Absolute stereochemical assignment of SCH 71450, a selective dopamine D4 receptor antagonist, through enantioselective epimer synthesis

Article abstract of DOI:10.1002/ejoc.201300072

The absolute stereochemical assignment of SCH 71450, a selective dopamine D₄ receptor antagonist, has been successfully confirmed through enantioselective epimer synthesis. An allyl substituent on the p-hydroxybenzyl group was demonstrated to be an appropriate protecting group for Noyori Ru-catalyzed asymmetric transfer hydrogenation of the imine derivative. The construction of the sugar moiety involved a β-glycosylation reaction assisted by neighboring group participation. By comparison with literature data, the absolute stereochemistry at the C-1 carbon on the tetrahydroisoquinoline core has been assigned the S configuration. Copyright

Full text of DOI:10.1002/ejoc.201300072

FULL PAPER
DOI: 10.1002/ejoc.201300072
Absolute Stereochemical Assignment of SCH 71450, a Selective Dopamine D4
Receptor Antagonist, Through Enantioselective Epimer Synthesis
Hsin-Pei Wu,[a] Tai-Ni Lu,[a] Nai-Yun Hsu,[a] and Che-Chien Chang*[a]
Keywords: Natural products / Medicinal chemistry / Structure elucidation / Receptors / Enantioselectivity / Glycosylation
The absolute stereochemical assignment of SCH 71450, a se-
lective dopamine D4 receptor antagonist, has been success-
fully confirmed through enantioselective epimer synthesis.
An allyl substituent on the p-hydroxybenzyl group was dem-
onstrated to be an appropriate protecting group for Noyori
Ru-catalyzed asymmetric transfer hydrogenation of the imine
derivative. The construction of the sugar moiety involved a
β-glycosylation reaction assisted by neighboring group par-
ticipation. By comparison with literature data, the absolute
stereochemistry at the C-1 carbon on the tetrahydroiso-
quinoline core has been assigned the S configuration.
selectivity for D4 receptors 10-fold. These SAR results
showed that the structural modification of SCH 71450
could serve as a potential approach for preparing new types
of antipsychotic medications. Furthermore, it has recently
been used as new pharmaceutical compositions for the
treatment of ADHD[7] and sexual disorders.[8] Regarding its
structural analysis, exhaustive NMR analyses have con-
firmed that the sugar unit is a d-glucose and the anomeric
carbon of the glucose is attached through a β-glycosidic
bond. Nevertheless, the absolute stereochemistry of the C-
1 carbon on the tetrahydroisoquinoline core remained am-
Introduction
Schizophrenia is a chronic, neuropathic, and disabling
mental disorder that affects about 1% of the worldwide
population.[1] Since knowledge of how schizophrenia de-
velops is very limited, the medical treatments currently in
use focus on the elimination of the symptoms of the disease,
including the use of antipsychotic medication.[2] The long-
term use of typical antipsychotic drugs, such as butyro-
phenone haloperidol, can induce motor toxicities, including
tardive dyskinesia, as side-effects.[3] Although clozapine
(clozaril), an atypical antipsychotic drug, is still an efficient
clinical drug for the treatment of psychotic symptoms, its
clinical use has been limited by the 1–2% incidence of
agranulocytosis.[4] Several bodies of evidence suggest that
the selective antagonism of dopamine D4 receptors is a pos-
sible approach to the treatment of schizophrenia and atten-
tion-deficit hyperactivity disorder (ADHD).[5]
SCH 71450, a novel glycoside derivative of a tetrahydro-
isoquinoline alkaloid in which a glucosyl moiety is attached
to the p-hydroxybenzyl unit (Figure 1), was isolated from
the fruit of Phoebe chekiangensis, a Chinese plant.[6] It exhi-
bits better dopamine D4 selectivity over D2 receptors than
standard dopaminergic antagonists such as clozapine. Pre-
liminary structure–activity relationship (SAR) studies
showed that N-methylation of its parent compound, N-
methylnorcoclaurine (or N-methylhigenamine), resulted in
a five-fold increase in the selectivity for D4 receptors. The
attachment of a glucose unit (SCH 71450) improved the
[a] Department of Chemistry, Fu Jen Catholic University,
New Taipei City, Taiwan 24205, R.O.C
Fax: +886-2-2902-3209
E-mail: 080686@mail.fju.edu.tw
Homepage: http://140.136.176.3/joom/data/eng/Faculty/
C-C%20Chang.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300072.
Figure 1. Structures of clozapine, norcoclaurine (or higenamine),
and SCH 71450.
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Stereochemical Assignment of a Dopamine D4 Receptor Antagonist
biguous.[9] Hence, the development of a synthetic method be constructed stereoselectively by asymmetric transfer hy-
for the synthesis of SCH 71450 would be highly desirable drogenation of the imine derivative 2 by using the Noyori
in terms of its stereochemical assignment and for potential Ru catalyst.[11] The imine 2 was envisioned to arise from
medical treatments of ADHD and sexual disorders.
