Scandium perchlorate as a superior Lewis acid for regioselective ring opening of aziridine carboxylate with indoles

Article abstract of DOI:10.1055/s-2002-33645

In the synthesis of optically active tryptophan derivatives, Lewis acid-promoted coupling between indole and optically active serine-derived aziridine carboxylate is attractive because of the flexibility and convergence. Scandium perchlorate has been found to be a superior Lewis acid to the previously reported scandium triflate with respect to the yields as well as the regioselectivity of aziridine ring opening. The scope and limitation of this Lewis acid are also described.

Full text of DOI:10.1055/s-2002-33645

1
658
PAPER
Scandium Perchlorate as a Superior Lewis Acid for Regioselective Ring
Opening of Aziridine Carboxylate with Indoles
R
T
egioselective
R
o
ing Openin
s
g of
A
zirid
h
ine Carboxy
i
late
w
i
o
th Indole
s
Nishikawa, Shigeo Kajii, Kyoko Wada, Miyuki Ishikawa, Minoru Isobe*
Laboratory of Organic Chemistry, Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya, 464-8601, Japan
Fax +81(52)7894111; E-mail: isobem@agr.nagoya-u.ac.jp
Received 3 April 2002; revised 7 May 2002
reaction.11 The extensive examination finally led us to
Abstract: In the synthesis of optically active tryptophan deriva-
find that Sc(ClO ) as an alternative superior Lewis acid,
4
3
tives, Lewis acid-promoted coupling between indole and optically
active serine-derived aziridine carboxylate is attractive because of
which was applicable to the synthesis of mannosyltryp-
7
the flexibility and convergence. Scandium perchlorate has been tophan. This paper discloses the full details of our study.
found to be a superior Lewis acid to the previously reported scandi-
um triflate with respect to the yields as well as the regioselectivity
pling between 2-methylindole (1) and the aziridine methyl
of aziridine ring opening. The scope and limitation of this Lewis
Initially, we surveyed the effect of Lewis acids in the cou-
ester 2.12 The typical results are summarized in Table 1.
acid are also described.
BF OEt , as a conventional Lewis acid for the opening of
3
2
Key words: tryptophan, indole, aziridine, scandium triflate, scan-
dium perchlorate
1
3
3
-substituted aziridine-carboxylates with indole, effect-
ed a low yield with poor regioselectivity (entry 1).
Zn(OTf) 21 exhibited high reactivity in this specific
4
substrate to give 3a in good yield with high regioselec-
In 1989, Kozikowski and Sato reported a novel tryp-
tivity (entry 2), while the reactions with other indoles un-
der the same reaction conditions were reported to afford
tophan synthesis via a Zn(OTf) -mediated coupling of in-
2
1
dole with optically active aziridine carboxylate ester.
1
the corresponding products in lower yields. As men-
Although the reaction scheme seems to be attractive with
3
tioned above, Sc(OTf) introduced by Bennani et al.
3
respect to high convergence and flexibility, little applica-
showed higher reactivity but with low selectivity (entry
2
tion has been reported so far, probably because of the low
3
). In spite of the many attempts to reproduce the reported
yields in most of the cases. In 1998, Bennani and co-work-
high regioselectivity in different experimental conditions,
we could not significantly improve regioselectivity by
ers reported that scandium triflate [Sc(OTf) ] was an alter-
3
native Lewis acid for this reaction to give the tryptophan
means of Sc(OTf) . We were concerned about the quality
3
,4
3
derivatives in better yields.
and dryness of the reagent we used in accordance with
Murai and co-workers’ report, that endo/exo selectivity in
In the course of our synthetic studies on -C-mannosyl-
5
6
tryptophan, a naturally occurring C-glycosylamino acid,
we planned to employ the above coupling between C-
La(OTf) -mediated cyclization of hydroxy epoxides
3
1
5
strongly depended on the trace amount of water. The re-
7
1
6
mannosylindole and the aziridine. However, our prelim- agent Sc(OTf) purchased from different suppliers and
3
inary experiments revealed that 2-methylindole (1) as a self-made Sc(OTf) reagent according to the original pro-
3
8
model substrate coupled with the aziridine 2 in the pres- cedure,17 showed similar selectivity. Interestingly, when
18
ence of Sc(OTf) as a Lewis acid to give a 3:2 mixture of Sc(OTf) azeotropically dried with benzene was em-
3
3
9
,10
tryptophan 3a and the regioisomer 3b (Scheme 1),
ployed, the reaction was very sluggish, indicating the im-
while a similar reaction between 2-methylindole (1) and portance of trace amounts of water. Fortunately, further
the benzyl ester of 2 under the same conditions was re- extensive efforts led us to find that Sc(ClO4)319 was a su-
ported to give exclusively the benzyl ester of 3a in 66%
perior Lewis acid to give 3a with high regioselectivity
entry 4) with reproducibility, although the difference be-
tween Sc(OTf) and Sc(ClO ) has not been well docu-
3
yield. This unexpected result prompted us to re-examine
(
the conditions including the Lewis acid for this coupling
3
4 3
Scheme 1
Synthesis 2002, No. 12, Print: 06 09 2002.
