A general strategy for the highly stereoselective synthesis of HR22C16-like mitotic kinesin Eg5 inhibitors from both l- and d-tryptophans

Article abstract of DOI:10.1016/j.tetasy.2011.10.011

An efficient and general strategy for the highly stereoselective synthesis of HR22C16-like mitotic kinesin Eg5 inhibitors 1 from both l- and d-tryptophan methyl ester hydrohalides is described. (1R,3S)-trans-1,3-Disubstituted 1,2,3,4-tetrahydro-β-carbolines (1R,3S)-trans-2 could be obtained in high yields and with high stereoselectivities from the Pictet-Spengler reaction of l-tryptophan methyl ester hydrohalide with some 3-acyloxyl benzaldehydes via a CIAT (crystal induced asymmetric transformation) process, whereas (1R,3R)-cis-1,3-disubstituted 1,2,3,4-tetrahydro-β-carbolines (1R,3R)-cis-2 could also be obtained in high yields and with high stereoselectivities from a Pictet-Spengler reaction of d-tryptophan methyl ester hydrohalide with some other 3-acyloxyl benzaldehydes via a CIAT process. Both compounds (1R,3S)-trans-2 and (1R,3R)-cis-2 were efficiently converted into HR22C16-like mitotic kinesin Eg5 inhibitors 1 by the same one-pot procedure through tandem reactions. A total of eighteen target compounds 1 were obtained from six intermediate compounds 2 in 87-95% yields.

Full text of DOI:10.1016/j.tetasy.2011.10.011

Tetrahedron: Asymmetry 22 (2011) 1865–1873
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A general strategy for the highly stereoselective synthesis of HR22C16-like
mitotic kinesin Eg5 inhibitors from both L- and D-tryptophans
⇑
Jing Dong, Tien Ha Trieu, Xiao-Xin Shi , Qiang Zhang, Sen Xiao, Xia Lu
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:
An efficient and general strategy for the highly stereoselective synthesis of HR22C16-like mitotic kinesin
Received 18 September 2011
Accepted 19 October 2011
Available online 19 November 2011
Eg5 inhibitors 1 from both
Disubstituted 1,2,3,4-tetrahydro-b-carbolines (1R,3S)-trans-2 could be obtained in high yields and with
high stereoselectivities from the Pictet–Spengler reaction of -tryptophan methyl ester hydrohalide with
L- and D-tryptophan methyl ester hydrohalides is described. (1R,3S)-trans-1,3-
L
some 3-acyloxyl benzaldehydes via a CIAT (crystal induced asymmetric transformation) process, whereas
(1R,3R)-cis-1,3-disubstituted 1,2,3,4-tetrahydro-b-carbolines (1R,3R)-cis-2 could also be obtained in high
yields and with high stereoselectivities from a Pictet–Spengler reaction of D-tryptophan methyl ester
hydrohalide with some other 3-acyloxyl benzaldehydes via a CIAT process. Both compounds (1R,3S)-
trans-2 and (1R,3R)-cis-2 were efficiently converted into HR22C16-like mitotic kinesin Eg5 inhibitors 1
by the same one-pot procedure through tandem reactions. A total of eighteen target compounds 1 were
obtained from six intermediate compounds 2 in 87–95% yields.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
O
10
11a
2
N
11
5
9
8
1
3
R1
Mitotic kinesin Eg5, also known as kinesin spindle protein (KSP),
plays an important role in the formation and separation of bipolar
spindles during human cell division. As a result, it is one of the most
attractive target enzymes in antimitotic drug discovery.1–9 Recently,
antimitotic agents that target Eg5 rather than microtubules, have at-
tracted great interest worldwide, because research on these agents
might lead to the discovery of a new generation of anticancer
drugs10–31 without the mechanism-based side effects caused by
the inhibition of tubulin.32–35 HR22C16 and its analogues were se-
lected using a phenotype-based screen for antimitotic agents and
were subsequently identified as effective Eg5 inhibitors.36 The struc-
ture of HR22C16 and its analogues 1 (Fig. 1) has a tetracyclic hydan-
toin-fused 1,2,3,4-tetrahydro-b-carboline scaffold, which bears a
meta-hydroxy group on the aromatic ring at the C-5 position and
possesses two stereogenic centers at C-5 and C-11a with the respec-
tive (R)- and (S)-configurations. Not only is the meta-hydroxyl phe-
nyl group necessary, but also the absolute configurations of both the
stereogenic centers are very important for the inhibitory activities
on Eg5.36,37 As a result, it is pivotal to construct the correct stereo-
chemistry of both stereogenic centers with high stereoselectivities
during the synthesis of HR22C16 and its analogues.
6
N
1a
HR22C16
(R1 = n-Bu, R = H)
N
4
7
H
O
OH
R
Figure 1. The structure of HR22C16 and its analogues 1.
analogues.38 However, the substituent at the C-5 position is only
limited to the 3-hydroxyphenyl group (R = H, Fig. 1), whereas the
synthesis of HR22C16-like compounds that bear substituted
3-hydroxyphenyl groups (R – H, Fig. 1) at the C-5 position remains
a challenge. In order to solve this problem, we herein report a gen-
eral strategy for a highly stereoselective synthesis of structurally
diversified HR22C16-like mitotic kinesin Eg5 inhibitors with
various 4-substituted 3-hydroxyphenyl groups at the C-5 position.
2. Results and discussion
We first attempted the Pictet–Spengler reaction of L-tryptophan
methyl ester hydrohalides (X = Cl, Br) with various 3-acyloxyl
benzaldehydes. As depicted in Scheme 1, a Pictet–Spengler reaction
We have recently reported the first highly stereoselective
approach to the mitotic kinesin Eg5 inhibitor HR22C16 and its
of L-tryptophan methyl ester hydrohalides with 3-acyloxyl benzal-
dehydes in isopropanol produced an epimeric mixture of cis- and
trans-1,3-disubstituted 1,2,3,4-tetrahydro-b-carboline hydrohalides
⇑
Corresponding author.
E-mail address: xxshi@ecust.edu.cn (X.-X. Shi).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.10.011

1866
J. Dong et al. / Tetrahedron: Asymmetry 22 (2011) 1865–1873
3
CO2CH3
1
NH2X
N
H
3
CO2CH3
CHO
R2
OR3
1
NH2X
CO2CH3
R2
N
H
a
b
+
or
2-
trans- HX
NH3X
X = Cl, Br
CIAT
OR3
N
H
OR3
3
CO2CH3
L-tryptophan methyl ester
hydrohalide
R2
1
NH2X
N
mix-2-HX
H
OR3
R2
2-
cis- HX
-tryptophan methyl ester hydrohalides with 4-substituted (R2 – H) or non-substituted (R2 = H) 3-acyloxyl benzaldehydes to afford
Scheme 1. Pictet–Spengler reaction of
L
compounds trans- or cis-2-HX via a CIAT process. Reagents and conditions: (a) reflux for 5 h, in isopropanol; (b) reflux for 5–48 h in the mixed solvent of toluene and
nitromethane with ratios as indicated in Table 1.
mix-2-HX (cis/trans ꢀ 50:50). Isopropanol was then removed, and
the subsequent CIAT (crystal induced asymmetric transforma-
tion)39–50 process of a diastereomeric mixture mix-2-HX in a mixed
solvent of toluene and nitromethane gave (1R,3S)-trans-2-HX or
(1S,3S)-cis-2-HX in high yields and with excellent diastereoselectiv-
ities (Table 1). As can be seen from Table 1, both the trans- and
cis-dominant diastereomer of 1,3-disubstituted 1,2,3,4-tetrahydro-b-
carbolines 2 can be obtained from the above CIAT process. Although
the yields of all products 2a–2f are excellent, the stereoselectivities
of the CIAT process depend significantly on the following factors:
(a) protecting groups (R3) of the meta-hydroxyl group; (b) substitu-
ents (R2) on the m-acyloxyl benzaldehydes; (c) counter ions (X = Cl
or Br) of the tryptophan methyl ester ammonium salts; and (d) the
ratio of toluene and nitromethane in the mixed solvent. Herein, it is
noteworthy that the conversion of the diastereomeric mixture mix-
2-HX into the diastereomerically pure (1R,3S)-trans-2-HX or
(1S,3S)-cis-2-HX might be the result of a CIAT process39 rather than
the thermodynamic control of a possibly reversible Pictet–Spengler
reaction. The following interesting observations might also support
this assumption. After refluxing in a mixed solvent of toluene and
nitromethane (2:1), mix-2d-HCl was turned into trans-2d-HCl
(Table 1, entry 7) whereas mix-2d-HBr was turned into cis-2d-HBr
(Table 1, entry 8). Similarly, after refluxing in nitromethane,
mix-2e-HCl was turned into trans-2e-HCl (Table 1, entry 9) whereas
mix-2e-HBr was turned into cis-2e-HBr (Table 1, entry 10). The
mechanism for the CIAT process of hydrochloride salts has been
extensively studied in a previous article39; the CIAT process of
hydrobromide salts is likely to follow the same mechanism
pathway.
The trans- and cis-stereochemistry for each compound 2 listed
in Table 1 was determined unequivocally by analyzing the correla-
tion spots in its 1H–1H NOESY spectra. As depicted in Figure 2, for
trans-2, there were two correlation spots (NOE) between H-3 and
two neighboring protons (ortho-protons) on the aryl group at C-
1, meaning that H-3 and the aryl group at C-1 were located on
the same side of the piperidine ring; for cis-2, there was one corre-
lation spot (NOE) between H-1 and H-3, meaning that H-1 and H-3
were located on the same side of the piperidine ring.
