Enantioselective Synthesis of Hydantoin and Diketopiperazine-Fused Tetrahydroisoquinolines via Pictet-Spengler Reaction

Article abstract of DOI:10.1021/acscombsci.9b00005

An enantioselective synthesis of iso-, isothio-, and isoselenohydantoin and diketopiperazine-fused tetrahydroisoquinolines from l-Dopa was reported. The route consists of an Pictet-Spengler reaction of (S)-2-amino-3-(3,4-dimethoxyphenyl)propanoates with v

Full text of DOI:10.1021/acscombsci.9b00005

Research Article
Cite This: ACS Comb. Sci. XXXX, XXX, XXX−XXX
pubs.acs.org/acscombsci
Enantioselective Synthesis of Hydantoin and Diketopiperazine-
Fused Tetrahydroisoquinolines via Pictet−Spengler Reaction
†
†
†,§
†
,†,‡
Shih-I Liu, Jia-Yun Haung, Indrajeet J. Barve, Sheng-Cih Huang, and Chung-Ming Sun*
†
Department of Applied Chemistry, National Chiao-Tung University, Hsinchu 300, Taiwan
‡
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807-08, Taiwan
§
Department of Chemistry, MES Abasaheb Garware College, Pune, Maharashtra 411004, India
*
S Supporting Information
ABSTRACT: An enantioselective synthesis of iso-, isothio-, and isoselenohydantoin and diketopiperazine-fused
tetrahydroisoquinolines from L-Dopa was reported. The route consists of an Pictet−Spengler reaction of (S)-2-amino-3-
(
3,4-dimethoxyphenyl)propanoates with various aldehydes to afford diastereomeric tetrahydroisoquinolines. Next step, the
tetrahydroisoquinolines were further reacted with iso-, isothio-, or isoselenocyanates to construct hydantoin. Similarly, the
diketopiperazine moiety was constructed by subjecting tetrahydroisoquinolines to a condensation reaction with chloroacetyl
chloride followed by nucleophilic addition with various primary amines.
KEYWORDS: enantioselective synthesis, diketopiperazine-fused tetrahydroisoquinolines, hydantoin-fused tetrahydroisoquinolines,
molecular hybridization, Pictet−Spengler reaction
INTRODUCTION
and ability to mimic peptide properties make them a useful
pharmacophore in drug discovery. For example, cyclo[Dmt-
■
11
Hydantoin is a privileged scaffold found in various natural
products and bioactive compounds. Notably, indoline
1
Tic] is an opioid antagonist showing a good δ-selective binding
12
affinity (Figure 1).
thiohydantoin acts as an antiproliferative agent against prostate
2
Assembling two or more dissimilar privileged scaffolds in a
tumor, benzylidene-thiohydantoin shows potent tyrosinase
3
single framework to yield hybrid molecules is an interesting
inhibition, and enzalutamide is used for the treatment of
13
4
strategy in drug discovery. This method has successfully
castration-resistant prostate cancer. From many years,
1
4
15
provided potent anticonvulsant, antimycobacterial, bone
selenium-containing compounds are restrained to utilize in
the medicines due to their presumed toxic nature until the
discovery of L-selenomethionine, methylselenocysteine, and
various selenoproteins which are beneficial to human health.
Some selenoorganic compounds exhibit promising bioactiv-
ities. For example, Ebselen acts as an antioxidant, whereas 2-
selenohydantoin displays good anticancer activity.
Among various heterocycles, in particular, the tetrahydroi-
soquinoline motif is an integral part of numerous natural
products and bioactive compounds. For example, dihydroiso-
16
17
18,19
anabolic2, tankyrase inhibitor, antitumor,
and antitu-
0
bercular agents (Figure 2).
5
An exhaustive literature survey revealed several methods for
the synthesis of tetrahydro-β-carboline-fused (thio)-
2
1
hydantoins. However, tetrahydroisoquinoline-embedded
thio(seleno)hydantoin and tetrahydroisoquinoline-fused dike-
topiperazine are less explored (Figure 3). Prompted by the
scarcity of the related reports and as a part of our continuing
6
,7
22
effort toward the synthesis of fused heterocycles, we report
8
herein an enantioselective of hydantoin-fused tetrahydroiso-
quinoline carbothioamide is an agonist for capsaicin receptor
and almorexant is a dual orexin receptor antagonist.
,5-Diketopiperazines are naturally occurring cyclic dipep-
9
,10
2
Received: January 6, 2019
Revised: February 21, 2019
tides found in marine organisms, fungi and bacteria. Their
structural simplicity, conformationally constrained scaffold,
©
XXXX American Chemical Society
A
DOI: 10.1021/acscombsci.9b00005
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ACS Combinatorial Science
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Figure 1. Bioactive hydantoins, tetrahydroisoquinolines, and 2,5-diketopiperazines.
