Syntheses of chiral 1,3-disubstituted tetrahydro-β-carbolines via CIAT process: highly stereoselective Pictet-Spengler reaction of d-tryptophan ester hydrochlorides with various aldehydes

Article abstract of DOI:10.1016/j.tetasy.2009.01.026

A highly stereoselective Pictet-Spengler reaction of d-tryptophan methyl ester hydrochloride 1-HCl with various aldehydes via a CIAT (crystallization-induced asymmetric transformation) process is described. It was revealed that the CIAT process should be

Full text of DOI:10.1016/j.tetasy.2009.01.026

Tetrahedron: Asymmetry 20 (2009) 430–439
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Syntheses of chiral 1,3-disubstituted tetrahydro-b-carbolines via CIAT
process: highly stereoselective Pictet–Spengler reaction of D-tryptophan
ester hydrochlorides with various aldehydes
*
Sen Xiao, Xia Lu, Xiao-Xin Shi , Yu Sun, Li-Li Liang, Xin-Hong Yu, Jing Dong
Department of Pharmaceutical Engineering, School of Pharmacy, East China University of Science and Technology, PO Box 363, 130 Mei-Long Road, Shanghai 200237, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly stereoselective Pictet–Spengler reaction of D-tryptophan methyl ester hydrochloride 1-HCl with
Received 15 December 2008
Accepted 20 January 2009
Available online 25 March 2009
various aldehydes via a CIAT (crystallization-induced asymmetric transformation) process is described. It
was revealed that the CIAT process should be performed in a mixed solvent of nitromethane and toluene,
and a fine tuning of the ratio of nitromethane and toluene for each epimer mixture of 2-HCl was neces-
sary in order to get as high yields and stereoselectivities as possible. Enantiomerically pure cis (or trans)
1,3-disubstituted tetrahydro-b-carbolines 2a–2v were obtained by recrystallization or flash chromatog-
raphy after neutralization of the corresponding hydrochloride salts cis-2-HCl or trans-2-HCl.
Ó 2009 Elsevier Ltd. All rights reserved.
Dedicated to Professor Li-Xin Dai in
Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences on the
occasion of his 85th birthday
1. Introduction
Unfortunately, when we tried to extend this successful CIAT
process to the P–S reaction of
chloride with other aldehydes, or even to the P–S reaction of piper-
D-tryptophan methyl ester hydro-
The asymmetric P–S (Pictet–Spengler) reaction of tryptamine1–6
or tryptophan7–12 with aldehydes provides an important and
useful tool to construct chiral synthons containing tetrahydro-b-
carbolines structural moieties which are present in many alka-
loids13–15 and in related biologically active molecules.16–19
onal with other D-tryptophan ester hydrochlorides, we failed to
obtain high stereoselectivity.23 This observation prompted us to
investigate the scope and limitation of this particular CIAT process
in detail. After an extensive study by our research group, finally we
found that the selection of the solvent for this CIAT process is
crucial, and the reaction can be successfully applied to other alde-
Recently, the P–S reaction of D-tryptophan methyl ester with
piperonal has attracted much attention from chemists and has
been well studied by several groups20–28 in order to obtain high
cis stereoselectivity, as it is the key step in the synthesis of tadalafil,
which is a cGMP-specific Type V phosphodiesterase (PDE5) inhib-
itor.29–31 Orme et al.22 have developed a practical method for
obtaining high stereoselectivity (cis:trans = 97:3) for this reaction.
Our group became interested in this particular reaction, and we
have extensively studied the impact of solvents on the P–S reaction
hydes and other
D-tryptophan ester hydrochlorides. Herein, we
report our recent work about this CIAT process.
2. Results and discussion
We have demonstrated that the P–S reaction of D-tryptophan
methyl ester hydrochloride 1-HCl with piperonal could give high
selectivities and yields in isopropanol, butanol, pentanol, nitro-
methane, acetonitrile, 1,2-dichloroethane, and 1,2-dimethoxyeth-
ane;23 as a result we first tried the direct P–S reaction of 1-HCl
with various other aldehydes in the above solvents. Unfortunately,
the reaction did not give high stereoselectivities in most cases, be-
cause the CIAT process did not work well in the above solvents.
However, we did observe that nitromethane seemed to be better
than the other solvents, for example, the P–S reaction of 1-HCl with
3,4,5-trimethoxybenzaldehyde in nitromethane gave the corre-
sponding 1,3-trans disubstituted tetrahydro-b-carboline 2a-HCl in
high stereoselectivity and good yield (Table 1, entry 1). When we
tried the same reaction in a mixed solvent of nitromethane and
toluene (nitromethane/toluene = 1:1), it worked very well and pro-
duced 2a-HCl in better stereoselectivity and a better yield (Table 1,
entry 2). We found that the use of a mixed solvent of nitromethane
of D
-tryptophan methyl ester hydrochloride with piperonal.23 We
have found that excellent cis stereoselectivity (cis:trans = 99:1)
could be obtained when the reaction was performed in acetonitrile
or nitromethane. A process of crystallization-induced asymmetric
transformation (CIAT)32–43,22,23 took place in the P–S reaction of
D-tryptophan methyl ester hydrochloride with piperonal in an
appropriate solvent, the large difference of solubility of both the
diastereomer products, that is, hydrochloride salts of cis and trans
1,3-disubstituted tetrahydro-b-carbolines, played an important
role and would shift the equilibrium between these two hydro-
chloride salts to the less soluble cis product, and thus caused high
stereoselectivity.
* Corresponding author.
E-mail address: xxshi@ecust.edu.cn (X.-X. Shi).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.01.026

S. Xiao et al. / Tetrahedron: Asymmetry 20 (2009) 430–439
431
Table 1
Direct Pictet–Spengler reaction of D-tryptophan methyl ester hydrochloride 1-HCl with aldehydes in a mixed solvent of CH3NO2 and toluene (see also Scheme 1)
Entry
Aldehyde
CH3NO2/toluene
Time (h)a
2 (cis/trans)b
Yieldc (%)
1
2
3
4
5
6
7
8
9
3,4,5-(OMe)3–PhCHO
3,4,5-(OMe)3–PhCHO
3,4-(OMe)2–PhCHO
4-OMe–PhCHO
PhCHO
3-OMe-4-OH–PhCHO
4-OH–PhCHO
4-NO2–PhCHO
2-NO2–PhCHO
i-PrCHO
1:0
1:1
1:1
1:1
1:10
1:1
1:1
1:1
1:4
1:1
1:1
8
8
8
8
22
8
8
18
7
18
26
2a (2:98)
2a (1:99)
2b (1:99)
2c (1:99)
2d (98:2)
2e (98:2)
2f (99:1)
2g (99:1)
2h (99:1)
2i (1:99)
2j (98:2)
82
92
85
80
76
83
75
81
78
64
66
10
11
n-C6H13CHO
a
Under reflux.
Determined by HPLC or 1H NMR.
Isolated yield.
b
c
O
O
and toluene was crucial; high stereoselectivities for the P–S
reaction of 1-HCl with various aldehydes could be obtained by tun-
ing the ratio of nitromethane and toluene for each aldehyde.
Several aldehydes were tried, and the results are summarized in
Table 1 (see also Scheme 1). As we can see from Table 1, in the case
of aromatic aldehydes, the reaction gave high stereoselectivities
and good yields, but for aliphatic aldehydes, the yields were
moderate.
OR1
OR1
NH2Cl
R2
NH3Cl
R2CHO
CIAT
i-PrOH
N
H
N
H
1
-HCl
2
mix- -HCl
O
O
O
O
OR1
OR1
OMe
OMe
NH Cl
R
NH2Cl
NH2Cl
RCHO
NH3Cl
+
R2
cis- -HCl
R2
trans- -HCl
CH3NO2/toluene
N
N
H
H
N
N
2
2
H
H
1-HCl
Scheme 2. Two-step synthesis of cis-2-HCl and trans-2-HCl from 1-HCl via CIAT
process.
O
O
OMe
OMe
NH2Cl
NH2Cl
R
Some observations on the above CIAT process should be
discussed. Firstly, the yields of a two-step procedure (Table 2) are
obviously better than the yields of a one-step procedure (Table 1)
because in the one-step procedure, the P–S reaction probably com-
peted against the Henry reaction44–46 of the aldehydes with nitro-
methane, while in the two-step procedure, the P–S reaction was
carried out in isopropanol, thus the Henry reaction could be avoided.
Secondly, in the CIAT process, tuning the ratio of nitromethane and
toluene for each epimer mixture of 2-HCl was necessary in order
to obtain as high yields and stereoselectivities as possible. While
2-HCl was more soluble in nitromethane, more toluene was needed,
or otherwise less toluene was needed. Thirdly, domination of the
product cis-2-HCl or trans-2-HCl could not be predicted for all
instances in Tables 1 and 2, the ratio of cis-2-HCl and trans-2-HCl
probably depended only on the solubility difference between cis-
2-HClandtrans-2-HClinthemixedsolvent. For example, thesolubil-
ity of cis-2c-HCl, trans-2c-HCl, cis-2d-HCl, and trans-2d-HCl was
measured in the mixed CH3NO2/toluene (see also Table 3), the ratio
of solubility of cis- and trans-2c-HCl is 6.3:1 at room temperature
and is 9.4:1 at refluxing temperature, while the ratio of solubility
of cis- and trans-2d-HCl is 1:6.5 at room temperature and is 1:9.2
at refluxing temperature. The big difference of the solubility
between cis- and trans-2c-HCl, as well as between cis- and trans-
2d-HCl, favors high stereoselectivity; the CIAT process accordingly
producesless soluble trans-2c-HCland cis-2d-HCl as themajorprod-
ucts. Fourthly, the stereochemistry of the major product cis-2 or
trans-2 can be assigned by analyzing the corresponding 1H–1H
NOESY spectra of each epimer shown in Tables 1 and 2. For example,
as depicted in Figure 1, the proton at the C-3 position has an obvious
+
R
N
H
N
H
trans-2-HCl
cis-2-HCl
Scheme 1. Direct P–S reaction of 1-HCl with aldehydes.