With the above obtained (1R,3S)-trans- and (1S,3S)-cis-1,
3-disubstituted 1,2,3,4-tetrahydro-b-carbolines 2 in hand, we next
attempted the conversions of both trans-2 and cis-2 compounds
into the target molecules HR22C16 and its analogues 1. Our studies
showed that trans-compounds (1R,3S)-trans-2, which have the de-
sired configurations, can be readily converted into the title com-
pounds 1 according to the synthetic route outlined in Scheme 2.
However, the above cis-compounds (1S,3S)-cis-2 have undesired
Table 1
CIAT (crystal induced asymmetric transformation) process of mix-2-HX at reflux in a mixed solvent of toluene and nitromethane to afford either cis- or trans-1,3-disubstituted
1,2,3,4-tetrahydro-b-carbolines 2 (see also Scheme 1)
Entry
R2
R3
X
Tol./CH3NO2 (ratio)
Timea (h)
Product 2b (cis/trans)
Yieldc (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
OMe
OMe
OMe
OMe
OAc
OAc
OBz
OBz
Bz
Bz
Ac
Ac
Bz
Bz
Ac
Ac
Ac
Ac
Bz
Bz
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
0:1d
0:1d
4:1
4:1
18
10
18
12
8
2a (1:99)
2a (1:99)
2b (99:1)
2b (99:1)
2c (1:99)
2c (1:99)
2d (1:99)
2d (99:1)
2e (1:99)
2e (99:1)
2f (5:95)
2f (3:97)
95
96
95
96
94
95
96
93
93
91
90
91
5
6
20
10
18
48
36
10
11
12
a
b
c
At reflux.
The cis/trans ratios were determined by both high resolution 1H NMR and HPLC analysis.
Isolated yield based on two steps from
Nitromethane was used as the solvent.
L-tryptophan methyl ester hydrohalides (see Scheme 1).
d

J. Dong et al. / Tetrahedron: Asymmetry 22 (2011) 1865–1873
1867
3
3
COOMe
H
COOMe
H
In the following text, compounds (1R,3S)-trans-2a, 2c, 2e and
(1R,3R)-cis-2b, 2d, 2e were used as the key intermediates for the
synthesis of HR22C16-like Eg5 inhibitors 1; a total of eighteen
compounds 1a–1r were obtained in 87–95% yields; all of the re-
sults are summarized in Table 2.
1
1
NH
NH
H
NOE
N
H
N
H
NOE
H
NOE
H
OR3
OR3
As depicted in Scheme 2, trans-compounds (1R,3S)-trans-2 can
be efficiently converted into the title compounds 1 by a one-pot
procedure. A stepwise method for the conversion of (1R,3S)-
trans-2 into 1 has been described in a previous article,38 but the
one-pot method shown in Scheme 2 is more efficient and practical.
When (1R,3S)-trans-2a, 2c, and 2e were treated successively with
0.5 equiv of triphosgene, 5 equiv of Et3N and 10 equiv of a primary
amine (R1NH2) in dichloromethane, intermediate compounds
(1R,3S)-trans-3 were formed at first, which then underwent
simultaneous cyclization to afford hydantoin-fused tetrahydro-
b-carbolines (5R,11aS)-trans-4. After the dichloromethane was
removed, crude compounds (5R,11aS)-trans-4 were treated with
3 equiv of Et3N at reflux in methanol to furnish title compounds
R2
trans-2
R2
cis-2
Figure 2. Determination of trans- and cis-stereochemistry of compounds 2 by
NOEs.
configurations, and thus cannot be transformed into the target
compounds 1. However, (1R,3R)-cis-2, which should be prepared
from the Pictet–Spengler reaction of D-tryptophan methyl ester
hydrohalides with aldehydes via the same CIAT process as de-
scribed in Scheme 1, can be transformed into target compounds
1 according to another synthetic route as outlined in Scheme 3.
O
11a
3
COOCH3
3
COOCH3
NHR1
O
N
R1
1
NH
1
N
5
N
a
N
H
N
H
N
H
O
OR3
OR3
OR3
R2
R2
R2
(5R,11aS)-trans-4
(1R,3S)-trans-2
(1R,3S)-trans-3
O
11a
N
R1
5
N
b
N
H
O
one-pot conversion
2
1
from trans- to
OH
R
(5R,11aS)-1
HR22C16-like Eg5 inhibitors
Scheme 2. One-pot synthesis of HR22C16-like Eg5 inhibitors (5R,11aS)-1 from compounds (1R,3S)-trans-2. Reagents and conditions: (a) 0.5 equiv of triphosgene, 5 equiv of
Et3N, 0 °C for 15 min in CH2Cl2; then 10 equiv of R1NH2, 0 °C for 15 min and then refluxing for 3 h in CH2Cl2; (b) 3 equiv of Et3N, refluxing for 3 h in CH3OH.
O
11a
3
COOCH3
3
COOCH3
NHR1
O
N
R1
1
NH
1
N
5
N
a
N
H
N
H
N
H
O
OR3
OR3
OR3
R2
R2
R2
4
2
3
(5R,11aR)-cis-
(1R,3R)-cis-
(1R,3R)-cis-
O
O
11a
11a
N
R1
N
R1
5
N
5
N
b
N
N
H
H
O
O
one-pot conversion
from cis-2 to 1
OR3
OH
R2
R
4
(5R,11aS)-trans-
1
(5R,11aS)-
HR22C16-like Eg5 inhibitors
Scheme 3. One-pot synthesis of HR22C16-like Eg5 inhibitors (5R,11aS)-1 from compounds (1R,3R)-cis-2. Reagents and conditions: (a) 0.5 equiv of triphosgene, 5 equiv of
Et3N, 0 °C for 15 min in CH2Cl2; then 10 equiv of R1NH2, 0 °C for 15 min and then refluxing for 3 h in CH2Cl2; (b) 3 equiv of Et3N, refluxing for 3 h in CH3OH.

1868
J. Dong et al. / Tetrahedron: Asymmetry 22 (2011) 1865–1873
Table 2
Synthesis of HR22C16-like Eg5 inhibitors 1 from trans- and cis-1,3-disubstituted tetrahydro-b-carbolines (THBCs) (1R,3S)-trans-2 and (1R,3R)-cis-2 via a one-pot procedure (see
also Schemes 2 and 3)
Entry
THBCs 2a,b
R1
R2
R3
R
Product 1
Yieldc (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
(1R,3S)-trans-2a
(1R,3S)-trans-2a
(1R,3S)-trans-2a
(1R,3S)-trans-2a
(1R,3S)-trans-2c
(1R,3S)-trans-2c
(1R,3S)-trans-2c
(1R,3S)-trans-2e
(1R,3R)-cis-2b
(1R,3R)-cis-2b
(1R,3R)-cis-2b
(1R,3R)-cis-2d
(1R,3R)-cis-2d
(1R,3R)-cis-2d
(1R,3R)-cis-2d
(1R,3R)-cis-2e
(1R,3R)-cis-2e
(1R,3R)-cis-2e
n-Bu
n-Pr
Hydroxyethyl
Bn
i-Pr
5-Azido-pentyl
Phenethyl
i-Pr
5-Azido-pentyl
i-Pr
Phenethyl
n-Pr
n-Bu
H
H
H
H
OMe
OMe
OMe
OAc
H
Bz
Bz
Bz
Bz
Bz
Bz
Bz
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
H
H
H
H
OMe
OMe
OMe
OH
H
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
95
94
92
95
92
92
87
93
93
94
88
90
92
87
90
91
90
94
H
H
H
H
OMe
OMe
OMe
OMe
OAc
OAc
OAc
OMe
OMe
OMe
OMe
OH
OH
OH
Hydroxyethyl
Bn
5-Azido-pentyl
Hydroxyethyl
Bn
a
b
c
THBCs (1R,3S)-trans-2a, 2c, and 2e were prepared from
L
-tryptophane methyl ester hydrohalide via CIAT process (see also Scheme 1).
THBCs (1R,3R)-cis-2b, 2d, and 2e were prepared from
D-tryptophane methyl ester hydrohalide via CIAT process (see also Scheme 1).
Isolated yield.
was performed in one pot without isolation of the intermediate
compounds (1R,3R)-cis-3, (5R,11aR)-cis-4, and (5R,11aS)-trans-4.
A plausible mechanism for the base-catalyzed epimerization of
the less stable compounds (5R,11aR)-cis-4 into more stable com-
pounds (5R,11aS)-trans-4 is proposed in Scheme 4. An enolate A-
1 might be involved in this base-catalyzed epimerization.51 The
reaction of the base (Et3N or R1NH2) with the acidic proton at C-
11a of compounds (5R,11aR)-cis-4 produced the anion A-1 which
then underwent protonation to give the more stable compounds
(5R,11aS)-trans-4. The epimerization seems to be reversible, since
compounds (5R,11aS)-trans-4 also underwent epimerization to
form compounds (5R,11aR)-cis-4. However, the one-pot conversion
of compounds (1R,3R)-cis-2 into the title compounds (5R,11aS)-
trans-1 only gave the trans-diastereomer without contamination
of the cis-diastereomer, implying that the epimerization of the
cis-compounds (5R,11aR)-cis-4 into the much more stable trans
compounds (5R,11aR)-trans-4 was fully complete during the one-
pot conversion.
O
O
11a
11a
N
R1
N
R1
5
5
N
N
N
H
N
H
O
O
base-catalyzed
epimerization
OR3
OR3
R2
R2
(5R,11aS)-trans-4
(5R,11aR)-cis-4
(more stable)
(less stable)
base
O
H+
11a
N
R1
5
N
N
H
O
enolate A-1
OR3
R2
Scheme 4. Possible mechanism for the base-catalyzed epimerization of compounds
(5R,11aR)-cis-4 into compounds (5R,11aS)-trans-4.
