(+)-9-Benzyloxy-α-dihydrotetrabenazine as an important intermediate for the VMAT2 imaging agents: Absolute configuration and chiral recognition

Article abstract of DOI:10.1002/chir.22126

This article reports, for the first time, on the absolute configuration of (+)-9-benzyloxy-α-dihydrotetrabenazine (8), as determined from the perspective of X-ray crystallography. Compound 8 was prepared by a six-step reaction using 3-benzyloxy-4-methoxybenzaldehyde (1) as a starting material. The X-ray crystal diffraction structure of two compounds, racemic 9-benzyloxy-tetrabenazine (5) and the diastereomeric salt of compound 8, is also described for the first time in this article. The X-ray results and the chiral HPLC helped elucidate that compound 8 has an absolute configuration as 2R,3R,11bR. The crystal structure of racemic compound 5 contains two symmetry- independent molecules in the unit cell. Interestingly, while they are structural isomers, they are enantiomers, too, i.e., in solution, because they are not mirror images of each other in the crystal lattice. In order to elucidate the intermolecular interaction mechanism of the diastereomeric salt of compound 8, its crystal packing was investigated with regard to the weak interactions, such as salt bridge, OH.O and CH.O hydrogen bonds, and intermolecular CH.π interaction. The results showed that the carbonyl-assisted salt bridges and the OH.O hydrogen bonds formed polar columns in the crystal structure of the diastereomeric salt of compound 8, resembling butterflies with open wings as viewed along the c-axis. These polar columns were extended to three-dimensional network by intermolecular CH.O hydrogen bonds and intermolecular CH.π interactions. Chirality, 2013. 2013 Wiley Periodicals, Inc. Copyright

Full text of DOI:10.1002/chir.22126

CHIRALITY 25:215–223 (2013)
(+)-9-Benzyloxy-a-Dihydrotetrabenazine as an Important Intermediate
for the VMAT2 Imaging Agents: Absolute Configuration and Chiral
Recognition
*
CHUNYI LIU, ZHENGPING CHEN, XIAOMIN LI, JIE TANG, AND XIAOFENG QIN
Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear
Medicine, Wuxi, Jiangsu, China, 214063
ABSTRACT
This article reports, for the first time, on the absolute configuration of
(+)-9-benzyloxy-a-dihydrotetrabenazine (8), as determined from the perspective of X-ray crystal-
lography. Compound 8 was prepared by a six-step reaction using 3-benzyloxy-4-methoxybenzaldehyde
(1) as a starting material. The X-ray crystal diffraction structure of two compounds, racemic 9-benzy-
loxy-tetrabenazine (5) and the diastereomeric salt of compound 8, is also described for the first time
in this article. The X-ray results and the chiral HPLC helped elucidate that compound 8 has an absolute
configuration as 2R,3R,11bR. The crystal structure of racemic compound 5 contains two symmetry-
independent molecules in the unit cell. Interestingly, while they are structural isomers, they are enan-
tiomers, too, i.e., in solution, because they are not mirror images of each other in the crystal lattice. In
order to elucidate the intermolecular interaction mechanism of the diastereomeric salt of compound
8, its crystal packing was investigated with regard to the weak interactions, such as salt bridge,
OH. ..O and CH.. .O hydrogen bonds, and intermolecular CH.. .p interaction. The results showed
that the carbonyl-assisted salt bridges and the OH.. .O hydrogen bonds formed polar columns in
the crystal structure of the diastereomeric salt of compound 8, resembling butterflies with open
wings as viewed along the c-axis. These polar columns were extended to three-dimensional network
by intermolecular CH. . .O hydrogen bonds and intermolecular CH. . .p interactions. Chirality
25:215–223, 2013. © 2013 Wiley Periodicals, Inc.
