A general method for the asymmetric synthesis of both enantiomers of 1-substituted 1,2,3,4-tetrahydro-β-carbolines employing pyroglutamic acid derivatives as chiral auxiliaries

Article abstract of DOI:10.1016/S0040-4020(03)00420-4

9-(S)-Pyroglutaminyl-β-carbolines were allowed to react with a nucleophile (allyltributyltin or a silyl enol ether) in the presence of 2,2,2-trichloroethyl chloroformate to give 1,2-addition products in good yields and high diastereoselectivity. The chiral auxiliary at N-9 was readily removed by a mild hydrolysis. The same chiral source afforded both enantiomers by simply altering a protecting group of the amide nitrogen. That is, (S)-pyroglutaminyl groups which had an N-alkyl group afforded the (S) isomer, whereas the ones having an N-acyl group produced the (R) isomer of the addition products.

Full text of DOI:10.1016/S0040-4020(03)00420-4

Tetrahedron 59 (2003) 3527–3536
A general method for the asymmetric synthesis of both
enantiomers of 1-substituted 1,2,3,4-tetrahydro-b-carbolines
employing pyroglutamic acid derivatives as chiral auxiliaries
Takashi Itoh, Michiko Miyazaki, Sachiko Ikeda, Kazuhiro Nagata, Masashi Yokoya,
*
Yuji Matsuya, Yasuko Enomoto and Akio Ohsawa
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Received 17 February 2003; accepted 14 March 2003
Abstract—9-(S)-Pyroglutaminyl-b-carbolines were allowed to react with a nucleophile (allyltributyltin or a silyl enol ether) in the presence
of 2,2,2-trichloroethyl chloroformate to give 1,2-addition products in good yields and high diastereoselectivity. The chiral auxiliary at N-9
was readily removed by a mild hydrolysis. The same chiral source afforded both enantiomers by simply altering a protecting group of the
amide nitrogen. That is, (S)-pyroglutaminyl groups which had an N-alkyl group afforded the (S) isomer, whereas the ones having an N-acyl
group produced the (R) isomer of the addition products. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
it was revealed that the N-alkyl- and N-acylpyroglutamic
acids afforded opposite enantiomers by the attack of the
same nucleophiles. This paper describes these results.7
b-Carboline (1) is a common nucleus of various indole
alkaloids, and many of these have a chiral center at its C-1
position.1 Thus, there have been several studies concerning
the synthesis of chiral 1-substituted 1,2,3,4-tetrahydro-b-
carboline derivatives using Pictet–Spengler reaction,2
nucleophilic addition,3 electrophilic substitution,4 and
reduction.5 We have recently developed the asymmetric
addition of allyltin reagents to a b-carboline derivative
which has an (S)-proline-derived chiral auxiliary at N-9
position.6 In addition, it was found that both enantiomers of
a 1-allyl-1,2-dihydro-b-carboline derivative were obtained
using allyltributyltin or tetraallyltin as a nucleophile in the
presence of the same chiral auxiliary. The results indicate
that the stereoselectivity of the allylation is not governed
only by steric bias originated from the chiral auxiliary, and
there might be some electrostatic interaction between the
substrate and the nucleophiles. In fact, this peculiar
stereoselectivity was not observed in the cases of other
nucleophiles such as silyl enol ethers.
2. Results and discussion
At first, we tried reactions using standard amino acids such
as alanine, valine, or phenylalanine as a chiral auxiliary, and
they were found not to install at N-9 position of 1 in good
yields.8 Thus, we chose (S)-pyroglutamic acid as a
candidate for a new chiral auxiliary, because it has a
similar, but more rigid conformation with compared to
proline due to carbonyl group in the pyrrolidine ring.
Although pyroglutamic acid has been used for versatile
building blocks for asymmetric synthesis,9 there are few
examples using its derivatives as chiral auxiliaries.10 An
N-protection step and succeeding addition to b-carboline
proceeded without an event. Thus, t-butyl (S)-pyrogluta-
mate (2) reacted with various N-protecting reagents in the
presence of sodium hydride to give the derivatives 3, which
were transformed to the corresponding carboxylic acid 4
(Scheme 1 and Table 1).
In order to develop a more general asymmetric addition, we
have investigated other chiral auxiliaries than the proline
derivatives and found that the one derived from (S)-
pyroglutamic acid afforded good stereoselectivity using
both allyltin and silyl enol ethers as nucleophiles. Moreover,
The compound 4 thus obtained readily reacted with
b-carboline by the use of 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDCI) to give 9-acyl-b-
carbolines 5 (Scheme 2 and Table 2). Therefore, the
substrates 5 for asymmetric addition were prepared in
good yields via three steps.
Keywords: b-carboline; (S)-pyroglutamic acid; chiral auxiliary;
asymmetric addition; allyltributyltin; silyl enol ether; indole alkaloid.
*
Corresponding author. Tel.: þ81-3-3784-8183; fax: þ81-3-3784-5982;
e-mail: ohsawa@pharm.showa-u.ac.jp
Firstly, asymmetric addition reaction was carried out using
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00420-4

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T. Itoh et al. / Tetrahedron 59 (2003) 3527–3536
Scheme 1.
Table 1. Synthesis of the chiral auxiliary 4 from t-butyl (S)-pyroglutamate
Entry
Compound
R
Temperature
Time 1 (h)
Yield of 3 (%)
Time 2 (h)
Yield of 4 (%)
1
2
3
4
5
6
7
8
9
10
a
b
c
d
e
f
g
h
i
Me
PhCH2
1-Naphthylmethyl
2-Naphthylmethyl
9-Anthracenylmethyl
MeCO
Room temperature
Reflux
Reflux
Reflux
Reflux
Reflux
Room temperature
Reflux
Room temperature
Room temperature
1
1
4
94
81
83
83
75
75
74
83
69
69
4
7
7
71
91
87
97
94
73
90
85
91
76
1
7
10
4.5
24
9
17
1
22a
24
24
25
43
15
PhCO
9-Anthracenyl-CO
p-NO2–PhCO
PhSO2
j
a
10 equiv. of TFA was used for the deprotection.
Scheme 2.
Table 2. Synthesis of 9-(pyroglutamyl)-b-carbolines (5)
In the cases of entries 1–5, the steric hindrance of the
N-protecting group played an important role in the induction
of the stereoselectivity, that is, the ee of the S isomer was
increased with the bulkiness of the protecting groups. In the
cases of N-acyl groups, however, the bulkiness seldom
affected the selectivity, and only the chemical yields were
lowered (entries 6–10).
Entry Compound
R
Time (h) Yield of 5 (%)
1
2
3
4
5
6
7
8
9
10
a
b
c
d
e
f
g
h
i
Me
PhCH2
1-Naphthylmethyl
2-Naphthylmethyl
9-Anthracenylmethyl
MeCO
3
2
1.5
1.5
4
24
20
6
24
2
86
71
77
88
95
71
99
73
74
91
Secondly, silyl enol ethers were used as nucleophiles,11 and
the results are summarized in Table 4 (Scheme 4).
PhCO
9-Anthracenyl-CO
p-NO2–PhCO
PhSO2
j
In the previous system using a (S)-proline derivative as the
auxiliary, silyl enol ethers added to the substrate only in low
stereoselectivity.12 In the present system, however, the
reaction proceeded in a highly diastereoselective manner to
give the dihydro adducts 8a–e in good yields after a mild
hydrolysis. The change of the stereoselectivity was also
observed in the cases of entries 6–8, and the same
configurations (see below) as in the cases of Table 3 were
obtained according to the used chiral auxiliaries. Thus, a
general method for the synthesis of both enantiomers of
1-substituted 1,2,3,4-tetrahydro-b-carboline was accom-
plished using (S)-pyroglutamic acid as a chiral auxiliary.
allyltributyltin as a nucleophile (Scheme 3 and Table 3). In
the event, the compound 5 was allowed to react with
allyltributyltin and 2,2,2-trichloroethyl chloroformate to
give a 1,2-dihydro adduct 6, which was subsequently
hydrolyzed to 7 in a quantitative yield. The chiral auxiliary
was completely recovered under mild hydrolytic conditions.
The absolute configuration of the product 7 was determined
according to the method reported earlier.6
As shown in Table 3, the chiral auxiliaries which have an
alkyl N-protecting group afforded the S isomer of the
product, while the use of the auxiliaries having an acyl
N-protecting group resulted in the formation of the R
isomer. Thus, it was revealed that both enantiomers
were obtained in good to high chemical and optical yields
by the simple change of N-protecting groups of the
auxiliary.