3. Conclusion
In conclusion, an efficient and general method for highly stere-
oselective synthesis of HR22C16-like mitotic kinesin Eg5 inhibitors
has been developed. By using this method, HR22C16 and its ana-
(5R,11aS)-trans-1a–1h in high yields (Table 2, entries 1–8). The
whole conversion from (1R,3S)-trans-2 into (5R,11aS)-trans-1 was
performed in one pot without isolation of the intermediates
(1R,3S)-trans-3 and (5R,11aS)-trans-4.
logues 1 can be synthesized from both
ester hydrohalides. If the CIAT process afforded trans intermediates
2, then -tryptophan was used as the starting material; conversely
if the CIAT process afforded cis intermediates 2, the -tryptophan
L- and D-tryptophan methyl
As depicted in Scheme 3, cis-compounds (1R,3R)-cis-2 can also be
efficiently converted into title compounds 1 by the same one-pot
procedure. When (1R,3R)-cis-2b, 2d, and 2e were treated succes-
sively with 0.5 equiv of triphosgene, 5 equiv of Et3N and 10 equiv
of a primary amine (R1NH2) in dichloromethane, intermediate com-
pounds (1R,3R)-cis-3 were formed at first, which then underwent
simultaneous cyclization to afford hydantoin-fused tetrahydro-b-
carbolines (5R,11aR)-cis-4, which were unstable and would rapidly
change into more stable compounds (5R,11aS)-trans-4 via a base-
catalyzed epimerization at the C-11a position. After the dichloro-
methane was removed, crude compounds (5R,11aS)-trans-4 were
treated with 3 equiv of Et3N at reflux in methanol to furnish title
compounds (5R,11aS)-trans-1i–1r in high yields (Table 2, entries
9–18). Although four steps were involved, the whole conversion
from compounds (1R,3R)-cis-2 into compounds (5R,11aS)-trans-1
L
D
was used as the starting material. Since the CIAT process can be
applicable for various substituted m-acyloxyl-benzaldehydes by
tuning the ratio of toluene and nitromethane in a mixed solvent,
the above method should be a general one. In addition, since the
dominance of the trans- or cis-configurations of intermediates 2
cannot be predicted for the CIAT process for each aldehyde, the
HR22C16-like Eg5 inhibitors 1 might be synthesized either from
L-tryptophan methyl ester hydrohalides or from
D-tryptophan
methyl ester hydrohalides.
Herein, three trans-compounds (1R,3S)-trans-2a, 2c, 2e and
three cis-compounds (1R,3R)-cis-2b, 2d, 2e were prepared; these
six intermediate compounds were efficiently converted into
HR22C16-like mitotic kinesin Eg5 inhibitors
1 by the same

J. Dong et al. / Tetrahedron: Asymmetry 22 (2011) 1865–1873
1869
one-pot procedure through tandem reactions. A total of eighteen ti-
4.3.1. (1R,3S)-Methyl 1-(3-(benzoyloxy)phenyl)-1,2,3,4-tetra-
tle compounds 1a–1r were obtained from the one-pot method in
87–95% yields.
hydro-9H-pyrido[3,4-b]indole-3-carboxylate (1R,3S)-trans-2a
Mp 185–186 °C (lit.38 mp 185–186 °C). ½a 2D0
¼ ꢂ33:7 (c 0.8,
ꢁ
CHCl3) {lit.38
½
a 2D0
ꢁ
¼ ꢂ33:5 (c 0.9, CHCl3)}. 1H NMR (CDCl3) d 2.37
(br s, 1H), 3.14 (ddd, J1 = 15.4 Hz, J2 = 6.8 Hz, J3 = 1.2 Hz, 1H), 3.28
(dd, J1 = 15.5 Hz, J2 = 5.4 Hz, 1H), 3.72 (s, 3H), 3.99 (dd, J1 = 6.3 Hz,
J2 = 5.9 Hz, 1H), 5.43 (s, 1H), 7.12–7.24 (m, 6H), 7.39 (dd,
J1 = 7.9 Hz, J2 = 7.8 Hz, 1H), 7.48 (dd, J1 = 7.9 Hz, J2 = 7.7 Hz, 2H),
7.54 (d, J = 7.6 Hz, 1H), 7.62 (dd, J1 = 7.5 Hz, J2 = 7.6 Hz, 1H), 7.77
(br s, 1H, NH on the indole ring), 8.15 (d, J = 7.8 Hz, 2H). 13C NMR
(CDCl3) d 174.6, 165.9, 151.8, 144.6, 136.9, 134.3, 133.3, 130.8,
130.2, 129.9, 129.2, 127.4, 126.5, 122.5, 122.3, 122.04, 120.01,
118.8, 111.9, 109.0, 55.1, 52.73, 52.71, 25.5. MS (EI) m/z (%) 426
(M+, 100), 411 (10), 365 (15), 321 (12), 261 (7), 234 (19), 229 (15),
217 (12), 206 (9), 169 (18), 144 (13), 105 (78), 77 (17). IR (KBr)
4. Experimental
4.1. General
Melting points are uncorrected. 1H and 13C NMR spectra were
acquired on a Bruker AM-400, chemical shifts were given on the
delta scale as parts per million (ppm) with tetramethylsilane
(TMS) as the internal standard. IR spectra were recorded on a Nico-
let Magna IR-550. Mass spectra were recorded on HP5989A. Opti-
cal rotations were measured on a WZZ-1S automatic polarimeter at
room temperature. Column chromatography was performed on sil-
ica gel (Qingdao Ocean Chemical Corp.). All chemicals were analyt-
3395, 2980, 1735, 1605, 1454, 1271, 1225, 1065, 750, 705 cmꢂ1
HRMS (EI) calcd for C26H22N2O4: 426.1580; found: 426.1585.
.
ically pure. The
L- or D-tryptophan methyl ester hydrochloride was
prepared according to a known procedure.52
4.3.2. (1R,3R)-Methyl 1-(3-acetoxyphenyl)-1,2,3,4-tetrahydro-
9H-pyrido[3,4-b]indole-3-carboxylate (1R,3R)-cis-2b
Mp 221–222 °C (lit.38 mp 220–221 °C). ½a 2D0
¼ þ7:1 (c 3.0, CHCl3)
ꢁ
4.2. Procedure for the preparation of
ester hydrobromide
L- or D-tryptophan methyl
{lit.38
½
a 2D0
ꢁ
¼ ꢂ7:2 (c 3.3, CHCl3) for the enantiomer}. 1H NMR (CDCl3)
d 2.26 (s, 3H), 3.00 (ddd, J1 = 15.0 Hz, J2 = 11.1 Hz, J3 = 2.4 Hz, 1H),
3.22 (ddd, J1 = 15.1 Hz, J2 = 4.2 Hz, J3 = 1.8 Hz, 1H), 3.81 (s, 3H), 3.97
(dd, J1 = 11.0 Hz, J2 = 4.2 Hz, 1H), 5.26 (s, 1H), 7.08–7.16 (m, 4H),
7.22 (d, J = 7.4 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.39 (dd, J1 = 7.8 Hz,
J2 = 7.7 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.55 (br s, 1H, NH on the in-
dole ring). 13C NMR (CDCl3) d 173.6, 170.1, 151.4, 143.1, 136.8,
134.6, 130.3, 127.4, 126.6, 122.40, 122.38, 122.2, 120.0, 118.6,
111.6, 109.2, 58.6, 57.3, 52.7, 26.1, 21.5. MS (EI) m/z (%) 364 (M+,
100), 349 (7), 305 (55), 277 (32), 261 (25), 235 (64), 229 (27), 218
(28), 191 (5), 169 (29), 144 (28), 130 (4), 115 (6). IR (KBr) 3390,
2975, 1745, 1739, 1600, 1452, 1370, 1268, 1211, 744 cmꢂ1. HRMS
(EI) calcd for C21H20N2O4: 364.1423; found: 364.1426.
At first, L- or D-tryptophan methyl ester (10.00 g, 45.82 mmol)
was dissolved in ethyl acetate (100 mL). The solution was then
cooled to 0 °C with an ice-bath while being stirred. An aqueous
solution of hydrobromic acid (9.28 g, 48% w/w, 55.05 mmol) was
added dropwise over 15 min. and stirring was continued at 0 °C
for one more hour. The product as an off-white solid was collected
on a Büchner funnel by suction and washed with a small amount of
ethyl acetate. The product was dried in warm air to produce L- or D-
tryptophan methyl ester hydrobromide (12.88 g, 43.05 mmol) in a
94% yield, mp 204–205 °C. ½a D20
ꢁ
¼ þ15:2 (c 3.1, CH3OH) for the
L-
isomer; and ½a 2D0
ꢁ
¼ ꢂ15:3 (c 3.2, CH3OH) for the
D
-isomer. 1H
NMR (D2O) d 3.25–3.40 (m, 2H), 3.71 (s, 3H), 4.32 (t, J = 6.5 Hz,
1H), 7.10 (dd, J1 = 7.6 Hz, J2 = 7.5 Hz, 1H), 7.19 (dd, J1 = 8.1 Hz,
J2 = 7.5 Hz, 1H), 7.20 (s, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.48 (d,
J = 7.6 Hz, 1H). MS (EI) m/z (%) 218 (M+, 100), 203 (10), 159 (12),
130 (21), 105 (1), 77 (1). IR (KBr) 3359, 3298, 1723, 1568, 1452,
4.3.3. (1R,3S)-Methyl 1-(3-benzoyloxy-4-methoxyphenyl)-
1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate
(1R,3S)-trans-2c
Mp 197–198 °C. ½a D20
ꢁ
¼ ꢂ36:3 (c 1.0, CHCl3). 1H NMR (CDCl3) d
1231, 749, 705 cmꢂ1
.