KEY WORDS: VMAT2; dihydrotetrabenazine; chiral recognition; absolute configuration
INTRODUCTION
the synthesis of this compound9 in 2008. Until now, however,
its absolute configuration has not been determined. We report
here, for the first time, the X-ray crystal structure analysis of
the diastereomeric salt of compound 8 (namely, compound 7),
which allows the assignment of the absolute configuration of
compound 8. In the synthesis of the title compound, in order
to know the chiral configuration of intermediate compounds,
the single crystal of racemic 9-benzyloxy-tetrabenazine (5) was
also determined by X-ray diffraction in this article. In addition,
the total synthesis of compound 8 used by our group is shown
in Scheme 1.
9-Benzyloxy-dihydrotetrabenazine has three chiral carbon
atoms. Therefore, in theory, 9-benzyloxy-dihydrotetrabena-
zine has eight isomers, as shown in Figure 1. By means of
X-ray diffraction, we used the most effective way to confirm
that compound 8 has 2R,3R,11bR stereochemistry. X-ray
diffraction for determination of the absolute configuration of
The vesicular monoamine transporter (VMAT) is a transport
protein integrated into the membrane of intracellular vesicles of
presynaptic neurons. It acts to transport monoamines into the
synaptic vesicles. The VMAT exists in two pharmacologically
distinct forms: VMAT1 and VMAT2. In humans, VMAT1 is
primarily found in the adrenal tissue and VMAT2 is expressed
nearly exclusively in the brain. Therefore, imaging VMAT2 in
the brain with positron emission tomography (PET) and related
imaging agents provides a measurement reflecting the integrity
of monoaminergic neurons, and is used to monitor or diagnose
neurodegenerative disorders such as Parkinson’s, Alzheimer’s,
Tourette’s, and Huntington’s disease.1
Recently, (+)-9-desmethyl-a-dihydrotetrabenazine (DTBZ)
has been labeled with carbon-11 and fluorine-18 radioisotopes
and used for in vitro and in vivo studies of VMAT2 in both the
animal and human brain. For example, 11C-(+)-a-DTBZ2–5 and
18F-(+)-FP-a-DTBZ6–8 have been prepared as PET imaging
agents targeting VMAT2. Two preparation methods of (+)-9-
desmethyl-a-dihydrotetrabenazine were found in the litera-
ture.8–10 One method was selective O-demethylation of
(Æ)-DTBZ, followed by enantiomeric separation by chiral high-
performance liquid chromatography (HPLC). This method
was not suitable for large-scale preparation of (+)-9-desmethyl-
a-dihydrotetrabenazine. On the contrary, deprotection of the
benzyl group of (+)-9-benzyloxy-a-dihydrotetrabenazine (8) via
hydrogenolysis gave the precursor for the VMAT2 imaging
agents, (+)-9-desmethyl-a-dihydrotetrabenazine, in a good yield.
Therefore, compound 8 is an important intermediate for the
VMAT2 imaging agents and it is necessary to confirm its
absolute configuration. Boldt and colleagues first reported
© 2013 Wiley Periodicals, Inc.
Additional Supporting Information may be found in the online version of this
article.
Contract grant sponsor: National Natural Science Foundation of China; Contract
grant number: 30970844.
Contract grant sponsor: Outstanding Professionals Foundation of Jiangsu
Health Bureau; Contract grant number: RC2011096.
Contract grant sponsor: Natural Science Foundation of Jiangsu Province; Con-
tract grant number: BK2010155.
Contract grant sponsor: Youth Research Foundation of Jiangsu Institute of
Nuclear Medicine; Contract grant number: QN201109.
*Correspondence to: Zhengping Chen, 20 Qianrong Road, Wuxi 214063, P.R.
China. E-mail: chenzhengping@hotmail.com
Received for publication 12 July 2012; Accepted 21 September 2012
DOI: 10.1002/chir.22126
Published online in Wiley Online Library
(wileyonlinelibrary.com).

216
LIU ET AL.
Scheme 1. Synthesis of (+)-9-benzyloxy-a-dihydrotetrabenazine.