dehydration of amide 3 under Bischler–Napieralski cycliza-
Because the absolute stereochemistry at C-1 of the tetra- tion conditions.[12] The amide bond-forming reaction could
hydroisoquinoline core is uncertain, our objective was to be carried out between dopamine derivative 4 and acid 5 by
develop a synthetic method that would permit the construc- using a standard amide bond coupling method. So far, only
tion of the tetrahydroisoquinoline core with a defined ste- methyl and benzyl substituents on the phenolic group have
reochemistry at C-1 and also allow us to differentiate the p- been verified as viable protecting groups in the Noyori Ru-
hydroxybenzyl group for further glycosylation reaction with catalyzed asymmetric transfer hydrogenation of imine de-
a glucose unit. The retrosynthetic plan is shown in rivatives.[13] Therefore to find an appropriate substituent
Scheme 1. SCH 71450 was envisioned to arise from glycos- (R2) for the p-hydroxybenzyl group that is compatible with
ylation of the tetrahydroisoquinoline core 1 with a glucose asymmetric transfer hydrogenation reactions and the selec-
unit. β-Glycosylation reactions can be achieved by neigh- tive deprotection of the three phenolic substituents is the
boring group participation.[10] The core structure 1 could key for a successful synthesis. The allyl group was selected
as the substituent R2 for the protection of the p-hy-
droxybenzyl group because it can be selectively removed in
the presence of benzyl substituents (R1) by palladium-cata-
lyzed reactions.[14]
Results and Discussion
The dopamine derivative 4 for the amide bond coupling
reaction was readily prepared from commercially available
dopamine hydrochloride by a known procedure.[15] The acid
5 was synthesized starting from (4-hydroxyphenyl)acetic
acid (Scheme 2). The phenolic and carboxylic groups were
both protected by allyl groups and the subsequent hydroly-
sis of the corresponding ester gave the desired acid 5 (84%,
over two steps) with an allyl substituent on the phenolic
group. To prepare amide 6, different conditions for amide
bond coupling reactions were examined, including the use
of reagents such as DCC/HOBt/NEt3, (COCl)2/NEt3, and
neat/heating. However, none of them resulted in satisfactory
yields. Either a low yield or the desired product contami-
nated with trace amounts of impurity was observed. We
finally found that in situ generation of the acid chloride
followed by direct coupling with the amine 4 in a hetero-
geneous solution (15% NaOH/CH2Cl2)[16] resulted in the
optimal yield of 66% and the sufficiently pure product 6.
Note that the purity of the amide 6 is crucial for the
Bischler–Napieralski cyclization reaction and subsequent
Scheme 1. Retrosynthesis of SCH 71450.
asymmetric transfer hydrogenation.
Scheme 2. Preparation of amide 6. Reagents and conditions: (a) K2CO3, allyl bromide, DMF, room temp., 6 h; (b) NaOH, MeOH, 35 °C,
2 h, 84% (over two steps); (c) (COCl)2, 5, room temp., 2 h, then 15% NaOH, 4, DCM, room temp., 10 h, 66%.
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Scheme 3. Synthesis of the tetrahydroisoquinoline core 10 and confirmation of its absolute configuration. Reagents and conditions:
(d) POCl3, CH3CN, 90 °C, 1 h; (e) Noyori’s (S,S)-Ru catalyst (5 mol-%), DMF, HCO2H/NEt3, room temp., 2 h, 48% (over two steps);
(f) CbzCl, DMAP, NEt3, DCM, 50 °C, 1.5 h, 75%; (g) [Pd(PPh3)4], K2CO3, MeOH, THF, 68 °C, 3 h, 90%; (h) Pd(OH)2, H2, MeOH,
room temp., 4.5 h, 95%.
With the amide 6 in hand, the Bischler–Napieralski cycli- glycosyl donor. The glycosyl donor 11, bearing an acetyl
zation reaction was carried out (POCl3/CH3CN) to give the substituent at the C-2 hydroxy, permits the β-selective glyc-
imine 7, which was sufficiently pure that it could be used in osylation reaction to proceed. By using a known procedure,
the next step without further purification (Scheme 3). The the glycosyl donor 11 was readily prepared in three steps
presence of an allyl substituent on the phenolic group con- starting from d-glucose.[22]
stitutes the first attempt at an asymmetric transfer hydro-
The BF3·OEt2-catalyzed β-glycosylation reaction[23] be-
genation of an imine. The reaction was catalyzed with tween the core 10 and the glycosyl donor 11 was success-
5 mol-% of Noyori’s (S,S)-Ru catalyst[17] in a co-solvent sys- fully performed and resulted in the formation of the main
tem (DMF, HCO2H/NEt3) and resulted in the formation of skeleton 12 in 80% yield (Scheme 4). The effective removal
the secondary amine 8 in 48% yield (over two steps). The of moisture by using molecular sieves was crucial for this
enantiomeric excess of the amine 8 was determined (95% glycosylation reaction. The following steps to produce
ee) by HPLC on a chiral phase.[11] To facilitate the following SCH 71450 relied on the mild and sequential deprotection
synthesis, the secondary amine group was protected by a of three different protecting groups (Ac, Bn, and Cbz
benzyloxycarbonyl (Cbz) group;[18] the carbamate 9 was ob- groups) without influencing the newly formed β-glycosidic
tained in 75% yield as a diastereomeric mixture of rotamers bond. The acetyl groups were first removed by treatment
(ratio = 1.3:1). The allyl group was successfully selectively with potassium carbonate in methanol[24] to give compound
deprotected in the presence of benzyl groups to give the 13 in 82% yield. Secondly, to produce the desired natural
desired tetrahydroisoquinoline core 10 in 90% yield.[19] To product, different catalysts for hydrogenolysis were tested
verify the absolute stereochemistry at C-1 of the tetrahydro- for their ability to simultaneously deprotect both benzyl
isoquinoline core 10, the benzyl and Cbz protecting groups and Cbz groups without affecting the sugar moiety. Again,
were removed by using Pearlman’s catalyst [Pd(OH)2][20] to Pearlman’s catalyst [Pd(OH)2][20] was found to be an ef-
give (–)-norcoclaurine [or (–)-higenamine]. The specific ro- ficient catalyst for this transformation, giving SCH 71450
tation is in agreement with the literature data[21] and in a yield of 99%. Thus, the first enantioselective synthesis
showed that the product indeed has an R configuration.
of the putative SCH 71450 was accomplished in nine steps
The tetrahydroisoquinoline core 10 was now ready to act (the longest linear steps). The allyl substituent on the p-
as a glycosyl acceptor. Because the sugar moiety in hydroxybenzyl group plays a crucial role in the overall syn-
SCH 71450 contains a glucose unit connected through a β- thesis. It not only serves as a substituent on phenolic groups
glycosidic bond, the glucosyl trichloroimidate 11 with for asymmetric transfer hydrogenation, but could also be
acetyl substituents on the hydroxy groups was used as the readily deprotected for the subsequent glycosylation reac-
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Stereochemical Assignment of a Dopamine D4 Receptor Antagonist
Scheme 4. Completed synthesis of the putative SCH 71450. Reagents and conditions: (i) 11, BF3·OEt2, molecular sieves (4 Å), DCM,
10 °C, 2.5 h, 80%; (j) K2CO3, MeOH, THF, room temp., 1 h, 82%; (k) [Pd(OH)2], H2, MeOH, room temp., 4.5 h, 99%.
tion. This method provides a useful synthetic approach to
Unfortunately, the NMR spectroscopic data for the syn-
the construction of glycosidic bonds on specific phenolic thetic putative SCH 71450 was not consistent with literature
groups. Moreover, this approach also represents a useful data (shown in Table 1 and Table 2).[6] In addition, the spe-
synthetic methodology for the synthesis of other structure- cific rotation of the synthetic putative SCH 71450 (+42.6, c
related alkaloids such as aporphine glycosides.[25]
= 1.46, MeOH) does not agree with the value noted for
natural SCH 71450 (–2.3, c = 0.44 mg/mL, MeOH). The d-
Table 1. NMR spectroscopic data of natural and epimeric
SCH 71450 in CD3OD.