2.30 (br s, 1H, NH), 3.09 (ddd, J1 = 15.4 Hz, J2 = 7.1 Hz, J3 = 1.3 Hz,
1H), 3.24 (dd, J1 = 15.4 Hz, J2 = 5.4 Hz, 1H), 3.71 (s, 3H), 3.78 (s,
3H), 3.95 (dd, J1 = 7.1 Hz, J2 = 5.4 Hz, 1H), 5.30 (s, 1H), 6.93 (d,
J = 8.4 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 7.07–7.18 (m, 3H), 7.23 (d,
J = 8.0 Hz, 1H), 7.47 (dd, J1 = 7.9 Hz, J2 = 7.5 Hz, 2H), 7.53 (d,
J = 7.3 Hz, 1H), 7.60 (dd, J1 = 7.4 Hz, J2 = 7.2 Hz, 1H), 7.87 (s, 1H,
NH on the indole ring), 8.15 (dd, J1 = 7.2 Hz, J2 = 1.4 Hz, 2H). 13C
NMR (CDCl3) d 173.0, 163.7, 150.0, 138.8, 135.2, 133.8, 132.5,
132.1, 129.2, 128.1, 127.4, 125.75, 125.72, 121.9, 120.7, 118.2,
117.0, 111.3, 110.2, 107.1, 54.9, 52.9, 51.0, 50.9, 23.9. MS (EI) m/z
(%) 456 (M+, 100), 441 (12), 397 (23), 351 (12), 264 (8), 248 (9),
204 (8), 169 (14), 105 (52), 77 (11). IR (KBr) 3373, 2952, 2878,
1739, 1723, 1543, 1510, 1317, 1267, 1209, 1120, 1024, 745,
708 cmꢂ1. Anal. Calcd for C27H24N2O5: C, 71.04; H, 5.30; N, 6.14.
Found: C, 71.31; H, 5.13; N, 6.10.
4.3. General procedure for the preparation of intermediate
compounds 2
To a solution of 4-substituted (or nonsubstituted) 3-acyloxyl
benzaldehyde (12.00 mmol) in isopropanol (25 mL) was added
powdered L- or D-tryptophan methyl ester hydrohalide (10.00
mmol). The mixture was heated at reflux while being stirred, and
then stirring was continued for around 5 h at reflux. The reaction
solution was then concentrated to dryness under vacuum to give a
crude solid product. The crude solid product was then suspended
in a mixed solvent (20 mL) of nitromethane and toluene with a ratio
as indicated in Table 1. The suspension was heated at reflux, and
then stirring was continued at reflux for 5–48 h (see also Table 1).
The mixture was then cooled down to room temperature. A pale yel-
low solid was collected in a Büchner funnel by suction and rinsed
with a small amount of a freshly mixed solvent of nitromethane
and toluene. The solid was then partitioned between ethyl acetate
(50 mL) and a saturated aqueous solution of K2CO3 (20 mL, 15% w/
v). The organic layer was separated and dried over anhydrous
MgSO4. Evaporation of the solvent under vacuum gave a crude prod-
uct which was purified by flash chromatography to afford com-
pounds 2 in 90–96% yield (see also Table 1). Characterization data
for all compounds 2 are as follows.
4.3.4. (1R,3S)-Methyl 1-(3-acetoxy-4-methoxyphenyl)-1,2,3,4-
tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate (1R,3S)-trans-
2d
Mp 85–86 °C. ½a 2D0
ꢁ
¼ ꢂ29:8 (c 1.0, CHCl3). 1H NMR (CDCl3) d 2.25
(s, 3H), 2.30 (br s, 1H, NH), 3.08 (dd, J1 = 15.5 Hz, J2 = 6.8 Hz, 1H), 3.23
(dd, J1 = 15.5 Hz, J2 = 5.1 Hz, 1H), 3.70 (s, 3H), 3.79 (s, 3H), 3.91 (dd,
J1 = 6.8 Hz, J2 = 5.6 Hz, 1H), 5.27 (s, 1H), 6.88 (d, J = 8.7 Hz, 1H),
6.90 (d, J = 2.3 Hz, 1H), 7.05–7.18 (m, 3H), 7.23 (d, J = 7.4 Hz, 1H),
7.54 (d, J = 7.4 Hz, 1H), 7.87 (s, 1H, NH on the indole ring). 13C NMR
(CDCl3) d 174.1, 169.2, 150.9, 139.7, 136.3, 134.8, 133.2, 126.9,

1870
J. Dong et al. / Tetrahedron: Asymmetry 22 (2011) 1865–1873
126.8, 122.9, 121.9, 119.4, 118.1, 112.3, 111.3, 108.3, 56.0, 54.0, 52.1,
52.0, 25.0, 20.6. MS (EI) m/z (%) 394 (M+, 100), 379 (10), 335 (35), 278
(10), 248 (10), 204 (9), 169 (15), 144 (8), 115 (2), 103 (1), 77 (1). IR
(KBr) 3382, 2950, 2842, 1764, 1736, 1511, 1450, 1369, 1268, 1202,
1119, 1023, 744 cmꢂ1. Anal. Calcd for C22H22N2O5: C, 66.99; H,
5.62; N, 7.10. Found: C, 66.89; H, 5.48; N, 7.33.
134.1, 134.2, 133.7, 129.54, 129.53, 129.52, 129.51, 128.87,
128.86, 128.85, 128.84, 128.04, 128.02, 126.7, 126.5, 123.3, 123.1,
121.0, 118.4, 117.7, 111.2, 106.8, 53.3, 51.8, 51.7, 24.8. MS (EI)
m/z (%) 546 (M+, 19), 529 (5), 487 (4), 441 (5), 425 (2), 354 (2),
261 (3), 169 (3), 106 (6), 105 (100), 77 (16). IR (KBr) 3313, 3171,
1741, 1725, 1504, 1453, 1248, 1142, 1058, 1124, 1024, 750,
710 cmꢂ1. Anal. Calcd for C33H26N2O6: C, 72.52; H, 4.79; N, 5.13.
Found: C, 72.33; H, 4.71; N, 5.10.
4.3.5. (1R,3R)-Methyl 1-(3-acetoxy-4-methoxyphenyl)-1,2,3,4-
tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate (1R,3R)-cis-2d
Mp 102–103 °C. ½a D20
ꢁ
¼ þ9:5 (c 5.0, CHCl3). 1H NMR (CDCl3) d
4.4. General procedure for the one-pot synthesis of HR22C16-
like Eg5 inhibitors 1 from compounds 2
2.27 (s, 3H), 2.98 (ddd, J1 = 15.0 Hz, J2 = 11.2 Hz, J3 = 2.5 Hz, 1H),
3.21 (ddd, J1 = 15.0 Hz, J2 = 4.2 Hz, J3 = 1.8 Hz, 1H), 3.80 (s, 3H),
3.83 (s, 3H), 3.95 (dd, J1 = 11.2 Hz, J2 = 4.2 Hz, 1H), 5.17 (s, 1H),
6.94 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 2.1 Hz, 1H), 7.07–7.17 (m, 2H),
7.19–7.28 (m, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.78 (s, 1H, NH on the
indole ring). 13C NMR (CDCl3) d 173.2, 169.5, 151.2, 139.7, 136.4,
134.7, 133.6, 127.3, 127.0, 123.2, 121.8, 119.4, 118.1, 112.6,
111.2, 108.6, 57.8, 56.9, 56.0, 52.3, 25.7, 20.6. MS (EI) m/z (%) 394
(M+, 100), 335 (34), 307 (20), 265 (15), 248 (16), 234 (10), 204
(7), 169 (11), 144 (7), 115 (1), 102 (1). IR (KBr) 3384, 2950, 2843,
1761, 1739, 1512, 1440, 1368, 1267, 1205, 1120, 787, 743,
699 cmꢂ1. Anal. Calcd for C22H22N2O5: C, 66.99; H, 5.62; N, 7.10.
Found: C, 67.14; H, 5.46; N, 7.02.
A solution of (1R,3S)-trans-2 or (1R,3R)-cis-2 (3.00 mmol) and
triethylamine (15.00 mmol) in dichloromethane (20 mL) was
cooled to 0 °C in an ice-bath. A freshly prepared solution of triphos-
gene (1.50 mmol) in dichloromethane (2 mL) was added dropwise
over 1 min, and the reaction mixture was then stirred at 0 °C for
around 15 min. A primary amine R1NH2 (30.00 mmol) was added,
and the mixture was then stirred at 0 °C for around 15 min. The
ice-bath was removed, and the mixture was heated and stirred at
reflux for around 3 h. The reaction solution was then concentrated
to dryness under vacuum, after which the residue was dissolved in
methanol (20 mL). Triethylamine (9.00 mmol) was added, and the
solution was heated and stirred at reflux for around 3 h. Removal of
the solvent by vacuum distillation produced an oily residue which
was then allowed to partition between ethyl acetate (40 mL) and
dilute aqueous HCl solution (2 M, 20 mL). The organic phase was
separated, washed with a saturated aqueous solution of sodium
bicarbonate (15 mL), and dried over anhydrous sodium sulfate.
Evaporation of the solvent under vacuum gave a crude product
which was purified by flash chromatography to afford compounds
1 in 87–95% yield (see also Table 2). Characterization data for all
compounds 1a–1r are as follows.