Figure 2. Biologically potent hybrid molecules.
quinolines 9 and diketopiperazine-fused tetrahydroisoquino-
lines 12 via Pictet−Spengler condensation of (S)-2-amino-3-
conditions. Accordingly, treatment of 5{1} with 4-nitro-
benzaldehyde 6{1} in the presence of K CO in methanol
2
3
(
3,4-dimethoxyphenyl)propanoates 5 with aldehydes. The
did not afford any product and the starting materials were
t
tetrahydroquinolines 7 thus obtained were reacted either
with isocyanates or chloroacetyl chloride and amines.
recovered (Table 1, entry 1). The use of strong base KO Bu or
organic bases like triethyl amine or piperidine yielded only
imine. (Table 1, entries 2−4). The refluxing of a mixture of
5{1} and 4-nitrobenzaldehyde 6{1} in the presence of catalytic
amount of p-TSA in acetonitrile gave 7{1,1} as a
diastereomeric mixture in only 20% yield because of electron
deficient nature of tertahydroquinoline ring compared to
tryptophan moiety (Table 1, entry 5). The diastereomers
RESULTS AND DISCUSSION
■
The synthesis of methyl (S)-2-amino-3-(3,4-
dimethoxyphenyl)propanoate 5{1} was started with the
esterification of L-Dopa in the presence of thionyl chloride
and methanol to yield ester 2 in a good yield. Boc protection,
followed by alkylation afforded compound 4{1} in 88% yield.
Finally, TFA-mediated deprotection of the Boc group yielded
methyl ester amine 5{1} in 98% yield (Scheme 1). The optical
purity of 5{1} was confirmed by chiral HPLC (see SI, page
S17).
7
{1,1}-cis and 7{1,1}-trans were separated by column
chromatography in 4:1 ratio and the relative stereochemistry
of the compounds was assigned on the basis of NOE study and
crystallographic analysis. Accordingly, when C
7{1,1}-cis was irradiated, enhancement of the signal of C
was observed indicating corresponding protons were on the
−H proton of
3
−H
1
The reaction between 5{1} and 4-nitrobenzaldehyde 6{1}
was chosen as a model reaction to examine various reaction
same side of the tertahydroquinoline ring, whereas C −H and
3
B
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To our surprise, further analysis of the new product by a chiral
HPLC revealed two peaks on the chromatogram (see SI, page
36).
Subsequently, we decided to investigate the current reaction
by treating both the diastereomers 7{1,1}-cis and 7{1,1}-trans,
separately. Accordingly, the treatment of 7{1,1}-cis with
methyl isothiocyanate yielded 9{1,1,1}-epimer (trans) as the
only product. The complete conversion of 7{1,1}-cis to
9
{1,1,1}-epimer (trans) was observed because of the epimeri-
zation of the chiral center adjacent to the carbonyl carbon to
yield the thermodynamically more stable trans isomer.
Conversely, the 7{1,1}-trans afforded 9{1,1,1}-trans ex-
clusively under similar condition (Scheme 2). A representative
example of the isomer 9{2,7,2} was confirmed by X-ray crystal
structure analysis (Figure 5).
With the optimized condition in hand, we then examined
the substrate scope by reaction of substituted 7-trans with a
variety of iso-, isothiocyanates, and isoselenocyanates. The
required isoselonocyanates were prepared from selenium
powder and in situ generated isocyanide from N-formyl
amines and triphosgene. All the corresponding products were
obtained in good to excellent yield; and no racemization was
observed in each case (Table 2).
The scope of this strategy was further extended for the
synthesis of fused pyrazino tetrahydroisoquinolines 12.
Accordingly, when a mixture of 7{1,1}-cis and 7{1,1}-trans
was treated with chloroacetyl chloride under basic condition
followed by double nucleophilic addition reaction with amine
Figure 3. Molecular hybridization of tetrahydroisoquinoline with
hydantoin and 2,5-diketopiperazine.
23
C- H of 7{1,1}-trans did not show any correlation (S34−S35).
1
ORTEP diagram of 7{1,1}-cis and 7{1,1}-trans showed that
the tertahydroquinoline ring adopted half-chair conformation.
The bulky methyl ester and 4-nitrophenyl groups oriented
themselves in a pseudo equatorial position, whereas C −H and
1
C −H hydrogens acquired axial position and oriented in a cis
3
and trans way, respectively. (Figure 4).
