Convenient synthesis of chiral tryptophan derivatives using Negishi cross-coupling

Article abstract of DOI:10.1016/j.tet.2011.06.053

A facile synthetic procedure for chiral tryptophan derivatives using Negishi cross-coupling reaction of serine-derived iodoalanine with 3-haloindole is described. The best result was obtained when the reaction of N-tosyl-3-bromoindole with N-Cbz-iodoalani

Full text of DOI:10.1016/j.tet.2011.06.053

Tetrahedron 67 (2011) 5897e5901
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Convenient synthesis of chiral tryptophan derivatives using Negishi
cross-coupling
*
Minoru Tanaka, Hidemasa Hikawa, Yuusaku Yokoyama
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 May 2011
Received in revised form 20 June 2011
Accepted 20 June 2011
Available online 25 June 2011
A facile synthetic procedure for chiral tryptophan derivatives using Negishi cross-coupling reaction of
serine-derived iodoalanine with 3-haloindole is described. The best result was obtained when the re-
action of N-tosyl-3-bromoindole with N-Cbz-iodoalanine methyl ester was carried out by the combi-
nation of Pd2(dba)3 and sterically hindered ferrocenyl ligand Q-PHOS. This reaction condition not only
gave the desired tryptophan derivative as high as 76% yield, but also suppressed the formation of un-
desired products, the dehalogenated indole and the homodimer of indole, which were difficult to sep-
arate. This reaction was extended to the synthesis of various tryptophan derivatives having substituents
on the benzene ring. The characteristic of this reaction is the practical biomimetic synthesis of chiral
tryptophan derivatives in one-step.
Keywords:
Tryptophan
Negishi cross-coupling
Biomimetic synthesis
Unusual amino acids
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
In biological systems, the syntheses of compounds essential for
life are accomplished efficiently via enzymatic catalysis. One of the
most attractive goals for a synthetic chemist is to develop a syn-
thetic pathway similar to the biosynthetic one without the use of
enzymes. Tryptophan, which is biosynthesized from indole and
serine (Scheme 1), is not only important as a component of proteins
but also as a source of bioactive compounds, such as serotonin.
Although numerous synthetic methods for chiral tryptophan have
been reported to date, there are few biomimetic syntheses that
directly couple at the C3-position of indole with serine or its
equivalents.1e4 A typical example is the ring opening reaction of
serine-derived aziridine with 3-H-indole;3 however the yield is
unsatisfactory, especially in substituted indole (Scheme 2).
Scheme 2. Ring opening reaction of aziridine with 3-H-indole.
In the course of our investigation into the total synthesis of ergot
alkaloids,5e9 we developed two biomimetic syntheses of trypto-
phan derivatives: (a) selective Pd-catalyzed vinylation of 4-
bromoindole with dehydroalanine5e7 and (b) one-step synthesis
of N-acetyltryptophan from indole and serine in the presence of
Ac2O8,9 (Scheme 3). However, these synthetic methods required
asymmetric hydrogenation5e7 or kinetic resolution using acylase.8,9
Herein, we describe a new synthetic method for chiral tryptophan
derivatives using the direct Negishi cross-coupling reaction of op-
tically active serine-derived iodoalanine to 3-haloindole.
Since Jackson reported the asymmetric synthesis of substituted
phenylalanine derivatives from aryl halides and readily available
serine-derived iodoalanine using Negishi cross-coupling,10 there
have been several reports for Negishi cross-coupling reaction in
order to synthesize various chiral aromatic amino acids,11e14 but
only limited reports for tryptophan synthesis utilizing this reaction.
Recently, Rainier applied Negishi cross-coupling reaction of 3-
iodoindole derivative to the synthesis of tryptophan unit in total
synthesis of Kapakahine E for the first time.15 However, it required
equimolar amount of phosphine ligand and was limited to unsub-
stituted indole on the benzene ring. Therefore, we decided to es-
tablish the general synthetic method for chiral tryptophan
Scheme 1. Biosynthesis of tryptophan.