4.3.6. (1R,3S)-Methyl 1-(3,4-diacetoxyphenyl)-1,2,3,4-tetra-
hydro-9H-pyrido[3,4-b]indole-3-carboxylate (1R,3S)-trans-2e
Mp 75–76 °C. ½a 2D0
ꢁ
¼ ꢂ38:5 (c 0.6, CHCl3). 1H NMR (CDCl3) d 2.22
(s, 3H), 2.26 (s, 3H), 2.33 (br s, 1H, NH), 3.07 (ddd, J1 = 15.5 Hz,
J2 = 7.5 Hz, J3 = 1.2 Hz, 1H), 3.24 (dd, J1 = 15.5 Hz, J2 = 5.1 Hz, 1H),
3.71 (s, 3H), 3.90 (dd, J1 = 7.5 Hz, J2 = 5.1 Hz, 1H), 5.26 (s, 1H), 7.03
(s, 1H), 7.09–7.21 (m, 4H), 7.25 (d, J = 7.2 Hz, 1H), 7.55 (d,
J = 7.2 Hz, 1H), 8.04 (s, 1H, NH on the indole ring). 13C NMR (CDCl3)
d 174.0, 168.5, 168.4, 142.1, 141.7, 141.0, 136.4, 132.6, 126.8, 126.6,
123.5, 123.4, 122.0, 119.4, 118.2, 111.4, 108.4, 54.0, 52.2, 51.9, 25.0,
20.6, 20.5. MS (EI) m/z (%) 422 (M+, 100), 363 (27), 321 (21), 277 (8),
234 (9), 169 (8), 144 (5), 115 (1). IR (KBr) 3386, 3057, 2951, 1773,
1736, 1502, 1452, 1436, 1371, 1258, 1210, 1178, 1107, 1011, 901,
744 cmꢂ1. Anal. Calcd for C23H22N2O6: C, 65.39; H, 5.25; N, 6.63.
Found: C, 65.23; H, 5.23; N, 6.76.
4.4.1. (5R,11aS)-2-Butyl-5-(3-hydroxyphenyl)-6H-1,2,3,5,11,11a-
hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione 1a
Mp 107–108 °C (lit.38 107–108 °C). ½a 2D0
¼ ꢂ231:5 (c 0.3, CHCl3).
ꢁ
1H NMR (DMSO-d6) d 0.86 (t, J = 7.3 Hz, 3H), 1.20–1.28 (m, 2H),
1.45–1.52 (m, 2H), 2.78 (dd, J1 = 13.9 Hz, J2 = 11.2 Hz, 1H), 3.32–
3.42 (m, 3H), 4.48 (dd, J1 = 10.8 Hz, J2 = 5.7 Hz, 1H), 6.12 (s, 1H),
6.70 (d, J = 7.7 Hz, 1H), 6.71 (s, 1H), 6.76 (d, J = 7.7 Hz, 1H), 7.01
(dd, J1 = 7.3 Hz, J2 = 7.2 Hz, 1H), 7.08 (dd, J1 = 7.2 Hz, J2 = 7.6 Hz,
1H), 7.15 (dd, J1 = 7.9 Hz, J2 = 8.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H),
7.53 (d, J = 7.8 Hz, 1H), 9.46 (s, 1H), 10.93 (s, 1H, NH on the indole
ring). 13C NMR (DMSO-d6) d 172.6, 157.7, 154.3, 141.4, 136.7,
131.2, 129.8, 125.8, 121.7, 118.8, 118.5, 118.2, 115.1, 114.8,
111.4, 106.0, 52.8, 51.4, 37.7, 29.7, 22.8, 19.4, 13.5. MS (EI) m/z
(%) 389 (M+, 100), 296 (35), 261 (18), 234 (41), 218 (14), 206 (6),
196 (3), 169 (9), 115 (2). IR (KBr) 3340, 2954, 2929, 2870, 1757,
1701, 1591, 1458, 1426, 1328, 1240, 749 cmꢂ1. HRMS (EI) calcd
for C23H23N3O3: 389.1739; found: 389.1734.
4.3.7. (1R,3R)-Methyl 1-(3,4-diacetoxyphenyl)-1,2,3,4-tetra-
hydro-9H-pyrido[3,4-b]indole-3-carboxylate (1R,3R)-cis-2e
Mp 78–79 °C. ½a 2D0
ꢁ
¼ þ5:6 (c 7.0, CHCl3). 1H NMR (CDCl3) d 2.25
(s, 3H), 2.29 (s, 3H), 2.99 (ddd, J1 = 15.0 Hz, J2 = 11.2 Hz, J3 = 2.5 Hz,
1H), 3.22 (ddd, J1 = 15.0 Hz, J2 = 4.1 Hz, J3 = 1.7 Hz, 1H), 3.80 (s, 3H),
3.95 (dd, J1 = 11.2 Hz, J2 = 4.1 Hz, 1H), 5.24 (s, 1H), 7.08–7.24 (m,
5H), 7.28 (dd, J1 = 8.3 Hz, J2 = 2.0 Hz, 1H), 7.53 (d, J = 7.1 Hz, 1H),
7.67 (s, 1H, NH on the indole ring). 13C NMR (CDCl3) d 173.0,
168.39, 168.37, 142.3, 142.2, 139.8, 136.4, 134.0, 126.9, 123.8,
122.0, 119.6, 118.2, 111.2, 108.9, 57.9, 56.8, 52.3, 25.6, 20.6, 20.5.
MS (EI) m/z (%) 422 (M+, 100), 363 (34), 335 (21), 277 (12), 250
(18), 234 (19), 233 (14), 229 (11), 204 (9), 169 (15), 144 (10),
115 (2). IR (KBr) 3385, 2951, 2848, 1771, 1739, 1503, 1436, 1210,
1108, 900, 744 cmꢂ1. Anal. Calcd for C23H22N2O6: C, 65.39; H,
5.25; N, 6.63. Found: C, 65.31; H, 5.13; N, 6.88.
4.4.2. (5R,11aS)-2-Propyl-5-(3-hydroxyphenyl)-6H-
1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
1b
Mp 122–123 °C (lit.37 120 °C). ½a D20
ꢁ
¼ ꢂ202:4 (c 0.5, CHCl3). 1H
NMR (DMSO-d6) d 0.83 (t, J = 7.4 Hz, 3H), 1.45–1.62 (m, 2H), 2.81
(ddd, J1 = 15.0 Hz, J2 = 11.9 Hz, J3 = 1.4 Hz, 1H), 3.31–3.43 (m, 3H),
4.50 (dd, J1 = 10.8 Hz, J2 = 5.7 Hz, 1H), 6.15 (s, 1H), 6.69–6.76 (m,
2H), 6.79 (d, J = 7.8 Hz, 1H), 7.02 (dd, J1 = 7.6 Hz, J2 = 7.8 Hz, 1H),
7.10 (dd, J1 = 8.0 Hz, J2 = 8.2 Hz, 1H), 7.17 (dd, J1 = 8.2 Hz,
J2 = 7.6 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H),
9.46 (s, 1H), 10.94 (s, 1H). 13C NMR (DMSO-d6) d 172.6, 157.6,
154.3, 141.4, 136.6, 131.2, 129.7, 125.7, 121.6, 118.8, 118.4,
118.2, 115.0, 114.7, 111.4, 106.0, 52.7, 51.3, 39.6, 22.7, 20.9,
11.04. MS (EI) m/z (%) 375 (M+, 100), 282 (30), 261 (18), 234
4.3.8. (1R,3S)-Methyl 1-(3,4-dibenzoyloxyphenyl)-1,2,3,4-tetra-
hydro-9H-pyrido[3,4-b]indole-3-carboxylate (1R,3S)-trans-2f
Mp 231–232 °C. ½a D20
ꢁ
¼ ꢂ47:5 (c 0.4, CHCl3). 1H NMR (CDCl3) d
3.19 (dd, J1 = 15.4 Hz, J2 = 7.0 Hz, 1H), 3.35 (dd, J1 = 15.4 Hz,
J2 = 5.2 Hz, 1H), 3.73 (s, 3H), 4.07 (dd, J1 = 7.0 Hz, J2 = 6.0 Hz, 1H),
5.53 (s, 1H), 7.07–7.20 (m, 2H), 7.27–7.39 (m, 8H), 7.47–7.57 (m,
3H), 7.97 (dd, J1 = 8.5 Hz, J2 = 1.3 Hz, 2H), 8.02 (dd, J1 = 8.5 Hz,
J2 = 1.3 Hz, 2H), 8.11 (s, 1H, NH on the indole ring). 13C NMR
(DMSO-d6) d 173.8, 163.60, 163.59, 142.4, 141.9, 141.2, 136.2,

J. Dong et al. / Tetrahedron: Asymmetry 22 (2011) 1865–1873
1871
(31), 218 (13), 169 (11), 140 (2), 115 (3). IR (KBr) 3335, 2934, 1763,
1698, 1456, 1425, 1239, 745, 713 cmꢂ1
Anal. Calcd for
22H21N3O3: C, 70.38; H, 5.64; N, 11.19. Found: C, 70.41; H, 5.68;
N, 11.13.
8.24 (s, 1H). 13C NMR (CDCl3) d 173.1, 154.8, 147.1, 145.8, 136.7,
132.5, 130.8, 126.1, 122.6, 120.0, 119.9, 118.4, 114.4, 111.3,
110.9, 107.4, 55.9, 53.2, 51.7, 51.2, 38.4, 28.3, 27.7, 23.8, 23.3. MS
(EI) m/z (%) 474 (M+, 25), 446 (33), 416 (12), 388 (20), 362 (10),
317 (9), 291 (100), 276 (23), 248 (14), 234 (15), 204 (22), 169
(17), 115 (5). IR (KBr) 3336, 2934, 2096, 1764, 1702, 1454, 1273,
1128, 747 cmꢂ1. Anal. Calcd for C25H26N6O4: C, 63.28; H, 5.52; N,
17.71. Found: C, 63.02; H, 5.64; N, 17.89.
.
