Highly stereoselective transformation of (1S,3S)-cis-1,3-disubstituted tetrahydro-β-carbolines into (1S,3R)-trans-1,3-disubstituted tetrahydro-β-carbolines: An improved asymmetric synthesis of tadalafil from l-tryptophan

Article abstract of DOI:10.1016/j.tetasy.2013.06.006

An efficient and general method for the highly stereoselective transformation of (1S,3S)-cis-1,3-disubstituted 1,2,3,4-tetrahydro-β- carbolines (THBCs) into (1S,3R)-trans-1,3-disubstituted THBCs is described. The method contains the following three steps: the enantiomerically pure (1S,3S)-cis-1,3-disubstituted THBCs 1 were first converted into (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 by N-1-naphthylmethylation/benzylation; (1S,3S)-cis-1,2,3-trisubstituted THBCs2 were then converted into (1S,3R)-trans-1,2,3-trisubstituted THBCs 3 in high yields and with high stereoselectivities via a base-catalyzed epimerization at C-3; (1S,3R)-trans-1,2,3-trisubstituted THBCs 3 were subsequently converted into (1S,3R)-trans-1,3-disubstituted THBCs 4 after reductive removal of the 1-naphthylmethyl/benzyl group. In addition, as an application of this method, an improved and highly stereoselective synthesis of the PDE5 inhibitor tadalafil (Cialis) starting from natural and less expensive l-tryptophan was developed.

Full text of DOI:10.1016/j.tetasy.2013.06.006

Tetrahedron: Asymmetry 24 (2013) 883–893
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Highly stereoselective transformation of (1S,3S)-cis-1,3-disubstituted
tetrahydro-b-carbolines into (1S,3R)-trans-1,3-disubstituted
tetrahydro-b-carbolines: an improved asymmetric synthesis of
tadalafil from L-tryptophan
⇑
Jing Dong, Tian-Zhuo Meng, Xiao-Xin Shi , Wen-Hui Zou, Xia Lu
Department of Pharmaceutical Engineering, School of Pharmacy, East China University of Science and Technology, 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:
An efficient and general method for the highly stereoselective transformation of (1S,3S)-cis-1,3-disubsti-
tuted 1,2,3,4-tetrahydro-b-carbolines (THBCs) into (1S,3R)-trans-1,3-disubstituted THBCs is described.
The method contains the following three steps: the enantiomerically pure (1S,3S)-cis-1,3-disubstituted
THBCs 1 were first converted into (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 by N-1-naphthylmethyla-
tion/benzylation; (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 were then converted into (1S,3R)-trans-1,2,3-
trisubstituted THBCs 3 in high yields and with high stereoselectivities via a base-catalyzed epimerization
at C-3; (1S,3R)-trans-1,2,3-trisubstituted THBCs 3 were subsequently converted into (1S,3R)-trans-1,3-
disubstituted THBCs 4 after reductive removal of the 1-naphthylmethyl/benzyl group. In addition, as
an application of this method, an improved and highly stereoselective synthesis of the PDE5 inhibitor tad-
Received 29 April 2013
Accepted 10 June 2013
Available online 24 July 2013
alafil (CialisÒ) starting from natural and less expensive
L
-tryptophan was developed.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
expensive
ceived less attention. In 2009, we reported the first synthesis of
tadalafil starting from
-tryptophan,9 but it suffered from lower
L-tryptophan, which could be more attractive, has re-
The 1,2,3,4-tetrahydro-b-carboline (THBC) nucleus exists in the
structures of a wide range of indole alkaloids and physiologically
active compounds.1 Recently, enantiomerically pure (1R,3R)-cis-
1,3-disubstituted THBCs have been employed as key intermediates
for the syntheses of tadalafil-like tetracyclic compounds,2 which
are an important type of cGMP specific phosphodiesterase-V
PDE5 inhibitors.2d,e Moreover, enantiomerically pure (1R,3S)-trans-
and (1R,3R)-cis-1,3-disubstituted THBCs have been employed as
key intermediates for the syntheses of HR22C16 and its analogues,3
which are an important type of mitotic kinesin Eg5 inhibitors.4
Both cis- and trans-chiral 1,3-disubstituted THBCs can usually be
obtained from stereoselective Pictet–Spengler reactions5 of trypto-
phan esters with aldehydes; the cis-selectivity of 1,3-disubstituted
THBCs has been particularly studied by several researchers.6 We
have also reported on the synthesis of cis- and trans-enantiomeri-
cally pure 1,3-disubstituted THBCs via highly stereoselective CIAT
processes.7 Herein we report an efficient and general method for
the highly stereoselective transformation of (1S,3S)-cis-1,3-disub-
stituted THBCs into (1S,3R)-trans-1,3-disubstituted THBCs.
L
overall yield and the moderate stereoselectivity of the base-cata-
lyzed 3-epimerization of an intermediate. Herein we report an im-
proved and highly stereoselective synthesis of tadalafil from
natural and less expensive L-tryptophan, in which the aforemen-
tioned method for the highly stereoselective transformation of
(1S,3S)-cis-1,3-disubstituted THBCs into (1S,3R)-trans-1,3-disubsti-
tuted THBCs was successfully applied.
2. Results and discussion
As shown in Scheme 1, the enantiomerically pure (1S,3S)-cis-
1,3-disubstituted THBCs 1 were first converted into (1S,3S)-cis-1,2,
3-trisubstituted THBCs 2 by N-alkylation with 1-naphthylmethyl
bromide or benzyl bromide (R3 = 1-NpCH2 or Bn) in the presence
of N,N-diisopropylethylamine (DIPEA) by means of Cook’s
method.10 The (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 were then
treated with base to undergo a base-catalyzed 3-epimerization
(epimerization at the C-3 position) to furnish (1S,3R)-trans-1,2,3-
trisubstituted THBCs 3. Subsequently, reductive removal of the R3
(Bn or 1-NpCH2) group from (1S,3R)-trans-1,2,3-trisubstituted
Tadalafil (CialisÒ) can normally be synthesized from unnatural
D
-tryptophan,2,8 but the synthesis of tadalafil from natural and less
THBCs
THBCs 4.
3 afforded the desired (1S,3R)-trans-1,3-disubstituted
⇑
Corresponding author. Tel.: +86 2164252052.
E-mail address: xxshi@ecust.edu.cn (X.-X. Shi).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.06.006

884
J. Dong et al. / Tetrahedron: Asymmetry 24 (2013) 883–893
CO2R1
3
CO2R1
R3
3
CO2R1
R3
3
b
a
1
NH
N
1
N
1
N
H
N
H
N
H
R2
R2
R2
(1S,3S)-cis-1,3-di-
substituted THBCs 1
(1S,3S)-cis-1,2,3-tri-
substituted THBCs 2
(1S,3R)-trans-1,2,3-tri-
substituted THBCs 3
3
CO2R1
c
NH
1
N
H
R2
(1S,3R)-trans-1,3-di-
4
substituted THBCs
Scheme 1. Transformation of (1S,3S)-cis-1,3-disubstituted THBCs 1 into (1S,3R)-trans-1,3-disubstituted THBCs 4 via base-catalyzed 3-epimerization of (1S,3S)-cis-1,2,3-
trisubstituted THBCs 2. Reagents and conditions: (a) 1.1 equiv of benzyl bromide or 1-naphthylmethyl bromide, 1.5 equiv of DIPEA, reflux for 5 h in CH3CN; (b) 0.5–2.0 equiv
of DBU, reflux for 15–25 h in CH3CN under N2; (c) Pd/C (10%, w/w), 1.0–1.1 atm of H2, 60 °C for 8 h in CH3CN.
We first attempted the base-catalyzed 3-epimerization of
(1S,3S)-cis-1,2,3-trisubstituted THBC 2a [R1 = Me, R2 = 3,4-(OCH2-
O)-Ph, R3 = 1-NpCH2] to (1S,3R)-trans-1,2,3-trisubstituted THBC
3a [R1 = Me, R2 = 3,4-(OCH2O)-Ph, R3 = 1-NpCH2] under various
reaction conditions (Table 1). As can be seen from Table 1, five sol-
vents such as methanol, dimethylsulfoxide (DMSO), 1,4-dioxane,
toluene, and acetonitrile (CH3CN) were tested, and several bases,
such as sodium methoxide, sodium carbonate, potassium carbon-
ate, triethylamine, 1,8-diazabicyclo [5,4,0]undec-7-ene (DBU),
and 4-N,N-dimethylaminopyridine (DMAP) were used as catalysts.
It was found that the 3-epimerization of compound 2a in methanol
or DMSO with DBU as the catalyst worked very well to afford com-
pound 3a in high yields and with excellent stereoselectivities (Ta-
ble 1, entries 2 and 7), but the reaction in CH3CN with 0.5 or
1.0 equiv of DBU gave the best yield and stereoselectivity (entries
14 and 15).
DBU-catalyzed 3-epimerization in CH3CN at reflux to afford the
corresponding (1S,3R)-trans-1,2,3-trisubstituted THBCs 3a–3n in
high yields. When the R2 substituents at the C-1 position were aryl
groups (Table 2, entries 1–9), the stereoselectivities were excellent
(P99:1). In some instances, almost only the trans-isomers could be
detected (entries 1, 3–5, 8, and 9). When the R2 substituents at the
C-1 position were alkyl groups (entries 10–14), the 3-epimeriza-
tion was hard to complete even after refluxing for a long period
of time. It should be noted that having 1-naphthylmethyl (R3 = 1-
NpCH2) at the N-2 position gave better stereoselectivities than
benzyl (entry 1 vs 2, and entry 10 vs 11) probably due to larger
bulk of 1-NpCH2 versus a Bn. In addition, when the R2 substituents
contained a hydroxyl group in the aryl ring (entry 6), 2.0 equiv of
DBU should be used, because the phenol might consume 1 equiv
of DBU.
A plausible mechanism for the above base-catalyzed 3-epimer-
ization is proposed in Figure 1.9 The cis-THBCs 2 were first reacted
with a base to form enolate intermediates, and then protonation of
the enolates led to the formation of the trans-THBCs 3. The 3-epi-
merization might be reversible, but when R2 is an aryl group,
3-epimerization of cis-THBCs 2 to trans-THBCs 3 was almost
We then attempted the DBU-catalyzed 3-epimerization of
various (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 to (1S,3R)-trans-
1,2,3-trisubstituted THBCs 3 (Table 2). As can be seen from Table 2,
a total of fourteen (1S,3S)-cis-1,2,3-trisubstituted THBCs 2a–2n
were examined, all of these cis-THBCs 2a–2n smoothly underwent
Table 1
Base-catalyzed 3-epimerization of compound 2a to compound 3a under various conditions with different bases as the catalyst
Entry
Solvent
Base (equiv)
T (°C)
t (h)
Product (ratio)
Yielda (%)
1
2
3
4
5
6
7
8
MeOH
MeOH
MeOH
MeOH
DMSO
CH3ONa (0.5)
DBUc (1.0)
Na2CO3(1.0)
K2CO3 (1.0)
Na2CO3 (1.0)
K2CO3 (1.0)
DBUc (0.5)
DBUc (1.0)
DBUc (1.0)
Na2CO3 (1.0)
K2CO3(1.0)
DMAPd (1.0)
Et3N (1.0)
65b
65
65
12
30
30
30
24
24
10
24
30
24
24
24
24
12
18
20
3a/2a (99:1)
3a/2a (99:1)
3a/2a (8:92)
3a/2a (91:9)
3a/2a (55:45)
3a/2a (63:37)
3a/2a (99:1)
3a/2a (62:38)
3a/2a(77:23)
3a/2a (5:95)
3a/2a (6:94)
3a/2a (10:90)
3a/2a (2:98)
3a/2a (100:0)e
3a/2a (100:0)e
3a/2a (92:8)
81
92
87
88
90
90
93
95
96
91
90
97
98
96
96
96
65
110
110
110
101b
110b
81b
81
81
81
81
81
DMSO
DMSO
1,4-Dioxane
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
9
10
11
12
13
14
15
16
DBUc (1.0)
DBUc (0.5)
DBUc (0.25)
81
a
b
c
Combined isolated yields of compounds 2a and 3a.
Refluxing under N2.
1,8-Diazabicyclo[5,4,0]undec-7-ene.
4-N,N-Dimethylaminopyridine.
d
e
Only the trans-isomer 3a was detected by HPLC.