* Corresponding author. Tel.: þ81 47 472 1589; fax: þ81 47 472 1595; e-mail
address: yokoyama@phar.toho-u.ac.jp (Y. Yokoyama).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.053

5898
M. Tanaka et al. / Tetrahedron 67 (2011) 5897e5901
Next, we tried various combinations of palladium and phos-
phine ligands (Table 2). We initially used more reactive 3-
iodoindole 1e with a small excess of 2b. Under standard condi-
tions, no improvement was observed (entry 1). With PdCl2(PPh3)2,
which Jackson successfully used in the synthesis of pyridyl amino
acids,12 the reaction did not proceed (entry 2). Since Fu used Pd[P(t-
Bu)3]2 for Negishi cross-coupling of aryl chlorides,16 we used the
same catalyst but the yield was still low (entry 3). Recently, Knochel
reported the Negishi cross-coupling of aryl halides bearing acidic
protons catalyzed by Pd(OAc)2/S-PHOS in high yield.17 Under this
combination, significant improvement was observed (entry 4). In
all cases, the major side products were the dehalogenated indole
and the homodimer of indole, which were difficult to separate.
Since Buchwald reported that the reactivity for the oxidative ad-
dition toward aryl bromides sometimes more reactive than aryl
iodide,18 we considered that acceleration of transmetalation would
suppress undesirable side reaction. We changed 1e to 3-
bromoindole 1c. In all cases, the formation of side products was
suppressed. Surprisingly, remarkable improvement was achieved
in the combination of Pd(OAc)2 and S-PHOS to give the desired
product in 60% yield (entry 7). However, the reaction was slow and
1c was not consumed completely under heating (50 ꢀC, 5 h). Re-
cently, Jackson reported the improved synthesis of phenylalanine
derivatives using Pd2(dba)3 and S-PHOS.19 We applied that system
to our tryptophan synthesis; however the yield of 3d was not sat-
isfactory (43% yield, entry 8). Since unreacted 1c was remained
under the heating conditions, catalyst deactivation might be a main
reason for the low yields in above both cases.
Scheme 3. Biomimetic syntheses of tryptophan.
The best result was obtained by the combination of Pd2(dba)3
and sterically hindered ferrocenyl ligand Q-PHOS.20 Starting ma-
terial 1c was consumed within 3 h at room temperature to give the
product in 66% yield (entry 9). The complex generated from Pd/Q-
PHOS is highly active, long-lived catalyst.21 Complete conversion at
lower temperature and improvement of yield might be explained
by those natures of Pd/Q-PHOS system. The use of ferrocenyl
bidentate ligand PdCl2(dppf) did not give 3d (entry 10).
derivatives having various substituents on the benzene ring using
Negishi cross-coupling.
2. Results and discussion
The ee of 3d was determined to be 97.2% by chiral HPLC analysis.
Therefore, racemization did not occur in this reaction. It is note-
worthy that the racemization also did not occur in every reported
case.10e13
Initially, we applied Jackson’s condition13 for the reaction of
organozinc reagent 2a with N-Boc-protected 3-bromoindole 1a.
Disappointingly, the isolated yield of 3a was extremely low (11%),
and the purification step was troublesome due to weak UV ab-
sorption and many minor side products (Table 1, entry 1). We
then changed the protecting groups of 1 and 2. At first, the
protecting group of 2 was changed to Cbz from Boc for easy
detection on TLC (entry 2) to give a complex mixture. The pro-
tecting group of indole affected the isolated yields of tryptophan
3. In the cases of Boc and TIPS groups, the reaction systems were
complicated and we were unable to isolate target compounds
(entries 2 and 3). Although the Ts group gave desired product
(3d) in low yield (22%), the reaction was clean without formation
of side products, allowing recovery of starting material (1c)
(entry 4). Therefore, further investigation was accomplished with
this combination. With unprotected indole 1d, the reaction did
not proceed at all (entry 5).
In order to investigate the scope and limitations, various kinds
of substituted indoles were reacted under optimized conditions
(Pd2(dba)3/Q-PHOS). The results are shown in Table 3. Negishi
cross-coupling with chlorine-substituted indoles gave modest to
high yield; the 4-chloroindole derivative especially gave the highest
yield (76%, entry 1). Electron-rich and electron-deficient sub-
stituents at the C4-position of indole gave moderate yields (44 and
31%, entries 5 and 6). In the ring opening reaction of aziridine,3 4-
NO2 and 6-Cl derivatives gave poor results (3 and 12%). Sterically
hindered 4-CO2Me derivative gave low yields (entry 7). The re-
actions with N-Ts-2-methyl-3-bromoindole or N-Ts-3-chloroindole
did not proceed (data not shown). The Rainier’s condition14
(equimolar amount of P(o-tol)3 and catalytic CuBr$DMS) did not
work well (23% for 3f, 11% for 3j).