For the determination of the configuration of the product in
the reaction of silyl enol ethers, the adduct 8d (entry 4 of
Table 4) was transformed to a tetrahydro derivative 10
according to the process mentioned in Scheme 5. The
dihydro adduct was reduced with triethylsilane to give the
corresponding tetrahydro derivative 9, which was further
reduced with zinc–acetic acid, and succeeding esterification

T. Itoh et al. / Tetrahedron 59 (2003) 3527–3536
3529
Scheme 3.
Table 3. Asymmetric addition reaction of allyltributyltin with b-carboline which has a chiral auxiliary derived from pyroglutamic acid at N-9
Entry
Compound
R
Yield of 6 (%)
Ee of 7 (%)a
Config. of 7
1
2
3
4
5
6
7
8
9
10
a
b
c
d
e
f
g
h
i
Me
PhCH2
1-Naphthylmethyl
2-Naphthylmethyl
9-Anthracenylmethyl
MeCO
22
95
87
Quant.
98
Quant.
92
56
Quant.
51
7
S
S
S
S
21
58
66
91
89
83
83
88
79
S
R
R
R
R
R
PhCO
9-Anthracenyl-CO
p-NO2–PhCO
PhSO2
j
a
The ee was estimated by HPLC after removal of the chiral auxiliary.
Table 4. Asymmetric addition reaction of silyl enol ethers with 9-(N-protected)-b-carboline
Entry
R
R1
R2
Temperature (8C)
Time (h)
Product
Yield (%)
Ea (%)a
Config. of 8
1
2
3
4
5
6
7
8
Anthracenylmethyl
Anthracenylmethyl
Anthracenylmethyl
Anthracenylmethyl
Anthracenylmethyl
MeCO
Me
Ph
H
H
Me
H
H
H
H
H
0
0
0
240
240
278
278
278
24
2.5
0.5
12
19
40
40
40
8a
8b
8c
8d
8e
8d
8d
8d
40
79
Quant.
81
83
93
Quant.
Quant.
79
86
82
88
87
76
76
75
S
S
S
S
S
R
R
R
OMe
OBn
SBn
OBn
OBn
OBn
PhCO
p-NO2–PhCO
a
The ee was estimated by HPLC after removal of the chiral auxiliary.
Scheme 4.
Scheme 5.

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T. Itoh et al. / Tetrahedron 59 (2003) 3527–3536
The unique stereoselectivities of the present reaction
prompted us to consider factors controlling the stereo-
chemistry. In the reaction using N-alkyl pyroglutaminyl
groups (entries 1–5 in Table 3), the increment of the steric
hindrance linearly increased the stereoselectivity of the
addition. These results indicate that the selectivity was
originated from shielding of one side of the substrate plane.
Thus, PM3 calculations14 were carried out for the
intermediary N2-acylated quaternary salts of b-carboline
whose optimized structures are shown in Figures 1 and 2.
In the optimized conformation in Figure 1, anthracenyl
group is located on the syn position to the b-carboline group
due to the p–p interaction of these two groups. The Re face
of the reaction site (C1) of b-carboline ring is considerably
shielded. A conformation in which the Si face is shielded
was obtained as a local minimum structure as shown in
Figure 2, but it is 3.22 kcal/mol less stable than that of
Figure 1. Thus, the stereoselectivity using N-alkylpyro-
glutaminyl groups could be accounted for by the shielding
of the Re face by the anthracenyl group.
Figure 1. Calculated PM3 structures of 2-(trichloroethoxycarbonyl)-9-(N-
anthracenylmethylpyroglutamyl)-b-carbolinium cation (11). The
optimized conformation in which the Re face is blocked DHf¼117.4253
kcal/mol.
In the cases of N-acylpyroglutaminyl groups (entries 6–10
of Table 3), however, the opposite stereoisomer was
obtained. The bulkiness of the protecting group had little
effect on the selectivity, and sterically less demanding
N-acetyl derivative afforded the best result (entry 6).
These facts indicate that entirely different mechanism
controls the stereochemistry. The PM3 calculation of the
intermediates 12a and 12b showed that the carbonyl group
A (in Figure 3) bends the methyl (in 12a) or phenyl (in 12b)
group toward the far side of the reaction site because the
carbonyl group A and another carbonyl group B in the
pyroglutaminyl ring tend to reside in an antiperiplanar
position to each other probably due to dipolar repulsion. It is
suggested from the conformation that the steric influence of
the methyl or phenyl group is weak. Though the reason of R
selectivity (Re face attack) in the case of the substrate 12
remained unclear, the coordination of the nucleophiles to
two carbonyl groups A and C might cause the Re face attack
because these two groups exist near the reaction site on the
Re face.15 In fact, the addition of hexamethylphosphoric
triamide (HMPA), which can act as a ligand for organo-
metallic reagents, to the reaction system lowered the
stereoselectivity.16 The result suggests that the coordination
Figure 2. Calculated PM3 structures of 2-(trichloroethoxycarbonyl)-9-(N-
anthracenylmethylpyroglutamyl)-b-carbolinium cation (11). A local mini-
mal conformation in which the Si face is blocked DHf¼120.6484 kcal/mol.
of a free carboxylic acid afforded methyl ester of tetrahydro-
b-carboline 1-acetic acid 10. The absolute configuration
was determined as S in comparison with the specific rotation
of the reported one.13 Thus, it was proved that the reaction
proceeded in an S selective manner using the chiral auxiliary
5e irrespective of the nucleophile to be allyltributyltin or
silyl enol ether.
Figure 3. The Optimized structure of 2-(trichloroethoxycarbonyl)-9-(N-acylpyroglutamyl-b-carbolinium cation (12a and 12b). (a) The optimized
conformation of 12a. DHf¼6.5927 kcal/mol. (b) The optimized conformation of 12b. DHf¼43.1778 kcal/mol.

T. Itoh et al. / Tetrahedron 59 (2003) 3527–3536
3531
of the nucleophiles to the substrate might affect the
selectivity.
mp 76–778C; [a]D20¼þ51.5 (c 0.53, CHCl3); 1H NMR
(CDCl3) d: 1.40 (9H, s), 1.90–1.98 (1H, m), 2.09 (1H, ddd,
J¼18.8, 13.3, 9.2 Hz), 2.40 (1H, ddd, J¼16.9, 9.6, 3.8 Hz),
2.52–2.62 (1H, m), 3.61 (1H, dd, J¼9.2, 3.2 Hz), 4.39 (1H,
d, J¼14.6 Hz), 5.56 (1H, d, J¼14.6 Hz), 7.34 (1H, dd,
J¼6.8, 1.0 Hz), 7.40 (1H, dd, J¼8.1, 7.0 Hz), 7.48–7.56
(2H, m), 7.81–7.88 (2H, m), 8.08 (1H, dt, J¼6.8, 1.1 Hz);
13C NMR (CDCl3) d: 22.9, 28.0, 29.8, 43.8, 59.4, 82.0,
123.7, 125.0, 126.0, 126.7, 128.0, 128.5, 128.8, 131.3,
131.6, 133.7, 170.7, 174.5. Anal. calcd for C20H23NO3: C,
73.82; H, 7.12; N, 4.30. Found: C, 73.84; H, 7.22; N, 4.30.
3. Conclusion
In this paper, we described a new method for the
asymmetric addition of allyltributyltin or silyl enol ethers
to b-carboline at C-1 position using a novel chiral auxiliary
derived from (S)-pyroglutamic acid. The auxiliary was
readily recovered quantitatively by hydrolysis. Application
of the adducts obtained by this method to the total synthesis
of indole alkaloids is now under investigation.17
4.2.5. tert-Butyl N-(naphthalen-2-ylmethyl)-(S)-pyro-
glutamate (3d). Yield 83%; colorless needles from hexane;
mp 98–998C; [a]D20¼þ69.7 (c 0.54, CHCl3); 1H NMR
(CDCl3) d: 1.41 (9H, s), 1.98–2.05 (1H, m), 2.19 (1H, ddd,
J¼18.7, 13.2, 9.2 Hz), 2.42 (1H, ddd, J¼16.9, 9.7, 4.0 Hz),
2.53–2.62 (1H, m), 3.83 (1H, dd, J¼9.2, 3.3 Hz), 4.14 (1H,
d, J¼14.7 Hz), 5.21 (1H, d, J¼14.7 Hz), 7.35 (1H, dd,
J¼8.4, 1.7 Hz), 7.43–7.50 (2H, m), 7.65 (1H, s), 7.77–7.83
(3H, m); 13C NMR (CDCl3) d: 22.8, 27.9, 29.6, 45.7, 59.4,
82.0, 125.8, 126.1, 126.2, 127.3, 127.4, 127.5, 128.4, 132.6,
133.0, 133.2, 170.5, 174.8. Anal. calcd for C20H23NO3: C,
73.82; H, 7.12; N, 4.30. Found: C, 73.74; H, 7.23; N, 4.32.