The screening of various Lewis acids, such as TiCl , AlCl ,
4
3
and BF ·Et O, afforded expected products in poor to moderate
3
2
1
1{1}, surprisingly, no epimerization was observed and the
yields (Table 1, entries 6−8). When 20 mol % of TFA was
used, the product was obtained in only 52% yield after 48 h
reflux (Table 1, entry 9). The use of toluene as a solvent
diminished the yield of the products (Table 1, entry 10). When
the same reaction was carried out in refluxing chloroform in 20
mol % TFA the yield was 70% albeit, in longer reaction time
reaction yielded corresponding 12{1,1,1}-cis and 12{1,1,1}-
trans in 4:1 diastereomeric ratio after column separation
(Scheme 3) (S37).
The conformational analysis of compounds 12{1,1,1}-cis
and 12{1,1,1}-trans were made based on NOESY experiment.
Proton attached to C3 carbon displayed characteristic through-
space interaction with proton attached to C1 carbon for the
compound 12{1,1,1}-cis, whereas these interactions were
absent in the case of 12{1,1,1}-trans (S38−S39). A single
crystal X-ray analysis of 12{1,1,4} exhibited that the bicyclic
fused-ring framework existed in cis-decalin-like conformation
(
6
Table 1, entry 11). Finally, when 5{1} and nitrobenzaldehyde
{1} were treated with two equivalents of TFA in refluxing
chloroform for 24 h, the desired products were obtained in an
excellent yield (Table 1, entry 12).
With the diastereomeric compound 7{1,1} in hand, we then
carried out the construction of hydantoin moiety through one-
pot urea formation followed by intramolecular cyclization
(
Figure 6).
(
Scheme 2).
Subsequently, substrate scope of the reaction for the
Consequently, the diastereomeric mixture was treated with
synthesis of pyrazino tetrahydroisoquinolines 12 from acyl
methyl isothiocyanate in the presence of K CO in dichloro-
2
3
24
chloride and various amines was investigated (Table 3). All
the desired products were obtained in an excellent yield with
high diastereoselectivity.
methane at room temperature and only a new spot was
1
observed on TLC. Chromatographic isolation and the H
NMR analysis indicated the formation of a single trans-isomer.
Scheme 1. Synthesis of Methyl (S)-2-Amino-3-(3,4-dimethoxyphenyl)propanoate 5{1}
C
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a
Table 1. Optimization of the Reaction Conditions
entry
catalyst (mol %)
base (equiv)
K CO (1.5)
KOtBu (1.5)
solvent
MeOH
time (h)
7{1,1}-cis/7{1,1}-trans
yield (%)
N.R.
1
2
3
4
5
6
7
8
9
24
24
24
24
24
24
48
24
48
36
48
24
2
3
b
CH CN
0
0
0
3
Et N (1.5)
3
CH CN
3
piperidine (20)
p-TSA (20)
CH CN
3
CH CN
4:1
4:1
4:1
4:1
4:1
4:1
4:1
4:1
20
69
62
27
52
43
70
92
3
TiCl (20)
CH CN
4
3
AlCl (20)
CH CN
3
3
BF ·Et O (20)
CH CN
3
2
3
TFA (20)
TFA (20)
TFA (20)
TFA (200)
CH CN
3
10
11
12
toluene
CHCl3
CHCl3
a
Reaction conditions: 5{1} (0.41 mmol), 4-nitrobenzaldehyde 6{1} (0.62 mmol), base (1.5 equiv), catalyst, MgSO (0.41 mmol), solvent (10
4
b
mL), and reflux. Imine formation
Figure 4. ORTEP diagrams of diastereomers 7{1,1}-cis and 7{1,1}-trans. (Atomic displacement ellipsoids are drawn at the 50% probability level.)
Scheme 2. Treatment of 7{1,1}-cis and 7{1,1}-trans with Methyl Isothiocyanate 8{1}
CONCLUSION
afford hydantoin-embedded tetrahydroisoquinolines. Likewise,
the synthesis of diketopiperazine-embedded tetrahydroisoqui-
nolines employed condensation reaction of cis-tetrahydroiso-
quinolines with chloroacetyl chloride, followed by double
nucleophilic addition with primary amines. A direct synthesis,
enantioselectivity, and broad substrate scope are the key
features of this method.
■
In conclusion, a straightforward synthesis of optically pure
hydantoin-fused tetrahydroisoquinolines and diketopiperazine-
fused tetrahydroisoquinolines has developed. Initially, (S)-2-
amino-3-(3,4-dimethoxyphenyl)propanoates were obtained by
a series of functional group transformations from L-Dopa and
reacted with aldehydes via Pictet−Spengler reaction to deliver
tetrahydroisoquinolines as a diastereomeric mixture in 4:1 (cis/
trans) ratio. trans-Tetrahydroisoquinolines were readily reacted
with iso-, isothio-, and isoselenocyanates, and the reaction
proceeded through urea formation, followed by cyclization to
EXPERIMENTAL SECTION
■
General Methods. H NMR (400 MHz) and 13C NMR
1
(101 MHz) spectra were recorded on 400-MR automated
D
DOI: 10.1021/acscombsci.9b00005
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Figure 5. ORTEP diagram of imidazo[1,5-b]isoquinolin-10(6H)-one 9{2,7,2}. (Atomic displacement ellipsoids are drawn at the 50% probability
level.)
spectrometer. Chemical shifts are reported in parts per million
ppm) on the δ scale from an internal standard (TMS).