High stereoselectivities could be obtained for various aldehydes,
but the yields were unsatisfactory, especially for the aliphatic alde-
hydes. Fortunately, this drawback could be overcome by performing
the CIAT-based process according to a modified two-step procedure
(Scheme 2); we first performed the P–S reaction in isopropanol to
obtain an epimeric mixture of the hydrochloride salts of cis and
trans-1,3-disubstituted tetrahydro-b-carbolines mix-2-HCl, and
then carried out the CIAT process in a mixed solvent with different
ratios of nitromethane and toluene. The modified two-step proce-
dure was quite efficient, giving not only high yields, but also high
stereoselectivities. Furthermore, it could be applicable to both aro-
matic aldehydes and aliphatic aldehydes. The P–S reaction of a vari-
ety of D-tryptophan ester hydrochlorides with various aldehydes in
isopropanolwasmuchfasterthaninthemixedsolventof nitrometh-
ane and toluene; it took around only 3–5 h to complete at reflux and
produce mix-2-HCl in almost quantitative yields with low cis/trans
selectivities at the range of 70:30 to 30:70. The results of the CIAT
process of mix-2-HCl into cis-2-HCl or trans-2-HCl are listed in
Table 2. Thirteen aromatic aldehydes (entries 1–8, 11–13, 16, and
17) and four aliphatic aldehydes (entries 9, 10, 14 and 15) have been
examined, and three
D-tryptophan ester hydrochlorides (entries
1–17, 18–21, and 22) have been tested.

432
S. Xiao et al. / Tetrahedron: Asymmetry 20 (2009) 430–439
Table 2
Crystallization induced transformation (CIAT) of the cis/trans mixture (mix-2-HCl) into a single diastereomer of 1,3-disubstituted tetrahydro-b-carbolines (cis-2-HCl or trans-2-
HCl)
Entry
mix-2
R2
Solvents
Timea (h)
2 (cis/trans)b
Yieldc (%)
R1
CH3NO2/toluene
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
3,4,5-(OMe)3–Ph
3,4-(OMe)2–Ph
4-OMe–Ph
Ph
3-OMe-4-OH–Ph
4-OH–Ph
4-NO2–Ph
2-NO2–Ph
i-Pr
n-Hexyl
2-OMe–Ph
2-OEt–Ph
2-Cl–Ph
Me
Et
3-OMe-4-OAc–Ph
3-OMe-4-OBz–Ph
3,4,5-(OMe)3–Ph
3,4-(OMe)2–Ph
4-OMe–Ph
3,4-(OCH2O)–Ph
3,4-(OCH2O)–Ph
1:1
1:1
1:1
1:10
1:1
1:1
1:1
1:4
1:1
1:1
1:9
1:9
1:10
1:1
1:1
1:1
1:1
1:6
1:5
1:5
1:5
1:8
8
8
12
20
8
8
18
7
18
26
16
16
25
28
28
16
16
18
26
20
18
20
2a (1:99)
2b (1:99)
2c (1:99)
2d (98:2)
2e (99:1)
2f (99:1)
2g (99:1)
2h (99:1)
2i (1:99)
2j (98:2)
2k (95:5)
2l (98:2)
2m (95:5)
2n (97:3)
2o (98:2)
2p (2:98)
2q (99:1)
2r (99:1)
2s (2:98)
2t (2:98)
2u (99:1)
2v (98:2)
98
97
88
85
94
96
95
96
93
92
91
89
92
95
93
88
89
95
92
85
87
86
Et
Et
Et
n-Pr
a
Under reflux.
b
c
Determined by HPLC or 1H NMR.
Isolated yield based on two steps (Scheme 2).
Table 3
In order to gain a better understanding of the proposed mecha-
nism (Scheme 3), we designed and attempted the three following
Solubility of cis-2c-HCl, trans-2c-HCl, cis-2d-HCl, and trans-2d-HCl in the mixed
CH3NO2/toluene
experiments. We first tried the P–S reaction of
D-tryptophan
Entry
2-HCl
CH3NO2/toluene
T (°C)
Solubility (mg/100 mL)
methyl ester hydrochloride 1-HCl with deuterated 3,4-dimethoxy-
benzaldehyde 3 which was prepared according to a modified
procedure of the known method50–52 (Scheme 4). After a CIAT pro-
cess in CH3NO2/toluene (1:1), trans-d1-2b-HCl was obtained in 97%
yield (Scheme 5). This result means that path A could be excluded
here, otherwise the above CIAT process (Scheme 5) should produce
a mixture of non-deuterated trans-2b-HCl and deuterated trans-d1-
2b-HCl, because the feature of the acid-catalyzed path A is the pro-
ton-exchange between tetrahydro-b-carboline scaffold and the
solvent media. We next attempted to trap the intermediates of
path B and path C by adding 5 equiv of zinc powder into the solu-
tion of trans-2b-HCl in methanol,53 after refluxing for 8 h, the cis-
2b, trans-2b, and compound 4 (Scheme 6) were obtained in 43%,
45%, and 5% yield, respectively. The detection of the compound 4
implies that the mechanism of the CIAT process most likely follows
path C, because compound 4 would be derived from the reduction
of the intermediate of path C. However, we could not detect imine
intermediate 5 (Scheme 6) of path B or its reduction product 6 after
careful monitoring of the CIAT process by TLC and HPLC. Moreover,
when adding 2 equiv of hydroxylamine hydrochloride into the sus-
pension of cis-2b-HCl in the mixed solvent CH3NO2/toluene (1:1),
trans-2b-HCl was obtained almost quantitatively after refluxing
for 8 h; no oxime 7, which would be derived from the imine inter-
mediate 5, was observed after careful analysis by TLC and HPLC.
The failure to detect compounds 5–7 implies that the CIAT process
probably does not follow the retro P–S reaction pathway (path B in
Scheme 3).
1
2
3
4
5
6
7
8
trans-2c-HCl
cis-2c-HCl
trans-2c-HCl
cis-2c-HCl
cis-2d-HCl
trans-2d-HCl
cis-2d-HCl
1:1
1:1
1:1
20a
6
38
47
441
2
13
12
110
20a
97b
97b
20a
1:1
1:10
1:10
1:10
1:10
20a
101b
101b
trans-2d-HCl
a
Room temperature.
Refluxing.
b
correlationwith the proton at C-1 position in the 1H–1H NOESY spec-
tra of the compound cis-2b or cis-2d, while the proton at the C-3
position does not correlate with the proton at C-1 position in the
1H–1H NOESY spectra of the compound trans-2b or trans-2d, but cor-
relates with the neighboring protons on the substituent at the C-1
position. Fifthly, when we attempted to purify hydrochloride salts
cis-2-HCl or trans-2-HCl by recrystallization in order to remove the
minor epimer impurity, we failed to obtain pure cis-2-HCl or trans-
2-HCl, because solubilization of cis-2-HCl or trans-2-HCl during the
course of the recrystallization shifted the equilibrium between cis-
2-HCl and trans-2-HCl to the mid-point to give a mixture of epimers
instead of pure compound. However, we were able to obtain pure
compounds 2a–2v by recrystallization or flash chromatography
after neutralization of the corresponding hydrochloride salts (cis-
or trans-2-HCl).
A plausible mechanism for the CIAT process is proposed in
Scheme 3. There are three reasonable pathways10,11,47–49 for the
CIAT process. Path A involves double migration of the double bond
catalyzed by acid. Path B involves a retro P–S reaction to form an
imine intermediate. Path C involves the splitting of a carbon–nitro-
gen bond, rotation of a carbon–carbon bond, and reformation of a
carbon–nitrogen bond.
3. Conclusion
In conclusion, we have developed a general method to syn-
thesize enantiomerically pure cis (or trans) 1,3-disubstituted
tetrahydro-b-carbolines 2a–2v from
CIAT process. A direct Pictet–Spengler reaction of
D
-tryptophan esters via a
-tryptophan
D

S. Xiao et al. / Tetrahedron: Asymmetry 20 (2009) 430–439
433
C1-H C3-H
ortho-Ph-H
C1-H
C3-H
NOE between
ortho-Ph-H and C3-H
NOE between
C1-H and C3-H
NOE
NOE
O
O
OMe
OMe
H
H
NOE
NOE
OMe
3
1
3
1
NH
H
NH
H
H
NOE
OMe
N
N
H
H
H
OMe
OMe
cis-2b
trans-2b
C3-H
C1-H
ortho-Ph-H
C1-H
C3-H
NOE between
C1-H and C3-H
NOE
NOE
NOE between
ortho-Ph-H and C3-H
O
O
OMe
OMe
H
H
NOE
NOE
3
1
3
1
NH
H
NH
H
H
N
H
N
H
cis-2d
trans-2d
Figure 1. 1H–1H NOESY spectra and stereochemistry of cis-2b and cis-2d versus trans-2b and trans-2d.
ester hydrochlorides with various aldehydes in a mixed solvent
of nitromethane and toluene (see also Table 1) and a modified
two-step procedure (see also Table 2) were studied extensively.
It was found that a fine tuning of the ratio of nitromethane
and toluene for each epimer mixture of 2-HCl was necessary
in order to get as high stereoselectivities and yields as possible.
plausible mechanism for the CIAT process has also been
discussed, which most likely involves the splitting of a C–N
bond, rotation of a C–C bond and reformation of a C–N bond
(path C in Scheme 3).
A

434
S. Xiao et al. / Tetrahedron: Asymmetry 20 (2009) 430–439
COOR1
O
O
COOR1
NH2Cl
R2
OMe
NH2
OMe
NH2Cl
H
R2
path C
N
R
N
N
H
H
N
N
R
H
H
(retro P-S)
path B
4
5
R=3,4-(OMe)2-Ph
R=3,4-(OMe)2-Ph
H+
path A
H
COOR1
NH2Cl
R2
COOR1
O
OMe
NH
R2
Cl
OH
(rotation )
path C
N
NH
N
H
N
H
MeO
N
R
OMe
H
6
R=3,4-(OMe)2-Ph
7
H+
path B
(retro P-S)
path A
COOR1
NH2Cl
R2
COOR1
Scheme 6. Some proposed intermediates.
NH2Cl
H
R2
path C
chemicals were analytically pure. The
D
-tryptophan ester hydro-
chloride 1-HCl was prepared according to a known procedure.22
N
H
N
H
4.2. Typical procedure for the direct Pictet–Spengler reaction of
Scheme 3. Plausible mechanism for the CIAT of 2-HCl.
D-tryptophan methyl ester hydrochloride with an aldehyde
D
To
12.03 mmol) in a mixed solvent of nitromethane (12 mL) and tolu-
ene (12 mL) was added the powder of -tryptophan methyl ester
a
solution of 3,4,5-trimethoxybenzaldehyde (2.36 g,
O
a
b
S
S
R
R
R
D
S
D
S
93%
90%
3
hydrochloride (2.57 g, 10.09 mmol). The suspension was heated
at reflux and stirred for around 8 h, and the reaction was moni-
tored by TLC after neutralization. When the reaction was complete,
the mixture was cooled down to room temperature. A pale yellow
solid was collected on a Buchner funnel by suction and rinsed with
a small amount of freshly mixed solvent of nitromethane and tol-
uene (1:1). The solid was then partitioned between ethyl acetate
(40 mL) and an aqueous solution of potassium carbonate (1.80 g,
13.03 mmol) in water (20 mL). The organic layer was separated
and dried over anhydrous MgSO4. Evaporation of the solvent under
a vacuum gave a crude product, which was purified by recrystalli-
zation or flash chromatography to afford compound 2a (3.67 g,
9.26 mmol) in 92% yield.