J. Dong et al. / Tetrahedron: Asymmetry 24 (2013) 883–893
885
Table 2
DBU-catalyzed 3-epimerization of (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 into (1S,3R)-trans-1,2,3-trisubstituted THBCs 3 in CH3CNa
Entry
2
R1
R2
R3
DBU (equiv)
Time (h)
Product (ratio)
Yieldb (%)
c
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
Me
Me
Et
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
3,4-(OCH2O)-Ph
3,4-(OCH2O)-Ph
3,4-(OCH2O)-Ph
4-F-Ph
3,4,5-(MeO)3-Ph
3-HO-Ph
Ph
3,4-(MeO)2-Ph
3-MeO-4-EtO-Ph
Me
1-NpCH2
Bn
0.5
1.0
0.5
0.5
0.5
2.0e
1.0
0.5
1.0
1.0
1.0
1.0
1.0
1.0
18
18
16
18
16
20
15
18
15
25
26
25
25
25
3a/2a (100:0)d
3b/2b (99:1)
3c/2c (100:0)d
3d/2d (100:0)d
3e/2e (100:0)d
3f/2f (99:1)
3g/2g (99:1)
3h/2h (100:0)d
3i/2i (100:0)d
3j/2j (95:5)
96
94
95
94
98
91
93
95
96
95
94
95
97
92
1-NpCH2
1-NpCH2
1-NpCH2
1-NpCH2
1-NpCH2
1-NpCH2
1-NpCH2
1-NpCH2
Bn
9
10
11
12
13
14
Me
Et
n-Pr
n-Hex
3k/2k (86:14)
3l/2l (96:4)
3m/2m (96:4)
3n/2n (97:3)
1-NpCH2
1-NpCH2
1-NpCH2
a
b
c
The reactions were performed at reflux in CH3CN under N2 with DBU as the catalyst.
Combined isolated yields of compounds 2 and 3.
1-Naphthylmethyl.
Only trans-isomers were detected by HPLC.
Phenol might consume 1.0 equiv of DBU.
d
e
O
CO2R1
H
HN
R2
OR1
H+
HN
R2
HN
R2
base
H+
3
3
1
1
1
base
H
2
CO2R1
2
2
R3
R3
R3
N
N
H
N
H
H
Twist-chair conformer
of cis-THBCs 2
Twist-chair conformer
of trans-THBCs 3
enolate intermediates
Figure 1. Possible mechanism for the base-catalyzed 3-epimerization of (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 into (1S,3R)-trans-1,2,3-trisubstituted THBCs 3.
complete (3/2 P99:1, Table 2, entries 1–9), implying that there
may be a large energy difference between cis-THBCs 2 and trans-
THBCs 3, which is consistent with Cook’s reports.10,11 Since all
three substituents (CO2R1, R2, and R3) lie in equatorial positions,
trans-THBCs 3 are thermodynamically more stable than cis-THBCs
2, changes of enthalpies (4H) from cis-THBCs to trans-THBCs were
reported to be approximately 150 KJ/mol.11
With (1S,3R)-trans-1,2,3-trisubstituted THBCs 3a–3n in hand,
we next wanted to remove 1-naphthylmethyl or Bn group in order
to obtain the desired (1S,3R)-trans-1,3-disubstituted THBCs 4. Cook
et al. have reported a method for the debenzylation of (1S,3R)-
trans-1,2,3-trisubstituted THBCs via Pd/C-catalyzed hydrogenation
under a high pressure of H2 in a mixed solvent of methanol (or eth-
anol) and acetic acid.12 However, when we applied Cook’s hydroge-
nation method11 for the denaphthylmethylation (or debenzylation)
of (1S,3R)-trans-1,2,3-trisubstituted THBCs 3a–3n, a significant
amount (>25%) of the undesired over-hydrogenation products
(R)-2-amino-3-(2-substituted-indol-3-yl) propanoates were also
formed, especially when R2 was an aryl group.
In order to diminish the over-hydrogenation, we have at-
tempted the hydrogenation of (1S,3R)-trans-1,2,3-trisubstituted
THBCs 3a–3n under a normal pressure (1.0–1.1 atm) of H2 with
Pd/C (10%, w/w) as the catalyst in various solvents. Several solvents
such as methanol, isopropanol, tetrahydrofuran, ethyl acetate,
dichloromethane, acetone, DMSO, and CH3CN were tested; CH3CN
seemed to be the most appropriate solvent for hydrogenation.
When the hydrogenation of (1S,3R)-trans-1,2,3-trisubstituted
THBCs 3a–3n were performed in CH3CN at 60 °C under a normal
pressure (1.0–1.1 atm) of H2 with Pd/C (10%, w/w) as the catalyst,
the desired (1S,3R)-trans-1,3-disubstituted THBCs 4a–4l were ob-
tained in excellent yields (95–99% yields, see Section 4), while only
low yields (<5%) of the undesired over-hydrogenation products
could be observed by HPLC.
It is worth noting that the stereochemistry of (1S,3R)-trans-1,3-
disubstituted THBCs 4a–4l can be assigned by using 2D 1H NMR
techniques.7 In the 1H–1H NOESY spectra of (1S,3R)-trans-1,3-
disubstituted THBCs 4a–4l, the proton at the C-3 position does
not correlate with the proton at C-1 position, but correlates with
the neighboring protons on the substituent R2, meaning that the
proton at the C-3 position and the substituent R2 are on the same
side of the piperidine ring. Moreover, in the structure of (1S,3R)-
trans-1,2,3-trisubstituted THBCs 3a–3n, the proton at the C-3 posi-
tion and the R2substituent at the C-1 position should also be on the
same side of the piperidine ring, since the Pd/C-catalyzed hydroge-
nation does not change the stereochemistry of C-1 and C-3.
As an application of the aforementioned method for the highly
stereoselective transformation of (1S,3S)-cis-1,3-disubstituted
THBCs 2 into (1S,3R)-trans-1,3-disubstituted THBCs 4, we per-
formed a novel, efficient, and highly stereoselective synthesis of
tadalafil (CialisÒ) starting from
chloride through the synthetic route as depicted in Scheme 2.
-Tryptophan methyl ester hydrochloride was first converted into
L-tryptophan methyl ester hydro-
L
(1S,3S)-cis-disubstituted THBC 1a in 95% yield according to a
known procedure.9 Compound 1a then underwent a tandem N-
naphthylmethylation and DBU-catalyzed 3-epimerization in a
one-pot procedure to afford (1S,3S)-trans-trisubstituted THBC 3a
in 96% yield. Next, compound 3a was converted into (1S,3R)-
trans-disubstituted THBC 4a in 98% yield after Pd/C-catalyzed
denaphthylmethylation in CH3CN. Salt formation of compound 4a
with HCl in CH3CN and the highly stereoselective simultaneous
1-epimerization via a CIAT process8a furnished the hydrochloride
salt of (1R,3R)-cis-disubstituted THBC ent-1a-HCl in 91% yield.

886
J. Dong et al. / Tetrahedron: Asymmetry 24 (2013) 883–893
3
CO2Me
Np
3
CO2Me
1
N
1
NH
CO2Me
NH3Cl
Ref.9
95%
N
H
N
H
a
96%
N
H
O
L-tryptophan methy ester
hydrochloride
O
O
O
3a
1a
CO2Me
NH2Cl
CO2Me
3
3
1
NH
1
Ref.9
N
N
H
b
H
c
tadalafil
98%
2-steps
89%
91%
O
O
O
O
4a
1a
ent- -HCl
Scheme 2. A novel asymmetric synthesis of tadalafil starting from
L-tryptophan methyl ester hydrochloride. Reagents and conditions: (a) 1.1 equiv of 1-naphthylmethyl
bromide, 1.5 equiv of DIPEA, reflux for 5 h in CH3CN; then 1.3 equiv of K2CO3, 1.0 equiv of DBU, reflux for 18 h in CH3CN; (b) Pd/C (10%, w/w), 1.0–1.1 atm of H2, 60 °C for 8 h in
CH3CN; (c) 1.2 equiv of HCl, azetropic distillation with CH3CN for 1 h; then reflux for 8 h in CH3CN.
Finally, ent-1a-HCl was converted into tadalafil in 89% yield via
4.2. General procedure for the preparation of (1S,3S)-cis-1,2,3-
trisubstituted THBCs 2
two steps as described previously.9
To a solution of compounds 1 (4.000 mmol) in CH3CN (15 mL),
were added DIPEA (0.776 g, 6.004 mmol) and 1-naphthylmethyl
bromide (0.975 g, 4.410 mmol). The resulting solution was heated
at reflux at 81 °C, and then stirred at this temperature for 5 h. The
reaction was monitored by TLC. After the reaction was complete,
the solvent was removed by vacuum distillation. The residue was
partitioned between ethyl acetate (40 mL) and an aqueous solution
of potassium carbonate (10% w/w, 20 mL). The two phases were
separated, and the aqueous solution was extracted twice with
ethyl acetate (2 ꢀ 20 mL). The extracts were combined and dried
over anhydrous MgSO4, the organic solution was then concen-
trated to give a crude product, which was purified by flash chroma-
tography (eluent: EtOAc/hexane = 1:5) to afford compounds 2 in
88–96% yields. Characterization data of compounds 2a–2n are as
follows:
3. Conclusion
In conclusion, an efficient and general method for the highly
stereoselective transformation of (1S,3S)-cis-1,3-disubstituted
THBCs 2 into (1S,3R)-trans-1,3-disubstituted THBCs 4 has been
developed. The key point of this method, the base-catalyzed 3-epi-
merization of 1,2,3-trisubstituted THBCs 3 was investigated in de-
tail. Moreover, by applying this method, the synthesis of tadalafil
(CialisÒ) starting from less expensive
L-tryptophan methyl ester
hydrochloride was greatly improved. Compared with our previous
synthesis,9 the overall yield of tadalafil was increased from 42.3%9
to 72.4%.
It is worth noting that this method for the highly stereoselective
transformation of (1S,3S)-cis-1,3-disubstituted THBCs into (1S,3R)-
trans-1,3-disubstituted THBCs should also be applicable for the
highly stereoselective transformation of (1R,3R)-cis-1,3-disubsti-
tuted THBCs into (1R,3S)-trans-1,3-disubstituted THBCs.
4.2.1. (1S,3S)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-2-(naphthal-
en-1-yl-methyl) -1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-
carboxylate 2a
95% Yield. White solid, mp 135–136 °C. ½a D20
¼ ꢂ83:4 (c 1.00,
ꢁ
4. Experimental
4.1. General
CH3OH). 1H NMR (400 MHz, acetone-d6) d 9.67 (br s, 1H), 8.46 (d,
J = 6.8 Hz, 1H), 7.89 (d, J = 6.7 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H),
7.60 (d, J = 7.1 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.53–7.48 (m, 2H),
7.42 (dd, J1 = 8.0 Hz, J2 = 7.1 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.09
(dd, J1 = 7.8 Hz, J2 = 7.6 Hz, 1H), 7.04 (dd, J1 = 7.7 Hz, J2 = 7.6 Hz,
1H), 6.56 (d, J = 7.9 Hz, 1H), 6.50 (s, 1H), 6.47 (d, J = 7.9 Hz, 1H),
5.85 (d, J = 12.2 Hz, 2H), 5.14 (s, 1H), 4.63 (d, J = 13.6 Hz, 1H),
4.37 (d, J = 13.6 Hz, 1H), 3.93 (dd, J1 = 5.6 Hz, J2 = 4.2 Hz, 1H), 3.35
(dd, J1 = 15.5 Hz, J2 = 4.2 Hz, 1H), 3.15 (s, 3H), 3.04 (dd,
J1 = 15.5 Hz, J2 = 5.6 Hz, 1H). 13C NMR (100 MHz, acetone-d6) d
174.26, 148.07, 147.51, 137.87, 137.72, 135.67, 134.88, 133.85,
133.70, 133.46, 129.20, 128.95, 128.69, 127.97, 126.56, 126.53,
126.05, 126.06, 123.63, 122.23, 119.73, 118.97, 112.00, 110.57,
107.83, 101.78, 61.58, 59.87, 57.97, 51.49, 22.54. HRMS (ESI) m/z
calcd for (C31H26N2O4+H)+ 491.1971; found 491.1974. IR (KBr film)
1H NMR and 13C NMR spectra were acquired on Bruker AM-500,
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. Optical rotations were measured on WZZ-
1S automatic polarimeter at room temperature. Column chroma-
tography was performed on silica gel (Qingdao Ocean Chemical
Corp.). All chemicals were analytically pure. Acetonitrile was dried
by distillation over calcium hydride. L-Tryptophan methyl (or
ethyl) ester hydrochloride was prepared according to a known pro-
cedure.13 The (1S,3S)-cis-1,3-disubstituted THBCs 1 were prepared
from
L-tryptophan methyl (or ethyl) ester hydrochloride and alde-
hydes via CIAT process according to a previous report.7
3393, 2919, 2848, 1728, 1484, 1438, 1253, 1037, 796, 742 cmꢂ1
.

