Toward breast cancer resistance protein (BCRP) inhibitors: design, synthesis of a series of new simplified fumitremorgin C analogues

Article abstract of DOI:10.1016/j.tet.2007.04.045

In this study, we report the design and synthesis of a series of new simplified fumitremorgin C analogues. The preliminary biological study indicated some of these simplified fumitremorgin C might be developed into breast cancer resistance inhibitors.

Full text of DOI:10.1016/j.tet.2007.04.045

Tetrahedron 63 (2007) 5510–5528
Toward breast cancer resistance protein (BCRP) inhibitors:
design, synthesis of a series of new simplified
fumitremorgin C analogues
a
Guofeng Wu,a Jiawang Liu,a Lanrong Bi,b Ming Zhao,b, Chao Wang,
*
d
Michele Baudy-Floc’h, Jingfang Ju and Shiqi Peng
c,
b,
*
*
ꢀ
aCollege of Pharmaceutical Sciences, Peking University, Beijing 100083, PR China
bCollege of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China
cMitchell Cancer Institute, University of South Alabama, 307 N. University Blvd, Mobile, AL 36688-0002, USA
d
´
´ ´
UMR 6226 CNRS, Groupe ‘Ciblage et Autoassemblages Fonctionnels’, Universite de Rennes I, 263 Av. du General Leclerc,
F-35042 Rennes Cedex, France
Received 16 October 2006; revised 6 April 2007; accepted 12 April 2007
Available online 19 April 2007
Abstract—In this study, we report the design and synthesis of a series of new simplified fumitremorgin C analogues. The preliminary bio-
logical study indicated some of these simplified fumitremorgin C might be developed into breast cancer resistance inhibitors.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
with that of Pgp, suggesting that BCRP has a similar role to
Pgp in the pharmacokinetics of substrate drugs.4 BCRP is
able to transport Pgp substrates and is not inhibited by Pgp
chemosensitizers such as calcium channel blockers, cardio-
vascular drugs, and immunosuppressors. Besides an overlap
in substrate specificity, there may also be an overlap in mod-
ulating activity, illustrated, for example, by ‘dual specificity
inhibitor’ GF 120918.5 In addition, BCRP is able to efflux
a broad range of anti-cancer drugs through cellular mem-
brane, thus limiting their anti-proliferative effects.6,7
Chemoresistance is one of the major obstacles in cancer che-
motherapy due to intrinsic or acquired drug resistance. A
broad-spectrum resistance to structurally and mechanisti-
cally diverse antitumor agents is known as multidrug resis-
tance (MDR). The multidrug resistance phenotype is often
associated with overexpression of members of the ATP-bind-
ing cassette (ABC) transporter family proteins. They are
plasma membrane proteins that can actively extrude a wide
variety of structurally diverse xenobiotic agents, thereby
reducing intracellular drug concentrations.1 P-glycoprotein
(Pgp) and multidrug resistance-associated protein (MRP)
are two of the most extensively studied ABC transporters.
Breast cancer resistance protein (BCRP) is an additional
member of the ABC transporter family. BCRP has been
shown to have awell-defined role in the transport of clinically
relevant drugs and mediate cellular resistance to these drugs
in vitro.2 Similar to Pgp, BCRP localizes primarily on the
plasma membrane, in accordance with its capacity to effi-
ciently efflux drug substrates from the cell.3 Furthermore,
the substrate specificity of BCRP overlaps considerably
More recently, it has become apparent that the BCRP is
potentially an important mediator of multidrug resistance.8
Inhibitors of BCRP could be used not only to reverse
MDR mediated by this transporter but also to alter the
pharmacokinetics of BCRP substrate drugs, including their
intestinal absorption, biliary excretion, and brain penetra-
tion, causing either beneficial or adverse drug interactions.9
In this context and in order to overcome BCRP-mediated
multidrug resistance, BCRP-specific inhibitors are highly
desired.10,11
Several BCRP-specific inhibitors have been reported in the
past decade. Such inhibitors include the antifungal agent,
fumitremorgin C (FTC), GF120918, imatinib mesylate
(Gleevec), Ko132, Ko134, and so on (Fig. 1). FTC, a member
of a group of indole alkaloids, is a selective inhibitor of
the breast cancer resistance protein (BCRP/ABCG2).12–14
However, this natural product of fungal origin also has
Keywords: Fumitremorgin C analogues; Breast cancer resistance protein
inhibitors; Enantioselective synthesis; Racemization; Coupling.
* Corresponding authors. Mitchell Cancer Institute, University of South
Alabama, 307 N. University Blvd, Mobile, AL 36688-0002, USA. Tel.:
+1 251 460 7393; fax: +1 251 460 6994 (J.J.); tel./fax: +86 10 8280
2482 (M.Z.); tel./fax: +86 10 8391 1528 (S.P.); e-mail addresses: jju@
usouthal.edu; sqpeng@bjmu.edu.cn
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.045

G. Wu et al. / Tetrahedron 63 (2007) 5510–5528
5511
N
N
O
12
N
A
E
C
B
D
18
MeO
N
O
6
N
Me
N
3
H
O
N
H
N
H
N
N
Fumitremorgin C
O
Gleevec
O
O
NH
O
NH
N
N
N
HN
O
N
H
H
O
O
O
Ko132
Ko134
O
OMe
OMe
N
H
N
OMe
O
N
H
GF120918
Figure 1. Structure of some known BCRP inhibitors.
tumor-inducing activity and causes cell cycle arrest at the
G2/M transition.15,16 To improve the specificity and selectiv-
ity of FTC while eliminating the potential for toxicity, we
have designed and synthesized a new class of FTC simplified
structural analogues. Compared with the native pentacyclic
FTC, the new simplified FTC analogues developed in this
study retain the tetracyclic core of FTC. This is similar to
the other FTC analogues, i.e., Ko132 and Ko134, all lack
the E ring derived from L-proline. In addition, the methoxy
group at C-18 in the indole moiety was omitted.
reported the preparation of fumitremorgina analogues using
a solid phase synthesis.18 This approach inevitably led to the
compounds formed as a mixture of four diastereoisomers,
which is due to the fact that two diastereoisomers are formed
in the Pictet–Spengler condensation and that racemization of
the stereogenic center of the finally introduced building
block did occur during the coupling of the activated Fmoc-
amino acid. A simple and efficient route toward diastereo-
pure fumitremorgin analogues is of great importance for
construction of the molecular libraries. Through the screen-
ing of these new diastereopure fumitremorgin analogues, we
will further investigate the accurate structure–activity rela-
tionship information to facilitate the discovery of effective
BCRP inhibitors. In this study, we report a concise and
efficient synthetic route to generate a series of new diaste-
reopure FTC simplified structural analogues and some
preliminary biological study result.
It was reported that the replacement of the proline moiety (E
ring) by acyclic substituent might allow the adjacent diketo-
piperazine ring to assume a different conformation that
renders the analogues less neurotoxic than native FTC.16
Therefore, our efforts in this study are mainly focused on ex-
ploring the influence of C-6 substituents on their biological
activities. Herein, we report the synthesis of these simplified
FTC analogues in a concise and efficient method and some
preliminary biological results.
Fumitremorgin analogues belong to the class of indolyl dike-
topiperazine alkaloids, which contains the 1,4-dioxo-2,3,6,
7,12,12a-hexahydropyrazino[10,20:1,6]pyrido[3,4-b]indoles
skeleton (Fig. 2). One of the most straightforward ways for
construction of the key skeleton is based on the Pictet–
Spengler reaction, which involves the acid-catalyzed intra-
molecular condensation between an iminium ion and an
aromatic C-nucleophile. The main advantage of this reaction
is the formation of a product with a stable C–C bond in a
single step.
2. Results and discussion
A large number of synthetic fumitremorgin analogues are
marked as racemic mixtures. Since it is nearly always the
case that only one enantiomer has the desired effect, the
elimination of the other enantiomer with undesirable effects
has a number of clinical advantages including improvement
in pharmacological profile and simplified pharmacokinetics.
The lack of an efficient stereoselective synthetic route to
fumitremorgin analogues is one of the main reasons that
most of biological studies are usually carried out with diaste-
reomeric mixtures of fumitremorgin analogues. For instance,
Koomen et al. reported the BCRP inhibitory assay using
a panel of 42 diastereomeric mixtures of fumitremorgin
analogues17. More specifically, Koomen et al. previously
Starting from optically pure L-tryptophan, compound 1 was
readily obtained by treating it with formaldehyde using 5%
TFA as catalyst (75% yield). With the available tetrahydro-
b-carboline derivative 1, we next constructed the diketo-
piperazine ring of fumitremorgin analogues, which can be
created from the amino acid coupling followed by intra-
molecular cyclization. Apparently, the chiral amino acid side
chains can be installed from either the C-terminal or the

5512
G. Wu et al. / Tetrahedron 63 (2007) 5510–5528
O
O
remained difficult. More favorable condition for the hin-
dered secondary amide bond formation was [2-bromopyr-
idinium salt (1.1 equiv)/DIEA (3.2 equiv)/CH2Cl2 (3–5 ml/
mmol)], stirred for 1 min at 0 ꢀC and then for 1 h at room
temperature.22 Moreover, we further tested the generality
of the pyridinium-type coupling methodology. When differ-
ent amino acid side chains were introduced to tetrahydro-
b-carboline system, the key intermediates corresponding to
products 3a–t (84–88% yield) were obtained with excellent
purity and diastereoselectivity, suggesting that the coupling
methodology is applicable to a range of natural amino acid
residues at this sterically demanding position.
NH
N
N
H
Figure 2. The skeleton of 1,4-dioxo-2,3,6,7,12,12a-hexahydropyrazino-
[10,20:1,6]pyrido[3,4-b]indoles.
N-terminal. We therefore investigated two different syn-
thetic routes to discover the optimal conditions. In the first
approach (Scheme 1), compound 1 was easily transformed
into its methylester 2 (92% yield) under the treatment of
SOCl2/MeOH at the room temperature. However, subse-
quent coupling of the resulting 2 with protected amino acids
remained elusive under various conditions, despite the use of
PyBrop,19 PyBrop/HOAt,20 and HATU,21 particularly effec-
tive reagents for the coupling of sterically demanding com-
ponents. These reagents resulted in high racemization during
coupling and with very low yield, probably due to severe ste-
ric restrictions, acylation of the secondary amine of tetra-
hydro-b-carbolines obtained from Pictet–Spengler reaction
Next, Boc deprotection and subsequent intramolecular cycli-
zation of 3a–t were carried out in a one-pot reaction at room
temperature. Reaction times for this step depend on the
amino acid residues being attached on the diketopiperazine
unit. After chromatography purification, the desired products
4a–t were obtained in good yields and high diastereopurity.
An alternative coupling approach was also investigated. As
shown in Scheme 2, tetrahydro-b-carboline derivative 2
O
O
H
H
O
H
N
ii
OCH3
OH
OCH3
iii
NHBoc
NH
NH
N
H
N
H
N
H
2
R
1
3a-t
O
O
O
H
i
iv
H
N
OH
NH
R
NH2
N
H
N
H
4a-t
O
No 3 (% Yield) 4 (% Yield)
a
93
93
87
93
90
87
92
93
91
91
92
92
89
88
95
92
86
91
87
88
96
96
92
89
96
91
90
91
90
85
93
91
90
90
95
87
93
91
87
98
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
t
Scheme 1. Synthetic route to 4a–t via approach A. Reagents: (i) formaldehyde and TFA, 75% yield; (ii) methanol and thionyl chloride, rt, 92% yield; (iii) Boc-
L-amino acid, BEP, DIEA; (iv) HCl in ethyl acetate (4 mol/l); 3a and 4a R¼CH3; 3b and 4b R¼CH2C6H5; 3c and 4c R¼CH(CH3)2; 3d and 4d R¼CH2OH; 3e
and 4e R¼CH(OH)CH3; 3f and 4f R¼CH2C6H4–OH-p; 3g and 4g R¼tetrahydropyrrol-2-yl; 3h and 4h R¼CH2SH; 3i and 4i R¼CH2CH2SCH3; 3j
R¼CH2CH2CO2CH3, 4j R¼CH2CH2CO2H; 3k R¼CH2CO2CH3, 4k R¼CH2CO2H; 3l and 4l R¼1,3-imidazol-5-methylene; 3m and 4m R¼indol-3-methyl-
ene; 3n and 4n R¼CH2(CH2)2NHC(NH2)]NH, 3o and 4o R¼H; 3p R¼CH2(CH2)3NHZ, 4p R¼CH2(CH2)3NH2; (After cyclization a colorless powder of
922 mg (2.0 mmol) of the product was mixed with 50 mg of Pd/C (5%) and 25 ml of formic acid in methanol (4.4%), and agitated with hydrogen at room tem-
perature for 24 h. The reaction mixture was filtrated and evaporated to give 4p as colorless powder.) 3q and 4q R¼CH2CH2CONH2; 3r and 4r R¼CH2CONH2;
3s and 4s R¼CH2CH(CH3)2; 3t and 4t R¼CH(CH3)CH2CH3.

G. Wu et al. / Tetrahedron 63 (2007) 5510–5528
5513
R
O
H
O
NH
O
H
H
CO2CH3
OH
i, ii
OH
iii
NBoc
R
NH2
NBoc
N
H
N
H
N
H
5
6a-t
R
iv
O
O
H
O
H
H
N
NH
CO2H
NH
CO2H
NH
vi
v
NH
NBoc
N
H
N
H
R
N
4a-t
8a-t
O
7a-t
H
No
a
b
c
d
e
f
6 (% Yield)
96
7 (% Yield)
79
8 (% Yield)
94
4 (% Yield)
90
98
94
95
95
95
71
95
85
92
84
89
85
92
78
88
92
93
67
89
90
g
h
i
97
83
94
87
92
78
92
86
97
72
90
85
j
93
76
92
85
k
l
90
72
92
85
93
76
92
86
m
n
o
p
q
r
93
70
90
89
88
81
91
87
97
95
94
92
90
92
90
83
90
90
92
93
92
92
94
87
s
t
95
95
92
88
92
96
95
87
Scheme 2. Synthetic route to 4a–t via approach B. Reagents: (i) formaldehyde and TFA; (ii) Boc-N3 and triethylamine; (iii) L-amino acid methylester and DCC;
(iv) aqueous NaOH (2 mol/l); (v) hydrogen chloride in ethyl acetate (4 mol/l); (vi) DCC/HOBt. In 6a, 7a, 8a, and 4a R¼CH3; 6b, 7b, 8b, and 4b R¼CH2C6H5;
6c, 7c, 8c, and 4c R¼CH(CH3)2; 6d, 7d, 8d, and 4d R¼CH2OH; 6e, 7e, 8e, and 4e R¼CH(OH)CH3; 6f, 7f, 8f, and 4f R¼CH2C6H4–OH-p; 6g, 7g, 8g, and 4g
R¼tetrahydropyrrol-2-yl; 6h, 7h, 8h, and 4h R¼CH2SH; 6i, 7i, 8i, and 4i R¼CH2CH2SCH3; 6j R¼CH2CH2COOCH3, 7j, 8j, and 4j R¼CH2CH2COOH; 6k
R¼CH2COOCH3, 7k, 8k, and 4k R¼CH2COOH; 6l, 7l, 8l, and 4l R¼1,3-imidazol-5-methylene; 6m, 7m, 8m, and 4m R¼indol-3-methylene; 6n, 7n, 8n, and
4n R¼CH2(CH2)2NHC(NH2)]NH, 6o, 7o, 8o, and 4o R¼H; 6p, 7p, and 8p R¼CH2(CH2)3NHZ; 4p R¼CH2(CH2)3NH2; (After cyclization, a colorless powder
of 922 mg (2.0 mmol) of the product was mixed with 50 mg of Pd/C (5%) and 25 ml of formic acid in methanol (4.4%), and agitated with hydrogen at room
temperature for 24 h. The reaction mixture was filtrated and evaporated to give 4p as colorless powder.) 6q, 7q, 8q, and 4q R¼CH2CH2CONH2; 6r, 7r, 8r, and
4r R¼CH2CONH2; 6s, 7s, 8s, and 4s R¼CH2CH(CH3)2; 6t, 7t, 8t, and 4t R¼CH(CH3)CH2CH3.
was selectively protected with Boc-N3 to yield compound 5
(76% yield), which was then subjected to the coupling
reaction with a series of amino acid methylesters in the
presence of DCC and HOBt. Compounds 6a–t were pre-
pared with high yield (90–98% yield). After saponification,
the resulting 7a–t were easily obtained in high yield. The
fourth ring was then furnished by the following two steps:
deprotection of tert-butoxycarbonyl group and intramole-
cular cyclization under classical HOBT/DCC conditions.
Finally, the desired compounds 4a–t were generated in
high diastereopurity and good yield. Compared to the sec-
ond approach, the first approach provides a simpler (four
step) and practical route to synthesize a plurality of struc-
turally varied FTC analogues in almost diastereomerically
pure form.
In all cases, the diastereopurity of compounds 4a–t was
found to be higher than 98%. The optical rotations of 4a–t
are listed in Table 1.
The impact of these new compounds on doxorubicin (a
known BCRP substrate) chemosensitivity was examined in
the BCRP-overexpressing MES-SA/Dx5 cells and the data
were listed in Table 2. It seems that different amino acid
residues influence their biological activities. Compared with
doxorubicin alone (IC50: 1.55ꢁ0.26 mmol/l, resistance in-
dex: 4.47), compounds 4c,e,g,l,r significantly reversed
BCRP-mediated resistance of MES-SA/Dx5 cells to doxoru-
bicin. In the presence of 0.1 mmol of 4c,e,g,l,r the IC50 values
of doxorubicin for MES-SA/Dx5 cells were 0.86ꢁ0.06,
0.75ꢁ0.08, 0.80ꢁ0.05, 0.82ꢁ0.06, and 0.66ꢁ0.04 mmol/l
(resistance index: 2.48, 2.16, 2.31, 2.37, 1.89), respectively.
Whereas other compounds (i.e., 4h,i) showed a weak action
(IC50: 1.30ꢁ0.12; 1.14ꢁ0.30 mmol/l; resistance index: 3.75;
3.29). The preliminary biological study suggested that C-6
substitution might be important to the potency of this class
To determine if any racemization of the preexisting stereo-
genic center had occurred during the course of the synthesis,
upon removal of the solvent and volatile side products, the
crude products 4a–t were then directly analyzed by HPLC.

5514
G. Wu et al. / Tetrahedron 63 (2007) 5510–5528
Table 1
O
O
O
O
H
N
H
NH
CH3
NH
N
N
N
4a
4b
H
H
[a]2D0 ꢂ150 (c 1.0, CH3OH)
[a]2D0 ꢂ53 (c 1.0, CH3OH)
O
H
O
H
NH
NH
CH3
N
N
OH
N
H
N
4c
O
4d
H
O
CH3
[a]2D0 ꢂ141 (c 1.0, CH3OH)
[a]2D0 ꢂ84 (c 1.0, CH3OH)
O
O
H
H
OH
NH
NH
OH
N
N
N
N
H
4e
H
O
4f
O
[a]2D0 ꢂ109 (c 1.0, CH3OH)
[a]2D0 ꢂ122 (c 1.0, CH3OH)
O
O
H
H
NH
N
N
O
SH
N
N
4h
N
H
H
O
H
4g
[a]2D0 ꢂ89 (c 1.0, CH3OH)
[a]2D0 ꢂ49 (c 1.00, CH3OH)
O
O
H
H
NH
NH
N
O
N
N
4j
CO2H
S
N
H
4i
H
O
[a]2D0 ꢂ65 (c 1.0, CH3OH)
[a]2D0 ꢂ109 (c 1.0, CH3OH)
O
O
H
H
NH
N
NH
NH
CO2H
N
N
N
H
N
4l
O
H
O
4k
[a]2D0 ꢂ70 (c 1.0, CH3OH)
[a]2D0 ꢂ88 (c 1.0, CH3OH)
O
O
H
H
NH
NH
H
N
N
N
4m
NH2
NH
N
N
H
N
4n
H
O
H
O
[a]2D0 ꢂ182 (c 0.34, CHCl3/CH3OH, 1:1, v/v)
[a]2D0 ꢂ91 (c 1.0, CH3OH)
O
O
H
H
NH
NH
N
N
N
N
NH2
4p
H
H
O
O
4o
[a]2D0 ꢂ135 (c 1.0, CH3OH)
[a]2D0 ꢂ48 (c 1.0, CH3OH)
O
O
H
H
NH
N
O
NH
O
N
N
4r
CONH2
NH2
N
H
H
O
4q
[a]2D0 ꢂ62 (c 1.0, CH3OH)
[a]2D0 ꢂ45 (c 1.0, CH3OH)
O
O
H
H
NH
NH
N
N
4s
N
N
H
H
O
O
4t
[a]2D0 ꢂ52 (c 1.0, CH3OH)
[a]2D0 ꢂ74 (c 1.0, CH3OH)