Art Id.1437-210X,E;2002,0,12,1658,1662,ftx,en;F02502SS.pdf.
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Regioselective Ring Opening of Aziridine Carboxylate with Indoles
1659
2
0
21
mented. Indium triflate In(OTf) and ytterbium triflate and 6 gave much better yields (entries 3-6), indicating that
3
2
2
24
Yb(OTf)3 which have been employed as Lewis acids for N-benzylindole (6) might be an alternative substrate for
opening simple aziridines with a variety of nucleophiles, indole because the benzyl group of the indole nitrogen
were examined (entries 5 and 6). Although Yb(OTf)3 was removable. 4-Chlorotryptophan, a plausible biosyn-
showed the best regioselectivity in the reaction of this spe- thetic precursor of 4-chloroindole-3-acetic acid as a po-
cific substrate, this reagent was not applicable to the syn- tent naturally occurring auxin type of plant hormone,25
2
3
thesis of -C-mannosyltryptophan.
was synthesized in moderate yield from 4-chloroindole
entries 7 and 8). In this substrate, the selectivity was sig-
(
Table 1 The Coupling Between 2-Methylindole (1) and the Aziri-
dine 2 in the Presence of a Variety of Lewis Acids
nificantly improved although the yield was not improved.
The reaction of indoles substituted with strong electron-
withdrawing or -donating groups such as nitro (8) and
methoxy (9) were investigated. In the former case, ex-
tremely low yields of the product were obtained under
both conditions utilizing of Sc(OTf) and Sc(ClO ) (en-
tries 9 and 10). In the latter case, coupled products were
not obtained under both conditions, while 5-methoxyin-
dole (9) decomposed under the reaction conditions (en-
tries 11 and 12).
Entry Conditionsa
Lewis acid
Product
Solvent Temp Time Yield Selectivity
(
°C)
(h)
21
19
20
13
49
20
5
(%) 3a:3bc
b
3
4 3
1
2
3
4
5
6
BF Et O
CH Cl
0
28
69
68
70
57
34
68
40:60
90:10
60:40
90:10
100:0
40:60
55:45
3
2
2
2
Zn(OTf)2
Sc(OTf)3
CHCl3
80
0
CH Cl
2
2
2
2
2
2
Sc(ClO4)
3
CH Cl
2
0
Table 2 The Coupling Between a Variety of Indoles and the Aziri-
dine 2 in the Presence of Sc(OTf) and Sc(ClO )
3
4 3
Yb(OTf)3
In(OTf)3
CH Cl
r.t.
0
2
En- Indole
try
Conditionsa
Product
CH Cl
2
7
InCl3
CH Cl
0
No. R1 R2 R3
2
Lewis
acid
Time
(h)
Yield Selectiv-
(%) ity (a:b)c
b
a
All reactions were carried out using 0.4–0.5 mmol of 2-methylindole
(
1) and the 0.5 equiv of the aziridine 2 and Lewis acid, see experimen-
1
2
4
5
6
7
8
9
H
H
H
H
Cl
H
H
H
H
H
H
Sc(OTf)3 23
Sc(ClO4)3 18.5
10 29
51
50:50
90:10
tal.
b
Yield based on the aziridine 2.
The ratios were determined by integration values of the H NMR
c
1
3
4
Me
Bn
H
Sc(OTf)3
Sc(ClO4)3
3.5 11 66
3
62:38
95:5
spectrum.
75
5
6
Sc(OTf)3
2
12 69
71:29
92:8
Next, solvent effects in the reaction with Sc(ClO ) were
Sc(ClO4)3 8.5
61
4
3
examined. The reaction in acetonitrile showed no regiose-
lectivity (3a:3b = 1:1). When THF was used as a solvent,
coupling products were not obtained while the aziridine 2
decomposed under the reaction conditions. Toluene was
not a suitable solvent because of the low solubility of the
Lewis acid. These experiments indicated that Sc(ClO ) in
7
8
Sc(OTf)3
Sc(ClO4)3
6
8
13 31
69:31
88:12
36
9
0
H
NO2 Sc(OTf)3 19.5 14 10
100:0
100:0
1
1
Sc(ClO4)3 10.5
2
4
3
d
d
1
H
OMe Sc(OTf)3 25
15
0
0
–
–
CH Cl was the best combination with respect to the yield
2
2
12
Sc(ClO4)3
6
and regioselectivity.
a
All reactions were carried out using 0.4–0.5 mmol of indole 4–9 and
0.5 equiv of aziridine 2 and Lewis acid, see experimental.