125.5, 123.6, 111.4, 110.4, 58.0, 55.8, 52.1, 51.8, 30.8; HRMS
+
(
(ESI) m/z [M + H] Calcd for C H N O 373.1400, Found
1
9
21
2
6
2
7
Analytical thin-layer chromatography (TLC) was performed
using 0.25 mm silica gel-coated Kiselgel 60 F254 plates. Flash
chromatography was performed using the indicated solvent
and silica gel 60 (Merck, 230−400 mesh). High-resolution
mass spectra (HRMS) were recorded in ESI mode using TOF
mass spectrometer. IR spectra were obtained using FT-IR
spectrometer. Enantiomeric excess (ee) was determined by
chiral HPLC equipped with a Lux 5 μ cellulose-1 (250 × 4.6
mm) analytical column. Melting point was recorded with
Yanaco micromelting point apparatus and was uncorrected. All
materials were purchased from commercial sources and used
without further purification.
373.1399; [α] = +80.36 (c = 0.004, CH Cl ); HPLC analysis
D 2 2
column- Lux 5 μ cellulose-1 (250 × 4.6 mm), 15% i-PrOH/
−
1
hexane, 0.3 mL min , 254 nm); 99% dr t = 18.1 min; IR
R
−
1
(cm , neat) 3338, 2999, 1517, 1347.
Representative Procedure for the Synthesis of
(5R,10aS)-7,8-Dimethoxy-5-(4-nitrophenyl)-2-pheneth-
yl-3-thioxo-2,3,10,10a-tetrahydroimidazo[1,5-b]-
isoquinolin-1(5H)-one 9{1,1,1}. To the stirred solution of
methyl (1R,3S)-6,7-dimethoxy-1-(4-nitrophenyl)-1,2,3,4-tetra-
hydroisoquinoline-3-carboxylate 7{1,1}-trans (200 mg, 0.537
mmol) in dichloromethane (10 mL) was added K CO (0.22
2
3
mg, 1.611 mmol) and phenethyl isothiocyanate (96 mg, 0.590
mmol) and the reaction mixture was stirred at room
temperature for 8 h. After completion of the reaction, reaction
mixture was filtered and the crude product was purified by
flash column chromatography (20−22% ethyl acetate in
hexanes) to afford (5R,10aS)-7,8-dimethoxy-5-(4-nitrophen-
yl)-2-phenethyl-3-thioxo-2,3,10,10a-tetrahydroimidazo[1,5-b]-
isoquinolin-1(5H)-one 9{1,1,1}.
General Procedure for the Synthesis of Methyl
1R,3S)-Methyl 6,7-dimethoxy-1-(4-nitrophenyl)-
,2,3,4-tetrahydroisoquinoline-3-carboxylate 7{1,1}. To
(
1
a stirred solution of methyl (S)-2-amino-3-(3,4-
dimethoxyphenyl)propanoate 5{1} (1 g, 4.17 mmol) in
chloroform was added 4-nitrobenzaldehyde 6{1} (0.947 g,
6
.26 mmol) and trifluoroacetic acid (200 mmol) at room
1
temperature and the reaction mixture was refluxed for 24 h.
After completion of the reaction, the solvent was evaporated.
The reaction mixture was neutralized with sat. NaHCO3
solution (30 mL) and extracted with dichloromethane (2 ×
Yellow solid, (91%, 191 mg); mp 154−156 °C; H NMR
(400 MHz, CDCl ) δ 8.03 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4
3
Hz, 2H), 7.06−7.16 (m, 5H), 6.88 (s, 1H), 6.68 (s, 1H), 6.38
(s, 1H), 4.19 (dd, J = 11.2 Hz, J = 5.2 Hz, 1H), 3.96−4.03 (m,
2H), 3.81 (s, 3H), 3.63 (s, 3H), 3.19 (dd, J = 16.0 Hz, J = 5.2
Hz, 1H), 2.84−2.98 (m, 2H), 2.92 (dd, J = 12.0 Hz, J = 3.6
2
0 mL). The combined organic layers were washed with brine
solution (20 mL), dried over MgSO , and concentrated in
4
1
3
vacuo. The crude product was purified by flash column
chromatography (15−20% ethyl acetate in hexanes) to afford
Hz, 1H); C NMR (101 MHz, CDCl ) δ 180.0, 172.7, 149.0,
3
148.7, 147.7, 147.6, 137.7, 129.9, 129.0, 128.4, 126.6, 124.3,
123.9, 123.2, 111.3, 110.5, 56.9, 56.0, 56.0, 54.5, 42.4, 33.4,
(
1R,3S)-methyl 6,7-dimethoxy-1-(4-nitrophenyl)-1,2,3,4-tetra-
+
hydroisoquinoline-3-carboxylate 7{1,1} (1.33 g, 86%).
