Efficient and Practical Syntheses of Enantiomerically Pure (S)-(-)-Norcryptostyline I, (S)-(-)-Norcryptostyline II, (R)-(+)-Salsolidine and (S)-(-)-Norlaudanosine via a Resolution-Racemization Method

Article abstract of DOI:10.1002/cjoc.201400471

Four racemic tetrahydroisoquinolines (RS)-(±)-1-4 were prepared from homoveratrylamine via amidation, Bischler-Napieralski reaction and the subsequent reduction. The enantiomerically pure tetrahydroisoquinolines (S)- (-)-norcryptostyline I [(S)-(-)-1], (S)-(-)-norcryptostyline II [(S)-(-)-2], (R)-(+)-salsolidine [(R)-(+)-3] and (S)-(-)-norlaudanosine [(S)-(-)-4] were then obtained in 45%, 40%, 41% and 38% yields, respectively, via resolution of the racemic compounds (RS)-(±)-1-4 with half equivalent of chiral acids. In addition, the enantiomerically enriched compounds (R)-(+)-1, (R)-(+)-2, (S)-(-)-3 and (R)-(+)-4 from the mother liquors were efficiently racemized via a one-pot redox method in almost quantitative yields.

Full text of DOI:10.1002/cjoc.201400471

FULL PAPER
DOI: 10.1002/cjoc. 201400471
Efficient and Practical Syntheses of Enantiomerically Pure
(S)-(−)-Norcryptostyline I, (S)-(−)-Norcryptostyline II,
(R)-(＋)-Salsolidine and (S)-(−)-Norlaudanosine via
a Resolution-Racemization Method†
Ruiheng Zhu, Zhangli Xu, Wei Ding, Shiling Liu, Xiaoxin Shi,* and Xia Lu
Department of Pharmaceutical Engineering, School of Pharmacy, East China University of Science and
Technology, 130 Mei-Long Road, Shanghai 200237, China
Four racemic tetrahydroisoquinolines (RS)-(±)-1－4 were prepared from homoveratrylamine via amidation,
Bischler-Napieralski reaction and the subsequent reduction. The enantiomerically pure tetrahydroisoquinolines (S)-
(−)-norcryptostyline I [(S)-(−)-1], (S)-(−)-norcryptostyline II [(S)-(−)-2], (R)-(＋)-salsolidine [(R)-(＋)-3] and
(S)-(−)-norlaudanosine [(S)-(−)-4] were then obtained in 45%, 40%, 41% and 38% yields, respectively, via resolu-
tion of the racemic compounds (RS)-(±)-1－4 with half equivalent of chiral acids. In addition, the enantiomerically
enriched compounds (R)-(＋)-1, (R)-(＋)-2, (S)-(−)-3 and (R)-(＋)-4 from the mother liquors were efficiently ra-
cemized via a one-pot redox method in almost quantitative yields.
Keywords tetrahydroisoquinolines, norcryptostyline, salsolidine, norlaudanosine, resolution, racemization
Introduction
sponding alkaloids (S)-(＋)-cryptostyline I,[5] (S)-(＋)-
cryptostyline II,[5,6] (R)-(＋)-carnegine[7] and (S)-(＋)-
laudanosine.[8] (S)-(−)-Norlaudanosine [(S)-(−)-4] can
also be easily transformed to the alkaloid (S)-(−)-
xylopinine.[8,9] Both (R)-(＋)-salsolidine [(R)-(＋)-3]
and its enantiomer (S)-(−)-salsolidine [(S)-(−)-3] are
naturally occuring compounds, they can be isolated
from various plant sources.[10] Many synthetic methods
for enantioselective syntheses of 1-substituted THIQs
and their derivatives have been explored,[10a,11] but the
resolution method of 1-substituted THIQs is less stud-
Although stereoselective synthesis of chiral com-
pounds has made a great progress in past decades,[1]
resolution remains one of the most important methods
for preparing chiral compounds especially in large scale
or industrial syntheses,[2] because it has some advan-
tages such as simplicity, easy operation, free of expen-
sive chiral reagents or ligands, no harsh reaction condi-
tions, and so on. Normally, the maximum yield of reso-
lution is limited to 50%, but if the unwanted enantiomer
could be efficiently racemized for re-resolution, and the
cycle of resolution-racemization[3] could be repeated
many times, thus the yield of the wanted enantiomer
could be theoretically increased to 100%. Furthermore,
from a sustainable chemistry point of view, the un-
wanted enantiomer should be better converted to the
desired enantiomer via the racemization-resolution
process to minimize the waste as far as possible.
NH
NH
OMe
OMe
MeO
MeO
MeO
MeO
O
O
(S)-(-)-1
(S)-(-)-2
(S)-(-)-Norcryptostyline I
(S)-(-)-Norcryptostyline II
1,2,3,4-Tetrahydroisoquinolines (THIQs), especially
1-substituted THIQs, are a very important kind of het-
erocyclic compounds because of their various biological
activities.[4] (S)-(−)-Norcryptostyline I [(S)-(−)-1],
(S)-(−)-norcryptostyline II [(S)-(−)-2], (R)-(＋)-
salsolidine [(R)-(＋)-3] and (S)-(−)-norlaudanosine
[(S)-(−)-4] are the four useful 1-substituted THIQs (see
Figure 1), which can be readily converted to the corre-
MeO
MeO
NH
OMe
OMe
MeO
MeO
NH
(R)-(+)-3
(R)-(+)-Salsolidine
(S)-(-)-4
(S)-(-)-Norlaudanosine
Figure 1 Structures of the four targeted 1-substituted THIQs.
*
E-mail: xxshi@ecust.edu.cn; Tel.: 0086-021-64252052; Fax: 0086-021-64252052
Received July 10, 2014; accepted September 21, 2014; published online September 29, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400471 or from the author.
Dedicated to Professor Chengye Yuan and Professor Li-Xin Dai on the occasion of their 90th birthdays.
†
Chin. J. Chem. 2014, 32, 1039—1048
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Zhu et al.
FULL PAPER
ied.[12] Herein, we want to report efficient and practical
syntheses of the four useful enantiomerically pure
1-substituted THIQs 1－4 via a resolution-racemization
method.
3,4-dihydropapaveraldine[15] 7 could be obtained in 90%
yield via the benzylic oxidation.