Yield based on the aziridine 2.
The ratio was determined by separation of the two regioisomers.
The aziridine 2 was not consumed at the indicated time.
In order to ascertain the general usefulness of Sc(ClO ) ,
the coupling of a variety of substituted indoles with aziri-
dine 2 was examined in comparison with Sc(OTf)3
4
3
b
c
d
(
Scheme 2, Table 2). The reaction of indole (4) in the
presence of Sc(OTf) gave a mixture of 10a and 10b in
3
low yield with no selectivity (entry 1). In sharp contrast,
In summary, we have shown that Sc(ClO ) was a superior
4
3
the same reaction with Sc(ClO ) as a Lewis acid gave the
4
3
Lewis acid to Sc(OTf) with respect to regioselectivity
3
products in a moderate yield with higher regioselectivity
entry 2). Furthermore, the reactions of N-alkylindoles 5
and reproducibility. Since this coupling strategy is
(
26
straightforward, this improved method by means of
Scheme 2
Synthesis 2002, No. 12, 1658–1662 ISSN 0039-7881 © Thieme Stuttgart · New York

1
660
T. Nishikawa et al.
PAPER
Sc(ClO ) has potential applicability to the syntheses of 1H NMR (300 MHz, CDCl
): = 2.37(3 H br s, ArCH
), 3.59 (1 H,
4
3
3
3
dt, J = 14, 6.5 Hz, CH H NH), 3.66 (3 H, s, OCH ), 3.88 (1 H, ddd,
optically active tryptophan derivatives for components of
A
B
3
J = 14, 8.5, 6.5 Hz, CH H NH), 4.13 (1 H, dd, J = 8.5, 7 Hz,
A
B
peptidomimetics, chiral building block for the synthesis of
CHCO Me), 5.05 (1 H, d, J = 12 Hz, OCH H Ph), 5.13 (1 H, d,
indole-containing biologically active compounds.27
2
A
B
J = 12 Hz, OCH H Ph), 5.18 (1 H, br t, J = 6.5 Hz, NHCbz), 7.06
A
B
(
1 Harom, br t, J = 7 Hz), 7.12 (1 Harom, td, J = 7, 1 Hz), 7.26 (1 Harom
,
1
9
Scandium Perchlorate [Sc(ClO ) ]
4
3
br d, J = 8 Hz), 7.30–7.40(5 Harom, m), 7.52 (1 Harom, d, J = 7.5 Hz),
.97 (1 H, br s, NH of indole).
To a stirred solution of HClO (70%, 1.57 mL) in H O (1.57 mL)
was added Sc O as a powder (496 mg). The suspension was heated
at 100 °C for 4 h, and then cooled to r.t. The resulting mixture was
filtered through a pad of Super-Cel, and the precipitate was washed
with H O. The combined filtrate was evaporated in vacuo. The res-
idue (white solid) was dried with Kugelrohr distillation apparatus
under vacuum (0.8 mmHg) at 50–130 °C over ca. 5 h and dried at
30 °C for an additional 33 h. The white solid was crushed and pul-
verized and further dried for 64 h at 130 °C to afford Sc(ClO4)3
1.87 g, 89%).
4
2
7
2
3
13C NMR (75 MHz, CDCl3): = 11.6, 42.0, 42.4, 52.0, 66.6, 106.3,
1
1
10.5, 118.4, 119.8, 121.4, 127.0, 128.1, 128.6, 133.1, 135.2, 156.5,
74.0.
2
MS (EI): m/z = 366 (M+).
HRMS (FAB): m/z calcd for C H O N (M + H), 367.1658, found
3
2
1
23
4
2
1
67.1609.
(
N -(Benzyloxycarbonyl)-L-tryptophan Methyl Ester (10a)
[
[ ]D –11.4 (c = 1.1, MeOH)}.
CAUTION! We have never encountered any problem of explosion
of Sc(ClO ) , however, we suggest that Sc(ClO ) should be han-
20
20
29
]D +42.0 (c = 1.85, CHCl ); [ ] –7.2 (c = 1.42, MeOH), {Lit.
3 D
20
30
4
3
4 3
dled with special care, because metal perchlorates have potentially
–
1
explosive property.28 In particular, drying of the reagent with heat-
IR (KBr): 3408, 2952, 1706, 1510, 1341, 1215, 1059 cm .
1
ing under vacuum should be conducted in a hood with a safety
shield.
