A diastereoselective construction of pyrazinoisoquinoline skeletons via tandem cyclization of phenylalanine derivatives: A facile synthesis of optically active pyrazinoisoquinolines

Article abstract of DOI:10.1016/j.tet.2014.04.045

A facile and stereocontrolled construction of optically active pyrazinoisoquinoline skeletons based on tandem cyclization of enantiopure phenylalanine derivatives was examined. The reaction provided optically active 6,11b-trans pyrazinoisoquinoline ring systems in excellent diastereoselectivity, and this method was applicable to the cyclization of phenylalanine derivatives with diverse substituents.

Full text of DOI:10.1016/j.tet.2014.04.045

Tetrahedron xxx (2014) 1e7
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Tetrahedron
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A diastereoselective construction of pyrazinoisoquinoline skeletons
via tandem cyclization of phenylalanine derivatives: a facile
synthesis of optically active pyrazinoisoquinolines
*
Maki Seki , Tsuyoshi Ogiku
Medicinal Chemistry Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama
227-0033, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and stereocontrolled construction of optically active pyrazinoisoquinoline skeletons based on
tandem cyclization of enantiopure phenylalanine derivatives was examined. The reaction provided op-
tically active 6,11b-trans pyrazinoisoquinoline ring systems in excellent diastereoselectivity, and this
method was applicable to the cyclization of phenylalanine derivatives with diverse substituents.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 25 February 2014
Received in revised form 12 April 2014
Accepted 14 April 2014
Available online xxx
Keywords:
PicteteSpengler cyclization
1,3-Chirality transfer
N-Acyliminium ion
Pyrazinoisoquinolines
1. Introduction
A series of pyrazinoisoquinoline derivatives is of considerable
interest recently because of their various biological activities, such
as antischistosomal, antifungal, and antiprotozoal actions.1 The
skeleton is a simple tricyclic ring system possessing a stereogenic
center at C-11b, which are closely related to biological differences.1a
Whereas synthetic routes for racemic pyrazinoisoquinolines have
intensively been studied, only several methods for the construction
of the optically active ring systems have been reported, in which
the PicteteSpengler cyclization employing chiral auxiliaries2 or
amino acids3 as chiral inductors, radical cyclization from peptide
acetals,4 and asymmetric transfer hydrogenation of dihy-
droisoquinoline using a chiral catalyst5 were utilized as a key step.
However, these approaches by the PicteteSpengler cyclization,
one of the most widely used method in this field, have difficulty in
synthesizing optically active pyrazinoisoquinolines with diversity.
A chiral auxiliary mediated PicteteSpengler reaction of phenyl-
ethylamines generally requires alkoxy or hydroxy groups on the
aromatic ring (Fig. 1a) and thus has limitations in synthesizing
tetrahydroisoquinolines without electron-donating substituents
(Fig. 1b) as described by Koomen et al.6 In fact, almost all the
(a)
(b)
Fig. 1. Reported asymmetric PicteteSpengler cyclization.
reported methods using asymmetric or stereocontrolled Pictete-
Spengler cyclization2b,3 were limited to synthesizing pyr-
azinoisoquinolines bearing alkoxyl groups.7 In addition, most of the
approaches required multistep processes for the construction of the
tricyclic ring systems due to stepwise cyclization.
N-Acyliminium ions are versatile intermediates particularly for
the synthesis of natural alkaloids.8 It has been reported that
intramolecular reactions of cyclic N-acyliminium ions with
p-nu-
cleophiles led to a preference for the formation of 1,3-trans prod-
ucts due to steric control by the substituents already present in the
ring9 or along the chain connecting the
p-nucleophile and nitrogen
atom.10 We envisage that (i) the tricyclic ring system would be
constructed in one step from amido-acetal 1 that generates a cyclic
* Corresponding author. Tel.: þ81 45 963 7239; fax: þ81 45 963 7257; e-mail
address: Seki.Maki@ma.mt-pharma.co.jp (M. Seki).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.045
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2
M. Seki, T. Ogiku / Tetrahedron xxx (2014) 1e7
N-acyliminium ion intermediate in situ by the PicteteSpengler cy-
clization and (ii) incorporation of enantiopure amino acid as a chi-
ral inductor into 1 would introduce a new chiral center during the
ring-closing step through 1,3-chirality transfer preferentially to
afford a 6,11b-trans pyrazinoisoquinoline skeleton (Scheme 1). Our
goal is an effective synthesis of optically active pyrazinoisoquino-
line derivatives with diverse sets of electron-donating and
electron-withdrawing substituents on the aromatic ring. In this
paper, we report a stereocontrolled construction of 6R,11bR-trans
pyrazinoisoquinoline skeletons based on our new approach from
substituted D-phenylalanines.
Scheme 2. Synthesis of amido-acetal 1.
Table 1
The PicteteSpengler cyclization of 1a
Entry Acid
Solvent Temperature Yield
Diastereomeric
of 4a (%)b excess (%)c
1
2
3
4
5
6
7
8
H2SO4 (concd)d
d
rt
rt
rt
rt
rt
rt
70 ꢂC
70 ꢂC
58
80
47h
di
5
26
80
63
96.1
99.0
74.7
d
CH3SO3H
CF3SO3H
TFA
d
d
d
Scheme 1. The PicteteSpengler reaction of a cyclic N-acyliminium ion intermediate.
e
TiCl4
CH2Cl2
CH2Cl2
d
98.2
98.9
97.4
97.3
e
BF3$OEt2
CH3SO3Hf
CH3SO3Hg
d
2. Results and discussion
a
Unless otherwise noted, the reaction was carried out with 1 (0.3 mmol) and acid
To examine suitable conditions for the stereocontrolled Pic-
teteSpengler-type cyclization, amido-acetal 1 as an N-acyliminium
(3 mmol) for 48 h.
b
Isolated yield after column chromatography.
Determined by HPLC analysis of the crude product mixture.
H2SO4 (1.8 mmol), 14 h.
TiCl4 (1.5 mmol) or BF3$OEt2 (1.5 mmol) in CH2Cl2 (2 mL).
0.5 h.
13 h.
c
ion precursor was prepared from
D-phenylalanine methyl ester
d
hydrochloride (2) (Scheme 2). Treatment of chloroacetyl chloride
with 2, followed by amination of 3 using aminoacetaldehyde di-
methyl acetal afforded 1 in a good yield. Then, Brønsted or Lewis
acid was employed as a catalyst to generate the cyclic N-acylimi-
nium ion intermediate and to promote subsequent cyclization. The
results are listed in Table 1. All acids except CF3SO3H and TFA pro-
vided the desired product, 4a, as a single isomer at room temper-
ature.11 Concentrated H2SO4 afforded 4a smoothly in a moderate
yield (entry 1).12 CH3SO3H gave the highest level of the yield and
diastereoselectivity (entry 2). Under the lower acidic conditions,
none of the cyclized products was obtained probably due to de-
composition of the N-acyliminium ion intermediate (entry 4),
whereas increased acidity lowered the diastereoselectivity (entry
3). Although the elevation of reaction temperature accelerated cy-
clization using CH3SO3H, the diastereoselectivity slightly decreased
(entry 7). Moreover, elongated reaction time under heat conditions
resulted in a lowering of the yield of 4a and an increase in degra-
dation products (entry 8). Compared to Brønsted acids, Lewis acids
gave 4a in lower yields (entries 5 and 6).
e
f
g
h
Compound 4b was isolated in 8% yield.