With the racemic THIQs (RS)-(±)-1－4 in hands, we
then attempted the chiral resolutions of them to prepare
enantiomerically pure THIQs (S)-(−)-1, (S)-(–)-2,
(R)-(＋)-3 and (S)-(–)-4. A literature search showed that
the resolution of racemic THIQs (RS)-(±)-1 and 2 with
L-(–)-diacetone-2-keto-gulonic acid as the resolving
agent,[5] the resolution of racemic THIQ (RS)-(±)-3
with L-(＋)-tartaric acid as the resolving agent,[16] and
the reslution of racemic THIQ (RS)-( ± )-4 with
(＋)-α-bromocamphorsulphonic acid as the resolving
agent[17] have been reported. However, all of these re-
ported resolutions suffered from low yields and the use
of excessive chiral resolving agents. Herein, we want to
report novel efficient resolutions of racemic THIQs
(RS)-(±)-1－4 with 0.5 equiv. of inexpensive chiral
acids as the resolving agents. As can be seen from the
Table 1, N-tosyl-L-phenylalanine was used as the re-
solving agent for the resolution of racemic THIQ
(RS)-(±)-1; L-mandelic acid was used as the resolving
agent for the resolution of racemic THIQ (RS)-(±)-3;
N-acetyl-L-phenylalanine was used as the resolving
agent for the resolutions of racemic THIQs (RS)-(±)-2
and (RS)-( ± )-4. Enantiomerically pure THIQs
(S)-( −)-1, (S)-( −)-2, (R)-(＋)-3 and (S)-( −)-4 were ob-
tained in 45%, 40%, 41% and 38% yields, respectively.
High pressure liquid chromatography (HPLC)
method using a chiral column is often a good choice for
determining the enantiomeric purity of chiral com-
pounds, but NMR method using a chiral solvating agent
(CSA)[18] might be another more time-efficient and in-
expensive choice. The enantiomeric purities of the
above four chiral THIQs (S)-(−)-1, (S)-(−)-2, (R)-(＋)-3
and (S)-(−)-4 are greater than 99% (ee＞98%), which
can be determined by the NMR method with CSAs in
Results and Discussion
(±)-Norcryptostyline I [(RS)-(±)-1] and (±)-norc-
ryptostyline II [(RS)-(±)-2] can be directly prepared by
Pictet-Spengler reaction in moderate yields according to
Coskun’s report,[13] but this method is obviously not
practical because of use of the corrosive trifluoroacetic
acid (CF3COOH) as the solvent. Herein, it was found
that the synthetic method as shown in Scheme 1 could
be used for the scalable and practical preparations of the
racemic THIQs (RS)-(±)-1－4.
As shown in Scheme 1, homoveratrylamine was first
treated with 1.2 equiv. of carboxylic chlorides RCOCl
[R＝3,4-(OCH2O)-Ph, 3,4-(MeO)2-Ph and 3,4-(MeO)2-
PhCH2] or acetic anhydride (R＝CH3) in the presence of
2.0 equiv. of sodium hydroxide in a biphasic mixed
solvent of dichloromethane and water (CH2Cl2/H2O＝
2∶1), the corresponding amides 5a－5d were obtained
in almost quantitative yields. The amides 5a－5d were
then exposed to 2.0 equiv. of phosphoryl trichloride at
reflux in ethyl acetate to furnish 3,4-dihydroisoquino-
lines 6a－6d via Bischler-Napieralski reaction.[14] Sub-
sequently, the above compounds 6a－6d could be used
as such for the next step, and were reduced by 2.0 equiv.
of KBH4 in methanol to afford the racemic THIQs 1－4
in 96%, 97%, 95% and 81% yields, respectively. The
yield of THIQ (RS)-(±)-4 is relatively low, because the
intermediate 3,4-dihydroisoquinoline 6d could be
smoothly oxidized by O2 (air) under basic or even neu-
tral conditions. As can be seen from Scheme 2, when a
solution of 3,4-dihydroisoquinoline 6d in ethyl acetate
was stirred at room temperature under air for 10 h,
1
CDCl3. As can be seen from Figure 2, in the H NMR
Scheme 1 Preparations of racemic THIQs (RS)-(±)-1－4
RCOCl or Ac2O
NaOH, 0 oC, 1 h
H
POCl3, EtOAc
reflux, 6 h
MeO
MeO
MeO
N
R
CH2Cl2-H2O (2:1)
NH2
O
MeO
99% for 5a - 5d
Homoveratrylamine
5a: R = 3,4-(CH2O2)-Ph
5b: R = 3,4-(MeO)2-Ph
5c: R = Me
5d: R = 3,4-(MeO)2-PhCH2
CH3OH, KBH4
4
MeO
MeO
3
3
4
r.t., 5 h
1
N
NH
MeO
MeO
96% for (RS)-1 from 5a
R
R
97% for (RS)-2 from 5b
(RS)- -1: R = 3,4-(CH O )-Ph
(±)
95% for (RS)-3 from 5c
81% for (RS)-4 from 5d
(2 steps)
6a: R = 3,4-(CH2O2)-Ph
6b: R = 3,4-(MeO)2-Ph
6c: R = Me
2
2
(RS)- -2: R = 3,4-(MeO) -Ph
(±)
2
(RS)- -3: R = Me
(±)
(RS)-(±)-4: R = 3,4-(MeO)2-PhCH2
6d: R = 3,4-(MeO)2-PhCH2
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Efficient and Practical Syntheses of Enantiomerically Pure (S)-(−)-Norcryptostyline I
Table 1 Resolution of racemic THIQs (RS)-(±)-1－4 by using 0.5 equiv. of chiral acids as the resolving agents
THIQs
Chiral acid (0.5 equiv.)
Solvent
eea/%
Yield/%
45
[α]2D0 (R/S)
−23.7d (S)
Ib: EtOH
1
N-Ts-L-Phenylalanine
＞98
IIc: EtOAc/EtOH (1∶1)
Ib: EtOH
IIc: EtOAc/EtOH (3∶1)
Ib: EtOAc/i-PrOH (5∶1)
IIc: EtOAc/i-PrOH (7∶1)
Ib: EtOAc/EtOH (5∶1)
IIc: EtOAc
2
3
4
N-Ac-L-Phenylalanine
L-Mandelic acid
−35.0e (S)
＋59.7f (R)
−27.9g (S)
＞98
＞98
＞98
40
41
38
N-Ac-L-Phenylalanine
a Determined by 1H NMR (CDCl3, 500 MHz) with chiral acids as the CSAs (see Figure 2). b Resolution: the mixture was stirred at reflux
for 3 h in the designated solvent. c Purification: the suspension of the salt was stirred at reflux for 6 h in the designated solvent. d Optical
rotation of (S)-(−)-1: [α]2D0 ＝−23.7 (c 1.10, CHCl3) {lit.[5] [α]D20 ＝−23.0 (CHCl3)}. e Optical rotation of (S)-(−)-2: [α]2D0 ＝−35.0 (c
f
1.00, CHCl3) {lit.[5] [α]2D0 ＝−34.0 (CHCl3)}. Optical rotation of (R)-(＋)-3: [α]D20 ＝＋59.7 (c 1.10, EtOH) {lit.[16a] [α]2D0 ＝＋59.5 (c
4.39, EtOH)}. g Optical rotation of (S)-(−)-4: [α]D20 ＝−27.9 (c 1.20, CHCl3) {lit.[9] [α]D20 ＝−27.6 (c 2.50, CHCl3)}.
Scheme 2 Conversion of compound 6d to compound 7
spectra of each of the above described chiral THIQs
(S)-(−)-1, (S)-(–)-2, (R)-(＋)-3 and (S)-(−)-4, only one
absorbing peak of H-1 appeared in the presence of the
same CSA, meaning that only one enantiomer existed in
each of the chiral THIQs to be measured.