C
4.4.3. (5R,11aS)-2-Hydroxyethyl-5-(3-hydroxyphenyl)-6H-
1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione 1c
Mp 256–257 °C. ½a D20
ꢁ
¼ ꢂ238:1 (c 0.6, CH3OH). 1H NMR (DMSO-
d6) d 2.85 (dd, J1 = 14.1 Hz, J2 = 11.0 Hz, 1H), 3.30–3.42 (m, 1H),
3.44–3.61 (m, 4H), 4.46 (dd, J1 = 11.0 Hz, J2 = 5.8 Hz, 1H), 4.84
(dd, J1 = 5.8 Hz, J2 = 5.7 Hz, 1H), 6.15 (s, 1H), 6.70–6.85 (m, 3H),
7.04 (dd, J1 = 7.4 Hz, J2 = 7.2 Hz, 1H), 7.11 (dd, J1 = 7.4 Hz,
J2 = 7.2 Hz, 1H), 7.17 (dd, J1 = 7.8 Hz, J2 = 7.7 Hz, 1H), 7.32 (d,
J = 8.0 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 9.48 (s, 1H), 10.93 (s, 1H).
13C NMR (DMSO-d6) d 172.7, 157.6, 154.4, 141.4, 136.6, 131.2,
129.8, 125.8, 121.6, 118.8, 118.5, 118.1, 115.1, 114.8, 111.4,
106.0, 57.6, 52.7, 51.3, 40.9, 22.6. MS (EI) m/z (%) 377 (M+, 100),
360 (2), 332 (2), 284 (22), 261 (20), 234 (37), 218 (12), 204 (6),
169 (10), 115 (2). IR (KBr) 3291, 2940, 1763, 1699, 1455, 1426,
1237, 1045, 755, 714 cmꢂ1. Anal. Calcd for C21H19N3O4: C, 66.83;
H, 5.07; N, 11.13. Found: C, 66.72; H, 5.14; N, 11.12.
4.4.7. (5R,11aS)-2-Phenethyl-5-(3-hydroxy-4-methoxyphenyl)-
6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-
dione 1g
Mp 117–118 °C. ½a D20
ꢁ
¼ ꢂ192:4 (c 0.6, CHCl3). 1H NMR (CDCl3) d
2.69 (ddd, J1 = 15.2 Hz, J2 = 11.1 Hz, J3 = 1.6 Hz, 1H), 2.92 (t,
J = 7.8 Hz, 2H), 3.35 (dd, J1 = 15.2 Hz, J2 = 5.5 Hz, 1H), 3.65–3.78
(m, 2H), 3.81 (s, 3H), 4.17 (dd, J1 = 11.1 Hz, J2 = 5.5 Hz, 1H), 5.75
(s, 1H), 6.13 (s, 1H), 6.72–6.78 (m, 2H), 6.82 (dd, J1 = 8.3 Hz,
J2 = 2 Hz, 1H), 7.12–7.29 (m, 8H), 7.53 (d, J = 7.3 Hz, 1H), 8.12 (s,
1H). 13C NMR (CDCl3) d 172.8, 154.6, 147.1, 145.9, 137.8, 136.7,
132.5, 130.8, 128.96, 128.95, 128.55, 128.54, 126.7, 126.2, 122.6,
120.1, 119.9, 118.4, 114.4, 111.4, 110.9, 107.5, 55.9, 53.2, 51.6,
39.8, 34.0, 23.2. HRMS (ESI) calcd for C28H25N3O4Na [M+Na]+:
490.1743; found: 490.1735. IR (KBr) 3339, 3059, 3026, 2935,
4.4.4. (5R,11aS)-2-Benzyl-5-(3-hydroxyphenyl)-6H-1,2,3,5,11,11a-
hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione 1d
1765, 1704, 1511, 1454, 1272, 1129, 747, 701 cmꢂ1
.
Mp 151–152 °C (lit.38 150–151 °C). ½a 2D0
¼ ꢂ162:5 (c 0.8, CHCl3)
ꢁ
{lit.38
½
a 2D0
ꢁ
¼ ꢂ162:6 (c 0.9, CHCl3)}. 1H NMR (DMSO-d6) d 2.82 (dd,
4.4.8. (5R,11aS)-2-Isopropyl-5-(3,4-dihydroxyphenyl)-6H-
J1 = 14.1 Hz, J2 = 11.3 Hz, 1H), 3.40 (dd, J1 = 15.1 Hz, J2 = 5.7 Hz, 1H),
4.56–4.63 (m, 3H), 6.14 (s, 1H), 6.70 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H),
6.77 (d, J = 7.7 Hz, 1H), 7.01 (dd, J1 = 7.2 Hz, J2 = 7.6 Hz, 1H), 7.09
(dd, J1 = 7.5 Hz, J2 = 7.6 Hz, 1H), 7.15 (dd, J1 = 7.6 Hz, J2 = 7.7 Hz, 1H),
7.22–7.34 (m, 6H), 7.54 (d, J = 7.8 Hz, 1H), 9.46 (s, 1H), 10.94 (s, 1H).
13C NMR (DMSO-d6) d 172.5, 157.7, 154.1, 141.4, 136.7, 136.6,
131.2, 129.8, 128.61, 128.60, 127.47, 127.42, 127.41, 125.8, 121.7,
118.9, 118.5, 118.2, 115.2, 114.9, 111.4, 106.0, 53.0, 51.6, 41.5, 22.8.
MS (EI) m/z (%) 423 (M+, 100), 422 (10), 345 (2), 332 (28), 261 (29),
234 (25), 218 (9), 206 (4), 169 (4), 115 (2). IR (KBr) 3411, 2980,
1765, 1703, 1602, 1453, 1240, 1142, 749, 702 cmꢂ1. HRMS (EI) calcd
for C26H21N3O3: 423.1583; found: 423.1579.
1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione 1h
Mp 94–95 °C. ½a 2D0
ꢁ
¼ ꢂ192:5 (c 0.6, CHCl3). 1H NMR (CDCl3) d
1.32 (d, J = 6.9 Hz, 3H), 1.33 (d, J = 6.9 Hz, 3H), 2.73 (dd,
J1 = 14.3 Hz, J2 = 11.5 Hz, 1H), 3.32 (dd, J1 = 15.2 Hz, J2 = 5.5 Hz,
1H), 4.15 (dd, J1 = 10.6 Hz, J2 = 5.3 Hz, 1H), 4.20–4.32 (m, 1H),
6.00 (s, 1H), 6.54 (dd, J1 = 8.1 Hz, J2 = 1.4 Hz, 1H), 6.65 (d,
J = 8.1 Hz, 1H), 6.76 (s, 2H), 6.92 (s, 1H), 7.06–7.17 (m, 2H), 7.20
(d, J = 7.4 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H), 8.34 (s, 1H). 13C NMR
(CDCl3) d 173.3, 155.2, 144.4, 144.2, 136.6, 131.8, 130.7, 126.0,
122.7, 120.5, 119.9, 118.4, 115.8, 115.4, 111.3, 107.2, 53.0, 51.8,
44.1, 23.2, 19.7, 19.6. HRMS (ESI) calcd for
[M+Na]+: 414.1430; found: 414.1431. IR (KBr) 3351, 2976, 2934,
1758, 1696, 1435, 1391, 1283, 1110, 745, 688 cmꢂ1
C22H21N3O4Na
.
4.4.5. (5R,11aS)-2-Isopropyl-5-(3-hydroxy-4-methoxyphenyl)-
6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-
dione 1e
4.4.9. (5R,11aS)-2-(5-Azido-pentyl)-5-(3-hydroxyphenyl)-6H-
1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione 1i
Mp 221–222 °C. ½a D20
ꢁ
¼ ꢂ231:9 (c 0.6, CHCl3). 1H NMR (CDCl3) d
Mp 127–128 °C (lit.38 127–128 °C). ½a 2D0
¼ ꢂ204:6 (c 0.3, CHCl3)
ꢁ
1.39 (d, J = 6.9 Hz, 3H), 1.40 (d, J = 6.9 Hz, 3H), 2.79 (dd, J1 = 15.3 Hz,
J2 = 11.0 Hz, 1H), 3.39 (dd, J1 = 15.3 Hz, J2 = 5.6 Hz, 1H), 3.79 (s, 3H),
4.17 (dd, J1 = 11.0 Hz, J2 = 5.6 Hz, 1H), 4.24–4.37 (m, 1H), 5.78 (s,
1H), 6.12 (s, 1H), 6.72–6.80 (m, 2H), 6.83 (dd, J1 = 8.2 Hz,
J2 = 1.7 Hz, 1H), 7.11–7.23 (m, 2H), 7.26 (d, J = 7.3 Hz, 1H), 7.53
(d, J = 7.5 Hz, 1H), 8.20 (s, 1H). 13C NMR (DMSO-d6) d 172.4,
153.8, 147.6, 146.6, 136.6, 132.7, 131.5, 125.8, 121.6, 118.8,
118.1, 115.2, 112.4, 111.3, 105.9, 55.7, 52.1, 51.0, 42.7, 22.8, 19.5,
19.4. MS (EI) m/z (%) 405 (M+, 100), 388 (8), 374 (9), 362 (6), 291
(12), 265 (14), 234 (15), 204 (7), 169 (7), 115 (2). IR (KBr) 3335,
2965, 2930, 1758, 1703, 1430, 1278, 1127, 805, 729 cmꢂ1. Anal.
Calcd for C23H23N3O4: C, 68.13; H, 5.72; N, 10.36. Found: C,
67.94; H, 5.74; N, 10.51.