J. Dong et al. / Tetrahedron: Asymmetry 24 (2013) 883–893
887
4.2.2. (1S,3S)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-2-benzyl-1,2,
3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 2b
J = 7.4 Hz, 1H), 7.12–7.02 (m, 2H), 6.07 (s, 2H), 5.06 (s, 1H), 4.68
(d, J = 13.3 Hz, 1H), 4.28 (d, J = 13.3 Hz, 1H), 4.04 (dd, J1 = 5.9 Hz,
J2 = 3.9 Hz, 1H), 3.75 (dq, J1 = 10.7 Hz, J2 = 7.1 Hz, 1H), 3.55 (s,
3H), 3.39 (s, 6H), 3.38 (dd, J1 = 15.6 Hz, J2 = 3.9 Hz, 1H), 3.28 (dq,
J1 = 10.7 Hz, J2 = 7.1 Hz, 1H), 3.11 (dd, J1 = 15.6 Hz, J2 = 5.9 Hz, 1H),
0.97 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d 173.69,
153.30, 153.29, 137.82, 137.65, 137.30, 136.04, 134.98, 133.65,
133.16, 133.02, 129.10, 129.01, 127.94, 126.90, 126.52, 126.49,
126.01, 122.14, 119.59, 118.94, 111.83, 107.71, 107.45, 107.44,
60.89, 60.81, 60.75, 60.16, 59.35, 55.86, 55.85, 21.62, 14.24. HRMS
(ESI) m/z calcd for (C34H34N2O5+H)+ 551.2546; found 551.2551. IR
(KBr film) 3357, 2931, 2837, 1727, 1593, 1504, 1459, 1325, 1237,
92% Yield. White solid, mp 178–179 °C. ½a D20
¼ ꢂ87:0 (c 1.60,
ꢁ
CHCl3). 1H NMR (400 MHz, acetone-d6) d 9.53 (br s, 1H), 7.51 (d,
J = 7.3 Hz, 1H), 7.38 (d, J = 7.1 Hz, 2H), 7.34–7.18 (m, 4H), 7.10–
6.98 (m, 2H), 6.82–6.72 (m, 3H), 5.94 (d, J = 1.9 Hz, 2H), 4.96 (s,
1H), 4.05 (d, J = 14.6 Hz, 1H), 3.93 (d, J = 14.6 Hz, 1H), 3.82 (dd,
J1 = 6.1 Hz, J2 = 5.2 Hz, 1H), 3.32 (s, 3H), 3.31 (dd, J1 = 15.2 Hz,
J2 = 6.1 Hz, 1H), 3.03 (dd, J1 = 15.2 Hz, J2 = 5.2 Hz, 1H). 13C NMR
(100 MHz, acetone-d6) d 174.07, 148.55, 147.97, 139.59, 137.85,
135.77, 134.49, 130.01, 130.00, 128.90, 128.89, 127.83, 127.75,
123.62, 122.10, 119.66, 118.81, 111.88, 110.25, 108.30, 107.15,
101.96, 61.94, 61.13, 57.90, 51.65, 24.26. HRMS (ESI) m/z calcd
for (C27H24N2O4+H)+ 441.1814; found 441.1809. IR (KBr film)
3324, 3054, 2896, 2850, 1728, 1488, 1439, 1255, 1174, 1071,
1125, 1037, 795, 742 cmꢂ1
.
4.2.6. (1S,3S)-Methyl 1-(3-hydroxyphenyl)-2-(naphthalen-1-yl-
methyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxyl-
ate 2f
1038, 938, 738 cmꢂ1
.
4.2.3. (1S,3S)-Ethyl 1-(benzo[d][1,3]dioxol-5-yl)-2-(naphthalen-
1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carb-
oxylate 2c
88% Yield. White solid, mp 121–122 °C. ½a D20
¼ ꢂ77:3 (c 1.00,
ꢁ
CH3OH). 1H NMR (400 MHz, acetone-d6) d 9.69 (br s, 1H), 8.46–
8.39 (m, 1H), 8.17 (s, 1H), 7.93–7.87 (m, 1H), 7.83 (d, J = 8.2 Hz,
1H), 7.62 (d, J = 7.2 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.53–7.47 (m,
2H), 7.43 (dd, J1 = 8.0 Hz, J2 = 7.2 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H),
7.13–7.04 (m, 2H), 7.01 (dd, J1 = 8.0 Hz, J2 = 7.8 Hz, 1H), 6.63 (d,
J = 7.8 Hz, 1H), 6.59 (d, J = 7.8 Hz, 1H), 6.48 (s, 1H), 5.18 (s, 1H),
4.64 (d, J = 13.8 Hz, 1H), 4.45 (d, J = 13.8 Hz, 1H), 3.89 (dd,
J1 = 6.0 Hz, J2 = 3.3 Hz, 1H), 3.35 (dd, J1 = 15.5 Hz, J2 = 3.2 Hz, 1H),
3.04 (s, 3H), 2.99 (dd, J1 = 15.5 Hz, J2 = 6.0 Hz, 1H). 13C NMR
(100 MHz, acetone-d6) d 174.26, 157.91, 142.79, 137.80, 135.65,
134.93, 133.68, 133.50, 129.40, 129.21, 128.91, 128.64, 128.01,
126.58, 126.52, 126.05, 125.97, 122.11, 121.86, 119.61, 118.87,
117.13, 114.96, 111.94, 107.92, 61.52, 58.79, 57.78, 51.21, 22.19.
HRMS (ESI) m/z calcd for (C30H26N2O3+H)+ 463.2022; found
463.2022. IR (KBr film) 3366, 3053, 2940, 1704, 1599, 1454,
91% Yield. White solid, mp 109–110 °C. ½a D20
¼ ꢂ69:4 (c 1.00,
ꢁ
CH3OH). 1H NMR (400 MHz, acetone-d6) d 9.67 (br s, 1H), 8.54–
8.49 (m, 1H), 7.91–7.86 (m, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.60–
7.53 (m, 2H), 7.52–7.47 (m, 2H), 7.42 (dd, J1 = 8.0 Hz, J2 = 5.0 Hz,
1H), 7.31 (d, J = 7.8 Hz, 1H), 7.14 (dd, J1 = 7.8 Hz, J2 = 7.9 Hz, 1H),
7.06 (dd, J1 = 7.8 Hz, J2 = 8.0 Hz, 1H), 6.54 (d, J = 8.0 Hz, 1H), 6.45
(s, 1H), 6.43 (d, J = 8.0 Hz, 2H), 5.84 (d, J = 10.2 Hz, 2H), 5.11 (s,
1H), 4.63 (d, J = 13.5 Hz, 1H), 4.36 (d, J = 13.5 Hz, 1H), 3.90 (dd,
J1 = 5.9 Hz, J2 = 4.0 Hz, 1H), 3.69 (dq, J1 = 10.8 Hz, J2 = 7.1 Hz, 1H),
3.37–3.32 (m, 2H), 3.01 (dd, J1 = 15.5 Hz, J2 = 5.9 Hz, 1H), 0.98 (t,
J = 7.1 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d 173.84, 148.02,
147.50, 137.84, 135.76, 135.70, 134.91, 133.75, 133.49, 129.16,
128.98, 128.72, 126.54, 126.49, 126.33, 126.02, 123.61, 122.21,
119.70, 118.95, 111.96, 111.91, 110.64, 107.83, 107.73, 101.75,
61.31, 60.95, 59.93, 58.37, 22.26, 14.15. HRMS (ESI) m/z calcd for
(C32H28N2O4+H)+ 505.2127; found 505.2125. IR (KBr film) 3386,
2921, 1731, 1485, 1442, 1305, 1239, 1191, 1103, 1037, 799,
1277, 1254, 1220, 1166, 792, 744 cmꢂ1
.
4.2.7. (1S,3S)-Methyl 1-phenyl-2-(naphthalen-1-ylmethyl)-1,2,
3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 2g
745 cmꢂ1
.
92% Yield. White solid, mp 89–90 °C, ½a D20
¼ ꢂ43:9 (c 1.00,
ꢁ
CHCl3). 1H NMR (400 MHz, DMSO-d6) d 10.68 (br s, 1H), 8.45–
8.38 (m, 1H), 7.96–7.90 (m, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.58–
7.50 (m, 4H), 7.45 (dd, J1 = 8.0, J2 = 7.8 Hz, 1H), 7.27 (d, J = 7.9 Hz,
1H), 7.19–7.10 (m, 3H), 7.09 (dd, J1 = 7.8, J2 = 7.9 Hz, 1H), 7.02
(dd, J1 = 7.8, J2 = 8.0 Hz, 1H), 6.89 (dd, J1 = 7.8, J2 = 1.7 Hz, 2H),
5.16 (s, 1H), 4.58 (d, J = 13.5 Hz, 1H), 4.32 (d, J = 13.5 Hz, 1H),
3.94 (dd, J1 = 6.0 Hz, J2 = 2.6 Hz, 1H), 3.34 (s, 3H), 3.21 (dd,
J1 = 15.5 Hz, J2 = 2.6 Hz, 1H), 2.98 (dd, J1 = 15.5 Hz, J2 = 6.0 Hz, 1H).
13C NMR (100 MHz, DMSO-d6) d 173.52, 140.80, 136.85, 134.94,
134.00, 132.58, 129.54, 129.53, 128.74, 128.49, 128.48, 128.16,
127.84, 127.83, 127.31, 127.01, 126.21, 126.20, 125.67, 125.50,
121.40, 118.80, 118.36, 111.56, 106.66, 59.69, 57.72, 57.32, 51.11,
20.76. HRMS (EI) m/z calcd for (C30H26N2O2)+ 446.1994; found
446.1997. IR (KBr film) 3397, 2944, 2106, 1722, 1453, 1256,
4.2.4. (1S,3S)-Methyl 1-(4-fluorophenyl)-2-(naphthalen-1-yl-
methyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxyl-
ate 2d
95% Yield. White solid, mp 108–109 °C. ½a D20
¼ ꢂ98:7 (c 1.00,
ꢁ
CH3OH). 1H NMR (400 MHz, acetone-d6) d 9.74 (br s, 1H), 8.49 (d,
J = 8.2 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H),
7.61–7.55 (m, 2H), 7.55–7.48 (m, 2H), 7.42 (dd, J1 = 8.0 Hz,
J2 = 7.2 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.13–7.03 (m, 2H), 7.00–
6.92 (m, 2H), 6.88–6.80 (m, 2H), 5.20 (s, 1H), 4.64 (d, J = 13.4 Hz,
1H), 4.37 (d, J = 13.4 Hz, 1H), 3.96 (dd, J1 = 5.9 Hz, J2 = 3.4 Hz, 1H),
3.35 (dd, J1 = 15.6 Hz, J2 = 3.4 Hz, 1H), 3.07 (s, 3H), 3.06 (dd,
J1 = 15.6 Hz, J2 = 5.9 Hz, 1H). 13C NMR (100 MHz, acetone-d6) d
174.06, 137.85, 137.74, 137.71, 135.56, 134.94, 133.49, 133.16,
132.10, 132.02, 129.21, 129.09, 128.81, 127.99, 126.59, 126.58,
126.17, 126.04, 122.30, 119.75, 119.00, 114.93, 114.72, 111.97,
107.98, 60.43, 59.38, 58.39, 51.37, 21.85. HRMS (ESI) m/z calcd
for (C30H25FN2O2+H)+ 465.1978; found 465.1981. IR (KBr film)
3398, 3052, 2920, 2847, 1729, 1601, 1505, 1455, 1436, 1219,
1174, 1100, 1009, 786, 741 cmꢂ1
.
4.2.8. (1S,3S)-Methyl 1-(3,4-dimethoxyphenyl)-2-(naphthalen-
1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carb-
oxylate 2h
1156, 832, 796, 742 cmꢂ1
.