Fig. 1. Structures of eight 9-benzyloxy-dihydrotetrabenazine isomers.
molecules includes direct and indirect methods. Our test
sample contains only C, H, N, and O elements and no heavy
elements that may help to directly determine absolute config-
uration, so we adopted the indirect method. The absolute
Chirality DOI 10.1002/chir
configuration of compound 8 was established using a reference
molecule ((2R,3R)-(À)-di-p-toluoyl-L-tartaric acid). Further-
more, as X-ray diffraction analysis of the sample was conducted
on a single crystal, the result was not universal. The chiral

ABSOLUTE CONFIGURATION AND CHIRAL RECOGNITION OF (+)-9-BENZYLOXY-a-DIHYDROTETRABENAZINE
217
extracts were combined and concentrated in vacuum. The crude product
was purified by crystallization with methanol, giving racemic compound 5
(4.20 g, 10.67 mmol) as colorless crystals. Yield: 32%. mp: 133–135ꢀC. MS
m/z: 394 [M+ H]+; 416 [M+Na]+. 1H NMR(CDCl3, 400 MHz), d: 7.46–7.30
(m, 5H), 6.67 (s, 1H), 6.60 (s, 1H), 5.14 (s, 2H), 3.86 (s, 3H), 3.53 (d,
J= 10.92 Hz, 1H), 3.32–3.28 (m, 1H), 3.14–3.06 (m, 2H), 2.95–2.91 (m, 1H),
2.77–2.53 (m, 4H), 2.37 (t, J= 11.51 Hz, 1H), 1.86–1.79 (m, 1H), 1.72–1.65
(m, 1H), 1.09–1.02 (m, 1H), 0.94 (d, J= 4.77 Hz, 3H), 0.92 (d, J= 4.77 Hz, 3H).
HPLC analysis was applied to racemic 9-benzyloxy-a-dihydrote-
trabenazine (6) and compound 8.
Compound 7 was formed by compound 8 and (2R,3R)-(À)-
di-p-toluoyl-L-tartaric acid. The (2R,3R)-(À)-di-p-toluoyl-L-tar-
trate anion and the (+)-9-benzyloxy-a-dihydrotetrabenazine
cation acted as a proton acceptor and donor, respectively.
The crystal structure of compound 7 was investigated for
weak interactions, such as salt bridge, NH. . .O and CH. . .O
hydrogen bonds, and intermolecular CH. . .p interactions.
The identification of these weak intermolecular interactions
in the crystal would be useful in understanding the chiral
recognition mechanism of the parent structure of compound
8 for the amino acids in the VMAT2.
Synthesis of racemic 9-benzyloxy-a-dihydrotetrabenazine (6). Race-
mic compound 6 (1.82 g, 4.60 mmol) was prepared from racemic compound
5 (3.62 g, 9.20 mmol) and sodium borohydride (3.50 g, 92 mmol). The reac-
tion time was 12 h. See Ref. 9 for details. Yield: 50%. mp: 178–180ꢀC. MS m/z:
396 [M + H]+; 378 [M – OH]+. 1H NMR(CDCl3, 400 MHz), d: 7.43–7.29 (m,
5H), 6.70 (s, 1H), 6.61 (s, 1H), 5.11 (s, 2H), 3.85 (s, 3H), 3.43–3.35 (m, 1H),
3.13–2.94 (m, 4H), 2.61–2.55 (m, 2H), 2.46–2.39 (td, J = 10.79, 3.48 Hz, 1H),
1.96 (t, J = 11.36 Hz, 1H), 1.76–1.65 (m, 2H), 1.58–1.44 (m, 3H), 1.09–1.03
(m, 1H), 0.94 (d, J = 6.49 Hz, 3H), 0.91 (d, J= 6.45 Hz, 3H).