G. Wu et al. / Tetrahedron 63 (2007) 5510–5528
5515
Table 2. The DxIC50 values of doxorubicin for MES-SA/Dx5 cells in the
presence of 4a–t (0.1 mmol)
filtration. After recrystallization, 3.97 g (75%) of the title
compound was obtained as a colorless powder. Mp 280–
282 ꢀC; EIMS: 217 [M+H]+; IR (KBr): 3450, 3200, 3000,
AA residue
IC50 (mmol/l)
Resistance index
1
2950, 2850, 1700, 1601, 1452, 1070, 900 cmꢂ1; H NMR
Doxorubicin alone
Doxorubicin plus 4a
Doxorubicin plus 4b
Doxorubicin plus 4c
Doxorubicin plus 4d
Doxorubicin plus 4e
Doxorubicin plus 4f
Doxorubicin plus 4g
Doxorubicin plus 4h
Doxorubicin plus 4i
Doxorubicin plus 4j
Doxorubicin plus 4k
Doxorubicin plus 4l
Doxorubicin plus 4m
Doxorubicin plus 4n
Doxorubicin plus 4o
Doxorubicin plus 4p
Doxorubicin plus 4q
Doxorubicin plus 4r
Doxorubicin plus 4s
Doxorubicin plus 4t
1.55ꢁ0.26
1.56ꢁ0.21
1.55ꢁ0.28
0.86ꢁ0.06
1.54ꢁ0.28
0.75ꢁ0.08
1.54ꢁ0.22
0.80ꢁ0.05
1.30ꢁ0.12
1.14ꢁ0.30
1.49ꢁ0.25
1.55ꢁ0.24
0.82ꢁ0.06
1.55ꢁ0.26
1.61ꢁ0.23
1.55ꢁ0.32
1.61ꢁ0.23
1.53ꢁ0.28
0.66ꢁ0.04
1.55ꢁ0.26
1.55ꢁ0.26
4.47
4.50
4.47
2.48
4.44
2.16
4.44
2.31
3.75
3.29
4.29
4.47
2.37
4.47
4.64
4.47
4.64
4.41
1.89
4.47
4.47
(BHSC-500, DMSO-d6): d¼10.99 (s, 1H), 9.89 (s, 1H),
7.30 (t, J¼7.5 Hz, 1H), 7.22 (t, J¼8.0 Hz, 1H), 7.01 (d,
J¼8.0 Hz, 1H), 6.81 (d, J¼7.5 Hz, 1H), 4.01 (t, J¼4.8 Hz,
1H), 3.75 (dd, J¼10.5, 5.0 Hz, 1H), 3.64 (dd, J¼10.5,
2.4 Hz, 1H), 2.91 (d, J¼10.5 Hz, 2H), 2.86 (s, 1H). Anal.
Calcd for C12H12N2O2: C, 66.65; H, 5.59; N, 12.96. Found:
C, 66.45; H, 5.72; N, 12.79.
3.1.2. (3S)-1,2,3,4-Tetrahydro-b-carboline-3-carboxylic
acid methylester (2). At 0 ꢀC, 10 ml of thionyl chloride
was added dropwise to 50 ml of methanol, after which
5.0 g (23.1 mmol) of 3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxylic acid was added. The reaction mixture was stirred
at room temperature for 15 h and then TLC (ethyl acetate/
petroleum, 5:12) was used to indicate the completion of
the reaction. The excess methanol and thionyl chloride
were removed by evaporation. The residue was dissolved
in 30 ml of ethyl acetate and washed successively with sat-
urated NaCO3 in water (3ꢃ30 ml), saturated NaCl in water
(30 mlꢃ3), and KHSO4 in water (5%, 3ꢃ30 ml). The sepa-
rated ethyl acetate layer was dried with anhydrous MgSO4,
evaporated, and purified with flash chromatography
(CHCl3/CH3OH, 30:1) to provide 4.9 g (92%) of the title
compound as a colorless powder. Mp 143–145 ꢀC; FABMS:
231 [M+H]+; 1H NMR (BHSC-500, DMSO-d6): d¼9.79 (s,
1H), 7.28 (t, J¼7.5 Hz, 1H), 7.18 (t, J¼7.5 Hz, 1H), 7.01 (t,
J¼7.5 Hz, 1H), 6.99 (t, J¼7.5 Hz, 1H), 4.22 (d, J¼4.8 Hz,
2H), 3.69 (dd, J¼10.5, 5.0 Hz, 1H), 3.56 (s, 3H), 3.14 (dd,
J¼10.5, 2.4 Hz, 1H), 2.83 (ddd, J¼10.5, 5.0, 2.4 Hz, 1H),
2.66 (s, 1H). Anal. Calcd for C13H14N2O2: C, 67.81; H,
6.13; N, 12.17. Found: C, 67.98; H, 6.04; N, 12.30.
MES-SA/Dx5 cells were exposed to doxorubicin in the presence of 1 mM
4a–t for 48 h and IC50 was determined by MTTassay. Values are meanꢁSD
of three experiments. IC50 for MES-SA and MES-SA/Dx5 were calculated
to be 0.347 and 1.55 mmol/l, respectively. Resistance index of doxorubicine
alone¼4.47.
of compounds to inhibit BCRP. The detailed in vitro and in
vivo biological activity data will be reported elsewhere.
In summary, we have developed a straightforward and effi-
cient method to give a series of new FTC analogues in
four steps with high diastereopurity and good yields. This
method was easily scaled up to yield gram scale quantity
of this new class compounds.
3.1.3. 2-Bromo-1-ethyl pyridinium tetrafluoroborate
(BEP).22 To a 10 ml solution of triethyloxonium tetrafluo-
roborate (10 mmol) in ClCH2CH2Cl, 2-bromopyridine
(10 mmol) was added slowly under the argon atmosphere.
After stirring at room temperature for 1 h and heating to
50 ꢀC for additional 30 min, the reaction mixture was
cooled. After dilution with anhydrous ether, it was filtered
and washed again with ether. The crude product was crystal-
lized from acetone/ether to give the corresponding pyridi-
nium-type reagents as colorless crystals.
3. Experimental
3.1. General
The protected amino acids with L-configuration were pur-
chased from Sigma Chemical Co. All of the coupling and
deprotective reactions were carried out under anhydrous
conditions. Chromatography was performed on Qingdao sil-
ica gel H. The purities of the intermediates and the products
were confirmed by TLC (Merck silica gel plates of type
60 F254, 0.25 mm layer thickness) and HPLC (Waters, C18
column 4.6ꢃ150 mm). The amino acid analysis was deter-
mined with a Hitachi 835-50 instrument. FABMS was
determined by VG-ZAB-MS high resolution GC/MS/DS
and HP ES-5989x. Optical rotations were determined with a
Schmidt+Haensch Polartromic D instrument. The statistical
analysis of all the biological data was performed by ANOVA
test with p<0.05 cut-off.
3.2. General procedure for the preparation of (3S)-
N-(Boc-aminoacyl)-1,2,3,4-tetrahydro-b-carboline-3-
carboxylic acid methylester (3a–t)
To a solution of Boc-L-amino acids (2.2 mmol), 500 mg
(2.17 mmol) of 3S-1,2,3,4-tetrahydro-b-carboline-3-carb-
oxylic acid methylester, BEP (0.603 g, 2.2 mmol) in 3 ml
CH2Cl2, and DIEA (1.1 ml, 6.4 mmol) were added. The re-
action mixture was stirred at 0 ꢀC for 1 min and then room
temperature for 1 h. The crude product was purified with
flash chromatography (CHCl3/CH3OH, 30:1) to yield the
title compound as colorless powder.
3.1.1. (3S)-1,2,3,4-Tetrahydro-b-carboline-3-carboxylic
acid (1). To a mixture of 5.0 g (24.5 mmol) of L-tryptophane
in 50 ml of dichloromethane, 25 ml of 5% TFA and 8 ml of
formaldehyde (36–38%) were added. The reaction mixture
was stirred at room temperature for 2 h, and pH was adjusted
to pH 6–7 with concentrated ammonia liquor. The mixture
was kept at 0 ꢀC for 12 h and precipitates were collected by
3.2.1. (3S)-N-(Boc-L-alanyl)-1,2,3,4-tetrahydro-b-carbo-
line-3-carboxylic acid methylester (3a). Yield 93%. Mp
148–150 ꢀC; FABMS: 403 [M+H]+; IR (KBr): 3340, 3006,

5516
G. Wu et al. / Tetrahedron 63 (2007) 5510–5528
2953, 2840, 1748, 1642, 1605, 1450, 1391, 1072, 902 cmꢂ1
;
(s, 3H), 2.95 (d, J¼5.4 Hz, 2H), 2.21 (d, J¼3.6 Hz, 1H),
1.45 (s, 9H), 1.21 (d, J¼5.6 Hz, 3H). Anal. Calcd for
C22H29N3O6: C, 61.24; H, 6.77; N, 9.74. Found: C, 61.11;
H, 6.65; N, 9.89.
1H NMR (BHSC-500, DMSO-d6): d¼9.93 (s, 1H), 8.03 (s,
1H), 7.28 (t, J¼7.5 Hz, 1H), 7.18 (t, J¼7.5 Hz, 1H), 6.97
(t, J¼7.5 Hz, 1H), 6.94 (t, J¼7.5 Hz, 1H), 4.76 (t,
J¼5.8 Hz, 1H), 4.66 (m, J¼5.3 Hz, 1H), 3.84 (s, 2H), 3.62
(dd, J¼10.2, 5.2 Hz, 1H), 3.61 (s, 3H), 3.20 (dd, J¼10.2,
2.8 Hz, 1H), 1.48 (d, J¼5.3 Hz, 3H), 1.45 (s, 9H). [a]D20
ꢂ131 (c 0.38, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for
C21H27N3O5: C, 62.83; H, 6.78; N, 10.47. Found: C,
62.66; H, 6.61; N 10.29.
3.2.6. (3S)-N-(Boc-L-Tyrosinyl)-1,2,3,4-tetrahydro-b-
carboline-3-carboxylic acid methylester (3f). Yield 87%.
Mp 145–147 ꢀC; FABMS: 494 [M+H]+; IR (KBr): 3337,
3004, 2945, 2845, 1752, 1641, 1600, 1452, 1390, 1070,
1
903 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼10.02 (s,
1H), 8.00 (s, 1H), 7.27 (t, J¼7.5 Hz, 1H), 7.19 (t,
J¼7.5 Hz, 1H), 6.96 (d, J¼7.6 Hz, 2H), 6.89 (d, J¼7.5 Hz,
1H), 6.88 (d, J¼7.5 Hz, 1H), 6.68 (d, J¼7.6 Hz, 2H), 5.02
(s, 1H), 4.94 (t, J¼5.4 Hz, 1H), 4.83 (t, J¼5.4 Hz, 1H),
3.93 (s, 2H), 3.64 (dd, J¼10.0, 5.1 Hz, 1H), 3.63 (s, 3H),
3.31 (dd, J¼10.0, 2.7 Hz, 1H), 3.07 (d, J¼5.4 Hz, 2H),
1.46 (s, 9H). [a]2D0 ꢂ26 (c 0.36, CHCl3/CH3OH, 1:1, v/v).
Anal. Calcd for C27H31N3O6: C, 65.71; H, 6.33; N, 8.51.
Found: C, 65.54; H, 6.46; N, 8.70.
3.2.2. (3S)-N-(Boc-L-phenylalanyl)-1,2,3,4-tetrahydro-
b-carboline-3-carboxylic acid methylester (3b). Yield
93%. Mp 147–149 ꢀC; FABMS: 478 [M+H]+; IR (KBr):
3338, 3010, 2943, 2840, 1752, 1640, 1602, 1458, 1390,
1070, 902 cmꢂ1
;
1H NMR (BHSC-500, DMSO-d6):
d¼9.97 (s, 1H), 7.89 (s, 1H), 7.27 (t, J¼7.4 Hz, 1H), 7.20
(t, J¼7.8 Hz, 2H), 7.16 (t, J¼7.4 Hz, 1H), 7.11 (d,
J¼7.8 Hz, 2H), 7.07 (t, J¼7.8 Hz, 1H), 6.99 (t, J¼7.4 Hz,
1H), 6.95 (t, J¼7.4 Hz, 1H), 5.01 (t, J¼5.6 Hz, 1H), 4.79
(t, J¼5.6 Hz, 1H), 3.88 (s, 2H), 3.64 (dd, J¼10.0, 5.1 Hz,
1H), 3.63 (s, 3H), 3.26 (dd, J¼10.0, 2.9 Hz, 1H), 3.06 (d,
J¼5.6 Hz, 2H), 1.46 (s, 9H). [a]2D0 ꢂ89 (c 0.37, CHCl3/
CH3OH, 1:1, v/v). Anal. Calcd for C27H31N3O5: C, 67.91;
H, 6.54; N, 8.80. Found: C, 67.73; H, 6.70; N, 9.00.
3.2.7. (3S)-N-(Boc-prolinyl)-1,2,3,4-tetrahydro-b-carbo-
line-3-carboxylic acid methylester (3g). Yield 92%. Mp
118–120 ꢀC; ESIMS: 428 [M+H]+; IR (KBr): 3431, 3206,
3003, 2954, 2842, 1730, 1643, 1605, 1456, 1394, 1370,
1065, 904 cmꢂ1
;
1H NMR (BHSC-500, DMSO-d6):
d¼9.97 (s, 1H), 7.32 (t, J¼7.2 Hz, 1H), 7.22 (t, J¼7.4 Hz,
1H), 7.03 (d, J¼7.4 Hz, 1H), 6.93 (d, J¼7.2 Hz, 1H),
4.85 (t, J¼5.3 Hz, 1H), 4.31 (t, J¼5.5 Hz, 1H), 4.25 (d,
J¼5.4 Hz, 2H), 3.62 (s, 3H), 3.44 (t, J¼5.5 Hz, 2H), 2.97
(d, J¼5.5 Hz, 2H), 2.25 (d, J¼5.4 Hz, 2H), 1.95 (t,
J¼5.1 Hz, 2H), 1.47 (s, 9H). Anal. Calcd for
C23H29N3O5: C, 64.62; H, 6.84; N, 9.83. Found: C, 64.75;
H, 6.92; N, 9.97.
3.2.3. (3S)-N-(Boc-L-valinyl)-1,2,3,4-tetrahydro-b-carbo-
line-3-carboxylic acid methylester (3c). Yield 87%. Mp
137–139 ꢀC; FABMS: 430 [M+H]+; IR (KBr): 3343, 3000,
2952, 2845, 1743, 1640, 1605, 1455, 1391, 1375, 1070,
1
900 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼9.92 (s,
1H), 8.00 (s, 1H), 7.25 (t, J¼7.2 Hz, 1H), 7.13 (t,
J¼7.2 Hz, 1H), 6.95 (t, J¼7.2 Hz, 1H), 6.91 (t, J¼7.2 Hz,
1H), 4.73 (t, J¼5.6 Hz, 1H), 4.52 (d, J¼5.2 Hz, 1H), 3.86
(s, 2H), 3.62 (dd, J¼10.3, 5.1 Hz, 1H), 3.64 (s, 3H), 3.22
(dd, J¼10.3, 3.2 Hz, 1H), 2.66 (m, J¼5.2 Hz, 1H), 1.45 (s,
9H), 1.03 (d, J¼5.4 Hz, 6H). [a]2D0 ꢂ46 (c 0.35, CHCl3/
CH3OH, 1:1, v/v). Anal. Calcd for C23H31N3O5: C, 64.32;
H, 7.27; N, 9.78. Found: C, 64.16; H, 7.20; N, 9.92.
3.2.8. (3S)-N-(Boc-cysteinyl)-1,2,3,4-tetrahydro-b-car-
boline-3-carboxylic acid methylester (3h). Yield 93%.
Mp 133–135 ꢀC; ESIMS: 434 [M+H]+; IR (KBr): 3441,
3205, 3004, 2940, 2842, 1734, 1640, 1605, 1450, 1392,
1
1370, 1064, 900 cmꢂ1; H NMR (BHSC-500, DMSO-d6):
d¼10.02 (s, 1H), 7.99 (s, 1H), 7.30 (t, J¼7.3 Hz, 1H), 7.20
(t, J¼7.5 Hz, 1H), 7.03 (d, J¼7.5 Hz, 1H), 6.85 (d,
J¼7.3 Hz, 1H), 4.90 (t, J¼5.1 Hz, 1H), 4.73 (t, J¼5.3 Hz,
1H), 4.23 (d, J¼5.4 Hz, 2H), 3.63 (s, 3H), 3.13 (d,
J¼5.2 Hz, 2H), 2.99 (d, J¼5.3 Hz, 2H), 1.47 (s, 9H), 1.64
(s, 1H). Anal. Calcd for C21H27N3O5S: C, 58.18; H, 6.28;
N, 9.69. Found: C, 58.25; H, 6.38; N, 9.86.
3.2.4. (3S)-N-(Boc-L-serinyl)-1,2,3,4-tetrahydro-b-carbo-
line-3-carboxylic acid methylester (3d). Yield 93%. Mp
155–157 ꢀC; FABMS: 418 [M+H]+; IR (KBr): 3339, 3006,
2945, 2842, 1750, 1643, 1605, 1459, 1391, 1072,
1
900 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼10.01 (s,
1H), 8.03 (s, 1H), 7.29 (t, J¼7.6 Hz, 1H), 7.19 (t,
J¼7.6 Hz, 1H), 7.02 (t, J¼7.6 Hz, 1H), 6.90 (t, J¼7.6 Hz,
1H), 4.78 (t, J¼5.7 Hz, 1H), 4.65 (t, J¼5.5 Hz, 1H), 4.05
(d, J¼5.5 Hz, 1H), 3.91 (s, 2H), 3.62 (dd, J¼10.1, 5.0 Hz,
1H), 3.60 (s, 3H), 3.28 (dd, J¼10.1, 2.7 Hz, 1H), 3.08 (d,
J¼5.5 Hz, 2H), 1.48 (s, 9H). [a]2D0 ꢂ77 (c 0.39, CHCl3/
CH3OH, 1:1, v/v). Anal. Calcd for C21H27N3O6: C, 60.42;
H, 6.52; N, 10.07. Found: C, 60.60; H, 6.71; N, 9.88.
3.2.9. (3S)-N-(Boc-methioninyl)-1,2,3,4-tetrahydro-b-
carboline-3-carboxylic acid methylester (3i). Yield 91%.
Mp 133–135 ꢀC; ESIMS: 462 [M+H]+; IR (KBr): 3443,
3205, 3007, 2950, 2844, 1730, 1645, 1602, 1455, 1392,
1
1375, 1064, 902 cmꢂ1; H NMR (BHSC-500, DMSO-d6):
d¼10.01 (s, 1H), 7.99 (s, 1H), 7.30 (t, J¼7.3 Hz, 1H), 7.20
(t, J¼7.5 Hz, 1H), 6.97 (d, J¼7.5 Hz, 1H), 6.83 (d,
J¼7.3 Hz, 1H), 4.83 (t, J¼5.2 Hz, 1H), 4.47 (t, J¼5.3 Hz,
1H), 4.27 (d, J¼5.3 Hz, 2H), 3.66 (s, 3H), 2.95 (d,
J¼5.4 Hz, 2H), 2.45 (t, J¼5.3 Hz, 2H), 2.25 (d, J¼5.3 Hz,
2H), 2.11 (s, 3H), 1.47 (s, 9H). Anal. Calcd for
C23H31N3O5S: C, 59.85; H, 6.77; N, 9.10. Found: C,
59.69; H, 6.85; N, 9.26.
3.2.5. (3S)-N-(Boc-L-threoninyl)-1,2,3,4-tetrahydro-b-
carboline-3-carboxylic acid methylester (3e). Yield 90%.
Mp 128–130 ꢀC; ESIMS: 432 [M+H]+; IR (KBr): 3433,
3205, 3000, 2955, 2841, 1730, 1643, 1605, 1452, 1390,
1
1372, 1060, 904 cmꢂ1; H NMR (BHSC-500, DMSO-d6):
d¼10.02 (s, 1H), 7.89 (s, 1H), 7.30 (t, J¼7.3 Hz, 1H), 7.22
(t, J¼7.3 Hz, 1H), 6.90 (d, J¼7.4 Hz, 1H), 6.70 (d,
J¼7.3 Hz, 1H), 4.82 (t, J¼5.3 Hz, 1H), 4.63 (m, J¼5.3 Hz,
1H), 4.44 (t, J¼5.3 Hz, 1H), 4.03 (m, J¼5.2 Hz, 2H), 3.62
3.2.10. (3S)-N-[Boc-glutamyl(OMe)]-1,2,3,4-tetrahydro-
b-carboline-3-carboxylic acid methylester (3j). Yield