{lit.38
½
a 2D0
ꢁ
¼ ꢂ204:8 (c 0.2, CHCl3)}. 1H NMR (DMSO-d6) d 1.23–
1.31 (m, 2H), 1.49–1.57 (m, 4H), 2.80 (dd, J1 = 14.0 Hz,
J2 = 11.2 Hz, 1H), 3.28 (t, J = 6.9 Hz, 2H), 3.34–3.43 (m, 3H), 4.48
(dd, J1 = 10.8 Hz, J2 = 5.7 Hz, 1H), 6.12 (s, 1H), 6.71 (d, J = 7.0 Hz,
1H), 6.72 (s, 1H), 6.77 (d, J = 7.7 Hz, 1H), 7.01 (dd, J1 = 7.5 Hz,
J2 = 7.3 Hz, 1H), 7.09 (dd, J1 = 7.2 Hz, J2 = 7.4 Hz, 1H), 7.15 (dd,
J1 = 8.0 Hz, J2 = 8.3 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.53 (d,
J = 7.6 Hz, 1H), 9.46 (br s, 1H), 10.93 (br s, 1H). 13C NMR (DMSO-
d6) d 172.6, 157.7, 154.3, 141.4, 136.7, 131.2, 129.8, 125.8, 121.7,
118.9, 118.5, 118.2, 115.1, 114.8, 111.4, 106.0, 52.8, 51.4, 50.5,
37.8, 27.8, 27.1, 23.3, 22.8. MS (EI) m/z (%) 444 (M+, 31), 416
(41), 386 (13), 372 (11), 358 (22), 345 (5), 332 (12), 304 (4), 294
(22), 287 (11), 274 (3), 261 (100), 246 (5), 234 (41), 218 (15),
206 (12), 195 (3), 169 (13), 115 (4), 105 (4), 84 (5), 70 (7). IR
(KBr) 3328, 2936, 2861, 2096, 1766, 1702, 1589, 1459, 1356,
1327, 1239, 1141, 749 cmꢂ1. HRMS (EI) calcd for C24H24N6O3:
444.1910; found: 444.1913.
4.4.6. (5R,11aS)-2-(5-Azido-pentyl)-5-(3-hydroxy-4-methoxy-
phenyl)-6H-1,2,3,5, 11,11a-hexahydro-imidazo[1,5-b]-b-
carboline-1,3-dione 1f
Mp 98–99 °C. ½a 2D0
ꢁ
¼ ꢂ205:4 (c 0.8, CHCl3). 1H NMR (CDCl3) d
1.30–1.41 (m, 2H), 1.52–1.68 (m, 4H), 2.81 (dd, J1 = 15.1 Hz,
J2 = 11.1 Hz, 1H), 3.22 (t, J = 6.9 Hz, 2H), 3.35–3.56 (m, 3H), 3.79
(s, 3H). 4.24 (dd, J1 = 11.0 Hz, J2 = 5.5 Hz, 1H), 5.80 (s, 1H), 6.14 (s,
1H), 6.71–6.79 (m, 2H), 6.82 (dd, J1 = 8.2 Hz, J2 = 1.9 Hz, 1H),
7.12–7.24 (m, 2H), 7.27 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 7.4 Hz, 1H),
4.4.10. (5R,11aS)-2-Isopropyl-5-(3-hydroxyphenyl)-6H-
1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
1j
Mp 177–178 °C. ½a D20
ꢁ
¼ ꢂ223:8 (c 0.8, CHCl3). 1H NMR (DMSO-
d6) d 1.33 (d, J = 6.9 Hz, 3H), 1.34 (d, J = 6.9 Hz, 3H), 2.80 (ddd,

1872
J. Dong et al. / Tetrahedron: Asymmetry 22 (2011) 1865–1873
J1 = 15.0 Hz, J2 = 10.9 Hz, J3 = 1.3 Hz, 1H), 3.30–3.43 (m, 1H), 4.15–
4.28 (m, 1H), 4.43 (dd, J1 = 10.9 Hz, J2 = 5.7 Hz, 1H), 6.13 (s, 1H),
6.71–6.76 (m, 2H), 6.79 (d, J = 7.6 Hz, 1H), 7.03 (dd, J1 = 7.6 Hz,
J2 = 7.5 Hz, 1H), 7.10 (dd, J1 = 7.6 Hz, J2 = 7.5 Hz, 1H), 7.17 (dd,
J1 = 8.1 Hz, J2 = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.54 (d,
J = 7.7 Hz, 1H), 9.48 (s, 1H) 10.93 (s, 1H). 13C NMR (DMSO-d6) d
172.4, 157.6, 154.0, 141.4, 136.6, 131.2, 129.8, 125.8, 121.6,
118.8, 118.5, 118.1, 115.1, 114.8, 111.4, 105.9, 52.2, 51.3, 42.7,
22.7, 19.5, 19.4. MS (EI) m/z (%) 375 (M+, 100), 332 (4), 282 (23),
261 (22), 234 (46), 218 (15), 169 (14), 115 (4). IR (KBr) 3344,
2979, 1758, 1689, 1435, 1235, 747, 712 cmꢂ1. Anal. Calcd for
Calcd for C24H25N3O4: C, 68.72; H, 6.01; N, 10.02. Found: C,
68.81; H, 5.98; N, 10.22.
4.4.14. (5R,11aS)-2-Hydroxyethyl-5-(3-hydroxy-4-
methoxyphenyl)-6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-
b-carboline-1,3-dione 1n
Mp 228–229 °C. ½a D20
ꢁ
¼ ꢂ230:7 (c 1.0, CH3OH). 1H NMR (DMSO-
d6) d 2.83 (dd, J1 = 14.1 Hz, J2 = 11.2 Hz, 1H), 3.41 (dd, J1 = 11.2 Hz,
J2 = 5.7 Hz, 1H), 3.42–3.60 (m, 4H), 3.75 (s, 3H), 4.41 (dd,
J1 = 10.8 Hz, J2 = 5.7 Hz, 1H), 4.81 (dd, J1 =5.6 Hz, J2 = 5.5 Hz, 1H),
6.06 (s, 1H), 6.71–6.82 (m, 2H), 6.91 (d, J = 8.3 Hz, 1H), 7.03 (dd,
J1 = 7.7 Hz, J2 = 7.1 Hz, 1H), 7.11 (dd, J1 = 7.7 Hz, J2 = 7.1 Hz, 1H),
7.32 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 9.06 (s, 1H), 10.91
(s, 1H). 13C NMR (DMSO-d6) d 172.8, 154.3, 147.6, 146.6, 136.6,
132.7, 131.5, 125.8, 121.6, 118.8, 118.1, 115.2, 112.3, 111.3,
106.0, 57.6, 55.7, 52.6, 51.0, 40.9, 22.6. MS (EI) m/z (%) 407 (M+,
100), 390 (6), 376 (8), 291 (11), 284 (12), 264 (12), 234 (11), 204
(7), 169 (7), 115 (2). IR (KBr) 3308, 2976, 2845, 1766, 1704,
1511, 1451, 1274, 1233, 1122, 1017, 750, 657, 610 cmꢂ1. Anal.
Calcd for C22H21N3O5: C, 64.86; H, 5.20; N, 10.31. Found: C,
64.77; H, 5.34; N, 10.15.
C22H21N3O3: C, 70.38; H, 5.64; N, 11.19. Found: C, 70.51; H, 5.60;
N, 11.28.
4.4.11. (5R,11aS)-2-Phenethyl-5-(3-hydroxyphenyl)-6H-
1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
1k
Mp 107–108 °C. ½a D20
ꢁ
¼ ꢂ213:1 (c 0.4, CHCl3). 1H NMR (DMSO-
d6) d 2.67 (ddd, J1 = 15.0 Hz, J2 = 10.9 Hz, J3 = 1.3 Hz, 1H), 2.81–
2.95 (m, 2H), 3.31 (dd, J1 = 15.0 Hz, J2 = 5.7 Hz, 1H), 3.65 (dd,
J1 = 7.4 Hz, J2 = 7.3 Hz, 2H), 4.38 (dd, J1 = 10.9 Hz, J2 = 5.7 Hz, 1H),
6.13 (s, 1H), 6.70–6.80 (m, 3H), 7.02 (dd, J1 = 7.6 Hz, J2 = 7.7 Hz,
1H), 7.06–7.24 (m, 7H), 7.31 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz,
1H), 9.47 (s, 1H), 10.95 (s, 1H). 13C NMR (DMSO-d6) d 172.2,
157.6, 154.0, 141.2, 138.0, 136.6, 131.1, 129.7, 128.65, 128.64,
128.30, 128.31, 126.4, 125.7, 121.6, 118.8, 118.4, 118.2, 115.0,
114.7, 111.4, 106.0, 52.6, 51.3, 39.2, 33.1, 22.6. MS (EI) m/z (%)
437 (M+, 100), 420 (2), 408 (1), 359 (2), 344 (15), 261 (13), 247
(7), 234 (25), 218 (8), 169 (7), 104 (2), 91 (4). IR (KBr) 3328,
2929, 1765, 1700, 1599, 1455, 1238, 1135, 747, 701 cmꢂ1. Anal.
Calcd for C27H23N3O3: C, 74.12; H, 5.30; N, 9.60. Found: C, 74.23;
H, 5.34; N, 9.85.
4.4.15. (5R,11aS)-2-Benzyl-5-(3-hydroxy-4-methoxyphenyl)-6H-
1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
1o
Mp 121–122 °C. ½a D20
ꢁ
¼ ꢂ191:3 (c 1.2, CHCl3). 1H NMR (CDCl3) d
2.70 (ddd, J1 = 15.2 Hz, J2 = 11.1 Hz, J3 = 1.6 Hz, 1H), 3.35 (dd,
J1 = 15.2 Hz, J2 = 5.6 Hz, 1H), 3.75 (s, 3H), 4.23 (dd, J1 = 11.1 Hz,
J2 = 5.6 Hz, 1H), 4.53 (d, J = 14.6 Hz, 1H), 4.66 (d, J = 14.6 Hz, 1H),
5.82 (s, 1H), 6.10 (s, 1H), 6.70 (d, J = 8.3 Hz, 1H), 6.73 (d,
J = 2.1 Hz, 1H), 6.80 (dd, J1 = 8.2 Hz, J2 = 2.1 Hz, 1H), 7.08–7.30 (m,
6H), 7.33–7.39 (m, 2H), 7.43–7.50 (m, 1H), 8.21 (s, 1H). 13C NMR
(CDCl3) d 172.7, 154.6, 147.1, 145.9, 136.7, 136.1, 132.4, 130.7,
128.74, 128.73, 128.64, 128.63, 128.0, 126.1, 122.6, 120.2, 119.9,
118.4, 114.4, 111.3, 110.9, 107.4, 55.9, 53.3, 51.7, 42.3, 23.2. HRMS
(ESI) calcd for C27H23N3O4Na [M+Na]+: 476.1586; found: 476.1581.