Table 1
Effect of the protecting group (Scheme 3)a
3. Conclusion
Entry
3-Haloindole
Organozinc reagent
Product
Yield (%)b
1
2
3
4
5
1a
1a
1b
1c
1d
2a
2b
2b
2b
2b
3a
3b
3c
3d
3e
11
In summary, a one-step synthesis of tryptophan derivatives
using Negishi cross-coupling from 3-haloindoles and iodoalanine
derived from L-serine was developed. The reaction was found to
proceed under mild conditions with yields as high as 76% without
a loss of enantiomeric purity after optimization of reaction condi-
tions. This method was also shown to be applicable to the synthesis
of various optically active tryptophan derivatives having various
substituents on the benzene ring.
dc
dc
22
No reaction
a
Conditions: 1 (0.65 mmol), 2 (0.5 mmol), Pd2(dba)3 (0.013 mmol), P(o-tol)3
(0.05 mmol), DMF (0.67 mL), 50 ꢀC, 3 h.
b
Yield is based on organozinc reagent 2.
Mixture of unidentified products.
c

M. Tanaka et al. / Tetrahedron 67 (2011) 5897e5901
5899
Table 2
Combination of palladium and phosphine ligands (Scheme 3)a
Entry
3-Haloindole
Organozinc reagent
Palladium
Ligand
Temp/ꢀC
Time/h
Product
Yield (%)b
1
2
3
4
5
6
7
8
9
1e
1e
1e
1e
1c
1c
1c
1c
1c
1c
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
Pd2(dba)3
P(o-tol)3
d
50
50
50
35
50
50
50
50
35
80
3
3
3
3
5
5
5
5
3
5
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
20
PdCl2(PPh3)2
Pd[P(t-Bu3)]2
Pd(OAc)2
Pd2(dba)3
Pd[P(t-Bu3)]2
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
PdCl2(dppf)
No reaction
18
40
22
17
60
43
66
d
S-PHOS
P(o-tol)3
d
S-PHOS
S-PHOS
Q-PHOSc
d
10
No reaction
a
Conditions: 1 (0.5 mmol), 2 (0.65 mmol), Palladium (0.025 mmol), Ligand (0.05 mmol), DMF (0.67 mL).
Yield is based on 3-haloindole 1.
Q-PHOS (0.025 mmol) was used.
b
c
added and stirred at 0 ꢀC for 15 min. The reaction mixture was
concentrated in vacuo, the residue was purified by silica gel column
chromatography (hexaneeethyl acetate) to give the product.
Table 3
Negishi cross-coupling of 2b with substituted indolesa
O
e
M
O
r
B
O
a
Pd2 db
(
)
3
z
Cb
N
H
n
IZ
e
M
R
O
4.2.1. 3-Bromo-4-methoxy-1-(toluene-4-sulfonyl)-1H-indole (1j). Yield
+
N
T
-
48%. Colorless solid; 1H NMR (400 MHz, CDCl3):
d
¼7.75 (d, J¼8.0 Hz,
R
HN
PH
OS
Q
z
Cb
s
N
T
~
2H), 7.60 (d, J¼8.0 Hz, 1H), 7.50 (s, 1H), 7.22e7.27 (m, 3H), 6.66 (d,
s
1f 1l
~
2b
3f 3l
J¼8.0 Hz, 1H), 3.88 (s, 3H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼153.8, 145.3, 135.9, 134.7, 130.0, 127.0, 126.6, 124.2, 118.4, 110.3,
Entry
R
Product
Yield (%)
106.4, 105.9, 104.6, 96.2, 55.6, 21.6; MS (ESI): m/z¼380 [MþH], 382
[Mþ2þH]; HRMS (EI): C16H14BrNO3S requires m/z 378.9878, found
1
2
3
4
5
6
7
4-Cl
5-Cl
6-Cl
7-Cl
3f
3g
3h
3i
76
50
47
45
44
31
18
m/z 378.9873; IR (ATR): 1367, 1166, 1099 cmꢂ1
.