G. Wu et al. / Tetrahedron 63 (2007) 5510–5528
5517
91%. Mp 122–124 ꢀC; ESIMS: 474 [M+H]+; IR (KBr): 3443,
3205, 3004, 2940, 2834, 1735, 1642, 1601, 1452, 1395,
1H), 7.01 (d, J¼7.5 Hz, 1H), 6.93 (d, J¼7.4 Hz, 1H), 4.91
(d, J¼5.1 Hz, 1H), 4.40 (t, J¼4.3 Hz, 1H), 4.27 (d, J¼
5.1 Hz, 2H), 3.67 (s, 3H), 2.92 (d, J¼4.3 Hz, 2H), 2.66 (t,
J¼5.5 Hz, 2H), 1.93 (m, J¼5.3 Hz, 2H), 1.57 (m, J¼
5.4 Hz, 2H), 1.55 (s, 9H). Anal. Calcd for C24H34N6O5: C,
59.24; H, 7.04; N, 17.27. Found: C, 59.10; H, 6.95; N, 17.40.
1
1370, 1063, 901 cmꢂ1; H NMR (BHSC-500, DMSO-d6):
d¼9.92 (s, 1H), 8.01 (s, 1H), 7.35 (t, J¼7.2 Hz, 1H), 7.26
(t, J¼7.2 Hz, 1H), 7.00 (d, J¼7.5 Hz, 1H), 6.86 (d,
J¼7.3 Hz, 1H), 4.87 (d, J¼5.3 Hz, 1H), 4.45 (t, J¼5.5 Hz,
1H), 4.24 (d, J¼5.4 Hz, 2H), 3.67 (s, 3H), 3.65 (s, 3H),
2.97 (d, J¼5.3 Hz, 2H), 2.29 (t, J¼5.4 Hz, 2H), 2.23 (t,
J¼5.5 Hz, 2H), 1.47 (s, 9H). Anal. Calcd for C24H31N3O7:
C, 60.88; H, 6.60; N, 8.87. Found: C, 60.75; H, 6.47; N, 9.05.
3.2.15. (3S)-N-(Boc-glycyl)-1,2,3,4-tetrahydro-b-carbo-
line-3-carboxylic acid methylester (3o). Yield 95%. Mp
150–152 ꢀC; FABMS: 388 [M+H]+; IR (KBr): 3342, 3003,
2950, 2844, 1745, 1645, 1603, 1452, 1390, 1070,
1
3.2.11. (3S)-N-[Boc-L-aspartyl(OBzl)]-1,2,3,4-tetra-
hydro-b-carboline-3-carboxylic acid methylester (3k).
Yield 92%. Mp 144–146 ꢀC; FABMS: 536 [M+H]+; IR
(KBr): 3340, 3004, 2948, 2845, 1748, 1642, 1600, 1455,
900 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼9.91 (s,
1H), 8.11 (s, 1H), 7.29 (t, J¼7.6 Hz, 1H), 7.16 (t,
J¼7.6 Hz, 1H), 7.00 (t, J¼7.6 Hz, 1H), 6.97 (t, J¼7.6 Hz,
1H), 4.76 (t, J¼5.6 Hz, 2H), 4.52 (d, J¼4.9 Hz, 2H), 3.87
(s, 2H), 3.65 (dd, J¼10.5, 5.0 Hz, 1H), 3.58 (s, 3H), 3.17
(dd, J¼10.5, 2.4 Hz, 1H), 1.44 (s, 9H). [a]2D0 ꢂ100 (c 0.34,
CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for C20H25N3O5: C,
62.00; H, 6.50; N, 10.85. Found: C, 62.18; H, 6.34; N, 10.67.
1
1391, 1072, 904 cmꢂ1; H NMR (BHSC-500, DMSO-d6):
d¼9.95 (s, 1H), 8.02 (s, 1H), 7.29 (t, J¼7.6 Hz, 1H), 7.22 (t,
J¼7.2 Hz, 2H), 7.20 (d, J¼7.2 Hz, 2H), 7.18 (t, J¼7.5 Hz,
1H), 7.16 (t, J¼7.2 Hz, 1H), 6.97 (t, J¼7.5 Hz, 1H), 6.93
(t, J¼7.5 Hz, 1H), 5.36 (s, 2H), 5.14 (t, J¼5.5 Hz, 1H),
4.77 (t, J¼5.7 Hz, 1H), 3.62 (dd, J¼10.2, 5.1 Hz, 1H),
3.64 (s, 3H), 3.24 (dd, J¼10.2, 2.7 Hz, 1H), 3.06 (d,
J¼5.6 Hz, 2H), 2.75 (d, J¼5.5 Hz, 2H), 1.46 (s, 9H). [a]D20
ꢂ61 (c 0.39, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for
C29H33N3O7: C, 65.03; H, 6.21; N, 7.85. Found: C, 65.18;
H, 6.06; N, 7.99.
3.2.16. (3S)-N-[Boc-L-lysinyl(Z)]-1,2,3,4-tetrahydro-b-
carboline-3-carboxylic acid methylester (3p). Yield
92%. Mp 95–97 ꢀC; FABMS: 593 [M+H]+; IR (KBr):
3342, 3003, 2940, 2845, 1752, 1641, 1602, 1456, 1390,
1070, 902 cmꢂ1
;
1H NMR (BHSC-500, DMSO-d6):
d¼9.97 (s, 1H), 8.05 (s, 1H), 8.00 (s, 1H), 7.27 (t,
J¼7.5 Hz, 1H), 7.22 (t, J¼7.2 Hz, 1H), 7.17 (t, J¼7.5 Hz,
1H), 7.15 (d, J¼7.2 Hz, 2H), 7.13 (t, J¼7.2 Hz, 2H), 7.00
(t, J¼7.5 Hz, 1H), 6.88 (t, J¼7.5 Hz, 1H), 5.36 (s, 2H),
4.76 (t, J¼5.6 Hz, 1H), 4.55 (t, J¼5.6 Hz, 1H), 3.63 (dd,
J¼10.2, 5.1 Hz, 1H), 3.64 (s, 3H), 3.30 (dd, J¼10.1,
2.7 Hz, 1H), 3.08 (d, J¼5.5 Hz, 2H), 2.95 (t, J¼5.4 Hz,
2H), 1.75 (t, J¼5.5 Hz, 2H), 1.58 (t, J¼5.3 Hz, 2H), 1.48
(s, 9H), 1.27 (m, J¼5.6 Hz, 2H). [a]2D0 ꢂ29 (c 0.35,
CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for C32H40N4O7: C,
64.85; H, 6.80; N, 9.45. Found: C, 64.69; H, 6.71; N, 9.62.
3.2.12. (3S)-N-(Boc-L-histidinyl)-1,2,3,4-tetrahydro-b-
carboline-3-carboxylic acid methylester (3l). Yield 92%.
Mp 140–142 ꢀC; ESIMS: 468 [M+H]+; IR (KBr): 3445,
3203, 3005, 2944, 2837, 1731, 1645, 1602, 1451, 1393,
1
1370, 1060, 900 cmꢂ1; H NMR (BHSC-500, DMSO-d6):
d¼12.95 (s, 1H), 9.98 (s, 1H), 8.02 (s, 1H), 7.45 (s, 1H),
7.32 (t, J¼7.2 Hz, 1H), 7.18 (t, J¼7.5 Hz, 1H), 7.18 (d,
J¼7.5 Hz, 1H), 6.99 (t, J¼7.2 Hz, 1H), 6.87 (s, 1H), 4.94 (t,
J¼5.1 Hz, 1H), 4.81 (t, J¼5.3 Hz, 1H), 4.23 (d, J¼5.1 Hz,
2H), 3.67 (s, 3H), 3.17 (d, J¼5.2 Hz, 2H), 2.95 (d,
J¼5.1 Hz, 2H), 1.47 (s, 9H). Anal. Calcd for C24H29N5O5:
C,61.66;H,6.25;N,14.98.Found:C, 61.79;H, 6.34;N, 14.82.
3.2.17. (3S)-N-(Boc-L-glutaminyl)-1,2,3,4-tetrahydro-b-
carboline-3-carboxylic acid methylester (3q). Yield
86%. Mp 145–147 ꢀC; FABMS: 459 [M+H]+; IR (KBr):
3342, 3011, 2949, 2844, 1750, 1640, 1603, 1456, 1391,
3.2.13. (3S)-N-(Boc-L-tryptophanyl)-1,2,3,4-tetrahydro-
b-carboline-3-carboxylic acid methylester (3m). Yield
89%. Mp 126–128 ꢀC; FABMS: 517 [M+H]+; IR (KBr):
3335, 3009, 2942, 2842, 1750, 1643, 1604, 1453, 1391,
1072, 905 cmꢂ1
;
1H NMR (BHSC-500, DMSO-d6):
d¼10.00 (s, 1H), 8.02 (s, 1H), 7.29 (t, J¼7.6 Hz, 1H), 7.17
(t, J¼7.6 Hz, 1H), 6.86 (d, J¼7.6 Hz, 1H), 6.83 (d,
J¼7.6 Hz, 1H), 6.12 (s, 2H), 4.90 (t, J¼5.4 Hz, 1H), 4.55
(t, J¼5.4 Hz, 1H), 3.95 (s, 2H), 3.62 (dd, J¼10.2, 5.0 Hz,
1H), 3.60 (s, 3H), 3.32 (dd, J¼10.1, 2.9 Hz, 1H), 2.19 (t,
J¼4.9 Hz, 2H), 2.01 (m, J¼4.9 Hz, 2H), 1.42 (s, 9H).
[a]2D0 ꢂ27 (c 0.38, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd
for C23H30N4O6: C, 60.25; H, 6.59; N, 12.22. Found: C,
60.38; H, 6.77; N, 12.37.
1072, 900 cmꢂ1
;
1H NMR (BHSC-500, DMSO-d6):
d¼9.99 (s, 1H), 9.96 (s, 1H), 8.02 (s, 1H), 7.29 (t,
J¼7.6 Hz, 1H), 7.21 (t, J¼7.4 Hz, 1H), 7.19 (t, J¼7.4 Hz,
1H), 7.18 (t, J¼7.4 Hz, 1H), 7.17 (t, J¼7.4 Hz, 1H), 7.16
(t, J¼7.6 Hz, 1H), 7.01 (t, J¼7.6 Hz, 1H), 6.89 (t,
J¼7.6 Hz, 1H), 6.82 (s, 1H), 4.90 (t, J¼5.5 Hz, 1H), 4.85
(t, J¼5.4 Hz, 1H), 3.92 (s, 2H), 3.62 (dd, J¼10.1, 5.0 Hz,
1H), 3.65 (s, 3H), 3.32 (dd, J¼10.1, 2.9 Hz, 1H), 2.92 (t,
J¼5.5 Hz, 2H), 1.48 (s, 9H). [a]2D0 ꢂ97 (c 0.38, CHCl3/
CH3OH, 1:1, v/v). Anal. Calcd for C29H32N4O5: C, 67.43;
H, 6.24; N, 10.85. Found: C, 67.59; H, 6.40; N, 10.72.
3.2.18. (3S)-N-(Boc-L-asparaginyl)-1,2,3,4-tetrahydro-b-
carboline-3-carboxylic acid methylester (3r). Yield 91%.
Mp 137–139 ꢀC; ESIMS: 445 [M+H]+; IR (KBr): 3443,
3205, 3001, 2932, 2833, 1734, 1630, 1604, 1457, 1391,
1
3.2.14. (3S)-N-(Boc-L-argininyl)-1,2,3,4-tetrahydro-b-
carboline-3-carboxylic acid methylester (3n). Yield
88%. Mp 137–139 ꢀC; ESIMS: 487 [M+H]+; IR (KBr):
3445, 3209, 3004, 2945, 2840, 1733, 1642, 1600, 1451, 1392,
1370, 1061, 900 cmꢂ1; H NMR (BHSC-500, DMSO-d6):
d¼9.97 (s, 1H), 8.01 (s, 1H), 7.22 (t, J¼7.3 Hz, 1H), 7.14
(t, J¼7.1 Hz, 1H), 7.01 (d, J¼7.3 Hz, 1H), 6.85 (d,
J¼7.3 Hz, 1H), 6.03 (s, 2H), 4.91 (d, J¼5.3 Hz, 1H), 4.41
(t, J¼5.3 Hz, 1H), 4.24 (d, J¼5.3 Hz, 2H), 3.65 (s, 3H),
2.92 (d, J¼5.1 Hz, 2H), 2.55 (t, J¼5.3 Hz, 2H), 1.49 (s,
9H). [a]2D0 ꢂ38 (c 0.30, CHCl3/CH3OH, 1:1, v/v). Anal.
1
1370, 1064, 900 cmꢂ1; H NMR (BHSC-500, DMSO-d6):
d¼10.20 (s, 1H), 8.43 (s, 2H), 8.25 (s, 1H), 8.20 (s, 1H),
8.03 (s, 1H), 7.27 (t, J¼7.4 Hz, 1H), 7.17 (t, J¼7.5 Hz,

5518
G. Wu et al. / Tetrahedron 63 (2007) 5510–5528
Calcd for C22H28N4O6: C, 59.45; H, 6.35; N, 12.60. Found:
C, 59.62; H, 6.44; N, 12.43.
of anhydrous THF, 1.2 g (8.9 mmol) of HOBt was added,
and 10 min later 1.75 g (8.5 mmol) of DCC was added.
The suspension of 6.96 mmol of HCl$L-AA-OMe in 3 ml
of anhydrous THF was adjusted pH to 8–9 with N-methyl
morpholine and stirred at room temperature for 20 min.
This suspension was then added to the solution of N-Boc-
3S-1,2,3,4-tetrahydro-b-carboline-3-carboxylic acid and
the reaction mixture was stirred at 0 ꢀC for 2 h and at
room temperature for 16 h. On evaporation, the residue
was dissolved in 30 ml of ethyl acetate. The solution was
washed successively with 5% sodium bicarbonate, 5% citric
acid, and saturated sodium chloride and the organic phase
was separated and dried over anhydrous sodium sulfate.
After filtration and evaporation under reduced pressure, the
title compound was obtained as powder.
3.2.19. (3S)-N-(Boc-L-leucyl)-1,2,3,4-tetrahydro-b-carb-
oline-3-carboxylic acid methylester (3s). Yield 87%.
Mp 135–137 ꢀC; FABMS: 444 [M+H]+; IR (KBr): 3344,
3002, 2950, 2842, 1745, 1640, 1603, 1452, 1390, 1070,
1
900 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼9.87 (s,
1H), 8.00 (s, 1H), 7.27 (t, J¼7.4 Hz, 1H), 7.15 (t,
J¼7.4 Hz, 1H), 6.99 (t, J¼7.4 Hz, 1H), 6.96 (t, J¼7.4 Hz,
1H), 4.75 (t, J¼5.9 Hz, 1H), 4.55 (d, J¼5.4 Hz, 1H), 3.88
(s, 2H), 3.60 (dd, J¼10.0, 5.0 Hz, 1H), 3.62 (s, 3H), 3.22
(dd, J¼10.0, 2.9 Hz, 1H), 1.88 (m, J¼5.4 Hz, 1H), 1.78 (t,
J¼5.0 Hz, 2H), 1.46 (s, 9H), 1.03 (d, J¼5.4 Hz, 6H). [a]D20
ꢂ52 (c 0.35, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for
C24H33N3O5: C, 64.99; H, 7.50; N, 9.47. Found: C, 65.16;
H, 7.63; N, 9.32.
3.4.1. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-alanine methylester (6a). Yield 96%. Mp
144–146 ꢀC; ESIMS: 402 [M+H]+; IR (KBr): 3451, 3011,
2949, 2847, 1730, 1604, 1450, 1392, 1370, 1066,
3.2.20. (3S)-N-(Boc-L-isoleucyl)-1,2,3,4-tetrahydro-b-
carboline-3-carboxylic acid methylester (3t). Yield 88%.
Mp 130–132 ꢀC; FABMS: 444 [M+H]+; IR (KBr): 3344,
3002, 2950, 2842, 1745, 1640, 1603, 1452, 1390, 1070,
1
897 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼9.89 (s,
1H), 7.98 (s, 1H), 7.32 (t, J¼7.5 Hz, 1H), 7.23 (t,
J¼7.8 Hz, 1H), 6.97 (d, J¼7.8 Hz, 1H), 6.81 (d, J¼7.5 Hz,
1H), 4.88 (d, J¼5.2 Hz, 1H), 4.59 (m, J¼5.5 Hz, 1H), 4.25
(dd, J¼10.0, 4.7 Hz, 1H), 4.17 (dd, J¼10.1, 3.5 Hz, 1H),
3.64 (s, 3H), 2.94 (d, J¼10.1 Hz, 2H), 1.55 (d, J¼5.2 Hz,
3H), 1.43 (s, 9H). Anal. Calcd for C21H27N3O5: C, 62.83;
H, 6.78; N, 10.47. Found: C, 62.92; H, 6.74; N, 10.30.
1
900 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼9.89 (s,
1H), 8.03 (s, 1H), 7.27 (t, J¼7.4 Hz, 1H), 7.15 (t,
J¼7.4 Hz, 1H), 6.99 (t, J¼7.4 Hz, 1H), 6.96 (t, J¼7.4 Hz,
1H), 4.75 (t, J¼5.9 Hz, 1H), 4.55 (d, J¼5.4 Hz, 1H), 3.88
(s, 2H), 3.60 (dd, J¼10.0, 5.0 Hz, 1H), 3.62 (s, 3H), 3.22
(dd, J¼10.0, 2.9 Hz, 1H), 2.48 (m, J¼5.4 Hz, 1H), 1.33
(m, J¼5.0 Hz, 2H), 1.46 (s, 9H), 1.06 (d, J¼5.4 Hz, 3H),
1.00 (t, J¼5.0 Hz, 3H). [a]2D0 ꢂ40 (c 0.35, CHCl3/CH3OH,
1:1, v/v). Anal. Calcd for C24H33N3O5: C, 64.99; H, 7.50;
N, 9.47. Found: C, 65.16; H, 7.63; N, 9.32.
3.4.2. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-phenylalanine methylester (6b). Yield 98%.
Mp 150–152 ꢀC; ESIMS: 478 [M+H]+; IR (KBr): 3446,
3205, 3006, 2948, 2847, 1731, 1645, 1603, 1451, 1392,
1
3.3. (3S)-N-Boc-1,2,3,4-tetrahydro-b-carboline-3-
carboxylic acid (5)
1370, 1069, 904 cmꢂ1; H NMR (BHSC-500, DMSO-d6):
d¼9.92 (s, 1H), 7.97 (s, 1H), 7.31 (t, J¼7.5 Hz, 1H), 7.28 (t,
J¼7.9 Hz, 2H), 7.19 (t, J¼7.6 Hz, 1H), 7.14 (d, J¼7.6 Hz,
2H), 7.02 (t, J¼7.6 Hz, 1H), 6.96 (d, J¼7.8 Hz, 1H), 6.80 (d,
J¼7.6 Hz, 1H), 4.93 (d, J¼5.4 Hz, 1H), 4.82 (t, J¼5.4 Hz,
1H), 4.27 (dd, J¼10.2, 4.5 Hz, 1H), 4.18 (dd, J¼10.2,
3.4 Hz, 1H), 3.62 (s, 3H), 3.17 (d, J¼5.4 Hz, 2H), 2.93 (d,
J¼10.2 Hz, 2H), 1.48 (s, 9H). Anal. Calcd for C27H31N3O5:
C, 67.91; H, 6.54; N, 8.80. Found: C, 67.72; H, 6.62; N, 8.67.
The suspension of 1.08 g (5.0 mmol) of compound 1 in
15 ml of DMF and 1.4 ml of triethylamine was vigorously
stirred at room temperature, to which 1.62 g (7.5 mmol) of
Boc-N3 was added in 30 min. The reaction mixture was
stirred at room temperature for 24 h and at 40 ꢀC for 80 h.
Five milliliters of citrate solution (20%) was added to the re-
action mixture, and the solution was extracted with ethyl
acetate (3ꢃ30 ml). The separated ethyl acetate layer was
dried with anhydrous MgSO4. After removal of MgSO4 by
filtration the filtrate was evaporated to dryness. The residue
obtained was crystallized in CHCl3 to give 1.20 g (76%) of
the title compound. Mp 165–170 ꢀC; ESIMS: 317 [M+H]+;
IR (KBr): 3452, 3205, 3001, 2952, 2848, 1705, 1645, 1600,
3.4.3. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-valine methylester (6c). Yield 95%. Mp 138–
140 ꢀC; ESIMS: 430 [M+H]+; IR (KBr): 3443, 3202,
3001, 2951, 2845, 1729, 1648, 1602, 1450, 1392, 1370,
1067, 902 cmꢂ1
;
1H NMR (BHSC-500, DMSO-d6):
d¼10.04 (s, 1H), 7.96 (s, 1H), 7.29 (t, J¼7.4 Hz, 1H), 7.21
(t, J¼7.7 Hz, 1H), 7.00 (d, J¼7.7 Hz, 1H), 6.89 (d,
J¼7.4 Hz, 1H), 4.84 (t, J¼5.4 Hz, 1H), 4.42 (d, J¼5.4 Hz,
1H), 4.22 (dd, J¼10.2, 4.5 Hz, 1H), 4.03 (dd, J¼10.2,
3.7 Hz, 1H), 3.62 (s, 3H), 3.10 (m, J¼5.4 Hz, 1H), 2.95 (d,
J¼6.7 Hz, 2H), 1.47 (s, 9H), 1.05 (d, J¼5.4 Hz, 6H). Anal.
Calcd for C23H31N3O5: C, 64.32; H, 7.27; N, 9.78. Found:
C, 64.43; H, 7.09; N, 9.67.
1
1450, 1072, 901 cmꢂ1; H NMR (BHSC-500, DMSO-d6):
d¼10.87 (s, 1H), 9.86 (s, 1H), 7.32 (t, J¼7.6 Hz, 1H), 7.21
(t, J¼7.9 Hz, 1H), 7.00 (d, J¼7.9 Hz, 1H), 6.84 (t,
J¼7.6 Hz, 1H), 4.84 (t, J¼5.0 Hz, 1H), 4.20 (dd, J¼10.2,
4.8 Hz, 1H), 3.98 (dd, J¼10.2, 3.2 Hz, 1H), 2.93 (d, J¼
10.2 Hz, 2H), 1.46 (s, 9H). Anal. Calcd for C17H20N2O4:
C, 64.54; H, 6.37; N, 8.86. Found: C, 64.41; H, 6.25; N, 8.74.
3.4. General procedure for the preparation of
N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-amino acid methylesters (6a–t)
3.4.4. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-serine methylester (6d). Yield 92%. Mp
139–141 ꢀC; ESIMS: 418 [M+H]+; IR (KBr): 3442, 3200,
3001, 2952, 2845, 1730, 1644, 1606, 1455, 1392, 1370,
At 0 ꢀC, to the solution of 2.0 g (6.33 mmol) N-Boc-3S-
1,2,3,4-tetrahydro-b-carboline-3-carboxylic acid in 30 ml
1067, 900 cmꢂ1 1H NMR (BHSC-500, DMSO-d6):
;
d¼9.95 (s, 1H), 7.97 (s, 1H), 7.29 (t, J¼7.6 Hz, 1H), 7.22