Chiral compounds usually can be racemized by ther-
mal methods, base-catalyzed methods, acid-catalyzed
methods, enzyme-catalyzed methods, redox methods,
and so on.[19] In this article, we have tried the racemiza-
tion of the enantiomerically enriched THIQs (R)-(＋)-1,
(R)-(＋)-2, (S)-(−)-3 and (R)-(＋)-4 from the mother
liquors by both base-catalyzed and redox methods.
We first examined a base-catalyzed method for the
racemization of THIQs (R)-(＋)-1, (R)-(＋)-2, (S)-(−)-3
4
4
MeO
MeO
3
3
EtOAc, Air
r.t., 10 h
N
N
MeO
MeO
MeO
MeO
90%
O
MeO
MeO
6d
3,4-Dihydropapaveraldine 7
spectra of each of the racemic THIQs (RS)-(±)-1－4,
the absorbing peak of H-1 (proton at the C-1 position)
split into two groups in the presence of various CSAs as
1
indicated in Figure 2. In comparison, in the H NMR
Figure 2 Determination of purities of chiral THIQs 1－4 by NMR method using chiral acids as the chiral solvating agents (CSAs). CSA:
(A) 1 equiv. of dibenzoyl-D-tartaric acid; (B) 1 equiv. of N-(p-tosyl)-L-phenylalanine; (C) 1 equiv. of L-mandelic acid; (D) 3 equiv. of
N-(p-tosyl)-L-leucine.
Chin. J. Chem. 2014, 32, 1039—1048
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Zhu et al.
FULL PAPER
and (R)-(＋)-4. As shown in Scheme 3, 1-aryl-THIQs
(R)-(＋)-1 and (R)-(＋)-2 smoothly underwent racemi-
zation at 120 ℃ in aqueous dimethyl sulfoxide
(DMSO/H2O＝10∶1) in the presence of 3.0 equiv. of
KOH and 2.0 equiv. of KBH4 under an atmosphere of
nitrogen (or argon) to afford racemic THIQs (RS)-(±)-1
and (RS)-(±)-2 in 90% and 91% yields, respectively.
Exclusive removal of oxygen was necessary, otherwise
THIQs (R)-(＋)-1 and (R)-(＋)-2 could be oxidized by
oxygen. The above base-catalyzed racemization of
1-aryl-THIQs (R)-(＋)-1 and (R)-(＋)-2 might follow
the same mechanism as proposed in a previous report.[3a]
Regrettably, the above base-catalyzed racemization was
not applicable for 1-alkyl-THIQs (S)-(−)-3 and
(R)-(＋)-4 probably because of the low acidity of the
H-1 protons of 1-alkyl-THIQs (S)-(−)-3 and (R)-(＋)-4.
We next examined two redox methods (Schemes 4
and 5) for the racemization of THIQs (R)-( ＋ )-1,
(R)-(＋)-2, (S)-(−)-3 and (R)-(＋)-4. As shown in
Scheme 4, the first redox method can only be applied to
the racemization of 1-aryl-THIQs (R)-( ＋ )-1 and
(R)-( ＋ )-2. It contained the following three steps:
THIQs (R)-(＋)-1 and (R)-(＋)-2 were treated with 1.1
equiv. of p-toluenesulfonyl chloride and 2.0 equiv. of
triethylamine in dichloromethane to afford N-Ts-THIQs
8a and 8b in nearly quantitative yields. N-Ts-THIQs 8a
and 8b were then treated with 3.0 equiv. of NaOH at 70
℃ in aqueous DMSO (DMSO/H2O＝10∶1) to give
dihydroisoquinolines 6a and 6b by β-elimination.[20]
Subsequently, compounds 6a and 6b were reduced by
2.0 equiv. of KBH4 in methanol to furnish the racemic
THIQs (RS)-(±)-1 and (RS)-(±)-2 in 85% and 86%
overall yields, respectively.
Scheme
3
Base-catalyzed racemization of 1-aryl THIQs
(R)-(＋)-1 and (R)-(＋)-2
KOH, KBH4,
120 oC for 4 h in
MeO
MeO
MeO
MeO
DMSO-H2O (10:1)
NH
NH
90% for (RS)-1
91% for (RS)-2
R
R
As shown in Scheme 5, the second redox method
can be applicable for the racemization of both 1-aryl-
THIQs and 1-alkyl-THIQs. It contained the following
(±)
(RS)- -1
(R)-(+)-1
(R)-(+)-2
(RS)-(±) -2
Scheme 4 Redox racemization of THIQs (R)-(＋)-1 and (R)-(＋)-2 via N-Ts-THIQs intermediates
TsCl, Et3N
0 oC, 1 h in CH2Cl2
NaOH, 70 oC
MeO
MeO
MeO
MeO
0.5 h in DMSO-H2O (10:1)
NH
NTs
R
R
(R)-(+)-1
8a: R = 3,4-(CH2O2)-Ph
8b: R = 3,4-(MeO)2-Ph
(R)-(+)-2
MeO
MeO
MeO
KBH4, r.t., 5 h in CH3OH
N
NH
R
85% for (RS)-1
86% for (RS)-2
(over 3 steps)
MeO
(RS)-(±)-1
(±)
R
6a: R = 3,4-(CH2O2)-Ph
6b: R = 3,4-(MeO)2-Ph
(RS)- -2
Scheme 5 One-pot redox racemization of THIQs (R)-(＋)-1, (R)-(＋)-2, (S)-(–)-3 and (R)-(＋)-4 via N-Cl-THIQs intermediates
NaClO, 0 oC,
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeOH-H2O (6:1)
or
or
NH
NH
N
N
Cl
Cl
R
R
(R)-(+)-1
(S)-(-)-3
9a: R = 3,4-(CH2O2)-Ph
9b: R = 3,4-(MeO)2-Ph
9d: R = 3,4-(MeO)2PhCH2
9c
(R)-(+)-2
(R)-(+)-4
NaOH, 0 oC, 2 h
MeOH-H2O (6:1)
AcOH, KBH4, 0 oC to r.t., 1 h,
MeOH-H2O (6:1)
MeO
MeO
MeO
MeO
N
NH
98% for (RS)-1, 98% for (RS)-2
97% for (RS)-3, 95% for (RS)-4
3 steps in one-pot
(over 3 steps)
R
R
6a - 6d
(±)
(RS)- -1-4
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Chin. J. Chem. 2014, 32, 1039—1048

Efficient and Practical Syntheses of Enantiomerically Pure (S)-(−)-Norcryptostyline I
dichloromethane (40 mL), and the resulting solution
was sealed with a drying tube (CaCl2), and should be
immediately used.
three steps: THIQs (R)-(＋)-1, (R)-(＋)-2, (S)-(−)-3 and
(R)-(＋)-4 were treated with 1.5 equiv. of NaClO and
2.0 equiv. of NaOH at 0 ℃ in aqueous methanol
(MeOH/H2O＝6∶1) to give N-Cl-THIQs 9a－9d,[21]
which immediately underwent β-elimination to afford
the corresponding dihydroisoquinolines 6a－6d. Sub-
sequently, compounds 6a－6d were reduced by 2.0
equiv. of KBH4 in the presence of 5.0 equiv. of AcOH in
the same solvent to afford the racemic THIQs (RS)-(±)-
1－4 in 98%, 98%, 97% and 95% overall yields, re-
spectively. Notably, the above redox racemizations of
THIQs (R)-(＋)-1, (R)-(＋)-2, (S)-( −)-3 and (R)-(＋)-4
were accomplished in a one-pot procedure without iso-
lation of intermediates N-Cl-THIQs 9a－9d and com-
pounds 6a－6d.