4.2.2. 3-Bromo-4-nitro-1-(toluene-4-sulfonyl)-1H-indole (1k). Yield
39%. Pale yellow solid; 1H NMR (400 MHz, CDCl3):
4-OMe
4-NO2
4-CO2Me
3j
3k
3l
d¼8.28 (d,
J¼8.0 Hz,1H), 7.84 (s,1H), 7.79 (d, J¼8.0 Hz, 2H), 7.75 (d, J¼8.0 Hz,1H),
7.45 (t, J¼8.0 Hz, 1H), 7.30 (d, J¼8.0 Hz, 2H), 2.39 (s, 3H); 13C NMR
a
Conditions: 1 (0.5 mmol), 2 (0.65 mmol), Pd2(dba)3 (0.013 mmol), Q-PHOS
(0.025 mmol), DMF (0.67 mL), 35 ꢀC, 3 h.
(100 MHz, CDCl3):
d
¼146.4, 143.2, 135.8, 134.1, 130.4, 129.5, 127.1,
124.8, 120.6, 120.0, 117.9, 94.9, 21.7; MS (ESI): m/z¼395 [MþH], 397
[Mþ2þH]; HRMS (EI): C15H11BrN2O4S requires m/z 393.9623, found
m/z 393.9620; IR (ATR): 1517, 1360, 1346, 1167 cmꢂ1
.
4. Experimental
4.1. General experimental
4.2.3. 3-Bromo-1-(toluene-4-sulfonyl)-1H-indole-4-carboxylic acid me-
thyl ester (1l). Yield 35%. Pale yellow oil; 1H NMR (400 MHz, CDCl3):
Silica gel column chromatography was performed using Fuji
Silysia PSQ100B. 1H NMR spectra were recorded on a Bruker Avance
400 (400 MHz) spectrometer. Chemical shifts are expressed in parts
per million relative to TMS as an internal standard. Mass spectra
were measured in a combination with a Waters Acquity UPLC
system (0.05% TFA in acetonitrile/0.05% TFA in water) and a Micro-
mass ZQ (ESI) spectrometer. High-resolution (HR) mass spectra
were performed on a JEOL GC mate spectrometer. IR spectra were
recorded on a PerkineElmer FT-IR Spectrum One spectrometer.
Optical rotations were measured with the JASCO DIP-1000. High
performance liquid chromatography (HPLC) was performed on
a Waters 2695 Series chromatographs using Chiralpak IC column
(15 cm) in mixture of hexane/ethanol/Diethylamine (70:30:0.1).
d
¼8.16 (d, J¼8.0 Hz, 1H), 7.75e7.77 (m, 3H), 7.54 (d, J¼8.0 Hz, 1H), 7.39
(t, J¼8.0 Hz, 1H), 7.25 (d, J¼8.0 Hz, 2H), 3.96 (s, 3H), 2.36 (s, 3H); 13C
NMR (100 MHz, CDCl3):
d¼167.5, 145.8, 134.9, 134.4, 130.2, 127.7, 127.0,
125.9, 124.9, 124.7, 116.3, 97.1, 52.3, 21.6; MS (ESI): m/z¼408 [MþH],
410 [Mþ2þH]; HRMS (EI): C17H14BrNO4S requires m/z 406.9827,
found m/z 406.9819; IR (ATR): 1724, 1374, 1151 cmꢂ1
.
4.3. Synthesis of racemic-2-benzyloxycarbonylamino-3-[1-
(toluene-4-sulfonyl)-1H-indol-3-yl]propionic acid methyl
ester (racemic-3d)
Benzyl chloroformate (157 mL, 1.1 mmol) was added to a stir-
red solution of 2-amino-3-(1H-indol-3-yl)propionic acid methyl
ester hydrochloride (255 mg, 1.0 mmol) in dichloromethane
(4.0 mL) and saturated aqueous solution of sodium hydrogen
carbonate (4.0 mL), and the mixture was stirred for 2 h. The re-
action mixture was extracted with dichloromethane (2ꢁ50 mL).
The combined organic layers were washed with brine (2ꢁ50 mL),
dried over sodium sulfate, and concentrated in vacuo. The resi-
due was dissolved in dichloromethane (6.3 mL), sodium hy-
4.2. General procedure for the synthesis of substituted
3-bromoindole derivatives
Sodium hydride (132 mg, 3.3 mmol) was added to a stirred so-
lution of the indole (3 mmol) in DMF (6.0 mL) at 0 ꢀC, then stirred
for 30 min. To the reaction mixture, tosyl chloride (629 mg,
3.3 mmol) was added and stirred at room temperature for 2 h. After
pouring into water, the mixture was extracted with ethyl acetate
(2ꢁ50 mL). The combined organic layers were washed with brine
(2ꢁ50 mL), dried over sodium sulfate, and concentrated in vacuo.