4. Experimental
4.1. General remarks
Melting points are uncorrected. 1H and 13C NMR spectra of
CDCl3 and CD3OD solutions were recorded at 500 and
125 MHz, respectively, with tetramethylsilane (TMS) as an
internal standard. High-resolution mass spectra (FAB-
HRMS) were measured using p-nitrobenzyl alcohol as a
matrix.
4.2.6. tert-Butyl N-(anthracen-9-ylmethyl)-(S)-pyro-
glutamate (3e). Yield 75%; Yellow needles from isopropyl
4.2. Preparation of the chiral auxiliaries
ether; mp 169–1728C; [a]2D0¼þ141.4 (c 0.48, CHCl3); H
1
NMR (CDCl3) d: 1.35 (9H, s), 1.82–1.89 (1H, m), 1.90–
2.01 (1H, m), 2.38 (1H, ddd, J¼16.9, 9.3, 2.6 Hz), 2.50–
2.59 (1H, m), 3.43 (1H, dd, J¼9.5, 2.0 Hz), 5.22 (1H, d,
J¼15.3 Hz), 5.94 (1H, d, J¼15.3 Hz), 7.47 (2H, ddd, J¼7.7,
6.4, 1.1 Hz), 7.52 (2H, ddd, J¼8.1, 6.4, 1.5 Hz), 8.01 (2H,
dd, J¼8.1, 1.5 Hz), 8.33 (2H, dd, J¼7.7, 1.1 Hz), 8.46 (1H,
s); 13C NMR (CDCl3) d: 23.6, 27.9, 29.5, 37.5, 58.7, 82.0,
123.9, 125.0, 126.50, 126.52, 128.3, 129.0, 131.0, 131.2,
171.2, 174.5. Anal. calcd for C24H25NO3: C, 76.77; H, 6.71;
N, 3.73. Found: C, 76.56; H, 6.70; N, 3.49.
4.2.1. N-Protection of tert-butyl (S)-pyroglutamate (2).
To the suspension of NaH (2 mmol) in THF (5 ml) was
added tert-butyl (S)-pyroglutamate (2) (2 mmol), and the
mixture was allowed to react for 5 min at room temperature,
and an alkyl halide or acyl halide (2 mmol) was added to the
mixture. The reaction was continued until the starting
material was entirely consumed, then water was added and
the mixture was extracted with CH2Cl2. The organic layer
was dried over MgSO4, and evaporated off to leave a
residue, which was chromatographed on silica gel to give
the product 3.
4.2.7. tert-Butyl N-acetyl-(S)-pyroglutamate (3f). Yield
75%; colorless oil; [a]2D3¼237.6 (c 0.61, CHCl3); 1H NMR
(400 MHz, CDCl3) d: 1.47 (9H, s), 2.01–2.07 (1H, m),
2.25–2.36 (1H, m), 2.52 (3H, s), 2.52–2.59 (1H, m), 2.66–
2.76 (1H, m), 4.63 (1H, dd, J¼9.4, 2.2 Hz); 13C NMR
(100 MHz, CDCl3) d: 21.2, 24.6, 27.8, 31.8, 58.4, 82.3,
170.1, 170.9, 174.6. HRMS (FABþ) m/z: Calcd for
C11H18O4N 228.1236, found 228.1218.
4.2.2. tert-Butyl N-methyl-(S)-pyroglutamate (3a). Yield
94%; colorless plates from hexane; mp 69–718C;
1
[a]2D0¼210.8 (c 0.50, CHCl3); H NMR (CDCl3) d: 1.48
(9H, s), 2.01–2.08 (1H, m), 2.26–2.38 (2H, m), 2.43–2.51
(1H, m), 2.85 (3H, s), 3.98 (1H, dd, J¼8.7, 3.6 Hz); 13C
NMR (CDCl3) d: 22.6, 28.0, 28.8, 29.3, 62.6, 82.3, 170.9,
175.3. Anal. calcd for C10H17NO3: C, 60.28; H, 8.60; N,
7.03. Found: C, 60.31; H, 8.84; N, 6.95.
4.2.8. tert-Butyl N-benzoyl-(S)-pyroglutamate (3g). Yield
74%; colorless needles from hexane–dichloromethane; mp
4.2.3. tert-Butyl N-benzyl-(S)-pyroglutamate (3b). Yield
i
1
150.9–151.48C; [a]D23¼230.6 (c 0.35, CHCl3); H NMR
81%; colorless needles from Pr2O–AcOEt; mp 51.0–
58.98C; [a]2D0¼þ40.3 (c 0.51, CHCl3); 1H NMR (CDCl3) d:
1.44 (9H, s), 1.99–2.06 (1H, m), 2.16–2.26 (1H, m), 2.40
(1H, ddd, J¼13.6, 9.6, 4.0 Hz), 2.51–2.60 (1H, m), 3.83
(1H, dd, J¼9.2, 3.3 Hz), 3.96 (1H, d, J¼14.7 Hz), 5.06 (1H,
d, J¼14.7 Hz), 7.20–7.23 (2H, m), 7.26–7.35 (3H, m); 13C
NMR (CDCl3) d: 22.9, 28.0, 29.7, 45.6, 59.6, 82.2, 127.6,
128.4, 128.6, 135.8, 170.6, 174.9. Anal. calcd for
C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.65;
H, 7.55; N, 5.09.
(CDCl3) d: 1.98 (9H, s), 2.10 (1H, ddt, J¼13.4, 9.0, 4.7 Hz),
2.42 (1H, dq, J¼13.4, 9.0 Hz), 2.55 (1H, ddd, J¼17.5, 9.0,
4.7 Hz), 2.70 (1H, dt, J¼17.5, 9.0 Hz), 4.77 (1H, dd, J¼9.0,
4.7 Hz), 7.41 (2H, t, J¼7.6 Hz), 7.52 (1H, t, J¼7.6 Hz), 7.66
(2H, d, J¼7.6 Hz); 13C NMR (CDCl3) d: 21.8, 27.9, 31.8,
59.5, 82.5, 127.8, 129.1, 132.2, 133.9, 170.0, 170.4, 173.6.
Anal. calcd for C16H19NO4: C, 66.42; H, 6.62; N, 4.84.
Found: C, 66.38; H, 6.62; N, 4.84.
4.2.9. tert-Butyl N-(9-anthracenecarbonyl)-(S)-pyro-
glutamate (3h). Yield 83%; mp 82.9–84.38C;
4.2.4. tert-Butyl N-(naphthalen-1-ylmethyl)-(S)-pyro-
glutamate (3c). Yield 83%; colorless needles from hexane;
1
[a]2D3¼288.1 (c 0.60, CHCl3); H NMR (CDCl3) d: 1.65

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T. Itoh et al. / Tetrahedron 59 (2003) 3527–3536
(9H, s), 2.08–2.14 (1H, m), 2.29–2.40 (2H, m), 2.51–2.62
(1H, m), 5.08 (1H, dd, J¼9.2, 3.1 Hz), 7.41–7.50 (3H, m),
7.54–7.57 (1H, m), 7.77 (1H, d, J¼7.6 Hz), 8.02 (2H, d,
J¼8.2 Hz), 8.26 (1H, d, J¼8.5 Hz), 8.52 (1H, s); 13C NMR
(CDCl3) d: 21.4, 27.9, 31.2, 58.6, 82.7, 123.9, 124.7, 125.1,
125.3, 126.5, 126.7, 127.6, 128.2, 128.3, 128.4, 128.7, 129.9,
130.8, 130.9, 169.7, 170.1, 172.2. Anal. calcd for C24H23NO4:
C, 74.02; H, 5.95; N, 3.60. Found: C, 73.87; H, 6.23; N, 3.36.