R=3,4-(OMe)2-Ph
Scheme 4. Preparation of the deuterated 3,4-dimethoxy benzaldehyde 3. Reagents
and conditions: (a) 1.5 equiv of n-BuLi, ꢀ50 °C to ꢀ40 °C for 5 h in toluene, then
large excess of D2O; (b) 1.5 equiv of H5IO6, rt for 10 min in THF.
O
O
3
OMe
OMe
O
NH3Cl
NH2Cl
D
R
i-PrOH
1
+
R
D
N
H
N
H
[R=3,4-(OMe)2-Ph]
mix-d1-2b-HCl
1-HCl
3
4.3. Typical two-step procedure of the reaction of
ester hydrochloride with an aldehyde
D-tryptophan
O
O
OMe
OMe
3
3
To
12.03 mmol) in isoproponal (25 mL), was added the powder of
D-tryptophan methyl ester hydrochloride (powder, 2.57 g,
10.09 mmol). The suspension was heated to reflux while stirring,
the mixture gradually turned into a clear solution, and the reaction
was monitored by TLC after neutralization. The reaction completed
in around 4 h, and the reaction solution was then concentrated to
dryness under a vacuum to give a crude solid product which was
washed twice with toluene to remove excessive 3,4,5-
trimethoxybenzaldehyde.
a
solution of 3,4,5-trimethoxybenzaldehyde (2.36 g,
NH2Cl
D
R
NH2Cl
D
R
CIAT
1
1
+
CH3NO2/toluene
(1:1)
N
N
H
H
cis-d1-2b-HCl
trans-d1-2b-HCl
(cis : trans = 1 : 99)
Scheme 5. The deuterium labeling test for the CIAT of 2b-HCl.
4. Experimental
The above washed crude solid product was then suspended in a
mixed solvent of nitromethane (12 mL) and toluene (12 mL), and
the suspension was heated at reflux. After the stirring was contin-
ued at reflux for 8 h, the mixture was cooled down to room tem-
perature. A pale yellow solid was collected on a Buchner funnel
by suction and rinsed with a small amount of freshly mixed solvent
of nitromethane and toluene (1:1). The solid was then partitioned
between ethyl acetate (40 mL) and an aqueous solution of potas-
sium carbonate (1.80 g, 13.03 mmol) in water (20 mL). The organic
layer was separated and dried over anhydrous MgSO4. Evaporation
of the solvent under a vacuum gave a crude product which was
4.1. General method
Melting points are uncorrected. NMR spectra were acquired on
Bruker AM-500, chemical shifts of 1H NMR 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. Optical rotations
were measured on WZZ-1S automatic polarimeter at room temper-
ature. Column chromatography was performed on silica gel. All

S. Xiao et al. / Tetrahedron: Asymmetry 20 (2009) 430–439
435
purified by recrystallization or flash chromatography to afford
compound 2a (3.91 g, 9.86 mmol) in 98% yield.
(relative intensity) 337 (M++1, 17), 336 (M+, 100), 335 (22), 319
(18), 287 (4), 277 (35), 262 (16), 248 (21), 233 (8), 218 (25), 204
(12), 191 (4), 169 (11), 144 (7), 134 (5), 115 (3), 77 (1). IR (KBr)
3285, 2945, 1742, 1610, 1510, 1454, 1271, 1252, 1203, 1175,
4.4. Characterization data of 1,3-disubstituted tetrahydro-b-
carbolines 2a–2v is as follows
1116, 1031, 840, 737 cmꢀ1
.
4.4.1. (1S,3R)-Methyl 1-(3,4,5-trimethoxyphenyl)-2,3,4,9-tetra-
hydro-1H-pyrido [3,4-b]indole-3-carboxylate trans-2a
White solid,54 Rf on silica 0.45 (hexane–ethyl acetate, 1:1), mp
4.4.5. (1R,3R)-Methyl 1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-
b]indole-3-carboxylate cis-2d
White solid, Rf on silica 0.44 (hexane–ethyl acetate, 2:1), mp
182–183 °C. ½a 2D0
ꢁ
¼ þ11:3 (c 1.3, CHCl3). 1H NMR (acetone-d6) d
226–227 °C (lit.55 184–185 °C). ½a 2D0
ꢁ
¼ þ14:2 (c 1.5, CHCl3). 1H
2.81 (br s, N–H, 1H), 3.04 (ddd, J1 = 15.2 Hz, J2 = 6.4 Hz,
J3 = 1.5 Hz, 1H), 3.17 (ddd, J1 = 15.2 Hz, J2 = 5.4 Hz, J3 = 1.3 Hz, 1H),
3.66 (s, 3H), 3.70 (s, 3H), 3.73 (s, 6H), 4.02 (t, J = 5.8 Hz, 1H), 5.38
(s, 1H), 6.68 (s, 2H), 7.00 (td, J1 = 7.1 Hz, J2 = 1.2 Hz, 1H), 7.04 (td,
J1 = 7.1 Hz, J2 = 1.3 Hz, 1H), 7.26 (dd, J1 = 6.9 Hz, J2 = 1.2 Hz, 1H),
7.48 (d, J = 7.6 Hz, 1H), 9.63 (br s, NH on the indole ring, 1H). MS
(EI) m/z (relative intensity) 397 (M++1, 19), 396 (M+, 100), 395
(21), 381 (19), 365 (6), 337 (23), 320 (13), 278 (20), 229 (7), 219
(4), 194 (4), 180 (4), 169 (14), 144 (4), 115 (2), 77 (1). IR (KBr)
3348, 3308, 2950, 1743, 1592, 1508, 1460, 1417, 1233,
1128 cmꢀ1. Anal. Calcd for C22H24N2O5: C, 66.65; H, 6.10; N, 7.07.
Found: C, 66.25; H, 6.13; N, 6.83.
NMR (CDCl3) d 3.02 (ddd, J1 = 15.0 Hz, J2 = 11.1 Hz, J3 = 2.5 Hz,
1H), 3.23 (ddd, J1 = 15.1 Hz, J2 = 4.2 Hz, J3 = 1.9 Hz, 1H), 3.81 (s,
3H), 3.99 (dd, J1 = 11.1 Hz, J2 = 4.2 Hz, 1H), 5.25 (t, J = 2.0 Hz, 1H),
7.11 (td, J1 = 7.0 Hz, J2 = 1.4 Hz, 1H), 7.15 (td, J1 = 7.0 Hz,
J2 = 1.6 Hz, 1H), 7.21 (dd, J1 = 6.5 Hz, J2 = 2.0 Hz, 1H), 7.34–7.42
(m, 5H), 7.43 (br s, NH on the indole ring, 1H), 7.54 (dd,
J1 = 7.5 Hz, J2 = 1.8 Hz, 1H). MS (EI) m/z (relative intensity) 307
(M++1, 15), 306 (M+, 82), 305 (21), 291 (6), 247 (38), 229 (12),
218 (100), 204 (9), 189 (3), 169 (13), 144 (10), 115 (5), 77 (2). IR
(KBr) 3396, 3338, 2951, 2789, 1740, 1456, 1439, 1356, 1328,
1207, 747, 699 cmꢀ1
.
4.4.6. (1S,3R)-Methyl 1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-
b]indole-3-carboxylate trans-2d
4.4.2. (1S,3R)-Methyl 1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-
1H-pyrido [3,4-b]indole-3-carboxylate trans-2b
White solid, Rf on silica 0.34 (hexane–ethyl acetate, 2:1). mp
White solid, Rf on silica 0.51 (hexane–ethyl acetate, 1:1), mp
220–221 °C (lit.55 161–162 °C). ½a 2D0
ꢁ
¼ þ44:5 (c 1.0, CHCl3). 1H
191–192 °C (lit.30 194–196 °C). ½a 2D0
ꢁ
¼ þ25:4 (c 1.7, CHCl3). 1H
NMR (CDCl3) d 3.14 (ddd, J1 = 15.3 Hz, J2 = 6.7 Hz, J3 = 1.1 Hz, 1H),
3.23 (dd, J1 = 14.5 Hz, J2 = 4.4 Hz, 1H), 3.71 (s, 3H), 3.97 (dd,
J1 = 11.1 Hz, J2 = 4.2 Hz, 1H), 5.40 (s, 1H), 7.13 (td, J1 = 7.1 Hz,
J2 = 1.3 Hz, 1H), 7.16 (td, J1 = 7.0 Hz, J2 = 1.3 Hz, 1H), 7.18–7.36
(m, 6H), 7.55 (d, J = 7.0 Hz, 1H), 7.60 (br s, NH on the indole ring,
1H). MS (EI) m/z (relative intensity) 307 (M++1, 20), 306 (M+,
100), 305 (17), 289 (17), 274 (2), 257 (5), 247 (36), 232 (17), 218
(56), 204 (7), 169 (12), 144 (12), 115 (4). IR (KBr) 3401, 3052,
NMR (acetone-d6) d 3.00 (ddd, J1 = 15.1 Hz, J2 = 7.0 Hz, J3 = 1.4 Hz,
1H), 3.15 (ddd, J1 = 15.1 Hz, J2 = 5.3 Hz, J3 = 1.0 Hz, 1H), 3.66 (s,
3H), 3.73 (s, 3H), 3.77 (s, 3H), 3.93 (dd, J1 = 6.9 Hz, J2 = 5.4 Hz,
1H), 5.36 (s, 1H), 6.74 (dd, J = 8.2 Hz, J2 = 2.0 Hz, 1H), 6.85 (d,
J = 8.2 Hz, 1H), 6.97–7.07 (m, 3H), 7.27 (d, J = 7.7 Hz, 1H), 7.48 (d,
J = 7.6 Hz, 1H), 9.63 (br s, NH on the indole ring, 1H). MS (EI) m/z
(relative intensity) 367 (M++1, 20), 366 (M+, 100), 365 (24), 351
(19), 349 (28), 335 (4), 317 (4), 307 (29), 305 (17), 290 (17), 279
(8), 264 (6), 248 (27), 229 (7), 217 (5), 204 (9), 191 (4), 169 (13),
144 (5), 115 (2), 77 (1). IR (KBr) 3371, 2952, 1730, 1513, 1463,
1453, 1421, 1257, 1232, 1026, 818, 742 cmꢀ1. Anal. Calcd for
C21H22N2O4: C, 68.84; H, 6.05; N, 7.65. Found: C, 68.85; H, 5.89;
N, 7.70.