EXPERIMENTAL
Materials and Physical Measurements
All solvents and reagents were of analytical grade and were used with-
out further purification. 6-Benzyloxy-7-methoxy-3,4-dihydroisoquinoline
(4) was synthesized according to literature methods.11–13 3-Dimethyl-
aminomethylheptan-2-one (12) was synthesized by our own methods.
Melting points were determined by using a Yanagimoto micro melting
point apparatus. MS spectra were recorded with a Waters Platform
ZMD 4000 mass spectrometer. Proton NMR spectra were obtained on a
Bruker Avance III 400MHz Digital NMR Spectrometer in CDCl3. A Bruker
CCD APEX2 diffractometer was used for the X-ray structure study.
Synthesis of (+)-9-benzyloxy-a-dihydrotetrabenazine (8). Com-
pound 8 (0.13 g, 0.33 mmol) was prepared from racemic compound 6
(0.63 g, 1.59 mmol) and (2R,3R)-(À)-di-p-toluoyl-L-tartaric acid (0.61 g,
20
1.58 mmol). See Ref. 9 for details. Yield: 21%. mp: 139–141ꢀC. [a]
=
D
1
+58.3ꢀ (c = 1, chloroform); MS m/z: 396.3 [M + H]+; 378.3 [M – OH]+. H
NMR(CDCl3, 400 MHz), d: 7.43–7.26 (m, 5H), 6.70 (s, 1H), 6.61 (s, 1H),
5.11 (s, 2H), 3.85 (s, 3H), 3.42–3.35 (m, 1H), 3.13–2.94 (m, 4H),
2.61–2.55 (m, 2H), 2.46–2.39 (td, J = 10.85, 3.54 Hz, 1H), 1.96 (t, J = 11.35
Hz, 1H), 1.73–1.44 (m, 5H), 1.09–1.02 (m, 1H), 0.94 (d, J = 6.49 Hz, 3H),
0.91 (d, J = 6.45 Hz, 3H).
Synthesis of racemic 9-benzyloxy-tetrabenazine (5). 3-Dimethyl-
aminomethylheptan-2-one (12) (8.00 g, 46.71 mmol), 6-benzyloxy-7-
methoxy-3,4-dihydroisoquinoline (4) (9.05 g, 33.85 mmol), and
triethylbenzylammonium chloride (2.40 g, 10.54 mmol) were dissolved in
water (100 ml). The mixture was stirred and heated under reflux at 95ꢀC
for 6 h. The residue was extracted thoroughly with ethyl ether. Organic
X-ray Crystallography
The X-ray diffraction data for the crystals of compound 5 and
compound 7 were collected on a Bruker APEX2 diffractometer equipped
with graphite-monochromatic Mo-Ka radiation (l = 0.71073 Å). The
°
C
°
C
Scheme 2. Synthesis of racemic 9-benzyloxy-tetrabenazine.
Fig. 2. The molecular structure of racemic compound 5; 30% probability ellipsoids are shown.
Chirality DOI 10.1002/chir

218
LIU ET AL.
TABLE 1. Crystallographic data and structure refinement
details for racemic compound 5 and compound 7
RESULTS AND DISCUSSION
Synthesis
In this article, on the basis of previous work and our experi-
Compound racemic compound 5 compound 7
CCDC deposit number 857040
mental study, we report the total synthesis of (+)-9-benzyloxy-
a-dihydrotetrabenazine (8) by using a commercial compound
as starting material in moderate conditions.
857041
C35H44NO8
606.71
Molecular formula
Formula weight
C25H31NO3
393.51
Synthesis of 6-benzyloxy-7-methoxy-3,4-dihydroisoquinoline
(4) was performed as previously reported.11–13 The process
was as follows. A mixture of 3-benzyloxy-4-methoxybenzalde-
hyde (1), nitromethane, ammonium acetate, and acetic acid
was heated under reflux, which gave 3-benzyloxy-4-meth-
oxy-b-nitrostyrene (2). Reduction of compound 2 via lithium
aluminum hydride generated 3-benzyloxy-4-methoxy phen-
ylethylamine (3). Under the presence of acetic acid and
trifluoroacetic acid, compound 3 and hexamethylenetetra-
mine yielded compound 4.