The residue was solved in dichloromethane (30 mL) and cooled on
droxide (120 mg,
3 mmol), tetrabutylammonium hydrogen
sulfide (17 mg, 0.050 mmol), and p-toluenesulfonyl chloride
(229 mg, 1.2 mmol) were added, and the mixture was stirred for
4 h. After pouring into water, the mixture was extracted with
dichloromethane (2ꢁ50 mL). The combined organic layers were
iced bath. To the reaction mixture, bromine (170 mL, 3.3 mmol) was

5900
M. Tanaka et al. / Tetrahedron 67 (2011) 5897e5901
washed with brine (2ꢁ50 mL), dried over sodium sulfate, and
concentrated in vacuo. The residue was purified by silica gel
column chromatography (hexaneeethyl acetate) to give the title
compound (456 mg, 90%) as colorless oil; 1H NMR (400 MHz,
NMR (100 MHz, CDCl3):
d
¼171.4, 155.5, 145.3, 136.0, 134.8, 133.4, 132.1,
130.0, 129.3, 128.6, 128.3, 128.2, 126.7, 125.9, 125.2, 119.1, 116.4, 114.8,
67.3, 53.8, 52.6, 27.6, 21.6; MS (ESI): m/z¼563 [MþNa], 565
[Mþ2þNa]; HRMS (EI): C27H25ClN2O6S requires m/z 540.1122, found
CDCl3):
d
¼7.95 (d, J¼8.0 Hz, 1H), 7.69 (d, J¼8.0 Hz, 2H), 7.26e7.42
m/z 540.1115; IR (ATR): 3301, 1738, 1690, 1374, 1168 cmꢂ1; ½a D15
ꢂ22.5
ꢃ
(m, 9H), 7.16e7.20 (m, 3H), 5.29 (d, J¼8.0 Hz, 1H), 5.12 (dd,
(c 0.20, MeOH).
J¼24.0, 12.0 Hz, 2H), 4.68e4.73 (m, 1H), 3.64 (s, 3H), 3.17e3.28
(m, 2H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼171.6, 155.6,
4.4.4. (S)-2-Benzyloxycarbonylamino-3-[6-chloro-1-(toluene-4-
144.9, 136.1, 135.1, 130.8, 130.0, 128.6, 128.3, 128.2, 126.7, 124.9,
124.5, 123.3, 119.3, 116.9, 113.7, 67.1, 53.9, 52.5, 27.8, 21.5; MS
(ESI): m/z¼529 [MþNa]; HRMS (EI): C27H26N2O6S requires m/z
506.1512, found m/z 506.1515.
sulfonyl)-1H-indol-3-yl]propionic acid methyl ester (3h). Yield 47%,
Brown solid; 1H NMR (400 MHz, CDCl3):
d¼7.87 (d, J¼8.0 Hz, 1H), 7.67
(d, J¼8.0 Hz, 2H), 7.40 (s, 1H), 7.33e7.36 (m, 6H), 7.25 (d, J¼4.0 Hz, 1H),
7.18 (d, J¼4.0 Hz, 2H), 5.28 (d, J¼8.0 Hz, 1H), 5.13 (s, 2H), 4.66e4.71 (m,
1H), 3.68 (s, 3H), 3.13e3.27 (m, 2H), 2.32 (s, 3H); 13C NMR (100 MHz,
4.4. General procedure for the synthesis of tryptophan
derivatives using Negishi cross-coupling reaction
CDCl3):
d
¼171.4, 155.5, 145.3, 136.0, 134.8, 133.4, 132.1, 130.0, 129.3,
128.6, 128.3, 128.2, 126.7, 125.9, 125.2, 119.1, 116.4, 114.8, 67.3, 53.8,
52.6, 27.6, 21.6; MS (ESI): m/z¼563 [MþNa], 565 [Mþ2þNa]; HRMS
(EI): C27H25ClN2O6S requires m/z 540.1122, found m/z 540.1122; IR
1,2-Dibromoethane (17 mL, 0.20 mmol) was added to a stirred
suspension of zinc dust (255 mg, 3.9 mmol) in DMF (0.33 mL),
and the mixture was stirred at 50 ꢀC for 30 min. The reaction
mixture was allowed to cool to room temperature. Chloro-
(ATR): 3357, 1716, 1367, 1171 cmꢂ1; ½a D15
ꢂ17.6 (c 0.50, MeOH).