Homoveratrylamine (18.12 g, 99.98 mmol) was dis-
solved in dichloromethane (160 mL), and a solution of
sodium hydroxide (8.000 g, 200.0 mmol) in water (100
mL) was added. While the biphasic solution was vigor-
ously stirred and cooled to 0 ℃ by an ice-bath, a solu-
tion of the above prepared carboxylic chloride RCOCl
(120.0 mmol) or acetic anhydride (7.206 g, 120.0 mmol)
in dichloromethane (40 mL) was slowly added over 30
min. After the addition was finished, the biphasic mix-
ture was further stirred at 0 ℃ for 1 h. Two phases
were then separated, and the aqueous phase was ex-
tracted twice with dichloromethane (50 mL×2). Ex-
tracts were combined, and dried over anhydrous magne-
sium sulfate. Solvent was then removed by vacuum dis-
tillation. The solid residue was triturated in aqueous
ethanol (EtOH/H2O＝1∶1), pure amides 5a－5d as
off-white crystals were obtained in almost quantitative
yields by suction through a Buchner funnel.
Conclusions
In conclusion, a resolution-racemization process of
1-substituted THIQs (RS)-(±)-1－4 has been investi-
gated. Accordingly, enantiomerically pure (S)-(−)-nor-
cryptostyline I [(S)-(−)-1], (S)-(−)-norcryptostyline II
[(S)-(−)-2], (R)-(＋)-salsolidine [(R)-(＋)-3] and (S)-(−)-
norlaudanosine [(S)-(−)-4] were efficiently synthesized.
Several methods for the racemization of the enantio-
merically enriched THIQs (R)-( ＋ )-1, (R)-( ＋ )-2,
(S)-(−)-3 and (R)-(＋)-4 from the mother liquors have
been studied, and it was found that the mild one-pot
redox racemization via N-Cl-THIQs intermediates was
the most efficient and convenient method. In addition,
NMR method using appropriate CSAs for determining
the enantiomerical purities of chiral THIQs (S)-(−)-1,
(S)-(−)-2, (R)-(＋)-3 and (S)-(−)-4 was discussed.
Characterization data of amides 5a－5d are as fol-
lows:
N-(3,4-Dimethoxyphenethyl)-3,4-methylenedioxy-
benzamide (5a) Off-white crystals. m.p. 113－114
℃; 1H NMR (CDCl3, 400 MHz) δ: 2.85 (t, J＝7.0 Hz, 2
H, (MeO)2PhCH2), 3.64 (td, J1＝7.0 Hz, J2＝5.3 Hz, 2H,
CH2N), 3.82 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 5.99 (s,
2H, OCH2O), 6.39 (t, J＝5.3 Hz, 1H, NH), 6.70－6.85
(m, 4H, Ar-H), 7.18－7.25 (m, 2H, Ar-H); 13C NMR
(CDCl3, 100 MHz) δ: 35.23, 41.38, 55.79, 55.89, 101.66,
107.52, 107.93, 111.32, 111.90, 120.65, 121.41, 128.80,
131.47, 147.62, 147.90, 148.97, 150.22, 166.79; IR
(KBr) ν: 3304, 2968, 2938, 2842, 1765 (weak), 1641,
1608, 1548, 1517, 1488, 1315, 1262, 1241, 1143, 1027,
936, 808, 700 cm−1. HRMS calcd for C18H19NO5 [M＋]:
329.1263, found 329.1262.
Experimental
General methods
N-(3,4-Dimethoxyphenethyl)-3,4-dimethoxyben-
zamide (5b) Off-white crystals. m.p. 152－153 ℃;
1H NMR (CDCl3, 400 MHz) δ: 2.87 (t, J＝7.0 Hz, 2H,
(MeO)2PhCH2), 3.66 (td, J1＝7.0 Hz, J2＝5.3 Hz, 2H,
CH2N), 3.82 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.88 (s,
3H, OCH3), 3.89 (s, 3H, OCH3), 6.48 (t, J＝5.3 Hz, 1H,
NH), 6.73－6.77 (m, 2H, Ar-H), 6.81 (d, J＝8.5 Hz, 2H,
Ar-H), 7.22 (dd, J1＝8.5 Hz, J2＝1.9 Hz, 1H, Ar-H),
7.41 (d, J＝1.9 Hz, 1H, Ar-H); 13C NMR (CDCl3, 100
MHz) δ: 35.27, 41.37, 55.78, 55.87, 55.91, 55.95,
110.20, 110.45, 111.28, 111.94, 119.25, 120.65, 127.18,
131.51, 147.61, 148.87, 148.96, 151.60, 167.06; IR
(KBr) ν: 3293, 2966, 2928, 2839, 1732 (weak), 1630,
1546, 1516, 1457, 1320, 1258, 1233, 1137, 1021, 823,
713 cm−1. HRMS calcd for C19H23NO5 [M＋]: 345.1576;
found 345.1578.
1H NMR and 13C NMR spectra were acquired on
Bruker AM-500 or AM-400, chemical shifts were given
on the delta scale as parts per million (ppm) with
tetramethylsilane (TMS) as the internal standard. IR
spectra were recorded on Nicolet Magna IR-550. Mass
spectra were recorded on HP5989A. Melting points
were determined on a Mel-TEMP II apparatus. Optical
rotations of chiral compounds were measured on
WZZ-1S automatic polarimeter at room temperature.
Column chromatography was performed on silica gel
(Qingdao Ocean Chemical Corp.). All chemicals were
analytically pure, and were used as such from commer-
cial suppliers.
General procedure for preparation of amides 5a－5d
A mixture of the carboxylic acid RCOOH (120.0
mmol), chloroform (20 mL) and thionyl chloride (28.55
g, 240.0 mmol) was stirred at reflux for 2 h, chloroform
and the excessive thionyl chloride were then removed
by vacuum distillation. The residue was dissolved in
N-(3,4-Dimethoxyphenethyl)acetamide
(5c)
1
Off-white solid crystals. m.p. 96－97 ℃; H NMR
(CDCl3, 500 MHz) δ: 1.95 (s, 3H, CH3 in Ac), 2.77 (t,
J＝7.0 Hz, 2H, (MeO)2PhCH2), 3.46－3.54 (m, 2H,
CH2N), 3.86 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 5.60
Chin. J. Chem. 2014, 32, 1039—1048
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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1043

Zhu et al.