Compound 5 was first synthesized by our own concise
means as shown in Scheme 2. 3-Dimethyl-aminomethylheptan-
2-one (12) was prepared using the three-component one-pot
Mannich reaction. Utilizing concentrated hydrochloric acid
and ethanol as a catalyst system, the Mannich reaction of
5-methyl-2-hexanone (9), dimethylamine (10), and formaldehyde
solution (11) occurred directly. This three-component one-pot
synthesis strategy makes the preparation of the Mannich base
easier and more convenient, and it could have potential
applications. To synthesize compound 5, a mixed solution of
3-dimethyl-aminomethylheptan-2-one (12), compound 4, and
triethylbenzylammonium chloride was stirred and heated
under reflux at 95 ꢀC for 6 h. This reaction occurred in aqueous
medium. Our preparation method was simple, mild, and met
the requirements of green chemistry.
Temperature(K)
Wavelength(Å)
Crystal system
Space group
a(Å)
296(2)
298(2)
0.71073
Triclinic
P-1
0.71073
Orthorhombic
P21212
14.6804(18)
26.824(3)
8.7820(10)
90.00
90.00
90.00
3458.2(7)
4
1.165
10.6228(10)
14.8996(14)
15.7681(15)
105.996(2)
107.034(2)
100.230(2)
2201.4(4)
4
b(Å)
c(Å)
a(º)
b(º)
g(º)
V(Å3)
Z
Dca.(g Á cmÀ3
)
1.187
848
F(000)
1300
Absorption coeff.
0.077
0.082
(mmÀ1
)
Y range(ꢀ)
1.44 -25.00
À12 ꢁ h ꢁ 12;
À17 ꢁ k ꢁ 17;
À18 ꢁ l ꢁ18
12314
1.52 -25.10
À17 ꢁ h ꢁ17;
À27ꢁ k ꢁ32;
À10 ꢁ l ꢁ10
19360
Index ranges
Reflections collected
Independent reflections 7676 [Rint = 0.0215]
6169 [Rint = 0.0398]
5145
6169/12/412
Observed reflections
Data/restraints/
parameters
5786
7676/0/529
Goodness-of-fit on F2
1.058
1.082
R, wR indices[I > 2s(I)] 0.0553, 0.1632
R, wR indices(all data) 0.0726, 0.1904
Largest diff. peak and 0.241, -0.228
0.0692, 0.2062
0.0815, 0.2188
0.496, -0.237
hole(e Á ÅÀ3
)
structure was solved by direct and difference Fourier map methods with
SHELXS-97.14 Non-hydrogen atoms were refined by full-matrix least-
squares techniques on F2 with anisotropic thermal parameters, using
SHELXL-97.15 All H atoms were allowed to ride on their parent atoms at
distances of 0.93 (C-H aromatic), 0.96 (C-H methyl), 0.97 (C-H
methylene), and 0.98 (C-H tert-methyl) with Uiso(H) values of 1.2–1.5
times Ueq of the parent atoms.*
Chromatographic Analysis of Compound 6 and
Compound 8
The analysis of compound 6 and compound 8 was investigated on
a chiral HPLC column (Phenomenex Chirex (S)-Val and (R)-NEA;
250 Â 4.6 mm) using isocratic 95% A/5%
B at 1.0 ml/min with
ultraviolet detection at 280 nm with solvent A being hexane/1,2-
dichloroethane (2:1) and solvent B being 0.1% trifluoroacetic acid
(TFA) ethanol solution.
*Crystallographic data for the structures of racemic compound 5 and com-
pound 7 reported in this article have been deposited in the Cambridge Crys-
tallographic Data Centre as supplementary publication numbers CCDC
857040 and 857041.These data can be obtained free of charge via www.ccdc.
cam.ac.uk/data_request/cif, by e-mailing data_request@ccdc.cam.ac.uk, or
by contacting the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44(0)1223À336033.