G. Wu et al. / Tetrahedron 63 (2007) 5510–5528
5519
(t, J¼7.9 Hz, 1H), 6.99 (d, J¼7.9 Hz, 1H), 6.83 (t, J¼7.6 Hz,
1H), 4.87 (d, J¼5.4 Hz, 1H), 4.52 (t, J¼5.6 Hz, 1H), 4.19 (d,
J¼5.2 Hz, 2H), 4.13 (d, J¼5.6 Hz, 2H), 3.63 (s, 3H), 2.95 (d,
J¼5.6 Hz, 1H), 2.92 (d, J¼5.6 Hz, 1H), 2.28 (s, 1H), 1.45 (s,
9H). Anal. Calcd for C21H27N3O6: C, 60.42; H, 6.52; N,
10.07. Found: C, 60.31; H, 6.36; N, 10.24.
159–161 ꢀC; ESIMS: 462 [M+H]+; IR (KBr): 3441, 3203,
3004, 2953, 2847, 1732, 1641, 1603, 1454, 1390, 1372,
1061, 900 cmꢂ1
;
1H NMR (BHSC-500, DMSO-d6):
d¼10.04 (s, 1H), 7.97 (s, 1H), 7.32 (t, J¼7.5 Hz, 1H), 7.22
(t, J¼7.8 Hz, 1H), 6.99 (d, J¼7.8 Hz, 1H), 6.81 (d,
J¼7.5 Hz, 1H), 4.86 (t, J¼5.3 Hz, 1H), 4.45 (t, J¼5.5 Hz,
1H), 4.28 (d, J¼5.1 Hz, 2H), 3.68 (s, 3H), 2.93 (d,
J¼5.3 Hz, 2H), 2.42 (t, J¼5.4 Hz, 2H), 2.28 (d, J¼5.6 Hz,
2H), 2.10 (s, 3H), 1.44 (s, 9H). Anal. Calcd for
C23H31N3O5S: C, 59.85; H, 6.77; N, 9.10. Found: C,
59.67; H, 6.59; N, 9.04.
3.4.5. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-threonine methylester (6e). Yield 92%. Mp
140–142 ꢀC; ESIMS: 432 [M+H]+; IR (KBr): 3437, 3200,
3002, 2951, 2844, 1735, 1649, 1600, 1450, 1392, 1370,
1065, 901 cmꢂ1
;
1H NMR (BHSC-500, DMSO-d6):
d¼9.98 (s, 1H), 7.87 (s, 1H), 7.34 (t, J¼7.4 Hz, 1H), 7.25
(t, J¼7.6 Hz, 1H), 6.95 (d, J¼7.6 Hz, 1H), 6.72 (d,
J¼7.4 Hz, 1H), 4.87 (t, J¼5.4 Hz, 1H), 4.67 (m, J¼
5.6 Hz, 1H), 4.48 (t, J¼5.6 Hz, 1H), 3.99 (m, J¼5.2 Hz,
2H), 3.65 (s, 3H), 2.97 (d, J¼5.7 Hz, 2H), 2.19 (d,
J¼3.7 Hz, 1H), 1.47 (s, 9H), 1.19 (d, J¼5.6 Hz, 3H). Anal.
Calcd for C22H29N3O6: C, 61.24; H, 6.77; N, 9.74. Found:
C, 61.40; H, 6.91; N, 9.55.
3.4.10. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-glutamic acid dimethylester (6j). Yield 93%.
Mp 154–156 ꢀC; ESIMS: 474 [M+H]+; IR (KBr): 3441,
3203, 3000, 2944, 2831, 1731, 1645, 1604, 1455, 1390,
1
1372, 1067, 903 cmꢂ1; H NMR (BHSC-500, DMSO-d6):
d¼9.89 (s, 1H), 8.04 (s, 1H), 7.39 (t, J¼7.6 Hz, 1H), 7.28
(t, J¼7.6 Hz, 1H), 7.01 (d, J¼7.7 Hz, 1H), 6.84 (d,
J¼7.6 Hz, 1H), 4.90 (d, J¼5.4 Hz, 1H), 4.43 (t, J¼5.6 Hz,
1H), 4.22 (d, J¼5.5 Hz, 2H), 3.66 (s, 3H), 3.64 (s, 3H),
2.96 (d, J¼5.4 Hz, 2H), 2.28 (t, J¼5.6 Hz, 2H), 2.24 (t,
J¼5.7 Hz, 2H), 1.43 (s, 9H). Anal. Calcd for C24H31N3O7:
C, 60.88; H, 6.60; N, 8.87. Found: C, 60.73; H, 6.49; N, 8.69.
3.4.6. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-tyrosine methylester (6f). Yield 93%. Mp
143–145 ꢀC; ESIMS: 494 [M+H]+; IR (KBr): 3439, 3203,
3001, 2955, 2847, 1732, 1644, 1601, 1453, 1391, 1372,
1062, 903 cmꢂ1
;
1H NMR (BHSC-500, DMSO-d6):
3.4.11. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-aspartic acid dimethylester (6k). Yield 90%.
Mp 158–160 ꢀC; ESIMS: 460 [M+H]+; IR (KBr): 3441,
3210, 3004, 2955, 2841, 1732, 1643, 1604, 1453, 1390,
d¼9.99 (s, 1H), 8.02 (s, 1H), 7.37 (t, J¼7.6 Hz, 1H), 7.22
(t, J¼7.7 Hz, 1H), 7.15 (d, J¼7.5 Hz, 2H), 7.02 (d,
J¼7.5 Hz, 1H), 6.96 (d, J¼7.7 Hz, 1H), 6.91 (d, J¼7.5 Hz,
2H), 4.98 (s, 1H), 4.93 (d, J¼5.4 Hz, 1H), 4.80 (t,
J¼5.6 Hz, 1H), 4.29 (m, J¼5.2 Hz, 2H), 3.64 (s, 3H), 3.15
(d, J¼5.2 Hz, 2H), 2.97 (d, J¼5.0 Hz, 2H), 1.49 (s, 9H).
Anal. Calcd for C27H31N3O6: C, 65.71; H, 6.33; N, 8.51.
Found: C, 65.67; H, 6.50; N, 8.67.
1
1371, 1061, 903 cmꢂ1; H NMR (BHSC-500, DMSO-d6):
d¼10.05 (s, 1H), 8.05 (s, 1H), 7.37 (t, J¼7.4 Hz, 1H), 7.25
(t, J¼7.4 Hz, 1H), 7.00 (d, J¼7.6 Hz, 1H), 6.95 (d,
J¼7.4 Hz, 1H), 4.92 (d, J¼5.5 Hz, 1H), 4.77 (t, J¼5.5 Hz,
1H), 4.24 (d, J¼5.6 Hz, 2H), 3.62 (s, 3H), 3.58 (s, 3H),
2.91 (d, J¼5.2 Hz, 2H), 2.85 (d, J¼5.4 Hz, 2H), 1.49 (s,
9H). Anal. Calcd for C23H29N3O7: C, 60.12; H, 6.36; N,
9.14. Found: C, 60.03; H, 6.49; N, 8.99.
3.4.7. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-proline methylester (6g). Yield 97%. Mp
139–141 ꢀC; ESIMS: 428 [M+H]+; IR (KBr): 3435, 3202,
3000, 2950, 2846, 1732, 1645, 1602, 1454, 1390, 1371,
3.4.12. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-histidine methylester (6l). Yield 93%. Mp
162–164 ꢀC; ESIMS: 468 [M+H]+; IR (KBr): 3442, 3206,
3004, 2949, 2839, 1730, 1643, 1601, 1454, 1391, 1368, 1062,
1063, 900 cmꢂ1
;
1H NMR (BHSC-500, DMSO-d6):
d¼10.01 (s, 1H), 7.35 (t, J¼7.4 Hz, 1H), 7.20 (t,
J¼7.7 Hz, 1H), 7.07 (d, J¼7.7 Hz, 1H), 6.91 (d, J¼7.4 Hz,
1H), 4.88 (t, J¼5.4 Hz, 1H), 4.35 (t, J¼5.6 Hz, 1H), 4.22
(d, J¼5.3 Hz, 2H), 3.59 (s, 3H), 3.47 (t, J¼5.6 Hz, 2H),
2.95 (d, J¼5.6 Hz, 2H), 2.29 (d, J¼5.6 Hz, 2H), 1.97 (t,
J¼4.9 Hz, 2H), 1.45 (s, 9H). Anal. Calcd for C23H29N3O5:
C, 64.62; H, 6.84; N, 9.83. Found: C, 64.57; H, 6.90; N, 9.67.
1
902 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼12.98 (s,
1H), 9.96 (s, 1H), 8.05 (s, 1H), 7.47 (s, 1H), 7.36 (t, J¼
7.4 Hz, 1H), 7.20 (t, J¼7.7 Hz, 1H), 7.16 (d, J¼7.7 Hz,
1H), 6.98 (t, J¼7.4 Hz, 1H), 6.85 (s, 1H), 4.93 (t, J¼
5.3 Hz, 1H), 4.83 (t, J¼5.4 Hz, 1H), 4.26 (d, J¼5.2 Hz,
2H), 3.64 (s, 3H), 3.19 (d, J¼5.4 Hz, 2H), 2.92 (d,
J¼5.2 Hz, 2H), 1.49 (s, 9H). Anal. Calcd for C24H29N5O5:
C, 61.66; H, 6.25; N, 14.98. Found: C, 61.52; H, 6.38; N,
14.79.
3.4.8. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-cysteine methylester (6h). Yield 92%. Mp
151–153 ꢀC; ESIMS: 434 [M+H]+; IR (KBr): 3445, 3203,
3000, 2944, 2840, 1731, 1643, 1601, 1453, 1390, 1372,
1061, 898 cmꢂ1
;
1H NMR (BHSC-500, DMSO-d6):
3.4.13. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-tryptophan methylester (6m). Yield 93%.
Mp 161–163 ꢀC; ESIMS: 517 [M+H]+; IR (KBr): 3442,
3204, 3000, 2948, 2839, 1729, 1642, 1604, 1448, 1391,
d¼9.93 (s, 1H), 7.97 (s, 1H), 7.32 (t, J¼7.5 Hz, 1H), 7.22
(t, J¼7.8 Hz, 1H), 7.00 (d, J¼7.8 Hz, 1H), 6.88 (d,
J¼7.5 Hz, 1H), 4.93 (t, J¼5.3 Hz, 1H), 4.72 (t, J¼5.5 Hz,
1H), 4.21 (d, J¼5.3 Hz, 2H), 3.68 (s, 3H), 3.16 (d,
J¼5.5 Hz, 2H), 3.01 (d, J¼5.6 Hz, 2H), 1.45 (s, 9H), 1.62
(s, 1H). Anal. Calcd for C21H27N3O5S: C, 58.18; H, 6.28;
N, 9.69. Found: C, 58.27; H, 6.33; N, 9.57.
1
1372, 1062, 900 cmꢂ1; H NMR (BHSC-500, DMSO-d6):
d¼9.87 (s, 1H), 9.86 (s, 1H), 8.09 (s, 1H), 7.32 (t,
J¼7.5 Hz, 1H), 7.30 (t, J¼7.4 Hz, 1H), 7.12 (d, J¼7.8 Hz,
1H), 7.11 (t, J¼7.8 Hz, 1H), 7.10 (d, J¼7.6 Hz, 1H), 7.09
(t, J¼7.8 Hz, 1H), 7.04 (d, J¼7.6 Hz, 1H), 6.98 (d,
J¼7.5 Hz, 1H), 6.83 (s, 1H), 4.94 (d, J¼5.4 Hz, 1H), 4.76
(t, J¼5.3 Hz, 1H), 4.29 (d, J¼5.2 Hz, 2H), 3.64 (s, 3H),
3.4.9. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-methionine methylester (6i). Yield 97%. Mp

5520
G. Wu et al. / Tetrahedron 63 (2007) 5510–5528
3.19 (d, J¼5.4 Hz, 2H), 2.95 (d, J¼6.4 Hz, 2H), 1.49 (s, 9H).
Anal. Calcd for C29H32N4O5: C, 67.43; H, 6.24; N, 10.85.
Found: C, 67.55; H, 6.34; N, 10.72.
3.4.18. N-[(3S)-N-Boc-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl]-L-asparagine methylester (6r). Yield 92%. Mp
129–131 ꢀC; ESIMS: 445 [M+H]+; IR (KBr): 3440, 3203,
3005, 2936, 2830, 1730, 1632, 1600, 1455, 1394, 1372,
3.4.14. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-arginine methylester (6n). Yield 88%. Mp
168–170 ꢀC; ESIMS: 487 [M+H]+; IR (KBr): 3443, 3207,
3001, 2948, 2842, 1731, 1645, 1602, 1453, 1390, 1372,
1062, 903 cmꢂ1 1H NMR (BHSC-500, DMSO-d6):
;
d¼9.94 (s, 1H), 8.03 (s, 1H), 7.25 (t, J¼7.2 Hz, 1H), 7.17
(t, J¼7.2 Hz, 1H), 7.04 (d, J¼7.2 Hz, 1H), 6.82 (d,
J¼7.2 Hz, 1H), 6.01 (s, 2H), 4.95 (d, J¼5.4 Hz, 1H), 4.43
(t, J¼5.4 Hz, 1H), 4.26 (d, J¼5.4 Hz, 2H), 3.63 (s, 3H),
2.90 (d, J¼5.2 Hz, 2H), 2.15 (t, J¼5.3 Hz, 2H), 1.49 (s,
9H). [a]2D0 ꢂ50 (c 0.30, CHCl3/CH3OH, 1:1, v/v). Anal.
Calcd for C22H28N4O6: C, 59.45; H, 6.35; N, 12.60. Found:
C, 59.28; H, 6.26; N, 12.77.
1061, 904 cmꢂ1
;
1H NMR (BHSC-500, DMSO-d6):
d¼10.22 (s, 1H), 8.45 (s, 2H), 8.27 (s, 1H), 8.22 (s, 1H),
8.01 (s, 1H), 7.29 (t, J¼7.6 Hz, 1H), 7.18 (t, J¼7.7 Hz,
1H), 7.04 (d, J¼7.7 Hz, 1H), 6.96 (d, J¼7.6 Hz, 1H), 4.90
(d, J¼5.3 Hz, 1H), 4.42 (t, J¼4.2 Hz, 1H), 4.25 (d,
J¼5.0 Hz, 2H), 3.65 (s, 3H), 2.94 (d, J¼4.1 Hz, 2H), 2.68
(t, J¼5.4 Hz, 2H), 1.92 (m, J¼5.5 Hz, 2H), 1.58 (m,
J¼5.5 Hz, 2H), 1.57 (s, 9H). Anal. Calcd for C24H34N6O5:
C, 59.24; H, 7.04; N, 17.27. Found: C, 59.38; H, 7.19; N,
17.31.
3.4.19. N-[(3S)-N-Boc-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl]-L-leucine methylester (6s). Yield 95%. Mp
131–133 ꢀC; ESIMS: 444 [M+H]+; IR (KBr): 3442, 3203,
3001, 2955, 2840, 1731, 1640, 1600, 1451, 1390, 1375,
1063, 900 cmꢂ1
;
1H NMR (BHSC-500, DMSO-d6):
3.4.15. N-[(3S)-N-Boc-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl]-L-glycine methylester (6o). Yield 97%. Mp
133–135 ꢀC; ESIMS: 388 [M+H]+; IR (KBr): 3448, 3010,
2945, 2843, 1732, 1600, 1453, 1390, 1371, 1062,
d¼9.90 (s, 1H), 8.03 (s, 1H), 7.25 (t, J¼7.2 Hz, 1H), 7.19
(t, J¼7.2 Hz, 1H), 7.00 (d, J¼7.2 Hz, 1H), 6.84 (d,
J¼7.2 Hz, 1H), 4.95 (t, J¼5.3 Hz, 1H), 4.44 (t, J¼5.3 Hz,
1H), 4.25 (dd, J¼10.1, 4.4 Hz, 1H), 4.06 (dd, J¼10.1,
3.6 Hz, 1H), 3.64 (s, 3H), 2.93 (d, J¼6.4 Hz, 2H), 2.85 (d,
J¼5.0 Hz, 2H), 1.51 (s, 9H), 1.36 (m, J¼5.0 Hz, 1H), 1.09
(d, J¼5.2 Hz, 6H). [a]D20 ꢂ41 (c 0.31, CHCl3/CH3OH, 1:1,
v/v). Anal. Calcd for C24H33N3O5: C, 64.99; H, 7.50; N,
9.47. Found: C, 65.16; H, 7.61; N, 9.30.
1
899 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼9.93 (s,
1H), 8.02 (s, 1H), 7.30 (t, J¼7.5 Hz, 1H), 7.20 (t,
J¼7.6 Hz, 1H), 6.95 (d, J¼7.6 Hz, 1H), 6.83 (d, J¼7.6 Hz,
1H), 4.89 (d, J¼5.4 Hz, 1H), 4.22 (dd, J¼10.2, 4.5 Hz,
1H), 4.18 (s, 2H), 4.19 (dd, J¼10.2, 3.7 Hz, 1H), 3.66 (s,
3H), 2.95 (d, J¼10.1 Hz, 2H), 1.45 (s, 9H). [a]2D0 ꢂ101 (c
0.36, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for
C20H25N3O5: C, 62.00; H, 6.50; N, 10.85. Found: C,
62.15; H, 6.68; N, 10.68.
3.4.20. N-[(3S)-N-Boc-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl]-L-isoleucine methylester (6t). Yield 92%. Mp
122–125 ꢀC; ESIMS: 444 [M+H]+; IR (KBr): 3440, 3205,
3006, 2952, 2844, 1736, 1645, 1603, 1454, 1380, 1390,
3.4.16. N-[(3S)-N-Boc-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl]-L-(Z)lysine methylester (6p). Yield 90%. Mp
134–136 ꢀC; ESIMS: 593 [M+H]+; IR (KBr): 3442, 3007,
2940, 2848, 1730, 1605, 1455, 1391, 1370, 1066,
1060, 905 cmꢂ1 1H NMR (BHSC-500, DMSO-d6):
;
d¼9.93 (s, 1H), 8.02 (s, 1H), 7.29 (t, J¼7.3 Hz, 1H), 7.22
(t, J¼7.3 Hz, 1H), 7.02 (d, J¼7.3 Hz, 1H), 6.89 (d,
J¼7.3 Hz, 1H), 4.97 (t, J¼5.2 Hz, 1H), 4.40 (t, J¼5.2 Hz,
1H), 4.22 (dd, J¼10.0, 4.2 Hz, 1H), 4.01 (dd, J¼10.0,
3.4 Hz, 1H), 3.69 (s, 3H), 2.96 (d, J¼6.2 Hz, 2H), 2.93 (m,
J¼5.4 Hz, 1H), 1.49 (s, 9H), 1.33 (m, J¼5.5 Hz, 2H), 1.07
(d, J¼5.1 Hz, 3H), 0.97 (t, J¼5.5 Hz, 3H). [a]2D0 ꢂ49 (c
0.37, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for
C24H33N3O5: C, 64.99; H, 7.50; N, 9.47. Found: C, 64.80;
H, 7.39; N, 9.62.
1
897 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼9.95 (s,
1H), 8.03 (s, 1H), 7.96 (s, 1H), 7.28 (t, J¼7.6 Hz, 1H),
7.22 (t, J¼7.2 Hz, 1H), 7.19 (t, J¼7.6 Hz, 1H), 7.17 (d,
J¼7.2 Hz, 2H), 7.15 (t, J¼7.2 Hz, 2H), 6.96 (d, J¼7.6 Hz,
1H), 6.85 (d, J¼7.6 Hz, 1H), 5.36 (s, 2H), 4.90 (d,
J¼5.5 Hz, 1H), 4.41 (t, J¼4.4 Hz, 1H), 4.20 (dd, J¼10.0,
4.5 Hz, 1H), 4.18 (dd, J¼10.0, 3.7 Hz, 1H), 3.64 (s, 3H),
2.98 (t, J¼4.4 Hz, 2H), 2.93 (d, J¼10.0 Hz, 2H), 1.91 (m,
J¼4.4 Hz, 2H), 1.55 (m, J¼4.4 Hz, 2H), 1.46 (s, 9H), 1.29
(m, J¼4.4 Hz, 2H). [a]2D0 ꢂ22 (c 0.39, CHCl3/CH3OH,
1:1, v/v). Anal. Calcd for C32H40N4O7: C, 64.85; H, 6.80;
N, 9.45. Found: C, 64.98; H, 6.69; N, 9.62.
3.5. General procedure for the preparation of N-(N-Boc-
3S-1,2,3,4-tetrahydro-b-carboline-3-carboxyl)-L-amino
acids (7a–t)
At 0 ꢀC, to the solution of 2.5 mmol of 6a–t in 4 ml of meth-
anol and 2 ml of chloroform, 0.45 g (11.34 mmol) of NaOH
was added. The reaction mixture was stirred at 0 ꢀC for
70 min and TLC analysis (chloroform/methanol, 30:1) indi-
cated complete disappearance of 3a–t. On evaporation, the
residue was dissolved in 30 ml of water and extracted with
ethyl acetate (3ꢃ20 ml). The organic phase was washed suc-
cessively with 5% sodium bicarbonate, 5% citric acid, and
saturated sodium chloride and then dried over anhydrous so-
dium sulfate. After filtration and evaporation under reduced
pressure, the title compound was obtained as powder.
3.4.17. N-[(3S)-N-Boc-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl]-L-glutamine methylester (6q). Yield 90%. Mp
122–124 ꢀC; ESIMS: 459 [M+H]+; IR (KBr): 3445, 3200,
3001, 2940, 2835, 1733, 1640, 1602, 1452, 1391, 1370,
1065, 900 cmꢂ1
;
1H NMR (BHSC-500, DMSO-d6):
d¼9.91 (s, 1H), 8.00 (s, 1H), 7.29 (t, J¼7.4 Hz, 1H), 7.20
(t, J¼7.4 Hz, 1H), 7.00 (d, J¼7.4 Hz, 1H), 6.80 (d,
J¼7.4 Hz, 1H), 6.05 (s, 2H), 4.92 (d, J¼5.5 Hz, 1H), 4.41
(t, J¼5.5 Hz, 1H), 4.24 (d, J¼5.6 Hz, 2H), 3.67 (s, 3H),
2.94 (d, J¼5.4 Hz, 2H), 2.18 (t, J¼5.5 Hz, 2H), 2.14 (t,
J¼5.5 Hz, 2H), 1.46 (s, 9H). [a]2D0 ꢂ56 (c 0.38, CHCl3/
CH3OH, 1:1, v/v). Anal. Calcd for C23H30N4O6: C, 60.25;
H, 6.59; N, 12.22. Found: C, 60.73; H, 6.49; N, 8.69.
3.5.1. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-alanine (7a). Yield 79%. Mp 169–171 ꢀC;