2951, 1730, 1456, 1353, 1329, 1206, 744, 701 cmꢀ1
.
4.4.7. (1R,3R)-Methyl 1-(4-hydroxy-3-methoxyphenyl)-2,3,4,9-
tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate cis-2e
White solid, Rf on silica 0.44 (hexane–ethyl acetate, 1:1), mp
179–180 °C. ½a 2D0
ꢁ
¼ þ39:8 (c 1.1, CHCl3). 1H NMR (CDCl3) 3.01
(ddd, J1 = 15.1 Hz, J2 = 11.1 Hz, J3 = 2.4 Hz, 1H), 3.22 (ddd,
J1 = 15.1 Hz, J2 = 4.4 Hz, J3 = 1.8 Hz, 1H), 3.81 (s, 3H), 3.82 (s, 3H),
3.97 (dd, J1 = 11.1 Hz, J2 = 4.2 Hz, 1H), 5.18 (s, 1H), 6.85–6.93 (m,
3H), 7.12 (td, J1 = 7.1 Hz, J2 = 1.4 Hz, 1H), 7.15 (td, J1 = 7.0 Hz,
J2 = 1.5 Hz, 1H), 7.23 (dd, J1 = 6.3 Hz, J2 = 1.5 Hz, 1H), 7.46 (br s,
NH on the indole ring, 1H), 7.54 (dd, J1 = 7.7 Hz, J2 = 1.6 Hz, 1H).
4.4.3. (1R,3R)-Methyl 1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-
1H-pyrido [3,4-b]indole-3-carboxylate cis-2b
White solid, Rf on silica 0.55 (hexane–ethyl acetate, 1:1), mp
174–175 °C (lit.30 174–176 °C). ½a 2D0
ꢁ
¼ þ21:9 (c 1.6, CHCl3). 1H
NMR (acetone-d6) d 2.90 (ddd, J1 = 15.1 Hz, J2 = 7.0 Hz, J3 = 1.4 Hz,
1H), 3.11 (ddd, J1 = 15.1 Hz, J2 = 5.3 Hz, J3 = 1.0 Hz, 1H), 3.72 (s,
3H), 3.76 (s, 3H), 3.80 (s, 3H), 3.92 (dd, J1 = 10.9 Hz, J2 = 4.1 Hz,
1H), 5.21 (s, 1H), 6.88–7.05 (m, 5H), 7.24 (dd, J1 = 6.9 Hz,
J2 = 2.0 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 9.42 (br s, NH on the indole
ring, 1H). MS (EI) m/z (relative intensity) 367 (M++1, 21), 366 (M+,
100), 365 (37), 351 (14), 335 (3), 307 (39), 289 (10), 279 (27), 248
(55), 229 (11), 217 (6), 169 (15), 144 (9). IR (KBr) 3353, 2935, 1737,
1517, 1454, 1263, 1165, 1139, 1027, 745 cmꢀ1. HRMS (EI) calcd for
C21H22N2O4: 366.1580; found: 366.1578.
13C NMR (CDCl3)
d 173.18, 147.08, 146.01, 146.00, 136.13,
134.93, 127.20, 121.91, 121.54, 119.62, 118.18, 114.34, 110.97,
110.71, 108.67, 58.68, 56.99, 56.02, 52.26, 25.60. MS (EI) m/z (rel-
ative intensity) 353 (M++1, 19), 352 (M+, 100), 351 (34), 337 (14),
293 (31), 276 (11), 265 (26), 248 (12), 234 (15), 204 (9), 191 (3),
169 (10), 150 (3), 144 (5), 115 (2). IR (KBr) 3405, 3328, 2950,
1742, 1519, 1451, 1269, 1223, 746 cmꢀ1
. Anal. Calcd for
C20H20N2O4: C, 68.17; H, 5.72; N, 7.95. Found: C, 68.53; H, 5.64;
N, 8.04.
4.4.4. (1S,3R)-Methyl 1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-
1H-pyrido[3,4-b] indole-3-carboxylate trans-2c
4.4.8. (1R,3R)-Methyl 1-(4-hydroxyphenyl)-2,3,4,9-tetrahydro-
1H-pyrido[3,4-b] indole-3-carboxylate cis-2f
White solid, Rf on silica 0.58 (hexane–ethyl acetate, 1:1), mp
White solid, Rf on silica 0.44 (hexane–ethyl acetate, 1:1), mp
219–220 °C (lit.55 193–194 °C). ½a 2D0
ꢁ
¼ þ44:0 (c 2.0, CHCl3). 1H
228–229 °C. ½a 2D0
ꢁ
¼ þ34:2 (c 1.0, acetone). 1H NMR (acetone-d6) d
NMR (acetone-d6) d 2.72 (br s, N–H, 1H), 2.99 (ddd, J1 = 15.1 Hz,
J2 = 7.3 Hz, J3 = 1.2 Hz, 1H), 3.14 (ddd, J1 = 15.1 Hz, J2 = 5.2 Hz,
J3 = 1.0 Hz, 1H), 3.66 (s, 3H), 3.76 (s, 3H), 3.89 (dd, J1 = 7.1 Hz,
J2 = 5.5 Hz, 1H), 5.36 (s, 1H), 6.86 (d, J = 8.6 Hz, 2H), 6.98–7.07 (m,
2H), 7.19 (d, J = 8.7 Hz, 2H), 7.27 (d, J = 7.4 Hz, 1H), 7.49 (d,
J = 7.6 Hz, 1H), 9.64 (br s, NH on the indole ring, 1H). MS (EI) m/z
2.45 (br s, N–H, 1H), 2.88 (ddd, J1 = 14.7 Hz, J2 = 11.1 Hz,
J3 = 2.5 Hz, 1H), 3.10 (ddd, J1 = 14.9 Hz, J2 = 4.1 Hz, J3 = 1.8 Hz, 1H),
3.75 (s, 3H), 3.92 (dd, J1 = 11.1 Hz, J2 = 4.1 Hz, 1H), 5.19 (s, 1H),
6.79 (d, J1 = 8.6 Hz, 2H), 6.98 (td, J1 = 7.1 Hz, J2 = 1.3 Hz, 1H), 7.02
(td, J1 = 7.1 Hz, J2 = 1.4 Hz, 1H), 7.20 (d, J = 8.5 Hz, 2H), 7.25 (d,
J = 7.0 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 8.26 (s, ArOH, 1H), 9.42 (br

436
S. Xiao et al. / Tetrahedron: Asymmetry 20 (2009) 430–439
s, NH on the indole ring, 1H). MS (EI) m/z (relative intensity) 323
(M++1, 22), 322 (M+, 100), 321 (32), 307 (14), 263 (44), 248 (9),
235 (57), 234 (59), 218 (21), 206 (14), 191 (4), 169 (14), 144
(12), 120 (5), 77 (1). IR (KBr) 3371, 3300, 3269, 2980, 1732, 1616,
J3 = 1.8 Hz, 1H), 3.72 (dd, J1 = 11.1 Hz, J2 = 4.1 Hz, 1H), 3.76 (s,
3H), 4.20 (dd, J1 = 6.2 Hz, J2 = 1.8 Hz, 1H), 6.98 (td, J1 = 7.1 Hz,
J2 = 1.0 Hz, 1H), 7.04 (td, J1 = 7.2 Hz, J2 = 1.2 Hz, 1H), 7.30 (d,
J = 7.9 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 9.89 (br s, NH on the indole
ring, 1H). MS (EI) m/z (relative intensity) 314 (M+, 10), 296 (1), 267
(1), 255 (4), 229 (100), 197 (2), 169 (20), 156 (3), 144 (4), 115 (1),
85 (1), 73 (2), 60(3), 56 (4), 43(4). IR (KBr) 3397, 3056, 2927, 2852,
1734, 1452, 1327, 1270, 1216, 1170, 1046, 1009, 846, 741,
594 cmꢀ1. HRMS (EI) calcd for C19H26N2O2: 314.1994; found:
314.1995.
1520, 1459, 1439, 1325, 1279, 1216, 1178, 830, 751, 741 cmꢀ1
.
Anal. Calcd for C19H18N2O3: C, 70.80; H, 5.63; N, 8.69. Found: C,
70.51; H, 5.43; N, 8.65.
4.4.9. (1R,3R)-Methyl 1-(4-nitrophenyl)-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b] indole-3-carboxylate cis-2g
White solid, Rf on silica 0.45 (hexane–ethyl acetate, 2:1), mp
171–173 °C (lit.55 171–172 °C). ½a 2D0
ꢁ
¼ þ5:4 (c 1.0, CHCl3). 1H
4.4.13. (1R,3R)-Methyl 1-(2-methoxyphenyl)-2,3,4,9-tetrahydro-
1H-pyrido[3,4-b] indole-3-carboxylate cis-2k
NMR (CDCl3) d 3.03 (ddd, J1 = 15.0 Hz, J2 = 11.1 Hz, J3 = 2.5 Hz,
1H), 3.26 (ddd, J1 = 15.2 Hz, J2 = 4.1 Hz, J3 = 1.8 Hz, 1H), 3.83 (s,
3H), 3.99 (dd, J1 = 11.1 Hz, J2 = 4.1 Hz, 1H), 5.39 (s, 1H), 7.14 (td,
J1 = 7.0 Hz, J2 = 1.4 Hz, 1H), 7.17 (td, J1 = 6.9 Hz, J2 = 1.4 Hz, 1H),
7.22 (dd, J1 = 7.2 Hz, J2 = 1.3 Hz, 1H), 7.37 (br s, NH on the indole
ring, 1H), 7.56 (d, J = 7.0 Hz, 1H), 7.60 (d, J = 8.7 Hz, 2H), 8.22 (d,
J = 8.7 Hz, 2H). 13C NMR (CDCl3) d 172.83, 148.32, 147.46, 136.30,
132.95, 129.45, 126.66, 123.65, 122.09, 119.61, 118.13, 110.98,
108.98, 57.75, 56.40, 52.19, 25.36. MS (EI) m/z (relative intensity)
352 (M++1, 24), 351 (M+, 100), 350 (18), 334 (46), 317 (7), 304
(29), 292 (65), 275 (6), 264 (49), 257 (13), 245 (34), 229 (18),
218 (72), 217 (74), 204 (9), 189 (6), 169 (22), 144 (13), 130 (5),
115 (6), 77 (2). IR (KBr) 3432, 2954, 1737, 1604, 1521, 1438,
White solid, Rf on silica 0.35 (hexane–ethyl acetate, 2:1), mp
184–185 °C (lit.29 195 °C). ½a D20
ꢁ
¼ ꢀ14:1 (c 1.5, CHCl3). 1H NMR
(CDCl3) d 3.00 (ddd, J1 = 14.9 Hz, J2 = 11.0 Hz, J3 = 2.5 Hz, 1H),
3.21 (ddd, J1 = 15.1 Hz, J2 = 4.2 Hz, J3 = 1.8 Hz, 1H), 3.80 (s, 3H),
3.90 (s, 3H), 3.99 (dd, J1 = 11.0 Hz, J2 = 4.2 Hz, 1H), 5.72 (s, 1H),
6.94 (t, J = 7.6 Hz, 1H), 6.98 (d, J1 = 8.2 Hz,1H), 7.09 (td,
J1 = 7.0 Hz, J2 = 1.4 Hz, 1H), 7.13 (td, J1 = 7.0 Hz, J2 = 1.5 Hz, 1H),
7.22 (dd, J1 = 6.2 Hz, J2 = 1.6 Hz, 1H), 7.31 (td, J1 = 8.2 Hz,
J2 = 1.7 Hz, 1H), 7.36 (dd, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H), 7.51 (dd,
J1 = 7.5 Hz, J2 = 1.7 Hz, 1H), 7.71 (br s, NH on the indole ring,
1H). 13C NMR (CDCl3) d 173.26, 157.13, 135.80, 134.73, 129.07,
129.00, 128.86, 126.94, 121.34, 121.01, 119.13, 117.74, 110.73,
110.72, 108.21, 56.65, 55.44, 51.93, 51.50, 25.54. MS (EI) m/z
(relative intensity) 337 (M++1, 20), 336 (M+, 100), 335 (26),
321 (8), 305 (9), 277 (44), 260 (9), 249 (40), 234 (12), 218
(33), 204 (7), 191 (2), 169 (9), 144 (5), 130 (2), 115 (2), 77
(1). IR (KBr) 3423, 2949, 1736, 1600, 1493, 1463, 1438, 1243,
1349, 1264, 1220, 860, 746 cmꢀ1
.