96% Yield. White solid, mp 207–208 °C, ½a D20
¼ ꢂ77:2 (c 1.00,
ꢁ
CHCl3). 1H NMR (400 MHz, DMSO-d6) d 10.66 (br s, 1H), 8.52 (d,
J = 8.1 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H),
7.60–7.50 (m, 3H), 7.49–7.38 (m, 2H), 7.30 (d, J = 7.8 Hz, 1H),
7.08 (dd, J1 = 7.6 Hz, J2 = 7.8 Hz, 1H), 7.02 (dd, J1 = 7.6 Hz,
J2 = 7.8 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.40 (d, J = 1.6 Hz, 1H),
6.30 (dd, J = 8.4 Hz, J2 = 1.6 Hz, 1H), 5.02 (s, 1H), 4.57 (d,
J = 13.5 Hz, 1H), 4.21 (d, J = 13.5 Hz, 1H), 4.03 (dd, J1 = 6.0 Hz,
J2 = 2.6 Hz, 1H), 3.62 (s, 3H), 3.30 (s, 3H), 3.21 (dd, J = 15.6 Hz,
4.2.5. (1S,3S)-Ethyl 2-(naphthalen-1-ylmethyl)-1-(3,4,5-trimeth-
oxyphenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxyl-
ate 2e
96% Yield. White solid, mp 105–106 °C. ½a D20
¼ ꢂ67:0 (c 1.05,
ꢁ
CH3OH). 1H NMR (400 MHz, acetone-d6) d 9.65 (br s, 1H), 8.63 (d,
J = 8.1 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H),
7.60–7.47 (m, 4H), 7.43 (dd, J1 = 8.1 Hz, J2 = 7.4 Hz, 1H), 7.30 (d,

888
J. Dong et al. / Tetrahedron: Asymmetry 24 (2013) 883–893
J2 = 2.6 Hz, 1H), 3.01 (dd, J = 15.6 Hz, J2 = 6.0 Hz, 1H), 2.91 (s, 3H).
13C NMR (100 MHz, DMSO-d6) d 172.91, 147.94, 147.62, 136.11,
134.66, 133.56, 132.91, 132.06, 131.83, 128.22, 128.05, 127.82,
126.49, 125.71, 125.67, 125.38, 125.15, 120.88, 120.55, 118.27,
117.87, 112.85, 110.96, 110.36, 105.89, 58.11, 57.90, 57.16, 55.42,
54.69, 50.71, 19.82. HRMS (EI) m/z calcd for (C32H30N2O4)+
506.2206; found 506.2208. IR (KBr film) 3358, 2939, 2837, 1726,
4.2.12. (1S,3S)-Methyl 1-ethyl-2-(naphthalen-1-ylmethyl)-1,2,
3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 2l
91% Yield. White solid, mp 82–84 °C. ½a D20
¼ ꢂ42:2 (c 1.02, CH3-
ꢁ
OH). 1H NMR (400 MHz, acetone-d6): d = 9.81 (br s, 1H), 8.57 (d,
J = 8.1 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H),
7.62–7.48 (m, 4H), 7.45 (dd, J1 = 7.6 Hz, J2 = 7.9 Hz, 1H), 7.32 (d,
J = 7.8 Hz, 1H), 7.07 (dd, J1 = 7.9 Hz, J2 = 7.6 Hz, 1H), 7.02 (dd,
J1 = 7.8 Hz, J2 = 7.6 Hz, 1H), 4.51 (d, J = 13.5 Hz, 1H), 4.29 (d,
J = 13.5 Hz, 1H), 4.05 (dd, J1 = 6.3 Hz, J2 = 2.9 Hz, 1H), 3.92 (dd,
J1 = 8.2 Hz, J2 = 5.0 Hz, 1H), 3.56 (s, 3H), 3.25 (dd, J1 = 15.7 Hz,
J2 = 2.9 Hz, 1H), 3.08 (dd, J1 = 15.7 Hz, J2 = 6.3 Hz, 1H), 1.62–1.42
(m, 2H), 0.76 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d
174.72, 137.53, 136.14, 135.56, 134.98, 133.65, 129.15, 128.99,
128.50, 128.27, 126.56, 126.48, 126.42, 126.00, 121.80, 119.49,
118.73, 111.75, 105.99, 59.42, 59.37, 58.98, 51.70, 28.32, 19.68,
11.64. HRMS (ESI) m/z calcd for (C26H26N2O2+H)+ 399.2073; found
399.2074. IR (KBr film) 3400, 2926, 1730, 1462, 1332, 1299, 1203,
1512, 1450, 1265, 1230, 1139, 1028, 801, 743 cmꢂ1
.
4.2.9. (1S,3S)-Methyl 1-(4-ethoxy-3-methoxy-phenyl)-2-(naph-
thalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]ind-
ole-3-carboxylate 2i
91% Yield. White solid, mp 179–180 °C, ½a D20
¼ ꢂ68:1 (c 3.00,
ꢁ
CHCl3). 1H NMR (400 MHz, DMSO-d6) d 10.67 (br s, 1H), 8.53
(d, J = 7.9 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 7.8 Hz,
1H), 7.62–7.44 (m, 5H), 7.29 (d, J = 8.0 Hz, 1H), 7.08 (dd, J1 = 7.8
HZ, J2 = 7.6 Hz, 1H), 7.02 (dd, J1 = 7.8 Hz, J2 = 7.6 Hz, 1H), 6.66 (d,
J = 8.2 Hz, 1H), 6.40 (s, 1H), 6.26 (d, J = 8.2 Hz, 1H), 5.03 (s, 1H),
4.59 (d, J = 13.4 Hz, 1H), 4.22 (d, J = 13.4 Hz, 1H), 4.05 (dd,
J1 = 4.2 Hz, J2 = 3.5 Hz, 1H), 3.87 (q, J = 6.8 Hz, 2H), 3.31 (s, 3H),
3.20 (dd, J1 = 13.4 Hz, J2 = 3.5 Hz, 1H), 3.01 (dd, J1 = 13.4 Hz,
J2 = 4.2 Hz, 1H), 2.92 (s, 3H), 1.24 (t, J = 6.8 Hz, 3H). 13C NMR
(100 MHz, DMSO-d6) d 173.38, 148.68, 147.25, 136.75, 135.19,
134.06, 133.43, 132.58, 132.47, 128.71, 128.54, 128.33, 127.04,
126.19, 126.15, 125.90, 125.64, 121.33, 121.05, 118.72, 118.35,
113.51, 112.10, 111.49, 106.41, 64.11, 58.62, 58.31, 57.67,
55.17, 51.19, 20.30, 15.16. HRMS (EI): m/z calcd for
(C33H32N2O4)+ 520.2362; found 520.2364. IR (KBr film) 3336,
2972, 2941, 2883, 1734, 1512, 1452, 1271, 1284, 1138, 1033,
1159, 1052, 797, 742 cmꢂ1
.
4.2.13. (1S,3S)-Methyl 2-(naphthalen-1-ylmethyl)-1-propyl-1,2,
3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 2m
93% Yield. Mp 73–74 °C, ½a D20
ꢁ
¼ ꢂ33:2 (c 1.00, CHCl3). 1H NMR
(400 MHz, acetone-d6) d 9.82 (br s, 1H), 8.58 (d, J = 8.0 Hz, 1H),
7.93 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.62–7.52 (m, 4H),
7.48 (dd, J1 = 8.0 Hz, J2 = 7.6 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.09
(dd, J1 = 7.8 Hz, J2 = 7.6 Hz, 1H), 7.03 (dd, J1 = 7.9 Hz, J2 = 7.6 Hz,
1H), 4.53 (d, J = 13.4 Hz, 1H), 4.30 (d, J = 13.4 Hz, 1H), 4.09 (dd,
J1 = 6.3 Hz, J2 = 2.2 Hz, 1H), 4.04 (dd, J1 = 8.1 Hz, J2 = 6.7 Hz, 1H),
3.60 (s, 3H), 3.28 (dd, J1 = 15.8 Hz, J2 = 2.2 Hz, 1H), 3.11 (dd,
J1 = 15.8 Hz, J2 = 6.3 Hz, 1H), 1.54–1.38 (m, 3H), 1.25–1.16 (m,
1H), 0.56 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d
173.80, 136.62, 135.25, 134.71, 134.10, 132.75, 128.21, 128.11,
127.60, 127.41, 125.65, 125.55, 125.50, 125.09, 120.86, 118.57,
117.79, 110.82, 105.01, 58.52, 58.11, 56.25, 50.92, 36.77, 19.31,
18.58, 13.14. HRMS (EI) m/z calcd for (C27H28N2O2)+ 412.2151;
found 412.2153. IR (KBr film) 3403, 2953, 2926, 2853, 1734,
796, 740 cmꢂ1
.
4.2.10. (1S,3S)-Methyl 1-methyl-2-(naphthalen-1-ylmethyl)-1,2,
3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 2j
94% Yield. White solid, mp 93–94 °C. ½a D20
¼ ꢂ22:5 (c 1.10, CH3-
ꢁ
OH). 1H NMR (400 MHz, acetone-d6) d 9.86 (br s, 1H), 8.38 (dd,
J1 = 6.5 Hz, J2 = 3.4 Hz, 1H), 7.90 (dd, J1 = 6.4 Hz, J2 = 3.4 Hz, 1H),
7.84 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 7.0 Hz, 1H), 7.52–7.44 (m, 4H),
7.29 (d, J = 7.9 Hz, 1H), 7.06 (dd, J1 = 7.2 Hz, J2 = 7.0 Hz, 1H), 7.00
(dd, J1 = 7.2 Hz, J2 = 7.1 Hz, 1H), 4.62 (s, 2H), 4.32 (q, J = 6.9 Hz,
1H), 4.00 (dd, J1 = 6.2 Hz, J2 = 2.9 Hz, 1H), 3.60 (s, 3H), 3.25 (dd,
J1 = 15.3 Hz, J2 = 2.9 Hz, 1H), 2.91 (dd, J1 = 15.3 Hz, J2 = 6.2 Hz, 1H),
1.39 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d 175.20,
137.50, 137.07, 136.12, 135.00, 133.37, 129.29, 128.82, 128.24,
128.21, 126.61, 126.53, 126.15, 125.59, 121.75, 119.53, 118.70,
111.74, 106.25, 58.41, 55.83, 52.59, 51.68, 22.92, 18.15. HRMS
(ESI) m/z calcd for (C25H24N2O2+H)+ 385.1916; found 385.1916.
IR (KBr film) 3402, 3051, 2924, 2849, 1725, 1453, 1304, 1196,
1460, 1270, 1217, 1170, 793, 741 cmꢂ1
.
4.2.14. (1S,3S)-Methyl 1-hexyl-2-(naphthalen-1-ylmethyl)-1,2,
3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 2n
92% Yield. White solid, mp 55–56 °C. ½a D20
¼ ꢂ60:4 (c 1.10, CH3-
ꢁ
OH). 1H NMR (400 MHz, acetone-d6) d 9.81 (br s, 1H), 8.61 (d,
J = 8.1 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H),
7.59–7.48 (m, 4H), 7.44 (dd, J1 = 8.1 Hz, J2 = 7.6 Hz, 1H), 7.31 (d,
J = 7.6 Hz, 1H), 7.07 (dd, J1 = 7.8 Hz, J2 = 7.6 Hz, 1H), 7.02 (dd,
J1 = 8.0 Hz, J2 = 7.6 Hz, 1H), 4.52 (d, J = 13.3 Hz, 1H), 4.24 (d,
J = 13.3 Hz, 1H), 4.12 (dd, J1 = 6.3 Hz, J2 = 2.1 Hz, 1H), 3.98 (dd,
J1 = 8.9 Hz, J2 = 5.5 Hz, 1H), 3.59 (s, 3H), 3.27 (dd, J1 = 15.7 Hz,
J2 = 2.1 Hz, 1H), 3.10 (dd, J1 = 15.7 Hz, J2 = 6.3 Hz, 1H), 1.50–1.40
(m, 2H), 1.36–1.25 (m, 1H), 1.12–0.99 (m, 3H), 0.96–0.78 (m,
4H), 0.76 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d
174.66, 137.53, 136.21, 135.59, 135.06, 133.77, 129.11, 129.10,
128.62, 128.33, 126.69, 126.54, 126.43, 125.92, 121.73, 119.45,
118.68, 111.70, 105.87, 59.76, 59.33, 56.80, 51.84, 35.57, 32.62,
29.77, 27.00, 23.20, 19.35, 14.44. HRMS (ESI) m/z calcd for (C30H34-
N2O2+H)+ 455.2699; found 455.2704. IR (KBr film) 3394, 2924,
1163, 1016, 781, 743 cmꢂ1
.