Table 2. NMR spectroscopic data of natural and epimeric
SCH 71450 in [D5]pyridine.
Natural SCH 71450
δC [ppm][a] δH [ppm][a]
Epimeric SCH 71450
δC [ppm][b] δH [ppm]
Natural SCH 71450
δC [ppm][a] δH [ppm][a]
Epimeric SCH 71450
δC [ppm][b]
δH [ppm]
158.7
146.9
7.25 (d, J = 8 Hz, 1 H) 158.0 (s)
7.1 (d, J = 8 Hz, 2 H) 145.3 (s)
7.18 (d, J = 8.4 Hz, 2 H, p-
H)
7.07 (d, J = 8.4 Hz, 2 H, p-
H)
157.6
7.26 (d, J = 8 Hz, 2 H) 157.5 (s)
7.33–7.26 (2 d overlapped
at 7.32 and 7.27, J =
8.9 Hz, overlapped with s
at 7.31, 5 H)
145.9
131.7
125.7
6.62 (s, 1 H)
6.58 (s, 1 H)
4.6 (m, 1 H)
144.7 (s)
133.5 (d)
131.4 (s)
6.64 (s, 1 H)
6.51 (s, 1 H)
4.91–4.89 (m, overlapped
with H2O, 1 H)
4.08 (dd, J = 9.0, 4.2 Hz, 1
H, ArCHNH),
147.0
145.9
7.2 (s, 2 H)
7.14 (d, J = 8 Hz, 2 H) 145.8 (s)
146.1 (s)
7.08 (s, 1 H)
5.63 (d, J = 6.9 Hz, 1 H,
anomeric)
123.8
118.4
116.2
4.6 (m, 1 H)
129.4 (d)
126.7 (d)
131.1
5.35 (m, 1 H)
133.8 (s)
4.58 (dd, J = 11.9, 2.0 Hz,
1 H)
3.9 (dd, J = 2, 10 Hz,
1 H)
3.67 (dt, J = 6.5, 2 Hz, 118.0 (d)
1 H)
3.89 (d, J = 12.0 Hz, 1 H,
130.6
123.9
123.0
4.85 (t, 1 H)
4.55 (dd, 1 H)
4.4 (m, 1 H)
131.2 (d)
130.7 (s)
127.0 (s)
4.47–4.28 (m, 5 H)
4.10–4.17 (m, 1 H)
3.31 (dd, J = 14.0, 3.5 Hz,
1 H)
gluco-H6Јa
3.70 (dd, J = 12.0, 5.0 Hz, 1
H, gluco-H6Јb
)
)
114.2
102.3
78.3
78.0
74.9
3.4–3.6 (m, 2 H)
3.5 (m, 3 H),
3.45 (m, 2 H)
3.4 (m, 1 H)
2.95 (dt, J = 2, 7 Hz, 2 78.0 (d)
H)
116.4 (d)
114.1 (d)
102.4 (d)
78.1 (d)
3.48–3.38 (m, 4 H)
3.21–3.12 (m, 2 H)
2.89–2.79 (m, 2 H)
2.67 (q, J = 5.7 Hz, 2 H)
117.0
116.4
114.4
102.1
78.7
78.3
74.7
71.7
62.2
56.7
40.3
39.8
26.0
4.3 (m, 1 H)
4.1 (m, 1 H)
3.6–3.4 (m, 2 H)
3.5 (m, 2 H)
3.4 (m, 2 H)
3.1 (dt, 1 H)
2.9 (dt, 1 H)
117.2 (d)
117.2 (d)
114.9 (d)
102.6 (d)
79.2 (d)
78.9 (d)
75.3 (d)
71.6 (d)
62.7 (t)
3.26–3.20 (m, 1 H)
3.05–2.65 (m, 4 H)
71.4
62.6
57.9
40.9
40.5
25.9
74.9 (d)
71.4 (d)
62.5 (t)
57.9 (d)
42.2 (t)
41.5 (t)
29.1 (t)
57.8 (d)
42.8 (t)
41.8 (t)
30.0 (t)
[a] Please see ref.[6] [b] s: quaternary carbon; d: tertiary carbon; t:
secondary carbon.
[a] Please see ref.[6] [b] s: quaternary carbon; d: tertiary carbon; t:
secondary carbon.
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otherwise stated. THF was distilled by heating it at reflux over
traces of sodium metal using benzophenone as indicator under N2.
Dichloromethane, acetonitrile, N,N-dimethylformamide, triethyl-
amine, and pyridine were dried with CaH2 and then distilled. Meth-
anol was dried with magnesium and iodine and then distilled. For-
mic acid and phosphorus oxychloride were distilled before use. All
reactions were performed under a blanket of N2 or Ar.
glucose unit attached through a β-glycosidic bond to the
p-hydroxybenzyl group was confirmed previously; the only
uncertainty associated with the structural analysis of
SCH 71450 was the stereochemistry at C-1 of the tetrahy-
droxyisoquinoline core. Therefore we concluded that the
absolute stereochemistry of natural SCH 71450 has an S
configuration. This assignment is very important for cur-
rent medical treatments for neuropathic disorders.