The cyclized products were not detected.
i
proton at 4.99 ppm and C-6 proton at 5.73 ppm, whereas a selective
excitation of the C-11b proton resulted in an observation of NOE
crosspeaks at the methyl ester protons (3.66 ppm) in the 1D NOESY
experiment, suggesting that the relative conformation of 4a is
6,11b-trans. In addition, 4a was converted into (R)-(ꢀ)-praziquantel
in two steps to confirm its stereochemistry unequivocally (Scheme
3). Thus, hydrolysis of 4a with hydrochloric acid, followed by N-
acylation with cyclohexanecarbonyl chloride provided 5 in 67%
yield. Compound 5 was subjected to the Barton decarboxylation13
to give 6 in 52% yield and high enantiomeric excess (ꢁ99.5%),
which was confirmed by chiral HPLC in comparison with the ra-
cemic sample, and its physical and spectroscopic data were iden-
tical with the reported data for (R)-(ꢀ)-praziquantel.1a,5,14 On the
basis of these results, the stereochemistry of 4a was confirmed as
6R,11bR-trans.
The relative conformation of 4a and 4b was implied by NOESY
experiments. The 2D NOESY of minor isomer 4b (cis) showed
a
decisive correlation neither between the C-11b proton at
The high stereoselectivity observed in this cyclization is eluci-
dated by the difference of transition states determining a favorable
attack of the aromatic ring onto the face of the N-acyliminium ion
intermediate (Scheme 4). Thus, the cyclization pathway would
4.62 ppm and C-6 proton at 4.98 ppm nor between the C-11b
proton and methyl ester protons at 3.53 ppm. In contrast, that of 4a
(trans) did not show a decisive correlation between the C-11b
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M. Seki, T. Ogiku / Tetrahedron xxx (2014) 1e7
3
bearing the electron-withdrawing group (p-Cl), which was much
less nucleophilic in the ring-closing step did not provide the
cyclized product (entry 4). Unlike the reaction of 1, elevated re-
action temperature in the CH3SO3H-catalyzed cyclization of 11c
resulted in a decomposition of 11c and/or the N-acyliminium ion
intermediate, and the cyclized product was not obtained (entry
5). In contrast, it was found that H2SO4 was sufficient for clean
conversion in the case of electron-deficient substrates 11cee
(Table 2, entry 6e8, condition B), and the desired products 12cee
were obtained as a single isomer in moderate yields (43e61%).
However, treatment of 11b in the presence of H2SO4 afforded
a complex mixture instead of the cyclized product 12b, probably
because this cyclization conditions toward 11b led to a polymer-
ization of 11b and/or the N-acyliminium ion intermediate. Al-
though mildly acidic conditions were employed for the
cyclization of 11b, the desired product 12b was not obtained.
Thus, treatment of 11b with CH3SO3H in dichloromethane (entry
3) gave unreacted amido-acetal and 12b, which was inseparable
from a complex product mixture. Treatment of 11b with TFA also
afforded a complex product mixture and unreacted amido-acetal,
and none of the cyclized products was detected in the crude
product by 1H NMR and LC/MS. We suppose that the low re-
activity of 11b would result from a mesomeric effect of the
methoxy group on the meta position. The cyclization using
CH3SO3H and H2SO4 provided the desired trans products in ex-
cellent diastereoselectivity.16
Scheme 3. Conversion of 4a into (R)-(ꢀ)-praziquantel.
3. Conclusions
In conclusion, a facile and stereocontrolled construction of op-
tically active pyrazinoisoquinoline skeletons via tandem cyclization
of phenylalanine derivatives was achieved. The Brønsted acid-
catalyzed PicteteSpengler reaction of cyclic N-acyliminium ion
intermediates readily generated from
D-phenylalanines directly
provided 6R,11bR-trans pyrazinoisoquinolines in excellent diaster-
eoselectivity through 1,3-chirality transfer. Furthermore, electron-
deficient phenylalanine derivatives successfully cyclized using
H2SO4 as an acid catalyst to afford the desired products in satis-
factory yields and excellent diastereoselectivity. Therefore, this
method is applicable to the synthesis of optically active pyr-
azinoisoquinolines with diverse functional groups and would pro-
vide easy access to a wide range of pharmacologically interesting
pyrazinoisoquinolines.
4. Experimental
4.1. General
Scheme 4. Stereochemical outcome of N-acyliminium cyclization.
€
Melting point (mp) was determined on a Buchi B-535 melting
point apparatus and uncorrected. 1H and 13C NMR spectra were
proceed via a chair-like transition state (A or B), and conformation
B would be disfavored because of A(1,3) strain between the pseudo-
equatorial carbomethoxy and piperazinone carbonyl groups in the
transition state.15
recorded on a Bruker AVANCE 400 or AVANCE 600 spectrometer,
and chemical shifts were expressed in
d (ppm) values with tetra-
methylsilane as an internal standard. IR spectra were obtained with
a PerkinElmer Spectrum One FT-IR spectrometer. Analytical HPLC
Substituted N-acyliminium ion precursors 11aee were then
subjected to the optimized PicteteSpengler conditions to clarify
scope and limitations. Compounds 11aee were prepared by the
same procedure as described in Scheme 2 from 9aee, which were
was conducted on a Capcellpak C18 column (5
m
m, 4.6ꢃ250 mm)
eluted with 0.05% (v/v) TFA in water (solvent A) and 0.05% (v/v) TFA
in acetonitrile (solvent B), according to the following elution gra-
dient: 5e100% B over 40 min at a flow rate of 1.0 mL/min. LC/MS
spectra were recorded on a Waters LC/MS system using a Acquity
UPLC BEH C18 column (2ꢃ50 mm) coupled with micromass ZQ as
a MS detector, and the elution gradient of 5e98% B over 1 min was
used. HRMS spectra were recorded on a LTQ Orbitrap Velos Pro
mass spectrometer equipped with an ESI Lockspray source for ac-
curate mass values. Specific optical rotations were recorded on
a Jasco P-2000 polarimeter.
derivatized from commercially available -phenylalanines 7aec
D
and 8a,b (Scheme 5). CH3SO3H was applied as a catalyst for the
PicteteSpengler cyclization of para-substituted 11aec (Table 2,
condition A). The cyclization reaction of 11a bearing the methyl
group proceeded smoothly to give 12a in a high yield (entry 1),
whereas that of 11b bearing the electron-donating group (p-
methoxy) afforded 12b in a low yield (entry 2) and that of 11c
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M. Seki, T. Ogiku / Tetrahedron xxx (2014) 1e7
Scheme 5. Synthesis of amido-acetals 11aee.
Table 2
9a as a colorless solid, which was used in the next step without
Scope and limitations of the PicteteSpengler cyclization
further purification.
4.2.1.1. (R)-4-Methylphenylalanine methyl ester hydrochloride
(9a). 1H NMR (400 MHz, DMSO-d6)
d
: 2.28 (s, 3H), 3.05 (dd, J¼13.9,
6.1 Hz, 1H), 3.13 (dd, J¼13.9, 6.7 Hz, 1H), 3.67 (s, 3H), 4.23 (t,
J¼6.4 Hz, 1H), 7.10e7.16 (m, 4H), 8.58 (br s, 3H); LC/MS (ESI) m/z:
194.3 [MþH]þ.
a 2D5
c
Conditionsa
Product (yield)b
½ ꢄ
4.2.1.2. (R)-3-Chlorophenylalanine methyl ester hydrochloride
Entry
Amido-acetal 11
(9d). Yield 94%, amorphous solid. 1H NMR (400 MHz, DMSO-d6)
d:
1
2
3
4
5
6
7
8
11a (R¼4-Me)
11b (R¼4-OMe)
11b (R¼4-OMe)
11c (R¼4-Cl)
11c (R¼4-Cl)
11c (R¼4-Cl)
11d (R¼3-Cl)
11e (R¼2-Cl)
A
12a: R¼10-Me (80%)
12b: R¼10-OMe (18%)
dg
dh
dh
ꢀ149.8
ꢀ188.3
d
Ad
Ae
A
3.10 (d, J¼6.2 Hz, 2H), 3.71 (s, 3H), 4.38 (t, J¼6.0 Hz, 1H), 7.19e7.20
(m, 1H), 7.35e7.40 (m, 3H), 8.38 (br s, 3H); LC/MS (ESI) m/z: 214.3
[MþH]þ.