ꢃ
4.4.5. (S)-2-Benzyloxycarbonylamino-3-[7-chloro-1-(toluene-4-
trimethylsilane (5
m
L, 0.039 mmol) was added to the mixture, and
sulfonyl)-1H-indol-3-yl]propionic acid methyl ester (3i). Yield 45%.
the mixture was stirred for a further 30 min vigorously. N-Cbz-3-
iodoalanine methyl ester (236 mg, 0.65 mmol) in DMF (0.33 mL)
was added to the reaction mixture, which was then stirred at
room temperature for 2 h. The reaction mixture was then
standing for another 30 min, the supernatant liquid was trans-
ferred to the 3-bromo-1-(toluene-4-sulfonyl)-1H-indole (175 mg,
0.50 mmol), Pd2(dba)3 (11 mg, 0.013 mmol), and Q-PHOS (18 mg,
0.025 mmol) via syringe. The reaction mixture was stirred at
35 ꢀC for 4 h. After pouring into water, the mixture was extracted
with ethyl acetate (2ꢁ50 mL). The combined organic layers were
washed with brine (2ꢁ50 mL), dried over sodium sulfate, and
concentrated in vacuo. The residue was purified by silica gel
column chromatography (hexaneeethyl acetate) to give the
product.
Brown solid; 1H NMR (400 MHz, CDCl3):
d
¼7.69 (s, 1H), 7.64 (d,
J¼4.0 Hz, 2H), 7.32e7.39 (m, 6H), 7.19e7.24 (m, 3H), 7.07 (t,
J¼8.0 Hz, 1H), 5.39 (d, J¼8.0 Hz, 1H), 5.08e5.17 (m, 2H), 4.72e4.76
(m, 1H), 3.73 (s, 3H), 3.19e3.34 (m, 2H), 2.37 (s, 3H); 13C NMR
(100 MHz, CDCl3):
d
¼171.6, 155.6, 144.7, 136.9, 136.1, 134.6, 131.9,
129.7, 128.6, 128.3, 128.2, 127.2, 127.1, 124.1, 119.2, 117.9, 115.0,
67.1, 54.1, 52.6, 27.8, 21.6; MS (ESI): m/z¼563 [MþNa], 565
[Mþ2þNa]; HRMS (EI): C27H25ClN2O6S requires m/z 540.1122,
found m/z 540.1126; IR (ATR): 3358, 1716, 1358, 1171 cmꢂ1; ½a D15
ꢃ
þ16.3 (c 0.10, MeOH).
4.4.6. (S)-2-Benzyloxycarbonylamino-3-[4-methoxy-1-(toluene-4-
sulfonyl)-1H-indol-3-yl]propionic acid methyl ester (3j). Yield 44%.
Brown oil; 1H NMR (400 MHz, CDCl3):
d
¼7.69 (d, J¼8.0 Hz, 2H), 7.56 (s,
J¼4.0 Hz, 1H), 7.29e7.38 (m, 5H), 7.15e7.23 (m, 3H), 6.62 (d, J¼8.0 Hz,
1H), 5.59 (d, J¼4.0 Hz, 1H), 5.11 (s, 1H), 5.03 (s, 2H), 4.63e4.68 (m,1H),
3.86 (s, 3H), 3.67 (s, 3H), 3.36 (dd, J¼16.0, 4.0 Hz), 3.19 (dd, J¼12.0,
4.4.1. (S)-2-Benzyloxycarbonylamino-3-[1-(toluene-4-sulfonyl)-1H-in-
dol-3-yl]propionic acid methyl ester (3d). Yield 66%, 97.2% ee. Colorless
oil; 1H NMR (400 MHz, CDCl3):
d¼7.95 (d, J¼8.0 Hz, 1H), 7.69 (d,
8.0 Hz, 1H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3):
d¼172.4, 155.7,
J¼8.0 Hz, 2H), 7.26e7.42 (m, 9H), 7.16e7.20 (m, 3H), 5.29 (d, J¼8.0 Hz,
1H), 5.12 (dd, J¼24.0, 12.0 Hz, 2H), 4.68e4.73 (m, 1H), 3.64 (s, 3H),
153.9, 144.9, 136.6, 136.3, 135.1, 129.8, 128.6, 128.5, 128.3, 128.2, 128.1,
127.9,126.8,125.8,123.5,120.0,117.2,106.8,103.8, 67.0, 66.8, 55.2, 55.0,
29.3, 21.5; MS (ESI): m/z¼559 [MþNa]; HRMS (EI): C28H28N2O7S re-
quires m/z 536.1617, found m/z 536.1612; IR (ATR): 3364, 1717, 1363,
3.17e3.28 (m, 2H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3):
d¼171.6,
155.6, 144.9, 136.1, 135.1, 130.8, 130.0, 128.6, 128.3, 128.2, 126.7, 124.9,
124.5, 123.3, 119.3, 116.9, 113.7, 67.1, 53.9, 52.5, 27.8, 21.5; MS (ESI): m/
z¼529 [MþNa]; HRMS (EI): C27H26N2O6S requires m/z 506.1512,
found m/z 506.1511.