4.2.11. (1S,3S)-Methyl 2-benzyl-1-methyl-1,2,3,4-tetrahydro-9H-
pyrido[3,4-b] indole-3-carboxylate 2k
90% Yield. White solid, mp 51–52 °C. ½a D20
¼ ꢂ6:1 (c 2.6, CH3-
ꢁ
OH). 1H NMR (400 MHz, acetone-d6) d 9.85 (br s, 1H), 7.52–7.45
(m, 3H), 7.35–7.28 (m, 3H), 7.24 (dd, J1 = 7.2 Hz, J2 = 7.3 Hz, 1H),
7.05 (dd, J1 = 7.2 Hz, J2 = 7.6 Hz, 1H), 7.00 (dd, J1 = 7.2 Hz,
J2 = 7.6 Hz, 1H), 4.22 (q, J = 6.8 Hz, 1H), 4.11 (d, J = 1.7 Hz, 2H),
3.91 (dd, J1 = 5.8, J2 = 4.4 Hz, 1H), 3.61 (s, 3H), 3.22 (dd,
J1 = 15.3 Hz, J2 = 4.4 Hz, 1H), 2.95 (dd, J1 = 15.3 Hz, J2 = 5.8 Hz,
1H), 1.35 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d
174.95, 141.29, 137.53, 137.01, 129.36, 129.35, 129.07, 129.06,
128.22, 127.73, 121.77, 119.59, 118.68, 111.79, 106.29, 59.83,
56.77, 53.22, 51.77, 23.13, 18.49. HRMS (ESI) m/z calcd for
(C21H22N2O2+H)+ 335.1760; found 335.1765. IR (KBr film) 3399,
2922, 2849, 1730, 1453, 1356, 1320, 1269, 1219, 1172, 1142,
2851, 1731, 1461, 1330, 1204, 1159, 796, 741 cmꢂ1
.
4.3. General procedure for the DBU-catalyzed 3-epimerization
of (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 to (1S,3R)-trans-1,2,3-
trisubstituted THBCs 3
To a solution of compounds 2 (3.000 mmol) in anhydrous CH3-
CN (10 mL), added was DBU (0.5–2.0 equiv, see Table 2). The solu-
tion was heated to reflux (81 °C), and stirred under N2 at this
temperature for 15–25 h. The reaction was monitored by HPLC.
739, 698 cmꢂ1
.

J. Dong et al. / Tetrahedron: Asymmetry 24 (2013) 883–893
889
After the reaction was complete, the solvent was removed by vac-
uum distillation to give crude product, which was purified by flash
chromatography to afford compounds 3 in 91–98% yields (see Ta-
ble 2). Characterization data of compounds 3a–3n are as follows:
7H), 7.25 (d, J = 7.9 Hz, 1H), 7.15–6.95 (m, 4H), 5.48 (s, 1H), 4.45
(d, J = 13.2 Hz, 1H), 4.24 (d, J = 13.2 Hz, 1H), 3.83 (dd, J1 = 5.7 Hz,
J2 = 4.4 Hz, 1H), 3.64 (s, 3H), 3.23 (dd, J1 = 15.5 Hz, J2 = 4.4 Hz,
1H), 3.09 (dd, J1 = 15.5 Hz, J2 = 5.7 Hz, 1H). 13C NMR (100 MHz, ace-
tone-d6) d 173.86, 164.45, 162.02, 139.47, 139.44, 138.07, 135.28,
134.93, 133.35, 132.09, 132.01, 129.28, 129.03, 128.61, 127.82,
126.67, 126.62, 126.24, 125.58, 122.17, 119.76, 118.81, 115.93,
115.72, 111.97, 106.88, 61.41, 57.07, 53.22, 51.75, 24.55. HRMS
(ESI) m/z calcd for (C30H25FN2O2+H)+ 465.1978; found 465.1982.
IR (KBr film) 3400, 3049, 2919, 2850, 1730, 1601, 1505, 1458,
4.3.1. (1S,3R)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-2-(naphth-
alen-1-yl-methyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-
carboxylate 3a
Mp 120–122 °C.
½
a 2D0
ꢁ
¼ þ67:3 (c 1.20, CH3OH). 1H NMR
(400 MHz, acetone-d6) d 9.62 (br s, 1H), 8.19 (d, J = 8.0 Hz, 1H),
7.90 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.54–7.42 (m, 5H),
7.26 (d, J = 7.9 Hz, 1H), 7.05 (dd, J1 = 7.9 Hz, J2 = 7.8 Hz, 1H), 7.01
(dd, J1 = 7.8 Hz, J2 = 7.6 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 6.89 (s,
1H), 6.80 (d, J = 7.9 Hz, 1H), 5.96 (d, J = 6.1 Hz, 2H), 5.42 (s, 1H),
4.46 (d, J = 13.3 Hz, 1H), 4.30 (d, J = 13.3 Hz, 1H), 3.86 (dd,
J1 = 5.6 Hz, J2 = 4.5 Hz, 1H), 3.64 (s, 3H), 3.22 (dd, J1 = 15.4 Hz,
J2 = 4.5 Hz, 1H), 3.11 (dd, J1 = 15.4 Hz, J2 = 5.6 Hz, 1H). 13C NMR
(100 MHz, acetone-d6) d 173.96, 148.86, 148.27, 137.89, 137.30,
135.77, 135.46, 134.94, 133.37, 129.29, 128.95, 128.47, 127.83,
126.66, 126.63, 126.27, 125.64, 123.61, 122.08, 119.69, 118.77,
111.92, 109.94, 108.48, 106.64, 102.07, 61.86, 57.11, 53.17, 51.73,
24.61. HRMS (ESI) m/z calcd for (C31H26N2O4+H)+ 491.1971; found
491.1975. IR (KBr film) 3403, 2920, 2850, 1730, 1483, 1440, 1239,
1221, 1193, 1014, 836, 795, 743 cmꢂ1
.
4.3.5. (1S,3R)-Ethyl 2-(naphthalen-1-ylmethyl)-1-(3,4,5-trimeth
oxyphenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carbox
ylate 3e
White solid, mp 115–116 °C. ½a D20
ꢁ
¼ þ44:3 (c 1.00, CH3OH). 1H
NMR (400 MHz, acetone-d6) d 9.68 (br s, 1H), 8.36 (d, J = 8.0 Hz,
1H), 7.90 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.52–7.40 (m,
5H), 7.25 (d, J = 7.8 Hz, 1H), 7.03 (dd, J1 = 7.8 Hz, J2 = 7.6 Hz, 1H),
6.99 (dd, J1 = 7.8 Hz, J2 = 7.7 Hz, 1H), 6.81 (s, 2H), 5.42 (s, 1H),
4.48 (d, J = 13.2 Hz, 1H), 4.29 (d, J = 13.2 Hz, 1H), 4.20–4.02 (m,
2H), 3.87 (dd, J1 = 5.8 Hz, J2 = 3.7 Hz, 1H 1H), 3.73 (s, 6H), 3.68 (s,
3H), 3.23 (dd, J1 = 15.4 Hz, J2 = 3.7 Hz, 1H), 3.11 (dd, J1 = 15.4 Hz,
J2 = 5.8 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, ace-
tone-d6) d 173.46, 154.33, 138.91, 138.51, 137.97, 137.82, 135.75,
135.52, 134.99, 133.41, 129.33, 129.03, 128.66, 127.96, 126.66,
126.55, 126.26, 125.87, 122.01, 119.66, 118.73, 111.92, 111.87,
106.89, 106.48, 62.35, 60.88, 60.53, 57.49, 56.33, 56.32, 53.84,
24.46, 14.70. HRMS (ESI) m/z calcd for (C34H34N2O5+H)+
551.2546; found 551.2539. IR (KBr film) 3357, 2933, 2836, 1728,
1174, 1038, 797, 742 cmꢂ1
.
4.3.2. (1S,3R)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-2-benzyl-1,2,
3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 3b
White solid, mp 191–192 °C. ½a D20
ꢁ
¼ þ91:4 (c 1.00, CHCl3). 1H
NMR (400 MHz, acetone-d6) d 9.58 (br s, 1H), 7.47 (d, J = 7.6 Hz,
1H), 7.38–7.28 (m, 4H), 7.27–7.21 (m, 2H), 7.08–6.94 (m, 4H),
6.80 (d, J = 7.8 Hz, 1H), 5.95 (d, J = 7.6 Hz, 2H), 5.39 (s, 1H), 3.96–
3.84 (m, 3H), 3.60 (s, 3H), 3.25–3.16 (m, 2H). 13C NMR (100 MHz,
acetone-d6) d 173.80, 148.92, 148.23, 140.54, 137.97, 137.57,
136.08, 129.39, 129.38, 129.26, 129.25, 127.97, 127.89, 123.32,
121.99, 119.63, 118.71, 111.87, 109.47, 108.52, 106.27, 102.03,
61.55, 56.97, 54.88, 51.61, 24.91. HRMS (ESI) m/z calcd for (C27H24-
N2O4+H)+ 441.1814; found 441.1811. IR (KBr film) 3418, 2915,
2850, 1730, 1499, 1441, 1301, 1244, 1174, 1138, 1038, 925,
1592, 1504, 1459, 1418, 1328, 1232, 1182, 1126, 796, 742 cmꢂ1
.
4.3.6. (1S,3R)-Methyl 1-(3-hydroxyphenyl)-2-(naphthalen-1-yl
methyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxyl
ate 3f
White solid, mp 126–127 °C. ½a D20
ꢁ
¼ þ67:1 (c 1.06, CH3OH). 1H
NMR (400 MHz, acetone-d6) d 9.66 (br s, 1H), 8.32 (s, 1H), 8.18
(d, J = 8.0 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H),
7.52–7.39 (m, 5H), 7.26 (d, J = 8.0 Hz, 1H), 7.18 (dd, J1 = 8.0 Hz,
J2 = 7.8 Hz, 1H), 7.08–6.92 (m, 4H), 6.77 (dd, J1 = 8.0 Hz,
J2 = 1.9 Hz, 1H), 5.40 (s, 1H), 4.43 (d, J = 13.1 Hz, 1H), 4.30 (d,
J = 13.1 Hz, 1H), 3.82 (dd, J1 = 5.6 Hz, J2 = 4.3 Hz, 1H), 3.63 (s, 3H),
3.21 (dd, J1 = 15.5 Hz, J2 = 4.3 Hz, 1H), 3.05 (dd, J1 = 15.4 Hz,
J2 = 5.6 Hz, 1H). 13C NMR (100 MHz, acetone-d6) d 173.94, 158.51,
144.93, 138.01, 136.00, 135.43, 134.92, 133.43, 130.19, 129.21,
128.97, 128.59, 127.83, 126.64, 126.63, 126.22, 125.80, 122.01,
121.48, 119.66, 118.69, 116.95, 115.75, 111.95, 106.54, 62.23,
56.93, 53.33, 51.69, 24.73. HRMS (ESI) m/z calcd for (C30H26N2O3+-
H)+ 463.2022; found 463.2023. IR (KBr film) 3395, 3049, 2921,
747 cmꢂ1
.
4.3.3. (1S,3R)-Ethyl 1-(benzo[d][1,3]dioxol-5-yl)-2-(naphthalen-
1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxy-
late 3c
White solid, mp 140–141 °C. ½a D20
ꢁ
¼ þ71:7 (c 1.00, CH3OH). 1H
NMR (400 MHz, acetone-d6) d 9.68 (br s, 1H), 8.21 (d, J = 8.0 Hz,
1H), 7.90 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.52–7.40 (m,
5H), 7.26 (d, J = 7.9 Hz, 1H), 7.06–6.93 (m, 3H), 6.89 (s, 1H), 6.81
(d, J = 7.9 Hz, 1H), 5.96 (d, J = 5.6 Hz, 2H), 5.41 (s, 1H), 4.46 (d,
J = 13.2 Hz, 1H), 4.29 (d, J = 13.2 Hz, 1H), 4.20–4.11 (m, 1H), 4.10–
4.00 (m, 1H), 3.82 (dd, J1 = 5.7 Hz, J2 = 4.0 Hz, 1H), 3.22 (dd,
J1 = 15.4 Hz, J2 = 4.0 Hz, 1H), 3.08 (dd, J1 = 15.4 Hz, J2 = 5.7 Hz, 1H),
1.18 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 173.29,
148.23, 147.58, 136.55, 135.98, 134.95, 134.59, 133.85, 132.46,
128.43, 128.02, 127.34, 127.09, 125.77, 125.75, 125.41, 124.71,
122.63, 121.68, 119.36, 118.28, 110.89, 109.15, 107.87, 106.74,
101.14, 61.16, 60.31, 56.26, 52.61, 24.33, 14.30. HRMS (ESI) m/z
calcd for (C32H28N2O4+H)+ 505.2127; found 505.2124. IR (KBr film)
3406, 2920, 2851, 1725, 1483, 1441, 1239, 1182, 1037, 796,
2849, 1717, 1595, 1455, 1271, 1225, 1140, 1013, 788, 742 cmꢂ1
.