Fig. 3. The molecular structure of compound 7.
Chirality DOI 10.1002/chir

ABSOLUTE CONFIGURATION AND CHIRAL RECOGNITION OF (+)-9-BENZYLOXY-a-DIHYDROTETRABENAZINE
219
Fig. 4. Chiral recognitions in compound 7.
TABLE 2. Hydrogen bond parameters of compound 7
D—H. . .A
D—A
D—H. . .A
( )
(ꢀ)
O8i—H. . .O2ii
N1—H1. . .O2ii
N1—H1. . .O1ii
O9iii—H. . .O1ii
O9iii—H. . .O9iv
O8iii—H. . .O9iii
O5—H. . .O8iii
2.68 (1) [d1]
3.17 (1) [d2]
2.65 (1) [d3]
2.63 (1) [d4]
2.28 (1) [d5]
2.45 (1) [d6]
2.73 (1) [d7]
125.97 (54)
121.35 (17)
173.80 (18)
118.47 (85)
117.80 (100)
143.93 (69)
80.35 (31)
Interatomic distance ( )
O2ii. . .H1 [=L1]
2.60 (1)
The van der Waals radii ( ): H, 1.20; O, 1.52; N, 1.55.
Symmetry operators: i) 2-x,1-y,z; ii) 2-x,2-y,z; iii) 2-x,1-y,-1 + z; iv) x,1 + y,-1 + z.
Chirality DOI 10.1002/chir

220
LIU ET AL.
Compounds 6 and 8 were also synthesized through proce-
two isomers, the dihedral angles between the phenyl ring and
isoquinoline aromatic ring were 69.35(8)ꢀ and 3.25(9)ꢀ, respec-
tively. There were four rings in every isomer: two aromatic
rings and two six-membered heterocyclic rings. They did not
share a common plane. The aromatic rings were planar in
conformation, and the other two heterocyclic rings were chair
conformations. The two oxygen atoms of the benzyloxy and
methoxy groups were all in the isoquinoline aromatic ring
plane. Additional detailed single crystal X-ray investigations of
compound 5 are shown in supporting information.
dures described in the literature9 and the synthesis steps were
achieved through slight optimization of some reaction condi-
tions. Compound 5 was reduced with sodium borohydride in
ethanol to give compound 6. (2R,3R)-(À)-Di-p-toluoyl-L-tartaric
acid was utilized to separate the isomers of compound 6, and
then the title compound was obtained.
Crystal Structure of Compound 5
The single crystal of racemic compound 5 was grown from
ethanol solution by slow evaporation at room temperature; it
was a colorless prism. The molecular ellipsoid diagram of
racemic compound 5 is shown in Figure 2 and the crystal
data and refinement details are listed in Table 1. Racemic
compound 5 crystallized in the triclinic system, space group
Crystal Structure and Chiral Recognition of Compound 7
(2R,3R)-(À)-Di-p-toluoyl-L-tartaric acid was used to resolve
20
the isomers of compound 6, and then compound 7 ([a]
=
D
À15.8ꢀ (c = 1, methanol); mp: 143–145ꢀC) was obtained. The
single crystal of compound 7 was grown from ethanol solu-
tion by slow evaporation at room temperature; it was also a
colorless prism. The molecular structure of compound 7 is
ꢀ
P 1 with two sets of molecules in a unit cell.