4.4.10. (1R,3R)-Methyl 1-(2-nitrophenyl)-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b] indole-3-carboxylate cis-2h
White solid, Rf on silica 0.48 (hexane–ethyl acetate, 2:1), mp
173–174 °C (lit.55 177–178 °C). ½a 2D0
ꢁ
¼ þ22:6 (c 6.6, CHCl3). 1H
1028, 755, 741 cmꢀ1
.
HRMS (EI) calcd for C20H20N2O3:
NMR (acetone-d6)
d
2.96 (ddd, J1 = 15.0 Hz, J2 = 10.9 Hz,
336.1474; found: 336.1475.
J3 = 2.4 Hz, 1H), 3.12–3.23 (m, 2H), 3.76 (s, 3H), 3.96–4.04 (m,
1H), 5.81 (t, J = 1.7 Hz, 1H), 7.03 (td, J1 = 7.0 Hz, J2 = 1.4 Hz, 1H),
7.07 (td, J1 = 7.0 Hz, J2 = 1.5 Hz, 1H), 7.24 (dd, J1 = 7.7 Hz,
J2 = 1.6 Hz, 1H), 7.48–7.58 (m, 2H), 7.63 (d, J = 5.0 Hz, 2H), 7.94
(d, J = 8.2 Hz, 1H), 9.64 (br s, NH on the indole ring, 1H). MS (EI)
m/z (relative intensity) 351 (M+, 11), 334 (100), 333 (64), 317 (5),
304 (68), 292 (6), 274 (8), 257 (16), 245 (68), 229 (6), 217 (17),
204 (4), 189 (3), 169 (10), 149 (6), 130 (7), 115 (4), 77 (2), 41 (1).
IR (KBr) 3402, 2952, 2850, 1736, 1627, 1527, 1453, 1354, 1265,
4.4.14. (1R,3R)-Methyl 1-(2-ethoxyphenyl)-2,3,4,9-tetrahydro-
1H-pyrido[3,4-b] indole-3-carboxylate cis-2l
White solid, Rf on silica 0.48 (hexane–ethyl acetate, 2:1), mp
174–175 °C. ½a 2D0
ꢁ
¼ þ1:6 (c 4.1, CHCl3). 1H NMR (acetone-d6) d
1.21 (t, J = 7.0 Hz, 3H), 2.65 (br s, N–H, 1H), 2.77 (ddd,
J1 = 14.7 Hz, J2 = 10.9 Hz, J3 = 2.5 Hz, 1H), 2.98 (ddd, J1 = 14.8 Hz,
J2 = 4.1 Hz, J3 = 1.8 Hz, 1H), 3.61 (s, 3H), 3.80 (dd, J1 = 10.9 Hz,
J2 = 4.1 Hz, 1H), 3.86–3.95 (m, 1H), 3.99–4.08 (m, 1H), 5.56 (s,
1H), 6.75 (td, J1 = 7.5 Hz, J2 = 0.8 Hz, 1H), 6.82–6.91 (m, 3H),
7.07–7.15 (m, 2H), 7.20 (dd, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H), 7.33
(dd, J1 = 6.6 Hz, J2 = 1.8 Hz, 1H), 9.30 (br s, NH on the indole ring,
1H). MS (EI) m/z (relative intensity) 351 (M++1, 22), 350 (M+,
100), 349 (28), 335 (9), 321 (7), 305 (8), 291 (39), 276 (5),
263 (38), 248 (11), 234 (19), 218 (18), 204 (9), 191 (2), 182
(4), 169 (11), 157 (7), 144 (4), 130 (3), 115 (3), 77 (1). IR
(KBr) 3396, 2977, 1736, 1597, 1494, 1455, 1328, 1242, 1117,
1220, 744 cmꢀ1
.
4.4.11. (1S,3R)-Methyl 1-isopropyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-
b]indole-3-carboxylate trans-2i
White solid, Rf on silica 0.47 (hexane–ethyl acetate, 2:1), mp
148–149 °C. ½a 2D0
ꢁ
¼ ꢀ53:4 (c 1.6, CHCl3). 1H NMR (acetone-d6) d
0.83 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.9 Hz, 3H), 2.16–2.27 (m, 1H),
2.43 (br s, N–H, 1H), 2.99 (dd, J1 = 5.5 Hz, J2 = 1.3 Hz, 2H), 3.62 (s,
3H), 4.00 (t, J = 5.4 Hz, 1H), 4.20 (d, J = 4.3 Hz, 1H), 6.96 (td,
J1 = 7.2 Hz, J2 = 1.2 Hz, 1H), 7.02 (td, J1 = 7.1 Hz, J2 = 1.2 Hz, 1H),
7.29 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 9.76 (br s, NH on
the indole ring, 1H). MS (EI) m/z (relative intensity) 272 (M+, 7),
229 (100), 213 (9), 197 (4), 169 (32), 142 (1), 130 (1), 115 (2). IR
(KBr) 3332, 2962, 2888, 1733, 1468, 1456, 1427, 1336, 1271,
1224, 1194, 1132, 1004, 835, 742, 629 cmꢀ1. Anal. Calcd for-
C16H20N2O2: C, 70.56; H, 7.40; N, 10.29. Found: C, 70.17; H, 7.36;
N, 10.05.
1044, 919, 744 cmꢀ1
.
HRMS (EI) calcd for C21H22N2O3:
350.1630; found: 350.1632.
4.4.15. (1R,3R)-Methyl 1-(2-chlorophenyl)-2,3,4,9-tetrahydro-
1H-pyrido[3,4-b] indole-3-carboxylate cis-2m
White solid, Rf on silica 0.71 (hexane–ethyl acetate, 2:1), mp
165–166 °C (lit.55 170–171 °C). ½a 2D0
ꢁ
¼ ꢀ20:6 (c 0.9, CHCl3). 1H
NMR (acetone-d6) d 2.65 (br s, N–H, 1H), 2.92 (ddd, J1 = 14.9 Hz,
J2 = 10.9 Hz, J3 = 2.4 Hz, 1H), 3.15 (ddd, J1 = 14.8 Hz, J2 = 4.1
Hz, J3 = 1.7 Hz, 1H), 3.75 (s, 3H), 4.00 (dd, J1 = 10.5 Hz, J2 = 3.1 Hz,
1H), 5.82 (s, 1H), 6.98–7.07 (m, 2H), 7.23–7.38 (m, 4H), 7.42–
7.53 (m, 2H), 9.60 (br s, NH on the indole ring, 1H). MS (EI) m/z (rel-
ative intensity) 342 (M++2, 34), 341 (M++1, 26), 340 (M+, 94), 325
(7), 305 (15), 281 (62), 279 (26), 253 (43), 245 (10), 229 (13),
218 (100), 217 (66), 204 (4), 189 (5), 169 (19), 144 (19), 115 (7),
77 (2). IR (KBr) 3413, 3058, 2952, 1736, 1468, 1439, 1322, 1268,
4.4.12. (1R,3R)-Methyl 1-hexyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-
b]indole-3- carboxylate cis-2j
White solid, Rf on silica 0.66 (hexane–ethyl acetate, 2:1), mp
95–96 °C. ½a 2D0
ꢁ
¼ þ57:8 (c 1.6, CHCl3). 1H NMR (acetone-d6) d
0.87 (t, J = 6.7 Hz, 3H), 1.23–1.58 (m, 8H), 1.67–1.78 (m, 1H),
2.01–2.11(m, 1H), 2.15 (br s, N–H, 1H), 2.71 (ddd, J1 = 14.7 Hz,
J2 = 11.1 Hz, J3 = 2.5 Hz, 1H), 3.00 (ddd, J1 = 14.8 Hz, J2 = 4.1 Hz,
1219, 1051, 1035, 743 cmꢀ1
.

S. Xiao et al. / Tetrahedron: Asymmetry 20 (2009) 430–439
437
4.4.16. (1R,3R)-Methyl 1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-
b]indole-3- carboxylate cis-2n
351 (4), 335 (7), 291 (5), 264 (10), 248 (34), 229 (11), 204 (9),
169 (10), 144 (9), 105 (100), 77 (18). IR (KBr) 3994, 2965, 2848,
1738, 1605, 1453, 1268, 1202, 1122, 1062, 709 cmꢀ1. HRMS (EI)
calcd for C27H24N2O5: 456.1685; found: 456.1687.