{1,1}-trans. Yellow solid (15%, 120 mg); mp 141−143 °C;
H NMR (400 MHz, CDCl ) δ 8.20 (d, J = 8.0 Hz, 2H), 7.54
30.0; HRMS (ESI) m/z [M + H] Calcd for C H N O S
28
26
3
5
2
7
7
504.1553, Found 504.1587; [α] = −522.69 (c = 0.82,
D
1
3
CH Cl ); HPLC analysis: column- Lux 5 μ cellulose-1 (250 ×
2
2
−
1
(
d, J = 8.0 Hz, 2H), 6.66 (s, 1H), 6.05 (s, 1H), 5.23 (s, 1H),
4.6 mm), 15% i-PrOH/Hexane, 0.8 mL min , 254 nm); 99%
−
1
3
3
1
1
.89 (m, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.59 (s, 3H), 3.06−
ee t = 50.4 min; IR (cm , neat) 3002, 2853, 1748, 1348.
R
.16 (m, 2H), 2.30 (s, 1H); 13C NMR (101 MHz, CDCl ) δ
General Procedure for the Synthesis of (6S,11aS)-8,9-
dimethoxy-6-(4-nitrophenyl)-2-propyl-2,3,11,11a-tetra-
hydro-4H-pyrazino[1,2-b]isoquinoline-1,4(6H)-dione
12{1,1,1}. A solution of methyl (1S,3S)-6,7-dimethoxy-1-(4-
nitrophenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
7{1,1}-cis (0.1 g, 0.268 mmol) and triethylamine (0.029 g,
0.295 mmol) in dichloromethane (15 mL) was cooled at 0 °C.
To the above reaction mixture was added chloroacetyl chloride
(0.088 g, 0.295 mmol) in a dropwise manner and the reaction
mixture was stirred at room temperature for 1 h. After
completion of the reaction, reaction mixture was diluted with
3
72.5, 151.2, 148.1, 147.6, 130.0, 128.3, 126.1, 123.8, 111.5,
10.0, 61.9, 56.0, 55.8, 52.3, 31.9; HRMS (ESI) m/z: [M +
+
27
D
H] Calcd for C H N O 373.1400, Found 373.1399; [α]
1
9
21
2
6
=
−94.44 (c = 0.034, CH Cl ); HPLC analysis: column- Lux 5
2
2
μ cellulose-1 (250 × 4.6 mm), 15% i-PrOH/Hexane, 0.3 mL
min , 254 nm); 99% dr t = 12.1 min; IR (cm neat) 3338,
−
1
−1
R
,
2
999, 1517, 1347.
{1,1}-cis. Yellow solid (77%, 120 mg); mp 126−128 °C;
H NMR (400 MHz, CDCl ) δ 8.16 (d, J = 8.0 Hz, 2H), 7.40
7
1
3
(
d, J = 8.0 Hz, 2H), 6.66 (s, 1H), 6.25 (s, 1H), 5.34 (s, 1H),
3
.88 (s, 3H), 3.76 (dd, J = 8.0 Hz, J = 3.0 Hz, 1H), 3.71 (s,
sat. NaHCO solution (20 mL) and extracted with dichloro-
3
3
H), 3.68 (s, 3H), 3.17 (dd, J = 16.0 Hz, J = 3.0 Hz, 1H), 3.02
dd, J = 20.0 Hz, J = 8.0 Hz, 1H); C NMR (101 MHz,
methane (2 × 10 mL). The combined organic layers were
13
(
washed with brine solution (15 mL), dried over MgSO , and
4
CDCl ) δ 173.6, 151.9, 148.2, 147.7, 147.2, 129.5, 126.6,
concentrated in vacuo. The crude product was purified by flash
3
E
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a
Table 2. Substrate Scope for the Synthesis of Imidazo[1,5-b]isoquinolinones 9
F
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Table 2. continued
a
b
Reaction conditions: 7-trans (0.53 mmol), cyanate 8 (0.59 mmol), K CO (3 equiv), CH Cl (10 mL). NaH (3 equiv) was used.
2
3
2
2
Scheme 3. Treatment of a Mixture of 7{1,1}-cis and 7{1,1}-trans with Acyl Chloride and Amine 11{1}
organic layers were washed with brine solution (15 mL), dried
over MgSO and concentrated under reduced pressure. The
4
crude product was purified by flash column chromatography
(
25−35% ethyl acetate in hexanes) to afford 12{1,1,1}-cis.