G. Wu et al. / Tetrahedron 63 (2007) 5510–5528
5521
ESIMS: 388 [M+H]+; IR (KBr): 3439, 3234, 3215, 3000,
2952, 2847, 1732, 1645, 1602, 1453, 1390, 1373, 1061,
J¼7.2 Hz, 1H), 4.89 (d, J¼5.3 Hz, 1H), 4.46 (d, J¼5.4 Hz,
1H), 4.37 (m, J¼5.1 Hz, 1H), 4.27 (d, J¼4.8 Hz, 2H),
2.95 (d, J¼5.5 Hz, 2H), 2.16 (s, 1H), 1.48 (s, 9H), 1.26
(d, J¼5.2 Hz, 3H). [a]D20 ꢂ49 (c 0.39, CHCl3/CH3OH, 1:1,
v/v). Anal. Calcd for C21H27N3O6: C, 60.42; H, 6.52; N,
10.07. Found: C, 60.28; H, 6.39; N, 10.16.
1
904 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼11.02 (s,
1H), 9.95 (s, 1H), 7.98 (s, 1H), 7.29 (t, J¼7.6 Hz, 1H),
7.17 (t, J¼7.9 Hz, 1H), 7.03 (d, J¼7.9 Hz, 1H), 6.94 (d,
J¼7.6 Hz, 1H), 4.93 (d, J¼5.4 Hz, 1H), 4.66 (m,
J¼5.4 Hz, 1H), 4.27 (d, J¼6.3 Hz, 2H), 2.97 (d, J¼9.5 Hz,
2H), 1.48 (d, J¼5.4 Hz, 3H), 1.45 (s, 9H). [a]2D0 ꢂ46
(c 0.39, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for
C20H25N3O5: C, 62.00; H, 6.50; N, 10.85. Found: C,
62.18; H, 6.39; N, 10.71.
3.5.6. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-tyrosine (7f). Yield 67%. Mp 147–149 ꢀC;
ESIMS: 480 [M+H]+; IR (KBr): 3441, 3236, 3217, 3004,
2955, 2846, 1731, 1647, 1600, 1450, 1392, 1371, 1058,
1
899 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼10.97 (s,
3.5.2. N-[(3S)-N-Boc-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl]-L-phenylalanine (7b). Yield 94%. Mp 129–
131 ꢀC; ESIMS: 464 [M+H]+; IR (KBr): 3446, 3205,
3006, 2948, 2847, 1731, 1645, 1603, 1451, 1392, 1370,
1H), 9.60 (s, 1H), 8.15 (s, 1H), 7.32 (t, J¼7.2 Hz, 1H),
7.14 (t, J¼7.4 Hz, 1H), 7.01 (d, J¼7.2 Hz, 1H), 6.96 (d,
J¼7.2 Hz, 1H), 6.94 (d, J¼7.5 Hz, 2H), 6.88 (d, J¼7.2 Hz,
2H), 5.03 (s, 1H), 4.94 (d, J¼5.2 Hz, 1H), 4.84 (d,
J¼5.3 Hz, 1H), 4.27 (d, J¼5.2 Hz, 2H), 3.07 (m,
J¼3.4 Hz, 2H), 2.92 (d, J¼4.5 Hz, 2H), 1.48 (s, 9H). [a]D20
ꢂ61 (c 0.36, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for
C26H29N3O6: C, 65.12; H, 6.10; N, 8.76. Found: C, 65.28;
H, 6.17; N, 8.59.
1069, 904 cmꢂ1
;
1H NMR (BHSC-500, DMSO-d6):
d¼10.94 (s, 1H), 9.93 (s, 1H), 7.97 (s, 1H), 7.30 (t,
J¼7.3 Hz, 1H), 7.26 (t, J¼7.4 Hz, 2H), 7.17 (t, J¼7.6 Hz,
1H), 7.15 (d, J¼7.4 Hz, 2H), 7.10 (t, J¼7.4 Hz, 1H), 7.02
(t, J¼7.4 Hz, 1H), 6.97 (d, J¼7.4 Hz, 1H), 4.93 (d,
J¼5.2 Hz, 1H), 4.78 (t, J¼5.2 Hz, 1H), 4.27 (d, J¼5.2 Hz,
2H), 3.07 (d, J¼4.5 Hz, 2H), 2.98 (d, J¼5.2 Hz, 2H), 1.49
(s, 9H). [a]2D0 ꢂ30 (c 0.36, CHCl3/CH3OH, 1:1, v/v); [a]D20
ꢂ66 (c 0.36, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for
C26H29N3O5: C, 67.37; H, 6.31; N, 9.07. Found: C, 67.22;
H, 6.39; N, 10.21.
3.5.7. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-proline (7g). Yield 83%. Mp 136–138 ꢀC;
ESIMS: 414 [M+H]+; IR (KBr): 3440, 3236, 3217, 3004,
2956, 2841, 1735, 1641, 1605, 1450, 1392, 1370, 1044,
1
897 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼10.95 (s,
1H), 9.70 (s, 1H), 7.32 (t, J¼7.2 Hz, 1H), 7.14 (t,
J¼7.5 Hz, 1H), 7.08 (d, J¼7.5 Hz, 1H), 6.96 (d, J¼7.2 Hz,
1H), 4.92 (d, J¼5.1 Hz, 1H), 4.32 (t, J¼5.3 Hz, 1H), 4.22
(m, J¼5.3 Hz, 2H), 3.47 (t, J¼5.2 Hz, 2H), 2.95 (d,
J¼5.2 Hz, 2H), 2.17 (dd, J¼5.2, 3.4 Hz, 2H), 1.94 (t,
J¼4.5 Hz, 2H), 1.47 (s, 9H). [a]2D0 ꢂ49 (c 0.35, CHCl3/
CH3OH, 1:1, v/v). Anal. Calcd for C22H27N3O5: C, 63.91;
H, 6.58; N, 10.16. Found: C, 64.14; H, 6.47; N, 10.32.
3.5.3. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-valine (7c). Yield 71%. Mp 148–150 ꢀC;
ESIMS: 416 [M+H]+; IR (KBr): 3441, 3236, 3212, 3002,
2951, 2845, 1731, 1643, 1600, 1450, 1392, 1374, 1060,
1
900 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼10.94 (s,
1H), 9.23 (s, 1H), 7.96 (s, 1H), 7.29 (t, J¼7.5 Hz, 1H),
7.18 (t, J¼7.6 Hz, 1H), 7.06 (d, J¼7.4 Hz, 1H), 6.97 (d,
J¼7.5 Hz, 1H), 4.95 (d, J¼5.2 Hz, 1H), 4.48 (d, J¼5.2 Hz,
1H), 4.27 (d, J¼5.1 Hz, 2H), 2.92 (d, J¼5.5 Hz, 2H), 2.78
(m, J¼4.5 Hz, 1H), 1.49 (s, 9H), 1.25 (d, J¼5.6 Hz, 6H).
[a]2D0 ꢂ72 (c 0.38, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd
for C22H29N3O5: C, 63.60; H, 7.04; N, 10.11. Found: C,
63.42; H, 7.19; N, 10.21.
3.5.8. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-cysteine (7h). Yield 78%. Mp 150–152 ꢀC;
ESIMS: 420 [M+H]+; IR (KBr): 3436, 3232, 3217, 3004,
2950, 2844, 1731, 1647, 1600, 1455, 1392, 1375, 1058,
1
902 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼10.89 (s,
1H), 9.95 (s, 1H), 7.99 (s, 1H), 7.27 (t, J¼7.3 Hz, 1H),
7.15 (t, J¼7.6 Hz, 1H), 7.05 (d, J¼7.6 Hz, 1H), 6.95 (t,
J¼7.2 Hz, 1H), 4.91 (t, J¼5.0 Hz, 1H), 4.75 (t, J¼5.2 Hz,
1H), 4.24 (m, J¼5.0 Hz, 2H), 3.06 (d, J¼5.0 Hz, 2H), 2.89
(d, J¼4.5 Hz, 2H), 1.55 (s, 1H), 1.52 (s, 9H). [a]2D0 ꢂ45
(c 0.38, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for
C20H25N3O5S: C, 57.26; H, 6.01; N, 10.02. Found: C,
57.19; H, 6.13; N, 10.12.
3.5.4. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-serine (7d). Yield 84%. Mp 136–138 ꢀC;
ESIMS: 390 [M+H]+; IR (KBr): 3437, 3236, 3213, 3005,
2950, 2846, 1730, 1641, 1600, 1451, 1392, 1370, 1058,
1
897 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼10.92 (s,
1H), 9.93 (s, 1H), 7.97 (s, 1H), 7.30 (t, J¼7.3 Hz, 1H),
7.19 (t, J¼7.6 Hz, 1H), 7.06 (d, J¼7.6 Hz, 1H), 6.98 (d,
J¼7.3 Hz, 1H), 4.92 (d, J¼5.5 Hz, 1H), 4.46 (t, J¼5.2 Hz,
1H), 4.27 (d, J¼5.0 Hz, 2H), 4.06 (d, J¼5.1 Hz, 2H), 2.93
(d, J¼5.4 Hz, 2H), 2.07 (s, 1H), 1.51 (s, 9H). [a]2D0 ꢂ70
(c 0.35, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for
C20H25N3O6: C, 59.54; H, 6.25; N, 10.42. Found: C,
59.42; H, 6.19; N, 10.29.
3.5.9. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-methionine (7i). Yield 72%. Mp 148–150 ꢀC;
ESIMS: 448 [M+H]+; IR (KBr): 3436, 3232, 3213, 3007,
2953, 2849, 1735, 1648, 1600, 1450, 1393, 1375, 1055,
1
897 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼11.01 (s,
1H), 9.97 (s, 1H), 8.01 (s, 1H), 7.33 (t, J¼7.0 Hz, 1H), 7.18
(t, J¼7.5 Hz, 1H), 7.05 (d, J¼7.5 Hz, 1H), 6.95 (t,
J¼7.0 Hz, 1H), 4.44 (t, J¼5.5 Hz, 1H), 4.25 (m, J¼5.2 Hz,
1H), 4.23 (m, J¼5.0 Hz, 2H), 2.89 (d, J¼4.4 Hz, 2H), 2.46
(t, J¼5.4 Hz, 2H), 2.16 (m, J¼5.6 Hz, 2H), 2.09 (s, 3H),
1.50 (s, 9H). [a]2D0 ꢂ38 (c 0.39, CHCl3/CH3OH, 1:1, v/v).
Anal. Calcd for C22H29N3O5S: C, 59.04; H, 6.53; N, 9.39.
Found: C, 59.20; H, 6.44; N, 9.22.
3.5.5. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-threonine (7e). Yield 78%. Mp 143–145 ꢀC;
ESIMS: 405 [M+H]+; IR (KBr): 3444, 3235, 3217, 3005,
2950, 2843, 1730, 1641, 1600, 1450, 1389, 1370, 1055,
1
896 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼10.97 (s,
1H), 8.92 (s, 1H), 7.95 (s, 1H), 7.29 (t, J¼7.2 Hz, 1H),
7.15 (t, J¼7.4 Hz, 1H), 7.05 (d, J¼7.4 Hz, 1H), 6.98 (d,

5522
G. Wu et al. / Tetrahedron 63 (2007) 5510–5528
3.5.10. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-glutamic acid (7j). Yield 76%. Mp 160–
162 ꢀC; ESIMS: 446 [M+H]+; IR (KBr): 3444, 3231,
3212, 3008, 2954, 2843, 1730, 1642, 1600, 1450, 1391,
1H), 8.55 (s, 2H), 8.31 (s, 2H), 8.23 (s, 1H), 7.98 (s, 1H),
7.29 (t, J¼7.5 Hz, 1H), 7.11 (t, J¼7.6 Hz, 1H), 7.02 (d,
J¼7.6 Hz, 1H), 6.98 (d, J¼7.5 Hz, 1H), 4.87 (t, J¼5.4 Hz,
1H), 4.41 (t, J¼4.3 Hz, 1H), 4.25 (d, J¼4.8 Hz, 2H), 2.89
(d, J¼4.9 Hz, 2H), 2.66 (t, J¼5.2 Hz, 2H), 1.81 (m,
J¼5.1 Hz, 2H), 1.59 (m, J¼5.3 Hz, 2H), 1.56 (s, 9H).
[a]2D0 ꢂ66 (c 0.37, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd
for C23H32N6O5: C, 58.46; H, 6.83; N, 17.78. Found: C,
58.38; H, 6.96; N, 17.57.
1
1371, 1058, 900 cmꢂ1; H NMR (BHSC-500, DMSO-d6):
d¼11.02 (s, 2H), 9.87 (s, 1H), 8.11 (s, 1H), 7.28 (t,
J¼7.2 Hz, 1H), 7.14 (t, J¼7.2 Hz, 1H), 7.06 (d, J¼7.4 Hz,
1H), 6.97 (t, J¼7.2 Hz, 1H), 4.90 (t, J¼5.1 Hz, 1H), 4.42
(t, J¼5.4 Hz, 1H), 4.21 (d, J¼5.1 Hz, 2H), 2.87 (d,
J¼5.3 Hz, 2H), 2.22 (t, J¼5.2 Hz, 2H), 2.08 (t, J¼5.2 Hz,
2H), 1.47 (s, 9H). [a]D20 ꢂ51 (c 0.33, CHCl3/CH3OH, 1:1,
v/v). Anal. Calcd for C22H27N3O7: C, 59.32; H, 6.11; N,
9.43. Found: C, 59.24; H, 6.01; N, 9.29.
3.5.15. N-[(3S)-N-Boc-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl]-L-glycine (7o). Yield 95%. Mp 148–150 ꢀC;
ESIMS: 374 [M+H]+; IR (KBr): 3444, 3230, 3008, 2942,
1
2841, 1730, 1602, 1455, 1391, 1370, 1064, 898 cmꢂ1; H
3.5.11. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-aspartic acid (7k). Yield 72%. Mp 141–
143 ꢀC; ESIMS: 432 [M+H]+; IR (KBr): 3442, 3236,
3217, 3005, 2950, 2843, 1728, 1642, 1600, 1450, 1392,
NMR (BHSC-500, DMSO-d6): d¼11.03 (s, 1H), 9.98 (s,
1H), 8.01 (s, 1H), 7.29 (t, J¼7.5 Hz, 1H), 7.18 (t,
J¼7.6 Hz, 1H), 6.97 (d, J¼7.6 Hz, 1H), 6.85 (d, J¼7.6 Hz,
1H), 4.90 (d, J¼5.4 Hz, 1H), 4.24 (dd, J¼10.2, 4.5 Hz,
1H), 4.17 (s, 2H), 4.16 (dd, J¼10.2, 3.7 Hz, 1H), 2.93 (d,
J¼10.0 Hz, 2H), 1.46 (s, 9H). [a]2D0 ꢂ98 (c 0.38, CHCl3/
CH3OH, 1:1, v/v). Anal. Calcd for C19H23N3O5: C, 61.11;
H, 6.21; N, 11.25. Found: C, 61.30; H, 6.40; N, 11.09.
1
1370, 1058, 896 cmꢂ1; H NMR (BHSC-500, DMSO-d6):
d¼10.99 (s, 2H), 9.94 (s, 1H), 7.98 (s, 1H), 7.26 (t,
J¼7.1 Hz, 1H), 7.11 (t, J¼7.1 Hz, 1H), 7.05 (d, J¼7.2 Hz,
1H), 6.94 (d, J¼7.2 Hz, 1H), 4.87 (t, J¼5.2 Hz, 1H), 4.76
(t, J¼5.3 Hz, 1H), 4.20 (m, J¼4.8 Hz, 2H), 2.89 (d,
J¼5.2 Hz, 2H), 2.66 (d, J¼5.2 Hz, 2H), 1.47 (s, 9H). [a]D20
ꢂ47 (c 0.35, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for
C21H25N3O7: C, 58.46; H, 5.84; N, 9.74. Found: C, 58.55;
H, 6.02; N, 9.91.
3.5.16. N-[(3S)-N-Boc-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl]-L-lys(Z)-OH (7p). Yield 92%. Mp 155–157 ꢀC;
ESIMS: 579 [M+H]+; IR (KBr): 3438, 3234, 3215, 3009,
2944, 2845, 1733, 1602, 1453, 1390, 1372, 1064,
1
899 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼10.88 (s,
3.5.12. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-histidine (7l). Yield 76%. Mp 156–158 ꢀC;
ESIMS: 454 [M+H]+; IR (KBr): 3445, 3231, 3212, 3007,
2947, 2842, 1730, 1642, 1600, 1450, 1388, 1370, 1059,
1H), 9.97 (s, 1H), 8.01 (s, 1H), 7.98 (s, 1H), 7.29 (t,
J¼7.5 Hz, 1H), 7.21 (t, J¼7.3 Hz, 1H), 7.18 (t, J¼7.5 Hz,
1H), 7.17 (d, J¼7.3 Hz, 2H), 7.16 (t, J¼7.3 Hz, 2H), 6.98
(d, J¼7.5 Hz, 1H), 6.88 (d, J¼7.5 Hz, 1H), 5.33 (s, 2H),
4.92 (d, J¼5.6 Hz, 1H), 4.45 (t, J¼4.6 Hz, 1H), 4.23 (dd,
J¼10.0, 4.5 Hz, 1H), 4.19 (dd, J¼10.0, 3.7 Hz, 1H), 2.94
(t, J¼4.6 Hz, 2H), 2.95 (d, J¼10.0 Hz, 2H), 1.84 (m,
J¼4.6 Hz, 2H), 1.54 (m, J¼4.6 Hz, 2H), 1.46 (s, 9H), 1.29
(m, J¼4.6 Hz, 2H). [a]2D0 ꢂ34 (c 0.36, CHCl3/CH3OH,
1:1, v/v). Anal. Calcd for C31H38N4O7: C, 64.34; H, 6.62;
N, 9.68. Found: C, 64.18; H, 6.44; N, 9.83.
1
899 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼11.85 (s,
1H), 11.62 (s, 1H), 9.94 (s, 1H), 7.89 (s, 1H), 7.45 (s, 1H),
7.29 (t, J¼7.2 Hz, 1H), 7.15 (t, J¼7.5 Hz, 1H), 7.06 (d,
J¼7.5 Hz, 1H), 6.98 (d, J¼7.2 Hz, 1H), 6.82 (s, 1H), 4.89
(t, J¼5.0 Hz, 1H), 4.82 (t, J¼5.1 Hz, 1H), 4.20 (m,
J¼5.1 Hz, 2H), 3.02 (d, J¼5.0 Hz, 2H), 2.92 (d, J¼5.2 Hz,
2H), 1.50 (s, 9H). [a]D20 ꢂ50 (c 0.36, CHCl3/CH3OH, 1:1,
v/v). Anal. Calcd for C23H27N5O5: C, 60.92; H, 6.00; N,
15.44. Found: C, 61.05; H, 6.09; N, 15.26.
3.5.17. N-[(3S)-N-Boc-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl]-L-glutamine (7q). Yield 90%. Mp 129–131 ꢀC;
ESIMS: 445 [M+H]+; IR (KBr): 3448, 3230, 3215, 3005,
2942, 2833, 1738, 1642, 1604, 1450, 1390, 1372, 1063,
3.5.13. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-tryptophan (7m). Yield 70%. Mp 158–
160 ꢀC; ESIMS: 503 [M+H]+; IR (KBr): 3445, 3238,
3217, 3008, 2951, 2842, 1728, 1641, 1600, 1450, 1393,
1
901 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼10.96 (s,
1H), 9.88 (s, 1H), 8.02 (s, 1H), 7.28 (t, J¼7.5 Hz, 1H),
7.21 (t, J¼7.5 Hz, 1H), 7.01 (d, J¼7.5 Hz, 1H), 6.82 (d,
J¼7.5 Hz, 1H), 6.02 (s, 2H), 4.90 (d, J¼5.6 Hz, 1H), 4.45
(t, J¼5.4 Hz, 1H), 4.25 (d, J¼5.5 Hz, 2H), 2.92 (d,
J¼5.5 Hz, 2H), 2.17 (t, J¼5.5 Hz, 2H), 2.07 (t, J¼5.5 Hz,
2H), 1.42 (s, 9H). [a]D20 ꢂ54 (c 0.39, CHCl3/CH3OH, 1:1,
v/v). Anal. Calcd for C22H28N4O6: C, 59.45; H, 6.35; N,
12.60. Found: C, 59.63; H, 6.20; N, 12.79.
1
1370, 1058, 897 cmꢂ1; H NMR (BHSC-500, DMSO-d6):
d¼10.98 (s, 1H), 9.87 (s, 1H), 9.84 (s, 1H), 8.01 (s, 1H),
7.30 (t, J¼7.1 Hz, 1H), 7.16 (t, J¼7.1 Hz, 1H), 7.14 (t,
J¼7.4 Hz, 1H), 7.12 (t, J¼7.2 Hz, 1H), 7.06 (d, J¼7.4 Hz,
1H), 7.05 (d, J¼7.2 Hz, 1H), 6.99 (d, J¼7.1 Hz, 1H), 6.96
(d, J¼7.1 Hz, 1H), 6.82 (s, 1H), 4.89 (t, J¼5.2 Hz, 1H),
4.84 (t, J¼5.1 Hz, 1H), 4.25 (m, J¼5.0 Hz, 2H), 2.91 (d,
J¼5.0 Hz, 2H), 2.88 (d, J¼5.1 Hz, 2H), 1.53 (s, 9H). [a]D20
ꢂ47 (c 0.38, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for
C28H30N4O5: C, 66.92; H, 6.02; N, 11.15. Found: C,
66.79; H, 5.94; N, 11.27.
3.5.18. N-[(3S)-N-Boc-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl]-L-asparagine (7r). Yield 92%. Mp 155–157 ꢀC;
ESIMS: 431 [M+H]+; IR (KBr): 3445, 3225, 3008, 2939,
2834, 1735, 1639, 1602, 1452, 1391, 1370, 1060,
1
3.5.14. N-(N-Boc-3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl)-L-arginine (7n). Yield 81%. Mp 144–146 ꢀC;
ESIMS: 473 [M+H]+; IR (KBr): 3441, 3230, 3212, 3007,
2950, 2844, 1730, 1640, 1600, 1450, 1392, 1375, 1057,
905 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼10.92 (s,
1H), 9.86 (s, 1H), 8.00 (s, 1H), 7.27 (t, J¼7.3 Hz, 1H),
7.19 (t, J¼7.3 Hz, 1H), 7.02 (d, J¼7.3 Hz, 1H), 6.80 (d,
J¼7.3 Hz, 1H), 6.04 (s, 2H), 4.92 (d, J¼5.5 Hz, 1H), 4.46
(t, J¼5.5 Hz, 1H), 4.23 (d, J¼5.5 Hz, 2H), 2.94 (d,
1
896 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼10.94 (s,