4-(Allyloxy)phenylacetic Acid (5): Solid K2CO3 (7.28 g,
52.64 mmol) was added to a solution of p-hydroxyphenylacetic acid
(2.00 g, 13.15 mmol) in DMF (26 mL) followed by the dropwise
addition of allyl bromide (2.85 mL, 32.90 mmol) at 0 °C under Ar.
The reaction mixture was stirred at room temp. for 6 h, and then
diluted with diethyl ether (200 mL). The organic layer was washed
with H2O (3ϫ50 mL) and brine (50 mL), dried with MgSO4, fil-
tered, and concentrated to give allyl (p-allyloxyphenyl)acetate as a
white solid (2.62 g, 86%). The product was pure enough to be used
in the next step. Solid NaOH (0.90 g) was added to a solution of
allyl (p-allyloxyphenyl)acetate (2.62 g, 11.28 mmol) in MeOH
(1.00 mL). The reaction mixture was stirred at 35 °C for 2 h, diluted
with H2O (20 mL), and acidified with aqueous 6 n HCl until pH 2.
The reaction mixture was washed with diethyl ether (3ϫ50 mL).
The organic layers were dried with MgSO4, filtered, and concen-
trated to give compound 5 as a white solid (2.13 g, 98%). The prod-
uct was pure enough to be used in the next step. M.p. 69.5–71.9 °C.
Conclusions
The absolute stereochemical assignment of SCH 71450,
a selective dopamine D4 receptor antagonist, has been suc-
cessfully confirmed through enantioselective epimer synthe-
sis. The epimeric SCH 71450 was prepared in nine steps
(longest linear steps, overall 12.3% yield) from commer-
cially available dopamine hydrochloride. The allyl substitu-
ent on the p-hydroxybenzyl group was demonstrated to be
an appropriate protecting group in the asymmetric transfer
hydrogenation of the imine functionality. β-Selective glyc-
osylation was accomplished by neighboring group partici-
pation. By comparison with literature data, the absolute
stereochemistry at C-1 of the tetrahydroisoquinoline core of
the natural SCH 71450 was assigned the S configuration.
This procedure has the potential to serve as a practical syn-
thetic approach to other types of structurally related alk-
aloids such as aporphine glycosides. With this synthetic
method in hand, structural modifications to this natural
product to produce more potent and selective dopamine D4
receptor antagonists are underway. Because SCH 71450 has
recently been used as new pharmaceutical compositions for
the treatment of ADHD and sexual disorders, our work is
particularly important.
IR (neat): ν = 2921 (OH), 1704 (C=O), 1640, 1614, 1511, 1401,
˜
1300, 1251, 1179, 1142, 1018, 998, 983, 928, 900, 818, 805, 731,
702, 641, 630, 611 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.20 (d,
J = 8.4 Hz, 2 H), 6.89 (d, J = 8.4 Hz, 2 H), 6.06 (ddt, J = 17.1,
10.5, 5.3 Hz, 1 H), 5.42 (dq, J = 17.1, 1.5 Hz, 1 H), 5.30 (dq, J =
10.5, 1.5 Hz, 1 H), 4.53 (dt, J = 5.4, 1.5 Hz, 2 H), 3.59 (s, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 178.3 (s), 157.9 (s), 133.2 (d),
130.4 (d), 125.5 (d), 117.7 (t), 114.9 (d), 68.9 (t), 40.2 (t) ppm.
HRMS (ESI): calcd. for C11H12O13 [M + H]+ 193.0864; found
193.0858.
N-[2,4-Bis(benzyloxy)phenethyl]-2-(4-allyloxyphenyl)acetamide (6):
(COCl)2 (11.8 mL, 135 mmol) was added to 4-(allyloxy)phenylace-
tic acid (5; 0.22 g, 1.14 mmol), and the mixture was stirred at room
temp. for 2 h. The solution was then concentrated to give the crude
acid chloride product. A solution of O,O-dibenzyldopamine (4;
0.32 g, 0.95 mmol) in dry CH2Cl2 (8.90 mL) was added to a solu-
tion of the acid chloride in dry CH2Cl2 (8.90 mL), followed by the
addition of 15% NaOH (6.50 mL), and then the reaction was
stirred at room temp. overnight. After washing the solution with
CH2Cl2 (100 mL), H2O (30 mL), saturated NaHCO3 (30 mL), and
brine (30 mL), the combined organic layers were dried with
MgSO4, filtered, and concentrated to give the crude product, which
was purified by flash chromatography with the eluent of EtOAc/
hexanes/Et2NH (60:40:0.1) to give a white solid product (0.32 g,
Experimental Section
1
General: H (300 MHz) and 13C NMR (75 MHz) spectra were re-
corded with a Bruker Avance 300 MHz spectrometer. The NMR
spectra were recorded in CDCl3, CD3OD, or [D5]pyridine. The re-
sidual peaks of chloroform (δ = 7.26 ppm in 1H NMR; δ =
1
77.0 ppm in 13C NMR), methanol (δ = 3.31 ppm in H NMR; δ =
1
49.00 ppm in 13C NMR), and pyridine (δ = 8.74 ppm in H NMR;
δ = 150.30 ppm in 13C NMR) were used as internal standards,
respectively. Splitting patterns were reported as follows: s: singlet;
d: doublet; t: triplet; q: quartet; m: multiplet. Coupling constants
(J) are reported in Hz. IR spectra were recorded with a Perkin–
Elmer Spectrum 100 FT-IR spectrometer. High-resolution mass
spectra (HRMS) were recorded with a Shimadzu LCMS-IT-TOF
spectrometer (ESI-MS). HPLC was performed with an Agilent
1100 Series instrument. Optical rotations were measured with a
Horiba SEPA-300 Digital polarimeter. Enantiomeric excesses were
measured with a Daicel Chiralcel OD column. Precoated sheets
(Merck Art. 60 F254, 0.25 mm) were used for TLC. The reaction
products were isolated by flash chromatography performed on
Merck Art. Geduran Si 60 (0.040–0.063 mm) silica gel. The yields
of products refer to chromatographically purified products unless
66%). M.p. 111.2–113.5 °C. IR (neat): ν = 3297 (NH), 3065, 3035,
˜
2925, 2867, 1639 (C=O), 1586, 1549, 1511, 1454, 1427, 1379, 1338,
1178, 1141, 1013, 925, 845, 802, 732, 695 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 7.47–7.29 (m, 10 H), 7.05 (d, J = 8.6 Hz,
2 H), 6.84 (d, J = 8.6 Hz, 2 H), 6.82 (d, J = 7.8 Hz, 1 H), 6.72 (d,
J = 1.8 Hz, 1 H), 6.54 (dd, J = 7.8, 1.8 Hz, 1 H), 6.03 (ddt, J =
17.3, 10.7, 5.3 Hz, 1 H), 5.48 (t, J = 5.3 Hz, 1 H, NH), 5.40 (dd, J
= 17.3, 1.2 Hz, 1 H), 5.28 (dd, J = 10.7, 1.2 Hz, 1 H), 5.12 (d, J =
8.7 Hz, 4 H, 2 OCH2Ph), 4.49 (d, J = 5.3 Hz, 2 H, allyl-H), 3.40
(q, J = 6.6 Hz, overlapped with s at 3.40, 4 H), 2.64 (t, J = 6.9 Hz,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.2 (s), 157.7 (s),
149.0 (s), 147.5 (s), 137.3 (s), 137.1 (s), 133.0 (d), 132.0 (s), 130.3
(d), 128.3 (d), 127.7 (d), 127.6 (d), 127.3 (d), 127.2 (d), 126.8 (s),
121.5 (d), 117.5 (t), 115.6 (d), 115.3 (d), 115.0 (d), 71.3 (t), 71.2 (t),
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Stereochemical Assignment of a Dopamine D4 Receptor Antagonist
68.7 (t), 42.8 (t), 40.5 (t), 34.8 (t) ppm. HRMS (ESI): calcd. for
C33H33NO4 [M + H]+ 508.2488; found 508.2471.