White solid, Rf on silica 0.54 (dichloromethane–acetone, 3:1),
mp 73–74 °C (lit.56 75–76 °C). ½a D20
ꢁ
¼ þ93:6 (c 2.5, CHCl3). 1H
NMR (acetone-d6)
d
1.48 (d, J = 6.6 Hz, 1H), 2.72 (ddd,
J1 = 14.8 Hz, J2 = 11.2 Hz, J3 = 2.5 Hz, 1H), 3.00 (ddd, J1 = 14.8 Hz,
J2 = 4.2 Hz, J3 = 1.8 Hz, 1H), 3.75 (dd, J1 = 11.1 Hz, J2 = 4.1 Hz, 1H),
3.76 (s, 3H), 4.20–4.28 (m, 1H), 6.98 (td, J1 = 7.8 Hz, J2 = 1.1 Hz,
1H), 7.04 (td, J1 = 7.2 Hz, J2 = 1.2 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H),
7.42 (d, J = 7.7 Hz, 1H), 9.92 (br s, NH on the indole ring, 1H). MS
(EI) m/z (relative intensity) 245 (M++1, 16), 244 (M+, 100), 229
(92), 213 (2), 197 (4), 185 (41), 183 (25), 169 (59), 157 (72), 144
(9), 130 (10), 115 (8), 103 (2), 77 (2), 41 (1). IR (KBr) 3407, 2956,
4.4.20. (1R,3R)-Ethyl 1-(3,4,5-trimethoxyphenyl)-2,3,4,9-tetrahydro-
1H-pyrido [3,4-b]indole-3-carboxylate cis-2r
White solid, Rf on silica 0.55 (hexane–ethyl acetate, 1:1), mp
107–108 °C. ½a 2D0
ꢁ
¼ þ20:5 (c 0.4, CHCl3). 1H NMR (acetone-d6) d
1.30 (t, J = 7.1 Hz, 3H), 2.60 (br s, N–H, 1H), 2.90 (ddd,
J1 = 14.8 Hz, J2 = 11.1 Hz, J3 = 2.4 Hz, 1H), 3.12 (ddd, J1 = 14.9 Hz,
J2 = 4.1 Hz, J3 = 1.7 Hz, 1H), 3.72 (s, 3H), 3.76 (s, 6H), 3.93 (dd,
J1 = 11.1 Hz, J2 = 4.2 Hz, 1H), 4.17–4.30 (m, 2H), 5.23 (s, 1H), 6.75
(s, 2H), 6.99 (td, J1 = 7.0 Hz, J2 = 1.3 Hz, 1H), 7.03 (td, J1 = 7.0 Hz,
J2 = 1.4 Hz, 1H), 7.23 (dd, J1 = 6.3 Hz, J2 = 1.5 Hz, 1H), 7.48 (dd,
J1 = 7.5 Hz, J2 = 1.6 Hz, 1H), 9.47 (br s, NH on the indole ring, 1H).
MS (EI) m/z (relative intensity) 411 (M++1, 22), 410 (M+, 100),
409 (28), 393 (4), 381 (21), 337 (59), 322 (5), 309 (26), 294 (6),
278 (45), 262 (6), 247 (7), 234 (5), 219 (3), 194 (6), 180 (3), 169
(15), 144 (7), 117 (1). IR (KBr) 3347, 2939, 2841, 1735, 1595,
1507, 1462, 1422, 1330, 1267, 1233, 1181, 1127, 744 cmꢀ1. HRMS
(EI) calcd for C23H26N2O5: 410.1842; found: 410.1843.
2850, 1736, 1455, 1438, 1317, 1271, 1219, 1176, 1120, 745 cmꢀ1
.
4.4.17. (1R,3R)-Methyl 1-ethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-
b]indole-3- carboxylate cis-2o
White solid, Rf on silica 0.35 (hexane–ethyl acetate, 2:1), mp
83–84 °C. ½a 2D0
ꢁ
¼ þ9:8 (c 1.6, CHCl3). 1H NMR (acetone-d6) d 0.98
(t, J = 7.4 Hz, 3H), 1.70–1.82 (m, 1H), 2.00–2.13 (m, 1H), 2.71
(ddd, J1 = 14.8 Hz, J2 = 10.9 Hz, J3 = 2.5 Hz, 1H), 3.01 (ddd,
J1 = 14.8 Hz, J2 = 4.1 Hz, J3 = 1.8 Hz, 1H), 3.73 (dd, J1 = 11.1 Hz,
J2 = 4.1 Hz, 1H), 3.76 (s, 3H), 4.16 (dd, J1 = 5.1 Hz, J2 = 2.5 Hz, 1H),
6.99 (td, J1 = 7.0 Hz, J2 = 1.2 Hz, 1H), 7.03 (td, J1 = 7.1 Hz,
J2 = 1.2 Hz, 1H), 7.30 (dd, J1 = 7.8 Hz, J2 = 1.0 Hz, 1H), 7.42 (d,
J = 7.7 Hz, 1H), 9.87 (br s, NH on the indole ring, 1H). MS (EI) m/z
(relative intensity) 258 (M+, 16), 234 (3), 229 (100), 197 (14), 182
(7), 169 (48), 156 (7), 144 (3), 130 (3), 115 (4), 102 (1), 77 (1). IR
(KBr) 3399, 2960, 2849, 1736, 1452, 1437, 1331, 1271, 1218,
1174, 1046, 1008, 744 cmꢀ1. HRMS (EI) calcd for C15H18N2O2:
258.1368; found: 258.1369.
4.4.21. (1S,3R)-Ethyl-1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-
1H-pyrido [3,4-b]indole-3-carboxylate trans-2s
White solid, Rf on silica 0.40 (hexane–ethyl acetate, 1:1), mp
167–168 °C. ½a 2D0
ꢁ
¼ þ26:0 (c 1.9, CHCl3). 1H NMR (CDCl3) d 1.26
(t, J = 7.1 Hz, 3H), 3.16 (dd, J1 = 14.8 Hz, J2 = 6.0 Hz, 1H), 3.29 (dd,
J1 = 14.3 Hz, J2 = 5.5 Hz, 1H), 3.82 (s, 3H), 3.86 (s, 3H), 4.00 (t,
J = 5.7 Hz, 1H), 4.10–4.25 (m, 2H), 5.39 (s, 1H), 6.76–6.84 (m, 1H),
6.80 (s, 1H), 6.89 (br s, NH on the indole ring, 1H), 7.09–7.14 (m,
2H), 7.25 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 6.3 Hz, 2H). MS (EI) m/z (rel-
ative intensity) 381 (M++1, 21), 380 (M+, 100), 363 (19), 351 (32),
335 (3), 317 (3), 307 (42), 305 (17), 290 (16), 279 (11), 264 (7),
248 (30), 233 (6), 217 (5), 204 (8), 191 (3), 169 (11), 144 (7), 115
(2). IR (KBr) 3362, 2980, 1731, 1600, 1514, 1465, 1454, 1256,
4.4.18. (1S,3R)-Methyl-1-(4-acetoxy-3-methoxyphenyl)-2,3,4,9-
tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate trans-2p
White solid, Rf on silica 0.35 (hexane–ethyl acetate, 2:1), mp
121–122 °C. ½a 2D0
ꢁ
¼ þ30:4 (c 1.2, CHCl3). 1H NMR (CDCl3) 2.31 (s,
3H), 3.16 (dd, J1 = 15.4 Hz, J2 = 6.0 Hz, 1H), 3.27 (dd, J1 = 15.4 Hz,
J2 = 5.7 Hz, 1H), 3.72 (s, 3H), 3.75 (s, 3H), 4.00 (t, J = 5.8 Hz, 1H),
5.38 (s, 1H), 6.82 (dd, J1 = 8.1 Hz, J2 = 1.6 Hz, 1H), 6.95 (d,
J = 1.2 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 7.12 (t, J = 7.4 Hz, 1H), 7.16
(t, J = 6.7 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H),
7.71 (br s, NH on the indole ring, 1H). 13C NMR (CDCl3) d 173.96,
169.12, 151.20, 140.87, 139.30, 136.16, 132.87, 126.70, 122.45,
121.74, 120.40, 119.22, 117.98, 112.32, 111.05, 107.97, 55.75,
54.51, 52.32, 51.97, 24.63, 20.49. MS (EI) m/z (relative intensity)
395 (M++1, 24), 394 (M+, 100), 393 (11), 379 (9), 351 (22), 335
(76), 321 (8), 293 (31), 278 (19), 264 (18), 248 (27), 229 (17),
204 (14), 169 (25), 144 (19), 115 (4). IR (KBr) 3401, 2960, 1764,
1736, 1508, 1455, 1274, 1218, 1198, 1162, 1122 cmꢀ1. HRMS (EI)
calcd for C22H22N2O5: 394.1529; found: 394.1532.
1186, 1138, 1026, 858, 743 cmꢀ1
C22H24N2O4: 380.1736; found: 380.1737.
.
HRMS (EI) calcd for
4.4.22. (1S,3R)-Ethyl-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-
1H-pyrido[3,4-b] indole-3-carboxylate trans-2t
White solid, Rf on silica 0.40 (hexane–ethyl acetate, 2:1), mp
166–167 °C. ½a 2D0
ꢁ
¼ þ49:7 (c 0.3, CHCl3). 1H NMR (CHCl3) d 1.26
(t, J = 7.1 Hz, 3H), 3.11 (ddd, J1 = 15.3 Hz, J2 = 6.8 Hz, J3 = 1.3 Hz,
1H), 3.25 (ddd, J1 = 15.3 Hz, J2 = 5.3 Hz, J3 = 1.3 Hz, 1H), 3.79 (s,
3H), 3.94 (t, J = 6.5 Hz, 1H), 4.10–4.25 (m, 2H), 5.38 (s, 1H), 6.85
(d, J = 8.7 Hz, 2H), 7.10–7.27 (m, 5H), 7.55 (d, J = 6.4 Hz, 2H). MS
(EI) m/z (relative intensity) 351 (M++1, 21), 350 (M+, 100), 349
(16), 333 (20), 321 (28), 304 (4), 287 (3), 277 (43), 262 (17), 248
(17), 234 (7), 218 (17), 204 (7), 191 (2), 169 (8), 144 (10), 134
(5), 115 (2). IR (KBr) 3425, 3279, 3213, 2950, 1737, 1609, 1510,
4.4.19. (1R,3R)-Methyl-1-(4-benzoyloxy-3-methoxyphenyl)-
2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate cis-2q
White solid, Rf on silica 0.45 (hexane–ethyl acetate, 2:1), mp
1453, 1368, 1272, 1252, 1193, 1181, 1110, 1030, 847, 740 cmꢀ1
.
Anal. Calcd for C21H22N2O3: C, 71.98; H, 6.33; N, 7.99. Found: C,
71.79; H, 6.12; N, 7.80.