4.3.3. N-(Naphthalen-1-ylmethyl)-(S)-pyroglutamic acid
(4c). Yield 87%; colorless needles from isopropyl ether; mp
184–1858C; [a]D20¼þ97.5 (c 0.53, CHCl3); 1H NMR
(CD3OD) d: 1.97–2.08 (1H, m), 2.10–2.18 (1H, m),
2.35–2.43 (1H, m), 2.50–2.58 (1H, m), 3.72 (1H, dd,
J¼9.4, 3.1 Hz), 4.36 (1H, d, J¼14.7 Hz), 5.56 (1H, d,
J¼14.7 Hz), 7.35–7.43 (2H, m), 7.49–7.51 (2H, m), 7.83–
7.89 (2H, m), 8.01–8.04 (1H, m); 13C NMR (CD3OD) d:
23.8, 30.7, 44.6, 60.0, 124.2, 126.1, 126.9, 127.5, 128.9,
129.7, 129.9, 132.0, 132.7, 135.2, 174.4, 177.2. Anal. calcd
for C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C, 71.18;
H, 5.42; N, 5.15.
4.2.10. tert-Butyl N-(p-nitrobenzoyl)-(S)-pyroglutamate
(3i). Yield 69%; Pale yellow powder from hexane–
dichloromethane; mp 111.1–120.08C; [a]2D3¼217.3 (c
1
0.5, CHCl3); H NMR (CDCl3) d: 1.51 (9H, s), 2.17 (1H,
ddt, J¼13.2, 9.4, 4.2 Hz), 2.48 (1H, ddt, J¼13.2, 9.2,
9.0 Hz), 2.59 (1H, ddd, J¼17.8, 9.3, 4.5 Hz), 2.74 (1H, dt,
J¼18.0 Hz), 4.82 (1H, dd, J¼8.9, 3.9 Hz), 7.77 (2H, d,
J¼9.0 Hz), 8.27 (2H, d, J¼9.0 Hz); 13C NMR (CDCl3) d:
21.8, 27.9, 31.5, 59.0, 83.0, 123.1, 129.6, 139.9, 149.5,
168.5, 169.6, 173.7. Anal. calcd for C16H18N2O6: C, 57.48;
H, 5.43; N, 8.38. Found: C, 57.54; H, 5.31; N, 8.23.
4.3.4. N-(Naphthalen-2-ylmethyl)-(S)-pyroglutamic acid
(4d). Yield 97%; colorless needles from hexane–iPr2O; mp
149–1528C; [a]D20¼þ73.6 (c 0.50, CH3OH); 1H NMR
(CDCl3) d: 2.11–2.17 (1H, m), 2.25 (1H, ddd, J¼18.9, 13.4,
9.5 Hz), 2.44 (1H, ddd, J¼16.8, 9.5, 3.7 Hz), 2.56–2.63
(1H, m), 3.96 (1H, dd, J¼9.3, 3.3 Hz), 4.18 (1H, d,
J¼14.9 Hz), 5.24 (1H, d, J¼14.9 Hz), 7.37 (1H, dd,
J¼8.5, 1.8 Hz), 7.44–7.49 (2H, m), 7.68 (1H, s), 7.79–
7.82 (3H, m); 13C NMR (CDCl3) d: 22.9, 29.7, 45.6, 58.6,
126.0, 126.2, 126.4, 127.3, 127.6, 127.8, 128.6, 132.8,
133.3, 133.6, 173.7, 175.4. Anal. calcd for C16H15NO3: C,
71.36; H, 5.61; N, 5.20. Found: C, 71.10; H, 5.59; N, 5.18.
4.2.11. tert-Butyl N-benzenesulfonyl-(S)-pyroglutamate
(3j). Yield 69%; colorless viscous oil; [a]2D0¼247.8 (c 0.52,
CHCl3); 1H NMR (CDCl3) d: 1.49 (9H, s), 2.01–2.08 (1H,
m), 2.33–2.45 (2H, m), 2.46–2.59 (1H, m), 4.74 (1H, dd,
J¼9.0, 2.6 Hz), 7.52 (2H, t, J¼8.0 Hz), 7.64 (1H, tt, J¼8.0,
1.3 Hz), 8.08 (2H, dd, J¼8.0, 1.3 Hz); 13C NMR (CDCl3) d:
23.2, 27.7, 30.3, 60.0, 82.7, 128.3, 128.5, 133.8, 137.7,
169.4, 172.4. HRMS (FABþ): Calcd for C15H20NO5S
(MþH)þ: 326.1062. Found: 326.1031.
4.3.5. N-(Anthracen-9-ylmethyl)-(S)-pyroglutamic acid
(4e). Yield 94%; Pale green prisms from ethanol; mp 277–
2808C; [a]2D0¼þ151.2 (c 0.50, CHCl3); 1H NMR (CDCl3) d:
1.83–2.00 (2H, m), 2.31 (1H, ddd, J¼16.9, 9.5, 2.4 Hz),
2.39–2.48 (1H, m), 3.41 (1H, dd, J¼9.4, 1.7 Hz), 5.13 (1H,
d, J¼15.1 Hz), 5.84 (1H, d, J¼15.1 Hz), 7.55 (2H, t,
J¼8.2 Hz), 7.60 (2H, t, J¼8.2 Hz), 8.12 (2H, d, J¼8.2 Hz),
8.35 (2H, d, J¼8.2 Hz), 8.62 (1H, s); 13C NMR (CDCl3) d:
22.7, 28.9, 36.8, 57.5, 123.4, 125.0, 126.4, 126.6, 128.0,
129.0, 130.4, 130.7, 173.4, 173.7. Anal. calcd for
C20H17NO3: C, 75.22; H, 5.37; N, 4.39. Found: C, 74.86;
H, 5.18; N, 4.33.
4.3. Transformation of 3 to corresponding carboxylic
acid 4
To the CH2Cl2 solution of N-protected tert-butyl (S)-
pyroglutamate 3, trifluoroacetic acid (5 equiv.) was added
dropwise, and the mixture was allowed to react at room
temperature. Then CH2Cl2 was added and the mixture was
extracted with saturated aqueous NaHCO3. The aqueous
layer was acidified with dil. HCl, and extracted with
CH2Cl2. The organic layer was dried over MgSO4, and
evaporated off to leave a residue. The residue was
suspended in hexane to precipitate crystals, which was
separated from the solution by filtration, and dried under
vacuum to give N-protected pyroglutamic acid 4.
4.3.6. N-Acetyl-(S)-pyroglutamic acid (4f). Yield 73%;
colorless powder from hexane; mp 75.9–77.08C;
[a]2D0¼229.90 (c 0.54, CHCl3); 1H NMR (400 MHz,
CDCl3) d: 2.19 (1H, ddt, J¼13.4, 9.5, 3.0 Hz), 2.33–2.48
(1H, m), 2.55 (3H, s), 2.60 (1H, ddd, J¼17.8, 9.3, 3.1 Hz),
2.76 (1H, dt, J¼17.8, 10.1 Hz), 4.79 (1H, dd, J¼9.7,
2.6 Hz), 9.16 (1H, bs); 13C NMR (100 MHz, CDCl3) d:
21.1, 24.5, 31.7, 57.5, 171.3, 174.4, 176.2. Anal. calcd for
C7H9NO4: C, 49.12; H, 5.30; N, 8.18. Found: C, 49.01; H,
5.12; N, 8.01.
4.3.1. N-Methyl-(S)-pyroglutamic acid (4a). Yield 71%;
colorless prisms from iPr2O–AcOEt; mp 148–1508C;
1
[a]2D0¼220.8 (c 0.15, CHCl3); H NMR (CDCl3) d: 2.16–
2.24 (1H, m), 2.38–2.64 (3H, m), 2.92 (3H, s), 4.19 (1H, dd,
J¼9.2, 3.4 Hz), 10.61 (1H, bs); 13C NMR (CDCl3) d: 20.8,
22.8, 29.4, 62.1, 174.0, 176.9. Anal. calcd for C6H9NO3: C,
50.35; H, 6.34; N, 9.79. Found: C, 50.32; H, 6.34; N, 9.76.
4.3.7. N-Benzoyl-(S)-pyroglutamic acid (4g). Yield 90%;
colorless needles from hexane–ethyl acetate; mp 168.2–
168.68C; [a]2D5¼þ15.43 (c 0.3, CH3OH); 1H NMR (CDCl3)
d: 2.27 (1H, ddt, J¼13.2, 9.2, 4.5 Hz), 2.51 (1H, dq, J¼13.2,
9.2 Hz), 2.62 (1H, ddd, J¼17.7, 9.2, 4.5 Hz), 2.78 (1H, dt,
J¼17.7, 9.2 Hz), 4.92 (1H, dd, J¼9.2, 4.5 Hz), 7.42 (2H, tt,
J¼7.5, 1.4 Hz), 7.54 (1H, tt, J¼7.5, 1.5 Hz), 7.65–7.68 (2H,
m); 13C NMR (CDCl3) d: 21.7, 31.6, 58.5, 127.9, 129.2,
132.5, 133.4, 170.5, 173.3, 175.5. Anal. calcd for
C12H11NO4: C, 61.80; H, 4.75; N, 6.01. Found: C, 61.77;
H, 4.54; N, 5.80.