G. Wu et al. / Tetrahedron 63 (2007) 5510–5528
5523
J¼5.5 Hz, 2H), 2.18 (t, J¼5.5 Hz, 2H), 1.52 (s, 9H). [a]D20
ꢂ44 (c 0.33, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for
C21H26N4O6: C, 58.59; H, 6.09; N, 13.02. Found: C,
58.42; H, 6.00; N, 13.22.
v/v). Anal. Calcd for C15H17N3O3: C, 62.71; H, 5.96; N,
14.63. Found: C, 62.55; H, 5.79; N, 14.55.
3.6.2. N-[(3S)-1,2,3,4-Tetrahydro-b-carboline-3-carb-
oxyl]-L-phenylalanine (8b). Yield 95%. ESIMS: 364
[M+H]+; IR (KBr): 3435, 3231, 3213, 3003, 2950, 2844,
3.5.19. N-[(3S)-N-Boc-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl]-L-leucine (7s). Yield 95%. Mp 144–146 ꢀC;
ESIMS: 430 [M+H]+; IR (KBr): 3441, 3233, 3207, 3010,
2950, 2840, 1731, 1642, 1600, 1455, 1390, 1375, 1060,
1730, 1642, 1600, 1450, 1060, 901 cmꢂ1
;
1H NMR
(300 MHz, DMSO-d6): d¼11.33 (s, 1H), 10.05 (s, 1H),
9.93 (s, 1H), 8.01 (s, 1H), 7.33 (t, J¼6.8 Hz, 1H), 7.30 (t,
J¼6.4 Hz, 2H), 7.20 (t, J¼7.6 Hz, 1H), 7.17 (d, J¼7.8 Hz,
2H), 7.10 (t, J¼6.8 Hz, 1H), 7.02 (d, J¼7.6 Hz, 1H), 6.89
(d, J¼7.4 Hz, 1H), 4.86 (t, J¼5.4 Hz, 1H), 4.00 (m,
J¼5.4 Hz, 1H), 3.88 (d, J¼6.2 Hz, 2H), 3.07 (d, J¼6.5 Hz,
2H), 2.81 (d, J¼6.2 Hz, 2H). [a]2D0 ꢂ30 (c 0.35, CHCl3/
CH3OH, 1:1, v/v). Anal. Calcd for C21H21N3O3: C, 69.41;
H, 5.82; N, 11.56. Found: C, 69.56; H, 5.75; N, 11.34.
1
900 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼9.96 (s,
1H), 9.90 (s, 1H), 8.02 (s, 1H), 7.22 (t, J¼7.3 Hz, 1H),
7.17 (t, J¼7.3 Hz, 1H), 6.91 (d, J¼7.3 Hz, 1H), 6.82 (d,
J¼7.3 Hz, 1H), 4.93 (t, J¼5.5 Hz, 1H), 4.40 (t, J¼5.5 Hz,
1H), 4.17 (dd, J¼10.0, 4.5 Hz, 1H), 4.00 (dd, J¼10.0,
3.8 Hz, 1H), 2.94 (d, J¼5.4 Hz, 2H), 2.80 (d, J¼5.4 Hz,
2H), 1.45 (s, 9H), 1.39 (m, J¼5.4 Hz, 1H), 1.11 (d,
J¼5.4 Hz, 6H). [a]D20 ꢂ39 (c 0.35, CHCl3/CH3OH, 1:1,
v/v). Anal. Calcd for C23H31N3O5: C, 64.32; H, 7.27; N,
9.78. Found: C, 64.48; H, 7.37; N, 9.64.
3.6.3. N-[(3S)-1,2,3,4-Tetrahydro-b-carboline-3-carb-
oxyl]-L-valine (8c). Yield 95%. ESIMS: 316 [M+H]+; IR
(KBr): 3441, 3236, 3212, 3002, 2951, 2845, 1731, 1643,
1600, 1450, 1060, 900 cmꢂ1; 1H NMR (300 MHz, DMSO-
d6): d¼11.68 (s, 1H), 10.19 (s, 1H), 9.88 (s, 1H), 8.03 (s,
1H), 7.32 (t, J¼7.5 Hz, 1H), 7.17 (t, J¼7.8 Hz, 1H), 7.05
(d, J¼7.4 Hz, 1H), 6.98 (d, J¼7.4 Hz, 1H), 4.48 (t,
J¼5.2 Hz, 1H), 3.94 (t, J¼5.2 Hz, 1H), 3.90 (d, J¼5.2 Hz,
2H), 2.82 (d, J¼5.4 Hz, 2H), 2.80 (m, J¼6.9 Hz, 1H), 1.06
(d, J¼6.9 Hz, 6H). [a]D20 ꢂ70 (c 0.38, CHCl3/CH3OH, 1:1,
v/v). Anal. Calcd for C17H21N3O3: C, 64.74; H, 6.71; N,
13.32. Found: C, 64.89; H, 6.85; N, 13.44.
3.5.20. N-[(3S)-N-Boc-1,2,3,4-tetrahydro-b-carboline-3-
carboxyl]-L-isoleucine (7t). Yield 96%. Mp 144–146 ꢀC;
ESIMS: 430 [M+H]+; IR (KBr): 3445, 3237, 3212, 3003,
2955, 2844, 1734, 1645, 1602, 1457, 1382, 1062,
1
904 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼10.98 (s,
1H), 9.93 (s, 1H), 8.04 (s, 1H), 7.26 (t, J¼7.3 Hz, 1H),
7.21 (t, J¼7.3 Hz, 1H), 6.94 (d, J¼7.3 Hz, 1H), 6.85 (d,
J¼7.3 Hz, 1H), 4.97 (t, J¼5.4 Hz, 1H), 4.43 (t, J¼5.4 Hz,
1H), 4.20 (dd, J¼10.2, 4.3 Hz, 1H), 4.02 (dd, J¼10.2,
3.9 Hz, 1H), 2.96 (d, J¼5.3 Hz, 2H), 1.82 (m, J¼5.3 Hz,
1H), 1.47 (s, 9H), 1.30 (m, J¼5.3 Hz, 2H), 1.09 (d,
J¼5.2 Hz, 3H), 0.95 (t, J¼5.2 Hz, 3H). [a]2D0 ꢂ57 (c
0.37, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for
C23H31N3O5: C, 64.32; H, 7.27; N, 9.78. Found: C, 4.16;
H, 7.09; N, 9.62.
3.6.4. N-[(3S)-1,2,3,4-Tetrahydro-b-carboline-3-carb-
oxyl]-L-serine (8d). Yield 89%. ESIMS: 304 [M+H]+; IR
(KBr): 3437, 3236, 3213, 3005, 2950, 2846, 1730, 1641,
1600, 1451, 1058, 897 cmꢂ1; 1H NMR (300 MHz, DMSO-
d6): d¼11.50 (s, 1H), 10.19 (s, 1H), 9.96 (s, 1H), 8.10 (s,
1H), 7.31 (t, J¼7.5 Hz, 1H), 7.18 (t, J¼7.8 Hz, 1H), 7.09
(d, J¼7.8 Hz, 1H), 6.89 (d, J¼7.5 Hz, 1H), 4.59 (t,
J¼5.1 Hz, 1H), 4.04 (d, J¼5.1 Hz, 2H), 3.96 (t, J¼5.1 Hz,
1H), 3.81 (d, J¼5.9 Hz, 2H), 2.78 (d, J¼5.5 Hz, 2H), 2.30
(s, 1H). [a]2D0 ꢂ70 (c 0.38, CHCl3/CH3OH, 1:1, v/v). Anal.
Calcd for C15H17N3O4: C, 59.40; H, 5.65; N, 13.85. Found:
C, 59.56; H, 5.81; N, 13.79.
3.6. General procedure for the preparation of N-[(3S)-
1,2,3,4-tetrahydro-b-carboline- 3-carboxyl]amino acids
8a–t from 7a–t
At 0 ꢀC, to the solution of 2.5 mmol of 7a–t in 4 ml of meth-
anol and 2 ml of chloroform, 450 mg (11.34 mmol) of
NaOH was added. The reaction mixture was stirred at 0 ꢀC
for 70 min and TLC (chloroform/methanol, 30:1) indicated
the completion of the reaction. The reaction mixture was ad-
justed to pH 2 with hydrochloric acid (2 mol/l). Upon evap-
oration, the residue was dissolved in 30 ml of ethyl acetate.
The organic phase was washed with saturated aqueous so-
dium chloride and then dried over anhydrous sodium sulfate.
After filtration, the title compound was obtained as pale yel-
low powder upon evaporation under reduced pressure and
purified with flash chromatography.
3.6.5. N-[(3S)-1,2,3,4-Tetrahydro-b-carboline-3-carbox-
yl]-L-threonine (8e). Yield 88%. ESIMS: 318 [M+H]+; IR
(KBr): 3446, 3238, 3213, 3007, 2952, 2840, 1732, 1645,
1
1602, 1455, 1372, 1051, 895 cmꢂ1; H NMR (BHSC-500,
DMSO-d6): d¼10.99 (s, 1H), 8.90 (s, 1H), 8.12 (s, 1H),
7.98 (s, 1H), 7.27 (t, J¼7.0 Hz, 1H), 7.13 (t, J¼7.2 Hz, 1H),
7.02 (d, J¼7.2 Hz, 1H), 6.96 (d, J¼7.0 Hz, 1H), 4.87 (d,
J¼5.2 Hz, 1H), 4.44 (d, J¼5.2 Hz, 1H), 4.35 (m, J¼5.2 Hz,
1H), 4.23 (d, J¼4.7 Hz, 2H), 2.97 (d, J¼5.4 Hz, 2H), 2.14
(s, 1H), 1.25 (d, J¼5.1 Hz, 3H). [a]2D0 ꢂ62 (c 0.39, CHCl3/
CH3OH, 1:1, v/v). Anal. Calcd for C16H19N3O4: C, 60.56;
H, 6.03; N, 13.24. Found: C, 60.40; H, 6.12; N, 13.41.
3.6.1. N-[(3S)-1,2,3,4-Tetrahydro-b-carboline-3-carb-
oxyl]-L-alanine (8a). Yield 94%. Mp 177–179 ꢀC; ESIMS:
288 [M+H]+; IR (KBr): 3439, 3234, 3215, 3000, 2952,
1
2847, 1732, 1645, 1602, 1453, 1061, 904 cmꢂ1; H NMR
3.6.6. N-[(3S)-1,2,3,4-Tetrahydro-b-carboline-3-carbox-
yl]-L-tyrosine (8f). Yield 89%. ESIMS: 380 [M+H]+; IR
(KBr): 3443, 3234, 3215, 3002, 2950, 2842, 1735, 1643,
(300 MHz, DMSO-d6): d¼11.06 (s, 1H), 10.01 (s, 1H),
9.97 (s, 1H), 8.01 (s, 1H), 7.29 (t, J¼6.5 Hz, 1H), 7.18 (t,
J¼7.8 Hz, 1H), 6.84 (d, J¼7.8 Hz, 1H), 6.80 (d, J¼7.6 Hz,
1H), 4.64 (m, J¼5.4 Hz, 1H), 3.96 (m, J¼5.5 Hz, 1H),
3.86 (d, J¼5.3 Hz, 2H), 2.83 (d, J¼5.4 Hz, 2H), 1.45
(d, J¼5.4 Hz, 3H). [a]D20 ꢂ80 (c 0.38, CHCl3/CH3OH, 1:1,
1
1602, 1453, 1372, 1055, 896 cmꢂ1; H NMR (BHSC-500,
DMSO-d6): d¼11.05 (s, 1H), 8.98 (s, 1H), 8.17 (s, 1H),
8.03 (s, 1H), 7.30 (t, J¼7.0 Hz, 1H), 7.10 (t, J¼7.2 Hz,
1H), 7.00 (d, J¼7.0 Hz, 1H), 6.97 (d, J¼7.0 Hz, 1H), 6.90

5524
G. Wu et al. / Tetrahedron 63 (2007) 5510–5528
(d, J¼7.2 Hz, 2H), 6.85 (d, J¼7.0 Hz, 2H), 5.00 (s, 1H),
4.92 (d, J¼5.0 Hz, 1H), 4.80 (d, J¼5.1 Hz, 1H), 4.25
(d, J¼5.0 Hz, 2H), 3.05 (m, J¼3.5 Hz, 2H), 2.90 (d,
J¼4.4 Hz, 2H). [a]D20 ꢂ69 (c 0.36, CHCl3/CH3OH, 1:1,
v/v). Anal. Calcd for C21H21N3O4: C, 66.48; H, 5.58;
N, 11.08. Found: C, 66.62; H, 6.67; N, 11.24.
[M+H]+; IR (KBr): 3442, 3236, 3217, 3005, 2950, 2843,
1
1728, 1642, 1600, 1450, 1392, 1370, 1058, 896 cmꢂ1; H
NMR (BHSC-500, DMSO-d6): d¼10.99 (s, 2H), 9.94 (s,
1H), 7.98 (s, 1H), 7.26 (t, J¼7.1 Hz, 1H), 7.11 (t,
J¼7.1 Hz, 1H), 7.05 (d, J¼7.2 Hz, 1H), 6.94 (d, J¼7.2 Hz,
1H), 4.87 (t, J¼5.2 Hz, 1H), 4.76 (t, J¼5.3 Hz, 1H), 4.20
(m, J¼4.8 Hz, 2H), 2.89 (d, J¼5.2 Hz, 2H), 2.66 (d,
J¼5.2 Hz, 2H), 1.47 (s, 9H). [a]2D0 ꢂ47 (c 0.35, CHCl3/
CH3OH, 1:1, v/v). Anal. Calcd for C21H25N3O7: C, 58.46;
H, 5.84; N, 9.74. Found: C, 58.55; H, 6.02; N, 9.91.
3.6.7. N-[(3S)-1,2,3,4-Tetrahydro-b-carboline-3-carb-
oxyl]-L-proline (8g). Yield 94%. ESIMS: 314 [M+H]+; IR
(KBr): 3443, 3232, 3215, 3000, 2951, 2845, 1730, 1644,
1603, 1452, 1046, 899 cmꢂ1
;
1H NMR (BHSC-500,
DMSO-d6): d¼10.98 (s, 1H), 8.96 (s, 1H), 8.13 (s, 1H),
7.30 (t, J¼7.0 Hz, 1H), 7.12 (t, J¼7.2 Hz, 1H), 7.02 (d,
J¼7.2 Hz, 1H), 6.94 (d, J¼7.0 Hz, 1H), 4.94 (d, J¼5.2 Hz,
1H), 4.35 (t, J¼5.1 Hz, 1H), 4.28 (m, J¼5.1 Hz, 2H), 3.44
(t, J¼5.3 Hz, 2H), 2.92 (d, J¼5.1 Hz, 2H), 2.13 (dd,
J¼5.0, 3.5 Hz, 2H), 1.92 (t, J¼4.4 Hz, 2H). [a]2D0 ꢂ60
(c 0.35, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for
C17H19N3O3: C, 65.16; H, 6.11; N, 13.41. Found: C,
65.01; H, 6.03; N, 13.58.
3.6.12. N-[(3S)-1,2,3,4-Tetrahydro-b-carboline-3-carb-
oxyl]-L-histidine (8l). Yield 92%. ESIMS: 354 [M+H]+;
IR (KBr): 3442, 3236, 3210, 3002, 2945, 2840, 1733,
1
1645, 1602, 1451, 1055, 901 cmꢂ1; H NMR (BHSC-500,
DMSO-d6): d¼11.92 (s, 1H), 11.02 (s, 1H), 9.90 (s, 1H),
8.00 (s, 1H), 7.85 (s, 1H), 7.47 (s, 1H), 7.27 (t, J¼7.0 Hz,
1H), 7.13 (t, J¼7.2 Hz, 1H), 7.02 (d, J¼7.2 Hz, 1H), 6.95
(d, J¼7.0 Hz, 1H), 6.84 (s, 1H), 4.85 (t, J¼5.1 Hz, 1H),
4.80 (t, J¼5.2 Hz, 1H), 4.23 (m, J¼5.0 Hz, 2H), 3.05 (d,
J¼5.1 Hz, 2H), 2.93 (d, J¼5.2 Hz, 2H). [a]2D0 ꢂ59 (c 0.36,
CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for C18H19N5O3: C,
61.18; H, 5.42; N, 19.82. Found: C, 61.35; H, 5.51; N, 19.67.
3.6.8. N-[(3S)-1,2,3,4-Tetrahydro-b-carboline-3-carb-
oxyl]-L-cysteine (8h). Yield 92%. ESIMS: 320 [M+H]+;
IR (KBr): 3439, 3235, 3212, 3005, 2953, 2840, 1734,
1
1644, 1603, 1450, 1055, 900 cmꢂ1; H NMR (BHSC-500,
3.6.13. N-[(3S)-1,2,3,4-Tetrahydro-b-carboline-3-carb-
oxyl]-L-tryptophan (8m). Yield 90%. Mp 159–161 ꢀC;
ESIMS: 403 [M+H]+; IR (KBr): 3445, 3238, 3217, 3008,
DMSO-d6): d¼10.99 (s, 1H), 8.98 (s, 1H), 8.10 (s, 1H),
8.01 (s, 1H), 7.25 (t, J¼7.1 Hz, 1H), 7.13 (t, J¼7.2 Hz,
1H), 7.02 (d, J¼7.2 Hz, 1H), 6.98 (t, J¼7.0 Hz, 1H), 4.93
(t, J¼5.0 Hz, 1H), 4.77 (t, J¼5.1 Hz, 1H), 4.21 (m,
J¼5.1 Hz, 2H), 3.09 (d, J¼5.1 Hz, 2H), 2.92 (d, J¼4.6 Hz,
2H), 1.53 (s, 1H). [a]D20 ꢂ57 (c 0.38, CHCl3/CH3OH, 1:1,
v/v). Anal. Calcd for C15H17N3O3S: C, 56.41; H, 5.37; N,
13.16. Found: C, 56.58; H, 5.44; N, 113.33.
1
2951, 2842, 1728, 1641, 1600, 1450, 1058, 897 cmꢂ1; H
NMR (300 MHz, DMSO-d6): d¼11.52 (s, 1H), 11.15 (s,
1H), 10.97 (s, 1H), 10.21 (s, 1H), 8.02 (s, 1H), 7.31 (t,
J¼7.2 Hz, 1H), 7.18 (t, J¼7.3 Hz, 1H), 7.14 (t, J¼7.5 Hz,
1H), 7.12 (t, J¼7.5 Hz, 1H), 7.12 (d, J¼7.5 Hz, 1H), 7.10
(d, J¼7.5 Hz, 1H), 7.04 (d, J¼7.5 Hz, 1H), 6.98 (d,
J¼7.2 Hz, 1H), 6.85 (s, 1H), 4.87 (t, J¼5.5 Hz, 1H), 3.95
(t, J¼5.5 Hz, 1H), 3.86 (d, J¼5.4 Hz, 2H), 2.94 (d,
J¼5.4 Hz, 2H), 2.79 (d, J¼5.5 Hz, 2H). [a]2D0 ꢂ64 (c 0.38,
CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for C23H22N4O3: C,
68.64; H, 5.51; N, 13.92. Found: C, 68.55; H, 5.43; N, 13.79.
3.6.9. N-[(3S)-1,2,3,4-Tetrahydro-b-carboline-3-carb-
oxyl]-L-methionine (8i). Yield 90%. ESIMS: 348 [M+H]+;
IR (KBr): 3441, 3236, 3215, 3002, 2950, 2843, 1732,
1
1645, 1604, 1452, 1052, 899 cmꢂ1; H NMR (BHSC-500,
DMSO-d6): d¼11.03 (s, 1H), 8.97 (s, 1H), 8.11 (s, 1H),
8.03 (s, 1H), 7.29 (t, J¼7.1 Hz, 1H), 7.15 (t, J¼7.2 Hz,
1H), 7.02 (d, J¼7.2 Hz, 1H), 6.93 (t, J¼7.1 Hz, 1H), 4.42
(t, J¼5.4 Hz, 1H), 4.25 (m, J¼5.1 Hz, 1H), 4.20 (m,
J¼5.1 Hz, 2H), 2.92 (d, J¼4.6 Hz, 2H), 2.42 (t, J¼5.2 Hz,
2H), 2.13 (m, J¼5.4 Hz, 2H), 2.07 (s, 3H). [a]2D0 ꢂ46 (c
0.39, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for
C17H21N3O3S: C, 58.77; H, 6.09; N, 12.09. Found: C,
58.61; H, 6.00; N, 12.26.
3.6.14. N-[(3S)-1,2,3,4-Tetrahydro-b-carboline-3-carb-
oxyl]-L-arginine (8n). Yield 91%. ESIMS: 373 [M+H]+;
IR (KBr): 3443, 3235, 3214, 3002, 2953, 2840, 1732,
1
1644, 1602, 1454, 1052, 901 cmꢂ1; H NMR (BHSC-500,
DMSO-d6): d¼11.04 (s, 1H), 10.00 (s, 1H), 8.51 (s, 2H),
8.27 (s, 2H), 8.11 (s, 1H), 8.01 (s, 1H), 7.27 (t, J¼7.2 Hz,
1H), 7.08 (t, J¼7.2 Hz, 1H), 7.00 (d, J¼7.3 Hz, 1H), 6.95
(d, J¼7.2 Hz, 1H), 4.85 (t, J¼5.3 Hz, 1H), 4.43 (t,
J¼4.2 Hz, 1H), 4.22 (d, J¼4.6 Hz, 2H), 2.91 (d, J¼4.8 Hz,
2H), 2.69 (t, J¼5.1 Hz, 2H), 1.83 (m, J¼5.1 Hz, 2H), 1.55
(m, J¼5.1 Hz, 2H). [a]2D0 ꢂ57 (c 0.37, CHCl3/CH3OH,
1:1, v/v). Anal. Calcd for C18H24N6O3: C, 58.05; H, 6.50;
N, 22.57. Found: C, 58.22; H, 6.61; N, 22.31.
3.6.10. N-[(3S)-1,2,3,4-Tetrahydro-b-carboline-3-carb-
oxyl]-L-glutamic acid (8j). Yield 92%. ESIMS: 346
[M+H]+; IR (KBr): 3445, 3234, 3210, 3002, 2951, 2840,
1734, 1645, 1602, 1453, 1052, 903 cmꢂ1
;
1H NMR
(BHSC-500, DMSO-d6): d¼11.00 (s, 2H), 8.97 (s, 1H),
8.10 (s, 1H), 8.00 (s, 1H), 7.25 (t, J¼7.0 Hz, 1H), 7.11 (t,
J¼7.0 Hz, 1H), 7.02 (d, J¼7.2 Hz, 1H), 6.95 (t, J¼7.0 Hz,
1H), 4.92 (t, J¼5.2 Hz, 1H), 4.40 (t, J¼5.2 Hz, 1H), 4.23
(d, J¼5.2 Hz, 2H), 2.85 (d, J¼5.1 Hz, 2H), 2.20 (t,
J¼5.3 Hz, 2H), 2.06 (t, J¼5.1 Hz, 2H). [a]2D0 ꢂ57 (c 0.33,
CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for C17H19N3O5: C,
59.12; H, 5.55; N, 12.17. Found: C, 59.28; H, 5.64; N, 12.35.
3.6.15. N-[(3S)-1,2,3,4-Tetrahydro-b-carboline-3-carb-
oxyl]glycine (8o). Yield 94%. Mp 181–183 ꢀC; ESIMS:
274 [M+H]+; IR (KBr): 3434, 3230, 3213, 3004, 2950,
1
2844, 1730, 1646, 1601, 1455, 1062, 900 cmꢂ1; H NMR
(BHSC-500, DMSO-d6): d¼11.05 (s, 1H), 9.94 (s, 1H),
8.00 (s, 1H), 7.27 (t, J¼7.6 Hz, 1H), 7.19 (t, J¼7.6 Hz,
1H), 6.95 (d, J¼7.6 Hz, 1H), 6.87 (d, J¼7.6 Hz, 1H), 4.16
(s, 2H), 4.08 (dd, J¼5.4, 4.5 Hz, 1H), 3.89 (d, J¼5.3 Hz,
2H), 2.83 (d, J¼5.4 Hz, 2H), 2.05 (s, 1H). [a]2D0 ꢂ104
(c 0.38, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for
3.6.11. N-[(3S)-1,2,3,4-Tetrahydro-b-carboline-3-carb-
oxyl]-L-aspartic acid (8k). Yield 92%. ESIMS: 332