1176 cmꢂ1; ½a 1D5
ꢂ23.7 (c 0.50, MeOH).
ꢃ
4.4.7. (S)-2-Benzyloxycarbonylamino-3-[4-nitro-1-(toluene-4-
sulfonyl)-1H-indol-3-yl]propionic acid methyl ester (3k). Yield 31%,
4.4.2. (S)-2-Benzyloxycarbonylamino-3-[4-chloro-1-(toluene-4-
sulfonyl)-1H-indol-3-yl]propionic acid methyl ester (3f). Yield 76%,
Brown solid; 1H NMR (400 MHz, CDCl3):
d
¼8.28 (d, J¼8.0 Hz, 1H), 7.88
(d, J¼8.0 Hz, 1H), 7.68e7.72 (m, 3H), 7.32e7.39 (m, 6H), 7.19 (d,
J¼8.0 Hz, 2H), 5.23 (d, J¼8.0 Hz, 1H), 5.06 (s, 2H), 4.62e4.67 (m, 1H),
3.696 (s, 3H), 3.45 (dd, J¼16.0, 4.0 Hz, 1H), 3.19 (dd, J¼16.0, 8.0 Hz, 1H),
Colorless solid; 1H NMR (400 MHz, CDCl3):
d
¼7.88 (d, J¼8.0 Hz, 1H),
7.70 (d, J¼8.0 Hz, 2H), 7.43 (s, 1H), 7.30e7.37 (m, 4H), 7.16e7.20 (m,
5H), 5.28 (d, J¼8.0 Hz,1H), 5.06 (s, 2H), 4.72e4.78 (m,1H), 3.70 (s, 3H),
3.58 (dd, J¼16.0, 4.0 Hz, 1H), 3.30 (dd, J¼16.0, 8.0 Hz, 1H), 2.31 (s, 3H);
2.32 (s, 3H); 13C NMR (100 MHz, CDCl3):
d¼172.0, 155.7, 145.9, 143.4,
136.9, 136.0, 134.4, 130.2, 129.3, 128.6, 128.2, 128.1, 126.9, 123.9, 122.8,
120.5, 118.9, 115.7, 67.1, 54.2, 52.6, 30.1, 21.6; MS (ESI): m/z¼574
[MþNa]; HRMS (EI): C27H25N3O8S requires m/z 551.1362, found m/z
13C NMR (100 MHz, CDCl3):
d
¼172.1, 155.7, 145.3, 136.4, 136.1, 134.7,
130.0, 128.6, 128.2, 128.1, 127.2, 126.8, 126.6, 125.9, 125.4, 124.6, 117.0,
112.4, 67.0, 54.5, 52.5, 29.1, 21.6; MS (ESI): m/z¼563 [MþNa], 565
[Mþ2þNa]; HRMS (EI): C27H25ClN2O6S requires m/z 540.1122, found
551.1359; IR (ATR): 3344,1740, 1682, 1520,1379,1361,1169 cmꢂ1; ½a D15
ꢃ
ꢂ47.4 (c 0.20, MeOH).
m/z 540.1111; IR (ATR): 3358,1716,1371,1171 cmꢂ1; ½a D15
ꢂ41.4 (c 0.50,
ꢃ
MeOH).