4.3.7. (1S,3R)-Methyl 1-phenyl-2-(naphthalen-1-ylmethyl)-1,2,
3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 3g
White solid, mp 142–143 °C, ½a D20
ꢁ
¼ þ127 (c 1.00, CHCl3). 1H
NMR (400 MHz, DMSO-d6) d 10.60 (br s, 1H), 8.07 (d, J = 8.0 Hz,
1H), 7.92 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.54–7.40 (m,
5H), 7.38–7.18 (m, 6H), 7.04 (dd, J1 = 7.2 Hz, J2 = 7.6 Hz, 1H), 6.98
(dd, J1 = 7.2 Hz, J2 = 7.6 Hz, 1H), 5.29 (s, 1H), 4.37 (d, J = 13.3 Hz,
1H), 4.12 (d, J = 13.3 Hz, 1H), 3.78 (dd, J1 = 4.8 Hz, J2 = 5.2 Hz, 1H),
3.63 (s, 3H), 3.16 (dd, J1 = 15.5 Hz, J2 = 4.8 Hz, 1H), 3.04 (dd,
J1 = 15.5 Hz, J2 = 5.2 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) d
173.29, 142.63, 137.03, 134.81, 134.41, 133.90, 132.31, 129.37,
129.36, 128.78, 128.68, 128.67, 128.45, 128.06, 127.94, 126.76,
126.26, 126.25, 125.87, 124.83, 121.32, 118.89, 118.24, 111.60,
105.53, 60.86, 56.22, 52.20, 51.95, 23.51. HRMS (EI) m/z calcd for
(C30H26N2O2)+ 446.1994; found 446.2004. IR (KBr film) 3332,
741 cmꢂ1
.
4.3.4. (1S,3R)-Methyl 1-(4-fluorophenyl)-2-(naphthalen-1-yl-
methyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxy-
late 3d
White solid, mp 102–103 °C. ½a D20
ꢁ
¼ þ67:5 (c 1.07, CH3OH). 1H
NMR (400 MHz, acetone-d6) d 9.69 (br s, 1H), 8.12 (d, J = 8.0 Hz,
1H), 7.90 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.52–7.40 (m,

890
J. Dong et al. / Tetrahedron: Asymmetry 24 (2013) 883–893
3053, 3031, 2948, 2849, 1704, 1453, 1233, 1173, 1143, 783, 737,
699 cmꢂ1
7.37–7.28 (m, 3H), 7.25 (dd, J1 = 7.2 Hz, J2 = 7.5 Hz, 1H), 7.06 (dd,
J1 = 7.6 Hz, J2 = 8.0 Hz, 1H), 7.00 (dd, J1 = 7.6 Hz, J2 = 7.8 Hz, 1H),
4.24 (q, J = 6.6 Hz, 1H), 4.01 (dd, J1 = 6.7 Hz, J2 = 5.4 Hz, 1H), 3.91
(d, J = 14.4 Hz, 1H), 3.89 (d, J = 14.4 Hz, 1H), 3.65 (s, 3H), 3.12 (dd,
J1 = 15.5 Hz, J2 = 6.7 Hz, 1H), 2.98 (dd, J1 = 15.5 Hz, J2 = 5.4 Hz, 1H),
1.48 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d 174.02,
141.42, 137.65, 137.57, 129.28, 129.27, 129.15, 129.14, 128.15,
127.77, 121.85, 119.68, 118.62, 111.80, 106.21, 57.94, 54.78,
52.20, 51.86, 23.32, 21.53. HRMS (ESI) m/z calcd for (C21H22N2O2+-
H)+ 335.1760; found 335.1764. IR (KBr film) 3399, 2946, 2848,
.
4.3.8. (1S,3R)-Methyl 1-(3,4-dimethoxyphenyl)-2-(naphthalen-
1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carbo
xylate 3h
White solid, mp 185–186 °C, ½a D20
ꢁ
¼ þ102 (c 1.00, CHCl3). 1H
NMR (400 MHz, DMSO-d6) d 10.56 (br s, 1H), 8.28 (d, J = 7.6 Hz,
1H), 7.93 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.56–7.37 (m,
5H), 7.26 (d, J = 8.0 Hz, 1H), 7.05 (dd, J1 = 7.6 Hz, J2 = 7.2 Hz, 1H),
6.98 (dd, J1 = 7.6 Hz, J2 = 7.1 Hz, 1H), 6.92–6.78 (m, 3H), 5.19 (s,
1H), 4.37 (d, J = 13.2 Hz, 1H), 4.12 (d, J = 13.2 Hz, 1H), 3.81 (dd,
J1 = 5.3 Hz, J2 = 5.5 Hz, 1H), 3.70 (s, 3H), 3.65 (s, 3H), 3.57 (s, 3H),
3.16 (dd, J1 = 15.6 Hz, J2 = 5.3 Hz, 1H), 3.04 (dd, J1 = 15.6 Hz,
J2 = 5.5 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) d 173.33, 149.10,
148.72, 137.00, 134.84, 134.60, 133.98, 132.36, 128.80, 128.47,
128.01, 126.86, 126.24, 126.19, 125.86, 125.11, 121.29, 121.28,
118.87, 118.25, 112.35, 111.63, 111.59, 11.58, 105.50, 60.24,
56.35, 55.91, 55.58, 52.36, 51.94, 23.15. HRMS (EI) m/z calcd for
(C32H30N2O4)+ 506.2206; found 506.2207. IR (KBr film) 3360,
2948, 2899, 2848, 1724, 1511, 1462, 1257, 1232, 1175, 1135,
1725, 1453, 1322, 1304, 1272, 1196, 1163, 1018, 738, 698 cmꢂ1
.
4.3.12. (1S,3R)-Methyl 1-ethyl-2-(naphthalen-1-ylmethyl)-1,2,
3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 3l
White solid, mp 97–98 °C. ½a D20
ꢁ
¼ ꢂ29:2 (c 1.60, CH3OH). 1H
NMR (400 MHz, acetone-d6) d 9.88 (br s, 1H), 8.58 (d, J = 7.8 Hz,
1H), 7.91 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.56–7.48 (m,
3H), 7.48–7.38 (m, 2H), 7.33 (d, J = 7.8 Hz, 1H), 7.06 (dd,
J1 = 8.1 Hz, J2 = 7.6 Hz, 1H), 7.01 (dd, J1 = 8.0 Hz, J2 = 7.6 Hz, 1H),
4.41 (d, J = 13.3 Hz, 1H), 4.20 (d, J = 13.3 Hz, 1H), 4.09 (dd,
J1 = 8.0 Hz, J2 = 5.6 Hz, 1H), 4.01 (dd, J1 = 7.4 Hz, J2 = 4.8 Hz, 1H),
3.75 (s, 3H), 3.26 (dd, J1 = 15.7 Hz, J2 = 7.4 Hz, 1H), 2.96 (dd,
J1 = 15.7 Hz, J2 = 4.8 Hz, 1H), 1.92–1.75 (m, 2H), 0.66 (t, J = 7.3 Hz,
3H). 13C NMR (100 MHz, acetone-d6) d 174.04, 137.67, 136.28,
135.82, 134.92, 133.60, 129.13, 128.77, 128.61, 128.14, 126.52,
126.43, 126.08, 126.07, 121.78, 119.60, 118.58, 111.80, 106.97,
57.67, 57.49, 52.27, 51.94, 27.41, 21.93, 10.60. HRMS (ESI) m/z
calcd for (C26H26N2O2+H)+ 399.2073; found 399.2070. IR (KBr film)
3401, 2925, 2852, 1732, 1459, 1268, 1218, 1170, 1142, 798, 789,
1022, 774, 740 cmꢂ1
.
4.3.9. (1S,3R)-Methyl 1-(4-ethoxy-3-methoxy-phenyl)-2-(naph
thalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-
3-carboxylate 3i
White solid, mp 165–166 °C, ½a D20
ꢁ
¼ þ100 (c 1.50, CHCl3). 1H
NMR (400 MHz, DMSO-d6) d 10.57 (br s, 1H), 8.29 (d, J = 7.6 Hz,
1H), 7.93 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.59–7.38 (m,
5H), 7.26 (d, J = 8.0 Hz, 1H), 7.05 (dd, J1 = 7.6 Hz, J2 = 7.2 Hz, 1H),
6.98 (dd, J1 = 7.5 Hz, J2 = 7.2 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 6.83
(s, 1H), 7.78 (d, J = 7.5 Hz, 1H), 5.17 (s, 1H), 4.37 (d, J = 13.2 Hz,
1H), 4.12 (d, J = 13.2 Hz, 1H), 3.95 (q, J = 6.9 Hz, 2H), 3.81 (dd,
J1 = 5.6 Hz, J2 = 5.5 Hz, 1H), 3.65 (s, 3H), 3.58 (s, 3H), 3.16 (dd,
J1 = 15.5 Hz, J2 = 5.6 Hz, 1H), 3.03 (dd, J1 = 15.5 Hz, J2 = 5.5 Hz, 1H),
1.28 (t, J = 6.9 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) d 173.32,
149.23, 147.90, 136.99, 134.78, 134.77, 134.60, 133.98, 132.37,
128.79, 128.48, 128.05, 126.86, 126.23, 126.16, 125.85, 125.14,
121.28, 121.27, 118.86, 118.24, 112.65, 112.45, 111.58, 105.50,
64.10, 60.20, 56.33, 55.54, 52.34, 51.94, 23.14, 15.21. HRMS (EI)
m/z calcd for (C33H32N2O4)+ 520.2362; found 520.2365. IR (KBr
film) 3353, 2950, 1733, 1509, 1464, 1255, 1255, 1134, 1036, 777,
741 cmꢂ1
.
4.3.13. (1S,3R)-Methyl 2-(naphthalen-1-ylmethyl)-1-propyl-1,2,
3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 3m
White solid, mp 91–92 °C, ½a D20
ꢁ
¼ ꢂ42:9 (c 1.30, CHCl3). 1H NMR
(400 MHz, acetone-d6) d 9.89 (br s, 1H), 8.65–8.58 (m, 1H), 7.96–
7.90 (m, 1H), 7.89–7.82 (m, 1H), 7.60–7.52 (m, 3H), 7.48–7.42
(m, 2H), 7.34 (d, J = 7.8 Hz, 1H), 7.11 (dd, J1 = 8.0 Hz, J2 = 7.6 Hz,
1H), 7.05 (dd, J1 = 8.0 Hz, J2 = 7.7 Hz, 1H), 4.43 (d, J = 13.1 Hz, 1H),
4.20–4.10 (m, 2H), 4.03 (dd, J1 = 8.6 Hz, J2 = 4.9 Hz, 1H), 3.81 (s,
3H), 3.29 (dd, J1 = 15.8 Hz, J2 = 8.6 Hz, 1H), 2.98 (dd, J1 = 15.8 Hz,
J2 = 4.9 Hz, 1H), 1.88–1.63 (m, 2H), 1.32–1.04 (m, 2H), 0.49 (t,
J = 7.4 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d 173.13, 136.75,
135.54, 134.92, 134.03, 132.82, 128.16, 127.93, 127.92, 127.30,
125.61, 125.47, 125.33, 125.11, 120.87, 118.71, 117.68, 110.90,
105.89, 56.50, 54.83, 51.18, 51.13, 36.05, 20.56, 18.50, 12.96. HRMS
(EI) m/z calcd for (C27H28N2O2)+ 412.2151; found 412.2154. IR (KBr
film) 3406, 2953, 2927, 1734, 1460, 1270, 1217, 1170, 793,
742 cmꢂ1
.
4.3.10. (1S,3R)-Methyl 1-methyl-2-(naphthalen-1-ylmethyl)-1,2,
3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 3j
White solid, mp 106–107 °C. ½a D20
ꢁ
¼ ꢂ27:4 (c 1.00, CH3OH). 1H
NMR (400 MHz, acetone-d6) d 9.94 (br s, 1H), 8.52–8.45 (m, 1H),
7.96–7.88 (m, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H),
7.55–7.49 (m, 2H), 7.45 (dd, J1 = 8.1 Hz, J2 = 7.2 Hz, 2H), 7.32 (d,
J = 7.9 Hz, 1H), 7.06 (dd, J1 = 7.9 Hz, J2 = 7.0 Hz, 1H), 7.01 (dd,
J1 = 7.9 Hz, J2 = 7.0 Hz, 1H), 4.46 (d, J = 13.9 Hz, 1H), 4.38 (d,
J = 13.9 Hz, 1H), 4.36 (q, J = 6.6 Hz, 1H), 4.00 (dd, J1 = 5.8 Hz,
J2 = 5.4 Hz, 1H), 3.67 (s, 3H), 3.19 (dd, J1 = 15.5 Hz, J2 = 5.8 Hz,
1H), 2.95 (dd, J1 = 15.5 Hz, J2 = 5.4 Hz, 1H), 1.53 (d, J = 6.6 Hz, 3H).