d
Af
B
d
12c: R¼10-Cl (61%)
12d: R¼9-Cl (61%)
12e: R¼8-Cl (43%)
ꢀ153.3
ꢀ164.5
ꢀ147.8
4.2.2. Synthesisof 9b,c,e. To a solution of (R)-N-(tert-butoxycarbonyl)-
4-methoxyphenylalanine (7a) (1.0 g, 3.4 mmol) in DMF (10 mL) was
added K2CO3 (0.51 g, 3.7 mmol) and iodomethane (0.22 mL,
3.6 mmol). After stirring at room temperature for 3 h, H2O was added,
and the whole was extracted with diethyl ether. The extract was dried
over anhydrous MgSO4, and the solvent was evaporated under re-
duced pressure to give crude N-Boc-phenylalanine methyl ester. To
a solution of the obtained compound in EtOAc (5 mL) was added 4 M
HCl/EtOAc solution (15 mL). After stirring for 3 h at room temperature,
the solution was evaporated under reduced pressure. The resulting
precipitate was collected by filtration and washed with diethyl ether
to give 9b as a colorless solid (0.72 g, 92% yield).
B
B
a
Unless otherwise noted, the reaction was carried out under the following con-
ditions. Condition A: amido-acetal 11 (0.3 mmol) and CH3SO3H (3 mmol) at room
temperature for 48 h. Condition B: amido-acetal 11 (0.3 mmol) and concentrated
H2SO4 (1.8 mmol) at room temperature for 14 h.
b
Isolated yield after column chromatography.
c 0.5, CHCl3.
8 h.
CH3SO3H (1.5 mmol) in CH2Cl2 (0.2 mL).
70 ꢂC, 1 h.
Complex mixture.
The cyclized product was not detected.
c
d
e
f
g
h
4.2.2.1. (R)-4-Methoxyphenylalanine methyl ester hydrochloride
4.2. Synthesis of
D-phenylalanine methyl ester hydrochlorides
(9b). Yield 92%, colorless solid. Mp 181e182 ꢂC; 1H NMR (400 MHz,
9aee
DMSO-d6)
d
: 3.03 (dd, J¼13.8, 6.7 Hz,1H), 3.10 (dd, J¼13.9, 5.9 Hz,1H),
3.68 (s, 3H), 3.74 (s, 3H), 4.22 (t, J¼6.6 Hz, 1H), 6.89 (d, J¼8.7 Hz, 2H),
4.2.1. Synthesis of 9a,d. Acetyl chloride (1.0 mL, 14.1 mmol) was
7.15 (d, J¼8.7 Hz, 2H), 8.56 (br s, 3H); LC/MS (ESI) m/z: 210.3 [MþH]þ.
added dropwise to MeOH (15 mL) at 0 ꢂC. After stirring for 15 min at
0
ꢂC,
D
-4-methylphenylalanine (8a) (1.0 g, 5.6 mmol) was added,
4.2.2.2. (R)-4-Chlorophenylalanine methyl ester hydrochloride
and the reaction mixture was heated to reflux for 38 h. After
(9c). Yield 95%, colorless solid. Mp 202e203 ꢂC; 1H NMR (400 MHz,
cooling, the solvent was evaporated under reduced pressure to give
DMSO-d6)
d
: 3.15 (ddd, J¼22.9, 14.2, 6.7 Hz, 2H), 3.69 (s, 3H), 4.29 (t,
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M. Seki, T. Ogiku / Tetrahedron xxx (2014) 1e7
5
J¼6.7 Hz, 1H), 7.28 (d, J¼8.7 Hz, 2H), 7.39e7.42 (m, 2H), 8.64 (br s,
(400 MHz, CDCl3)
d
: 3.10 (dd, J¼13.9, 6.2 Hz, 1H), 3.16 (dd, J¼13.9,
3H); LC/MS (ESI) m/z: 214.2 [MþH]þ.
5.7 Hz, 1H), 3.76 (s, 3H), 4.04 (s, 2H), 4.86 (dt, J¼7.7, 5.9 Hz, 1H),
6.99e7.02 (m, 2H), 7.12 (s, 1H), 7.24e7.26 (m, 2H); 13C NMR
4.2.2.3. (R)-2-Chlorophenylalanine methyl ester hydrochloride
(100 MHz, CDCl3) d: 37.50, 42.38, 52.64, 53.27, 127.39, 127.60,
(9e). Yield 98%, colorless solid. Mp 155 ꢂC; 1H NMR (400 MHz,
129.45, 129.94, 134.51, 137.43, 165.66, 170.98; IR (ATR) n 3299, 3063,
DMSO-d6)
d
: 3.26 (ddd, J¼24.1, 13.9, 7.7 Hz, 2H), 3.61 (s, 3H), 4.17
2954,1740,1661,1527,1477,1435,1361,1214,1179,1080 cmꢀ1; HPLC
(dd, J¼8.7, 6.6 Hz, 1H), 7.32e7.36 (m, 2H), 7.38e7.42 (m, 1H),
(220 nm) 92.9% (tR¼23.8 min); LC/MS (ESI) m/z: 290.3 [MþH]þ.
7.45e7.50 (m, 1H), 8.73 (br s, 3H); LC/MS (ESI) m/z: 214.2 [MþH]þ.
4.3.6. (R)-N-(2-Chloroacetyl)-2-chlorophenylalanine methyl ester
4.3. Synthesis of (R)-N-(2-chloroacetyl)phenylalanine methyl
esters 3 and 10aee
(10e). Yield 95%, colorless oil. ½a D25
ꢄ
ꢀ21.6 (c 0.5, CHCl3); 1H NMR
(400 MHz, CDCl3)
d
: 3.21 (dd, J¼13.9, 7.7 Hz, 1H), 3.37 (dd, J¼13.9,
6.1 Hz, 1H), 3.75 (s, 3H), 3.99 (dd, J¼22.4, 15.2 Hz, 2H), 4.90 (dt,
To a solution of -phenylalanine methyl ester hydrochloride (2)
D
J¼8.0, 5.6 Hz, 1H), 7.05 (br s, 1H), 7.18e7.23 (m, 3H), 7.36e7.39 (m,
(10.0 g, 46.4 mmol) and Et3N (14 mL, 102 mmol) in CH2Cl2 (100 mL)
was added chloroacetyl chloride (4.4 mL, 55.6 mmol) at 0 ꢂC. After
stirring at room temperature for 1 h, H2O was added, and the whole
was extracted with CHCl3. The extract was dried over anhydrous
MgSO4, and the solvent was evaporated under reduced pressure.
The residue was purified by silica gel column chromatography
(0e50% hexane/EtOAc) to give 3 as colorless oil (11.8 g, 99% yield).
1H); 13C NMR (100 MHz, CDCl3)
d: 35.37, 42.33, 52.68, 52.74, 127.04,
128.84, 129.78, 131.30, 133.66, 134.50, 165.73, 171.30; IR (ATR)
n
3300, 3063, 2954, 1741, 1661, 1527, 1476, 1436, 1363, 1265, 1214,
1178, 1053 cmꢀ1; HPLC (220 nm) 94.3% (tR¼23.0 min); LC/MS (ESI)
m/z: 290.3 [MþH]þ.