FULL PAPER
(brs, 1H, NH), 6.72 (s, 1H, Ar-H), 6.73 (d, J＝7.9 Hz,
1H, Ar-H), 6.82 (d, J＝7.9 Hz, 1H, Ar-H); 13C NMR
(CDCl3, 100 MHz) δ: 23.11, 35.14, 40.86, 55.74, 55.81,
111.26, 111.81, 120.56, 131.47, 147.48, 148.84, 170.28;
IR (KBr) ν: 3253, 3086, 2993, 2929, 2841, 1730 (weak),
1633, 1568, 1520, 1473, 1263, 1236, 1157, 1140, 1020,
815, 766, 611 cm−1; MS (EI) m/z (%): 223 [M＋] (8), 164
(100), 151 (38), 149 (17), 137 (2), 121 (2), 107 (4), 91
(1). HRMS calcd for C12H17NO3 [M＋]: 223.1208, found
223.1209.
6.86 (d, J＝8.0 Hz, 1H, Ar-H), 7.11 (dd, J1＝8.0 Hz,
J2＝1.4 Hz, 1H, Ar-H), 7.14 (d, J＝1.4 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ: 26.03, 47.49, 56.01, 56.17,
101.26, 107.83, 109.25, 110.21, 111.50, 121.45, 123.08,
132.75, 133.28, 147.00, 147.60, 148.59, 150.84, 165.96;
IR (KBr) ν: 2935, 2834, 1734 (weak), 1603, 1560, 1512,
1488, 1443, 1355, 1279, 1238, 1112, 1037, 933, 800
cm−1. HRMS calcd for C18H17NO4 [M＋]: 311.1158,
found 311.1157.
1-(3,4-Dimethoxyphenyl)-6,7-dimethoxy-3,4-dihy-
droisoquinoline (6b) Pale yellow crystals. mp. 169－
N-(3,4-Dimethoxyphenethyl)-2-(3,4-dimethoxy-
phenyl)acetamide (5d)
Off-white crystals. m.p.
1
170 ℃; H NMR (CDCl3, 400 MHz) δ: 2.72 (t, J＝7.2
1
123－124 ℃; H NMR (CDCl3, 400 MHz) δ: 2.68 (t,
J＝6.9 Hz, 2H, (MeO)2PhCH2CH2N), 3.44 (td, J1＝6.9
Hz, J2＝5.7 Hz, 2H, CH2N), 3.47 (s, 2H, CH2CON),
3.83 (s, 6H, two OCH3), 3.86 (s, 3H, OCH3), 3.88 (s, 3H,
OCH3), 5.53 (t, J＝5.7 Hz, 1H, NH), 6.53 (dd, J1＝8.1
Hz, J2＝1.8 Hz, 1H, Ar-H), 6.62 (d, J＝1.8 Hz, 1H,
Ar-H), 6.65－6.75 (m, 3H, Ar-H), 6.80 (d, J＝8.0 Hz,
1H, Ar-H); 13C NMR (CDCl3, 100 MHz) δ: 34.97, 40.69,
43.41, 55.79, 55.81, 55.83, 55.87, 111.06, 111.36,
111.63, 112.32, 120.55, 121.56, 127.20, 131.03, 147.57,
148.22, 148.95, 149.18, 171.23; IR (KBr) ν: 3325, 3062,
3005, 2914, 2838, 1731 (weak), 1642, 1544, 1517, 1470,
1232, 1143, 1026, 856, 765 cm−1; MS (EI) m/z (%): 359
[M＋] (9), 195 (4), 164 (100), 151 (29), 107 (4). HRMS
calcd for C20H25NO5 [M＋]: 359.1733, found 359.1732.
Hz, 2H, both H-4), 3.76 (s, 3H, OCH3), 3.79 (t, J＝7.2
Hz, 2H, both H-3), 3.93 (s, 3H, OCH3), 3.94 (s, 3H,
OCH3), 3.96 (s, 3H, OCH3), 6.80 (s, 1H, Ar-H), 6.89 (s,
1H, Ar-H), 6.92 (d, J＝8.3 Hz, 1H, Ar-H), 7.17 (dd,
J1＝8.3 Hz, J2＝1.6 Hz, 1H, Ar-H), 7.25 (d, J＝1.6 Hz,
1H, Ar-H); 13C NMR (CDCl3, 100 MHz) δ: 26.06, 47.53,
55.91, 55.92, 56.00, 56.11, 110.19, 110.26, 111.53,
111.66, 121.52, 121.82, 131.77, 132.79, 146.92, 148.69,
150.00, 150.74, 166.07; IR (KBr) ν: 2938, 2888, 2837,
1738 (weak), 1602, 1563, 1514, 1462, 1355, 1279, 1256,
1210, 1160, 1113, 1017, 865, 801 cm−1. HRMS (ESI)
calcd for C19H21NO4 [M＋]: 327.1471, found 327.1473.
6,7-Dimethoxy-1-methyl-3,4-dihydroisoquinoline
(6c) Pale yellow crystals. m.p. 108－109 ℃; 1H
NMR (CDCl3, 500 MHz) δ: 2.37 (s, 3H, CH3), 2.64 (t,
J＝7.5 Hz, 2H, both H-4), 3.63 (t, J＝7.5 Hz, 2H, both
H-3), 3.91 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 6.69 (s,
1H, Ar-H), 6.99 (s, 1H, Ar-H); 13C NMR (CDCl3, 100
MHz) δ: 23.39, 25.65, 46.95, 55.85, 56.09, 108.83,
110.11, 122.36, 130.98, 147.30, 150.67, 163.49; IR
(KBr) ν: 2945, 2925, 2839, 1627, 1604, 1574, 1516,
1288, 1277, 1215, 1159, 1063, 874, 810 cm−1; MS (EI)
m/z (%): 205 [M＋] (100), 204 (53), 190 (48), 188 (8),
174 (11), 160 (7), 147 (6), 131 (3), 118 (4), 103 (3), 91
(4), 77 (4). HRMS calcd for C12H15NO2 [M＋]: 205.1103,
found 205.1102.
General procedure for the preparation of 1-substi-
tuted 6,7-dimethoxy-3,4-dihydroisoquinolines (6a－
6d)
An amide 5 (60.00 mmol) was dissolved in EtOAc
(200 mL), and POCl3 (18.40 g, 120.0 mmol) was drop-
wise added over 5 min. The mixture was then heated
and stirred at reflux under an atmosphere of nitrogen (or
argon) for 6 h. After the Bischler-Napieralski reaction
was finished as monitored by TLC (EtOAc/hexane＝
2∶1), the solvent was removed by vacuum distillation.
The residue was then partitioned between CH2Cl2 (200
mL) and an aqueous solution of K2CO3 (15% w/w, 200
mL). Two phases were separated, and the aqueous phase
was extracted twice with CH2Cl2 (100 mL×2). Organic
extracts were combined, and dried over anhydrous
MgSO4. Solvent was removed by vacuum distillation to
give 1-substituted 6,7-dimethoxy-3,4-dihydroisoquino-
lines (6a－6d) as pale yellow crystals. Compounds
6a－6c were pure enough, and could be used as such for
the next step. Compound 6d was purified by flash
chromatography (eluent: CH2Cl2/MeOH＝25∶1).