1 H), 5.28 (d, J = 10.8 Hz, 1 H), 5.23–5.08 (m, 3 H), 5.05–4.59 (m,
3 H), 4.49 (d, J = 4.2 Hz, 2 H, allyl-H), 4.13–4.22 (m, 0.57 H,
Hmajor, ArCHNH), 3.91–3.82 (m, 0.43 H, Hminor, ArCHNH), 3.35–
3.19 (m, 1 H), 3.08–2.42 (m, 5 H) ppm. HRMS (ESI): calcd. for
C41H39NO5 [M + H]+ 626.2905; found 626.2921.
(1R)-1,2,3,4-Tetrahydro-1-[(4-allyloxyphenyl)methyl]-6,7-bis(benz-
yloxy)isoquinoline (8): POCl3 (0.47 mL, 5.00 mmol) was added to a
solution of amide 6 (0.51 g, 1.00 mmol) in dry acetonitrile (2 mL).
The reaction mixture was stirred at 90 °C for 1 h and then directly
concentrated to give a residue, which was diluted with CH2Cl2
(10 mL) and neutralized by the addition of a saturated NaHCO3
solution until pH 9. The reaction mixture was extracted with
CH2Cl2 (3ϫ60 mL) and washed with brine (20 mL). The organic
layers were dried with MgSO4, filtered, and concentrated to give
the crude imine product 7, which was used directly in the next step.
[RuCl(p-cymene){(S,S)-Ts-DPEN}] (71.6 mg, 5 mol-%) was added
to a solution of imine 7 (1.10 g, 2.25 mmol) in dry degassed DMF
(4.74 mL). After cooling the solution to 0 °C, a solution of formic
acid/triethylamine azeotrope (5:2, 2.00 mL) was added. The reac-
tion mixture was stirred at room temp. for 2 h. After neutralizing
the solution with a saturated K2CO3 solution until pH 9, the reac-
tion mixture was extracted with ethyl acetate (3ϫ60 mL). The
combined organic layers were washed with brine (20 mL), dried
with MgSO4, filtered, and concentrated to give a crude residue,
which was purified by flash chromatography with 2-propanol/hex-
anes/Et2NH (55:45:1) as eluent to give a green solid (0.53 g, 48%).
A 95% ee was determined by HPLC with a chiral phase column.
The absolute stereochemistry was later confirmed following hydro-
genolysis of compound 10 and comparison of the specific rotation
with literature data.[21] [α]D26 = –324.56 (c = 0.1, CHCl3); m.p. 81.7–
Compound 10:
A catalytic amount of [Pd(PPh3)4] (47.4 mg,
0.05 equiv.) was added to a solution of compound 9 (0.51 g,
0.82 mmol) in methanol (1.64 mL) and THF (0.49 mL) under Ar.
The solution was stirred for 10 min, and then solid K2CO3 (0.34 g,
2.46 mmol) was added. The reaction mixture was stirred at 68 °C
for 3 h and then directly concentrated in vacuo. H2O (10 mL) was
added to the residue, and the mixture was acidified by the addition
of aqueous 6 n HCl until pH = 2. It was then washed with CH2Cl2
(3.50 mL) and brine (15 mL). The organic layers were dried with
MgSO4, filtered, and concentrated to give a crude product, which
was purified by flash column chromatography with EtOAc/hexanes
(35:65) as eluent to give compound 10 as a yellow viscous liquid
(0.43 g, 90%). A mixture of rotamers in a ratio of 1.3:1 was ob-
tained. Due to difficulties in the NMR analysis, we could only ob-
tain the following data. IR (neat): ν = 3659 (OH), 3032, 2924, 2854,
˜
1955, 1880, 1667, 1613, 1595, 1514, 1453, 1378, 1332, 1259, 1239,
1172, 1120, 1095, 1015, 911, 855, 823, 804, 734 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 7.48–7.27 (m, 14 H), 7.19 (d, J = 6.0 Hz,
1 H), 6.92 (d, J = 8.4 Hz, 1 H), 6.84 (d, J = 8.1 Hz, 1 H), 6.72–
6.65 (m, 2 H), 6.55 (s, 0.57 H, Hmajor), 6.42 (s, 0.43 H, Hminor),
5.27–4.94 (m, 5 H), 4.83 (d of AB, J = 12.3 Hz, 1 H), 4.25–4.15
(m, 1 H, Hmajor, ArCHNH), 4.02–3.92 (m, 1 H, Hminor, ArCHNH),
3.41–3.19 (m, 1 H), 3.05–2.68 (m, 4 H), 2.60–2.48 (m, 1 H) ppm.