4.4. Synthesis of amido-acetals 1 and 11aee
4.3.1. (R)-N-(2-Chloroacetyl)phenylalanine
methyl
ester
To a solution of 3 (5.0 g, 19.6 mmol) in CH2Cl2 (50 mL) was added
NaI (2.9 g, 19.6 mmol) and aminoacetaldehyde dimethyl acetal
(4.3 mL, 40.1 mmol). After stirring at room temperature for 24 h,
additional aminoacetaldehyde dimethyl acetal (2.1 mL, 19.6 mmol)
was added, and the reaction mixture was stirred at room temper-
ature for 24 h. The whole was washed with H2O, and the aqueous
layer was extracted with CH2Cl2. The extract was dried over an-
hydrous MgSO4, and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel column chroma-
tography (0e5% CHCl3/MeOH) to give 1 as colorless oil (4.7 g, 74%
yield).
(3). Colorless oil. ½a D25
ꢄ
ꢀ54.4 (c 0.5, CHCl3); 1H NMR (400 MHz,
CDCl3)
d
: 3.15 (ddd, J¼20.1, 13.9, 6.2 Hz, 2H), 3.74 (s, 3H), 4.03 (dd,
J¼17.0, 15.4 Hz, 2H), 4.87 (dt, J¼8.2, 6.2 Hz, 1H), 6.95 (br s, 1H),
7.11e7.13 (m, 2H), 7.24e7.33 (m, 3H); 13C NMR (100 MHz, CDCl3)
37.79, 42.37, 52.49, 53.38, 127.35, 128.70, 129.20, 135.30, 165.55,
171.23; IR (ATR) 3326, 3031, 2944, 1728, 1645, 1536, 1496, 1446,
d:
n
1368, 1350, 1225, 1205, 1154, 1117 cmꢀ1; HRMS (ESI) calcd for
C
12H15ClNO3 ([MþH]þ): 256.0735, found: 256.0732.
4.3.2. (R)-N-(2-Chloroacetyl)-4-methylphenylalanine methyl ester
(10a). Yield 73% from 8a, colorless oil. ½a D25
ꢄ
ꢀ57.0 (c 0.5, CHCl3); 1H
NMR (400 MHz, CDCl3)
d
: 2.32 (s, 3H), 3.11 (ddd, J¼18.0,13.9, 5.6 Hz,
4.4.1. (R)-N-[N-(2,2-Dimethoxyethyl)glycinyl]phenylalanine methyl
2H), 3.74 (s, 3H), 4.03 (dd, J¼15.9, 15.4 Hz, 2H), 4.84 (dt, J¼7.8,
ester (1). Colorless oil. ½a D25
ꢄ
ꢀ43.2 (c 0.5, CHCl3); 1H NMR
5.6 Hz, 1H), 6.94 (br s, 1H), 6.99 (d, J¼7.7 Hz, 2H), 7.11 (d, J¼7.7 Hz,
(400 MHz, CDCl3)
d
: 2.60 (dd, J¼12.3, 5.7 Hz, 1H), 2.66 (dd, J¼12.3,
2H); 13C NMR (100 MHz, CDCl3)
d
: 21.09, 37.36, 42.42, 52.48, 53.44,
5.1 Hz, 1H), 3.10 (dd, J¼13.8, 6.7 Hz, 1H), 3.18 (dd, J¼13.8, 6.1 Hz,
1H), 3.26 (dd, J¼22.2, 17.2 Hz, 2H), 3.34 (s, 3H), 3.35 (s, 3H), 3.73 (s,
3H), 4.31 (t, J¼5.4 Hz, 1H), 4.88 (dt, J¼8.2, 6.2 Hz, 1H), 7.13 (d,
J¼6.7 Hz, 2H), 7.23e7.32 (m, 3H), 7.64 (d, J¼8.2 Hz, 1H); 13C NMR
129.08, 129.43, 132.13, 136.99, 165.56, 171.33; IR (ATR) n 3342, 3023,
2942, 1730, 1655, 1533, 1445, 1368, 1353, 1261, 1229, 1150,
1119 cmꢀ1; HPLC (220 nm) 99.6% (tR¼23.4 min); LC/MS (ESI) m/z:
270.3 [MþH]þ.
(100 MHz, CDCl3) d: 37.91, 50.92, 52.12, 52.27, 52.60, 54.02, 54.04,
103.45, 127.08, 128.55, 129.18, 136.01, 171.39, 172.00; IR (ATR)
n
4.3.3. (R)-N-(2-Chloroacetyl)-4-methoxyphenylalanine methyl ester
3335, 2951, 2833, 1741, 1668, 1512, 1455, 1439, 1361, 1197, 1126,
1056 cmꢀ1; HRMS (ESI) calcd for C16H25N2O5 ([MþH]þ): 325.1758,
found: 325.1754.
(10b). Yield 94%, colorless oil. ½a D25
ꢄ
ꢀ56.4 (c 0.5, CHCl3); 1H NMR
(400 MHz, CDCl3)
d
: 3.10 (ddd, J¼16.5, 13.9, 5.7 Hz, 2H), 3.74 (s, 3H),
3.79 (s, 3H), 4.03 (dd, J¼16.2, 15.2 Hz, 2H), 4.83 (dt, J¼8.2, 5.7 Hz,
1H), 6.83e6.86 (m, 2H), 6.95 (br s, 1H), 7.03 (d, J¼8.7 Hz, 2H); 13C
4.4.2. (R)-N-[N-(2,2-Dimethoxyethyl)glycinyl]-4-methylphenylalanine
NMR (100 MHz, CDCl3)
d
: 36.96, 42.42, 52.48, 53.52, 55.23, 114.14,
methyl ester (11a). Yield 79%, colorless oil. ½a D25
ꢀ43.2 (c 0.5, CHCl3);
ꢄ
127.22, 130.25, 158.88, 165.55, 171.34; IR (ATR)
n
3300, 3006, 2954,
1H NMR (400 MHz, CDCl3)
d
: 2.31 (s, 3H), 2.60 (dd, J¼12.3, 5.7 Hz,
2838, 1741, 1662, 1612, 1511, 1439, 1364, 1245, 1215, 1177, 1118,
1031 cmꢀ1; HPLC (220 nm) 98.6% (tR¼21.0 min); LC/MS (ESI) m/z:
286.3 [MþH]þ.
1H), 2.66 (dd, J¼12.3, 5.1 Hz, 1H), 3.06 (dd, J¼13.8, 6.7 Hz, 1H), 3.13
(dd, J¼13.8, 6.2 Hz, 1H), 3.26 (dd, J¼21.5, 16.9 Hz, 2H), 3.34 (s, 3H),
3.35 (s, 3H), 3.73 (s, 3H), 4.31 (t, J¼5.4 Hz,1H), 4.85 (dt, J¼8.2, 6.2 Hz,
1H), 7.01 (d, J¼7.7 Hz, 2H), 7.09 (d, J¼7.7 Hz, 2H), 7.61 (d, J¼8.2 Hz,
4.3.4. (R)-N-(2-Chloroacetyl)-4-chlorophenylalanine methyl ester
1H); 13C NMR (100 MHz, CDCl3)
d: 21.06, 37.50, 50.94, 52.17, 52.26,
a 25
(10c). Yield 99%, colorless oil. ½ ꢄD ꢀ53.8 (c 0.5, CHCl3); 1H NMR
52.68, 54.02, 103.48, 129.07, 129.29, 132.86, 136.66, 171.38, 172.09; IR
(400 MHz, CDCl3)
d
: 3.10 (dd, J¼13.9, 5.6 Hz, 1H), 3.16 (dd, J¼13.9,
(ATR) n 3334, 2950, 2833, 1742, 1668, 1513, 1441, 1362, 1197, 1126,
5.6 Hz, 1H), 3.75 (s, 3H), 4.03 (dd, J¼16.4, 15.4 Hz, 2H), 4.86 (dt,
J¼7.9, 5.6 Hz, 1H), 6.96 (br s, 1H), 7.03e7.06 (m, 2H), 7.26e7.30 (m,
1056 cmꢀ1; HPLC (220 nm) 99.1% (tR¼18.6 min); LC/MS (ESI) m/z:
339.5 [MþH]þ.