H NMR (300 MHz, CDCl ): = 3.30 (2 H, d, J = 5 Hz, ArCH2),
3
3.66 (3 H, s, CO CH ), 4.71 (1 H, dt, J = 8, 5 Hz, CH CH), 5.06 (1
2
3
2
H, d, J = 11 Hz, CH H Ph), 5.12 (1 H, d, J = 11 Hz, CH H Ph),
A
B
A
B
N -(Benzyloxycarbonyl)-2-methyl-L-tryptophan Methyl Ester
5.34 (1 H, d, J = 8 Hz, CHNHCbz), 6.91 (1 H, d, J = 2 Hz, H-2 of
indole), 7.08 (1 Harom, td, J = 8, 1 Hz), 7.17 (1 Harom, td, J = 8, 1 Hz),
7.22–7.40 (6 Harom, m), 7.51 (1 Harom, d, J = 8 Hz), 8.16 (1 H, br s,
NH of indole).
(
3a) and -[(Benzyloxycarbonylamino)methyl]-2-methylindol-
-acetic Acid Methyl Ester (3b); Typical Procedure (Tables 1
and 2)
3
2
2
-Methylindole (1; 52.4 mg, 0.400 mmol) and aziridine carboxylate
(47.0 mg, 0.200 mmol), dried azeotropically with benzene before
13C NMR (75 MHz, CDCl3):
1
1
= 27.8, 52.3, 54.4, 66.9, 109.8, 111.3,
18.6, 119.7, 122.2, 122.9, 127.5, 128.1, 128.2, 128.5, 136.2, 136.3,
55.9, 172.5.
use were dissolved in anhyd CH Cl (1.6 mL) and the solution was
cooled to 0 °C. To this solution was added Sc(ClO ) (68.6 mg,
0
2
2
4
3
Anal. Calcd for C H N O : C, 68.17; H, 5.72; N, 7.95. Found: C,
.200 mmol). After stirring at the same temperature for 13 h, the re-
20 20
2
4
6
8.16; H, 5.93; N, 7.89.
action was quenched with aq sat. NaHCO solution (1.5 mL). The
3
mixture was diluted with CH Cl (1.5 mL) and extracted with
2
2
-
[(Benzyloxycarbonylamino)methyl]indole-3-acetic Acid Me-
CH Cl (3 1.5 mL). The combined organic extracts were passed
2
2
thyl Ester (10b)
through a column packed with anhyd Na SO and a thin layer of
2
4
2
6
[
]
+
4
6
.
0
(
c
=
0
.
3
9
,
C
H
C
l
)
.
Na CO , and concentrated. The residue was purified by column
D
3
2
3
–
1
chromatography (silica gel, 10 g, EtOAc–hexane, 1:5 to 1:2) to give
IR (KBr): 3358, 2954, 1717, 1522, 1437, 1249 cm .
1
a mixture of 3a and 3b (51.2 mg, 70%, 3a:3b = 10:1 by H NMR).
1
H NMR (300 MHz, CDCl ): = 3.68 (3 H, s, CO CH ), 3.62–3.82
2 H, m, CHCH NH), 4.21 (1 H, dd, J = 8, 6.5 Hz, CHCH ), 5.08 (1
H, d, J = 12 Hz, CH H Ph), 5.12 (1 H, d, J = 12 Hz, CH H Ph),
3
2
3
A part of these two products were separated by repeated TLC
(
2
2
(
CH Cl , 5 times).
2 2
A
B
A
B
5
.16 (1 H, m, CH NH), 7.10–7.18 (2 Harom, m), 7.21 (1 Harom, td,
2
3
[
[
a
J = 7, 1 Hz), 7.29–7.40 (6 Harom, m), 7.69 (1 Harom, d, J = 8 Hz),
]D2 +57.2 (c = 1.14, CHCl ) {Lit. D-tryptophan analog
4
2
3
8
.14 (1 H, br s, NH of indole).
13C NMR (100 MHz, CDCl3): = 43.1, 43.2, 52.1, 66.8, 111.0,
11.3, 119.1, 120.1, 122.4, 122.5, 126.3, 128.1, 128.5, 136.2, 136.5,
2
0
]D –59.2 (c = 1.0, CHCl )}.
3
–
1
IR (KBr): 3393, 2952, 1717, 1507, 1215, 1064 cm .
1H NMR (300 MHz, CDCl3): = 2.30 (3 H, s, ArCH ), 3.25 (2 H,
d, J = 5.5 Hz, ArCH CH), 3.65 (3 H, s, CO CH ), 4.63–4.72 (1 H,
m, CHCO Me), 5.07 (1 H, d, J = 12 Hz, CH H Ph), 5.13 (1 H, d,
1
3
156.3, 173.7.
2
2
3
HRMS (FAB): m/z calcd for C H N O (M + H) 352.1423, found
3
2
0
21
2
4
2
A
B
52.1500.
J = 12 Hz, CH H Ph), 5.31 (1 H, br d, J = 8 Hz, NHCbz), 7.04 (1
A
B
Harom, t, J = 8 Hz), 7.10 (1 Harom, t, J = 8 Hz), 7.24 (1 Harom, d,
J = 8.5 Hz), 7.41 (1 Harom, d, J = 8 Hz), 7.86 (1 H, br s, NH of in-
dole).