Characterization data of amides 6a－6d are as fol-
lows:
1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-3,4-dihy-
droisoquinoline (6d) Pale yellow crystals. m.p. 99－
1
100 ℃; H NMR (CDCl3, 400 MHz) δ: 2.65 (t, J＝7.6
Hz, 2H, both H-4), 3.73 (t, J＝7.6 Hz, 2H, both H-3),
3.76 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.83 (s, 3H,
OCH3), 3.88 (s, 3H, OCH3), 3.99 (s, 2H, (MeO)2PhCH2),
6.66 (s, 1H, Ar-H), 6.78 (d, J＝8.7 Hz, 1H, Ar-H),
6.82－6.90 (m, 2H, Ar-H), 7.00 (s, 1H, Ar-H); 13C NMR
(CDCl3, 100 MHz) δ: 25.79, 43.04, 47.16, 55.78, 55.81,
55.88, 55.97, 109.55, 110.20, 111.21, 111.56, 120.64,
121.56, 130.59, 131.79, 147.16, 147.59, 148.97, 150.62,
165.59; IR (KBr) ν: 2934, 2834, 1606, 1573, 1516, 1465,
1447, 1356, 1447, 1234, 1147, 1022, 856, 811, 764 cm−1;
MS (EI) m/z (%): 341 [M＋] (57), 340 (100), 326 (40),
310 (36), 294 (12), 279 (6), 266 (4), 252 (3), 155 (7),
151 (8), 107 (2). HRMS calcd for C20H23NO4 [M＋]:
341.1627, found 341.1628.
1-(3,4-Methylenedioxyphenyl)-6,7-dimethoxy-3,4-
dihydroisoquinoline (6a) Pale yellow crystals. m.p.
1
109－110 ℃; H NMR (CDCl3, 500 MHz) δ: 2.71 (t,
J＝7.3 Hz, 2H, both H-4), 3.768 (s, 3H, OCH3), 3.770 (t,
J＝7.3 Hz, 2H, both H-3), 3.95 (s, 3H, OCH3), 6.02 (s,
2H, OCH2O), 6.78 (s, 1H, Ar-H), 6.85 (s, 1H, Ar-H),
1044
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 1039—1048

Efficient and Practical Syntheses of Enantiomerically Pure (S)-(−)-Norcryptostyline I
General procedure for preparation of racemic
1-substituted 6,7-dimethoxy-1,2,3,4-tetrahydroisoqui-
nolines (RS)-(±)-1－4
6,7-Dimethoxy-1-methyl-1,2,3,4-tetrahydroisoqui-
noline (RS)-(±)-3 White crystals. m.p. 48－49 ℃;
1H NMR (CDCl3, 500 MHz) δ: 1.44 (d, J＝6.6 Hz, 3H,
CH3), 1.80 (brs, 1H, NH), 2.61－2.68 (m, 1H, H-4),
2.75－2.84 (m, 1H, another H-4), 2.96－3.05 (m, 1H,
H-3), 3.22－3.28 (m, 1H, another H-3), 3.85 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 4.05 (q, J＝6.6 Hz, 1H,
H-1), 6.57 (s, 1H, Ar-H), 6.63 (s, 1H, Ar-H); 13C NMR
(CDCl3, 125 MHz) δ: 23.15, 29.81, 42.09, 51.56, 56.24,
56.39, 109.51, 112.21, 127.14, 132.72, 147.66, 147.74;
IR (KBr) ν: 3408, 2966, 2935, 2837, 1612, 1520, 1464,
1404, 1257, 1227, 1136, 1115, 997, 860 cm−1; MS (EI)
m/z (%): 207 [M＋] (6), 192 (100), 176 (10), 163 (2), 148
(5), 131 (2), 91 (2), 77 (2). HRMS calcd for C12H17NO2
[M＋]: 207.1259, found 207.1258.
1-Substituted 3,4-dihydro-6,7-dimethoxylisoquinolines
6 (50.00 mmol) was dissolved in methanol (150 mL),
KBH4 (5.400 g, 100.1 mmol) was added in small por-
tions over 20 min. After the addition was finished, the
mixture was further stirred at room temperature for 5 h.
Methanol was removed by vacuum distillation, the
residue was then partitioned between dichloromethane
(200 mL) and water (100 mL). Two phases were sepa-
rated, and the aqueous phase was extracted twice with
dichloromethane (50 mL×2). Extracts were combined
and dried over anhydrous MgSO4. Evaporation of di-
chloromethane under vacuum gave crude solid products.
Crude compounds (RS)-(±)-1－3 were triturated in a
mixed solvent of ethyl acetate and hexane (1∶2), and
the suspension was filtered by suction to afford pure
(RS)-(±)-1－3 in 96%, 97% and 95% yields, respec-
tively. Crude compound (RS)-(±)-4 was purified by
flash chromatography (eluent: CH2Cl2/MeOH＝20∶1)
to afford pure compound (RS)-(±)-4 in 81% yield.
Characterization data of racemic THIQs (RS)-(±)-
1－4 are as follows:
1-(3,4-Methylenedioxyphenyl)-6,7-dimethoxy-1,2,
3,4-tetrahydroisoquinoline (RS)-(±)-1 White crys-
tals. m.p. 135－136 ℃; 1H NMR (CDCl3, 500 MHz) δ:
2.04 (brs, 1H, NH), 2.68－2.76 (m, 1H, H-4), 2.86－
2.95 (m, 1H, another H-4), 2.98－3.06 (m, 1H, H-3),
3.16－3.25 (m, 1H, another H-3), 3.67 (s, 3H, OCH3),
3.87 (s, 3H, OCH3), 4.98 (s, 1H, H-1), 5.94 (s, 2H,
OCH2O), 6.27 (s, 1H, Ar-H), 6.62 (s, 1H, Ar-H), 6.69－
6.79 (m, 3H, Ar-H); 13C NMR (CDCl3, 125 MHz) δ:
29.89, 42.49, 56.41, 56.47, 61.80, 101.54, 108.41,
109.72, 111.50, 111.99, 122.77, 128.22, 130.55, 139.64,
147.36, 147.64, 148.21, 148.28; IR (KBr) ν: 3425, 3253,
2910, 1610, 1519, 1488, 1445, 1251, 1216, 1124, 1043,
943, 835, 762 cm−1; MS (EI) m/z (%): 313 [M＋] (58),
312 (77), 298 (14), 282 (6), 268 (3), 254 (7), 239 (2),
192 (100), 181 (8), 176 (8), 148 (6), 81 (3). HRMS
calcd for C18H19NO4 [M＋]: 313.1314, found 313.1312.