1
Yellow solid, (97%, 178 mg); mp 132−134 °C; H NMR
(
400 MHz, CDCl ) δ 8.04 (d, J = 8.9 Hz, 2H), 7.28 (d, J = 8.5
3
Hz, 2H), 6.81 (s, 1H), 6.79 (s, 1H), 6.45 (s, 1H), 4.12 (dd, J =
6.8, 1.0 Hz, 1H), 4.07 (dd, J = 12.6, 4.1 Hz, 1H), 3.94 (d, J =
16.8 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.54−3.46 (m, 1H),
1
Figure 6. ORTEP diagram of pyrazino tetrahydroisoquinoline
2{1,1,4}. (Atomic displacement ellipsoids are drawn at the 50%
probability level.)
1
3
2
0
1
.38 (dt, J = 13.7, 7.2 Hz, 1H), 3.27 (dd, J = 15.8, 4.0 Hz, 1H),
.89 (dd, J = 15.5, 12.5 Hz, 1H), 1.60 (hept, J = 7.4 Hz, 2H),
1
3
.91 (t, J = 7.4 Hz, 3H); C NMR (101 MHz, CDCl ) δ
3
column chromatography (15−20% ethyl acetate in hexanes) to
afford methyl (1S,3S)-2-(2-chloroacetyl)-6,7-dimethoxy-1-(4-
nitrophenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate 10-
cis (0.108 g, 90%). To the stirred solution of 10-cis (0.108 g,
66.7, 166.7, 149.1, 148.7, 148.6, 147.1, 127.4, 126.2, 126.2,
123.8, 111.5, 110.6, 57.6, 56.2, 56.1, 56.0, 50.7, 48.0, 29.8, 20.5,
+
11.1; HRMS (ESI) m/z [M + H] Calcd for C H N O
4
2
3
26
3
6
0
.24 mmol) in dicholoromethane (15 mL) was added propyl
27
40.1816; Found 440.1816; [α]D = −62.19 (c = 0.062,
amine 11{1} (0.071 g, 1.2 mmol), and the reaction mixture
was at room temperature for 24 h. After completion of the
reaction, reaction mixture was diluted with water (15 mL) and
extracted with dichloromethane (2 × 10 mL). The combined
CH Cl ); HPLC analysis column-Lux 5 μ cellulose-1 (250 ×
2
2
−
1
4
.6 mm), 66.7% i-PrOH/hexane, 0.8 mL min , 254 nm); 99%
−
1
ee t = 16.9 min; IR (cm , neat) 3075, 2962, 1669, 1517.
R
G
DOI: 10.1021/acscombsci.9b00005
ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
a
Table 3. Substrate Scope for the Synthesis of Pyrazino[1,2-b]isoquinolinones 11
a
Reaction conditions: Step 1, 7-cis (0.26 mmol), triethyl amine (0.29 mmol), chloroacetyl chloride (0.29 mmol), CH Cl (15 mL); Step 2, 10-cis
2
2
(
0.24 mmol), amine 11 (1.2 mmol), CH Cl (15 mL).
2 2
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscombs-
ci.9b00005.
ACKNOWLEDGMENTS
■
■
*
S
The authors thank Ministry of Science and Technology
(MOST) of Taiwan for financial assistance and the authorities
of the National Chiao Tung University for providing the
laboratory facilities.
Full spectroscopic data ( H, 13C NMR, HRMS, chiral
HPLC, and IR) of compounds 9 and 12 (PDF)
X-ray crystallographic data of compound 7{1,1}-cis
1
REFERENCES
■
(1) Konnert, L.; Lamaty, F.; Martinez, J.; Colacino, E. Recent
Advances in the Synthesis of Hydantoins: The State of the Art of a
Valuable Scaffold. Chem. Rev. 2017, 117, 13757−13809.
(
CCDC 1888820) (CIF)
X-ray crystallographic data of compound 7{1,1}-
trans(CCDC 1888816) (CIF)
X-ray crystallographic data of compound 9{2,7,2}
(
2) Zuo, M.; Xu, X.; Xie, Z.; Ge, R.; Zhang, Z.; Li, Z.; Bian, J. Design
and synthesis of indoline thiohydantoin derivatives based on
enzalutamide as antiproliferative agents against prostate cancer. Eur.
J. Med. Chem. 2017, 125, 1002−1022.
(3) Kim, H. R.; Lee, H. J.; Choi, Y. J.; Park, Y. J.; Woo, Y.; Kim, S. J.;
Park, M. H.; Lee, H. W.; Chun, P.; Chung, H. Y.; Moon, H. R.
Benzylidene-linked thiohydantoin derivatives as inhibitors of
tyrosinase and melanogenesis: importance of the β-phenyl-α,β-
unsaturated carbonyl functionality. MedChemComm 2014, 5, 1410−
1417.