N -(Benzyloxycarbonyl)-N-methyl-L-tryptophan Methyl Ester
(
[
11a)
2
4
]D +50.0 (c = 0.97, CHCl3).
1
3
C NMR (75 MHz, CDCl ): = 11.4, 27.1, 52.3, 54.5, 66.8, 105.5,
3
IR (KBr): 3344, 2952, 1718, 1508, 1327, 1213, 1058 cm–1.
1
1
10.3, 117.8, 119.5, 121.2, 128.0, 128.1, 128.5, 128.8, 132.9, 135.2,
36.3, 155.7, 172.6.
1H NMR (300 MHz, CDCl
.68 (3 H, br s, CH ), 3.72 (3 H, s, CH ), 4.70 (1 H, td, J = 8, 5 Hz,
): = 3.30 (2 H, d, J = 5 Hz, ArCH CH),
2
3
3
MS (EI): m/z = 366 (M+).
3
3
CH CH), 5.07 (1 H, d, J = 12 Hz, CH H Ph), 5.13 (1 H, d, J = 12
2
A
B
HRMS (FAB): m/z calcd for C H N O (M + H), 367.1658, found
2
1
23
2
4
Hz, CH H Ph), 5.31 (1 H, br d, J = 8 Hz, CHNHCbz), 6.81 (1 H, s,
A B
3
67.1689.
H-2 of indole), 7.08 (1 Harom, td, J = 7, 1 Hz), 7.21 (1 Harom, td,
J = 7, 1 Hz), 7.14–7.40 (7 Harom, m), 7.49 (1 Harom, br d, J = 8 Hz).
13C NMR (75 MHz, CDCl3): = 27.7, 32.6, 52.3, 54.4, 66.8, 108.1,
3
[
b
]D24 +84.0 (c = 0.91, CHCl3).
1
09.3, 118.7, 119.2, 121.8, 127.5, 128.2, 128.5, 136.4, 136.9, 155.8,
–
1
IR (KBr): 3398, 2951, 1716, 1508, 1458, 1248 cm .
172.5.
Synthesis 2002, No. 12, 1658–1662 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Regioselective Ring Opening of Aziridine Carboxylate with Indoles
1661
Anal. Calcd for C H N O : C, 68.84; H, 6.05; N, 7.65. Found: C,
13C NMR (75 MHz, CDCl3): = 28.8, 52.3, 55.3, 66.8, 110.2, 110.6,
120.9, 122.7, 123.1, 124.1, 124.4, 126.1, 128.1, 128.5, 136.3, 137.7,
55.9, 172.9.
2
1
22
2
4
6
8.93; H, 6.32; N, 7.50.
1
-
[(Benzyloxycarbonylamino)methyl]-1-methylindole-3-acetic
Anal. Calcd for C H ClN O : C, 62.10; H, 4.95; N, 7.24. Found:
C, 61.96; H, 5.16; N, 7.14.
2
0
19
2
4
Acid Methyl Ester (11b)
25
[
]D +78.0 (c = 0.90, CHCl3).
–1
IR (KBr): 3357, 2950, 1717, 1522, 1332, 1254, 1045 cm .
-[(Benzyloxycarbonylamino)methyl]-4-chloroindole-3-acetic
1H NMR (300 MHz, CDCl3): = 3.68 (3 H, s, CH ), 3.74 (3 H, s,
Acid Methyl Ester (13b)
3
25
[
]D +14.1 (c = 0.29, CHCl3).
CH ), 3.64–3.83 (2 H, m, CH NH), 4.18 (1 H, t, J = 7 Hz, CHCH ),
3
2
2
–
1
5
.07 (1 H, d, J = 12 Hz, CH H Ph), 5.12 (1 H, d, J = 12 Hz, CH
IR (KBr): 3335, 2951, 1706, 1522, 1436, 1341, 1255, 1046 cm .
1H NMR (300 MHz, CDCl3): = 3.70 (3 H, s, CO CH ), 3.78 (2 H,
A
B
A-
H Ph), 5.15 (1 H, m, CH NH), 6.99 (1 H, s, H-2 of indole), 7.12 (1
Harom, t, J = 7 Hz), 7.20–7.40 (7 Harom, s), 7.67 (1 Harom, br d, J = 8
Hz).
B
2
2
3
m, CHCH NH), 4.80 (1 H, t, J = 7 Hz, ArCH), 5.04 (1 H, d, J = 12
Hz, CH H Ph), 5.10 (1 H, d, J = 12 Hz, CH H Ph), 5.21 (1 H, m,
CH NHCbz), 7.06–7.38 (9 Harom, m), 8.32 (1 H, br s, NH of indole).