HRMS (ESI): calcd. for C38H35NO5 [M + H]+ 586.2593; found
586.2587.
82.6 °C. IR (neat): ν = 3342 (NH), 3032, 2897, 1607, 1509, 1455,
˜
1443, 1416, 1370, 1324, 1300, 1260, 1240, 1218, 1179, 1124, 1050,
1023, 996, 932, 889, 851, 828, 778, 737, 724, 692, 637 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 7.47–7.29 (m, 10 H), 7.11 (d, J =
8.4 Hz, 2 H), 6.87 (d, J = 8.4 Hz, 2 H), 6.74 (s, 1 H), 6.68 (s, 2 H),
6.06 (ddt, J = 17.3, 10.5, 5.3 Hz, 1 H), 5.42 (dd, J = 17.3, 1.2 Hz,
1 H), 5.29 (dd, J = 10.5, 1.2 Hz, 1 H), 5.13 (s, 2 H, OCH2Ph), 5.09
(s, 2 H, OCH2Ph), 4.53 (d, J = 5.3 Hz, 2 H, allyl-H), 4.04 (dd, J =
9.0, 4.0 Hz, 1 H, ArCHNH), 3.21–3.13 (m, 1 H), 3.05 (dd, J =
13.7, 4.0 Hz, 1 H), 2.93–2.59 (m, 4 H), 1.80 (br. s, 1 H, NH) ppm.
13C NMR (75 MHz, CDCl3): δ = 157.3 (s), 147.7 (s), 146.9 (s),
137.5 (s), 137.4 (s), 133.4 (d), 131.4 (s), 131.2 (s), 130.3 (d), 128.4
(d), 127.8 (d), 127.5 (d), 127.4 (d), 117.6 (t), 115.5 (d), 114.9 (d),
114.0 (d), 71.8 (t), 71.3 (t), 68.9 (t), 56.9 (d), 41.6 (t), 40.8 (t), 29.5
(t) ppm. HRMS (ESI): calcd. for C33H33NO3 [M + H]+ 492.2538;
found 492.2527.
(–)-Norcoclaurine: To a solution of 10 (0.16 g, 0.27 mmol) in a co-
solvent system (MeOH/THF = 1:5, 3.24 mL) was added Pd(OH)2
(23.8 mg, 25 wt.-%). The air in the reaction vessel was removed in
vacuum and replaced by H2 gas using a balloon. The reaction mix-
ture was stirred at room temp. for 4.5 h. After TLC analysis indi-
cated that the starting material had been consumed completely, the
reaction mixture was filtered and then concentrated to give a yellow
viscous liquid (69.9 mg, 95%). The product was sufficiently pure.
The spectrometric data is in agreement with the literature data.[21]
Compound 12: Molecular sieves (4 Å, 0.7 g) were added to a stirred
solution of compound 10 (0.28 g, 0.49 mmol) and glycosyl donor
11 (0.40 g, 0.81 mmol) in CH2Cl2 (4.9 mL). The reaction mixture
was stirred at –10 °C for 1 h. BF3·OEt2 (0.15 mL, 1.23 mmol) was
added dropwise to this suspension at –10 °C, and the mixture was
stirred at the same temperature for 2.5 h. After neutralizing the
solution with a saturated aqueous solution of NaHCO3 until pH
= 9, the solution was washed with CH2Cl2 (3.50 mL) and brine
(15 mL). The combined organic layers were dried with MgSO4, fil-
Compound 9: CbzCl (2.73 mL, 2.73 mmol) was added dropwise to
a solution of compound 8 (0.53 g, 1.09 mmol), Et3N (0.43 mL,
3.27 mmol), and DMAP (26.6 mg, 0.23 mmol) in dry CH2Cl2
(2.18 mL) at 10 °C. The reaction mixture was warmed to 50 °C and
then stirred at the same temperature for 1.5 h. It was then diluted
with CH2Cl2 (5 mL) and neutralized with aqueous NaHCO3 until
pH 9. The resulting mixture was washed with CH2Cl2 (3ϫ20 mL) tered, and concentrated to give a crude product, which was purified
and the combined organic layers were washed with brine (5 mL),
dried with MgSO4, filtered, and concentrated to give a crude prod-
uct, which was purified by flash chromatography with EtOAc/hex-
anes (25:75) as eluent to give compound 9 as a pale-yellow viscous
liquid (0.51 g, 75%) as a mixture of E/Z isomers. A mixture of
by flash chromatography with EtOAc/hexanes (45:55) as eluent to
give compound 12 as a yellow viscous liquid (0.36 g, 80%) as a
mixture of E/Z isomers. A mixture of rotamers in a ratio of 1.3:1
was obtained. Due to difficulties in the NMR analysis, we could
only obtain the following data. IR (neat): ν = 3056, 1755, 1693
˜
rotamers as a ratio of 1.3:1 was obtained. IR (neat): ν = 3056,
(C=O), 1610, 1510, 1428, 1368, 1265, 1224, 1039, 909, 701 cm–1.
˜
2929, 1693 (C=O), 1610, 1510, 1455, 1428, 1381, 1265, 1243, 1178,
1H NMR (300 MHz, CDCl3): δ = 7.46–7.27 (m, 14 H), 7.17–7.13
1
1096, 1017, 857, 737, 700 cm–1. H NMR (300 MHz, CDCl3): δ = (m, 1 H), 6.95–6.83 (m, 4 H), 6.69 (s, 0.57 H, Hmajor), 6.64 (s, 0.43
7.50–7.20 (m, 15 H, aromatic), 6.93–6.87 (two overlapped d at 6.91
and 6.88, J = 9.9, 8.7 Hz, 2 H, p-H), 6.79–6.75 (two overlapped d
at 6.79 and 6.76, J = 8.1, 5.1 Hz, 2 H, p-H), 6.69 (s, 0.57 H, Hmajor),
6.65 (s, 0.43 H, Hminor), 6.43 (s, 0.57 H, Hmajor), 6.32 (s, 0.43 H,
Hminor), 6.05 (ddt, J = 17.1, 10.8, 5.3 Hz, 1 H), 5.40 (d, J = 17.1 Hz,
H, Hminor), 6.46 (s, 0.57 H, Hmajor), 6.34 (s, 0.43 H, Hminor), 5.59–
4.72 (m, 9 H), 4.30–4.00 (m, 3 H), 3.90–3.70 (m, 1 H), 3.33–3.16
(m, 1 H), 3.06–2.24 (m, 5 H), 2.08 (s, 1.29 H, Hminor), 2.07 (s, 1.29
H, Hminor), 2.05 (s, 3 H), 2.04 (s, 3 H), 2.02 (s, 3 H) ppm. HRMS
(ESI): calcd. for C52H53NO14 [M + H]+ 916.3544; found 916.3573.