(4) Tran, C.; Ouk, S.; Clegg, N. J.; Chen, Y.; Watson, P. A.; Arora,
V.; Wongvipat, J.; Smith-Jones, P. M.; Yoo, D.; Kwon, A.;
Wasielewska, T.; Welsbie, D.; Chen, C. D.; Higano, C. S.; Beer, T.
M.; Hung, D. T.; Scher, H. I.; Jung, M. E.; Sawyers, C. L.
Development of a Second-Generation Antiandrogen for Treatment of
Advanced Prostate Cancer. Science 2009, 324, 787−790.
(
CCDC 1888845) (CIF)
X-ray crystallographic data of compound 12{1,1,4}
CCDC 1888846) (CIF)
(
AUTHOR INFORMATION
Corresponding Author
E-mail: cmsun@nctu.edu.tw.
■
*
ORCID
Chung-Ming Sun: 0000-0002-1804-1578
Notes
The authors declare no competing financial interest.
H
DOI: 10.1021/acscombsci.9b00005
ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
(
5) (a) Alaejos, M. S.; Díaz Romero, F. J.; Díaz Romero, C.
Selenium and cancer: some nutritional aspects. Nutrition 2000, 16,
76−383. (b) Brown, K. M.; Arhur, J. R. Selenium, selenoproteins
and human health: a review. Public Health Nutr 2001, 4, 593−599.
c) Papp, L. V.; Lu, J.; Holmgren, A.; Khanna, K. From selenium to
pyrimidine-fused 3-alkenyloxindoles as potential anticancer agents.
Tetrahedron Lett. 2016, 57, 4113−4118.
(20) Yempala, T.; Sriram, D.; Yogeeswari, P.; Kantevari, S.
Molecular hybridization of bioactives: Synthesis and antitubercular
evaluation of novel dibenzofuran embodied homoisoflavonoids via
Baylis−Hillman reaction. Bioorg. Med. Chem. Lett. 2012, 22, 7426−
7430.
(21) (a) Bonnet, D.; Ganesan, A. Solid-Phase Synthesis of
Tetrahydro-β-carbolinehydantoins via the N-Acyliminium Pictet−
Spengler Reaction and Cyclative Cleavage. J. Comb. Chem. 2002, 4,
546−548. (b) Van Linn, M. L.; Cook, J. M. Mechanistic Studies on
the Cis to Trans Epimerization of Trisubstituted 1,2,3,4-Tetrahydro-β-
carbolines. J. Org. Chem. 2010, 75, 3587−3599.
(22) (a) Barve, I. J.; Chen, C. H.; Kao, C. H.; Sun, C. M.
Regioselective Piperidine-Catalyzed Tandem Imination−Isocyanate
Annulation to Fused Tricyclic Triazines. ACS Comb. Sci. 2014, 16,
3
(
selenoproteins: synthesis, identity, and their role in human health.
Antioxid. Redox Signaling 2007, 9, 775−806.
(
6) Nakamura, Y.; Feng, Q.; Kumagai, T.; Torikai, K.; Ohigashi, H.;
Osawa, T.; Noguchi, N.; Niki, E.; Uchida, K. Ebselen, a Glutathione
Peroxidase Mimetic Seleno-organic Compound, as a Multifunctional
Antioxidant. J. Biol. Chem. 2002, 277, 2687−2694.
(
7) Ivanenkov, Y. A.; Veselov, M. S.; Rezekin, I. G.; Skvortsov, D. A.;
Sandulenko, Y. B.; Polyakova, M. V.; Bezrukov, D. S.; Vasilevsky, S.
V.; Kukushkin, M. E.; Moiseeva, A. A.; Finko, A. V.; Koteliansky, V.
E.; Klyachko, N. L.; Filatova, L. A.; Beloglazkina, E. K.; Zyk, N. V.;
Majouga, A. G. Synthesis, isomerization and biological activity of
novel 2-selenohydantoin derivatives. Bioorg. Med. Chem. 2016, 24,
2
44−249. (b) Barve, I. J.; Dalvi, P. B.; Thikekar, T. U.; Chanda, K.;
Liu, Y. L.; Fang, C. P.; Liu, C. C.; Sun, C. M. Design, synthesis and
diversification of natural product-inspired hydantoin-fused tetrahy-
droazepino indoles. RSC Adv. 2015, 5, 73169−73179.
8
(
02−811.
8) Walpole, C. S. J.; Bevan, S.; Bovermann, G.; Boelsterli, J. J.;
Breckenridge, R.; Davies, J. W.; Hughes, G. A.; James, I.; Oberer, L.;
Winter, J.; Wrigglesworth, R. The Discovery of Capsazepine, the First
Competitive Antagonist of the Sensory Neuron Excitants Capsaicin
and Resiniferatoxin. J. Med. Chem. 1994, 37, 1942−1954.