2H); 13C NMR (100 MHz, CDCl3)
d: 37.23, 42.38, 52.62, 53.29,128.88,
130.57, 133.34, 133.89, 165.61, 171.04; IR (ATR)
n
3296, 3048, 2943,
4 . 4 . 3 . ( R ) - N - [ N - ( 2 , 2 - D i m e t h o x y e t h y l ) g l y c i n y l ] - 4 -
1740, 1729, 1661, 1537, 1491, 1445, 1366, 1265, 1203, 1120,
1087 cmꢀ1; HPLC (220 nm) 98.0% (tR¼23.9 min); LC/MS (ESI) m/z:
290.3 [MþH]þ.
methoxyphenylalanine methyl ester (11b). Yield 75%, colorless oil.
½
a 2D5
ꢄ
ꢀ37.7 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3)
d: 2.61 (dd,
J¼12.3, 5.7 Hz, 1H), 2.67 (dd, J¼12.3, 5.1 Hz, 1H), 3.04 (dd, J¼14.2,
6.2 Hz, 1H), 3.11 (dd, J¼14.2, 5.9 Hz, 1H), 3.27 (dd, J¼20.6, 17.0 Hz,
2H), 3.35 (s, 3H), 3.36 (s, 3H), 3.72 (s, 3H), 3.78 (s, 3H), 4.32 (t,
J¼5.4 Hz, 1H), 4.84 (dt, J¼8.2, 6.0 Hz, 1H), 6.81e6.84 (m, 2H),
4.3.5. (R)-N-(2-Chloroacetyl)-3-chlorophenylalanine methyl ester
(10d). Yield 92%, colorless oil. ½a D25
ꢄ
ꢀ47.8 (c 0.5, CHCl3); 1H NMR
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6
M. Seki, T. Ogiku / Tetrahedron xxx (2014) 1e7
7.02e7.06 (m, 2H), 7.61 (d, J¼8.2 Hz,1H); 13C NMR (100 MHz, CDCl3)
(m, 3H); 13C NMR (150 MHz, CDCl3)
51.93, 54.55, 124.22, 126.52, 126.79, 128.63, 131.38, 132.45, 167.46,
d: 29.93, 49.15, 49.16, 49.20,
d
: 37.11, 50.99, 52.19, 52.25, 52.78, 54.01, 54.05, 55.21, 103.50, 114.01,
127.98, 130.21, 158.71, 171.36, 172.11; IR (ATR)
n
3335, 2951, 2835,
170.46; IR (ATR) n 3315, 2953, 1736, 1636, 1455, 1434, 1406, 1316,
1742,1669,1612,1511,1442,1362,1246,1178,1126,1057,1032 cmꢀ1
;
1200, 1177, 1120, 1030 cmꢀ1; HRMS (ESI) calcd for C14H17N2O3
HPLC (220 nm) 96.7% (tR¼16.9 min); LC/MS (ESI) m/z: 355.5
([MþH]þ): 261.1234, found: 261.1228.
[MþH]þ.
4.5.2. (6R,11bR)-10-Methyl-4-oxo-1,3,4,6,7,11b-hexahydro-2H-pyr-
4.4.4. (R)-N-[N-(2,2-Dimethoxyethyl)glycinyl]-4-chlorophenylalanine
azino[2,1-a]isoquinoline-6-carboxylic acid methyl ester (12a). Yield
methyl ester (11c). Yield 74%, colorless oil. ½a D25
ꢄ
ꢀ37.7 (c 0.5, CHCl3);
80%, colorless oil. ½a D25
ꢄ
ꢀ149.8 (c 0.5, CHCl3); 1H NMR (400 MHz,
1H NMR (400 MHz, CDCl3)
d
: 2.61 (dd, J¼12.4, 5.4 Hz, 1H), 2.68 (dd,
CDCl3)
d
: 2.32 (s, 3H), 2.93 (dd, J¼13.3, 10.2 Hz, 1H), 3.11 (dd, J¼16.1,
J¼12.4, 5.2 Hz, 1H), 3.07 (dd, J¼13.9, 6.2 Hz, 1H), 3.16 (dd, J¼14.1,
5.9 Hz, 1H), 3.27 (dd, J¼20.0, 17.0 Hz, 2H), 3.35 (s, 3H), 3.36 (s, 3H),
3.73 (s, 3H), 4.32 (t, J¼5.2 Hz, 1H), 4.87 (dt, J¼8.2, 6.2 Hz, 1H),
7.06e7.08 (m, 2H), 7.24e7.28 (m, 2H), 7.66 (d, J¼8.2 Hz, 1H); 13C
6.1 Hz, 1H), 3.21 (dd, J¼16.1, 3.6 Hz, 1H), 3.60 (d, J¼17.9 Hz, 1H), 3.65
(s, 3H), 3.68 (dd, J¼13.8, 4.1 Hz,1H), 3.76 (d, J¼17.9 Hz,1H), 4.95 (dd,
J¼10.2, 4.1 Hz, 1H), 5.73 (dd, J¼6.1, 3.6 Hz, 1H), 6.93 (s, 1H), 7.03 (d,
J¼8.2 Hz, 1H), 7.07 (d, J¼8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d:
NMR (100 MHz, CDCl3)
d: 37.34, 51.04, 52.18, 52.38, 52.50, 54.09,
21.21, 30.13, 49.70, 49.75, 49.84, 52.43, 55.16, 125.33, 128.19, 128.80,
54.15, 103.50,128.73,130.57, 133.03, 134.60, 171.41, 171.79; IR (ATR)
n
129.03, 132.76, 136.67, 168.02, 171.07; IR (ATR) n 3316, 2953, 1737,
3331, 2951, 2833, 1742, 1668, 1511, 1492, 1438, 1361, 1197, 1126, 1091,
1057, 1015 cmꢀ1; HPLC (220 nm) 98.2% (tR¼19.2 min); LC/MS (ESI)
m/z: 359.4 [MþH]þ.
1639, 1433, 1404, 1315, 1199, 1177, 1151, 1029 cmꢀ1; HRMS (ESI)
calcd for C15H19N2O3 ([MþH]þ): 275.1390, found: 275.1385.