2
A
B
A
B
1
3
C NMR (75 MHz, CDCl ): = 32.7, 43.0, 43.1, 52.1, 66.7, 109.2,
3
2
1
1
09.4, 119.2, 119.6, 122.1, 126.8, 127.1, 128.1, 128.6, 136.5, 137.0,
56.4, 173.9.
13C NMR (100 MHz, CDCl3):
11.3, 121.3, 122.9, 124.0, 125.9, 128.0, 128.1, 128.5, 137.5, 156.3,
174.1.
= 42.8, 44.4, 52.2, 66.7, 110.2,
1
HRMS (FAB): m/z calcd for C H N O (M + H) 366.1580, found
2
1
23
2
4
3
66.1643.
HRMS (FAB): m/z calcd for C H ClN O (M + H) 386.1033,
2
0
20
2
4
found 386.1109.
N -(Benzyloxycarbonyl)-N-benzyl-L-tryptophan Methyl Ester
(
[
12a)
N -(Benzyloxycarbonyl)-5-nitro-L-tryptophan Methyl Ester
14a)
[ ]D +71.0 (c = 0.39, CHCl3).
25
]D +47.0 (c = 1.76, CHCl3).
(
–1
26
IR (KBr): 3338, 2951, 1718, 1508, 1340, 1213, 1060 cm .
1
IR (KBr): 3333, 2955, 1716, 1522, 1335, 1217, 1062 cm–1.
H NMR (300 MHz, CDCl ): = 3.31 (2 H, d, J = 5 Hz, ArCH CH),
3
2
3
.62 (3 H, s, CO CH ), 4.71 (1 H, td, J = 8, 5.5 Hz, CH CH), 5.07
1H NMR (300 MHz, CDCl3): = 3.34 (1 H, dd, J = 15, 5 Hz, Ar-
CH CH CH), 3.42 (1 H, dd, J = 15, 5 Hz, ArCH CH CH), 3.75 (3
2
3
2
(
1 H, d, J = 12 Hz, OCH H Ph), 5.13 (1 H, d, J = 12 Hz, OCH H-
A
B
A
A
B
A
B
Ph), 5.25 (2 H, s, NCH Ph of indole), 5.32 (1 H, br d, J = 8 Hz,
B
2
H, s, CO CH ), 4.74 (1 H, dt, J = 8, 5 Hz, CH CH), 5.12 (2 H, s,
2
3
2
CHNHCbz), 6.88 (1 H, s, H-2 of indole), 7.02–7.40 (13 Harom, m),
7
CH Ph), 5.36 (1 H, br d, J = 8 Hz, CHNH), 7.11 (1 H, d, J = 2.5 Hz,
2
.52 (1 Harom, d, J = 8 Hz).
H-2 of indole), 7.28–7.42 (7 Harom, m), 8.11 (1 Harom, dd, J = 9, 2
Hz), 8.45 (1 H, br s, NH of indole), 8.51 (1 H, d, J = 2 Hz, H-4 of
indole).
1
3
C NMR (75 MHz, CDCl ): = 27.9, 49.8, 52.2, 54.6, 66.8, 109.1,
3
1
1
09.8, 118.9, 119.5, 122.0, 126.7, 126.9, 127.6, 128.2, 128.5, 128.8,
36.4, 136.6, 137.5, 155.8, 172.4.
13C NMR (100 MHz, CDCl3):
= 43.2, 50.1, 52.1, 66.7, 109.9,
Anal. Calcd for C H N O : C, 73.28; H, 5.92; N, 6.33. Found: C,
119.3, 119.8, 122.2, 126.5, 126.9, 127.0, 127.7, 128.1, 128.5, 128.8,
136.6, 137.1, 156.3, 173.7.
2
7
26
2
4
7
3.28; H, 6.04; N, 6.31.
HRMS (FAB): m/z calcd for C H N O (M + H) 398.1352, found
2
0
20
3
6
-
[(Benzyloxycarbonylamino)methyl]-1-benzylindole-3-acetic
3
98.1334.
Acid Methyl Ester (12b)
26
[
]D +51.0 (c = 0.28, CHCl3).
–
1
Acknowledgments
IR (KBr): 3348, 2950, 1725, 1515, 1455, 1336, 1249, 1063 cm .