125–126 °C. ½a 2D0
ꢁ
¼ þ8:1 (c 1.4, CHCl3). 1H NMR (CDCl3) 3.02
(ddd, J1 = 14.7 Hz, J2 = 11.1 Hz, J3 = 2.3 Hz, 1H), 3.24 (ddd,
J1 = 15.1 Hz, J2 = 4.1 Hz, J3 = 1.5 Hz, 1H), 3.73 (s, 3H), 3.82 (s, 3H),
3.98 (dd, J1 = 11.2 Hz, J2 = 4.2 Hz, 1H), 5.25 (s, 1H), 7.00 (dd,
J1 = 8.1 Hz, J2 = 1.7 Hz, 1H), 7.04 (d, J = 1.5 Hz, 1H), 7.10–7.17 (m,
3H), 7.24 (d, J = 6.0 Hz, 1H), 7.48–7.55 (m, 3H), 7.62 (d, J = 7.5 Hz,
1H), 7.64 (br s, NH on the indole ring, 1H), 8.21 (d, J = 7.4 Hz,
2H). 13C NMR (CDCl3) d 173.08, 164.76, 151.66, 139.99, 139.71,
136.18, 134.38, 133.49, 130.22, 129.15, 128.46, 126.97, 123.01,
121.83, 120.78, 119.46, 118.04, 112.70, 111.07, 108.61, 58.58,
56.86, 55.87, 52.15, 25.58. MS (EI) m/z (relative intensity) 457
(M++1, 16), 456 (M+, 61), 455 (17), 441 (8), 397 (27), 369 (11),
4.4.23. (1R,3R)-Ethyl-1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetra-
hydro-1H-pyrido [3,4-b]indole-3-carboxylate cis-2u
White solid, Rf on silica 0.61 (hexane–ethyl acetate, 2:1).
½
a 2D0
ꢁ
¼ þ32:2 (c 1.0, ethyl acetate). 1H NMR (C6D6) d 0.95 (t,
J = 7.2 Hz, 3H), 3.07 (ddd, J1 = 14.8 Hz, J2 = 11.0 Hz, J3 = 2.5 Hz,
1H), 3.20 (ddd, J1 = 15.0 Hz, J2 = 4.2 Hz, J3 = 1.7 Hz, 1H), 3.70 (dd,
J1 = 11.0 Hz, J2 = 4.2 Hz, 1H), 3.95–4.04 (m, 2H), 4.73 (s, 1H), 5.31
(s, 2H), 6.56–6.64 (m, 2H), 6.79 (br s, NH on the indole ring, 1H),
6.85 (s, 1H), 6.87–6.92 (m, 1H), 7.15–7.22 (m, 2H), 7.52–7.55 (m,
1H). MS (EI) m/z (relative intensity) 365 (M++1, 19), 364 (M+,
100), 363 (19), 347 (31), 335 (48), 318 (6), 301 (10), 291 (72),

438
S. Xiao et al. / Tetrahedron: Asymmetry 20 (2009) 430–439
274 (44), 262 (50), 233 (35), 204 (95), 191 (10), 169 (60), 144 (47),
115 (22), 102 (19), 77 (16), 51 (6). IR (KBr) 3399, 2925, 1731, 1487,
1442, 1243, 1037, 811, 743 cmꢀ1. HRMS (EI) calcd for C21H20N2O4:
364.1423; found: 364.1429.
by suction and rinsed with a small amount of freshly mixed solvent
of nitromethane and toluene (1:1). The solid was then partitioned
between ethyl acetate (20 mL) and an aqueous solution of potas-
sium carbonate (665 mg, 4.81 mmol) in water (5 mL). The organic
layer was separated and dried over anhydrous MgSO4. Evaporation
of the solvent under a vacuum gave a crude product, which was
purified by flash chromatography to afford compound trans-d1-
2b (1.33 g, 3.62 mmol) as a white solid in 98% yield, mp 179–
4.4.24. (1R,3R)-Propyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetra-
hydro-1H-pyrido [3,4-b]indole-3-carboxylate cis-2v
White solid, Rf on silica 0.63 (hexane–ethyl acetate, 2:1).
½
a 2D0
ꢁ
¼ þ36:2 (c 1.0, ethyl acetate). 1H NMR (C6D6) d 0.72 (t,
180 °C, Rf on silica 0.51 (hexane–ethyl acetate, 1:1), ½a D20
¼ þ24:5
ꢁ
J = 7.4 Hz, 3H), 1.40–1.48 (m, 2H), 3.09 (ddd, J1 = 14.8 Hz,
J2 = 12.1 Hz, J3 = 1.5 Hz, 1H), 3.22 (ddd, J1 = 14.9 Hz, J2 = 4.1 Hz,
J3 = 1.5 Hz, 1H), 3.72 (dd, J1 = 11.0 Hz, J2 = 4.2 Hz, 1H), 3.90–4.01
(m, 2H), 4.73 (s, 1H), 5.31 (s, 2H), 6.56–6.67 (m, 2H), 6.75 (br s,
NH on the indole ring, 1H), 6.86 (s, 1H), 6.87–6.91 (m, 1H), 7.15–
7.21 (m, 2H), 7.51–7.57 (m, 1H). MS (EI) m/z (relative intensity)
379 (M++1, 20), 378 (M+, 100), 377 (11), 361 (24), 335 (55), 318
(8), 301 (6), 291 (73), 274 (49), 262 (50), 233 (32), 204 (94), 191
(17), 169 (50), 144 (41), 115 (21), 102 (16), 77 (11), 43 (24). IR
(KBr) 3391, 2966, 1732, 1487, 1442, 1243, 1207, 1038, 928, 810,
741 cmꢀ1. HRMS (EI) calcd for C22H22N2O4: 378.1580; found:
378.1579.
(c 1.0, CHCl3). 1H NMR (acetone-d6) d 3.00 (dd, J1 = 15.1 Hz,
J2 = 7.0 Hz, 1H), 3.14 (dd, J1 = 15.1 Hz, J2 = 5.3 Hz, 1H), 3.66 (s,
3H), 3.73 (s, 3H), 3.77 (s, 3H), 3.94 (dd, J1 = 6.9 Hz, J2 = 5.4 Hz,
1H), 6.73 (dd, J1 = 8.2 Hz, J2 = 2.0 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H),
6.97–7.07 (m, 3H), 7.27 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H),
9.67 (br s, NH on the indole ring, 1H). MS (EI) m/z (relative inten-
sity) 368 (M++1, 22), 367 (M+, 100), 365 (14), 352 (16), 349 (24),
317 (6), 308 (34), 290 (18), 280 (11), 249 (32), 230 (10), 218 (5),
205 (8), 170 (20), 145 (11). IR (KBr) 3374, 2970, 1730, 1514,
1464, 1443, 1409, 1261, 1238, 1172, 1138, 1025, 740 cmꢀ1. HRMS
(EI) calcd for C21H21DN2O4: 367.1642; found: 367.1643.
4.7. CIAT process of trans-2b-HCl in methanol in the presence
4.5. Preparation of deuterated 3,4-dimethoxybenzaldehyde 3
of zinc powder
A
solution of 2-(3,4-dimethoxyphenyl)-1,3-dithiane (1.51 g,
5.89 mmol) in dry toluene (15 mL) was cooled to ꢀ78 °C under
N2 by dry-ice bath. solution of n-BuLi (1.6 M, 5.5 mL,
To a solution of trans-2b-HCl (1.10 g, 2.73 mmol) in methanol
(15 mL) were added zinc powder (893 mg, 13.65 mmol) and con-
centrated hydrochloric acid (0.25 mL). The mixture was heated at
reflux, and then stirring was continued under reflux for 8 h. The
reaction mixture was filtered by suction to remove the excessive
zinc powder, and the filtrate was concentrated under vacuum to
give a residue which was partitioned between ethyl acetate
(50 mL) and an aqueous solution of potassium carbonate (15%,
20 mL). The organic phase was separated and dried over anhydrous
MgSO4, and then removal of solvent gave a crude oil, which was
chromatographed to afford cis-2b (431 mg, 1.18 mmol) in 43%
yield, trans-2b (451 mg, 1.23 mmol) in 45% yield, and (R)-methyl
2-amino-3-(2-(3,4-dimethoxybenzyl)-1H-indol-3-yl) propanoate
4 (52 mg, 0.14 mmol) in 5% yield, respectively. Characterization
a
A
8.80 mmol) in cyclohexane was then injected into the above cooled
solution via syringe. The reaction temperature was kept in the
range of ꢀ50 °C to ꢀ40 °C, and the mixture was stirred at this tem-
perature for around 5 h. Heavy water (0.5 mL) was added drop-
wise, and the mixture was warmed to room temperature.
Toluene (20 mL) and water (10 mL) were added, and the organic
phase was separated and dried over anhydrous MgSO4. After evap-
oration of solvents and purification by chromatography, 2-deutero-
2-(3,4-dimethoxyphenyl)-1,3-dithiane (1.41 g, 5.48 mmol) was
obtained in 93% yield.
To a solution of 2-deutero-2-(3,4-dimethoxyphenyl)-1,3-dithi-
ane (1.20 g, 4.66 mmol) in THF (20 mL), was added periodic acid
(1.59 g, 6.98 mmol).52 After stirring was continued at room tem-
perature for 10 min, the mixture was diluted with ethyl acetate
(50 mL). The organic solution was transferred into a separatory
funnel and washed twice with an aqueous solution of sodium sul-
fite (10%, 2 ꢂ 50 mL). Concentration of the organic solution under
vacuum gave a crude product, which was purified by flash chroma-
tography to produce the aldehyde 3 (702 mg, 4.20 mmol) in 90%
yield, mp 45–46 °C. 1H NMR (CDCl3) d 3.96 (s, 3H), 3.98 (s, 3H),
6.99 (d, J = 8.2 Hz, 1H), 7.43 (d, J = 1.7 Hz, 1H), 7.48 (dd,
J1 = 8.2 Hz, J2 = 1.8 Hz, 1H). MS (EI) m/z (relative intensity) 168
(M++1, 9), 167 (M+, 100), 165 (39), 152 (16), 137 (5), 122 (3), 96
(14), 78 (7), 51 (3). IR (KBr) 3018, 2998, 2983, 2947, 2121, 1677,
1587, 1468, 1420, 1273, 1249, 1160, 1139, 1019, 890, 795, 717,
data of compound 4: ½a D20
ꢁ
¼ þ17:3 (c 1.2, CHCl3). 1H NMR (CDCl3)
d 3.06 (dd, J1 = 14.4 Hz, J2 = 8.1 Hz, 1H), 3.31 (dd, J1 = 14.4 Hz,
J2 = 5.2 Hz, 1H), 3.69 (s, 3H), 3.80 (s, 3H), 3.82–3.87 (m, 1H), 3.85
(s, 3H), 4.08 (s, 2H), 6.73 (d, J = 7.9 Hz, 1H), 6.80 (d, J = 7.8 Hz,
1H), 7.06–7.15 (m, 2H), 7.21 (d, J = 7.1 Hz, 1H), 7.57 (d, J = 7.2 Hz,
1H), 7.82 (br s, NH on the indole ring, 1H). MS (EI) m/z (relative
intensity) 368 (M+, 2), 351 (1), 309 (1), 281 (15), 280 (100), 264
(4), 248 (8), 234 (4), 204 (4), 191 (2), 151 (6), 144 (23), 115 (2),
77 (1). IR (KBr) 3363, 2937, 2837, 1728, 1591, 1514, 1462, 1261,
1234, 1140, 1028, 744 cmꢀ1. HRMS (EI) calcd for C21H24N2O4:
368.1736; found: 368.1738.