4.5.3. (6R,11bR)-10-Methoxy-4-oxo-1,3,4,6,7,11b-hexahydro-2H-pyr-
4.4.5. (R)-N-[N-(2,2-Dimethoxyethyl)glycinyl]-3-chlorophenylalanine
azino[2,1-a]isoquinoline-6-carboxylic acid methyl ester (12b). Yield
a 25
a 25
methyl ester (11d). Yield 66%, colorless oil. ½ ꢄD ꢀ39.7 (c 0.5, CHCl3);
18%, colorless oil. ½ ꢄD ꢀ188.3 (c 0.5, CHCl3); 1H NMR (400 MHz,
1H NMR (400 MHz, CDCl3)
d
: 2.63 (dd, J¼12.4, 5.6 Hz, 1H), 2.69 (dd,
CDCl3)
d
: 2.94 (dd, J¼13.4, 10.3 Hz, 1H), 3.08 (dd, J¼15.7, 6.2 Hz, 1H),
J¼12.4, 5.1 Hz, 1H), 3.07 (dd, J¼13.9, 6.7 Hz, 1H), 3.16 (dd, J¼13.9,
5.7 Hz, 1H), 3.28 (dd, J¼20.6, 17.0 Hz, 2H), 3.35 (s, 3H), 3.37 (s, 3H),
3.74 (s, 3H), 4.35 (t, J¼5.4 Hz, 1H), 4.87 (dt, J¼8.5, 6.2 Hz, 1H),
7.01e7.04 (m, 1H), 7.13 (s, 1H), 7.20e7.23 (m, 2H), 7.70 (d, J¼8.2 Hz,
3.19 (dd, J¼15.7, 3.6 Hz, 1H), 3.60 (d, J¼18.0 Hz, 1H), 3.65 (s, 3H),
3.66 (dd, J¼13.4, 4.1 Hz, 1H), 3.75 (dd, J¼18.0, 1.1 Hz, 1H), 3.79 (s,
3H), 4.95 (dd, J¼10.3, 4.1 Hz, 1H), 5.73 (dd, J¼6.2, 3.6 Hz, 1H), 6.64
(d, J¼2.1 Hz, 1H), 6.78 (dd, J¼8.7, 2.6 Hz, 1H), 7.10 (d, J¼8.2 Hz, 1H);
1H); 13C NMR (100 MHz, CDCl3)
d: 37.61, 51.07, 52.18, 52.39, 52.51,
13C NMR (100 MHz, CDCl3)
d: 29.74, 49.68, 49.83, 49.84, 52.44,
54.08, 54.16, 103.50, 127.32, 127.37, 129.45, 129.83, 134.31, 138.19,
171.49, 171.70; IR (ATR) 3331, 2951, 2833, 1742, 1669, 1510, 1477,
55.22, 55.30, 110.49, 112.92, 123.91, 130.13, 134.02, 158.54, 167.97,
n
171.06; IR (ATR) n 3316, 2953, 2838, 1736, 1638, 1505, 1432, 1405,
1434, 1360, 1201, 1126, 1056 cmꢀ1
;
HPLC (220 nm) 93.7%
1314, 1263, 1199, 1175, 1031 cmꢀ1; HRMS (ESI) calcd for C15H19N2O4
(tR¼19.1 min); LC/MS (ESI) m/z: 359.4 [MþH]þ.
([MþH]þ): 291.1339, found: 291.1336.
4 . 4 . 6 . ( R ) - N - [ N - ( 2 , 2 - D i m e t h o x y e t h y l ) g l y c i n y l ] - 2 -
4.5.4. (6R,11bR)-10-Chloro-4-oxo-1,3,4,6,7,11b-hexahydro-2H-pyr-
azino[2,1-a]isoquinoline-6-carboxylic acid methyl ester (12c). Yield
chlorophenylalanine methyl ester (11e). Yield 66%, colorless oil. ½a D25
ꢄ
ꢀ17.9 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3)
d
: 2.63 (dd, J¼12.3,
61%, colorless oil. ½a D25
ꢄ
ꢀ153.3 (c 0.5, CHCl3); 1H NMR (400 MHz,
5.6 Hz, 1H), 2.68 (dd, J¼12.3, 5.1 Hz, 1H), 3.19 (dd, J¼14.2, 8.4 Hz,
1H), 3.24 (dd, J¼25.6, 17.5 Hz, 2H), 3.32e3.37 (m, 1H), 3.36 (s, 3H),
3.37 (s, 3H), 3.73 (s, 3H), 4.38 (t, J¼5.4 Hz,1H), 4.92 (td, J¼8.4, 6.1 Hz,
CDCl3)
d
: 2.93 (dd, J¼13.4, 10.3 Hz, 1H), 3.10 (dd, J¼16.4, 6.2 Hz, 1H),
3.23 (dd, J¼16.4, 3.1 Hz, 1H), 3.60 (d, J¼17.4 Hz, 1H), 3.66 (s, 3H),
3.67 (ddd, J¼13.4, 4.1, 1.0 Hz, 1H), 3.76 (dd, J¼18.0, 1.0 Hz, 1H), 4.95
(dd, J¼10.3, 4.1 Hz, 1H), 5.77 (dd, J¼6.2, 3.1 Hz, 1H), 7.11 (s, 1H), 7.13
(d, J¼5.1 Hz, 1H), 7.20 (dd, J¼8.2, 1.5 Hz, 1H); 13C NMR (100 MHz,
1H), 7.18e7.22 (m, 3H), 7.34e7.37 (m, 1H), 7.72 (d, J¼8.2 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) d: 35.41, 50.99, 51.87, 52.14, 52.44, 54.04,
54.10, 103.50, 126.92, 128.55, 129.65, 131.20, 134.27, 134.49, 171.54,
CDCl3) d: 29.99, 49.36, 49.63, 49.68, 52.58, 54.87, 125.08, 127.60,
172.01; IR (ATR)
n
3301, 2948, 2838, 1738, 1650, 1519, 1475, 1439,
130.42, 130.60, 132.82, 134.69, 167.87, 170.71; IR (ATR) n 3314, 2953,
1230, 1181, 1126, 1048 cmꢀ1; HPLC (220 nm) 99.1% (tR¼18.5 min);
1736, 1639, 1487, 1430, 1401, 1313, 1201, 1178, 1029 cmꢀ1; HRMS
LC/MS (ESI) m/z: 359.2 [MþH]þ.
(ESI) calcd for C14H16ClN2O3 ([MþH]þ): 295.0844, found: 295.0841.
4.5. Synthesis of pyrazinoisoquinoline derivatives 4a,b and
4.5.5. (6R,11bR)-9-Chloro-4-oxo-1,3,4,6,7,11b-hexahydro-2H-pyr-
12aee
azino[2,1-a]isoquinoline-6-carboxylic acid methyl ester (12d). Yield
61%, colorless oil. ½a D25
ꢄ
ꢀ164.5 (c 0.5, CHCl3); 1H NMR (400 MHz,
To amido acetal 1 or 11aee (0.3 mmol) was added CH3SO3H
(3.0 mmol) or concentrated H2SO4 (1.8 mmol), and the reaction
mixture was stirred at room temperature for the time indicated on
Table 1 or Table 2. The resulting reaction mixture was neutralized
with 1 M NaOH, and the whole was extracted with CHCl3. The ex-
tract was dried over anhydrous MgSO4, and the solvent was evap-
orated under reduced pressure. The residue was purified by silica
gel column chromatography (0e9% CHCl3/MeOH) to give 4a or
11aee as an oily product.
CDCl3)
d
: 2.90 (dd, J¼13.3, 10.2 Hz, 1H), 3.12 (dd, J¼16.4, 6.1 Hz, 1H),
3.24 (dd, J¼16.4, 3.1 Hz, 1H), 3.60 (d, J¼17.9 Hz, 1H), 3.67 (s, 3H),
3.67 (dd, J¼13.3, 4.1 Hz,1H), 3.76 (d, J¼17.9 Hz,1H), 4.96 (dd, J¼10.2,
4.1 Hz, 1H), 5.79 (dd, J¼6.1, 3.1 Hz, 1H), 7.06 (d, J¼8.7 Hz, 1H), 7.19 (s,
1H), 7.22 (dd, J¼8.2, 2.0 Hz,1H); 13C NMR (100 MHz, CDCl3)
d: 30.29,
49.17, 49.63, 49.82, 52.60, 54.87, 126.37, 127.36, 129.10, 131.41,
133.10, 133.87, 167.86, 170.64; IR (ATR)
n 3315, 2953, 1737, 1640,
1434, 1403, 1314, 1296, 1199, 1031 cmꢀ1; HRMS (ESI) calcd for
C
14H16ClN2O3 ([MþH]þ): 295.0844, found: 295.0841.