G. Wu et al. / Tetrahedron 63 (2007) 5510–5528
5525
C14H15N3O3: C, 61.53; H, 5.53; N, 15.38. Found: C, 61.38;
H, 5.38; N, 15.51.
ESIMS: 330 [M+H]+; IR (KBr): 3436, 3232, 3217, 3008,
2950, 2840, 1730, 1645, 1602, 1453, 1382, 1065,
1
904 cmꢂ1; H NMR (BHSC-500, DMSO-d6): d¼10.95 (s,
3.6.16. N-[(3S)-1,2,3,4-Tetrahydro-b-carboline-3-car-
boxyl]-L-Lys(Z)-OH (8p). Yield 90%. ESIMS: 479
[M+H]+; IR (KBr): 3440, 3236, 3217, 3004, 2940, 2846,
1H), 9.83 (s, 1H), 8.02 (s, 1H), 7.26 (t, J¼7.3 Hz, 1H),
7.18 (t, J¼7.3 Hz, 1H), 6.98 (d, J¼7.3 Hz, 1H), 6.89 (d,
J¼7.3 Hz, 1H), 4.48 (t, J¼5.2 Hz, 1H), 3.95 (t, J¼5.3 Hz,
1H), 3.94 (d, J¼5.2 Hz, 2H), 2.92 (d, J¼5.3 Hz, 2H), 1.83
(m, J¼5.3 Hz, 1H), 1.49 (s, 9H), 1.32 (m, J¼5.2 Hz, 2H),
1.10 (d, J¼5.2 Hz, 3H), 0.93 (t, J¼5.2 Hz, 3H). [a]2D0 ꢂ67
(c 0.35, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for
C18H23N3O3: C, 65.63; H, 7.04; N, 12.76. Found: C,
65.46; H, 7.15; N, 12.63.
1
1736, 1604, 1455, 1062, 898 cmꢂ1; H NMR (BHSC-500,
DMSO-d6): d¼10.92 (s, 1H), 9.95 (s, 1H), 8.03 (s, 1H),
8.00 (s, 1H), 7.27 (t, J¼7.5 Hz, 1H), 7.20 (t, J¼7.3 Hz,
1H), 7.19 (t, J¼7.5 Hz, 1H), 7.17 (d, J¼7.3 Hz, 2H), 7.14
(t, J¼7.3 Hz, 2H), 6.96 (d, J¼7.5 Hz, 1H), 6.89 (d,
J¼7.5 Hz, 1H), 5.35 (s, 2H), 4.46 (t, J¼4.6 Hz, 1H), 3.99
(d, J¼5.6 Hz, 1H), 3.88 (dd, J¼10.0, 4.5 Hz, 1H), 3.86
(dd, J¼10.0, 3.7 Hz, 1H), 2.96 (t, J¼4.6 Hz, 2H), 2.83 (d,
J¼10.0 Hz, 2H), 1.80 (m, J¼4.6 Hz, 2H), 2.10 (s, 1H),
1.56 (m, J¼4.6 Hz, 2H), 1.29 (m, J¼4.6 Hz, 2H). [a]D20
ꢂ39 (c 0.38, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for
C26H30N4O5: C, 65.26; H, 6.32; N, 11.71. Found: C,
65.41; H, 6.49; N, 11.53.
3.7. General procedure for the preparation of
(12aS)-3-substituted-1,4-dioxo-2,3,6,7,12,12a-
hexahydropyrazino[10,20:1,6]-pyrido-[3,4-b]indole
(4a–t)
(A) While stirring at 0 ꢀC, 2.0 mmol of compound 3 was dis-
solved in 10 ml of hydrogen chloride/ethyl acetate (5 mol/l).
The reaction mixture was stirred at 0 ꢀC for 10 min and at
room temperature for 1 h and TLC (ethyl acetate/petroleum,
5:12) indicated the completion of the reaction. The reaction
mixture was evaporated. After evaporation, the residue was
diluted in 10 ml of ethyl acetate and then evaporated to dry-
ness, and this procedure was repeated three times. The resi-
due was dissolved in 20 ml of methanol, to which 2 ml of
triethylamine was added. The solution was stirred at room
temperature for 1 h and evaporated to give the title com-
pounds as colorless powder. (B) At 0 ꢀC, to the solution of
2.0 mmol of 8, 297 mg (2.0 mmol) of HOBt and 515 mg
(2.5 mmol) of DCC in 30 ml of anhydrous THF were added
and stirred at pH 8–9 with N-methyl morpholine. The reac-
tion mixture was stirred at 0 ꢀC for 2 h and at room temper-
ature for 16 h, and TLC (ethyl acetate/petroleum, 5:12)
indicated the completion of the reaction. Upon evaporation,
the residue was dissolved in 30 ml of ethyl acetate. The so-
lution was washed successively with 5% sodium bicarbo-
nate, 5% citric acid, and saturated sodium chloride and the
organic phase was separated and dried over anhydrous so-
dium sulfate. After filtration and evaporation under reduced
pressure, the title compounds were obtained as pale yellow
powder after purification with flash chromatography
(CHCl3/CH3OH, 30:1).
3.6.17. N-[(3S)-1,2,3,4-Tetrahydro-b-carboline-3-car-
boxyl]-L-glutamine (8q). Yield 92%. ESIMS: 345
[M+H]+; IR (KBr): 3443, 3236, 3219, 3001, 2945, 2830,
1733, 1645, 1601, 1452, 1065, 900 cmꢂ1
;
1H NMR
(BHSC-500, DMSO-d6): d¼11.01 (s, 1H), 9.98 (s, 1H),
8.09 (s, 1H), 8.00 (s, 1H), 7.25 (t, J¼7.2 Hz, 1H), 7.18 (t,
J¼7.2 Hz, 1H), 7.03 (d, J¼7.2 Hz, 1H), 6.85 (d, J¼7.2 Hz,
1H), 6.05 (s, 2H), 4.93 (d, J¼5.5 Hz, 1H), 4.42 (t,
J¼5.2 Hz, 1H), 4.23 (d, J¼5.3 Hz, 2H), 2.90 (d, J¼5.3 Hz,
2H), 2.15 (t, J¼5.3 Hz, 2H), 2.03 (t, J¼5.2 Hz, 2H). [a]D20
ꢂ63 (c 0.39, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for
C17H20N4O4: C, 59.29; H, 5.85; N, 16.27. Found: C,
59.12; H, 5.77; N, 16.43.
3.6.18. N-[(3S)-1,2,3,4-Tetrahydro-b-carboline-3-car-
boxyl]-L-asparagine (8r). Yield 94%. ESIMS: 331
[M+H]+; IR (KBr): 3443, 3231, 3002, 2935, 2838, 1730,
1
1634, 1600, 1450, 1062, 901 cmꢂ1; H NMR (BHSC-500,
DMSO-d6): d¼11.03 (s, 1H), 9.98 (s, 1H), 8.11 (s, 1H),
8.02 (s, 1H), 7.25 (t, J¼7.1 Hz, 1H), 7.15 (t, J¼7.1 Hz,
1H), 7.00 (d, J¼7.1 Hz, 1H), 6.83 (d, J¼7.1 Hz, 1H), 6.06
(s, 2H), 4.91 (d, J¼5.6 Hz, 1H), 4.42 (t, J¼5.6 Hz, 1H),
4.25 (d, J¼5.6 Hz, 2H), 2.92 (d, J¼5.5 Hz, 2H), 2.15 (t,
J¼5.6 Hz, 2H). [a]D20 ꢂ57 (c 0.33, CHCl3/CH3OH, 1:1,
v/v). Anal. Calcd for C16H18N4O4: C, 58.17; H, 5.49; N,
16.96. Found: C, 58.34; H, 5.40; N, 16.80.
3.7.1. (3S,12aS)-3-Methyl-2,3,6,7,12,12a-hexahydropyr-
azino[10,20:1,6]pyrido[3,4-b]indole-1,4-dion (4a). (A)Yield
96%, (B) yield 90%. Mp 233–235 ꢀC, ESIMS: (m/z) 270
3.6.19. N-[(3S)-1,2,3,4-Tetrahydro-b-carboline-3-car-
boxyl]-L-leucine (8s). Yield 92%. ESIMS: 330 [M+H]+;
IR (KBr): 3445, 3239, 3202, 3003, 2952, 2844, 1734,
[M+H]+; IR (KBr): 3337, 2926, 1678, 1455, 1326, 744 cmꢂ1
;
1H NMR (DMSO-d6, 300 MHz): d¼10.97 (s, 1H), 8.46 (d,
J¼2.1 Hz, 1H), 7.46 (d, J¼7.5 Hz, 1H), 7.35 (t, J¼7.5 Hz,
1H), 7.07 (t, J¼7.5 Hz, 1H), 6.96 (t, J¼7.5 Hz, 1H), 5.33
(d, J¼16.8 Hz, lH), 4.73 (m, J¼6.9 Hz, 1H), 4.28 (dd,
J¼4.2, 11.7 Hz, 1H), 4.20 (d, J¼16.5 Hz, 1H), 3.26 (dd,
J¼4.2, 15.0 Hz, 1H), 2.80 (t, J¼4.8 Hz, 1H), 1.35 (d, J¼
6.9 Hz, 3H). 13C NMR (DMSO-d6, 300 MHz): d¼167.21,
166.82, 136.02, 134.55, 131.00, 126.26, 121.36, 120.12,
119.15, 111.09, 59.80, 52.98, 42.87, 24.75, 17.31. [a]D20
ꢂ150 (c 1.0, CH3OH). Anal. Calcd for C15H15N3O2: C,
66.90; H, 5.61; N, 15.60. Found: C, 66.70; H, 5.41; N, 15.81.
1
1645, 1603, 1450, 1062, 901 cmꢂ1; H NMR (BHSC-500,
DMSO-d6): d¼11.03 (s, 1H), 9.99 (s, 1H), 8.10 (s, 1H),
8.00 (s, 1H), 7.25 (t, J¼7.1 Hz, 1H), 7.15 (t, J¼7.1 Hz,
1H), 6.93 (d, J¼7.1 Hz, 1H), 6.80 (d, J¼7.1 Hz, 1H), 4.91
(t, J¼5.4 Hz, 1H), 4.43 (t, J¼5.4 Hz, 1H), 4.15 (dd,
J¼10.1, 4.4 Hz, 1H), 4.02 (dd, J¼10.1, 3.9 Hz, 1H), 2.92
(d, J¼5.3 Hz, 2H), 2.83 (d, J¼5.3 Hz, 2H), 1.35 (m,
J¼5.2 Hz, 1H), 1.13 (d, J¼5.5 Hz, 6H). [a]2D0 ꢂ55 (c 0.35,
CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for C18H23N3O3: C,
65.63; H, 7.04; N, 12.76. Found: C, 65.78; H, 7.14; N, 12.61.
3.6.20. N-[(3S)-1,2,3,4-Tetrahydro-b-carboline-3-car-
boxyl]-L-isoleucine (8t). Yield 95%. Mp 169–171 ꢀC;
3.7.2. (3S,12aS)-3-Benzyl-2,3,6,7,12,12a-hexahydropyr-
azino[10,20:1,6]pyrido[3,4-b]indole-1,4-dione (4b). (A)

5526
G. Wu et al. / Tetrahedron 63 (2007) 5510–5528
Yield 96%, (B) yield 95%. Mp 242–245 ꢀC; EIMS: (m/z)
249–251 ꢀC; ESIMS: 362 [M+H]+; IR (KBr): 3342, 2936,
1
346 [M+H]+; IR (KBr): 3328, 2936, 1669, 1455, 1328,
1682, 1643, 1464, 1333, 743 cmꢂ1; H NMR (BHSC-500,
1
744 cmꢂ1; H NMR (DMSO-d6, 300 MHz): d¼10.81 (s,
DMSO-d6): d¼10.02 (s, 1H), 8.01 (s, 1H), 7.31 (t,
J¼7.0 Hz, 1H), 7.23 (t, J¼7.2 Hz, 1H), 7.16 (d, J¼7.0 Hz,
2H), 7.13 (d, J¼7.0 Hz, 2H), 7.01 (t, J¼7.2 Hz, 1H), 6.89
(d, J¼7.0 Hz, 1H), 4.97 (s, 1H), 4.85 (d, J¼5.2 Hz, 1H),
4.78 (t, J¼5.4 Hz, 1H), 4.21 (m, J¼5.2 Hz, 2H), 3.13 (d,
J¼5.2 Hz, 2H), 2.90 (d, J¼5.4 Hz, 2H). [a]2D0 ꢂ122.3 (c
1.0, CH3OH). Anal. Calcd for C21H19N3O3: C, 69.79; H,
5.30; N, 11.63. Found: C, 69.61; H, 5.41; N, 11.47.
1H), 8.46 (d, J¼1.8 Hz, 1H), 7.42 (d, J¼7.5 Hz, 1H), 7.31
(t, J¼7.5 Hz, 1H), 7.22 (t, J¼7.2 Hz, 2H), 7.14 (d,
J¼7.2 Hz, 2H), 7.06 (t, J¼7.2 Hz, 1H), 7.02 (t, J¼7.5 Hz,
1H), 6.93 (t, J¼7.5 Hz, 1H), 5.32 (d, J¼16.5 Hz, 1H), 4.37
(s, 2H), 4.07 (d, J¼16.8 Hz, 1H), 3.98 (dd, J¼11.7,
4.5 Hz, 1H), 3.17 (dd, J¼13.2, 3.3 Hz, 1H), 2.88 (dd,
J¼13.5, 5.1 Hz, 1H), 2.64 (dd, J¼14.7, 3.6 Hz, 1H). [a]D20
ꢂ53 (c 1.0, CH3OH). Anal. Calcd for C21H19N3O2: C,
73.03; H, 5.54; N, 12.17. Found: C, 73.30; H, 5.76; N, 12.01.
3.7.7. (5aS,14aS)-1,2,3,5,5a,6,11,12,14,14a-Decahydro-
pyrrolo[100,200:4050]pyrazino[10,20:1,6]pyrido[3,4-b]in-
dole-1,4-dione (4g). (A) Yield 90%, (B) yield 87%. Mp
233–235 ꢀC; ESIMS 296 [M+H]+; IR (KBr): 3344, 2934,
3.7.3. (3S,12aS)-3-(Isopropyl)-2,3,6,7,12,12a-hexahydro-
pyrazino[10,20:1,6]pyrido[3,4-b]indole-1,4-dione (4c).
(A) Yield 92%, (B) yield 86%. Mp 216–218 ꢀC, ESIMS:
(m/z) 298 [M+H]+; IR (KBr): 3331, 2939, 1662, 1457, 1384,
1
1684, 1643, 1460, 1332, 743 cmꢂ1; H NMR (BHSC-500,
DMSO-d6): d¼10.03 (s, 1H), 7.21 (t, J¼7.2 Hz, 1H), 7.15
(t, J¼7.2 Hz, 1H), 7.05 (t, J¼7.2 Hz, 1H), 6.95 (d,
J¼7.2 Hz, 1H), 4.86 (t, J¼5.5 Hz, 1H), 4.33 (t, J¼5.4 Hz,
1H), 4.24 (d, J¼5.5 Hz, 2H), 3.45 (t, J¼5.4 Hz, 2H), 2.93
(d, J¼5.3 Hz, 2H), 2.25 (d, J¼5.4 Hz, 2H), 1.95 (t,
J¼5.4 Hz, 2H). [a]2D0 ꢂ89.1 (c 1.0, CH3OH). Anal. Calcd
for C17H17N3O2: C, 69.14; H, 5.80; N, 14.23. Found: C,
69.01; H, 5.70; N, 14.14.
1
1365, 746 cmꢂ1; H NMR (DMSO-d6, 300 MHz): d¼10.82
(s, 1H), 8.60 (d, J¼2.7 Hz, 1H), 7.36 (d, J¼7.1 Hz, 1H),
7.25 (t, J¼7.1 Hz, 1H), 7.02 (t, J¼7.1 Hz, 1H), 6.93 (t,
J¼7.1 Hz, 1H), 5.22 (d, J¼15.2 Hz, 1H), 4.21 (dd, J¼11.3,
4.2 Hz, 1H), 4.19 (d, J¼17.0 Hz, 1H), 3.27 (dd, J¼14.6,
3.7 Hz, 1H), 2.99 (m, J¼13.3 Hz, 1H), 2.89 (t, J¼13.3 Hz,
1H), 2.74 (m, J¼6.2 Hz, 1H), 1.07 (d, J¼6.2 Hz, 6H). 13C
NMR (DMSO-d6, 300 MHz): d¼169.05, 168.48, 135.09,
133.71, 130.93, 122.59, 121.47, 118.99, 113.44, 111.27,
66.99, 63.10, 41.72, 28.75, 24.38, 16.82. [a]2D0 ꢂ84 (c 1.0,
CH3OH). Anal. Calcd for C17H19N3O2: C, 68.67; H, 6.44;
N, 14.13. Found: C, 68.50; H, 6.27; N, 14.00.
3.7.8. (3S,12aS)-3-Mercaptomethyl-2,3,6,7,12,12a-hexa-
hydropyrazino[10,20:1,6]pyrido[3,4-b]indole-1,4-dione
(4h). (A) Yield 91%, (B) yield 86%. Mp 237–239 ꢀC;
ESIMS: 302 [M+H]+; IR (KBr): 3343, 2936, 1647, 1641,
1
1459, 1333, 741 cmꢂ1; H NMR (BHSC-500, DMSO-d6):
3.7.4. (3S,12aS)-3-Hydroxymethyl-2,3,6,7,12,12a-hexa-
hydropyrazino[10,20:1,6]pyrido[3,4-b]indole-1,4-dione
(4d). (A) Yield 89%, (B) yield 85%. Mp 264–267 ꢀC, ESIMS
(m/z) 286 [M+H]+; IR (KBr): 3344, 2926, 1683, 1642, 1463,
1334, 744 cmꢂ1; 1H NMR (DMSO-d6, 300 MHz): d¼10.92
(s, 1H), 8.24 (d, J¼2.4 Hz, 1H), 7.43 (d, J¼7.5 Hz, 1H),
7.32 (t, J¼7.5 Hz, 1H), 7.04 (t, J¼7.5 Hz, 1H), 6.93 (t,
J¼7.5 Hz, 1H), 5.42 (d, J¼16.5 Hz, 1H), 5.23 (t, J¼4.8 Hz,
1H), 4.25 (dd, J¼11.4, 4.2 Hz, 1H), 4.15 (d, J¼16.5 Hz,
1H), 4.05 (d, J¼4.8 Hz, 1H), 3.94 (s, 1H), 3.17 (dd,
J¼15.0, 3.6 Hz, 1H), 2.98 (t, J¼13.5 Hz, 2H). 13C NMR
(DMSO-d6, 300 MHz): d¼166.88, 163.82, 135.86, 129.77,
126.33, 120.86, 118.56, 117.46, 110.96, 105.82, 62.66,
57.37, 55.82, 27.00. [a]D20 ꢂ141 (c 1.0, CH3OH). Anal. Calcd
for C15H15N3O3: C, 63.15; H, 5.30; N, 14.73. Found: C,
63.48; H, 5.52; N, 14.54.
d¼10.03 (s, 1H), 8.00 (s, 1H), 7.28 (t, J¼7.0 Hz, 1H), 7.15
(d, J¼7.0 Hz, 1H), 7.08 (d, J¼7.0 Hz, 1H), 6.89 (d,
J¼7.0 Hz, 1H), 4.93 (t, J¼5.4 Hz, 1H), 4.79 (t, J¼5.6 Hz,
1H), 4.29 (d, J¼5.2 Hz, 2H), 2.92 (d, J¼5.4 Hz, 2H), 3.07
(d, J¼5.6 Hz, 2H), 1.65 (s, 1H). [a]2D0 ꢂ48.7 (c 1.00,
CH3OH). Anal. Calcd for C15H15N3O2S: C, 59.78; H,
5.02; N, 13.94. Found: C, 59.92; H, 5.13; N, 13.76.
3.7.9. (3S,12aS)-3-Methylmercaptoethyl-2,3,6,7,12,12a-
hexahydropyrazino[10,20:1,6]pyrido[3,4-b]indole-1,4-di-
one (4i). (A) Yield 90%, (B) yield 85%. Mp 216–217 ꢀC;
ESIMS: 330 [M+H]+; IR (KBr): 3341, 2934, 1648, 1643,
1
1458, 1332, 742 cmꢂ1; H NMR (BHSC-500, DMSO-d6):
d¼10.00 (s, 1H), 7.99 (s, 1H), 7.27 (t, J¼7.0 Hz, 1H), 7.19
(t, J¼7.0 Hz, 1H), 7.08 (t, J¼7.0 Hz, 1H), 6.87 (d,
J¼7.0 Hz, 1H), 4.87 (t, J¼5.4 Hz, 1H), 4.49 (t, J¼5.2 Hz,
1H), 4.29 (d, J¼5.3 Hz, 2H), 2.94 (d, J¼5.4 Hz, 2H), 2.43
(t, J¼5.3 Hz, 2H), 2.17 (d, J¼5.3 Hz, 2H), 2.10 (s, 3H).
[a]2D0 ꢂ65.3 (c 1.0, CH3OH). Anal. Calcd for
C17H19N3O2S: C, 61.98; H, 5.81; N, 12.76. Found: C,
62.14; H, 5.89; N, 12.90.
3.7.5. (3S,12aS)-3-(10-Hydroxyeth-10-yl)-2,3,6,7,12,12a-
hexahydropyrazino[10,20:1,6]pyrido[3,4-b]indole-1,4-di-
one (4e). (A) Yield 96%, (B) yield 92%. Mp 242–244 ꢀC;
ESIMS 300 [M+H]+; IR (KBr): 3340, 2929, 1686, 1642,
1
1465, 1333, 744 cmꢂ1; H NMR (BHSC-500, DMSO-d6):
d¼10.00 (s, 1H), 7.98 (s, 1H), 7.29 (t, J¼7.1 Hz, 1H), 7.25
(t, J¼7.1 Hz, 1H), 7.09 (t, J¼7.1 Hz, 1H), 6.97 (d, J¼
7.1 Hz, 1H), 4.81 (t, J¼5.3 Hz, 1H), 4.63 (m, J¼5.2 Hz,
1H), 4.45 (t, J¼5.4 Hz, 2H), 4.22 (m, J¼5.6 Hz, 1H), 2.90
(d, J¼5.4 Hz, 2H), 2.15 (s, 1H), 1.22 (d, J¼5.6 Hz, 3H).
[a]2D0 ꢂ108.5 (c 1.0, CH3OH). Anal. Calcd for C16H17N3O3:
C,64.20;H,5.72;N,14.04.Found:C, 64.32;H,5.80;N,14.22.
3.7.10. (3S,12aS)-3-Carboxylethyl-2,3,6,7,12,12a-hexa-
hydropyrazino[10,20:1,6]pyrido[3,4-b]indole-1,4-dione
(4j). (A) Yield 85%, (B) yield 85%. Mp 236–238 ꢀC;
ESIMS: 417 [M+H]+; IR (KBr): 3342, 3000, 2940, 1675,
1
1602, 1586, 1457, 1333, 750 cmꢂ1; H NMR (BHSC-500,
DMSO-d6): d¼9.99 (s, 1H), 8.00 (s, 1H), 7.30 (t,
J¼7.1 Hz, 1H), 7.22 (t, J¼7.1 Hz, 1H), 7.18 (t, J¼7.0 Hz,
2H), 7.13 (d, J¼7.0 Hz, 2H), 7.08 (t, J¼7.0 Hz, 1H), 7.06
(t, J¼7.0 Hz, 1H), 7.01 (d, J¼7.2 Hz, 1H), 6.85 (d,
J¼7.2 Hz, 1H), 5.33 (s, 2H), 4.92 (d, J¼5.0 Hz, 1H), 4.43
(t, J¼5.2 Hz, 1H), 4.21 (d, J¼5.1 Hz, 2H), 2.94 (d,
3.7.6. (3S,12aS)-3-(p-Hydroxyphenylmethyl)-
2,3,6,7,12,12a-hexahydropyrazino[10,20:1,6]pyrido[3,4-
b]indole-1,4-dione (4f). (A) Yield 91%, (B) yield 90%. Mp