The X-ray crystal diffraction structure of racemic compound
5 showed that it consists of (R,R) and (S,S) isomers. In the
TABLE 3. Interatomic distances and interatomic angles of compound 7
Interatomic distance ( )
H14(B). . .p
(=d1)
(=d2)
(=d3)
3.24 (1)
2.86 (1)
2.75 (1)
O2ii. . .H33iii
(=d4)
(=d5)
(=d6)
2.46 (1)
2.67 (1)
2.67 (1)
H19(A). . .C26i
H10(A)ii. . .O4iv
H10(A). . .O4
H19(A). . .C25i
Interatomic angle (ꢀ)
C33iii—H33iii . . .O2ii
C10—H10(A). . .O4
161.06 (47)
126.37 (34)
C10ii—H10(A)ii. . .O4iv
126.37 (34)
The van der Waals radii ( ): C, 1.70; H, 1.20; O, 1.52; the half-thickness of aromatic ring, 1.77.
Symmetry operators: i) 0.5 + x,1.5-y,2-z; ii) 2-x,2-y,z; iii) 1 + x,y,-1 + z; iv) 2-x,2-y,1 + z.
Chirality DOI 10.1002/chir

ABSOLUTE CONFIGURATION AND CHIRAL RECOGNITION OF (+)-9-BENZYLOXY-a-DIHYDROTETRABENAZINE
221
shown in Figure 3. One molecule of compound 7 consisted of
one molecule of (2R,3R)-(À)-di-p-toluoyl-L-tartaric acid, two
molecules of compound 8, and two molecules of water. The
crystal data and refinement details are listed in Table 1. Com-
pound 7 crystallized in the orthorhombic system, space
group P21212, with three sets of molecules in a unit cell.
Compound 7 does not contain a heavy atom. The data on
its crystal were collected on a Bruker APEX2 diffractometer
equipped with graphite-monochromatic Mo-Ka radiation
(l = 0.71073 Å). Therefore, the Flack parameter was not sig-
nificant for absolute configuration of compound 7. However,
the configuration of (2R,3R)-(À)-di-p-toluoyl-L-tartaric acid is
known. The absolute configuration of compound 8 was estab-
lished using this reference molecule. This indirect method
showed that compound 8 has the absolute configuration
of R,R,R.
recognition between ammonium and carboxylate ion was consid-
ered to enhance the robustness of this synthon.16
Sakai and colleagues proposed the concept of a space filler.
They believed that the diastereomeric salt method was
the most suitable way to separate the enantiomers, when
the chiral resolving agent and the racemic substrate had the
same molecular length, namely the same number of bonds
between the most distant carbon atom and the carboxy or
amino groups.17 Obviously, the molecular lengths of the
(2R,3R)-(À)-di-p-toluoyl-L-tartrate anion and the (+)-9-benzy-
loxy-a-dihydrotetrabenazine cation were not identical.
According to this theory, compound 7 should have an exter-
nal solvent molecule as space filler, such as water, acetone,
or ethanol. This was consistent with the actual situation.
The water molecules were connected tightly with the ammo-
nium cation and the carboxylate anion by OH. . .O hydrogen
bond interactions in the crystal structure.
In the (+)-9-benzyloxy-a-dihydrotetrabenazine cation, the
phenyl ring and the isoquinoline aromatic ring were not
coplanar and their dihedral angle was 76.33(15)ꢀ. The
dihedral angle between the two phenyl rings in the (2R,3R)-
(À)-di-p-toluoyl-L-tartrate anion was 29.86(15)ꢀ. Some short
distances were also observed among the various molecules
in compound 7. Table 3 shows the details. The interatomic
distance between the hydrogen atom H14(B) and the isoqui-
noline aromatic ring was 3.24(1) , and the hydrogen atom
H14(B) almost faced the center of the adjacent isoquinoline
aromatic ring. In addition, the carbon atom C25i and the
neighboring hydrogen atom H19(A) were at a distance of
2.75(1) , which was shorter than the sum of the C. . .H van
der Waals radii. This phenomenon indicated that there was
a weak intermolecular CH. . .p interaction between the hydro-
gen atom H14(B) and the isoquinoline aromatic ring. The
In 1967, Corey introduced the concept of synthon in the
field of organic synthesis and Desiraju modified it later.16
This concept is also suitable for all kinds of supramolecular
systems. It is the common spatial arrangements of intermo-
lecular interaction in crystal. In compound 7, the ammo-
nium-carboxylate ion pair was formed by a supramolecular
synthon and some OH. . .O hydrogen bond interactions as
shown in Figure 4. The supramolecular synthon consisted of a
carbonyl-assisted salt bridge. Table 2 shows the hydrogen bond
parameters of compound 7. The interatomic distance between
the ammonium nitrogen atom N1 and the carboxylate oxygen
atom O1ii was 2.65(1) and the angle of N1—H1...O1ii was
173.80(18)ꢀ, suggesting that N1—H1...O1ii was a salt bridge in-
teraction. In addition, the sum of O...H van der Waals radii was
2.72 and the oxygen atom O2ii and the neighboring hydrogen
atom H1 were at a distance of 2.60(1) . This indicated that
N1—H1...O2ii was a weak hydrogen bond. The multi-point
Fig. 5. One-dimensional supramolecular chain of compound 7 as viewed along the the a-axis.