IR (KBr) 3341, 3060, 3032, 2931, 2843, 1767, 1706, 1511, 1445,
4.4.12. (5R,11aS)-2-Propyl-5-(3-hydroxy-4-methoxyphenyl)-6H-
1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
1l
Mp 127–128 °C. ½a D20
ꢁ
¼ ꢂ223:7 (c 0.6, CHCl3). 1H NMR (CDCl3) d
1128, 749, 698 cmꢂ1
.
0.88 (t, J = 7.4 Hz, 3H), 1.52–1.70 (m, 2H), 2.80 (dd, J1 = 14.6 Hz,
J2 = 11.6 Hz, 1H), 3.32–3.51 (m, 3H), 3.77 (s, 3H), 4.21 (dd,
J1 = 11.0 Hz, J2 = 5.5 Hz, 1H), 5.83 (s, 1H), 6.12 (s, 1H), 6.69–6.77
(m, 2H), 6.80 (d, J = 8.2 Hz, 1H), 7.11–7.23 (m, 2H), 7.26 (d,
J = 7.8 Hz, 1H), 7.52 (d, J = 7.5 Hz, 1H), 8.34 (s, 1H). 13C NMR (CDCl3)
d 173.2, 154.9, 147.0, 145.8, 136.7, 132.5, 130.9, 126.1, 122.6,
120.1, 119.9, 118.4, 114.4, 111.3, 110.9, 107.4, 55.8, 53.2, 51.6,
40.3, 23.4, 21.5, 11.2. MS (EI) m/z (%) 405 (M+, 100), 388 (8), 374
(10), 282 (15), 264 (14), 234 (15), 204 (7), 169 (8), 115 (2). IR
(KBr) 3341, 2934, 2963, 1765, 1702, 1511, 1454, 1273, 1126,
744 cmꢂ1. Anal. Calcd for C23H23N3O4: C, 68.13; H, 5.72; N, 10.36.
Found: C, 68.23; H, 5.91; N, 10.18.
4.4.16. (5R,11aS)-2-(5-Azido-pentyl)-5-(3,4-dihydroxyphenyl)-
6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-
dione 1p
Mp 152–153 °C. ½a D20
ꢁ
¼ ꢂ180:9 (c 0.6, CH3OH). 1H NMR (DMSO-
d6) d 1.21–1.35 (m, 2H), 1.44–1.60 (m, 4H), 2.79 (dd, J1 = 12.1 Hz,
J2 = 10.5 Hz, 1H), 3.22–3.50 (m, 5H), 4.43 (dd, J1 = 10.5 Hz,
J2 = 5.6 Hz, 1H), 6.07 (s, 1H), 6.59 (d, J = 7.7 Hz, 1H), 6.70 (s, 1H),
6.71 (d, J = 7.9 Hz, 1H), 7.02 (dd, J1 = 7.4 Hz, J2 = 7.2 Hz, 1H), 7.09
(dd, J1 = 7.6 Hz, J2 = 7.2 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.53 (d,
J = 7.6 Hz, 1H), 8.95 (s, 1H), 8.96 (s, 1H), 10.92 (s, 1H). 13C NMR
(DMSO-d6) d 172.6, 154.0, 145.4, 145.2, 136.6, 131.7, 131.0,
125.8, 121.5, 118.9, 118.7, 118.1, 115.6, 115.2, 111.3, 105.9, 52.5,
51.1, 50.4, 37.7, 27.7, 27.1, 23.3, 22.8. HRMS (ESI) calcd for
4.4.13. (5R,11aS)-2-Butyl-5-(3-hydroxy-4-methoxyphenyl)-6H-
1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
C
24H24N6O4Na [M+Na]+: 483.1757; found: 483.1757. IR (KBr)
3334, 2932, 2857, 2097, 1761, 1696, 1455, 1426, 1282, 1114,
746, 697 cmꢂ1
1m
Mp 119–120 °C. ½a D20
ꢁ
¼ ꢂ226:9 (c 0.7, CHCl3). 1H NMR (CDCl3) d
.
0.91 (t, J = 7.3 Hz, 3H), 1.26–1.37 (m, 2H), 1.54–1.65 (m, 2H), 2.83
(ddd, J1 = 15.2 Hz, J2 = 11.0 Hz, J3 = 1.7 Hz, 1H), 3.41–3.57 (m, 3H),
3.82 (s, 3H), 4.25 (dd, J1 = 11.0 Hz, J2 = 5.5 Hz, 1H), 5.70 (s, 1H),
6.17 (s, 1H), 6.75–6.82 (m, 2H), 6.85 (dd, J1 = 8.2 Hz, J2 = 2.1 Hz,
1H), 7.13–7.24 (m, 2H), 7.28 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 7.5 Hz,
1H), 8.08 (s, 1H). 13C NMR (CDCl3) d 173.1, 154.9, 147.0, 145.8,
136.7, 132.5, 130.9, 126.1, 122.6, 120.1, 119.9, 118.4, 114.4,
111.3, 110.9, 107.4, 55.9, 53.2, 51.6, 38.6, 30.2, 23.4, 20.0, 13.6.
MS (EI) m/z (%) 419 (M+, 100), 402 (10), 388 (11), 296 (14), 265
(13), 250 (10), 234 (12), 204 (5), 169 (6), 115 (1). IR (KBr) 3342,
2956, 2931, 1764, 1702, 1511, 1454, 1273, 1127, 744 cmꢂ1. Anal.
4.4.17. (5R,11aS)-2-Hydroxyethyl-5-(3,4-dihydroxyphenyl)-6H-
1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
1q
Mp 242–243 °C. ½a D20
ꢁ
¼ ꢂ219:6 (c 0.5, CH3OH). 1H NMR (DMSO-
d6) d 2.83 (dd, J1 = 14.1 Hz, J2 = 11.2 Hz, 1H), 3.30–3.40 (m, 1H),
3.42–3.58 (m, 4H), 4.41 (dd, J1 = 10.8 Hz, J2 = 5.7 Hz, 1H), 4.81
(dd, J1 = 5.3 Hz, J2 = 5.5 Hz, 1H), 6.06 (s, 1H), 6.59 (dd, J1 = 8.1 Hz,
J2 = 1.9 Hz, 1H), 6.65–6.75 (m, 2H), 7.02 (t, J = 7.3 Hz, 1H), 7.09 (t,
J = 7.3 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H),
8.94 (s, 1H), 8.96 (s, 1H), 10.90 (s, 1H). 13C NMR (DMSO-d6) d

J. Dong et al. / Tetrahedron: Asymmetry 22 (2011) 1865–1873
1873
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20, 1491.
172.8, 154.2, 145.3, 145.2, 136.6, 131.7, 131.0, 125.8, 121.6, 119.0,
118.7, 118.1, 115.6, 115.3, 111.3, 105.9, 57.6, 52.4, 51.0, 40.8, 22.7.
HRMS (ESI) calcd for C21H19N3O5Na [M+Na]+: 416.1222; found:
416.1228. IR (KBr) 3642, 3274, 1758, 1697, 1519, 1457, 1391,
1286, 1031, 761, 654 cmꢂ1
.
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4.4.18. (5R,11aS)-2-Benzyl-5-(3,4-dihydroxyphenyl)-6H-
1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
1r
Mp 118–119 °C. ½a D20
ꢁ
¼ ꢂ179:0 (c 0.6, CHCl3). 1H NMR (DMSO-
25. Lahue, B. R.; Ma, Y.; Shipps, G. W., Jr.; Seghezzi, W.; Herbst, R. Bioorg. Med.
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d6) d 2.81 (dd, J1 = 14.1 Hz, J2 = 11.5 Hz, 1H), 3.35–3.50 (m, 1H),
4.55 (dd, J1 = 10.8 Hz, J2 = 5.7 Hz, 1H), 4.61 (s, 2H), 6.11 (s, 1H),
6.61 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 6.73 (s, 1H), 7.02
(dd, J1 = 7.5 Hz, J2 = 7.4 Hz, 1H), 7.10 (dd, J1 = 7.5 Hz, J2 = 7.4 Hz,
1H), 7.20–7.38 (m, 6H), 7.54 (d, J = 7.7 Hz, 1H), 8.97 (s, 2H), 10.93
(s, 1H). 13C NMR (DMSO-d6) d 172.5, 153.9, 145.5, 145.3, 136.6,
136.6, 131.7, 130.9, 128.55, 128.54, 127.4, 127.35, 127.34, 125.8,
121.6, 119.0, 118.8, 118.1, 115.6, 115.3, 111.4, 105.8, 52.7, 51.2,
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W.; Davide, J. P.; Diehl, R. E.; Abrams, M. T.; South, V. J.; Huber, H. E.; Torrent,
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41.4, 22.8. HRMS (ESI) calcd for
C
26H21N3O4Na [M+Na]+:
462.1430; found: 462.1431. IR (KBr) 3353, 3061, 3033, 2930,
1763, 1700, 1451, 1329, 1284, 1237, 748, 698 cmꢂ1
.
30. DeBonis, S.; Skoufias, D. A.; Indorato, R.-L.; Liger, F.; Marquet, B.; Laggner, C.;
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33. Rowinski, E. K.; Chaudhry, V.; Cornblath, D. R.; Donehower, R. C. J. Natl. Cancer
Inst. 1993, 15, 107.
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Acknowledgements
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. T. H. Trieu would like to thank the Ministry of Educa-
tion and Training, Vietnam.
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