(
23) Chang, W. J.; Kulkarni, M. V.; Sun, C. M. Regioselective one-
pot three component synthesis of chiral 2-iminoselenazolines under
sonication. RSC Adv. 2015, 5, 97113−97120.
(24) When the reaction was carried out using 3-chloropropionyl
(
9) Neubauer, D. N. Almorexant, A dual orexin receptor antagonist
for the treatment of insomnia. Curr. Opin. Investig. Drugs 2010, 11,
01−110.
10) Naoi, M.; Maruyama, W.; Nagy, G. M. Dopamine-derived
chloride, only O- and N-acryloylated product was obtained via
dehydrochlorination.
1
(
salsolinol derivatives as endogenous monoamine oxidase inhibitors:
occurrence, metabolism and function in human brains. Neuro-
Toxicology 2004, 25, 193−204.
(
11) Borthwick, A. D. 2,5-Diketopiperazines: Synthesis, Reactions,
Medicinal Chemistry, and Bioactive Natural Products. Chem. Rev.
012, 112, 3641−3716.
12) Crescenzi, O.; Fraternali, F.; Picone, D.; Tancredi, T.; Balboni,
2
(
G.; Guerrini, R.; Lazarus, L. H.; Salvadori, S.; Temussi, P. A. Design
and solution structure of a partially rigid opioid antagonist lacking the
basic center- Models of antagonism. Eur. J. Biochem. 1997, 247, 66−
7
(
3.
13) Viegas, C., Jr.; Danuello, A.; da Silva Bolzani, V.; Barreiro, E. J.;
Fraga, C. A. Molecular Hybridization: A Useful Tool in the Design of
New Drug Prototypes. Curr. Med. Chem. 2007, 14, 1829−1852.
(
14) Kamins
Kiec-
evaluation of new hybrid anticonvulsants derived from N-benzyl-2-
2,5-dioxopyrrolidin-1- yl)propanamide and 2-(2,5-dioxopyrrolidin-1-
yl)butanamide derivatives. Bioorg. Med. Chem. 2015, 23, 2548−2561.
15) Bharkavi, C.; Vivek Kumar, S.; Ashraf Ali, M.; Osman, H.;
́
ki, K.; Rapacz, A.; Łuszczki, J. J.; Latacz, G.; Obniska, J.;
́
Kononowicz, K.; Filipek, B. Design, synthesis and biological
(
(
Muthusubramanian, S.; Perumal, S. A facile stereoselective synthesis
of dispiro-indeno pyrrolidine/ pyrrolothiazole−thiochroman hybrids
and evaluation of their antimycobacterial, anticancer and AchE
inhibitory activities. Bioorg. Med. Chem. 2016, 24, 5873−5883.
(
16) Sashidhara, K. V.; Kumar, M.; Khedgikar, V.; Kushwaha, P.;
Modukuri, R. K.; Kumar, A.; Gautam, J.; Singh, D.; Sridhar, B.;
Trivedi, R. Discovery of Coumarin−Dihydropyridine Hybrids as Bone
Anabolic Agents. J. Med. Chem. 2013, 56, 109−122.
(
17) Anumala, U. R.; Waaler, J.; Nkizinkiko, Y.; Ignatev, A.;
Lazarow, K.; Lindemann, P.; Olsen, P. A.; Murthy, S.; Obaji, E.;
Majouga, A. G.; Leonov, S.; von Kries, J. P.; Lehtio, L.; Krauss, S.;
Nazare, M. Discovery of a Novel Series of Tankyrase Inhibitors by a
Hybridization Approach. J. Med. Chem. 2017, 60, 10013−10025.
18) Bahia, S. B. B. B.; Reis, W. J.; Jardim, G. A. M.; Souto, F. T.; de
Simone, C. A.; Gatto, C. C.; Menna-Barreto, R. F. S.; de Castro, S. L.;
Cavalcanti, B. C.; Pessoa, C.; Araujo, M. H.; da Silva Junior, E. N.
̈
́
(
́
Molecular hybridization as a powerful tool towards multitarget
quinoidal systems: synthesis, trypanocidal and antitumor activities of
naphthoquinone-based 5-iodo-1,4-disubstituted-1,4- and 1,5-disubsti-
tuted-1,2,3-triazoles. MedChemComm 2016, 7, 1555−1563.
(
19) Liu, X. L.; Feng, T. T.; Wang, D. D.; Liu, H. H.; Yang, C.; Li, X.
N.; Lin, B.; Zhao, Z.; Zhou, Y. Synthesis and in vitro evaluation of
I
DOI: 10.1021/acscombsci.9b00005
ACS Comb. Sci. XXXX, XXX, XXX−XXX