4.3.2. N-Benzyl-(S)-pyroglutamic acid (4b). The mp and
NMR spectra of this compound were identical to those of
the reported data.18 Yield 91%; colorless powder; mp 85–
888C (lit.18 mp 92–938C); [a]D20¼þ78.6 (c 0.50, CHCl3); 1H
NMR (CDCl3) d: 2.13–2.21 (1H, m), 2.30 (1H, ddd,
J¼18.9, 13.4, 9.3 Hz), 2.52 (1H, ddd, J¼17.1, 9.3, 3.7 Hz),
2.60–2.69 (1H, m), 3.99 (1H, d, J¼14.8 Hz), 4.03 (1H, dd,
J¼9.3, 3.1 Hz), 5.16 (1H, d, J¼14.8 Hz), 7.21–7.23 (2H,
m), 7.26–7.35 (3H, m), 10.06 (1H, bs).
4.3.8. N-(Anthracene-9-carbonyl)-(S)-pyroglutamic acid

T. Itoh et al. / Tetrahedron 59 (2003) 3527–3536
3533
(4h). Yield 85%; Pale yellow powder; mp 150–1558C;
[a]1D7¼236.38 (c 0.40, CH3OH); 1H NMR (CDCl3) d: 2.32
(1H, ddt, J¼12.6, 9.8, 2.7 Hz), 2.40–2.47 (1H, m), 2.54
(1H, dq, J¼12.9, 9.2 Hz), 2.67 (1H, dt, J¼16.7, 9.5 Hz),
5.24 (1H, dd, J¼9.2, 2.6 Hz), 7.43–7.51 (4H, m), 7.73–7.75
(1H, m), 8.00–8.04 (2H, m), 8.22 (1H, d, J¼7.9 Hz), 8.52
(1H, s); 13C NMR (CDCl3) d: 21.8, 31.5, 57.9, 123.9, 124.8,
125.3, 125.6, 126.8, 126.9, 127.7, 128.4, 128.5, 128.6,
128.9, 130.0, 130.9, 131.1, 170.3, 172.7, 173.0. HRMS
(FABþ) m/z: Calcd for C20H16NO4 (MþH)þ 334.1079,
found 334.1061.
23.8, 29.3, 45.9, 60.2, 114.2, 116.1, 121.5, 124.5, 124.6,
127.7, 128.2, 128.7, 130.3, 132.9, 134.6, 135.3, 137.4,
138.3, 143.9, 170.6, 174.8. Anal. calcd for C23H19N3O2: C,
74.78; H, 5.18; N, 11.37. Found: C, 74.47; H, 4.79; N, 11.46.
4.4.3. 9-[N-(Naphthalen-1-ylmethyl)-(S)-pyroglutamyl]-
b-carboline (5c). Yield 77%; colorless powder; mp 88–
928C; [a]2D0¼2114.1 (c 0.17, CHCl3); 1H NMR (CDCl3) d:
2.21 (1H, ddt, J¼11.9, 9.5, 2.4 Hz), 2.46 (1H, ddd, J¼19.2,
13.1, 9.5 Hz), 2.60 (1H, ddd, J¼16.8, 9.5, 2.4 Hz), 2.76 (1H,
dt, J¼16.8, 9.5 Hz), 4.47 (1H, d, J¼14.6 Hz), 4.79 (1H, dd,
J¼9.5, 2.4 Hz), 5.62 (1H, d, J¼14.6 Hz), 6.95 (1H, dd,
J¼8.2, 7.0 Hz), 7.06 (1H, d, J¼7.0 Hz), 7.40–7.54 (4H, m),
7.55 (1H, d, J¼7.9 Hz), 7.72–7.75 (1H, m), 7.87 (1H, dd,
J¼4.9, 0.9 Hz), 8.05 (2H, d, J¼8.9 Hz), 8.61 (1H, d,
J¼4.9 Hz); 13C NMR (CDCl3) d: 23.5, 29.5, 43.9, 59.8,
114.2, 121.5, 123.5, 124.7, 124.8, 126.2, 126.9, 127.8,
128.7, 129.0, 130.3, 130.9, 131.6, 132.8, 133.7, 144.2,
170.9, 174.8. Anal. calcd for C27H21N3O2·1/2H2O: C,
75.68; H, 5.17; N, 9.81. Found: C, 75.61; H, 5.21; N, 9.37.
4.3.9. N-(p-Nitrobenzoyl)-(S)-pyroglutamic acid (4i).
Yield 91%; Pale yellow powder; mp 150.4–151.08C;
1
[a]2D0¼þ12.46 (c 0.5, CH3OH); H NMR (CDCl3) d: 2.32
(1H, ddt, J¼13.1, 9.4, 3.7 Hz), 2.57 (1H, ddt, J¼13.3, 9.3,
9.1 Hz), 2.66 (1H, ddd, J¼17.7, 8.9, 3.7 Hz), 2.79 (1H, ddt,
J¼17.6, 9.0, 8.9 Hz), 4.98 (1H, dd, J¼9.1, 3.6 Hz), 7.77
(2H, d, J¼9.0 Hz), 8.29 (2H, d, J¼9.0 Hz); 13C NMR
(CDCl3þCD3OD) d: 21.9, 31.6, 58.4, 123.2, 129.6, 140.0,
149.5, 168.8, 172.6, 174.3. Anal. calcd for C12H10N2O6: C,
51.80; H, 3.62; N, 10.07. Found: C, 51.45; H, 3.30; N, 9.68.
4.4.4. 9-[N-(Naphthalen-2-ylmethyl)-(S)-pyroglutamyl]-
b-carboline (5d). Yield 88%; colorless needles from
iPr2O–AcOEt; mp 149–1528C; [a]2D0¼2104.2 (c 0.52,
4.3.10. N-(Benzenesulfonyl)-(S)-pyroglutamic acid (4j).
Yield 76%; colorless powder; mp 158–160.58C;
[a]2D0¼241.0 (c 0.50, CH3OH); 1H NMR (CDCl3) d:
2.20–2.29 (1H, m), 2.43–2.70 (3H, m), 4.94 (1H, dd,
J¼9.2, 2.5 Hz), 5.72 (1H, br), 7.56 (2H, t, J¼8.0 Hz), 7.68
(1H, t, J¼8.0 Hz), 8.11 (2H, dd, J¼8.0, 1.3 Hz); 13C NMR
(CDCl3) d: 23.4, 30.5, 59.0, 128.7, 128.8, 134.3, 137.5,
172.3, 175.0. Anal. calcd for C11H11NO5S: C, 49.06; H,
4.12; N, 5.20. Found: C, 48.97; H, 3.74; N, 5.15.
1
CHCl3); H NMR (CDCl3) d: 2.31–2.35 (1H, m), 2.55–
2.67 (2H, m), 2.71–2.81 (1H, m), 4.19 (1H, d, J¼14.9 Hz),
5.04 (1H, dd, J¼9.0, 2.4 Hz), 5.27 (1H, d, J¼14.9 Hz),
7.26–7.43 (6H, m), 7.50 (1H, t, J¼7.4 Hz), 7.67 (2H, t,
J¼8.1 Hz), 7.81 (1H, d, J¼4.9 Hz), 7.86 (1H, br), 7.99 (1H,
d, J¼7.7 Hz), 8.57 (1H, d, J¼4.9 Hz), 9.29 (1H, bs); 13C
NMR (CDCl3) d: 23.8, 29.4, 46.2, 60.1, 114.1, 116.0 (br),
121.5, 124.4, 124.6, 125.92, 125.94, 126.1, 127.3, 127.4,
128.7, 130.2, 132.57, 132.64, 132.8, 132.9, 134.5 (br), 137.3
(br), 138.2 (br), 143.7, 170.7, 174.9. Anal. calcd for
C27H21N3O2: C, 77.31; H, 5.05; N, 10.02. Found: C,
77.07; H, 4.80; N, 9.98.
4.4. The synthesis of 9-pyroglutaminyl-b-carbolines 5
To the CH2Cl2 (1 ml) solution of N-substituted pyro-
glutamic acid 4 (0.5 mmol) and b-carboline (0.5 mmol)
was added EDCI (0.6 mmol), and the mixture was allowed
to react for 1–3 h at room temperature. Then the mixture
was chromatographed on silica gel (AcOEt) to give the
product.