13C NMR (100 MHz, acetone-d6) d 174.03, 137.69, 137.60, 136.05,
134.95, 133.33, 129.28, 128.69, 128.15, 127.91, 126.61, 126.59,
126.30, 125.52, 121.85, 119.67, 118.63, 111.81, 106.19, 57.76,
53.02, 52.32, 51.83, 23.32, 21.23. HRMS (ESI) m/z calcd for (C25H24-
N2O2+H)+ 385.1916; found 385.1911. IR (KBr film) 3402, 2923,
741 cmꢂ1
.
4.3.14. (1S,3R)-Methyl 1-hexyl-2-(naphthalen-1-ylmethyl)-1,2,
3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 3n
White solid, mp 69–70 °C. ½a D20
ꢁ
¼ ꢂ34:7 (c 1.00, CH3OH). 1H
NMR (400 MHz, acetone-d6) d 9.88 (br s, 1H), 8.66 (d, J = 7.6 Hz,
1H), 7.90 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.58–7.46 (m,
3H), 7.44–7.35 (m, 2H), 7.32 (d, J = 7.7 Hz, 1H), 7.08 (dd,
J1 = 7.6 Hz, J2 = 8.0 Hz, 1H), 7.03 (dd, J1 = 7.7 Hz, J2 = 8.0 Hz, 1H),
4.43 (d, J = 12.9 Hz, 1H), 4.16 (dd, J1 = 9.6 Hz, J2 = 4.9 Hz, 1H), 4.09
(d, J = 12.9 Hz, 1H), 4.00 (dd, J1 = 9.1 Hz, J2 = 3.8 Hz, 1H), 3.82 (s,
3H), 3.27 (dd, J1 = 15.6 Hz, J2 = 9.6 Hz, 1H), 2.96 (dd, J1 = 15.6 Hz,
J2 = 4.9 Hz, 1H), 1.82–1.74 (m, 1H), 1.74–1.64 (m, 1H), 1.16–1.05
(m, 2H), 1.02–0.92 (m, 2H), 0.92–0.80 (m, 2H), 0.78–0.62 (m, 2H),
0.73 (t, J = 7.4 Hz, 1H). 13C NMR (100 MHz, acetone-d6) d 174.08,
137.69, 136.50, 135.82, 135.00, 133.82, 129.09, 129.02, 128.93,
128.22, 126.49, 126.46, 126.39, 125.95, 121.77, 119.61, 118.60, 111.83,
106.80, 57.45, 55.56, 55.53, 52.19, 52.07, 34.72, 32.52, 26.19,
23.24, 21.33, 14.42. HRMS (ESI) m/z calcd for (C30H34N2O2+H)+
2850, 1731, 1454, 1318, 1269, 1220, 1171, 791, 743 cmꢂ1
.
4.3.11. (1S,3R)-Methyl 2-benzyl-1-methyl-1,2,3,4-tetrahydro-
9H-pyrido[3,4-b] indole-3-carboxylate 3k
White solid, mp 71–72 °C. ½a D20
ꢁ
¼ ꢂ18:4 (c 1.10, CH3OH). 1H
NMR (400 MHz, acetone-d6) d 9.89 (br s, 1H), 7.46–7.40 (m, 3H),

J. Dong et al. / Tetrahedron: Asymmetry 24 (2013) 883–893
891
455.2699; found 455.2704. IR (KBr film) 3392, 3050, 2924, 2851,
1734, 1460, 1268, 1215, 1169, 1096, 780, 740 cmꢂ1
2926, 2851, 1701, 1505, 1450, 1335, 1299, 1258, 1219, 1150,
836, 746 cmꢂ1
.
.
4.4. General procedure for the Pd/C-catalyzed hydrogenation of
(1S,3R)-trans-1,2,3-trisubstituted THBCs 4
4.4.4. (1S,3R)-Ethyl 1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetra-
hydro-9H-pyrido[3,4-b]indole-3-carboxylate 4d
96% Yield from compound 3e. White solid, mp 96–97 °C.
A solution of compounds 3 (3.000 mmol) in CH3CN (30 mL) was
placed into a three-necked round flask (150 mL), which was
equipped with a magnetic stirring bar, an inlet, and an outlet of
hydrogen gas. Palladium on charcoal (10% w/w, 200 mg) was
added in one portion, and then the flask was purged with H2 sev-
eral times. The black suspension was heated to 60 °C, and stirred
at this temperature under 1.05–1.10 atm of H2 for approximately
8 h. After the reaction was complete (checked by TLC), the suspen-
sion was cooled down to room temperature. Next, the Pd/C was re-
moved by filtration. Evaporation of CH3CN produced a crude solid
product, which was washed with a mixed solvent of hexane and
ethyl acetate (EtOAc/hexane = 1:9) to furnish compounds 4 in
95–99% yields. Characterization data of compounds 4a–4l are as
follows:
½
a 2D0
ꢁ
¼ þ27:3 (c 1.60, CH3OH). 1H NMR (400 MHz, acetone-d6) d
9.68 (br s, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H),
7.05 (dd, J1 = 7.5 Hz, J2 = 7.3 Hz, 1H), 7.00 (dd, J1 = 7.5 Hz,
J2 = 7.3 Hz, 1H), 6.68 (s, 2H), 5.39 (s, 1H), 4.22–4.06 (m, 2H), 4.00
(dd, J1 = 6.4 Hz, J2 = 5.4 Hz, 1H), 3.73 (s, 6H), 3.71 (s, 3H), 3.17
(dd, J1 = 15.1 Hz, J2 = 5.4 Hz, 1H), 3.05 (dd, J1 = 15.1 Hz, J2 = 6.4 Hz,
1H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d
174.37, 154.31, 154.30, 139.62, 138.61, 137.61, 135.23, 128.11,
122.06, 119.64, 118.67, 111.92, 108.04, 106.64, 106.63, 61.22,
60.56, 56.41, 56.40, 55.87, 53.71, 25.45, 14.59. HRMS (ESI) m/z
calcd for (C23H26N2O5+H)+ 411.1920; found 411.1918. IR (KBr film)
3347, 2935, 2837, 1731, 1592, 1505, 1459, 1419, 1326, 1234, 1185,
1126, 1005, 743 cmꢂ1
.
4.4.5. (1S,3R)-Methyl 1-(3-hydroxyphenyl)-1,2,3,4-tetrahydro-
9H-pyrido[3,4-b] indole-3-carboxylate 4e
4.4.1. (1S,3R)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-1,2,3,4-tetra
hydro-9H-pyrido [3,4-b]indole-3-carboxylate 4a
98% Yield from compound 3f. White solid, mp 104–105 °C.
a 2D0
ꢁ
¼ þ35:5 (c 1.00, CH3OH). 1H NMR (400 MHz, acetone-d6) d
98% and 95% Yields from compounds 3a and 3b, respectively.
½
White solid, mp 187–188 °C. ½a D20
ꢁ
¼ þ33:0 (c 1.00, CHCl3). 1H
9.75 (br s, 1H), 8.27 (br s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.30 (d,
J = 7.8 Hz, 1H), 7.14 (dd, J1 = 7.8 Hz, J2 = 7.7 Hz, 1H), 7.11–6.98 (m,
2H), 6.81 (d, J = 7.9 Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H), 6.69 (s, 1H),
5.34 (s, 1H), 3.90 (dd, J1 = 7.6 Hz, J2 = 5.2 Hz, 1H), 3.67 (s, 3H),
3.14 (dd, J1 = 15.2 Hz, J2 = 5.2 Hz, 1H), 2.99 (dd, J1 = 15.2 Hz,
J2 = 7.6 Hz, 1H). 13C NMR (100 MHz, acetone-d6) d 174.64, 158.29,
145.50, 137.58, 135.08, 130.21, 128.02, 122.07, 120.45, 119.65,
118.63, 116.12, 115.30, 111.93, 108.28, 55.60, 53.04, 52.09, 25.69.
HRMS (ESI) m/z calcd for (C19H18N2O3+H)+ 323.1396; found
323.1391. IR (KBr film) 3389, 2922, 2850, 1733, 1595, 1456,
NMR (acetone-d6) d 3.01 (dd, J1 = 15.2 Hz, J2 = 6.5 Hz, 1H), 3.16
(dd, J1 = 15.2 Hz, J2 = 5.6 Hz, 1H), 3.66 (s, 3H), 3.93 (dd, J1 = 6.5 Hz,
J2 = 5.6 Hz, 1H), 5.36 (s, 1H), 5.96 (d, J = 3.3 Hz, 2H), 6.75 (d,
J = 8.2 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.82 (s, 1H), 7.03 (dd,
J1 = 7.5 Hz, J2 = 7.8 Hz, 1H), 7.07 (dd, J1 = 8.0 Hz, J2 = 7.8 Hz, 1H),
7.28 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 9.71 (br s, 1H). 13C
NMR (acetone-d6)
d 174.69, 148.66, 147.97, 138.02, 137.44,
135.05, 127.98, 122.56, 122.08, 119.62, 118.66, 111.83, 109.56,
108.50, 108.11, 101.99, 55.24, 53.15, 52.06, 25.46. HRMS (ESI) m/
z calcd for (C20H18N2O4+H)+ 351.1345; found 351.1348. IR (KBr
1352, 1272, 1221, 744 cmꢂ1
.
film) 3316, 2950, 2893, 1705, 1479, 1438, 1238, 1040, 744 cmꢂ1
.
4.4.6. (1S,3R)-Methyl 1-phenyl-1,2,3,4-tetrahydro-9H-pyrido-
[3,4-b]indole-3-carboxylate 4f
4.4.2. (1S,3R)-Ethyl 1-(benzo[d][1,3]dioxol-5-yl)-1,2,3,4-tetra-
hydro-9H-pyrido [3,4-b]indole-3-carboxylate 4b
95% Yield from compound 3g. White solid, mp 220–221 °C.
98% Yield from compound 3c. White solid, mp 78–79 °C.
a 2D0
ꢁ
¼ þ44:5 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) d 7.69
½
a 2D0
ꢁ
¼ þ33:2 (c 1.50, CH3OH). 1H NMR (400 MHz, acetone-d6) d
½
(br s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.36–7.28 (m, 2H), 7.26–7.05
(m, 6H), 5.34 (s, 1H), 3.94 (dd, J1 = 6.8 Hz, J2 = 5.5 Hz, 1H), 3.69 (s,
3H), 3.25 (dd, J1 = 15.4 Hz, J2 = 5.5 Hz, 1H), 3.10 (dd, J1 = 15.4 Hz,
J2 = 6.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 174.14, 142.04,
136.24, 133.21, 128.76, 128.75, 128.48, 128.47, 128.13, 126.97,
121.95, 119.49, 118.24, 111.04, 108.44, 54.94, 52.39, 52.16, 24.82.
HRMS (EI) m/z calcd for (C19H18N2O2)+ 306.1368; found
306.1371. IR (KBr film) 3401, 3052, 2951, 1730, 1456, 1353,
9.71 (br s, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H),
7.06 (dd, J1 = 7.7 Hz, J2 = 7.2 Hz, 1H), 7.01 (dd, J1 = 7.8 Hz,
J2 = 7.2 Hz, 1H), 6.82 (s, 1H), 6.80–6.72 (m, 2H), 5.96 (d, J = 3.4 Hz,
2H), 5.36 (s, 1H), 4.18–4.05 (m, 2H), 3.90 (dd, J1 = 7.0 Hz,
J2 = 5.4 Hz, 1H), 3.15 (dd, J1 = 15.2 Hz, J2 = 5.4 Hz, 1H), 3.00 (dd,
J1 = 15.2 Hz, J2 = 7.0 Hz, 1H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, acetone-d6) d 174.28, 148.67, 147.96, 138.13, 137.58,
135.23, 128.05, 122.56, 122.09, 119.65, 118.66, 111.92, 109.58,
108.53, 108.29, 102.00, 61.21, 55.36, 53.21, 25.63, 14.57. HRMS
(ESI) m/z calcd for (C21H20N2O4+H)+ 365.1501; found 365.1508. IR
(KBr film) 3393, 2921, 1729, 1486, 1443, 1237, 1184, 1037,
1329, 1206, 744, 701 cmꢂ1
.