1
H NMR (300 MHz, CDCl ): = 3.68 (3 H, s, CO CH ), 3.66–3.82
We are grateful to Dr. Y. Bennani (Abbot Laboratories) for provi-
3
2
3
(
2 H, m, CH NH), 4.20 (1 H, dd, J = 8, 6.5 Hz, ArCH), 5.07 (1 H,
ding us their experimental details of the Sc(OTf) -mediated cou-
2
3
d, J = 12 Hz, OCH H Ph), 5.11 (1 H, d, J = 12 Hz, OCH H Ph),
pling. We also thank Dr. K. Fujiwara (Hokkaido University) for
A
B
A
B
5
.16 (1 H, m, CH NH), 5.26 (2 H, s, NCH Ph of indole), 7.04–7.42
exchanging information on La(OTf) -mediated reactions. Elemen-
2
2
3
(
14 Harom, m), 7.69 (1 Harom, d, J = 7.5 Hz).
tal analyses, measurements of 2D-NMR spectra and HR-MS were
performed by Mr. S. Kitamura, Mr. K. Koga (analytical laboratory,
Nagoya University) and Dr. M. Kuse (Chemical instrument center
of Nagoya University), whom we thank. This work was financially
supported by JSPS-RFTF and a Grant-in-Aid for Scientific Rese-
arch from the Ministry of Education, Science, Sports, and Culture
of Japan.
13C NMR (100 MHz, CDCl3): = 43.2, 50.2, 52.1, 66.7, 109.9,
1
1
19.3, 119.8, 122.2, 126.5, 126.9, 127.0, 127.7, 128.1, 128.5, 128.8,
36.6, 137.1, 156.3, 173.7.
HRMS (FAB): m/z calcd for C H N O (M + H) 442.1893, found
4
2
7
27
2
4
43.1936.
N -(Benzyloxycarbonyl)-4-chloro-L-tryptophan Methyl Ester
(
[
13a)
References
2
4
]D –5.6 (c = 0.77, CHCl3).
(
1) Sato, K.; Kozikowski, A. P. Tetrahedron Lett. 1989, 30,
073.
IR (KBr): 3340, 2953, 1706, 1522, 1436, 1341, 1219, 1047, 936
cm .
1H NMR (300 MHz, CDCl3): = 3.37 (1 H, dd, J = 15, 8 Hz, CHA-
H CHC), 3.64 (1 H, dd, J = 15, 5.5 Hz, ArCH H CH), 3.71 (3 H,
s, CO CH ), 4.73 (1 H, td, J = 8, 5.5 Hz, CHNHCbz), 5.03 (2 H, s,
4
–
1
(
2) (a) Fukami, T.; Yamakawa, T.; Niiyama, K.; Kojima, H.;
Amano, Y.; Kanda, F.; Ozaki, S.; Fukuroda, T.; Ihara, M.;
Yano, M.; Ishikawa, K. J. Med. Chem. 1996, 39, 2313.
(b) Buciarelli, M.; Forni, A.; Moretti, I.; Prati, F.; Torre, G.
Tetrahedron: Asymmetry 1995, 6, 2073.
B
A
B
2
3
CH Ph), 5.38 (1 H, br d, J = 8 Hz, NHCbz), 6.96 (1 H, s, H-2 of in-
2
dole), 7.02–7.36 (8 Harom, m), 8.32 (1 H, br s, NH of indole).
(3) Bennani, Y. L.; Zhu, G.-D.; Freeman, J. C. Synlett 1998,
54.
7
Synthesis 2002, No. 12, 1658–1662 ISSN 0039-7881 © Thieme Stuttgart · New York

1
662
T. Nishikawa et al.
PAPER
(
4) Sc(OTf) -catalyzed reaction of 1,3-dimethyindole with Cbz-
(16) Sc(OTf) purchased from Aldrich, TCI and Taiheiyo
3
3
aziridine was reported: Nakagawa, M.; Kawahara, M. Org.
Lett. 2000, 2, 953.
5) Nishikawa, T.; Ishikawa, M.; Isobe, M. Synlett 1999, 123.
6) (a) Hofsteenge, J.; Müller, D. R.; de Beer, T.; Löffler, A.;
Richter, W. J.; Vliegenthart, J. F. G. Biochemistry 1994, 33,
Kinzoku Corporation were examined.
(17) Kobayashi S., Hachiya I., Araki M., Ishitani H.; Tetrahedron
Lett.; 1993, 34: 3755.
(
(
(18) We thank Dr. N. Nomura of Nagayo University for a
valuable advice about this procedure: Nomura, N.; Taira, A.;
Yomioka, T.; Okada, M. Macromolecules 2000, 33, 1497.
(19) Hachiya, I.; Kobayashi, S. Tetrahedron Lett. 1994, 35, 3319.
(20) For theoretical treatment of this type of reaction: Dubois, L.;
Mehta, A.; Tourette, E.; Dodd, R. H. J. Org. Chem. 1994, 59,
434.
(21) Yadav, J. S.; Subba Reddy, B. S.; Srinivasa Rao, R.;
Veerendhar, G.; Nagaiah, K. Tetrahedron Lett. 2001, 42,
8067.
13524. (b) de Beer, T.; Vliegenthart, J.; Löffler, A.;
Hofsteenge, J. Biochemistry 1995, 34, 11785.