4.4.5. 9-[N-(Anthracen-9-ylmethyl)-(S)-pyroglutamyl]-
b-carboline (5e). Yield 95%; colorless powder; mp 190–
1
1938C (decomp.); [a]D20¼275.9 (c 0.51, CHCl3); H NMR
(CDCl3, 608C) d: 2.10–2.15 (1H, m), 2.28–2.36 (1H, m),
2.57 (1H, ddd, J¼16.8, 9.5, 2.1 Hz), 2.82 (1H, dt, J¼17.1,
9.5 Hz), 4.56 (1H, dd, J¼9.1, 1.5 Hz), 5.34 (1H, d, J¼
15.3 Hz), 5.79 (1H, d, J¼15.3 Hz), 7.04 (2H, t, J¼7.6 Hz),
7.15 (2H, t, J¼8.2 Hz), 7.35 (1H, br), 7.65 (2H, d, J¼
8.5 Hz), 7.71 (1H, d, J¼4.9 Hz), 7.88–7.90 (1H, m), 8.02 (1H,
s), 8.07 (2H, d, J¼8.9 Hz), 8.51 (1H, br); 13C NMR (CDCl3,
608C) d: 23.7, 29.4, 37.8, 59.3, 113.9, 121.2 (br), 123.3, 124.5
(br), 124.9, 125.5, 126.6, 128.4, 129.1, 130.0 (br), 130.9, 131.1,
132.8 (br), 143.7, 171.4, 174.9. Anal. calcd for C31H23N3O2:
C, 79.30; H, 4.94; N, 8.95. Found: C, 78.93; H, 5.00; N, 8.77.
4.4.1. 9-(N-Methyl-(S)-pyroglutamyl)-b-carboline (5a).
Yield 86%; colorless powder; mp 175–1788C; [a]2D0¼2148.9
1
(c 0.30, CH3OH); H NMR (CDCl3) d: 2.31–2.37 (1H, m),
2.51–2.80 (3H, m), 2.95 (3H, s), 5.19 (1H, dd, J¼9.3, 1.8 Hz),
7.52 (1H, t, J¼7.3 Hz), 7.68 (1H, ddd, J¼8.6, 7.3, 1.3 Hz),
7.94 (1H, dd, J¼5.1, 0.9 Hz), 8.12 (1H, dd, J¼7.3, 0.6 Hz),
8.18 (1H, br), 8.68 (1H, d, J¼5.1 Hz), 9.55 (1H, s); 13C NMR
(CDCl3) d: 23.6, 28.8, 29.2, 63.4, 114.1, 116.1, 121.5, 122.0,
124.6, 132.8, 134.6, 137.6, 138.2, 144.0, 147.5, 170.1, 174.9.
Anal. calcd for C17H15N3O2: C, 69.61; H, 5.15; N, 14.33.
Found: C, 69.35; H, 5.02; N, 14.15.
4.4.6. 9-(N-Acetyl-(S)-pyroglutamyl)-b-carboline (5f).
Yield 71%; colorless needles from iPr2O–CH2Cl2; mp 195–
1968C; [a]2D0¼268.39 (c 0.59, CHCl3); 1H NMR (CDCl3) d:
2.30–2.38(1H, m), 2.57–2.79(2H, m), 2.63(3H, s), 7.50(1H,
td, J¼7.6, 0.8 Hz), 7.64 (1H, ddd, J¼8.6, 7.3, 1.3 Hz), 7.93
(1H, dd, J¼5.1, 1.1 Hz), 8.11 (1H, ddd, J¼7.8, 1.3, 0.6 Hz),
8.17 (1H, bs), 8.66(1H, d, J¼5.1 Hz), 9.50 (1H, bs); 13C NMR
(125 MHz, CDCl3) d: 21.7, 24.6, 31.6, 59.0, 114.5, 116.4,
121.7, 124.7, 124.8, 130.5, 133.3, 135.0, 137.5, 138.7, 143.8,
170.2, 171.2, 174.2. Anal. calcd for C18H15N3O3: C, 67.28; H,
4.71; N, 13.08. Found: C, 67.00; H, 4.50; N, 12.85.
4.4.2. 9-(N-Benzyl-(S)-pyroglutamyl)-b-carboline (5b).
Yield 99%; colorless needles from Et2O–AcOEt; mp
175–1788C; [a]D20¼2124.7 (c 0.13, CHCl3); 1H NMR
(CDCl3) d: 2.26–2.32 (1H, m), 2.55–2.64 (2H, m), 2.66–
2.75 (1H, m), 4.00 (1H, d, J¼14.8 Hz), 5.01 (1H, dd, J¼8.9,
1.9 Hz), 5.22 (1H, d, J¼14.8 Hz), 7.12–7.18 (5H, m), 7.48
(1H, t, J¼8.4 Hz), 7.60 (1H, t, J¼8.4 Hz), 7.85–8.20 (1H,
br), 7.91 (1H, dd, J¼5.1, 0.9 Hz), 8.09 (1H, d, J¼8.4 Hz),
8.64 (1H, d, J¼5.1 Hz), 9.31 (1H, bs); 13C NMR (CDCl3) d:

3534
T. Itoh et al. / Tetrahedron 59 (2003) 3527–3536
4.4.7. 9-[N-(Benzoyl)-(S)-pyroglutamyl]-b-carboline
(5g). Yield 99%; colorless powder from hexane; mp
chloroformate (0.2 mmol) at 2788C under Ar atmosphere,
and the reaction was continued for 24 h at the same
temperature. After 3 M aqueous KF solution (10 ml) and
CH2Cl2 (10 ml) were added, the mixture was stirred
vigorously for another 1 h. Then the organic layer was
separated, dried over MgSO4, and evaporated off. The
residue was chromatographed on silica gel (CH2Cl2–
AcOEt) to give the adduct 6 as a colorless oil. The
compound 6 was found to be unstable, and its NMR spectra
were given as those of a mixture of diastereomers and
conformational isomers. Thus, the adduct 6 was subjected to
alkaline hydrolysis without further purification. To the THF
solution (1 ml) of 6 was added 1 M aqueous NaOH solution
(2 ml), and the mixture was allowed to react for 30 min at
room temperature. After H2O was added, the mixture was
extracted with CH2Cl2, and the organic layer was dried over
MgSO4 and evaporated. A residue thus obtained was
confirmed by NMR to be a pure compound 7.6 The aqueous
layer was acidified with dil. HCl and extracted with CH2Cl2.
The organic layer thus obtained was dried over MgSO4, and
evaporated off to leave almost pure compound 4 in a
quantitative yield.
1
170.0–171.28C; [a]D25¼þ13.91 (c 0.5, CHCl3); H NMR
(CDCl3) d: 2.36–2.43 (1H, m), 2.68–2.79 (2H, m), 2.91–
3.03 (1H, m), 6.00 (1H, dd, J¼8.9, 2.3 Hz), 7.43 (2H, t,
J¼7.6 Hz), 7.49–7.57 (2H, m), 7.65–7.73 (3H, m), 7.98
(1H, dd, J¼5.1, 0.9 Hz), 8.12 (1H, d, J¼7.1 Hz), 8.2 (1H, d,
J¼5.9 Hz), 8.67 (1H, d, J¼5.1 Hz), 9.57 (1H, bs); 13C
NMR(CDCl3) d: 22.1, 31.4, 59.9, 114.3, 116.3, 121.6,
124.7, 124.7, 127.8, 129.2, 130.3, 132.3, 133.0, 133.3,
135.0, 137.8, 138.5, 144.1, 170.30, 170.34, 173.1. Anal.
calcd for C23H17N3O3: C, 72.05; H, 4.47; N, 10.96. Found:
C, 72.24; H, 4.21; N, 10.90.
4.4.8. 9-[N-(Anthracene-9-carbonyl)-(S)-pyroglutamyl]-
b-carboline (5h). Yield 73%; colorless powder; mp 180–
1838C (decomp); [a]D23¼2139.36 (c 0.6, CHCl3); 1H NMR
(CDCl3) d: 2.44–2.48 (1H, m), 2.53–2.61 (1H, m), 2.80–
2.88 (2H, m), 6.41 (1H, dd, J¼9.0, 1.4 Hz), 7.45–7.57 (4H,
m), 7.65 (1H, t, J¼7.2 Hz), 7.76 (1H, td, J¼7.8, 1.1 Hz),
7.84 (1H, d, J¼8.2 Hz), 8.02–8.05 (3H, m), 8.16 (1H, d,
J¼7.6 Hz), 8.30 (1H, bs), 8.34 (1H, d, J¼8.9 Hz), 8.54 (1H,
s), 8.66 (1H, d, J¼5.2 Hz), 9.77 (1H, bs); 13C NMR
(125 MHz, CDCl3) d: 22.1, 31.1, 59.1, 114.5, 116.4, 121.8,
123.8, 124.9, 125.2, 125.7, 126.7, 127.2, 127.7, 128.45,
128.53, 128.7, 129.0, 129.4, 130.5, 130.8, 131.1, 133.3,
135.2, 138.0, 138.7, 144.2, 170.1, 170.2, 171.8. Anal. calcd
for C31H21N3O3: C, 77.00; H, 4.38; N, 8.69. Found: C,
76.80; H, 4.11; N, 8.58.