Eur. J. Org. Chem. 2013, 2898–2905
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2903

H.-P. Wu, T.-N. Lu, N.-Y. Hsu, C.-C. Chang
FULL PAPER
[4]
[5]
a) J. M. J. Alvir, P. H. Jeffrey, J. A. Lieberman, N. Engl. J. Med.
1993, 329, 162–167; b) D. E. Casey, Psychopharmacologia 1989,
99, S47–S53.
Compound 13: Solid K2CO3 (0.04 g, 0.32 mmol) was added to a
solution of compound 12 (0.15 g, 0.16 mmol) in MeOH/THF (1:5,
9.60 mL) and the resulting mixture was stirred at room temp. for
1 h. The solution was then concentrated to give a crude product,
which was purified by flash chromatography with CH2Cl2/MeOH
(13:1) as eluent to give compound 13 as a pale-yellow viscous liquid
(0.10 g, 82%) as a mixture of E/Z isomers. A mixture of rotamers
as a ratio of 1.3:1 was obtained. Due to difficulties in the NMR
a) O. Prante, R. Tietze, C. Hocke, S. Löber, H. Hübner, T.
Kuwert, P. Gmeiner, J. Med. Chem. 2008, 51, 1800–1810; b) F.
Boeckler, H. Russig, W. Zhang, S. Löber, J. Schetz, H. Hübner,
B. Ferger, P. Gmeiner, J. Feldon, Psychopharmacology 2004,
175, 7–17; c) A. H. C. Wong, H. H. M. Van Tol, Prog. Neuro-
Psychopharmacol. Biol. Psychiatry 2003, 27, 1091–1099; d) J. N.
Oak, J. Oldenhof, H. H. M. Van Tol, Eur. J. Pharmacol. 2000,
405, 303–327; e) S. Patel, S. Freedman, K. L. Chapman, F.
Emms, A. E. Fletcher, M. Knowles, R. Marwood, G. Mcallis-
ter, J. Myers, S. Patel, N. Curtis, J. J. Kulagowski, P. D. Leeson,
M. Ridgill, M. Graham, S. Matheson, D. Rathbone, A. P.
Watt, L. J. Bristow, N. M. J. Rupniak, E. Baskin, J. J. Lynch,
C. I. Ragan, J. Pharmacol. Exp. Ther. 1997, 283, 636–647; f)
J. J. Kulagowski, H. B. Broughton, N. R. Curtis, I. M. Mawer,
M. P. Ridgill, R. Baker, F. Emms, S. B. Freeman, R. Marwood,
S. Patel, S. Patel, C. I. Ragan, P. D. Leeson, J. Med. Chem.
1996, 39, 1941–1942; g) P. Seeman, H. C. Guan, H. H. M.
Van Tol, Nature 1993, 365, 441–445.
V. R. Hegde, P. Dai, C. Ladislaw, M. G. Patel, M. S. Puar, J. A.
Pachter, Bioorg. Med. Chem. Lett. 1997, 7, 1207–1212.
B. Ferger, A. Ceci, Boehringer Ingelheim, WO 2007/093624A2,
2007.
K. Mendla, R. Pyke, W. Eisenreich, T. Friedl, Boehringer In-
gelheim, WO 2005/102342A1, 2005.
Most of the information, such as Scifinder, indicated that the
absolute stereochemistry at C-1 of the tetrahydroisoquinoline
core is an R configuration. However, an S configuration has
also been reported: N. Cabedo, I. Berenguer, B. Figadère, D.
Cortes, Curr. Med. Chem. 2009, 16, 2441–2467.
T. Nukada, A. Berces, M. Z. Zgierski, D. M. Whitfield, J. Am.
Chem. Soc. 1998, 120, 13291–13295.
analysis, we could only obtain the following data. IR (neat): ν =
˜
3372 (OH), 3064, 2926, 1756, 1688, 1610, 1510, 1454, 1428, 1332,
1264, 1227, 1096, 1074, 1042, 1016, 911, 855, 697, 620 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 7.42–7.17 (m, 13 H), 7.08–7.04 (m,
2 H), 6.88 (br. s, 4 H), 6.61 (s, 0.57 H, Hmajor), 6.58 (s, 0.43 H,
Hminor), 6.53 (s, 0.57 H, Hmajor), 6.42 (s, 0.43 H, Hminor), 5.20–4.82
(m, 6 H), 4.57 (d of AB, J = 12.3 Hz, 1 H), 4.18–4.08 (m, 1 H) ppm.
HRMS (ESI): calcd. for C44H45NO10 [M + H]+ 748.3121; found
748.3105.
Epimeric SCH 71450: [Pd(OH)2] (37.9 mg, 25wt.-%) was added to
a solution of compound 13 (0.15 g, 0.20 mmol) in MeOH/THF
(1:5, 2.40 mL). The reaction vessel was evacuated under vacuum
and filled with H2 gas by using a hydrogen balloon. The reaction
mixture was stirred at room temp. for 4.5 h. After TLC analysis
had indicated that the starting material had been completely con-
sumed, the reaction mixture was filtered and then concentrated to
give epimeric SCH 71450 as a yellow viscous liquid (85.9 mg, 99%).
