9c (0.10 g, 0.25 mmol) and SnCl2 2H2O (0.22 g, 1.00 mmol)
in EtOH/EtOAc (20 mL, 7:3) was heated to reflux for 1.5 h. After
the removal of the solvent, the residue was diluted with 10%
NaHCO3 and EtOAc and stirred vigorously for 30 min. After
filtration, the organic phase was separated, and the aqueous phase
was extracted with EtOAc (20 mL ×2). The combined organic
phase was dried over Na2SO4. The removal of the solvent and
purification by flash chromatography (EtOAc/MeOH/triethylamine
95:4:1) gave (-)-9d: 0.05 g (52%, [R]D (-) 47.3, c)1, acetone).
1H NMR (300 MHz, CDCl3): 1.22-1.34 (m, 1H), 1.44-1.67
(m, 2H), 1.86-1.96 (m, 2H), 2.16 (d, J ) 5.2 Hz, 2H), 2.62 (s,
1H), 3.48-3.56 (dd, J ) 11.6 Hz, 1.6 Hz, 1H), 3.58-3.70 (m,
2H), 3.92-4.18 (m, 3H), 6.55-6.65 (m, 2H), 7.05-7.37 (m, 12H).
The free base was converted into oxalate salt: mp 184-186 °C.
Anal. [C25H28N2O 2(COOH)2] C, H, N.
Acknowledgment. This work was supported by the National
Institute on Drug Abuse, Grant No. DA 12449 (to A.K.D.).
Supporting Information Available: Crystal structure, ad-
ditional 1H NMR, elemental analysis, and molecular modeling data.
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) Amara, S. G.; Kuhar, M. J. Neurotransmitter transporters: Recent
progress. Annu. ReV. Neurosci. 1993, 16, 73-93.
(2) Rudnick, G. Mechanisms of biogenic amine neurotransmitter trans-
porters. In Neurotransmitter Transporters: Structure and Function,
2nd ed.; Reith, M. E. A. Ed.; Human Press: Totowa, NJ, 2002; pp
381-432.
Synthesis of cis-(3R-6R)-(6-Benzhydryl-tetrahydropyran-3-
yl)-(4-aminobenzyl)amine ((+)-9d). A mixture of (+)-9c (0.02
g, 0.05 mmol) and SnCl2 2H2O (0.04 g, 0.20 mmol) in EtOH/EtOAc
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FW ) 502.44, monoclinic space group P21, a ) 10.964(4) Å, b )
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