1-(3,4-Dimethoxyphenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (RS)-(±)-2 White crystals.
m.p. 104－105 ℃; 1H NMR (CDCl3, 500 MHz) δ: 2.20
(brs, 1H, NH), 2.68－2.78 (m, 1H, H-4), 2.90－3.00(m,
1H, another H-4), 3.02－3.10(m, 1H, H-3), 3.19－3.28
(m, 1H, another H-3), 3.65 (s, 3H, OCH3), 3.83 (s, 3H,
OCH3), 3.876 (s, 3H, OCH3), 3.878 (s, 3H, OCH3), 5.00
(s, 1H, H-1), 6.27 (s, 1H, Ar-H), 6.63 (s, 1H, Ar-H),
6.75－6.86 (m, 3H, Ar-H); 13C NMR (CDCl3, 125 MHz)
δ: 29.73, 42.72, 56.31, 56.355, 56.358, 56.361, 61.93,
111.19, 111.41, 111.90, 112.31, 121.73, 128.06, 130.60,
137.84, 147.48, 148.08, 148.80, 149.47; MS (EI) m/z
(%): 329 [M＋] (68), 328 (91), 314 (19), 298 (9), 286 (3),
269 (13), 254 (3), 238 (4), 192 (100), 176 (7), 164 (3).
HRMS (ESI) calcd for C19H23NO4 [M＋]: 329.1627;
found: 329.1628.
1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (RS)-(±)-4 White crystals.
1
m.p. 79－80 ℃; H NMR (CDCl3, 400 MHz) δ: 1.85
(brs, 1H, NH), 2.64－2.81 (m, 2H, both H-4), 2.81－
2.95 (m, 2H, CH2 beside C-1), 3.12－3.25 (m, 2H, both
H-3), 3.84 (s, 3H, OCH3), 3.86 (s, 6H, two OCH3), 3.88
(s, 3H, OCH3), 4.13 (dd, J1＝9.1 Hz, J2＝4.1 Hz, 1H,
H-1), 6.60 (s, 1H, Ar-H), 6.67 (s, 1H, Ar-H), 6.76 (s, 1H,
Ar-H), 6.78－6.86 (m, 2H, Ar-H); 13C NMR (CDCl3,
100 MHz) δ: 29.46, 40.90, 42.19, 55.81, 55.84, 55.89,
55.96, 56.83, 109.29, 111.24, 111.76, 112.33, 121.41,
127.37, 130.32, 131.37, 146.95, 147.39, 147.62, 148.89;
IR (KBr) ν: 3598, 3332, 2995, 2934, 2833, 1608, 1514,
1464, 1262, 1233, 1113, 1029, 858, 803, 768 cm−1; MS
(EI) m/z (%): 343 [M＋] (1), 340 (4), 206 (1), 192 (100),
176 (7), 151 (3), 148 (3), 131 (1), 118 (1), 107 (1).
HRMS calcd for C20H25NO4 [M＋]: 343.1784, found
343.1788.
Formation of 3,4-dihydropapaveraldine (7)
Compound 6d (1.000 g, 2.929 mmol) was dissolved in
ethyl acetate (15 mL). The solution was stirred at room
temperature under air for 10 h. Ethyl acetate was re-
moved by vacuum distillation, and the residue was puri-
fied by flash chromatography (eluent: EtOAc/hexane＝
1∶5) to afford 3,4-dihydropapaveraldine 7 (936.5 mg,
2.635 mmol) in 90% yield. m.p. 188－190 ℃; 1H NMR
(CDCl3, 400 MHz) δ: 2.82 (t, J＝8.0 Hz, 2H, both H-4),
3.79 (s, 3H, OCH3), 3.93 (t, J＝8.0 Hz, 2H, both H-3),
3.94 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 3.96 (s, 3H,
OCH3), 6.76 (s, 1H, Ar-H), 6.88 (d, J＝8.4 Hz, 1H,
Ar-H), 6.91 (s, 1H, Ar-H), 7.60 (dd, J1＝8.4 Hz, J2＝1.9
Hz, 1H, Ar-H), 7.67 (d, J＝1.9 Hz, 1H, Ar-H); 13C
NMR (CDCl3, 100 MHz) δ: 25.44, 47.27, 56.01, 56.02,
56.12, 56.14, 109.68, 110.05, 110.53, 111.29, 119.53,
126.57, 128.63, 131.07, 147.67, 149.18, 151.69, 154.18,
164.63, 192.77; IR (KBr) ν: 2969, 2833, 1728, 1660,
1583, 1515, 1460, 1361, 1278, 1269, 1134, 1024, 866,
631 cm−1. HRMS (ESI) calcd for C20H21NO5 [M＋]:
355.1420, found 355.1421.
Typical procedure for the resolution of racemic
1-substituted 6,7-dimethoxy-1,2,3,4-tetrahydroisoqui-
nolines (RS)-(±)-1－4
Racemic compound (RS)-(±)-1 (4.010 g, 12.80
Chin. J. Chem. 2014, 32, 1039—1048
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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1045

Zhu et al.
FULL PAPER
Base-catalyzed racemization of the enantiomerically
enriched 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinolines (R)-(＋)-1 and (R)-(＋)-2
mmol) was dissolved in absolute ethanol (80 mL), and
the resulting solution was transferred into a three-
necked round bottom flask, which was equipped with a
mechanical stirrer and a condenser. The powdered
N-tosyl-L-phenylalanine (2.045 g, 6.403 mmol) was
added in portions. After the addition was finished, the
mixture was vigorously stirred at reflux for 3 h. After
the mixture was cooled down to room temperature, the
white solid was collected on Buchner funnel by suction.
The solid was totally transferred into the above
three-necked round bottom flask, a mixed solvent of
ethyl acetate (50 mL) and ethanol (50 mL) was added.
The suspension was then vigorously stirred at reflux for
6 h. After the suspension was cooled down to room
temperature, it was filtered by suction. White solid was
then partitioned between dichloromethane (100 mL) and
an aqueous solution of ammonia (60 mL, 10% w/w).
Two phases were separated, and the aqueous phase was
twice extracted with dichloromethane (50 mL×2). The
extracts were combined, and dried over anhydrous
MgSO4. Evaporation of the solvent under vacuum af-
forded pure (S)-(−)-norcryptostyline I (S)-(−)-1 (1.805 g,
5.760 mmol) as white crystals in 45% yield, [α]2D0 ＝
−23.7 (c 1.10, CHCl3) {lit.[5] [α]D20 ＝−23.0 (CHCl3)}.
The mother liquors of the above suctions were com-
bined in a flask, and were then concentrated under vac-
uum to give a viscous oil. An aqueous solution of am-
monia (65 mL, 10% w/w) and dichloromethane (120 mL)
were then added into the flask. After the mixture was
vigorously stirred for 15 min, two phases were sepa-
rated with a separatory funnel, and the aqueous phase
was twice extracted with dichloromethane (60 mL×2).
The extracts were combined, and dried over anhydrous
MgSO4. Evaporation of the solvent under vacuum af-
forded (R)-(＋)-norcryptostyline I (R)-(＋)-1 (2.208 g,
7.046 mmol) as off-white crystals in 55% yield and with
82% ee, [α]2D0 ＝＋19.4 (c 1.25, CHCl3).