[6]
[7]
[8]
[9]
The product was sufficiently pure for analytical purposes. [α]D27
=
+42.60 (c = 1.46, MeOH). IR (neat): ν = 3347 (OH), 2926 (NH),
˜
2145, 1642, 1511, 1453, 1237, 1076, 1016, 695, 611 cm–1. The 1H
and 13C/DEPT NMR spectroscopic data are reported in Table 1
and Table 2. HRMS (ESI): calcd. for C22H27NO8 [M + H]+
434.1815; found 434.1821.
[10]
[11]
[12]
N. Uematsu, A. Fujii, S. Hashiguchi, T. Ikariya, R. Noyoki, J.
Am. Chem. Soc. 1996, 118, 4916–4917.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C/DEPT NMR spectra of compounds 5, 6, 8–10,
12, 13, and epimeric SCH 71450, and HPLC chromatograms of
compound 8.
For selected literature citations on the total synthesis of natural
products involving the Bischler–Napieralski cyclization, see: a)
E. Awuah, A. Capretta, J. Org. Chem. 2010, 75, 5627–5634; b)
M. Movassaghi, M. D. Hill, Org. Lett. 2008, 10, 3485–3488.
a) S.-I. Murahashi, Ruthenium in Organic Synthesis, Wiley-
VCH, Weinheim, 2005; b) M. Kitamura, H. Nakatsuka, Chem.
Commun. 2011, 47, 842–846; c) L. F. Tietze, N. Rackelmann,
G. Sekar, Angew. Chem. 2003, 115, 4386; Angew. Chem. Int.
Ed. 2003, 42, 4254–4257.
[13]
Acknowledgments
[14]
[15]
[16]
P. G. M. Wuts, T. W. Greene, Greene’s protective groups in or-
ganic synthesis, 4th ed., Wiley, New York, 2007, pp. 390–393.
C. Xu, K. Xu, H. Gu, R. Zheng, H. Liu, X. Zhang, Z. Guo,
B. Xu, J. Am. Chem. Soc. 2004, 126, 9938–9939.
J. H. Schrittwieser, V. Resch, S. Wallner, W.-D. Lienhart, J. H.
Sattler, J. Resch, P. Macheroux, W. Kroutil, J. Org. Chem. 2001,
76, 6703–6714.
In accord with the Scifinder database, we assumed it has the R
configuration. Hence, to prepare the isomer with the R config-
uration, Noyori’s (S,S)-Ru catalyst was used for this work.
E. Vedejs, P. Trapencieris, E. Suna, J. Org. Chem. 1999, 64,
6724–6729.
The authors thank the National Science Council (NSC), Taiwan
and the Department of Chemistry, Fu Jen Catholic University for
financial support. T. N. L. thanks the NSC for an undergraduate
research grant. N. Y. H. was a recipient of a Master’s Student Fel-
lowship from the Department of Chemistry, Fu Jen Catholic Uni-
versity. Ms. Hsu-Ting Chan is also acknowledged for preliminary
experiments.
[17]
[18]
[19]
[20]
[1] a) R. J. Baldessarini, in: Pharmacological Basis of Therapeutics
(Eds.: G. A. Goodman, T. W. Rall, A. S. Nies, P. Taylor), Perga-
mon Press, New York, 1990, pp. 383–435; b) a detailed booklet
on schizophrenia was published in 2009 by the National Insti-
tute of Mental Health (NIMH). Free download at http://
www.nimh.nih.gov/health/publications/schizophrenia/com-
plete-index.shtml.
[2] T. L. Lemke, D. A. Williams, V. F. Roche, S. W. Zito, Foye’s
Principles of Medicinal Chemistry, 6th ed., Lippincott Wil-
liams & Wilkins, Baltimore, MD, 2008, pp. 601–630.
[3] a) D. Tarsy, R. J. Baldessarini, Annu. Rev. Med. 1984, 35, 605–
623; b) T. L. Lemke, D. A. Williams, V. F. Roche, S. W. Zito,
Foye’s Principles of Medicinal Chemistry, 6th ed., Lippincott
Williams & Wilkins, Baltimore, MD, 2008, pp. 609–611.
D. R. Vutukuri, P. Bharathi, Z. Yu, K. Rajasekaran, M.-H.
Tran, S. Thayumanavan, J. Org. Chem. 2003, 68, 1146–1149.
K. C. Nicolaou, J. Hao, M. V. Reddy, P. B. Rao, G. Rassias,
S. A. Snyder, H. Huang, D. Y.-K. Chen, W. E. Brenzovich, N.
Giuseppone, P. Giannakakou, A. O’Brate, J. Am. Chem. Soc.
2004, 126, 12897–12906.
24
[21]
The specific rotation of (S)-(+)-higenamine, [α]D = +85 (c =
0.74, CHCl3), was reported by Y.-C. Chang, F.-R. Chang, A. T.
Khalil, P.-W. Hsieh, Y.-C. Wu, Z. Naturforsch. C 2003, 58,
521–526. However, the specific rotation of (–)-higenamine pre-
pared by the hydrogenolysis of compound 10 is [α]2D7 = –86.59
(c = 6.11, MeOH). Therefore, the R configuration was obtained
2904
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2898–2905

Stereochemical Assignment of a Dopamine D4 Receptor Antagonist
in this work. The compound was not soluble in CHCl3 in our
case.
[22] C.-W. T. Chang, Y. Hui, B. Elchert, J. Wang, J. Li, R. Rai, Org.
Lett. 2002, 4, 4603–4606.
[23] a) K. Kawamura, H. Horikiri, J. Hayakawa, C. Seki, K.-i.
Yoshizawa, Chem. Pharm. Bull. 2004, 52, 670–674; b) R. T.
Brown, N. E. Carter, S. P. Mayalarp, F. Scheinmann, Tetrahe-
dron 2000, 56, 7591–7594.
[24]
J. J. Plattner, R. D. Gless, H. Rapoport, J. Am. Chem. Soc.
1972, 94, 8613–8615.
[25] N. Kashiwaba, M. Ono, J. Toda, H. Suzuki, T. Sano, J. Nat.
Prod. 2000, 63, 477–479.
Received: January 15, 2013
Published Online: March 27, 2013
Eur. J. Org. Chem. 2013, 2898–2905
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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