G. Wu et al. / Tetrahedron 63 (2007) 5510–5528
5527
J¼5.2 Hz, 2H), 2.25 (t, J¼5.5 Hz, 2H), 2.22 (t, J¼5.5 Hz,
2H). [a]2D0 ꢂ109.4 (c 1.0, CH3OH). Anal. Calcd for
C24H23N3O4: C, 69.05; H, 5.55; N, 10.07. Found: C,
68.90; H, 5.62; N, 10.21.
1H), 7.02 (d, J¼7.0 Hz, 1H), 6.95 (d, J¼7.0 Hz, 1H), 4.92
(d, J¼5.2 Hz, 1H), 4.35 (t, J¼4.6 Hz, 1H), 4.23 (d, J¼
5.2 Hz, 2H), 2.91 (d, J¼4.7 Hz, 2H), 2.66 (t, J¼5.2 Hz, 2H),
1.95 (m, J¼5.2 Hz, 2H), 1.56 (m, J¼5.2 Hz, 2H). [a]D20
ꢂ90.6 (c 1.0, CH3OH). Anal. Calcd for C18H22N6O2: C,
61.00; H, 6.26; N, 23.71. Found: C, 61.18; H, 6.33; N, 23.53.
3.7.11. (3S,12aS)-3-Carboxylmethyl-2,3,6,7,12,12a-hexa-
hydropyrazino[10,20:1,6]pyrido[3,4-b]indole-1,4-dione
(4k). (A) Yield 93%, (B) yield 85%. Mp 255–257 ꢀC;
ESIMS: (m/z) 404 [M+H]+; IR (KBr): 3346, 2923, 1678,
3.7.15. (12aS)-2,3,6,7,12,12a-Hexahydropyrazino-
[10,20:1,6]pyrido[3,4-b]indole-1,4-dione (4o). (A) Yield
95%, (B) yield 92%. Mp 247–249 ꢀC; ESIMS: (m/z) 256
[M+H]+; IR (KBr): 3307, 2986, 1646, 1455, 1328,
1600, 1589, 1507, 1460, 1335, 747 cmꢂ1
;
1H NMR
(DMSO-d6, 300 MHz): d¼9.98 (s, 1H), 8.20 (s, 1H), 7.30
(d, J¼7.4 Hz, 1H), 7.23 (t, J¼7.4 Hz, 1H), 7.20 (t,
J¼7.2 Hz, 2H), 7.13 (t, J¼7.2 Hz, 2H), 7.10 (t, J¼7.2 Hz,
1H), 7.03 (t, J¼7.4 Hz, 1H), 6.92 (t, J¼7.3 Hz, 1H), 5.35
(d, J¼16.6 Hz, 1H), 5.33 (s, 2H), 4.22 (dd, J¼11.0,
3.6 Hz, 1H), 4.17 (d, J¼16.5 Hz, 1H), 4.12 (d, J¼14.3 Hz,
1H), 3.16 (dd, J¼14.0, 3.6 Hz, 1H), 2.96 (t, J¼13.0 Hz,
1H), 2.81 (d, J¼10.0 Hz, 2H). [a]2D0 ꢂ70 (c 1.0, CH3OH).
Anal. Calcd for C23H21N3O4: C, 68.47; H, 5.25; N, 10.42.
Found: C, 68.35; H, 5.09; N, 10.27.
1
748 cmꢂ1; H NMR (DMSO-d6, 300 MHz): d¼10.94 (s,
1H), 8.26 (s, 1H), 7.43 (d, J¼7.5 Hz, 1H), 7.33 (t,
J¼7.5 Hz, 1H), 7.08 (t, J¼7.5 Hz, 1H), 6.96 (t, J¼7.5 Hz,
1H), 5.36 (d, J¼16.5 Hz, 1H), 4.22 (m, J¼13.0 Hz, 2H),
4.05 (d, J¼17.7 Hz, 1H), 3.86 (d, J¼17.7 Hz, 1H), 3.20
(m, J¼13.5 Hz, 1H), 2.88 (t, J¼13.5 Hz, 1H). 13C NMR
(DMSO-d6, 300 MHz): d¼168.87, 167.66, 136.11, 134.02,
130.34, 124.63, 121.55, 120.21, 119.44, 111.22, 59.75,
52.76, 42.80, 24.77. [a]2D0 ꢂ135 (c 1.0, CH3OH). Anal.
Calcd for C14H13N3O2: C, 65.87; H, 5.13; N, 16.46. Found:
C, 65.65; H, 5.01; N, 16.67.
3.7.12. (3S,12aS)-3-(10,30-Imidazol-50-methylene)-
2,3,6,7,12,12a-hexahydropyrazino[10,20:1,6]pyrido[3,4-
b]indole-1,4-dione (4l). (A) Yield 91%, (B) yield 86%. Mp
207–209 ꢀC; ESIMS: 336 [M+H]+; IR (KBr): 3344, 2925,
3.7.16. (3S,12aS)-3-Aminobutyl-2,3,6,7,12,12a-hexahy-
dropyrazino[10,20:1,6]pyrido[3,4-b]indole-1,4-dione (4p).
(A) Yield 87%, (B) yield 83%. Mp 216–218 ꢀC; EIMS:
(m/z) 327 [M+H]+; IR (KBr): 3324, 2936, 1683, 1463,
1
1677, 1601, 1587, 1505, 1458, 1333, 751 cmꢂ1; H NMR
(BHSC-500, DMSO-d6): d¼12.99 (s, 1H), 10.03 (s, 1H),
7.98 (s, 1H), 7.45 (s, 1H), 7.33 (t, J¼7.0 Hz, 1H), 7.25 (t,
J¼7.0 Hz, 1H), 7.09 (t, J¼7.0 Hz, 1H), 6.99 (t, J¼7.0 Hz,
1H), 6.87 (s, 1H), 4.92 (t, J¼5.2 Hz, 1H), 4.83 (t,
J¼5.5 Hz, 1H), 4.27 (d, J¼5.5 Hz, 2H), 3.20 (d, J¼5.5 Hz,
2H), 2.92 (d, J¼5.1 Hz, 2H). [a]2D0 ꢂ88.3 (c 1.0, CH3OH).
Anal. Calcd for C18H17N5O2: C, 64.47; H, 5.11; N, 20.88.
Found: C, 64.62; H, 5.20; N, 21.03.
1
1336, 745 cmꢂ1; H NMR (DMSO-d6, 300 MHz): d¼9.92
(s, 1H), 8.21 (d, J¼1.8 Hz, 1H), 7.41 (d, J¼7.5 Hz, 1H),
7.28 (t, J¼7.5 Hz, 1H), 7.08 (t, J¼7.5 Hz, 1H), 6.95 (t, 1H,
J¼7.5 Hz, 1H), 5.36 (d, J¼16.5 Hz, 1H), 4.60 (t, J¼6.8 Hz,
1H), 4.30 (dd, J¼11.7, 4.5 Hz, 1H), 4.13 (dd, J¼11.7,
4.5 Hz, 1H), 3.26 (dd, J¼13.2, 3.3 Hz, 1H), 2.79 (dd,
J¼13.5, 5.1 Hz, 1H), 2.70 (t, J¼4.8 Hz, 2H), 2.01 (s, 2H),
1.80 (m, J¼4.8 Hz, 2H), 1.60 (m, J¼4.8 Hz, 2H), 1.32 (m,
J¼4.8 Hz, 2H). [a]2D0 ꢂ48 (c 1.0, CH3OH). Anal. Calcd for
C18H22N4O2: C, 66.24; H, 6.79; N, 17.17. Found: C, 66.01;
H, 6.58; N, 17.41. In the preparation of 4p, both procedure
A and B included a procedure of removing Z: After the cycli-
zation, a colorless powder of 922 mg (2.0 mmol) of the cycli-
zation product was mixed with 50 mg of Pd/C (5%) and
25 ml of formic acid in methanol (4.4%), and agitated with
hydrogen at room temperature for 24 h. The reaction mixture
was filtrated and evaporated to givethe title compound as col-
orless powder. The yield given here was the total yield.
3.7.13. (3S,12aS)-3-Indolylmethyl-2,3,6,7,12,12a-hexahy-
dropyrazino[10,20:1,6]pyrido[3,4-b]indole-1,4-dione
(4m). (A) Yield 90%, (B) yield 89%. Mp 176–180 ꢀC;
ESIMS: (m/z) 385 [M+H]+; IR (KBr): 3329, 2938, 1683,
1
1465, 1338, 746 cmꢂ1; H NMR (DMSO-d6, 300 MHz):
d¼10.76 (s, 1H), 10.74 (s, 1H), 8.43 (d, 1H, J¼1.8 Hz,
1H), 7.50 (d, J¼7.5 Hz, 1H), 7.28 (t, J¼7.5 Hz, 1H), 7.26
(t, J¼7.2 Hz, 1H), 7.24 (t, J¼7.2 Hz, 1H), 7.22 (d,
J¼7.2 Hz, 1H), 7.20 (t, J¼7.2 Hz, 1H), 7.08 (t, J¼7.5 Hz,
1H), 6.95 (t, 1H, J¼7.5 Hz, 1H), 6.82 (s, 1H), 5.27 (d,
J¼16.2 Hz, 1H), 4.31 (d, J¼2.4 Hz, 1H), 4.05 (d, J¼
16.5 Hz, 1H), 3.95 (dd, J¼12.0, 4.5 Hz, 1H), 3.28 (dd,
J¼14.1, 3.6 Hz, 1H), 3.07 (dd, J¼14.1, 4.2 Hz, 1H), 2.93
(d, J¼3.5 Hz, 2H); 13C NMR (DMSO-d6, 300 MHz):
d¼165.65, 164.64, 135.80, 135.71, 129.11, 127.62, 126.19,
124.00, 120.58, 118.45, 118.36, 118.10, 117.25, 110.81,
108.02, 105.42, 79.06, 55.77, 55.36, 30.17, 25.6. [a]D20
ꢂ182 (c 0.34, CHCl3/CH3OH, 1:1, v/v). Anal. Calcd for
C23H20N4O2: C, 71.86; H, 5.24; N, 14.57. Found: C,
72.04; H, 5.56; N, 14.33.
3.7.17. (3S,12aS)-3-(Propionamide-20-yl)-2,3,6,7,12,12a-
hexahydropyrazino[10,20:1,6]pyrido[3,4-b]indole-1,4-di-
one (4q). (A) Yield 93%, (B) yield 93%. Mp 251–253 ꢀC;
ESIMS: 327 [M+H]+; IR (KBr): 3344, 2939, 1684, 1465,
1332, 746 cmꢂ1
;
1H NMR (BHSC-500, DMSO-d6): d¼
10.01 (s, 1H), 7.98 (s, 1H), 7.27 (t, J¼7.2 Hz, 1H), 7.19 (t,
J¼7.2 Hz, 1H), 7.03 (d, J¼7.2 Hz, 1H), 6.85 (d, J¼7.2 Hz,
1H), 6.11 (s, 2H), 4.93 (d, J¼5.5 Hz, 1H), 4.44 (t,
J¼5.4 Hz, 1H), 4.27 (d, J¼5.5 Hz, 2H), 2.92 (d, J¼5.2 Hz,
2H), 2.17 (t, J¼5.4 Hz, 2H), 2.11 (t, J¼5.4 Hz, 2H). [a]D20
ꢂ62 (c 1.0, CH3OH). Anal. Calcd for C17H18N4O3: C,
62.57; H, 5.56; N, 17.17. Found: C, 62.71; H, 5.64; N, 17.35.
3.7.14. (3S,12aS)-3-(30-Guanidinopropyl)-2,3,6,7,12,12a-
hexahydropyrazino[10,20:1,6]pyrido[3,4-b]indole-1,4-di-
one (4n). (A) Yield 90%, (B) yield 87%. Mp 240–242 ꢀC;
ESIMS: 355 [M+H]+; IR (KBr): 3339, 2941, 1680, 1456,
3.7.18. (3S,12aS)-3-(Acetylamine-10-yl)-2,3,6,7,12,12a-
hexahydropyrazino[10,20:1,6]pyrido[3,4-b]indole-1,4-di-
one (4r). (A) Yield 91%, (B) yield 87%. Mp 247–249 ꢀC;
ESIMS: 313 [M+H]+; IR (KBr): 3341, 2942, 1681, 1463,
1342, 743 cmꢂ1
;
1H NMR (BHSC-500, DMSO-d6):
d¼10.03 (s, 1H), 8.44 (s, 2H), 8.20 (s, 1H), 8.16 (s, 1H),
8.01 (s, 1H), 7.23 (t, J¼7.0 Hz, 1H), 7.15 (t, J¼7.0 Hz,

5528
G. Wu et al. / Tetrahedron 63 (2007) 5510–5528
1336, 741 cmꢂ1
;
1H NMR (BHSC-500, DMSO-d6):
Acknowledgements
d¼10.03 (s, 1H), 8.00 (s, 1H), 7.27 (t, J¼7.2 Hz, 1H), 7.19
(t, J¼7.2 Hz, 1H), 7.05 (d, J¼7.2 Hz, 1H), 6.87 (d,
J¼7.2 Hz, 1H), 6.06 (s, 2H), 4.93 (d, J¼5.3 Hz, 1H), 4.45
(t, J¼5.2 Hz, 1H), 4.23 (d, J¼5.3 Hz, 2H), 2.92 (d,
J¼5.4 Hz, 2H), 2.65 (t, J¼5.3 Hz, 2H). [a]2D0 ꢂ45.2 (c 1.0,
CH3OH). Anal. Calcd for C16H16N4O3: C, 61.53; H, 5.16;
N, 17.94. Found: C, 61.38; H, 5.08; N, 17.76.
We appreciate the critical review of our manuscript from
Mrs. Elaine Gavin. This work was supported by Beijing
area major laboratory of peptide and small molecular drugs,
973 Project of China (2006CB708501) and Beijing Munici-
pal Commission of Education (KZ 200510025015).
3.7.19. (3S,12aS)-3-(20-Methylpropyl)-2,3,6,7,12,12a-
hexahydropyrazino[10,20:1,6]pyrido[3,4-b]indole-1,4-di-
one (4s). (A) Yield 87%, (B) yield 88%. Mp 231–233 ꢀC;
ESIMS: 312 [M+H]+; IR (KBr): 3343, 2943, 1682, 1465,
References and notes
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Deliv. 2004, 1, 27–42.
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1335, 743 cmꢂ1
;
1H NMR (BHSC-500, DMSO-d6):
d¼10.02 (s, 1H), 7.98 (s, 1H), 7.27 (t, J¼7.2 Hz, 1H), 7.19
(t, J¼7.2 Hz, 1H), 7.03 (d, J¼7.2 Hz, 1H), 6.85 (d,
J¼7.2 Hz, 1H), 4.93 (t, J¼5.3 Hz, 1H), 4.45 (t, J¼5.2 Hz,
1H), 4.26 (dd, J¼10.0, 4.4 Hz, 1H), 4.15 (dd, J¼10.0,
3.9 Hz, 1H), 2.92 (d, J¼6.2 Hz, 2H), 2.65 (t, J¼5.3 Hz,
2H), 1.83 (m, J¼5.3 Hz, 1H), 1.07 (d, J¼5.3 Hz, 6H). [a]D20
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69.43; H, 6.80; N, 13.49. Found: C, 69.60; H, 6.71; N, 13.66.
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hexahydropyrazino[10,20:1,6]pyrido[3,4-b]indole-1,4-di-
one (4t). (A) Yield 98%, (B) yield 87%. Mp 219–220 ꢀC,
ESIMS: (m/z) 312 [M+H]+; IR (KBr): 3328, 2936, 1669,
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1455, 1388, 1369, 744 cmꢂ1
;
1H NMR (DMSO-d6,
300 MHz): d¼11.12 (s, 1H), 8.64 (d, J¼2.1 Hz, 1H), 7.40
(d, J¼7.3 Hz, 1H), 7.30 (t, J¼7.3 Hz, 1H), 7.00 (t,
J¼7.3 Hz, 1H), 6.95 (t, J¼7.3 Hz, 1H), 5.30 (d, J¼16.0 Hz,
1H), 4.25 (dd, J¼11.0, 4.0 Hz, 1H), 4.17 (d, J¼17.3 Hz,
1H), 3.22 (dd, J¼15.0, 3.3 Hz, 1H), 2.96 (m, J¼13.0 Hz, 1H),
2.83 (t, J¼13.0 Hz, 1H), 2.61 (m, J¼6.0 Hz, 1H), 1.35 (m,
J¼6.0 Hz, 2H), 1.07 (d, J¼6.0 Hz, 3H), 0.97 (t, J¼6.0 Hz,
6H). 13C NMR (DMSO-d6, 300 MHz): d¼167.00, 166.48,
136.13, 130.37, 126.51, 121.44, 118.96, 117.40, 111.20,
105.81, 56.30, 53.11, 46.12, 26.75, 34.34, 23.30, 14.82,
11.77. [a]2D0 ꢂ73.7 (c 1.0, CH3OH). Anal. Calcd for
C18H21N3O2: C, 69.43; H, 6.80; N, 13.49. Found: C, 69.22;
H, 6.61; N, 13.68.
3.8. The racemization detection condition during the
synthesis of 4a–t
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Upon removal of the reaction solvent and the volatile side
products (i.e., CH3OH, (CH3)3COH, CO2, and H2O), the
crude compounds 4a–t were directly analyzed by HPLC.
The compounds 4a–t were analyzed using reverse-phase
HPLC on a C18-Si column (NovaPak 3.9ꢃ150 mm, Waters).
Mobile phase: A, 0.1% TFA in water; B, 0.8% TFA in aceto-
nitrile; Elution was performed with 5% B for 40 min and
followed by a linear gradient of 5–80% B for 40 min, after
maintaining 80% B for 10 min, and followed by a linear
gradient of 80–5% B within 10 min. In all cases, the purity
of compounds 4a–t was found to be higher than 98%.