Fig. 6. One-dimensional supramolecular chain of compound 7 as viewed along the the c-axis.
Chirality DOI 10.1002/chir

222
LIU ET AL.
distances between H33iii and O2ii and between H10(A) and
O4 were 2.46(1) and 2.67(1) , respectively, which
suggested contribution of weak intermolecular CH. . .O
hydrogen bond interactions.
Compound 7 displayed a polar column through the carbonyl-
assisted salt bridges and the OH. . .O hydrogen bonds as
shown in Figure 5. This polar column skeleton played a solid
supportive role in the whole crystal structure. The polar column
was a one-dimensional supramolecular chain. Figure 6 shows
that it resembles a butterfly with open wings as viewed along
the c-axis. Owing to the weak intermolecular CH. . .O hydrogen
bond interactions and the weak intermolecular CH. . .p interac-
tions, one-dimensional polar columns extended to a three-
dimensional network structure along the a-axis and b-axis,
respectively. This three-dimensional network structure is
shown in Figure 7. As mentioned above, the multiple interac-
tions helped stabilize the crystal structure of compound 7.
Configuration of Compound 5, Compound 6, and
Compound 8
As reported by Yao18 and Yu,19 the cis-isomer of compound
5 was thermodynamically unstable. Under the synthesis
conditions in this work, only the enantiomers of compound
5 [(R,R) and (S,S) isomers] were formed. Our earlier work
on using 1H NMR to determine the composition of tetrabena-
zine (TBZ) could be used to confirm this point.20 If compound
1
5 consisted of diastereomers, in the H NMR spectrum of
compound 5, the two aromatic ring proton resonances at
C-8 and C-11 (the numbered compound 5 shown in Scheme 2)
would split into multiple peaks, rather than two singlet peaks.
The two aromatic ring proton resonances in compound 5
were two singlet peaks. Therefore, compound 5 consisted
of (R,R) and (S,S) enantiomers or (R,S) and (S,R)
Fig. 7. Crystal packing of compound 7 as viewed along the the c-axis.
Fig. 8. The chiral HPLC graph of racemic compound 6.
Fig. 9. The chiral HPLC graph of compound 8.
Chirality DOI 10.1002/chir

ABSOLUTE CONFIGURATION AND CHIRAL RECOGNITION OF (+)-9-BENZYLOXY-a-DIHYDROTETRABENAZINE
223
enantiomers. Combined with the X-ray crystal diffraction
LITERATURE CITED
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ACKNOWLEDGMENTS
We are grateful for the financial support provided by the
National Natural Science Foundation of China (30970844)
and the Outstanding Professionals Foundation of Jiangsu
Health Bureau (RC2011096). This work was also additionally
supported in part by the Natural Science Foundation of
Jiangsu Province (BK2010155) and the Youth Research Foun-
dation of Jiangsu Institute of Nuclear Medicine (QN201109).
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Chirality DOI 10.1002/chir