(
(
7) Nishikawa, T.; Ishikawa, M.; Wada, K.; Isobe, M. Synlett
2001, 945.
8) (a) Nakajima, K.; Takai, F.; Tanaka, T.; Okawa, K. Bull.
Chem. Soc. Jpn. 1978, 51, 1577. (b) Kato, S.; Harada, H.;
Morie, T. J. Chem. Soc., Perkin Trans. 1 1997, 3219.
9) The product 3b was optically active, although the
configuration has not been determined. For discussion of the
stereochemistry of the similar products to 3b in this type of
aziridine ring opening, see: Davoli, P.; Forni, A.; Moretti, I.;
Prati, F. Tetrahedron: Asymmetry 1995, 6, 2011.
(
(22) For Yb(OTf) , see: (a) Mataubara, S.; Kodama, T.; Utimoto,
3
K. Tetrahedron Lett. 1990, 44, 6379. (b) Meguro, M.;
Asano, N.; Yamamoto, Y. Tetrahedron Lett. 1994, 35,
7395. (c) Meguro, M.; Yamamoto, Y. Heterocycles 1996,
43, 2473.
(
10) The similar byproducts to the regioisomer 3b were reported,
see Ref.1
,2b
(23) The Yb(OTf) -mediated coupling of indole 4 (see Table 2)
3
(
11) For reviews of aziridine chemistry, see: (a) Tanner, D.
Angew. Chem., Int. Ed. Engl. 1994, 33, 599.
with aziridine 2 gave 48% yield of 10 as a single product
after 20 h at r.t., while the coupling of 4-chloroindole(7) was
very sluggish and gave a complex mixture.
(
b) Zwanenburg, B.; ten Holte, P. Top. Curr. Chem. 2001,
2
16, 93. (c) McCoull, W.; Davis, F. A. Synthesis 2000,
(24) Heaney, H.; Ley, S. V. Org. Synth., Coll. Vol. 6; Wiley: New
York, 1988, 104.
(25) (a) Sakagami, Y.; Manabe, K.; Aitani, T.; Thiruvikraman, S.
V.; Marumo, S. Tetrahedron Lett. 1993, 34, 1057.
(b) Marumo, S.; Hattori, H.; Abe, H.; Munakata, K. Nature
(London) 1968, 218, 959.
(26) For another important methodology for a variety of optically
active tryptophanes, see: Ma, C.; Liu, X.; Li, X.; Flippen-
Anderson, J.; Yu, S.; Cook, J. M. J. Org. Chem. 2001, 66,
4525.
1347.
1
3
(
(
12) Kozikowski and Bennani had estimated the effects of the
Lewis acids such as Zn(OTf) , Sc(OTf) , AlCl , EtAlCl ,
2
3
3
2
Me AlCl, TiCl , SnCl , Mg(OTf) , ZnBr BF ·OEt , BBr
2
4
4
2
2
3
2
3
and lanthanide triflates.
13) For examples, see: (a) Styngach, E. P.; Kuchkova, K. I.;
Efremova, T. M.; Semenov, A. A. Chem. Heterocyl. Comp.
973, 1378; Chem. Abstr. 1974, 80, 70734. (b) Apparao, S.;
Singh, G.; Ila, H.; Junjappa, H. Indian J. Chem., Sect. B
984, 23, 15. (c) Shima, I.; Shimazaki, N.; Imai, K.; Hemmi,
K.; Hashimoto, M. Chem. Pharm. Bull. 1990, 38, 564.
d) Legters, J.; Thijis, L.; Zwanenburg, B. Recl. Trav. Chim.
1
1
(27) Application of the Lewis acid Sc(ClO ) to synthesize the
4
3
analogs of -C-mannosyltryptophan such as galactosyl- and
glucosyl-analogs will be reported elsewhere.
(28) Birnbaum, E. D.; Stratton, S. Inorg. Chem. 1973, 12, 379.
(29) Ito, A.; Takahashi, R.; Baba, Y. Chem. Pharm. Bull. 1975,
23, 3081.
(
Pays-Bas 1992, 111, 16. (e) Legters, J.; Johanmes, G. H.;
Thijis, L.; Zwanenburg, B. Recl. Trav. Chim. Pays-Bas
1992, 111, 59.
(
(
14) As it turned out later, 2-methylindole(1) is the best suitable
substrate for this type of coupling.
15) (a) Fujiwara, K.; Mishima, H.; Amano, A.; Tokiwano, T.;
Murai, A. Tetrahedron Lett. 1998, 39, 393. (b) Tokiwano,
T.; Fujiwara, K.; Murai, A. Chem. Lett. 2000, 272.
(30) The optical rotation of 10a depends on the solvent used for
measurement.
Synthesis 2002, No. 12, 1658–1662 ISSN 0039-7881 © Thieme Stuttgart · New York