4.4.8. (S)-3-(2-Benzyloxycarbonylamino-2-methoxycarbonyl-ethyl)-1-
(toluene-4-sulfonyl)-1H-indole-4-carboxylic acid methyl ester (3l). Yield
4.4.3. (S)-2-Benzyloxycarbonylamino-3-[5-chloro-1-(toluene-4-
18%. Brown solid; 1H NMR (400 MHz, CDCl3):
d
¼8.18 (d, J¼8.0 Hz, 1H),
sulfonyl)-1H-indol-3-yl]propionic acid methyl ester (3g). Yield 50%.
7.69e7.73 (m, 3H), 7.58 (s, 1H), 7.28e7.38 (m, 6H), 7.16e7.17 (m, 2H),
5.51 (d, J¼8.0 Hz, 1H), 5.02 (s, 2H), 4.55e4.60 (m, 1H), 3.92 (s, 3H), 3.65
(s, 3H), 3.45 (dd, J¼16.0, 8.0 Hz, 1H), 3.31 (dd, J¼16.0, 8.0 Hz), 2.30 (s,
Colorless solid; 1H NMR (400 MHz, CDCl3):
7.67 (d, J¼8.0 Hz, 2H), 7.40 (s, 1H), 7.33e7.36 (m, 6H), 7.25 (d, J¼4.0 Hz,
1H), 7.18 (d, J¼4.0 Hz, 2H), 5.29 (d, J¼8.0 Hz, 1H), 5.13 (s, 2H),
4.68e4.71 (m, 1H), 3.68 (s, 3H), 3.13e3.27 (m, 2H), 2.32 (s, 3H); 13C
d
¼7.87 (d, J¼8.0 Hz, 1H),
3H); 13C NMR (100 MHz, CDCl3):
134.8, 130.0, 128.6, 128.5, 128.3, 128.2, 128.1, 127.9, 127.6, 126.8, 126.1,
d
¼172.3, 168.0, 155.8, 145.3, 136.1,

M. Tanaka et al. / Tetrahedron 67 (2011) 5897e5901
5901
6. Yokoyama, Y.; Kondo, K.; Mitsuhashi, M.; Murakami, Y. Tetrahedron Lett. 1996,
37, 9309.
7. Osanai, K.; Yokoyama, Y.; Kondo, K.; Murakami, Y. Chem. Pharm. Bull.1999, 47,1587.
8. Yokoyama, Y.; Hikawa, H.; Mitsuhashi, M.; Uyama, A.; Murakami, Y. Tetrahedron
Lett. 1999, 40, 7803.
124.9, 123.9, 117.5, 66.9, 54.8, 52.6, 52.4, 29.4, 21.6; MS (ESI): m/z¼587
[MþNa]; HRMS (EI): C29H28N2O8S requires m/z 564.1566, found m/z
564.1563; IR (ATR): 3361, 1739, 1694, 1376, 1167 cmꢂ1; ½a D15
ꢂ23.0 (c
ꢃ
0.10, MeOH).
9. Yokoyama, Y.; Hikawa, H.; Mitsuhashi, M.; Uyama, A.; Hiroki, Y.; Murakami, Y.
Eur. J. Org. Chem. 2004, 6, 1244.
Supplementary data
10. Jackson, R. F. W.; Wythes, M. J.; Wood, A. Tetrahedron Lett. 1989, 30, 5941.
11. Jackson, R. F. W.; Wishart, N.; Wood, A.; James, K.; Wythes, M. J. J. Org. Chem.
1992, 57, 3397.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.06.053.
12. Tabanella, S.; Valancogne, I.; Jackson, R. F. W. Org. Biomol. Chem. 2003, 1, 4254.
ꢀ
13. Oswald, C. L.; Marquez, T. C.; Caggiano, L.; Jackson, R. F. W. Tetrahedron 2008,
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References and notes
1. Metzler, D. E.; Ikawa, M.; Snell, E. E. J. Am. Chem. Soc. 1954, 76, 648.
2. Weiner, W.; Winkler, J.; Zimmerman, S. C.; Czarnik, W.; Breslow, R. J. Am. Chem.
Soc. 1985, 107, 4093.
3. Sato, K.; Kozikowski, A. P. Tetrahedron Lett. 1989, 30, 4073.
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21. Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553.
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