4.4.7. (1S,3R)-Methyl 1-(3,4-dimethoxyphenyl)-1,2,3,4-tetra
hydro-9H-pyrido[3,4-b]indole-3-carboxylate 4g
743 cmꢂ1
.
98% Yield from compound 3h. White solid, mp 191–192 °C.
½
a 2D0
ꢁ
¼ þ26:0 (c 1.90, CHCl3). 1H NMR (400 MHz, acetone-d6) d
4.4.3. (1S,3R)-Methyl 1-(4-fluorophenyl)-1,2,3,4-tetrahydro-9H-
pyrido[3,4-b]indole-3-carboxylate 4c
9.71 (br s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H),
7.10–6.98 (m, 3H), 6.87 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H),
5.38 (s, 1H), 3.96 (dd, J1 = 6.8 Hz, J2 = 5.4 Hz, 1H), 3.79 (s, 3H),
3.75 (s, 3H), 3.68 (s, 3H), 3.17 (dd, J1 = 15.2 Hz, J2 = 5.4 Hz, 1H),
3.03 (dd, J1 = 15.2 Hz, J2 = 6.8 Hz, 1H). 13C NMR (100 MHz, ace-
tone-d6) d 173.84, 149.45, 149.00, 136.65, 135.65, 134.59, 127.18,
121.05, 120.47, 118.66, 117.69, 112.35, 111.43, 110.94, 107.13,
55.22, 55.18, 54.51, 52.41, 51.11, 24.64. HRMS (EI) m/z calcd for
(C21H22N2O4)+ 366.1580; found 366.1581. IR (KBr film) 3362,
2980, 1731, 1600, 1514, 1465, 1454, 1256, 1186, 1138, 1026,
97% Yield from compound 3d. White solid, mp 173–174 °C.
½
a 2D0
ꢁ
¼ þ30:8 (c 1.05, CH3OH). 1H NMR (400 MHz, acetone-d6) d
9.74 (br s, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.38–7.24 (m, 3H), 7.12–
6.98 (m, 4H), 5.44 (s, 1H), 3.89 (dd, J1 = 6.9 Hz, J2 = 5.5 Hz, 1H),
3.65 (s, 3H), 3.15 (dd, J1 = 15.2 Hz, J2 = 5.5 Hz, 1H), 3.01 (dd,
J1 = 15.2 Hz, J2 = 6.9 Hz, 1H). 13C NMR (100 MHz, acetone-d6) d
174.70, 164.27, 161.84, 140.23, 140.20, 137.62, 134.98, 131.24,
131.16, 128.04, 122.18, 119.72, 118.71, 115.81, 115.59, 111.93,
108.35, 54.85, 53.19, 52.08, 25.61. HRMS (ESI) m/z calcd for (C19-
H17FN2O2+H)+ 325.1352; found 325.1350. IR (KBr film) 3335,
858, 743 cmꢂ1
.

892
J. Dong et al. / Tetrahedron: Asymmetry 24 (2013) 883–893
4.4.8. (1S,3R)-Methyl 1-(4-ethoxy-3-methoxyphenyl)-1,2,3,4-
tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 4h
9.90 (br s, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H),
7.03 (dd, J1 = 7.9 Hz, J2 = 7.4 Hz, 1H), 6.97 (dd, J1 = 7.7 Hz,
J2 = 7.4 Hz, 1H), 4.24 (dd, J1 = 9.1 Hz, J2 = 3.5 Hz, 1H), 3.94 (dd,
J1 = 7.1 Hz, J2 = 5.2 Hz, 1H), 3.68 (s, 3H), 3.00 (dd, J1 = 14.9 Hz,
J2 = 5.2 Hz, 1H), 2.89 (dd, J1 = 14.9 Hz, J2 = 7.1 Hz, 1H), 2.54 (br s,
1H), 1.91–1.79 (m, 1H), 1.78–1.65 (m, 1H), 1.60–1.45 (m, 2H),
1.42–1.25 (m, 6H), 0.88 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, ace-
tone-d6) d 174.99, 137.41, 137.20, 128.23, 121.69, 119.48, 118.40,
111.69, 106.82, 53.38, 52.06, 50.95, 36.00, 32.67, 30.15, 26.83,
25.87, 23.40, 14.49. HRMS (ESI) m/z calcd for (C19H26N2O2+H)+
315.2073; found 315.2069. IR (KBr film) 3395, 2924, 2853, 1732,
97% Yield. White solid from compound 3i, mp 155–156 °C,
½
a 2D0
ꢁ
¼ þ17:9 (c 2.00, CHCl3). 1H NMR (400 MHz, acetone-d6) d
9.72 (br s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H),
7.12–6.96 (m, 3H), 6.86 (d, J = 8.2 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H),
5.38 (s, 1H), 4.03 (q, J = 7.0 Hz, 2H), 3.96 (dd, J1 = 7.0 Hz,
J2 = 5.4 Hz, 1H), 3.76 (s, 3H), 3.68 (s, 3H), 3.17 (dd, J1 = 15.2 Hz,
J2 = 5.4 Hz, 1H), 3.02 (dd, J1 = 15.2 Hz, J2 = 7.0 Hz, 1H), 1.37 (t,
J = 7.0 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d 174.79, 150.55,
149.13, 137.57, 136.49, 135.48, 128.09, 122.01, 121.43, 119.61,
118.64, 113.61, 113.39, 111.91, 108.07, 64.91, 56.09, 55.44, 53.28,
1453, 1332, 1453, 1332, 1269, 1218, 741 cmꢂ1
.
+
52.09, 25.57, 15.31. HRMS (EI) m/z calcd for (C22H24N2O4)
380.1736; found 380.1735. IR (KBr film) 3355, 2931, 1735, 1512,
4.5. One-pot procedure for the conversion of compound 1a into
compound 3a (see also Scheme 2)
1452, 1264, 1136, 1033, 743 cmꢂ1
.
4.4.9. (1S,3R)-Methyl 1-methyl-1,2,3,4-tetrahydro-9H-pyrido-
[3,4-b]indole-3-carboxylate 4i
To a solution of compound 1a (1.460 g, 4.167 mmol) in CH3CN
(16 mL), were added DIPEA (808.0 mg, 6.252 mmol) and 1-naph-
thylmethyl bromide (1.015 g, 4.591 mmol). The resulting solution
was heated at reflux at 81 °C, and then stirred at this temperature
for 5 h. Potassium carbonate (752.0 mg, 5.441 mmol) and DBU
(635.0 mg, 4.171 mmol) were then added, and the mixture was
further stirred under N2 at reflux for 18 h. When the reaction
was complete (checked by HPLC), the mixture was cooled down
to room temperature. The mixture was filtered by suction, and
the cake was rinsed twice with CH3CN (2 ꢀ 5 mL). The organic
solution was concentrated under vacuum to give a crude solid
product, which was purified by flash chromatography (eluent:
EtOAc/hexane = 1:5) to afford compound 3a (1.961 g, 3.998 mmol)
as a white solid in 96% yield.
99% and 96% Yields from compounds 3j and 3k, respectively.
White solid, mp 186–187 °C. ½a D20
ꢁ
¼ ꢂ16:4 (c 1.10, CH3OH). 1H
NMR (400 MHz, acetone-d6) d 9.91 (br s, 1H), 7.42 (d, J = 7.8 Hz,
1H), 7.29 (d, J = 7.9 Hz, 1H), 7.04 (dd, J1 = 7.8 Hz, J2 = 7.2 Hz, 1H),
6.98 (dd, J1 = 7.9 Hz, J2 = 7.2 Hz, 1H), 4.41 (q, J = 6.7 Hz, 1H), 3.97
(dd, J1 = 5.3 Hz, J2 = 6.7 Hz, 1H), 3.67 (s, 3H), 3.01 (dd, J1 = 15.0 Hz,
J2 = 5.3 Hz, 1H), 2.91 (dd, J1 = 15.0 Hz, J2 = 6.7 Hz, 1H), 2.68 (br s,
1H), 1.44 (d, J = 6.7 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d
174.87, 138.08, 137.16, 128.23, 121.69, 119.49, 118.44, 111.64,
106.44, 53.43, 51.97, 46.39, 25.72, 21.81. HRMS (ESI) m/z calcd for
(C14H16N2O2+H)+ 245.1290; found 245.1296. IR (KBr film) 3155,
3002, 2851, 1738, 1455, 1434, 1337, 1269, 1216, 1138, 747 cmꢂ1
.
4.4.10. (1S,3R)-Methyl 1-ethyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-
b]indole-3-carboxylate 4j
4.6. Preparation of ent-1a-HCl from compound 4a
98% Yield from compound 3l. White solid, mp 116–117 °C.
To
a
well-stirred solution of compound 4a (1.531 g,
½
a 2D0
ꢁ
¼ ꢂ27:5 (c 1.00, CH3OH). 1H NMR (400 MHz, acetone-d6) d
4.370 mmol) in CH3CN (25 mL), was added a concentrated aqueous
solution of HCl (0.45 mL, 12 M, 5.4 mmol). White crystals formed
immediately. The suspension was heated at reflux, and some
amount of CH3CN (10–15 mL) was gradually removed by distilla-
tion over 1 h, during which, water was also removed by azetropic
distillation. The remaining suspension was further stirred at reflux
for a further 8 h. After the reaction (CIAT) was complete (checked
by TLC), the mixture was cooled down to room temperature. Filtra-
tion by suction and drying in warm air afforded the hydrochloride
salt ent-1a-HCl (1.540 g, 3.981 mmol) as pale yellow crystals in
91% yield. Characterization data of compound ent-1a (after neu-
tralization) are identical with the previously reported data.9
9.87 (br s, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H),
7.04 (dd, J1 = 7.7 Hz, J2 = 7.2 Hz, 1H), 6.98 (dd, J1 = 7.9 Hz,
J2 = 7.2 Hz, 1H), 4.18 (dd, J1 = 8.7 Hz, J2 = 3.6 Hz, 1H), 3.94 (dd,
J1 = 7.0 Hz, J2 = 5.3 Hz, 1H), 3.67 (s, 3H), 2.99 (dd, J1 = 15.0 Hz,
J2 = 5.3 Hz, 1H), 2.89 (dd, J1 = 15.0 Hz, J2 = 7.0 Hz, 1H), 2.71 (br s,
1H), 1.95–1.82 (m, 1H), 1.80–1.66 (m, 1H), 1.02 (d, J = 7.3 Hz,
3H). 13C NMR (100 MHz, acetone-d6) d 175.01, 137.20, 137.12,
128.19, 121.72, 119.49, 118.43, 111.70, 106.95, 53.41, 52.23,
52.06, 28.73, 25.78, 10.88. HRMS (ESI) m/z calcd for (C15H18N2O2+-
H)+ 259.1447; found 259.1444. IR (KBr film) 3390, 2957, 2921,
2524, 1720, 1444, 1327, 1273, 1216, 1176, 1047, 743 cmꢂ1
.
4.4.11. (1S,3R)-Methyl 1-propyl-1,2,3,4-tetrahydro-9H-pyrido-
[3,4-b]indole-3-carboxylate 4k
Acknowledgments
99% Yield from compound 3m. White solid, mp 112–113 °C.
We thank the National Natural Science Foundation of China
(No. 20972048) and the Shanghai Educational Development Foun-
dation (The Dawn Program: No. 03SG27) for the financial support
of this work.
½
a 2D0
ꢁ
¼ ꢂ4:5 (c 3.0, CHCl3). 1H NMR (400 MHz, acetone-d6) d 9.88
(br s, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.03 (dd,
J1 = 7.7 Hz, J2 = 7.5 Hz, 1H), 6.96 (dd, J1 = 7.9 Hz, J2 = 7.5 Hz, 1H),
4.25 (dd, J1 = 9.1 Hz, J2 = 3.7 Hz, 1H), 3.94 (dd, J1 = 7.3 Hz, J2 = 5.2
H, 1H), 3.67 (s, 3H), 2.99 (dd, J1 = 15.0 Hz, J2 = 5.2 Hz, 1H), 2.87
(dd, J1 = 15.0 Hz, J2 = 7.3 Hz, 1H), 1.82–1.64 (m, 2H), 1.60–1.44 (m,
2H), 0.95 (t, J = 7.4, 3H). 13C NMR (100 MHz, acetone-d6) d 174.15,
136.66, 136.45, 127.39, 120.85, 118.65, 117.54, 110.87, 106.03,
52.54, 51.22, 49.94, 37.28, 25.08, 19.11, 13.62. HRMS (EI) m/z calcd
for (C16H20N2O2)+ 272.1525; found 272.1527. IR (KBr film) 3399,
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