Acknowledgments
640, 569 cmꢀ1
.
We thank the Chinese National Science Foundation (No.
A-20172015) and Shanghai Educational Development Foundation
(The Dawn Program: No. 03SG27) for the financial support of this
work.
4.6. Deuterium labeling test for the CIAT of 2b-HCl
To a solution of the deuterated 3,4-dimethoxybenzaldehyde 3
(680 mg 4.07 mmol) in isoproponal (10 mL) was added D-trypto-
References
phan methyl ester hydrochloride (powder, 943 mg, 3.70 mmol).
The mixture was heated at reflux, and stirring was continued for
4 h. The reaction solution was then concentrated to dryness under
a vacuum to give a crude solid product.
1. Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558.
2. Wanner, M. J.; van der Haas, R. N. S.; de Cuba, K. R.; van Maarseveen, J. H.;
Hiemstra, H. Angew. Chem., Int. Ed. 2007, 46, 7485.
3. Bi, L.; Zhao, M.; Wang, C.; Peng, S.; Winterfeldt, E. J. Org. Chem. 2002, 67, 22.
4. Maresh, J. J.; Giddings, L.-A.; Friedrich, A.; Loris, E. A.; Panjikar, S.; Trout, B. L.;
Stockigt, J.; Peters, B.; O’Connor, S. E. J. Am. Chem. Soc. 2008, 130, 710.
5. Silveira, C. C.; Felix, L. A.; Braga, A. L.; Kaufman, T. S. Org. Lett. 2005, 7, 3701.
6. Srinivasan, N.; Ganesan, A. Chem. Commun. 2003, 916.
Nitromethane (6 mL) and toluene (6 mL) were added, and the
resulting suspension was heated at reflux. After the stirring was
continued at reflux for 8 h, the mixture was cooled down to room
temperature. A pale yellow solid was collected on a Buchner funnel

S. Xiao et al. / Tetrahedron: Asymmetry 20 (2009) 430–439
439
7. Pulka, K.; Kulis, P.; Tymecka, D.; Frankiewicz, L.; Wilczek, M.; Kozminski, W.; 31. Sorbera, L. A.; Martin, L.; Leeson, P. A.; Castaner, J. Drugs Future 2001, 26, 15.
Misicka, A. Tetrahedron 2008, 64, 1506.
32. Yoshioka, R. Top. Curr. Chem. 2007, 269, 83.
8. Alberch, L.; Bailey, P. D.; Clingan, P. D.; Mills, T. J.; Price, R. A.; Pritchard, R. G.
Eur. J. Org. Chem. 2004, 1887.
33. Fogassy, E.; Nogradi, M.; Kozma, D.; Egri, G.; Palovics, E.; Kiss, V. Org. Biomol.
Chem. 2006, 4, 3011.
9. Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086.
10. Cox, E. D.; Hamaker, L. K.; Li, J.; Yu, P.; Czerwinski, K. M.; Deng, L.; Bennett, D.
W.; Cook, J. M.; Watson, W. H.; Krawiec, M. J. Org. Chem. 1997, 62, 44.
11. Horiguchi, Y.; Nakamura, M.; Saitoh, T.; Sano, T. Chem. Pharm. Bull. 2003, 51,
1368.
12. Singh, K.; Deb, P. K.; Venugopalan, P. Tetrahedron 2001, 57, 7939.
13. van der Heijden, R.; Jacobs, D. I.; Snoeijer, W.; Hallard, D.; Verpoorte, R. Curr.
Med. Chem. 2004, 11, 607.
14. O’Connor, S. E.; Maresh, J. J. Nat. Prod. Rep. 2006, 23, 532.
15. Aube, J.; Ghosh, S.; Tanol, M. J. Am. Chem. Soc. 1994, 116, 9009.
16. Bailey, P. D.; Cochrane, P. J.; Lorenz, K.; Collier, I. D.; Pearson, D. P. J.; Rosair, G.
M. Tetrahedron Lett. 2001, 42, 113.
17. Sunder-Plassmann, N.; Sarli, V.; Gartner, M.; Utz, M.; Seiler, J.; Huemmer, S.;
Mayer, T. U.; Surrey, T.; Giannis, A. Bioorg. Med. Chem. 2005, 13, 6094.
18. Lin, M.-J.; Zhang, W.; Sun, C.-M. J. Comb. Chem. 2007, 9, 951.
19. Hotha, S.; Yarrow, J. C.; Yang, J. G.; Garrett, S.; Renduchintala, K. V.; Mayer, T.
U.; Kapoor, T. M. Angew. Chem., Int. Ed. 2003, 42, 2379.
34. Berkes, D.; Jakubec, P.; Winklerova, D.; Povazanec, F.; Daich, A. Org. Biomol.
Chem. 2007, 5, 121.
35. Katoh, T.; Noguchi, C.; Kimura, H.; Fujiwara, T.; Ichihashi, S.; Nishide, K.;
Kajimoto, T.; Node, M. Tetrahedron: Asymmetry 2006, 17, 2943.
36. Anderson, N. G. Org. Process Res. Dev. 2005, 9, 800.
37. Jakubec, P.; Berkes, D.; Siska, R.; Gardianova, M.; Povazanec, F. Tetrahedron:
Asymmetry 2006, 17, 1629.
38. Kolarovic, A.; Berkes, D.; Baran, P.; Povazanec, F. Tetrahedron Lett. 2005, 46, 975.
39. Berkes, D.; Kolarovic, A.; Manduch, R.; Baran, P.; Povazanec, F. Tetrahedron:
Asymmetry 2005, 16, 1927.
40. Komatsu, H.; Awano, H. J. Org. Chem. 2002, 67, 5419.
41. Vedejs, E.; Donde, Y. J. Org. Chem. 2000, 65, 2337.
42. Vedejs, E.; Chapman, R. W.; Lin, S.; Muller, M.; Powell, D. R. J. Am. Chem. Soc.
2000, 122, 3047.
43. Boesten, W. H. J.; Seerden, J.-P. G.; de Lange, B.; Dielemans, H. J. A.; Elsenberg,
H. L. M.; Kaptein, B.; Moody, H. M.; Kellogg, R. M.; Broxterman, Q. B. Org. Lett.
2001, 3, 1121.
20. Sajja, E.; Vetukuri, V. N. K. V. P. R.; Ningam, S. R.; Vedantham, R.; Bodepudi, R.
World Patent WO 07/100387.
21. Orme, M. W.; Sawyer, J. S.; Schultze, L. M. World Patent WO 02/036593.
22. Orme, M. W.; Martinelli, M. J.; Doecke, C. W.; Pawlak, J. M.; Chelius, E. C. World
Patent WO 04/011463.
23. Shi, X.-X.; Liu, S.-L.; Xu, W.; Xu, Y.-L. Tetrahedron: Asymmetry 2008, 19, 435.
24. Dolitzky, B.; Diller, D. World Patent WO 06/091975.
25. Dunn, P. J. Org. Process Res. Dev. 2005, 9, 88.
44. Hass, H. B.; Riley, E. F. Chem. Rev. 1943, 32, 373.
45. Barrett, A. G. M.; Graboski, G. G. Chem. Rev. 1986, 86, 751.
46. Luzzio, F. A. Tetrahedron 2001, 57, 915.
47. Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797.
48. Repke, D. B.; Artis, D. R.; Nelson, J. T.; Wong, E. H. F. J. Org. Chem. 1994, 59,
2164.
49. Han, D.; Forsterling, F. H.; Deschamps, J. R.; Parrish, D.; Liu, X.; Yin, W.; Huang,
S.; Cook, J. M. J. Nat. Prod. 2007, 70, 75.
26. Daugan, A. C. -M. U.S. Patent 5,859,006.
50. Seebach, D.; Erickson, B. W.; Singh, G. J. Org. Chem. 1966, 31, 4303.
51. Mayer, K. K.; Prior, S.; Wiegrebe, W. Monatsh. Chem. 1986, 117, 511.
52. Shi, X.-X.; Khanapure, S. P.; Rokach, J. Tetrahedron Lett. 1996, 37, 4331.
53. Zhang, L.-H.; Gupta, A. K.; Cook, J. M. J. Org. Chem. 1989, 54, 4708.
54. Wang, H.; Usui, T.; Osada, H.; Ganesan, A. J. Med. Chem. 2000, 43, 1577.
55. Muthukrishnan, M.; More, S. V.; Garud, D. R.; Ramana, C. V.; Joshi, R. R.; Joshi, R.
A. J. Heterocycl. Chem. 2006, 43, 767.
27. Crasto, A. M.; Joshi, N. S.; Pradhan, N. S. C. World Patent WO 07/110734.
28. Orme, M. W.; Sawyer, J. S.; Schultze, L. M.; Daugan, A. C. -M.; Gellibert, F. U.S.
Patent 6,911,542.
29. Daugan, A.; Grondin, P.; Ruault, C.; Le Monnier de Gouville, A.-C.; Coste, H.;
Kirilovsky, J.; Hyafil, F.; Labaudiniere, R. J. Med. Chem. 2003, 46, 4525.
30. Daugan, A.; Grondin, P.; Ruault, C.; Le Monnier de Gouville, A.-C.; Coste, H.;
Linget, J. M.; Kirilovsky, J.; Hyafil, F.; Labaudiniere, R. J. Med. Chem. 2003, 46,
4533.
56. Zhao, M.; Bi, L.; Wang, W.; Wang, C.; Baudy-Floc’h, M.; Ju, J.; Peng, S. Bioorg.
Med. Chem. 2006, 14, 6998.