4.5.1. (6R,11bR)-4-Oxo-1,3,4,6,7,11b-hexahydro-2H-pyrazino[2,1-a]
4.5.6. (6R,11bR)-8-Chloro-4-oxo-1,3,4,6,7,11b-hexahydro-2H-pyr-
isoquinoline-6-carboxylic acid methyl ester (4a). Yield 80%, colorless
azino[2,1-a]isoquinoline-6-carboxylic acid methyl ester (12e). Yield
oil. ½a 2D5
ꢄ
ꢀ130.2 (c 0.5, CHCl3); 1H NMR (600 MHz, CDCl3)
d: 2.95
43%, colorless oil. ½a D25
ꢄ
ꢀ147.8 (c 0.5, CHCl3); 1H NMR (400 MHz,
(dd, J¼13.3, 10.2 Hz, 1H), 3.16 (dd, J¼16.1, 6.2 Hz, 1H), 3.26 (dd,
J¼16.1, 3.6 Hz, 1H), 3.60 (d, J¼17.7 Hz, 1H), 3.66 (s, 3H), 3.71 (ddd,
J¼13.3, 4.2, 1.3 Hz, 1H), 3.76 (dd, J¼17.8, 1.3 Hz, 1H), 4.99 (dd, J¼10.2,
4.0 Hz, 1H), 5.73 (dd, J¼6.2, 3.6 Hz, 1H), 7.12e7.14 (m, 1H), 7.17e7.25
CDCl3)
d
: 2.89 (dd, J¼13.1, 10.0 Hz, 1H), 3.05 (dd, J¼17.2, 6.6 Hz, 1H),
3.52 (dd, J¼17.2, 2.6 Hz, 1H), 3.59 (d, J¼17.9 Hz, 1H), 3.67 (s, 3H),
3.68 (m, 1H), 3.76 (dd, J¼17.9, 1.0 Hz, 1H), 5.01 (dd, J¼10.0, 4.1 Hz,
1H), 5.87 (dd, J¼6.6, 2.6 Hz, 1H), 7.05 (d, J¼7.7 Hz, 1H), 7.20 (t,
Please cite this article in press as: Seki, M.; Ogiku, T., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.045

M. Seki, T. Ogiku / Tetrahedron xxx (2014) 1e7
7
J¼7.7 Hz, 1H), 7.31 (d, J¼8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
:
lit.1a
½
a 2D0
ꢄ
ꢀ149.4; 1H NMR (400 MHz, CDCl3)
d
: 1.26e1.31 (m, 3H),
27.89, 48.77, 49.56, 50.01, 52.63, 54.80, 123.37, 127.77, 128.06,
1.50e1.82 (m, 7H), 2.44e2.56 (m, 1H), 2.77e3.03 (m, 3.8H), 3.25 (m,
0.2H), 3.87 (d, J¼17.5 Hz, 0.2H), 4.08 (d, J¼17.5 Hz, 0.8H), 4.36 (m,
0.2H), 4.47 (d, J¼17.5 Hz, 0.8H), 4.79e4.88 (m, 2.2H), 5.16 (m, 0.8H),
130.19, 134.68, 135.17, 167.81, 170.67; IR (ATR)
n 3314, 2953, 1737,
1640, 1447, 1405, 1314, 1230, 1201, 1177, 1033 cmꢀ1; HRMS (ESI)
calcd for C14H16ClN2O3 ([MþH]þ): 295.0844, found: 295.0841.
7.17e7.28 (m, 4H); 13C NMR (100 MHz, CDCl3)
d: 25.7, 28.7, 29.0,
29.2, 39.1, 40.8, 45.2, 49.0, 55.0, 125.5, 127.0, 127.5, 129.3, 132.8,
4.5.7. (6R,11bS)-4-Oxo-1,3,4,6,7,11b-hexahydro-2H-pyrazino[2,1-a]
isoquinoline-6-carboxylic acid methyl ester (4b). The title com-
pound was obtained as the minor isomer by CF3SO3H-catalyzed
cyclization (Table 1, entry 3). Yield 8%, colorless oil. 1H NMR
134.8, 164.4, 174.8; IR (ATR) n ;
2924, 2854, 1642, 1440, 757 cmꢀ1
HRMS (ESI) calcd for C19H25N2O2 ([MþH]þ): 313.1911, found:
313.1906.
(600 MHz, CDCl3)
d
: 3.17 (dd, J¼15.2, 6.1 Hz, 1H), 3.25 (dd, J¼15.2,
References and notes
2.5 Hz, 1H), 3.31 (dd, J¼12.4, 10.3 Hz, 1H), 3.53 (s, 3H), 3.65 (d,
J¼17.4 Hz, 1H), 3.72 (d, J¼17.4 Hz, 1H), 3.91 (dd, J¼12.4, 3.8 Hz, 1H),
4.62 (dd, J¼10.3, 4.0 Hz, 1H), 4.98 (dd, J¼6.1, 2.5 Hz, 1H), 7.13e7.19
1. (a) Andrews, P.; Thomas, H.; Pohlke, R.; Seubert, J. Med. Res. Rev. 1983, 3, 147; (b)
Tang, H.; Zheng, C.-H.; Zhu, J.; Fu, B.-Y.; Zhou, Y.-J.; Lv, J.-G. Arch. Pharm. 2010,
343, 360; (c) Hudack, R. A.; Barta, N. S.; Guo, C.; Deal, J.; Dong, L.; Fay, L. K.;
Caprathe, B.; Chatterjee, A.; Vanderpool, D.; Bigge, C.; Showalter, R.; Bender, S.;
Augelli-Szafran, C. E.; Lunney, E.; Hou, X. J. Med. Chem. 2006, 49, 1202; (d) Dong,
Y.; Chollet, J.; Vargas, M.; Mansour, N. R.; Bickle, Q.; Alnouti, Y.; Huang, J.; Keiser,
J.; Vennerstrom, J. L. Bioorg. Med. Chem. Lett. 2010, 20, 2481; (e) Tang, H.; Zheng,
C.; Lv, J.; Wu, J.; Li, Y.; Yang, H.; Fu, B.; Li, C.; Zhou, Y.; Zhu, J. Bioorg. Med. Chem.
Lett. 2010, 20, 979; (f) Sadhu, P. S.; Kumar, S. N.; Chandrasekharam, M.; Pica-
Mattoccia, L.; Cioli, D.; Rao, V. J. Bioorg. Med. Chem. Lett. 2012, 22, 1103; (g) Duan,
W.-W.; Qiu, S.-J.; Zhao, Y.; Sun, H.; Qiao, C.; Xia, C.-M. Bioorg. Med. Chem. Lett.
(m, 2H), 7.25e7.29 (m, 2H); 13C NMR (150 MHz, CDCl3)
d: 31.15,
46.72, 50.02, 52.20, 54.03, 54.47, 122.81, 127.42, 127.56, 127.97,
133.65, 135.05, 168.19, 170.94; LC/MS (ESI) m/z: 261.3 [MþH]þ.
4.6. Synthesis of (R)-(L)-praziquantel 6
4.6.1. (6R,11bR)-2-Cyclohexanecarbonyl-4-oxo-1,3,4,6,7,11b-hexahy-
dro-2H-pyrazino[2,1-a]isoquinoline-6-carboxylic acid (5). A solution
of 4a (0.50 g, 1.9 mmol) in 6 M HCl (5 mL) was heated to reflux for
39 h. After cooling, the reaction mixture was concentrated under
reduced pressure. The residue was triturated with EtOAc/EtOH (10:
1), and the solid was collected by filtration to give crude (6R,11bR)-
4-oxo-1,3,4,6,7,11b-hexahydro-2H-pyrazino[2,1-a]isoquinoline-6-
carboxylic acid hydrochloride (0.50 g). To a suspension of the ob-
tained carboxylic acid (0.30 g) in CH2Cl2 (6 mL) was added Et3N
(0.3 mL, 2.2 mmol) and cyclohexanecarbonyl chloride (0.16 g,
1.1 mmol) at 0 ꢂC. After stirring at 0 ꢂC for 1 h, 1 M HCl was added,
and the whole was extracted with CHCl3. The extract was dried over
anhydrous MgSO4, and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel column chroma-
tography (0e45% CHCl3/MeOH) to give 5 as an amorphous solid
€
€
2012, 22, 1587; (h) Kolzer, M.; Weitzel, K.; Goringer, H. U.; Thines, E.; Opatz, T.