The enantiomerically enriched 1-aryl-THIQ (R)-
(＋)-1 or (R)-(＋)-2 (5.000 mmol) was dissolved in
DMSO (20 mL). An aqueous solution of KOH (842.0
mg, 15.01 mmol) in H2O (2 mL) was added, and KBH4
(540.0 mg, 10.01 mmol) was also added. The mixture
was then heated to 120 ℃, and stirred at this tempera-
ture for 4 h under an atmosphere of nitrogen. The mix-
ture was cooled down to room temperature, and water
(50 mL) was slowly added. When the mixture was
stirred for about 15 min, off-white crystals precipitated.
The suspension was filtered by suction, racemic com-
pound (RS)-(±)-1 (1.410 g, 4.500 mmol) or (RS)-(±)-2
(1.500 g, 4.554 mmol) was then obtained in 90% or
91% yield after drying overnight.
Redox racemization of the enantiomerically enriched
1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines
(R)-(＋)-1 and (R)-(＋)-2 via N-tosyl-THIQs inter-
mediates
The enantiomerically enriched 1-aryl-THIQ (R)-(＋)-
1 or (R)-(＋)-2 (5.000 mmol) was dissolved in di-
chloromethane (40 mL). After the solution was cooled
down to 0 ℃ by an ice-bath, Et3N (1.015 g, 10.03
mmol) and TsCl (1.050 g, 5.508 mmol) were added in
turn. The resulting solution was then stirred at 0 ℃ for
1 h, and an aqueous solution of K2CO3 (20 mL, 10%
w/w) was added. After the mixture was vigorously
stirred for 10 min, two phases were separated, and the
aqueous phase was extracted twice with dichloro-
methane (20 mL×2). Organic extracts were combined
and dried over anhydrous MgSO4. After dichloro-
methane was removed by evaporation, N-Ts-THIQs 8a
or 8b was obtained, and was then used as such for the
next step.
N-Ts-THIQs 8a or 8b was dissolved in DMSO (15
mL), and an aqueous solution of NaOH (600.0 mg,
15.00 mmol) in water (1.5 mL) was added. The mixture
was warmed to 70 ℃, and stirred at this temperature for
2.5 h under an atmosphere of nitrogen (or argon). After
the reaction mixture was cooled down to room tem-
perature, dichloromethane (80 mL) and water (60 mL)
were added. Two phases were separated, and the aque-
ous phase was extracted twice with dichloromethane (50
mL×2). Extracts were combined, and dried over anhy-
drous MgSO4. Removal of the solvent gave compound
6a or 6b, which was immediately dissolved in methanol
(30 mL). KBH4 (540.0 mg, 10.01 mmol) was added in
portions, and the mixture was stirred at room tempera-
ture for 5 h. Methanol was then removed by vacuum
distillation, and the residue was partitioned between
dichloromethane (50 mL) and water (40 mL). Two
phases were separated, and the aqueous phase was ex-
tracted twice with dichloromethane (25 mL×2). Ex-
tracts were combined, and dried over anhydrous MgSO4.
Evaporation of the solvent gave an oily residue, which
The results for the resolution of the other racemic
THIQs (RS)-(±)-2－4 are as follows:
(S)-(–)-Norcryptostyline II (S)-(–)-2 was obtained in
40% yield, [α]2D0 ＝−35.0 (c 1.00, CHCl3) {lit.[5] [α]2D0
＝ −34.0 (CHCl3)}. (R)-( ＋ )-Norcryptostyline II
(R)-(＋)-2 was recovered from the mother liquor in 60%
yield and with 67% ee, [α]2D0 ＝＋23.4 (c 1.05, CHCl3).
(R)-(＋)-Salsolidine (R)-(＋)-3 was obtained in 41%
yield, [α]2D0 ＝＋59.7 (c 1.10, EtOH) {lit.[16a] [α]D20 ＝
＋59.5 (c 4.39, EtOH)}. (S)-(−)-Salsolidine (S)-(−)-3
was recovered from the mother liquor in 59% yield and
with 69% ee, [α]2D0 ＝−41.3 (c 1.10, EtOH).
(S)-(−)-Norlaudanosine (S)-(−)-4 was obtained in
38% yield, [α]2D0 ＝ −27.9 (c 1.20, CHCl3) {lit.[9]
[α]2D0 ＝−27.6 (c 2.50, CHCl3)}. (R)-(＋)-Norlaudano-
sine (R)-(＋)-4 was recovered from the mother liquor in
62% yield and with 61% ee, [α]2D0 ＝−27.9 (c 1.20,
CHCl3).
1046
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 1039—1048

Efficient and Practical Syntheses of Enantiomerically Pure (S)-(−)-Norcryptostyline I
(h) He, X.-C.; Qi, C.-Y. Chin. J. Chem. 2007, 25, 583.
was purified by flash chromatography (eluent: CH2Cl2/
MeOH＝20∶1) to afford racemic compound (RS)-(±)-
1 (1.332 g, 4.251 mmol) or (RS)-(±)-2 (1.417 g, 4.302
mmol) in 85% or 86% yield.
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Typical procedure for one-pot redox racemization of
the enantiomerically enriched 1-substituted 6,7-di-
methoxy-1,2,3,4-tetrahydroisoquinolines (R)-( ＋ )-1,
(R)-(＋)-2, (S)-(−)-3 and (R)-(＋)-4 via N-chloro-
THIQs intermediates
The enantiomerically enriched 1-aryl-THIQs (R)-
(＋)-1 (5.000 mmol) was dissolved in methanol (30 mL),
and the solution was cooled down to 0 ℃ by an ice-
bath. A freshly prepared aqueous solution (5 mL) of
sodium hypochloride (1.5 mol/L) and sodium hydroxide
(2.0 mol/L) was dropwise added over 10 min, and the
mixture was further stirred at 0 ℃ for 2 h. TLC
showed that N-chloro-THIQs 9a was first formed during
the reaction, but then absolutely changed into compound
6a. Acetic acid (1.500 g, 24.99 mmol) was added, KBH4
(540.0 g, 10.01 mml) was then added in small portions
over 15 min. After the addition was finished, the mix-
ture was further stirred at 0 ℃ for 1 h. Methanol was
removed by vacuum distillation, the residue was parti-
tioned between dichloromethane (50 mL) and water (40
mL). Two phases were separated, and the aqueous phase
was extracted twice with dichloromethane (25 mL×2).
Extracts were combined, and dried over anhydrous
MgSO4. Evaporation of dichloromethane gave racemic
compound (RS)-(±)-1 (1.535 g, 4.899 mmol) as white
crystals in 98% yield.
Supporting Information
Copies of spectra of 1H and 13C NMR of compounds
1－4, 5a－5d, 6a－6d and 7.
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Acknowledgement
We thank the National Natural Science Foundation
of China (No. 20972048) for the financial support of
this work.
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 1039—1048