4.6. The reaction of 9-pyroglutamyl-b-carboline 5 with
silyl enol ethers
2,2,2-Trichloroethyl chloroformate (0.2 mmol) was added
to the mixture of compound 5 (0.1 mmol) and a silyl enol
ether (0.3 mmol) in CH2Cl2 (1 ml) at the temperature shown
in Table 4 under Ar, and the mixture was allowed to react
for 0.5–40 h until the complete consumption of 5. After
diluted with THF (1 ml), 1 M NaOH (1 ml) was added to the
mixture, which was allowed to stir for 1 h at room
temperature. Then the mixture was diluted with water and
extracted with CH2Cl2. The organic layer was dried over
MgSO4, and evaporated off to leave the residue, which was
chromatographed on silica gel to give the product 8. The
aqueous layer was acidified with dil. HCl and extracted with
CH2Cl2. The organic layer thus obtained was dried over
MgSO4, and evaporated off to leave almost pure compound
4 in a quantitative yield.
4.4.9. 9-[N-(p-Nitrobenzoyl)-(S)-pyroglutamyl]-b-carbo-
i
line (5i). Yield 74%; Pale yellow needles from Pr2O–
CH2Cl2; mp 223–2258C; [a]2D0¼þ8.12 (c 0.30, CHCl3);
1H NMR (CDCl3) d: 2.42–2.50 (1H, m), 2.73–2.87
(2H, m), 2.91–3.04 (1H, m), 6.07 (1H, dd, J¼9.0, 2.0 Hz),
7.54(1H, td, J¼7.6, 0.6 Hz), 7.70(1H, td, J¼7.9,1.3 Hz), 7.85
(2H, d, J¼8.8 Hz), 7.98 (1H, dd, J¼5.1, 0.7 Hz), 8.15 (1H, dd,
J¼7.8, 0.6 Hz), 8.23 (1H, bs), 8.31 (2H, d, J¼8.8 Hz), 8.70
(2H, d, J¼5.1 Hz), 9.57 (1H, bs); 13C NMR (CDCl3) d: 22.2,
31.2, 59.7, 114.5, 116.4, 121.8, 123.2, 124.96, 125.01, 129.7,
130.6, 135.0, 137.8, 138.6, 139.4, 144.4, 149.6, 168.4, 169.8,
173.3. HRMS (FABþ) m/z: Calcd for C23H17O5N4 (MþH)þ
429.1199, found 429.1245.
4.6.1. 1,2-Dihydro-1-(2-oxopropyl)-2-(2,2,2-trichloro-
ethoxycarbonyl)-b-carboline (8a). Yield 40%; Pale
yellow powder; mp 145–1508C; [a]2D0¼2219.4 (c 0.22,
CHCl3). The product was obtained as a mixture of two
4.4.10. 9-[N-(Benzenesulfonyl)-(S)-pyroglutamyl]-b-car-
boline (5j). Yield 91%; colorless plates from iPr2O–AcOEt;
mp 203.1–204.08C; [a]2D0¼294.6 (c 0.29, CHCl3); 1H
NMR (CDCl3) d: 2.32–2.40 (1H, m), 2.57–2.66 (1H, m),
2.71–2.85 (2H, m), 6.07 (1H, dd, J¼9.2, 1.5 Hz), 7.53–7.60
(3H, m), 7.69–7.75 (2H, m), 8.01 (1H, d, J¼4.9 Hz), 8.03–
8.16 (1H, br), 8.09–8.12 (2H, m), 8.16 (1H, d, J¼7.5 Hz),
8.71 (1H, d, J¼4.9 Hz), 9.59 (1H, bs); 13C NMR (CDCl3) d:
23.9, 30.2, 60.7, 114.3, 115.9, 121.8, 124.8, 128.5, 129.3,
130.4, 133.1, 134.3, 134.9, 137.1, 138.0, 144.2, 169.5,
172.1. Anal. calcd for C22H17N3O4S: C, 63.00; H, 4.09; N,
10.02. Found: C, 62.94; H, 3.74; N, 9.96.
1
conformational isomers. The H and 13C NMR spectra of
1
minor one are shown in parentheses. H NMR (CDCl3,
608C) d: 2.12 (3H, s), 2.97–3.20 (2H, m), 4.73 (4.64) (1H, d,
J¼11.9 Hz), 4.99 (5.13) (1H, d, J¼11.9 Hz), 6.03 (6.09)
(1H, dd, J¼10.3, 3.0 Hz (9.8, 2.8 Hz)), 6.16 (6.22) (1H, d,
J¼7.7 Hz), 6.69 (6.71) (1H, d, J¼7.7 Hz), 7.11–7.20 (2H,
m), 7.34 (7.33) (1H, d, J¼7.8 Hz), 7.57 (1H, d, J¼7.5 Hz),
8.76 (8.68) (1H, s); 13C NMR (CDCl3) d: 30.3 (30.2), 48.4
(48.8), 48.9 (50.2), 75.5 (75.2), 95.0 (95.1), 104.0, 106.3
(106.4), 111.52 (111.47), 117.1 (118.0), 118.0 (118.2),
120.21 (120.23), 122.17 (122.19), 123.40 (123.44), 130.6
(130.5), 135.78 (135.81), 151.5 (151.3), 208.3 (208.2).
Anal. calcd for C17H15Cl3N2O3: C, 50.83; H, 3.76; N, 6.97.
Found: C, 50.60; H, 3.42; N, 6.69.
4.5. Asymmetric addition of allyltributyltin to 9-pyro-
glutamyl-b-carbolines 5 in the presence of 2,2,2-tri-
chloroethyl chloroformate
To the CH2Cl2 solution (1 ml) of 5 (0.1 mmol) and
allyltributyltin (0.3 mmol) was added 2,2,2-trichloroethyl
4.6.2. 1,2-Dihydro-1-(2-oxo-2-phenylethyl)-2-(2,2,2-tri-
chloroethoxycarbonyl)-b-carboline (8b). Yield 79%;

T. Itoh et al. / Tetrahedron 59 (2003) 3527–3536
3535
colorless needles from hexane–AcOEt; mp 152–1558C;
[a]2D0¼2335.0 (c 0.30, CHCl3); The product was obtained
trifluoroacetic acid (100 ml, 1.30 mmol), and the mixture
was allowed to react for 15 min. Then the mixture was
diluted with CH2Cl2, washed with 10% Na2CO3, dried
over MgSO4, and evaporated off in vacuo to leave a
residue, which was chromatographed on silica gel
(CH2Cl2) to give compound 9 (21 mg, 0.042 mmol,
87% yield). To the THF (0.35 ml)/H2O (0.25 ml) solution
of compound 9 (20 mg, 0.04 mmol) was added acetic acid
(20 ml, 0.35 mmol) and zinc powder (11 mg, 0.17 mmol)
successively, and the mixture was allowed to react for
3 h. Then ethyl acetate (15 ml) was added, and the
organic layer was washed with 5% Na2CO3 (3 ml) and
brine (1 ml) respectively, dried over MgSO4, and
evaporated off. The residue was dissolved in MeOH
(1 ml), and the solution was treated with sodium
methoxide (0.016 mmol) for 2.5 h at room temperature.