ChemMedChem 2010, 5, 1456.
2. (a) Ma, C.; Zhang, Q.-F.; Tan, Y.-B.; Wang, L. J. Chem. Res. 2004, 186; (b) Znabet,
A.; Zonneveld, J.; Janssen, E.; De Kanter, F. J. J.; Helliwell, M.; Turner, N. J.;
Ruijter, E.; Orru, R. V. A. Chem. Commun. 2010, 7706.
3. (a) Zawadzka, A.; Leniewski, A.; Maurin, J. K.; Wojtasiewicz, K.; Siwicka, A.;
Blachut, D.; Czarnocki, Z. Eur. J. Org. Chem. 2003, 2443; (b) Zawadzka, A.; Le-
niewski, A.; Maurin, J. K.; Wojtasiewicz, K.; Czarnocki, Z. Org. Lett. 2001, 3, 997;
(c) Siwicka, A.; Wojtasiewicz, K.; Rosiek, B.; Leniewski, A.; Maurin, J. K.; Czar-
nocki, Z. Tetrahedron: Asymmetry 2005, 16, 975.
4. Todd, M. H.; Ndubaku, C.; Bartlett, P. A. J. Org. Chem. 2002, 67, 3985.
5. Roszkowski, P.; Maurin, J. K.; Czarnocki, Z. Tetrahedron: Asymmetry 2006, 17,
1415.
6. Gremmen, C.; Wanner, M. J.; Koomen, G.-J. Tetrahedron Lett. 2001, 42, 8885.
7. We retested the asymmetric PicteteSpengler cyclization reported by Ma et al.2a
However, our trial did not reproduced their results. Thus, unlike as reported,2a
the cyclization of enantiopure N-(p-tolylsulfinyl)phenylethylamine lacking
electron-donating substituents with N-(2,2-dimethoxyethyl)pthalimide under
the described conditions did not afford the desired product, and the starting
material was recovered instead. Moreover, elevated reaction temperature re-
sulted in a decomposition of the starting material. These results meet the
(0.28 g, 67% yield). ½a D25
ꢄ
ꢀ42.0 (c 0.5, CHCl3); 1H NMR (400 MHz,
CDCl3) d: 1.26e1.88 (m, 10H), 2.43e2.48 (m, 1H), 3.11e3.26 (m, 3H),
ꢀ
findings of Laurent, et al. See: Laurent, S. A.-L.; Boissier, J.; Cosledan, F.; Gor-
4.05e5.04 (m, 4H), 5.49e5.56 (m,1H), 7.20 (m, 4H); IR (ATR) n 3285,
2926, 2853, 1617, 1410, 1300, 1217, 748 cmꢀ1; HRMS (ESI) calcd for
nitzka, H.; Robert, A.; Meunier, B. Eur. J. Org. Chem. 2008, 895.
8. Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem.
Rev. 2004, 104, 1431 and references therein.
9. For selected examples, see: (a) Aubry, S.; Pellet-Rostaing, S.; Lemaire, M. Eur. J.
Org. Chem. 2007, 5212; (b) Gonzalez, J. F.; de la Cuesta, E.; Avendano, C. Tetra-
hedron Lett. 2003, 44, 4395.
C
20H25N2O4 ([MþH]þ): 357.1809, found: 357.1803.
ꢀ
~
4.6.2. (R)-2-Cyclohexanecarbonyl-1,2,3,6,7,11b-hexahydro-pyrazino
[2,1-a]isoquinolin-4-one, (R)-(ꢀ)-praziquantel (6). To a solution of 5
(0.15 g, 0.42 mmol) in THF (2 mL) was added N-methylmorpholine
10. For selected examples, see: (a) Amat, M.; Santos, M. M. M.; Bassas, O.; Llor, N.;
ꢀ
ꢀ
Escolano, C.; Gomez-Esque, A.; Molins, E.; Allin, S. M.; McKee, V.; Bosch, J. J. Org.
Chem. 2007, 72, 5193; (b) Allin, S. M.; James, S. L.; Martin, W. P.; Smith, T. A. D.
Tetrahedron Lett. 2001, 42, 3943; (c) Allin, S. M.; James, S. L.; Martin, W. P.;
Smith, T. A. D.; Elsegood, M. R. J. J. Chem. Soc., Perkin Trans. 1 2001, 3029; (d)
Allin, S. M.; Towler, J.; Gaskell, S. N.; Saha, B.; Martin, W. P.; Page, P. C. B.; Edgar,
M. Tetrahedron 2010, 66, 9538; (e) García, E.; Arrasate, S.; Ardeo, A.; Lete, E.;
Sotomayor, N. Tetrahedron Lett. 2001, 42, 1511; (f) García, E.; Arrasate, S.; Lete, E.;
Sotomayor, N. J. Org. Chem. 2005, 70, 10368.
(51 mL, 0.46 mmol) and isobutyl chloroformate (63 mg, 0.46 mmol)
at ꢀ15 ꢂC. After stirring at the same temperature for 30 min, a so-
lution of N-hydroxy-2-thiopyridone (64 mg, 0.51 mmol) and Et3N
(70 mL, 0.51 mmol) in THF (0.5 mL) was added. The mixture was
stirred at ꢀ15 ꢂC for 1 h under nitrogen atmosphere, sheltered from
the light (aluminum foil). The precipitate of N-methylmorpholine
hydrochloride was filtered and washed with THF. The yellow filtrate
was irradiated in the presence of 2-methyl-2-propanethiol
(0.47 mL, 4.2 mmol) with a lamp (200 W) at room temperature in
a water bath until the color has disappeared. Then, H2O was added,
and the whole was extracted with EtOAc. The solvent was evapo-
rated under reduced pressure. The residue was purified by silica gel
column chromatography (0e90% hexane/EtOAc) to give 6 as a col-
orless solid (68 mg, 52% yield), which was recrystallized from
heptane/EtOAc (1: 1). Mp 106e107 ꢂC, lit.5 mp 113e115 ꢂC, lit.14 mp
11. Minor isomer 4b (cis) was not detected by TLC analysis of the crude reaction
mixture, and 4a (trans) was isolated in a high enantiomeric excess (ꢁ98.1%),
which was determined by chiral HPLC using a Chiralpak IA column in com-
parison with the racemic sample.
12. The LC/MS data of the crude product indicated that the hydrolysis of the methyl
ester of 4a would occur as the main side reaction.
ꢀ
13. Barton, D. H. R.; Herve, Y.; Potier, P.; Thierry, J. Tetrahedron 1988, 44, 5479.
14. Seubert, J.; Thomas, H.; Andrews, P. U.S. Patent 4,001,411, Chem. Abstr. 1977, 84,
5007.
15. (a) Hart, D. J. J. Am. Chem. Soc. 1980, 102, 397; (b) Maryanoff, B. E.; McComsey, D.
F.; Duhl-Emswiler, B. A. J. Org. Chem. 1983, 48, 5062.
16. Any cis-isomers of 12aee were not detected in the crude reaction mixture by
400 MHz 1H NMR and LC/MS, and the distereoselectivity could not be
calculated.
107e108 ꢂC; ½a 2D5
ꢄ
ꢀ153.6 (c 1.0, CHCl3), lit.5 ½a D23
ꢀ135.0 (c 1, CHCl3),
ꢄ
Please cite this article in press as: Seki, M.; Ogiku, T., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.045