Then the solution was neutralized with 1N HCl, and the
methanol was evaporated off. The aqueous layer thus
obtained was basified by the addition of 5% Na2CO3, and
extracted with CH2Cl2 (8 ml£2). The organic layer was
dried over MgSO4, and evaporated off to leave a residue,
which was chromatographed on silica gel (AcOEt–
EtOH¼5:1) to give the product 10 (9.0 mg,
0.037 mmol) in 92% yield.
as a mixture of two conformational isomers. The 1H and 13
C
1
NMR spectra of minor one are shown in parentheses. H
NMR (CDCl3, 608C) d: 3.48 (3.61) (1H, dd, J¼18.0,
2.7 Hz), 3.65 (3.70) (1H, dd, J¼18.0, 10.4 Hz), 4.76 (4.67)
(1H, d, J¼11.9 Hz), 4.99 (5.07) (1H, d, J¼11.9 Hz), 6.21
(6.27) (1H, d, J¼7.6 Hz), 6.28 (6.33) (1H, dd, J¼10.4,
2.7 Hz), 6.77 (6.78) (1H, d, J¼7.6 Hz), 7.10–7.18 (2H, m),
7.36 (7.35) (1H, d, J¼7.9 Hz), 7.41–7.45 (2H, m), 7.54–
7.58 (2H, m), 7.89 (1H, d, J¼8.2 Hz), 8.91 (8.84) (1H, s);
13C NMR (CDCl3) d: 43.9 (45.7), 49.4 (49.3), 75.6 (75.3),
95.1 (95.0), 104.3 (104.2), 106.5 (106.6), 111.63 (111.57),
117.3 (118.2), 118.1 (118.3), 120.29 (120.31), 122.26
(122.28), 123.56 (123.60), 127.9 (128.0), 128.7 (128.8),
131.0 (130.9), 133.8 (133.9), 135.95 (135.94), 136.1
(136.00), 151.7 (151.6), 199.60 (199.56). Anal. calcd for
C22H17Cl3N2O3: C, 56.98; H, 3.69; N, 6.04. Found: C,
57.28; H, 3.49; N, 5.77.
4.6.3. 1,2-Dihydro-1-(1-methoxycarbonyl-1-methyl-
ethyl)-2-(2,2,2-trichloroethoxycarbonyl)-b-carboline
(8c). Yield quant; colorless powder; mp 146–1488C;
[a]1D8¼þ110.52 (c 2.32, CHCl3); The product was obtained
as a mixture of two conformational isomers. The 1H and 13
C
1
NMR spectra of minor one are shown in parentheses. H
NMR (CDCl3, 608C) d: 1.10 (3H, s), 1.32 (1.40) (3H, s),
3.71 (3H, s), 4.76 (4.82) (1H, d, J¼11.9 Hz), 5.06 (4.90)
(1H, d, J¼11.9 Hz), 6.24–6.35 (2H, m), 6.78 (1H, d,
J¼7.5 Hz), 7.12–7.20 (2H, m), 7.35 (1H, d, J¼7.7 Hz),
7.59 (1H, d, J¼7.7 Hz), 8.53 (8.47) (1H, s); 13C NMR
(CDCl3) d: 19.3 (18.8), 23.1 (23.8), 50.5 (50.4), 32.3, 56.36
(56.43), 75.3 (75.6), 95.0 (94.5), 106.1 (106.8), 108.7
(109.0), 111.2, 117.9 (118.0), 119.4 (120.1), 120.0 (120.6),
121.97 (122.03), 123.2, 128.7 (128.6), 135.6, 153.2 (152.7),
177.7 (178.0). Anal. calcd for C19H19Cl3N2O4: C, 51.20; H,
4.30; N, 6.28. Found: C, 51.33; H, 4.22; N, 6.06.
4.7.1. 1-Benzyloxycarbonylmethyl-1,2,3,4-tetrahydro-2-
(2,2,2-trichloroethoxycarbonyl)-b-carboline (9). Color-
less needles from hexane; mp 114–1158C; [a]2D0¼þ200.7 (c
0.27, CHCl3); The product was obtained as a mixture of two
1
conformational isomers. The H and 13C NMR spectra of
1
minor one are shown in parentheses. H NMR (CDCl3) d:
2.79 (1H, dt, J¼15.9, 4.6 Hz), 2.86–2.95 (1H, m), 3.01 (1H,
d, J¼7.0 Hz), 3.06 (1H, d, J¼7.0 Hz), 3.18 (3.24) (1H, td,
J¼12.8, 4.6 Hz), 4.55 (1H, td, J¼12.8, 4.9 Hz), 4.79 (4.63)
(1H, d, J¼11.9 Hz), 4.83 (4.98) (1H, d, J¼11.9 Hz), 5.18
(5.17) (1H, d, J¼12.2 Hz), 5.25 (5.29) (1H, d, J¼12.2 Hz),
5.72 (5.73) (1H, t, J¼7.0 Hz), 7.08–7.12 (1H, m), 7.16–
7.19 (1H, m), 7.27 (1H, d, J¼8.6 Hz), 7.34–7.39 (5H, m),
7.48 (1H, t, J¼7.9 Hz), 8.67 (8.63) (1H, s); 13C NMR
(CDCl3) d: 21.6 (21.1), 39.67 (39.2), 39.70 (39.9), 48.0
(47.8), 67.2, 75.2 (75.1), 95.6 (95.5), 108.4 (108.6), 111.2,
118.2 (118.3), 119.5 (119.6), 122.2 (122.3), 126.2, 128.4
(128.5), 128.6 (128.7), 128.8, 131.9 (132.3), 135.2, 135.7
(135.8), 153.4 (153.0), 172.3 (172.6). Anal. calcd for
C23H21Cl3N2O4: C, 55.72; H, 4.27; N, 5.65. Found: C,
55.60; H, 3.96; N, 5.48.
4.6.4. 1-Benzyloxycarbonylmethyl-1,2-dihydro-2-(2,2,2-
trichloroethoxycarbonyl)-b-carboline (8d). Yield 81%;
colorless powder; mp 138–1428C; [a]2D0¼2200.7 (c 0.27,
CHCl3); The product was obtained as a mixture of two
1
conformational isomers. The H and 13C NMR spectra of
1
minor one are shown in parentheses. H NMR (CDCl3,
608C) d: 2.87–3.04 (2H, m), 4.74 (4.70) (1H, d,
J¼11.9 Hz), 4.98 (5.04) (1H, d, J¼11.9 Hz), 5.05 (5.03)
(1H, d, J¼12.2 Hz), 5.19 (5.23) (1H, d, J¼12.2 Hz),
6.05–6.10 (1H, m), 6.17 (6.23) (1H, d, J¼7.9 Hz), 6.69
(6.70) (1H, d, J¼7.9 Hz), 7.12–7.20 (2H, m), 7.27–7.31
(3H, m), 7.33–7.36 (3H, m), 7.58 (1H, d, J¼7.9 Hz),
8.57 (8.54) (1H, s); 13C NMR (CDCl3) d: 38.6 (40.3),
49.44 (49.46), 67.0 (66.9), 75.6 (75.4), 95.05 (94.96),
104.13 (104.11), 106.87 (106.92), 111.61 (111.57), 117.2,
118.2 (118.3), 120.4, 122.4, 123.5 (123.6), 128.4 (128.3),
128.28 (128.61), 128.7, 130.04 (129.96), 135.1 (135.2),
135.99 (136.03), 151.7 (151.4), 171.7 (171.9). Anal. calcd
for C23H19Cl3N2O4: C, 55.95; H, 3.88; N, 5.67. Found: C,
55.83; H, 3.58; N, 5.54.
4.7.2. 1,2,3,4-Tetrahydro-1-methoxycarbonylmethyl-b-
carboline (10). Colorless powder; mp 140–1438C. The
NMR spectrum of 10 was identical with that of the reported
one.13 1H NMR (CDCl3) d: 2.22–2.31 (1H, m), 2.59 (1H,
ddd, J¼17.6, 6.6, 4.2 Hz), 2.79–2.98 (3H, m), 4.82 (1H, dd,
J¼13.6, 4.0 Hz), 4.98–5.06 (1H, m), 5.27 (1H, d,
J¼17.3 Hz), 5.32 (1H, d, J¼17.3 Hz), 6.06 (1H, dd,
J¼9.7, 2.9 Hz), 6.53 (1H, ddd, J¼9.7, 6.6, 2.0 Hz),
6.96–6.99 (1H, m), 7.11–7.17 (3H, m), 7.25–7.32 (3H,
m), 7.36–7.38 (1H, m), 7.57–7.61 (1H, m).
4.8. Molecular orbital calculations
4.7. Transformation of compound 8d to 10
The molecular orbital calculations were carried out using
the PM3 procedure14 with the standard parameters, as
implemented in the MOPAC2000 program.
To the CH2Cl2 solution (2 ml) of 8d (24 mg, 0.049 mmol)
and triethylsilane (200 ml, 1.26 mmol) was added

3536
T. Itoh et al. / Tetrahedron 59 (2003) 3527–3536
10. (a) Menezes, R. F.; Zazza, C. A.; Sheu, J.; Smith, M. B.
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¨
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